Kidney Function Decline Research Articles

The renoprotective potential of montelukast: a scoping review

Introduction: Kidney damage can result from various factors, leading to structural and functional changes in the kidney. Acute kidney injury (AKI) refers to a sudden decline in kidney function, while chronic kidney disease involves a gradual deterioration lasting more than 3 months. Mechanisms of renal injury include impaired microcirculation, inflammation, and oxidative stress. Cysteinyl-leukotrienes (CysLTs) are inflammatory substances contributing to tissue damage. Montelukast, a leukotriene receptor antagonist, has shown potential renoprotective effects in experimental models of kidney injury. Methods: The authors conducted a scoping review using PubMed, Scopus, and Web of Science databases to identify relevant studies investigating the impact of montelukast on renal diseases. Articles published until 2022 were included and evaluated for quality. Data extraction and analysis were performed based on predetermined inclusion criteria. Results: The scoping review included 30 studies from 8 countries. Montelukast demonstrated therapeutic effects in various experimental models of nephrotoxicity and AKI induced by agents such as cisplatin, lipopolysaccharide, diclofenac, amikacin, Escherichia coli, cyclosporine, methotrexate, cobalt-60 gamma radiation, doxorubicin, and cadmium. Studies involving human subjects with nephrotic syndrome, pyelonephritis, and other renal diseases also reported positive outcomes with montelukast treatment. Montelukast exhibited anti-inflammatory, anti-apoptotic, antioxidant, and neutrophil-inhibiting properties, leading to improved kidney function and histopathological changes. Conclusions: Montelukast shows promise as a renoprotective medication, particularly in early-stage kidney injury. Its ability to mitigate inflammation, oxidative stress, and neutrophil infiltration contributes to its therapeutic effects. Further research is needed to explore the clinical applications and mechanisms underlying the renoprotective action of montelukast.

Centella asiatica ameliorates AlCl3 and D-galactose induced nephrotoxicity in rats via modulation of oxidative stress.

Nephrotoxicity is a condition caused by toxic effects of medications and poisons resulting in the rapid decline of kidney function. Centella asiatica is a medicinal herb with antioxidative and anti-inflammatory characteristics that is used to treat a variety of ailments. The present study intends to explore the ability of Centella asiatica in preventing AlCl3 and D-Galactose-induced nephrotoxicity in rats. In this study 30 male albino Wistar rats were induced with nephrotoxicity using AlCl3 and D-galactose, and oral administration of Centella asiatica extract (100, 200, and 300mg/kg/day) was administered for 70 days. The kidneys were extracted after treatment and levels of oxidative and antioxidative enzymes, serum creatinine, and serum albumin were measured. The kidney's histopathological changes were studied. Administration of Centella asiatica extract significantly increased serum albumin, superoxide dismutase (SOD), and catalase levels in kidney homogenates while suppressing serum creatinine and malondialdehyde (MDA) levels and attenuating histopathological changes associated with nephrotoxicity. Centella asiatica extract lowered serum creatinine and oxidative stress levels in a drug-induced nephrotoxicity rat model, while simultaneously increasing serum albumin levels, as evidenced by mitigation of histological changes and normalisation of biomarkers of oxidative stress in the kidney.

Low Protein Diet Reduces Proteinuria and Decline in Glomerular Filtration Rate in Advanced, Heavy Proteinuric Diabetic Kidney Disease.

Low protein diet (LPD) seems beneficial in ameliorating the complications of chronic kidney disease (CKD), in reducing proteinuria and the decline in kidney function, thus postponing the need for kidney replacement therapy (KRT). However, this type of intervention was less investigated in diabetic kidney disease (DKD). This is a single-center, prospective, interventional study that aims to assess the efficacy of reducing proteinuria and the rate of decline in the estimated glomerular filtration rate (eGFR). Patients with advanced DKD (stable proteinuria > 3 g/g and eGFR < 30 mL/min) with a good nutritional status and accepting a LPD were evaluated for inclusion. Ninety-two of the 452 screened patients (66% males, median age 61 years, proteinuria 4.8 g/g creatininuria, eGFR 11.7 mL/min/1.73 m2) completed the study. Intervention consisted of LPD supplemented with ketoanalogues of essential amino acids (KA) along with conventional nephroprotective therapy. Efficacy parameters were the variation in proteinuria and in eGFR from baseline to the end of the study. Proteinuria decreased 3-fold, and the rate of decline in eGFR decreased 5-fold in the intervention phase. No patient initiated KRT or died. LPD supplemented with KA seems effective in safely postponing KRT by reducing proteinuria and the decline in kidney function in advanced DKD.

Metabolomic and Physiological Effects of a Cardiorenal Protective Diet Intervention in African American Adults with Chronic Kidney Disease.

Chronic kidney disease (CKD) impacts 14% of adults in the United States, and African American (AA) individuals are disproportionately affected, with more than 3 times higher risk of kidney failure as compared to White individuals. This study evaluated the effects of base-producing fruit and vegetables (FVs) on cardiorenal outcomes in AA persons with CKD and hypertension (HTN) in a low socioeconomic area. The "Cardiorenal Protective Diet" prospective randomized trial evaluated the effects of a 6-week, community-based FV intervention compared to a waitlist control (WL) in 91 AA adults (age = 58.3 ± 10.1 years, 66% female, 48% income ≤ USD 25K). Biometric and metabolomic variables were collected at baseline and 6 weeks post-intervention. The change in health outcomes for both groups was statistically insignificant (p > 0.05), though small reductions in albumin to creatinine ratio, body mass index, total cholesterol, and systolic blood pressure were observed in the FV group. Metabolomic profiling identified key markers (p < 0.05), including C3, C5, 1-Met-His, kynurenine, PC ae 38:5, and choline, indicating kidney function decline in the WL group. Overall, delivering a directed cardiorenal protective diet intervention improved cardiorenal outcomes in AA adults with CKD and HTN. Additionally, metabolomic profiling may serve as a prognostic technique for the early identification of biomarkers as indicators for worsening CKD and increased CVD risk.

#368 Matching-Adjusted Indirect Comparisons of eGFR slopes in the PROTECT study with UK RaDaR IgA nephropathy population and the control arm of NefIgArd

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is a rare kidney disorder characterized by deposition of IgA in the glomeruli leading to an increased risk of kidney failure. The PROTECT clinical trial in IgAN was designed to determine the long-term (approximately 2 year) nephroprotective potential of treatment with sparsentan compared to a blinded active control angiotensin receptor blocker (ARB) irbesartan, titrated to the maximum labelled dose after randomization (achieved in 97% of patients). To understand PROTECT clinical trial results relative to delivery of standard of care (SoC) treatment for IgAN in other clinical settings, this study compared two-year eGFR total slope outcomes between the two arms of PROTECT and delivery of SoC in two populations applying similar eligibility criteria: Method Using individual patient data (IPD) from PROTECT, unanchored matching-adjusted indirect comparisons (MAICs) were performed. Patients in both arms of PROTECT were weighted to match key baseline characteristics of the two comparator populations. Matching was based on published clinical characteristics using the method of moments. After weighting, two-year eGFR total slopes were calculated using random coefficients models. Two-tailed z-tests with pooled standard errors were used for indirect comparison. Results Based on assessment of cross-data source characteristics, populations were found to be sufficiently comparable for unanchored MAIC. After weighting IPD from PROTECT, all matched baseline patient characteristics were well-balanced between data sources. Comparative results showed that patients treated with maximally titrated irbesartan or sparsentan in PROTECT exhibited a slower decline in kidney function compared to SoC delivered in a real-world setting (RaDaR), with differences of: Similar results were observed compared to SoC delivered in a clinical trial (NefIgArd), with differences of: Conclusion Both “maximally tolerated dose of ARB” (as recommended in the KDIGO guideline for IgAN) using irbesartan in PROTECT and sparsentan were associated with significantly slower decline in kidney function compared to real-world SoC treatment for IgAN (RaDaR) and delivery of physician defined, optimized SoC (&amp; placebo) in the context of a clinical trial (NefIgArd). 2-year eGFR slope differences between clinical trials in IgAN need to be considered in the context of what is achieved in current clinical practice. With existing real-world and emerging clinical trial data in IgAN, MAIC is an approach that can be applied to compare outcomes between relevant, sufficiently aligned data sources.

#1375 Association of NT-proBNP and kidney function progression in chronic kidney disease patients without heart failure

Abstract Background and Aims Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) is reported to be associated with higher risk of decline in kidney function. However, little evidence exists about the relationship between NT-proBNP and kidney function progression stratified by estimated glomerular filtration rate (eGFR) in chronic kidney disease (CKD) patients without heart failure. Therefore, we aim to investigate the association of NT-proBNP and CKD progression in different CKD stages for CKD patients without heart failure. Method A multicentric retrospective cohort study recruited 23860 patients diagnosed with CKD from China Renal Data System (CRDS) database. Eligible participants were classified into five groups according to eGFR. CKD progression was defined as a composite of an increase in serum creatinine ≥50% or a decrease in eGFR ≥40% from baseline or a need for kidney replacement therapy. A linear regression model evaluated the relationship between eGFR and NT-proBNP. Cox regression analysis assessed the association between NT-proBNP and CKD progression. We also performed restricted cubic spline (RCS) and threshold effect analysis to investigate non-linear relationships between NT-proBNP and CKD progression. Results In a linear regression model, NT-proBNP was negatively correlated with eGFR in CKD patients. Each decrease of 15 ml/min/1.73 m2 in eGFR was associated with 1.06-fold, 1.50-fold, 1.52-fold, 1.94-fold, 3.37-fold higher levels of log (NT-proBNP) in CKD patients with stage 1-2, 3a, 3b, 4 and 5 respectively. In the multivariable Cox hazard model, elevated NT-proBNP was associated with a greater risk of kidney function progression, particularly among CKD stage 3 patients (stage 3a: HR, 1.42, 95% CI, 1.32-1.53; stage 3b: HR, 1.43, 95% CI, 1.32-1.54), with P-interaction≤0.001. However, the correlation of NT-proBNP and CKD progression had no statistical significance among CKD patients with stages 4-5 after sensitivity analyses. RCS and two-segment Cox regression model showed reversed L-shaped non-linear relationships between NT-proBNP and CKD progression in CKD patients with stages 1-4, with the inflection point at 250 pg/mL, 750 pg/mL, 653 pg/mL, 526 pg/mL, but not in stage 5 (Figure). Conclusion NT-proBNP may be a reliable biomarker to predict CKD progression in stages 1-3 CKD (mainly for stage 3) without heart failure. This helps clinicians predict a decline in kidney function early and set the threshold for therapy. However, the predictive role of NT-proBNP in in advanced CKD patients is insignificant.

#898 Acceleration in kidney function decline after COVID-19 infection: the Stockholm CREAtinine Measurements (SCREAM) project

Abstract Background and Aims Severe COVID-19 infection, which usually presents as a viral pneumonia, has been observed to frequently be accompanied by acute kidney injury (AKI). However, possible effects of COVID-19 on long-term kidney function decline are not well quantified. We investigated whether kidney function decline is accelerated after COVID-19 infection, and whether the progression of decline differs from other respiratory tract infections. Method We undertook an observational study using the SCREAM project, including adults from Stockholm who survived COVID-19 infection (February 2020-December 2021), and adults who survived pneumonia caused by other pathogens (February 2018-December 2019, historical comparison cohort). We used generalized estimating equations to examine the age- and sex-adjusted slopes of estimated glomerular filtration rate (eGFR) decline in the 2 years before versus after each infection (i.e., intra-individual changes). We also compared to post-infection eGFR slopes of COVID-19 versus pneumonia (i.e., inter-individual changes) adjusting for a broad range of demographic, socioeconomic and clinical covariates (including pre-infection eGFR slope). We stratified analyses by whether the infection required hospitalization, hypothesizing more severe infection may lead to more rapid eGFR decline. Results We identified 59 267 COVID-19 survivors and 20 138 pneumonia survivors with repeated outpatient eGFR measurements. The pneumonia group was older, with lower income, and more comorbidities and healthcare utilization than the COVID-19 group. Both infections resulted in an accelerated decline of the observed eGFR slope, but with a greater magnitude of intraindividual slope changes after COVID-19 (Fig. 1): eGFR decline was 6.14 (95% confidence interval [95% CI] 5.88-6.41) ml/min/1.73 m2/year faster after COVID-19, and 2.52 (95% CI 2.17-2.88) ml/min/1.73 m2/year faster after pneumonia. When adjusting for pre-infection slope and other identified confounders (Fig. 2), COVID-19 survivors had an eGFR decline that was 0.47 (95% CI 0.29-0.66) ml/min/1.73 m2/year faster than that of pneumonia survivors. Observed intra- and inter-individual differences were larger in magnitude among participants whose infection required hospitalization. Conclusion COVID-19 infection is associated with a subsequent acceleration in eGFR decline, of a larger magnitude than other respiratory tract infections, and particularly among more severe cases that required hospitalization. We propose that survivors of severe COVID-19 receive monitoring of kidney function, and that policymakers consider implications for future healthcare planning and renal service provision.

#2834 Analysis of cyst hetero- and homogeneity to unravel common pathways in autosomal dominant polycystic kidney disease

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, with a prevalence of 1 in ca. 1000 individuals and accounting for 10% of the European dialysis population. It is most frequently (75-80%) caused by mutations in the PKD1 gene encoding Polycystin-1. Besides systemic manifestations such as liver cysts, hypertension and cardiac abnormalities, the most prominent phenotype is the gradual development of kidney cysts, leading to kidney enlargement and a decline in kidney function leading to end-stage kidney disease at an average age of ca. 50 years. The cysts arise from tubular epithelial cells in the nephron that start to dedifferentiate, proliferate and eventually secrete fluid into the cyst lumen promoting its swelling. This process is molecularly regulated by changes in Ca2+, cAMP, PKA and PI3K-Akt-mTOR signaling, among others. The renal cysts are further characterized by ciliary dysfunction, altered signal transduction, loss of polarity, apoptosis, mitochondrial abnormalities, metabolic reprogramming, inflammation, oxidative stress and epigenetic changes. However, the exact sequence of events and their relative importance in the process of cyst formation remains unclear. Therefore, we analyzed the transcriptomic cyst hetero- and homogeneity to identify the pathways that were different, but also shared among individual cysts. Method We performed RNA-Seq analysis on 40 individual cystic membranes of nephrectomized kidneys of 4 PKD1 patients. We included 4 samples of macroscopically healthy tissue from 2 ADPKD kidneys (histologically confirmed to have microcysts) and 4 samples from 4 healthy kidneys. Principal component, cluster and trajectory analysis was performed to explore cyst heterogeneity. Adjacent pieces of cystic membrane were analyzed for histology (H&amp;E, Sirius Red) or stained with FITC-tagged Lotus Tetragonolobus Lectin (LTL) or Dolichos Biflorus Agglutinin (DBA), a proximal and distal tubular marker, respectively. Results Although the cysts clearly separated from the healthy tissues in the analyses, there was also a distinct heterogeneity observed among the cysts that was independent of patient, gender, cyst size, location or fluid color. Pathway analysis revealed that these changes were characterized by a gradual increase of interstitial (remodeling) and inflammation markers, and a gradual decrease in differentiation markers (e.g. development, intercellular junctions, basement membrane) along the trajectory pseudotime. We could identify 6 clusters of cystic samples, with 2 clusters deviating from the main trajectory. With respect to tubular/epithelial dedifferentiation, the decrease in proximal tubular markers already occurred in microcystic tissue and was stronger compared to the other tubular segments. Consequently, none of the analyzed cystic membranes stained positive for LTL, while others showed clear staining for DBA. Microcysts on the other hand stained positive for LTL or DBA. Several cysts showed RNA marker expression of multiple tubular segments. Indeed, smaller macrocysts (diameter in the mm range) were lined by both LTL- and DBA-positive regions. Conclusion By analyzing transcriptomic hetero- and homogeneity among individual cysts, the molecular alterations in ADPKD progression can be tracked down and determined whether they occur similarly in all cysts or at different levels. Our data also suggest that loss of proximal tubular markers in macrocysts is more prominent compared to the decrease in distal markers. Finally, inner cyst walls can consist of cyst-lining cells of multiple origins.

#2959 Correlation of urinary MCP-1 with different histopathological classes of lupus nephritis

Abstract Background and Aims Lupus nephritis (LN) affects almost two-thirds of Systemic lupus erythematosus (SLE) patients. Renal biopsy is the gold standard for the classification of LN. Minimally invasive techniques, as urinary biomarkers, are promising tools for the diagnosis and monitoring of SLE. This study aimed to determine urinary MCP-1 level association with different LN histopathological classes. Method This study included 40 patients with active lupus nephritis proteinuria &amp;gt;0.5 gm and/or active urinary sediment and/or decline in kidney function indicated for renal biopsy by the nephrology team. Morning urine samples were collected to measure MCP-1 level by enzyme-linked immunosorbent assay (ELISA). Full blood cell count, serum creatinine level, blood urea nitrogen (BUN) was collected. Biopsies were classified according to ISN /RPS, and biopsy results were correlated with MCP-1 level. We excluded patients with overlap syndrome, active infection, and malignancy. All the patients were diagnosed according to the American College of Rheumatology (ACR) diagnostic criteria. Results Mean age 28.75 ± 6.37 years. Female patients were 33 (82.5%) and 7 (17.5%) male patients. Mean creatinine was 2.71 ± 0.55 mg/dl in the active cases and 0.84 ± 0.10 mg/dl in the control group. The mean albumin was 3.1 ± 0.61 mg/dl in the active cases, and 4.05 ± 0.42 mg/dl in the control group. The mean eGFR was 56.14 ± 20.40 ml/min/1.73 m in the active cases, and 99.63 ± 6.90 40 ml/min/1.73 m in the control group. Our study showed a significant correlation between disease activity and urinary MCP-1 level. The Median MCP-1 level was 618.4 ng/l in patients with active LN and 120.05 ± 87.53 ng/l in patients with inactive LN with a sensitivity of 97.5% and specificity 95%. Level of urinary MCP-1 was highest in class IV with median of 998 followed by class III 567 then class V with median 357 ng/ml Conclusion Urinary MCP-1 level provided an auxiliary noninvasive tool to distinguish between different histopathological classes of active LN.

#546 Decline of kidney function before and after start of peritoneal dialysis (PD)

Abstract Background and Aims Residual kidney function (RKF) is a key component for PD adequacy and associated with improved volume status, nutrition and quality of life as well as with increased survival. The aim of the present study was to compare decline of kidney function before and after start of PD. Method We studied patients starting PD (during 2000-2019) in an ongoing prospective study of patients starting dialysis. Study inclusion in almost all PD patients coincided with PD catheter insertion. Patients were included in the present analysis if they had at least one urinary collection before, and one after PD initiation (a), PD initiation less than six months after study inclusion (b) and &amp;gt; 6 months PD treatment (c). P-creatinine to calculate eGFR was retrospectively collected for 12 months before start of PD. During a large part of the study period, it was a clinical routine to collect 24-hour urine collections regularly in CKD5 patients, and these data were retrieved when available. After start of PD, regular 24-hour urine collections were part of the clinical routine to follow up and were retrieved for up to 12 months after PD start. eGFR was measured using the CKD-epi 2021 equation and GFR was calculated as the average of urinary creatinine and urea clearance corrected for BSA. The decline of eGFR before start of PD, the decline of GFR from 24-hour urine collections and the decline of GFR after start of PD were compared to each other. Results We studied 138 patients starting PD. The mean age was 55 ± SD13 years, and there were 80 males and 58 females. The mean blood pressure was 153 ± SD21/89 ± SD11 mmHg and BMI was 25 ± SD4 kg/m2. The etiologies of end stage kidney disease were nephrosclerosis 17%, diabetic nephropathy 22%, glomerulonephritis 25%, polycystic kidney disease 14% and other 22%. The GFR at PD start was 8.5 ± SD 2.3 mL/min/1,73 m² and eGFR was 5.8 ± SD 1.9 mL/min/1,73 m². The results show a significantly slower kidney function decline rate after start of PD, with an average of −0.59 mL/min/1,73 m²/month before PD initiation compared to −0.34 mL/min/1,73 m²/month after. Conclusion Decline of GFR was slower after start of PD suggesting that earlier initiation of dialysis may be beneficial for the preservation of RKF. Notably, there was a marked attenuation after 3 months of dialysis. Furthermore, the decline rate of GFR before PD start was similar using eGFR or GFR from 24-h urine collection, though for eGFR at somewhat lower levels. However, there were pronounced differences between those two methods in individual patients demonstrating that eGFR is unreliable with very low GFR. Further study will be performed to analyze what factors that are associated with better preservation of RKF.

#2754 Long-term renal outcomes in ICI-associated acute interstitial nephritis: a comprehensive comparative study

Abstract Background and Aims Immune checkpoint inhibitors (ICI) have transformed cancer treatment, but they may lead to immune-mediated acute interstitial nephritis (ICI-AIN), in 2-5% of patients. About 35-40% show full kidney function recovery three months post ICI-AIN. Limited evidence exists for long-term renal toxicity. The unknown difference in long-term renal function evolution between partial and complete recovery of the acute episode in ICI-AIN is an unexplored area for future research. Additionally, there's no comparative study on the long-term renal function evolution between ICI-AIN and cases associated with other drugs (Drug-AIN) or autoimmune causes (AI-AIN). Method Retrospective, descriptive and observational study. The medical records of all AIN cases diagnosed in the Nephrology Unit of the Bellvitge University Hospital between 2010 and 2023 were reviewed. Longitudinal data on treatments, comorbidities and kidney function were collected. Data was analyzed using descriptive statistics, Chi-square tests, Mann-Whitney U tests and Kaplan Meier analyses. Results A total of 94 out of 96 screened patients were diagnosed with AIN (AI-AIN n = 26; Drug-AIN n = 30; ICI-AIN n = 38). Of those, 89.4% were biopsy-confirmed. Median follow-up was 36.64 months (IQR 12.32-74.28). There were not differences in baseline serum creatinine (sCreat) across the groups, defined as sCreat 6 months prior to AIN. At diagnosis, sCreat was lower in ICI-AIN compared to Drug-AIN (267.62 ± 116.44 vs 553.20 ± 317.46, p &amp;lt; 0.001), but significant differences were not found comparing to AI-AIN. There were not differences in the cumulative dose and days of treatment with prednisone between the three groups. In the first year, 35.5% of ICI-AIN patients and 10.3% with Drug-AIN returned to baseline kidney function (p = 0.020). Over the course of three years, 45.9% reverted to baseline in the ICI-AIN cohort compared to 18.5% in the Drug-AIN cohort (p = 0.023). This trend continued at 5 years, with 45.9% in ICI-AIN and 22.2% in Drug-AIN recovering to baseline (p = 0.051). The proportion of patients who recovered baseline kidney function was comparable between the group diagnosed with ICI-AIN and the group diagnosed with AI-AIN at all evaluated time points. Kaplan-Meier analysis at 1, 3, and 5 years of follow-up revealed a shorter time to sCreat recovery to baseline in the ICI-AIN group compared to the Drug-AIN group, with Log-rank (Mantel-Cox) p-values of 0.016, 0.004, and 0.006, respectively. On the contrary, Kaplan-Meier analysis at the same time points did not reveal differences in time to basal sCreat recovery in ICI-AIN compared to AI-AIN. Among the evaluated variables, only baseline sCreat influenced the recovery of baseline kidney function in in the univariate analysis, with an odds ratio of 0.95 (95% CI 0.903-1, p-value 0.049) in the ICI-AIN group. The mean nadir sCreat and estimated glomerular filtration rate (eGFR) after treating AIN were comparable between ICI-AIN and Drug-AIN patients (nadir sCreat: 107.46 µmol/L and 102.24 µmol/L, respectively; nadir eGFR: 61.89 ml/min and 56.96 ml/min, respectively; p-value ns). However, ICI-AIN patients reached nadir renal function more rapidly after treatment initiation (10.99 vs. 28.06 months, p-value = 0.020). After reaching nadir function, 73.7% of ICI-AIN patients showed decline, similar to Drug-AIN (73.3%) and AI-AIN (88.5%, p ns). Yet, ICI-AIN patients had a higher yearly eGFR decline post-nadir compared to Drug-AIN (−17.05 (ml/min)/year vs. −3.99 (ml/min)/year, p-value 0.006) and autoimmune AIN (−4.09 (ml/min)/year, p-value 0.009). Conclusion In summary, the results of our study suggest that ICI-AIN patients demonstrate a distinctive pattern of recovery after the acute episode and long-term decline in kidney function after reaching the nadir kidney function compared to the Drug-AIN and AI-AIN groups. They exhibit a faster recovery to nadir kidney function but experience a higher yearly decline post-nadir in eGFR. The influence of baseline sCreat on recovery underscores the importance of considering individual patient characteristics in predicting outcomes and optimizing kidney function before initiating treatment with ICI.

#3115 Effectiveness of SGLT2 inhibitors in patients with glomerulonephritis: a single center experience

Abstract Background and Aims Sodium-glucose cotransporter 2 (SGLT2) inhibitors have become widely used in recent years because of favorable outcomes on kidney function in people with diabetes mellitus and chronic kidney disease (CKD). The main effect of SGLT2 inhibitors is inhibiting sodium and glucose reabsorption, acting precisely in the early proximal tubule of the renal nephron. Although these drugs developed as glucose-lowering agents for their capability to induce glycosuria, cardiovascular outcome studies found that the reduction in kidney function was significantly delayed, and the incidence of severe decline in kidney function was reduced in patients taking SGLT2 inhibitors. Later on, these outcomes were confirmed by the results of the DAPA-CKD, EMPA-KIDNEY, and CREDENCE studies, which were specific outcome trials in patients with CKD. However, data about the use of SGLT2 inhibitors in patients with glomerulonephritis at routine clinical practice are still limited. The purpose of this study is to investigate the impact of SGLT2 inhibitors use in patients with glomerulonephritis. Method Patients diagnosed with biopsy-proven GN who continued their routine follow-up in Etlik City Hospital nephrology clinic were retrospectively examined. Patients with a steroid treatment history for GN were excluded from this study. We identified 29 patients who were treated with SGLT2 inhibitors for proteinuria. We analyzed the baseline characteristics, comorbidities, GN types, and laboratory parameters (baseline, sixth and twelfth months at the follow-up). Each patient was matched to the control with a similar baseline feature under conservative therapy (n = 29). Both patient groups were treated in line with the KDIGO glomerulonephritis guideline and were received RAAS blockers at the maximum tolerated dose. According to baseline levels, the reduction rate in proteinuria and eGFR of the sixth and twelfth months were calculated as percentages. The study was performed in accordance with the Declaration of Helsinki. The local ethical committee approved the study design. Results Our study involved 58 patients diagnosed with 32 (55%) IgA nephropathy, 16 (28%) with membranous nephropathy, and 10 (17%) with focal segmental glomerulosclerosis. In the treatment group, 23 (79%) patients used dapagliflozin, and 6 (21%) used empagliflozin as SGLT2 inhibitors. Baseline proteinuria levels at [1940 (1780-2700 mg/d) vs. 1890 (1670-2400 mg/d); p = 0.8], eGFRs [60 (44-82) vs. 64 (46-80) ml/min/1.73 m2; p = 0.8] and serum albumin levels (39.6 ± 0.3 vs. 39.1 ± 0.2; p = 0.4) were similar between both groups. The proteinuria reduction rate in the sixth month was 34% (27.3-40.5) for the treatment group and 12% (6.9-20.7) for the control group (&amp;lt;0.0001). Besides, the reduction rate was still higher in the treatment group at the 12th month [50.5% (39-52.6) vs. 26.3% (17.2-35.4); p ≤ 0.0001]. eGFR declining rate at 6th months and 12th months were lower in SGLT2 group than the control group [3.1% (0-6.2) vs. 8.6% (4.1-16.6); p = 0.004 and 0.8% (0-5) vs. 5.9% (3.3-15.2); 0.005, respectively] (Table 1). Proteinuria levels at 6th months were 1170 (970-1890) mg/d and 1730 (1180-2100) mg/d for treatment and control group, respectively. At 12th months, median proteinuria level of SGLT2 group was 940 (840-1480) mg/d and control group was 1250 (1120- 2040) mg/d (Fig. 1). Conclusion In this study with a well-matched control group, we found that SGLT2 inhibitors demonstrate efficacy in mitigating the decline in estimated GFR and reducing albuminuria in patients with GN. However, randomized-controlled trials are still required specific to patients with GN.

#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 &amp;lt; 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.

#2478 Multiparametric magnetic resonance imaging predicts decline of kidney function but does not perform better than diffusion-weighted MRI alone

Abstract Background and Aims Renal cortical interstitial fibrosis, typically measured by biopsy, is a critical factor for kidney function prognosis. Diffusion-weighted magnetic resonance imaging (DW-MRI) has emerged as a novel promising non-invasive method to assess the degree of fibrosis. We have previously shown that there is a strong correlation between the cortico-medullary apparent diffusion coefficient difference (ΔADC) and histologically assessed fibrosis. We also developed a model based on ΔADC, eGFR and proteinuria that calculates a risk score for future renal function decline. Multiparametric MRI combines DW-MRI with other sequences and can provide synchronized insights into perfusion, diffusion, oxygenation, and tissue characterization (T1 and T2 mappings). Our current research evaluates whether additional multiparametric MRI sequences increase the power of the DW-MRI based model to predict renal function decline. Method We used data from 197 patients with either chronic kidney disease (42) or allograft kidneys (155). Each participant underwent a biopsy followed by a multiparametric MRI within the following week. The median follow-up period was 2.2 years, during which laboratory parameters were recorded. The primary endpoint was defined as a rapid decline in kidney function, characterized by a reduction in eGFR of over 30%, or the initiation of dialysis. Prognostic factors for the primary outcome were analyzed using both univariable and multivariable Cox regression models, incorporating MRI parameters (ΔADC, cortical and ΔT1, cortical and ΔT2), eGFR, and proteinuria. Results At baseline, mean eGFR was 54.5 ml/min/1.73 m2 (SD 23.8) and mean proteinuria was 0.90 g/24 h (SD 2.4). Rapid decline of renal function occurred in 54 patients after a median time of 1.1 years (interquartile range, 0.9–2.1 years). In univariable survival analysis, cortical T1 measure and cortico-medullar difference ΔT2 have showed the best association to rapid kidney function decline. Compared to our previously established model incorporating ΔADC, eGFR, and proteinuria, adding cortical T1 did not significantly improve the hazard ratio (from 4.62 (95% CI: 1.56–13.67) to 4.36 (95% CI: 1.46–13.02) with cortical T1 inclusion). Harrell's C-index marginally increased with cortical T1, suggesting no significative improvement in prognostic capacity (0.77 versus 0.79 with cortical T1). Additionally, adjusting the regression model for ΔT2 yielded no enhancement in predictive power. Conclusion Our results did not demonstrate an enhancement of the prognostic power of the composite score with the inclusion of additional MRI sequences. Consequently, no clear benefit of multiparametric MRI on top of DW-MRI was observed. Additional research is required to investigate this issue more thoroughly.

#1968 IgA nephropathy and impact of proteinuria and kidney function decline on healthcare resource utilisation among adults in the United Kingdom

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis and can result in kidney failure, especially if left untreated. Proteinuria ≥1.0 g/day is a major risk factor for IgAN progression and rapid kidney function decline. This study describes the characteristics of patients with IgAN in the United Kingdom (UK) and the impact of proteinuria and chronic kidney disease (CKD) stage on healthcare resource utilisation (HRU) and costs. Method In this retrospective, descriptive analysis, eligible patients had at least one code among ICD-9 583.9, ICD-10 N02.8, and ICD-10 N02.9 between 1 October 2015 and 1 October 2022. They were stratified by CKD stage and proteinuria level. CKD stage was defined by ICD-10 N18 code and estimated glomerular filtration rate. Proteinuria level was grouped as low or high by protein excretion rate (&amp;lt;1 g/day vs ≥1 g/day), protein/creatinine ratio (&amp;lt;0.88 g/g vs ≥0.88 g/g), or albumin/creatinine ratio (&amp;lt;100 mg/mmol vs ≥100 mg/mmol). HRU data for 1 year from the index date were obtained from electronic medical records, and costs were obtained from the National Schedule of the National Health Service 2021/22. Weighted average costs were calculated for inpatient, outpatient, and emergency visits. Results We identified 6 940 patients with IgAN. The mean age was 62 years, and most patients (n = 3 980; 57%) were male. For all visit types, HRU (Fig.) and costs (Table) increased with advancing CKD. For all visit types combined, the mean total cost per patient was &amp;gt;23 times higher for CKD stage 5 than stage 1 (£60 259 vs £2 609). Of 2 080 patients with proteinuria data, 560 (27%) had high proteinuria. Annual costs per patient (Table) and the numbers of all visit types (Figure) were higher for patients with a protein excretion rate ≥1 g/day than those with a rate &amp;lt;1 g/day (£12 622 vs £2 822). Conclusion In patients with IgAN in the UK, elevated proteinuria and advanced CKD stage were associated with higher HRU and costs across visit types. Treatments that reduce proteinuria can slow disease progression and prevent rapid decline in kidney function while potentially reducing IgAN-related resource utilisation and costs.

#1306 Online medical education advances physicians’ understanding of the clinical benefits of SGLT 2 inhibition in chronic kidney disease management

Abstract Background and Aims Patients with chronic kidney disease (CKD) have a substantially impaired cardio-renal health prognosis and a reduced life expectancy. Several recent cardio-renal outcomes trials have demonstrated the clinical benefits conveyed by Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors with respect to improved cardiovascular (CV) risk and reduced decline in kidney function. The goal of this online medical education activity was for learners to be better able to detect CKD early in clinical practice and integrate reno-protective therapies, such as SGLT2 inhibitors, into their management of suitable patients with CKD. Method Five nephrology experts participated in a 30-min online video program with synchronized slides and written transcript. Educational effect was assessed using a repeated-pair design with pre-/post-assessment. 3 multiple choice questions assessed knowledge/competence, 1 question rated on a Likert-type scale assessed confidence. A paired samples t-test was conducted on overall average number of correct responses and for confidence rating, a McNemar's test was conducted at the question level (5% significance level). Cohen's d with correction for paired samples estimated the effect size of the education on number of correct responses. Data collection from 28 December 2022 to 1 March 2023. Results Conclusion Participation of PCP in an online video expert program improved their understanding of the close association between metabolic, renal, and cardiovascular diseases, the latest results of CKD outcome trials with SGLT2 inhibition in CKD management, as well as their competence in the practical use of these reno-protective medications in suitable patients with CKD.

#2662 Octreotide-LAR in ADPKD patients with very low kidney function: a monocentric real-life experience

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease, characterized by development of fluid-filled renal cysts leading to progressive expansion of kidney volume, with decline in kidney function up to end-stage renal disease (ESRD). Octreotide long-acting release (OCT-LAR) is a synthetic somatostatin analogue, which has been shown to reduce kidney and cysts growth and to slow the progression of kidney function decline in ADPKD patients. Although the evidence of the literature supporting the protective effect of the OCT-LAR against progression of the disease in ADPKD patients with both early and later-stages, to date no data are available in ADPKD patients treated with this somatostatin analogue in a real-world clinical setting. In August 2018 OCT-LAR was approved only in Italy for the treatment of ADPKD adult patients with eGFR ranging from 30 to 15 mL/min/1.73 m2 at elevated risk of progression towards ESRD. The present study is aimed to report for the first time the effects on renal function of OCT-LAR in ADPKD patients with severe renal insufficiency (stage 4 CKD) receiving this somatostatin analogue for therapeutic indication in a real-world clinical setting. Method We conducted a retrospective, ADPKD-population-based cohort study using healthcare data from the medical records of patients with ADPKD referred to the Department of Nephrology of University “Federico II” of Naples from November 2018 to April 2023 aimed to analyse within-patient clinical outcomes, including eGFR decline, before and after treatment with OCT-LAR. We include adult ADPKD patients (≥18 years) with GFR (eGFR) between 30 and 15 mL/min/1.73 m2, stably treated from at least 1 years with the regular dose of OCTR-LAR. The primary endpoint was the assessment of eGFR decline from 1 year before the start of the treatment (T-1) to baseline (T0), and after 1 year of therapy with OCT-LAR (T1) in the overall population and in two subgroups of patients with eGFR ≥ or &amp;lt; 25 ml/min/1.73 m2. Results 31 ADPKD patients were analysed (18 with eGFR ≥ 25 and 13 with eGFR &amp;lt; 25). Compared to pre-treatment period, eGFR decline significantly slowed during therapy with OCT-LAR in both eGFR groups (Table 1), while no difference was found between eGFR groups. After the first year of observation, 7 patients required dialysis (all with eGFR &amp;lt;25). Conclusion This is the first study reporting the effects of OCT-LAR on eGFR of ADPKD patients with advanced chronic kidney disease (CKD) in a real-world clinical setting. Our results suggest that, compared the last year of follow-up pre-treatment, OCT-LAR slows eGFR decline after 1 year.

#1941 About a case: ABBA disease in a patient with thymoma

Abstract Background and Aims ABBA (antibrush border antibody) disease is a rare autoimmune tubulointerstitial kidney disease with few descriptions in the literature. Diagnosis is based on light microscopy, immunofluorescence, electron microscopy and immunostaining for LRP2 (LDL receptor related protein 2), also known as megalin. Method We report the case of a 47-year-old Caucasian man admitted in January 2023 for oedema and acute kidney injury (creatinine 3 mg/dl). Biology revealed nephrotic syndrome with hypoalbuminemia (12 g/L) and albuminuria (13 g/g). Haematuria was also noted (75/mm3). His medical history was notable for myasthenia gravis and epithelial Gougerot. Serological tests were negative for HIV, hepatitis B and hepatitis C. Anti-GBM and anti-PLA2R were negative, antinuclear antibodies and antineutrophil cytoplasmic antibodies were both positive at 1/80 without specificity. Serum complement (C3 and C4) and protein electrophoresis were normal. Renal biopsy showed membranous nephropathy, anti-PLA2R, anti-THSD7A, NELL1 and EXT1/2 negative. There was also IgG staining along Bowman's capsule and along part of the tubular basement membrane (TBM). The acute tubular injury was severe. Morphological studies with thoracic tomodensitometry, thoracic MRI and PET scan revealed a thymoma. The patient underwent surgery in May. It was a stage 3 thymoma with pulmonary and pericardial invasion. In June 2023, the patient started haemodialysis due to progression of chronic renal failure. We performed a second renal biopsy, which confirmed the atypical membranous nephropathy with glomerular and tubular deposits and 10% interstitial sclerosis. The patient received two injections of RITUXIMAB (30 June and 14 July 2023). Results In October 2023, we performed a third renal biopsy due to dialysis dependency three months after RITUXIMAB. The glomerular lesions were similar to the previous biopsy, with minimal extra-membranous deposits. However, tubulointerstitial lesions were more pronounced than before. There was 25% tubular atrophy and 25% interstitial sclerosis associated with interstitial inflammation. We also identified anti-LRP2 immune deposits along the TBM. All these histopathological features lead to the diagnosis of ABBA. Conclusion Anti-LRP2 nephropathy is an orphan disease. It's caused by autoantibodies directed against the proximal tubular brush border, leading to a progressive decline in kidney function. The largest recently published cohort includes 67 patients. Many patients may be misdiagnosed due to the insidious onset and atypical presentation with concomitant glomerular or tubulointerstitial disease. In the cohort, 30% of patients had cancer, including solid organ malignancies (including 1 thymoma). It seems that combined treatment with corticosteroids and another immunosuppressive therapy (cyclophosphamide or rituximab) has better results. In our case, despite his thymoma surgery and rituximab perfusions, the patient is still on dialysis. The immunosuppressive treatment will be discussed with the oncologist soon.

#2027 Activation of histone deacetylase-1 in fibroblasts and pericytes induces renal interstitial fibrosis after ischemia-reperfusion injury

Abstract Background and Aims Following an acute kidney ischemic event the chromatin remodelling enzyme, histone deacetylase-1 (HDAC1), is activated in many cell types of the kidney including fibroblasts and pericytes. During kidney injury, the fibroblasts/pericytes differentiate into the myofibroblasts and produce extracellular matrix that can lead to a permanent decline in kidney function. Pharmacological inhibition of HDACs can attenuate ischemia-reperfusion-injury (IRI) mediated interstitial fibrosis. The hypothesis of this study was that fibroblast/pericyte HDAC1 activation promotes myofibroblast differentiation and interstitial fibrosis. Method Tamoxifen inducible, fibroblast/pericyte HDAC1 knockout (KO) mice (HDAC1Fl/Fl; Col1a2-CreEr) and littermate controls (HDAC1Fl/Fl) were used. Male and female mice were given tamoxifen by ip at 8-10 weeks of age and IRI or sham surgery completed after a 2-week tamoxifen washout period. A mild, 18 min, bilateral, warm IRI model was used, and samples collected over 4 weeks. Glomerular filtration rate (GFR) was assessed using transdermal FITC-Sinistrin clearance. In vitro experiments with kidney fibroblast cells (NRK49F) overexpressing empty vector or HDAC1 were used for RNA-sequencing to determine the HDAC1-dependent myofibroblast transcriptome. Results We confirmed that HDAC1 was knockdown in myofibroblast cells from KO mice with co-localization of HDAC1 and PDGFRβ or α-smooth muscle actin in the kidneys of IRI mice. Twenty-four hours post-surgery, all IRI mice exhibited 2-3 times increase in serum creatinine and a ∼50% reduction in GFR compared to sham mice (control IRI = 513 ± 129 μl /min/100 g body mass, control sham = 1010 ± 218, n = 4-5, p = 0.02; KO IRI = 529 ± 116, KO sham = 1187 ± 59 μl/min/100 g body mass, n = 4-5, p = 0.004). Subsequent GFR measurements over the next 4 weeks showed a gradual recovery of renal function of IRI mice starting at week 2 and fully restored to sham values by week 4. However, the male control IRI mice had significant focal interstitial fibrosis 2- and 4-weeks post injury (4-week data: sham = 0.3 ± 0.09 % of cortical area, IRI = 1.2 ± 0.2%, n = 6/group, p = 0.0011) but this was attenuated in the KO male IRI mice (sham = 0.4 ± 0.07% n = 4, IRI = 0.5 ± 0.1%, n = 7, p = 0.93). The female mice, regardless of genotype, had very little kidney damage or interstitial fibrosis at 4 weeks. Transcriptomes of NRK49F cells overexpressing HDAC1 had an upregulation of 55 genes related to pro-inflammatory cytokines and tumour necrosis factor signalling and downregulation of 367 genes related to cell junctions, cytoskeleton proteins, and cell adhesion compared to the empty vector control cells. Fibroblast proliferation rates were not statistically different among the groups, suggesting HDAC1 does not affect myofibroblast proliferation but rather pro-inflammatory gene expression. Conclusion In male mice, fibroblast/pericyte activation of HDAC1 leads to the production of pro-inflammatory cytokines that we predict will lead to immune cell infiltration and crosstalk that leads to the excessive production of interstitial fibrosis following IRI.

#2247 Influence of the diagnosis of atopic dermatitis in childhood on the course of kidney function in young adulthood: a single-center study

Abstract Background and Aims Several studies demonstrated non-osmotic sodium-storage, especially in the skin. Patients with chronic kidney disease often suffer from skin symptoms and furthermore an association of advanced CKD-stages with inflammatory skin diseases has been shown. Additionally, in inflammatory skin disease atopic dermatitis an increased salt content was found in the affected skin areas. Thus we hypothesized that atopic dermatitis might have a detrimental effect on kidney function later in life. Method The retrospective case-control study using the patient files of a general medical practice included a randomly selected sample with a 2:1 matching technique. Initially, data of 114 patients who underwent J1-screening exam for adolescents (age 12-14) and also a follow-up examination in adulthood (over the age of 18) between January 1980 and April 2022 have been examined. By the time of inclusion they had to be over 18 years old and did not suffer knowingly from a kidney disease. Over the course of the study, patients for whom no creatinine value was recorded during the following examinations were excluded. Serum creatinine levels and eGFR were compared between the two groups at two assessment times (J1 in adolescence and Follow-Up in young adulthood) and within each group using a one-tailed t-test. A point-biserial correlation analysis was then performed. Results Biometric characteristics, gender distribution and kidney function for J1 as the first measurement point and for follow-up in young adulthood as the second one for both atopic dermatitis and control group are shown in Table 1. The statistical analysis showed that the two groups did not differ significantly in terms of gender distribution at both the first (X²(89) = 0.4918, p = 0.483103) and the second measuring point (X²(73) = 0.45, p = 0.50), therefore a gender bias in the results is unlikely. Furthermore, it was shown by a one-tailed, unpaired t-test for serum creatinine levels ​​at time J1 did not differ from those in the control group (t = 0.60, p = 0.28). This applies too for the corresponding eGFR according to Schwartz-Bedside (t = -0.47, p = 0.32). At the time of follow-up, 16 patients, 8 per group, were excluded due to a lack of creatinine values ​​- in this study using a hypothesis test, no significant difference in the creatinine values ​​was found between the two groups (t = 0.91, p = 0.18), consequently also not in the comparison of eGFR after CKD-Epi (t = -1.28, p = 0.10). Only when comparing creatinine values ​​and eGFR over time within the individual groups, a significant difference for each group was found. In the atopic dermatitis group, the creatinine levels and the eGFR differed significantly in between J1 and the follow-up examination (creatinin: t = 4.29, p = 0.00015, eGFR: t = 1.83, p = 0.042). Likewise did the creatinine levels and the eGFR differ significantly over time in the control group (creatinine: t = 4.77, p &amp;lt; 0.00001 and eGFR: t = 5.72, p &amp;lt; 0.0001). In the point-biserial correlation analysis, no connection between the presence of atopic dermatitis and the level of the serum creatinine value could be confirmed (t = 0.6, df = 89, p = 0.55, 95% CI [-0.14, 0.27], r = 0.063). Conclusion In our study, the diagnosis of atopic dermatitis in childhood does not seem to be a determinant risk factor for a decline in kidney function in young adulthood.