Decline In GFR Research Articles

Renal endowment in men and women: start from the beginning.

The development of the human kidney leads to the establishment of nephron endowment through a process influenced by both genetic and environmental factors. There is individual variability regarding nephron endowment and factors including aging and pathological conditions contribute to the decline in the number of nephrons, impacting renal function. Genetic determinants, such as mutations in crucial developmental genes like Pax2, and epigenetic mechanisms mediated by key enzymes including sirtuin 3, play critical roles in the regulation of the number of nephrons, with implications for kidney disease susceptibility. Sexual dimorphism significantly influences kidney development and function, with the number of nephrons being significantly lower in females, consistent with lower female birth weight, which is considered a surrogate for nephron endowment. Also, although females have fewer nephrons, they experience a slower decline in GFR compared to males. Gender disparity in chronic kidney disease progression has been attributed to factors such as metabolism, oxidative stress, renal hemodynamics, and sex hormones. Understanding the complexities of nephron endowment variability, genetic determinants, and sexual dimorphism in kidney development and function is crucial for elucidating the mechanisms underlying individual kidney disease susceptibility and progression. Further research in this field holds promise for the development of personalized approaches to kidney disease prevention, management, and treatment.

Albuminuria and Rapid Kidney Function Decline as Selection Criteria for Kidney Clinical Trials in Type 1 Diabetes Mellitus.

The optimal criteria to select individuals with type 1 diabetes mellitus (T1D) and albuminuric or normoalbuminuric diabetic kidney disease (DKD), who are at risk of rapid kidney function decline, for clinical trials are unclear. This study analyzed data from the Preventing Early Renal Loss in Diabetes (PERL) clinical trial, which investigated whether allopurinol slowed kidney function decline in persons with T1D and early-to-moderate DKD. Rates of iohexol GFR (iGFR) and estimated GFR (eGFR) decline during the three-year study were compared by linear mixed effect regression between participants enrolled based on a history of moderately or severely increased albuminuria (N=394) and those enrolled based on a recent history of rapid kidney function decline (≥3 ml/min/1.73 m2/year) in the absence of a history of albuminuria (N=124). The association between baseline albuminuria and iGFR/eGFR decline during the trial was also evaluated. Rates of eGFR decline during the trial were higher in participants with a history of albuminuria than in those with a history of rapid kidney function decline (-3.56 [95% confidence intervals {CI} -3.17, -3.95] versus -2.35 [95% CI: -1.86, -2.84] ml/min/1.73 m2/year, p=0.001). Results were similar for iGFR decline, although the difference was not significant (p=0.07). Within the history of albuminuria group, the rate of eGFR decline was -5.30 (95% CI -4.52, -6.08) ml/min/1.73m2/year in participants with severely increased albuminuria as compared to -2.97 (95% CI 2.44, -3.50) and -2.32 (95% CI -1.61, -3.03) ml/min/1.73m2/year in those with moderately increased or normal/mildly increased albuminuria at baseline (p<0.001). Severely increased albuminuria at screening is a powerful criterion for selecting persons with T1D at high risk of kidney function decline. A history of rapid eGFR decline without a history of albuminuria is less effective for this purpose but it can still identify individuals with T1D who will lose kidney function more rapidly than expected from physiological aging. ClinicalTrials.gov, NCT02017171.

Estimated GFR Decline is Causally Associated with Acute Pulmonary Embolism: A Nested Case-Control and Mendelian Randomization Study.

Renal dysfunction is highly prevalent among patients with pulmonary embolism (PE). This study combined population-based study and Mendelian randomization to observe the relationship between renal function and PE. A nested case-control study were performed using data of PE patients and controls were from two nationwide cohorts, the China pUlmonary thromboembolism REgistry Study (CURES) and China Health and Retirement Longitudinal Survey (CHARLS). Baseline characteristics were balanced using propensity score matching and inverse probability of treatment weighting. Restricted cubic spline models were applied for the relationship between estimated glomerular filtration rate (eGFR) decline and the risk of PE. Bidirectional two-sample Mendelian randomization (MR) analyses were performed using Genome-wide association study summary statistics for eGFR involving 1,201,909 individuals and for PE from the FinnGen consortium. The nested case-control study including 17,547 participants (6,322 PE patients) found that eGFR distribution was significantly different between PE patients and controls (P<0.001), PE patients had a higher proportion of eGFR<60 mL/min/1·73 m2. eGFR below 88 mL/min/1·73 m2 was associated with a steep elevation in PE risk. MR analyses indicated a potential causal effect of eGFR decline on PE (OR=4·26, 95%CI 2·07-8·79), with no evidence of horizontal pleiotropy and reverse causality. Our findings support the hypothesis that renal function decline contributes to an elevated PE risk. Together with the high prevalence of chronic kidney diseases globally, there arises the necessity for monitoring and modulation of renal function in effective PE prevention.

8626 Associations Between Low Serum Bilirubin Levels and the Progression of Diabetic Kidney Disease in Individuals with Type 2 Diabetes, Including Those in a Normoalbuminuric State

Abstract Disclosure: E. Kim: None. Y. Cho: None. O. Hong: None. K. Jo: None. J. Han: None. S. Moon: None. Objective: This study aimed to investigate the potential correlation between serum bilirubin levels and the progression of diabetic nephropathy, assessing whether low serum bilirubin levels are associated with a decline in renal function, while considering the baseline albumin excretion status. Methods: The longitudinal observation, spanning 11 years, involved 1167 Korean subjects aged 20 years or older, diagnosed with type 2 diabetes mellitus (T2DM), and having a baseline estimated glomerular filtration rate (eGFR) greater than 60 ml/min per 1.73 m2. Albuminuria was assessed by the 24-hour urinary albumin to creatinine excretion rate (ACR) and categorized into normoalbuminuria (ACR &amp;lt;30 mg/g), micro- or macroalbuminuria (ACR &amp;gt;300/g). Cox regression analysis was employed to explore connections between serum bilirubin levels and eGFR decline ≥40%, with adjustments for potential confounding variables. Results: Over a median follow-up of 8.2 years, 128 individuals experienced a decline in eGFR &amp;gt;40%. The hazard ratio (HR) of incident GFR decline was 1.72 (95% CI: 1.04-2.85, P=0.036) in the lowest total bilirubin (TB) tertile compared to the highest TB tertile after multivariable adjustment. When stratified by baseline albuminuria status, low bilirubin levels were significantly associated with eGFR decline, even in the normoalbuminuria group (HR: 2.21, 95% CI: 1.26-3.90, P=0.006), with a gradually increasing risk according to the absence of low TB levels and albuminuria (HR: 2.92, 95% CI: 1.65-5.19, P&amp;lt;0.001), and low TB levels and albuminuria (HR: 3.01, 95% CI: 1.65-5.46, P&amp;lt;0.001). Conclusion: Low serum TB levels are associated with an increased risk of rapid GFR decline in Korean patients with T2DM. Serum bilirubin levels may serve as a prognostic marker for the development and progression of diabetic kidney disease. Presentation: 6/1/2024

Abstract 03: Glomerular Hyperfiltration Promotes Chronic Kidney Disease through Interleukin 17A-Mediated Inflammation

Impaired renal autoregulation in obesity, diabetes and hypertension (HTN) causes elevated glomerular capillary pressure and glomerular hyperfiltration, initiating progressive glomerulosclerosis (GS), nephron loss and chronic kidney disease (CKD). Increased renal perfusion pressure drives renal T cell infiltration. T helper (Th) 17 cells promote vascular stiffening in HTN and renal interstitial fibrosis post AKI, but their roles in GS and CKD are poorly understood. We hypothesized that glomerular hyperfiltration promotes CKD through Th17-mediated GS and tested the hypothesis in 129S6 mice using the reduced kidney mass model (RKM) induced by uninephrectomy and partial renal artery ligation in the remaining kidney (functional renal mass reduced by ~ 5/6). BP (radiotelemetry) and GFR (FITC-sinistrin) of RKM mice were identical to sham controls at baseline (BL, n=4-6). Immediately after the RKM procedure, GFR dropped to 22% of BL, consistent with the extent of renal mass ablation. Mean BP increased by 29 mmHg first week after 5/6 ablation (144 ± 8 vs BL 112 ± 2 mmHg, p&lt;0.05, 2-way ANOVA) and remained elevated through week 12, exposing the remnant nephrons to increased renal perfusion pressure. Serum creatinine, BUN and urinary albumin were significantly elevated after 5/6 ablation. In RKM mice, GFR gradually increased to 38% of BL at day 3, 57% at week 1 and 68% at week 2, suggesting that systemic HTN and impaired renal autoregulation may have caused substantial single-nephron hyperfiltration in the remnant kidney. GFR plateaued at ~ 70% of BL in week 3-4 then declined to 48% at week 8 when glomerular, interstitial, and microvascular fibrosis developed as evidence by Periodic Acid Schiff and Picro Sirius Red staining. Importantly, the early adaptive increase of GFR in the first 2 weeks post 5/6 ablation was accompanied by a striking increase of renal interleukin (IL)-17A+ T cells, which preceded the late infiltration of CD11b+ myeloid cells, F4/80+ monocyte/macrophages, and T regulatory cells. Anti-IL17A antibodies (eBioMM17F3, 100 μg i.p. twice weekly) attenuated the early hyperfiltration, abolished aortic/renal inflammation, and prevented GFR decline and GS at week 8 in male but not female RKM mice, likely due to the anti-hypertensive and anti-inflammatory effects of IL-17A neutralization. We conclude that glomerular hyperfiltration causes progressive nephron loss and kidney fibrosis in CKD, at least in part, through IL-17A mediated renal inflammation.

Reconstituted HDL ameliorated renal injury of diabetic kidney disease in mice.

Diabetic kidney disease (DKD) is a devastating kidney disease and lacks effective therapeutic interventions. The present study was aimed to determine whether reconstituted high-density lipoprotein (rHDL) ameliorated renal injury in eNOS-/- dbdb mice, a mouse model of DKD. Three groups of mice, wild type C57BLKS/J (non-diabetes), eNOS-/- dbdb (diabetes), and eNOS-/- dbdb treated with rHDL (diabetes+rHDL) with both males and females were used. The rHDL nanoparticles were administered to eNOS-/- dbdb mice at Week 16 at 5 μg/g body weight in ~100 μL of saline solution twice per week for 4 weeks via retroorbital injection. We found that rHDL treatment significantly blunted progression of albuminuria and GFR decline observed in DKD mice. Histological examinations showed that the rHDLs significantly alleviated glomerular injury and renal fibrosis, and inhibited podocyte loss. Western blots and immunohistochemical examinations showed that increased protein abundances of fibronectin and collagen IV in the renal cortex of eNOS-/- dbdb mice were significantly reduced by the rHDLs. Taken together, the present study suggests a renoprotective effect of rHDLs on DKD.

Longitudinal Analysis of Renal Function Changes in Elderly Populations: Health Status Evaluation and Risk Factor Assessment.

This study aims to investigate GFR decline in elderly subjects with varying physical conditions and analyze key risk factors impacting renal function changes. We obtained data from patients between 2017 and 2019, and matched healthy elderly subjects based on gender and age. Data collected for all subjects included annual measurements of fast blood glucose (GLU), glycated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-c), blood albumin (ALB), blood uric acid (UA), urine protein (UP), and systolic blood pressure (SBP). Additionally, information on coexisting diseases was gathered. The Full Age Spectrum (FAS) equation was used to calculate eGFR. A total of 162 patients with complete 3-year renal dynamic imaging were included, including 84 patients in the kidney disease group (K group) and 78 patients in the non-kidney disease group (NK group). Ninety individuals were selected as the healthy group (H group). The annual decline rate in the K group was the fastest, which exceeded 5mL/min/1.73m2 (P < 0.05). Group (K group: β=-40.31, P<0.001; NK group: β=-26.96, P<0.001), ALB (β=-0.38, P=0.038) and HbA1c (β=1.36, P=0.029) had a significant negative impact on the eGFR changes. For participants who had negative proteinuria: K group had the most significant annual eGFR decline. The presence of kidney disease, along with proteinuria nor not, can lead to a marked acceleration in kidney function decline in elderly. We categorize elderly individuals with an annual eGFR decline of more than 5 mL/min/1.73m2 as the "kidney accelerated aging" population.

Sex and the Relationship Between Cardiometabolic Risk Factors and Estimated GFR Decline: A Population-Based Cohort Study

Rationale & ObjectiveFemales have a higher prevalence of chronic kidney disease (CKD) than males, but are less likely to be treated with kidney replacement therapy (KRT). We studied the interaction between sex and the association of cardiometabolic risk factors for the decline in kidney function over time. Study DesignA population-based cohort study. Setting & Participants1,127,731 adults living in Wales, UK, within the Secure Anonymised Information Linkage Databank. ExposuresSex and risk factors including age, estimated glomerular filtration rate (eGFR), cardiometabolic conditions, smoking, and socioeconomic deprivation. These risk factors were defined using primary care records. OutcomesThe yearly declines in eGFR and the risk of incident kidney failure defined as long-term KRT and/or sustained eGFR<15mL/min/1.73m2. Analytical ApproachLinear mixed effects models and Cox proportional hazards analysis. ResultsThe average decline in eGFR age ≤73 was equal in males and females. After age 73, eGFR decline was faster in males than females, particularly for males with heart failure (males -1.22 mL/min/1.73m2 per year: 95% confidence interval (CI) -1.25 to -1.20 versus females -0.87mL/min/1.73m2: CI -0.89 to -0.85) and current smokers (males -1.58 mL/min/1.73m2 per year: CI -1.60 to -1.55 versus females -1.27 mL/min/1.73m2: CI -1.29 to -1.25). Socioeconomic deprivation was one of the most impactful risk factors on eGFR decline among females age >73, whereas cardiometabolic risk factors were more important among males. Older females at baseline were less likely to develop incident kidney failure than older males (p-value for age<0.001). LimitationsStudy of people who were almost exclusively White and who had blood laboratory test data. Reliance on creatinine-based eGFR. Albuminuria and body mass index data were incomplete. ConclusionseGFR decline was faster in males than in females especially in the setting of heart failure and smoking. Socioeconomic deprivation was an important risk factor associated with eGFR decline, particularly for females. While further work is required to explore less well-recognised risk factors these findings may inform clinical management strategies of CKD overall and within sex-specific groups.

#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.

#1042 A real-life experience with dapagliflozin in the treatment of patients with IgA Nephropathy at high risk of progression

Abstract Background and Aims Even though IgA nephropathy is the most common primary glomerular disease worldwide, being accounted with 22% of kidney biopsy results in Europe and despite great advances in comprehending its pathogenesis, little has changed in the standard of care over the last decades. According to recent studies, dapagliflozin reduced the progression of chronic kidney disease in chronic forms of IgA Nephropathy. The study sought to investigate the impact of dapagliflozin use in a compiled cohort of patients diagnosed with IgA Nephropathy. Method This is a prospective, observational study, that included 52 patients with IgA Nephropathy, based on a prior kidney biopsy, actively monitored from 2021 to 2023, in the Nephrology Department of Fundeni Clinical Institute, Bucharest. The inclusion criteria were: patients with IgA nephropathy diagnosed upon evaluation of a kidney biopsy, with GFR&amp;gt;30 ml/min/1.73 m2 and proteinuria above 0.3 g/day, who received dapagliflozin 10 mg, daily, with a follow-up of 6 and 12 months. The baseline parameters were considered those that were on the onset of SGLT2 inhibitors therapy with dapagliflozin. Results The study population had a mean age of 48 ± 11 years old and 69.2% were male. The mean value of baseline serum creatinine was 1.68 ± 0.75 mg/dl and the mean value of GFR was 54 ± 27 ml/min/1.73 m2, while the mean value of baseline proteinuria was 1.55 ± 2.1 g/day. Also, the risk of chronic kidney disease progression was very high in 59.6% cases, high in 34.6% cases and moderate in 5.8% cases. The majority of the study cohort (90.4%) already received a stable dose of angiotensin-converting-enzyme inhibitors or angiotensin receptor blocker. After 6 months of dapagliflozin administration, the absolute decline of proteinuria was 0.94 ± 1.9 g/day, while after 12 months was 1.06 ± 2.97 g/day, which in terms of percents translates as a decline of—44.7% and—50%, respectively. A mild decrease in GFR was observed, the absolute decline being represented by 4 (−6.25; 3) ml/min/1.73 m2 after 6 months and 3.5 (−9;2) ml/min/1.73 m2 after 12 months. Patients who had proteinuria less than 1 g/day at baseline experienced an absolute decline in GFR with 2.5 (−5.75; 3.75) ml/min/1.73 m2, while the study group with proteinuria above 1 g/day had an absolute decline in GFR of 5 (−7.2; 3) ml/min/1.73 m2 after 6 months, while after 12 months of treatment, the GFR drop was 4 (−8.5;1.5) ml/min/1.73 m2 and 3 (−9;2) ml/min/1.73 m2, respectively. A GFR decline over 30% was observed with a prevalence of 17.6% in the group with proteinuria above 1 g/day and 9.5% in the group with proteinuria under 1 g/day, while the prevalence was 8.7% in the group with GFR&amp;gt;45 ml/min/1.73 m2 and 20% among the group with GFR&amp;lt;45 ml/min/1.73 m2. The mean value of baseline proteinuria was 0.42 ± 0.21 g/day in the cohort with proteinuria&amp;lt;1 g/day and 3.09 ± 2.53 g/day in the cohort with proteinuria&amp;gt;1 g/day (p &amp;lt; 0.001). At 6 months, the absolute decrease of proteinuria was 0.18 ± 0.18 g/day in the group with proteinuria under 1 g/day and with 1.79 ± 2.53 g/day in the group with proteinuria above 1 g/day (p &amp;lt; 0.001), whereas after 12 months it was 0.15 ± 0.21 g/day and 2.17 ± 2.54 g/day (p &amp;lt; 0.001); also, after 12 months, proteinuria was reduced with 1.42 ± 2.37 g/day at patients with GFR&amp;gt;45 ml/min/1.73 m2 and with 0.48 ± 0.85 g/day at patients with GFR&amp;lt;45 ml/min/1.73 m2, a difference which tends to reach statistical significance. Conclusion There was a decline in proteinuria after 6 months and 12 months of dapagliflozin treatment, with a statistically significant difference between the two groups: the patients with proteinuria above 1 g/day experienced a more remarkable reduction than the group with proteinuria under 1 g/day. Patients with GFR&amp;gt;45 ml/min/1.73 m2 experienced a higher drop in proteinuria. A mild decrease of GFR was noticed during the follow-up period, with a higher prevalence of a GFR dip over 30% in the group with proteinuria above 1 g/day and with GFR&amp;lt;45 ml/min/1.73 m2, but the difference was not statistically significant.

#2295 Can we detect the evolution of GFR with estimated GFR in patients with ADPKD?

Abstract Background and Aims ADPKD affects about 10% of the patients with CKD. In the disease the formation of cysts replace normal renal parenchyma leading to renal function loss. The evolution of the disease is irregular: some patients lose renal function very fast while others remain stable or have a slow loss. This may have consequences in clinical care. In day-to-day practice, GFR is evaluated by means of formulas, which are algorithms that use creatinine and others markers like age and gender to estimate GFR. However, the accuracy and precision of eGFR in reflecting real GFR in ADPKD is not clear, being this the objective of our study. Method To analyse the capacity of eGFR by creatinine-based formulas in predicting mGFR changes over time. We evaluated patients with ADPKD, who underwent mGFR and eGFR by a group 5 equations at baseline, month 6 and then annually. mGFR was evaluated by the clearance of iohexol using dried blood spots (iohexol-DBS) and eGFR with the following creatinine-based equations: Cockcroft-Gault, aMDRD, CKD-EPI, FAS and EKFC. We calculated renal function decline (GFR decline) using repeated measured with mGFR and eGFR. All subjects have at least 3 repeated evaluations of renal function. The agreement between mGFR and eGFR declines was analysed by the concordance correlation coefficient (CCC). Also, we evaluated the capacity of eGFR decline in detecting diverse degree of GFR decline (a) rapid progressors: mGFR of −5 ml/min/y; (b) moderate progressors: −2 to −5 ml/min/y; (c) stable: &amp;gt; −2 ml/min/y. Results We evaluated 111 (43; 37% men); age: 42 y ± 14, with a 5 ± 1 evaluations of GFR over time (mGFR and eGFR). The average GFR decline was: −2,8 ml/min/year (mGFR); −3,1 (Cockcroft-Gault), −2,9 (aMDRD), −3,0 (CKD-EPI), −2,8 (FAS) and −2,6 (EFKC) According with mGFR decline, 21 patients (19%) were rapid progressors; 46 (41%) moderate progressors and 44 (40%) stable. The agreement between eGFR decline and mGFR decline was poor, reflected by a low CCC: 0.37 (Cockcroft-Gault); 0.76 (aMDRD); 0.80 (CKD-EPI), 0.77 (FAS); 0.81 (EFKC). In general, eGFR decline failed to detect progression of renal function over time. On average, 43% of the rapid progressors, 53% of the moderate progressors and 54% of the stable patients were not detected by any formula, respectively. Finally, a total of 12% and 6% of those stable or moderate progressors were falsely classified as rapid progressors. Conclusion eGFR is not able to reflect properly renal function changes over time in patients with ADPKP in about half of the patients. A relevant number of cases are erroneously considered as rapid progressors or even stable patients. This may have clinical consequences. Whenever possible, mGFR could be considered in this population.

#1703 Role of early AV fistula creation among elderly and its impact on estimated decline in GFR among pre dialysis patients

Abstract Background and Aims Recent evidence suggests that AVF creation may slow estimated glomerular filtration rate (eGFR) decline. The aim of the present study was to assess the impact of the pre dialysis AVF creation on eGFR decline and the need for dialysis, after controlling for key confounding factors among elderly population with advanced renal failure . Method A retrospective cohort study among patients attending Nephrology, Urology and General Surgery OPD between Jan 2019-Jan 2022 in Tertiary care hospital, Lucknow for AV fistula creation and assessed their stage of CKD and trajectory of fall in eGFR within a year's time and the time to initiation of dialysis from AV fistula creation was assessed. Results 34 men and 23 females (&amp;gt; 65 years ) of age who at time of AV fistula creation had an median eGFR at time of AVF creation of 15.5 (10.3–16.9) mL/min/1.73m2. The factors like frailty, diabetes, psychosocial issues were matched between the two genders . Males were more in age with better BMI .Baseline eGFRs were 14.4± 2.0 mL/min/1.73m2 in men and 13.8.0 ± 1.2 mL/min/1.73m2 in women. The crude annual eGFR decline rates were − 3.20 ± 2.50 mL/min/1.73 m2 pre- and − 2.45 ± 2.16 mL/min/1.73 m2 post-AVF. In a mixed effect linear regression model, monthly eGFR decline was − 0.43 mL/min/1.73m2/month.. The period after AVF creation was associated with a relatively higher eGFR . There was a significant association between follow-up time and the period pre/post AVF such that eGFR decline was more attenuated each month after AVF creation. There was better preservation of GFR from the pre AV fistula creation . Conclusion In this cohort, AVF creation was associated with a significant reduction of eGFR decline among elderly population . Further prospective studies are needed to confirm this association

#968 Impact of the presence of acute kidney injury at the time of renal biopsy on long-term prognosis of IgA nephropathy

Abstract Background and Aims IgA nephropathy is the most common primary glomerular disease and an important cause of end-stage renal disease. Factors such as decreased renal function, persistent proteinuria, hypertension, and older age predict a poor prognosis in IgA nephropathy. Current international prediction tools for IgA nephropathy determine prognosis based on renal function using estimated glomerular filtration rate (eGFR) at the time of kidney biopsy. However, we observed differences in prognosis between patients with and without concurrent acute kidney injury (AKI) at the time of kidney biopsy. Therefore, we aimed to investigate whether renal function at the time of renal biopsy is a suitable indicator for assessing the long-term prognosis of patients with IgA nephropathy with AKI. Method We retrospectively analyzed a total of 185 patients who were diagnosed with IgA nephropathy between 2009 and 2016 at the Gyeongsang National University Hospital. Clinical data, including pathological, demographic, and laboratory findings of patients, were used. We divided the patients into two groups based on the progression rate of kidney function per year, ‘Progression’ or ‘Non-progression group’. AKI was defined according to the KDIGO Clinical Practice Guidelines. Results Among a total of 185 patients, 113 showed a sustained decline in eGFR of more than 1 ml/min/1.73 m2 per year. The mean eGFR level of the non-progression group was significantly lower than that of the progression group (p = 0.027). The percentage of patients with AKI in the non-progression group was 25%, which was higher than that in the progression group (p &amp;lt; 0.001). The two groups had no significant differences in comorbid disease, medications at kidney biopsy, and treatment. In sub-analysis, the mean eGFR at kidney biopsy was significantly lower than that in the non-AKI group (p &amp;lt; 0.001). The mean estimated risk, calculated by the international prediction tool, was significantly lower in the AKI group. On the other hand, the mean rate of actual GFR decline per year was higher in the non-AKI group (p &amp;lt; 0.001). Conclusion We confirmed a discrepancy between the predicted prognosis and the actual decline in GFR, particularly in the AKI group. We found that AKI at the time of renal biopsy was a good long-term prognostic factor. There is a need to conduct further research to confirm whether this is due to early detection of AKI and early active treatment.

#2997 Characterising the natural history of renal recovery after AKI in a prospective cohort—does timing matter?

Abstract Background and Aims Acute kidney injury (AKI) is associated with an increased risk of chronic kidney disease (CKD). Failure of recovery of serum creatinine by 90 days after AKI strongly associates with subsequent long-term reductions in renal function, however there is no consensus agreement on the definition of renal recovery. Further, detailed prospective descriptions of the ‘renal recovery phase’ between AKI and 90 days are lacking. Here we describe outcomes at serial timepoints (days 30, 60 and 90) for a prospective cohort of hospitalised patients with AKI. Method Single centre, prospective cohort study of participants with all stages of AKI. Each participant was characterised in detail, including AKI aetiology, co-morbidities and frailty. Baseline blood and urine samples were obtained at the time of consent. Participants were then followed up at days 30, 60 and 90 with clinical measurements and blood and urine sample collection. Blood tests included serum creatinine and GFR measured by the CKD-EPI equation. The proportion of participants with renal recovery at different creatinine above baseline thresholds as well as major adverse kidney events (MAKE) a composite outcome of death, new dialysis, and persistent renal dysfunction, defined as a 25% or greater decline in GFR was determined at day 30, 60 and 90. Where data was missing, last creatinine / GFR was carried forward for day 60 and 90, or discharge creatinine for day 30. Results A total of 124 participants were recruited. 63% of patients had AKI on hospital admission. The median baseline creatinine was 88 (IQR 70–117) μmol/L and median GFR was 68 (46–87) mL/min/1.73 m2. Median peak creatinine of 306 (IQR 177–458) μmol/L. The majority of AKI was severe (stage 1 (24%) vs stages 2 &amp; 3 (76%)). The most common primary aetiology of AKI was dehydration (46%) followed by sepsis (22%). Table 1 demonstrates the number of participants with ‘recovered’ renal function as defined by a creatinine above baseline of 10%, 20% and 50% from baseline (the latter being reversal of KDIGO AKI stage 1) across the timepoints. Non-recovery of renal function was common across all time points, ranging from 22% to 59% at day 90 depending on which definition of recovery was applied. Table 2 summarises the rate of major adverse kidney events (MAKE) for day 30, 60 and 90, that was predominantly driven by persistent renal dysfunction. Conclusion This study is one of the few prospective descriptions of the AKI recovery from time of AKI to day 90. Whilst it is known that failure to recover creatinine by day 90 is predictive of future renal dysfunction, these data suggest that there is little dynamic change after day 30 and suggests that interventions to prevent the AKI to CKD transition should be targeted in the first 30 days after AKI in order to have the biggest impact. These data also highlight the need for a consensus definition of non-recovery of renal function. Future work on this cohort will therefore include relating different thresholds of renal recovery to outcomes.

#1206 Combination therapy with Lisinopril and Dapagliflozin rescues GFR decline and glomerular damage in the KKAy mouse model of diabetic kidney disease

Abstract Background and Aims Male KKAy mice develop diabetic kidney disease (DKD) with progressive decline of GFR upon high fat diet feeding which is accelerated by the vasoconstrictor LNNA. In this study, efficacy of combination therapy with clinical relevant therapeutics in the form of an ACE-inhibitor (Lisinopril) and SGLT2-inhibitor (Dapagliflozin) on renal function and histopathology was investigated. Method Male KKAy mice underwent uninephrectomy (UNX). After recovery mice received high fat diet (45% LARD) and 50 mg/L LNNA in drinking water (wk0). At week 4, Lisinopril (2.5 mg/kg/day in drinking water) and at week 8 Dapagliflozin (5 and 20 mg/kg/day in diet) were started. Body weight, blood glucose, food and water intake and albuminuria were determined regularly. GFR was measured transdermally by FITC-sinistrin clearance. Mice were terminated at week 16 and renal histology was scored by a team of renal histopathologists. Non-induced and induced non-treated mice were used as controls. Results Treatment of KKAy mice on HFD+LNNA with Dapagliflozin reduced blood glucose immediately. Combination therapy with Lisinopril and Dapagliflozin (5 mg/kg/day) rescued the progressive GFR decline to levels seen in non-induced chow-controls (p &amp;lt; 0.05 vs UNX+HFD+LNNA). Pathology showed that the percentage of healthy glomeruli increased from 14% to 26% after combination therapy (Dapa 5). Interstitial fibrosis and tubular atrophy were significantly reduced by combination therapy (p &amp;lt; 0.05 vs UNX+HFD+LNNA). Conclusion Male KKAy mice on a HFD and LNNA developed DKD resulting in CKD. Combination therapy with Lisinopril and Dapagliflozin rescued GFR decline and reduced glomerular damage and interstitial fibrosis and tubular atrophy This indicates the clinical relevance of the model which can be used to study compound efficacy in both early and more advanced stages of DKD.

#2617 Impact of CKD screening in high‑risk populations and guideline-directed therapy on RRT, CV events, and mortality in Europe: an IMPACT CKD analysis

Abstract Background and Aims Despite the rising and substantial burden of chronic kidney disease (CKD), there is a lack of recognition of CKD as a health priority in Europe. This contributes to underdiagnosis of CKD despite the potential for early detection and effective intervention to delay progression to late-stages (associated with costly and resource-intensive renal replacement therapy [RRT; i.e., dialysis and transplantation]). Further, diagnosed patients are undertreated when compared to current and upcoming CKD guidelines, leading to increased risk for progression to RRT and cardiovascular (CV) or other events. Early detection and intervention in high-risk populations, such as those with diabetes mellitus (DM) and hypertension (HTN) have shown cost-effectiveness; however, the broader implications of these strategies on CKD progression and clinical outcomes in a European context remains underexplored. Our study aims to illustrate the clinical benefit of targeted screening followed by an optimal compliance to guideline-directed treatment use to provide insight into potential CKD policies across Europe. Method Four country populations (Germany, Netherlands, Spain, United Kingdom [UK]) were simulated for 10-years (baseline: 2022; simulated years: 2023-2032) using the validated IMPACT CKD model to compare two scenarios: targeted screening for people with DM and/or HTN followed by 90% compliance to guideline-directed therapy versus current practice (i.e., underdiagnosis without screening and low treatment rates). Annual targeted screening was modelled using estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) testing. Initiation of therapies for people with diagnosed CKD was based on Kidney Disease Improving Global Outcomes guidelines. A 90% compliance to guideline-directed therapies was assumed to approximate maximum clinical benefit. Current practice was modelled based on the observed diagnosed rate without screening and the observed treatment rate in each country. The incremental population initiated on recommended therapies were modelled to experience a multiplicative treatment effect on GFR decline, CV events, and acute kidney injury (AKI) events. The model projected CKD and RRT prevalence, incidence of CV and AKI events with results shown for year 10 (2032), as well as cumulative all-cause mortality over the simulated 10-years. Results Results compare the high-risk population screening followed by guideline-directed treatment scenario to continuation of current practices for the four countries (Fig. 1). The identification of undiagnosed CKD, as well as lower rates of progression due to guideline-directed treatment was associated with a small rise in the number of total CKD patients, with increases in stage 1-2 by 3.5% to 5.0%, and stage 3-5 by 0.2% to 1.2%. There was a reduction in the number of undiagnosed CKD stage 1-2 patients by 49.2% to 71.6%, and stage 3-5 by 60.2% to 69.8%. The largest reductions were predicted for CV events (44.6% to 49.1%) followed by dialysis (22.6% to 41.9%). The strategy resulted in a decrease in cumulative 10-year all-cause mortality between 4.5% to 9.1% in CKD patients. Conclusion The study predicted significant clinical benefits from targeted CKD screening followed by guideline-directed interventions across all four European countries. Notably, this approach was forecasted to reduce undiagnosed CKD cases, dialysis, CV events, and mortality. These findings underscore the potential of acting earlier on CKD to mitigate the future CKD burden.

#2415 Estimated glomerular filtration rate thresholds associated with poor long-term outcomes in older patients with diabetes

Abstract Background and Aims Considering the natural decline of GFR with renal senescence, an age-adjusted estimated glomerular filtration rate (eGFR)-based chronic kidney disease (CKD) definition was recently proposed, which has been supported by that mortality risks start to increase at GFR &amp;lt;45 mL/min/1.73 m2 in older adults (≥65 years). However, the eGFR threshold for mortality and kidney outcomes in older patients with diabetes was less understood. We aimed to evaluate eGFR levels that raise the risk of mortality or end-stage kidney disease (ESKD) in older patients with diabetes. Method Older adult patients (≥65 years) with type 2 diabetes who visited our outpatient diabetes center during 2009 were retrospectively identified and followed up until 2017. Patients were categorized into four groups per their CKD-EPI equation-based eGFR: ≥60, 45–59, 30–44, and 15–29 mL/min/1.73 m2. Cox proportional hazard analysis for all-cause mortality and competing-risk analysis for ESKD (with a competing event of pre-ESKD death) were performed. Results Among 3,065 patients, 19%, 8%, and 2% of patients had eGFR 45–59, 30–44, and 15–29 mL/min/1.73 m2 at baseline, respectively. After adjusting various clinical covariates, including blood pressure, diabetes duration, urine albumin/creatinine ratio, HbA1c, serum cholesterol levels, and major comorbidities, patients with eGFR 30–44 and 15–29 mL/min/1.73 m2 had 1.51-fold (95% confidence interval [CI] 1.17–1.95, P &amp;lt; 0.001) and 2.66-fold (95% CI 1.87–3.79, P &amp;lt; 0.001) higher risks of mortality, respectively, whereas patients with eGFR 45–59 mL/min/1.73 m2 had a comparable risk (1.18, 95% CI 0.96–1.45, P = 0.127) to those with eGFR ≥60 mL/min/1.73 m2. Substitution hazard ratios for ESKD were 2.29 (95% CI 1.41–3.71, P = 0.001), 5.25 (95% CI 3.27–8.41, P &amp;lt; 0.001), and 16.74 (95% CI 9.73–28.80, P &amp;lt; 0.001) in patients with eGFR 45–59, 30–44, 15–29 mL/min/1.73 m2, respectively. In a subgroup of patients 75 or older (n = 800), patients with eGFR 45–59 mL/min/1.73 m2 exhibited comparable risks for both ESKD and mortality. Conclusion Reduced eGFR &amp;lt; 60 mL/min/1.73 m2 predicted an increased risk of ESKD in older patients with diabetes, suggesting that the current traditional eGFR threshold appears feasible. Thus, some high-risk individuals may be missed if age-adapted eGFR criteria with a lower eGFR threshold than 60 mL/min/1.73 m2 are universally applied for older adults ≥65 years.

#1422 Exploring BAFF, APRIL, and clinical characteristics in IgA nephropathy: a decade-long study in the Bulgarian population

Abstract Background and Aims IgA nephropathy (IgAN) represents a significant global health concern, contributing substantially to chronic kidney disease and renal failure. Despite its widespread impact, the Bulgarian population lacks comprehensive epidemiological data and specific biomarkers for IgAN. This decade-long retrospective study, conducted at a tertiary Nephrology Clinic in Bulgaria, aims to explore the clinical characteristics and serum levels of BAFF and APRIL in biopsy-confirmed IgAN patients and healthy controls. Method The study includes 125 biopsy-confirmed IgAN patients and 30 healthy controls. Notably, 70.4% of IgAN patients were male, with an average age of 35.94 ± 11.91 years. Baseline characteristics reveal advanced disease stages at diagnosis, possibly linked to delayed biopsy (24.22 ± 32.9 months from initial symptoms) and the absence of a screening program. Analyses of serum biomarkers (C3, BAFF, and APRIL) are conducted to identify any significant variations between IgAN patients and healthy volunteers. Results The average baseline estimated glomerular filtration rate (eGFR) was 61.78 ± 27.72 ml/min/1.73 m², with a mean serum creatinine of 126 ± 67.83 μmol/l at the time of kidney biopsy. Among the patients, 51.2% had an eGFR below 60 ml/min, indicating CKD stage 3 or worse according to the KDIGO classification Binary logistic regression analysis identifies anemia as a significant contributor to disease progression, with a risk influence approximately 3.3 times higher for GFR decline over time. Anemia emerges as a crucial predictor for serum creatinine doubling, carrying a higher risk than hyperuricemia. Analyses of C3 (p = 0.658), BAFF (p = 0.432), and APRIL (p = 0.227), demonstrated no significant differences in their serum levels between IgAN patients and healthy volunteers. Conclusion This study provides comprehensive insights into IgAN in the Bulgarian population, addressing the dearth of epidemiological data and biomarkers. Anemia emerges as a significant predictor for disease progression, emphasizing its potential clinical relevance. However, C3, BAFF, and APRIL exhibit no notable variations, underscoring the need for additional biomarker exploration to enhance understanding of IgAN dynamics in this population.

#1671 Prevalence and factors predicting non diabetic kidney disease in type 2 diabetic patients

Abstract Background and Aims Renal involvement in type 2 diabetes is mostly presumed to be due to diabetic nephropathy, however a significant majority of diabetic patients can have pure non diabetic kidney disease (NDKD) or NDKD superimposed on diabetic kidney disease (DKD). Kidney biopsy cannot be routinely performed for all diabetic patients and hence short of conclusive biomarkers we need to explore various factors that can predict the occurrence of NDKD. Method We conducted a retrospective review of all native kidney biopsies conducted in patients with type 2 diabetes at our institute to identify the prevalence and factors that predict NDKD. The demographic data, clinical data, laboratory parameters, and histological results of the patients were obtained from their medical records. Binary logistic regression analysis was performed to evaluate the predictive factors for NDKD. Patients were categorized into 3 groups-DKD alone (presence of Kimmelstiel-Wilson nodules, capsular drops, fibrin caps and absence of any other NDKD features), NDKD along (presence of vasculopathy, interstitial fibrosis and specific glomerular changes in absence of classical DKD changes) and lastly DKD+NDKD (presence of histological changes of both DKD+NDKD). Results We analyzed a total of 69 patients. The mean (SD) age of the cohort was 51.94 ± 12.7 years and males constituted the majority (68%). Around 2/3rd of the entire cohort had hypertension, with no significant differences among the groups. Mean 24-hour urinary proteinuria was 6.6 ± 4.9 g/TV and 15.9% patients had microscopic hematuria. The mean (SD) duration of diabetes was 6.9 ± 6.2 years. Patients with pure DKD, pure NDKD and NDKD superimposed on DKD constituted 46.3%, 33.3% and 20% respectively of the cohort. The most common indication for renal biopsy in our cohort was rapid GFR decline in 38 patients (54.2%), followed by massive proteinuria in 27 (38.5%) and lastly positive serological work up for multiple myeloma in 5 patients (7.1%). Around 2/3rd of pure DKD patients in our cohort had diabetic retinopathy (DR), whereas only around 1/5th (26%) of pure NDKD patients had DR (p=0.005). DR was absent in around 74% of our diabetic patients who had pure NDKD. Non diabetic kidney disease in our cohort was seen in 46.3% patients and combined with DKD in 20% of patients. Among patients with NDKD, the most common cause was membranous glomerulonephritis (MGN) (43.4%) followed by acute tubulointerstitial nephritis (ATIN) (17.3%). Among combined DKD and NDKD, most common histological diagnosis was MGN (32.4%) followed by ATIN (16.2%). Independent factors predicting NDKD were shorter duration of diabetes (OR 0.74, CI 0.59–0.94, P=0.01) and absence of diabetic retinopathy (OR 0.15, 95% CI 0.09–0.26, P = 0.01). Conclusion Judicious use of kidney biopsy revealed NDKD in nearly half of T2DM patients especially in those with short duration of diabetes and absence of diabetic retinopathy (DR). Kidney biopsy is strongly recommended for T2DM patients with atypical presentation and in absence of DR.

Functional Characterization of an Ammonia Transporter RhBG Mutation Identified in Diabetic Kidney Disease Patients

Metabolic acidosis is a major complication of CKD (chronic kidney disease) and DKD (diabetic kidney disease). The kidney responds to metabolic acidosis by eliminating acid, primarily by producing and excreting NH4+ in the urine. Two Rh glycoproteins, RhBG and RhCG, expressed in the collecting duct are directly involved in NH3/NH4+transport. We previously determined that RhBG transports both NH4+ and NH3 across the basolateral membrane of intercalated cells. Impaired NH3/NH4+ production and/or transport may be a factor in increasing acid load and worsening kidney disease. In type 2 diabetes, net endogenous acid production is significantly elevated, and the proportion of acid excreted as NH4+ is decreased even after accounting for diet and renal function. This is significant given that the association between acidosis and faster decline in GFR is now well established. In DKD, impaired NH4+ excretion as a potential risk factor for progression of kidney disease remains poorly understood. Specifically, the genetic risk factors contributing to DKD are unclear. Hypothesis: Defined RhBG variant(s) linked to DKD cause impaired NH3/NH4+ transport that may contribute to DKD development and progression. Methods: We conducted whole-exome sequencing (WES) analysis using data from A therosclerosis R isk i n C ommunities (ARIC) study and the C hronic R enal I nsuffciency C ohort (CRIC) study. We selected DKD patients with the most rapid GFR decline and compared them with: 1) subjects without kidney disease (healthy control); 2) diabetic patients without CKD (DM control); 3) CKD patients without diabetes (CKD control). This approach will identify single nucleotide variants (SNVs) of RhBG associated with DKD. This will also determine if the detected variants contribute to the development of kidney disease per se and whether they contribute to the development of diabetes and/or fast GFR decline. To study function, we expressed RhBG variants (and wild-type RhBG) in Xenopus oocytes by microinjecting oocytes with the respective mRNA. The effect of defined SNV of RhBG on NH3/NH4+ transport was assessed from measurements of changes in intracellular pH (pHi), membrane potential (Vm), whole cell currents (I) or surface pH (pHs) induced by exposing the oocytes to bath solutions containing NH4Cl or methyl ammonium chloride (MA/MA+). Results: We identified an SNV, rs3748569 (minor allele frequency MAF &gt; 0.05), that was significantly associated with DKD. Significance was determined compared to DM control (OR=1.38, p=0.0026) and healthy control (OR=1.26, p=0.01). This variant has also been predicted to be deleterious by 4 bioinformatic tools. Our electrophysiological measurements showed that the resultant amino acid switch, G315R, completely inhibited transport of NH3 and NH4+ (p&lt;0.001) and the transport of MA and MA+ (p&lt;0.0001), compared with RhBG-WT. Conclusions: WES results suggest that this naturally occurring RhBG mutation, G315R, contributes to DKD occurrence. This effect is through the development of kidney disease and less likely due to development of diabetes. It is therefore likely a general CKD risk factor. Inhibition of NH3/NH4+ transport by this mutation is a contributing factor to its deleterious effect. This work provides experimental validation of computational predictions concerning CKD and diabetes. NIH-U54 GM104940, Paul Teschan Research, NIH-R01, Carol Lavin Bernick, Tulane institutional. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.