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Background: d-alanine administration prevented kidney damage in a murine acute kidney injury model. Further data are needed on the influence of d-alanine on kidney function in humans. Objective: This study investigated the effects of d-alanine intake on amino acid metabolism and kidney function in healthy volunteers. Methods: This multicenter pilot study randomly assigned individuals from the general Japanese population to receive 3 g or 6 g of d-alanine intake per day for 7 d in a 1:1 ratio. The primary endpoint was the mean change in plasma and urine d-alanine levels from baseline to 7 d after intake. The secondary endpoints were mean changes in kidney function and other clinical factors. Safety was assessed by evaluating adverse events and clinical parameters. Results: We randomly assigned 24 participants to the 3-g (n = 12) and 6-g d-alanine (n = 12) groups. The mean baseline estimated glomerular filtration rate (eGFR) was 73 mL/min/1.73 m2. The mean plasma d-alanine concentration increased from baseline by 77.5 ± 34.3 and 192.1 ± 80.9 nmol/mL in the 3-g and 6-g d-alanine groups (both p < 0.0001), respectively, in a dose-dependent manner (between-group difference: 114.6 nmol/mL; 95% CI: 62.1-167.2; P = 0.0002). A similar increase was observed for the urine d-alanine to creatinine ratio. The mean eGFR was elevated by 5.7 ± 8.8 mL/min/1.73 m2 in the 6-g d-alanine group (P = 0.045) but did not significantly change in the 3-g d-alanine group. Nonserious adverse events were reported in 11 participants. Conclusions: d-alanine intake increased plasma and urine d-alanine levels and was well tolerated in participants with normal kidney function. These results will be useful in future trials investigating the effects of d-alanine intake on kidney disease progression in patients with chronic kidney disease.This trial was registered at the UMIN Clinical Trials Registry as UMIN000051466.
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Introduction: Autoantibodies to erythropoietin receptor (anti-EPOR antibodies) have been identified in patients with various kidney diseases. However, data in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) is limited. We assessed the prevalence of anti-EPOR antibodies and their association with clinical outcomes in this population. Methods: The CREDENCE randomized patients with T2D and CKD to canagliflozin or placebo. Serum anti-EPOR antibodies, the exposure of interest, were measured using enzyme-linked immunosorbent assay. The primary outcome was doubling of serum creatinine, end-stage kidney disease, or death from kidney or cardiovascular (CV) causes. Secondary outcomes included CV and all-cause mortality. Multivariable Cox-regression models estimated associations between anti-EPOR antibodies and outcomes. The effects of canagliflozin on hemoglobin and hematocrit, stratified by the presence of anti-EPOR antibodies were assessed with a repeated measures mixed effects model. Results: Of 2600 participants with available biosamples, 191 (7.3%) were positive for anti-EPOR antibodies. Higher baseline anti-EPOR antibodies were associated with increased risk of primary outcome (hazard ratio [HR] per 1-SD increase = 1.12, 95% confidence interval [CI] = 1.01-1.24, P = 0.04), with CV death (HR = 1.27, 95% CI = 1.08-1.48, P < 0.01) and all-cause mortality (HR = 1.26, 95% CI = 1.11-1.43, P < 0.01). During follow-up, canagliflozin, compared to placebo, increased hemoglobin and hematocrit by 7.0 g/l (95% CI = 6.2-7.9) and 2.4% (2.2-2.7), respectively. These effects were consistent across patients with and without anti-EPOR antibodies (P-interaction = 0.24 and 0.36, respectively). Conclusion: In patients with T2D and CKD, anti-EPOR antibodies were associated with the composite kidney and CV outcome, as well as CV and all-cause mortality. Canagliflozin increased hemoglobin and hematocrit regardless of anti-EPOR antibodies.
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BACKGROUND: This post-hoc analysis of the DELIGHT trial assessed effects of the SGLT2 inhibitor dapagliflozin on iron metabolism and markers of inflammation. METHODS: Patients with type 2 diabetes and albuminuria were randomized to dapagliflozin, dapagliflozin and saxagliptin, or placebo. We measured hemoglobin, iron markers (serum iron, transferrin saturation, and ferritin), plasma erythropoietin, and inflammatory markers (urinary MCP-1 and urinary/serum IL-6) at baseline and week 24. RESULTS: 360/461 (78.1%) participants had available biosamples. Dapagliflozin and dapagliflozin-saxagliptin, compared to placebo, increased hemoglobin by 5.7 g/L (95%CI 4.0, 7.3; p < 0.001) and 4.4 g/L (2.7, 6.0; p < 0.001) and reduced ferritin by 18.6% (8.7, 27.5; p < 0.001) and 18.4% (8.7, 27.1; p < 0.001), respectively. Dapagliflozin reduced urinary MCP-1/Cr by 29.0% (14.6, 41.0; p < 0.001) and urinary IL-6/Cr by 26.6% (9.1, 40.7; p = 0.005) with no changes in other markers. CONCLUSIONS: Dapagliflozin increased hemoglobin and reduced ferritin and urinary markers of inflammation, suggesting potentially important effects on iron metabolism and inflammation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02547935.
Subject(s)
Diabetes Mellitus, Type 2 , Renal Insufficiency, Chronic , Humans , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/drug therapy , Iron/metabolism , Iron/therapeutic use , Erythropoiesis , Interleukin-6/metabolism , Hypoglycemic Agents/therapeutic use , Benzhydryl Compounds/adverse effects , Hemoglobins/metabolism , Hemoglobins/therapeutic use , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/drug therapy , Inflammation/diagnosis , Inflammation/drug therapy , Ferritins , Double-Blind MethodSubject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Fatty Liver , Renal Insufficiency, Chronic , Humans , Canagliflozin/therapeutic use , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Fatty Liver/complications , Fatty Liver/drug therapy , Fibrosis , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/drug therapyABSTRACT
BACKGROUND: In the DAPA-CKD (Dapagliflozin in Patients with Chronic Kidney Disease) trial, dapagliflozin improved kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD) with or without type 2 diabetes (T2D). In this post hoc analysis of DAPA-CKD, we assessed the effects of dapagliflozin on the correction and prevention of anemia. METHODS: The DAPA-CKD trial randomized patients (1:1) with an estimated glomerular filtration rate of 25 to 75 ml/min/1.73 m2 and a urinary albumin-to-creatinine ratio of 200 to 5000 mg/g to receive dapagliflozin 10 mg or placebo daily. Hematocrit was measured at baseline, 2 weeks, 2 and 4 months, and every 4 months thereafter. Anemia was defined as hematocrit less than 39% in men and less than 36% in women. Correction and incidence of anemia were defined as two consecutive measurements above or below these thresholds relative to baseline, respectively, during follow-up. We classified anemia-related adverse events using data from site investigator reports. RESULTS: Mean age of the 4304 participants was 61.8 years, and 67.5% had T2D. Among the 4292 (99.7%) participants with baseline hematocrit data, 1716 (40.0%) had anemia. Over the 2.4-year median follow-up, patients assigned to dapagliflozin had an increase in hematocrit of 2.3 percentage points (95% confidence interval [CI], 2.1 to 2.5) greater than those assigned to placebo. Among patients with anemia at baseline, anemia was corrected in 443 (53.3%) patients randomized to receive dapagliflozin and 247 (29.4%) patients randomized to receive placebo (hazard ratio, 2.29; 95% CI, 1.96 to 2.68). Among patients without anemia at baseline, 10.4% of patients assigned to dapagliflozin developed incident anemia compared with 23.7% in the placebo group (hazard ratio, 0.39; 95% CI, 0.31 to 0.48). Anemia-related adverse events occurred in 2.2% of patients assigned to dapagliflozin compared with 3.8% assigned to placebo. Effects of dapagliflozin on the correction and prevention of anemia were consistent in patients with and without T2D. The adverse event profile was similar to that known for dapagliflozin. CONCLUSIONS: This exploratory analysis suggests that dapagliflozin is associated with the prevention or correction of anemia in patients with CKD with and without T2D. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT03036150.)
Subject(s)
Anemia , Diabetes Mellitus, Type 2 , Glucosides , Renal Insufficiency, Chronic , Humans , Benzhydryl CompoundsABSTRACT
OBJECTIVE: The inflammatory cytokine interleukin-6 (IL-6) is associated with cardiovascular (CV) and kidney outcomes in various populations. However, data in patients with type 2 diabetes are limited. We assessed the association of IL-6 with CV and kidney outcomes in the Canagliflozin Cardiovascular Assessment Study (CANVAS) and determined the effect of canagliflozin on IL-6. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes at high CV risk were randomly assigned to canagliflozin or placebo. Plasma IL-6 was measured at baseline and years 1, 3, and 6. The composite CV outcome was nonfatal myocardial infarction, nonfatal stroke, or CV death; the composite kidney outcome was sustained ≥40% estimated glomerular filtration rate decline, end-stage kidney disease, or kidney-related death. Multivariable-adjusted Cox proportional hazards regression was used to estimate the associations between IL-6 and the outcomes. The effect of canagliflozin on IL-6 over time was assessed with a repeated-measures mixed-effects model. RESULTS: The geometric mean IL-6 at baseline, available in 3,503 (80.2%) participants, was 1.7 pg/mL. Each doubling of baseline IL-6 was associated with 14% (95% CI 4, 24) and 21% (95% CI 1, 45) increased risk of CV and kidney outcomes, respectively. Over 6 years, IL-6 increased by 5.8% (95% CI 3.4, 8.3) in the placebo group. Canagliflozin modestly attenuated the IL-6 increase (absolute percentage difference vs. placebo 4.4% [95% CI 1.3, 9.9; P = 0.01]). At year 1, each 25% lower level of IL-6 compared with baseline was associated with 7% (95% CI 1, 22) and 14% (95% CI 5, 22) lower risks for the CV and kidney outcome, respectively. CONCLUSIONS: In patients with type 2 diabetes at high CV risk, baseline IL-6 and its 1-year change were associated with CV and kidney outcomes. The effect of IL-6-lowering therapy on CV, kidney, and safety outcomes remains to be tested.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Sodium-Glucose Transporter 2 Inhibitors , Humans , Canagliflozin , Cardiovascular Diseases/complications , Diabetes Mellitus, Type 2/complications , Interleukin-6 , Kidney , Sodium-Glucose Transporter 2 Inhibitors/therapeutic useABSTRACT
Recently, several cases of novel apolipoprotein E (apoE)-related glomerular disease known as membranous nephropathy (MN)-like apoE deposition disease with apoE Toyonaka (Ser197Cys) and homozygous apoE2/2 have been reported. However, the clinical and pathological characteristics are uncertain due to the small number of reports. Here, we report an additional case with various clinical and pathological characteristics. A 28-year-old Japanese man with mild proteinuria and hematuria underwent a kidney biopsy. Examination under a light microscope revealed mesangial proliferation, mesangial matrix expansion, and segmental spike lesion. An immunofluorescence study showed no immunoglobulin or complement depositions. In the electron microscopic (EM) examination, massive deposits with various electron densities in the subepithelial, subendothelial, and paramesangial areas were more prominent than those reported in previous cases, which resembled microbubbles or microcysts on higher magnification. The glomerular basement membrane (GBM) structure was partly degenerated by these deposits. Serum triglyceride and cholesterol levels were within the normal range. However, the serum apoE concentration was significantly high, and glomerular apoE accumulation was detected in immunohistochemistry. The DNA sequence revealed apoE Toyonaka and homozygous apoE2/2 similar to that of the previous cases with MN-like apoE deposition disease. MN-like apoE deposition disease can manifest as only mild hematuria and proteinuria without dyslipidemia. Various characteristic deposits associated with GBM degeneration can be observed in the EM study.
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AIMS: To test the hypothesis that the reduction in urinary kidney injury molecule-1 (KIM-1) observed with the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin is mediated through its effects on urine albumin to creatinine ratio (UACR) and monocyte chemoattractant protein-1 (MCP-1) by assessing the proportion of the effect of canagliflozin on KIM-1 that is mediated through its effects on MCP-1 and UACR in patients with type 2 diabetes and albuminuric kidney disease. MATERIAL AND METHODS: We measured KIM-1 and MCP-1 levels in urine samples from the CANVAS trial at baseline and Week 52 with the Mesoscale QuickPlex SQ 120 platform. KIM-1 and MCP-1 were standardized by urinary creatinine (Cr). The proportion of the effect of canagliflozin that is mediated through UACR and MCP-1/Cr on KIM-1/Cr was estimated with G-computation. RESULTS: In total, 763 patients with micro- or macroalbuminuria (17.6% of the total cohort) were included. Baseline characteristics were well balanced between the canagliflozin and placebo group. At Year 1, canagliflozin compared to placebo reduced UACR, MCP-1/Cr and KIM-1/Cr by 40.4% (95% CI 31.0, 48.4), 18.1% (95% CI 8.9, 26.4) and 30.9% (95% CI 23.0, 38.0), respectively. The proportion of the effect of canagliflozin on KIM-1/Cr mediated by its effect on UACR and in turn on MCP-1/Cr was 15.2% (95% CI 9.4, 24.5). CONCLUSION: Canagliflozin reduces urinary KIM-1, suggesting decreased tubular damage. This effect was partly mediated through a reduction in MCP-1, indicative of reduced tubular inflammation, which was in turn mediated by a reduction in UACR. This post hoc analysis suggests that urinary albumin leakage may lead to tubular inflammation and induction of injury, and provide mechanistic insight for how canagliflozin may ameliorate tubular damage, but further research is required to confirm these findings.
Subject(s)
Diabetes Mellitus, Type 2 , Sodium-Glucose Transporter 2 Inhibitors , Albumins , Canagliflozin/therapeutic use , Creatinine/urine , Diabetes Mellitus, Type 2/chemically induced , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Glucose/therapeutic use , Humans , Inflammation/chemically induced , Inflammation/drug therapy , Mediation Analysis , Sodium , Sodium-Glucose Transporter 2 , Sodium-Glucose Transporter 2 Inhibitors/therapeutic useABSTRACT
INTRODUCTION: We examined the impact of autoantibodies on the erythropoietin receptor (EPOR) in type 2 diabetic patients with chronic kidney disease (CKD). METHODS: A total of 112 Japanese patients with type 2 diabetes who had CKD were enrolled in this study and followed for a mean of 45 months. Sera from these patients were screened for anti-EPOR antibodies using enzyme-linked immunosorbent assays. RESULTS: Anti-EPOR antibodies were detected in 26 patients (23%). Anti-EPOR antibodies were associated with low hemoglobin concentrations and decreased renal function. In patients with biopsy-proven diabetic nephropathy, anti-EPOR antibodies were associated with increased levels of interstitial inflammation. A decrease in renal function was observed more frequently in patients with antibodies than in those without antibodies, and the presence of the antibodies together with well-known clinical parameters, including proteinuria and low glomerular filtration rate, was a significant risk factor for end-stage renal disease. In human tubular epithelial HK-2 cells, IgG fractions containing anti-EPOR antibodies upregulated the expression of monocyte chemoattractant protein-1 mRNA under a high concentration of glucose. CONCLUSION: Anti-EPOR antibodies might be involved in the progression of renal lesions and in the impaired erythropoiesis in type 2 diabetic patients with CKD. Furthermore, the presence of anti-EPOR antibodies may be an additional predictor for end-stage renal disease in type 2 diabetes.