the spectrum of renal disease in diabetes
TRANSCRIPT
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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