Renin-angiotensin System Inhibitors Research Articles

Revisiting Race and the Benefit of RAS Blockade in Heart Failure: A Meta-Analysis of Randomized Clinical Trials.

Concerns have arisen that renin-angiotensin system (RAS) blockers are less effective in Black patients than non-Black patients with heart failure and reduced ejection fraction (HFrEF). To determine whether the effects of RAS blockers on cardiovascular outcomes differ between Black patients and non-Black patients with HFrEF. MEDLINE and Embase databases through December 31, 2023. Randomized trials investigating the effect of RAS blockers on cardiovascular outcomes in adults with HFrEF that enrolled Black and non-Black patients. Individual-participant data were extracted following Preferred Reporting Items for Systematic Reviews and Meta-analyses Independent Personal Data (PRISMA-IPD) reporting guidelines. Effects were estimated using a mixed-effects model using a 1-stage approach. The primary outcome was first hospitalization for HF or cardiovascular death. The primary analysis, based on the 3 placebo-controlled RAS inhibitor monotherapy trials, included 8825 patients (9.9% Black). Rates of death and hospitalization for HF were substantially higher in Black than non-Black patients. The hazard ratio (HR) for RAS blockade vs placebo for the primary composite was 0.84 (95% CI, 0.69-1.03) in Black patients and 0.73 (95% CI, 0.67-0.79) in non-Black patients (P for interaction = .14). The HR for first HF hospitalization was 0.89 (95% CI, 0.70-1.13) in Black patients and 0.62 (95% CI, 0.56-0.69) in non-Black patients (P for interaction = .006). Conversely, the corresponding HRs for cardiovascular death were 0.83 (95% CI, 0.65-1.07) and 0.84 (95% CI, 0.77-0.93), respectively (P for interaction = .99). For total hospitalizations for HF and cardiovascular deaths, the corresponding rate ratios were 0.82 (95% CI, 0.66-1.02) and 0.72 (95% CI, 0.66-0.80), respectively (P for interaction = .27). The supportive analyses including the 2 trials adding an angiotensin receptor blocker to background angiotensin-converting enzyme inhibitor treatment (n = 16 383) gave consistent findings. The mortality benefit from RAS blockade was similar in Black and non-Black patients. Despite the smaller relative risk reduction in hospitalization for HF with RAS blockade in Black patients, the absolute benefit in Black patients was comparable with non-Black patients because of the greater incidence of this outcome in Black patients.

The epigenetic legacy of renin-angiotensin system inhibition in preventing hypertension.

The epigenetic legacy of renin-angiotensin system inhibition in preventing hypertension.

Association between socioeconomic position and discontinuation of pharmacotherapy for heart failure after cardiac resynchronization therapy.

Pharmacological therapy remains a cornerstone in heart failure (HF) treatment despite implantation of a cardiac resynchronization therapy (CRT) device. The aim of this study was to investigate the association between 1) drug discontinuation, and 2) long-term adherence to HF pharmacotherapy after CRT implantation and socioeconomic position and multimorbidity. We conducted a registry-based cohort study including all patients who underwent a first-time CRT implantation at Aarhus University Hospital from 2000-2017. HF pharmacotherapy included beta blockers (BBs), renin angiotensin system inhibitors (ACEI/ARB), and mineralocorticoid receptor antagonists (MRAs). Patients were identified using the Danish Pacemaker and ICD Registry, and information about medication and comorbidities was obtained through linkage to the Danish health registries. We identified 2,007 patients of whom 1,880 (94%) were eligible for inclusion. The cumulative incidence of drug discontinuation at 10 years was 6% (95% confidence interval [CI] 5-8%) for BB, 10% (95% CI 9-12%) for ACEI/ARB, and 24% (95% CI 20-27%) for MRAs. Living alone was associated with higher BB discontinuation rates (hazard ratio [HR] 1.83, 95%CI 1.20-2.79), whereas patients with multimorbidity were more likely to discontinue ACEI/ARB- (HR 1.92, 95%CI 1.33-2.80) and MRA therapy (HR 1.51, 95% CI 1.10-2.09). Income- and educational level did not influence drug discontinuation rates, and similar adherence patterns were observed across all strata of socioeconomic position and multimorbidity. In patients with CRTs, drug discontinuation rates were low, and adherence to HF pharmacotherapy was comparable regardless of socioeconomic position. Living alone and multimorbidity were associated with discontinuation of specific HF drugs.

#762 Hyperkalemia and discontinuation of RAS blockade after initiating SGLT-2i vs. DPP-4i in patients with type 2 diabetes; a population-based cohort study

Abstract Rate of hyperkalemia and discontinuation of renin-angiotensin system blockade after initiating SGLT-2 inhibitors vs. DPP-4 inhibitors in patients with type 2 diabetes; a population-based cohort study Background and Aims Post-hoc analyses of clinical trials have suggested that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) lower the rate of hyperkalemia and facilitate the use of renin-angiotensin system inhibitors (RASi) in people with type 2 diabetes and CKD. Whether these effects are generalizable to patients treated in routine clinical practice is unclear. Here, we evaluated the comparative effects of SGLT-2i and dipeptidyl peptidase-4 inhibitors (DPP-4i) on the rate of hyperkalemia and RASi discontinuation. Method We conducted a population-based active-comparator, new-user cohort study using data from the Stockholm CREAtinine Measurements (SCREAM) project of people with type 2 diabetes who newly initiated SGLT-2i or DPP-4i between January 2014 and December 2021. The primary outcomes were time to first outpatient hyperkalemia (plasma potassium >5.0 mmol/L) occurrence and recurrent hyperkalemia. The secondary outcomes were mild (potassium >5-≤5.5 mmol/L) and moderate-severe (potassium >5.5 mmol/L) hyperkalemias. Among RASi users, we also studied time to RASi discontinuation through evaluation of pharmacy fills. Cox regression with inverse probability of treatment weighting was used to estimate hazard ratios (HRs) and rate differences for time to first hyperkalemia. Weighted Poisson regression was used to estimate incidence rate ratios (IRRs) for hyperkalemia recurrence. Results We included 24 417 individuals (of which 14 470 initiated SGLT-2i and 9, 947 DPP-4i therapy), followed for median 2.0 (Q1-Q3 0.8-3.7) years. Mean age was 67 years and 37% were women. Compared with DPP-4i, initiation of SGLT-2i was associated with a lower rate of first hyperkalemia (adjusted hazard ratio [HR] 0.83; 95% CI 0.72-0.96) and recurrent hyperkalemia (incidence rate ratio [IRR] 0.75; 0.64-0.85). Similar findings were observed among people with eGFR ≥60 (HR 0.73; 95% CI 0.63-0.86) and <60 (HR 0.87; 95% CI 0.63-1.16) ml/min/1.73 m2, as well as for mild (HR 0.82; 95% CI 0.71-0.95) and moderate-severe (HR 0.67; 95% CI 0.52-0.84) hyperkalemias. Out of 15 746 participants that were prevalent RASi users, 17% discontinued RASi therapy during 2.0 (IQR 0.8-3.7) years of follow-up. Initiation of SGLT-2i vs. DPP-4i was not associated with the rate of RASi discontinuation (HR: 1.00; 0.91-1.11). Conclusion In patients with type 2 diabetes managed in routine clinical care, the use of SGLT-2i was associated with a lower rate of first and recurrent hyperkalemia compared with DPP-4i. However, this was not accompanied by higher persistence on RASi therapy.

#1704 GLP-1RA versus DPP-4 inhibitors and rates of hyperkalemia and discontinuation of renin-angiotensin system (RAS) blockade in Swedish routine care

Abstract Background and Aims Emerging evidence suggest that glucagon-like peptide-1 receptor agonists (GLP-1RA) influence tubular handling of electrolytes and increase potassium excretion, which may translate into reduced risk of hyperkalemia. Hyperkalemia is a common complication that limits persistence on guideline-recommended RAS inhibitors (RASi). Here, we quantified and compared rates of hyperkalemia and RASi discontinuation among users of GLP-1RA versus dipeptidyl peptidase-4 inhibitors (DPP-4i) in a large healthcare system. Method We used data from the SCREAM project (Jan 2008-Dec 2021) to conduct a population-based active-comparator, new-user cohort study of adults with type-2 diabetes who started GLP-1RA or DPP-4i. The primary outcome was hyperkalemia occurrence, overall (plasma potassium>5.0 mmol/L) and by severity (mild -potassium >5-≤5.5 mmol/L- and moderate-severe -potassium >5.5 mmol/L- hyperkalemia). Among ongoing RASi users, we assessed time to RASi discontinuation through evaluation of subsequent RASi dispensations. Cox regression with inverse probability of treatment weighting (IPTW) was used to estimate pooled hazard ratios (HRs) and rate differences. Major cardiovascular events (MACEs) served as positive control outcome to evaluate unmeasured confounding bias. Results During a median follow-up of 3.0 (Interquartile range [IQR] 1.2-5.6) years, we identified 33 280 eligible participants, of which 13 633 started GLP-1RA and 19 647 DPP-4i. Mean age was 64 years and 40% were women. Compared with DPP-4i, starting GLP-1RA was associated with a lower rate of hyperkalemia (Hazard ratio [HR] 0.91; 95% CI: 0.84-0.99, Fig. 1), with no suggestion of effect modification by baseline eGFR strata (HR 0.91 (0.78-1.07) for eGFR ≥60 and HR 0.92 (0.83-1.01) for eGFR <60 ml/min/1.73 m2, P for interaction >0.05). Similar findings were observed for mild (HR 0.90; 0.83-0.98) and moderate-severe (HR 0.92; 0.80-1.06) hyperkalemia. Out of 21 751 participants that were using RASi, 8 463 discontinued this therapy during median 2.0 (0.7, 4.1) years of follow-up. Initiation of GLP-1RA vs. DPP-4i was associated with lower rate of RASi discontinuation (HR: 0.93; 0.87-0.98), with no interaction across strata of baseline eGFR (HR 0.97 (0.83-1.12) for eGFR ≥60 and HR 0.93 (0.87-0.99) for <60 ml/min/1.73 m2, P for interaction >0.05). Consistent with trial evidence, we observed a lower rate of MACE for GLP-1RA vs DPP-4i (HR 0.87; 0.78-0.98). Conclusion In patients with diabetes managed in routine care, the use of GLP-1RA was associated with lower rates of hyperkalemia and discontinuation of RASi compared with DPP-4i, providing further observational evidence in support of the use of these medications.

#2679 Prediction of acute eGFR decline after first initiation of RASI inhibitors and its impact on clinical outcomes

Abstract Background and Aims The objective of this study is to investigate the correlation between acute eGFR (estimated glomerular filtration rate) decline after initiation of ACEI (angiotensin-converting enzyme inhibitor)/ARB (angiotensin receptor blocker) medications and clinical outcomes in a real-world setting. Additionally, we aim to establish a risk prediction model to identify high-risk individuals who are more likely to experience a rapid decline in eGFR after drug initiation. Method A total of 2026 adult new users of ACEI/ARB were selected from the China Renal Data System (CRDS). Patients in acute clinical states and those using nephrotoxic drugs were excluded, and it was required that patients had at least one creatinine measurement during the baseline period and one week to four weeks after drug initiation. Cox proportional hazards models were used to compare the relative risks of adverse long-term outcomes in patients with different degrees of acute eGFR decline. A multivariable logistic regression model was employed to analyze the factors influencing acute eGFR decline. Lasso regression was used to select predictive factors, resulting in a logistic regression model with 18 predictive factors. Results Among the 2026 patients, 1148 (57%), 473 (23%), and 405 (20%) experienced eGFR decline <5% or increase, 5-20% decline, and ≥20% decline, respectively, after initiation of RASI (renin-angiotensin system inhibitor). Following adjustment for multiple variables, an eGFR decline ≥20% was found to be associated with a higher risk of long-term renal disease progression, with a hazard ratio of 1.84 (95% confidence interval 1.19-2.85), but not significantly associated with an increased risk of all-cause mortality and cardiovascular events. Factors associated with an eGFR decline ≥20% after RASI initiation included higher BMI and Charlson index, more severe proteinuria, lower hemoglobin levels, presence of hypertension, diabetic nephropathy, arrhythmias, and concomitant use of thiazide diuretics or loop diuretics. The predictive model had a C-statistic of 0.75. Conclusion This study demonstrates that a short-term eGFR decline after RASI initiation is associated with a higher risk of long-term renal disease progression but not significantly associated with increased risks of all-cause mortality and cardiovascular events. We have developed a prediction model to estimate the risk of eGFR decline ≥20% after the initial use of RASI, which can aid clinicians in identifying patients with poorer renal outcomes following RASI initiation and facilitate timely intervention.

#1432 Prevalence, risks and treatment of incident chronic kidney disease stage 3-4: an observational study in Finland between 2016-2022

Abstract Background and Aims The rising burden of chronic kidney disease (CKD) calls for early detection and targeted interventions. Kidney-protective treatments (renin–angiotensin system inhibitors [RASis] and sodium-glucose co-transporter-2 inhibitors [SGLT2is]) can delay chronic kidney disease (CKD) progression, cardiovascular events and death. However, contemporary differences between CKD patients with and without type 2 diabetes (T2D) is limited. This study aimed to describe the prevalence, patient characteristics, the use of kidney protective treatments (RASi or SGLT2i) and event risks among patients with incident stage 3-4 CKD in Finland. Method We used comprehensive real-world clinical data from electronic health records from primary and hospital care in five municipalities in Finland between 1st January 2016 to 31st December 2022 to identify stage 3-4 CKD patients aged ≥18 years, defined as having either one estimated glomerular filtration rate (eGFR) measurement between 15 to 60 ml/min/1.73 m2 followed by a second one ≥90 days apart, or a registered CKD diagnosis. Two cohorts from primary care were identified: a prevalent cohort indexed at a fixed date, 1st Jan 2022 and an incident cohort indexed at the date of new CKD. The incident CKD patients were followed from CKD incident index date until death, emigration, or end of study on 31 December 2022. Analyses were also stratified by CKD patients with T2D and non-diabetes (T1D and gestational diabetes excluded), respectively. Risks were estimated as event rates per 1000 patient-years. The proportion of patients on/off treatment were estimates as a function of time and divided into pre- vs. post-index. Results In 2022 the prevalent cohort of 16,380 CKD stage 3-4 patients, represented a prevalence of 6.2% in the total background population of 263,383 individuals. The 12,129 incident Stage 3-4 CKD patients had a median eGFR of 55 ml/min/1.73 m2, similar in both non-T2D and T2D. Most patients were non-T2D; 73% (n = 8859). At index, 1.7% had a CKD diagnosis, lower in non-T2D (1.0%) vs T2D (3.5%) patients. The use of urine albumin creatinine ratio (UACR) was generally very low (21% had a measurement), 9% in the non-T2D and 53% in the T2D patients. Non-T2D, compared to T2D patients, were similar in age (76 vs 75 years) and had slightly less comorbidities like HF (12% vs 18%), myocardial infarction (9% vs 14%), stroke (15% vs 16%), atrial fibrillation (21% vs 25%) and less treated with statins (38% vs 64%). During follow-up, 10% had died within 1-year (97 deaths per 1000 patient years), similar in non-T2D (95 deaths per 1000 patient years) and T2D patients (104 deaths per 1000 patient years). One year risk of any hospitalization was also high, 49% and 64%, respectively. The use of kidney-protective treatments (renin angiotensin system inhibitor [RASi] or SGLT2i) at index (date of incident CKD) was lower in patients without T2D (47%) compared to those with T2D (69%). No change was observed in their use in the 12 months after incident CKD (Fig.). Finally, when studying the proportion of all non-T2D patients receiving SGLT2i after approval for CKD treatment, less than 1% of all CKD patients in the study group were treated with SGLT2i on 31st December 2022. Conclusion This study shows that CKD stage 3-4 is highly prevalent in Finland. Newly detected CKD stage 3-4 patients were little diagnosed and the use of UACR was low, especially among those who were non-diabetic. More than 2 out of 3 CKD patients were non-diabetic. Importantly, these non-diabetic CKD patients had similarly high disease burden, similar high risk of dying and had less kidney/cardiovascular prevention compared to those with T2D. The high mortality risks, substantial kidney-protective treatment inertia and UACR underutilization in stage 3-4 CKD patients all call for an urgent need for improved awareness and risk management, especially in the larger group of non-T2D.

#1468 Alport syndrome family screening and management—experience of a tertiary center

Abstract Background and Aims Alport syndrome (AS) is the most common cause of inherited chronic kidney disease. This disorder is caused by deleterious variants on COL4A3, COL4A4 or COL4A5 genes. These genes codify the proteins that constitute collagen type IV of the glomerular basement membrane (GBM). Importantly, AS patients can develop chronic kidney disease (CKD) kidney disease that can be delayed or possibly prevented by timely initiation of therapy. The identification of at-risk relatives and their genetic testing allow to identify AS patients and initiate appropriate renal care and avoid unnecessary vigilance if the test is negative. Our aim was to assess the outcomes of Alport Syndrome cascade family screening in a tertiary hospital. Method In this study, we retrospectively assessed familial relatives at risk of AS index cases in our Nephrogenetics consult, from January 2018 to November 2023. After referral, routine tests to detect renal disease were done and AS gene panel was performed. Demographic and clinical data were also compiled. Results A total of 75 at-risk relatives were assessed, belonging to 26 families with a COL4A variant identified in the index case. Relatives at risk were mostly referred by primary care doctors (n = 52, 69.3%), with other 15 patients (20%) directly scheduled for consultation, and 8 (10.7%) referred by a nephrology clinic. In this cohort, an AS diagnosis was confirmed in 43 relatives (57.3%), with an additional 13 (17.3%) of the at-risk relatives with ongoing biochemical or molecular analyses. In 19 (25.4%) relatives the molecular study allowed the exclusion of AS. In the subgroup of patients diagnosed with AS (n = 43): median age at molecular diagnosis was 40.5 years (IQR 20.2-56.5years) and 26 (60.5%) were female. Thirty-five patients (81.4%) patients had autosomal dominant AS: 32 had a variant in COL4A3 (6 different variants were found: 4 were pathogenic or likely pathogenic and 2 were of uncertain significance) and 3 patients on COL4A4. COL4A5 variants were identified in 8 patients, 5 of them were female. Three (7%) patients presented with intermittent hematuria, 14 (32.6%) patients presented isolated hematuria, 10 (23.2%) patients had urinary protein/creatine (Up/cr) <0,3g/g, 7 (16.2%) presented Up/cr between 0.3g/g and 1g/g, 3 (7%) patients had Up/cr >1g/g; Six (14%) had CKD. Twenty-two (51.2%) patients were started on a renin angiotensin system inhibitor (RASi) and 5 (11.6%) were already under a RASi. At the last visit in this group of AS patients, the mean epiTFG was 104.2 ml/min (IQ 85.6-120-5 ml/min) and 6 (14%%) patients had epiTFG below 60 ml/min; mean Uprot/creat was 0.11g/g (IQR 0.06-0.32), 12 (28%) patients had no proteinuria. In the subgroup of relatives at risk were AS excluded (n = 19): median age was 38.5 years (IQR 20.2-56.0) and 11 (58%) were female. One patient had CKD, 7 (36.8%) had no signs of renal disease and 8 (42%) patients had intermittent hematuria. Conclusion Our retrospective review showed that the systematic screening of relatives at risk in our hospital was met with a high discovery rate of AS patients. Since there is clinical benefit in an early AS diagnosis, namely through improved renal care and prevention of disease progression, timely genetic/biochemical screening of at-risk relatives is advisable. Additionally, by discharging the relatives with a negative test, this is a more cost-effective approach than providing continuous vigilance to all.

#2638 SGLT2i in CKD with high albuminuria: an observational real-world study

Abstract Background and Aims Dapagliflozin, a sodium–glucose co-transporter-2 inhibitor (SGLT2i), is indicated to treat chronic kidney disease (CKD). Clinical trials have shown that dapagliflozin significantly reduces albuminuria in patients with urine albumin-creatinine ratio (UACR) 200–5000 mg/g and has beneficial effects on estimated glomerular filtration rate (eGFR) decline and combined kidney outcomes. In the DAPA-CKD trial, dapagliflozin led to substantial reductions in the composite of sustained eGFR decline of ≥50%, end-stage kidney disease, and renal or cardiovascular death (hazard ratio [HR], 0.61; 95% confidence interval [CI]: 0.51, 0.72; p < 0.001), with similar reductions observed across UACR subgroups. Furthermore, compared with placebo, dapagliflozin reduced geometric mean UACR by 29.3% (95% CI: –33.1, –25.2; p < 0.0001), with no difference in relative UACR reduction by baseline UACR above or below 1000 mg/g. In the ZENITH-CKD study, over 12 weeks the combination of zibotentan (a novel endothelin A receptor antagonist) and dapagliflozin showed a robust reduction in UACR of 47.7% vs 28.3% for dapagliflozin alone, with this effect maintained in patients with UACR >700 mg/g. It is well known that renal disease progresses more quickly in patients with higher degree of albuminuria than in those with lower levels. We aimed to further characterize renal risk in patients with different levels of residual albuminuria despite standard of care treatment with renin–angiotensin system inhibitors (RASi) and SGLT2i. Methods We used a large USA claims database (Optum's de-identified Clinformatics® Data Mart Database [CDM]) to identify patients aged ≥18 years with CKD, defined as either two eGFR measurements ≤60 mL/min/1.73 m2 taken ≥90 days apart or a first eGFR ≤60 mL/min/1.73 m2 and a CKD diagnosis. Patients were indexed at the date of dapagliflozin 10 mg initiation between 30 April 2021 (date of approval for dapagliflozin in CKD) and March 2023. Patients with prior use of SGLT2i, immunosuppressive drugs, hydroxychloroquine, CKD stage 5 (based on eGFR <15 mL/min/1.73 m2 or dialysis), polycystic kidney disease, or type 1 or gestational diabetes were excluded. Patients were indexed on 1st January 2022 and grouped into two UACR groups: ≥700UACR group (≥700 mg/g) and <700UACR group (200–699 mg/g). Outcomes were UACR changes, eGFR slopes and CKD-associated hospitalizations within 1 year after dapagliflozin initiation. Hazard ratios were estimated using adjusted Cox survival regression. UACR follow-up analyses were restricted to patients with at least one follow-up measurement. Results In the 5908 patients with CKD, median UACRs at index in the ≥700UACR and <700UACR groups were 1414 mg/g and 102 mg/g, respectively. Patients in the ≥700UACR group vs <700UACR group had lower eGFR (40 vs 48 mL/min/1.73 m2), were younger (71 vs 74 years), and both groups had a high burden of comorbidities (heart failure: 38% vs 42%; type 2 diabetes: 74% vs 75%). RASi use was 81% and 74%, respectively. During follow-up, 22% of patients in the ≥700UACR group experienced a CKD-related hospitalization (25.1 events per 100 patient years) as compared to 19.5 events per 100 patient years in the <700UACR group (HR 1.38 [95% CI: 1.16, 1.64, p < 0.001]; Fig. panel A). The eGFR slope (95% Cl) of patients in the ≥700UACR group was –2.44 mL/min/1.73 m2 per year (–3.49, –1.65), compared with a flat eGFR trajectory in patients in the <700UACR group (0.39 [–0.11, 0.96]). In the ≥700UACR group with at least one follow-up measurement (n = 431), UACR lowered from 2077 mg/g to 1674 mg/g (–36.3%) within 1 month of dapagliflozin initiation but remained above 1200 mg/g throughout the 12-month follow-up period (Fig. panel B). Conclusions While treatment with RASi and SGLT2i are associated with reduced risk of renal outcomes in patients with CKD, awareness and management of residual albuminuria remains an area of unmet clinical need. The novel combination of zibotentan/dapagliflozin currently under investigation in the ZENITH High Proteinuria phase III trial (NCT06087835) seeks to address this need.

#1638 Long-term mortality trends in IgA nephropathy: a study of an Eastern European cohort

Abstract Background and Aims IgA Nephropathy (IgAN), recognized as the most prevalent form of primary glomerulonephritis, has been thoroughly researched in terms of renal outcomes. However, there is a scarcity of data regarding patient survival, especially in Eastern Europe. Our study focuses on exploring the long-term survival rates of IgAN patients and identifying associated risk factors within an Eastern European population. Method In our retrospective study, we analyzed 215 patients with biopsy proven IgAN (median age 44 years, 71% male, median eGFR 40.9 mL/min/1.73 m2, median proteinuria 1.24g/g) diagnosed at a tertiary center in Romania from 2010 to 2017. Our study primarily focused on all-cause mortality and secondarily on the development of ESKD (start of kidney replacement therapy or renal transplantation). The follow-up for patients continued until they reached either of these endpoints or until January 1, 2022, whichever came first. Results During a median follow-up of 7.3 years, 20% of the patients died. The main causes of death were cardiovascular diseases (60%), followed by infectious (19%), gastroenterological (12%), and neoplasia (9%) diseases. Mean survival of the entire cohort was 117.5 months (95% CI: 111.2, 123.8) and mean kidney survival was 98.4 months (95% CI: 90.5, 106.2). Survival rates at 1 year, 5 years and 10 years were 93%, 84% and 77% respectively, and kidney survival rates at 1 year, 5 years and 10 years were 87%, 72% and 58% respectively. When compared to the survivors, deceased patients were significantly older (60 vs 42 years, p 0.001) and had an increased prevalence of diabetes mellitus (26 vs 4%, p 0.001) and higher Charlson comorbidity index (5 vs 2, p 0.001). Deceased patients also had significantly higher serum creatinine levels (3.3 vs 1.6 mg/dL, p 0.001), lower eGFR (18 vs 46 mL/min, p 0.001), and more haematuria (230 vs 183cells/HPF, p 0.01). There was no significant difference in proteinuria between the two groups (1.1 vs 1.2g/g, p 0.3). In the univariate Cox regression analysis, all-cause mortality was significantly associated with several factors: advancing age (HR 1.08, 95% CI: 1.05, 1.11), an increased Charlson comorbidity index (HR 1.60, 95% CI: 1.42, 1.80), the presence of diabetes mellitus (HR 5.13, 95% CI: 2.57, 10.25), lower eGFR (HR 0.95, 95% CI: 0.93, 0.97), increased proteinuria (HR 1.12, 95% CI: 1.00, 1.25), the presence of haematuria (HR 1.26, 95% CI: 1.03, 1.53), lower serum albumin (HR 0.35, 95% CI: 0.22, 0.56), higher MEST-C score (HR 1.38, 95% CI 1.13, 1.69) and absence of renin-angiotensin-system inhibitors (RASI) (HR 0.32, 95% CI 0.17, 0.60). However, in the multivariate analysis, only an increased Charlson comorbidity index (HR 1.31, 95% CI: 1.09, 1.57), lower eGFR (HR 0.98, 95% CI: 0.96-1.00) and absence of RASI (HR 0.21, 95% CI: 0.15, 0.28) retained their statistical significance. Conclusion We report a 20% mortality rate in our Eastern European IgAN cohort, primarily due to cardio-vascular diseases. Death correlates with increased age, comorbidity burden, decreased renal function at diagnosis, and absence of RASI use. RASI treatment may potentially improve survival, highlighting its importance in managing IgAN.

#487 Treating chronic kidney disease in Danish primary care: results from the observational ATLAS study

Abstract Background and Aims Little is known about the clinical characteristics and medical treatment of individuals with chronic Kidney Disease (CKD) in primary care clinics, including uptake of cardio-renoprotective treatments like renin-angiotensin-system inhibitors (RASi) and sodium glucose co-transporter 2 inhibitors (SGLT2i). Therefore, the aim of this study were to describe the clinical characteristics, comorbidity, and medical treatment in the primary care population with decreased estimated glomerular filtration rate (eGFR) and albuminuria. Additionally, to examine the awareness and habits of primary care physicians (PCP) in regard to CKD and treatment patterns in this high-risk patient population. Method An observational study of current CKD prevalence, treatment patterns and comorbidities in primary care based on patient record data, Data was drawn from 128/211 randomly invited primary care clinics throughout Denmark. A computerized selection identified 12 random individuals with CKD per clinic with ≥2 measurements of eGFR <60 mL/min/1.73 m2 or UACR >30 mg/g within two years. Pre-specified data collected from individual electronic health records included demographics, clinical variables, comorbidities, and relevant prescribed medications. Our analyses was strengthened by 125/128 PCP completing a questionnaire with responses regarding diagnosis, management and treatment of impaired kidney function in a real-world, primary care setting. Results Of the identified CKD study population (N = 1497), 80% had hypertension, 32% diabetes (DM), 13% heart failure (HF), 59% no DM/HF. RASi were prescribed to 65%, statins to 56%, SGTL2is to 14%, and MRAs to 8% of all individuals. Treatment patterns differed between individuals with varying comorbidities, e.g., RASi usage was higher in DM (76%) or HF (74%) vs. no DM/HF (58%), as was statin usage (76% in DM vs. 45% in no DM/HF). SGTL2i usage in CKD without DM/HF was low. Questionnaire results showed that most PCPs identified CKD using threshold eGFR <60 mL/min/1.73 m2 (62%) or UACR >30 mg/g (58%) and 62% reported initiating treatment to retard kidney function decline. 53% of PCPs reported using SGLT2is as second-line treatment for CKD. 38% of PCPs often spoke to patients with an eGFR <60 mL/min/1.73 m2 as having CKD, whilst 38% reported rarely doing so and 19% never did so. The voluntary nature of PCP study participation (accepting an invitation to participate) may have generated bias towards those with an interest in CKD. Conclusion Despite good PCP awareness and wish to use relevant guidelines, a gap exists in implementation of cardio-renoprotective treatment, especially in individuals without DM or HF. Data from both patient files and questionnaires emphasizes a need for clear recommendations to PCPs to optimize early cardio-renal protection in individuals with CKD. Applying the same systematic screening as in individuals with DM to non-diabetic populations could offer a paradigm shift for the identification, diagnosis and monitoring of CKD. Boehringer Ingelheim supported this study, but had no role in the design, analysis or interpretation of the results.

#1091 Quantifying the potential contribution of drugs to the occurrence of acute kidney injury in patients with chronic kidney disease

Abstract Background and Aims Patients with CKD have high risk of AKI. Quantifying the contribution of drugs to the occurrence of AKI in this population and assessing its risk factors is important to design preventive interventions. We sought to comprehensively describe drug-related components associated with AKI in patients with CKD. We documented the incidence of drug-related AKI, the proportion of preventable AKI, identified the various drugs potentially associated with it, explored the risk factors, and assessed the one-year incidences of the recurrence of drug-related AKI, kidney failure, and death. Method The CKD-REIN study is a national prospective cohort of 3,033 nephrology outpatients with a confirmed diagnosis of CKD (eGFR <60 mL/min/1.73 m²) in France. AKIs and adverse drug reactions (ADRs) were prospectively identified from hospital charts, medical records, and patient interviews. Nephrologists used the Kidney Disease: Improving Global Outcomes criteria to adjudicate all stages of AKI, and expert pharmacologists used validated tools to adjudicate ADRs (including drug-related AKIs). A drug-related AKI was considered serious when the outcome is death, a life-threatening situation, hospital admission, disability, permanent damage, or another important medical event. We used cause-specific Cox proportional hazard models to investigate the patients’ baseline clinical characteristics associated with the risk of drug-related AKI. Results Over a median [interquartile range] period of 4.9 [3.4-5.1] years, 832 cases of AKI were reported in 639 (21%) of the 3,033 study participants. Over a quarter of the AKI events were drug-related (n = 236, 28%); from those, 47% were hospital- and 53% community-acquired AKI. From the 168 serious drug-related AKI events, 28% were considered preventable or potentially preventable. The three most frequently implicated drug classes were diuretics, renin-angiotensin system inhibitors, and contrast agents. At least two concomitant medications were implicated in more than half of the AKIs with a drug-related component, RASis and diuretics, two diuretics, and diuretics and antibiotics were the 3 most frequent associations (Figure). A history of cardiovascular events, and the presence of diabetes, lower levels of hemoglobin and eGFR, poor medication adherence, and ≥5 drugs being taken daily were associated with a greater risk of drug-related AKI. The one-year cumulative incidences of recurrent drug-related AKI, kidney replacement therapy, and death were 7%, 15%, and 11%, respectively, after the first drug-related AKI. Conclusion Drug-related AKI is prevalent among patients with CKD. Further training in drug management for both CKD patients and healthcare professionals involved in their care might mitigate the incidence of drug-related AKI.

#1614 Fenofibrates and chronic kidney disease – Is there anything to worry about?

Abstract Background and Aims Chronic Kidney Disease (CKD) patients have increased risk of cardiovascular disease and dyslipidemia is a frequent comorbidity. Many patients are medicated with anti-lipidemic agents to reduce atherosclerotic disease and coronary vascular events. Fenofibrates are lipid-lowering agents used to treat mixed dyslipidemia and hypertriglyceridemia and are widely used by primary care physicians. Many studies described reversible increase in serum creatinine (SCr) associated with fenofibrates use, but the underlying mechanism is poorly understood. Whether hypercreatinemia is secondary to alterations in creatinine metabolism, tubular handling, or reflects a true impairment in kidney function remains unknown. This phenomenon is also fairly unknown to many primary care providers and, as a result, patients with a SCr rise while on fenofibrates are often referred to nephrology consultation. In this study, we have analyzed the effect of fenofibrate withdrawal on SCr, eGFR and hemoglobin (Hb) in patients referred to nephrology consultation for CKD or decrease of eGFR. Our aim was to understand the impact of fenofibrates withdrawal on kidney function and to look for factors that might influence the risk of fenofibrate nephrotoxicity. Methods We conducted a retrospective observational study, reviewed electronic medical records and collected data of all adult patients discontinued on fenofibrates at first nephrology consultation, between January 2022 and October 2023. Ninety patients were included, of which four were excluded due to simultaneous suspension of antihypertensive drugs. Patients were subsequently evaluated for clinical reasons from 2 to 6 months after the first appointment, with new laboratory data collected, including Hb, SCr and lipid profile. eGFR was calculated using MDRD 4 formula. Continuous variables were compared by t-test and categorical variables were compared by chi-square test. A p value of < 0.05 was considered statistically significant. All data was analyzed using Stata software. Results A total of eighty-six patients were included in this study, 65% (n=56) were male, mean age of 71.2 ± 11.4 years old; all patients were medicated with fenofibrates due to dyslipidemia and 77% (n=66) were also on statins; 94% (n=81) had hypertension, 60% (n=52) had type 2 diabetes mellitus, and 20% (n=17) had ischemic cardiopathy. Ninety-two percent (n=79) were taking renin-angiotensin system inhibitors (RASi). Nearly half the patients (49% n = 42) had stage 4 CKD and 45% (n = 39) had stage 3 CKD; Main causes of CKD were presumed diabetic kidney disease (34% n = 29) and ischemic nephropathy (15% n = 13), 30% (n = 26) of patients had undetermined etiology. Upon fibrate discontinuation, mean SCr was 2.1 ± 0.6 mg/dL and mean eGFR was 31.3 ± 10.9 mL/min/1.73 m2. Mean Hb was 12.5 ± 2.0 g/dL. After fenofibrate discontinuation, eGFR significantly improved in mean 15.2 mL/min/1.73 m2 (31.3 vs 46.5 mL/min/1.73 m2, p < 0.0001) with a mean reduction of SCr of 0.6 mg/dL (2.1 vs 1.5 mg/dL, p < 0.0001). Mean Hb increased 0.4 g/dL (12.4 vs 12.7 g/dL, p = 0.112). Mean total cholesterol was 168.4 ± 56.4 mg/dL and mean triglycerides was 234.8 ± 285.3 mg/dL. Only one patient was restarted on fenofibrate due to severe hypertriglyceridemia. Fenofibrate discontinuation effect on eGFR improvement remained statistically significant when adjusted for diabetes, hypertension, CKD etiology and RASi use. Conclusion Our study reports a consistent increase in eGFR and SCr decrease following discontinuation of fenofibrate, as other reports before. A true effect on eGFR could be supported by the Hb rise, though it did not reach statistical significance. The exact mechanism by which fenofibrates increase SCr remains to be clarified. Cardiovascular disease is the main cause of death amongst CKD population and the potential benefits of fenofibrates should not be disregarded. Our results suggest that patients started on fenofibrates should be carefully selected, specially if CKD is present, and kidney function monitoring should be considered. A drop in eGFR should prompt physicians to weigh on the strict indications for fenofibrates use.

#367 PROTECT and NefIgArd two-year proteinuria and eGFR outcomes in adults with IgA nephropathy: matching-adjusted indirect comparison

Abstract Background and Aims Immunoglobulin A (IgA) nephropathy is a rare kidney disorder characterized by deposition of IgA in the glomeruli causing progressive loss of kidney function and increased risk of kidney failure. In the absence of a head-to-head trial, this study used unanchored matching-adjusted indirect comparison (MAIC) of clinical trial data to compare two-year efficacy outcomes between Sparsentan in PROTECT and targeted-release formulation (TRF) budesonide plus real-world optimized and stable renin-angiotensin system inhibition (RASi) standard-of-care (SoC) in NefIgArd. Method We conducted an unanchored MAIC using individual patient level data from the PROTECT trial and aggregate data from the NefIgArd trial. Patients in the sparsentan arm of PROTECT were weighted to match key baseline characteristics of patients in the targeted-release formulation (TRF) budesonide + RASi SoC arm of NefIgArd based on publicly accessible, clinically pertinent baseline characteristics and prognostic factors using the method of moments. After weighting, percentage reduction of urine protein-creatinine ratio (UPCR) relative to baseline and two-year eGFR total slope (based on available data, chronic slope estimates are currently not available from NefIgArd) were estimated. A mixed model for repeated measures (MMRM) was used for UPCR relative percentage reduction and a random effect coefficient model for eGFR total slope. A two-tailed z-test with a pooled standard error was conducted for the indirect comparison. Results After assessing PROTECT and NefIgArd cross-trial characteristics on key outcome definitions, inclusion and exclusion criteria, and patient population, the two trials were considered sufficiently similar for unanchored MAIC. After weighting individual patient data from PROTECT, all matched baseline patient characteristics were well-balanced between arms of the two trials. Comparative results showed patients treated with sparsentan in PROTECT (−43.2% relative reduction in UPCR) exhibited a greater mean percentage reduction in proteinuria at two-years compared to TRF budesonide + RASi SoC (−30.7% relative reduction in UPCR), a relative percentage reduction of 18.1% (p = 0.03; Fig. 1A). For eGFR total slope, patients treated with sparsentan exhibited a slower decline in kidney function compared to TRF budesonide + RASi SoC, a difference of 0.54 ml/min/1.73 m2 per year; however, this difference was not statistically significant (p = 0.35; Fig. 1B). Conclusion Aligned to an earlier analysis of percentage reduction in proteinuria at 9-months (−37%, p < 0.0001 favoring sparsentan), our MAIC results show that sparsentan in PROTECT was associated with a greater relative percentage reduction in proteinuria at two-years compared to TRF budesonide plus real-world optimized and stable RASi SoC in NefIgArd. eGFR total slope for sparsentan in PROTECT was comparable to that reported for TRF budesonide plus real-world optimized and stable RASi SoC in NefIgArd. Results comparing chronic slope may provide a better indication of the long-term nephroprotective value of both therapies.

#853 Kidney-protective medication and risk of adverse clinical outcomes in patients with chronic kidney disease: preliminary findings from DISCOVER CKD

Abstract Background and Aims Renin-angiotensin-system inhibitors (RASi) have been a foundational therapy in chronic kidney disease (CKD) for several decades. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have also emerged as a critical disease-modifying therapy in CKD, with contemporary data from trials showing SGLT2i to significantly improve kidney and cardiovascular (CV) outcomes in patients with or without diabetes. Nonetheless, several studies have revealed sub-optimal prescribing of RASi and/or SGLT2i therapy (both herein referred to as kidney-protective medication) in patients with CKD. Using prospective data from the DISCOVER CKD study, we conducted an exploratory analysis to assess the association of kidney-protective medication real-world use with mortality risk, CV events (fatal and non-fatal), and hospitalisation in patients with CKD. Method DISCOVER CKD (NCT04034992) is a multi-country, non-interventional cohort study designed to characterise the epidemiology of CKD, including describing patient characteristics, disease progression, clinical outcomes, patient journey, practice patterns, and clinical management. In the prospective phase, patients with CKD were recruited from the UK, USA, Spain, Italy, Sweden and Japan between September 2019 and June 2022. Clinical data were extracted manually from patients’ health records into a standardised case report form. The current analysis includes 12 months’ follow-up data. A Cox proportional hazards model was used to compare the risk of all-cause mortality and CV events and a negative binomial regression model was used to compare the risk of all-cause hospitalisation between patients receiving and not receiving kidney-protective medication at baseline, with adjustments for age, sex, CKD stage, diabetes mellitus, hyperkalaemia, and heart failure. DISCOVER CKD received research ethics board approval, and informed consent was obtained from all patients. Results Of the 1052 patients enrolled in DISCOVER CKD, 643 (61.1%) were receiving kidney-protective medication in the form of RASi (n = 618) and SGLT2i (n = 147) at baseline. The mean age of participants receiving and not receiving kidney-protective medication was 62.4 years and 62.7 years, respectively; 34.4% and 40.8%, respectively, were female. Most patients had CKD stage 3A (n = 332, 31.6%) or 3B (n = 308, 29.3%), and 8.4% (n = 88) had ongoing dialysis. Body mass index (30.4 vs 29.4 kg/m2) and blood pressure were similar for those receiving kidney-protective medication versus those who were not. Laboratory assessments were also generally similar, although estimated glomerular filtration rate (eGFR; 40.9 vs 33.7 mL/min/1.73 m2) and haemoglobin (132.0 g/L vs 124.0 g/L) were higher in patients receiving kidney-protective medication versus those not. During the follow-up, patients receiving kidney-protective medication had a 67% lower risk of all-cause mortality (hazard ratio [HR] 0.33; 95% confidence interval [CI] 0.12–0.80, p = 0.019), and a 20% lower risk of all-cause hospitalisation (HR, 0.80; 95% CI 0.64–0.99, p = 0.042) compared with patients not receiving kidney-protective medication. In the population without pre-existing CV disease, a trend towards a lower rate of CV events was observed in patients with kidney-protective medication (CV events rates: 2.2 vs 3.2 per 100 person-years; HR, 0.38; 95% CI 0.12–1.08, p = 0.074 (Figure). Conclusion In this multinational CKD cohort, preliminary analysis indicates that using kidney-protective medication was associated with lower risks of adverse outcomes including death. Further analysis to mitigate potential confounding will be performed to confirm these preliminary findings.

#456 Efficacy and safety of iptacopan in patients with primary IgA nephropathy: interim analysis results of the Phase 3 APPLAUSE-IgAN study

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis. An unmet need for targeted disease-modifying treatments addressing its pathophysiology remains. There is compelling evidence for involvement of the alternative complement pathway (AP) in IgAN. Iptacopan binds to Factor B and specifically inhibits the AP. The APPLAUSE-IgAN trial is evaluating the efficacy and safety of iptacopan vs placebo, on top of optimized supportive therapy, in patients with IgAN. Here we present the results of the pre-specified interim analysis (IA) with a focus on the results for key subgroups. Method APPLAUSE-IgAN (NCT04578834), a Phase 3, multicentre, randomised, double-blind, placebo-controlled trial, enrolled adults with biopsy-confirmed IgAN with proteinuria ≥1 g/g by urine−protein creatinine ratio from 24-hour urine collection (UPCR-24h) despite being on a stable dose of maximally tolerated renin-angiotensin-system inhibition (RASi) for 3 months, with or without other background therapy such as sodium-glucose transport protein 2 inhibition (SGLT2i). Patients were randomized 1:1 to iptacopan 200 mg or placebo twice daily for 24 months while remaining on stable supportive therapy. The primary objective of the prespecified IA was to demonstrate superiority of iptacopan vs placebo in reducing UPCR-24h at Month 9 (M9) in the main study population (estimated glomerular filtration rate [eGFR] ≥30 mL/min/1.73 m2 at baseline). Subgroup analyses included baseline age, sex, Asia vs non-Asia region, proteinuria, eGFR, and SGLT2i use. Efficacy analyses were performed on the first 250 patients (n = 125 each for iptacopan and placebo) who reached the M9 visit or discontinued from the study. Safety analyses included all patients of the main population who had received treatment by the time of the IA (iptacopan, n = 222; placebo, n = 221). Results Baseline demographics and disease characteristics were similar between the two arms (Table) and indicative of patients at high risk of IgAN disease progression. Iptacopan was superior to placebo in reducing proteinuria, with reduction in UPCR-24h at M9 relative to baseline of 38.3% (95% CI: 26.0%, 48.6%; 1-sided p < 0.0001) vs placebo (Figure). Subgroup analyses showed that treatment effect consistently favoured iptacopan regardless of baseline age, sex, Asia vs non-Asia region, UPCR-24h or eGFR levels, or SGLT2i use as part of the supportive care (Figure). Treatment-emergent adverse events (TEAEs) occurred in 138 (62.2%) iptacopan vs 153 (69.2%) placebo patients, with the majority being of mild to moderate severity. Treatment-emergent serious AEs were reported in 18 (8.1%) and 11 (5.0%) patients in the iptacopan and placebo arms, respectively. TEAEs leading to treatment discontinuation occurred in 6 patients (2.7%) in each arm. No deaths were reported. Iptacopan treatment did not lead to clinically relevant differences in total cholesterol, low-density lipoprotein cholesterol, and serum triglycerides compared with placebo. Conclusion APPLAUSE-IgAN, the first Phase 3 study confirming the relevance of the AP in IgAN, demonstrated superiority of iptacopan vs placebo, with a significant reduction in proteinuria at M9 (38.3%) that was consistent across key subgroups evaluated. Iptacopan was well tolerated with a favourable safety profile.

#150 Effect of dapagliflozin in patients with CKD depending on primary kidney disease

Abstract Background and Aims Multiple trials have reported that SGLT2 inhibitors reduce the risk of its primary composite outcome of kidney disease progression or cardiovascular death in a wide range of patients with CKD. Our aim was to compare effects on kidney outcomes among the different types of kidney diseases. Method Eligible patients with eGFRs ≥30-45, or ≥45-90 ml/min/1.73 m2 with a urinary albumin-to-creatinine ratio of ≥300 mg/g, and receiving renin angiotensin system inhibitor, where indicated and tolerated were randomized to dapagliflozin 10 mg once daily vs placebo. Kidney disease progression was defined as a sustained ≥30% eGFR decline from randomization or to <10 mL/min/1.73 m2, start of maintenance dialysis or receipt of a kidney transplant, or renal death, and the effects of dapagliflozin were analyzed using a pre-specified Cox model. Testing for heterogeneity of effect between pre-specified kidney disease subgroups was performed, including exploratory analyses by specific glomerular disease etiologies. Results 362 participants were followed for a median of 2.0 years. 90 (24.8%) had diabetic kidney disease, 126 (34.8%) had glomerular disease, 94 (26%) had hypertensive or renovascular disease, and 52 (14.4%) had other or unknown causes. Overall, dapagliflozin reduced the risk of kidney disease progression by 34% (dapagliflozin 29/178 vs placebo 48/184; hazard ratio 0.62, 95% CI 0.51-0.78). This relative risk reduction appeared broadly similar in subgroup analyses by primary cause of kidney disease and by different types of glomerular disease. Conclusion Our study with a few numbers of patients with diabetic and non-diabetic causes of CKD showed that dapagliflozin reduced risk of kidney disease progression with relative risk reductions that were broadly similar across the different CKD etiologies.

#2022 Clinical outcomes in US patients initiating finerenone – a report from the FOUNTAIN platform

Abstract Background and Aims Evidence from clinical trials demonstrates that finerenone reduces the risk of cardiovascular and renal complications among patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). What is lacking is the evidence on finerenone use in real-world clinical practice. Method The present analysis is based on a longitudinal single-arm cohort study of patients initiating finerenone between July 2021 and August of 2023 and with prior diagnoses of CKD and T2D. Data were obtained from US electronic health records and insurance claims (OM1 Real-World Data CloudTM). CKD was defined as either having 1 diagnostic code for CKD stage 2-4 or unspecified stage, two estimated glomerular filtration rate (eGFR) measurements between 15 and 60 ml/min/1.73 m2, or two urine albumin to creatinine ratio (UACR) measurements over 30 mg/g; T2D was defined as having a diagnostic code for T2D. We described patient demographics, comorbidities, and comedications at baseline (365 days prior and including index date), and incidence rates of cardiovascular and renal outcomes, including eGFR and UACR changes over time. The presented analysis (NCT05703880) is part of the multi-national, multi-database observational research platform FOUNTAIN. Results We identified 28,056 new users of finerenone with prior CKD and T2D. The users had a mean (SD) age of 68.8 (10.8) years and 44.8% were female. Comorbidities of interest at baseline were hypertension (89.8%), cardiovascular disease (21.2%), neuropathy (13.4%), retinopathy (8.1%), heart failure (7.9%), and cerebrovascular disease (4.2%). Assessment of comedication use at baseline indicates that patients who initiate finerenone had exposure to renin–angiotensin system inhibitors (52.5%), sodium-glucose cotransporter-2 inhibitors (39.2%), or glucagon-like peptide-1 receptor agonists (27.4%) within 180 days prior to initiating finerenone. Overall, 82.5% of patients initiated finerenone at 10 mg/d, while 17.5% of patients started with 20 mg/d. Complete results including incidence rates of cardiovascular and renal outcomes, hyperkalemia events, and changes in kidney function measures (eGFR, UACR) during follow-up will be presented as part of the conference presentation. Conclusion Data from patients receiving finerenone as part of clinical practice in the USA suggest that finerenone is used concurrently with other renal and cardiovascular protective medication-classes recommended for patients with CKD and T2D.

#425 Felzartamab (anti-CD38) in patients with IgA Nephropathy—interim results from the IGNAZ study

Abstract Background and Aims Most patients with IgA nephropathy (IgAN) will progress to kidney failure within 10-15 years of diagnosis. Sustained proteinuria is the best predictor of adverse long-term kidney outcomes and is a surrogate marker for efficacy. CD38+ plasma cells are likely the main source of pathogenic Gd-IgA1, and the related autoantibodies in IgAN. Felzartamab (felza; HIB202) is a recombinant purified human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to CD38 on plasma cells and is being studied across immune-mediated kidney diseases such as IgAN, Primary Membranous Nephropathy, Lupus Nephritis, and Antibody Mediated Rejection. The primary aims of the IGNAZ study were to assess: 1) efficacy of felza compared to placebo on urine protein:creatinine ratio (UPCR) and estimated glomerular filtration rate (eGFR) change from baseline, and 2) the relationship between exposure, safety, and efficacy in each of 3 dose groups vs. placebo. Interim results with 15 months of follow-up from this 24-month trial are presented. Method In Part 1, 48 IgAN subjects were randomized in a 1:1:1:1 ratio across a placebo and 3 active arms in this multicenter, double-blind placebo-controlled, phase IIa trial. The M1, M2, and M3 active arms received 2 doses in 15 days, 5 doses in 2 months, and 9 doses in 5 months, respectively. In Part 2, 6 Japanese subjects received the M3 regimen, open-label, and have been followed for 9 months. Key inclusion criteria included ages 18-80 years, biopsy confirmed diagnosis of IgAN within the past 8 years, proteinuria at screening ≥1.0 g/d, eGFR ≥30 ml/min/1.73 m2 (by CKD-EPI), and background stable and maximally tolerated renin angiotensin system inhibitors. Results 48 randomized subjects were enrolled at 28 sites in the US and in 14 different countries in Europe and in Asia, of which 46 completed the treatment phase. Mean (SD) baseline characteristics (Parts 1 and 2 combined): age 41.6 (12.3) yrs, UPCR 1.67 (1.0) g/g, eGFR 74.6 (30.3) ml/min/1.73 m2. 67% of subjects were male. Intention-to-treat with felza demonstrated rapid, clinically meaningful reductions in UPCR with the maximal treatment effect being observed in the M3 9-dose regimen. In Part 1, percentage change from baseline in UPCR was −14% for placebo and −25% for M3 9-dose arm at month 3, and +9% for placebo and −35% for M3 at month 6 (Fig. A). Reductions in proteinuria observed at month 6 persisted until Month 15, 10 months after the last dose: +6% and −38% mean UPCR change from baseline for placebo and the M3 9-dose arm, respectively (Fig. B). Relatively stable eGFR values were observed for the felza arms compared to loss of eGFR in the placebo arm. Rapid, durable reductions in IgA and Gd-IgA1 levels were seen across the dosing arms, with reductions lasting 10 months after the last dose (Fig. C). IgG recovery occurred faster off-treatment than IgA. Results in the Part 2 subjects were similar to the Part 1 M3 cohort through 9 months. There were no apparent dose-dependent adverse events and no exposure-safety relationship. Treatment-emergent adverse events (TEAEs) were generally of mild or moderate intensity or toxicity grade. The most common TEAE assessed as related by study investigator was infusion related reactions (IRR), most of which occurred on the first infusion. There was one treatment-related serious AE due to an IRR. Five subjects discontinued treatment due to IRRs or drug hypersensitivity; for four of the five subjects, the infusion rate was higher than protocol-specified or had an error in pre-medication. TEAE infections were comparable between placebo and felza arms: Placebo (33.3%), M1 (33.3%), M2 (36.4%), M3 (38.5%), Part 2 (50.0%); all were Grades 1 or 2, and non-serious. Conclusion This proof-of-concept study highlights the potential for disease modification in IgAN with the anti-CD38 mAb felza and supports continued research as a potential treatment for high-risk IgAN patients. Felza treatment resulted in clinically meaningful, prolonged UPCR reductions and eGFR stabilization sustained ≥10 months after dosing was completed. Felza was generally well tolerated with rapid recovery of IgG with durable reductions in IgA and pathogenic Gd-IgA1 levels.

#2459 Matching-adjusted indirect comparison of eGFR in patients with immunoglobulin A nephropathy treated with Nefecon (TRF budesonide) or sparsentan

Abstract Background and Aims Primary immunoglobulin A nephropathy (IgAN) is an immune-mediated disease that can lead to kidney failure, need for dialysis and kidney transplantation, and early death. IgAN is the most common type of primary glomerulonephritis globally, with an estimated worldwide incidence of 2.5 per 100 000 individuals per year. Estimated glomerular filtration rate (eGFR) is a measure of renal function and is accepted as a surrogate endpoint for clinical trials evaluating kidney function deterioration. In December 2023, the US Food and Drug Administration (FDA) granted full approval to Nefecon (marketed as Tarpeyo® by Calliditas Therapeutics), a targeted-release formulation of budesonide, to reduce the loss of kidney function in adults with IgAN at risk of disease progression, based on the Phase 3 NefIgArd clinical trial. In February 2023, sparsentan (marketed as Filspari™ by Travere Therapeutics) was granted accelerated approval by the FDA to reduce proteinuria in adults with primary IgAN at risk of rapid disease progression, generally a urine protein–creatinine ratio (UPCR) ≥1.5 g/g, based on the Phase 3 PROTECT study. Matching-adjusted indirect comparison (MAIC) is a widely accepted and relevant methodology for comparing treatments across trials in the absence of head-to-head comparisons. In this analysis, we aimed to compare the effects of Nefecon and sparsentan on kidney function deterioration in patients with IgAN, as assessed by eGFR. Method An anchored MAIC was performed to estimate the relative effect of Nefecon and sparsentan on the absolute eGFR change from baseline at 9, 12 and 24 months, with common comparators of optimized renin–angiotensin system inhibition for NefIgArd and irbesartan for PROTECT. Patient-level data from NefIgArd were used to select a population matched to PROTECT, and the following baseline characteristics were used to determine the weights: mean age (years), sex (% male), race (% white), mean eGFR (mL/min/1.73 m2), mean UPCR (g/g), urine albumin–creatinine ratio (UACR) (% with UACR >1.1 g/g), and urinary protein excretion (% with urinary protein excretion >1.8 g/day). Absolute change in eGFR was analyzed using a mixed model for repeated measures (MMRM) method, including baseline, 3-, 6-, 9-, 12-, 18- and 24-month data, baseline eGFR, baseline eGFR-by-time interaction, treatment, and treatment-by-time interaction. The MAIC weights were incorporated into the MMRM. A Bayesian fixed-effects network meta-analysis was performed on the relative effect from PROTECT and the weighted relative effect from NefIgArd, measured by the estimated absolute change from baseline in eGFR. Results The matching-adjustment of the NefIgArd patient population to the PROTECT population is shown in Table 1. The weighted NefIgArd population exhibits very similar baseline characteristics to the PROTECT population. The effective sample size of the weighted NefIgArd population is 208. Results from the anchored MAIC showed statistically and clinically significant favorable effects of Nefecon versus sparsentan on eGFR for all time points analyzed (Fig. 1). Mean differences in the absolute change in eGFR of 5.68 mL/min/1.73 m2 (95% credible interval [Crl] 3.14, 8.20; p < 0.001), 3.48 mL/min/1.73 m2 (95% Crl 0.97, 5.97; p = 0.006) and 3.28 mL/min/1.73 m2 (95% Crl 0.02, 6.51; p = 0.048) were observed when comparing Nefecon with sparsentan at 9 months vs 36 weeks, 12 months vs 48 weeks, and 24 months vs 106 weeks, respectively. Conclusion After accounting for differences in the patient populations from the NefIgArd and PROTECT trials, the anchored MAIC showed that treatment with Nefecon 16 mg/day for 9 months was associated with greater eGFR benefit compared with continuous treatment with sparsentan 400 mg/day over 2 years, with significant differences observed as early as 9 months after treatment initiation and sustained up to 2-years of follow-up.