Urinary excretion of RAS, BMP, and WNT pathway components in diabetic kidney disease.

Abstract The renin-angiotensin system (RAS), bone morphogenetic protein (BMP), and WNT pathways are involved in pathogenesis of diabetic kidney disease (DKD). This study characterized assays for urinary angiotensinogen (AGT), gremlin-1, and matrix metalloproteinase 7 (MMP-7), components of the RAS, BMP, and WNT pathways and examined their excretion in DKD. We measured urine AGT, gremlin-1, and MMP-7 in individuals with type 1 diabetes and prevalent DKD (n = 20) or longstanding (n = 61) or new-onset (n = 10) type 1 diabetes without DKD. These urine proteins were also quantified in type 2 DKD (n = 11) before and after treatment with candesartan. The utilized immunoassays had comparable inter- and intra-assay and intraindividual variation to assays used for urine albumin. Median (IQR) urine AGT concentrations were 226.0 (82.1, 550.3) and 13.0 (7.8, 20.0) μg/g creatinine in type 1 diabetes with and without DKD, respectively (P < 0.001). Median (IQR) urine gremlin-1 concentrations were 48.6 (14.2, 254.1) and 3.6 (1.7, 5.5) μg/g, respectively (P < 0.001). Median (IQR) urine MMP-7 concentrations were 6.0 (3.8, 10.5) and 1.0 (0.4, 2.9) μg/g creatinine, respectively (P < 0.001). Treatment with candesartan was associated with a reduction in median (IQR) urine AGT/creatinine from 23.5 (1.6, 105.1) to 2.0 (1.4, 13.7) μg/g, which did not reach statistical significance. Urine gremlin-1 and MMP-7 excretion did not decrease with candesartan. In conclusion, DKD is characterized by markedly elevated urine AGT, MMP-7, and gremlin-1. AGT decreased in response to RAS inhibition, suggesting that this marker reflects therapeutic response. Urinary components of the RAS, BMP, and WNT pathways may identify risk of DKD and aid development of novel therapeutics

Effects of amino acids and glucose on mesangial cell aminopeptidase a and angiotensin receptors

Effects of amino acids and glucose on mesangial cell aminopeptidase a and angiotensin receptors.BackgroundHigh protein diets and diabetes increase renal renin angiotensin system (RAS) activity, which is associated with glomerular injury. Aminopeptidase A (APA) is a cell surface metalloprotease that degrades angiotensin II (AII) in the mesangium. Mesangial cells (MC) also possess receptors for AII; the type 1 (AT1 receptor) promotes proliferation and fibrosis, while the type 2 (AT2 receptor) opposes these effects. We evaluated whether amino acids and glucose alter expression of APA, AT1 receptor and AT2 receptor in a manner that further augments RAS activity.MethodsConfluent rat MC were grown in serum-free media for 48 hours prior to exposing to experimental conditions: control (C), high amino acids (HA, mixed amino acid solution added to raise concentrations 5- to 6-fold over C), high glucose (HG 30, mM glucose). Semi-quantitative RT-PCR was used to assess mRNA for APA, AT1 receptor, AT2 receptor, and β-actin. Values are expressed relative to βbgr; actin.ResultsBoth HA and HG reduced APA mRNA (HG 1.13 ± 0.19, HA 1.12 ± 0.16 versus C 1.27 ± 0.16 P < 0.05, N = 8). HA increased AT1 receptor mRNA (HA 2.11 ± 0.43 versus C 1.14 ± 0.28 P < 0.05, N = 8). HG increased AT2 receptor mRNA (HG 1.31 ± 0.43 versus C 0.82 ± 0.33 P < 0.05, N = 6).ConclusionsA reduction of APA, in response to high levels of amino acids or glucose, could contribute to increased AII as a result of decreased degradation in MC. The effect of amino acids to increase AT1 receptor expression may further enhance adverse hemodynamic and pro-fibrotic actions of AII. Conversely, glucose increased AT2 receptor expression, which could modulate responses mediated by the AT1 receptor

New strategies to improve clinical outcomes for diabetic kidney disease

BACKGROUND: Diabetic kidney disease (DKD), the most common cause of kidney failure and end-stage kidney disease worldwide, will develop in almost half of all people with type 2 diabetes. With the incidence of type 2 diabetes continuing to increase, early detection and management of DKD is of great clinical importance. MAIN BODY: This review provides a comprehensive clinical update for DKD in people with type 2 diabetes, with a special focus on new treatment modalities. The traditional strategies for prevention and treatment of DKD, i.e., glycemic control and blood pressure management, have only modest effects on minimizing glomerular filtration rate decline or progression to end-stage kidney disease. While cardiovascular outcome trials of SGLT-2i show a positive effect of SGLT-2i on several kidney disease-related endpoints, the effect of GLP-1 RA on kidney-disease endpoints other than reduced albuminuria remain to be established. Non-steroidal mineralocorticoid receptor antagonists also evoke cardiovascular and kidney protective effects. CONCLUSION: With these new agents and the promise of additional agents under clinical development, clinicians will be more able to personalize treatment of DKD in patients with type 2 diabetes

Safety of Empagliflozin in Patients With Type 2 Diabetes and Chronic Kidney Disease: Pooled Analysis of Placebo-Controlled Clinical Trials

OBJECTIVE: To assess the safety of empagliflozin in patients with type 2 diabetes and moderate to severe chronic kidney disease (CKD) (category G3-4) enrolled in clinical trials. RESEARCH DESIGN AND METHODS: This analysis pooled data from 19 randomized, placebo-controlled, phase 1-4 clinical trials and 1 randomized, placebo-controlled extension study in which patients received empagliflozin 10 mg or 25 mg daily. Time to first occurrence of adverse events (AEs) was evaluated using Kaplan-Meier analysis and multivariable Cox regression models. RESULTS: Among a total of 15,081 patients who received at least one study drug dose, 1,522, 722, and 123 were classified as having G3A, G3B, and G4 CKD, respectively, at baseline. Demographic and clinical characteristics were similar between treatment groups across CKD categories. Rates of serious AEs, AEs leading to discontinuation, and events of special interest (including lower limb amputations and acute renal failure [ARF]) were also similar between empagliflozin and placebo across CKD subgroups. In adjusted Cox regression analyses, risks for volume depletion and ARF were similar for empagliflozin and placebo in the combined group with CKD categories G3B and G4 and the G3A group. Notably lower risks were observed in both groups for hyperkalemia (hazard ratio 0.59 [95% CI 0.37-0.96, P = 0.0323] and 0.48 [0.26-0.91, P = 0.0243], respectively) and edema (0.47 [0.33-0.68, P < 0.0001] and 0.44 [0.28-0.68, P = 0.0002], respectively). CONCLUSIONS: Use of empagliflozin in patients with type 2 diabetes and advanced CKD raised no new safety concerns and may have beneficial effects on the development of hyperkalemia and edema

Effects of Tirzepatide Versus Insulin Glargine on Cystatin C–Based Kidney Function:A SURPASS-4 Post Hoc Analysis

OBJECTIVE Tirzepatide reduces HbA1c and body weight, and creatinine-based estimated glomerular filtration rate (eGFR) decline. Unlike creatine-derived eGFR (eGFR-creatinine), cystatin C–derived eGFR (eGFR-cystatin C) is unaffected by muscle mass changes. We assessed effects of tirzepatide on eGFR-creatinine and eGFR-cystatin C. RESEARCH DESIGN AND METHODS Our primary outcome was eGFR change from baseline at 52 weeks with pooled tirzepatide (5, 10, and 15 mg) and titrated insulin glargine in adults with type 2 diabetes and high cardiovascular risk (SURPASS-4). RESULTS Least squares mean (SE) eGFR-creatinine (mL/min/1.73 m2) changes from baseline with tirzepatide and insulin glargine were 22.5 (0.38) and 23.9 (0.38) (between-group difference, 1.4 [95% CI 0.3–2.4]) and 23.5 (0.37) and 25.3 (0.37) (between-group difference, 1.8 [95% CI 0.8–2.8]) for eGFR-cystatin C. Baseline, 1-year, and 1-year change from baseline values significantly correlated between eGFR-cystatin C and eGFR-creatinine. Measures of eGFR changes did not correlate with body weight changes. CONCLUSIONS Tirzepatide slows the eGFR decline rate, supporting a kidney-protective effect.</p

Rationale and design of a multicenter Chronic Kidney Disease (CKD) and at-risk for CKD electronic health records-based registry: CURE-CKD.

BACKGROUND: Chronic kidney disease (CKD) is a global public health problem, exhibiting sharp increases in incidence, prevalence, and attributable morbidity and mortality. There is a critical need to better understand the demographics, clinical characteristics, and key risk factors for CKD; and to develop platforms for testing novel interventions to improve modifiable risk factors, particularly for the CKD patients with a rapid decline in kidney function. METHODS: We describe a novel collaboration between two large healthcare systems (Providence St. Joseph Health and University of California, Los Angeles Health) supported by leadership from both institutions, which was created to develop harmonized cohorts of patients with CKD or those at increased risk for CKD (hypertension/HTN, diabetes/DM, pre-diabetes) from electronic health record data. RESULTS: The combined repository of candidate records included more than 3.3 million patients with at least a single qualifying measure for CKD and/or at-risk for CKD. The CURE-CKD registry includes over 2.6 million patients with and/or at-risk for CKD identified by stricter guide-line based criteria using a combination of administrative encounter codes, physical examinations, laboratory values and medication use. Notably, data based on race/ethnicity and geography in part, will enable robust analyses to study traditionally disadvantaged or marginalized patients not typically included in clinical trials. DISCUSSION: CURE-CKD project is a unique multidisciplinary collaboration between nephrologists, endocrinologists, primary care physicians with health services research skills, health economists, and those with expertise in statistics, bio-informatics and machine learning. The CURE-CKD registry uses curated observations from real-world settings across two large healthcare systems and has great potential to provide important contributions for healthcare and for improving clinical outcomes in patients with and at-risk for CKD

Development of an international standard set of value-based outcome measures for patients with chronic kidney disease : a report of the International Consortium for Health Outcomes Measurement (ICHOM) CKD working group

Value-based health care is increasingly promoted as a strategy for improving care quality by benchmarking outcomes that matter to patients relative to the cost of obtaining those outcomes. To support the shift toward value-based health care in chronic kidney disease (CKD), the International Consortium for Health Outcomes Measurement (ICHOM) assembled an international working group of health professionals and patient representatives to develop a standardized minimum set of patient-centered outcomes targeted for clinical use. The considered outcomes and patient-reported outcome measures were generated from systematic literature reviews. Feedback was sought from patients and health professionals. Patients with very high-risk CKD (stages G3a/A3 and G3b/A2-G5, including dialysis, kidney transplantation, and conservative care) were selected as the target population. Using an online modified Delphi process, outcomes important to all patients were selected, such as survival and hospitalization, and to treatment-specific subgroups, such as vascular access survival and kidney allograft survival. Patient-reported outcome measures were included to capture domains of health-related quality of life, which were rated as the most important outcomes by patients. Demographic and clinical variables were identified to be used as case-mix adjusters. Use of these consensus recommendations could enable institutions to monitor, compare, and improve the quality of their CKD care

Rationale and design of a randomised phase III registration trial investigating finerenone in participants with type 1 diabetes and chronic kidney disease:The FINE-ONE trial

Aims: Despite guideline-recommended treatments, including renin angiotensin system inhibition, up to 40 % of individuals with type 1 diabetes develop chronic kidney disease (CKD) putting them at risk of kidney failure. Finerenone is approved to reduce the risk of kidney failure in individuals with type 2 diabetes. We postulate that finerenone will demonstrate benefits on kidney outcomes in people with type 1 diabetes. Methods: FINE-ONE (NCT05901831) is a randomised, placebo-controlled, double-blind phase III trial of 7.5 months’ duration in ∼220 adults with type 1 diabetes, urine albumin/creatinine ratio (UACR) of ≥ 200–&lt; 5000 mg/g (≥ 22.6–&lt; 565 mg/mmol) and eGFR of ≥ 25–&lt; 90 ml/min/1.73 m2. Results: The primary endpoint is relative change in UACR from baseline over 6 months. UACR is used as a bridging biomarker (BB), since the treatment effect of finerenone on UACR was associated with its efficacy on kidney outcomes in the type 2 diabetes trials. Based on regulatory authority feedback, UACR can be used as a BB for kidney outcomes to support registration of finerenone in type 1 diabetes, provided necessary criteria are met. Secondary outcomes include incidences of treatment-emergent adverse events, treatment-emergent serious adverse events and hyperkalaemia. Conclusions: FINE-ONE will evaluate the efficacy and safety of finerenone in type 1 diabetes and CKD. Finerenone could become the first registered treatment for CKD associated with type 1 diabetes in almost 30 years. Trial registration: ClinicalTrials.gov NCT05901831.</p

Executive summary of the KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease:an update based on rapidly emerging new evidence

The Kidney Disease: Improving Global Outcomes (KDIGO) 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (CKD) represents a focused update of the KDIGO 2020 guideline on the topic. The guideline targets a broad audience of clinicians treating people with diabetes and CKD. Topic areas for which recommendations are updated based on new evidence include Chapter 1: Comprehensive care in patients with diabetes and CKD and Chapter 4: Glucose-lowering therapies in patients with type 2 diabetes (T2D) and CKD. The content of previous chapters on Glycemic monitoring and targets in patients with diabetes and CKD (Chapter 2), Lifestyle interventions in patients with diabetes and CKD (Chapter 3), and Approaches to management of patients with diabetes and CKD (Chapter 5) has been deemed current and was not changed. This guideline update was developed according to an explicit process of evidence review and appraisal. Treatment approaches and guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence, and the strength of recommendations followed the “Grading of Recommendations Assessment, Development and Evaluation” (GRADE) approach. Limitations of the evidence are discussed, and areas for which additional research is needed are presented