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 REVIEWS
The pathogenesis and diagnosis of acute
kidney injury in multiple myeloma
Colin A. Hutchison, Vecihi Batuman, Judith Behrens, Frank Bridoux, Christophe Sirac,
Angela Dispenzieri, Guillermo A. Herrera, Helen Lachmann and Paul W. Sanders on behalf of the
International Kidney and Monoclonal Gammopathy Research Group
Abstract | Renal failure remains a principal cause of morbidity for patients with multiple myeloma. Once
reversible factors such as hypercalcemia have been corrected, the most common cause of severe renal failure
in these patients is a tubulointerstitial pathology that results from the very high circulating concentrations
of monoclonal immunoglobulin free light chains. These endogenous proteins can result in isolated proximal
tubule cell cytotoxicity, tubulointerstitial nephritis and cast nephropathy (myeloma kidney). Less frequently,
high levels of free light chains can lead to immunoglobulin light chain amyloidosis and light chain deposition
disease, although these conditions are usually associated with insidious progression of renal failure rather
than acute kidney injury. Unless there is rapid intervention, progressive and irreversible damage occurs,
particularly interstitial fibrosis and tubular atrophy. Despite advances in our understanding of the pathogenesis
of these processes there has been a gap in translating these achievements into improved patient outcomes.
Renal Institute of
The International Kidney and Monoclonal Gammopathy Research Group was formed to address this need. In Birmingham, University
this Review, we discuss the mechanisms of disease and diagnostic approaches to patients with acute kidney Hospital Birmingham
and University of
injury complicating multiple myeloma. Birmingham,
Birmingham, UK
Hutchison, C. A. et al. Nat. Rev. Nephrol. advance online publication 1 November 2011; corrected online 18 November 2011; (C. A. Hutchison).
doi:10.1038/nrneph.2011.168 Section of Nephrology
and Hypertension,
Department of
Introduction Medicine, Tulane
Despite 40 years of advances in the management of both myeloma by improving our understanding of the under- University School of
multiple myeloma and acute kidney injury (AKI), the lying disease processes, thereby identifying potential Medicine, New Orleans,
LA, USA (V. Batuman).
outcomes for patients with severe AKI complicating mul- targets for early intervention. Subsequent strategies and Department of
tiple myeloma remain poor. A report from the UK in the care pathways designed to protect patients’ kidneys from Hematology, St Helier
Hospital, Carshalton,
early 1970s found that patients with multiple myeloma monoclonal proteins could then be developed. Surrey, UK (J. Behrens).
and severe AKI had a median survival of 2 months com- As with many rare diseases, one of the key barriers Department of
pared with 3 years for patients presenting with moder- to changing clinical practice has been the lack of suit- Nephrology, Poitiers
University Hospital,
ate renal impairment.1 More recent data from the UK able evidence on which to base any recommendations. Poitiers, France
have shown that the survival of patients with severe Research in this field has largely been confined to small (F. Bridoux). CNRS UMR
6101, Limoges
AKI compli­cating multiple myeloma has improved, but populations and is often uncontrolled. The International University Hospital,
only to 10 months.2 There is therefore still a great unmet Kidney and Monoclonal Gammopathy Research Group Limoges, France
(C. Sirac). Department
clinical need to improve outcomes for this population. was founded in late 2010 to enable a more coordinated, of Medicine, Division of
A potential starting point is to develop treatment strate- cross-disciplinary and multicenter approach to future Hematology, Mayo
gies that enable an early recovery of renal function in research in the field of AKI complicating multiple Clinic, Rochester, MN,
USA (A. Dispenzieri).
this setting, as this approach alone can greatly improve myeloma. In this Review, we provide an update on the Nephrocor, Bostwick
patient survival.3–5 Essential to achieving such renal pathogenesis and diagnostic approaches to patients with Laboratories, Orlando,
FL, USA (G. A. Herrera).
recovery is a rapid reduction in serum concentrations AKI and monoclonal FLC. National Amyloidosis
of immunoglobulin (Ig) free light chains (FLCs),4,6 the Centre and Centre for
nephrotoxic proteins that are responsible for the major- Mechanisms of injury Nephrology, University
College London Medical
ity of severe AKI in patients with multiple myeloma. In The past 25 years have witnessed considerable advances School, London, UK
addition, there is great potential to further reduce the in the characterization and pathogenesis of tubulo­ (H. Lachmann). Division
of Nephrology,
incidence and severity of AKI in patients with multiple interstitial renal injury caused by Ig FLCs, and in elucida­ Department of
tion of the structure–function relationships involved in Medicine, University of
FLC-mediated renal tubular damage (Figure 1).7–33 FLCs Alabama, Birmingham,
AL, USA (P. W. Sanders).
Competing interests were originally described by Henry Bence Jones in the
C. A. Hutchison declares an association with the following
urine of a patient with mollities ossium as a protein that Correspondence to:
company: Binding Site. See the article online for full details of C. A. Hutchison
the relationship. The other authors declare no competing precipitated on warming, but then redissolved when c.a.hutchison@
interests. heated to 75 °C.34 These proteins constitute a family of bham.ac.uk

NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 1

© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS

Key points be hundreds of fold higher than normal.36 When this

■■ The tubulointerstitial injury, cast nephropathy, is the most common cause of
increase occurs, the capacity of the multiligand endo-
severe acute kidney injury in patients with multiple myeloma cytic receptor complex of the proximal tubule is quickly
■■ Histology findings of acute tubular necrosis and acute tubulointerstitial
exceeded, and high concentrations of FLCs appear in the
nephritis should raise a ‘red flag’ for potential injury from high levels of free tubular fluid and finally in the urine. Substantial accu-
light chains in patients with multiple myeloma mulation of FLCs within the proximal tubular epithelium
■■ Standard assessment of renal histology by light microscopy, can occur; the FLCs that appear in the urine are tradi-
immunofluorescence and electron microscopy might require the addition of tionally termed Bence Jones proteins.35
specialist techniques to detect subtle injuries in patients with a monoclonal Monoclonal FLCs are known to induce isolated proxi-
protein mal tubular injury, cast nephropathy or a combination of
■■ Serum immunoassays can provide a rapid alternative to urine electrophoresis both. FLC interaction with proximal tubule cells (PTCs)
for the identification of monoclonal free light chains can activate inflammatory cascades that lead to tubulo­
■■ Early diagnosis and intervention remain key to preventing irreversible renal interstitial fibrosis, a major feature of myeloma kidney.
injuries in patients with multiple myeloma Similarly, FLC interaction with Tamm-Horsfall proteins
(THPs; also known as uromodulin) and cast formation in
the distal tubule can block glomerular flow and produce
low-molecular-weight proteins that, unlike most endo­ tubular atrophy and also contribute to interstitial fibro-
genously produced proteins, have a strong propensity to sis. Insight into the pathophysiological mechanisms
cause tubular damage. Patterns of tubulointerstitial renal involved in the toxic effects of FLCs in the kidney is likely
injury occurring in the setting of plasma cell dyscrasias to improve our ability to treat kidney disease associated
include isolated proximal tubule epithelial cell cyto­ with multiple myeloma.
toxicity, tubulointerstitial nephritis and cast nephropathy
(also known as myeloma kidney).21 Proximal tubule cell injury
About 500 mg of polyclonal FLCs are produced daily FLCs can exert direct toxic effects on PTCs, the most
by the normal lymphoid system and catabolized by the abundant cell type in the kidney, and many of the renal
proximal tubule. This system is highly efficient and only consequences of myeloma involvement of the kidney are
about 1–10 mg of polyclonal FLCs normally appear in the related to proximal tubular injury.10,15–19,28–30,37–46 Studies
urine each day.35 However, in the setting of a plasma cell have shown that FLCs purified from the urine of myeloma
dyscrasia, FLC production increases considerably, pro- patients without glomerular disease inhibited substrate
ducing circulating levels of monoclonal FLCs that can transport in isolated brush border membrane vesicles,

Glomerulus
Proximal
tubule
Light chains and 5–10 mg/day
THPs FLCs in urine
produce casts

Cast

Distal tubule

Ultrafiltrate
FLCs
Lumen
Cubilin–megalin THP 9 amino acid Potential triggers
complex Excessive binding region for cast formation
endocytosis FLC CDR3 FLC
domain of THP interacts ■ Dehydration
Redox NFκB + with CDR3 ■ Furosemide
pathways MAPK domain of FLC ■ Contrast agents
Proximal Endocytosis
tubule Ultrafiltrate THP ■ Infective agents
cells THP
Lysozyme Precipitation Giant cells
Transcription of
IL-6, IL-8, CCL2, TGF-β1
Interstitium Tubular cell Atrophy of tubule proximal to cast
apoptosis
Eventual
Progressive Epithelial–mesenchymal Leakage Inflammation interstitial
renal fibrosis transition Peritubular inflammatory fibrosis
cell infiltrate (lymphocytes,
plasma cells and eosinophils)
and migration into lumen
Figure 1 | Mechanisms of FLC-induced acute kidney injury. The very high concentrations of FLCs present in the ultrafiltrate of patients with multiple
myeloma can result in direct injury to PTCs. The excessive endocytosis of FLCs by the cubilin–megalin complex expressed on PTCs can trigger
apoptotic, proinflammatory and fibrotic pathways. Activation of redox pathways occurs, with increased expression of NFκB and MAPK, which in turn
leads to the transcription of both inflammatory and profibrotic cytokines, such as IL‑6, IL‑8, CCL2 and TGF-β1. In the distal tubules, FLCs can bind
to a specific binding domain on THPs and co-precipitate to form casts. These casts result in tubular atrophy proximal to the cast and lead to
progressive interstitial inflammation and fibrosis. Abbreviations: CCL2, C-C motif chemokine 2; CDR, complementarity determining region; FLC, free
light chain; IL, interleukin; MAPK, mitogen-activated protein kinase; NFκB, nuclear factor κB; PTC, proximal tubule cell; TGF-β1, transforming growth
factor β1; THP, Tamm-Horsfall protein.

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 REVIEWS

cultured PTCs in vitro10,11,41,42 and in perfused proximal although they have also been found in proximal tubular
tubules in rats in vivo.19,38,39 These studies shed light on segments and even in glomeruli in renal biopsy speci-
the pathophysiology of the clinical proximal tubulopathy mens.50 However, these casts also contained THP, sug-
occasionally seen in patients with multiple myeloma also gesting intraluminal reflux of co-precipitated THP and
referred to as light chain Fanconi syndrome.10,11,37,41–43,45,46 FLC into the proximal nephron.50
Although FLCs can be directly toxic to PTCs by blocking Cast formation in vivo is a complex process that is
transport of glucose, amino acids or phosphate,10,11,41–43 dictated by multiple variables, including the ionic com-
and by activating redox signaling upon contact with position of the tubule fluid, tubule fluid flow rates, the
PTCs,28–30 most of the toxicity seems to be mediated after concentration of THP and FLC, the strength of binding
endocytosis of FLCs through the tandem endocytic recep- interaction between THP and FLC, and the presence
tors cubilin and megalin.12–14,29,42 Excessive FLC endo­ of furosemide.19,20,22,23,25,31,32,51 These observations have
cytosis can induce a spectrum of inflammatory effects direct clinical relevance as many of these factors (except
that include activation of redox pathways and expres- the intrinsic binding interaction between THP and FLC)
sion of nuclear factor κB (NFκB) and mitogen-­activated can be modified with current treatment modalities.
protein kinases (MAPKs), leading to transcription of
inflammatory and profibrotic cyto­kines, such as IL‑6, Identifying nephrotoxic light chains
C-C motif chemokine 2 (CCL2; also known as monocyte Not all monoclonal FLCs are nephrotoxic. Although
chemo­attractant protein), IL‑8 and transforming growth the risk of AKI in patients with multiple myeloma is
factor (TGF)‑β1.15–18,28,30,42 Excessive FLC endocytosis can increased when FLC proteinuria reaches 2 g per day,
also trigger apoptotic pathways and alter the phenotype some patients do not develop kidney disease despite high
of PTCs towards a fibroblastic one through epithelial–­ FLC urine concentrations.52 As no tool to predict toxicity
mesenchymal transition in vitro 15,16,43 and in vivo. 44 of a given FLC is currently available, preventive measures
Studies have shown that blocking FLC endo­c ytosis, and removal of precipitating factors are mandatory.
either by inhibition of endocytosis9,17,18 or by silencing The mechanisms involved in the renal pathogenic
the endocytic receptors cubilin and megalin, abrogates effects of individual monoclonal FLCs remain incom-
cytotoxicity.14,29 These observations support the principal pletely understood. Nephrotoxicity appears to be an
that endocytosis is a prerequisite for these inflammatory intrinsic property of some FLCs, as indicated by the
processes and are the basis of three potential therapeutic recurrence of similar renal lesions after kidney trans-
strategies to prevent tubular injury: first, to eliminate or plantation, and by animal studies that have specifi-
reduce the FLC burden in myeloma patients with renal cally reproduced human FLC-related nephropathies
involvement; second, to block the inflammatory pathways using injections of purified human FLCs, 22 intra­
that are activated as a result of FLC toxicity; and third, to peritoneal injections of transfected plasmacytomas
potentially block FLC endocytosis. secreting a pathogenic human FLC,53,54 or gene-targeted
insertion.55 Growing evidence shows that the pattern of
Cast nephropathy renal injury is governed by both structural peculiarities
A major mechanism of FLC-mediated tubule damage of mono­clonal FLCs, particularly of the variable (V)
is intratubular obstruction from precipitation of domain, and is influenced by environmental factors,
FLCs in the lumen of the distal nephron, which leads such as pH, urea concentration or local tissue proteo­lysis.
to interstitial inflammation and fibrosis. 21 The clini- In addition, intrinsic host factors are likely to have an
cal relevance of cast formation was initially revealed important role in determining both the type and severity
by intravenous infusion of nephrotoxic human FLCs of any renal response to a given FLC.
in rats, which increased proximal tubule pressure and Pathogenic FLCs purified from patients’ urine are
simultaneously decreased single-nephron glomerular character­ized by their propensity to form high-order
filtration rate. Intraluminal protein casts were identi- aggregates or polymers in vitro, which differ according
fied in these kidneys.47 Persistence of intraluminal casts to the sequence variability of the V domain.56 The pecu-
in vivo reduces single-nephron glomerular blood flow liarities of the V domain are observed in many types of
to the obstructed nephron and results in atrophy of the renal disease induced by light chains. Myeloma-associated
nephron proximal to the obstruction.48,49 When infused Fanconi syndrome, for example, is characterized by proxi-
directly into the rat nephron in vivo, monoclonal FLCs mal tubule dysfunction secondary to FLC reabsorption
from patients with cast nephropathy produced dose- and crystallization within the lysosomal compartment of
dependent intraluminal obstruction by precipitating in PTCs. FLCs associated with Fanconi syndrome are nearly
the distal nephron; casts were not observed before the always of the Vκ1 subgroup and are derived from only two
tip of the loop of Henle.22 Obstruction was accelerated germ line genes, IGKV1‑39 and IGKV1‑33. These proteins
by the presence of furosemide. Pretreatment of rats with display unique sequence peculiarities in their complemen-
colchicine decreased urinary levels of THP and pre- tarity determining regions (CDRs); replacement of polar
vented intraluminal cast formation and obstruction.22 residues by nonpolar or hydro­phobic residues in the CDR
Additional studies demonstrated an integral relationship can induce resistance of the Vκ domain to proteolysis and
between monoclonal FLCs and THPs in cast formation result in light chain crystalliza­tion.57–60 In one study, an
and the associated kidney injury. In humans, casts are experimental mouse model of Fanconi syndrome was
generally observed in the distal portion of the nephron, developed by administering intraperitoneal injections

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REVIEWS

New AKI constant domains in amyloid fibril formation.71,72 Finally,

differences in FLC structure probably influence cellular
effects, as demonstrated by human mesangial cells that
Exclude myeloma kidney undergo either a myofibroblastic or a macrophage-like
Assessment for FLC clone* phenotypic transformation in vitro after incubation with
FLCs involved in light chain deposition disease or AL
FLC clone No FLC clone
amyloidosis, respectively.73
The role of the molecular characteristics of FLCs in
myeloma kidney is less clear. In high-mass myeloma, the
Clonal FLC ≥500 mg/l Clonal FLC <500 mg/l AKI of
capacity of the proximal tubule to reabsorb and degrade
another cause FLCs is rapidly overwhelmed by the dramatic increase
Either in the burden of filtered FLCs. Large amounts of FLCs
reach the distal tubule lumen where they interact with
THP. Huang and Sanders identified a binding domain for
Probable FLC tubular Alternative monoclonal Incidental MGUS
interstitial pathology FLC pathology FLCs on THP, which consisted of nine amino acids and
was termed LCBD.25 Importantly, all FLCs tested bound
to this FLC-binding domain.25 In turn, the CDR3 domain
■ Requires hematology work-up ■ Requires renal biopsy in the variable region of both κ and λ FLCs interacted with
■ Initiation of disease-specific ■ Consider hematology work-up THP.26 The binding affinities of FLCs for THP are related
treatment to reduce serum
FLC levels‡ to the amino acid composition of the CDR3 domain.26
Figure 2 | Screening algorithm for monoclonal disease in AKI. Patients with AKI can The other key mechanism of injury in myeloma kidney
be initially screened for a monoclonal protein by serum FLC assays, which enable is the massive reabsorption of FLCs in PTCs, which
the rapid identification of a monoclonal FLC as the possible cause of a tubular induces the generation of hydrogen peroxide,29 activa-
interstitial process. *To exclude the presence of an intact monoclonal tion of NFκB and phosphorylation of MAPKs, result-
immunoglobin, serum FLC assays should be combined with serum protein ing in the release of IL‑6, IL‑8, CCL2 and TGF‑β1.7,30
electrophoresis (many units would also include immunofixation electrophoresis as Oxidative stress, morphological changes,15 and tubulo­
standard of care). For the assessment of immunoglobulin light chain amyloidosis
interstitial inflammation that rapidly progresses to fibro-
and light chain deposition disease, urinary assessment is required. Where serum
FLC assays are not used, urgent urinary assessment for monoclonal FLCs is sis,74 partici­pate in the development of renal failure. Pote
necessary. ‡Emergency treatment designed to achieve a rapid reduction in serum et al. have shown that purified monoclonal FLCs cultured
FLC levels is based on high-dose dexamethasone. The full benefit of adding FLC with human PTCs induced cytoskeletal injury and DNA
removal strategies to this therapy remains to be determined. Abbreviations: AKI, damage consistent with apoptosis, followed by second-
acute kidney injury; FLC, free light chain; MGUS, monoclonal gammopathy of ary necrosis.16 Toxicity was variable among the different
undetermined significance. FLCs, but the effect was dose-dependent, suggesting that
both FLC structure and concentration determine cellular
of murine hybridoma SP2/O cells transfected with DNA toxicity in cast nephropathy.16
encoding a human Fanconi syndrome Vκ1 FLC.54 Using Despite our growing understanding of the pathogenic
site-directed mutagenesis in these mice, sequential mechanisms by which Ig FLCs induce renal injury, there
replacement of hydrophobic residues at position 30 or are currently no clinically relevant tools for identifying the
94 of the V region by their germ line polar counterparts potential nephrotoxicity of a specific monoclonal FLC.
abolished crystal forma­tion in the PTCs.54
In immunoglobulin light chain (AL) amyloidosis Diagnostic approaches
and light chain deposition disease, the pathogenic role Identifying monoclonal FLCs by immunoassays
of V regions is suggested by overrepresentation of the During the assessment of an individual with AKI it is
Vλ661 and Vκ462 subgroups, respectively, N‑glycosylation often appropriate and necessary to screen for the pres-
of the V region,61 and substitutions of key amino acids ence of a potentially nephrotoxic monoclonal FLC. In
induced by somatic mutations that might account for such cases, it is essential that the nephrologist and labora­
the propensity of certain FLCs to aggregate and influ- tories work together to minimize diagnostic delays to
ence tropism of deposition.53,63–67 In AL amyloidosis, a enable the rapid initiation of disease-specific treatment
role for V sequences is also suggested by the high poten- (Figure 2). This assessment is usually undertaken by
tial of V domain dimerization in vitro 68 and in vivo.69 evaluating the patient’s urine by protein electro­phoresis
FLCs associated with light chain deposition disease are (with or without immunofixation). An alternative to
characterized by cationic isoelectric points, whereas the this technique is the quantitative measurement of FLC
isoelectric point profile of FLCs involved in AL amyloid­ in the serum by nephelometric immunoassays.75,76 These
osis is heterogeneous. This observation suggests that immunoassays provide a quantitative measurement of
fibrillar amyloid deposits form by electrostatic interac- both κ and λ FLCs; an overproduction of one of these
tion between oppositely charged polypeptides, whereas monoclonal FLCs will lead to a ratio of the two FLCs
granular deposits in light chain deposition disease result that deviates outside the normal range (0.26–1.65).77 Use
from the binding of cationic polypeptides to anionic of these assays as a screening tool can help overcome
basement membranes.70 Two studies have also high- logistical delays and analytical inaccuracies associated
lighted a previously underestimated role for the FLC with other laboratory methods used for the identification

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 REVIEWS

of monoclonal FLCs (such as serum and urine protein Renal disease

electrophoresis and immunofixation).78 In an assessment +
Monoclonal protein
of 1,877 patients with plasma cell dyscrasias, Katzmann
et al. found that serum protein electrophoresis and a
quantitative serum FLC assay identified 100% of patients Full assessment of monoclonal protein:
with multiple myeloma and macroglobulinemia, 99.5% serum SPE, IFE and FLC + urine IFE
of patients with smoldering multiple myeloma, 96.5% of
patients with AL amyloidosis and 78% of patients with
light chain deposition disease.79 International guidelines Evaluation of urinary albumin level

now recommend that screening of serum alone (with

serum protein electrophoresis and a quantitative serum
FLC assay) for plasma cell dyscrasias is a viable alter- High-level FLC clone High-level FLC clone Low-level FLC clone Low-level FLC clone
+ + + +
native to urinary assessment.80,81 Despite the accumula- low urinary albumin high urinary albumin high urinary albumin low urinary albumin
tion of serum polyclonal FLCs in renal impairment, the
assay remains useful in patients with renal failure, but
absolute values are raised and the normal range for the If AKI: Possible LCDD Likely incidental MGUS
probable myeloma kidney or AL amyloidosis
FLC ratio is changed from that in the general popula- If CKD:
consider Fanconi syndrome,
tion81 to 0.37–3.17.82 By utilizing this renal range in a amyloidosis, LCDD
dialysis-dependent AKI population the number of false
positives was reduced.76 In addition to these diagnostic
■ Requires histology
advantages, the FLC immunoassays offer the ability to ■ Requires hematology assessment
monitor clonal disease response,80 which has particular work-up (salivary, adipose, kidney)
■ Renal biopsy in CKD ■ Hematology work-up
relevance in patients with myeloma kidney in whom an
early reduction in serum FLC concentrations is associated Figure 3 | Diagnostic approach to a patient with renal disease and a monoclonal
with renal recovery.4,6 protein. Combining the evaluation of urinary albumin concentration with the level of
the FLC clone can guide the management of a patient with renal injury and a
monoclonal protein. Tubulointerstitial pathologies are more likely when urinary
Renal biopsy and monoclonal FLC albumin levels are low and FLC levels are high. By contrast, patients with AL
Clinical indications amyloidosis and LCDD frequently have high urinary albumin levels. These
Renal disorders relating to plasma cell dyscrasias are pathologies are often associated with a lower level of FLC clone, but can occur with
the primary diagnosis in approximately 3% of native any FLC level. Where diagnostic uncertainty remains, assessment of histology is
renal biopsy samples. A renal biopsy in a patient with a essential. Abbreviations: AKI, acute kidney injury; AL, amyloid light chain; CKD,
monoclonal gammopathy and renal dysfunction helps chronic kidney disease; FLC, free light chain; IFE, immunofixation electrophoresis;
to define the type of renal injury present, determines the LCDD, light chain deposition disease; MGUS, monoclonal gammopathy of
undetermined significance; SPE, serum protein electrophoresis.
degree of activity of the pathological process, and defines
chroni­city status, which can influence how aggressive
therapy should be and predict possible outcome and interstitial lesions (Figure 4). FLC cast nephropathy is
eventual prognosis.21,24,37,83–88 the most frequent of these lesions and is fairly well recog-
Renal biopsies are indicated in various clinical set- nized by pathologists. However, the other two principal
tings in patients with a circulating monoclonal FLC lesions are not always correctly identified. These lesions
(Figure 3). Some of the indications are perhaps much include proximal tubulopathy (also referred to as acute
more apparent than others. For example, a patient with a tubular necrosis or acute tubulopathy)37,83,84,86–88 and an
diagnosed lymphoproliferative disorder and a circulating inflamma­tory tubular interstitial process without casts
monoclonal FLC who develops abrupt renal dysfunction that has morphological features identical to those seen in
would benefit from a renal biopsy to identify the type of classical acute tubulointerstitial nephritis (and is some-
injury present, which can be used to design an appropri- times referred to as such).91 Although the main patho-
ate therapeutic intervention. Similarly, a patient with a logical processes seen in the latter two entities may be
diagnosis of monoclonal gammopathy of undetermined recognized by pathologists in renal biopsy samples, the
significance who develops AKI should be a prime candi­ association of those lesions with an underlying plasma
date for a biopsy to determine whether the circulating cell dyscrasia is frequently missed. Even in the diag­nosis
monoclonal FLC is responsible for the renal injury. A of FLC cast nephropathy there is currently a need to
patient with a known lymphoproliferative disorder and define definitive criteria as to how many distal nephron
renal dysfunction may also be considered for renal trans- casts are needed to make a diagnosis, with the under-
plantation. A renal biopsy in this setting would enable standing that sampling can have an important role in
identification of the renal lesion present, and assessment this situation.83 Carefully controlled studies are therefore
of the probability of recurrence and eventual prognosis required to define parameters in renal biopsy samples
after transplantation.89,90 that correlate with recovery or irreversibility of renal
damage although some parameters, such as the degree of
Technical considerations interstitial damage, are intuitive. Another question that
The most common renal lesions seen in patients with remains is whether the obstructive process in FLC cast
circulating monoclonal FLC and AKI are tubular nephropathy is the main pathological process responsible

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REVIEWS

for renal failure or whether the accompanying inflam- in association with plasma cell dyscrasias merges concep-
matory reaction is the real culprit. Thus, the entity of tually speaking with FLC cast nephropathy. Other renal
inflammatory tubulointerstitial nephritis, which is seen lesions related to monoclonal light and heavy chains,
such as AL amyloidosis, heavy chain (AH) amyloidosis
or light/heavy chain deposition disease, tend to present
a b
less acutely, but can also exhibit (or mimic) AKI and
need to be considered in the differential diagnosis of AKI
in patients with monoclonal gammopathies.
The work-up of these renal biopsy samples must
include staining for κ and λ FLCs and careful examina-
tion of the Ig stains used in the routine evaluation of
renal biopsy samples. This approach will help to deter-
mine isotype restriction for light and/or heavy chains and
enable the morphological manifestations to be directly
c d related to the underlying plasma cell dyscrasia.24,83,84
Heavy chains have not been documented to be involved
in tubular interstitial pathology although, in rare cases,
a coexisting FLC can result in a cast nephropathy.92 The
evaluations must carefully assess not only immuno­
fluorescence, but also ultrastructural findings93 and cor-
relate these with the light microscopic features (Figure 5).
Many of the clues or diagnostic findings leading to a
correct diagnosis are found in the careful evaluation of
these ancillary diagnostic techniques. The pathologists
evaluating these renal biopsy samples must be aware of
the subtle and early renal manifestations of these condi-
tions so as to not misinterpret them. In a few selected
Figure 4 | Renal injuries induced by free light chains in patients with acute kidney cases, the use of other diagnostic techniques, such as
injury. All samples were stained with hematoxylin and eosin. The classic ultrastructural immunolabeling 94 or mass spectroscopy
appearance of cast nephropathy can be seen in a | and b | (magnification ×150 is needed, for instance in some cases of amyloidosis, with
and ×350, respectively). Casts with fracture planes in distal nephrons and the purpose of determining the precursor protein and
surrounding reactive tubular cells can be seen (center). Note adjacent proximal
typing the amyloid.95 Mass spectroscopy could also be
tubular damage and mild inflammation surrounding the casts. c | Marked tubular
damage is observed, with inflammatory infiltrate that contains a mixture of
used to detect a monotypical light or heavy chain depos-
mononuclear inflammatory cells and scattered eosinophils (magnification ×250). ited in the renal parenchyma. The utilization of these
d | Tubular interstitial injury without casts (magnification ×750). A mitotic figure sophisticated diagnostic techniques may require sending
can be seen in a tubular cell, indicative of tubular regeneration. the biopsy sample to a center where these techniques are
available. In the case of ultrastructural labeling there
c
are specific fixation protocols that are needed to achieve
a
satisfactory results.94,96
Immunofluorescence evaluation is key in defining the
presence of monoclonal light or heavy chain deposi­tion
in the renal biopsy sample to make a definitive diag­
nosis. However, available commercial antibodies do not
detect some of the abnormal monoclonal Igs that may
be deposited in the various renal compartments and that
are directly responsible for renal dysfunction. This lack
b of recognition is due to the fact that the monoclonal pro-
teins can be quite abnormal physicochemically or trun-
cated to such an extent that the epitopes recognized by
routine polyclonal antibodies are no longer present.
In selected cases, a re-biopsy should be seriously con-
sidered. The results from a biopsy sample can establish
what therapy has accomplished and whether additional
therapy is recommended. In this situation, a renal biopsy
Figure 5 | Immunofluorescence and electron microscopy evaluation of can provide evidence of improvement (or lack thereof) by
tubulointerstitial damage associated with circulating monoclonal free light chains.
comparing the findings in the initial biopsy sample with
a | and b | show examples of immunofluorescence for κ light chains. Linear staining
along the tubular basement membranes represents κ light chains (negative for repeat biopsies. This approach has been documented in
λ light chains). c | Electron microscopy findings of prominent tubular damage and the literature primarily in patients with plasma cell dys­
interstitial inflammatory infiltrate. Focal punctate electron-dense material around crasias and glomerular lesions.97–99 A renal biopsy may
tubular basement membranes represents deposits of free light chains. also provide evidence that further treatment may be of

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 REVIEWS

no, or rather limited, value as the renal parenchymal Strategies to improve early diagnosis are urgently
damage is deemed to be extensive and/or irreversible.74 needed to identify patients at a time when FLC concen-
trations are low in order to avoid AKI. In 2007, 38% of
Avoiding AKI in multiple myeloma patients with multiple myeloma in the UK were diagnosed
A number of factors, including dehydration, hyper­ as a result of an emergency admission or referral, com-
calcemia, nephrotoxic drugs and infection, are frequently pared with an average of 23% across all cancer types.107
associated with reversible tubular injury in patients with This delayed diagnosis of myeloma is probably the result of
multiple myeloma.100–102 However, as discussed above, the relative rarity of the disease and the nonspecific nature
these factors can also trigger tubulointerstitial lesions of its early symptoms. Switching off production of FLCs
associated with cast nephropathy in patients who are at by eradication of the plasma cell clone is the most effec-
risk. Patients’ risk can be stratified by both serum FLC tive way of stopping progressive renal damage. High-dose
level and urinary FLC excretion.103,104 Only 2% of patients dexamethasone alone is effective as a single agent in this
without urinary FLC excretion have renal impair- setting and can lead to a 100-fold fall in serum FLC levels
ment whereas this percentage increases to 50% when within 2 weeks, in sensitive disease. Oral high-dose dexa­
urinary FLC concentrations are high. 104 In the case of methasone can be started without delay while decisions
AL amyloid­osis, FLC concentrations do not need to be about definitive chemotherapy are being made.
high, but the location and mechanism of damage is typi- The past decade has seen a range of novel chemo-
cally very different from that of the AKI seen in patients therapies developed for myeloma that can be used
with multiple myeloma. As renal impairment worsens, without dose reduction in renal impairment. These
absolute serum concentrations of FLCs rise as a result agents include bortezomib and thalidomide combina-
of reduced renal clearance. Higher concentrations of tions, and should be commenced as soon as possible
FLC are therefore delivered to the remaining functional in this setting. Use of these new agents in combination
tubules, which increases the burden on proximal tubules with close monitoring should lead to improved patient
and the risk of precipitation in the distal tubules. If cor- outcomes. For this purpose, serum FLC measurements
rection of dehydration and hypercalcemia, removal of in the first 2 weeks might identify patients who are not
nephrotoxic agents and treatment of infection is timely, responding to their antimyeloma therapy and in whom
this vicious cycle can be broken. early change of treatment might be indicated in order to
Clinicians need access to the best diagnostic tools and rescue the kidney.103
must establish clear clinical pathways to enable rapid
and accurate diagnosis and an early initiation of disease- Conclusions
specific treatment.105 For presentations of new AKI in AKI remains an important cause of morbidity and
patients not known to have multiple myeloma, adapta- mortal­ity in patients with multiple myeloma. Severe
tions of the screening algorithm in Figure 2 will almost cases are frequently a direct consequence of the high
certainly reduce diagnostic delays. For those patients clonal production rates of Ig FLCs. The resulting high
who are known to have multiple myeloma, but have no serum concentrations of these proteins often lead to
significant renal impairment, close monitoring is key tubular interstitial injuries as endocytic receptors in
to avoiding AKI. Particular attention should be paid to the proximal tubules are overwhelmed. Direct proxi-
patients with FLC only myeloma in whom serial moni- mal tubule epi­thelial cell cytotoxicity, tubulointerstitial
toring of FLC levels is required. Further work is required nephritis and cast nephropathy can occur in isolation or
to determine how this monitoring should be undertaken, together. The past 20 years has seen great advances in
with serum immunoassays or 24 h urine collections. our detailed understanding of these disease processes.
Clinicians should also be aware of FLC escape, which Coordinated translational research programs are now
can occur in patients with an intact Ig multiple myeloma required to translate these advances into improved out-
(5% of patients with IgG multiple myeloma and 15% of comes for patients with multiple myeloma.
patients with IgA multiple myeloma). This condition
refers to the rise in levels of FLCs independent of intact Review criteria
Ig, which can be easily missed if urine or serum are PubMed and MEDLINE were searched using the terms
not examined for FLCs.106 In addition, serum FLCs “multiple myeloma”, “monoclonal protein”, “free light
are abnormal in 95% of patients with intact Ig multiple chain”, “acute kidney injury”, “renal/kidney impairment”
myeloma at presentation. Those patients with FLC con- and “cast nephropathy”. No language restrictions were
centrations of >1,000 mg/l (10–15% of IgG and IgA cases) placed on the search and all publications from 1970 to
2010 were considered.
are at increased risk of developing renal failure.104

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76. Hutchison, C. A. et al. Serum free light chain microscopy to the understanding and diagnosis National Institutes of Health grant R01 DK46199 and
measurement aids the diagnosis of myeloma in of plasma cell dyscrasia-related renal lesions. P30 DK079337 (George M. O’Brien Kidney and
patients with severe renal failure. BMC Nephrol. Med. Electron Microsc. 34, 1–18 (2001). Urological Research Centers Program) and the Office
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77. Katzmann, J. A. et al. Serum reference intervals Ultrastructural immunolabeling in the diagnosis Service, Department of Veterans Affairs.
and diagnostic ranges for free κ and free λ of monoclonal light-and heavy‑chain‑related renal
immunoglobulin light chains: relative sensitivity diseases. Ultrastruct. Pathol. 34, 161–173 Author contributions
for detection of monoclonal light chains. Clin. (2010). C. A. Hutchison, V. Batuman, J. Behrens, F. Bridoux,
Chem. 48, 1437–1444 (2002). 95. Picken, M. M. & Herrera, G. A. The burden of C. Sirac, A. Dispenzieri, G. A. Herrera and P. W. Sanders
78. Hutchison, C. A., Basnayake, K. & Cockwell, P. “sticky” amyloid: typing challenges. Arch. Pathol. researched data to include in the manuscript. All
Serum free light chain assessment in Lab. Med. 131, 850–851 (2007). authors contributed equally to discussion of content
monoclonal gammopathy and kidney disease. 96. Sethi, S. et al. Mass spectrometry-based for the article, writing the manuscript and reviewing
Nat. Rev. Nephrol. 5, 621–628 (2009). proteomic diagnosis of renal immunoglobulin and editing of the manuscript before submission.

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REVIEWS

CORRECTION
The pathogenesis and diagnosis of acute kidney injury in multiple
myeloma
Colin A. Hutchison, Vecihi Batuman, Judith Behrens, Frank Bridoux,
Christophe Sirac, Angela Dispenzieri, Guillermo A. Herrera, Helen
Lachmann & Paul W. Sanders on behalf of the International Kidney
and Monoclonal Gammopathy Research Group
Hutchison, C. A. et al. Nat. Rev. Nephrol. advance online publication 1 November 2011;
corrected online 18 November 2011; doi:10.1038/nrneph.2011.168
In the version of this article initially published online, reference 2 was incorrect. The
error has been corrected for the print, HTML and PDF versions of the article.

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