Composite Renal Outcome Research Articles

The Renal Composite Benefit of Sodium Glucose Co-Transporter 2 Inhibitors Should Ideally Be Assessed Based on a Standardised Definition: A Meta-Analysis of Randomised Controlled Trials.

(1) Background: Chronic kidney disease (CKD) is extremely common against the backdrop of type 2 diabetes (T2D), accounting for nearly 30-40% of cases. The conventional management strategy relie predominantly on metabolic control and the renin-angiotensin-aldosterone system (RAAS) blockage. In the last decade, sodium glucose cotransporter 2 inhibitors (SGLT-2is) have emerged as the leading molecules preventing the development of, as well as retarding, the progression to CKD. Although the evidence in support of SGLT-2is is overwhelming, the definition of renal composite outcome in the trials varied considerably. The aim of the present meta-analysis was to explore the robustness of the renal composite benefits using a uniform definition. (2) Methods: A web-based search was conducted using the Cochrane Library to identify the relevant articles for meta-analysis. RStudio (1 July 2022, Build 554) software was used to conduct the meta-analysis. Hazard ratio (HR) was the effect size used to estimate the renal composite benefit, and prediction interval was used to detect heterogeneity. In view of the differing baseline characteristic of the trials as well as different molecules used, a random effects model was used. (3) Results: There were 12 trials including 78,781 patients, identified using the search strategy, and a five-point Cochrane risk-of-bias was used to assess quality of the publications. In the overall estimation (irrespective of the definition used for the renal composite) the HR was 0.68 (95% CI 0.60-0.76, prediction interval: 0.48-0.95) in favour of SGLT-2is, devoid of heterogeneity. While using a uniform definition of eGFR ≥ 40%decline, ESKD, or renal death, the HR was 0.64 (95% CI 0.53-0.78); using eGFR ≥ 50%decline, ESKD, or renal death the HR was 0.75 (95% CI 0.59-0.97); and with doubling of serum creatinine, renal replacement therapy, or renal death, the HR was 0.67 (95% CI 0.55-0.83) in favour of SGLT-2is. However, significant heterogeneity was encountered with all these three definitions. (4) Conclusion: There is a need to analyse the renal outcomes using a uniform definition in future trials. The presence of heterogeneity might disappear with the pooling of larger number of trials. However, if heterogeneity persists, we need to identify other clinical or laboratory attributes (in addition to SGLT-2is) responsible for the positive renal outcomes.

Effect of Lipid-Lowering Drugs on Renal and Cardiovascular Outcomes in Patients with Chronic Kidney Disease and Dyslipidemia: ARetrospective Cohort Study.

The effects of lipid-lowering drugs (LLDs) on cardiovascular and renal outcomes in patients with advanced chronic kidney disease (CKD) and dyslipidemia are not completely understood. We conducted a retrospective cohort study to evaluate the effect of LLDs on end-stage kidney disease (ESKD), major adverse cardiovascular events (MACEs), and mortality in adult patients with CKD stage 3b, 4, or 5, and dyslipidemia. Participants were recruited between January 1, 2008, and December 31, 2018, and classified as LLD or non-LLD users; the final follow-up date was December 31, 2020. The primary outcome was time to ESKD or death due to renal failure. Sub-distribution hazard regression models adjusted for multivariables, including time-varying lipid profile covariates, were used for the analysis. Among the 6,740 participants, 4,280 patients with CKD and dyslipidemia, including 872 using LLDs and 3,408 not using LLDs, completed the primary analysis. The multivariable analyses showed that LLD users had a significantly lower risk of time to the composite renal outcome (adjusted hazard ratio [aHR], 0.76, 95% confidence interval [CI], 0.65-0.89), and MACE incidence (aHR, 0.75, 95% CI, 0.62-0.93) than did non-LLD users. After adjusting for time-varying covariates of the lipid profile, there was a significant difference in the composite renal outcome (aHR, 0.78, 95% CI, 0.65-0.93) and MACEs (aHR, 0.77, 95% CI, 0.60-0.98). Among adult patients with advanced CKD and dyslipidemia, LLD users had a significantly lower risk of composite renal outcomes and MACEs than non-LLD users. In addition to reducing lipid profile, the use of LLD is associated with renal and cardiovascular protective effects.

THU287 Comparison Of Renal Protective Effects Between SGLT2 Inhibitors And DPP4 Inhibitors In Real-World Clinical Practice

Abstract Disclosure: H. Park: None. S. Park: None. S. Kwon: None. H. Kim: None. D. Byun: None. Recent prospective randomized studies have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors had renal protective effects compared to placebo. In this study, we compared the renal composite outcomes between patients with diabetes treated with SGLT2 inhibitors and those treated with dipeptidyl peptidase 4 (DPP4) inhibitors using real-world clinical data. This retrospective observational study used the Observational Medical Outcomes Partnership Common Data Model (OMOP-CDM) database at four different university hospitals (Soonchunhyang university hospitals in Seoul, Bucheon, Chunan, and Gumi) in Korea. Subjects prescribed SGLT2 inhibitors or DPP4 inhibitors for at least 90 days were included in the SGLT2 inhibitor or DPP4 inhibitor group, respectively. Subjects prescribed GLP-1 receptor agonist or insulin were excluded in both groups. Renal composite outcomes included a 30% decline in estimated glomerular filtration rate (eGFR) compared to baseline or creatinine doubling or dialysis or death from any cause. After propensity score matching, clinical characteristics in each group at each hospital were well balanced at baseline. Our results from hospitals in Seoul, Bucheon, and Gumi have shown that SGLT2 inhibitor decreased renal composite outcomes compared to DPP4 inhibitor (hazard ratio (HR) 0.644, p=0.020; HR 0.560, p<0.001; HR 0.657, p=0.010, respectively). Furthermore, when all the data were combined, renal composite outcomes were significantly lower in the SGLT2 inhibitor group compared to the DPP4 inhibitor group (HR 0.659, p<0.001). In conclusion, SGLT2 inhibitors effectively reduce renal composite outcomes compared to DPP4 inhibitors in real-world clinical practice. Presentation: Thursday, June 15, 2023

Chronic kidney outcomes associated with GLP-1 receptor agonists versus long-acting insulins among type 2 diabetes patients requiring intensive glycemic control: a nationwide cohort study

BackgroundEffectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus long-acting insulins (LAIs) on preventing progressive chronic kidney outcomes is uncertain for type 2 diabetes (T2D) patients requiring intensive glycemic control. This study aimed to evaluate comparative effectiveness of GLP-1RA versus LAI therapies on progressive chronic kidney outcomes among patients having poor glycemic control and requiring these injectable glucose-lowering agents (GLAs).Methods7279 propensity-score-matched pairs of newly stable GLP-1RA and LAI users in 2013–2018 were identified from Taiwan’s National Health Insurance Research Database and followed until death or 12/31/2019 (intention-to-treat). Subdistributional hazard model was utilized to assess the comparative effectiveness on a composite renal outcome (i.e., renal insufficiency [eGFR < 15 mL/min/1.73 m2], dialysis-dependent end-stage renal disease [ESRD], or renal death) and its individual components. Sensitivity analyses with the as-treated scenario, PS weighting, high-dimensional PS techniques, using cardiovascular diseases (CVDs) as positive control outcomes, and interaction testing were performed.ResultsIn primary analyses, subdistribution hazard ratios (95% CIs) for initiating GLP-1RAs versus LAIs for the composite renal outcome, renal insufficiency, dialysis-dependent ESRD, and renal death were 0.39 (0.30–0.51), 0.43 (0.32–0.57), 0.29 (0.20–0.43), and 0.28 (0.15–0.51), respectively. Sensitivity analysis results were consistent with the primary findings. CVD history and the medication possession ratio of prior oral GLAs possessed modification effects on GLP-1RA-associated kidney outcomes.ConclusionUsing GLP-1RAs versus LAIs was associated with kidney benefits in T2D patients requiring intensive glycemic control and potentially at high risk of kidney progression. GLP-1RAs should be prioritized to patients with CVDs or adherence to prior oral GLAs to maximize kidney benefits.

The concomitant use of sodium-glucose co-transporter 2 inhibitors improved the renal outcome of Japanese patients with type 2 diabetes treated with glucagon-like peptide 1 receptor agonists.

This study aimed to clarify the renal influence of glucagon-like peptide 1 receptor agonists (GLP1Ras) with or without sodium-glucose co-transporter 2 inhibitors (SGLT2is) on Japanese patients with type 2 diabetes mellitus (T2DM). We retrospectively extracted 547 patients with T2DM who visited the clinics of members of Kanagawa Physicians Association. The progression of albuminuria status and/or a ≥ 15% decrease in the estimated glomerular filtration rate (eGFR) per year was set as the renal composite outcome. Propensity score matching was performed to compare GLP1Ra-treated patients with and without SGLT2i. After matching, 186 patients in each group were compared. There was no significant difference of the incidence of the renal composite outcomes (17% vs. 20%, P = 0.50); however, the annual decrease in the eGFR was significantly smaller and the decrease in the urine albumin-to-creatinine ratio was larger in GLP1Ra-treated patients with the concomitant use of SGLT2is than in those without it (-1.1 ± 5.0 vs. -2.8 ± 5.1 mL/min/1.73 m2, P = 0.001; and -0.08 ± 0.61 vs. 0.05 ± 0.52, P = 0.03, respectively). The concomitant use of SGLT2i with GLP1Ra improved the annual decrease in the eGFR and the urine albumin-to-creatinine ratio in Japanese patients with T2DM.

Efficacy and safety of sodium-glucose cotransporter-2 inhibitors in patients with chronic kidney disease: a systematic review and meta-analysis.

Owing to the pharmacological mechanism, sodium-glucose cotransporter 2 inhibitors (SGLT2is) may be less effective in patients with reduced renal functions, but no systematic review or meta-analysis addressed chronic kidney disease (CKD) patients specifically. We aimed to assess the efficacy and safety of SGLT2is in CKD patients. We conducted a systematic review and meta-analysis of randomized controlled trials. Mean difference (MD) were pooled for the decline of glomerular filtration rate (eGFR) and change in urine albumin-to-creatinine ratio (uACR). Hazard ratio (HR) and rate ratio (RR) were pooled for composite of renal outcomes and adverse effects. Thirty articles were identified. Overall MD in rate of eGFR decline was 0.02 (P = 0.05), with a borderline significant difference favoring SGLT2is, while the change in uACR from baseline was - 141.34mg/g and hazard ratio of composite renal outcomes was 0.64 significantly favoring SGLT2is. Subgroup analyses showed that the long-term renal function, participants with baseline macroalbuminuria, and stage 4 CKD patients had significantly slower eGFR decline rate in SGLT2is compared to the placebo group. Risks of genital mycotic infection and ketoacidosis were significantly higher among the SGLT2is group than placebo. For CKD patients, no matter diabetic or non-diabetic, our study showed potential renoprotective effects favoring SGLT2is in overall and long-term phase, and in patients with macroalbuminuria or stage 4 CKD. However, only slight increased risk of adverse effects among the SGLT2is group is observed. Therefore, we concluded that in CKD patients, prescribing SGLT2is was safe and had renal benefits.

Racial, ethnic and regional differences in the effect of sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists on cardiovascular and renal outcomes: a systematic review and meta-analysis of cardiovascular outcome trials.

The cardiorenal protective effects of sodium-glucose co-transporter 2 inhibitors (SGLT2-Is) and glucagon-like peptide 1 receptor agonists (GLP1-RAs) across racial and ethnic groups are not well defined. By conducting a systematic review and meta-analysis of all randomised, placebo-controlled, cardiovascular disease (CVD) outcomes trials (CVOTs), we aimed to compare racial/ethnic as well as regional patterns in the effects of SGLT2-Is and GLP1-RAs on cardiovascular and renal outcomes in patients with type 2 diabetes (T2D). Trials were identified from MEDLINE, Embase, the Cochrane Library, and search of bibliographies to 7 July 2023. Setting North America, South/Central America, Europe (Eastern and Western), Asia, Australia-New Zealand (Pacific), Asia/Pacific, and Africa. North America, South/Central America, Europe (Eastern and Western), Asia, Australia-New Zealand (Pacific), Asia/Pacific, and Africa. people with type 2 diabetes enrolled in cardiovascular outcome trials of SGLT2-Is and GLP1-RAs. Outcomes were (i) major adverse cardiovascular events (MACE), (ii) composite CVD death/heart failure (HF) hospitalization; (iii) composite renal outcome; and (iv) their components. Study-specific hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled. In total, 14 unique CVOTs (7 comparing SGLT2-Is vs placebo and 7 comparing GLP1-RAs vs placebo) were eligible. The proportion of participants enrolled in the trials ranged from 66.6-93.2% for White populations, 1.2-21.6% for Asian populations, 2.4-8.3% for Black populations and 0.9-23.1% for Other populations. The HR (95% CI) for MACE comparing SGLT2-Is vs placebo was 0.92 (0.86-0.98), 0.69 (0.53-0.92) and 0.70 (0.54-0.91) for White, Asian and Hispanic/Latino populations, respectively. Comparing GLP1-RAs vs placebo, the corresponding HR (95% CI) was 0.88 (0.80-0.97), 0.76 (0.63-0.93) and 0.82 (0.70-0.95), respectively. SGLT2-Is reduced the risk of all other cardiorenal outcomes in White and Asian populations, except for HF hospitalizations in Asians. No effects were observed in Black populations except for a reduced risk of HF hospitalizations by SGLT2-I. SGLT1-Is reduced the risk of composite CVD death/HF hospitalization in North America and Europe, whereas GLP1-RAs reduced the risk of MACE in Europe. GRADE certainty of evidence ranged from moderate to high. There appears to be substantial racial/ethnic differences in the cardiorenal effects of SGLT2-Is and GLP1-RAs in patients with T2D, with consistent benefits observed among White and Asian populations and consistent lack of benefits in Black populations. Whether the differences are due to issues with under-representation of Black populations and low statistical power or racial/ethnic variations in the pharmacokinetics, pharmacodynamics and safety of SGLT2-Is and GLP1-RAs need further investigation.PROSPERO Registration: CRD42023401734.

Renal Outcomes in Older Adults with Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis: A New Prediction Model

Introduction: Older patients with antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) commonly experience renal impairment and poor prognoses. This study aimed to establish a risk-scoring system for predicting composite renal outcomes in older patients with AAV. Methods: This retrospective observational study included all patients with AAV hospitalized in a single-center tertiary hospital in China between January 2013 and April 2022. Patients aged ≥65 years were defined as older adults and short-term composite renal outcomes included a ≥25% reduction in estimated glomerular filtration rate (eGFR) (for AKI), renal replacement therapy, provision of renal replacement therapy (long-term dialysis, kidney transplant, or sustained eGFR <15 mL/min/1.73 m), or all-cause mortality. Patients were randomly divided into development and validation cohorts (2:1). Logistic regression analysis was performed in the development cohort to analyze risk factors. The scoring system was established accordingly and further validated in the validation cohort. Results: 1,203 patients were enrolled in the study, among whom the older adult group accounted for 36% with a mean age of 71. The older adult group had a worse prognosis, a higher mortality rate, a higher rate of end-stage renal disease, and worsening renal function. Logistic regression showed that age >75 years, chronic heart disease, and elevated serum creatinine and D-dimer values were risk factors for poor prognosis in patients with AAV. The development and validation cohorts in patients with AAV produced area under the curve values of 0.82 (0.78–0.86) and 0.83 (0.77–0.89), respectively. Conclusion: We established a risk-scoring system based on baseline clinical characteristics to predict composite renal outcomes in patients with AAV. Our results suggest that more attention should be paid to older patients with severe renal impairment and active inflammation.

The effects of canagliflozin in type 2 diabetes in subgroups defined by population-specific body mass index: Insights from the CANVAS Program and CREDENCE trial.

To assess the effects of canagliflozin on clinical outcomes and intermediate markers across population-specific body mass index (BMI) categories in the CANVAS Program and CREDENCE trial. Individual participant data were pooled and analysed in subgroups according to population-specific BMI. The main outcomes of interest were: major adverse cardiovascular events (MACE, a composite of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death); composite renal outcome; and changes in systolic blood pressure (SBP), body weight, albuminuria and estimated glomerular filtration rate (eGFR) slope. Cox proportional hazards models and mixed-effect models were used. A total of 14 520 participants were included, of whom 9378 (65%) had obesity. Overall, canagliflozin reduced the risk of MACE (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.75 to 0.93) with no heterogeneity of treatment effect across BMI subgroups (Pheterogeneity = 0.76). Similarly, canagliflozin reduced composite renal outcomes (HR 0.75, 95% CI 0.66 to 0.84) with no heterogeneity across subgroups observed (Pheterogeneity = 0.72). The effects of canagliflozin on body weight and SBP differed across BMI subgroups (Pheterogeneity <0.01 and 0.04, respectively) but were consistent for albuminuria (Pheterogeneity = 0.60). Chronic eGFR slope with canagliflozin treatment was consistent across subgroups (Pheterogeneity >0.95). The cardiovascular and renal benefits of canagliflozin and its safety profile were consistent across population-specific BMI subgroups for adults in the CANVAS Program and CREDENCE trial.

Venous bicarbonate and CKD progression: a longitudinal analysis by the group-based trajectory model.

Metabolic acidosis accelerates chronic kidney disease (CKD) progression towards kidney failure in animal models. Clinical trials testing the effect of bicarbonate on kidney outcomes are underpowered and/or of suboptimal quality. On the other hand, observational studies testing the same hypothesis are generally based on bicarbonate measured at a single time point. We studied the longitudinal relationship between repeated venous bicarbonate levels and a predefined composite renal outcome (a ≥30% estimated glomerular filtration rate reduction, dialysis or transplantation) by using group-based trajectory model (GBTM) analysis. The GBTM analysis was used to classify patients based on individual bicarbonate levels over time. The relationship between trajectory groups and renal outcomes was investigated using crude and adjusted Cox regression models. A total of 528 patients with stage 2-5 CKD were included in the analysis. The GBTM analysis identified four distinct trajectories of bicarbonate levels: low, moderate, moderate-high and high. During the follow-up period, 126 patients experienced the combined renal endpoint. The hazard rate of renal events decreased dose-dependently from the lowest to the highest bicarbonate trajectory. After adjusting for potential confounders, there was a 63% risk reduction for the composite renal endpoint for patients in the high trajectory category compared with those in the low trajectory category. The study found that higher bicarbonate trajectories were associated with a lower risk of adverse renal outcomes in CKD patients. These results suggest that strategies to maintain higher bicarbonate levels may benefit patients with CKD. However, further high-quality randomised trials are needed to confirm these findings and recommend bicarbonate supplementation as a strategy to delay CKD progression.

Correlation Analysis between Intrarenal Small Artery Intimal Thickening and Clinicopathological Features and Prognosis in Primary Membranous Nephropathy Patients

Background: Primary membranous nephropathy (PMN) is the most common pathological type of nephrotic syndrome in adults. Intrarenal small artery intimal thickening can be observed in most renal biopsies. The purpose of this study was to investigate the association between intrarenal small artery intimal thickening and clinicopathological features and prognosis in PMN patients. Methods: Data were continuously collected from patients who were diagnosed with PMN in Shenzhen Second People’s Hospital (The First Affiliated Hospital of Shenzhen University) from 2008 to 2021 for a retrospective cohort study. Regression analysis and survival analysis were used to analyze the relationship between intrarenal small artery intimal thickening and renal prognosis in PMN patients. Results: 300 PMN patients were enrolled in this study, including 165 patients (55%) with intrarenal small artery intimal thickening. Patients with intimal thickening were older, with higher BMI, systolic blood pressure and diastolic blood pressure, serum uric acid, a higher proportion of hypertension, acute kidney injury, nephrotic syndrome, more urine protein, and lower eGFR. Multivariate Cox regression analysis showed that after adjusting for age, gender, hypertension, BMI, urine protein, eGFR, and the use of ACEI/ARB and hormone immunosuppressants, intimal thickening was a risk factor for renal prognosis in PMN patients (HR = 3.68, 95% CI 1.36–9.96, p < 0.05). Kaplan-Meier survival curve analysis showed that the incidence of reaching the renal composite outcome was higher in the intimal thickening group (p < 0.05). Conclusion: The prognosis of PMN patients with intrarenal small artery intimal thickening is worse, so early intervention is very important for these patients.

Mineralocorticoid receptor antagonists with sodium-glucose co-transporter-2 inhibitors in heart failure: a meta-analysis.

To investigate the cardiovascular effects of sodium-glucose co-transporter-2 inhibitors (SGLT2i) with concomitant mineralocorticoid receptor antagonist (MRA) use in heart failure (HF) regardless of ejection fraction (EF) and explore the risk of MRA-associated adverse events in individuals randomized to SGLT2i vs. placebo. PubMed/MEDLINE, Web of Science, Embase, and clinical trial registries were searched for randomized controlled trials/post-hoc analyses evaluating SGLT2i in HF with or without MRA use (PROSPERO: CRD42023397129). The main outcomes were composite of first hospitalization or urgent visit for HF/cardiovascular death (HHF/CVD), HHF, and CVD. Others were all-cause mortality, composite renal and safety outcomes. Hazard ratios (HR)/risk ratios were extracted. Fixed-effects meta-analyses and subgroup analyses were performed. Five eligible studies were included, pooling data from 21 947 people with HF (type 2 diabetes mellitus, n = 10 805). Compared to placebo, randomization to SGLT2i showed a similar reduction in HHF/CVD and HHF in people who were or were not using MRAs [HHF/CVD: hazard ratio (HR) 0.75; 95% confidence interval (CI) 0.68-0.81 vs. HR 0.79; 95% CI 0.72-0.86; P-interaction = .43; HHF: HR 0.74; 95% CI 0.67-0.83 vs. HR 0.71; 95% CI 0.63-0.80; P-interaction = .53], with a suggestion of greater relative reduction in CVD in chronic HF people randomized to SGLT2i and using MRAs irrespective of EF (HR 0.81; 95% CI 0.72-0.91 vs. HR 0.98; 95% CI 0.86-1.13; P-interaction = .034). SGLT2i reduced all-cause mortality (P-interaction = .27) and adverse renal endpoints regardless of MRA use (P-interaction = .73) despite a higher risk of volume depletion with concomitant MRAs (P-interaction = .082). SGLT2i attenuated the risk of mild hyperkalaemia (P-interaction < .001) and severe hyperkalaemia (P-interaction = .051) associated with MRA use. MRAs did not influence SGLT2i effects on the composite of HHF/CVD, HHF or all-cause mortality; however, findings hinted at a more pronounced relative reduction in CVD in chronic HF patients regardless of EF who were randomized to SGLT2i and receiving an MRA compared to those randomized to SGLT2i and not receiving MRAs. SGLT2i attenuated the risk of MRA-associated treatment-emergent hyperkalaemia. These findings warrant further validation in well-designed randomized controlled trials.

Differential effects of sodium-glucose cotransporter 2 inhibitors on cardiovascular and renal outcomes according to renal function: a dose-response meta-analysis involving 10 randomized clinical trials and 71 553 individuals.

The main target of sodium-glucose cotransporter 2 inhibitors (SGLT2i), the sodium-glucose cotransporters 2, is found in the kidneys, and their activity is reduced in patients with chronic kidney disease (CKD). How the efficacy of SGLT2i may vary in patients with different levels of renal impairment has not been fully elucidated. We searched the PubMed databases for relevant studies published through May 25, 2022. Randomized control trials comparing SGLT2i with placebo and reporting cardiovascular or renal outcomes were included. The primary outcome was the composite of major adverse cardiovascular events (MACE), which were defined as cardiovascular death (CV death), nonfatal myocardial infarction (MI), and nonfatal ischemic stroke. Secondary outcomes included the components of MACE, all-cause mortality, hospitalization for heart failure (HHF), the composite of CV death and HHF, and composite renal outcomes. Linear meta-regression analysis was used to assess the effects of estimated glomerular filtration rate (eGFR) on the risks associated with SGLT2i treatment vs placebo for all outcomes. Nonlinear meta-regression analysis was also performed for MACE to investigate the combined influence of reduced drug efficacy in CKD but possible greater risk reduction in a population with higher risk at baseline. Further analyses were performed by including additional study-level covariates, including the prevalence of diabetes mellitus (DM), heart failure (HF), and atherosclerotic cardiovascular disease (ASCVD). Risk ratios for MACE, CV death, nonfatal MI, HHF, and composite renal outcomes associated with SGLT2i treatment were not significantly related to baseline eGFR values. A positive association was observed between eGFR values and the risk of stroke with SGLT2i use (regression coefficient β = .0109, 95% confidence interval [CI] 0.0029-0.0188). A similar positive association was observed between eGFR values and the composite outcome of CV death and HHF (β = .0025, 95% CI 0.0000-0.0051). The results of the meta-regression analyses, including the additional covariates of DM, HF, and ASCVD, were consistent with the results of the primary analyses for most outcomes. The protective effects of SGLT2i for reducing most adverse cardiovascular and renal outcomes persisted in patients with variable degrees of renal impairment. The observed benefits such as preventing CV death, HF worsening, or stroke may be greater for patients with more severe CKD. Considering the cardiovascular and renal benefits associated with SGLT2i treatment, patients with CKD should be treated aggressively to improve outcomes. CRD42021273500.

Insulin growth factor axis and cardio-renal risk in diabetic kidney disease: an analysis from the CREDENCE trial

BackgroundThe insulin-like growth factors (IGF) play a crucial role in regulating cellular proliferation, apoptosis, and key metabolic pathways. The ratio of IGF-1 to IGF binding protein-3 (IGFBP-3) is an important factor in determining IGF-1 bioactivity. We sought to investigate the association of IGF-1 and IGFBP-3 with cardio-renal outcomes among persons with type 2 diabetes.MethodsSamples were available from 2627 individuals with type 2 diabetes and chronic kidney disease that were randomized to receive canagliflozin or placebo and were followed up for incident cardio-renal events. Primary outcome was defined as a composite of end-stage kidney disease, doubling of the serum creatinine level, or renal/cardiovascular death. IGF-1 and IGFBP-3 were measured at baseline, Year-1 and Year-3. Elevated IGF-1 level was defined according to age-specific cutoffs. Cox proportional hazard regression was used to investigate the association between IGF-1 level, IGFBP-3, and the ratio of IGF-1/IGFBP-3 with clinical outcomes.ResultsElevated IGF-1 was associated with lower glomerular filtration rate at baseline. Treatment with canagliflozin did not significantly change IGF-1 and IGFBP-3 concentrations by 3 years (p-value > 0.05). In multivariable models, elevated IGF-1 (above vs below age-specific cutoffs) was associated with the primary composite outcome (incidence rate:17.8% vs. 12.7% with a hazard ratio [HR]: 1.52; 95% confidence interval CI 1.09–2.13;P: 0.01), renal composite outcome (HR: 1.65; 95% CI 1.14–2.41; P: 0.01), and all-cause mortality (HR: 1.52; 95% CI 1.00–2.32; P; 0.05). Elevations in log IGFBP-3 did not associate with any clinical outcomes. Increase in log IGF-1/IGFBP-3 ratio was also associated with a higher risk of the primary composite outcome (HR per unit increase: 1.57; 95% CI 1.09–2.26; P; 0.01).ConclusionsThese results further suggest potential importance of IGF biology in the risk for cardio-renal outcomes in type 2 diabetes. SGLT2 inhibition has no impact on the biology of IGF despite its significant influence on outcomes.Trial registration: CREDENCE; ClinicalTrials.gov Identifier: NCT02065791.

Dulaglutide and Kidney Function-Related Outcomes in Type 2 Diabetes: A REWIND Post Hoc Analysis.

Dulaglutide (DU) 1.5 mg was associated with improved composite renal outcomes that included new-onset macroalbuminuria in people with type 2 diabetes with previous cardiovascular disease or cardiovascular risk factors in the REWIND (Researching cardiovascular Events with a Weekly INcretin in Diabetes) trial. This exploratory post hoc analysis evaluated kidney function-related outcomes, excluding the new-onset macroalbuminuria component, among the REWIND participants. Intent-to-treat analyses were performed on REWIND participants (n = 4,949 DU, n = 4,952 placebo). Time to occurrence of a composite kidney function-related outcome (≥40% sustained decline in estimated glomerular filtration rate [eGFR], per the Chronic Kidney Disease Epidemiology Collaboration 2009 equation, end-stage renal disease, or renal-related death), and mean annual eGFR slope were examined. Analyses were conducted overall and within subgroups defined by baseline urinary albumin-to-creatinine ratio (UACR <30 or ≥30 mg/g) and baseline eGFR (<60 or ≥60 mL/min/1.73 m2). The post hoc composite kidney function-related outcome occurred less frequently among participants assigned to DU than placebo (hazard ratio [HR] 0.75, 95% CI 0.62-0.92, P = 0.004), with no evidence of a differential DU treatment effect by UACR or eGFR subgroup. A ≥40% sustained eGFR decline occurred less frequently among participants assigned to DU than placebo (HR 0.72, 95% CI 0.58-0.88, P = 0.002). The mean annual decline in eGFR slope was significantly smaller for participants assigned to DU than placebo (-1.37 vs. -1.56 mL/min/1.73 m2/year, P < 0.001); results were similar for all subgroups. The estimated 25% reduced hazard of a kidney function-related outcome among participants assigned to DU highlights its potential for delaying or slowing the development of diabetic kidney disease in people with type 2 diabetes.

892-P: Influence of Preceding Medications on the Renal Outcomes of Japanese Diabetics Treated with SGLT2 Inhibitors and GLP-1 Receptor Agonists

Background/Objective: Evidence of cardiovascular and renal outcomes has already been shown for SGLT2 inhibitors (SGLT2i) and GLP1 receptor agonists (GLP1Ras); therefore, combination therapy with these drugs is of clinical interest. This study aimed to evaluate the effect of the preceding drug for patients with the combination treatment of SGLT2i and GLP1Ra on renal outcomes. Methods: We retrospectively extracted data of patients with type 2 diabetes mellitus who had received both SGLT2i and GLP1Ra treatment for at least 1-year at 18 medical facilities in Japan. Finally, 341 patients in the GLP1Ra-preceding group and 319 in the SGLT2i-preceding group were analyzed. The renal composite outcome was progression of the albuminuria stage, ≥30% decrease in eGFR, or both. The multiple imputation method for missing values and an inverse probability weighting method using the propensity score were used for the comparison of outcome. Results: The median observation period and the incidence of the renal composite outcome in the SGLT2i-preceding group and the GLP1Ra-preceding group was 55.1months, 26.9% and 58.7months, 25.6%, respectively, with an odds ratio (OR) [95% confidence interval] of 1.50 [0.89, 2.53] (p=0.13). The ORs for the ≥30% decrease in eGFR and the progression of albuminuria stage were 0.96 [0.47, 2.00] (p=0.93) and 1.76 [0.97, 3.69] (p=0.06), respectively. Compared to the GLP1Ra-preceding group, the annual change in eGFR and change in the logarithmic value of urine albumin-to-creatinine ratio (LnACR) was 0.27mL/min/1.73 m2/year [-0.60, 1.14], and 0.18 [-0.10, 0.43] respectively. LnACR at baseline, pioglitazone use, and baseline mean arterial blood pressure were independent factors for renal composite outcome with ORs [95% CI] of 1.15 [1.01, 1.31], 0.47 [0.23, 0.96], and 1.03 [1.01, 1.05], respectively. Conclusion: In combination therapy with SGLT2i and GLP1Ra, the difference in the preceding drug did not affect the renal composite outcome. Disclosure K.Kobayashi: None. M.Toyoda: None.

1721-P: Patients with Metabolic Syndrome Are at Risk of Renal Outcome in CKD Stages 1-4 Regardless of Diabetes

Metabolic syndrome (MetS) is a cluster of risk factors predicting cariometabolic disease. MetS was associated with renal outcome in some studies. However, the effect of MetS seemed loss after the adjustment of proteinuria, late CKD stage or diabetes in advanced CKD. Whether MetS predicts renal outcome in established CKD is unknown. We investigated the prognostic effects of MetS in 2500 patients with CKD stage 1-4. 66.9% and 49.2% patients had MetS and DM, respectively. The MetS score was positively associated with proteinuria (p&amp;lt;0.001), inflammation (p=0.001), and nutrition markers (p&amp;lt;0.001). In fully-adjusted Cox regression model, hazard ratio (HR) (95% confidence interval) of MetS for composite renal outcome in DM and non-DM subgroup was 1.56 (1.15-2.12) (p&amp;lt;0.05) and 1.31 (1.02-1.70) (p&amp;lt;0.05), respectively, while that for all-cause mortality was 1.00 (0.71-1.40) and 1.27 (0.92-1.74). Blood pressure is the most important component of MetS for clinical outcomes (1.50 (1.08-2.08) (p&amp;lt;0.05)). In a 2 by 2 matrix, compared with non-MetS non-DM group, MetS DM group (HR: 1.62 (1.31-2.02) (p&amp;lt;0.05)) and MetS non-DM group (HR:1.33 (1.05-1.69) (p&amp;lt;0.05)) had higher risks for composite renal outcome, while MetS DM group had higher risk for all-cause mortality (HR: 1.43 (1.09-1.88) (p&amp;lt;0.05)). In conclusion, MetS could predict renal outcome in CKD stage 1-4 patients independent of diabetes. Disclosure H.Y.H.Lin: None. K.Chang: None. Funding Ministry of Science and Technology (110-2314-B-037-068-MY3); Municipal Ta-Tung Hospital (KMTTH-110-003)

#3424 RENAL OUTCOMES IN THE ELDERLY WITH ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODY-ASSOCIATED VASCULITIS: A NEW PREDICTION MODEL

Abstract Background and Aims Antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) is a type of necrotizing small vessel inflammatory disease, including alveolar hemorrhage and rapidly progressive glomerulonephritis. Elderly patients with antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) commonly experience renal impairment and poor prognosis. Based on the cohort of inpatients with AAV in Peking Union Medical College Hospital, this study aimed to analyze the clinical manifestations, diagnosis and treatment characteristics of elderly patients compared with non-elderly patients, and establish a risk scoring system for predicting composite renal outcomes in patients with AAV in elderly patients. Method This retrospective observational study included all AAV patients hospitalized in a single-center tertiary hospital in China between January 2013 and April 2022. Patients aged ≥ 65 years were defined as elderly and randomly divided into development and validation cohorts (2:1). Logistic regression analysis was performed in the development cohort to analyze risk factors. The scoring system was established accordingly and further validated in the validation cohort. Results A total of 1203 patients were enrolled in the study, among whom the elderly group accounted for 36% with a mean age of 71.4 ± 0.3 years. The elderly group had a worse prognosis, a higher mortality rate (8.9% vs. 3.5%, P &amp;lt; 0.001), a higher rate of end-stage renal disease (17.6% vs. 10.2%, P &amp;lt; 0.001), and worsening renal function (7.4% vs. 4.5%, P = 0.04). Logistic regression showed that age &amp;gt; 75 years, chronic heart disease, elevated serum creatine, and D-dimer values were risk factors for poor prognosis in patients with AAV. The development and validation cohorts in AAV patients produced area under the curve values of 0.823 (0.784–0.862) and 0.833 (0.777–0.888), respectively (Figure 1). When the risk score was ≥ 2 points, the risk of acquiring composite renal outcomes increased significantly with a sensitivity and specificity of 75.0% and 79.9%, respectively. Conclusion We established risk-scoring systems based on baseline clinical characteristics to predict composite renal outcomes in patients with AAV. Our results suggest that more attention should be paid to elderly patients who have severe renal impairment and active inflammation.

#6399 ROLE OF THERAPEUTIC PLASMAPHERESIS IN PAUCI-IMMUNE VASCULITIS – A SINGLE CENTRE EXPERIENCE

Abstract Background and Aims The indication for plasmapheresis (PLF) in pauci-immune vasculitis (PIV) is controversial. This study aimed to characterize the population and renal outcome of patients with PIV undergoing PLF in a hospital in the north of Portugal. Method We conduct a retrospective cohort study of patients followed by a multidisciplinary team, from diagnosis to death or May/22. Two groups were defined: patients undergoing PLF (group A, GA) and not undergoing PLF (group B, GB). Demographic variables, comorbidities, serological subtype, clinical presentation, histological classification and therapeutic were evaluated. Recorded outcomes were death and ESRD (end-stage renal disease) (eGFR,15 ml/min per 1.73 m2, dialysis, or transplantation). Renal survival was estimated using the Kaplan-Meier analysis and differences between curves were evaluated using the log-rank test. Results A total of 72 patients, 26 (36.1%) in group A and 46 (63.9%) in group B were included. In both groups the most frequent serotype was myeloperoxidase ((MPO) (n = 23, GA; n = 38, GB)). In both groups, most patients were male (61.5% in GA and 56.5% in GB), with a mean age at admission of 64 (SD±11.5) and 66.5 years (SD±12.2) in GA and GB, respectively (p = 0.362). Most GA patients had pulmonary and renal involvement on admission (80.7%, n = 21), versus GB (36.9%, n = 17), p&amp;lt;0.05. Mean serum creatinine was superior in GA (6.74 mg/dl, SD ± 2.75) versus GB (3.82 mg/dl, SD±2.95), p&amp;lt;0.05. Twenty patients from GA (76.9%) and 7 from GB (15.2%) required dialysis upon admission, p&amp;lt;0.05. In both groups, almost all patients underwent induction immunosuppression with cyclophosphamide (mean cumulative dose of 4.4 grams (SD ± 2.6) and 5.9 grams (SD ± 2.7), in GA and GB, respectively) and azathioprine in the maintenance phase, with a rapid corticosteroid weaning scheme in both phases. Median follow-up time (months) of GA and GB was 11 (IQR [4.8-37.5]) and 58.5 (IQR [14.5-92]) months. Regarding renal prognosis, 9 of 20 patients in GA and 3 of 7 patients in GB who needed dialysis on admission, partial recover of renal function (p = 1.00). About 37% (n = 17) of patients of GB and 73% (n = 19) of patients of GA reached the composite renal outcome, with a median time of 0 (IQR 0 - 21.8) and 38.5 months (IQR 5.3-92), respectively. GA showed worse renal survival, with a mean of 30.9 months vs. 116.5 months in GB, p = 0.01. Renal survival at 2 years was 68.7% in GB and 24% at GA. Patients in both groups with admission serum creatinine ≥ 5.7 mg/dl had similar renal survival (GA 39.9 and GB 32 months, p = 0.714). Regarding the histological classification, 91.7% and 38.9% in GA and GB belonged to the crescentic class, (p = 0.009). Renal survival in the subgroup of patients with crescentic class was worse in GA (16.6±10.2 vs 83.3±16.1, p = 0.015). The analysis of the Renal Risk Score showed no statistically significant difference between the groups, and between patients with crescentic class in both groups, p = 0.274. Mortality and hospitalization rate due to infection were similar in both groups (p&amp;gt;0.05). Conclusion Patients undergoing PLF had a worse renal outcome, consistent with the higher proportion of patients with severe azotemia and requiring dialysis at admission, in a sample that was mostly ANCA MPO. As described in the literature, the experience of our centre did not demonstrate benefit in the addition of PLF, despite the limitations inherent to an observational, retrospective study and the modest sample size. A better knowledge of etiopathogenesis is essential for the optimization of the therapeutic strategy, together with the promotion of measures that allow timely referral, an early diagnosis and consequent improvement of renal prognosis.

Higher hemoglobin levels using darbepoetin alfa and kidney outcomes in advanced chronic kidney disease without diabetes: a prespecified secondary analysis of the PREDICT trial.

In the primary analysis of the PREDICT trial, a higher hemoglobin target (11-13g/dl) with darbepoetin alfa did not improve renal outcomes compared with a lower hemoglobin target (9-11g/dl) in advanced chronic kidney disease (CKD) without diabetes. Prespecified secondary analyses were performed to further study the effects of targeting higher hemoglobin levels on renal outcomes. Patients with an estimated glomerular filtration rate (eGFR) 8-20ml/min/1.73m2 without diabetes were randomly assigned 1:1 to the high- and low-hemoglobin groups. The differences between the groups were evaluated for the following endpoints and cohort sets: eGFR and proteinuria slopes, assessed using a mixed-effects model in the full analysis set and the per-protocol set that excluded patients with off-target hemoglobin levels; the primary endpoint of composite renal outcome, evaluated in the per-protocol set using the Cox model. In the full analysis set (high hemoglobin, n = 239; low hemoglobin, n = 240), eGFR and proteinuria slopes were not significantly different between the groups. In the per-protocol set (high hemoglobin, n = 136; low hemoglobin, n = 171), the high-hemoglobin group was associated with reduced composite renal outcome (adjusted hazard ratio: 0.64; 95% confidence interval: 0.43-0.96) and an improved eGFR slope (coefficient: + 1.00ml/min/1.73m2/year; 95% confidence interval: 0.38-1.63), while the proteinuria slope did not differ between the groups. In the per-protocol set, the high-hemoglobin group demonstrated better kidney outcomes than the low-hemoglobin group, suggesting a potential benefit of maintaining higher hemoglobin levels in patients with advanced CKD without diabetes. Clinicaltrials.gov (identifier: NCT01581073).