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org chapter 9
Figure 73 | Diagnostic strategy in rapidly progressive glomerulonephritis. ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic
antibody; GBM, glomerular basement membrane.
Figure 74 | Frequency of organ involvement in AAV. Reproduced from The New England Journal of Medicine, Jennette JC, Falk RJ, Small-
Vessel Vasculitis, Volume 337, Pages 1512–1523, Copyright ª 1997 Massachusetts Medical Society. Reprinted with permission from
Massachusetts Medical Society.554 AAV, ANCA-associated vasculitis.
9.2.2 Kidney prognosis and treatment response crescentic class (>50% cellular crescents) and mixed class,
Kidney histology is predictive of long-term risk of kidney discrepancies in outcome have been reported.
failure; prognostic histologic scores have been developed (e.g., Importantly, kidney recovery can be seen in the face of
by Berden et al.553 and Brix et al.559; Figure 75553). advanced kidney damage, and induction treatment should not
In validation studies of the histopathologic classification by be withheld on the basis of unfavorable histologic findings.
Berden, >50% normal glomeruli in the focal class were Assessing response of kidney vasculitis can be difficult in the
associated with a favorable outcome, whereas >50% sclerotic presence of persistent hematuria and proteinuria, which are
glomeruli were associated with a poor outcome.560 Also, in seen in 50% of patients. A stable or falling creatinine level is a
the kidney risk score developed by Brix et al., a higher per- guide; control of extrarenal disease and normalization of in-
centage of normal glomeruli (>25%) was associated with flammatory markers (e.g., C-reactive protein) are also helpful
favorable kidney outcomes.559 However, regarding the but do not exclude ongoing kidney activity. Also, other causes
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9.3 Treatment
Treatment of AAV is generally divided into an initial phase,
commonly termed “induction,” followed by a “maintenance”
phase.
9.3.1 Induction
Recommendation 9.3.1.1: We recommend that

glucocorticoids in combination with cyclophospha-
mide or rituximab be used as initial treatment of
new-onset AAV (1B).
The best evidence is available for patients with new-onset AAV.

In patients with severe (SCr >4 mg/dl [>354 mmol/l]) kidney
disease, limited data for induction therapy with rituximab are
available.
Figure 75 | Histopathologic classification of ANCA-associated Key information
glomerulonephritis. Biopsies should be scored for glomerular Balance of benefits and harms. Cyclophosphamide, in
lesions in the following order: globally sclerotic glomeruli, normal
glomeruli, and glomeruli with cellular crescents. Biopsies that do not combination with glucocorticoids, has been used as induction
fit into a category based upon a predominant glomerular phenotype therapy in several RCTs. In 2 RCTs, rituximab alone or in
will be included in the mixed category.553 combination with 2 cyclophosphamide pulses was shown to be
equally as effective as cyclophosphamide, with a similar rate of
of AKI, not related to AAV, should be considered; therefore, a infectious complications (Supplementary Table S31566–569).
kidney biopsy should be considered at presentation and during However, post hoc analysis of the Rituximab in ANCA-
follow-up in case of poor treatment response (Figure 71). Associated Vasculitis (RAVE) trial found a superior remission
Histologic activity is unlikely in the absence of hematuria. rate for the PR3-ANCA subgroup at 6 months treated with
Persisting proteinuria can reflect disease activity or chronic rituximab, with an odds ratio (OR) of 2.11 (95% CI: 1.04–4.30)
parenchymal damage from preceding inflammation. Such in analyses adjusted for age, sex, and new-onset versus re-
chronic damage confers an adverse long-term kidney prog- lapsing disease at baseline.570 In patients with PR3-AAV and
nosis. The significance of persisting hematuria is unclear. In relapsing disease, more patients achieved remission at 6 and 12
a retrospective study, no difference was found in the months with rituximab, with an OR of 3.57 (95% CI: 1.43–
occurrence of ESKD between patients with and without 8.93) at 6 months and an OR of 4.32 (95% CI: 1.53–12.15) at 12
persisting hematuria, but more patients with hematuria months.570 No association between treatment drug and
experienced a relapse of kidney disease.561 More impor- remission was observed in patients with MPO-AAV (RAVE
tantly, a return of hematuria after initial resolution may trial; Supplementary Table S32567,569).
indicate kidney relapse. Regarding the route of cyclophosphamide administration,
oral and i.v. cyclophosphamide resulted in similar outcomes.
9.2.3 Relapses With i.v. cyclophosphamide, a reduction of the total cyclo-
Practice Point 9.2.3.1: The persistence of ANCA positivity, phosphamide dosage is achieved compared to oral cyclo-
an increase in ANCA levels, and a change in ANCA from phosphamide. In the Pulse Versus Continuous
negative to positive are only modestly predictive of future Cyclophosphamide for Induction of Remission in ANCA-
disease relapse and should not be used to guide treatment Associated Vasculitides (CYCLOPS) study, this resulted in a
decisions. lower rate of leukopenia (Supplementary Table S33569,571).
PR3- and MPO-AAV are characterized by the occurrence Nevertheless, more patients tended to experience relapses
of relapses. Patients who are PR3-ANCA-positive experience after i.v. cyclophosphamide during long-term follow-up.
more relapses than those who are MPO-ANCA positive.562 In patients with non-life-threatening disease, excluding
The achievement of ANCA-negativity after induction treat- those with rapidly progressive kidney disease, MMF might be
ment is associated with a lower risk of relapse.563,564 Both a an alternative to cyclophosphamide for the MPO-ANCA sub-
rise or persistence of ANCA are only modestly predictive of group. MMF had a similar remission rate to cyclophosphamide
future disease relapse.565 Also, a change in ANCA status from for patients with both PR3- and MPO-ANCA (Supplementary
negative to positive has been associated with a higher inci- Table S34569,572–575), but a much-increased relapse risk in those
dence of relapse, and more frequent clinical assessments with PR3-ANCA in the Clinical Trial of Mycophenolate Versus
should be considered. However, regarding the relapsing Cyclophosphamide in ANCA Vasculitis (MYCYC) trial.574
phenotype of AAV, ANCA measurements should not guide Methotrexate, with glucocorticoids, has been used for AAV
treatment decisions in individual patients. without kidney disease in the absence of irreversible tissue
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damage but is associated with a higher relapse rate and higher treatment arms; consequently, it was evaluated separately
late accrual of damage compared to cyclophosphamide (Supplementary Table S33569,571). The quality of the evidence
(Supplementary Table S35569,576,577). was low for all critical outcomes, due to imprecision, as there
Glucocorticoids are major contributors to adverse events. was only 1 study.
Intravenous methylprednisolone (doses of 1–3 g) is widely The RCTs comparing MMF versus cyclophosphamide
used for more severe presentations but has not been tested had few events for many critical and important outcomes
in an RCT. Oral prednisolone/prednisone starting at 1.0 (all-cause mortality, ESKD, malignancy, serious adverse
mg/kg/d has been used in most RCTs, again without direct events), and hence the quality of the evidence was low
RCT support. The rate of reduction of glucocorticoids (Supplementary Table S34569,572–575). However, for the
varies between studies, with some aiming for withdrawal by outcomes of infection and relapse, the quality of the evi-
month 5, while others continue 5–10 mg/d after 6 dence was rated as moderate due to study limitations from
months.578 The Plasma Exchange and Glucocorticoids for some studies (unclear blinding of outcome assessors). The
the Treatment of ANCA-Associated Vasculitis (PEXIVAS) MYCYC574 and Tuin et al.575 studies had an independent,
trial demonstrated that for patients with GFR <50 ml/min blinded adjudication committee assess the primary
per 1.73 m2, a more rapid reduction was as effective but endpoint of complete remission at 6 months, but the other
safer than a “standard” glucocorticoid tapering regimen.579 studies had concerns regarding blinding and hence the
In the RAVE trial, the rituximab group had a lower quality of the evidence for this outcome has been rated as
glucocorticoid exposure, and observational studies have moderate.
supported early glucocorticoid removal when rituximab is Values and preferences. This Work Group places a relatively
used (Figure 79). high value on achieving complete remission of disease, which
Complement-targeted therapy might be another strategy was the primary outcome of most evaluated studies. However,
to reduce glucocorticoid exposure. An oral C5a receptor extended immunosuppressive therapy should be associated
antagonist, avacopan, has been shown in the A Phase 3 with a minimum of adverse events. In subgroups of patients
Clinical Trial of CCX168 (Avacopan) in Patients with ANCA- for whom fertility is a concern, and in relapsing patients,
Associated Vasculitis (ADVOCATE) phase 3 trial to be an rituximab may be preferred.
effective alternative to glucocorticoid treatment in AAV with Intravenously pulsed versus oral continuous cyclophos-
potential to improve kidney outcomes.580 phamide results in a similar outcome. However, the cumu-
Quality of evidence. The overall quality of evidence is lative dosage of cyclophosphamide is lower with i.v.
moderate. The RCTs that compared rituximab with cyclo- cyclophosphamide. Patients treated with i.v. pulse cyclo-
phosphamide reported important outcomes of remission phosphamide may have an increased risk of relapse, as re-
and relapse, and the quality of the evidence was rated as ported in the CYCLOPS study.
moderate for these outcomes because of serious imprecision Glucocorticoids are disliked by patients and are major
(Supplementary Table S31566–569). The critical outcome, all- causes of adverse events. Use of rituximab or the combi-
cause mortality, was included; however, there were no cases nation of rituximab with cyclophosphamide may be asso-
reported for kidney failure in the 2 trials. Only the RAVE ciated with a lower glucocorticoid requirement, particularly
trial was blinded for both participants and personnel and is desirable in those at higher risk of glucocorticoid
regarded by the panel as the best evidence available. Effects toxicity.567,584 C5a receptor inhibition with avacopan is a
on complete remission at 6 months, relapse rate, and serious potential alternative to glucocorticoid treatment, which in
adverse events are graded as moderate. In a secondary paper, addition to its efficacy in controlling disease, has been
complete remission in ANCA subgroups was reported; this shown to improve patient quality of life when compared to
is graded as low due to imprecision (only 1 study). There prednisone in AAV.580
were no differences in kidney outcomes, and those with SCr Resource use and costs. Rituximab is typically more
>4 mg/dl (>354 mmol/l) were excluded. Finally, follow-up expensive than cyclophosphamide, although secondary
was short at 18 months. costs for cyclophosphamide (infusions and monitoring)
The studies comparing continuous oral versus i.v. pulse and reduced cost of generic rituximab can make the
cyclophosphamide were not blinded (participants and study total costs similar. Ease of administration, simpler
personnel; Supplementary Table S36569,581–583). Overall, the monitoring, glucocorticoid sparing, and reduced early
quality of evidence on the important endpoints of complete toxicity associated with rituximab compared to cyclo-
remission and leukopenia is graded as moderate because of phosphamide are additional factors that influence cost
study limitations. Other outcomes exhibited low quality of and resource use.
evidence because of serious imprecision due to very few Regarding i.v. versus oral cyclophosphamide, with intra-
events (relapse, all-cause mortality). The Work Group con- venous cyclophosphamide, a reduction of the total cyclo-
siders the CYCLOPS study the best available study on this phosphamide dosage is achieved compared to oral
topic because of the addition of azathioprine to both cyclophosphamide. However, oral cyclophosphamide is less

expensive. In patients treated with either i.v. or oral cyclo- seen in patients given i.v. cyclophosphamide. In the
phosphamide, frequent monitoring for treatment toxicity, in CYCLOPS study, a higher rate of relapse was reported with i.v.
particular leukopenia, is important. pulse cyclophosphamide.571 This reflects the 50% reduction
Considerations for implementation. The choice of treatment in cyclophosphamide exposure seen with i.v. regimens;
regimen depends on patient comorbidity, age, and preference, shorter-course oral cyclophosphamide regimens are also
as well as local availability and cost. associated with higher relapse risk.
In patients with non-severe disease, MMF and metho-
Rationale trexate have been compared to cyclophosphamide.
Cyclophosphamide, in combination with glucocorticoids, has Regarding MMF versus cyclophosphamide, no significant
been applied as induction therapy in multiple RCTs. In 2 differences were found, but cyclophosphamide tended to
RCTs, rituximab has been shown to be equally effective in show better efficacy and fewer relapses.569,572–575 Compared
inducing remission to cyclophosphamide.566,567 Rituximab to cyclophosphamide, methotrexate was associated with a
compared to cyclophosphamide probably has little or no higher relapse rate (RR: 1.50; 95% CI: 1.03–
difference in relapse rate at 1–6 months (RR: 0.63; 95% CI: 2.17).569,576,577,589 Effects on other critical and important
0.35–1.14). Rituximab and cyclophosphamide have similar outcomes are unclear, as they were not reported or occurred
rates of severe adverse events, including infections. However, infrequently.
risks of long-term comorbidities, such as malignancy, HBV Glucocorticoids are part of induction therapy. In the
and HCV reactivation, and secondary immunodeficiency, PEXIVAS study, all patients received oral prednisone/pred-
appear to differ between rituximab and cyclophosphamide nisolone at 1 mg/kg/d for the first week, followed by rapid
and may influence choice.585,586 or slow tapering schedules. This led to about a 50% dif-
In the RAVE study, patients with relapsing disease ference in oral glucocorticoid exposure during the first 6
more often achieved remission at 6 and 12 months in the months The lower-dose regimen was noninferior for efficacy
rituximab group compared to the cyclophosphamide– and is safer, and therefore is preferred.579,590 All patients in
azathioprine group.570,587 Analysis of the data according the PEXIVAS trial received an initial dose of i.v. methyl-
to ANCA status showed that patients with PR3-AAV were prednisolone of 1–3 g; the optimal dose is yet to be
significantly more often in complete remission at 6 determined.
months than patients treated with cyclophosphamide– Cyclophosphamide dose should be reduced for kidney
azathioprine.570 impairment and age, as these patients are at increased risk for
An important consideration when interpreting the RAVE infection (Figure 80).
trial is that it excluded patients with severe kidney disease Low-dose sulfamethoxazole/trimethoprim (TMP-SMX), or
(SCr >4 mg/dl [>354 mmol/l]). A recent single-center alternative, is advised for pneumocystis pneumonia prophy-
retrospective study found that rituximab was comparable laxis for the duration of the cyclophosphamide course or for 6
to cyclophosphamide in remission induction at 6 months.588 months following rituximab induction. Longer-term use may
However, no prospective data on the efficacy of remission be considered in those receiving repeated rituximab infusions,
induction of rituximab in severe kidney disease are available. for those with structural lung disease, or those requiring
In contrast, the Rituximab versus Cyclophosphamide in ongoing immunosuppressive or glucocorticoid therapy.
ANCA-Associated Vasculitis (RITUXVAS) study included In a retrospective study, the IgG level before rituximab
such patients and showed that rituximab combined with 2 correlated with hypogammaglobulinemia post-rituximab.591
cyclophosphamide pulses and glucocorticoids was compa- Therefore, IgG levels should be measured at baseline and
rable to cyclophosphamide for remission induction and every 6 months for patients treated with rituximab. A low level
number of adverse events.566 at baseline (defined as IgG <3 g/l; Figure 80) may predict a
Regarding the administration route of cyclophosphamide, greater risk of secondary immunodeficiency with rituximab.591
4 RCTs compared induction therapy with i.v. pulse versus
continuous oral cyclophosphamide.569,571,581–583 Intravenous Practice Point 9.3.1.1: A recommended treatment algo-
cyclophosphamide and oral cyclophosphamide resulted in a rithm for AAV with kidney involvement is given in
similar rate of complete remission, but less leukopenia was Figure 76.

Figure 76 | Recommended treatment regimen for AAV. AAV, ANCA-associated vasculitis.
Practice Point 9.3.1.2: In patients presenting with markedly still the preferred agent for induction of remission. In severe
reduced or rapidly declining GFR (SCr >4 mg/dl [>354 mmol/ kidney disease, combining 4 weekly infusions of rituximab and 2
l]), there are limited data to support rituximab and glucocor- i.v. cyclophosphamide pulses with glucocorticoids might be an
ticoids. Cyclophosphamide and glucocorticoids are preferred alternative to i.v. cyclophosphamide for 3–6 months. In the
for induction therapy. The combination of rituximab and RITUXVAS trial, this regimen resulted in a similar rate of
cyclophosphamide can also be considered in this setting. remission and adverse events as cyclophosphamide.566
No patients with a SCr >4 mg/dl (>354 mmol/l) were
included in the RAVE trial, and therefore in severe kidney disease, Practice Point 9.3.1.3: Considerations for choosing between
limited data for induction therapy with rituximab in combina- rituximab and cyclophosphamide for induction therapy are
tion with glucocorticoids are available, and cyclophosphamide is given in Figure 77.

Figure 77 | Factors for consideration when choosing between rituximab and cyclophosphamide for induction therapy of AAV. AAV,
ANCA-associated vasculitis; ANCA, antineutrophil cytoplasmic antibody; GN, glomerulonephritis; PR3, proteinase 3; SCr, serum creatinine.
Figure 78 | Considerations for the route of administration of cyclophosphamide for AAV. AAV, ANCA-associated vasculitis.
Practice Point 9.3.1.4: Considerations for choosing the Following rituximab induction, prednisolone can be with-
route of administration of cyclophosphamide are given in drawn by 6 months.
Figure 78. The dose of oral prednisolone is 1 mg/kg/d for the first
week, and then a programmed reduction is followed
Practice Point 9.3.1.5: Discontinue immunosuppressive
(Figure 79). Intravenous methylprednisolone is widely used
therapy after 3 months in patients who remain on dialysis
initially for patients with more severe presentations, at a dose
and who do not have any extrarenal manifestations of
of 1–3 g in total. This approach is not evidence-based and is
disease.
likely to contribute to glucocorticoid toxicity.
Practice Point 9.3.1.6: Recommendations for oral gluco-
corticoid tapering are given in Figure 79. Practice Point 9.3.1.7: Recommendations for immunosup-
Following cyclophosphamide induction, oral prednisolone pressive dosing are given in Figure 80.
should be reduced to a dose of 5 mg/d by 6 months.
Practice Point 9.3.1.8: Consider plasma exchange for pa-
tients with SCr >5.7 mg/dl (500 mmol/l) requiring dialysis
or with rapidly increasing SCr, and in patients with diffuse
alveolar hemorrhage who have hypoxemia.
The Methylprednisolone Versus Plasma Exchange for Renal
Vasculitis (MEPEX) trial showed improved kidney outcomes in
patients with severe kidney disease (SCr >5.7 mg/dl [>500
mmol/l]) who were treated with plasma exchange.592 Also, a
meta-analysis that looked at the addition of plasma exchange
showed a reduction in the occurrence of ESKD at 3 and 12
months after diagnosis (Supplementary Table S37566,569,592–
598
). The PEXIVAS trial failed to demonstrate that plasma ex-
change delayed the time to ESKD or death for patients with
AAV presenting with GFR <50 ml/min per 1.73 m2 or alveolar
hemorrhage over a median follow-up of 2.9 years.579 Post hoc
studies of the PEXIVAS dataset and meta-analysis may generate
results relevant to future recommendations. However, no
meta-analysis on the effect of plasma exchange in patients with
severe kidney disease (SCr >5.7 mg/dl [>500 mmol/l]),
Figure 79 | Prednisolone tapering regimen for AAV. AAV, ANCA- including the PEXIVAS study, is yet available. For now, the
associated vasculitis. routine use of plasma exchange is not recommended for

Figure 80 | Immunosuppressive drug dosing for AAV. AAV, ANCA-associated vasculitis; GFR, glomerular filtration rate; i.v., intravenous; MMF,
mycophenolate mofetil.
patients presenting with a GFR <50 ml/min per 1.73 m2, but unlike those with pure anti-GBM disease, these patients have a
plasma exchange can be considered in those with more severe tendency to relapse and should receive maintenance therapy.
presentations (SCr >5.7 mg/dl [>500 mmol/l], especially if
oliguric) or in those with alveolar hemorrhage and hypoxemia 9.3.2 Maintenance therapy
in whom early mortality is high.
Recommendation 9.3.2.1: We recommend mainte-
nance therapy with either rituximab or azathioprine
Practice Point 9.3.1.9: Add plasma exchange for patients and low-dose glucocorticoids after induction of
with an overlap syndrome of ANCA vasculitis and anti- remission (1C).
GBM.
In a single-center study, 5% of patients who were ANCA- This recommendation places a higher value on prevention of
positive were also positive for anti-GBM antibodies, and 32% relapses and a relatively lower value on adverse events related to
of patients who were anti-GBM-positive patients had detectable immunosuppressive drugs.
ANCA.599 Thus, double-positivity for both ANCA and anti-
GBM antibodies is common. These patients behave more like Key information
those with anti-GBM disease than like those with AAV, sup- Balance of benefits and harms. To date, most maintenance
porting the initiation of plasma exchange (Figure 81). However, studies have been done after induction of remission with
Figure 81 | Plasma exchange dosing and frequency for AAV. If a patient is at risk of bleeding, volume replacement should be with fresh,
frozen plasma. ANCA, antineutrophil cytoplasmic antibody.

cyclophosphamide plus glucocorticoids. Maintenance regi- from azathioprine duration, included data from single studies
mens have evolved over time, and several immunosuppressive with relatively low numbers of patients and limited follow-up,
medications have been evaluated. Azathioprine, given resulting in wide CIs and serious imprecision, in particular for
after $3 months of cyclophosphamide induction, was found the critical outcomes of all-cause mortality and kidney failure.
to be equally effective for relapse prevention with less The quality of the evidence for azathioprine as maintenance
leukopenia than extending cyclophosphamide for 12 months therapy was moderate for relapse in RCTs that compared
(Supplementary Table S38569,600). Compared to azathioprine, azathioprine with cyclophosphamide (Supplementary
MMF maintenance was less effective in relapse prevention Table S38569,600), methotrexate (Supplementary
569,602
and did not have a superior infection profile (Supplementary Table S40 ), MMF (Supplementary Table S39569,601), and
Table S39569,601). In contrast, methotrexate and azathioprine RCTs that compared extended with standard azathioprine
were found to be equally effective in relapse prevention with therapy (Supplementary Table S41569,577,603).The quality of
similar toxicity and long-term outcomes (Supplementary the evidence was downgraded because of imprecision, as
Table S40569,602). Overall, azathioprine has been the stan- there was only 1 study for each comparison. However, the
dard immunosuppressive used for maintenance of remission comparison of MMF with azathioprine exhibited low quality
in AAV over the past several years. of evidence for infection because of very wide CIs that
The duration of azathioprine maintenance has been indicated less certainty in the effect.
examined. Compared to tapering maintenance azathioprine There is currently limited evidence available for mainte-
after 12 months of treatment, tapering after 4 years of therapy nance therapy after induction therapy with rituximab and
decreased relapse rate and the incidence of kidney failure.577,603 glucocorticoids. There was low-quality evidence from RCTs
The benefits of longer-duration azathioprine maintenance that compared rituximab with azathioprine for major
therapy did not differ between PR3- or MPO-ANCA, or in relapse because of a lack of blinding of outcome assessors,
patients who remained ANCA-positive or became ANCA- and serious imprecision, as there are 2 RCTs that examined
negative after 12 months. In these studies, there were no dif- this comparison (Supplementary Table S42569,604 and
ferences in all-cause mortality, infection, or serious adverse Supplementary Table S43569,606). The RCT, which compared
events between treatment arms, but the quality of the evidence tailored rituximab therapy based on the reappearance of
was very low (Supplementary Table S41569,577,603). CD19þ B cells and ANCA-levels, exhibited low quality of
After rituximab was found to be effective for induction of evidence for major relapse and adverse events, including all-
remission in AAV, it was tested as a maintenance medication. cause mortality, infection, and malignancy (Supplementary
In new-onset disease, after cyclophosphamide induction, Table S42569,604). The quality of the evidence was down-
maintenance with rituximab decreased major, but not minor, graded from this RCT because of very serious imprecision,
relapses compared to azathioprine (MAINtenance of Remis- as there was only 1 study, and outcomes exhibited very
sion Using RITuximab in Systemic ANCA-associated Vascu- wide CIs, indicating less certainty regarding the treatment
litis [MAINRITSAN]; Supplementary Table S42569,604). effect.
However, after rituximab induction for relapsing AAV, rit- Data are also limited regarding the continuation of glu-
uximab maintenance decreased major and minor disease re- cocorticoids during maintenance. In most RCTs, glucocorti-
lapses compared to azathioprine (Rituximab versus coids were withdrawn within or shortly after the induction
azathioprine as therapy for maintenance of remission for window. However, in the Randomised controlled trial of
anti-neutrophil cytoplasm antibody-associated vasculitis prolonged treatment in the remission phase of ANCA-asso-
[RITAZAREM]).605 No difference in infection rate was found ciated vasculitis (REMAIN) trial, low-dose glucocorticoids
between azathioprine and rituximab (Supplementary were combined with azathioprine maintenance.577 In a meta-
Table S43569,606). analysis of observational studies and RCTs, a longer course of
As a maintenance drug, rituximab can be dosed on a fixed glucocorticoids in AAV was associated with fewer relapses.609
schedule or upon reappearance of CD19þ B cells and/or Values and preferences. This Work Group places a relatively
ANCA. Although both regimens prevented relapse equally high value on the prevention of relapses of disease, which are
well, dosing based on reappearance of B cells required associated with morbidity, and advises that maintenance therapy
fewer rituximab infusions. No differences in adverse events be given to all patients after induction of remission. However,
were reported (MAINRITSAN2; Supplementary extended immunosuppressive therapy should be associated with
Table S42569,604). a minimum of adverse events, and relapse risk may influence
Addition of TMP-SMX (160/800 mg) compared with maintenance initiation, choice of medication, and duration.
placebo in maintenance therapy may have little or no differ- Several AAV relapse risk factors have been identified,
ence on complete remission at 1 or 2 years (Supplementary including a prior history of relapse and having a PR3-ANCA
Table S44569,607,608). rather than an MPO-ANCA.562,610 In the RAVE study, pa-
Quality of evidence. The overall quality of the evidence was tients did not receive maintenance therapy after induction
rated as low due to the lower quality of the evidence for rit- with rituximab, and a high relapse rate was seen in both the
uximab as maintenance therapy, which is based on fewer RCTs rituximab and cyclophosphamide–azathioprine groups, but
compared with that for azathioprine. All comparisons, apart glucocorticoids were withdrawn before 6 months.570 Current

practice, and therefore expert opinion, varies on whether active disease, a validated scoring system such as the Bir-
maintenance therapy can be avoided in patients with MPO- mingham Vasculitis Activity Score (BVAS) can be used.613
AAV after induction of remission with rituximab. It also During follow-up, a structured clinical assessment in com-
varies on the use and duration of glucocorticoids in mainte- bination with inflammatory markers and kidney function
nance regimens. In the REMAIN trial, which studied patients should be conducted in all patients.
with a history of renal vasculitis, no difference in relapse risk Rituximab maintenance after cyclophosphamide induction
with ANCA serotype was seen. If maintenance therapy is not has been shown to be superior to azathioprine for preventing
used, such patients should be considered at higher risk of relapses in 1 RCT. It probably decreases major relapses; no
relapse, and monitored accordingly.577 difference in adverse events was reported (MAINRITSAN).604
In the subgroup of patients with MPO-AAV presenting Azathioprine maintenance up to 18 months after induction of
with kidney failure without extrarenal disease manifestations, remission with cyclophosphamide has been shown to be
the risk of relapses is low, so the risk of adverse infectious equally effective as continuing cyclophosphamide (Cyclo-
events from immunosuppression might outweigh the benefits phosphamide versus Azathioprine for Early Remission Phase
of relapse prevention.611 Therefore, in patients with MPO- of Vasculitis [CYCAZAREM]) for 1 year and then switching
ANCA who are treated with dialysis and have no extrarenal to azathioprine.600 MMF has not been shown to be more
manifestations of disease, despite thorough review including effective than azathioprine.601
chest computed tomography (CT) scanning, the risks of The evidence for the minimum duration of maintenance is
maintenance therapy could outweigh the benefit. Further, weak; longer maintenance reduces relapse rate but could be
when a complete clinical remission is achieved in the sub- associated with more adverse events. Azathioprine prolongation
group of patients with MPO-ANCA disease and abnormal (REMAIN trial; Extended versus standard azathioprine main-
kidney function, these patients may not need maintenance tenance therapy in newly diagnosed proteinase 3 anti-neutrophil
immunosuppression, but instead could be closely monitored cytoplasmic antibody-associated vasculitis patients who remain
with regular ANCA serologies. cytoplasmic anti-neutrophil cytoplasmic antibody-positive
In summary, the best evidence for effective relapse pre- after induction of remission: a randomized clinical trial
vention is available for rituximab maintenance or prolonged [AZA-ANCA]) limits relapse rate after 4 versus 2 years.577,603
azathioprine in combination with low-dose glucocorticoids. As the aim of maintenance therapy is the prevention of
However, there may be an advantage in favor of rituximab. In relapses, the risk of relapse should be considered for both the
the MAINRITSAN study, health-related quality of life was choice of the immunosuppressive agent and the duration of
compared between patients treated with rituximab and maintenance therapy.
azathioprine. Mean improvements of Health Assessment Reported risk factors for relapse are PR3-ANCA versus
Questionnaire (HAQ) scores from baseline to 24 months were MPO-ANCA, and CV or lung involvement.562,610 Persistent
significantly better for the rituximab group as compared to ANCA-positivity after induction of remission has also been
the azathioprine group.612 reported.577,614 The RCT that tested extended azathioprine
Therefore, this Work Group prefers rituximab for main- for 4 years versus azathioprine for 2 years in patients with
tenance therapy, particularly for patients with known re- PR3-AAV who remained ANCA-positive showed a nonsig-
lapsing disease, PR3-AAV, and azathioprine allergy, and after nificant difference (at 4 years, 48% standard vs. 24% extended
rituximab induction (RITAZAREM). However, some caution relapses) but was underpowered.603
should be exercised, as there is a paucity of data on the long- Comparison with other guidelines. Considering other guide-
term effects of rituximab maintenance treatment. Although lines, the European League Against Rheumatism/ European Renal
significant falls in IgG were not seen after rituximab in the Association-European Dialysis and Transplant Association
RCTs, longer-term observational data suggest an increasing (EULAR/ERA-EDTA) prefers azathioprine and glucocorticoids
risk of secondary immunodeficiency in this population. over rituximab for remission maintenance.578 According to the
Resource use and costs. Rituximab is relatively expensive evidence reviewed by the ERT, rituximab was found to be
and is not available worldwide; however, biosimilars will superior to azathioprine, due to lower rates of major relapse.
potentially generate global access to this drug. Additionally, Therefore, this panel prefers rituximab over azathioprine for
prevention of relapses reduces the costs of hospitalization, maintenance therapy in AAV. The EULAR/ERA-EDTA
and induction therapy with its frequent hospital visits. Rit- guideline advises maintenance therapy for at least 24 months
uximab also permits the withdrawal of glucocorticoids. following induction. This panel has not advised a fixed
duration of maintenance but an interval of 18 months to 4
Rationale years following induction of remission, tailored according to an
This Work Group advises maintenance therapy be given to all individual’s risk of relapse and the drug used for maintenance.
patients with AAV after induction of remission with either Additionally, in MPO-AAV after induction of remission with
cyclophosphamide or rituximab. The aim of this maintenance rituximab, maintenance therapy may sometimes be avoided if
therapy is to prevent relapse of disease after induction of the patient can be monitored intensively. However, this point is
remission. Remission is defined as the absence of manifesta- based on expert opinion; little evidence is available, and no
tions of vasculitis. To score the absence of clinical features of consensus was reached, even among experts.

Figure 82 | Factors that increase relapse risk for AAV. AAV, ANCA-associated vasculitis; ANCA, antineutrophil cytoplasmic antibody; PR3,
proteinase 3.
Practice Point 9.3.2.1: Following cyclophosphamide in- Practice Point 9.3.2.3: The optimal duration of azathio-
duction, either azathioprine plus low-dose glucocorticoids prine plus low-dose glucocorticoids is not known but
or rituximab without glucocorticoids should be used to should be between 18 months and 4 years after induction
prevent relapse. of remission.
Practice Point 9.3.2.2: Following rituximab induction, Practice Point 9.3.2.4: The optimal duration of rituximab
maintenance immunosuppressive therapy should be given maintenance is not known, but studies to date have
to most patients. evaluated a duration of 18 months after remission.
The preference of this Work Group, based upon observa- There is no role for the routine use of an oral gluco-
tional reports and unpublished data from the RITAZAREM corticoid or oral immunosuppressive with rituximab
study, is for rituximab maintenance. The RITAZAREM study maintenance.
showed that also after rituximab induction for relapsing AAV,
rituximab maintenance decreased major and minor disease Practice Point 9.3.2.5: When considering withdrawal of
relapses compared to azathioprine maintenance (RITA- maintenance therapy, the risk of relapse should be
ZAREM).615 However, azathioprine combined with gluco- considered, and patients should be informed of the need
corticoids can be considered as an alternative. for prompt attention if symptoms recur (Figure 82).
In the RAVE study, no maintenance was given following
induction of remission in AAV. The relapse rate was lower in Practice Point 9.3.2.6: Consider methotrexate for mainte-
MPO-AAV compared to PR3-AAV. This finding led some ex- nance therapy in patients, after induction with metho-
perts to opine that patients with MPO-AAV in complete clin- trexate or for those who are intolerant of azathioprine and
ical remission after induction therapy with rituximab with a MMF, but not if GFR is <60 ml/min per 1.73 m2.
low relapse risk may not need maintenance therapy, but instead
could be closely monitored with regular ANCA serologies and Practice Point 9.3.2.7: Considerations for choosing ritux-
home urine checks. Consensus regarding no maintenance was, imab or azathioprine for maintenance therapy are pre-
however, not reached within the KDIGO Work Group. sented in Figure 83.
Figure 83 | Considerations for using rituximab or azathioprine for AAV maintenance therapy. AAV, ANCA-associated vasculitis; ANCA,
antineutrophil cytoplasmic antibody; HBsAg, hepatitis B surface antigen; IgG, immunoglobulin G; PR3, proteinase 3.

Figure 84 | Immunosuppressive dosing and duration of AAV maintenance therapy. *RITAZAREM was in relapsing AAV. MAINRITSAN,
MAINtenance of Remission Using RITuximab in Systemic ANCA-associated Vasculitis; MMF, mycophenolate mofetil; RITAZAREM, Rituximab
versus azathioprine as therapy for maintenance of remission for antineutrophil cytoplasm antibody-associated vasculitis (AAV).
Practice Point 9.3.2.8: Recommendations for dosing and 9.4 Special situations
duration of maintenance therapy are given in Figure 84.
9.4.1 Refractory disease
9.3.3 Relapsing disease
Practice Point 9.4.1.1: Refractory disease can be treated by
Practice Point 9.3.3.1: Patients with relapsing disease (life- an increase in glucocorticoids (intravenous or oral), by the
or organ-threatening) should be reinduced (Recommen- addition of rituximab if cyclophosphamide induction had
dation 9.3.1.1.), preferably with rituximab. been used previously, or vice versa. Plasma exchange can be
Relapses respond to immunosuppression with a similar considered.
response rate as the initial presentation, and severe relapses The causes of refractory disease include drug intolerance,
should be treated by reintroducing induction therapy. When nonadherence, concomitant morbidities complicating treat-
deciding whether to use cyclophosphamide again, the cu- ment, a secondary drive for vasculitis such as malignancy, drugs
mulative dose of cyclophosphamide already given should be or infection, and true treatment failure. Progression of kidney
taken into account. Cumulative dosages above 36 g have failure can reflect chronic damage and does not necessarily imply
been associated with the occurrence of malignancies.616 In a active disease; a kidney biopsy can be considered to assess
post hoc analysis of the RAVE trial, higher remission rates ongoing kidney disease activity. Several small series suggest a role
were seen in relapsing patients treated with rituximab for rituximab in resistant ANCA vasculitis.
compared to cyclophosphamide, especially for patients with
PR3-AAV.570 Rituximab is therefore preferred for relapsing Practice Point 9.4.1.2: In the setting of diffuse alveolar
AAV. The RITAZAREM trial studied the effect of rituximab bleeding with hypoxemia, plasma exchange should be
induction in 187 patients with relapsing GPA/microscopic considered in addition to glucocorticoids with either
polyangiitis—there was a high rate of remission, >90% by 4 cyclophosphamide or rituximab.
months.605 In the absence of hypoxemia, diffuse alveolar hemorrhage
In patients with non-severe relapses, immunosuppression has a benign prognosis and responds as extrapulmonary disease
should be increased while avoiding cyclophosphamide. Apart is controlled. Alveolar hemorrhage with hypoxemia has a high
from MMF, which has been tested in combination with glu- early mortality risk, and plasma exchange should be considered
cocorticoids in RCTs for induction therapy in relapsing pa- in addition to glucocorticoids with either cyclophosphamide or
tients, there is no strong evidence to support other rituximab. Patients in the intensive care unit, such as those
regimens.574,575 However, if non-severe relapses are treated receiving assisted ventilation, have a particularly high risk of
with MMF, there is an increased rate of future relapse, and infection and death. Leukopenia should be avoided, with
glucocorticoid exposure will be increased accordingly; there- glucocorticoid use minimized. Plasma exchange and high-dose
fore, in the current guideline, rituximab is preferred. i.v. immunoglobulins can be considered in this setting.

9.4.2 Transplantation Research recommendations

" RCTs to incorporate patient-reported outcomes, to assess
Practice Point 9.4.2.1: Delay transplantation until patients long-term outcomes, to define the use of rituximab in se-
are in complete clinical remission for ‡6 months. Persis- vere AAV, and to assess therapies in ethnically diverse
tence of ANCA should not delay transplantation. populations
AAV can recur after kidney transplantation. The frequency " Biomarker studies to identify early markers of disease
of disease recurrence in AAV has been assessed in several relapse, markers to guide the choice of therapy, including
retrospective studies and is about 0.02–0.03 per patient- plasma exchange, markers to predict optimal dosing and
year.617,618 This relapse rate was not influenced by remission dosing interval for rituximab, and surrogate markers of
duration or ANCA status before transplantation.617 response

Chapter 10: Lupus nephritis
The reported lifetime incidence of lupus nephritis (LN) in the loci of immune deposits. Clinicians should pay attention
patients with SLE is 20%–60%, depending on the de- to the detailed description of both active and chronic histo-
mographics of the population studied.619–622 Kidney pathologic features affecting different elements of the kidney
involvement in SLE has been associated with higher mortality, parenchyma, especially regarding potentially reversible active
especially for patients progressing to kidney failure.623–625 The lesions versus chronic damage not reversible by immuno-
ultimate goal of treating LN is to preserve kidney function suppressive medications (Figure 86).
and reduce the morbidity and mortality associated with CKD
and kidney failure, while minimizing medication-associated 10.2 Treatment
toxicities.
10.2.1 General management of patients with lupus nephritis
This chapter makes management recommendations for
adults who have SLE with kidney involvement. The focus is Recommendation 10.2.1.1: We recommend that
on immune complex–mediated GN in the setting of SLE, patients with SLE, including those with lupus
commonly referred to as LN, but other types of kidney injury nephritis (LN), be treated with hydroxychloroquine
in patients with SLE are also discussed. Information for pe- or an equivalent antimalarial unless contraindicated
diatric populations is limited, but an approach to the man- (1C).
agement of children with LN is outlined in Practice Point
10.3.3.
This recommendation places a relatively higher value on the
10.1 Diagnosis various benefits associated with hydroxychloroquine use reported
in observational studies (including lower rates of disease flares,
Practice Point 10.1.1: Approach to the diagnosis of kidney progressive kidney damage, and vascular complications) and on
involvement in systemic lupus erythematosus (SLE) the generally favorable safety profile of hydroxychloroquine
(Figure 85) treatment. It places a relatively lower value on the lack of large-
Patients with SLE should be actively and regularly moni- scale prospective RCT data.
tored, as the clinical presentation of kidney involvement can
remain silent or asymptomatic for a significant period of Key information
time. As the incidence of LN varies by race/ethnicity and age, Balance of benefits and harms. The reported benefits of
a high index of suspicion should be maintained for patients of antimalarial use in SLE include lower flare (including kidney)
Asian, African/Caribbean, and Hispanic descent.619–622 There rates,641,642 higher response rates to therapy,641–644 lower
is a higher incidence of LN and more-severe disease in incidence of CV and thrombotic events in patients with
childhood-onset SLE compared to adult-onset SLE.626 antiphospholipid antibodies,645–648 less organ damage,649–654
Although a proteinuria level of 500 mg/d is suggested as a improved lipid profile,655,656 and better preservation of
threshold for further investigations, taking into consideration bone mass.657
physiological causes of low-level proteinuria and to avoid Hydroxychloroquine use in pregnancy has been associated
unnecessary kidney biopsies, it is important to note that the with a decrease in lupus activity and a satisfactory safety
severity of proteinuria varies considerably in severe active profile in both the mother and the fetus.658–660 Significant
nephritis and can appear relatively “insignificant” at times. A side effects are uncommon but include skin rash, increase in
holistic assessment including clinical, urinary, and laboratory skin pigmentation, muscle weakness, and visual change or
parameters, and also repeated investigations to note the loss of vision. Hydroxychloroquine may accumulate in lyso-
progression of abnormal findings over time, are important in somes and cause a form of phospholipidosis with accumu-
informing clinical management decisions. Because clinical lation of multilamellar zebra bodies in podocytes that can
findings do not always correlate with the extent or severity of mimic the appearance of Fabry disease.661,662
kidney involvement,627,628 a kidney biopsy is useful to Quality of evidence. Moderate-quality data support the
confirm the diagnosis and for the assessment of activity and benefit of hydroxychloroquine use in patients with SLE, but in
chronicity features that inform treatment decisions and LN, the available evidence is predominantly from observational
prognosis.627–637 Kidney biopsies should be read by an studies and post hoc analyses. In a 24-week RCT that included 47
experienced kidney pathologist and classified according to the patients, the Canadian Hydroxychloroquine Study Group
ISN/RPS scheme.638–640 Electron microscopy, where available, reported a higher incidence of SLE flares in patients who
is helpful in ascertaining ultrastructural details of histopa- stopped hydroxychloroquine compared to those who
thology such as the extent and severity of podocyte injury and continued treatment, with a hazard ratio (HR) of 2.50 (95%

Figure 85 | Diagnosis of kidney involvement in SLE. eGFR, estimated glomerular filtration rate.
CI: 1.08–5.58). The frequency of severe LN flares was also kidney benefits, protective effects against infection, and may
increased but did not reach statistical significance.663 A increase complete remission rate in patients with LN. The
systematic review that included 95 reports published between quality of the evidence is low because of study limitations,
1982 and 2007, 5 of which were RCTs, concluded that indirectness, or imprecision, but it has been upgraded because
hydroxychloroquine use could prevent SLE flares and increase of the large reported effect sizes (Supplementary
long-term patient survival, while toxicity was infrequent, mild, Table S45643,644,651–666). Two observational studies reported an
and usually reversible; and hydroxychloroquine use in association between hydroxychloroquine treatment and
pregnancy was associated with a decrease in lupus activity reduced mortality in patients with LN, but the quality of
without harm to the fetus.664 Low-quality observational evidence for this outcome is very low (Supplementary
studies have indicated that hydroxychloroquine may have Table S45654,666).

Figure 86 | Activity and chronicity items included in LN kidney biopsy report. NIH, National Institutes of Health, USA.
Values and preferences. The potential benefits of preventing eGFR <30 ml/min per 1.73 m2, the dose of hydroxychloro-
organ damage and vascular complications were judged as being quine should be reduced by $25%.
important to patients. The Work Group also judged that the
relatively low risk of adverse events associated with hydroxy- Rationale
chloroquine would also be important to patients. Therefore, Data from multiple observational cohort studies show various
the Work Group felt that nearly all well-informed patients in benefits of hydroxychloroquine treatment in SLE, notably a
the target population would choose to receive hydroxychloro- reduced incidence of flare and organ damage accrual, and a
quine treatment in comparison to no treatment. relatively low rate of drug-related adverse effects, including
Resource use and costs. Hydroxychloroquine can be an ocular toxicity. Despite the relatively low-quality evidence, the
expensive drug in some countries. Therefore, in low-resource overall balance between benefits and potential risks provides
settings, it may be acceptable to substitute structurally similar the basis for recommending its use as part of general man-
drugs such as chloroquine that have a similar mechanism of agement in patients with SLE.
action but are less expensive.
Considerations for implementation. Because of the risk of Practice Point 10.2.1.1: Adjunctive therapies to manage LN
hemolysis in patients who have glucose-6-phosphate and attenuate complications of the disease or its treatments
dehydrogenase (G6PD) deficiency, measurement of G6PD should be considered for all patients, as outlined in
levels is preferred in men, especially those of African, Figure 87.
Asian, or Middle Eastern origin, before starting Although many of the above recommendations also apply
hydroxychloroquine. However, this risk appeared low, to patients with proteinuric kidney diseases treated with
according to the findings of a recent report.667 All patients immunosuppression in general (Chapter 1), some risks are
should have a baseline retinal examination and then annual especially relevant to patients with SLE and LN. Patients with
eye testing, especially after 5 years of use. Clinicians should SLE show increased mortality rates when compared to age-
be aware that antimalarials may be cardiotoxic (e.g., and sex-matched controls in the general population.668,669
congestive heart failure, conduction abnormalities) after Infections, CV complications, and CKD, especially kidney
long-duration therapy or high cumulative exposure. The failure, are major causes of death.623–625,670 Early deaths are
dosing of hydroxychloroquine is 6.5 mg/kg ideal weight/ related to infections or lupus activity, while CV and malignant
d or 400 mg/d, and during the maintenance phase, this complications and deaths related to kidney failure account for
should be lowered to 4 to 5 mg/kg/d. In patients with late mortalities.671

Figure 87 | Measures to minimize the risk of complications related to LN or its treatment. HBV, hepatitis B virus; HCV, hepatitis C virus;
HIV, human immunodeficiency virus; LN, lupus nephritis; RAS, renin–angiotensin system.
Cardiovascular complications in patients with LN. Patients reactions are not infrequent in patients with lupus, and in
with SLE have both traditional (dyslipidemia, smoking, an early survey, 31% reported allergy to sulfonamide, with
obesity, etc.) and non-traditional (proteinuria, inflammation, one-fifth of these patients also reporting worsening of SLE
etc.) CV risk factors. A patient often has multiple risk factors, with the drug intolerance.674 In a retrospective study from
which can be secondary to disease-related organ damage Thailand that included 132 patients with various connective
(especially CKD, hypertension, proteinuria) or treatment tissue diseases, TMP-SMX was effective in preventing
(such as glucocorticoids and CNIs). Regular evaluation of pneumocystis pneumonia, and adverse drug reaction
various risk factors and timely treatment are essential to occurred in only 9.4% of patients with SLE given
prevent premature CV complications.672 prophylaxis.675 However, a recent retrospective study from
Infections in patients with LN. Infection is a leading cause of Japan reported a drug allergy rate of 41.9% in patients with
death in patients with LN, and infection-related deaths are lupus given TMP-SMX prophylaxis with conventional
more common during the initial phase of management dosing, but only 10.7% in those with gradual introduction
following exposure to intensive immunosuppressive of the drug over a 9-day period.676 Pneumocystis
therapy.665,668,673 There are data to suggest a higher pneumonia is a severe complication in patient who are
incidence of adverse outcomes related to infections in Asia, immunosuppressed and can result in fatality. Prophylaxis
which may be related to delayed presentation and the access should be actively considered, taking into consideration a
to care.673 Avoidance of overimmunosuppression is an patient’s allergic diathesis. The rate of Herpes zoster is 2–10
important measure to reduce the risk of infections and times higher in patients with SLE than in healthy controls,
adverse outcomes. Prophylaxis for Pneumocystis is standard but the role of antiviral prophylaxis is uncertain. Available
practice in organ transplant recipients, but its role in zoster vaccine preparations include the live-attenuated
patients on high-dose glucocorticoid therapy without HIV vaccine Zostavax! and the adjuvanted recombinant vaccine
infection remains controversial, and there are few data from Shingrix. In general, live vaccines should be avoided in
patients with SLE.618,619 Antibiotic-related adverse drug immunosuppressed subjects. There are no data on the

efficacy of the recombinant zoster vaccine in patients with in patients treated with cyclophosphamide, especially in
lupus, and there is concern about whether the adjuvant patients with high cumulative exposure.
might affect disease activity. There is also concern that the Bone health. Glucocorticoid therapy, especially when high
polio vaccination has been associated with lupus flares, doses are used for long durations, increases bone loss.680,681 In
whereas the data on influenza vaccination are conflicting. children, glucocorticoid cumulative dose affects peak bone
Response to vaccination is reduced following exposure to mass and growth.682 Individual evaluation of fracture risk can
high-dose immunosuppression.677 be estimated using patient demographics and clinical history,
Contraception and pregnancy. Pregnancy in patients with glucocorticoid dose, and the Fracture Risk Assessment Tool
LN is associated with increased maternal complications and (FRAX) score.683 Calcium (optimal intake 1000–1200 mg/d)
inferior fetal outcomes compared with the occurrence in and vitamin D supplementation are recommended for patients
healthy individuals, and the risks are higher when LN is active. with LN, as well as consideration for oral bisphosphonates
Some of the frequently used medications in patients with lupus according to individual risk assessment.684,685
are contraindicated during pregnancy, such as MMF, cyclo- Malignancies in patients with LN. Patients with SLE have
phosphamide, and warfarin. Counseling with regard to increased risk of malignant tumors, including non-Hodgkin’s
contraception and pregnancy should be done early in patients lymphoma, lung, liver, vulvar/vaginal, thyroid, nonmelanoma
of childbearing age. Patients should be seen by a gynecologist skin cancer, and the risk (especially with bladder cancer) is
to discuss the choice of methods for contraception. For patients increased in patients with a history of exposure to cyclophos-
who prefer oral hormonal contraception, estrogen–progestin phamide.686,687 In general, the surveillance for malignancies in
contraceptives with ethinyl estradiol dose at not higher than patients with LN follows the cancer-screening policies for the
30 mg may be used in patients who are negative for general population in the local community, and specific ma-
antiphospholipid antibodies and with stable low disease lignancy screening guidelines for patients with SLE are either
activity, whereas progestin-only contraceptives are preferable lacking or largely opinion-based.688 Although there is pre-
in patients with a moderate or high level of disease activity. liminary evidence showing efficacy and safety of human
Estrogen-containing contraceptives should be avoided in papillomavirus vaccines in patients with SLE, there is also
patients with antiphospholipid antibodies or a history of controversy about whether the vaccine may cause predisposi-
thrombosis, in view of the risk of thromboembolism.678 Data tion to the development of SLE or lupus-like disease.689,690
from women exposed to chemotherapy showed efficacy of
gonadotrophin-releasing hormone (GnRH) analogues in
10.2.2 Class I or Class II lupus nephritis
reducing the rate of premature ovarian failure, whereas the
putative gonadal protective effect of oral contraceptive pills Practice Point 10.2.2.1: Approach to immunosuppressive
appeared variable.679 Fertility protection with GnRH agonists, treatment for patients with Class I or Class II LN
or sperm and oocyte cryopreservation, should be considered (Figure 88)
Figure 88 | Immunosuppressive treatment for patients with Class I or Class II LN. LN, lupus nephritis.

Patients with Class I or Class II LN generally have normal alone in preserving long-term kidney survival in active severe
kidney function, or at most, low-grade proteinuria that is well LN.630,704–707
below the nephrotic-range, and sometimes microscopic he- For decades, the accepted standard of care for prolifera-
maturia. For these patients, no specific immunosuppressive tive LN was high-dose glucocorticoids plus cyclophospha-
therapy beyond what is being given for nonrenal lupus is mide, but the risk of severe side effects prompted
needed.691 investigation of alternative induction regimens. This led to
Patients with Class I or II histology but with nephrotic- several trials comparing other agents to cyclophosphamide
range proteinuria or NS are considered to have lupus podo- for initial treatment of LN, including azathioprine and
cytopathy. This diagnosis may be confirmed by demonstrating MPAA.
diffuse podocyte effacement on electron microscopy. Clinically MPAAs received considerable attention and were shown
and histologically, these patients are similar to those with MCD to have efficacy similar to that of cyclophosphamide for
or FSGS, often showing a good response to glucocorticoid initial treatment of LN.708,709 Although some studies sug-
treatment.692–694 Although there have been no RCTs, obser- gested that MPAAs were associated with fewer adverse ef-
vational data showed that over 90% of patients given gluco- fects than cyclophosphamide, several investigations
corticoid monotherapy achieved remission within a median demonstrated a similar prevalence but different profile of
time of 4 weeks.692,695–699 Data on relapse are even more adverse events.
limited, but there appears to be a significant risk of relapse after However, all studies used concomitant high-dose gluco-
glucocorticoids are tapered.700 Although optimal duration is corticoids, and these likely accounted for many treatment-
not known, maintenance with low-dose glucocorticoid plus an associated adverse events.629,631,708–710 The dose of MPAA
additional agent such as an MPAA, azathioprine, or a CNI is also differed between the studies. Nonetheless, based on
suggested, especially in patients with a history of relapse. relatively favorable “real-world” clinical experience, MPAA-
based regimens have mostly replaced cyclophosphamide-
10.2.3 Class III or Class IV lupus nephritis
based regimens for the initial treatment of proliferative LN.
The dose of MMF is typically 2–3 g/d. Figure 91 shows the
10.2.3.1 Initial therapy of active Class III/IV lupus nephritis details of cyclophosphamide-dosing regimens.
Based on the hypothesis that the risk–benefit ratio of initial
Recommendation 10.2.3.1.1: We recommend that LN treatment could be improved further, a reduced-dose
patients with active Class III or IV LN, with or cyclophosphamide regimen was compared to standard high-
without a membranous component, be treated dose cyclophosphamide in a study of 90 patients of Euro-
initially with glucocorticoids plus either low-dose
pean descent with active nephritis. The results showed no
intravenous cyclophosphamide or MPAA (1B).
statistically significant difference in efficacy both short- and
long-term and an improved side-effect profile.634,711 This
This recommendation places a high value on the data demon- regimen was also tested in a short-term trial that included 100
strating that glucocorticoids, in combination with MPAA or Indian patients and showed similar remission rates compared
standard-dose cyclophosphamide, will improve kidney outcomes to MPAA.709 In view of the scarcity of data on reduced-dose
in active severe LN. It also places a high value on the data cyclophosphamide in patients of African or Hispanic
demonstrating comparable efficacy between MMF and cyclo- descent, there is concern as to whether this regimen is
phosphamide in active severe LN. The Work Group recognizes effective in these patient groups.
that 2 new therapies have been approved for LN by the US FDA It is important to note that of all these treatment options,
recently. The data leading to the approvals have recently been only initial treatment with cyclophosphamide has long-term
published.701,702 This evidence has not yet been systematically data from controlled trials showing its higher efficacy in
reviewed in the context of current therapies, and it has not been preserving kidney function compared to treatment with
graded for quality. Nevertheless, these therapies are promising glucocorticoids alone.705,706 All the other regimens have
and are discussed in subsequent practice points. All potential shown comparable or superior short-term efficacy, but trials
approaches to initial treatment of proliferative LN are shown in have not been carried out to compare long-term efficacy on
Figure 89. kidney survival. There is increasing evidence, based on data
from observational studies,632,711–715 that effective induction
Key information of renal response after initial therapy, especially a complete
Balance of benefits and harms. The short-term prognosis of renal response, is associated with more-favorable long-term
patients with proliferative LN improved dramatically when kidney outcomes.
treatment with high-dose glucocorticoids was started in the In summary, Class III and Class IV LN are often very
1960s.703 However, the long-term kidney prognosis severe, and without treatment, they are associated with
continued to be poor as many patients progressed to kidney significant patient morbidity and mortality and a very high
failure despite treatment. In landmark studies during the risk of kidney loss. Four distinct approaches have evolved
1980s, the addition of cyclophosphamide to glucocorticoids to achieve renal response and prevent loss of kidney
was shown to be superior to treatment with glucocorticoids function. The attempt to reduce medication side effects

www.kidney-international.org
Kidney International (2021) 100, S1–S276

Figure 89 | Recommended approach for initial therapy of active Class III/IV LN. *Treatments in Recommendation 10.2.3.1.1. ‡Refer to Figure 90 for examples of corticosteroid treatment
regimen. §Refer to Figure 91 for comments on cyclophosphamide regimens. †Denotes treatments approved by the U.S. Food and Drug Administration. b.i.d., twice daily; eGFR, estimated
glomerular filtration rate; i.v., intravenous; MMF, mycophenolate mofetil; MPAA, mycophenolate acid analogs; p.o., oral; q2wk, every 2 weeks; q4wk, every 4 weeks; s.c., subcutaneous; SCr,
serum creatinine.
chapter 10
S213
has been modestly successful, shifting side-effect profiles economic analysis has not been done. Furthermore, there
away from the leukopenia, infertility, and future cancers have been no comparisons of quality of life between
associated with high cyclophosphamide exposure. Despite patients with CKD, patients with kidney failure receiving
the potential of important treatment-associated toxicities, kidney replacement therapy, and patients receiving
the benefits of treating proliferative LN outweigh the immunosuppression, especially with high-dose or prolonged
harms. administration of glucocorticoids. MPAA regimens were
Quality of evidence. In the 6 RCTs that compared i.v. associated with higher medication costs but lower facility
cyclophosphamide with glucocorticoids, there was moderate costs and a superior quality of life compared to i.v.
quality of evidence for a kidney benefit and decrease in kidney cyclophosphamide regimens.726–728
relapse. The quality of the evidence from these RCTs was Considerations for implementation. In view of the significant
downgraded to moderate because of study limitations (unclear treatment costs,728–730 the choice of therapy is often region-
blinding of participants and personnel, unclear allocation specific and depends on drug availability, reimbursement
concealment; Supplementary Table S46630,704,705,707,716–718). policies, and the financial means of individual patients.
High-dose versus low-dose cyclophosphamide has been Other considerations when choosing initial therapy for LN
compared in a few RCTs (Supplementary Table S47634,718– include likelihood of adherence, age, prior
721
). The results from these trials indicate that low-dose immunosuppressive exposure, disease tempo and severity,
cyclophosphamide is associated with fewer adverse events and race and ethnicity.
(such as infection, malignancy, leukopenia, and bone Physicians may choose an i.v. regimen if suboptimal
toxicity718; although in some studies, the efficacy also adherence is anticipated. Age is an important factor with
appeared lower than that of the high-dose regimen), with respect to preservation of fertility, as susceptibility to gonadal
moderate quality of the evidence because of serious impre- failure after cyclophosphamide use increases with age. Sus-
cision (only a few events, resulting in wide CIs indicating ceptibility to future malignancies increases with higher life-
appreciable benefit and harm). time cyclophosphamide exposure, so a detailed knowledge of
From the RCTs, there is moderate quality in the evidence prior therapies is important. Despite these considerations for
that MMF exhibits a similar efficacy, and a different side- cyclophosphamide, many physicians would initially choose
effect profile compared with i.v. cyclophosphamide. The standard-dose cyclophosphamide for patients in whom kid-
quality of the evidence was downgraded to moderate because ney function is rapidly deteriorating and whose biopsy shows
of unclear reporting of allocation concealment in trials severe activity (e.g., capillary necrosis, an abundance of
(Supplementary Table S48629,708–710,718,722–725). crescents). It should be noted that there are sparse data on
Values and preferences. Without treatment, the prognosis this group of patients who present with aggressive disease, as
for kidney survival in patients with proliferative LN is poor, so their clinical characteristics precluded them from inclusion in
the Work Group judged that most well-informed patients clinical trials. Physicians caring for patients of mixed ethnic
with Class III and IV LN would choose to be treated with background or Hispanic ethnicity may choose MPAA over
one of the immunosuppression regimens outlined cyclophosphamide as there are some post hoc analysis data
previously. Given the risks of infertility associated with suggesting it has higher efficacy,731,732 whereas physicians
cyclophosphamide and the spectra of future malignancy, caring for Chinese patients may want to choose MPAA and
most patients of childbearing age who anticipate conceiving glucocorticoids, or triple immunosuppression with gluco-
in the future, and most patients, in general, will likely opt corticoids plus low-dose MPAA plus low-dose CNI, as
for initial treatment with MPAA over standard-dose opposed to a cyclophosphamide-based regimen.636,733
cyclophosphamide. Low-dose i.v. cyclophosphamide has less
risk than standard-dose and is a reasonable alternative to Rationale
MPAA, but because the data favoring low-dose Class III or IV LN is an aggressive disease that requires
cyclophosphamide have largely come from White patients prompt and effective therapy to abate ongoing injury and
with mild to moderately severe LN, this alternative may not destruction of normal nephrons. Immunosuppressive treat-
be appropriate for the treatment of severe LN in patients of ment targets the active inflammatory lesions in kidney his-
African or Hispanic ancestry. topathology, in contrast to the chronic lesions, the extent of
Resource use and costs. Management of active LN with which portend CKD and long-term kidney prognosis.
immunosuppression is resource and labor intensive because The choice of initial treatment for Class III or IV LN entails
the medications and the surveillance for potential complica- personalized consideration of the balance between benefit and
tions are costly. Intravenous administration requires an risk and is informed by data on short-term response and long-
infusion center with supervision, and patients must be term efficacy and safety, potential adverse effects including
monitored frequently for treatment- or disease-related infections and cumulative toxicities, quality of life, and factors
complications, and require frequent clinical laboratory relevant to patient experience and adherence.
testing. However, it is likely that these costs are less over Patient and kidney survival rates in Class III or Class IV
time than those associated with managing CKD and kidney LN have improved since the 1970s, first with the use of glu-
failure resulting from no treatment, although a direct cocorticoids, and subsequently following the adoption of

combined immunosuppressive regimens with cyclophospha- extrarenal manifestations, such as central nervous system or
mide or MPAA as standard therapy. lung involvement.
Glucocorticoids remain an integral component in initial To minimize the side effects due to high cumulative
therapy for Class III or IV LN based on their anti- exposure to glucocorticoids, there is increasing use of initial
inflammatory and immunosuppressive actions. The addition i.v. glucocorticoid pulses followed by a lower starting dose
of cyclophosphamide or MPAA was associated with lower and/or more-rapid taper of oral glucocorticoid in recent
relapse rates and improved long-term kidney survival clinical trials.734 Results from a retrospective propensity
compared with glucocorticoid treatment alone. Combined analysis of data from 63 patients enrolled in the Aspreva
immunosuppressive regimens also facilitate glucocorticoid Lupus Management Study (ALMS) and the phase 2 Aurinia
minimization, thereby reducing their adverse effects Urinary Protein Reduction Active-Lupus with Voclosporin
(Figure 90). (AURA-LV) trial suggested that doses of glucocorticoids and
MPAA lower than those adopted in ALMS may result in
Practice Point 10.2.3.1.1: A regimen of reduced-dose glu- better long-term safety, including a reduction in lympho-
cocorticoids following a short course of methylpredniso- proliferative disorders, skin cancers, and glucocorticoid-
lone pulses may be considered during the initial treatment related side effects.735 In children, the avoidance of excessive
of active LN when both the kidney and extrarenal disease glucocorticoid exposure also has implications for growth,
manifestations show satisfactory improvement (Figure 90). psychosocial issues, and drug adherence.736 With accumulating
Glucocorticoids are used in all current treatment regimens data on the efficacy and glucocorticoid-sparing role of
of LN. These drugs have both immunosuppressive and anti- immunosuppressive medications such as cyclophosphamide
inflammatory effects and provide immediate treatment for and MMF, there is a move toward reducing exposure to glu-
the often extensive intrarenal inflammation that is seen in cocorticoids (Supplementary Table S49718,737). Examples of
patients with Class III and Class IV LN. This regimen is dosing and tapering regimens in initial treatment of LN, based
necessary because there is a lag before the immunosuppressive on published literature and recent clinical trials that investigate
effects of cyclophosphamide, MPAA, CNIs, or B cell–directed the efficacy and safety of new therapeutic agents, are shown in
therapies are seen. The dose, tapering regimen, and duration Figure 90. They serve to illustrate variations in exposure to
of glucocorticoid schemes vary considerably among clinicians glucocorticoids, but it is premature to recommend one over the
and are largely opinion-based. Examples are given in other, as the regimens have not been formally compared to one
Figure 90. another in prospective clinical trials.
The role of i.v. methylprednisolone pulses at the start of
treatment is not well-studied but is commonly given as up to Practice Point 10.2.3.1.2: Intravenous cyclophosphamide
3 daily doses of 500 mg each (range 250–1000 mg/d), espe- should be used as the initial therapy for active Class III and
cially in patients who present with a clinical syndrome of Class IV LN in patients who may have difficulty adhering to
RPGN—acute and severe deterioration of kidney function an oral regimen.
often accompanied by a high proportion of crescents or Cyclophosphamide may be given orally or intravenously,
vascular lesions in the kidney biopsy, or when there are severe and in a standard-dose (also known as the modified National
Figure 90 | Example of glucocorticoid regimens for LN. LN, lupus nephritis.

Figure 91 | Cyclophosphamide dosing regimens, combined with glucocorticoids, in initial treatment for active Class III/IV LN. i.v.,
intravenous; LN, lupus nephritis; max, maximum; NIH, National Institutes of Health, USA.; p.o., oral.
Institutes of Health (NIH) regimen or high-dose regimen) or Practice Point 10.2.3.1.3: An MPAA-based regimen is the
low-dose (also known as the Euro-Lupus regimen). The preferred initial therapy of proliferative LN for patients at
dosing and duration for these regimens are given in Figure 91. high risk of infertility, patients who have a moderate to
The choice of which regimen to use depends on several high prior cyclophosphamide exposure, and patients of
factors and can be individualized: Asian, Hispanic, or African ancestry.
! Efficacy: Oral and standard-dose i.v. cyclophosphamide Trials of MMF for initial treatment of proliferative LN have
regimens have been used in diverse ethnic populations and targeted dosing of 2–3 g/d. Several studies have shown that
for all levels of disease severity, and show equivalent effi- MMF has comparable short-term efficacy to oral or i.v.
cacy.635,738–741 Reduced-dose cyclophosphamide (Euro- cyclophosphamide for induction of complete and partial renal
Lupus regimen) shows equivalent efficacy to standard-dose responses (Supplementary Table S48629,631,632,710,718,722–725).
cyclophosphamide but was tested mainly in White pa- MMF has significant gastrointestinal toxicity, and at
tients.634,711 Emerging data suggest low-dose cyclophos- moderate-to-high doses, some patients may not tolerate it. In
phamide is effective in Asians, Hispanics, and Black patients with gastrointestinal intolerance, a trial of enteric-
patients, but these studies did not make direct comparisons coated MPA in a dose range of 1440–2160 mg is warranted,
to standard-dose i.v. cyclophosphamide (Supplementary in view of its greater gastrointestinal tolerance.737
Table S47634,718–721,742). Although MPAA does not predispose patients to gonadal
! Cost: Intravenous cyclophosphamide is more expensive failure or hematologic malignancies as does cyclophospha-
than oral and requires the availability of an infusion suite mide, the ALMS trial (target dose 3 g/d) showed a similar
and experienced staff. incidence of side effects between patients treated with MMF
! Convenience: Oral cyclophosphamide does not require pa- plus glucocorticoids and patients treated with cyclophos-
tients to stop work or family activities. phamide plus glucocorticoids.629 In this trial, 9 deaths
! Toxicity: The toxicities of cyclophosphamide may be consid- occurred in the MMF group, and 5 in the cyclophosphamide
ered immediate (e.g., gastrointestinal, susceptibility to infec- group. Seven of the 9 deaths in the MMF group were due to
tion) or delayed (e.g., loss of fertility, future malignancies). infections, and 7 of the 9 deaths in MMF-treated patients
! Standard-dose i.v. cyclophosphamide was shown to be less occurred in Asia. Concomitant high-dose glucocorticoids and
toxic than oral cyclophosphamide, but the dose and dura- the relatively high MPA exposure have been proposed as
tion of oral treatment in these reports were substantially contributory factors to the higher-than-expected infection-
higher and longer than those currently recommended related adverse outcomes in this trial. In this regard, data
(Supplementary Table S50630,718,741). The incidence of from kidney transplant clinical trials showed that, compared
bladder toxicity is also felt to be lower with i.v. cyclo- with an MMF dose of 2 g/d, an increased MMF dose of 3 g/
phosphamide. Reduced-dose i.v. cyclophosphamide has the d did not result in a higher efficacy in the non-Black patient
most favorable immediate toxicity profile among the 3 population, but was associated with more adverse events.743
cyclophosphamide regimens. Therefore, consideration of the race or ethnicity of a pa-
B The risk of future hematologic malignancy is related to tient, or the geographic locality, may also be relevant when
total lifetime exposure (>36 g), as is myelofibrosis (>80 deciding on the dose of MPAA to be used, in view of the
g). Total lifetime exposure plus age constitutes a signif- potential differences in risk profiles among patients.
icant risk factor for premature ovarian failure (>7.5–15 MPA pharmacokinetics varies considerably among pa-
g/m2 for young to older pediatric patients, respectively; tients, especially in the context of hypoalbuminemia and
300 mg/kg for adults). impaired kidney function. Data from small-scale studies

suggested that an MPA area under the concentration-versus- conducted in China, combined a fixed, relatively low-dose of
time curve of 35–45 mg/hr/l or a trough level of 3.0–4.5 tacrolimus (4 mg/d, achieved trough levels of 5.2–5.5 ng/ml
mg/l may serve to ensure adequate exposure during initial [6.4–6.8 nmol/l]) with low-dose MMF (1 g/d) in patients
therapy, but the role of therapeutic drug-level monitoring with a baseline serum creatinine level #3.0 mg/dl (265
remains to be established.744–748 mmol/l), and reported earlier attainment of renal response
MMF has been tested successfully in diverse ethnic groups. than in controls treated with NIH-cyclophosphamide
A more granular look at the efficacy of MMF in specific ethnic regimen with a higher complete renal response rate (46%
groups was done through a post hoc analysis of data from the vs. 26%) after 24 weeks of treatment.636 Extended follow-up,
ALMS study, the largest trial comparing MMF to i.v. cyclo- however, showed comparable renal response rates in both
phosphamide to date.629,731 The analysis showed higher groups during the second year of treatment.733 Similarly, a
treatment response rates for MMF compared to cyclophos- study from Japan reported a complete response rate of 80%
phamide in Hispanic patients (60.9% vs. 38.8%, P ¼ 0.011) after 6 months of treatment with a triple immunosuppres-
and patients from Latin America (60.7% vs. 32%, P ¼ 0.003), sive regimen that included glucocorticoids, reduced-dose
whereas the response to MMF was numerically higher but not cyclophosphamide, and tacrolimus.750
statistically different than that to cyclophosphamide in Black The evidence from the few RCTs that compared triple-
patients (53.9% vs. 40.0%, P ¼ 0.39). A higher response rate therapy to cyclophosphamide is judged as low quality because
to MMF than to cyclophosphamide in Hispanic patients was of study limitations and indirectness (Supplementary
also reported in cohort studies.732 In contrast, the response Table S51636,718,752). As these early trials mainly included pa-
rate to cyclophosphamide was numerically higher but not tients of Asian ethnicity, and some excluded patients with se-
statistically different than that to MMF in Asian patients vere disease, the generalizability of this therapy to the broader
(63.9% vs. 53.2%, P ¼ 0.24).629,731 LN population is unclear (see also Practice Point 10.2.3.1.5).
Cyclophosphamide has historically been the first-choice Of importance, in the large Chinese study, the number of
treatment for very severe proliferative LN. An analysis of infections was higher in patients who received triple therapy
pooled data from various clinical trials of patients with Class than in those who were treated with cyclophosphamide,
III/IV LN, crescents in >15% of glomeruli, and abnormal SCr although this difference did not reach statistical significance.
level at presentation showed a comparable early response to More data are also required on the incidence of acute and
glucocorticoids plus either cyclophosphamide or MMF.749 chronic CNI nephrotoxicity, the metabolic side effects of
However, the analysis also suggested that initial treatment CNIs and their effect on blood pressure control, as well as the
with cyclophosphamide might be associated with a more optimal duration of treatment and whether there may be a
sustained response and more favorable long-term kidney rebound of proteinuria after stopping CNI.751
outcome than initial treatment with MMF. In the mainte-
nance phase of ALMS,633 although not statistically different, Practice Point 10.2.3.1.5: In patients with baseline eGFR of
patients initially treated with cyclophosphamide had numer- at least 45 ml/min per 1.73 m2, voclosporin can be added to
ically lower rates of disease flare compared with those initially MPAA and glucocorticoids as initial therapy for 1 year.
treated with MMF. Voclosporin is an analogue of cyclosporine that exhibits
enhanced potency in calcineurin inhibition. Voclosporin was
Practice Point 10.2.3.1.4: Initial therapy with a triple noninferior to tacrolimus in the prevention of biopsy-proven
immunosuppressive regimen that includes a CNI (tacroli- acute rejection in a 6-month multicenter open-label phase 2b
mus or cyclosporine) with reduced-dose MPAA and glu- trial that involved 334 low-risk kidney transplant re-
cocorticoids is reserved for patients who cannot tolerate cipients.753 Voclosporin for the treatment of active biopsy-
standard-dose MPAA or are unfit for or will not use proven Class III, IV, or V lupus nephritis was investigated
cyclophosphamide-based regimens. in Aurinia Urinary Protein Reduction Active - Lupus With
Calcineurin inhibitors (CNI) are potent immunosuppres- Voclosporin (AURA-LV),734 a phase 2 RCT of 265 subjects
sive medications due to their inhibition of T lymphocyte and Aurinia Renal Response in Active Lupus With Voclo-
activation and release of interleukin-2. They also modulate sporin (AURORA),702,754 a phase 3 RCT of 357 subjects. Both
the podocyte cytoskeleton, leading to reduction of proteinuria trials included patients of diverse ancestry. Voclosporin was
in various glomerular diseases. The use of a CNI in the compared to placebo, and all patients received glucocorticoids
treatment of LN may therefore lead to more effective or more and MMF (target dose: 2 g/d) as background therapy. The
rapid reduction of proteinuria. rapidly tapered corticosteroid regimen used was novel. All
Data from short-term studies with follow-up of 6–12 patients received 2 doses of intravenous methylprednisolone
months suggest that a regimen of glucocorticoids combined (500 mg/dose) followed by 20–25 mg prednisone that was
with cyclosporine or tacrolimus, with or without reduced- rapidly tapered to 2.5 mg/d by 16 weeks. The primary
dose MPAA, as initial LN therapy has comparable efficacy endpoint of these trials was renal response (RR), defined as
to glucocorticoids combined with cyclophospha- urine PCR #0.5 mg/mg, eGFR $60 ml/min per 1.73m2, or
mide.636,750,751 Until recently, most of these trials had been no decline of >20% from baseline, and prednisone dose
done in Asia (see Practice Point 10.2.3.1.5). The largest trial, of <10 mg/d for the 8 weeks prior to endpoint measurement.

In AURA-LV, 33% of patients treated with voclosporin 23.7 duration of observation in the trials. Some trials using biologics
mg twice per day reached an RR at 24 weeks compared to 19% have yielded encouraging results. For example, in a prospective
of placebo-treated patients (OR 2.03, P < 0.05).734 Similarly, in single-center pilot study to investigate whether rituximab could
AURORA, 41% of voclosporin-treated patients achieved RR at facilitate corticosteroid avoidance, 50 patients with active LN
52 weeks, compared to 23% of placebo-treated patients (OR (22 Class V, 28 Class III/IV # V) were treated with rituximab 1 g
2.65, P < 0.001).702,754 A pooled analysis of the 2 trials showed and methylprednisolone 500 mg i.v. on day 1 and day 15 and
that patients treated with voclosporin added to standard ther- were maintained on MMF (maximum dose 1.5 g twice per day,
apy had an RR rate of 44% at 1 year, compared to 23% in target trough blood level of mycophenolic acid 1.2–2.4 mg/ml
placebo patients (P < 0.0001).755 Adverse events were similar [3.7–7.5 mmol/l]) without glucocorticoids, and by 52 weeks,
between the placebo and voclosporin arms. 52% of patients achieved complete remission and 34% achieved
Compared to other CNIs, such as cyclosporine and partial remission.767
tacrolimus, voclosporin has a more consistent The negative outcomes in previous clinical trials do not
pharmacokinetic–pharmacodynamic relationship due to preclude a therapeutic role for some of these novel agents in
enhanced binding of the voclosporin–cyclophilin complex to selected patients, including those who have not responded
calcineurin and reduced drug and metabolite load. Pre- well to or who do not tolerate standard therapy, or when
liminary evidence, based on data from the AURA-LV and steroid-sparing is attempted (Supplementary Tables S56–
AURORA trials, suggests that therapeutic drug monitoring S59718,742,757–759,764).767
may not be necessary in patients.756 Ongoing clinical trials continue to investigate the role of
Results from these 2 pivotal trials led to the US FDA biologics for the treatment of LN. A recent phase 2 study
approval of voclosporin to treat adult patients with LN in showed that in adult patients with active proliferative LN
January 2021. Of note, voclosporin is not recommended for treated with MPAA and glucocorticoids, the addition of
patients with a baseline eGFR #45 ml/min per 1.73 m2, as obinutuzumab resulted in higher complete renal response
these patients were excluded from the trials. Also, voclosporin rates at week 76 (40% vs. 18%, P ¼ 0.007), and at week 104
has not been studied with cyclophosphamide. compared to placebo (54% vs. 29%, P ¼ 0.005). The rate of
The positive results of AURA-LN and AURORA coupled serious adverse events and serious infections did not differ
with the Asian studies of tacrolimus and cyclosporine suggest between the 2 groups.760
triple immunosuppressive therapy incorporating a CNI can A phase 3 RCT of belimumab (10 mg/kg i.v. on days 1, 15,
be an effective treatment regimen for LN. An advantage of a and 29, then every 28 days to week 100) added to standard-of-
CNI-based regimen is the more rapid reduction of protein- care therapy resulted in approval of belimumab for LN by the
uria. However, more data on long-term efficacy and safety of U.S. FDA in December 2020.701 This trial, Efficacy and Safety
CNI use in LN are required. of Belimumab in Patients with Active Lupus Nephritis
(BLISS-LN), examined the 2-year primary efficacy renal
Practice Point 10.2.3.1.6: There is an emerging role for B- response (PERR) after belimumab or placebo was added to
lymphocyte targeting biologics in the treatment of LN. standard-of-care therapy, which was either MMF or the Euro-
Belimumab can be added to standard therapy in the Lupus reduced-dose cyclophosphamide regimen chosen by
treatment of active LN. Rituximab may be considered the site investigator. PERR was defined as a ratio of PCR
for patients with persistent disease activity or repeated of <0.7, an eGFR that was no worse than 20% below baseline
flares. or at least 60 ml/min per 1.73 m2, and no use of rescue
Results from phase 2 and phase 3 clinical trials did not therapy for treatment failure. At week 104, significantly more
demonstrate superiority in efficacy when B cell–targeting patients who received belimumab achieved a PERR compared
therapies (rituximab, ocrelizumab), costimulatory blockade to the number of those who received placebo (43% vs. 32%;
(abatacept), or anti-interleukin-6 monoclonal antibody were OR 1.60; P ¼ 0.03; Supplementary Table S60701). Key sec-
added to standard initial therapy of glucocorticoids and either ondary endpoints included complete renal response and the
MMF or cyclophosphamide.757–762 The negative outcomes risk of renal event or death. These also favored belimumab.
contrast with reports of case series that suggested efficacy when Subgroup analysis showed that the overall PERR response was
patients with suboptimal response to standard therapy were driven by the results in the larger subgroup (73.5%) of pa-
treated with rituximab.763–766 Interestingly, patients treated tients who received MMF as background therapy. Belimumab
with rituximab and abatacept in the RCTs showed more treatment was not associated with excess adverse events.
effective suppression of anti-double-stranded deoxy- In summary, there are accumulating data on the bio-
ribonucleic acid (dsDNA) levels and complement activation, logical and clinical efficacy of various biologics. Although
but this biological efficacy did not translate to conventional long-term results are awaited, results on these biologics
clinical indicators of treatment response.757,759 Reasons for the have expanded the armamentarium of therapeutic options
apparent discrepancy between biological efficacy versus clinical and potential combinations of treatments. The favorable
observations, and between the case series versus RCT results, safety profile associated with some of the new biologics
include the different populations of patients studied, the presents a distinct advantage. Further investigations are
outcome parameters used in the trials, and the relatively short necessary to define the profiles and characteristics of

patients who would benefit most from each of the various 10.2.3.2 Maintenance therapy for Class III and Class IV lupus
novel therapies. nephritis
Practice Point 10.2.3.1.7: Other therapies, such as azathi- Recommendation 10.2.3.2.1: We recommend that
oprine or leflunomide combined with glucocorticoids, may after completion of initial therapy, patients should
be considered in lieu of the recommended initial drugs for be placed on MPAA for maintenance (1B).
proliferative LN in situations of patient intolerance, lack of
availability, and/or excessive cost of standard drugs, but This recommendation places a high value on the data demon-
these alternatives may be associated with inferior efficacy, strating that long-term, reduced-dose MPAA decrease the risk of
including increased rate of disease flares and/or increased LN relapse compared to azathioprine or no treatment and that
incidence of drug toxicities. MPAA have effectiveness comparable to that of cyclophospha-
Azathioprine combined with methylprednisolone pulses mide but with a lower risk of adverse events. The recommen-
showed a comparable short-term renal response rate to that for dation places a lower value on the risk of adverse events
prednisolone combined with standard-dose i.v. cyclophospha- associated with long-term MPAA treatment as compared to no
mide in a study that included 87 patients in the Netherlands, but treatment (Figure 92).
the azathioprine and pulse methylprednisolone group had more
infections, and their extended follow-up data showed a higher Key information
relapse rate and greater progression of CKD (Supplementary Balance of benefits and harms. High-intensity immuno-
Table S52630,718,768,769). Nonetheless, some patients may not suppression for the initial treatment of LN is given for 3–6
tolerate MPAA, cyclophosphamide, or CNIs, or these drugs may months, depending on the regimen (Section 10.2.3.1). At the
be unavailable, too costly in some regions of the world, or end of initial therapy, only about 10% to 40% of patients
contraindicated, as in pregnant patients. achieve complete response as defined by clinical parame-
Short-term studies in Chinese patients compared leflu- ters,2,628,634,636 and approximately 20% achieve complete
nomide against i.v. cyclophosphamide, in both cases com- histologic remission, defined as an activity index of zero on
bined with glucocorticoids, and reported comparable renal repeat kidney biopsy.627 Also, LN relapses frequently, and
response rates of approximately 70% after 6 months.770,771 relapses predispose to additional kidney damage and pro-
Other therapies that have not shown significant benefit gression to kidney failure. Ongoing treatment is therefore
when added to standard therapy include plasmapheresis needed to consolidate initial responses into more complete
(Supplementary Table S53618,635,772–774), and the anti- and sustained responses, and to prevent disease flares. After
interleukin-6 antibody sirukumab (Supplementary initial therapy, ongoing immunosuppression is designated as
Table S54618,775). In a phase 2a trial, laquinimod was associ- maintenance therapy.
ated with a higher renal response rate (62.5% compared with The evolution of current maintenance therapy for prolif-
33.3% in the placebo group) when added to standard-of-care erative LN is an example of how investigators have tried to
treatment with glucocorticoids and MMF in patients with balance preservation of kidney function against the toxicities
active LN (Supplementary Table S55618,776). of long-term immunosuppressive therapy. After it became
Figure 92 | Maintenance therapy for Class III and Class IV LN. The target ranges for CNIs have been based on the transplant literature. The
KDIGO Work Group acknowledges that targets for glomerular diseases are not known. Most clinicians check these levels to verify adherence
and avoid CNI toxicity. At present, the most reasonable dosing of a CNI may be to titrate in the individual patient to obtain the desired effect on
proteinuria, balancing dose escalation against serum creatinine level, reducing the dose if serum creatinine level increases but does not plateau
or increases over 30% of baseline. If the serum creatinine level does not fall after dose reduction, the CNI should be discontinued. CNI,
calcineurin inhibitor; LN, lupus nephritis.

clear that the addition of a cytotoxic agent to glucocorticoids transaminitis in the azathioprine group.733 However, the
during the initial treatment of LN improved long-term kidney follow-up duration of 18 months was relatively short, and the
survival, patients were kept on oral, or in later studies i.v., generalizability of data needs further investigation. Also,
cyclophosphamide for months or years.716 This led to although the response rate was significantly higher in the
considerable lifetime cyclophosphamide exposure and “multitarget” group after 6 months of initial treatment, the
toxicity.777,778 A study reported in 2004 compared quarterly cumulative response rate was similar between the 2 groups
i.v. cyclophosphamide against oral MMF or azathioprine for during the second year of therapy, increasing to approxi-
LN maintenance, and the results showed not only a significant mately 90% by the end of 24 months. Other investigators
reduction in side effects in those treated with MMF or have reported relatively favorable results with various “mul-
azathioprine but also improved kidney and patient outcomes titarget” triple immunosuppressive maintenance treatment
compared to the cyclophosphamide group.779 This led to a regimens that comprised glucocorticoids with MPAA and
decrease in the use of quarterly cyclophosphamide as main- either cyclosporine782,783 or tacrolimus.784
tenance treatment. Favorable long-term results with sequen- Based on these considerations collectively, the Work Group
tial immunosuppressive regimen have been published by concluded that the benefits of maintenance immunosup-
others,712,713 and together, they ushered in the current era of pression far outweigh its potential harms, and MPAA is the
intense, high-dose immunosuppression for the initial treat- preferred drug based on the data to date (Practice Point
ment of proliferative LN, followed by prolonged immuno- 10.2.3.2.1).
suppression with a less intense regimen to reduce adverse Quality of evidence. Only 1 RCT compared long duration
events while ensuring the continued suppression of immune- (18 months) of cyclophosphamide therapy encompassing
mediated pathogenic processes so that the response following both the initial treatment period and the maintenance phase
initial therapy is consolidated, the disease remains quiescent, with short duration (6 months) of cyclophosphamide therapy
flares are prevented, and further damage to the kidney or as initial treatment followed by maintenance treatment with
other organs is avoided. variable immunosuppressive regimens. Due to study limita-
MMF and azathioprine were directly compared as main- tions and very serious imprecision (only 1 study, and very
tenance agents in 2 major clinical trials (Supplementary wide CIs, indicating appreciable benefit and harm), the
Table S61629,718,779–781).633,711 In an LN cohort of 227 ethni- quality of the evidence for this trial is very low
cally diverse patients, the maintenance phase of ALMS (Supplementary Table S62716).
showed that over 3 years of follow-up, the composite treat- Similarly, only 1 RCT (n ¼ 39) compared azathioprine
ment failure endpoint of death, ESKD, LN flare, sustained with quarterly pulse cyclophosphamide as maintenance
doubling of SCr, or requirement for rescue therapy was treatment, indicating very low quality of the evidence because
observed in 16% of MMF-treated patients and in 32% of of study limitations and very serious imprecision (only 1
azathioprine-treated patients (P ¼ 0.003).633 LN flares study, wide CIs) (Supplementary Table S63779).
occurred in 12.9% of MMF-treated patients and 23.4% of The ALMS trial compared azathioprine with MMF as
azathioprine-treated patients. In contrast, the Mycophenolate maintenance therapy in patients with proliferative LN and
Mofetil Versus Azathioprine for Maintenance Therapy of showed an increased rate of composite “treatment failure”
Lupus Nephritis (MAINTAIN) trial randomized 105 pre- endpoint and adverse effects (e.g., leukopenia) in patients
dominantly White patients to MMF or azathioprine and who received azathioprine.633 Despite the large sample size
glucocorticoid maintenance therapy after initial therapy with and the fact that this was an RCT, the quality of the evidence
the low-dose cyclophosphamide regimen and showed no was downgraded to moderate because of imprecision (few
difference in time to kidney flare between the 2 groups, with a events) or study limitations (unclear allocation concealment).
cumulative kidney flare rate of around 20% in both groups Data on the use of CNIs or mizoribine as maintenance
after 36 months.711 A higher proportion of patients in the treatment are generally of low quality (Practice Point
azathioprine group had adverse events leading to withdrawal 10.2.3.2.4785–788).
of therapy in the ALMS maintenance trial (39.6% vs. 25.2%), Values and preferences. In the judgment of the Work Group,
and there was a higher incidence of cytopenia in the azathi- most well-informed patients who have undergone aggressive
oprine group in the MAINTAIN trial. Thus, in most LN immunosuppression to control their LN would choose
populations, MMF (MPAA) is the maintenance drug of maintenance therapy to try to attain complete remission
choice. if it had not yet been achieved, and in all cases to avoid
An RCT compared maintenance treatment with triple disease relapses needing reinstitution of high-dose
immunosuppression that included low-dose MPAA, low-dose immunosuppression. In the judgment of the Work Group, the
tacrolimus, and low-dose glucocorticoids (“multitarget” better efficacy of MPAA with its generally favorable tolerability
regimen) against azathioprine in responders following profile, compared to azathioprine, attests that most well-
“multitarget” regimen or NIH i.v. cyclophosphamide as initial informed patients would choose MPAA as the first-line treatment.
treatment for 6 months in the 2 groups respectively, and the However, patients who have had severe adverse effects
results showed similar efficacy in preventing flares in the 2 while on MPAA, or who place a high value on becoming
groups and a higher incidence of adverse events due to pregnant, may choose azathioprine (or a CNI) over MPAA, as

may patients for whom MPAAs are unavailable or leukopenia and abnormal liver-enzyme levels. However,
unaffordable. azathioprine is much cheaper than MPAA, and financial
Resource use and costs. In general, it is reasonable to as- barriers may limit access to MPAA in many countries. Under
sume that the personal and societal cost of not using main- such circumstances, or in patients who do not tolerate
tenance therapy and risking disease relapse after investing in MPAA because of side effects, low-dose glucocorticoids
initial therapy would be higher than the cost of maintenance combined with azathioprine are an effective maintenance
medications. Compared with initial therapy, facility costs are immunosuppressive treatment. Observational cohort data
often lower, as maintenance regimens are oral, and outside of from Chinese patients showed that in patients who
medication expense, with major resource implications arising received MPAA as initial therapy, the disease flare rate was
from laboratory monitoring of lupus activity and immuno- increased when the total duration of MPAA was <2
suppression and managing complications of treatment. years,632,715 and that long-term maintenance treatment
Although the drug cost of MPAA is considerably higher than with MPAA was associated with a low disease flare rate.790
that of azathioprine, there are few cost-effectiveness analyses Overall, although the efficacy and safety data to date favor
of maintenance treatment for LN.789 Also, some drugs may MPAA as maintenance treatment, azathioprine is an
have limited accessibility in certain regions, and this may acceptable alternative, especially in the later phase of long-
influence choices. Drug-level monitoring is required in term management.
patients treated with CNIs, but not when azathioprine or
MPAA is used, and this also has implications for Practice Point 10.2.3.2.2: Glucocorticoids should be tapered
affordability and accessibility. to the lowest possible dose during maintenance, except
Considerations for implementation. Apart from availability when glucocorticoids are required for extrarenal lupus
and cost of MPAA, the major consideration for implementation manifestations; discontinuation of glucocorticoids can be
of maintenance therapy is safety during pregnancy. Although it considered after patients have maintained a complete
is not advisable to attempt pregnancy until LN and SLE have clinical renal response for ‡12 months.
been well-controlled for some time, which would give ample Prolonged glucocorticoid exposure is associated with
opportunity to switch patients over to a “pregnancy-friendly” continued and significant organ damage accrual and
regimen, pregnancy decisions are complex, and maintenance morbidity.737,791 At the end of the initial phase of treatment,
therapy often needs to be individualized on this basis the goal is to have reduced most patients to a daily dose of
(Section 10.3.2.). MPAA is contraindicated during pregnancy prednisone (or equivalent) that is #7.5 mg, and preferably as
and should be discontinued well in advance of trying to low as possible. The tapering regimen and duration of gluco-
conceive. In contrast, low-dose azathioprine and CNIs can be corticoid maintenance therapy vary considerably among cli-
used during pregnancy. nicians and are largely opinion-based, informed by
individualized considerations of a patient’s risk of developing
Rationale disease flare, and the risk–benefit balance of the prevailing dose
The use of maintenance combined immunosuppressive of immunosuppressive medications. A recent open-label
therapy in Class III/IV LN to consolidate response to initial controlled trial (Evaluation of the Discontinuation of Main-
immunosuppressive treatment and prevent disease flares is tenance Corticosteroid Treatment in Quiescent Systemic Lupus
supported by evidence of at least moderate quality. There are [CORTICOLUP] trial) compared continuation of prednisone
more robust data supporting the superiority of MPAA over 5 mg daily against discontinuation in 124 multiethnic patients
azathioprine as maintenance therapy, from clinical trials that in Paris with stable and quiescent SLE (history of LN in 34%
included patients of different races and ethnicities. and 41%, respectively).792 The results showed a significantly
increased flare rate over 52 weeks of follow-up in patients who
Practice Point 10.2.3.2.1: Azathioprine is an alternative to discontinued prednisone (HR: 0.2 in those who continued
MPAA after completion of initial therapy in patients who prednisone 5 mg daily, P ¼ 0.002), and 45 of 63 patients in the
do not tolerate MPAA, who do not have access to MPAA, or discontinuation group remained glucocorticoid-free. Gluco-
who are considering pregnancy. corticoid discontinuation in patients with stable quiescent
As discussed under Recommendation 10.2.3.2.1, the direct disease can be considered, but it should be undertaken with
comparison between MPAA and azathioprine as maintenance caution and careful monitoring for disease flare. Glucocorti-
treatment in LN, both combined with low-dose glucocorticoid avoidance in maintenance therapy has been attempted
coids, is mainly based on data from ALMS and the MAIN- with the use of rituximab, but the evidence to support this
TAIN trial.633,780 Although the results from the latter showed approach remains limited to one cohort.767
no statistically significant difference in time to disease flare or
long-term clinical outcomes in Caucasian patients, data from Practice Point 10.2.3.2.3: The dose of MMF in the early
ALMS based on a large sample size from different countries maintenance phase is approximately 750–1000 mg twice
with different ancestry demonstrated superior efficacy of daily, and for MPA, approximately 540–720 mg twice daily.
MPAA compared with azathioprine, and in both trials, The suggested dosages are largely based on data from the
azathioprine was associated with more adverse effects, such as ALMS and MAINTAIN trial.633,780 As mentioned before, the

Work Group recommends maintenance of these doses until Although most studies were done in patients of Asian
achievement of complete response and then tapering origin, it is reasonable to consider a CNI for maintenance
(Figure 93). Due to pharmacogenetic differences, the level of therapy in any patients who cannot take MPAA or azathio-
MPA exposure varies considerably among patients receiving prine. CNIs can also be used safely during pregnancy
the same dose of MPAA. Although there are insufficient data (Figure 93).
to date to provide recommendations on therapeutic drug The experience with mizoribine as maintenance therapy
monitoring, measurement of MPA exposure may be helpful in LN is largely limited to Japanese patients.787,799 Results
in patients with unsatisfactory treatment response or who from a post-marketing surveillance study that included
manifest drug toxicities. There are preliminary data associ- 559 mizoribine-treated patients showed that nearly all
ating disease flares with low MPA exposure, but optimal drug were receiving glucocorticoids, and 43.8% were receiving
level at different phases of clinical management remains to be tacrolimus as concomitant treatment. Overall, 63.3% of
determined.793 patients achieved complete or partial remission, and only
3.6% of patients experienced serious adverse drug reactions
Practice Point 10.2.3.2.4: If MPAA and azathioprine cannot within 2 years of mizoribine treatment, and the authors
be used for maintenance, CNIs or mizoribine should be concluded that mizoribine was safe and effective
considered. (Figure 93).800
Experience in Japanese patients suggested that low-dose
tacrolimus at 3 mg/d was safe and effective when given as Practice Point 10.2.3.2.5: The total duration of initial
long-term maintenance therapy together with low-dose immunosuppression plus combination maintenance
glucocorticoids.785,794 In a study of 70 Chinese patients immunosuppression for proliferative LN should not
who achieved remission after initial therapy with glucocor- be <36 months.
ticoids and either i.v. cyclophosphamide or tacrolimus, The optimal duration of maintenance immunosuppression
maintenance therapy with tacrolimus (trough blood level in patients with proliferative LN is not known. If withdrawn
target of 4–6 ng/ml [5–7.4 nmol/l]) was compared with too early, patients may relapse even after having had a good
azathioprine 2 mg/kg/d, both in combination with predni- response to treatment. Prolonged maintenance increases
sone 10 mg/d. Over 6 months of follow-up, kidney relapse exposure to immunosuppression and may not provide suffi-
occurred in 2 azathioprine-treated patients and in none in cient continued benefits to outweigh toxicity risk. The Work
the tacrolimus group (Figure 93).795 Group recommends that the total duration of immunosup-
Adding tacrolimus or cyclosporine to maintenance pression (initial therapy plus maintenance) for patients with
therapy was reported in case series as effective in reducing proliferative LN who have achieved a complete renal response
proteinuria in patients with unsatisfactory suppression of and have no ongoing extrarenal manifestations be $36
proteinuria following initial therapy with glucocorticoids months, based on considering the following evidence
and MMF, especially in patients who showed features of collectively:
MN in their baseline kidney biopsies.783,786,796–798 Caution ! In Chinese patients who received MMF as initial therapy,
is required when considering adding CNI for the purpose discontinuation of MMF before 2 years was associated with
of decreasing proteinuria. It is desirable that there be his- an increased risk of disease flare.632,715
tologic evidence of podocyte injury so that the CNI is likely ! During the third to fourth year of MMF maintenance
to be effective. Also, it is prudent to avoid over- therapy, kidney flare was associated with low 12-hour
immunosuppression and chronic CNI nephrotoxicity, trough MPA blood levels, whereas patients with trough
especially in patients with CKD. levels of approximately 2 mg/l remained in remission.801
Figure 93 | Maintenance immunosuppressive regimens in patients with LN. AZA, azathioprine; CNI, calcineurin inhibitor; LN, lupus
nephritis.

! The ALMS maintenance phase data reported a relatively findings do not correlate completely with ongoing kidney
high incidence of treatment failure (16%–32%) and kidney inflammation. A repeat kidney biopsy could be considered to
flares (13%–23%) despite 36 months of immunosuppres- inform the decision to continue or withdraw maintenance
sion and maintenance with low-dose glucocorticoids and immunosuppression.
either MMF or azathioprine.633
! In an Italian cohort, immunosuppression was tapered in
10.2.4 Class V lupus nephritis
patients who were in complete remission for >12 months,
and 27% relapsed. One of the predictors of successful Practice Point 10.2.4.1: A suggested approach to the man-
treatment discontinuation was a longer duration (median agement of patients with pure Class V LN is described in
of 4 years) of prior immunosuppressive therapy.802 Figure 94.
! Despite $36 months of immunosuppression and $12 Class V LN accounts for 5%–10% of all LN cases. Data on
months of sustained complete clinical renal response, 28%– clinical management are based on very few RCTs with small
50% of patients continue to show inflammatory histologic sample sizes, analyses of pooled data, and observational
activity on repeat kidney biopsy.803–805 Patients with studies. Because 10%–30% of patients with Class V LN and
persistent histologic activity have an increased risk of LN nephrotic proteinuria progress to kidney failure during long-
flare after maintenance immunosuppression is dis- term follow-up, heavy proteinuria does not usually sponta-
continued, compared to patients who have no residual in- neously remit, as it may in primary MN, and as heavy pro-
flammatory activity in their kidneys.804,805 teinuria increases CV morbidity and predisposes patients to
! Patients who have achieved a partial remission tend to be left thrombosis, treatment of Class V patients who have
on maintenance immunosuppression indefinitely. Kidney nephrotic-range proteinuria or NS is warranted.806–809
biopsy studies of such patients have shown that many have A small RCT demonstrated that remission was significantly
resolution of histologic activity803–805 but are clinically only more likely with prednisone plus cyclophosphamide (60%) or
in partial remission due to residual proteinuria. In such prednisone plus cyclosporine (84%) than prednisone alone
patients, proteinuria may reflect CKD as opposed to active (27%), but cyclophosphamide maintained remission longer
disease, and immunosuppression may be able to be dis- (no relapses within a year) than CNI treatment (40% relapsed
continued in the absence of ongoing kidney inflammation. within a year of discontinuing the CNI).738 Pooled data from
In summary, despite not knowing the optimal duration of 2 studies showed that prednisone plus either cyclophospha-
maintenance immunosuppression for proliferative LN, most mide or MMF had similar efficacy in lowering proteinuria
patients will require $3 years of therapy. Clinical response after 6 months of treatment.810 Other studies with relatively
Figure 94 | Management of patients with pure Class V LN. LN, lupus nephritis.

small sample sizes reported the efficacy of glucocorticoids However, there are no universally accepted criteria for the
combined with azathioprine,644,809 oral cyclophosphamide,811 level of improvement required, which makes direct compari-
i.v. cyclophosphamide,738,812 MMF,643,644,812–815 sons of different clinical trials more difficult.
738,797,814,816–818 767,819
CNIs, and rituximab, with response The definitions in Figure 95 are commonly used with
rates of 40%–60%. Tacrolimus was reported as effective when “baseline” kidney function referring to the level before disease
given together with glucocorticoids as initial therapy to pa- flare, which is not known in patients with no previous
tients with Class V LN who presented with NS, or when given medical record. Long-term data from 2 large European LN
as add-on therapy to patients with mixed Class V and Class trials showed that favorable kidney outcomes were predicted
III/IV LN whose proteinuria response was judged suboptimal by achieving a proteinuria level of 0.7–0.8 g/d after 12 months
after initial treatment with prednisolone and MMF.786 In the of therapy, a conclusion supported by other reports.714,823–825
phase 3 voclosporin trial (AURORA; see Practice Point In this regard, renal response at week 104 or week 52 have
10.2.3.1.5), 14% of the patients had pure Class V LN.754 been used as study endpoints in recent clinical trials such as
Although adding voclosporin to background therapy was the phase 3 BLISS-LN study.701
more effective than background immunosuppression alone in Another caveat is the lack of consensus on the appropriate
achieving renal response, the details on the patients with Class time when response should be assessed. For logistic and
V have not been presented. There is a lack of robust data in economic reasons, large clinical trials often evaluate response
the management of Class V LN, especially in patients who at 6–12 months, but improvement of proteinuria and eGFR is
present with NS. The data to date are more in favor of continuous over time, and the rate of improvement varies
combining glucocorticoids with MPAA, a CNI, or short-term considerably among patients. Also, there are marked differ-
cyclophosphamide than with other options. ences in baseline kidney abnormalities at disease presentation.
In addition to general methods to reduce urine protein, Therefore, the time to reach prespecified proteinuria and
such as RASi and meticulous BP control, MMF is a reasonable eGFR cutoffs, either absolute or relative to baseline, varies
first choice for treating patients with Class V and nephrotic- considerably among patients.629,631,632,739,797,826,827
range proteinuria. If ineffective, we suggest cyclophospha- Outside of a formal clinical trial setting, the Work Group
mide for #6 months next in an effort to induce long-term suggests that if patients are improving, allowing 18–24
remission, but long-term CNI or rituximab may also be months to achieve a complete response is reasonable in pa-
tried if the patient has had prior significant exposure to tients who show continuous improvement. A potential tool to
cyclophosphamide or is reluctant to take the medication in predict kidney outcomes was derived from a post hoc analysis
view of the associated toxicities. Appropriate measures to of the large ALMS trial. This analysis suggested favorable
prevent venous thrombosis should be considered in patients kidney outcomes are predicted by normalization of comple-
whose proteinuria persists despite treatments (Chapter 1). ment levels and $25% reduction of proteinuria after 8 weeks
of treatment.828
10.2.4.1 Assessing treatment response in LN. SLE is a systemic disease, and the kidney should not be
Practice Point 10.2.4.1.1: Definitions of response to therapy examined in isolation from other clinical manifestations.
in LN are provided in Figure 95. Several other clinical parameters have not been evaluated
All response criteria currently used in clinical trials of LN in detail in clinical studies but are relevant at individual
require improvement in proteinuria and stabilization or levels such as systemic activity of SLE (e.g., SLEDAI score),
improvement in kidney function. Several observational studies BP control, edema resolution, urine sediment, hemoglobin
suggest that long-term kidney health is considerably more and albumin improvements, and serologic parameters,
favorable in patients who respond to treatment.712,820–822 including dsDNA antibodies and serum complements. If
Figure 95 | Commonly used definitions of response to therapy in LN. *For children <18 years old, complete response is defined as
proteinuria <0.5 g/1.73 m2/d or <300 mg/m2/d based on a 24-h urine specimen. LN, lupus nephritis; PCR, protein–creatinine ratio.

lupus serologies are abnormal, it is reasonable to expect The role of nonadherence in unsatisfactory treatment
improvement with therapy for LN, although many patients response cannot be over-emphasized. The prevalence of
remain positive for anti-dsDNA and/or have low comple- nonadherence in patients with SLE could be >60%.829–832
ment levels despite resolution of proteinuria. Extrarenal Switching from oral immunosuppression to i.v. cyclophos-
lupus activity requiring continuation or a change in ther- phamide should be considered when nonadherence is sus-
apy could remain even if the kidney improves. Finally, pected or proven.
response is currently only assessed clinically. Considerable The quality of evidence on the management of LN “re-
data suggest that persistent intrarenal lupus activity may fractory” to standard initial therapy is marred by variable
remain, despite resolution of proteinuria and eGFR.803–805 definitions of treatment response or refractoriness, the
A repeat kidney biopsy may, therefore, be useful in con- disparity between kidney histology and clinical outcome pa-
firming renal response, especially before important major rameters, the legacy effect of prior therapy, and the impact of
treatment decisions such as discontinuation of immuno- factors other than disease activity on outcome parameters
suppression.627 such as proteinuria and kidney function. Available data on the
management of refractory disease are largely from uncon-
10.2.4.2 Management of unsatisfactory response to treatment trolled observational cohort studies, with varied inclusion
Practice Point 10.2.4.2.1: An algorithmic approach to pa- criteria and based on relatively small sample size.
tients whose response to therapy is deemed unsatisfactory The role of switching between therapeutic regimens has
is provided in Figure 96. not been formally investigated. In a US study that compared
Judging the response to therapy as unsatisfactory is mycophenolate with i.v. cyclophosphamide, patients who did
difficult because there are no robust data with which to not show response, defined as improvement by $30%, after
compare an individual’s response trajectory, and there needs 12 weeks of treatment were switched to the other treatment
to be a balance between giving a patient sufficient time to arm.710 Another study reported efficacy of MMF in patients
respond and the likelihood of ongoing nephron loss. refractory to or who had relapsed after cyclophosphamide
Nonetheless, patients are expected to show improvement treatment.833 However, a legacy effect of prior therapy could
over time after treatment. So, no improvement or worsening not be excluded. Unequivocal evidence on the efficacy of
despite treatment for 3–4 weeks is clearly unsatisfactory and switching therapies is lacking.
warrants early appraisal of potential causes for nonresponse Evidence supporting the use of rituximab for refractory
and early intervention, whereas patients who show response LN is from open-label observational studies that have re-
to treatment can be closely observed, and investigated when ported response rates of 50%–80%762,790,834–845 and a
the level of improvement after 3–4 months of therapy is meta-analysis of 31 studies with 1112 patients that showed
suboptimal or below expectation. A 2-month time frame to complete and partial response rates of 46% and 32%,
see improvement was suggested based on post hoc analysis of respectively, after rituximab was added.846 The role of other
data from the ALMS trial,828 but deterioration needs to be biologics with demonstrated efficacy in recent clinical trials,
evaluated on an individual basis in terms of rapidity and such as obinutuzumab or belimumab, warrants further
severity. investigation.
Figure 96 | Management of patients who show unsatisfactory response to initial therapy for active LN. i.v., intravenous; LN, lupus
nephritis.

Similarly, data from observational cohorts suggested efficacy proteinuria are due to active inflammatory kidney injury or
of CNIs, combined with either glucocorticoids and/or MMF, in reflect progression of chronic damage incurred during pre-
patients with refractory or relapsing LN.783,784,847–851 ceding episodes of active LN, because there is often discor-
dance between clinical findings and histologic findings.627,628
10.2.4.3 Treatment of LN relapse The tempo and magnitude of change in proteinuria may help
Relapses of LN are common, and LN flare is an important with rapid increases, and large changes often reflect active
predictor of poor long-term kidney survival.852–855 LN flare disease. SLE serologies (e.g., complement, anti-dsDNA) may
rates of 10%–50% have been reported, and relapses occur support a flare diagnosis but need to be evaluated in the
over time.856 Failure to achieve complete remission context of prior serologic trends. A change from normal to
increases the risk of subsequent relapse.706,712,857 Relapse abnormal is more useful than serologic studies that are always
rates of 39% and 64% were found in patients who achieved normal or always abnormal. Given the risks of immunosup-
complete remission or partial remission, respectively, and pression, if the diagnosis of flare remains uncertain, a repeat
time-to-relapse after complete response was 36 months, kidney biopsy to assess disease activity versus chronic damage
compared to 18 months after partial response.706 Similarly, is important to inform treatment decisions.861
an HR of 6.2 for relapse was reported in Chinese patients In lieu of waiting until LN flares before treating it, some
who did not achieve complete remission after initial investigators have examined preemptive treatment to prevent
therapy.712 flare. A trial in the Netherlands compared “early treatment” of
16 patients to conventional management of 23 patients who
Practice Point 10.2.4.3.1: After a complete or partial increased their anti-dsDNA levels by 25%.862 Prednisone was
remission has been achieved, LN relapse should be treated increased by 30 mg/d in the early treatment group and was
with the same initial therapy used to achieve the original tapered back to baseline over 18 weeks. After a mean follow-
response, or an alternative recommended first-line therapy. up of <2 years, 2 major relapses (12.5%, both with LN
There are no data that focus on the treatment of LN flares relapse) occurred in the early treatment group, compared to
alone. However, it is generally agreed that there is no major 20 relapses (87%), 7 of which were major (1 kidney relapse),
difference between management of an LN flare and that of de in the conventionally managed patients. A prospective trial in
novo active LN, and initial therapies are the same as outlined the US randomized 41 patients who showed an increase in
above. Although not yet ready for clinical management, both anti-dsDNA and C3a to prednisone (30 mg/d tapered
emerging data from a recent transcriptomic study of paired >4 weeks) or placebo. During a short follow-up (90 days), no
serial kidney biopsies showed slight differences in intrarenal patients given prednisone had a severe flare, but 6 placebo
inflammatory gene expression between the initial presentation patients did, and 3 of the flares were kidney-related.863 A
and LN relapse.858 All LN clinical trials testing initial, induction recently published retrospective study of Chinese patients
therapies for LN include both types of patients. Although these with LN suggested that a moderate increase in immunosup-
considerations form the basis for Practice Point 10.2.4.3.1, pressive treatment dose was effective in preventing kidney and
there are several caveats in choosing an approach: nonrenal flares without excessive treatment-related adverse
1. If patients had been treated with cyclophosphamide in the effects.793 Taken together, all of these data suggest that
past, it is important to calculate lifetime exposure. Ovarian impending LN flares may be preventable, at least for some
failure has been associated with age (and oocyte reserve) patients, but larger RCTs of sufficient duration are needed
and cumulative dose, with sustained amenorrhea occurring before this approach can be endorsed.
in up to 50% of patients aged >32 years with a cumulative
exposure of 8 g/m2.859,860 The chance of future malignancy 10.3 Special situations
increases after a total exposure of 36 g, so if a patient is
10.3.1 Lupus nephritis and thrombotic microangiopathy
approaching this level, cyclophosphamide is better avoided.
2. If patients relapse during pregnancy, treatment choices are Practice Point 10.3.1.1: Patients with LN and thrombotic
more limited. These are discussed in Section 10.3.2. microangiopathy (TMA) should be managed according to
3. Patient preference and/or tolerance of the initial regimen the underlying etiology of TMA, as shown in Figure 97864.
should be considered. Also, patient adherence should be TMA is a pathologic description of vascular endothelial
considered in the choice of treatment. injury secondary to various etiologies.865 The causes of TMA
4. Disease activity should be verified, as proteinuria may be most relevant to patients with LN are thrombotic thrombo-
secondary to CKD. cytopenic purpura (TTP), antiphospholipid syndrome (APS),
The last point is critical but complex. The same clinical and complement-mediated TMA. However, patients with
criteria used to diagnose de novo LN are used to diagnose LN lupus can also develop TMA due to Shiga-toxin-hemolytic
flares absent a kidney biopsy. That is, flares are generally uremic syndrome, infections, drugs, or malignancies.454,866
considered when proteinuria increases beyond a certain The key to a good outcome for TMA in LN is rapid diag-
threshold, with or without an active urinary sediment or nosis and prompt treatment. When appropriate expertise is
deterioration of kidney function. Without histology, it is available, it is preferable that patients with LN and TMA be
sometimes difficult to determine whether changes in comanaged with an experienced hematologist. However,

Figure 97 | Management of patients with LN and TMA. Bendapudi PK, Hurwitz S, Fry A, et al. Derivation and external validation of the
PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study. Lancet Haematol. 2017;4:e157–e164.864
ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; PLASMIC, Platelet count, combined
hemoLysis variable, absence of Active cancer, absence of Stem-cell or solid-organ transplant, MCV, INR, Creatinine.
some of the serologic and genetic testing needed for a specific an intermediate-to-high risk of TTP, adults should be started
diagnosis, such as ADAMTS13 activity or the presence of anti- on plasma exchange and glucocorticoids while waiting for the
ADAMTS13 antibodies in the case of TTP, antiphospholipid investigation results. In children, TTP is less common, and
antibodies, and complement studies may not be available, and plasma exchange has been associated with considerable
even when they are available, they often take considerable morbidity,867 so it is acceptable to defer plasma exchange for
time to complete (Figure 97). If TTP is suspected, one may 24–48 hours until the ADAMTS13 result is available to
consider using the PLASMIC score,864 and if the score defines confirm that the procedure is indicated.868

TMA due to lupus-associated TTP. The diagnosis of TTP is terminal complement complex C5b-C9, triggering endothelial
mainly reserved for patients with TMA and low ADAMST13 cell injury that predominantly affects the kidney vasculature in
activity (#10%).865,869 The treatment of confirmed TTP in the arterioles and interlobular arteries.
LN is extrapolated from that of acquired TTP and includes Complement-mediated TMA in LN does not respond well
plasma exchange,870,871 high-dose glucocorticoids,872,873 rit- to plasma exchange or immunosuppression with glucocorti-
uximab,874–877 and/or caplacizumab (von Willebrand factor coids and cyclophosphamide, and it may be best treated with
inhibitor; Figure 97).878,879 a complement inhibitor such as eculizumab, although the
TMA due to APS. Antiphospholipid antibodies (aPLA) are optimal dose and duration remain controversial.891–893 The
found in about 30% of patients with SLE and may be asso- limited data to date show a high response rate, with resolution
ciated with venous and/or arterial macro- or microvascular of TMA in 68% of patients with secondary aHUS.894 Data
thrombosis, thrombocytopenia, adverse pregnancy outcomes, from 31 adult patients (26 treated with plasma therapy and 5
and neurologic abnormalities. Kidney damage is a well- plasma-resistant patients treated with eculizumab) showed
recognized complication of APS, presenting as renal artery complete kidney recovery in 4 of 5 eculizumab-treated pa-
thrombosis or stenosis, RVT, or injury to the kidney tients.895 Efficacy of eculizumab treatment was also reported
microvasculature, also known as APS nephropathy.880 There in a patients with lupus and heterozygous deletion in com-
are few data on the management of APS nephropathy. In a plement factor H CFHR1-CFHR3 gene presenting with TMA,
retrospective study of 97 patients with kidney TMA, 62.9% and a review of 20 patients showed a kidney recovery rate of
tested positive for aPLA, 38.1% for lupus anticoagulant, and 85% in patients with SLE and/or APS after treatment with
13.4% had APS.881 Complete and partial response rates eculizumab.896 A recent report on 9 patients with TMA
were 38.1% and 22.6%, respectively, after 12 months of associated with SLE and/or APS showed that kidney function
immunosuppressive treatment. Thirty-seven of 61 patients improved by 25% in half of the patients after 4 weeks of
who were aPLA-positive also received anticoagulation eculizumab treatment, and 2 of 3 patients were able to dis-
therapy, and anticoagulated patients showed a higher continue dialysis.897
complete response rate (59.5% vs. 30.8%), and the partial Another recent report on 11 patients with TMA and LN
response rate was 18.9% and 26.9% in patients who had or showed complement regulatory protein mutations in 6 pa-
had not received anticoagulant therapy, respectively. tients, and response to eculizumab treatment in 10 patients.889
Therefore, it is reasonable to treat APS nephropathy with Prior to the advent of eculizumab, plasma exchange and/or
long-term anticoagulation with warfarin. Direct oral plasma infusion was the only treatment for aHUS, with effi-
anticoagulants are not recommended, as they were inferior cacy in less than half of patients and little benefit in patients
to warfarin in preventing thromboembolic events in this with membrane cofactor protein mutations.873,898,899 As
setting.882,883 complement studies often take some time to return, initiation
Catastrophic APS is characterized by thrombosis, often of of plasma exchange is warranted during the waiting period, or
rapid onset, affecting multiple organs, and it is associated if access to eculizumab is limited. The rationale and objectives
with high mortality. Treatment includes both total anti- of plasma infusion and plasma exchange include the
coagulation and high-dose glucocorticoids.884 Plasma ex- replacement of absent or mutated circulating complement
change is often used in catastrophic APS152 and has been regulators such as CFH and the removal of antibodies
associated with improved patient survival in retrospective directed to complement regulatory proteins or mutated fac-
studies.885 There are recent anecdotal reports on the potential tors that play a permissive role in aberrant complement
efficacy of rituximab in catastrophic APS.886,887 It has been activation. In the absence of eculizumab, the efficacy of
shown that complement activation is involved in the patho- plasma exchange and plasma infusion varies, and the duration
genesis of tissue injury induced by aPLA, and there is of therapy is dependent on the treatment response.900–903
emerging evidence on the efficacy of eculizumab in the Data from 31 adult patients (26 treated with plasma therapy
treatment of catastrophic APS.888–890 and 5 plasma-resistant patients treated with eculizumab)
Complement-mediated TMA and atypical hemolytic uremic showed recovery of kidney function in approximately 40% of
syndrome (aHUS). Many cases of kidney TMA with patients given plasma therapy.895
ADAMTS13 activity >10% and negative aPLA correspond to
complement-mediated TMA, and these patients ideally should
10.3.2 Pregnancy in patients with lupus nephritis
be evaluated with complement studies when they are
available.539,543 aHUS is a rare and severe form of TMA caused Practice Point 10.3.2.1: Patients with active LN should be
by dysregulation of the alternative complement pathway due to counseled to avoid pregnancy while the disease is active or
genetic or acquired functional defects in complement when treatment with potentially teratogenic drugs is
regulatory proteins, resulting in excessive production of the ongoing, and for ‡6 months after LN becomes inactive.

Practice Point 10.3.2.2: To reduce the risk of pregnancy results of adult regimens applied to this population. The data
complications, hydroxychloroquine should be continued are insufficient to confirm superiority of efficacy for any
during pregnancy, and low-dose aspirin should be started particular treatment regimen. Several issues must be addressed
before 16 weeks of gestation. when treating pediatric lupus, including adherence concerns,
which may favor i.v. medications; growth concerns, which may
Practice Point 10.3.2.3: Only glucocorticoids, hydroxy- favor limiting glucocorticoid exposure; fertility concerns,
chloroquine, azathioprine, and CNIs are considered safe especially as patients approach adolescence, which may favor
immunosuppressive treatments during pregnancy. limiting cyclophosphamide exposure; and psychosocial con-
Adverse pregnancy outcomes, such as preeclampsia, preterm cerns relating to school and socialization with peers. Special
birth, and fetal loss, are higher in patients with active LN.904,905 considerations regarding glucocorticoid dosing in children are
Commonly used medications for LN induction and mainte- included under Practice Point 10.2.3.1.1. Children with LN
nance therapy, particularly cyclophosphamide and MMF for- should be comanaged by pediatric nephrologists and rheu-
mulations, are toxic to the fetus or teratogenic, respectively. A matologists with expertise in lupus, and the expertise of other
discussion of acceptable methods of contraception should, professionals, such as clinical psychologists, psychiatrists, or
therefore, take place as part of initiating treatment for LN. social workers, can be helpful.
Because of the increased risk of clotting in patients with SLE and
antiphospholipid antibodies, use of estrogen-containing birth
control should be avoided or minimized. A risk-factor checklist 10.3.4 Management of lupus patients with kidney failure
has been proposed by some organizations to stratify, plan, and Practice Point 10.3.4.1: Patients with LN who develop
counsel pregnancy in patients with lupus.906 kidney failure may be treated with hemodialysis, peritoneal
Hydroxychloroquine is considered safe in pregnancy and dialysis, or kidney transplantation; and kidney trans-
may decrease the rate of preterm birth and intrauterine plantation is preferred to long-term dialysis.
growth retardation, whereas withdrawal of hydroxy- There are no data to favor one form of dialysis over
chloroquine has been associated with LN flare, so it should another in kidney failure due to LN. Patients with lupus
be continued when an LN patient becomes preg- receiving hemodialysis display similar 3-year survival rates
nant.659,664,907 Low-dose aspirin (#100 mg/d) may also and mortality due to CV or infectious complications to those
reduce the risk of preeclampsia and intrauterine growth of patients receiving peritoneal dialysis.915–917 Therefore,
retardation and can be started at conception or as soon as kidney replacement therapy should be individualized, taking
pregnancy is recognized.908,909 The incidence of LN flare in into account patient characteristics and preferences.
pregnancy has been reported to be 11%–28% and is higher if Kidney transplantation is preferred to dialysis. Kidney
patients have low serum complement levels or high anti- transplant outcomes are similar to those in patients who
dsDNA antibody titers.904 Active LN during pregnancy can developed kidney failure due to other types of kidney dis-
be treated with glucocorticoids plus azathioprine and/or a ease,918,919 and transplanted patients have lower mortality than
CNI, although in the first trimester, the use of glucocorti- patients with lupus who remain on dialysis.920 As clinical
coids is associated with an increased risk of gestational outcomes are better in patients with shorter durations of
diabetes and cleft palate. For patients on maintenance dialysis,921,922 transplantation may be carried out as soon as
therapy, if they are on azathioprine, this can be continued, disease is quiescent. Although lupus activity tends to decrease
but if they are on MPAA, this must be discontinued or after kidney failure develops, patients can still flare,923 so pe-
changed to azathioprine. riodic monitoring is required. LN can recur in kidney allo-
grafts, but the risk is low, and flares do not generally result in
10.3.3 Treatment of lupus nephritis in children allograft loss.924–926 One important consideration is that pa-
Practice Point 10.3.3.1: Treat pediatric patients with LN tients who have antiphospholipid antibodies may experience
using immunosuppression regimens similar to those used dialysis vascular access clotting or allograft thrombosis and may
in adults, but consider issues relevant to this population, require prophylactic anticoagulation.927–929
such as dose adjustment, growth, fertility, and psychosocial
factors, when devising the therapy plan. Research recommendations
Approximately 20% of SLE is diagnosed before the age of 18 ! Identify and validate biomarkers of kidney histology that
years, and genetic components are more common in childhood- can be used to follow the tissue response to treatment in
onset SLE.910–912 There is suggestive evidence that disease is real-time to help in managing immunosuppression.
often more severe in the pediatric population. In adolescent ! Identify and validate biomarkers of impending LN flare that
patients with SLE and isolated proteinuria, orthostatic or can be used to decide if preemptive immunosuppressive
postural proteinuria should be excluded, as this phenomenon therapy is indicated.
has been observed frequently in this population.913,914 ! Classify LN on the basis of molecular pathogenesis and
There are few large-scale RCTs to guide treatment of chil- histology as opposed to histology alone. This classification
dren with LN, and much of the current literature reports the ideally could be used in conjunction with novel, targeted

therapies for LN to select the most appropriate treatment, B What is the optimal therapy for pure Class V LN?
including biologic medications targeting specific pathogenic B Do antimalarials improve the responsiveness of LN to
pathways. treatment and/or help maintain disease quiescence and
! Establish renal response criteria that reflect resolution of prevent flares?
disease activity at the tissue level and are also predictive of B Is there a role for complement inhibition in the man-
long-term kidney survival and patient survival without agement of LN?
need of kidney replacement therapy. B What are the optimal or prioritized therapies for child-
! Establish criteria for duration of maintenance immuno- hood LN?
suppression and the safe withdrawal of therapy. B What are the efficacy and safety profiles of CNIs,
! RCTs are needed to test the following questions: including the optimal drug exposure when used as initial
B What is the optimal therapy for patients with severe or maintenance treatment of LN? What are the long-
Class III/IV LN (i.e., patients presenting with severe AKI term implications of such treatment?
and/or markedly abnormal SCr level or eGFR) who have B What are the optimal glucocorticoid-reduction protocols
been excluded from the majority of clinical trials to date? for LN management?

Chapter 11: Anti-glomerular basement membrane

(Anti-GBM) antibody glomerulonephritis
Anti-glomerular basement membrane (GBM) antibody GN is 11.2 Treatment

a rare glomerular disease with an incidence of 0.5–1 per
million population. It is caused by autoantibodies against the Recommendation 11.2.1: We recommend initiating
noncollagenous domain of the a3 chain of type IV collagen. immunosuppression with cyclophosphamide and
Anti-GBM GN may present either as an isolated kidney dis- glucocorticoids plus plasmapheresis in all patients
ease or as a pulmonary–renal syndrome (Goodpasture’s with anti-GBM GN except those who are treated
syndrome). Anti-GBM is usually a rapidly progressive cres- with dialysis at presentation, have 100% crescents
centic GN, and about 80% of patients have crescents in half or or >50% global glomerulosclerosis in an adequate
biopsy sample, and do not have pulmonary hem-
more of their glomeruli.930 Goodpasture’s syndrome occurs in
orrhage (1C).
40%–60% of patients, and kidney disease is accompanied by
sometimes massive and fatal pulmonary hemorrhage.931 Anti-
GBM disease with pulmonary involvement is more frequent This recommendation places a relatively higher value on pre-
in men (about 80%) and typically occurs during the second venting mortality and further loss of kidney function and a
decade.932 Isolated anti-GBM nephritis does not have clear relatively lower value on the potential adverse events that may
male preponderance and may also occur in older persons.933 occur with the intense immunosuppression regimen recom-
If untreated, anti-GBM disease has very high morbidity, with mended. Given the uniformly poor prognosis of untreated dis-
almost all patients going on to kidney failure, and it can have ease, almost every patient and physician would be expected to
significant mortality. In patients with Goodpasture’s syn- choose this treatment regimen.
drome, the mortality rate was 96% before the introduction of
immunosuppression, and 47% despite treatment with Key information
immunosuppression.934 Most patients died of respiratory Balance of benefits and harms. Untreated anti-GBM disease is
failure.932 The cornerstone of the treatment is rapid removal associated with considerable morbidity and mortality.
of the pathogenic autoantibodies and suppression of their Observational studies have shown that early mortality of anti-
production to prevent further kidney and pulmonary injury. GBM decreased from 47%932 to 8.5% with plasma exchange
This chapter makes management recommendations for adults and immunosuppression,933 and 5-year patient survival is
($18 years of age) who have anti-GBM GN with or without currently >90% with treatment.937 In contrast, although
pulmonary involvement. kidney survival has improved with plasma exchange and
immunosuppressive treatment, it still remains relatively poor,
11.1 Diagnosis
in part because of delayed diagnosis and initiation of
Practice Point 11.1.1: Diagnosis of anti-glomerular base- treatment. Since 2007, the 5-year kidney survival rate of
ment membrane (GBM) disease should be made without treated patients has improved from about 25% to 50%,
delay in all patients with suspected RPGN (Figure 98). probably because of both earlier diagnosis and a higher
In patients who present with a suspected RPGN, serologic proportion of patients being treated with plasma exchange.937,938
testing for the presence of anti-GBM antibodies should be Plasma exchange, in combination with immunosuppres-
done urgently using commercially available enzyme-linked sion is, undoubtedly, life-saving and helps prevent kidney
immunoassays. The immunoassays for anti-GBM antibodies failure in patients with independent kidney function at
may be negative in up to 10% of patients, and in these in- presentation.
dividuals, diagnosis may be established only by kidney biopsy Potential harms include infections associated with immu-
demonstrating linear IgG deposition along the GBM.935,936 nosuppression and bleeding after plasma exchange. Admin-
Diagnosis of diffuse alveolar hemorrhage is usually done istration of fresh frozen plasma after plasma exchange may be
clinically and confirmed by high-resolution CT scan. Bron- indicated, especially in patients with alveolar hemorrhage and
choscopy and pulmonary functional testing may be useful, after kidney biopsy.
but they are often unnecessary and may be difficult to Quality of evidence. The evidence is based mostly on the
perform in critically ill and unstable patients. Diagnosis comparison of treated patients with historical controls; there
should be made without delay, and kidney biopsy findings has been only one RCT, which is of very low quality. No
should be reported to the clinician by the pathologist on the systematic review of observational studies was undertaken by
day of the biopsy (Figure 98). the ERT. However, the observational studies that were

Figure 98 | Diagnosis and therapy in anti-GBM disease. CT, computed tomography; GBM, glomerular basement membrane.
identified by the Work Group exhibit strong mortality and Values and preferences. Because untreated anti-GBM GN
kidney benefit for patients treated with immunosuppression and Goodpasture’s syndrome carry a high risk of mortality
and plasma exchange, compared with those receiving and morbidity (kidney failure), it is likely all patients and
incomplete treatment or no treatment. Therefore, the overall physicians would opt for treatment with aggressive
quality of evidence was rated as low. immunosuppressive therapy.
One small (n ¼ 17) RCT compared plasma exchange with Resource use and costs. The management of anti-GBM
standard of care in patients with anti-GBM disease disease and Goodpasture’s syndrome is expensive and
(Supplementary Table S64939). The quality of the evidence for resource-intensive. Patients with suspected anti-GBM
critical outcomes (all-cause mortality, kidney failure, and disease optimally require a specialized center with available
infection) was very low because of study limitations (unclear intensive care, plasma exchange, nephropathology, and
randomization and allocation concealment methods used) acute hemodialysis capabilities, some or all of which may
and very serious imprecision (only 1 study, with few patients not be available in some regions. Costs are offset to some
and very wide CIs indicating less certainty in effect). Other extent if treatment results in preservation of independent
outcomes, such as anti-GBM antibodies, were not considered kidney function, and patients do not require long-term
to be critical and important outcomes for the guideline. kidney replacement therapy.

Considerations for implementation. Treatment for anti-GBM circulation and usually needs to be performed for 2–3 weeks
disease should be started as soon as possible for most patients. before anti-GBM antibodies disappear completely.933,935,944 In
However, the chance for recovery and preservation of patients with alveolar hemorrhage, or immediately after kidney
independent kidney function is low in patients presenting biopsy, plasma exchange should be done with fresh frozen
with certain clinical and pathologic conditions. Recovery of plasma. If albumin is used, administration of fresh frozen
kidney function is only about 5% in patients who have a plasma at the end of plasma exchange is warranted.
high proportion of crescents (85%–100%) on kidney
biopsy, oliguria, and/or advanced kidney failure requiring Practice Point 11.2.3: Cyclophosphamide should be
initiation of dialysis.940 In such patients, the decision to administered for 2–3 months and glucocorticoids for about
initiate therapy should take into account this low chance of 6 months (Figure 99931,945,946).
kidney recovery and the ability of the patients to withstand Formation of anti-GBM antibody ceases spontaneously after
intense immunosuppression based on their other clinical 6–9 months.947 However, based on available clinical experience,
characteristics. However, treatment is necessary in these oral cyclophosphamide daily for 3 months and gradually
patients if they have pulmonary hemorrhage. tapered glucocorticoids completely withdrawn within 6 months
Anti-GBM disease is more common in Caucasian patients. seem to be appropriate in most patients to prevent new antibody
In Chinese patients, the disease occurs more frequently in production.933,948 In patients with persistent anti-GBM anti-
older people.941 Pulmonary disease is more frequent in body after 3 months of cyclophosphamide, continuation of
smokers,942 and presence of pulmonary disease may be treatment with either azathioprine or mycophenolate (in
associated with better kidney outcomes,943 probably because combination with glucocorticoids) is suggested.945
of earlier diagnosis. Pulmonary–renal syndrome occurs more As the risk of infection in patients with kidney failure
frequently in young men; isolated anti-GBM nephritis may treated with cyclophosphamide is high,949 prophylaxis of
occur in older persons and with less male preponderance. Pneumocystis pneumonia with cotrimoxazole can be consid-
ered.945 In patients with serious infection during treatment
Rationale with plasma exchange, adding i.v. immunoglobulin therapy to
The aim of treatment is to suppress kidney inflammation, antibiotics can be considered. Intravenous immunoglobulin
remove circulating pathogenic autoantibodies (with plasma should be given immediately after plasma exchange to limit its
exchange), and suppress the formation of the autoantibodies removal, but the real impact of this approach is uncertain.950
(with immunosuppression). This treatment is able to prevent Practice Point 11.2.4: No maintenance therapy of anti-GBM
ongoing kidney damage, but it is unable to reverse already disease is necessary.
established chronic kidney damage. Treatment usually results Relapses of anti-GBM disease are uncommon (0%–6% of
in recovery from alveolar hemorrhage. cases). None of 41 patients with anti-GBM disease had
Formation of anti-GBM antibodies ceases spontaneously recurrent antibodies or relapsed beyond 6 months.935 Indi-
after several months and within weeks in patients treated with vidual patients with relapses many years after the first pre-
plasma exchange and immunosuppression. Relapses are rare sentation of the disease were, however, reported,951–954 and
(mostly in smokers), and long-term maintenance immuno- repeated relapses may occur in patients who do not stop
suppression is not necessary. When anti-GBM antibodies are smoking or who are exposed to lung irritants.955,956 Treat-
persistently negative, kidney transplantation is associated with ment of patients who do not have detectable anti-GBM an-
a very low recurrence rate. tibodies beyond 6 months is not recommended. Smoking
should be strongly discouraged.
Practice Point 11.2.1: Treatment for anti-GBM disease
should start without delay if this diagnosis is suspected, Practice Point 11.2.5: Patients with GN who are anti-GBM-
even before the diagnosis is confirmed. and ANCA-positive should be treated with maintenance
As anti-GBM antibodies are pathogenic, they should be therapy as for patients with AAV.
removed completely from the circulation as quickly as Double positivity of anti-GBM and ANCA is frequent.
possible. Antibodies are cleared in most patients treated with About 5% of patients with AAV will also have anti-GBM
plasma exchange combined with immunosuppression within antibodies, and up to one-third of patients with anti-GBM
8 weeks.933 Acceleration of the anti-GBM removal could GN may be ANCA-positive.599
improve the recovery of kidney function in anti-GBM disease. Double-positive patients also may have severe kidney dis-
If there is a high index of suspicion of anti-GBM disease, ease and often have lung hemorrhage at presentation, but
treatment should start without delay (within 24 hours), even they have a greater chance of kidney recovery from dialysis-
before the diagnosis is confirmed with a kidney biopsy. dependence than patients with only anti-GBM antibodies.
In contrast to patients with only anti-GBM antibodies,
Practice Point 11.2.2: Plasma exchange should be per- double-positive patients have a similar relapse rate as that of
formed until anti-GBM titers are no longer detectable. patients with AAV and require aggressive early treatment as
Plasma exchange gradually and relatively slowly (within for anti-GBM disease followed by maintenance immuno-
several weeks) eliminates anti-GBM antibodies from the suppression as for AAV (Chapter 9).935

Figure 99 | Treatment of anti-GBM disease. Adapted from Journal of the American Society of Nephrology, volume 10, issue 11, Kluth DC, Rees
AJ. Anti-glomerular basement membrane disease, pages 2446–2453, Copyright ª 1999, with permission from the American Society of
Nephrology.946 Adapted from Clinical Journal of the American Society of Nephrology, volume 12, issue 7, McAdoo SP, Pusey CD. Anti-glomerular
basement membrane disease, pages 1162–1172, Copyright ª 2017, with permission from the American Society of Nephrology.931 Adapted
from Kaplan AA, Appel GB, Pusey CE, et al. Anti-GBM (Goodpasture) disease: treatment and prognosis. UpToDate: Evidence-based Clinical
Decision Support. Available at: www.uptodate.com. Accessed September 7, 2021.945
Practice Point 11.2.6: In refractory anti-GBM disease, rit- Practice Point 11.2.7: Kidney transplantation in patients
uximab may be tried. with kidney failure due to anti-GBM disease should be
Refractory anti-GBM disease is rare (<10%).952 Experience postponed until anti-GBM antibodies remain undetectable
with rituximab in anti-GBM disease is limited to case reports, for ‡6 months.
along with 2 small case series of 8 patients who incompletely Survival of patients with anti-GBM disease after kidney
responded to standard treatment and were successfully rescued transplantation is comparable to that in patients with other
with rituximab,957 and 4 patients treated with dialysis primarily causes of kidney failure.965 Recurrence of anti-GBM disease
treated with rituximab instead of cyclophosphamide as first-line may be as high as 50% after transplantation in patients who
therapy for pulmonary remission with no effect on the kidney.958 have detectable anti-GBM antibodies at the time of trans-
There are several case reports of patients with anti-GBM plantation,966 but it is very rare (<3%) in patients who have
disease who were successfully treated with mycophenolate no antibodies.948
or MPA instead of cyclophosphamide.959–962 Mycophenolate Anti-GBM antibodies form in 5%–10% of patients with
could be used instead of cyclophosphamide in patients who Alport syndrome after kidney transplantation, but overt anti-
refuse cyclophosphamide or are intolerant of cyclophospha- GBM disease is less frequent. If clinical anti-GBM GN occurs,
mide because of its toxicity. it often does so early and results in graft loss.967
Imlifidase is an IgG-degrading endopeptidase from Strep-
tococcus pyogenes (IdeS) that cleaves human IgG into F(ab!)2
and Fc fragments, and inhibits antibody- and complement- Research recommendations
dependent cytotoxicity. IdeS treatment immediately cleared ! Compare:
anti-GBM antibodies from the circulation of 3 patients with B Rituximab to cyclophosphamide plus glucocorticoids
anti-GBM disease who were treated with dialysis, but none of and plasma exchange for induction of remission in anti-
these patients recovered independent kidney function.963 A GBM disease
clinical trial testing the utility and safety of IdeS in anti-GBM B MMF to cyclophosphamide plus glucocorticoids and
disease is currently underway (NCT03157037). plasma exchange for induction of remission in anti-
Immune adsorption removes anti-GBM antibody effec- GBM disease
tively. Among 10 patients with anti-GBM disease treated with B Immune adsorption to plasma exchange plus back-
immunoadsorption, dialysis dependency was successfully ground immunosuppression for induction of remission
reversed in 3 out of 6 patients.964 in anti-GBM disease

www.kidney-international.org methods for guideline development
Methods for guideline development
Aim The KDIGO Co-Chairs, KDIGO Methods Chair, Work Group

This is an update of the KDIGO Clinical Practice Guideline for Co-Chairs, and the ERT had a 1-day meeting in Houston, Texas,
Glomerulonephritis published in 2012.968 In November 2017, USA in February 2018 to discuss the previous guideline and the
KDIGO held a Controversies Conference to determine whether there findings from the KDIGO Controversies Conference on Glomeru-
was sufficient new evidence to support updating any of the guideline lonephritis,1,2 and finalize the guideline development process.
recommendations. It was decided that a guideline update was Guideline topics from the previous guideline and new guideline
required.1,2 topics were linked with appropriate clinical questions to underpin
The objective of this project was to update the evidence-based the systematic evidence review. The draft guideline topics and review
clinical practice guideline for the management of glomerular dis- topics were finalized with feedback from the Work Group.
eases. The guideline development methods are described below. Defining scope and topics and formulating key clinical
questions. The guideline Work Group, with assistance from the
Overview of the process ERT, determined the overall scope of the guideline. A preliminary list
This guideline adhered to international best practices for guideline of topics and key clinical questions was informed by the previous
development (Appendix B: Supplementary Tables S2 and S3).969 This KDIGO guideline968 and the KDIGO Controversies Conference on
guideline has been developed and reported in accordance with the Glomerular Diseases.1,2 Analytical frameworks were developed to
AGREE II reporting checklist.970 The processes undertaken for the present a visual representation of the clinical question and facilitate
development of the KDIGO 2021 Clinical Practice Guideline for the discussion about the scope of the guideline. The majority of clinical
Management of Glomerular Diseases are described below. questions for this guideline were based upon RCTs to avoid bias by
! Appointing Work Group members and the ERT design. Clinical questions adhered to the PICOM format (a list of
! Finalizing guideline development methodology critical and important outcomes was compiled after voting from the
! Defining scope and topics of the guideline Work Group [Table 1]). The Work Group and the ERT further
! Formulating clinical questions—identifying the Population, refined the clinical questions to finalize the inclusion and exclusion
Intervention, Comparator, Outcome, Methods (PICOM) criteria to guide literature searching and data extraction. Clinical
! Selecting topics for systematic evidence review and linking to questions were mapped to existing Cochrane Kidney and Transplant
existing Cochrane Kidney and Transplant systematic reviews systematic reviews. These systematic reviews were updated accord-
! Developing and implementing literature search strategies ingly. For clinical questions that did not map to any Cochrane
! Selecting studies according to predefined inclusion criteria Kidney and Transplant systematic reviews, de novo systematic re-
! Data extraction and critical appraisal of the literature views were undertaken. The previous guideline was reviewed to
! Evidence synthesis and meta-analysis ensure all identified studies were included in the evidence review.968
! Grading the quality of the evidence for each outcome across Details of the PICOM questions and associated Cochrane
studies Kidney and Transplant systematic reviews are provided in
! Grading the strength of the recommendation, based on the quality Table 295,112,146,192,218,253,294,317,385,475,569,718. All evidence reviews
of the evidence and other considerations were conducted in accordance with the Cochrane Handbook,971
! Convening a public review in June 2020 and guideline development adhered to the standards of GRADE
! Updating the guideline (Grading of Recommendations, Assessment, Development, and
! Finalizing and publishing the guideline Evaluation).972
Commissioning of Work Group and ERT. The KDIGO Co-
Chairs appointed the Work Group Co-Chairs, who then assembled
the Work Group, to include content experts in adult and pediatric Table 1 | Hierarchy of outcomes
nephrology, pathology, epidemiology, and public health. Cochrane Hierarchy Outcomes
Kidney and Transplant was contracted to conduct systematic
evidence review and provide expertise in guideline development Critical outcomes ! All-cause mortality
! Kidney failure (formerly known as
methodology. The ERT consisted of adult and pediatric
ESKD)
nephrologists, and methodologists with expertise in evidence ! $50% loss of GFR
synthesis and guideline development. The ERT coordinated the ! Infection
methodological and analytical processes of guideline development, ! Glucocorticoid-related adverse events
including literature searching, data extraction, critical appraisal, ! Malignancy
evidence synthesis and meta-analysis, grading the quality of the Important outcomes ! Complete remission/relapse
! Annual GFR loss (minimum 3 years
evidence per outcome, and grading the quality of the evidence for
follow-up)
recommendations. The Work Group was responsible for
writing the recommendations and practice points and ESKD, end-stage kidney disease; GFR, glomerular filtration rate.
The critical and important outcomes were voted on by the Work Group using an
underlying rationale, as well as grading the strength of each adapted Delphi process (1–9 Likert scale). Critical outcomes were rated 7–9, and
recommendation. important outcomes were rated 4–6 on the 9-point scale.

methods for guideline development www.kidney-international.org
Table 2 | Clinical questions and systematic review topics in PICOM format

Guideline Chapter 1 General principles in the management of glomerular diseases
Clinical question In patients with glomerular diseases, what are patient preferences and values for immunosuppressive and non-
immunosuppressive therapy?
Population Patients with glomerular disease
Factor of interest Values and preferences for immunosuppressive or non-immunosuppressive therapy
Outcomes Values and preferences
Study design All study types
SoF tables Supplementary Tables S65–S67
Guideline Chapter 2 IgAN/IgAV
Clinical question In patients with biopsy-proven IgAN, what non-immunosuppressive agents, compared to no treatment or placebo,
improve efficacy outcomes and reduce adverse effects?
Population Patients with IgAN
Intervention Fish oil, anticoagulants or antiplatelets, antioxidants, tonsillectomy, statins, traditional Chinese medicine, vitamin D, vitamin
E, allopurinol, etc.
Comparator No treatment or placebo
Outcomes Outcomes listed in Table 1
Study design RCTs
Cochrane systematic Reid SM, et al. Non-immunosuppressive agents for treating IgA nephropathy (Review). Cochrane Database of Systematic
review Reviews. 2011:3;CD00396295
SoF tables Supplementary Tables S4, S5, S7, and S87–S104
Clinical question In patients with biopsy-proven IgAN, what immunosuppressive agents, compared to no treatment or placebo,
improve efficacy outcomes and reduce adverse effects?
Population Patients with IgAN
Intervention Immunosuppressive therapy
Comparator No treatment or placebo
Study design RCTs
Cochrane systematic Natale P, et al. Immunosuppressive agents for treating IgA nephropathy (Review). Cochrane Database of Systematic Reviews.
review 2020:3;CD003965112
SoF tables Supplementary Tables S6 and S68–S86
Clinical question In patients with biopsy-proven IgAV (Henoch-Schönlein purpura nephritis), what immunosuppressive agents,
compared to no treatment, placebo, or standard of care, improve efficacy outcomes and reduce adverse effects?
Population Patients with IgAV (Henoch-Schönlein purpura nephritis)
Comparator No treatment, placebo, or standard of care
Additional outcomes—BMI
Study design RCTs
Cochrane systematic Hahn D, et al. Interventions for preventing and treating kidney disease in Henoch-Schönlein purpura (HSP) (Review).
review Cochrane Database of Systematic Reviews. 2015:8;CD005128146
SoF tables Supplementary Tables S8 and S105–S109
Guideline Chapter 3 MN
Clinical question In adults with biopsy-proven MN and NS, what immunosuppressive agents, compared to no treatment, placebo, or
other immunosuppressive therapies, improve efficacy outcomes and reduce adverse effects?
Population Adults with primary MN and NS
Comparator No treatment, placebo, or other immunosuppressive therapies
Study design RCTs
Cochrane systematic Chen Y, et al. Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome
review (Review). Cochrane Database of Systematic Reviews. 2014:10;CD004293192
SoF tables Supplementary Tables S9–S13 and S110–S131
Guideline Chapter 4 NS in children
Clinical question In children (3–18 years of age) with SSNS, what glucocorticoid therapy regimens, compared with no treatment,
placebo, or standard of care, improve efficacy outcomes and reduce adverse effects?
Population Children (3–18 years of age) with SSNS
Intervention Glucocorticoid therapy
Study design RCTs
Cochrane systematic Hahn D, et al. Corticosteroid therapy for nephrotic syndrome in children (Review). Cochrane Database of Systematic Reviews.
review 2020:8;CD001533218
(Continued on following page)

Table 2 | (Continued) Clinical questions and systematic review topics in PICOM format
Guideline Chapter 4 NS in children
Clinical question In children (3–18 years of age) with SSNS, what non-glucocorticoid immunosuppressive regimens, compared to no
treatment, placebo, or standard of care, improve efficacy outcomes and reduce adverse effects?
Population Children (3–18 years of age) with SSNS
Intervention Non-glucocorticoid immunosuppressive therapy
Study design RCTs
Cochrane systematic Larkins NG, et al. Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children
review (Review). Cochrane Database of Systematic Reviews. 2020:4;CD002290253
Clinical question In children (3–18 years of age) with SRNS, what immunosuppressive therapy, compared to no treatment, placebo,
or other immunosuppressive medication, improves efficacy outcomes and reduces adverse effects?
Population Children (3–18 years of age) with SRNS
Comparator No treatment, placebo, or other immunosuppressive therapies (including glucocorticoids)
Study design RCTs
Cochrane systematic Liu ID, et al. Interventions for idiopathic steroid-resistant nephrotic syndrome in children (Review). Cochrane Database of
review Systematic Reviews. 2019:11; CD003594294
Guideline Chapter 5 MCD in adults
Clinical question In adults with biopsy-proven MCD and NS, what immunosuppressive agents, compared to no treatment, placebo,
or other immunosuppressive therapy, improve efficacy outcomes and reduce adverse effects?
Population Adults with biopsy-proven MCD and NS
Study design RCTs
Cochrane systematic Palmer SC, et al. Interventions for minimal change disease in adults with nephrotic syndrome (Review). Cochrane Database
review of Systematic Reviews. 2008:1;CD001537317
SoF tables Supplementary Tables S25–S27 and S174
Guideline Chapter 6 FSGS in adults
Clinical question In adults with biopsy-proven FSGS, what immunosuppressive agents, compared to no treatment, placebo, or other
immunosuppressive therapy, improve efficacy outcomes and reduce adverse effects?
Population Adults with biopsy-proven FSGS
Study design RCTs
Cochrane systematic Braun N, et al. Immunosuppressive treatment of focal segmental glomerulosclerosis in adults. Cochrane Database of
reviews Systematic Reviews. 2008:3;CD003233385
Guideline Chapter 7 Infection-related glomerulonephritis
Clinical question In adult patients with HBV- or HCV-related GN, what antiviral treatment therapy, compared to no treatment,
placebo, or standard of care, improves efficacy outcomes and reduces adverse effects?
Population Adults with HBV- or HCV-related GN
Intervention Antiviral treatment therapy
Study design RCTs
Cochrane systematic None relevant
reviews
SoF tables Supplementary Tables S182–S184
Clinical question In patients with HIV-associated nephropathy, what antiretroviral treatment, compared to no treatment, placebo, or
standard of care, improves efficacy outcomes and reduces adverse effects?
Population HIV-associated nephropathy
Intervention Highly active antiretroviral therapy (HAART; alone or combined with antihypertensive agents, glucocorticoids, and
immunosuppressive therapies)

Guideline Chapter 7 Infection-related glomerulonephritis
Study design RCTs
Cochrane systematic Yahaya I, et al. Interventions for HIV-associated nephropathy (Review). Cochrane Database of Systematic Reviews.
reviews 2013:1;CD007183475
SoF tables Supplementary Table S185
Guideline Chapter 8 Immunoglobulin- and complement-mediated glomerular diseases with an MPGN pattern of injury
Clinical question In patients with complement-mediated disease, what immunosuppressive agents, compared to no treatment,
placebo, or standard of care, improve efficacy outcomes and reduce adverse effects?
Population Patients with C3-mediated GN, C3 DDD, CFHR5 nephropathy, C4-mediated GN, idiopathic MPGN
Study design RCTs and observational studies
reviews
SoF tables Supplementary Table S186 and S187
Clinical question In adults with proliferative GN (monoclonal immunoglobulin deposits [monoclonal immunoglobulin deposition
disease], immunotactoid GN, fibrillary GN, cryoglobulinemia-related kidney disease), compared to no treatment,
placebo, or standard of care, does immunosuppressive therapy improve clinically relevant outcomes and decrease
harms?
Population Adults with proliferative GN kidney with monoclonal immunoglobulin deposits (monoclonal immunoglobulin deposition
disease), immunotactoid GN, fibrillary GN, cryoglobulinemia-related kidney disease,
Outcomes Mortality, kidney failure, complete kidney remission, hematologic response, adverse events
reviews
SoF tables Supplementary Tables S188 and S189
Guideline Chapter 9 ANCA-associated vasculitis
Clinical question In adults with AAV, what immunosuppressive agents compared to no treatment, placebo, or other
immunosuppressive therapies improve clinical efficacy outcomes and reduce adverse effects?
Population Adults with AAV
Study design RCTs
Cochrane systematic Walters et al. Interventions for renal vasculitis in adults (Review). Cochrane Database of Systematic Reviews.
reviews 2020:1;CD003232569
Guideline Chapter 10 Lupus nephritis
Clinical question In patients with biopsy-proven LN, compared to no treatment, placebo, or standard of care, does antimalarial
therapy improve clinical efficacy outcomes and reduce adverse effects?
Population Patients with biopsy-proven LN
Intervention Antimalarial therapy
reviews
Clinical question In patients with nonproliferative (Class I, II, V, or VI) LN, what immunosuppressive agents, compared to no
treatment, placebo, or other immunosuppressive therapies, improve efficacy outcomes and reduce adverse effects?
Population Patients with biopsy-proven nonproliferative (Class I, II, V, or VI) LN
Study design RCTs
reviews
SoF tables Supplementary Tables S203, S204, and S205

Guideline Chapter 10 Lupus nephritis
Clinical question In patients with biopsy-proven proliferative (Class III, IV, III/V, or IV/V) LN, what immunosuppressive agents,
compared to no treatment, placebo, or other immunosuppressive therapies, improve efficacy outcomes and reduce
adverse effects?
Population Patients with biopsy-proven proliferative (Class III, IV, III/V, or IV/V) LN
Study design RCTs
Cochrane systematic Tunnicliffe DJ, et al. Immunosuppressive treatment for proliferative lupus nephritis. Cochrane Database of Systematic
reviews Reviews. 2018:6;CD002922718
SoF tables Supplementary Tables S46–S63, S201–S204, and S207–S218
Guideline Chapter 11 Anti-GBM antibody GN
Clinical question In patients with biopsy-proven anti-GBM, what immunosuppressive agents, compared to no treatment, placebo, or
other immunosuppressive therapies, improve efficacy outcomes and reduce adverse effects?
Population Patients with biopsy-proven anti-GBM
Study design RCTs
reviews
AAV, ANCA-associated vasculitis; ANCA, antineutrophil cytoplasmic antibody; BMI, body mass index; CFHR5, Complement factor-H–related protein 5; DDD, dense deposit
disease; FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane; GN, glomerulonephritis; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human
immunodeficiency virus; IgAN, immunoglobin A nephropathy; IgAV, immunoglobin A vasculitis; LN, lupus nephritis; MCD, minimal change disease; MN, membranous ne-
phropathy; MPGN, membranoproliferative glomerulonephritis; NS, nephrotic syndrome; PICOM, Population, Intervention, Comparator, Outcomes, Methods; RCT, randomized
controlled trial; SoF, summary of findings; SRNS, steroid-resistant nephrotic syndrome; SSNS, steroid-sensitive nephrotic syndrome.
Literature searches and article selection. Searches for RCTs manner were included. The ERT designed data extraction forms to
utilized the Cochrane Kidney and Transplant Registry of studies in capture data on study design, study participant characteristics,
October 2018 and supplemented until September 2019. An updated intervention and comparator characteristics, and critical and
search was undertaken in June 2020. The Cochrane Kidney and important outcomes. Any differences in extraction between mem-
Transplant Registry of studies is a database of RCTs in kidney disease bers of the ERT were resolved through discussion. A third reviewer
that is maintained by information specialists. The database is populated was included if consensus could not be achieved.
by monthly searches of the Cochrane Central Register of Controlled Critical appraisal of studies. The majority of reviews undertaken
Trials, weekly searches of MEDLINE OVID, yearly searches of Embase were intervention reviews that included RCTs. For these reviews, the
OVID, hand-searching of major kidney and transplant conference Cochrane Risk of Bias tool was used to assess individual study
proceedings, searches of trial registries, including clinicaltrials.gov limitations based on the following items973:
and the International Clinical Trials Register search portal. ! Was there adequate sequence generation (selection bias)?
For review topics that matched existing Cochrane Kidney and ! Was allocation adequately concealed (selection bias)?
Transplant systematic reviews, an updated search for the review ! Was knowledge of the allocated interventions adequately pre-
using the Cochrane Kidney and Transplant Registry of studies was vented during the study (detection bias)?
conducted. The Cochrane Kidney and Transplant Registry of studies B Participants and personnel (performance bias)
was searched for clinical questions that included only RCTs and were B Outcome assessors (detection bias)
not linked to any existing Cochrane systematic review. For clinical ! Were incomplete outcome data adequately addressed (attrition
questions that included other study types, for example, observational bias)?
studies, the medical literature databases MEDLINE and Embase were ! Are reports of the study free of suggestion of selective outcome
searched. The search strategies are provided in Supplementary reporting (reporting bias)?
Appendix A: Supplementary Table S1. ! Was the study apparently free of other problems that could put it
The titles and abstracts resulting from the searches were screened at risk of bias?
by 2 members of the ERT who independently assessed retrieved All critical appraisal was conducted independently by 2 members
abstracts, and if necessary, the full text, to determine which studies of the ERT, with disagreements regarding the risk of bias adjudica-
satisfied the inclusion criteria. Disagreement about inclusion was tions resolved by consultation with a third review author.
resolved by discussion with a third member of the ERT. Evidence synthesis and meta-analysis. Measures of
A total of 25,925 citations were screened. Of these, 479 RCTs and treatment effect. Dichotomous outcome (all-cause mortality, kid-
102 observational studies were included in the evidence review ney failure, $50% loss of GFR, infection, malignancy, complete
(Figure 100). remission/relapse) results were expressed as RR with 95% CI. When
Data extraction. Data extraction was performed independently continuous scales of measurement were used to assess the effects of
by 2 members of the ERT. Unclear data were clarified by contacting treatment, such as annual GFR loss, the mean difference (MD) with
the author of the study report, and any relevant data obtained in this 95% CI was used. Data synthesis. Data were pooled using the

Figure 100 | Search yield and study flow diagram.
Mantel-Haenszel random-effects model for dichotomous outcomes function (GFR, proteinuria, presence of albuminuria, presence of
and the inverse variance random-effects model for continuous out- macroscopic hematuria), histopathologic class of disease, primary
comes. The random-effects model was chosen because it provides a versus secondary forms of disease, sex, and adult versus pediatric.
conservative estimate of effect in the presence of known and un- The test of subgroup differences used the I2 statistic and a P value
known heterogeneity.971 of 0.10 (noting that this is a weak test).971
Assessment of heterogeneity. Heterogeneity was assessed by vi- Sensitivity analysis. The following sensitivity analyses were
sual inspection of forest plots of standardized mean effect sizes, and considered:
of risk ratios, and by c2 tests. A P value of <0.1 was used to denote ! Repeating the analysis excluding unpublished studies
statistical heterogeneity, and an I2 was calculated to measure the ! Repeating the analysis, taking account of the risk of bias, as
proportion of total variation in the estimates of treatment effect that specified
was due to heterogeneity beyond chance.971 We used conventions of ! Repeating the analysis excluding any very long or large studies, to
interpretation as defined by Higgins et al.974 establish how much they dominate the results
Assessment of publication bias. We made every attempt to ! Repeating the analysis excluding studies using the following filters:
minimize publication bias by including unpublished studies (for language of publication, source of funding (industry vs. other),
example, by searching online trial registries). To assess publication and country in which the study was conducted.
bias, we used funnel plots of the log odds ratio (effect vs. standard However, the available data were insufficient to determine the
error of the effect size) when a sufficient number of studies were influence of these factors on the effect size of critical and important
available (i.e., >10 studies).971 Other reasons for the asymmetry of outcomes.
funnel plots were considered. Grading the quality of the evidence and the strength of a
Subgroup analysis and investigation of heterogeneity. Subgroup guideline recommendation. Grading the quality of the
analysis was undertaken to explore whether there were clinical dif- evidence for each outcome across studies. The overall quality of
ferences among the studies that may have systematically influenced the evidence related to each critical and important outcome was
the differences that were observed in the critical and important assessed using the GRADE approach,972,975 which assesses the quality
outcomes. However, subgroup analyses are hypothesis-forming of the evidence for each outcome. For outcomes that are based on
rather than hypothesis-testing and should be interpreted with data from RCTs, the initial grade for the quality of the evidence is
caution. The following subgroups were considered: baseline kidney considered to be high. For observational studies, the initial quality of

Table 3 | Classification for quality and certainty of the evidence

Grade Quality of evidence Meaning
A High We are confident that the true effect is close to the estimate of the effect.
B Moderate The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
C Low The true effect may be substantially different from the estimate of the effect.
D Very low The estimate of the effect is very uncertain, and often it will be far from the true effect.
the evidence is low. The quality of the evidence is lowered in the face meetings (Amsterdam, The Netherlands, August 2018 and
event of study limitations; important inconsistencies in results across Budapest, Hungary, June 2019) and by email communication. The
studies; indirectness of the results, including uncertainty about the final draft was sent for external public review, and reviewers
population, intervention, and outcomes measured in trials and their provided open-ended responses. Based on the external stakeholder
applicability to the clinical question of interest; imprecision in the feedback, the draft was further revised by the Work Group. All
evidence review results; and concerns about publication bias. For Work Group members provided feedback on initial and final drafts
imprecision, data were benchmarked against optimal information of the guideline statements and text and approved the final version
size, low event rates in either arm, CIs that indicate appreciable of the guideline. The ERT also provided a descriptive summary of
benefit and harm (25% decrease and 25% increase in the outcome of the evidence quality in support of the recommendations.
interest), and sparse data (only 1 study), all indicating concerns Grading the strength of the recommendations. The strength of a
about the precision of the results.972 The final grade for the quality of recommendation is graded as strong or weak (Table 5). The strength
the evidence for an outcome could be high, moderate, low, or very of a recommendation was determined by the balance of benefits and
low (Table 3). For observational studies and other study types, it is harms across all critical and important outcomes, the grading of the
possible for the quality of the evidence to be upgraded from a rating overall quality of the evidence, patient values and preferences,
of low quality, according to the specified criteria. For further details resource use and costs, and considerations for implementation
on the GRADE approach for rating quality of the evidence, see (Table 6).
Table 4. Balance of benefits and harms. The Work Group and ERT
Summary of findings (SoF) tables. The SoF tables were developed determined the anticipated net health benefit on the basis of ex-
to include a description of the population, intervention, and pected benefits and harms across all critical and important outcomes
comparator. In addition, the SoF tables included results from the data from the underlying evidence review.
synthesis as relative and absolute effect estimates. The grading of the Quality of evidence. The overall quality of the evidence was based
quality of evidence for each critical and important outcome is also on the certainty of the evidence for all critical and important out-
provided in the SoF tables. The SoF tables were generated comes, taking into account the relative importance of each outcome
using MAGICapp, an online software application designed to support to the population of interest. The overall quality of the evidence was
guideline development, and they are available in the Data Supplement: graded (A, B, C, or D—Table 3).
Appendix C and Appendix D (https://kdigo.org/guidelines/gd/). Patient values and preferences. No patients or caregivers were
Developing the recommendations. The recommendations were involved in the Work Group. The Work Group, from their experi-
drafted by the Work Group Co-Chairs and Work Group members. ence in managing patients with glomerular disease and their un-
Recommendations were revised in a multistep process during face-to- derstanding of the best available scientific literature, made judgments
Table 4 | GRADE system for grading quality of evidence

Starting grade for the
Study design quality of evidence Step 2—Lower grade Step 3—Raise grade for observational evidence
RCT High Study limitations: Strength of association
–1, serious þ1, large effect size (e.g., <0.5 or >2)
–2, very serious þ2, very large effect size (e.g., <0.2 or >5)
Moderate Inconsistency:
–1, serious Evidence of a dose–response gradient
–2, very serious
Observational Low Indirectness: All plausible confounding would reduce the demonstrated effect
–1, serious
–2, very serious
Very low Imprecision:
–1, serious
–2, very serious
Publication bias:
–1, serious
–2, very serious
RCT, randomized controlled trial; GRADE, Grading of Recommendations Assessment, Development, and Evaluation.

Table 5 | KDIGO nomenclature and description for grading of recommendations

Implications
Grade Patients Clinicians Policy
Level 1 ‘Strong’ Most people in your situation would Most patients should receive the The recommendation can be evaluated
“We recommend” want the recommended course of recommended course of action. as a candidate for developing a policy
action, and only a small proportion or a performance measure.
would not.
Level 2 ‘Weak’ The majority of people in your situation Different choices will be appropriate for The recommendation is likely to require
“We suggest” would want the recommended course different patients. Each patient needs substantial debate and involvement of
of action, but many would not. help to arrive at a management stakeholders before policy can be
decision consistent with her or his determined.
values and preferences.
Table 6 | Determinants of the strength of recommendation

Factors Comment
Balance of benefits and harms The larger the difference between the desirable and undesirable effects, the more likely a strong recommendation
is provided. The narrower the gradient, the more likely a weak recommendation is warranted.
Quality of evidence The higher the quality of evidence, the more likely a strong recommendation is warranted. However, there are
exceptions for which low or very low quality of the evidence will warrant a strong recommendation.
Values and preferences The more variability in values and preferences, or the more uncertainty in values and preferences, the more likely a
weak recommendation is warranted. Values and preferences were obtained from the literature, when possible, or
were assessed by the judgment of the Work Group when robust evidence was not identified.
Resource use and costs The higher the costs of an intervention—that is, the more resources consumed—the less likely a strong
recommendation is warranted.
on the values and preferences of patients. Formal qualitative evidence points were sometimes formatted as a table, a figure, or an algorithm
synthesis on patient priorities and preferences was undertaken, but to make them easier to use in clinical practice.
there was limited evidence available to inform the formulation of
guideline recommendations (Appendix D).
Format for guideline recommendations
Resource use and costs. Healthcare and non-healthcare Each guideline recommendation provides an assessment of the
resources, including all inputs in the treatment management strength of the recommendation (strong, level 1; or weak, level 2)
pathway,976 were considered in grading the strength of a and the quality of the evidence (A, B, C, D). The recommendation
recommendation. The following resources were considered: direct statements are followed by Key information (Balance of benefits and
healthcare costs; non-healthcare resources, such as transportation harms, Quality of evidence, Values and preferences, Resource use and
and social services; informal caregiver resources (e.g., time of costs, Considerations for implementation), and Rationale. Each
family and caregivers); and changes in productivity. Economic recommendation is linked to relevant SoF tables. An underlying
evaluations, including cost-effectiveness analysis, were not rationale also may support a practice point.
conducted for any of the guideline topics.
Practice points Limitations of the guideline development process

In addition to graded recommendations, KDIGO guidelines now The evidence review prioritized RCTs as the primary source of evi-
include “practice points” to help clinicians better evaluate and dence. For a select number of clinical questions in this guideline, the
implement the guidance from the expert Work Group. Practice points ERT undertook a comprehensive evidence review beyond RCTs.
are consensus statements about a specific aspect of care, and they However, these reviews were not exhaustive, as specialty or regional
supplement recommendations for which a larger quantity of evidence databases were not searched, and manual searching of journals was
was identified. These were used when no formal systematic evidence not performed for these reviews. In the development of these
review was undertaken, or there was insufficient evidence to provide a guidelines, no scoping exercise with patients, limited searches of the
graded recommendation. Practice points represent the expert judg- qualitative literature, or formal qualitative evidence synthesis
ment of the guideline Work Group, but they also may be based on examining patient experiences and priorities were undertaken. As
limited evidence. For example, practice points were provided on noted, although resource implications were considered in the
monitoring, frequency of testing, dosing adjustments for the stage of formulation of recommendations, formal economic evaluations were
CKD, and use of therapies in specific subgroup populations. Practice not undertaken for all topics.

www.kidney-international.org biographic and disclosure information
Biographic and disclosure information
Jürgen Floege, MD (Work Group these studies to clinical trial development and design for
Co-Chair), received his training at investigator-initiated and industry-sponsored trials of novel
the Hannover Medical School, therapeutics.
Hannover, Germany; the Albert BHR reports consultancy for AstraZeneca/MedImmune,
Einstein College of Medicine, New Aurinia, Biogen Idec, Bristol Myers Squibb, Calliditas, Che-
York, NY, USA; and the University of moCentryx, EMD Serono, Genentech/Hoffmann-La Roche,
Washington, Seattle, WA, USA. He Omeros, Janssen, Lupus Foundation of America, MorphoSys,
was appointed as head of the Divi- Novartis, Pfizer, RILITE Foundation*, and Travere (formerly
sion of Nephrology and Immunology Retrophin); grant/research support from Lupus Clinical In-
at the University of Aachen, Aachen, Germany in 1999. vestigators Network* and the National Institutes of Health*
Professor Floege is a former executive council member of *Monies paid to institution.
the International Society of Nephrology (ISN), European
Renal Association-European Dialysis and Transplant Associ- Sharon G. Adler, MD, is Chief of
ation (ERA-EDTA), and KDIGO. He is a Distinguished Fellow Nephrology and Hypertension at
of the ERA-EDTA and recipient of the 2018 ERA-EDTA Harbor-University of California Los
Award for Outstanding Clinical Contributions to Angeles (UCLA) Medical Center, Los
Nephrology, past-president of the German Society of Angeles, CA, USA, and a Professor of
Nephrology, as well as an honorary member of the Japanese, Medicine at the Geffen School of
Polish, Portuguese, Serbian, and Slovakian Societies of Medicine at UCLA, Los Angeles, CA,
Nephrology. Together with Professors Richard Johnson, USA. Dr. Adler has made many
Marcello Tonelli, and John Feehally, he edits the best-selling contributions to our understanding
textbook Comprehensive Clinical Nephrology. He is associate of clinical and experimental diabetic kidney and glomerular
editor of Kidney International and a member of the editorial diseases. She is a member of several active clinical consortia,
board of Journal of the American Society of Nephrology, Journal including the Nephrotic Syndrome Study Network
of Nephrology, and other journals. Until 2017, he served as (NEPTUNE), Cure Glomerulonephropathy (CureGN), and
associate editor of Nephrology Dialysis Transplantation. the Kidney Research Network. With Karger Publishers, she
His research interests encompass progression of kidney founded a new journal to focus on the glomerulus, aptly
disease, in particular kidney fibrosis, immune-mediated renal called Glomerular Diseases, which is expected to launch in the
disease, in particular IgA nephropathy, as well as bone and first half of 2021. She has authored more than 100 publica-
mineral disorders (CKD-MBD) and cardiovascular disease in tions in peer-reviewed journals and over 50 chapters, reviews,
uremic patients. and editorials.
His scientific work encompasses about 600 original papers, SGA reports consultancy for Bayer and MorphoSys; and grants/
reviews, editorials, and 40 book chapters. research support from Bayer*, Bristol Myers Squibb*, Omeros*,
JF reports consultancy for Astellas, AstraZeneca, Bayer,
NIDDK (REBOOT), and Travere (formerly Retrophin).
Boehringer Ingelheim, Calliditas, MorphoSys, Novo Nordisk,
*Monies paid to institution.
Omeros, and Travere (formerly Retrophin); and speaker
bureau for Amgen and Fresenius-Vifor.
Jonathan Barratt, MBChB, PhD, is
Brad H. Rovin, MD, FACP, FASN the Mayer Professor of Renal Medi-
(Work Group Co-Chair), is the Lee cine, Department of Cardiovascular
A. Hebert Professor of Nephrology at Sciences at the University of
The Ohio State University Wexner Leicester, Leicesiter, UK. He leads
Medical Center, Columbus, OH, the Renal Research Group within
USA. He is the division director of the College of Life Sciences, Uni-
nephrology and medical director of versity of Leicester. His research is
The Ohio State University Clinical focused on a bench-to-bedside
Research Management Organization, approach to improving our understanding of the patho-
Columbus, OH, USA. Dr. Rovin conducts translational genesis of IgA nephropathy, a common global cause of
research on autoimmune glomerular diseases and applies kidney failure. Dr. Barratt is the IgA Nephropathy Rare

biographic and disclosure information www.kidney-international.org
Disease Group lead for the United Kingdom (UK) National Kelly A. Burdge, MD, received her
Registry of Rare Kidney Diseases (RaDaR), and a member BA in Art History and Chemistry
of the steering committee for the International IgA Ne- from Northwestern University,
phropathy Network. He works closely with pharmaceutical Evanston, IL, USA. She completed
companies interested in new treatments for IgA nephrop- her medical degree in 1999 at the
athy and is the chief investigator for several international Wright State University Boonshoft
randomized controlled Phase 2 and 3 clinical trials in IgA School of Medicine, Dayton, OH,
nephropathy. He was a Work Group member of the Food USA. She trained in internal medi-
and Drug Administration (FDA) and American Society of cine and pediatrics and completed a
Nephrology (ASN) Kidney Health Initiative “Identifying fellowship in adult nephrology at The Ohio State University,
Surrogate Endpoints for Clinical Trials in IgA Columbus, OH, USA.
Nephropathy.” Dr. Burdge has held clinical associate professorships at the
JB reports serving on Study Steering Committees for Alnylam, University of South Dakota, Vermillion, SD, USA and Tufts
Calliditas, Chinook, Novartis, Omeros, and Travere (formerly University School of Medicine, Boston, MA, USA. She
Retrophin); consultancy for Alnylam, Argenx, Astellas, Bio- currently practices general nephrology in Boston, MA, USA in
Cryst, Calliditas, Chinook, Dimerix, Galápagos, Novartis, private practice as part of the Mass General Brigham-Salem
Omeros*, Syncona, Takeda, Travere (formerly Retrophin), Hospital. She is passionate about patient care, efficiency, and
UCB, Vera Therapeutics, and Visterra; grant/research sup- reducing waste in medicine. In addition to her interest in
port for basic science work for 6 companies under confiden- clinical nephrology and patient management, Dr. Burdge is a
tiality agreements; and he is named in a patent to be participant in the Chronic Kidney Disease Outcomes and
submitted by Calliditas, based on analysis of exploratory data Practice Patterns (CKDopps) Trial. She is a fellow of the ASN,
generated from the NEFECON! trial, conducted at the a member of the National Kidney Foundation (NKF), and a
University of Leicester. member of Women in Nephrology.
*Monies paid to institution. KAB declared no competing interests.
Tak Mao Chan, MBBS, MD,

Frank Bridoux, MD, PhD, is pro- DSc, FHKCP, FHKAM, MD,
fessor of nephrology and head of the FRCP, FASN, obtained his MBBS,
Nephrology, Dialysis and Renal MD, and DSc from the University of
Transplantation Department at Poit- Hong Kong (HKU), Hong Kong,
iers University Hospital, Poitiers, China. He became Personal Chair
France. After completing his Professor at HKU in 2005, Yu Pro-
nephrology residency at Lille Uni- fessor in Nephrology in 2008, and Yu
versity, Lille, France in 1999, he was a Chiu Kwong Professor in Medicine
clinical assistant and senior consul- in 2011. Dr. Chan has been chief of nephrology since 2010.
tant at the Poitiers University Hospital. He completed his PhD He has served as associate dean, senate member, and Uni-
thesis in immunology at the French National Centre for versity Selection & Promotion Committee member at HKU,
Scientific Research (CNRS) Unit 7276 in Limoges, France, president of the Asian Pacific Society of Nephrology (APSN),
in 2003. and council member of the ISN. Since 2016, he has served as
Dr. Bridoux’s main area of work is clinical nephrology. vice-president and chairman of the Education and Accredi-
His research interests are mostly focused on the patho- tation Committee of the Hong Kong College of Physicians,
physiology and treatment of monoclonal immunoglobulin- Hong Kong, China.
associated kidney disorders, covering basic research on Dr. Chan’s research focuses on lupus nephritis and viral
experimental animal models and clinical studies, including hepatitis in patients with kidney diseases. His work has helped
randomized controlled trials. Dr. Bridoux has co-authored establish mycophenolate as the standard-of-care for lupus
more than 170 peer-reviewed publications and several nephritis and preventive antiviral therapy for hepatitis B in
book chapters. He is one of the co-founders and a past kidney transplant recipients, contributing to significant im-
president of the International Kidney and Monoclonal provements in clinical management and patient outcomes.
Gammopathy Research Group, and the current associate Translational studies from his laboratory have increased the
coordinator of amyloid light-chain (AL) amyloidosis and understanding of pathogenic mechanisms in kidney inflam-
other disorders associated with monoclonal immunoglob- mation and fibrosis. Dr. Chan’s publications have appeared in
ulin deposits at the CNRS. the New England Journal of Medicine, Kidney International,
FB reports consultancy for AstraZeneca, Baxter, and Pro- Journal of the American Society of Nephrology, Arthritis &
thena; grants/research support from Amgen; and speaker Rheumatology, Nature Reviews of Nephrology, Hepatology, and
bureaus for Amgen, AstraZeneca, Celgene, and Janssen. UpToDate. He received the Asian-Pacific Society of

Nephrology (APSN) Kenzo Oshima Award in 2014. He is also Keisha L. Gibson, MD, MPH,
the author of the chapter on “The Far East” in Brenner and received her medical degree and
Rector’s The Kidney, 11th Edition. Master of Public Health degree in
TMC reports consultancy for Novartis; and grant/research epidemiology from the University of
support from Astellas, AstraZeneca, and Baxter. North Carolina (UNC) Chapel Hill,
NC, USA. She completed a residency
in general pediatrics at the Medical
H. Terence Cook, MBBS, MRCP,
University of South Carolina,
MRCPath, FRCPath, FMedSci, is a
Charleston, SC, USA and a clinical
professor of renal pathology at Im-
fellowship in pediatric nephrology from UNC Chapel Hill.
perial College, London, UK, and a
She is currently an associate professor of medicine and pe-
consultant renal pathologist at
diatrics, the chief of pediatric nephrology in the Division of
Hammersmith Hospital, London,
Nephrology and Hypertension, and the Vice-Chair of Di-
UK. He qualified at St Mary’s Hos-
versity and Inclusion for the Department of Medicine at
pital Medical School, London, UK in
UNC Chapel Hill.
1980 and became a lecturer in
Dr. Gibson’s research and clinical interests focus on lupus
Experimental Pathology in 1983. Since then, he has pursued
nephritis and other glomerular diseases. In the area of epide-
research in experimental glomerulonephritis and human
miology, she is interested in ethnic and socioeconomic dispar-
glomerular disease at Imperial College, London, UK. He has
ities and their effect on patient outcomes. She has been involved
major interests in the role of complement activation in
as a co-investigator with large consortium studies such as the
glomerular disease and in how histologic features in human
Nephrotic Syndrome Network Study (NEPTUNE Study) and
kidney biopsies can be used to predict outcomes and re-
the Cure Glomerulonephropathy Network (CureGN Study).
sponses to treatment. He has organized international collab-
KLG reports serving as an advisory board member for Reata and
orative studies to develop consensus classifications of lupus
Travere (formerly Retrophin); and consultancy for Aurinia.
glomerulonephritis, IgA nephropathy, and C3 glomerulop-
athy. He is a past president of the Renal Pathology Society. He
has over 370 peer-reviewed publications.
Richard J. Glassock, MD, MACP,
HTC reports consultancy for Alexion, Apellis, Aurinia, and
graduated from the UCLA School of
Novartis; grant/research support from Achillion* and Ra
Medicine, Los Angeles, CA, USA, in
Pharmaceuticals*; and speaker bureau for Alexion.
1960 and received post-graduate
*Monies paid to institution.
training at UCLA, Los Angeles, CA,
USA; Harvard University, Cam-
Fernando C. Fervenza, MD, PhD, is bridge, MA, USA; and the Scripps
a professor of medicine at the Mayo Research Institute, La Jolla, CA, USA.
Graduate School of Medicine, His main interests are in glomerular
Rochester, MN, USA. He received his disease and clinical nephrology. He has published over 750
medical degree at the Pontificia original papers, books, book chapters, and reviews. He is the
Universidade Catolica do Rio Grande past-president of the ASN and the NKF (USA), and past-
do Sul, Porto Alegre, Brazil. Dr. chairman of the American Board of Internal Medicine. He
Fervenza underwent his clinical is the former chair of the Department of Medicine at the
nephrology and research training at University of Kentucky, Lexington, KY, USA (1992–1999) and
Oxford University, Oxford, UK, and the Oxford Renal Unit Harbor-UCLA Medical Center, Los Angeles, CA, USA (1980–
from 1985 to 1991. Subsequent training included a post- 1992). He is a Master of The American College of Physicians,
doctoral fellowship at Stanford University, Stanford, CA, USA Philadelphia, PA, USA and a fellow of The Royal College of
(1993–1997). Dr. Fervenza is a fellow of the ASN and the Physicians, London, UK.
American College of Physicians, a past member of the Dr. Glassock was the founding editor-in-chief of the
American Board of Internal Medicine nephrology section, Nephrology Self-Assessment Program (NephSAP) Journal of the
and an UpToDate section editor for glomerular disease. His American Society of Nephrology (2002). He is an editor of the
area of interest is pursuing patient-oriented research projects nephrology section of UpToDate, an associate editor of the
aiming to bring new bench research discoveries to the bedside American Journal of Nephrology, and a founding moderator of the
treatment of patients with glomerular diseases. ASN Communities website. He received the David Hume Me-
FCF reports serving as a board member of UpToDate— morial Award of the NKF, the Robert Narins Award of the ASN,
Associate Editor; consultancy for Alexion, Alnylam, BioCryst, and Distinguished Achievement Awards from UCLA and the
and Takeda; grant/research support from Achillion, Gen- Association of Professors of Medicine. He is currently Professor
entech, Janssen, MorphoSys, and Travere (formerly Emeritus at the David Geffen School of Medicine at UCLA, Los
Retrophin). Angeles, CA, USA and an independent medical consultant.

RJG reports consultancy for Apellis, Aurinia, BioCryst, Bristol settings through observational, intervention, and health
Myers Squibb, Calliditas, ChemoCentryx, Equillium Bio, systems research using innovative methodologies. He also
Horizon, Ionis, Natera (Renasight), Novartis, Omeros, Tra- has a translational program focused on finding markers of
vere (formerly Retrophin), and Walden Biosciences; providing kidney disease assessment, risk stratification, progression,
expert testimony for legal firms in the USA; speaker bureau and complications. He has led a number of clinical trials in
for Aurinia; providing manuscript preparation for Neph- membranous nephropathy, FSGS, and IgA nephropathy. He
SAP—Associate Editor, Karger, and Wolters Kluwer (UpTo- has served as a Work Group member on prior KDIGO
Date); owning stock/stock options in Reata; and receiving guidelines, including the Glomerulonephritis; Care of Kid-
travel expenses from various academic centers in the USA, ney Transplant Recipients; and Prevention, Diagnosis, Eval-
Europe, China, and South America. uation, and Treatment of Hepatitis C in CKD. He has also
participated in several KDIGO Controversies Conferences.
Dr. Jha is an expert in the effect of tropical ecology on
David R.W. Jayne, MD, FMedSci, is kidney diseases and the impact of infections on patients with
a professor of clinical autoimmunity kidney diseases. He has published over 300 papers and about
at the University of Cambridge, 50 textbook chapters.
Cambridge, UK, and director of the VJ reports consultancy for NephroPlus*; grants/research
Vasculitis and Lupus Service at support from Baxter Healthcare*, Biocon*, and GSK*; and
Addenbrooke’s Hospital, Cambridge, speaker bureaus for AstraZeneca* and Baxter Healthcare*.
UK. He trained at the Universities *Monies paid to institution.
of Cambridge and London, Cam-
bridge and London, UK, and in
nephrology at Harvard Medical School, Boston, MA, USA. Dr.
Jayne was a research fellow at Imperial College, London, UK Adrian Liew, MD, MBBS, MRCP,
and the University of Cambridge and was appointed as a senior FAMS, FASN, FRCP, MClinEpid, is
lecturer in Nephrology at St George’s Hospital, London, UK. a senior consultant nephrologist and
He is a co-founder and the current president of the European director of The Kidney & Transplant
Vasculitis Society, and his research focus has been ANCA Practice at Mount Elizabeth Novena
vasculitis, having led a sequence of international randomized Hospital in Singapore. He received
controlled trials over the past 25 years. His research group his medical degree from the Na-
conducted the first studies on disease trials of newer immu- tional University of Singapore,
nosuppressives and biologics in vasculitis and lupus. He has Singapore. Dr. Liew is an elected
published over 400 peer-reviewed papers and has contributed member of the executive committee and council of the ISN
to numerous guideline statements. The clinical service in and an elected executive and honorary secretary of the
Cambridge cares for over 2000 patients with complex multi- International Society for Peritoneal Dialysis (ISPD). He
system autoimmunity and receives tertiary referrals from chairs the ISN Oceania-Southeast Asia Regional Board, the
throughout the UK and beyond. ISN End-Stage Kidney Disease Strategy Dialysis Subgroup,
DRWJ reports consultancy for AstraZeneca, Bristol Myers and the ISN Renal Disaster Preparedness Working Group.
Squibb, Boehringer Ingelheim, ChemoCentryx, Chugai, CSL He is a member of the ISN Dialysis Working Group, the
Behring, GlaxoSmithKline (GSK), InflaRx, Janssen, Novar- ISN Continuing Medical Education (CME) Committee,
tis, Roche/Genentech, Takeda and Vifor; serving in the and the Asia-Pacific Society of Nephrology CME Com-
speaker bureau for Vifor; and grant/research support from mittee. He received the John Maher Award from the ISPD
GSK*, Medical Research Council*, National Institute for in 2020 for his contribution to peritoneal dialysis research.
Health Research*, and Roche/Genentech*. Dr. Liew is also an associate editor for the journal
*Monies paid to institution. Nephrology and serves on the editorial board for Kidney
International. His research interests include glomerular
diseases, peritoneal dialysis, and diabetic kidney disease. He
Vivekanand Jha, MD, DM, FRCP, sits on the steering committees and is the national leader
FAMS, is the executive director at the for several multicenter clinical trials. Dr. Liew chairs the
George Institute for Global Health, Southeast Asia Glomerulonephritis Network and the
New Delhi, India, chair of Global Southeast Asia Peritoneal Dialysis Network. He is the co-
Kidney Health at Imperial College, principal investigator for the PROMiSE study, a clinical
London, UK, and the current presi- registry for peritoneal dialysis across 8 countries in
dent of the ISN. Dr. Jha’s research is Southeast Asia.
focused on finding locally appro- AL reports consultancy for Alnylam, AstraZeneca, DaVita,
priate treatment and implementation and George Clinical; and speaker bureau for AstraZeneca and
strategies for patients with kidney diseases in low-resource Baxter Healthcare.

Zhi-Hong Liu, MD, is a professor of Carla M. Nester, MD, MSA, FASN, is

medicine and academician at the the Jean Robillard Professor of Pedi-
Chinese Academy of Engineering, atric Nephrology and the Division
Beijing, China, a director at the Na- Director of Pediatric Nephrology,
tional Clinical Research Center of Dialysis and Transplantation at the
Kidney Disease, Jinling Hospital, Stead Family Children’s Hospital,
Nanjing, China, and dean of the University of Iowa, Iowa City, IA,
Zhejiang University School of Medi- USA. She is the associate director of
cine, Hangzhou, China. Dr. Liu is the the Molecular Otolaryngology and
past-president of the Chinese Society of Nephrology. She was Renal Research Laboratory (MORL), the largest combined
an executive committee member of the ISN and KDIGO. She clinical and research laboratory in North America with a focus
is the editor-in-chief of Kidney Diseases, Chinese Journal of on complement biology.
Nephrology, and Dialysis & Transplantation. Dr. Nester is a National Institutes of Health–funded,
Dr. Liu has devoted herself to patient care, research, and tenured faculty member with a translational research pro-
medical education. Her primary interest is in the field of gram focusing on rare, complement-mediated kidney dis-
kidney disease, with a special interest in glomerulone- eases. She is the primary clinical investigator for the C3
phritis, diabetic nephropathy, and kidney replacement Glomerulopathy Natural History Study, the largest cohort of
therapy. She has published 650 articles, edited 5 books on rare C3G patients in North America. As a result of the latter,
kidney disease, and contributed chapters to textbooks on she is an advisor to KidNeeds, a global C3G family commu-
nephrology. She is the chief scientist of the National Basic nity. Finally, Dr. Nester is a clinical trialist; her clinical
Research Program of China (973 Program) and was hon- practice has become a hub for bringing a new generation of
ored with the National Science and Technology Progress anti-complement therapeutics to a rare disease population.
Award of China. Dr. Nester’s background in complement biology, com-
Z-HL declared no competing interests. bined with her unique training as an adult and pediatric
glomerular disease clinician, facilitates her role as a highly
sought-after speaker and educator in the area of complement
Juan Manuel Mejía-Vilet, MD, PhD,
biology and kidney disease.
is a consultant nephrologist at Insti-
CMN reports being on advisory boards for Achillion, Alexion,
tuto Nacional de Ciencias Médicas y
BioCryst, Novartis, and Pfizer; grant/research support from
Nutrición Salvador Zubirán, Mexico
Achillion, Alexion, BioCryst, Novartis, and Travere (formerly
City, Mexico, a clinical researcher for
Retrophin); and receiving author royalties from UpToDate.
the Mexican National Research Sys-
tem, Mexico City, Mexico, and a
professor of medicine for the Na- Jai Radhakrishnan, MD, MS,
tional University of Mexico, Mexico MRCP, FACC, FASN, is a professor
City, Mexico, Panamerican University, Mexico City, Mexico, of medicine at Columbia University
and the Monterrey Institute of Technology and Higher Edu- Medical Center, New York, NY, USA,
cation, Monterrey, Mexico. and the clinical director of the
Dr. Mejia-Vilet received his medical degree from the nephrology division at New York-
University of San Luis Potosi, San Luis Potosi, Mexico. He Presbyterian Hospital, New York,
was trained in internal medicine and nephrology at the NY, USA. After completing his initial
National University of Mexico and completed an ISN medical training in India and the
Glomerular Diseases fellowship at The Ohio State University, United Kingdom, he completed his nephrology training at the
Columbus, OH, USA. He received a Master of Medical Massachusetts General Hospital in Boston, MA, USA and
Science and a PhD degree from the National University of Columbia University Medical Center in New York, NY, USA.
Mexico for his study of lupus nephritis pathophysiology and He completed his master’s degree in biostatistics from the
biomarker development. Mailman School of Public Health, Columbia University, New
His primary research area is centered on non-invasive York, NY, USA.
biomarkers and prognosis of glomerular diseases, espe- His clinical and research interests are in glomerular diseases.
cially lupus nephritis and ANCA vasculitis. He currently He is an associate editor of Kidney International and founding
follows a local lupus nephritis cohort comprising editor/editor-in-chief of Kidney International Reports. As a
more than 700 subjects, the local glomerular diseases clinician–educator, Dr. Radhakrishnan has served on educa-
registry, and actively participates in clinical trials in these tional committees with the ASN and the ISN, and is a global
areas. education ambassador for the ISN. He has lectured extensively
JMMV declared no competing interests. both nationally and internationally.

JR reports being an advisory board member for Reata; con- glomerular diseases and to identify and evaluate novel
sultancy for Aurinia, Equillium Bio, Novartis, Reata, and therapeutic targets to improve outcomes of patients with
Travere; and grant/research support from Travere. glomerulonephritis. She has contributed to over 95 publi-
cations, and her work has been consistently supported by
Elizabeth M. Rave, MD, completed peer-reviewed awards from agencies including the Kidney
her undergraduate degree in chemi- Foundation of Canada and the Canadian Institutes of
cal engineering at the University of Health Research. She enjoys training future leaders in
Toledo, Toledo, OH, USA, and glomerulonephritis care and research, and she was the co-
worked in industry for several years director of the annual educational pre-course in glomeru-
before going to medical school. Dr. lonephritis for the ASN.
Rave attended medical school at the HNR reports consultancy for Calliditas, Omeros, Pfizer,
University of Toledo Medical School Retrophin; and the UHN GN Fellowship is supported by
(formerly Medical College of Ohio, the Louise Fast Foundation; conducting clinical trials
MCO) and completed both her internal medicine residency for Alnylam, Calliditas, ChemoCentryx, Omeros, and
and nephrology fellowship training at The Ohio State Uni- Pfizer; and speaker fees from Gilead Pharmaceuticals and
versity, Columbus, OH, USA. Omeros.
Dr. Rave has been busy as a private practice nephrologist
since graduation from fellowship but also enjoys teaching
Pierre Ronco, MD, PhD, is an
students and residents who are in community-based training at
Emeritus Professor of Nephrology at
several local hospitals in Columbus, Ohio. In addition to
Sorbonne Université, Paris, France.
clinical responsibilities, she is heavily involved with patient care
He received his PhD in immunology
improvement through several hospital committees, including
from University Paris 7, Paris,
the OhioHealth Clinical Guidance Council, and serves as the
France, and his MD from the Medi-
Section Chair of Nephrology at Riverside Methodist Hospital.
cal Faculty Saint-Antoine, Sorbonne
She has been a co-investigator in the Simplicity III and Reduce
Université, Paris, France. He has
Hypertension trials (with OhioHealth), as well as the Reata
devoted most of his career to the care
Bardoxolone Study. She is on the Information Technology
of patients with glomerular disease and identification of
board for DaVita. She has been a board member for the Co-
relevant mechanisms as head of the renal division (1995–
lumbus chapter of the NKF since 2015 and was recently
2018) and director of the INSERM Kidney Research Unit
honored as the NKF Medical Advisor Board member of the
(1998–2018) at the Tenon Hospital in Paris, France.
year for 2019. She is currently serving as the president of Ohio
Dr. Ronco’s major contributions to clinical science, renal
Kidney Consultants.
immunopathology, and rare kidney diseases resulted in
EMR reports being a board member for Davita.
over 500 research publications, including in the New En-
gland Journal of Medicine, Lancet, Science, Journal of
Heather N. Reich, MD, CM, PhD, Experimental Medicine, Journal of Cell Biology, and
FRCPC, is a graduate of McGill other major journals of nephrology, as well as 30 textbook
University Faculty of Medicine, chapters.
Montreal, Quebec, Canada. She He served as president of the Francophone Society of
completed her post-graduate clinical Nephrology and the 49th ERA-EDTA Congress in Paris
training and PhD at the University of (2012). He chaired or co-chaired the Scientific Programme
Toronto, Toronto, Ontario, Canada, Committee of 4 World Congresses of Nephrology (Madrid,
where she is an associate professor Milan, Cape Town, Mexico City). He is currently serving as
and holds the Gabor Zellerman the editor-in-chief of Kidney International, a position he has
Chair in Nephrology Research. She works as a nephrologist- held since January 1, 2018.
scientist at the University Health Network (UHN) and is He has been awarded international prizes and honors,
passionate about improving the clinical care and outcomes of including the Jean Hamburger Award (ISN) and the prize for
patients with glomerulonephritis. outstanding basic research (ERA-EDTA). He is Doctor
Dr. Reich directs the glomerulonephritis program at Honoris Causa of the Louvain Catholic University and a
Toronto General Hospital, Toronto, Ontario, Canada. This member of the Academia Europeae, the French Academy of
rich program spans clinical care of patients with glomer- Medicine, the Royal Academy of Medicine (Belgium), and the
ulonephritis, contribution to clinical trials, and trans- Institut Universitaire de France.
lational research. Her research program objective is to PR reports consultancy for Alexion, Amicus, Idorsia, and
identify clinical and molecular markers of progressive MorphoSys; grant/research support from Alexion* and

Amgen*; providing manuscript preparation for UpToDate; New diseases have been identified using this novel approach.
receiving travel expenses from the ASN, the French Society of These studies have resulted in over 225 peer-reviewed
Nephrology, and Sanofi-Genzyme. publications.
*Monies paid to institution. SS reports consultancy for Novartis.
Jan-Stephan F. Sanders, MD, PhD, Yusuke Suzuki, MD, PhD, is

is a nephrologist and the program currently a professor of nephrology
director of the Kidney and Pancreas at the Juntendo University Faculty
Transplantation Program at the of Medicine and Graduate School of
University Medical Center Gronin- Juntendo University, Tokyo, Japan.
gen (UMCG), Groningen, The His academic positions include di-
Netherlands. Dr. Sanders received rector of Japanese Society of
his MD degree in 2002 at the Uni- Nephrology (JSN), councilor of the
versity of Groningen. He did a Japanese Society of Internal Medi-
research fellowship at Hammersmith Hospital, Imperial cine, Japanese Society of Dialysis Therapy, Japanese Society
College London, UK. Thereafter, Dr. Sanders trained in of Hypertension, and the ISN council, deputy chair of the
internal medicine and nephrology at Medical Center Leeu- ISN North and East Asia Regional Board, sub-chief (2011–
warden, Leeuwarden, The Netherlands, and at University 2016) and chief (2017–present) researcher of the Special
Medical Center Groningen (UMCG). He combined this with Research Group of IgA Nephropathy in Progressive Renal
a PhD trajectory, which he completed in 2009 with his Diseases Research from the Ministry of Health, Labor and
thesis “Disease-activity in ANCA-associated Vasculitis.” Since Welfare of Japan. Dr. Suzuki is also the chief researcher of a
September 2010, he has been a staff member at the division biomarker project on IgA nephropathy from Research on
of nephrology at UMCG, focusing on kidney transplantation Intractable Disease from the Japan Agency for Medical
and ANCA-vasculitis. Since October 2019, he has served as Research and Development. His research mainly focused on
the program director of the Kidney and Pancreas Trans- the pathogenesis of IgA nephropathy. He has more than
plantation Program at UMCG. His primary research in- 160 English publications in peer-reviewed journals,
terests are ANCA vasculitis and kidney transplantation. He including Kidney International, Journal of the American
has received research grants from the Dutch Kidney Society Society of Nephrology, Journal of Clinical Investigation, JAMA
and the Netherlands Organisation for Health Research and Internal Medicine, JAMA Network, and Natural Medicine
Development. Journal. He is now an editorial board member for Kidney
J-SFS reports grant/research support from Chiesi, Dutch International, Nephrology, and the American Journal of
Kidney Society, The Netherlands Organisation for Health Kidney Diseases.
Research and Development, and Novartis. YS reports consultancy for Bayer, Chinook, Chugai, Daiichi
Sankyo, Kyowa Kirin, Mitsubishi Tanabe Pharma,
MorphoSys, Novartis Pharma, Travere (formerly Retro-
Sanjeev Sethi, MD, PhD, graduated phin), and Visterra; grant/research support from Astellas*,
from Assam Medical College, Bayer*, Chinook, Chugai*, Daiichi Sankyo*, Japan Agency
Dibrugarh, India. He pursued grad- for Medical Research and Development*, Japan Society for
uate studies thereafter at Albany the Promotion of Science*, Kyowa Kirin*, Ministry of
Medical College, Albany, NY, USA, Health, Labour and Welfare in Japan*, Moderna, MSD
and received his PhD in experimental K.K.*, Ono*, Sanwa Kagaku Kenkyusho*, Sumitomo
pathology in 1995. Subsequently, Dr. Dainippon Pharma*, Sunstar*, Suzuken Memorial Foun-
Sethi completed his pathology resi- dation*, Takeda*, Teijin Pharma*, Torii Pharmaceutical*,
dency at Yale University, New Haven, Travere (formerly Retrophin), and Visterra; speaker bureau
CT, USA (1995–1999) and his fellowship in renal pathology at for Asahi Kasei Pharma, Astellas, Bayer, Chugai, Daiichi
Brigham and Women’s Hospital, Harvard University, Boston, Sankyo, Kissei, Kowa, Kyowa Kirin, Mitsubishi Tanabe
MA, USA (1999–2001). He is currently a professor at the Pharma, MSD K.K., Novartis, Ono, and Sumitomo Dai-
Mayo Clinic, Rochester, MN, USA. His primary interests and nippon Pharma; and providing manuscript preparation for
research are in glomerulonephritis, with a focus on the Chugai-Igakusha, Fuji Medical Publishing, Japan Medical
management approach to glomerulonephritis, the role of Journal, Kagaku Hyoronsha Co., Ltd, Medicus Shuppan,
monoclonal gammopathy in glomerulonephritis, and the role Publishers Co., Ltd, Nankodo Co., Ltd., Shindan to Chiryo
of alternative pathways of complement in glomerulonephritis, Sha, Inc, and Tokyo-Igakusha.
as well as the application of proteomics in renal pathology. *Monies paid to institution.

Sydney C.W. Tang, MD, PhD, than 400 papers in international journals, mostly dedicated to
FRCP, FACP, FHKCP, FHKAM, is glomerular disease.
Chair of Renal Medicine and Yu VT reports consultancy for Abbvie, Amgen, Baxter, Bayer,
Professor in Nephrology at the Boehringer Ingelheim, Calliditas, ChemoCentryx, and Fre-
University of Hong Kong, Hong senius Medical Care, Omeros, and Travere; speaker bureaus
Kong, China and an honorary for Bayer and Boehringer Ingelheim; and receiving travel
consultant physician at Queen Mary expenses for AbbVie.
Hospital, Hong Kong. He trained in
internal medicine and nephrology
and has been a research fellow at King’s College London, Marina Vivarelli, MD, trained in
London, UK, and the University of Washington, Seattle, pediatrics at the University of Pavia,
WA, USA. As a clinician–scientist, his research interests are Pavia, Italy, is working in pediatric
in the pathogenesis of diabetic and chronic kidney disease rheumatology in Dr. Fabrizio De
and the treatment of IgA nephropathy. He has published Benedetti’s lab, on the pathogenesis
over 270 scientific papers and contributed over 30 book of juvenile idiopathic arthritis. She
chapters, including one on diabetic kidney disease (DKD) completed a 2-year research fellow-
in Comprehensive Clinical Nephrology. He is currently ship at Children’s Hospital, Boston,
editor-in-chief of Nephrology (Carlton), theme editor MA, USA with Professor Raif Geha,
(DKD) of Nephrology Dialysis Transplantation, associate studying a mouse deficient in RIP, a protein that is pivotal in
editor of Glomerular Diseases, and on the editorial boards B cell response to toll-like receptor 4.
of Kidney International, Clinical Journal of the American Since 2006, in the Division of Nephrology of the Bambino
Society of Nephrology, Seminars in Nephrology, American Gesù Pediatric Hospital in Rome, Italy, she has worked to
Journal of Nephrology, and Kidney Diseases. He is president- establish a new front of translational research in pediatric
elect (2019–2022) of the Asian Pacific Society of immune-mediated kidney diseases. Her focus has been on
Nephrology, a member of the KDIGO Executive Com- nephrotic syndrome, and her expertise in B cell biology has
mittee (from 2020), deputy chair (from 2018) of the CME led her to address the question of why B cell–depleting
Advisory Committee of the ISN, an International Honorary therapy is effective in some forms of this disease.
Member of the Japanese Society of Nephrology, and past- She has designed and conducted a phase 1 trial on the use
chairman (2016–2018) of the Hong Kong Society of of mesenchymal stem cells in difficult forms of nephrotic
Nephrology. syndrome and has also contributed to the design and conduct
SCWT reports consultancy for Novartis and Travere of trials evaluating the use of belimumab and comparing
(formerly Retrophin); grants/research support from Sanofi; rituximab and mycophenolate mofetil in pediatric nephrotic
and speaker bureau for AstraZeneca. syndrome.
She treated the first patient with dense deposit disease
(DDD) with eculizumab and has participated in trials eval-
Vladimír Tesar, MD, PhD, FERA, uating complement inhibitors for children with aHUS and C3
FASN, is head of the Department of glomerulopathy.
Nephrology, 1st Faculty of Medicine MV reports consultancy for Apellis, Novartis, Roche, and
and General University Hospital, Travere (formerly Retrophin).
Charles University, Prague, Czech
Republic. He is a member of the
Executive Committee of the ISN, Jack F.M. Wetzels, MD, PhD, is a
former chair of the Immunoneph- professor of nephrology at Radboud
rology Working Group of ERA- University Nijmegen Medical Center,
EDTA, and the former member of the council of ERA- Nijmegen, The Netherlands. He
EDTA. He is a member of the editorial board of the Clinical studied medicine at the University of
Journal of the American Society of Nephrology; Nephrology Nijmegen and received his MD in
Dialysis Transplantation; and Journal of Nephrology, and 1980. He undertook his training in
former editor-in-chief of Kidney and Blood Pressure Research. internal medicine and nephrology at
His main interests are glomerular disease, inherited diseases the Radboud University Nijmegen
of the kidney, and cardiovascular complications of chronic Medical Center. He received his PhD in 1989. From 1990 to
kidney disease. He participated in many genetic and 1992, he studied ischemic kidney tubular injury as a post-
biomarker studies in glomerular diseases and on the steering doctoral fellow under the supervision of Robert W. Schrier at
committees of many randomized, controlled (including the University of Colorado Health Sciences Center, CO, USA.
investigator-initiated) clinical trials. He has co-authored more He has been a nephrologist since 1992. In 2002, he was

appointed professor of nephrology in the Department of Wolfgang C. Winkelmayer, MD,

Nephrology at Radboud University Nijmegen. His chair is MPH, ScD, is the Gordon A. Cain
committed to teaching and research with an emphasis on the Chair of Nephrology and professor of
diagnosis and treatment of patients with glomerular diseases. medicine at Baylor College of Medi-
Dr. Wetzels is a member of the steering committee of the cine in Houston, TX, USA. Dr.
European Reference Network for Rare Kidney Diseases Winkelmayer received his medical
(ERKnet) and co-chair of the Immune-glomerulopathies degree (1990) from the University of
Working Group within ERKnet. Vienna, Vienna, Austria, and later
JFMW reports serving as an international scientific advisory earned a Master of Public Health in
board member for Alexion*; consultancy for MorphoSys, healthcare management (1999) and a Doctor of Science in
Novartis, and Travere (formerly Retrophin); grant/research health policy (2001) from Harvard University, Cambridge,
support from Alexion, MorphoSys*, and Novartis; and MA, USA. He then spent 8 years on the faculty of Brigham
speaker bureau for Novartis.* and Women’s Hospital and Harvard Medical School, Boston,
*Monies paid to institution. MA, where he established himself as a prolific investigator and
leader in the discipline of comparative-effectiveness research
as it pertains to patients with kidney disease. From 2009 to
2014, he was the director of clinical research in the Division of
KDIGO Chairs
Nephrology at Stanford University School of Medicine, Palo
Michel Jadoul, MD, received his Alto, CA, USA. He assumed his current position as chief of
medical degree in 1983 at the nephrology at Baylor College of Medicine in September 2014.
Université Catholique de Louvain His main areas of research interest include comparative
(UCLouvain) in Brussels, Belgium. effectiveness and safety research of treatment strategies for
Dr. Jadoul trained in internal anemia, as well as of various interventions for cardiovascular
medicine and nephrology under the disease in patients with kidney disease. Dr. Winkelmayer is a
mentorship of Professor Charles member of the American Society of Clinical Investigation. His
van Ypersele de Strihou. He has clinical passion lies in providing quality kidney care to the
served as chair at the Department predominantly disadvantaged and un(der)insured population
of Nephrology of the Cliniques Universitaires Saint-Luc, in the public safety net health system of Harris County, Texas.
Brussels, Belgium since 2003 and is currently a full clinical Dr. Winkelmayer has authored over 300 peer-reviewed pub-
professor at UCLouvain. Dr. Jadoul’s clinical activities focus lications, and he has a particular interest in medical pub-
on the follow-up of hemodialysis and CKD patients, and lishing. He currently serves as an associate editor for the
his main research interests include b2-microglobulin Journal of the American Medical Association, was a co-editor of
amyloidosis, hepatitis C, and other complications (e.g., the American Journal of Kidney Disease from 2007 to 2016,
falls, bone fractures, sudden death) in hemodialysis pa- and has been appointed to several other editorial boards of
tients, as well as cardiovascular complications after kidney leading nephrology and epidemiology journals. He also vol-
transplantation and various causes of kidney disease (e.g., unteers his time toward important initiatives of the ASN (e.g.,
drug-induced). Public Policy Board). He joined the KDIGO Executive
Dr. Jadoul has co-authored over 260 scientific papers, most Committee in 2015 and has served as KDIGO Co-Chair since
of them published in major nephrology journals. He is 2016.
currently serving as a theme editor of Nephrology Dialysis WCW reports consultancy for Akebia, Amgen, AstraZeneca,
Transplantation, and he is also a country co-investigator for Bayer, Daiichi Sankyo, Relypsa, and Vifor Fresenius Medical
the Dialysis Outcomes and Practice Patterns Study (DOPPS; Care Renal Pharma.
2001–present). In 2008, he received the international distin-
guished medal from the US NKF. He was previously a
member of the KDIGO Executive Committee (2010–2015)
and the ERA-EDTA Council (2013–2016). Presently, Dr. METHODS Chair
Jadoul is a KDIGO Co-Chair. Marcello A. Tonelli, MD, SM, MSc,
MJ reports consultancy for Astellas*, AstraZeneca*, Merck FRCPC, is senior associate dean
Sharp & Dohme*, Mundipharma*, and Vifor Fresenius (clinical research) at the Cumming
Medical Care Renal Pharma*; providing expert testimony for School of Medicine in Calgary,
Vifor Fresenius Medical Care Renal Pharma*; grants/research Alberta, Canada. He is associate vice
support from Amgen*, Janssen-Cilag*, Otsuka*, and Roche*; president (health research) at the
speaker bureau for Amgen*, Menarini*, Merck Sharp & University of Calgary, Calgary,
Dohme*, Mundipharma, and Vifor Fresenius Medical Care Alberta, Canada. He received a
Renal Pharma*; and travel fees paid by Amgen* and Sanofi* medical degree from the University
*Monies paid to institution. of Western Ontario, Ontario, Canada, a Master of Science in

epidemiology from Harvard University, Cambridge, MA, University of Otago at Christchurch in New Zealand. She
USA, and a Master of Science in health policy from Imperial studied medicine at the University of Otago, graduating in
College London, UK. He is a nephrologist and professor at 1995. She became a fellow of the Royal Australasian College of
the University of Calgary. Physicians in Nephrology in 2005. She later completed a PhD
Dr. Tonelli has served in the past as president of the Ca- in 2010 on the link between kidney function and heart health,
nadian Society of Nephrology, councilor of the ISN, and a and a 2-year postdoctoral fellowship in Boston, MA, USA, at
member of the KDIGO Executive Committee. Dr. Tonelli is the Brigham and Women’s Hospital.
chair emeritus of the Canadian Task Force for Preventive Dr. Palmer began as an author with the Cochrane Kidney
Health Care, a national panel of experts that makes recom- and Transplant Group in 2004 during her training to become
mendations about preventive health services to Canada’s a nephrologist. Through systematic reviews, she discovered a
36,000 family physicians. passion for understanding more about the amount and
A unique aspect of Dr. Tonelli’s research program includes quality of evidence that are required to make good clinical
partnering with regional, provincial, and national decision decisions in nephrology. She is actively engaged in the
makers to ensure that the findings will be used to produce conduct of systematic reviews of interventions (the treatments
rational health policy. we use), prognosis (whether risk factors for disease link to
MT has received honoraria from AstraZeneca and Travere important outcomes), and trial quality (how good is the ev-
(formerly Retrophin).* idence on which to base our decisions).
*Monies donated to charity Dr. Palmer enjoys training others in systematic review and
meta-analysis using an evidence-based approach to research.
She has strong collaborative links with researchers in Italy,
Australia, Europe, and North America with an increasing
Evidence Review Team
research output, including recent publications in key internal
Jonathan C. Craig, MBChB, medicine and nephrology journals.
DipCH, FRACP, M Med (Clin Epi), SCP declared no competing interests.
PhD, Evidence Review Team Di-
rector, is an internationally recog- Giovanni F.M. Strippoli, MD, MPH, M Med (Clin Epi),
nized clinician and scientist and PhD, Evidence Review Team Co-Director, has made sig-
holds the position of vice president nificant contributions to clinical research in CKD, with
and executive dean of the College of particular focus on prevention of kidney disease and man-
Medicine & Public Health at Flinders agement of kidney failure, including hemodialysis, peritoneal
University, Adelaide, South Australia, dialysis, and kidney transplantation. He has contributed
Australia. Professor Craig has made a significant contribution strongly to the development of policy in the area of kidney
to the clinical research landscape in the prevention, identifi- disease management through an international network
cation, management, and treatment of CKD, particularly in designing and conducting epidemiologic studies in the field,
relation to children and in indigenous communities. including systematic reviews, randomized trials, and cohort
He has led the formation of state, national, and interna- studies, among others. Professor Strippoli has been an active
tional networks to conduct high-quality, relevant trials in contributor in his positions as chairman, deputy chairman,
children. He has been instrumental in the development and and council in nephrology societies, including the ISN and
implementation of best-practice methods and guidelines the Italian Society of Nephrology, as well as editorial positions
relating to CKD in Australia and globally. Professor Craig’s in nephrology and general medicine scientific journals.
many current advisory roles include member of the National GFMS declared no competing interests.
Health and Medical Research Council’s (NHMRC) Health
Translation Advisory Committee, the Pharmaceutical Benefits
Martin Howell, PhD, Assistant
Advisory Committee, Medical Services Advisory Committee,
Project Director, is a senior research
and Commonwealth Department of Health Life Savings Drug
fellow in health economics in the
Program.
Sydney School of Public Health
He is a past member of the World Health Organization
(University of Sydney), Sydney, New
expert review panel for global strategy and plan of action on
South Wales, Australia. Since 2009,
public health, innovation and intellectual property, a past
Martin has been responsible for evi-
chairman of the Steering Group of the Cochrane Collabora-
dence review and synthesis and the
tion, and a past member of the Expert Advisory Group for the
development of over 20 clinical
Structural Review of NHMRC’s Grant Program.
practice guidelines for the Kidney Health Australia—Caring
JCC declared no competing interests.
for Australasians with Renal Impairment (KHA-CARI)
Suetonia C. Palmer, MBChB, FRACP, PhD, Evidence Re- guidelines group. His research focuses on applied health
view Team Co-Director, is an academic nephrologist at the economics, predominantly in the areas of assessment of

preferences using discrete choice methods and economic companies, developing new system procedures and work-
evaluations. His PhD project involved the application of a flows, and providing training solutions for new and existing
type of choice experiment known as a Best Worst Scaling staff.
survey to elicit preferences of recipients of kidney transplants During her editorial career, Dr. Russell also gained a
for outcomes after transplantation. This methodology has bachelor’s degree in journalism, international relations, and
since been applied to address a diverse range of health-related literary studies, a graduate degree in cognitive science, and a
issues. He is currently leading the economic evaluations of 9 PhD in comparative cognition research. She has been the
active clinical trials. He is an author of 57 publications (first managing editor of Cochrane Kidney and Transplant since
author on 10). These publications show the broad application October 2015.
of his research from clinical trials to translation of clinical FR has grants/grants pending from the National Health and
evidence to clinical practice guidelines and patient-centered Medical Research Council of Australia.
care.
MH declared no competing interests.
Gail Y. Higgins, BA, Grad Ed, Grad Dip LibSc, Information
Specialist, completed a bachelor’s degree in arts, a graduate
David J. Tunnicliffe, PhD, Evidence diploma in education from the University of Sydney, Sydney,
Review Project Team Leader and New South Wales, Australia, and a graduate diploma in Li-
Project Manager, is a research fellow brary Science from Kuring-gai College of Advanced Educa-
at the University of Sydney, School of tion, Sydney, New South Wales, Australia. Following a
Public Health, Sydney, and the number of years as a teacher–librarian, she changed tack and
Centre for Kidney Research at the spent 3 years with the New South Wales Technical and
Children’s Hospital at Westmead, Further Education (NSW TAFE) Information Systems Divi-
New South Wales, Australia. He was sion. After that, she joined the University of Sydney Library
awarded his PhD in 2018 at the and worked as a pharmacy librarian and then as an internet
University of Sydney and was awarded a National Health and training librarian. She has worked as an information specialist
Medical Research Council (NHMRC) Emerging Leadership 1 for the Cochrane Haematological Malignancies Group in
Investigator Grant (APP1197337) to examine the imple- Cologne, Germany, and the Cochrane Cancer Network in
mentation and evaluation of living evidence in kidney disease. Oxford, UK. In 2007 and 2008, she completed a secondment
David has a research interest in meta-research of CKD and with the World Health Organization in Geneva, Switzerland,
teaching epidemiology, which he performs through the on the International Clinical Trials Registry Platform (ICTRP)
Masters (Medicine) Clinical Epidemiology program, as a unit project.
coordinator of introductions to systematic reviews. GYH declared no competing interests.
As part of Cochrane Kidney and Transplant, David Brydee Cashmore, MPH, Research Associate, has a Master
has served as the evidence review project team leader of Public Health from the University of Sydney, Sydney, New
and project manager for the 2020 KDIGO update of the South Wales, Australia, as well as a bachelor’s degree in sci-
KDIGO Clinical Practice Guideline on the Management ence, a double major in physiology and human nutrition, a
of Blood Pressure in CKD, providing methodological expertise graduate diploma in science in psychology, and a post-
on evidence synthesis and guideline development. His role was graduate diploma in science in human nutrition from Mas-
key in coordinating the formation of key clinical questions to sey University, Palmerston North, New Zealand. She is a
guide literature searching and leading data extraction, critical researcher at the Centre for Kidney Research at the University
appraisal, meta-analysis, and evidence grading. of Sydney, where she undertakes evidence review and syn-
DJT declared no competing interests. thesis for Cochrane Kidney and Transplant and the KHA-CARI
Fiona Russell, PhD, Cochrane Kidney and Transplant, Guideline group. She was involved across all of the KDIGO
Managing Editor, has more than 20 years’ experience at Clinical Practice Guideline for the Management of Glomer-
media organizations such as News Corp and Fairfax Media, ular Diseases subtopics and undertook key aspects of the
Sydney, Australia in a variety of editorial positions, including evidence review, including data extraction, evidence synthesis,
reporter, sub-editor, deputy editor, and production editor. and the writing and preparation of evidence summaries in
Two years as an information technology supervisor led to an MAGICapp.
ongoing technological change management role at both BC declared no competing interests.

acknowledgments www.kidney-international.org
Acknowledgments
A special debt of gratitude is owed to the KDIGO Co-Chairs, Anthony Cabrera, Ingoberg Rojas Calderón, Monica Calvo,
Michel Jadoul and Wolfgang Winkelmayer, and immediate Emigdio Mendez Camacho, Perez Canga, Fernando Cardenas,
past Co-Chair David Wheeler, for their invaluable oversight Antonio Carlos Cardoso, Marcia A. Carvalho, Dawn J. Caster,
throughout the development of this guideline. In particular, Giovani Cersosimo, Michael Chang, Payupol Chansomboon,
we thank Jonathan Craig, Martin Howell, David Tunnicliffe, Stephen Chew, Ho Jun Chin, Kiran Chintam, Hov Chom-
and the ERT members for their substantial contribution to the roeun, Hoon Loi Chong, Gabriel Choukroun, Hugo Cil-
rigorous assessment of the available evidence. We acknowl- ocioni, Melissa Cintra, Rolando Claure-Del Granado, Luis
edge Marcello Tonelli and Lyubov Lytvyn for their guidance Ernesto Gomez Contreras, Rosanna Coppo, Frank B. Corta-
on strengthening the linkage between the recommendations zar, Matija Crnogorac, Xiaoyun Cui, Richard D’Souza, Iara da
and evidence base and for striving to improve on the format Silva, Kader Daghastanli, Ian H. de Boer, Kirsten de Groot,
to better meet KDIGO’s aspiration for a “living guideline” Meltem Seziş Demirci, Inge Derad, Pedro Augusto Macedo de
that is consistently kept up-to-date, and above all, useful and Souza, Ajaya Kumar Dhakal, Manuel Fidalgo Diaz, Biagio
informative to practicing clinicians. We also acknowledge Raffaele Di Iorio, Cristiane Dias, Jonathan Dick, Ameth
Debbie Maizels for her vital contributions to the artwork Dieng, Nida Dinçel, Prodip Doley, Mary Anne Dooley, Linda
presented in this guideline. Egan, Rihab Elidrisi, Emma Elphick, Basim Elsawi, Magdy El-
Lastly, we are especially grateful to the Work Group Sharkawy, Montserrat Mercedes Díaz Encarnación, Lavinia
members for their expertise throughout the entire process of Ene, Mar Espino-Hernandez, Gerard Espinosa, Pasquale
literature review, data extraction, meeting participation, and Esposito, Pei Chun Fan, Rawan Farghal, Rehab Fatani, Val-
the critical writing and editing of the statements and ratio- kercyo Feitosa, Sandro Feriozzi, Loreto Fernandez, Jose
nale, which made the publication of this guideline possible. Enrique Fernandez, Isis Figueiredo, Jeanette Finderup, Juan
The generous gift of their time and dedication is greatly Carlos Flores, Alessia Fornoni, Kevin J. Fowler, Barry I.
appreciated. Finally, and on behalf of the Work Group, we Freedman, Emma Frew, David J. Friedman, Tibor Fülöp,
gratefully acknowledge the careful assessment of the draft Daniel P. Gale, Maurizio Gallieni, Joana Gameiro, Venkat
guideline by public external reviewers. The Work Group Gangaram, Alvaro Garcia, Ilse Garcia, Martha Nelida Lahoz
considered all of the valuable comments made, and where Garcia, Philippe Gauthier, Mohammed Abdel Gawad, Tamara
appropriate, suggested changes were incorporated into the Gcar!cia, Susie Gear, Duvuru Geetha, Jutta Gellermann, Bil-
final publication. The following individuals provided feed- jana Gerasimovska, Osama Gheith, Farhad Gholami, Glom-
back during the public review of the draft guideline: Con Latinoamerica, Abdellatif Goda, Natashia Gongora,
Samah Abdelrahman, Laleh Abedinzadeh, Patricia F. Marsha Gooden, Sreedas Gopalkrishnan, Cécile Gosset,
Abreu, Matías Abuchanab, Shivnarayan Acharya, Baris Afsar, Xhensila Grabocka, Noble Gracious, Jon Waarst Gregersen,
Bishal Agarwalla, Irene Agraz, Thurid Ahlenstiel-Grunow, Ryszard Grenda, Megan Griffith, Adriana Guardado, Felipe
Mohammed Ahmed, Yasmeen Ahmed, Marina Aksenova, Guedes, Patsy Gundim, Nimish Gupta, Jean Carlo Tibes
Abdullah Al Mamun, Muhamed Al Rohani, Laith Al-Rabadi, Hachmann, Fathin Hadi, Dieter Haffner, Rasha Hagag, Isa-
Eric Alamartine, Khalid Alhasan, Weiam Almaiman, Khuloud belle Haggiag, William E. Haley, Nabila Hamdan, Seung
Almutawa, Muhannad Alqudsi, Mohammed Hannon Also- Hyeok Han, Seungyeup Han, Jamey Hardesty, Elizabeth
dani, Francisco Hernandez Alvarado, Alfonso Alvarez, Maria Harrison, Alejandro Hernandez, Elizabeth Herrera, Ngô
Almerinda Ribeiro Alves, Elizabeth Alzate, Pablo Amair, Hoàng, Elisabeth M. Hodson, Yu Ah Hong, Lai Seong Hooi,
Yupaporn Amornchaicharoensuk, Ilyes Andrea, Mabel Aoun, Alvaro Hostia, Peter F. Hoyer, Zbigniew Hruby, Christine
Ibtissame Arbaoui, Andrés Arriagada, Mariano Arriola, Fer- Hsu, Chiu-Ching Huang, Azm ul Hussain, Nahla Hussein,
ruh Artunc, Naila Asif, Adanze Asinobi, Suheir Assady, Holly Hutton, Francesco Iannuzzella, Shivananda Illalu,
Ambarish Athavale, Vincent Audard, Karem Awad, Joana Kunitoshi Iseki, Renee Jack, Anjana Jagalur, Awatiff Jalaludin,
Azevedo, Hazim Aziz, Justine Bacchetta, Hugo Badani, Sunil Aamir Jamal, Maneesha Jayasiri, Chandra Mauli Jha, Prem
V. Badve, Arvind Bagga, Sapna Bai, Olga Balafa, Riteshkumar Mohan Jha, Shan Jian, Lilian Johnstone, Roshin Joseph,
Banode, Peter Bárány, Thomas D. Barbour, Rommel Bataclan, Mikhail Kagan, Antroula Pastelli Kakouri, Mahmoud Kallash,
Sunita Bavanandan, Laurence H. Beck, Jr, Nestor Bencosme, Manivarma Kamalanathan, Elaine Kamil, Nada Kanaan,
Mohammed Benyahia, Marcus Benz, Rajendra Bhimma, Ali Ammar Kanbar, Shuzo Kaneko, Hee Gyung Kang, Karthik
Evren Bilgiç, Rainer Birck, Vincent Boima, Jaime Bonilla, Kannegolla, Sergei Karpov, Hassani Kawtar, Rümeyza
Jerald Boseman, Jordi Bover, Carlo Briguori, Ion Dan Buca- Kazancio"glu, Junaid Khan, Basem Youssef Khedr, Masoud
loiu, Florian Buchkremer, Nikolay Bulanov, Rafael Burgos- Khosravi, Arif Khwaja, Dana Kidder, Chang Seong Kim,
Calderon, Stefan Büttner, Fayna González Cabrera, Mark SungGyun Kim, Aaron Kirkemo, Gianna Mastroianni

www.kidney-international.org acknowledgments
Kirsztajn, A. Richard Kitching, Wonngarm Kittana- Joel Pöysä, Ravindra A. Prabhu, Eric Prager, Eldar Priel,
mongkolchai, Radko Komers, Kirill Komissarov, Boonhuei Erasmia Psimenou, Margarita Catala Puigbo, Paola Pulcini,
Kong, Jonathan Kooiman, Jeffrey B. Kopp, Ghaly Kotb, Mikhail Pyatchenkov, Patrícia Queiroz, Edwin Quintero, B.L.
Magdalena Krajewska, Jens Kristensen, Vikram Sakaleshpur Raghavendra, Intan Rahmawati, Pradeep Kumar Rai, Raja
Kumar, Dirk Kuypers, Gaetano La Manna, Pedro Jesus Lab- Ramachandran, Francisco Ramirez, Dwarakanathan Ranga-
rador, Richard A. Lafayette, Jorge Laguna, Caroline Lamarche, nathan, Nisha Rao, Harun Rashid, Manish Rathi, Monica
Stewart Lambie, Ivo Laranjinha, Nicholas Larkins, Hajeong Repetto, Andres Reyes, Pablo Ríos, Saira Risdale, Maria Fer-
Lee, Lauren Lee, Alice Leite, Claudia F. Leiva, Kevin V. Lemley, nanda Slon Roblero, Kate J. Robson, Dario Roccatello, Javier
Adama Lengani, Rachel Lennon, Wenxue Liang, Miguel Liern, Rodas, Ignasi Rodriguez-Pinto, Johanna Rohlfing, Alison
Liz Lightstone, San Lin, Mark A. Little, Mieczysław Litwin, Nava Rojas, Jorge Rojas-Rivera, Nuria S. Perez Romano,
Wenbin Liu, José António Lopes, William Lopez, Khaled Amaia Ros Abando, David Roth, Debajyoti Roy, Liliana
Lotfy, Kuo-Cheng Lu, Eduardo Luciano, Leonella Luzardo, Rubio, Peter Rutherford, Mohamed Saad, David J. Salant,
Fabiani Palagi Machado, Valentina Madjova, John K. Mae- May Salem, Péter Sallay, Yousif Salman, Ratna Samanta,
saka, Manish Mahajan, Nicolas Maillard, Indradip Maity, Sunehra Samee, Krishnaswamy Sampathkumar, Ramalakshmi
Aruni Malaweera, Rakesh Malhotra, Samir Mallat, Anthony Santhanam, Mukund Sarda, Chandranath Sarkar, Francesco
Rivera Mallqui, Partha Pratim Mandal, Sreedhar Mandayam, P. Schena, Anne M. Schijvens, Michiel Schreuder, Arun
Lucila Maria, Joana Moita Marques, Silvia Marsili, Irene Sedhain, Michal Sedivy, Lokumeegodage Dona Sewwandi
Martin-Capon, Guillermo Martin-Reyes, Gilberto Martinez, Udeshika Senaratne, Angel M. Sevillano, Bao Shaojing, Sala-
Diana Masso, Naveen Kumar Mattewada, Drew Maxted, Yulia heldin Sharkawi, Tejasvi Sharma, Deepak Sharma, Hussein
Mazur, Sandro Mazzaferro, Florencio McCarthy, P. McKillen, Sheashaa, Alexander Shutov, Hector Raul Ibarra Sifuentes,
Mohamed Megahed, Francisco Calderon Mendieta, Nathalie Majid Sikosana, John J. Sim, Ravi Singh, Rasika Sirsat, Andrej
Menendez, Carlos Mercado, Asad Merchant, Guido Merlotti, #Skoberne, Hila Soetendorp, Maria José Soler, Daniel Sollinger,
Mohamed Mesmeh, Ingrid Viviana Raoch Michaels, Sharon Ali Solorzano, Constanza Soto, Karina Soto, Laura Sottini,
Millhouse, Nyi Minhan, Dana C. Miskulin, Gerardo Mogni, Bruce S. Spinowitz, Fabian Srugies, Rolf A.K. Stahl, Wei Su,
Abd El-Rahman Hassan Mohyeldein, Mahmoud Montasser, María Luisa Suarez, Praveen Sudhindra, Yan Sun, Munib
Vincent Mooren, Thyago P. Moraes, Eugen Mota, Bruno Syed, Wladimir Szpirt, Nonpisit Tangkitkiatkul, Ekamol
Moulin, Marwa Mounir, Shanza Mujeeb, Giovanna Arteaga Tantisattamo, Surjit Tarafadar, Eric Thervet, Danay Ticona,
Muller, Mariana Murea, Ghassan Mustafa, Nandhakumar Gustavo Guerrero Tinoco, Salin Tio, Jakhongir Tojiboev, Joji
Nagarajan, Oana Naidin, Dharmesh Nama, Sharat Kumar Tokita, Birgitte Tougaard, Hernan Trimarchi, Hernando
Naorem, Shoba Narayan, Anghelo Narváez, Alice Naseri, Trujillo, Yusuke Tsukamoto, Neil Turner, Mariela Uyaguari,
Shobhana Natarajan, Bharat Nathoo, Aaron Ng, John Ngigi, Renzo Valdivia-Vega, Lucila Valente, Carlos Federico Varela,
Anh Nguyen, Kathleen Nicholls, Mustafayeva Nilufar, Oscar Edwin Velazquez, Juan Carlos Velez, Krishna Kumar Ven-
Noboa, Maurizio Nordio, Achim Obergfell, Eshetu Obole, katachalam, Anthony Russell Villanueva, Damayanty Gomez
Budimir Obradovic, SE Won Oh, Andrzej Oko, Nestor Oliva- Villanueva, Ignacio Villanueva, Thilo von Groote, Liron
Damaso, Stephen Olson, Alvaro Orjuela, Leixuri Ortega, Walsh, Gerd Walz, Nicholas J. Webb, Lutz T. Weber, Stefanie
Alberto Ortiz, Marlies Ostermann, Maria Ottati, Leszek Weber, Badi Wehbi, Carissa Wehr, Talia Weinstein, Andre
Pa˛ czek, Aparna Padiyar, Sasanka Pakalapati, Lars Pape, Weinstock, Scott E. Wenderfer, Kerstin Westman, Katherine
Norman Valdivia Paredes, Sun-Hee Park, Rocio Meleiro D. Westreich, Tamara Williams, Edwin Wong, Robert Wor-
Pascual, Malagouda Patil, Bandana Paudyal-Nepal, Shko- oniecki, Viktoria Woronik, Chuanhui Xu, Erica Yama, Fan
divskyi Pavlo, Saime Paydas, Marcos Paz, Michail Pazarlogou, Xiao Yan, Iñigo Yañez, Helen Yeh, Saivani Yellampalli, Plamen
Adalberto Peña, Ana Cecilia Acosta Pena, Adriana Penalba, Yovchevski, Elena Zakharova, Loretta Zambianchi, Zamir
Gerson Marques Pereira Junior, Perla Perez, Ivan Perez, Hai Zamir, Sijie Zheng, and Carmine Zoccali.
An Ha Phan, Marie Philipneri, Phuoc Phung, Dilukshi Pila- Participation in the review does not necessarily constitute
pitiya, Evangéline Pillebout, Carlos Eduardo Poli-de-Figueir- endorsement of the content of this report by the above in-
edo, Martin R. Pollak, Wanjak Pongsittisak, Daman Poudel, dividuals or the organizations or institutions they represent.

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Recommendation 9.3.1.1: We recommend that

The best evidence is available for patients with new-onset AAV.

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Figure 76 | Recommended treatment regimen for AAV. AAV, ANCA-associated vasculitis.

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9.4.2 Transplantation Research recommendations

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Chapter 10: Lupus nephritis

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Figure 90 | Example of glucocorticoid regimens for LN. LN, lupus nephritis.

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Chapter 11: Anti-glomerular basement membrane

Anti-glomerular basement membrane (GBM) antibody GN is 11.2 Treatment

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Methods for guideline development

Aim The KDIGO Co-Chairs, KDIGO Methods Chair, Work Group

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Table 2 | Clinical questions and systematic review topics in PICOM format

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Figure 100 | Search yield and study ﬂow diagram.

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Table 3 | Classiﬁcation for quality and certainty of the evidence