Personal View

Non-proteinuric pathways in loss of renal function in

patients with type 2 diabetes
Esteban Porrini, Piero Ruggenenti, Carl Erik Mogensen, Drazenka Pongrac Barlovic, Manuel Praga, Josep M Cruzado, Radovan Hojs,
Manuela Abbate, Aiko P J de Vries, for the ERA-EDTA diabesity working group.

Lancet Diabetes Endocrinol Largely on the basis of data from patients with type 1 diabetes, the natural history of diabetic renal disease has been
2015; 3: 382–91 classified as a sequence of three stages: normoalbuminuria, microalbuminuria, and macroalbuminuria. Progressive
Center for Biomedical Research decline of glomerular filtration rate (GFR) was thought to parallel the onset of macroalbuminuria (overt nephropathy),
of the Canary Islands
whereas glomerular hyperfiltration was deemed a hallmark of early disease. However, researchers have since shown
(CIBICAN), University of La
Laguna, Tenerife, Spain that albuminuria is a continuum and that GFR can start to decline before progression to overt nephropathy. In
(E Porrini MD); Mario Negri addition to proteinuria, other risk factors might contribute to GFR deterioration including female sex, obesity,
Institute for Pharmacological dyslipidaemia (in particular hypertriglyceridaemia), hypertension, and glomerular hyperfiltration, at least in a
Research, Bergamo, Italy
subgroup of patients. This phenomenon could explain why patients with type 2 diabetes can have renal insufficiency
(P Ruggenenti MD);
Department of Medicine, even before the onset of overt nephropathy, and might also suggest why the heterogeneous phenotype of type 2
Aarhus University Hospital, diabetic renal disease does not necessarily associate with typical histological lesions of diabetic renal disease, unlike
Aarhus, Denmark in type 1 diabetic renal disease. Patients with renal insufficiency but without albuminuria are usually excluded from
(C E Mogensen MD,
randomised clinical trials in overt nephropathy, thus optimum treatment for this group of patients is unknown. The
M Abbate MsC); Department of
Endocrinology, Diabetes and wide inter-patient variability of the disease probably needs individually tailored intervention.
Metabolism, Ljubljana
University Medical Center, Introduction Diabetic renal disease is a clinical syndrome characterised
Ljubljana, Slovenia
(D P Barlovic MD); Department
The increasing prevalence of type 2 diabetes worldwide by overt proteinuria (>200 μg/min or 300 mg/day) and
of Nephrology, Hospital 12 de has led to a concomitant rise in the prevalence of declining renal function.15 This presentation is often
Octubre, Madrid, Spain diabetes-related complications, including renal disease.1 preceded by increased urinary albumin excretion
(M Praga MD); Department of In Europe and Canada, 30% of patients with end-stage (microalbuminuria, 30–300 mg/day), usually described as
Nephrology, Hospital
Universitario de Bellvitge,
renal disease have diabetic renal disease,2 reaching 50% incipient diabetic renal disease. Thus, from a temporal
Barcelona, Spain in the USA.3 Asian populations have a substantial risk perspective, the overall classic clinical presentation of renal
(J M Cruzado MD); Department of developing diabetic renal disease.4 Left untreated, disease in type 2 diabetes has been depicted as a
of Nephrology, Clinic for diabetic renal disease leads to end-stage renal disease in progression of stages characterised by a gradual increase
Internal Medicine, University
Clinical Centre and Faculty of
many cases. Notably, this number of cases has not in albuminuria and proteinuria. The sequence starts with
Medicine, University of changed substantially in the past 20 years, during which normoalbuminuria, is followed by microalbuminuria, and
Maribor, Maribor, Slovenia time important advances have been made in renal ends in overt proteinuria. Throughout these stages,
(R Hojs MD); and Division of disease prevention, especially the widespread use of glomerular filtration rate (GFR) is deemed to be normal or
Nephrology, Department of
Medicine, Leiden University
renin-angiotensin-aldosterone system (RAS) blockade.5,6 supra-normal (hyperfiltration) in both albuminuric stages,
Medical Center and Leiden The lack of change in prevalence of diabetic renal whereas accelerated loss of renal function is expected in
University, Leiden, Netherlands disease might be attributable to improved treatment of the proteinuric stage. These stages were first defined by
(A P J de Vries MD) diabetes-related cardiovascular complications, which Mogensen and coauthors in 1983,16 in people with type 1
Correspondence to: allows a larger proportion of patients to survive long diabetes, and have been a widely accepted classification of
Dr Esteban Porrini, Center for
Biomedical Research of the
enough to progress to end-stage renal disease despite diabetic renal disease for the past 30 years.
Canary Islands (CIBICAN), more effective renoprotection. However, RAS inhibitors However, during the past decade this framework has
University of La Laguna, Tenerife, do not seem to prevent or delay progression of renal been challenged by several studies that show an
Spain disease in type 2 diabetes7,8 as effectively as they do in accelerated decrease in GFR and renal function in the
estebanporrini72@hotmail.
com.
type 1 diabetes9 or in non-diabetic proteinuric nephro- absence of proteinuria in patients with type 2 diabetes.
pathies.10–13 A plausible interpretation of these findings These findings suggest the existence of different
is that in type 1 diabetes and in non-diabetic proteinuric phenotypes in type 2 diabetic renal disease. In this
nephropathies, proteinuria has a central role in Personal View, we present evidence supporting the notion
progression of the disease and proteinuria reduction of a non-proteinuric phenotype and discuss possible risk
mediates a large part of the renoprotective effects of factors and pathways associated with type 2 diabetes.
RAS inhibitors,10–12 whereas pathways additional to
proteinuria can sustain renal function loss in type 2 Microalbuminuria and macroalbuminuria do not
diabetes, in particular before progression to overt always precede loss of renal function in type 2
nephropathy.14 A better understanding of underlying diabetes
mechanisms could help improve prevention and Cross-sectional studies have shown that the absence of
treatment of type 2 diabetic renal disease, which is proteinuria in people with type 2 diabetes and reduced
crucial to reduce the burden of type 2 diabetes renal function (GFR <60 mL/min per 1·73 m²) or even
complications worldwide. advanced renal disease (GFR <30 mL/min per 1·73 m²), is

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not infrequent (table). In 2003, Kramer and colleagues17 patients with GFR lower than 60 mL/min per 1·73 m²,
first analysed the prevalence of normoalbuminuria, measured using a gold standard procedure. Similar results
microalbuminuria, and overt proteinuria in people with were noted in other studies,19,20 in which 40% Chinese
type 2 diabetes and GFR lower than 60 mL/min per people and 73% of Japanese people with GFR lower than
1·73 m². Reduced renal function was seen in 171 (14%) of 60 mL/min per 1·73 m² showed normoalbuminuria or
1197 individuals with type 2 diabetes from the third microalbuminuria. More than 80% of patients with GFR
National Health and Nutrition Examination Survey less than 60 mL/min per 1·73 m² from the National
(NAHNES III). Of these, 81% had normoalbuminuria or Evaluation of the Frequency of Renal Impairment
microalbuminuria and only 19% had macroalbuminuria Coexisting with type 2 Diabetes (NEFRON) study21 in
(table). In 2004, MacIsaac and colleagues18 described Australia had normoalbuminuria (55%) or
prevalence rates of 39% for normoalbuminuria, 35% for microalbuminuria (32%). The Renal Insufficiency And
microalbuminuria, and 26% for macroalbuminuria in 109 Cardiovascular Event (RIACE) study22 showed a 19%

N Outcomes Comments
GFR < 60 mL/min per 1·73 m² Albuminuria/proteinuria
Cross-sectional studies
Kramer et al (2003)17 1197 171 (14%) 36% normoalbuminuria 28% retinopathy; 30% no retinopathy plus microalbuminuria or
(NAHNES 1988–1994) 45% microalbuminuria microalbuminuria; similar results excluding users of ACE inhibitors
19% macroalbuminuria or proteinuria
MacIsaac et al (2004)18 301 109 (36%)* 39% normoalbuminuria Chronic kidney disease, normoalbuminuria and microalbuminuria
35% microalbuminuria more common in women than men; 26% retinopathy in
26% macroalbuminuria or proteinuria normoalbuminuria and 50% in microalbuminuria; use of ACE inhibitors
>70%
So et al (2006)19 4421 528 (12%) 14% normoalbuminuria 56% retinopathy; use of ACE inhibitors 60%
26% microalbuminuria
60% macroalbuminuria or proteinuria
Yokoyama et al (2009)20 3297 506 (15%) 52% normoalbuminuria Risk factors: female sex, obesity, triglyceride concentrations, smoking,
21% microalbuminuria cardiovascular disease, hypertension, retinopathy.
27% macroalbuminuria or proteinuria
Thomas et al (2009)21 3892 920 (23%) 55% normoalbuminuria Female sex a risk factor; 14% retinopathy; use of ACE inhibtors >80%
(NEPHRON 11) 32% microalbuminuria
13% macroalbuminuria or proteinuria
Penno et al (2011)22 15 773 2959 (19%) 57% normoalbuminuria Risk factors: female sex, obesity, triglyceride concentrations,
(RIACE study) 31% microalbuminuria hypertension
13% macroalbuminuria or proteinuria 32% retinopathy; 43% no retinopathy plus microalbuminuria or
proteinuria; use of ACE inhibitors >70%
Dwyer et al (2012)23 11 573 2586 (22%) 40% normoalbuminuria Risk factors: female sex, hypertension, retinopathy, dyslipidaemia,
(DEMAND study) 47% microalbuminuria smoking, hyperglycaemia
13% macroalbuminuria or proteinuria
Mottl et al (2013)24 2798 575 (21%) 52% normoalbuminuria Chronic kidney disease, normoalbuminuria and microalbuminuria
(NAHNES 2001-2008) 48% microproteinuria more frequent in women than in men; hypertension and
hyperglycaemia were protective factors
Boronat et al (2014)25 ·· 78 (GFR <30 ml/min) 22% normoalbuminuria Female sex a risk factor; hyperglycaemia and polyneuropathy were
20% microalbuminuria protective factors; 29% retinopathy in normoalbuminuria, 53% in
58% proteinuria microalbuminuria or proteinuria

Cohort studies
Retnakaran et al (2006)26 4006 575 (14%) 977 (24%) microalbuminuria, 557 (14%) developed chronic kidney disease and microalbuminuria or
(UKPDS-74) macroalbuminuria and proteinuria combined macroalbuminuria; follow-up: 15 years; risk factors: female sex,
smoking, systolic BP; reduced GFR preceded microalbuminuria in 16%
of cases
Bash et al (2009)27 1871* 361 (19%) No information Follow-up: 11 years; 53% with retinopathy; 47% without retinopathy;
(ARIC study) 29% retinopathy plus microalbuminuria or macroalbuminuria

Afghahi et al (2011)28 3667 290 (8%) 612 (17%) microalbuminuria, macro 117 (3%) developed chronic kidney disease and microalbuminuria or
(NDR study) albuminuria and proteinuria combined macroalbuminuria; follow-up: 5 years; risk factors: female sex,
triglyceride concentrations, systolic BP

GFR=glomerular filtration rate. ACE=angiotensin-converting enzyme inhibitor. CVD=cardiovascular disease. BP=blood pressure. *Only the number of cases with GFR lower than 60 mL/min per 1.73 m² or with
increased albuminuria are shown.

Table: Cross-sectional and cohort studies of the non-proteinuric phenotype of renal disease in type 2 diabetes

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prevalence of cases with chronic kidney disease (2959 of incidence of micralbuminuria or macroalbuminuria in
15 773).22 Of those with chronic kidney disease, 57% had the absence of chronic kidney disease was given. 47% of
normoalbuminuria, 31% microalbuminuria, and 13% patients with chronic kidney disease did not have
macroalbuminuria.22 In a similar study, Dwyer and retinopathy, and retinopathy, microalbuminuria, and
colleagues23 reported that 2586 (22%) of 11 573 patients macroalbuminuria were only observed in 30%. The
with type 2 diabetes had renal dysfunction, 2250 (87%) of Swedish National Diabetes Register study assessed 3667
whom had normoalbuminuria or microalbuminuria. An patients during 5 years of follow-up and reported that
extended analysis of the NAHNES cohort, 10 years after 407 (11%) of patients developed chronic kidney disease.
first publication, confirmed that 52% of patients with Of these, 29 (71%) developed only chronic kidney
reduced renal function had normoalbuminuria.24 Finally, disease, and 117 (29%) had chronic kidney disease and
in 78 consecutively enrolled Spanish patients with microalbuminuria or macroalbuminuria. 612 (17%) of
advanced renal disease (GFR <30 mL/min per 1·73 m²), patients in the whole cohort only developed
17 (22%) had normoalbuminuria, 16 (21%) had microalbuminuria or macroalbuminuria.28
microalbuminuria, and 45 (58%) overt proteinuria.25 Studies with repeated measurements to analyse GFR
Longitudinal cohort studies have provided important reduction provide a more detailed view of a non-
information about the incidence, evolution, and risk proteinuric pathway. The importance of these studies
factors of a non-proteinuric phenotype of renal disease. lies in an accurate quantification of GFR decline. In a
The UK Prospective Diabetes Study (UKPDS-74)26 cohort study by Ruggenenti and colleagues,29 600
investigated the incidence of reduced renal patients with type 2 diabetes and normoalbuminuria or
function, microalbuminuria, and macroalbuminuria microalbuminuria were reviewed with repeated measurements
in 4006 people with type 2 diabetes with of GFR every 6 months during a mean follow-up of
normoalbuminuria and GFR of more than 60 mL/min 4 years, using a gold standard method (plasma clearance of
per 1·73 m² at baseline. During 15 years of follow-up, iohexol). The most relevant finding was that the median GFR
14% developed renal function impairment only, 24% decrease in the whole group of male patients was
microalbuminuria or macroalbuminuria only, and 14% 3·37 mL/min per 1·73 m² (IQR 5·57–1·31), a rate of
developed both simultaneously. In 16% of the patients renal function loss that was 2–5 times faster than noted
who developed both disorders, albuminuria increased in the healthy general population (figure 1).30 GFR
after GFR declined to lower than 60 mL/min per decline was similar in patients with normoalbuminuria
1·73 m².26 Similar results were seen in the Atherosclerosis (3·50 mL/min per 1·73 m²) or microalbuminuria
Risk in Communities (ARIC) study27 during a follow-up (2·66 mL/min per 1·73 m²), (p=0·14). In a similar study,
of 11 years. In 19% of patients with type 2 diabetes, GFR Rossing and colleagues31 studied GFR decline assessed
declined to lower than 60 mL/min per 1·73 m². Of these, by Cr-EDTA in 156 patients with microalbuminuria and
58% had normoalbuminuria and 42% had micro- 227 with macroalbuminuria, followed up for up to
albuminuria or macroalbuminuria. No data on the 17 years. The investigation showed a fast GFR decrease
in patients with microalbuminuria (mean 4·1 mL/min
0 per 1·73 m², SD 4·1).31 Thus, accelerated loss of renal
–1
Age-related GFR decline function can be seen in the stages of normoalbuminuria
or microalbuminuria (figure 1). This acceleration of
–2
Diabetes-related
renal function loss does not diminish the relevance of
GFR decline (mL/min per year)

–3
GFR decline macroalbuminuria and overt proteinuria as progression
–4 factors for GFR decline in diabetes. Notably, the onset
–5 of overt proteinuria accelerates GFR decline even
–6 more. In the STENO clinic study,31 individuals with
–7 overt proteinuria (geometric mean 726 mg/day, 95% CI
122–4319) had an annual mean decline of 5·2 mL/min
–8
per year (SD 4·1). GFR decline was even faster (annual
–9 Proteinuria-related mean 10·08 mL/min per 1·73 m², SD 2·52) in patients
–10 GFR decline
with type 2 diabetes with nephrotic-range proteinuria
–11 included in the Ramipril Efficacy in Nephropathy
n

ria

ia

ia

ia

(REIN) study.32 Therefore, in type 2 diabetes,

io

ur

ur

ur
u
at

in

in

in

ein
l

um
pu

progressive renal function loss can be noted at any

ot
lbu

lbu
po

pr
alb
oa

oa
hy

ic
ro

stage of renal involvement and is greatly accelerated

ot
rm

icr
alt

ac

r
M

ph
No

M
He

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with the onset of macroalbuminuria or overt

proteinuria (figure 1).
Figure 1: Glomerular filtration rate (GFR) in healthy patients compared with patients with type 2 diabetes
and normoalbuminuria, microalbuminuria, macroalbuminuria, or severe proteinuria
Importantly, GFR decrease in early stage renal disease
Data from studies that did repeated measurements of GFR using gold standard procedures in patients with might not be detected properly with equations that
normoalbuminuria or microalbuminuria,29 macroalbuminuria,31 and severe proteinuria.32 merely estimate GFR because creatinine-based formulas

384 www.thelancet.com/diabetes-endocrinology Vol 3 May 2015

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underestimate GFR decrease, in particular in people disease. A subanalysis of the PREVEND cohort, which
with normal or increased GFR (hyperfiltration).33 This included people without diabetes, showed that
restriction is something to consider in the design of albuminuria was a risk factor for faster GFR decrease in
studies aimed at evaluating the evolution of renal men but not in women.39 This finding concurs with a
function or testing of novel renoprotective measures in high prevalence of non-proteinuric renal disease in
this population. women with type 2 diabetes. The large and well
phenotyped studies previously discussed show that in
Pathogenesis and risk factors type 2 diabetic nephropathy, women are less protected in
Diabetic renal disease is a heterogeneous disease. Several the evolution of non-proteinuric renal insufficiency than
factors have been associated with the pathogenesis of the are men.26,28,38,39 The causes of this reversed sexual
disease, including hypertension, hyperglycaemia, insulin dimorphism are not clear but are seemingly specific to
resistance, proteinuria, advanced glycation end products, type 2 diabetes.
and oxidative stress.34,35 Additional factors have been Several studies, mainly animal models and in-vitro
suggested to play a part in the progression of renal studies, have investigated the effect of sex steroids on renal
involvement before the onset of proteinuria (table). disease. The kidney has many oestrogen-regulated genes,40
A consistent finding across all the studies shown in and treatment with 17β-oestradiol has been shown to
the table is that women with type 2 diabetes are at greater attenuate diabetic renal disease; that is, reduced
risk than are men for accelerated GFR decrease in the glomerulosclerosis and tubulointerstitial fibrosis in
absence of proteinuria. This finding contrasts with data streptozotocin-induced diabetes (a model of type 1
from people without diabetes, in which men typically diabetes).41 17β-oestradiol increases nitric oxide con-
have a faster decline in renal function. In healthy, living centrations in the glomerulus,42 and oestrogen-stimulated
kidney donors aged 20–50 years, measured GFR nitric oxide production has been proposed to protect
decreased by about 8·1 mL/min per decade in men and women from accelerated age-related decline in renal
only 1·4 mL/min per decade in women.36 Women had function.43 Furthermore, 17β-oestradiol regulates signalling
preserved effective renal plasma flow, whereas men had of transforming growth factor β, a regulator of extracellular
lower renal plasma flow and increased filtration matrix with known implications in diabetic renal disease.44
fraction.36 A meta-analysis37 including patients with non- However, these studies used models of type 1 diabetes, and
diabetic chronic nephropathies showed that men had animal models of metabolic syndrome and type 2 diabetes
faster GFR decline than women. The protective effect of have yielded opposite results. In obese Zucker rats (a
female sex for chronic kidney disease seems reversed in genetic model of obesity, insulin resistance syndrome, and
type 2 diabetes, particularly in this non-proteinuric early diabetic renal disease) renal failure occurs earlier in
phenotype of renal disease. This effect is best shown by female animals than in male animals.45 Oestrogen has
the UKPDS-7426 and Swedish National Diabetes Register been associated with accelerated renal damage and proved
cohorts.28 Studies included patients with to potentiate triglyceride-induced renal injury (focal and
normoalbuminuria with estimated GFR of more than segmental glomerulosclerosis and mesangial matrix
60 mL/min per 1·73 m² at baseline, separately analysing expansion) in insulin-resistant female animals.46,47
those who developed either GFR of less than 60 mL/min To the best of our knowledge, no study has assessed the
per 1·73 m² or microalbuminuria or macroalbuminuria effect of menopause on renal disease in women with
during up to 15 years of follow-up. The major finding diabetes. Two cross-sectional studies reported that
was that women were at increased risk for the perimenopausal or postmenopausal women with
development of GFR lower than 60 mL/min per 1·73 m² metabolic syndrome are at increased risk for chronic
and men for increasing albuminuria.26,28 The association kidney disease.48,49 Thus, oestrogens and hormonal
between female sex and reduced GFR was quite robust, changes after menopause might interact with insulin
with an odds ratio of 4·03 (95% CI 2·97–5·48) compared resistance traits (eg, dyslipidaemia) in the induction of
with men.28 Female sex emerged as an independent risk renal damage in women. Finally, the few studies that
factor for renal disease progression in the Reduction of have assessed the effect of oestrogen supplementation
Endpoints in NIDDM with the Angiotensin II Antagonist on GFR decrease or the changes in albuminuria in
Losartan (RENAAL) study.38 In this substudy, renal women with diabetes have produced contradictory
disease was defined as a doubling of serum creatinine or results.50–55 These inconsistent findings could be
end-stage renal disease and was independent of changes accounted for by several methodological factors,
in albuminuria.38 Thus, it seems that the two major including short-term follow-up, insufficient power of
markers of renal involvement in diabetes (ie, impaired statistical analyses, or the use of serum creatinine-based
renal function and albuminuria), might be differently equations for the estimation of GFR and GFR decrease.
distributed in men and women.
A different way to explore sex-specific pathways of Metabolic syndrome and diabetic renal disease
renal damage is to investigate a possible effect Several components of metabolic syndrome have been
modification between sex, albuminuria, and renal associated with non-proteinuric GFR decline. Obesity,

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from the overweight category (BMI 25–29·9 kg/m²) to Retinal involvement and the non-proteinuric
severe obesity (>35 kg/m²), has been associated with renal phenotype
reduced renal function in the absence of micro- Diabetic retinopathy, a clinical manifestation of micro-
albuminuria or macroalbuminuria.28 Increased systolic angiopathy, is deemed useful in the diagnosis of diabetic
pressure, pulse pressure, and HbA1c concentrations renal disease. In type 2 diabetes, the prevalence of
predicted the incidence of chronic kidney disease in retinopathy is much lower than it is in type 1 diabetes.65 In
patients with normoalbuminuria.26–28 Furthermore, high the non-proteinuric phenotype of renal disease, the
triglyceride concentrations, a well-known marker of prevalence of diabetic retinopathy is especially low (table).
insulin resistance, predicted the prevalence of reduced In a cross-sectional analysis of more than 15 000 patients
renal function.28 This evidence suggests that metabolic from the RIACE study, only 175 (10%) of 1673 with GFR
syndrome traits (ie, insulin resistance) could play a part lower than 60 mL/min per 1·73 m² and normoalbuminuria
in this non-proteinuric phenotype. Insulin resistance had advanced retinopathy.66 By contrast, 288 (22%) of
and other metabolic syndrome traits are risk factors for 1286 patients with reduced GFR and microalbuminuria
renal disease in people with and without diabetes.29,56,57 or macroalbuminuria had advanced retinopathy
Some cross-sectional studies24,25 have reported that the compared with patients with reduced renal disease and
non-proteinuric phenotype is associated with improved normoalbuminuria (p<0·001). The reduced prevalence of
blood pressure and glucose control. These controversial retinopathy in patients with chronic kidney disease and
results could be attributable to the nature of the analysis, normoalbuminuria might exclude microangiopathy as a
because a cross-sectional design is not the best approach cause of the non-proteinuric GFR decrease noted in
to identify risk factors. some patients with type 2 diabetes. This absence of
Metabolic syndrome traits are differently expressed in association between microangiopathy and non-
men and women, which could partly explain some proteinuric renal disease might suggest a role of
differences in diabetic renal disease between the sexes.58,59 macroangiopathy in the pathogenesis of this phenotype.
For example, women with diabetes have higher post-load However, MacIsaac and colleagues67 recorded similar
glucose concentrations in oral glucose tolerance testing, resistance indices of renal interlobar arteries by use of
which suggests greater peripheral insulin resistance than duplex Doppler ultrasonography in individuals with
men.59 Women and men show different patterns of fat normoalbuminuria, microalbuminuria, or macro-
accumulation; generally, men show central (android) albuminuria and GFR lower than 60 mL/min per 1·73 m²,
adiposity, whereas women show peripheral (gluteal) which might exclude the role of mechanisms causing
adiposity. Central adiposity is linked to increased intrarenal atherosclerosis in the pathogenesis of this
concentrations of free fatty acids, tumour necrosis factor, phenotype.
interleukin 6, and C-reactive protein, which are among
several pro-inflammatory cytokines that promote insulin Glomerular hyperfiltration
resistance and cardiovascular disease, particularly in Glomerular hyperfiltration is a haemodynamic response
women.60,61 After menopause, fat deposition in women can to several factors including obesity, hyperglycaemia,
change into a more central phenotype, which portends an hypertension, insulin resistance, and reduced renal
increase in insulin resistance and cardiovascular risk mass.68–72 In the past 40 years, glomerular hyperfiltration
factors. Moreover, obesity in women is associated with has been regarded an early risk factor for renal disease in
worse cardiovascular outlook than it is in men.58,59 diabetes.73,74 The classic scenario of the evolution of renal
Diabetes-associated dyslipidaemia (ie, hypertrigly- function in diabetes includes an increase in GFR, which
ceridaemia) and low HDL-cholesterol are more severe in is followed by a rapid decrease in renal function, and
women than men with diabetes.62 A worsening progression towards overt proteinuria and chronic
cardiovascular risk profile is thought to explain the higher kidney disease (figure 2). However, one study suggested
cardiovascular risk seen in women with diabetes that the persistence of initial glomerular hyperfiltration
compared to men with the disorder.63 can likewise induce a fast GFR decrease even in early
Whether this sex-specific cardiovascular risk profile stages of renal disease (ie, in patients with normo-
has a role in rapid GFR decline and non-proteinuric albuminuria or microalbuminuria).29 90 (15%) of
renal disease in women with type 2 diabetes is worth 600 patients with type 2 diabetes with normoalbuminuria
investigating. Reduced renal function is an independent or microalbuminuria monitored by serial GFR measure-
risk factor for cardiovascular disease in all patients with ments every 6 months showed hyperfiltration. Those
type 2 diabetes, irrespective of albuminuria con- with persistent hyperfiltration despite optimised
centrations.64 So, non-proteinuric chronic kidney metabolic and blood pressure control showed rapid
disease could be implicated in the high rates of GFR reduction compared with those with ameliorated
cardiovascular morbidity and mortality seen in type 2 hyperfiltration (median 4·19, IQR 1·6–11·3 vs 1·72
diabetes, particularly in women. The fact that it is (−0·5 to 7) p=0·01) during a median follow-up of
seldom detected could increase the harm caused by 4·0 (IQR 1·7–8·1) years.29 Persistence of hyperfiltration
renal disease in diabetes. was associated with more severe insulin resistance.

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Another finding of this study was that early reduction of

Classic phenotype
GFR predicted a slower decrease in renal function over Non-proteinuric phenotype
200
time in all patients (with or without hyperfiltration).
Patients below the cutoff for hyperfiltration (in this case

GFR (mL/min)
120 mL/min per 1·73 m²) also had less rapid decline after
100
reduction of GFR.29 This finding suggests that the cutoff
definition of hyperfiltration could be arbitrary, because it 60
is not related to the usual reduction of renal function 30
associated with age;75 patients with low GFR might have 10

relative hyperfiltration. Thus, the sequential pattern of Normoalbuminuria Microalbuminuria Proteinuria

increased GFR followed by an accelerated decrease can Time
be noted in patients with normoalbuminuria or in those
with microalbuminuria (figure 2). More studies with Figure 2: Evolution of renal function in the classic versus non-proteinuric
direct GFR measurements are needed to assess the effect phenotype of diabetic renal disease
Increase and subsequent decrease of glomerular filtration rate in patients with
of hyperfiltration in patients with type 2 diabetes, type 2 diabetes and normoalbuminuria, microalbuminuria, or proteinuria.
normoalbuminuria, or microalbuminuria in terms of
accelerated GFR decline and prevalence of chronic
kidney diease. of ACE inhibitors and ARBs on reduction of albuminuria
could have helped unmask GFR decline in the absence of
RAS inhibitors proteinuria changing, at least in part, the natural history
Angiotensin-converting enzyme (ACE) inhibitors or of renal disease in type 2 diabetes. However, further
angiotensin-receptor blockers (ARBs) provide substantial studies are needed to investigate this important point in
clinical benefit in diabetic renal disease. Major studies diabetic renal disease.
have shown that ACE inhibitors or ARBs reduce the
incidence of renal events (two-fold increase of serum Is albuminuria a marker of underlying pathology?
creatinine, end-stage renal disease, or death)7 and the Evidence showing that about 50% of new cases of chronic
incidence of macroalbuminuria (>200 μg/min).76 The kidney disease in type 2 diabetes had normoalbuminuria
Bergamo Nephrologic Diabetes Complications Trial or microalbuminuria suggests that changes different
(BENEDICT-A),77 including 1204 individuals with from typical diabetic glomerulopathy might explain
normoalbuminuria at baseline, proved that ACE reduced kidney function in this context (table). Moreover,
inhibitors can prevent progression to microalbuminuria. in 16% of incident cases in the Swedish National Diabetes
However, little evidence exists to suggest that ACE Register study, albuminuria only increased after chronic
inhibitors or ARBs slow GFR decline in people with type 2 kidney disease had developed.26 Measured GFR decline
diabetes and normoalbuminuria or microalbuminuria. proved to be similar between patients with normo-
The combined data of the BENEDICT-B29 and the Delapril albuminuria and microalbuminuria,29 showing that no
and Manidipine for Nephroprotection in Diabetic clear difference in degree of renal disease can be deduced
nephropathy (DEMAND)29 clinical trials, in patients with according to classification of albuminuria. This absence
normoalbuminuria or microalbuminuria, showed that of association between GFR decline and albuminuria is
patients with or without treatment with ACE inhibitors consistent with the high degree of histological
(trandolapril or delapril) had similar decreases in heterogeneity in renal disease in type 2 diabetes, as
measured GFR (median 3·31 ml/min per 1·73 m² per described later in this Personal View.
year, IQR 5·33–1·31 for treated patients vs 3·53, Albuminuria has been associated with insulin
IQR 5·77–1·44 for untreated patients p=0·663).29 Similar resistance, unhealthy obesity (obesity associated with
data were recorded in a clinical trial involving metabolic syndrome), dyslipidaemia, endothelial
285 individuals with type 1 diabetes, normoalbuminuria, dysfunction, subclinical inflammation,79 and metabolic
and normotension, randomised to enalapril, losartan, or syndrome.80 Moreover, in a large cohort of 1204 patients
placebo and followed up with measured GFR and with type 2 diabetes and normoalbuminuria who were
repeated renal biopsies.78 The decrease of GFR over time, followed up for about 10 years, albuminuria was a
the change in mesangial fractional volume per continuous risk factor for cardiovascular events starting
glomerulus, and other structural changes apparent on from 1 μg/mL (ie, from any measurable amount).81 Thus,
renal biopsy were similar across all groups. Thus, ACE albuminuria in the normoalbuminuric or micro-
inhibitors and ARBs do not seem to appreciably affect albuminuric range seems to be a reliable marker for
GFR decline in the non-proteinuric stages of renal cardiovascular disease, but does not seem to predict the
disease. Most of the patients included in the studies risk of renal function decrease to a similar extent. In
summarised in the table, as well as in those studies that addition to albuminuria, other markers of renal
analysed GFR decline,29,31 received an ACE inhibitor or an involvement might help monitor disease progression and
ARB, as this is currently best clinical practice. The effect response to therapy in type 2 diabetes.82

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 Personal View

Diabetic renal disease beyond diabetic The dissociation between albuminuria and severity of
glomerulopathy renal changes in type 2 diabetes could be attributable to
Renal structural changes in type 2 diabetes include early the presence of atubular glomeruli and predominant
thickening of glomerular basement membrane and microvascular atherosclerotic disease and tubular
mesangial expansion, which reduces the filtration damage.87 Albuminuria could be limited by efficient
surface of the glomerulus and can lead to nodular or albumin reabsorption by well-preserved tubuli,88 as
diffuse glomerulosclerosis.83,84 More advanced lesions described in obesity-related glomerulopathy.89 However,
include late tubulointerstitial fibrosis, atrophy, and tubulointerstitial and vascular damage are typical
arterial hyalinosis.84 Glomerulosclerosis is typically features of the non-proteinuric phenotype of type 2
associated with overt proteinuria and reduced GFR. diabetic renal disease.88 Several factors might be
However, this presentation is mostly reported in studies implicated in tubular and vascular damage in type 2
of type 1 diabetes.83 Renal involvement in type 2 diabetes diabetes, such as hypertension, ageing, RAS activation,
is more heterogeneous, and the association between inflammation, hyperglycaemia, and lipotoxicity. These
histology and clinical variables is not as clear as it is in risk factors can cluster in the metabolic syndrome, which
type 1 diabetes.83,84 Moreover, about 30% of patients with in turn has been associated with the non-proteinuric
microalbuminuria can show either mild histological phenotype. Most studies are retrospective and might
changes, classic diabetic glomerulopathy, or atypical suffer from selection bias. Thus, prospective
patterns of renal injury (eg, mild glomerulopathy morphofunctional studies are needed to better clarify the
together with advanced tubulointerstitial fibrosis and actual role of the non-proteinuric phenotype in the onset
atrophy or arteriolar hyalinosis).85 In these studies, the and progression of type 2 diabetic renal disease.
GFR ranged from about 50 mL/min per 1·73 m² to
150 mL/min per 1·73 m². To our knowledge, only one Clinical implications
study86 has analysed the histology of renal disease in Randomised clinical trials testing the effect of
patients with GFR lower than 60 mL/min per 1·73 m² renoprotective interventions in overt nephropathy
without overt proteinuria. Budhiraja and colleagues86 associated with type 2 diabetes almost invariably exclude
analysed unaffected renal tissue from nephrectomies patients without albuminuria,7,8 who probably represent at
because of kidney cancer in ten patients with type 2 least 50% of the whole diabetic population with some
diabetes but without overt proteinuria. The investigators degree of renal impairment and are at risk of progression
reported that capillary wall thickening was present in all to end-stage renal disease (table). Therefore, optimum
patients, eight patients had Kimmelstiel-Wilson nodules, treatment of these patients is unknown. The risk–benefit
and two had severe diffuse mesangial expansion only profile of RAS inhibitor therapy in this context is also
with no nodules. Arterial hyalinosis was noted in afferent uncertain, at least in terms of renoprotection. Conceivably,
and efferent arterioles along with mild tubule-interstitial in view of the wide heterogeneity of this clinical disorder, a
atrophy.86 This investigation is relevant because it shows standard therapy is unlikely to be applicable to all patients
that advanced renal histological damage can occur with the non-proteinuric phenotype of diabetic renal
without proteinuria. These findings, however, should be disease. The best approach in this population is probably
interpreted with caution because of the very few cases in an individually tailored, response-driven intervention
the analyses and the possibility that proteinuria was titrated to metabolic and blood pressure control, with or
masked by concomitant RAS inhibitor therapy. without RAS inhibitors, and close monitoring of possible
side-effects including hypertension, hyperkalaemia, and
acute worsening of kidney function.
Panel: Key features of non-proteinuric renal disease in
type 2 diabetes Conclusion
• Decreased renal function without concomitant Taken together, the evidence described here supports the
proteinuria is reported in about 50% of people with type 2 existence of a non-proteinuric phenotype of diabetic
diabetes and renal disease renal disease predominantly seen in patients with type 2
• Declining glomerular filtration rate (GFR) can be recorded diabetes (panel). Our aim is not to add confusion to the
before (or without) progression to macroalbuminuria complex problem of diabetes and renal disease. On the
• High prevalence in women with metabolic syndrome contrary, this Personal View intends to warn against the
• Accelerated GFR decline and the sequential increment in application of a rigid model of thinking, and to include
albuminuria (normoalbuminuria, microalbuminuria, and evidence to provide a more comprehensive view of
macroalbuminuria) can be viewed as two different diabetic renal disease. Discussion and challenge of
pathways that might or might not converge in the same established notions is crucial in science, and helps to
patient improve our understanding of disease. The evidence
• Uncertain benefit from angiotensin-converting enzyme described in this Personal View calls for a more flexible
inhibitors or angiotensin-receptor blocker therapy approach to the classification of renal disease in people
with diabetes. Finally, awareness about the existence of a

388 www.thelancet.com/diabetes-endocrinology Vol 3 May 2015

 Personal View

6 Gregg E, Yanfeng L, Wang J, et al. Changes in diabetes-related

Search strategy and selection criteria complications in the Unites States, 1990-2010. N Engl J Med 2014;
17: 1514–23.
We searched PubMed for articles published in English with 7 Brenner BM, Cooper ME, de Zeeuw D, et al, and the RENAAL
the terms “diabetic nephropathy”, “non-albuminuric”, Study Investigators. Effects of losartan on renal and cardiovascular
outcomes in patients with type 2 diabetes and nephropathy.
“non-proteinuric”, “glomerular filtration rate decline”, N Engl J Med 2001; 345: 861–69.
“normoalbuminuric renal impairment”, “microalbuminuric 8 Lewis EJ, Hunsicker LG, Clarke WR, et al, and the Collaborative
renal impairment”, “glomerular hyperfiltration”, Study Group. Renoprotective effect of the angiotensin-receptor
antagonist irbesartan in patients with nephropathy due to type 2
“non-proteinuric phenotype”. No date restrictions were diabetes. N Engl J Med 2001; 345: 851–60.
placed on searches. 9 Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, and the The
Collaborative Study Group. The effect of angiotensin-converting-
enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;
329: 1456–62.
non-proteinuric phenotype is low in the medical
10 The GISEN Group (Gruppo Italiano di Studi Epidemiologici in
community, which contributes to renal function decline Nefrologia). Randomised placebo-controlled trial of effect of
in many patients with type 2 diabetes going undetected. ramipril on decline in glomerular filtration rate and risk of terminal
renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997;
Type 2 diabetes is reported in most cases of renal 349: 1857–63.
disease attributable to diabetes, and a large part of 11 Ruggenenti P, Perna A, Gherardi G, Gaspari F, Benini R,
relevant literature in the specialty pertains to type 2 Remuzzi G, on behalf of Gruppo Italiano di Studi Epidemiologici in
Nefrologia (GISEN). Renal function and requirement for dialysis in
diabetes. Therefore, we focused on type 2 diabetes rather chronic nephropathy patients on long-term ramipril: REIN follow-
than on the much the less prevalent type 1 diabetes. up trial. Lancet 1998; 352: 1252–56.
However, the non-proteinuric phenotype might also 12 Ruggenenti P, Perna A, Benini R, et al. In chronic nephropathies
occasionally be seen in people with type 1 diabetes.90,91 prolonged ACE inhibition can induce remission: dynamics of
time-dependent changes in GFR. Investigators of the GISEN
Individuals with type 2 diabetes, particularly women, Group. Gruppo Italiano Studi Epidemiologici in Nefrologia.
can develop chronic kidney disease or even advanced J Am Soc Nephrol 1999; 10: 997–1006.
renal disease while showing low amounts of albumin 13 Schieppati A, Remuzzi G. The June 2003 Barry M. Brenner
Comgan lecture. The future of renoprotection: frustration and
excretion. The causes of this phenotype in diabetic renal promises. Kidney Int 2003; 64: 1947–55.
disease are not clear. Research is needed to identify new 14 Ruggenenti P, Lauria G, Iliev IP, et al, and the DEMAND Study
markers of renal disease in type 2 diabetes other than Investigators. Effects of manidipine and delapril in hypertensive
patients with type 2 diabetes mellitus: the delapril and manidipine
albuminuria, and to suggest possible therapeutic for nephroprotection in diabetes (DEMAND) randomized clinical
measures to reduce the burden of renal disease in trial. Hypertension 2011; 58: 776–83.
diabetes. 15 Remuzzi G, Schieppati A, Ruggenenti P. Clinical practice.
Nephropathy in patients with type 2 diabetes. N Engl J Med 2002;
Contributors 346: 1145–51.
EP conceived and designed the review. EP, PR, and APJdV contributed 16 Mogensen CE, Christensen CK, Vittinghus E. The stages in diabetic
to the writing. PR, CEM, MP, JMC, DPB, RH, MA, and APJdV renal disease. With emphasis on the stage of incipient diabetic
contributed to review and revision of intellectual content. CM nephropathy. Diabetes 1983; 32 (suppl 2): 64–78.
contributed to review and revision of the manuscript. EP, PR, CEM, MP, 17 Kramer HJ, Nguyen QD, Curhan G, Hsu CY. Renal insufficiency in
DPB, RH, MA, and APJdV performed literature search. EP, PR, and the absence of albuminuria and retinopathy among adults with
APJdV contributed to figures 1 and 2. type 2 diabetes mellitus. JAMA 2003; 289: 3273–77.
18 MacIsaac RJ, Tsalamandris C, Panagiotopoulos S, Smith TJ,
Declaration of interests
McNeil KJ, Jerums G. Nonalbuminuric renal insufficiency in type 2
We declare no competing interests. diabetes. Diabetes Care 2004; 27: 195–200.
Acknowledgments 19 So WY, Kong AP, Ma RC, et al. Glomerular filtration rate,
We thank the IMBRAIN project (FP7-RE6-POT-2012-CT2012–31637- cardiorenal end points, and all-cause mortality in type 2 diabetic
IMBRAIN) funded under the 7th Frameworks Programme (capacities), patients. Diabetes Care 2006; 29: 2046–52.
the Spanish Research Network for Kidney Diseases (REDINREN- 20 Yokoyama H, Sone H, Oishi M, Kawai K, Fukumoto Y,
RD/0021/0008), Fondos FEDER, and Federico González Rinne and Kobayashi M, and the Japan Diabetes Clinical Data Management
Antonio Delgado for technical assistance in the figures. Study Group. Prevalence of albuminuria and renal insufficiency
and associated clinical factors in type 2 diabetes: the Japan Diabetes
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