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Diabetic nephropathy (DN) is a progressive kidney disease, a well-known complication of long-standing diabetes. DN is the most frequent reason for dialysis in many Western countries. Early detection may enable development of specific drugs and early initiation of therapy, thereby postponing/preventing the need for renal replacement therapy. We evaluated urinary proteome analysis as a tool for prediction of DN. Capillary electrophoresis–coupled mass spectrometry was used to profile the low–molecular weight proteome in urine. We examined urine samples from a longitudinal cohort of type 1 and 2 diabetic patients (n = 35) using a previously generated chronic kidney disease (CKD) biomarker classifier to assess peptides of collected urines for signs of DN. The application of this classifier to samples of normoalbuminuric subjects up to 5 years prior to development of macroalbuminuria enabled early detection of subsequent progression to macroalbuminuria (area under the curve [AUC] 0.93) compared with urinary albumin routinely used to determine the diagnosis (AUC 0.67). Statistical analysis of each urinary CKD biomarker depicted its regulation with respect to diagnosis of DN over time. Collagen fragments were prominent biomarkers 3–5 years before onset of macroalbuminuria. Before albumin excretion starts to increase, there is a decrease in collagen fragments. Urinary proteomics enables noninvasive assessment of DN risk at an early stage via determination of specific collagen fragments.

Mesangial metrics reflect glomerular filtration surface area in diabetes. The point-sampled intercept (PSI) method is the conventional method to calculate these parameters. However, this is time consuming and subject to underestimation. We introduce a novel three-dimensional (3D) reconstruction method applicable to light microscopy to measure mesangial metrics. Transmission electron microscopy (TEM), PSI and our new 3D imaging methods were used to quantify mesangial metrics from 22 patients with type 2 diabetes, normo-, micro- and macroalbuminuria and an estimated glomerular filtration rate of <60 mL/min/1.73 m 2 . Repeated-measures ANOVA test was used to test the equality of the measurement means from the three methods and the degree of inter method variability. Repeated-measures and post-estimation ANOVA tests together with correlation coefficient measurements were used to compare the methods with TEM as reference. There was a statistically significant difference in mesangial volume measurements ( F (2, 16) = 15.53, p  = 0.0002). The PSI method underestimated measurements compared to TEM and 3D methods by 30% ( p  = 0.001) and 15%, respectively ( p  < 0.001). 3D and TEM measurements did not differ significantly. 3D reconstruction is a reliable and time efficient method for calculating mesangial metrics. It may prove to be a useful tool in clinical and experimental diabetic kidney disease.

Accumulation of advanced glycation endproducts (AGEs) is linked to decline in renal function, particularly in patients with diabetes. Major forms of AGEs in serum are protein-bound AGEs and AGE free adducts. In this study, we assessed levels of AGEs in subjects with and without diabetes, with normal renal function and stages 2 to 4 chronic kidney disease (CKD), to identify which AGE has the greatest progressive change with decline in renal function and change in diabetes. We performed a cross-sectional study of patients with stages 2–4 CKD, with and without diabetes, and healthy controls (n = 135). Nine protein-bound and free adduct AGEs were quantified in serum. Most protein-bound AGEs increased moderately through stages 2–4 CKD whereas AGE free adducts increased markedly. Methylglyoxal-derived hydroimidazolone MG-H1 free adduct was the AGE most responsive to CKD status, increasing 8-fold and 30-fold in stage 4 CKD in patients without and with diabetes, respectively. MG-H1 Glomerular filtration flux was increased 5-fold in diabetes, likely reflecting increased methylglyoxal glycation status. We conclude that serum MG-H1 free adduct concentration was strongly related to stage of CKD and increased in diabetes status. Serum MG-H1 free adduct is a candidate AGE risk marker of non-diabetic and diabetic CKD.

Nonalbuminuric Renal Insufficiency in Type 2 Diabetes Richard J. MacIsaac , PHD, MBBS, FRACP 1 2 , Con Tsalamandris , MBBS 1 2 , Sianna Panagiotopoulos , BSC (HONS), PHD 1 , Trudy J. Smith , BSC, MAPPSC 1 , Karen J. McNeil , MBBS 1 and George Jerums , MBBS, FRACP, MD 1 2 1 Endocrinology Unit, Austin Health, Heidelberg, Victoria, Australia 2 Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia Address correspondence and reprint requests to Dr. R.J. MacIsaac, Endocrinology Unit, Austin Health, Heidelberg, Victoria, 3084, Australia. E-mail: r.macisaac{at}austin.unimelb.edu.au Abstract OBJECTIVE —To determine the prevalence and characteristics of patients with type 2 diabetes who have impaired renal function, defined as a glomerular filtration rate (GFR) <60 ml · min −1 · 1.73 m −2 , and normoalbuminuria. RESEARCH DESIGN AND METHODS —A cross-sectional survey of 301 outpatients attending a single tertiary referral center using the plasma disappearance of isotopic 99m Tc-diethylene-triamine-penta-acetic acid to measure GFR and at least two measurements of urinary albumin excretion rate (AER) over 24 h to determine albuminuria. RESULTS —A total of 109 patients (36%) had a GFR <60 ml · min −1 · 1.73 m −2 . The overall prevalence of normo-, micro-, and macroalbuminuria was 43 of 109 (39%), 38 of 109 (35%), and 28 of 109 (26%), respectively. Compared with patients with macroalbuminuria, those with normoalbuminuria were more likely to be older and female. After excluding patients whose normoalbuminuric status was possibly related to the initiation of a renin-angiotensin system (RAS) inhibitor before the start of the study, the prevalence of a GFR <60 ml · min −1 · 1.73 m −2 and normoalbuminuria was 23%. Temporal changes in GFR in a subset of 34 of 109 (32%) unselected patients with impaired renal function were available for comparison over a 3- to 10-year period. The rates of decline in GFR (ml · min −1 · 1.73 m −2 · year −1 ) of −4.6 ± 1.0, −2.8 ± 1.0, and −3.0 ± 07 were not significantly different for normo- ( n = 12), micro- ( n = 12), and macroalbuminuric ( n = 10) patients, respectively. CONCLUSIONS —These results suggest that patients with type 2 diabetes can commonly progress to a significant degree of renal impairment while remaining normoalbuminuric. AER, albumin excretion rate CHD, coronary heart disease CVD, cerebrovascular disease DTPA, 99mTc-diethylene-triamine-penta-acetic acid GFR, glomerular filtration rate PVD, peripheral vascular disease RAS, renin-angiotensin system RIA, radioimmunoassay Footnotes A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Accepted October 5, 2003. Received March 11, 2003. DIABETES CARE

The evaluation of diabetic nephropathy from both research and clinical viewpoints depends on the assessment of two continuous variables, albumin excretion rate (AER) and glomerular filtration rate (GFR). Although increases in AER generally precede a decline in GFR, some patients follow a non-albuminuric pathway to renal impairment. In this Review, George Jerums and colleagues explain why serial assessments of both AER and GFR should be performed at an early stage in patients being evaluated for diabetic nephropathy. The evaluation of diabetic nephropathy from research and clinical viewpoints depends on the assessment of two continuous variables, albumin excretion rate (AER) and glomerular filtration rate (GFR). These two parameters form the basis of both the European classification of five stages of diabetic nephropathy, assessed according to changes in AER and GFR (hyperfiltration, normoalbuminuria, microalbuminuria, macroalbuminuria and end-stage renal disease), and the National Kidney Foundation classification of five stages of chronic kidney disease based on categories of estimated GFR. Although increases in AER generally precede a decline in GFR, some patients follow a non-albuminuric pathway to renal impairment. In addition, studies indicate that GFR decreases in a linear fashion from normal or above-normal levels. Whether hyperfiltration is part of the pathogenetic process leading to diabetic nephropathy remains unclear. Ideally, both AER and GFR should be assessed at an early stage in patients being evaluated for diabetic nephropathy. New methods such as the use of cystatin-C-based equations for estimating GFR should be considered because current creatinine-based estimates are inaccurate at normal or high GFRs. Serial assessments of both AER and GFR might allow diabetic nephropathy to be diagnosed at early stages of the disease process that are selectively responsive to new interventions. The successful integration of AER categories with the recently defined stages of GFR represents a new challenge in the management of diabetic nephropathy. Key Points Both albumin excretion rate (AER) and glomerular filtration rate (GFR) should be assessed at an early stage in evaluating patients for diabetic nephropathy In the assessment of diabetic nephropathy, the roles of AER and GFR are complementary rather than competitive Changes in AER are dynamic whereas changes in GFR are usually progressive Although increases in AER generally precede a decline in GFR, some patients follow a non-albuminuric pathway to renal impairment The course of renal abnormalities in type 1 and type 2 diabetes is similar, but more heterogeneous in type 2 diabetes

Serial Measurements of Cystatin C Are More Accurate Than Creatinine-Based Methods in Detecting Declining Renal Function in Type 1 Diabetes Erosha Premaratne , MBBS, FRACP 1 , Richard J. MacIsaac , PHD, MBBS, FRACP 1 , Sue Finch , PHD 2 , Sianna Panagiotopoulos , PHD 1 , Elif Ekinci , MBBS 1 and George Jerums , MBBS, FRACP, MD 1 1 Endocrine Centre, Austin Health, University of Melbourne, Melbourne, Australia 2 Statistical Consulting Centre, University of Melbourne, Melbourne, Australia Corresponding author: Dr. Erosha Premaratne, Endocrine Centre, Austin Health, Studley Road, Heidelberg, Victoria 3084, Australia. E-mail: erosha{at}aanet.com.au Abstract OBJECTIVE —Cystatin C–and creatinine-based methods were compared with 99m -technetium-diethylene-triamine-penta-acetic acid ( 99m Tc-DTPA) plasma clearance (isotopic glomerular filtration rate [iGFR]) for detecting declining renal function. RESEARCH DESIGN AND METHODS —Glomerular filtration rate (GFR) was monitored over a mean of 10.1 years in 85 subjects with type 1 diabetes (with an average of 5.6 measurements per individual). Baseline mean ± SD iGFR of the cohort was 106.1 ± 2.6 ml/min per 1.73 m 2 . The rates of decline in GFR (ΔGFR) were derived using linear regression. RESULTS —In 19 of 85 subjects with declining renal function (i.e., ΔiGFR >3.3 ml/min per 1.73 m 2 per year), ΔGFR (ml/min per 1.73 m 2 per year) was 6.5 by iGFR, 4.2 by 10 4 /creatinine, 3.6 by Cockcroft-Gault formula, 3.4 by the Modification of Diet in Renal Disease (MDRD)-6 equation, and 3.5 by the MDRD-4 variable equation ( P < 0.01 vs. iGFR). In comparison, ΔGFR was 6.1 using the formula Cys-GFR = (86.7/cystatin C concentration) − 4.2 (not significant). CONCLUSIONS —Cystatin C was more accurate in detecting decline in renal function than creatinine-based methods in this population of subjects with type 1 diabetes and a normal mean baseline GFR. GFR, glomerular filtration rate iGFR, isotopic GFR MDRD, Modification of Diet in Renal Disease 99mTc-DTPA, 99m-technetium-diethylene-triamine-penta-acetic acid Footnotes Published ahead of print at http://care.diabetesjournals.org on 4 March 2008. DOI: 10.2337/dc07-1588. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted January 28, 2008. Received August 11, 2007. DIABETES CARE

OBJECTIVE:--To investigate the role of intrarenal vascular disease in the pathogenesis of nonalbuminuric renal insufficiency in type 2 diabetes. RESEARCH DESIGN AND METHODS--We studied 325 unselected clinic patients who had sufficient clinical and biochemical information to calculate an estimated glomerular filtration rate (eGFR) using the Modified Diet in Renal Disease six-variable formula, at least two estimations of urinary albumin excretion rates (AER), and a renal duplex scan to estimate the resistance index of the interlobar renal arteries. The resistance index, measured as part of a complications surveillance program, was compared in patients with an eGFR < or >=60 ml/min per 1.73 m² who were further stratified into normo- (AER <20), micro- (20-200), or macroalbuminuria (> 200 μg/min) categories. RESULTS:--Patients with an eGFR <60 ml/min per 1.73 m² had a higher resistance index of the renal interlobar arteries compared with patients with an eGFR >=60 ml/min per 1.73 m². However, the resistance index was elevated to a similar extent in patients with an eGFR <60 ml/min per 1.73 m² regardless of albuminuric status (normo- 0.74 ± 0.01, micro- 0.73 ± 0.01, and macroalbuminuria resistance index 0.75 ± 0.11). Multiple regression analysis revealed that increased age (P < 0.0001), elevated BMI (P = 0.0001), decreased eGFR (P < 0.01), and decreased diastolic blood pressure (P < 0.01), but not an increased AER, were independently associated with an elevated resistance index in patients with impaired renal function. CONCLUSIONS:--Subjects with type 2 diabetes and reduced glomerular filtration rate had similar degrees of intrarenal vascular disease, as measured by the intrarenal arterial resistance index, regardless of their AER status. The pathological mechanisms that determine the relationship between impaired renal function and AER status in subjects with type 2 diabetes remain to be elucidated.

Effects of Salt Supplementation on the Albuminuric Response to Telmisartan With or Without Hydrochlorothiazide Therapy in Hypertensive Patients With Type 2 Diabetes Are Modulated by Habitual Dietary Salt Intake Elif I. Ekinci , MBBS 1 , Georgina Thomas , MBBS 1 , David Thomas , DIP APP SCI 2 , Cameron Johnson , MNUTRDIET 1 , Richard J. MacIsaac , PHD 1 , Christine A. Houlihan , MD 1 , Sue Finch , PHD 3 , Sianna Panagiotopoulos , PHD 1 , Chris O'Callaghan , MD 4 and George Jerums , MD 1 1 Endocrine Centre, Austin Health and University of Melbourne, Heidelberg Repatriation Hospital, Heidelberg West, Victoria, Australia; 2 Department of Nuclear Medicine, Austin Health, Melbourne, Victoria, Australia; 3 Statistical Consulting Centre, University of Melbourne, Melbourne, Victoria, Australia; 4 Department of Clinical Pharmacology, Austin Health, Melbourne, Victoria, Australia. Corresponding author: Elif Ekinci, eekinci2002{at}yahoo.com.au . Abstract OBJECTIVE This prospective randomized double-blind placebo-controlled crossover study examined the effects of sodium chloride (NaCl) supplementation on the antialbuminuric action of telmisartan with or without hydrochlorothiazide (HCT) in hypertensive patients with type 2 diabetes, increased albumin excretion rate (AER), and habitual low dietary salt intake (LDS; <100 mmol sodium/24 h on two of three consecutive occasions) or high dietary salt intake (HDS; >200 mmol sodium/24 h on two of three consecutive occasions). RESEARCH DESIGN AND METHODS Following a washout period, subjects ( n = 32) received 40 mg/day telmisartan for 4 weeks followed by 40 mg telmisartan plus 12.5 mg/day HCT for 4 weeks. For the last 2 weeks of each treatment period, patients received either 100 mmol/day NaCl or placebo capsules. After a second washout, the regimen was repeated with supplements in reverse order. AER and ambulatory blood pressure were measured at weeks 0, 4, 8, 14, 18, and 22. RESULTS In LDS, NaCl supplementation reduced the anti-albuminuric effect of telmisartan with or without HCT from 42.3% (placebo) to 9.5% ( P = 0.004). By contrast, in HDS, NaCl supplementation did not reduce the AER response to telmisartan with or without HCT (placebo 30.9%, NaCl 28.1%, P = 0.7). Changes in AER were independent of changes in blood pressure. CONCLUSIONS The AER response to telmisartan with or without HCT under habitual low salt intake can be blunted by NaCl supplementation. By contrast, when there is already a suppressed renin angiotensin aldosterone system under habitual high dietary salt intake, the additional NaCl does not alter the AER response. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received December 23, 2008. Accepted May 12, 2009. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. © 2009 by the American Diabetes Association.

Background There is an overwhelming burden of cardiovascular disease, type 2 diabetes and chronic kidney disease among Indigenous Australians. In this high risk population, it is vital that we are able to measure accurately kidney function. Glomerular filtration rate is the best overall marker of kidney function. However, differences in body build and body composition between Indigenous and non-Indigenous Australians suggest that creatinine-based estimates of glomerular filtration rate derived for European populations may not be appropriate for Indigenous Australians. The burden of kidney disease is borne disproportionately by Indigenous Australians in central and northern Australia, and there is significant heterogeneity in body build and composition within and amongst these groups. This heterogeneity might differentially affect the accuracy of estimation of glomerular filtration rate between different Indigenous groups. By assessing kidney function in Indigenous Australians from Northern Queensland, Northern Territory and Western Australia, we aim to determine a validated and practical measure of glomerular filtration rate suitable for use in all Indigenous Australians. Methods/Design A cross-sectional study of Indigenous Australian adults (target n = 600, 50% male) across 4 sites: Top End, Northern Territory; Central Australia; Far North Queensland and Western Australia. The reference measure of glomerular filtration rate was the plasma disappearance rate of iohexol over 4 hours. We will compare the accuracy of the following glomerular filtration rate measures with the reference measure: Modification of Diet in Renal Disease 4-variable formula, Chronic Kidney Disease Epidemiology Collaboration equation, Cockcroft-Gault formula and cystatin C- derived estimates. Detailed assessment of body build and composition was performed using anthropometric measurements, skinfold thicknesses, bioelectrical impedance and a sub-study used dual-energy X-ray absorptiometry. A questionnaire was performed for socio-economic status and medical history. Discussion We have successfully managed several operational challenges within this multi-centre complex clinical research project performed across remote North, Western and Central Australia. It seems unlikely that a single correction factor (similar to that for African-Americans) to the equation for estimated glomerular filtration rate will prove appropriate or practical for Indigenous Australians. However, it may be that a modification of the equation in Indigenous Australians would be to include a measure of fat-free mass.

Androgens determine male secondary sexual characteristics and influence a variety of metabolic pathways. Circulating levels of androgens are highly heritable; however, the genes involved are largely unknown. The 5α-reductase enzymes types 1 and 2 responsible for converting testosterone to the more potent androgen dihydrotestosterone are encoded by the SRD5A1 and SRD5A2 genes, respectively. We performed indirect genetic association studies of SRD5A1 and SRD5A2 and the dihydrotestosterone/testosterone ratio that reflects the activity of 5α-reductase in 57 males with type 2 diabetes. We found evidence of significant association between a single nucleotide polymorphism in SRD5A1 and the dihydrotestosterone/testosterone ratio (median 0.10, interquartile range 0.08 vs. median 0.06, interquartile range 0.04, P =0.009). The polymorphism was not associated with any diabetic phenotypes. These results suggest that functional genetic variants might exist in or around SRD5A1 that affect the activity of the 5α-reductase enzyme type 1 and influence androgen levels.