Renal Endpoints Research Articles

Abstract 4137996: Effects of Empagliflozin on diuresis in heart failure: Results from the CINNAMON-study and in-vivo experiments

Background and Purpose: Heart failure is associated with renal dysfunction suggesting a pathophysiological link between heart and kidney. Empagliflozin, a SGLT2 inhibitor, showed beneficial effects on both cardiovascular and renal endpoints. However, mechanistically, it is unclear if empagliflozin-dependent kidney protection is mediated via inhibition of tubular SGLT2 or more indirectly via improved cardiac function. We hypothesized that Empagliflozin treatment improves left ventricular ejection fraction (LVEF) independent of diuretic effect of renal SGLT2 inhibition. Methods: We evaluated NTproBNP, hematocrit, hemoglobin and bodyweight in patients with HF with reduced (n=32) and preserved ejection fraction (n=59) after 30 and 180 days (prospective, single-arm CINNAMON-study, DRKS00031101). Furthermore, we conducted transverse aortic constriction (TAC) or sham surgery in C57BL/6J (wildtype, WT) and SGLT2 deficient mice (SGLT2 -/- ). Animals received either Empagliflozin (10 mg/kg bodyweight) or vehicle by daily oral gavage. Water intake and output was evaluated by metabolic cages at 10 weeks and cardiac function by echocardiography. Results: Empagliflozin treatment reduced NT-proBNP levels and increased hematocrit and hemoglobin levels especially in patients with reduced ejection fraction (Fig. A-C). Surprisingly, there was no change in body weight (Fig. D), which would be expected if the diuretic effects were dominant. In mice after 10 weeks, echocardiography confirmed TAC induced pressure-overload, leading to reduced LVEF. Empagliflozin attenuated changes in LVEF (Fig. G) and improved diastolic dysfunction (isovolumetric relaxation time, data not shown). To test if direct inhibition of SGLT2 in the heart and kidney is mechanistically involved, TAC surgery was repeated in SGLT2-deficient mice (SGLT2-KO). In fact, exposure to TAC resulted in comparable reduction of LVEF in SGLT2-KO and Empagliflozin prevented this deterioration similar to WT mice (Fig. G vs. I). Surprisingly, Empagliflozin did not increase drinking and urine volume neither in wildtype nor in SGLT2 deficient mice, suggesting a mechanism of cardioprotection independent of diuretic effects. Conclusion and Outlook: This is the first study investigating the role of SGLT2 in Empagliflozin treated patients and mice with heart failure. Importantly, empagliflozin treatment prevented deterioration of LVEF independent of the presence of SGLT2 and diuresis.

NT-proBNP improves prediction of cardiorenal complications in type 2 diabetes: the Hong Kong Diabetes Biobank.

N-terminal pro B-type natriuretic peptide (NT-proBNP) is a natriuretic peptide that is strongly associated with congestive heart failure (CHF). The utility of NT-proBNP for prediction of cardiovascular events and renal endpoints, compared with clinical risk factors, has not been evaluated in detail. We hypothesise that NT-proBNP can improve risk stratification and prediction of cardiorenal events in type 2 diabetes, beyond that provided by clinical risk factors. NT-proBNP was measured in 1993 samples from the Hong Kong Diabetes Biobank, a multicentre prospective diabetes cohort and biobank. A cut-off of ≥125 pg/ml was used to define elevated NT-proBNP. Associations between elevated NT-proBNP and incident cardiovascular and renal endpoints were examined using Cox regression, adjusted for sex, age and duration of diabetes, as well as other covariates. Prognostic and incremental predictive values of NT-proBNP in diabetes cardiorenal complications, compared with those of the Joint Asia Diabetes Evaluation risk equations for CHD, CHF and kidney failure, were evaluated using the concordance index (C index), net reclassification improvement index, integrated discrimination improvement index and relative integrated discrimination improvement index. A total of 24.7% of participants had elevated NT-proBNP. Participants with elevated NT-proBNP at baseline had a more adverse cardiometabolic profile, with 2-4-fold higher frequency of complications at baseline. Adjusting for age at baseline, sex and duration of diabetes, elevated NT-proBNP was associated with incident atrial fibrillation (HR 4.64 [95% CI 2.44, 8.85]), CHD (HR 4.21 [2.46, 7.21]), CVD (HR 3.32 [2.20, 5.01]) and CHF (HR 4.18 [2.18, 8.03]; all p<0.001). All these associations remained significant after further adjustment for additional covariates. Elevated NT-proBNP had good discriminative ability for various cardiorenal endpoints, with C index of 0.83 (95% CI 0.76, 0.90) for CHD, 0.88 (0.81, 0.94) for atrial fibrillation, 0.89 (0.83, 0.95) for CHF, 0.81 (0.77, 0.84) for 40% drop in eGFR and 0.88 (0.84, 0.92) for kidney failure. Models incorporating NT-proBNP had improved prediction compared with established clinical risk models. Sensitivity analyses including alternative cut-off of NT-proBNP, as well as use of other risk engines of CHD, yielded similar results. NT-proBNP demonstrated a promising ability to serve as a prognostic marker for a variety of cardiorenal complications in type 2 diabetes. Considering NT-proBNP in clinical assessments could potentially help identify high-risk individuals who may benefit from more intensive therapies.

Effects of empagliflozin on cardio-renal interaction in heart failure with reduced ejection fraction: results from in-vivo experiments and the CINNAMON-study

Abstract Background Heart failure is often accompanied by renal dysfunction, which indicates a pathophysiological connection between the heart and kidneys. Empagliflozin, a SGLT2 inhibitor, showed beneficial effects on both cardiovascular and renal endpoints. Mechanistically, however, it is unclear whether the empagliflozin-dependent renal protection is mediated via the inhibition of renal SGLT2 or rather indirectly via improved cardiac function. Interestingly, in the EMPEROR trials, there was a significant interaction of empagliflozin-dependent kidney protection with systolic contractile dysfunction. We hypothesized that Empagliflozin treatment ameliorates heart failure in response to chronic pressure overload in mice leading to improved renal function. We correlated these findings with data from our prospective, single-armed trial. Methods Transverse aortic constriction (TAC) or sham surgery was performed in C57BL/6J (wildtype, WT) and SGLT2 deficient mice (SGLT2-/-). Animals received either Empagliflozin (10 mg/kg bodyweight) or vehicle by daily oral gavage. Cardiac function was evaluated by echocardiography and kidney function by transdermal FITC-Sinistrin measurement (GFR), urinary albumin/creatinine ratio (UACR) and Siriusred fibrosis staining. Results After 10 weeks, echocardiography confirmed TAC induced pressure-overload, leading to reduced left ventricular ejection fraction (LVEF) and diastolic dysfunction. Empagliflozin attenuated changes in LVEF (Fig. A) and improved diastolic dysfunction (data not shown). Interestingly, at 10 weeks, TAC reduced GFR, increased UACR and tended to increase renal fibrosis, which was attenuated by empagliflozin (Fig. B, C and D). To test if direct inhibition of SGLT2 in the heart and kidney is mechanistically involved, TAC surgery was repeated in SGLT2-deficient mice (SGLT2-/-). In fact, exposure to TAC resulted in comparable reduction of LVEF in SGLT2-/- mice and Empagliflozin prevented this deterioration similar to WT mice (Fig. E vs. A). Surprisingly, Empagliflozin also prevented GFR deterioration 10 weeks after TAC in mice lacking SGLT2 (SGLT2-/-) with comparable magnitude as in WT mice (Fig. F), suggesting that the reno-protective effect of Empagliflozin was independent from renal SGLT2 inhibition. The effect of empagliflozin on the heart and kidney was also investigated in patients with HF (prospective, single-arm CINNAMON-study, DRKS00031101). After 180 days of Empagliflozin treatment (10 mg), there was a significant improvement in LVEF, NT-proBNP levels and KCCQ-12 Scores (Fig. G-I) and the effects on UACR and GFR are subject of investigation. Conclusion This is the first study investigating the role of SGLT2 in Empagliflozin-dependent kidney protection of mice that develop heart failure after TAC. Importantly, empagliflozin treatment prevented deterioration of LVEF and GFR independent of the presence of SGLT2 in mice and improved cardiac markers and quality of life in patients.

Superior benefits of sodium-glucose co-transporter-2 inhibitors compared with dipeptidyl peptidase-4 inhibitors for diabetic kidney disease: A cohort study.

To compare cardiorenal outcomes of dipeptidyl peptidase-4 inhibitors (DPP-4is) and sodium-glucose co-transporter-2 inhibitors (SGLT-2is) in a national diabetic kidney disease (DKD) population. A cohort study was conducted using Taiwan's National Health Insurance Research Database and Laboratory Databases. Propensity score-matched prevalent new users of SGLT-2is (n = 1524) and DPP-4is (n = 6005) during 2017-2018 were selected from adults with DKD and an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73m2. Composite renal outcomes included sustained eGFR decrease, renal failure and renal mortality. Composite cardiovascular (CV) outcomes included acute myocardial infarction, stroke, hospitalization for heart failure and CV death. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). Compared with DPP-4i users, SGLT-2i users had a reduced risk of composite renal endpoint (HR: 0.16; CI: 0.12-0.24), consistently for a prolonged time to 50% or higher eGFR decrease (HR 0.17; CI: 0.11-0.27), renal failure (HR: 0.14; CI: 0.08-0.23) and decreased renal death (HR: 0.10; CI: 0.01-0.70). SGLT-2i users had a better composite CV outcome than DPP-4i users (HR: 0.74; CI: 0.64-0.85), and lower risks of stroke (HR: 0.76; CI: 0.62-0.92) and hospitalization for heart failure (HR: 0.68; CI: 0.55-0.84). Findings were consistent in analyses stratified by concomitant antidiabetic agents or intervals between DKD diagnosis and study drug initiation. This study shows the superior cardiorenal benefits of SGLT-2is compared with DPP-4is in the DKD population, regardless of concomitant antidiabetic agents or time from DKD onset to study drug initiation. SGLT-2is should be prioritized in adult patients with DKD.

Risk factors for renal progression in patients with CKD and coexisting COPD.

Chronic diseases rarely occur in isolation, and chronic kidney disease (CKD) is no exception. There has been considerable research on the interplay between the heart and kidneys, but studies on the relationship between the lungs and kidneys are less common. The interaction between pulmonary and renal functions in areas such as acid-base metabolism, chronic inflammation, and bone metabolism is increasingly gaining clinical attention. In this cohort study, we examined 480 patients with stages 3-4 CKD and COPD (GOLD stages 1 and 2) to identify risk factors that contribute to the progression of renal function to a composite endpoint, which includes a 40% decline in estimated glomerular filtration rate (eGFR) and the onset of end-stage renal disease during follow-up periods. A Cox proportional hazards regression model was used to investigate the risk factors associated with the timing of renal event endpoints in the study population. Additionally, the restricted cubic spline method was used to explore the relationship between quantitative variables and survival risk. Our study included 480 eligible patients with an average follow-up period of 21.41 ± 14.90months, during which 224 individuals (46.7%) experienced the composite renal endpoints. Multivariable Cox regression analysis revealed that systolic blood pressure (SBP) [1.01 (1.00-1.02), p = 0.002], hemoglobin (Hb) [HR 0.89 (0.83-0.96), p = 0.002], albumin (Alb) [0.96 (0.93-0.99), p = 0.009], and edema [1.73 (1.29-2.33), p < 0.001] were independent risk factors for the renal endpoints. The adjusted multivariable Cox regression analysis demonstrated that elevated SBP and edema were factors that promoted the occurrence of composite endpoints, while higher levels of Hb and Alb were protective factors.

Application of a validated prognostic plasma protein biomarker test for renal decline in type 2 diabetes to type 1 diabetes: the Fremantle Diabetes Study Phase II

BackgroundThere are scant data relating to prognostic biomarkers for chronic kidney disease (CKD) complicating type 1 diabetes. The aim of this study was to assess the performance of the plasma protein biomarker-based PromarkerD test developed and validated for predicting renal decline in type 2 diabetes in the context of type 1 diabetes.MethodsThe baseline PromarkerD test score was determined in 91 community-based individuals (mean age 46.2 years, 56.5% males) with confirmed type 1 diabetes recruited to the longitudinal observational Fremantle Diabetes Study Phase II. The performance of the PromarkerD test in predicting the risk of incident CKD (estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 in people without CKD at baseline) or an eGFR decline of ≥ 30% over the next four years was determined. The score can range from 0 to 100%, and is categorized as representing low (< 10%), moderate (10% to < 20%) or high (≥ 20%) risk.ResultsThe area under the receiver operating characteristic curve was 0.93 (95% confidence interval 0.87–0.99) for the composite renal endpoint, indicating strong predictive accuracy. The positive and negative predictive values at moderate (10% to < 20%) and high (≥ 20%) risk PromarkerD cut-offs were 46.7–50.0% and ≥ 92.0%, respectively.ConclusionsThese preliminary data suggest that PromarkerD is at least as good a prognostic test for renal decline in type 1 as type 2 diabetes.

Volume therapy: which preparation for which situation?

The most commonly used fluids for volume therapy are crystalloids and colloids. Crystalloids comprise 0.9% sodium chloride and balanced crystalloids (BC). Colloids can be divided into artificial colloids and human albumin (anatural colloid). Large studies show advantages for BC over 0.9% NaCl with respect to renal endpoints, probably due to the unphysiologically high chloride content of 0.9% NaCl. However, other studies, such as the BaSICS and PLUS trials, showed no significant differences in mortality in aheterogeneous population. Despite this, meta-analyses suggest advantages for BC. Therefore, BC should be preferred, especially in patients at increased risk of acute kidney injury, with acidemia and/or hyperchloremia. Except for specific indications (e.g., in patients with cirrhosis, sepsis resuscitation after initial volume therapy with BC), albumin should not be used. There is clear evidence of harm from hydroxyethyl starch in intensive care patients.

SGLT-2 Inhibitors Versus GLP-1 Receptor Agonists Effects on Kidney and Clinical Outcomes in Veterans with Type 2 Diabetes.

The primary aim compared kidney endpoints between patients with type 2 diabetes (T2D) 36 months after initiation on a sodium-glucose cotransporter-2 inhibitor (SGLT2i) or a GLP-1 receptor agonist (GLP-1RA). Secondary aims compared estimated glomerular filtration rate (eGFR), hemoglobin A1c (HbA1c), weight, and urine albumin-to-creatinine ratio (UACR) changes. We conducted a retrospective cohort study of propensity score matched veterans with T2D, baseline eGFR>20mL/min/1.73m2, and initiated on a SGLT2i vs GLP-1RA between 4/1/2009-9/1/2020. Cox proportional hazard models were constructed to evaluate effectiveness between both groups on composite endpoint (decline of >=40% in eGFR from baseline, ESRD event, and all-cause mortality) and its components adjusting for baseline characteristics. Spline models were constructed to evaluate eGFR change and linear mixed effects models were constructed to evaluate changes in HbA1c, weight, and UACR. We used an intent-to-treat (ITT) approach as our main analysis followed by a per-protocol (PP) approach excluding veterans who discontinued or switched therapy during the study period. A total of 29,146 propensity score matched veterans were included in SGLT2i and GLP-1RA groups (14,573 per group). In the ITT and PP analyses, veterans initiated on SGLT2i had a 35% (HR=0.65; 95% CI: 0.62, 0.68) and 34% (HR=0.66; 95% CI: 0.62, 0.69) reduction in the hazard of experiencing the composite endpoint compared to veterans initiated on GLP-1RA adjusting for baseline characteristics, respectively. Between 6-36 months, we found an improved chronic eGFR slope with SGLT2i compared to GLP-1RA in both ITT and PP analyses; +1.19 mL/min/1.73 m2 (95% CI: 0.93, 1.45) and +1.29 mL/min/1.73m2 (95% CI: 1.01, 1.57), respectively. The annual difference in chronic eGFR slope in both ITT and PP analyses were +0.97 mL/min/1.73m2/year (95% CI: 0.82, 1.11) and +1.08 mL/min/1.73m2/year (95% CI: 0.92, 1.25). Improved HbA1c, weight loss and UACR were reported for both groups. In this real-world study, veterans with T2D initiated on SGLT2i were associated with reduced hazard of experiencing mortality, worsening eGFR, or developing ESRD and improved glycemic, metabolic, and renal endpoints compared to GLP-1RA use.

Interpretation of cardiovascular outcome trials results of new antidiabetic agents

The incidence of diabetes is continuously increasing worldwide, resulting in a considerable socioeconomic burden. Glycemic control using traditional diabetes medications prevents microvascular complications; however, there is no objective evidence that it prevents macrovascular complications. In the 21st century, concerns have arisen that strict glycemic control and the diabetes drug rosiglitazone might increase mortality. This led the United States Food and Drug Administration to establish guidelines that require that cardiovascular outcome trials (CVOTs) with 3-point major adverse cardiovascular events (3-P MACE) as the primary endpoints be performed for new diabetes drugs. Since then, 20 CVOTs have been reported. Dipeptidyl peptidase 4 inhibitors do not increase the incidence of cardiovascular disease; however, saxagliptin increases the risk of heart failure. Sodium-glucose cotransporter inhibitors (SGLT2is) and glucagonlike peptide 1 receptor agonists (GLP-1RAs) not only have proven cardiovascular safety but also have shown results beyond expectations by reducing the incidence of cardiovascular diseases. Additionally, SGLT2is have been reported to markedly prevent heart failure and kidney disease. The reduction in 3-P MACE by GLP-1RAs was observed only with long-acting agents; long-acting GLP-1RAs also markedly reduced renal endpoints. However, no preventive effect against heart failure was observed with GLP-1RAs. The preventive effects of both drug types against cardiovascular and kidney diseases appear to be independent of glycemic control. In conclusion, based on CVOT results, it is necessary to actively prescribe SGLT2is and GLP-1RAs to prevent cardiovascular disease in patients with diabetes, regardless of glycemic control.

New drugs on the horizon for acute kidney injury.

Acute kidney injury (AKI) is a frequent and serious complication in critically ill patients. Currently, no effective therapy to prevent or treat AKI is available. This review highlights recently published developments on pharmacological treatments that aim to prevent AKI or to alleviate the severity of AKI in critical ill patients. Studies on pharmacological interventions aimed to improve hemodynamics, renal perfusion, to mediate inflammation-associated renal damage and to reduce oxidative stress are presented, including several observational studies and randomized trials focused on the potential renal protective effects in relevant patient populations. Different existing and novel compounds are being investigated for the effects on renal endpoints and several show potential to prevent or alleviate the occurrence of AKI. It is now acknowledged that different underlying pathophysiological processes are relevant in the development of AKI. Recognition of these sub-endotypes of AKI and knowledge of the therapeutic target of different compounds is of paramount importance to select the right patient for the right treatment at the right time. The discovery of reno-protective therapies is hampered by the timely detection and recognition of the overriding mechanism of AKI. Nevertheless, several compounds are under investigation, which hold promise for a future treatment.

A comprehensive review of finerenone-a third-generation non-steroidal mineralocorticoid receptor antagonist.

Multiple studies have shown that finerenone (BAY 94-8862), a third-generation non-steroidal mineralocorticoid receptor antagonist (MRA), possesses different or superior mechanisms of action to traditional MRAs. Specifically, animal and cell-based experiments have demonstrated that this compound exerts multiple effects including fibrosis inhibition, reduced pulmonary artery pressure, improved diabetic retinopathy, enhanced endothelial functions, metabolic optimization as well as reduced oxidative stress, thereby exerting overall positive effects on renal and cardiovascular diseases. Consequently, clinical research, such as the FIGARO-DKD and FIDELIO-DKD trials, has demonstrated dual benefits for patients with type 2 diabetes mellitus and chronic kidney disease (T2DM-CKD), especially by validating MRAs' potential in reducing risks of renal and cardiovascular composite endpoints. Currently, cardiovascular indications for finerenone are limited to patients with T2DM-CKD, while its use in non-T2DM CKD patients remains at clinical trial stages. Despite showing good safety and efficacy in T2DM-CKD patients, there are insufficient corresponding data for those presenting chronic kidney disease without diabetes (ndCKD). Furthermore, the application of this compound in diseases such as primary aldosteronism and its association with cancer risk need to be further validated through larger-scale and longer-term clinical studies. Nevertheless, the development of finerenone provides an additional option for treating cardiovascular and renal diseases. With further research, it is expected that finerenone will be relevant to a broader range of CKD patient populations by addressing current knowledge gaps to comprehensively evaluate its clinical value and potentially alter existing treatment strategies. The current review aims to comprehensively analyze the basic research and clinical advancements involving finerenone in order to explore its prospects for treating cardiovascular and renal diseases, while addressing unmet needs in current treatment strategies. Additionally, through a comprehensive analysis of relevant research findings, a deeper understanding of finerenone's drug characteristics will be provided alongside scientific guidance for future treatment strategies and their clinical significance.

Efficacy and safety of finerenone in individuals with type 2 diabetes mellitus complicated by diabetic kidney disease: A retrospective observational study

Aim/introductionEarly therapeutic interventions are necessary to reduce cardiovascular and renal composite endpoints in individuals with type 2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD). Clinical trials have shown that finerenone suppresses cardiovascular and renal composite endpoints by reducing the urinary albumin-to-creatinine ratio (UACR) and suppressing the decline in the Estimated Glomerular Filtration Rate (eGFR). However, the efficacy and safety of finerenone in real-world clinical practice remain unclear. This study aimed to evaluate the reduction in the UACR as an efficacy endpoint as well as changes in eGFR and serum potassium levels as safety endpoints before and after finerenone administration. Materials and methodsThis retrospective observational study collected data from outpatients with T2DM and DKD upon initiation of finerenone treatment and 3 months after treatment. The primary efficacy endpoint was the change in the UACR from the start of finerenone treatment to after 3 months, while the primary safety endpoints were the changes in serum potassium levels and eGFR over the same period. ResultsThe mean UACR significantly decreased from 668.6 mg/gCr at the start of finerenone treatment to 367.8 mg/gCr after 3 months (p < 0.001). Contrastingly, serum potassium levels, eGFRs, systolic and diastolic blood pressures, body mass indices, and HbA1c levels showed no significant changes between treatment initiation and 3 months post-treatment (all p > 0.05). ConclusionsIn individuals with T2DM and DKD, finerenone treatment significantly reduced the UACR, with no post-treatment changes in potassium levels or eGFRs. Trial registrationThis trial was registered with the University Hospital Medical Information Network Clinical Trial Registry (UMIN000054821).

Chronic kidney disease in type 2 diabetes: The size of the problem, addressing residual renal risk and what we have learned from the CREDENCE trial.

Chronic kidney disease (CKD) associated with type 2 diabetes (T2DM) is a global challenge; progression to end-stage kidney disease (ESKD) and increased risk of cardiovascular disease (CVD) associated with advancing nephropathy are a significant source of morbidity, mortality, and healthcare expenditure. Until recently, renin-angiotensin system (RAS) blockade was the mainstay of pharmacotherapy in diabetic kidney disease (DKD), representing a therapeutic paradigm shift towards interventions that delay disease progression independently of antihypertensive effects. However, a significant residual risk of DKD progression persisted in patients established on RAS blockade, highlighting the need for additional treatment options. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally licensed as glucose-lowering agents in people with T2DM, serendipitously demonstrated beneficial renal and cardiovascular outcomes in clinical trials designed primarily to evaluate their cardiovascular safety. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial was the first to study the effect of SGLT2 inhibition on a primary composite renal endpoint of ESKD, doubling of serum creatinine, or renal or cardiovascular death in 4401 people with T2DM and CKD established on RAS blockade. The trial was stopped early due to efficacy, demonstrating a 30% relative risk reduction in the primary endpoint in the canagliflozin group (hazard ratio 0.70, 95% confidence interval 0.59-0.82; p = 0.00001). Through discussion of the primary analysis from CREDENCE, and selected post hoc analyses, we review the significant benefits highlighted by this landmark study, its role in shaping clinical guidelines, and in re-establishing interest in interventions that reduce the residual risk of progression of DKD, alongside its interrelation with cardiovascular morbidity and heart failure. We also provide a brief narrative summary of key renal outcome trials since CREDENCE, which indicate emerging avenues for pharmacotherapy beyond SGLT2 inhibition.

Impact of mobile application and outpatient follow-up on renal endpoints and physiological indices in patients with chronic kidney disease: a retrospective cohort study in Southwest China

BackgroundChronic kidney disease (CKD) is a significant public health concern, and patient self-management is an effective approach to manage the condition. Mobile applications have been used as tools to assist in improving patient self-management, but their effectiveness in long-term outpatient follow-up management of patients with CKD remains to be validated. This study aimed to investigate whether using a mobile application combined with traditional outpatient follow-up can improve health outcomes of patients with CKD .MethodsThis retrospective cohort study recruited CKD patients with stage 1–5 who were not receiving renal replacement therapy from a CKD management center. Two groups were established: the APP + outpatient follow-up group and the traditional outpatient follow-up group. Baseline data was collected from January 2015 to December 2019, followed by a three-year long-term follow-up until December 2022. Laboratory data, all-cause mortality, and renal replacement treatment were then collected and compared between the two groups.Results5326 patients were included in the study, including 2492 in the APP + outpatient group and 2834 in the traditional outpatient group. After IPTW virtualization matching, the final matched the APP + outpatient group consisted of 2489 cases (IQR, 33–55) and 2850 (IQR, 33–55) in the traditional outpatient group. By the end of the study, it was observed that the laboratory data of Phosphorus, Sodium, Triglyceride, Hemoglobin showed significant improvements, Furthermore the APP + outpatient group demonstrated superior results compared to the traditional outpatient group (P < .05). And it was observed that there were 34 deaths (1.4%) in the APP + outpatient group and 46 deaths (1.6%) in the traditional outpatient group(P = .49). After matching for renal replacement therapy outcomes, the two groups were found to be comparable (95% CI [0.72–1.08], P = .23), with no significant difference. However, it was noted that the traditional outpatient group had a lower incidence of using temporary catheters during initial hemodialysis (95% CI [8.4-29.8%], P < .001).ConclusionThe development and application of an app combined with outpatient follow-up management can improve patient health outcomes. However, to ensure optimal preparation for kidney replacement therapy, patients in CKD stages 4–5 may require more frequent traditional outpatient follow-ups, and further develop an information-based decision-making support tool for renal replacement therapy.

Does Metabolic Syndrome and Its Components Have Prognostic Significance for Renal and Cardiovascular Outcomes in IgA Nephropathy?

Patients with IgA nephropathy (IgAN), a chronic kidney disease (CKD), are significantly more likely to have cardiovascular (CV) mortality and morbidity than the general population. The occurrence of metabolic syndrome (MetS) and metabolic risk factors are independent risk factors for CV disease and renal progression. The purpose of this study was to determine how metabolic characteristics in a homogeneous population of CKD patients relate to prognosis. A total of 145 patients with CKD stages 1-4 diagnosed with IgA nephropathy (92 men and 53 women, aged 54.7 ± 13 years) were examined and monitored for a median of 190 months. All-cause mortality and any CV event, such as stroke, myocardial infarction, revascularization (CV), end-stage renal disease, and renal replacement therapy (renal), have been included in the composite endpoints (CV and renal). Patients with MetS had significantly more primary endpoint events (23/65 patients vs. 15/60 patients, p < 0.001) compared to the non-MetS group. The MetS group had a statistically significant increase in both primary renal and CV endpoints (18/65 vs. 10/60, p = 0.001), and in CV endpoint events (7/65 vs. 6/60, p = 0.029) among the secondary endpoints (CV and renal separately). Based on Cox regression analysis, the main endpoint independent predictors of survival were dyslipidemia, eGFR, hemoglobin, urine albuminuria, and diabetes mellitus. Independent predictors of secondary renal endpoints were dyslipidemia, hemoglobin, urine albumin, and eGFR. Predictors of secondary cardiovascular endpoints were gender, BMI, and diabetes. When Kaplan-Meier curves were analyzed at the combined endpoints (CV and renal) or each endpoint independently, significant differences were seen between MetS and non-MetS. With more MetS components, the primary endpoint rate increased significantly (MetS comp. 0 vs. MetS comp. 2+, primary endpoints, p = 0.012). Our results show that the metabolic profile has a prognostic role not only for renal endpoints but also for CV endpoints in IgAN. BMI, hyperuricemia, hypertension, and diabetes have a predictive value for the prognosis of IgA nephropathy.

Plasma angiotensin-converting enzyme 2 (ACE2) is a marker for renal outcome of diabetic kidney disease (DKD) (U-CARE study 3)

IntroductionACE cleaves angiotensin I (Ang I) to angiotensin II (Ang II) inducing vasoconstriction via Ang II type 1 (AT1) receptor, while ACE2 cleaves Ang II to Ang (1–7) causing vasodilatation...

Effects of Empagliflozin in Type 2 Diabetes With and Without Chronic Kidney Disease and Nondiabetic Chronic Kidney Disease: Protocol for 3 Crossover Randomized Controlled Trials (SiRENA Project).

Sodium-glucose-cotransporter 2 inhibitors (SGLT2is) have revolutionized the treatment of type 2 diabetes mellitus (DM2) and chronic kidney disease (CKD), reducing the risk of cardiovascular and renal end points by up to 40%. The underlying mechanisms are not fully understood. The study aims to examine the effects of empagliflozin versus placebo on renal hemodynamics, sodium balance, vascular function, and markers of the innate immune system in patients with DM2, DM2 and CKD, and nondiabetic CKD. We conducted 3 double-blind, crossover, randomized controlled trials, each with identical study protocols but different study populations. We included patients with DM2 and preserved kidney function (estimated glomerular filtration rate >60 mL/min/1.73 m2), DM2 and CKD, and nondiabetic CKD (both with estimated glomerular filtration rate 20-60 mL/min/1.73 m2). Each participant was randomly assigned to 4 weeks of treatment with either 10 mg of empagliflozin once daily or a matching placebo. After a wash-out period of at least 2 weeks, participants were crossed over to the opposite treatment. End points were measured at the end of each treatment period. The primary end point was renal blood flow measured with 82Rubidium positron emission tomography-computed tomography (82Rb-PET/CT). Secondary end points include glomerular filtration rate measured with 99mTechnetium-diethylene-triamine-pentaacetate (99mTc-DTPA) clearance, vascular function assessed by forearm venous occlusion strain gauge plethysmography, measurements of the nitric oxide (NO) system, water and sodium excretion, body composition measurements, and markers of the complement immune system. Recruitment began in April 2021 and was completed in September 2022. Examinations were completed by December 2022. In total, 49 participants completed the project: 16 participants in the DM2 and preserved kidney function study, 17 participants in the DM2 and CKD study, and 16 participants in the nondiabetic CKD study. Data analysis is ongoing. Results are yet to be published. This paper describes the rationale, design, and methods used in a project consisting of 3 double-blind, crossover, randomized controlled trials examining the effects of empagliflozin versus placebo in patients with DM2 with and without CKD and patients with nondiabetic CKD, respectively. EU Clinical Trials Register 2019-004303-12; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004303-12, EU Clinical Trials Register 2019-004447-80; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004447-80, EU Clinical Trials Register 2019-004467-50; https://www.clinicaltrialsregister.eu/ctr-search/search?query=and+2019-004467-50. DERR1-10.2196/56067.

#322 Are platelet-related parameters prognostic predictors of renal and cardiovascular outcomes in IgA nephropathy?

Abstract Background and Aims IgA nephropathy (IgAN) is associated with chronic inflammation. Platelet-related parameters, such as platelet (PLT) count, platelet-to-albumin ratio (PAR) and platelet-to-lymphocyte ratio (PLR), were examined as potential prognostic indicators for renal and cardiovascular (CV) outcomes in IgAN. Method 150 IgAN patients were involved and divided into two groups based on the cut-off value of PAR. All-cause mortality, major CV events and end-stage renal disease were the primary combined endpoints. Secondary endpoints, such as CV or renal endpoints, were also analyzed separately. Results Seventy-four per cent of patients were male and had a mean age of 43.7 ± 13.5 years. Mean follow-up time: 124 ± 67 months. The K-M curve showed that PLT, PLR and PAR were strongly associated with primary combined and renal outcomes, but not with cardiovascular outcomes in IgAN. In the case of combining PAR with LVH, the K-M curves showed significant differences in both the primary (p &amp;lt; 0.001) and secondary outcomes (p = 0.001 and p = 0.038). When we combined PAR with metabolic syndrome, the primary (p &amp;lt; 0.001) and secondary (p = 0.001 and p = 0.015) outcomes were also significant in the low and high PAR groups. PAR was correlated with gender (r = -0.273, p = 0.001) and segmental glomerulosclerosis on histology (r = 0.161, p = 0.047). PLR correlated with microalbuminuria (r = -0.165, p = 0.033) and left ventricular hypertrophy (r = -0.178, p = 0.025). PLT was correlated with gender (r = -0.201, p = 0.013) and eGFR (r = 0.158, p = 0.040). PLR, gender, dyslipidemia and microalbuminuria were associated with the primary composite endpoints; left ventricular hypertrophy and microalbuminuria with the secondary renal endpoints; and gender, age and diabetes with the cardiovascular endpoints by multivariate Cox regression. Conclusion Elevated PAR and PLR may predict end-stage renal disease progression, but in combination with LVH and MetS, they showed CV events also in IgAN. The determination of PAR and PLR can be useful and cost-effective parameters for assessing both cardiovascular and renal risks in CKD.

#277 Update to the long-term safety and efficacy of iptacopan in C3G: 33-month extension study data from patients enrolled in a phase 2 study

Abstract Background and Aims Complement 3 glomerulopathy (C3G), due to dysregulation of the alternative complement pathway (AP), is an ultra-rare primary glomerulonephritis. Iptacopan (LNP023) is an oral, proximal complement inhibitor that specifically binds factor B and inhibits the AP. We previously reported the primary endpoint data from the Phase (Ph) 2 extension study (NCT03955445), showing proteinuria reduction (57% [p &amp;lt; 0.0001]) and estimated glomerular filtration rate (eGFR) improvement (by +6.83 mL/min/1.73 m2 [p = 0.0174]) from baseline, following 12 months (M) of treatment with iptacopan in patients with C3G. Here we present further long-term efficacy and safety data from patients with C3G and recurrent C3G (post-kidney transplantation), who completed 33M of treatment with iptacopan (NCT03955445). Method Adults with C3G disease (Cohort A) or C3G recurrence post-transplantation (Cohort B) received iptacopan 200 mg twice-daily (bid) for at least 12 weeks in the Ph2 study (NCT03832114) before entering the open label extension study (NCT03955445). Long-term efficacy was assessed by a number of renal endpoints, including a 2-component composite renal endpoint (eGFR stability [≤10% reduction] and ≥50% proteinuria reduction). Long-term safety and tolerability of iptacopan was continually monitored. Results Of 27 patients completing the Ph2 study (NCT03832114), 26 (16 Cohort A, 10 Cohort B) entered the extension study treatment with iptacopan 200 mg bid; 22 patients (14 Cohort A, 8 Cohort B) completed the 33M visit (i.e., 3M in the Ph2 study and 30M in the extension study). In Cohort A, 42.9% of patients met the 2-component composite renal endpoint criteria at 33M. Proteinuria (first morning void [FMV] urine protein–creatinine ratio [UPCR]) was reduced by 41% (p = 0.0097) compared to baseline. eGFR stabilized or improved in most patients (13/16) over time and change from baseline at the 33M time-point was −3.18 mL/min/1.73 m2 (p = 0.3512). C3 levels increased by 275% (p &amp;lt; 0.0001) from baseline. In Cohort B, eGFR change from baseline at the 33M time-point was −6.34 mL/min/1.73 m2 (p = 0.0571), and C3 levels increased by 102%. Baseline proteinuria values (FMV UPCR) were within the normal range for most participants in Cohort B and remained so during iptacopan treatment. Iptacopan was generally well-tolerated, and most adverse events were of mild severity in both cohorts. Biomarkers demonstrated substantial AP inhibition. Conclusion Long-term treatment with iptacopan was associated with sustained reduction in proteinuria in patients with C3G (Cohort A), and preservation of eGFR. These improvements in kidney function were associated with substantial inhibition of the AP leading to normalization of serum C3. Iptacopan was well-tolerated with no new safety findings in the long term, in patients with C3G, including those with recurrence post-transplantation on top of broad triple immunosuppression. The ongoing Ph3 APPEAR-C3G study (NCT04817618) is evaluating the efficacy and safety of iptacopan in patients with C3G.

#2500 Renal perfusion and SGLT2i

Abstract Background and Aims Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i) have revolutionized treatment of type 2 diabetes mellitus (DM2) and chronic kidney disease (CKD), improving cardiovascular and renal endpoints. This improvement could be due to a decrease in renal perfusion (RP), attenuating glomerular hyperfiltration thus leading to kidney protection. This has been demonstrated in patients with type 1 diabetes and in animal studies, but not in patients with DM2 and it has never before been investigated in patients with CKD. Our aim was to examine the effects of the SGLT2i empagliflozin on RP in patients with DM2, DM2 and CKD and non-diabetic CKD, respectively. Methods We conducted three randomized, double-blind placebo controlled cross-over studies, including patients with: Participants were randomized to four weeks' treatment with empagliflozin 10 mg or matching placebo and were, after a washout period of at least two weeks, crossed over to four weeks of the opposite treatment. At the end of each treatment period we measured RP using 82Rb-PET/CT and standardized GFR using 99mTc-DTPA-clearence. We also measured 24-hour ambulatory blood pressure (BP), urinary albumin/creatinine ratio (UACR) and Hb1Ac. Results A total of 49 patients completed the studies, 16 in the DM2-group, 17 in the DM2-CKD-group and 16 in the CKD-group. In the combined study-population empagliflozin reduced RP compared to placebo by 4% (geometric mean ratio: 0.96, 95% CI: 0.94; 0.99, p = 0.0171). This change was most pronounced in the DM2-CKD-group, with a reduction of 6% (geometric mean ratio: 0.94, 95% CI: 0.91; 0.97), p &amp;lt; 0.001). There was a decrease of 4% in the DM2-group and 1% in the CKD-group, though these changes were not statistically significant (p = 0.29 and 0.72, respectively, see Fig. 1). In the 29 patients with a UACR &amp;gt; 30 mg/g, empagliflozin treatment led to a significant decrease in UACR in the combined study-population (geometric mean ratio: 0.61, 95% CI: 0.46; 0.80, p = 0.001), again primarily driven by a decrease in the DM2-CKD-group (geometric mean ratio: 0.51, 95% CI: 0.31; 0.85, p = 0.014), with non-significant decreases in the remaining groups. Empagliflozin decreased standardized GFR and BP in the combined population as well as in all sub-groups, while we found no change in Hb1Ac. For further details, see Table 1. Conclusion Short-term empagliflozin treatment reduces RP, GFR, BP and albumin excretion. Relative changes in RP and UACR were most pronounced in patients with concomitant DM2 and CKD, whereas changes in BP and GFR were seen in all groups.