Explore the vast range of titles available.

Diabetic kidney disease (DKD) represents a major component of the health burden associated with type 1 and type 2 diabetes. Recent advances have produced an explosion of ‘novel’ assay‐based risk markers for DKD, though clinical use remains restricted. Although many patients with progressive DKD follow a classical albuminuria‐based pathway, non‐albuminuric DKD progression is now well recognized. In general, the following clinical and biochemical characteristics have been associated with progressive DKD in both type 1 and type 2 diabetes: increased hemoglobin A1c, systolic blood pressure, albuminuria grade, early glomerular filtration rate decline, duration of diabetes, age (including pubertal onset) and serum uric acid; the presence of concomitant microvascular complications; and positive family history. The same is true in type 2 diabetes for male sex category, in patients following an albuminuric pathway to DKD, and also true for the presence of increased pulse wave velocity. The following baseline clinical characteristics have been proposed as risk factors for DKD progression, but with further research required to assess the nature of any relationship: dyslipidemia (including low‐density lipoprotein, total and high‐density lipoprotein cholesterol); elevated body mass index; smoking status; hyperfiltration; decreases in vitamin D, hemoglobin and uric acid excretion (all known consequences of advanced DKD); and patient test result visit‐to‐visit variability (hemoglobin A1c, blood pressure and high‐density lipoprotein cholesterol). The development of multifactorial ‘renal risk equations’ for type 2 diabetes has the potential to simplify the task of DKD prognostication; however, there are currently none for type 1 diabetes‐specific populations. Significant progress has been made in the prediction of DKD progression using readily available clinical data, though further work is required to elicit the role of several variables, and to consolidate data to facilitate clinical implementation. Diabetic Kidney Disease represents a major component of the health burden associated with type 1 and type 2 diabetes. This article summarises clinical variables associated with the progression of Diabetic Kidney Disease; a brief discussion is also made of promising ‘novel’ biomarkers which may eventually become readily available to the practicing clinician.

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.

OBJECTIVE: Most diabetic patients with impaired renal function have a urinary albumin excretion rate in the normal range. In these patients, the etiology of renal impairment is unclear, and it is also unclear whether this nonalbumunuric renal impairment is unique to diabetes. RESEARCH DESIGN AND METHODS: In this study, we examined the frequency and predictors of nonalbumunuric renal impairment (estimated glomerular filtration rate [eGFR] <60 ml/min per 1.73 m²) in a nationally representative cohort of 3,893 patients with type 2 diabetes and compared our findings with rates observed in the general population from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) survey (n = 11,247). RESULTS: Of the 23.1% of individuals with type 2 diabetes who had eGFR <60 ml/min per 1.73 m² (95% CI 21.8-24.5%), more than half (55%) had a urinary albumin excretion rate that was persistently in the normal range. This rate of renal impairment was predictably higher than that observed in the general population (adjusted odds ratio 1.3, 95% CI 1.1-1.5, P < 0.01) but was solely due to chronic kidney disease associated with albuminuria. In contrast, renal impairment in the absence of albuminuria was less common in those with diabetes than in the general population, independent of sex, ethnicity, and duration of diabetes (0.6, 0.5-0.7, P < 0.001). CONCLUSIONS: Nonalbuminuric renal impairment is not more common in those with diabetes. However, its impact may be more significant. New studies are required to address the pathogenesis, prevention, and treatment of nonalbuminuric renal disease.

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 relationship between serial changes in soluble tumor necrosis factor receptor type 1 (TNFR1) levels and an early decline in estimated glomerular filtration rate (eGFR) decline remains to be defined. We found that in patients with an early decline in renal function (n = 30), soluble TNFR1 values increased (2,595 ± 683 vs 3,596 ± 1,203 pg/mL, P < 0.001) as eGFR decreased (89 ± 1 vs 51 ± 2 mL/min/1.73m2, P < 0.001) over an 8‐year period. In contrast, there were no significant changes in soluble TNFR1 levels in patients with stable renal function (n = 17). In a multilevel mixed effects regression model, changes in soluble TNFR1 levels were found to be independently associated with eGFR decline (Z = −4.31, P < 0.001). An early decline in eGFR is associated with an increase in soluble TNFR levels; however, the factors driving this increase and the possible pathological role that soluble TNFR1 plays in progressive diabetic kidney disease remain to be determined. An early decline in estimated glomerular filtration rate is associated with an increase in soluble tumor necrosis factor receptor levels; however, the factors driving this increase and the possible pathological role that soluble tumor necrosis factor receptor type 1 plays in progressive diabetic kidney disease remain to be determined.

OBJECTIVE:--There are limited data on the effects of resistance training on the capacity to perform activities of daily living (ADLs) and quality of life (QoL) for individuals with a high number of metabolic risk factors (HiMF). In this study, we examined the effect of resistance training on the capacity to perform ADLs and QoL in individuals with HiMF and compared any benefits with individuals with a low number of metabolic risk factors (LoMF). RESEARCH DESIGN AND METHODS--Fifty-five untrained individuals, aged 50.8 ± 6.5 years, were randomized to four groups: HiMF training (HiMFT), HiMF control, LoMF training (LoMFT), and LoMF control. At baseline and after 10 weeks of resistance training, participants underwent anthropometric measurements and assessments of aerobic power (VO₂peak), muscle strength, capacity to perform ADLs, and a self-perceived QoL questionnaire. A repeated-measures ANOVA was used to examine the effect of training over time among groups. RESULTS:--Training increased lean body mass in both HiMFT (P = 0.03) and LoMFT (P = 0.03) groups. Total fat content and VO₂peak improved in the LoMFT group only. Muscle strength improved in both training groups (P < 0.01). Time to complete ADLs was reduced by 8.8% in the LoMFT group (P < 0.01) and 9.7% in the HiMF group (P < 0.01). Only the HiMFT group reported improvement in QoL. CONCLUSIONS:-- Resistance training improved muscle strength and the capacity to perform ADLs in individuals with HiMF and LoMF. Resistance training improved QoL for the HiMF group, and this result was independent of changes in body fat content or aerobic power. Longer training regimens may be needed to improve QoL in individuals with LoMF.

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

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.

Background Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease in the Western world. Early and accurate identification of DKD offers the best chance of slowing the progression of kidney disease. An important method for evaluating risk of progressive DKD is abnormal albumin excretion rate (AER). Due to the high variability in AER, most guidelines recommend the use of more than or equal to two out of three AER measurements within a 3- to 6-month period to categorise AER. There are recognised limitations of using AER as a marker of DKD because one quarter of patients with type 2 diabetes may develop kidney disease without an increase in albuminuria and spontaneous regression of albuminuria occurs frequently. Nevertheless, it is important to investigate the long-term intra-individual variability of AER in participants with type 2 diabetes. Methods Consecutive AER measurements (median 19 per subject) were performed in 497 participants with type 2 diabetes from 1999 to 2012 (mean follow-up 7.9 ± 3 years). Baseline clinical characteristics were collected to determine associations with AER variability. Participants were categorised as having normo-, micro- or macroalbuminuria according to their initial three AER measurements. Participants were then categorised into four patterns of AER trajectories: persistent, intermittent, progressing and regressing. Coefficients of variation were used to measure intra-individual AER variability. Results The median coefficient of variation of AER was 53.3%, 76.0% and 67.0% for subjects with normo-, micro- or macroalbuminuria at baseline. The coefficient of variation of AER was 37.7%, 66% and 94.8% for subjects with persistent, intermittent and progressing normoalbuminuria; 43%, 70.6%, 86.1% and 82.3% for subjects with persistent, intermittent, progressing and regressing microalbuminuria; and 55.2%, 67% and 82.4% for subjects with persistent, intermittent and regressing macroalbuminuria, respectively. Conclusion High long-term variability of AER suggests that two out of three AER measurements may not always be adequate for the optimal categorisation and prediction of AER.

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