the spectrum of renal disease in diabetes

1

This article is protected by copyright. All rights reserved.

Journal name: Nephrology

Manuscript Type: Review Article (solicited)

Manuscript reference number: NEP-2014-0092.R2

Manuscript Title: The Spectrum of Renal Disease in Diabetes

Accept Date: 31-May-2014

Title Page

Title: The Spectrum of Renal Disease in Diabetes1

Authors:

Jessie Teng, MBBS (Hons), BMed Sci1

Karen M Dwyer, MBBS, FRACP, PhD 2,3

Prue Hill, MBBS, FRCPA, PhD4

Emily See, MBBS, BMed Sci2

Elif I Ekinci MBBS, FRACP, PhD3,5,6

George Jerums, MBBS, FRACP, MD 3,5

Richard J. MacIsaac, MBBS, FRACP, PhD1,3

1Department of Endocrinology and Diabetes, St Vincent’s Hospital

2Department of Nephrology, St Vincent’s Hospital

3Department of Medicine, University of Melbourne

4Department of Anatomical Pathology, St Vincent’s Hospital

5Endocrine Centre, Austin Health

6Menzies School of Health Research, Charles Darwin University, Australia

Corresponding authors:

This article has been accepted for publication and undergone full peer review but has not

been through the copyediting, typesetting, pagination and proofreading process, which may

lead to differences between this version and the Version of Record. Please cite this article as

doi: 10.1111/nep.12288

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Jessie Teng or Richard MacIsaac

Postal address: Department of Endocrinology & Diabetes, St Vincent’s Hospital, PO Box

2900, Fitzroy VIC 3065, Australia

Telephone: +61 3 9288 3568, fax: +61 3 92883340

E-mail address: [email protected], [email protected]

Running title: Renal disease in diabetes

Abstract

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. Diabetic kidney disease can manifest as varying degrees of renal insufficiency and

albuminuria, with heterogeneity in histology reported on renal biopsy. For patients with

diabetes and proteinuria, the finding of non-diabetic kidney disease alone or superimposed on

the changes of diabetic nephropathy is increasingly reported. It is important to identify non-

diabetic kidney disease as some forms are treatable, sometimes leading to remission. Clinical

indications for a heightened suspicion of non-diabetic kidney disease and hence consideration

for renal biopsy in patients with diabetes and nephropathy include absence of diabetic

retinopathy, short duration of diabetes, atypical chronology, presence of haematuria or other

systemic disease, and the nephrotic syndrome.

Key words

Diabetic kidney disease, non-diabetic kidney disease, renal biopsy, AER, eGFR

Disclosure

The authors have no conflict of interest to declare. Acc

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Introduction

The global burden of diabetes is increasing, with the largest increase in prevalence estimated

to occur in the Middle East, Sub-Saharan Africa and India1. This increase is principally

attributable to a rapid rise in cases of type 2 diabetes (T2DM), driven by a combination of

obesity, urbanisation and an ageing population. As such, the public health impact of diabetes-

related complications is enormous, and is no better exemplified than by the rapid increase in

chronic kidney disease (CKD) in people with diabetes. It is now well-documented that

diabetes is the leading cause of end-stage renal disease (ESRD) in the world2.

The current clinical classification of CKD, regardless of aetiology, is based on estimated

glomerular filtration rate (eGFR) and albumin excretion rate (AER)3, 4

, recognising the

relationship between these two factors and adverse outcomes. This has resulted in a

broadening spectrum of clinical presentations for diabetic kidney disease (DKD), with the

phenotype of non-albuminuric CKD being increasingly recognised. The term “diabetic

nephropathy” (DN) should therefore now only be reserved for patients with persistent

clinically detectable proteinuria that is usually associated with an elevation in blood pressure

and a decline in eGFR. However, the finding of subclinical proteinuria or microalbuminuria

is sometimes referred to as “incipient DN” 5.

There is also increasing awareness of the heterogeneity of renal biopsy findings in people

with diabetes. Most patients with T1DM and reduced eGFR have classic glomerular changes

of DN regardless of albuminuria status. Typical renal structural changes of DN are usually

also observed in patients with T2DM, reduced eGFR and albuminuria. However,

predominantly interstitial, tubular or vascular damage or near normal renal structure have Acc

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also been reported in biopsies obtained from patients with T2DM, regardless of eGFR or

albuminuria status, in the absence of any other known cause for renal dysfunction. Despite

the above, in people with diabetes and proteinuria, non-diabetic kidney disease (NDKD)

alone or superimposed on DN changes is not an uncommon finding6.

It is important that NDKD is diagnosed. Despite the attention to strict metabolic control and

blockade of the renin-angiotensin-aldosterone system, proteinuric DKD is usually

progressive, whereas NDKD is potentially treatable, depending on aetiology. Therefore, we

have briefly reviewed the contemporary spectrum of DKD, the histology and clinical

predictors of NDKD and present several clinical vignettes to illustrate the variability of renal

disease in diabetic patients that have presented to one of our hospitals.

Diabetic Kidney Disease (DKD)

The earliest clinical evidence of classical DKD is the appearance of microalbuminuria (≥ 30

mg/day or 20 μg/min). Without specific interventions, up to 80% of T1DM patients with

sustained microalbuminuria develop overt proteinuria (≥300 mg/day or ≥200 μg/min) over 10

to 15 years7-9

. ESRD develops in 50% of T1DM patients with overt proteinuria within 10

years and in >75% by 20 years. A higher proportion of T2DM individuals are found to have

established proteinuria at the time of diagnosis of their diabetes due to the delay in the

diagnosis of diabetes. Without specific interventions, up to 40% of T2DM patients with

microalbuminuria progress to overt nephropathy, but by 20 years after onset of overt

nephropathy, only approximately 20% will progress to ESRD10

.

The exact reasons why an individual with diabetes will progress to develop DKD and then

subsequently develop ESRD still remain to be fully defined. Despite this, there is most likely

a strong genetic determinant for the risk of developing DKD and ESRD. Indeed, recent Acc

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genomic-wide linkage studies have described the localisation of quantitative trait loci that

influence GFR in diabetes11, 12

. These findings may help to further elucidate the genetic

susceptibility to the development of advanced DKD.

Histopathology of DKD

The spectrum of histologic changes seen in DKD is variable. In 2010, a new pathological

classification of DKD was proposed for patients with diabetes13

, based on glomerular

features:

(i) Class I: Glomerular basement membrane thickening, diagnosed by transmission

electron microscopy;

(ii) Class II: Mesangial expansion - A: mild, B: severe;

(iii) Class III: Nodular glomerulosclerosis (Kimmelstiel-Wilson lesion);

(iv) Class IV: Advanced diabetic glomerulosclerosis (>50% global glomerulosclerosis).

The most characteristic lesion seen in patients with T1DM and DN is nodular

glomerulosclerosis14

. Other typical lesions include hyalinosis of afferent and efferent

arterioles, glomerular capsular drops, diffuse glomerular lesions with capillary wall

thickening and mesangial matrix expansion (Case 1, Figure 1).

Renal histology in patients with T2DM is also markedly heterogeneous (Case 2, Figure 2). A

study of T2DM patients with normal eGFR and microalbuminuria by Fioretto et al.

categorised renal biopsy findings into three patterns:

(i) 29% had normal or near normal renal structure- Fioretto class 1 (C1);

(ii) 29% had typical DN with predominant glomerular changes- Fioretto Class 2 (C2); Acc

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(iii)41% had atypical patterns with mild glomerular diabetic changes and

disproportionately severe tubular, interstitial or vascular damage Fioretto Class 3

(C3)15

.

The reasons for different kidney reactions to glycaemic injury are unclear, although potential

factors include degree and duration of metabolic control, co-existing hypertension, interlobar

renal vascular changes and presence of diabetic retinopathy as a marker of microvascular

damage16

.

Normoalbuminuric DKD

Recently, a new DKD phenotype has been described in diabetic patients with low GFR in the

absence of microalbuminuria5. Approximately 25% of patients with T1DM or T2DM have

been reported to develop normoalbuminuric CKD17-19

. Distinct sets of risk factors have been

described for the development of low eGFR or increased AER, suggesting that eGFR and

AER are complementary rather than obligatory markers of DKD 5. Some studies that have

attempted to document the natural history of normoalbuminuric DKD suggest a relatively

benign course compared to albuminuric DKD, with lower rates of dialysis and mortality20, 21

,

whilst others have reported similar rates of decline in renal function19

.

Renal biopsies of normoalbuminuric T1DM patients with preserved eGFR showed that

greater width of the glomerular basement membrane predicted progression of DKD22

.

Moreover, normoalbuminuric T1DM patients with reduced eGFR had more advanced

glomerular lesions compared to patients with preserved renal function23

. Similarly, in

T2DM, patients with normoalbuminuric CKD (eGFR <60mL/min/1.73m2) were found to

have more advanced glomerular, tubulointerstitial and vascular lesions compared to patients

with normoalbuminuria and preserved eGFR24

. However, compared to patients with micro- Acc

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or macroalbuminuria and CKD, the typical glomerular changes of DKD were less common in

patients with normoalbuminuric CKD25

.

The above suggests that renal structural changes are more heterogeneous in

normoalbuminuric than in albuminuric CKD (Figure 3). In particular, for patients with T2DM

and low eGFR, a recent biopsy study of 32 patients reported typical Fioretto C2

classification- typical DN changes for 22/23 micro- or macro-albuminuric patients with only

1/23 being classified as C3- atypical patterns of renal injury. For the patients with

normoalbuminuria and low GFR, 2/8 had C1- near normal biopsy findings, 3/8 had C2-

typical DN changes and 3/8 had C3- atypical patterns of renal damage. In contrast, as

mentioned above, a similar proportion of C1, C2 and C3 changes have been reported in renal

biopsies from patients with T2DM, microalbuminuria and preserved renal function15, 25

.

In summary, glomerular or non-glomerular renal structural changes in T2DM are more

heterogenous in normoalbuminuric than in albuminuric renal insufficiency. This implies that

age, blood pressure and intra-renal vascular disease may contribute to decreases in renal

function independently of changes in albuminuria.

Non-diabetic Kidney Disease (NDKD)

NDKD can either be independent of, or superimposed on, DN. Glomerular causes of NDKD

include immunoglobulin A (IgA) nephropathy, membranous nephropathy, membrano-

proliferative glomerulonephritis, acute interstitial nephritis (AIN), hypertensive renal disease,

focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis due to ANCA-

associated disease and anti-glomerular basement membrane (anti-GBM) glomerulonephritis

(Cases 3-6, Figures 4-7). Acc

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The prevalence and type of NDKD in patients with diabetes reported in the literature is

highly variable (Table 1). This disparity reflects different selection criteria and study design,

reporting bias, threshold for biopsy, and geographical and ethnic differences. Mazzucco et al

highlighted the impact of different biopsy criteria on reported prevalence of NDKD26

. They

showed that although patients were recruited from an ethnically homogenous population

belonging to the same geographic area, centres with unrestricted biopsy policies reported

50% of patients having DKD alone, with the remainder having features of mixed DKD and

NDKD; whereas centres with restricted biopsy policies had lower rates of DKD and the

majority of NDKD was not associated with DKD.

Further complicating the diagnosis of NDKD in diabetic patients is the overlap in histology

findings of mild glomerulonephritis with early DKD changes27

. Features of minimal change

disease under light microscopy may appear similar to Class I DN. Hence, electron

microscopy is important in renal biopsy assessment in diabetes.

Clinical Predictors of NDKD

Given the prevalence of NDKD and the potential for treatment, it is important to identify

clinical predictive factors of NDKD in diabetic patients and perform a renal biopsy to

confirm diagnosis. Recently, several retrospective studies have reported clinical parameters

to differentiate DKD from NDKD.

The presence of diabetic retinopathy (DR) prior to renal biopsy is strongly associated with

DKD28-32

. In one study analysing 110 renal biopsies of patients with T2DM, the presence of

DR was highly predictive of DKD (sensitivity 84%, specificity 63%)30

. In contrast, up to Acc

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70% of diabetic patients without retinopathy, but with albuminuria may have DKD33

,

suggesting that whilst the absence of DR is a strong predictor of NDKD, it cannot exclude

DKD. A recent analysis of DCCT found DR and DKD to be risk factors for development and

progression of the other, independent of other established microvascular risk factors,

suggesting a shared aetiological basis34

. However, up to 25% of patients with T1DM had

discordant DR progression and DN development, which would argue for a partly different

pathological mechanism34

. Furthermore, an analysis of Asian patients with diabetes suggests

that DR is only associated with albuminuric DKD, and not normoalbuminuric DKD35

.

Duration of diabetes is a significant predictive factor for NDKD. Given the natural history of

DN, the onset of proteinuria less than five years from onset of T1DM would be suggestive of

another disease process. Studies of T2DM patients have found that diabetes > 10 years

duration was associated with a higher likelihood of DKD6, 30

. Conversely, Tone et al showed

that duration of T2DM < 5 years was highly sensitive (75%) and specific (70%) for NDKD28

.

Chang et al also reported a mean diabetes duration of 5.9 years in patients with NDKD versus

10.6 years in patients with DKD alone (p<0.001)36

. However in T2DM patients without DR,

there appears to be no difference in duration of diabetes in those who developed DKD or

NDKD33

.

A recent meta- analysis by Liang et al also identified absence of DR and shorter duration of

diabetes as significant predictors of NDKD in patients with T2DM37

. Their results suggested

lower HbA1C, lower blood pressure and the presence of haematuria to be potentially helpful

in distinguishing NDKD, although heterogeneity between the studies prevented more

definitive conclusions.

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The relevance of microscopic haematuria in predicting NDKD remains controversial, partly

due to varying definitions of haematuria. Some studies recognise the importance of

microscopic haematuria in distinguishing NDKD (sensitivity 80%, specificity 57%)30

; others

have found it less discriminative28, 29

. Moreover, microscopic haematuria may be a feature of

T2DM patients with biopsy-proven DKD and overt proteinuria38

. A study involving patients

with biopsy-proven DKD and overt proteinuria, found an association between persistent

haematuria and arteriolar hyalinosis, but this did not provide prognostic clinical

significance39

. On the other hand, urinary acanthocytes are reported to have high specificity

for glomerular NDKD (100%), but low sensitivity31, 40

. The occurrence of acute renal failure

also has high specificity (97%) but poor sensitivity (45%) in predicting NDKD30

. Although

nephrotic-range proteinuria is common in DKD, nephrotic syndrome with gross oedema and

low albumin levels is uncommon, and should prompt renal biopsy.

Clinical findings of systemic illness are useful in predicting NDKD. Purpura and arthralgia

may suggest Henoch-Schonlein purpura often associated with IgA nephropathy, whereas

precedent infection is a strong indicator of acute post-streptococcal glomerulonephritis.

In terms of serologic abnormalities, positive ANA titres were not helpful in differentiating

between DKD and NDKD6, 31

. Some studies have found positive ANCA titres highly specific

for pauci-immune glomerulonephritis31

; others found no difference in ANCA positivity

between DKD and NDKD6.

The absence of peripheral neuropathy is not useful in predicting NDKD. One study found

that neuropathy occurred in < 10% of diabetic patients with renal impairment, although the

absence of neuropathy may have impacted on the initial decision for renal biopsy29

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Clinical Indications for Renal Biopsy

The routine presumption that DKD is the cause of renal impairment in diabetic patients may

be inaccurate; however the threshold for renal biopsy varies amongst nephrologists.

Biesenbach et al argued that for T2DM patients fulfilling the clinical criteria for DKD

(proteinuria, normal urinary sediment, normal kidney size and diabetes duration > 10 years),

and vascular nephropathy (normal urine status, normal or near normal protein excretion,

shrinkage of kidney, renal artery stenosis on ultrasonography), routine renal biopsy is not

required41

. Others advocate more extensive use of renal biopsies, given that NDKD is not

easily predictable based on clinical and laboratory findings26, 33

. Even in the presence of

diabetic retinopathy, prediction of DKD based on clinical course of disease and laboratory

findings had only 65% sensitivity and 76% specificity31

.

We suggest that renal biopsy be considered in diabetic patients with CKD (eGFR<

60mL/min/1.73m2) and the following features:

Absence of DR

Short duration of diabetes (<5 years)

Absence of typical chronology e.g. acute onset of proteinuria, progressive decline in

renal function

Presence of haematuria

Presence of other systemic disease

Nephrotic syndrome

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Summary

There is significant heterogeneity in the spectrum of renal disease seen in patients with

diabetes. Although DKD is a common cause of chronic kidney disease in patients with

diabetes, exclusion of NDKD is important because many forms of NDKD are potentially

treatable and reversible. Renal biopsy should be considered in a carefully selected population

where the disease course is atypical and clinical suspicion of NDKD is high. Absence of

retinopathy and short duration of diabetes are the strongest predictors of NDKD.

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Clinical Case Vignettes

Case 1. DKD in T1DM

A 47 year-old man was diagnosed with T1DM since childhood, with multiple complications

including proliferative retinopathy, 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-hour urinary protein

6.5g) and rapid deterioration in renal function; HbA1C was 9.8%. Renal biopsy confirmed

Class IV DN (Figure 1).

Case 2. DKD in T2DM

A 38 year-old obese woman presented with rapid weight gain (12kg in one week) associated

with bilateral oedema to her upper thighs. She had significant proteinuria (urinary

protein/creatinine ratio 378mg/mol) with impaired renal function (serum creatinine

122µmol/L). Past history was notable for gestational diabetes. She was diagnosed with

T2DM (HbA1c 13.4%) and renal biopsy confirmed Class III DN with nodular

glomerulosclerosis (Figure 2).

Case 3. FSGS causing nephrotic syndrome

A 43 year-old obese woman with 11-year history of T2DM, presented with nephrotic

syndrome (gross peripheral oedema, urinary protein/creatinine 913mg/mol, serum albumin

26g/L) and preserved renal function (eGFR 77ml/min). Her HbA1c was 7% with no known

diabetic complications. Renal biopsy demonstrated FSGS with mild chronic tubulointerstitial

damage (Figure 4).

Case 4. Hypertensive kidney disease

A 74 year-old man with T2DM for 7 years was referred with gradually worsening renal

impairment (eGFR 21ml/min). His HbA1C was 6.3% on oral agents with no vascular Acc

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complications. Other medical history included hypertension and obstructive sleep apnoea.

Urine sediment did not show any proteinuria; kidneys were small-sized on ultrasonography.

Renal biopsy revealed hypertensive nephrosclerosis (Figure 5).

Case 5. IgA nephropathy

A 50 year-old man presented with significant proteinuria, 5 years post-diagnosis of T2DM.

His medical history included obesity, hypertension and hyperlipidaemia. Urinary protein

excretion was 11g/day, with normal eGFR and active urinary sediment. HbA1C was 8%.

Renal biopsy showed features of mesangial proliferative IgA nephropathy with chronic

tubulointerstitial damage and nephrosclerosis (Figure 6).

Case 6. Membranous nephropathy and anti-GBM disease42

A 22 year-old male with T1DM presented with nephrotic syndrome (urinary protein

excretion 14g/day, serum albumin 23g/L), acute kidney injury (serum creatinine 387μmol/L)

and active urinary sediment (>1000 x 106/L dysmorphic erythrocytes). Renal biopsy showed

focal segmental necrotising glomerulonephritis on a background of moderate nodular

mesangial expansion and hypercellularity with several showing Kimmelstiel-Wilson nodules

(Figure 7). Immunofluorescence showed strong linear GBM staining for IgG. Electron

microscopy showed Stage 1 membranous nephropathy with small subepithelial electron

dense “immune-type” deposits with GBM membrane spike formation.

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Table

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

al43

China

(Hong Kong)

T2DM 68 14 65% IgA

nephropathy

Wong et

al44

China

(Hong Kong)

T2DM 51 2 33.3% IgA

nephropathy

Mak et al45

China

(Hunan)

T2DM 220 10 45.5% IgA

nephropathy

Bi et al46

China

(Shanghai)

T2DM 69 5 52.2% FSGS Mou et al47

India T2DM 18 NA 50% Membranous

nephropathy

Premalatha

et al48

India

T2DM 160 5 72.5% AIN Soni et al49

Japan T2DM 50 16 30% Membranous

nephropathy

Akimoto et

al38

Japan T2DM 97 NA 63.9% IgA

nephropathy

Tone et al28

Korea T2DM 110 2 62.7% IgA

nephropathy

Byun et

al50

Korea T2DM 126 8 60.3% IgA

nephropathy

Oh et al32

Malaysia T2DM 110 4 37.3% AIN Chong et

al30

Pakistan T2DM 68 4 69% AIN Yaqub et

al51

Table 1. Prevalence and type of NDKD in some studies from the Asia-Pacific region

reported in the literature. *including mixed DN and NDKD

NA= not available

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Figures

Figure 1. Case 1: Class IV DN. (A) >50% of glomeruli are globally sclerosed. (B) Preserved

glomeruli show severe mesangial expansion.

Figure 2. Case 2: Class III DN. (A) This glomerulus shows severe mesangial expansion with

Kimmelstiel-Wilson nodule (arrow). (B) Both afferent and efferent arterioles show marked

arteriolar hyalinosis (asterisks).

Figure 3. Histological spectrum of renal biopsy findings seen in patients with low eGFR and

normoalbuminuria. (A) Normal glomerulus and arteries, (B) Advanced diabetic

glomerulosclerosis and arteriosclerosis (inset), (C) Minimal glomerular mesangial expansion

and severe arteriosclerosis (inset). All images periodic acid–Schiff stain, original

magnification X 200 (Reproduced with permission from Ekinci et al25

).

Figure 4. Case 3: FSGS. Glomerulus with segmental sclerosis (arrow). Other glomeruli

showed no evidence of DN.

Figure 5. Case 4: Hypertensive nephrosclerosis. Of 3 glomeruli, one is sclerosed, one shows

ischemic change (arrow) and the other no evidence of DN.

Figure 6. Case 5: IgA nephropathy. (A) Glomerulus with mild mesangial hypercellularity but

no evidence of DN. (B) Immunoperoxidase stain shows strong granular mesangial staining

for IgA. Acc

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Figure 7. Case 6: Membranous nephropathy and anti-GBM disease. (A) Glomerulus with

segmental necrosis (arrow) and cellular crescent (asterisk). (B) Glomerulus with class III DN

with Kimmelstiel-Wilson nodule (arrow). (C) Strong linear GBM staining for IgG

characteristic of anti-GBM GN. Inset shows dual pattern of GBM staining, both granular and

linear, on confocal microscopy. (D) Electron microscopy shows GBM thickening and small

subepithelial electron dense deposits characteristic of early membranous nephropathy.

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Minerva Access is the Institutional Repository of The University of Melbourne

Author/s:

Teng, J; Dwyer, KM; Hill, P; See, E; Ekinci, EI; Jerums, G; Macisaac, RJ

Title:

Spectrum of renal disease in diabetes

Date:

2014-09-01

Citation:

Teng, J., Dwyer, K. M., Hill, P., See, E., Ekinci, E. I., Jerums, G. & Macisaac, R. J. (2014).

Spectrum of renal disease in diabetes. NEPHROLOGY, 19 (9), pp.528-536.

https://doi.org/10.1111/nep.12288.

Persistent Link:

http://hdl.handle.net/11343/44025

File Description:

Accepted version

the spectrum of renal disease in diabetes

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