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BackgroundCurrent equations for estimated glomerular filtration rate (eGFR) that use serum creatinine or cystatin C incorporate age, sex, and race to estimate measured GFR. However, race in eGFR equations is a social and not a biologic construct.MethodsWe developed new eGFR equations without race using data from two development data sets: 10 studies (8254 participants, 31.5% Black) for serum creatinine and 13 studies (5352 participants, 39.7% Black) for both serum creatinine and cystatin C. In a validation data set of 12 studies (4050 participants, 14.3% Black), we compared the accuracy of new eGFR equations to measured GFR. We projected the prevalence of chronic kidney disease (CKD) and GFR stages in a sample of U.S. adults, using current and new equations.ResultsIn the validation data set, the current creatinine equation that uses age, sex, and race overestimated measured GFR in Blacks (median, 3.7 ml per minute per 1.73 m2 of body-surface area; 95% confidence interval [CI], 1.8 to 5.4) and to a lesser degree in non-Blacks (median, 0.5 ml per minute per 1.73 m2; 95% CI, 0.0 to 0.9). When the adjustment for Black race was omitted from the current eGFR equation, measured GFR in Blacks was underestimated (median, 7.1 ml per minute per 1.73 m2; 95% CI, 5.9 to 8.8). A new equation using age and sex and omitting race underestimated measured GFR in Blacks (median, 3.6 ml per minute per 1.73 m2; 95% CI, 1.8 to 5.5) and overestimated measured GFR in non-Blacks (median, 3.9 ml per minute per 1.73 m2; 95% CI, 3.4 to 4.4). For all equations, 85% or more of the eGFRs for Blacks and non-Blacks were within 30% of measured GFR. New creatinine-cystatin C equations without race were more accurate than new creatinine equations, with smaller differences between race groups. As compared with the current creatinine equation, the new creatinine equations, but not the new creatinine-cystatin C equations, increased population estimates of CKD prevalence among Blacks and yielded similar or lower prevalence among non-Blacks.ConclusionsNew eGFR equations that incorporate creatinine and cystatin C but omit race are more accurate and led to smaller differences between Black participants and non-Black participants than new equations without race with either creatinine or cystatin C alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

Rationale and objectiveGlomerular filtration rate (GFR) estimation based on creatinine and cystatin C (eGFRcr-cys) is more accurate than estimated GFR (eGFR) based on creatinine or cystatin C alone (eGFRcr or eGFRcys, respectively), but the inclusion of creatinine in eGFRcr-cys requires specification of a person's race. β2-Microglobulin (B2M) and β-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine is.Study designStudy of diagnostic test accuracy.Setting and participantsDevelopment in a pooled population of 7 studies with 5,017 participants with and without chronic kidney disease. External validation in a pooled population of 7 other studies with 2,245 participants.Tests comparedPanel eGFR using B2M and BTP in addition to cystatin C (3-marker panel) or creatinine and cystatin C (4-marker panel) with and without age and sex or race.OutcomesGFR measured as the urinary clearance of iothalamate, plasma clearance of iohexol, or plasma clearance of [51Cr]EDTA.ResultsMean measured GFRs were 58.1 and 83.2 mL/min/1.73 m2, and the proportions of Black participants were 38.6% and 24.0%, in the development and validation populations, respectively. In development, addition of age and sex improved the performance of all equations compared with equations without age and sex, but addition of race did not further improve the performance. In validation, the 4-marker panels were more accurate than the 3-marker panels (P < 0.001). The 3-marker panel without race was more accurate than eGFRcys (percentage of estimates greater than 30% different from measured GFR [1 - P30] of 15.6% vs 17.4%; P = 0.01), and the 4-marker panel without race was as accurate as eGFRcr-cys (1 - P30 of 8.6% vs 9.4%; P = 0.2). Results were generally consistent across subgroups.LimitationsNo representation of participants with severe comorbid illness and from geographic areas outside of North America and Europe.ConclusionsThe 4-marker panel eGFR is as accurate as eGFRcr-cys without requiring specification of race. A more accurate race-free eGFR could be an important advance.

Background The role of glycemic control and its variability on the rate of kidney function decline after the onset of diabetic kidney disease (DKD) remains unclear. Methods The association between baseline glycated hemoglobin (HbA1c) and rates of estimated glomerular filtration rate (eGFR) loss during follow-up was examined by mixed-effects linear regression in 530 individuals with type 1 diabetes and early-to-moderate DKD from the Preventing Early Renal Loss (PERL) trial and 2378 individuals with type 2 diabetes and established DKD from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. The benefit of intensive vs standard glycemic control in slowing eGFR decline was examined in ACCORD. The associations between continuous glucose monitoring-derived short-term glycemic variability indices and rate of eGFR decline were also evaluated in PERL. Results A higher baseline HbA1c was associated with a more negative eGFR slope in both PERL and ACCORD (−0.87 and −0.27 mL/min/1.73 m2/year per Hba1c unit increment, P <.0001 and P =.0002, respectively). In both studies, the strength of this association progressively increased with increasing levels of albuminuria (P for interaction <.05). Consistent with this, the benefit of intensive glycemic control on eGFR decline was greater in ACCORD participants with severe rather than moderate albuminuria (+1.13 vs + 0.26 mL/min/1.73 m2/year, P =.01). No independent associations were found in PERL between short-term glycemic variability indices and rate of eGFR decline. Conclusion In both type 1 and type 2 diabetes, poor glycemic control is associated with a more rapid rate of glomerular filtration rate decline after DKD onset, especially in persons with severe albuminuria. [ABSTRACT FROM AUTHOR]

Metformin is the first-line treatment for type 2 diabetes (T2D). Although widely prescribed, the glucose-lowering mechanism for metformin is incompletely understood. Here, we used a genome-wide association approach in a diverse group of individuals with T2D from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial to identify common and rare variants associated with HbA1c response to metformin treatment and followed up these findings in four replication cohorts. Common variants in PRPF31 and CPA6 were associated with worse and better metformin response, respectively (P < 5 × 10-6), and meta-analysis in independent cohorts displayed similar associations with metformin response (P = 1.2 × 10-8 and P = 0.005, respectively). Previous studies have shown that PRPF31(+/-) knockout mice have increased total body fat (P = 1.78 × 10-6) and increased fasted circulating glucose (P = 5.73 × 10-6). Furthermore, rare variants in STAT3 associated with worse metformin response (q

Results of previous studies have suggested that cardiovascular autonomic neuropathy (CAN) may predict rapid kidney function decline among people with diabetes. We analyzed the association between baseline CAN and subsequent glomerular filtration rate (GFR) decline among individuals with type 1 diabetes (T1D) from the Preventing Early Renal Loss in Diabetes (PERL) study (N = 469) and with type 2 diabetes (T2D) from Action to Control Cardiovascular Risk in Diabetes (ACCORD) (N = 7,973). Baseline CAN was ascertained with electrocardiogram-derived heart rate variability indices. Its association with GFR slopes, rapid kidney function decline (GFR loss of ≥5 mL/min/1.73 m2/year), and ≥40% GFR loss was evaluated by linear mixed-effects, logistic, and Cox regression, respectively. Participants with CAN experienced more rapid GFR decline, by an excess 1.15 mL/min/1.73 m2/year (95% CI −1.93 to −0.37; P = 4.0 × 10−3) in PERL and 0.34 mL/min/1.73 m2/year (95% CI −0.49 to −0.19; P = 6.3 × 10−6) in ACCORD. This translated to 2.11 (95% CI 1.23–3.63; P = 6.9 × 10−3) and 1.39 (95% CI 1.20–1.61; P = 1.1 × 10−5) odds ratios of rapid kidney function decline in PERL and ACCORD, respectively. Baseline CAN was also associated with a greater risk of ≥40% GFR loss events during follow-up (hazard ratio 2.60 [95% CI 1.15–5.45], P = 0.02, in PERL and hazard ratio 1.54 [95% CI 1.28–1.84], P = 3.8 × 10−6, in ACCORD). These associations remained significant after adjustment for potential confounders, including baseline GFR and albuminuria. Our findings indicate that CAN is a strong, independent predictor of rapid kidney function decline in both T1D and T2D. Further studies of the link between these two complications may help with development of new therapies to prevent kidney function decline in patients with diabetes. Article Highlights: Cardiovascular autonomic neuropathy is a strong and independent predictor of rapid kidney function decline in both type 1 and type 2 diabetes. Autonomic nervous system dysfunction may serve as a novel target to develop new therapies to prevent kidney function loss in diabetes. Electrocardiogram-derived indices of cardiovascular autonomic neuropathy might be useful, when added to known clinical risk factors, to improve the identification of patients at high risk of rapid kidney function loss and select them for intensive preventive treatments. [ABSTRACT FROM AUTHOR]

Although mast cell functions have classically been related to allergic responses, recent studies indicate that these cells contribute to other common diseases such as multiple sclerosis, rheumatoid arthritis, atherosclerosis, aortic aneurysm and cancer. This study presents evidence that mast cells also contribute to diet-induced obesity and diabetes. For example, white adipose tissue (WAT) from obese humans and mice contain more mast cells than WAT from their lean counterparts. Furthermore, in the context of mice on a Western diet, genetically induced deficiency of mast cells, or their pharmacological stabilization, reduces body weight gain and levels of inflammatory cytokines, chemokines and proteases in serum and WAT, in concert with improved glucose homeostasis and energy expenditure. Mechanistic studies reveal that mast cells contribute to WAT and muscle angiogenesis and associated cell apoptosis and cathepsin activity. Adoptive transfer experiments of cytokine-deficient mast cells show that these cells, by producing interleukin-6 (IL-6) and interferon-gamma (IFN-gamma), contribute to mouse adipose tissue cysteine protease cathepsin expression, apoptosis and angiogenesis, thereby promoting diet-induced obesity and glucose intolerance. Our results showing reduced obesity and diabetes in mice treated with clinically available mast cell-stabilizing agents suggest the potential of developing new therapies for these common human metabolic disorders.