Resolving the Gestational Diabetes Diagnosis Conundrum: The Need for a Randomized Controlled Trial of Treatment.

The diagnosis of and criteria for gestational diabetes mellitus (GDM) continue to divide the scientific and medical community, both between and within countries. Many argue for universal adoption of the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria and feel that further clinical trials are unjustified and even unethical. However, there are concerns about the large increase in number of women who would be diagnosed with GDM using these criteria and the subsequent impact on health care resources and the individual. This Perspective reviews the origins of the IADPSG consensus and points out some of its less well-known limitations, particularly with respect to identifying women at risk for an adverse pregnancy outcome. It also questions the clinical and cost-effectiveness data often cited to support the IADPSG glycemic thresholds. We present the argument that adoption of diagnostic criteria defining GDM should be based on response to treatment at different diagnostic thresholds of maternal glycemia. This will likely require an international multicenter trial of treatment.

Prediction of Chronic Kidney Disease Stage 3 by CKD273, a Urinary Proteomic Biomarker.

INTRODUCTION: CKD273 is a urinary biomarker, which in advanced chronic kidney disease predicts further deterioration. We investigated whether CKD273 can also predict a decline of estimated glomerular filtration rate (eGFR) to <60 ml/min per 1.73 m2. METHODS: In analyses of 2087 individuals from 6 cohorts (46.4% women; 73.5% with diabetes; mean age, 46.1 years; eGFR ≥ 60 ml/min per 1.73 m2, 100%; urinary albumin excretion rate [UAE] ≥20 µg/min, 6.2%), we accounted for cohort, sex, age, mean arterial pressure, diabetes, and eGFR at baseline and expressed associations per 1-SD increment in urinary biomarkers. RESULTS: Over 5 (median) follow-up visits, eGFR decreased more with higher baseline CKD273 than UAE (1.64 vs. 0.82 ml/min per 1.73 m2; P < 0.0001). Over 4.6 years (median), 390 participants experienced a first renal endpoint (eGFR decrease by ≥10 to <60 ml/min per 1.73 m2), and 172 experienced an endpoint sustained over follow-up. The risk of a first and sustained renal endpoint increased with UAE (hazard ratio ≥ 1.23; P ≤ 0.043) and CKD273 (≥ 1.20; P ≤ 0.031). UAE (≥20 µg/min) and CKD273 (≥0.154) thresholds yielded sensitivities of 30% and 33% and specificities of 82% and 83% (P ≤ 0.0001 for difference between UAE and CKD273 in proportion of correctly classified individuals). As continuous markers, CKD273 (P = 0.039), but not UAE (P = 0.065), increased the integrated discrimination improvement, while both UAE and CKD273 improved the net reclassification index (P ≤ 0.0003), except for UAE per threshold (P = 0.086). DISCUSSION: In conclusion, while accounting for baseline eGFR, albuminuria, and covariables, CKD273 adds to the prediction of stage 3 chronic kidney disease, at which point intervention remains an achievable therapeutic target.

Laboratory Assessment of Diabetic Kidney Disease.

IN BRIEF Regardless of etiology, chronic kidney disease (CKD) is identified by two laboratory tests: 1) estimated glomerular filtration rate (eGFR), a measure of kidney function, and 2) urine albumin-to-creatinine ratio (UACR), a measure of kidney damage. It is crucial for all health professionals to understand the significance and limitations of these tests to appropriately identify CKD patients, guide therapy, and determine prognosis. This article provides information that will enable diabetes educators and other clinicians to properly interpret eGFR and UACR laboratory results in the identification and management of CKD.

Diabetic kidney disease: a report from an ADA Consensus Conference.

The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50% of cases in the developed world. Although incidence rates for ESRD attributable to DKD have recently stabilized, these rates continue to rise in high-risk groups such as middle-aged African Americans, Native Americans, and Hispanics. The costs of care for people with DKD are extraordinarily high. In the Medicare population alone, DKD-related expenditures among this mostly older group were nearly $25 billion in 2011. Due to the high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association in collaboration with the American Society of Nephrology and the National Kidney Foundation to appraise issues regarding patient management, highlighting current practices and new directions. Major topic areas in DKD included 1) identification and monitoring, 2) cardiovascular disease and management of dyslipidemia, 3) hypertension and use of renin-angiotensin-aldosterone system blockade and mineralocorticoid receptor blockade, 4) glycemia measurement, hypoglycemia, and drug therapies, 5) nutrition and general care in advanced-stage chronic kidney disease, 6) children and adolescents, and 7) multidisciplinary approaches and medical home models for health care delivery. This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD.

Diabetic kidney disease: a report from an ADA Consensus Conference.

The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50% of cases in the developed world. Although incidence rates for ESRD attributable to DKD have recently stabilized, these rates continue to rise in high-risk groups such as middle-aged African Americans, Native Americans, and Hispanics. The costs of care for people with DKD are extraordinarily high. In the Medicare population alone, DKD-related expenditures among this mostly older group were nearly $25 billion in 2011. Due to the high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association in collaboration with the American Society of Nephrology and the National Kidney Foundation to appraise issues regarding patient management, highlighting current practices and new directions. Major topic areas in DKD included (1) identification and monitoring, (2) cardiovascular disease and management of dyslipidemia, (3) hypertension and use of renin-angiotensin-aldosterone system blockade and mineralocorticoid receptor blockade, (4) glycemia measurement, hypoglycemia, and drug therapies, (5) nutrition and general care in advanced-stage chronic kidney disease, (6) children and adolescents, and (7) multidisciplinary approaches and medical home models for health care delivery. This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD.

Prevalence of atubular glomeruli in type 2 diabetic patients with nephropathy.

BACKGROUND: Atubular glomeruli have been identified in a number of chronic renal diseases and have been linked to declining renal function. In type 1 diabetes they are present predominantly in proteinuric patients. We investigated the prevalence of atubular glomeruli in type 2 diabetes and their relationship to renal function. METHODS: Renal biopsies from 12 type 2 diabetic patients with nephropathy were processed for light and electron microscopy and analysed using standard stereological techniques. Abnormalities at the glomerular tubular junction were quantified using an index of junctional atrophy (IJA). RESULTS: There was no relationship between the degree of proteinuria and the presence of atubular glomeruli or atrophic tubules. Creatinine clearance correlated with the IJA (r = -0.70, P = 0.011), percent sclerosed glomeruli (r = -0.59, P = 0.027) and interstitial volume fraction (r = -0.54, P = 0.037). The IJA also correlated with foot process width and volume fraction interstitium (r = 0.58, P = 0.049 for both). Percent sclerosed glomeruli correlated with mesangial (r = 0.65, P = 0.012) and interstitial (r = 0.69, P = 0.007) volume fractions. CONCLUSIONS: In contrast to type 1 diabetes, atubular glomeruli and atrophic tubules occur in type 2 diabetic patients with low levels of proteinuria; their development may influence the progressive change in GFR. Both glomerular and interstitial damage may lead to the development of atubular glomeruli in type 2 diabetic nephropathy.

Structural alterations to the podocyte are related to proteinuria in type 2 diabetic patients.

BACKGROUND: The podocyte is believed to play a key role in maintaining the integrity of the glomerular filtration barrier, and damage or loss has been linked to the development of albuminuria. METHODS: Renal biopsies from 16 type 2 diabetic patients with nephropathy and 28 non-diabetic controls were analysed using light and electron microscopy. RESULTS: Podocyte number per glomerulus was significantly lower in the type 2 patients compared with controls [mean (95% confidence interval) 464 (382-546) vs 589 (543-635), P = 0.004]. Mean glomerular volume was significantly increased in diabetic patients compared with controls [5.5 (4.9-6.1) vs 3.1 (2.7-3.5) x 10(6) microm(3), P<0.001], thus the diabetic patients demonstrated an even greater proportional reduction in podocyte density per glomerulus [88 (68-108) vs 201 (182-220)/10(6) microm(3), P<0.001]. Podocyte foot process width on both the filtration surface (FPWgbm) and mesangial surface (FPWmes) was significantly increased compared with controls [796 (708-884) vs 556 (460-908) nm, P = 0.001; 1108 (821-1394) vs 760 (555-1078) nm, P = 0.029, respectively]. There was a significant negative correlation between proteinuria and both podocyte number and podocyte density per glomerulus (r = -0.63, P = 0.009; r = -0.58, P = 0.018, respectively). There was a significant positive correlation between proteinuria and both FPWgbm and FPWmes (r = 0.64, P = 0.008, for both). CONCLUSION: Podocyte loss occurs in type 2 diabetic nephropathy and is related to increasing proteinuria. Whether the accompanying glomerular enlargement and widening of foot processes are a cause of podocyte loss is uncertain. Longitudinal studies are required to determine the sequence of events leading to podocyte loss in diabetic nephropathy.

Podocyte number in normotensive type 1 diabetic patients with albuminuria.

We estimated glomerular cell number in 50 normotensive type 1 diabetic patients with raised albumin excretion rate (AER) and investigated any change after 3 years in a subgroup of 16 placebo-treated patients. Biopsies from 10 normal kidney donors were used as controls. Mesangial and endothelial cell number was increased in the 50 diabetic patients at the start of the study compared with control subjects. There was no difference in podocyte number. Glomerular volume was increased in diabetic patients, but surface area of glomerular basement membrane (GBM) underlying the podocytes did not differ between groups. AER correlated positively with mesangial cell number in microalbuminuric patients (r = 0.44, P = 0.012) and negatively with podocyte number in proteinuric patients (r = -0.48, P = 0.040). In the 16 placebo-treated patients, glomerular volume increased after 3 years owing to matrix accumulation and increased GBM surface area. Although overall cell number did not differ significantly from baseline, the decrease in podocyte number during follow-up correlated with AER at follow-up (r = -0.72, P = 0.002). In conclusion, cross-sectional analysis of podocyte number in type 1 diabetic patients with raised AER but normal blood pressure shows no significant reduction compared with nondiabetic control subjects. Longitudinal data provide evidence for an association between podocyte loss and AER, but whether cellular changes are a response to, a cause of, or concomitant with the progression of nephropathy remains uncertain.