Rev iew Ar t ic le

Spectrum of renal disease in diabetesJESSIE TENG,1 KAREN M DWYER,2,3 PRUE HILL,4 EMILY SEE,2 ELIF I EKINCI,3,5,6 GEORGE JERUMS3,5 andRICHARD J MACISAAC1,3

1Department of Endocrinology and Diabetes, 2Department of Nephrology and 4Department of Anatomical Pathology, St Vincents Hospital, 3Department of

Medicine, University of Melbourne, 5Endocrine Centre, Austin Health, and 6Menzies School of Health Research, Charles Darwin University, Northern Territory,

Victoria, Australia

KEY WORDS:AER, diabetic kidney disease, diabetic

nephropathy, eGFR, non-diabetic kidney

disease, renal biopsy.

Correspondence:Dr Jessie Teng or Dr Richard MacIsaac,

Department of Endocrinology & Diabetes, St

Vincents Hospital, PO Box 2900, Fitzroy, Vic.

3065, Australia. E-mail: jessieth@outlook.com;

r.macisaac@unimelb.edu.au

Accepted for publication 31 May 2014.

Accepted manuscript online 4 June 2014.

doi:10.1111/nep.12288

Disclosure: The authors have no conict of inter-

est to declare.

SUMMARY AT A GLANCE

This review article highlights the

heterogeneity of renal disease in patients

with diabetes. The spectrum of renal

disease in patients with diabetes

encompasses both diabetic kidney disease

(including albuminuric and non-albuminuric

phenotypes) and non-diabetic kidney

disease which can be independent or

superimposed on albuminuric diabetic

kidney disease. It is important to

identifying non-diabetic kidney disease

because it is potentially reversible. The

clinical features suggestive of non-diabetic

kidney disease, which should prompt

consideration of renal biopsy, are

discussed.

ABSTRACT:

The spectrum of renal disease in patients with diabetes encompasses bothdiabetic kidney disease (including albuminuric and non-albuminuric phe-notypes) and non-diabetic kidney disease. Diabetic kidney disease canmanifest as varying degrees of renal insufficiency and albuminuria, withheterogeneity in histology reported on renal biopsy. For patients with dia-betes and proteinuria, the finding of non-diabetic kidney disease alone orsuperimposed on the changes of diabetic nephropathy is increasinglyreported. It is important to identify non-diabetic kidney disease as someforms are treatable, sometimes leading to remission. Clinical indications fora heightened suspicion of non-diabetic kidney disease and hence considera-tion for renal biopsy in patients with diabetes and nephropathy includeabsence of diabetic retinopathy, short duration of diabetes, atypical chro-nology, presence of haematuria or other systemic disease, and the nephroticsyndrome.

The global burden of diabetes is increasing, with the largestincrease in prevalence estimated to occur in the Middle East,Sub-Saharan Africa and India.1 This increase is principallyattributable to a rapid rise in cases of type 2 diabetes (T2DM),driven by a combination of obesity, urbanization and anageing population. As such, the public health impact ofdiabetes-related complications is enormous, and is no better

exemplified than by the rapid increase in chronic kidneydisease (CKD) in people with diabetes. It is now well-documented that diabetes is the leading cause of end-stagerenal disease (ESRD) in the world.2

The current clinical classification of CKD, regardless ofaetiology, is based on estimated glomerular filtration rate(eGFR) and albumin excretion rate (AER),3,4 recognizing the

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relationship between these two factors and adverseoutcomes. This has resulted in a broadening spectrum ofclinical presentations for diabetic kidney disease (DKD),with the phenotype of non-albuminuric CKD being increas-ingly recognized. The term diabetic nephropathy (DN)should therefore now only be reserved for patients withpersistent clinically detectable proteinuria that is usuallyassociated with an elevation in blood pressure and adecline in eGFR. However, the finding of subclinical pro-teinuria or microalbuminuria is sometimes referred to asincipient DN.5

There is also increasing awareness of the heterogeneity ofrenal biopsy findings in people with diabetes. Most patientswith type 1 diabetes (T1DM) and reduced eGFR have classicglomerular changes of DN regardless of albuminuria status.Typical renal structural changes of DN are usually alsoobserved in patients with T2DM, reduced eGFR and albumi-

nuria. However, predominantly interstitial, tubular or vascu-lar damage or near normal renal structure have also beenreported in biopsies obtained from patients with T2DM,regardless of eGFR or albuminuria status, in the absence ofany other known cause for renal dysfunction. Despite theabove, in people with diabetes and proteinuria, non-diabetickidney disease (NDKD) alone or superimposed on DNchanges is not an uncommon finding.6

It is important that NDKD is diagnosed. Despite the atten-tion to strict metabolic control and blockade of the reninangiotensin-aldosterone system, proteinuric DKD is usuallyprogressive, whereas NDKD is potentially treatable, depend-ing on aetiology. Therefore, we have briefly reviewed thecontemporary spectrum of DKD, the histology and clinicalpredictors of NDKD and present several clinical vignettes(Box 1) to illustrate the variability of renal disease in diabeticpatients that have presented to one of our hospitals.

Box 1 Clinical Case Vignettes

Case 1. DKD in T1DMA 47-year-old man was diagnosed with T1DM since childhood, with multiple complications including proliferativeretinopathy, peripheral neuropathy and cerebrovascular disease. Other medical history included obesity and hypertension;there was no family history of renal disease. He presented with worsening nephrotic-range proteinuria (24 h urinaryprotein 6.5 g) and rapid deterioration in renal function; HbA1C was 9.8%. Renal biopsy confirmed Class IV DN (Fig. 1).

Case 2. DKD in T2DMA 38-year-old obese woman presented with rapid weight gain (12 kg in one week) associated with bilateral oedema to herupper thighs. She had significant proteinuria (urinary protein/creatinine ratio 378 mg/mol) with impaired renal function(serum creatinine 122 mol/L). Past history was notable for gestational diabetes. She was diagnosed with T2DM (HbA1c13.4%) and renal biopsy confirmed Class III DN with nodular glomerulosclerosis (Fig. 2).

Case 3. FSGS causing nephrotic syndromeA 43-year-old obese woman with 11 year history of T2DM, presented with nephrotic syndrome (gross peripheral oedema,urinary protein/creatinine 913 mg/mol, serum albumin 26 g/L) and preserved renal function (eGFR 77 mL/min). HerHbA1c was 7% with no known diabetic complications. Renal biopsy demonstrated FSGS with mild chronictubulointerstitial damage (Fig. 4).

Case 4. Hypertensive kidney diseaseA 74-year-old man with T2DM for 7 years was referred with gradually worsening renal impairment (eGFR 21 mL/min).His HbA1C was 6.3% on oral agents with no vascular complications. Other medical history included hypertension andobstructive sleep apnoea. Urine sediment did not show any proteinuria; kidneys were small-sized on ultrasonography.Renal biopsy revealed hypertensive nephrosclerosis (Fig. 5).

Case 5. IgA nephropathyA 50-year-old man presented with significant proteinuria, 5 years post diagnosis of T2DM. His medical history includedobesity, hypertension and hyperlipidaemia. Urinary protein excretion was 11 g/day, with normal eGFR and active urinarysediment. HbA1C was 8%. Renal biopsy showed features of mesangial proliferative IgA nephropathy with chronictubulointerstitial damage and nephrosclerosis (Fig. 6).

Case 6. Membranous nephropathy and anti-GBM disease7

A 22-year-old male with T1DM presented with nephrotic syndrome (urinary protein excretion 14 g/day, serum albumin23 g/L), acute kidney injury (serum creatinine 387 mol/L) and active urinary sediment (>1000 106/L dysmorphicerythrocytes). Renal biopsy showed focal segmental necrotizing glomerulonephritis on a background of moderate nodularmesangial expansion and hypercellularity with several showing KimmelstielWilson nodules (Fig. 7). Immunofluorescenceshowed strong linear GBM staining for IgG. Electron microscopy showed Stage 1 membranous nephropathy with smallsubepithelial electron dense immune-type deposits with GBM membrane spike formation.

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DIABETIC KIDNEY DISEASE

The earliest clinical evidence of classical DKD is the appear-ance of microalbuminuria ( 30 mg/day or 20 g/min).Without specific interventions, up to 80% of T1DM patientswith sustained microalbuminuria develop overt proteinuria(300 mg/day or 200 g/min) over 1015 years.810 ESRDdevelops in 50% of T1DM patients with overt proteinuriawithin 10 years and in >75% by 20 years. A higher propor-tion of T2DM individuals are found to have established pro-teinuria at the time of diagnosis of their diabetes due to thedelay in the diagnosis of diabetes. Without specific interven-tions, up to 40% of T2DM patients with microalbuminuriaprogress to overt nephropathy, but by 20 years after onset ofovert nephropathy, only approximately 20% will progress toESRD.11

The exact reasons why an individual with diabetes willprogress to develop DKD and then subsequently developESRD still remain to be fully defined. Despite this, there ismost likely a strong genetic determinant for the risk of devel-oping DKD and ESRD. Indeed, recent genomic-wide linkagestudies have described the localization of quantitative traitloci that influence GFR in diabetes.12,13 These findings mayhelp to further elucidate the genetic susceptibility to thedevelopment of advanced DKD.

HISTOPATHOLOGY OF DKD

The spectrum of histologic changes seen in DKD is variable. In2010, a new pathological classification of DKD was proposedfor patients with diabetes,14 based on glomerular features:1 Class I: Glomerular basement membrane (GBM) thicken-ing, diagnosed by transmission electron microscopy.2 Class II: Mesangial expansion A: mild; B: severe.3 Class III: Nodular glomerulosclerosis (KimmelstielWilsonlesion).4 Class IV: Advanced diabetic glomerulosclerosis (>50%global glomerulosclerosis).The most characteristic lesion seen in patients with T1DM

and DN is nodular glomerulosclerosis.15 Other typical lesionsinclude hyalinosis of afferent and efferent arterioles,glomerular capsular drops, diffuse glomerular lesions withcapillary wall thickening and mesangial matrix expansion(Case 1, Fig. 1).Renal histology in patients with T2DM is also markedly

heterogeneous (Case 2, Fig. 2). A study of T2DM patientswith normal eGFR and microalbuminuria by Fioretto et al.categorized renal biopsy findings into three patterns:1 29% had normal or near normal renal structure Fiorettoclass 1 (C1).2 29% had typical DN with predominant glomerularchanges Fioretto Class 2 (C2).3 41% had atypical patterns with mild glomerular diabeticchanges and disproportionately severe tubular, interstitial orvascular damage Fioretto Class 3 (C3).16

The reasons for different kidney reactions to glycaemicinjury are unclear, although potential factors include degreeand duration of metabolic control, co-existing hypertension,interlobar renal vascular changes and presence of diabeticretinopathy as a marker of microvascular damage.17

NORMOALBUMINURIC DKD

Recently, a new DKD phenotype has been described in dia-betic patients with low GFR in the absence of microal-buminuria.5 Approximately 25% of patients with T1DM orT2DM have been reported to develop normoalbuminuricCKD.1820 Distinct sets of risk factors have been described forthe development of low eGFR or increased AER, suggestingthat eGFR andAERare complementary rather than obligatorymarkers of DKD.5 Some studies that have attempted to docu-ment the natural history of normoalbuminuric DKD suggest arelatively benign course compared with albuminuric DKD,with lower rates of dialysis and mortality,21,22 whilst othershave reported similar rates of decline in renal function.20

Fig. 1 Case 1: Class IV DN. (A) >50% of glomeruli are globally sclerosed. (B)Preserved glomeruli show severe mesangial expansion.

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Renal biopsies of normoalbuminuric T1DM patients withpreserved eGFR showed that greater width of the GBM pre-dicted progression of DKD.23 Moreover, normoalbuminuricT1DM patients with reduced eGFR had more advancedglomerular lesions compared with patients with preservedrenal function.24 Similarly, in T2DM, patients withnormoalbuminuric CKD (eGFR

Class I DN. Hence, electron microscopy is important in renalbiopsy assessment in diabetes.

CLINICAL PREDICTORS OF NDKD

Given the prevalence of NDKD and the potential for treat-ment, it is important to identify clinical predictive factors ofNDKD in diabetic patients and perform a renal biopsy to

confirm diagnosis. Recently, several retrospective studieshave reported clinical parameters to differentiate DKD fromNDKD.The presence of diabetic retinopathy (DR) prior to renal

biopsy is strongly associated with DKD.35,37,38,42,43 In onestudy analysing 110 renal biopsies of patients with T2DM,the presence of DR was highly predictive of DKD (sensitivity84%, specificity 63%).38 In contrast, up to 70% of diabeticpatients without retinopathy, but with albuminuria mayhave DKD,44 suggesting that whilst the absence of DR is astrong predictor of NDKD, it cannot exclude DKD. A recent

Fig. 3 Histological spectrum of renal biopsy ndings seen in patients with low eGFR and normoalbuminuria. (A) Normal glomerulus and arteries. (B) Advanceddiabetic glomerulosclerosis and arteriosclerosis (inset). (C) Minimal glomerular mesangial expansion and severe arteriosclerosis (inset). All images periodic

acidSchiff stain, original magnication 200 (reproduced with permission from Ekinci et al.26).

Fig. 4 Case 3: FSGS. Glomerulus with segmental sclerosis (arrow). Other glo-meruli showed no evidence of DN.

Fig. 5 Case 4: Hypertensive nephrosclerosis. Of three glomeruli, one issclerosed, one shows ischemic change (arrow) and the other no evidence of

DN.

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analysis of the Diabetes Control and Complications Trial(DCCT) which involved participants with T1DM, found DRand DKD to be risk factors for development and progressionof the other, independent of other established microvascularrisk factors, suggesting a shared aetiological basis.45 However,up to 25% of patients had discordant DR progression and DNdevelopment, which would argue for a partly differentpathological mechanism.45 Furthermore, an analysis of Asianpatients with diabetes suggests that DR is only associatedwith albuminuric DKD, and not normoalbuminuric DKD.46

Duration of diabetes is a significant predictive factor forNDKD. Given the natural history of DN, the onset of pro-teinuria less than five years from onset of T1DM would besuggestive of another disease process. Studies of T2DMpatients have found that diabetes >10 years duration was

associated with a higher likelihood of DKD.6,38 Conversely,Tone et al. showed that duration of T2DM

Biesenbach et al. argued that for T2DM patients fulfillingthe clinical criteria for DKD (proteinuria, normal urinarysediment, normal kidney size and diabetes duration >10years), and vascular nephropathy (normal urine status,normal or near normal protein excretion, shrinkage ofkidney, renal artery stenosis on ultrasonography), routinerenal biopsy is not required.51 Others advocate more exten-sive use of renal biopsies, given that NDKD is not easilypredictable based on clinical and laboratory findings.40,44

Even in the presence of diabetic retinopathy, prediction ofDKD based on clinical course of disease and laboratory find-ings had only 65% sensitivity and 76% specificity.43

We suggest that renal biopsy be considered in diabeticpatients with CKD (eGFR

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Table 1 Prevalence and type of NDKD in some studies from the Asia-Pacic region reported in the literature

Country Type of

diabetes

Number of

cases

Duration of

study (years)

NDKD

prevalence

Most common NDKD Study

China T2DM 244 9 7.8% IgA nephropathy Zhuo et al.27

China (Hong Kong) T2DM 68 14 65% IgA nephropathy Wong et al.28

China (Hong Kong) T2DM 51 2 33.3% IgA nephropathy Mak et al.29

China (Hunan) T2DM 220 10 45.5% IgA nephropathy Bi et al.30

China (Shanghai) T2DM 69 5 52.2% FSGS Mou et al.31

India T2DM 18 NA 50% Membranous nephropathy Premalatha et al.32

India T2DM 160 5 72.5% AIN Soni et al.33

Japan T2DM 50 16 30% Membranous nephropathy Akimoto et al.34

Japan T2DM 97 NA 63.9% IgA nephropathy Tone et al.35

Korea T2DM 110 2 62.7% IgA nephropathy Byun et al.36

Korea T2DM 126 8 60.3% IgA nephropathy Oh et al.37

Malaysia T2DM 110 4 37.3% AIN Chong et al.38

Pakistan T2DM 68 4 69% AIN Yaqub et al.39

Including mixed DN and NDKD. NA, not available; DN, diabetic nephropathy; NDKD, non-diabetic kidney disease; T2DM, type 2 diabetes. AIN, acute interstitial

nephritis; FSGD, focal segmental glomerulosclerosis.

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2014 Asian Pacic Society of Nephrology 535

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