Risk Of Kidney Failure Research Articles

Comparative Effectiveness of Rituximab- Versus Cyclophosphamide-Based Remission Induction Strategies in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis for the Risk of Kidney Failure and Mortality.

To compare rituximab- versus cyclophosphamide-based remission induction strategies for the long-term risks of kidney failure and death in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in a real-world cohort. We performed a cohort study using the Mass General Brigham AAV Cohort, which includes proteinase 3-ANCA+ and myeloperoxidase (MPO)-ANCA+ AAV patients diagnosed from January 1, 2002 to December 31, 2019. We included cases in which the initial remission induction strategy was based either on rituximab or cyclophosphamide. The primary outcome was the composite outcome of kidney failure or death. We used multivariable Cox proportional hazards models and propensity score-matched analyses to assess the association of rituximab- versus cyclophosphamide-based treatment strategies with the composite outcome of kidney failure or death. Of 595 included patients, 352 patients (~60%) received rituximab-based and 243 patients (~40%) received cyclophosphamide-based regimens. The mean age was 61 years, 58% of patients were female, 70% of patients were MPO-ANCA+, and 69% of patients had renal involvement (median estimated glomerular filtration rate 37.3 ml/minute/1.73 m2 ). There were 133 events at 5 years, and the incidence rates in rituximab- and cyclophosphamide-based regimens were 6.8 and 6.1 per 100 person-years, respectively. The risk of kidney failure or death was similar in both groups in multivariable-adjusted analyses (hazard ratio [HR] 1.03 [95% confidence interval (95% CI) 0.55-1.93]) and in propensity score-matched analyses (HR 1.05 [95% CI 0.55-1.99]) at 5 years. Our findings were similar when outcomes were assessed at 1 and 2 years as well as in subgroups stratified according to renal involvement and severity as well as major organ involvement. Rituximab- and cyclophosphamide-based remission induction strategies for AAV are associated with similar risks of kidney failure and death.

Trends in the Incidence of End-Stage Kidney Disease in Type 1 and Type 2 Diabetes in Australia, 2010-2019

Trends in end-stage kidney disease (ESKD) among people with diabetes may inform clinical management and public health strategies. We estimated trends inthe incidence of ESKD among people with type 1 and type 2 diabetes in Australia from 2010-2019 and evaluated their associated factors. Cohort study. 71,700 people with type 1 and 1,112,690 people with type 2 diabetes registered on the Australian National Diabetes Services Scheme (NDSS). We estimated the incidence of kidney replacement therapy (KRT) via linkage to the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) and the incidence of KRT or death from ESKD by linking the NDSS to the ANZDATA and the National Death Index for Australia. Calendar time, sex, age, and duration of diabetes. Incidence of KRT and KRT or death from ESKD. Incidence of ESKD, trendsover time, and associations with factors related to these trends were modeled using Poisson regression stratified by diabetes type and sex. The median duration of diabetes increased from 15.3 to 16.8 years in type 1 diabetes, and from 7.6 to 10.2 years in type 2 diabetes between 2010 and 2019. The incidence of KRT and KRT or death from ESKD did not significantly change over this time interval among people with type 1 diabetes. Conversely, the age-adjusted incidence of KRT and KRT or death from ESKD increased among males with type 2 diabetes (annual percent changes [APCs]: 2.52% [95% CI, 1.54 to -3.52] and 1.27% [95% CI, 0.53 2.03], respectively), with no significant change among females (0.67% [95% CI,-0.68 to 2.04] and 0.07% [95% CI,-0.81 to 0.96], respectively). After further adjustment for duration of diabetes, the incidence of ESKD fell between 2010 and 2019, with APCs of-0.09% (95% CI,-1.06 to 0.89) and-2.63% (95% CI,-3.96 to-1.27) for KRT and-0.97% (95% CI,-1.71 to-0.23) and-2.75% (95% CI,-3.62 to-1.87) for KRT or death from ESKD among males and females, respectively. NDSS only captures 80%-90% of people with diabetes; lack of clinical covariates limits understanding of trends. While the age-adjusted incidence of ESKD increased for males and was stable for females over the last decade, after adjusting for increases in duration of diabetes the risk of developing ESKD has decreased for both males and females. Previous studies showed an increase in new cases of kidney failure among people with type 2 diabetes, but more recent data have not been available. Here, we report trends in the rate of kidney failure for people with type 2 diabetes from 2010 to 2019 and showed that while more people with type 2 diabetes are developing kidney failure, accounting for the fact that they are also surviving longer (and therefore have a higher chance of kidney failure) the growth in this population is not caused by a higher risk of kidney failure. Nevertheless, more people are getting kidney failure than before, which will impact health care systems for years to come.

Combining robust urine biomarkers to assess chronic kidney disease progression.

Urinary biomarkers may improve the prediction of chronic kidney disease (CKD) progression. Yet, data reporting the applicability of most commercial biomarker assays to the detection of their target analyte in urine together with an evaluation of their predictive performance are scarce. 30 commercial assays (ELISA) were tested for their ability to quantify the target analyte in urine using strict (FDA-approved) validation criteria. In an exploratory analysis, LASSO (Least Absolute Shrinkage and Selection Operator) logistic regression analysis was used to identify potentially complementary biomarkers predicting fast CKD progression, determined as the 51CrEDTA clearance-based measured glomerular filtration rate (mGFR) decline (>10% per year) in a subsample of 229 CKD patients (mean age, 61 years; 66% men; baseline mGFR, 38mL/min) from the NephroTest prospective cohort. Among the 30 assays, directed against 24 candidate biomarkers, encompassing different pathophysiological mechanisms of CKD progression, 16 assays fulfilled the FDA-approved criteria. LASSO logistic regressions identified a combination of five biomarkers including CCL2, EGF, KIM1, NGAL, and TGF-α that improved the prediction of fast mGFR decline compared to the kidney failure risk equation variables alone: age, gender, mGFR, and albuminuria. Mean area under the curves (AUC) estimated from 100 re-samples was higher in the model with than without these biomarkers, 0.722 (95% confidence interval 0.652-0.795) vs. 0.682 (0.614-0.748), respectively. Fully-adjusted odds-ratios (95% confidence interval) for fast progression were 1.87 (1.22, 2.98), 1.86 (1.23, 2.89), 0.43 (0.25, 0.70), 1.10 (0.71, 1.83), 0.55 (0.33, 0.89), and 2.99 (1.89, 5.01) for albumin, CCL2, EGF, KIM1, NGAL, and TGF-α, respectively. This study provides a rigorous validation of multiple assays for relevant urinary biomarkers of CKD progression which combination may improve the prediction of CKD progression. This work was supported by Institut National de la Santé et de la Recherche Médicale, Université de Paris, Assistance Publique Hôpitaux de Paris, Agence Nationale de la Recherche, MSDAVENIR, Pharma Research and Early Development Roche Laboratories (Basel, Switzerland), and Institut Roche de Recherche et Médecine Translationnelle (Paris, France).

A Predictive Model for Kidney Failure After Nephrectomy for Localized Kidney Cancer: The Kidney Cancer Risk Equation

Nephrectomy is the mainstay of treatment for individuals with localized kidney cancer. However, surgery can potentially result in the loss of kidney function or in kidney failure requiring dialysis/kidney transplantation. There are currently no clinical tools available to preoperatively identify which patients are at risk of kidney failure over the long term. Our study developed and validated a prediction equation for kidney failure after nephrectomy for localized kidney cancer. Population-level cohort study. Adults (n=1,026) from Manitoba, Canada, with non-metastatic kidney cancer diagnosed between January 1, 2004, and December 31, 2016, who were treated with either a partial or radical nephrectomy and had at least 1 estimated glomerular filtration rate (eGFR) measurement before and after nephrectomy. A validation cohort included individuals in Ontario (n=12,043) with a diagnosis of localized kidney cancer between October 1, 2008, and September 30, 2018, who received a partial or radical nephrectomy and had at least 1 eGFR measurement before and after surgery. Age, sex, eGFR, urinary albumin-creatinine ratio, history of diabetes mellitus, and nephrectomy type (partial/radical). The primary outcome was a composite of dialysis, transplantation, or an eGFR<15mL/min/1.73m2 during the follow-up period. Cox proportional hazards regression models evaluated for accuracy using area under the receiver operating characteristic curve (AUC), Brier scores, calibration plots, and continuous net reclassification improvement. We also implemented decision curve analysis. Models developed in the Manitoba cohort were validated in the Ontario cohort. In the development cohort, 10.3% reached kidney failure after nephrectomy. The final model resulted in a 5-year area under thecurve of 0.85 (95% CI, 0.78-0.92) in the development cohort and 0.86 (95% CI, 0.84-0.88) in the validation cohort. Further external validation needed in diverse cohorts. Our externally validated model can be easily applied in clinical practice to inform preoperative discussions about kidney failure risk in patients facing surgical options for localized kidney cancer. Patients with localized kidney cancer often experience a lot of worry about whether their kidney function will remain stable or will decline if they choose to undergo surgery for treatment. To help patients make an informed treatment decision, we developed a simple equation that incorporates 6 easily accessible pieces of patient information to predict the risk of reaching kidney failure 5 years after kidney cancer surgery. We expect that this tool has the potential to inform patient-centered discussions tailored around individualized risk, helping ensure that patients receive the most appropriate risk-based care.

Kidney and urological involvement in Down syndrome: frequent,underestimated, but associated with impaired quality of life and risk of kidney failure.

Patients with Down syndrome (DS) are at risk of multiorgan dysfunction; kidney and urological impairment are common. This is due to a likely increased risk of congenital kidney and urological malformations (odds ratio of 4.5 compared to the general population in one study), more frequent associated comorbidities at risk of kidney dysfunction (such as prematurity in 9-24% of children, intrauterine growth retardation or low birth weight in 20%, and congenital heart disease in 44%), and more frequent lower urinary tract dysfunction (reported in 27-77% of children with DS). If present, malformations and comorbidities at risk of kidney dysfunction warrant regular kidney monitoring in addition to their treatment. Serum creatinine in children with DS has been shown to be higher than in the general population and asymptomatic hyperuricemia is reported in 12-33% of children or young adults with DS. Moreover cryptorchidism and testicular cancer are also more common and should be detected by clinical examination. Thus, persons with DS at risk of presenting kidney and urological impairment should be identified by prenatal ultrasonography, comorbidities at risk of kidney sequelae considered, and during regular medical follow-up, clinically examined and questioned to diagnose testicular anomalies and lower urinary tract dysfunction. This is of importance as such kidney and urological impairments are associated with impaired quality of life and mental health, and risk of kidney failure.

Prevalence of Sodium Glucose Cotransporter 2 (SGLT-2) Inhibitor Prescribing in Patients with Type 2 Diabetes Mellitus and Reduced Estimated Glomerular Filtration Rate.

Sodium glucose cotransporter 2 (SGLT-2) inhibitors have demonstrated benefit in people with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD), including slowing the progression of CKD and lowering the risk of kidney failure and death. Despite this evidence, literature suggests SGLT-2 inhibitors are underutilized in this population. To assess prescribing practices and identify potential variables predictive of SGLT-2 inhibitor prescribing, a non-interventional, retrospective, cross-sectional study was conducted in patients with T2DM and reduced estimated glomerular filtration rate (eGFR). The primary outcome compared prevalence of SGLT-2 inhibitor prescribing in patients with T2DM and eGFR of 30-44mL/min/1.73m2 to patients with T2DM and eGFR 45-59mL/min/1.73m2. The secondary outcome described possible predictors of prescribing SGLT-2 inhibitors in this population. Of the 9,387 patients identified with T2DM and reduced eGFR, an SGLT-2 inhibitor was prescribed to 324 (12.2%) patients with eGFR of 30-44mL/min/1.73m2 versus 799 (11.9%) patients with eGFR of 45-59mL/min/1.73m2. Patients more likely to be prescribed SGLT-2 inhibitors were younger, male, had a higher body mass index (BMI), a higher hemoglobin A1c (HbA1c), were on other antihyperglycemic medications, had concomitant cardiovascular disease, or had concomitant heart failure. This study found no significant difference in prevalence of SGLT-2 inhibitor prescribing between patients with T2DM and eGFR 30-44mL/min/1.73m2 versus eGFR 45-59mL/min/1.73m2 (p=0.70). Further exploration into the causes of low SGLT-2 inhibitor prescribing prevalence is warranted given the growing evidence supporting the use of these agents in patients with T2DM and reduced renal function.

Discrepancies between Cystatin C-Based and Creatinine-Based eGFR.

Recent guidance suggests clinicians increase use of cystatin C for the estimation of GFR. Discrepant levels of creatinine- versus cystatin C-based eGFR (eGFRcr versus eGFRcys) can occur and might signify inaccurate estimation of GFR using creatinine alone. This study sought to enhance the knowledge of the risk factors and clinical implications of having a large eGFR discrepancy. Participants in the Atherosclerosis Risk in Communities Study, a prospective cohort study of US adults, were followed over 25 years. eGFR discrepancy was measured at five clinical visits and defined as eGFRcys either 30% lower or higher than eGFRcr, the current clinical standard of care. The associations between eGFR discrepancies and kidney-related laboratory parameters were assessed using linear and logistic regression and long-term adverse outcomes, including kidney failure, AKI, heart failure, and death, using Cox proportional hazards models. Among 13,197 individuals (mean age 57 [SD 6] years, 56% women, 25% Black race), 7% had eGFRcys 30% lower than eGFRcr at visit 2 (1990-1992), and this proportion increased over time to 23% by visit 6 (2016-2017). By contrast, the percent with eGFRcys 30% higher than eGFRcr was relatively stable (3%-1%). Independent risk factors for having eGFRcys 30% lower than eGFRcr included older age, female sex, non-Black race, higher eGFRcr, higher body mass index, weight loss, and current smoking. Those with eGFRcys 30% lower than eGFRcr had more anemia and higher uric acid, fibroblast growth factor 23, and phosphate levels as well as higher risk of subsequent mortality, kidney failure, AKI, and heart failure compared with those with similar eGFRcr and eGFRcys values. Having eGFRcys lower than eGFRcr was associated with worse kidney-related laboratory derangements and a higher risk of adverse health outcomes. This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_09_08_CJN0000000000000217.mp3.

1460-P: Prevalence of Chronic Kidney Disease Associated with Type 1 Diabetes in the U.S.

Background: Chronic kidney disease (CKD) is associated with an increased risk of kidney failure, cardiovascular events, and mortality in patients with type 1 diabetes (T1D). However, the prevalence of CKD associated with T1D in the US is unclear. The aim of this study was to estimate the prevalence of CKD in people with T1D in the US using data collected in the National Health Examinations Survey (NHANES). Methods: People with T1D were identified from NHANES using an established algorithm (Mosslemi et al. Cardiovasc Endocrinol Metab. 2020). Adults aged ≥18 years with CKD in this group were identified by single measurements of estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m2 or urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g. The NHANES data were used to create corresponding weighted variables to represent the US Results: During 2015 to 2018, diabetes was identified in 1647 of 19,225 adults surveyed in NHANES. Among those with diabetes, CKD was present in 20 out of 47 people with T1D with evaluable eGFR and UACR, corresponding to an unweighted estimate of 43%. CKD status was uncertain in 7 patients with T1D as their eGFR and/or UACR measurements were not available (unweighted estimate). In the CKD and T1D group, 59% were male and 60% were non-Hispanic White (weighted characteristics). Mean eGFR (SD) was 57 (4) mL/min/1.73 m2 and median UACR (IQR) was 89 (8-875) mg/g (weighted characteristics). Since the weighted overall number of adult people with T1D in the US was estimated at 1,202,739 (95% CI: 681,820-1,723,657), the corresponding number with T1D and CKD with evaluable eGFR and UACR was 258,196 (95% CI: 71,189-445,203), corresponding to a weighted estimate of 21%. Conclusions: CKD was common in people with T1D and evaluable eGFR and UACR based on recent US data. Since the absolute number in NHANES was small, these prevalence estimates should be interpreted cautiously and validated in other cohorts. Disclosure P.Rossing: Other Relationship; Abbott Diagnostics, AstraZeneca, Bayer Inc., Boehringer Ingelheim Inc., Novo Nordisk, Merck KGaA, Gilead Sciences, Inc., Sanofi. P.Groop: Advisory Panel; Boehringer-Ingelheim, Bayer Inc., Speaker's Bureau; AstraZeneca, Boehringer-Ingelheim, Bayer Inc., Merck Sharp &amp; Dohme Corp., Medscape, Nestlé Health Science. R.Singh: None. R.Lawatscheck: Employee; Bayer Inc. K.R.Tuttle: Consultant; Lilly, AstraZeneca, Gilead Sciences, Inc., Research Support; Bayer Inc., Boehringer Ingelheim (Canada) Ltd., Novo Nordisk, Goldfinch Bio, Inc., Traveere Pharmaceuticals. Funding Bayer AG

#4519 CAN WE REPLACE URINE TESTING AND DELIVER A STEP CHANGE IN ACCESS TO RENOPROTECTIVE MEDICATIONS?

Abstract Background and Aims Albuminuria is a medical condition characterized by leakage of albumin into the urine due to kidney damage. The condition is diagnosed by heightened Albumin to Creatinine ratio in the urine (ACR) and is typically categorized into microalbuminuria (ACR ≥ 30, &amp;lt; 300 mg/g mg/g) and macroalbuminuria (ACR ≥ 300 mg/g). Currently, despite compelling data, only a minority of patients with diabetes, and rarely individuals without diabetes, are screened for albuminuria in a systematic way. ACR tests also present high intra-person variability, making it harder to identify meaningful biologic changes and increasing complexity of clinical trials. In this study we develop a method using machine learning to predict ACR level from Electronic Health Records, excluding urine tests, and validated the model for identifying patients with albuminuria. Identifying patients with undiagnosed albuminuria could help slow progression of kidney disease and be used to speed up recruitment to, and reduce screen failures in, clinical trials. Method We developed a Quantile Regression model for ACR using US Limited IBM MarketScan Explorys Claims-EMR Data Set (LCED). We included subjects who had an ACR test (0 &amp;lt; ACR ≤ 5000 mg/g) and was of at least 18 years of age. Patient demographics (age, sex), vital signs (BMI, Blood Pressure) and 8 common blood tests (Albumin, Bilirubin, Creatinine, HbA1C, Triglyceride, Glucose, White Blood Cell count &amp; ALT) were used as covariates. A tree based gradient boosting framework (LightGBM) was used to train the quantile regression models, viz., the 25-, 50-, and 75-percentiles of ACR conditioned on the covariates. The model was then validated on all qualified subjects in Optum's de-identified Clinformatics® Data Mart Database (2007-2021). We evaluated performance using the metrics Area Under the Curve (AUC), precision (PPV), specificity (TNR), and sensitivity (TPR). Finally, we use Kaplan-Meier estimates to compare the risk of progression to kidney failure as identified by ICD codes (Chronic kidney disease, stage 5; End stage renal disease; Dependence on renal dialysis; Unspecified kidney failure; Kidney transplant) of both the predicted and measured ACR values. Results A final cohort of 63,459 individuals matched the inclusion and exclusion criteria in LCED and 5,857,385 individuals in Optum. Using the 25% quantile to predict patients at risk, the model consistently reaches a PPV greater than 0.8 and a specificity (TNR) greater than 0.99 (Table 1). The risk of progression to kidney failure increases with both increased predicted and measured ACR (Figure 1). Conclusion The results show that the models have discriminative power in all datasets. It predicts both micro- and macro-albuminuria with a PPV above 80% for the 25-quartile. However, classification performance is lacking in sensitivity, i.e., subjects suffering from albuminuria may not be classified as such. By using the median prediction of ACR we identify patient subpopulations that have a risk of kidney failure at least on par with the true ACR subpopulation targeted. This means that the method can be used confidently to identify at-risk individuals. Therefore, our model is advantageous in applications such as identifying undiagnosed albuminuria and pre-screening for clinical trials, where high PPV is more important than sensitivity. We intend to validate the model further for outcomes prediction in an upcoming CKD trial.

#4706 THERAPEUTIC AND PROGNOSTIC IMPACT OF KIDNEY BIOPSY FINDINGS IN PATIENTS AGED 80 YEARS AND OLDER: A MULTICENTER RETROSPECTIVE COHORT STUDY (KB-OLD)

Abstract Background and Aims The great phenotypic heterogeneity in the presentation of kidney diseases makes the diagnostic strategy all the more complex in the elderly. While kidney biopsy should play a pivotal role, its non-negligible risk of bleeding complications (2-5% in the general population) justifies a certain reluctance to its application in the elderly. To date, however, there is little data on the benefit-risk ratio of kidney biopsy in the elderly. Most of these studies have focused on a relatively young population (60-70 years old) and on a limited number of patients. Concerning patients aged 80 years and older, very few studies have described the real therapeutic influence of kidney biopsy findings with regard to the rate of complications. Moreover, none of these studies have evaluated the long-term prognostic impact of therapeutic changes induced by the results of the kidney biopsy. The main objectives of this study are to describe the indications, diagnoses, complication rate, therapeutic influence and the prognostic impact of a change in therapeutic management after native kidney biopsies performed in patients aged 80 years and older. Method The KB-Old study (Kidney Biopsy for Old) is a retrospective multicenter cohort that consecutively included all patients aged 80 years and older who underwent percutaneous native kidney biopsy in 17 centers in the northern region of France, between 2010 and 2020. Clinical, biological and anatomopathological data as well as post-biopsy follow-up (therapeutic strategy, occurrence of complications) were collected from medical records. All pathology examinations were analyzed centrally by a team of experienced nephropathologists. Events of death or kidney failure were identified by specific registry cross-linking. To analyze the prognostic impact of therapeutic management following kidney biopsy (either initiation of a specific treatment or simple nephroprotection) on the risk of kidney failure and death, we performed Cox models weighted by propensity score (Inverse Probability of Treatment Weighting -IPTW-) in the population potentially eligible for treatment (exclusion of diseases without specific treatment). The areas under Kaplan Meier curves were calculated up to 6 years of follow-up (Restricted Mean Survival Time - RMST) and compared according to the initiation of a specific treatment after the kidney biopsy. This study was approved by Institutional Review Board (#AUG-20-707). Results Overall, the cohort included 453 patients (54% men, median age 83 years), half of whom underwent biopsy in the context of acute kidney injury (median serum creatinine level 3.0 mg/dl). The main diagnoses were nephroangiosclerosis (15%), renal involvement of hematological malignancies (13%), acute tubulointerstitial nephritis (12%) and vasculitis (10%). The complication rate was approximately 10%, with only 2.8% of serious complications requiring therapeutic intervention (mostly transfusion). The kidney biopsy identified a disease potentially accessible to a specific treatment in 73% of cases. After exclusion of patients with ineligible diseases, a specific treatment was initiated in about one out of two cases (163/332, 49%). After weighting on propensity score, the two treatment groups were globally balanced. A beneficial effect of treatment on dialysis-free survival was observed (HR = 0.51 [0.28-0.92], p = 0.02), without any major influence on mortality (Figure 1). Over a 6-year follow-up period, there was a gain in dialysis-free survival in the treated group estimated by the delta RMST at +10.46 months [3.39 - 17.54] compared with the untreated group (p = 0.004), with no difference in overall life expectancy. Conclusion To the best of our knowledge, this is the largest multicenter cohort of patients aged 80 years and over who have undergone kidney biopsy. It seems to confirm the interest and safety of this examination for specific indications, and a potentially important benefit on the prognosis when it leads to an adapted therapeutic management.

#3875 ASSESSING THE 3-YEAR RISK OF 40% EGFR DECLINE OR KIDNEY FAILURE IN THE US POPULATION

Abstract Background and Aims Prognostication of CKD progression currently relies exclusively on eGFR and albuminuria and do not consider comorbid conditions. Recently, the Chronic Kidney Disease Prognosis Consortium (CKD-PC) equation was developed to predict the 3-year risk of 40% eGFR decline or kidney failure in the general population [1]. The goal of our study was to assess the distribution of this risk in the US population. Method We included US adults from the 1999-2020 United States National Health and Nutrition Examination Survey (NHANES; N = 51,699). We calculated eGFR using the CKD-EPI 2021 equation and the 3-year risk of 40% eGFR decline or kidney failure using the CKD-PC equation (3-year risk). We categorized the 3-year risk as &amp;lt;1%, 1%-&amp;lt;5%, 5%-&amp;lt;10%, ≥10% and compared this with the current KDIGO 2012 CKD staging (eGFR&amp;lt;60 mL/min/1.73 m2 or albuminuria≥30 mg/g). Results Among 199.8 million US adults, mean age was 46±15 years, 51% were female, 11% were non-Hispanic Black persons, and mean BMI was 29±6 kg/m2. 71 million (36%) had hypertension and 26 million (13%) had diabetes. Table 1 shows the distribution of 3-year risk across stages of eGFR and albuminuria. Among 26 million US adults with CKD, the 3-year risks were &amp;lt;1% in 4 million (15%), 1% to &amp;lt;5% in 15 million (56%), 5 to &amp;lt;10% in 4 million (17%), and ≥10% in 3 million (11%). Importantly, among persons without CKD by current criteria, 1 million persons (0.58%) had a ≥5% 3-year risk, whereas only 331,840 (6%) persons with CKD 3a A1 had a ≥5% 3-year risk of CKD progression or kidney failure. Conclusion Calculating the 3-year risk of a 40% decline in eGFR or kidney failure can identify at-risk persons beyond the current eGFR and albuminuria staging. Our findings highlight the importance of factors besides eGFR and albuminuria in considering the risk for CKD progression.

#3382 REASONS FOR DIALYSIS INITIATION AND SAFETY OF DAPAGLIFLOZIN AMONG DIALYSIS PARTICIPANTS: NEW INSIGHTS FROM DAPA-CKD

Abstract Background and Aims The DAPA-CKD trial demonstrated that dapagliflozin reduced the risk of kidney failure in patients with chronic kidney disease (CKD) with or without type 2 diabetes. In contrast to most other trials, participants who reached dialysis were allowed to continue study medication with dapagliflozin or placebo. In this pre-specified analysis of the DAPA-CKD trial, we assessed reasons for dialysis initiation and serious adverse events (SAEs) among participants who initiated dialysis and continued the study medication. Method The DAPA-CKD trial randomized 4304 patients with CKD (estimated glomerular filtration rate [eGFR] 25−75 mL/min/1.73m2) and albuminuria (urinary albumin-to-creatinine ratio 200−5000 mg/g) to dapagliflozin 10 mg daily or placebo in addition to standard of care. Chronic dialysis was defined as the need for dialysis for at least 28 days. Investigator reported reasons for dialysis and SAEs were summarized by treatment groups. Results During median 2.4 years follow-up, 68/2152 (3.2%) and 99/2152 (4.6%) participants in the dapaglifozin and placebo groups respectively required chronic dialysis. Reasons for dialysis initiation are shown in the Table below, with volume overload being the most frequently reported. Roughly one-third of patients in both groups had discontinued study drug in advance of dialysis initiation; in the dapagliflozin and placebo groups, 25/68 (37%) and 41/99 (41%) continued the blinded study medication while receiving chronic dialysis. Among these, SAEs were reported in 8/25 (32%) and 11/41 (27%), respectively. Conclusion Participants who continued dapagliflozin or placebo after dialysis initiation experienced similar rates of SAEs. To determine whether dapagliflozin provides cardiovascular or other benefits to patients with kidney failure on chronic dialysis, will require a dedicated prospective trial. Based on our prespecified exploratory analysis, we observed no safety concerns that might discourage the conduct of such a trial. Funding This study was funded by AstraZeneca

#4499 MATCHING-ADJUSTED INDIRECT COMPARISON OF SPARSENTAN VS DELAYED-RELEASE FORMULATION BUDESONIDE FOR PROTEINURIA REDUCTION IN ADULTS WITH IGA NEPHROPATHY

Abstract Background and Aims Immunoglobulin A (IgA) nephropathy is a rare kidney disorder characterized by deposition of IgA in the glomeruli and associated with a reduction in renal function and increased risk of kidney failure [1,2]. In the absence of head-to-head trials, this study used matching-adjusted indirect comparison (MAIC)[3] of randomized control trial data to compare 9-month efficacy outcomes between potential treatment options for IgA nephropathy, sparsentan and recently FDA and EMA approved delayed-release formulation budesonide [4,5]. Method An unanchored MAIC was conducted using individual patient level data from the PROTECT trial for sparsentan and aggregate data from the NefIgArd trial for delayed-release formulation budesonide. Patients in the sparsentan arm of PROTECT were weighted to match the key baseline characteristics of patients in the budesonide delayed-release formulation arm of NefIgArd. After matching, the percentage reduction of urine protein-creatinine ratio (UPCR) at Month 9 relative to baseline were compared between sparsentan and delayed-release formulation budesonide. A two-tailed z-test was performed to estimate the p-value. Results Assessment of cross-trial heterogeneities suggested that PROTECT and NefIgArd trials were sufficiently similar in terms of patient population, key inclusion and exclusion criteria, and outcome definitions; however, due to differences in control arms (renin-angiotensin system blocker [RASB] optimization), an unanchored MAIC (comparing treatment arms directly) was selected. After matching, all matched baseline patient characteristics were well-balanced between corresponding treatment arms of the two trials. The comparative results showed that patients treated with sparsentan achieved a greater mean percentage reduction in UPCR at 9 months from baseline compared to budesonide-treated patients (p-value withheld pending FDA approval of sparsentan due to regulatory requirements). Conclusion The MAIC results showed that sparsentan was associated with a significantly larger percentage reduction in UPCR, a recognized surrogate of long-term kidney outcomes, from baseline to month 9 compared with delayed-release formulation budesonide.

#3271 EXPRESSION OF THE COLLAGEN IV α345 MOLECULE ALONG THE RENAL TUBULE IN HEALTH AND DISEASE

Abstract Background and Aims Patients suffering from Alport Syndrome (AS) have a high life time risk of kidney failure and hearing loss. The underlying molecular cause is a germline mutation in one of the COL4A3/4/5 genes, whose gene products collectively form an important component of the glomerular basement membrane and the inner ear. Recent genetic studies have shown that the AS is much more prevalent than clinically recognized, suggesting that atypical clinical cases are frequent. Thus, patients with AS may phenocopy other kidney diseases. To date, pathomechanistic studies of the AS have focused exclusively on the glomerular membrane, yet equally strong expression of collagen IV can be found along the distal renal tubule. Structural disintegration of the distal tubular membrane may induce inflammation and fibrosis, thus progression of kidney disease. We hypothesize that genetic loss of the tubular collagen IV molecule contributes to kidney failure and may drive atypical phenotypes. Method Immunohistochemistry (IHC) and in situ hybridization (ISH, RNAscope) for COL IV α5, where IHC was performed on healthy human tissues as well as biopsies from patients with AS. Tubular marker staining for localization of COL IV α5 expression as well as spatial changes on consecutive sections. Human urinary primary tubular cells (huPTC) from healthy probands and patients with AS were generated and cultivated in cell culture, with analysis of COL IV mRNA by qPCR and detection of specifically expressed proteins by immunoblotting. Results COL IV α5 was detected within the tubular basement membrane (TBM) of the distal segments of renal tubules by IHC, including the thick ascending limb (TAL) of Henle (Tamm-Horsfall Protein), the distal convoluted tubule (11ß-Hydroxysteroid-Dehydrogenase) and the collecting duct (aquaporin 2). Spacial vicinity of these areas showed a predominance of interstitial fibrosis and inflammation in patient samples with AS, but not control samples with primary proteinuric diseases. Collagen IV protein is lost along the TBM of patients with AS, even in the hemizygous male and heterozygous female carriers of the hypomorphic but frequent COL4A5 mutation G624D. By ISH, COL4A5 expression was mainly observed in the glomerulus (most likely podocytes) and broadly in tubular epithelial cells, with only few tubulointerstitial cells showing mRNA expression. Likewise, the huPTC showed COL IV expression in qPCR, as well as COL IV α5 protein in immunoblotting. Conclusion Our studies show that the COL IV molecule is situated within the TBM of the complete distal tubule, starting from the TAL throughout the distant collecting duct. Although the epithelial cells have no detectable protein, in situ hybridization and primary cell cultures clearly suggest that tubular cells are a major source of the COL IV α345 molecule within the TBM. Renal biopsies of AS patients with diagnostic genetic COL IV variants indicate that tubulointerstitial fibrosis and inflammation starts in the vicinity of the distal tubule. Therefore, we postulate that the pathogenesis of AS may in part stem from the (distal) tubular apparatus, which is already known from other diseases such as ADTKD and nephronophthisis.

#4049 NEFECON® TREATMENT LIKELY MODULATES DOWNSTREAM PATHWAYS OF KIDNEY INFLAMMATION AND FIBROSIS IN IGA NEPHROPATHY

Abstract Background and Aims The lifetime risk of kidney failure in patients with IgA nephropathy (IgAN) is substantial. Since the original description of the disease, over 50 years ago, there has been little progress in how we manage this important cause of kidney failure in young adults. KDIGO 2021 Clinical Practice Guidelines recommend goal-directed supportive care as the treatment with the strongest evidence base for the management of all patients with IgAN. The NEFIGAN trial (NCT01738035) tested the safety and efficacy of a novel targeted-release formulation of budesonide (Nefecon®), designed to deliver budesonide to the gut-associated lymphoid tissue-rich distal ileum in patients with IgAN in addition to optimised supportive care. The trial comprised a 6-month run-in, 9-month treatment, and a 3-month follow-up phase. Forty-eight patients received Nefecon® 16 mg/day, 51 patients received Nefecon® 8 mg/day, and 50 patients received placebo. The headline result of the study was that Nefecon® 16 mg/day, added to optimised RAS blockade, reduced proteinuria and stabilised eGFR in patients with IgAN. These findings have now been replicated in the NefIgArd study, which reported in 2021 and provided the basis for the recent FDA and EMA approval of Nefecon® as a treatment for patients with IgAN at high risk of progressive disease. In this study, we determined the composition of urinary proteins from patients treated with placebo and 16 mg of Nefecon® in the NEFIGAN trial using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Method Urine samples from 18 patients from each of the placebo and 16-mg arms of the NEFIGAN trial collected at the start of treatment (SOT) and end of treatment (EOT) were analysed. Patients were only included if they had received at least 8 months of treatment and their urine sample was taken up to 2 days after the completion of tapering. Urine samples were treated to remove abundant albumin and immunoglobulins. The remaining proteins were desalted and then precipitated with 5% trichloroacetic acid and washed twice with ice-cold acetone. The air-dried pellets were dissolved in 45 µL of 100 mM triethylammonium bicarbonate buffer, reduced with 2 mM TCEP (tris(2-carboxyethyl)phosphine), and alkylated with 15 mM chloroacetamide. 500 ng of Sequencing Grade Trypsin was added for enzymatic digestion, carried out overnight at 37°C. The samples were dried to completeness and re-solubilised in 10 µL of MS sample buffer (3% acetonitrile, 0.1% formic acid). LC-MS/MS analysis was performed on an Q Exactive mass spectrometer equipped with a Digital PicoView source and coupled to a nanoAcquity UPLC. For protein identification and quantification, raw data were processed with FragPipe (V16) having at least two peptides per protein. Protein intensities were reported in the combined_protein.txt file generated by the FragPipe: These were Log_2-transformed and internally normalised against a group of peptides found in all samples, The normalised protein abundance at SOT was subtracted from the abundance at EOT for each patient, A probabilistic dropout model was fitted to the data to estimate fold changes between the treatment and placebo groups at EOT, The proteins were ranked using the t-statistic and a gene-set enrichment analysis was performed to determine the gene sets significantly affected by the treatment compared with the placebo group. Results Gene-ontology analysis revealed that treatment with 16 mg of Nefecon® led to a significant enrichment of multiple pathways (n = 57) involved in several processes previously shown to be important in the pathogenesis of kidney injury in IgAN. These included epigenetic pathways (n = 13), microvesicle formation (n = 3), kidney remodelling (n = 9), and regulation of local immune and inflammatory responses (n = 32). Conclusion We have previously shown that 16 mg of Nefecon® for 9 months positively impacts on multiple biomarkers of IgAN severity. These urine proteomic data support the positive impact of Nefecon® on downstream pro-inflammatory and profibrotic pathways within the kidneys. These data will be validated in the biomarker analyses currently underway as part of the NefIgArd study.

#5127 COMBINED ACTIVITY AND CHRONICITY SCORE FOR PROGNOSTIC ASSESSMENT IN ANCA-ASSOCIATED VASCULITIS WITH GLOMERULONEPHRITIS

Abstract Background and Aims Previous studies have shown that chronic changes on kidney biopsy are useful for stratifying the risk of kidney failure in patients with AAV-GN. We aimed to evaluate the impact of inflammatory activity for the prediction of renal outcomes. Method A retrospective cohort study of MPO- or PR3-ANCA positive patients with AAV and active renal disease. Inflammatory activity was assessed by the Activity Index (AI): a ratio between the number of crescents and/or necrosis and the total number of glomeruli (in percent). We calculated the AI score: 0-5 = 0; 6-10 = 1; 11-15 = 2; 16-20 = 3; 21-25 = 4; 26-37.5 = 5; 37.6-50 = 6; 51-65 = 7; 66-80 = 8; 80-90 = 9; 90-100 = 10. Chronicity was evaluated with the Mayo Clinic Chronicity Score (MCCS). For the combined score, we summed the MCCS and the AI. Results Results. We analyzed 326 patients with kidney biopsies available to score. The biopsies had in median (IQR), 13 glomeruli (9-20), 4 crescents (2-6) and an AI of 28.6% (15.3-47.6). The population was classified according with the risk of progression to kidney failure (KF) in 3 classes as (i) low (0-6) – 114 (35.0%), (ii) intermediate (7-11) – 152 (46.6%), and (iii) high (≥12) – 60 (18.4%). Median eGFR at baseline correlated with the overall risk categories: 42.2 vs. 22.1 vs. 13.4 mL/min/1.73 m2, p&amp;lt;0.0001. The proportion of patients with eGFR&amp;lt; 30 mL/min/1.73 m2 was increased in patients classified as high: 88.3% vs. 66.4% vs. 36.0%, p&amp;lt;0.0001. Renal recovery was more frequent in patients at low risk of progression: 87.7% vs. 64.6% vs. 36.6%, p&amp;lt;0.0001, whereas kidney failure at 12 months and dialysis were more frequent in patients at higher risk (36.7% vs. 12.4% vs. 3.8%, p&amp;lt;0.0001; 35.6% vs. 13.0% vs. 2.9%, p&amp;lt;0.0001, respectively). The combination of AI with MCCS independently predicted the risk of KF at 12 months (HR 1.916, 95%CI 1.210 - 3.033, p = 0.006), particularly increased in patients classified as high risk (HR 3.124, 95%CI 1.224 – 7.970, p = 0.017) and in patients with PR3-ANCA (HR 1.896, 95%CI 1.012 - 3.551, p = 0.046) independently of eGFR at AAV-GN diagnosis and adjusted for severity of renal involvement and age. Conclusion The combined assessment of acute inflammatory activity and chronic changes on kidney histology independently predicted renal outcomes in patients with AAV-GN. The impact of the inflammatory activity is cumulative to the chronic changes.

#4503 ESTIMATING DELAY IN TIME TO KIDNEY FAILURE OR DEATH FOR TREATMENT EFFECTS ON PROTEINURIA IN IGA NEPHROPATHY

Abstract Background and Aims Reduction in proteinuria is associated with lower risk of kidney failure (KF) in IgA nephropathy (IgAN) (Thompson et al, 2019). In phase 3 randomized controlled trials in IgAN patients, a treatment effect on proteinuria reduction is typically evaluated as a mean percent change in proteinuria from baseline at 6-9 months. In this study, we aim to estimate the delay in time to KF or death associated with treatment effects of 40% and 50% reduction of proteinuria at this timepoint. Method In this study, we used individual patient level data from the UK National Registry of Rare Kidney Disease (RaDaR) IgAN cohort. Adult IgAN patients (n = 535) with a urine protein-creatinine ratio ≥100 mg/mmol (0.88 g/g) ≥6 months from diagnosis (time point defined as baseline) and eGFR ≥30 mL/min at baseline (study population mean = 61 ml/min/1.73 m2 [SD 26]) were included. Predicted risk of KF (eGFR &amp;lt;15 mL/min, initiation of dialysis, transplantation)/doubling serum creatinine/death associated with treatment effects reducing proteinuria by 40% and 50% at 9 months were calculated from IgAN trial level analysis data (Thompson et al, 2019). Accelerated failure time modelling was used to analyse time to KF/death during follow up in the RaDaR IgAN study population, and to estimate the effect that changes in hazard ratio had on median survival time and 5-year survival rates. Weibull, Log-Logistic and Log-Normal distributions were applied with the fitted survivor function reported from the model with the lowest AIC. Results Treatment effects reducing proteinuria by 40% and 50% in IgAN patients predict a 59% and 67% lower risk of KF/death, respectively. A 59% reduction in risk, is estimated to extend the median time to KF/death by 6.3 years, from 8.6 years (95% CI 7.8, 9.5) to 14.9 years (95% CI 13.6, 16.4), while the corresponding extension in median time to KF/death estimate for a 67% reduction in risk is 8.5 years (from 8.6 years [95% CI 7.8, 9.5] to 17.1 years [95% CI 15.6, 18.8]) (Figure 1). Five-year KF/death free survival rate increased from 75% to 89% and 91%, for 59% and 67% reduced risk in KF/death, respectively. Conclusion Therapeutic interventions that reduce proteinuria and the risk of KF can confer important and clinically meaningful extensions in the time patients are alive and free from KF.

#5227 KIDNEY FAILURE RISK EQUATION (KFRE) VS GRAMS SCORE, WHICH ONE PREDICTS BETTER THE INITIATION OF RENAL REPLACEMENT THERAPY?

Abstract Background and Aims In patients with Advanced Chronic Kidney Disease (ACKD) stage G4 it is necessary to use prognostic tools to predict the need for Kidney Replacement Therapy (KRT), especially in elderly patients, the most used is the Kidney Failure Risk Equation (KFRE). The Grams Score (GS) predicts the risk of KRT, cardiovascular events and mortality, providing better prediction for the choice of KRT modality but requires more parameters in its equation. Ours objective was compare both KFRE and GS prognostic equations to validate which one better predicts the onset of KRT. Method Descriptive, retrospective study of a cohort of patients older than 65 years with G4 CKD attending for the first time in 2016–2017. Follow-up for 5 years or first clinical event defined as need for KRT (including Conservative Renal Treatment with GFR = &amp;lt;8 ml/min/1.72m2) or death. Variables needed to calculate KFRE and GS were collected, as well as events occurred. Results 271 patients who met the inclusion criteria were analyzed. The clinical characteristics are shown in Table 1. The Grams model showed good discrimination for initiating KRT at 2 and 4 years, AUC 0.84 [95%CI 0.77-0.91] and AUC 0.81 [95%CI 0.75-0.87], respectively. The ROC curves presented by both equations showed good discrimination, AUC 0.82 [95%CI 0.74-0.91] and AUC 0.80 [95%CI 0.74-0.87].When comparing the need for 2-year KRT with both equations, we observed both ROC curves were similar (p = 0.356). Table 2 shows results from logistic regression analysis. For the 2-year KRT event by Grams, patients with a score &amp;gt; = 17.85% were 11.53 [95%CI 5.16-27.78] times more likely to initiate KRT. However, compared to KFRE with a score &amp;gt; = 20.77%, they had 17.53 [95%CI 7.59-40.47] times higher probability of KRT (both p&amp;lt;0.001). When we compared both equations in multivariate analysis only the KFRE was significant (ODR 0.217 (95%CI 0.87-0.54). Conclusion In our population, both prognostic equations showed good discrimination to program initiation of KRT. However, the GS could underestimate this need while the KFRE seems to discriminate it better.

#2654 USE OF SUPERVISED DEEP LEARNING ALGORITHM TO PREDICT RISK OF RENAL REPLACEMENT THERAPY(RRT) IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD)

Abstract Background and Aims Chronic kidney disease (CKD) is one of the most common causes of mortality, affecting around 10% adults worldwide [1]. Although statistical models for predicting risk of renal replacement therapy (RRT) have been developed for a decade [2], referral of patients with CKD to nephrology service is often based on clinical experience of primary care physicians. The use of deep learning algorithms (DLAs) allow clinicians to capture complex, multidimensional, non-linear relationships instead of relying on linear relationships between independent variables and outcome. Our study aims to develop a DLA that has at least non-inferior performance compared to the Kidney Failure Risk Equation (KFRE), which is a well-established and validated risk prediction tool [3]. Method This is a retrospective cohort study carried out in 3 major acute hospitals in Hong Kong providing a total of 3000 beds from Jan 1, 2009 to Mar 31, 2022. All patients aged &amp;gt; 18 with an estimated glomerular filtration rate (eGFR)&amp;lt;30ml/min/1.73 m2 according to the CKD-EPI formula, who attended follow-up for at least 3 months in nephrology clinic of the 3 hospitals, were recruited. Those who were on chronic RRT, received renal transplantation or had an eGFR&amp;lt;15 ml/min/1.73 m2 before referral were excluded. Supervised DLAs of different structures and their combinations were created and trained. Data in the test set were fed into models to predict the risk of requiring RRT in 2 years and 5 years. Predictive performance of these models were compared with that of KFRE [3]. Results 4992 patients were recruited in the study. Data of 499 patients were isolated as test set and were not used for model training. 1576 patients progressed to stage 5 CKD during their follow-up, and 989 patients required initiation of RRT during the study timeframe. When compared with KFRE (4-variable: ROC-AUC = 0.84, 95%CI:0.835-0.852; 8-variable: ROC-AUC = 0.84, 95%CI:0.830-0.847), almost all DLAs showed statistically significant superior robustness in predicting the risk of requiring RRT (Figure 1). No significant difference was found between performance of DLAs combining different neural network layers and those with single structures (CNN+LSTM+ANN layers ROC-AUC = 0.90, 95%CI:0.896-0.902; CNN ROC-AUC = 0.91, 95%CI:0.907-0.914) (Table 1). Conclusion The use of DLAs provided better prediction in the risk of requiring RRT when compared with KFRE.

#5522 USING THE KIDNEY FAILURE RISK EQUATION TO PREDICT END-STAGE KIDNEY DISEASE IN CKD PATIENTS OF SOUTH ASIAN ETHNICITY: AN EXTERNAL VALIDATION STUDY

Abstract Background and Aims The Kidney Failure Risk Equation (KFRE) predicts the 2- and 5-year risk of needing kidney replacement therapy (KRT) using four risk factors – age, sex, urine albumin-to-creatinine ratio (ACR), and creatinine-based estimated glomerular filtration rate (eGFR). Although the KFRE has been recalibrated in a UK cohort, this did not consider minority ethnic groups. Further validation of the KFRE in different ethnicities is a research priority. The KFRE also does not consider the competing risk of death, which may lead to overestimation of KRT risk. This study externally validates the KFRE for patients of South Asian ethnicity and compares methods for accounting for ethnicity and the competing event of death. Method Data were gathered from an established UK cohort containing 35,539 individuals diagnosed with chronic kidney disease. The KFRE was externally validated and updated in several ways taking into account ethnicity, using recognised methods for time-to-event data, including the competing risk of death. A clinical impact assessment compared the updated models through consideration of referrals made to secondary care. Results The external validation showed risk of KRT differed by ethnicity. Model validation performance improved when incorporating ethnicity and its interactions with ACR and eGFR as additional risk factors. Further, accounting for the competing risk of death improved prediction. Using a criteria of 5 year ≥5% predicted KRT risk, the competing risks model resulted in an extra 3 unnecessary referrals (0.59% increase) but identified an extra 1 KRT case (1.92% decrease) compared to the previous best model. A hybrid criteria of predicted risk using the competing risks model and the previous guidelines should be used in referrals to secondary care. Conclusion The accuracy of KFRE prediction improves when updated to consider South Asian ethnicity and to account for the competing risk of death. This may reduce referrals whilst identifying risks of KRT and could further individualise the KFRE and improve its clinical utility. Further research should consider other ethnicities.