Progressive Decline In Kidney Function Research Articles

NELL-1 Associated Membranous Nephropathy - A Case Series from India

Neural epidermal growth factor-like 1 (NELL-1) is responsible for a substantial proportion of cases of PLA2R-negative primary membranous nephropathy (MN). To investigate the occurrence, association, and treatment responses, we carried out this ambispective study. In the study, nine (10%) of all patients with MN at our center were found to be NELL-1 positive. On follow up, all patients recieved immunosuppression (steroids, cyclophosphamide or rituximab). Five patients were in complete remission, while one patient had partial remission, two patients had a progressive decline in kidney function, and one patient was lost to follow-up early. No link was found with malignancies, traditional Indian medicines or infection.

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

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

#2145 Sexual dimorphism in kidney regenerative capacity decline and in progressive tubular cell polyploidization during aging

Abstract Background and Aims Aging is characterized by a progressive kidney function decline, resulting in chronic kidney disease (CKD), which is steeper in men than in women. However, sex-related differences in mechanisms underpinning CKD development during aging still remain to be clarified. In most organs regenerative capacity declines overtime from a pool of resident stem cells leading to tissue aging. In the kidney, we have revealed that two adaptive responses co-exist to recover kidney function after injury. On one hand a population of renal progenitors (RPC), which is interspersed among parietal epithelial cells of Bowman's capsule and tubular cells (TC) of nephron segments, proliferate and generate new podocytes and TC to recover structural integrity during the regenerative processes occurring in glomerular and tubular diseases. On the other, TC enter the alternative cell cycles to become polyploid in order to increase their functional capacity and maintain the residual kidney function after injury. However, a continuous TC polyploidization comes with the long term trade-offs (fibrosis and senescence), driving CKD. Here, we aimed to investigate the role of sexual dimorphism in these two different adaptive responses during aging. Method To trace RPC (Pax2+cells) we used the inducible Pax2/Confetti or Pax2/mTmG mice (RPC are randomly labelled by one of the four fluorescent reporter genes or with GFP respectively). To study polyploid TC, we used the inducible Pax8/FUCCI2aR mice (polyploid TC are identified by expression of cell cycle fluorescent proteins in combination with DNA content analysis). Mice were analyzed at 2, 5, 12 and 20 months of age. scRNA sequencing was performed at 2 and 20 months of age. Results Pax2/Confetti mice revealed that the number of Pax2+RPC either of the Bowman's capsule or in tubules was higher in female than in male mice at all ages. Specifically, tracing analysis during aging showed that in females Pax2+RPC of the Bowman's capsule generated new podocytes, resulting in glomeruli with a better integrity of the slit-diaphragm compared with aged males. Moreover, tubular Pax2+RPC in females clonally expanded, generating a higher number of clones, which were longer than those in males. scRNAseq analysis on kidneys showed that females were endowed with a greater number of Pax2+RPC with a higher expression of Pax2 than males, suggesting that RPC in females kept a higher regenerative capacity than males during aging. Simultaneously, analysis of tubular polyploidy demonstrated that, whereas in females the polyploid fraction progressively increased, it was drastically reduced in males during aging. These results suggested that whereas in females the increase of polyploid TC provided a better maintenance of kidney function overtime, loss of polyploid response in males made them more susceptible to develop CKD. Indeed, aged male mice showed a higher percentage of polyploid TC undergoing further cycles of polyploidization, which were associated with fibrosis and senescence. In agreement with these findings, we observed a progressive kidney function decline along with an increase of glomerulosclerosis, interstitial fibrosis and blood pressure, which were significantly greater in males than in females. Conclusion Female mice showed a higher regenerative and polyploid response compared to male mice, aimed likely to cope kidney function decline during aging. These results reveal the intriguing role of a new kidney adaptive response, which may explain the higher susceptibility of males to develop a more premature CKD during aging.

A Real-World Precision Medicine Program Including the KidneyIntelX Test Effectively Changes Management Decisions and Outcomes for Patients With Early-Stage Diabetic Kidney Disease.

The KidneyIntelX is a multiplex, bioprognostic, immunoassay consisting of 3 plasma biomarkers and clinical variables that uses machine learning to predict a patient's risk for a progressive decline in kidney function over 5 years. We report the 1-year pre- and post-test clinical impact on care management, eGFR slope, and A1C along with engagement of population health clinical pharmacists and patient coordinators to promote a program of sustainable kidney, metabolic, and cardiac health. The KidneyIntelX in vitro prognostic test was previously validated for patients with type 2 diabetes and diabetic kidney disease (DKD) to predict kidney function decline within 5 years was introduced into the RWE study (NCT04802395) across the Health System as part of a population health chronic disease management program from [November 2020 to April 2023]. Pre- and post-test patients with a minimum of 12 months of follow-up post KidneyIntelX were assessed across all aspects of the program. A total of 5348 patients with DKD had a KidneyIntelX assay. The median age was 68 years old, 52% were female, 27% self-identified as Black, and 89% had hypertension. The median baseline eGFR was 62 ml/min/1.73 m2, urine albumin-creatinine ratio was 54 mg/g, and A1C was 7.3%. The KidneyIntelX risk level was low in 49%, intermediate in 40%, and high in 11% of cases. New prescriptions for SGLT2i, GLP-1 RA, or referral to a specialist were noted in 19%, 33%, and 43% among low-, intermediate-, and high-risk patients, respectively. The median A1C decreased from 8.2% pre-test to 7.5% post-test in the high-risk group (P < .001). UACR levels in the intermediate-risk patients with albuminuria were reduced by 20%, and in a subgroup treated with new scripts for SGLT2i, UACR levels were lowered by approximately 50%. The median eGFR slope improved from -7.08 ml/min/1.73 m2/year to -4.27 ml/min/1.73 m2/year in high-risk patients (P = .0003), -2.65 to -1.04 in intermediate risk, and -3.26 ml/min/1.73 m2/year to +0.45 ml/min/1.73 m2/year in patients with low-risk (P < .001). Deployment and risk stratification by KidneyIntelX was associated with an escalation in action taken to optimize cardio-kidney-metabolic health including medications and specialist referrals. Glycemic control and kidney function trajectories improved post-KidneyIntelX testing, with the greatest improvements observed in those scored as high-risk.

Elevated plasma myoglobin level is closely associated with type 2 diabetic kidney disease.

Diabetic kidney disease (DKD) is the most frequent complication in patients with type 2 diabetes mellitus (T2DM). It causes a chronic and progressive decline in kidney function, and ultimately patients require renal replacement therapy. To date, an increasing number of clinical studies have been conducted to explore the potential and novel biomarkers, which can advance the diagnosis, estimate the prognosis, and optimize the therapeutic strategies at the early stage of DKD. In the current study, we sought to investigate the association of plasma myoglobin with DKD. A total of 355 T2DM patients with DKD and 710 T2DM patients without DKD were enrolled in this study. Laboratory parameters including blood cell count, hemoglobin A1c, biochemical parameters, and plasma myoglobin were recorded. Patients were classified on admission according to the tertile of myoglobin and clinical parameters were compared between the groups. Pearson correlation analysis, linear regression, logistic regression, receiver operating characteristics (ROC) analysis, and spline regression were performed. Plasma myoglobin significantly increased in patients with DKD and was associated with renal function and inflammatory parameters. Plasma myoglobin was an independent risk factor for the development of DKD. The area under ROC curve of myoglobin was 0.831. Spline regression showed that there was a significant linear association between DKD incidence and a high level of plasma myoglobin when it exceeded 36.4 mg/mL. This study shows that elevated plasma myoglobin level is closely associated with the development of kidney injury in patients with T2DM.

The Progressive Decline of Kidney Function: Can We Have an Answer?

The Progressive Decline of Kidney Function: Can We Have an Answer?

Deferasirox in Patients with Chronic Kidney Disease: Assessing the Potential Benefits and Challenges.

Chronic kidney disease (CKD) is a major global health concern, affecting millions of people worldwide. The progressive decline in kidney function often necessitates renal replacement therapy, such as hemodialysis (HD) or peritoneal dialysis (PD), to maintain a patient's health. Iron overload, which is common in CKD patients on dialysis, can lead to severe complications, including cardiovascular disease and infections where most of the existing iron chelators are deemed unsuitable due to their suboptimal clearance in patients with compromised renal function, it becomes a significant challenge to effectively manage iron overload. Deferasirox (DFX), an oral iron chelator, has emerged as a promising treatment option for managing iron overload in these patients. However, the use of DFX comes with its unique set of challenges, such as its cost, potential side effects, and the need for close monitoring of patients, as well as the noticeable scarcity of comprehensive and rigorous clinical studies confirming its efficacy and safety of DFX. In this review, we delve into both the promising prospects and the emerging challenges associated with DFX use in managing CKD patients on HD or PD, striving for a comprehensive understanding that informs better clinical practice and patient care.

Derivation and independent validation of kidneyintelX.dkd: A prognostic test for the assessment of diabetic kidney disease progression.

To develop and validate an updated version of KidneyIntelX (kidneyintelX.dkd) to stratify patients for risk of progression of diabetic kidney disease (DKD) stages 1 to 3, to simplify the test for clinical adoption and support an application to the US Food and Drug Administration regulatory pathway. We used plasma biomarkers and clinical data from the Penn Medicine Biobank (PMBB) for training, and independent cohorts (BioMe and CANVAS) for validation. The primary outcome was progressive decline in kidney function (PDKF), defined by a ≥40% sustained decline in estimated glomerular filtration rate or end-stage kidney disease within 5 years of follow-up. In 573 PMBB participants with DKD, 15.4% experienced PDKF over a median of 3.7 years. We trained a random forest model using biomarkers and clinical variables. Among 657 BioMe participants and 1197 CANVAS participants, 11.7% and 7.5%, respectively, experienced PDKF. Based on training cut-offs, 57%, 35% and 8% of BioMe participants, and 56%, 38% and 6% of CANVAS participants were classified as having low-, moderate- and high-risk levels, respectively. The cumulative incidence at these risk levels was 5.9%, 21.2% and 66.9% in BioMe and 6.7%, 13.1% and 59.6% in CANVAS. After clinical risk factor adjustment, the adjusted hazard ratios were 7.7 (95% confidence interval [CI] 3.0-19.6) and 3.7 (95% CI 2.0-6.8) in BioMe, and 5.4 (95% CI 2.5-11.9) and 2.3 (95% CI 1.4-3.9) in CANVAS, for high- versus low-risk and moderate- versus low-risk levels, respectively. Using two independent cohorts and a clinical trial population, we validated an updated KidneyIntelX test (named kidneyintelX.dkd), which significantly enhanced risk stratification in patients with DKD for PDKF, independently from known risk factors for progression.

DUBIOUS APPENDICITIS TO BE ACCOMPANIED BY RIGHT XANTHOGRANULOMATOUS PYELONEPHRITIS: A CASE REPORT

Xanthogranulomatous pyelonephritis (XGP) is a rare chronic kidney infection that can cause a progressive decline in kidney function and lead to kidney removal or death. Symptoms of right flank pain due to XGP, sometimes radiating to the lower abdomen were difficult to assess and distinguish from urinary tract diseases alone or accompanied by the involvement of other organs like appendicitis. We report a fifty-year-old woman was referred because of a suspected mass in the right kidney based on ultrasound, but the results of the Ct-Scan with contrast showed stones and chronic parenchymal kidney with a tendency to right pyelonephritis. There were no post-contrast enhancing masses in both kidneys. Then, decided to perform a nephroureterectomy and found inflammation in her appendices. Histopathology showed xanthogranulomatous pyelonephritis and chronic appendicitis. The patient was diagnosed with Chronic pyelonephritis based on CT-Scan, but the previous ultrasound showed no appendicitis, there was a mass in the right kidney. During nephroureterectomy, there were chronic appendicitis and Xanthogranulomatous Pyelonephritis after histopathology examination. This report describes uncommon pyelonephritis and confirms the difficulty of differentiating right XGP from appendicitis, even though it occurred in a large city. Moreover, it can be a lesson for general practitioners to be more thorough in diagnosing right abdominal or flank pain.

Neutrophils - to - Lymphocytes Ratio and Clinical Outcomes in Patients with Kidney Diseases in COVID 19

Introduction: Kidney Disease is structural and functional abnormality of Nephrons, where abrupt deterioration to progressive decline in Kidney function leads to acute to chronic Kidney Disease, respectively. The objective of this research was to find the Neutrophil-to-Lymphocyte ratio and Clinical outcomes of patients with Kidney Diseases in COVID-19.Methods: A descriptive cross-sectional study was conducted in the Department of Nephrology of College of Medical Sciences and Teaching Hospital, Bharatpur-10, Chitwan from 2021-04-01 to 2021-06-29 in among 31 Covid-19 positive cases. Collected data was entered and analyzed by using SPSS 20.Results: In this study 58% were male while 42% were female. Among the total cases 35.48% cases had NRL ratio &lt;8 while 65.52% cases had NRL ratio ≥8. Among total cases 48.38% were discharged whereas, 51.62% were declared dead. Also, among those cases whose NRL ratio &lt;8, 27.27%were declared dead while in NRL≥8, 65% cases were declared dead during treatment.Conclusions: In Covid-19 cases early diagnosis and supportiv e treatment, prognosis could be good. Regular follow-up could give insight about kidney function whereas in case Covid-19 various awareness programme and practice to prevent should be implied.

CKD Progression Prediction in a Diverse US Population: A Machine-Learning Model

Chronic kidney disease (CKD) is a major cause of morbidity and mortality. To date, there are no widely used machine-learning models that can predict progressive CKD across the entire disease spectrum, including the earliest stages. The objective of this study was to use readily available demographic and laboratory data from Sonic Healthcare USA laboratories to train and test the performance of machine learning-based predictive risk models for CKD progression. Retrospective observational study. The study population was composed of deidentified laboratory information services data procured from a large US outpatient laboratory network. The retrospective data set included 110,264 adult patients over a 5-year period with initial estimated glomerular filtration rate (eGFR) values between 15-89mL/min/1.73m2. Patient demographic and laboratory characteristics. Accelerated (ie,>30%) eGFR decline associated with CKD progression within 5 years. Machine-learning models were developed using random forest survival methods, with laboratory-based risk factors analyzed as potential predictors of significant eGFR decline. The 7-variable risk classifier model accurately predicted an eGFR decline of>30% within 5 years and achieved an area under the curve receiver-operator characteristic of 0.85. The most important predictor of progressive decline in kidney function was the eGFR slope. Other key contributors to the model included initial eGFR, urine albumin-creatinine ratio, serum albumin (initial and slope), age, and sex. The cohort study did not evaluate the role of clinical variables (eg, blood pressure) on the performance of the model. Our progressive CKD classifier accurately predicts significant eGFR decline in patients with early, mid, and advanced disease using readily obtainable laboratory data. Although prospective studies are warranted, our results support the clinical utility of the model to improve timely recognition and optimal management for patients at risk for CKD progression. Defined by a significant decrease in estimated glomerular filtration rate (eGFR), chronic kidney disease (CKD) progression is strongly associated with kidney failure. However, to date, there are no broadly used resources that can predict this clinically significant event. Using machine-learning techniques on a diverse US population, this cohort study aimed to address this deficiency and found that a 5-year risk prediction model for CKD progression was accurate. The most important predictor of progressive decline in kidney function was the eGFR slope, followed by the urine albumin-creatinine ratio and serum albumin slope. Although further study is warranted, the results showed that a machine-learning model using readily obtainable laboratory information accurately predicts CKD progression, which may inform clinical diagnosis and management for this at-risk population.

411-P: Extended Validation of KidneyIntelXTM in Diabetic Kidney Disease

We have previously shown that plasma TNFR1, TNFR2, and KIM-1 combined with clinical variables provides effective risk stratification for kidney outcomes in individuals with diabetic kidney disease (DKD) stages 1-3. With the recommended use of a race-free eGFR and a refinement of our progression endpoint, we sought to develop and independently validate a version 2.0 of KidneyIntelX assay in a previously untested, independent, contemporary cohort of subjects from BioMe Biobank (Mount Sinai Health System, NYC, NY). The primary outcome was a composite of ≥40% sustained decline in eGFR or kidney failure (sustained eGFR&amp;lt;15 ml/min/1.73 m2) within 5 years from enrollment. In a training cohort of 573 patients with DKD from the Penn Medicine Biobank (PMBB), 15.4% experienced the progressive decline in kidney function over a median of 3.1 years. The following features were selected in a training model utilizing optimized random forests to predict the kidney outcome: TNFR1, TNFR2, KIM-1, baseline UACR, HbA1c, and blood urea nitrogen. The external validation cohort (BioMe, n=657) had an 11.7% event rate over a median of 3.8 years. Based on risk categorization cutoffs derived from training, 57%, 35% and 8.3% of participants were classified as low, intermediate and high-risk, respectively. The cumulative event incidence probability in the low, intermediate, and high-risk groups were 5.9% (95% CI: 3.6-9.4%), 21.2% (95% CI: 15.6-28.3%) and 66.9% (95% CI:, 49.3-83.5%). The unadjusted HRs for high vs. low and intermediate vs. low were 18.4 (95% CI: 9.4 -34.6) and 4.2 (95% CI: 2.4-7.4), respectively. After adjustment for age, sex, race, baseline eGFR, uACR, SBP, and HbA1c, the adjusted HRs were 7.7 (95% CI: 3.0-19.6) and 3.7 (95% CI: 2.0-6.8), respectively. In summary, we developed and independently validated a version 2.0 KidneyIntelX with previously established biomarkers combined with selected clinical variables and demonstrated robust prediction of progressive decline in kidney function, independent of common risk factors. Disclosure G.N.Nadkarni: Advisory Panel; Renalytix, Consultant; Renalytix, Other Relationship; Renalytix, Speaker's Bureau; Daiichi Sankyo, GlaxoSmithKline plc., Menarini Group, Stock/Shareholder; Renalytix. F.Fleming: Employee; Renalytix. M.J.Donovan: Employee; Renalytix. S.Coca: Advisory Panel; Renalytix, Bayer Inc., Boehringer Ingelheim International GmbH, Consultant; Renalytix, Nuwellis, 3ive Labs, Reprieve Cardiovascular, Vifor Pharma Management Ltd., Stock/Shareholder; Renalytix. Funding Renalytix

12-LB: Clinical Impact of Risk Profiling with KidneyIntelX on DKD Progression in a Large Integrated Health Care System

KidneyIntelXTM combines 3 plasma biomarkers with clinical variables to categorize adults with DKD stages 1-3b for risk of a progressive decline in kidney function over 5 years. We previously demonstrated that using KidneyIntelX to assess risk and guide treatment does lead to optimized medication use, lifestyle changes, and specialist referrals. We now report the one-year pre and posttest clinical impact on eGFR slope and hemoglobin A1C (HbA1c) in the Mount Sinai Health System. Among the 1087 patients with follow-up data, the median age was 69 years, 52% were women, 32% self-identified Black, baseline eGFR 59 ml/min/1.73m2, baseline HbA1c was 7.2%, and 146 (13%), 439 (40%), and 502 (46%) were scored as high, intermediate, and low risk by KidneyIntelX. In high-risk patients, median eGFR slope slowed from -5.7 ml/min/year pre-test to -2.1 ml/min/year post-test (p&amp;lt;0.001), and from -1.8 ml/min/year to -1.0 ml/min/year in intermediate-risk (p=0.005) (Table). The median HbA1c decreased from 8.4 to 7.7% (p&amp;lt;0.001) in high risk, and from 7.5 to 7.2% (p&amp;lt;0.001) in intermediate risk. In conclusion, deployment and risk stratification by KidneyIntelX was associated with reduced rate of kidney function decline and improved glycemic control, particularly in those scored as high risk. Disclosure J. Tokita: Other Relationship; Renalytix. C. Sinfield: None. M. J. Donovan: Employee; Renalytix. T. McNicholas: Employee; Renalytix. M. Kattan: Research Support; Novo Nordisk. Consultant; Renalytix, Verici. Research Support; Bayer Inc. D. W. Lam: None.

413-P: Intensive Insulin Therapy Delays the “Breakpoint” to Progressive Kidney Function Decline—New Findings and Implications of eGFR Trajectory Analysis in DCCT/EDIC Data

Patterns of kidney function decline vary among those with T1D. End-stage kidney disease (ESKD) develops after progressive kidney function decline that begins when kidney function is normal, regardless of albuminuria. We aimed to determine if these findings were observed in the DCCT/EDIC cohort, which enrolled 1,441 individuals and randomly assigned them to intensive insulin therapy (n=711) or conventional insulin therapy (n=730). Baseline mean eGFR and AER were 125 ml/min/1.73m2 and 12 mg/24 hours, respectively. During 27 years of follow-up 129 individuals reached reduced eGFR &amp;lt;60ml/min/1.73m2 or ESKD. For these individuals we applied latent class trajectory analysis minimizing sum of squares of linear spline models with varying knot placement to identify patterns of eGFR decline. We identified two patterns: i) slow decline without eGFR breakpoint (n=56) and ii) fast decline with clear breakpoint (n=73). Slow decliners reached reduced eGFR but rarely ESKD (2%), while many fast decliners progressed to ESKD (35%) within 5-15 years after the breakpoint. Fast decline was less frequent in intensive compared to conventional insulin therapy [26 (3.7%) vs 47 (6.4%), respectively, p=0.022] and had longer median time from enrollment to breakpoint (18 vs 13 years, respectively, p=0.0004). However, the slope of annual loss of eGFR after breakpoint did not differ. In conclusion, we identified a unique phenotype - the “breakpoint” to fast decline in eGFR - as the main predictor of ESKD in T1D. This breakpoint started while eGFR was normal, subsequent decline was linear, and the onset of the breakpoint was substantially delayed by intensive insulin therapy rather than the slope of decline itself. Research on biomarkers that predict the onset of the eGFR ‘breakpoint’ is needed. Disclosure K.Ihara: None. J.K.Skupien: None. E.Satake: None. B.A.Perkins: Advisory Panel; Dexcom, Inc., Insulet Corporation, Novo Nordisk, Sanofi, Vertex Pharmaceuticals Incorporated, Other Relationship; Abbott, Medtronic, Sanofi, Research Support; Novo Nordisk, Bank of Montreal (BMO). A.Krolewski: None.

#5599 FEBUXOSTAT IN COMBINATION WITH ANAKINRA OR PH NEUTRALIZATION IMPROVE THE OUTCOMES IN HYPERURICEMIA-RELATED URIC ACID CRYSTALLURIA IN MICE

Abstract Background and Aims Currently, it is unknown whether CKD patients with hyperuricemia (HU)-related uric acid (UA) crystalluria, also known as chronic UA nephropathy, would benefit from targeting HU, UA crystallization, and/or inflammation to slow down the progressive decline of kidney function. Although large multi-center RCTs with xanthine oxidase inhibitors (XOIs) such as allopurinol and two Mendelian randomization studies have disproven a causal link between HU and CKD progression, one cannot rule out that XOIs may still represent a viable therapeutic approach for patients with HU-related UA crystalluria in order to prevent CKD progression. This issue requires clarification. To address this, we used our well-established CKD mouse model of HU with UA crystalluria and tested numerous therapeutic approaches including XOI and anakinra. Method Alb-creERT2;Glut9lox/lox (male and female) mice were injected with tamoxifen and placed on an acidogenic diet with the purine inosine to induce HU and crystalluria-related CKD. After chronic UA nephropathy was established on day 14, mice were treated either 1) with the XOIs allopurinol or febuxostat, 2) with sodium bicarbonate supplementation to neutralize urinary pH to prevent UA crystallization, or 3) with anakinra to inhibit IL-1β-driven inflammation, or 4) a combination of the aforementioned therapies for 2 weeks. Saline was used as control. On day 0, 14, and 28, GFR (as primary endpoint) as well as serum UA levels and urinary UA crystals (as secondary endpoints) were determined. At the end of the study, we quantified kidney injury, immune cell infiltration, inflammation, and interstitial fibrosis using histological analysis, ELISA, RT-qPCR, and flow cytometry. Results Therapy with XOIs but not with sodium bicarbonate and anakinra reduced serum UA levels in mice with HU and UA crystalluria. Treating mice with febuxostat improved kidney function (increase in GFR) by preventing kidney injury, UA crystalluria, UA crystal granuloma formation, and interstitial fibrosis compared with the control group, while allopurinol worsened the outcomes of chronic UA nephropathy. On the other hand, sodium bicarbonate supplementation had no effects on serum UA levels, kidney inflammation, immune cell infiltration and interstitial fibrosis but improved kidney function due to less urinary UA crystal deposition (neutralization of urine pH) and granuloma formation as compared with saline-treated mice. As expected, anakinra did not slow down the progression of chronic UA nephropathy as noticed by a similar GFR decline compared with the control group. Although, anakinra reduced the number of infiltrating immune cells and the mRNA expression of inflammatory mediators in the kidney as well as the serum IL-1β concentrations, we observed more interstitial fibrosis. In combination, allopurinol with anakinra did not improve the outcomes of chronic UA nephropathy despite the inhibitory effect of anakinra on the inflammatory response because allopurinol triggered tubulointerstitial nephritis and vasodilation. Interestingly, both combination therapies febuxostat with anakinra and febuxostat with sodium bicarbonate were protective by improving kidney function and preventing UA crystal deposition, kidney injury, inflammation, interstitial fibrosis and UA crystal granuloma formation compared with the single therapies. Conclusion Our interventional study is the first pre-clinical study, which reveals that the XOIs allopurinol and febuxostat have differential effects on the outcomes of HU-related UA crystalluria. While allopurinol contributes to the progression of CKD by causing tubulointerstitial nephritis in mice, febuxostat rather seems to be renoprotective similar to urinary pH neutralization with sodium bicarbonate. We identified both combination therapies febuxostat with anakinra or sodium bicarbonate as most beneficial in order to prevent CKD progression in mice. Thus, febuxostat in combination with IL-1β inhibition or prevention of urinary UA crystallization may represent therapeutic approaches for patients with chronic UA nephropathy.

#2776 KIDNEY INVOLVEMENT IN PATIENTS WITH RHEUMATOID ARTHRITIS

Abstract Background and Aims In rheumatoid arthritis (RA) kidney is commonly affected organ with clinical presentation characterized by proteinuria and microalbuminuria, followed by chronic renal failure. RA is associated with reduced kidney function, possibly due to chronic inflammation or the use of nephrotoxic therapies. Renal diseases occurring in patients with RA may have a variable clinicopathological picture. Little is known about the effects of using the novel biological agents on the risk of kidney diseases. The aim of this study was to determine the relationship between effect of therapy and kidney involvement in patients with RA and evaluated the histopathological findings and associated clinical manifestation. Method In this retrospective study 275 patients with diagnosis of RA were included. In 48 patients renal biopsy was performed. The patients were divided in three groups according to changes in management of RA: 1991-2001, 2002-2011 and 2012-2022 year. Data of demographic characteristics, clinical symptoms and pathological diagnosis were extracted from medical records and pathological reports. Results In our study amyloidosis was the most common histologic pattern, followed by chronic glomerulonephritis (GN) and tubulointerstitial nephritis. Renal amyloidosis was diagnosed in 13 patients, membranous GN – in 9, mesangioproliferative GN – in 7 patients, focal segmental necrotizing GN – in 5, focal segmental sclerosis – in 4, minimal change disease – in 3, tubulointerstitial nephritis – in 7 patients. Between 1991 and 2001 year the most common clinical manifestation was nephrotic syndrome and the most common histopathological findings – renal amyloidosis, followed by membranous GN and focal segmental necrotizing GN. The membranous GN was related to the use of gold and its frequency decreased after 2001. The mesangioproliferative GN was the leading cause of kidney disease between 2002–2011 years and focal segmental sclerosis – between 2012–2022. In our study 68 patients had a decrease of glomerular filtration rate (GFR) &amp;lt; 60 mL/min/m2. No kidney biopsies were performed in these cases because no urine abnormalities were detected. We found that age, duration of the disease, arterial hypertension, C-reactive protein were significant risk factors for GFR decline in patients with RA. Patients with RA who are treated with biologic agents are less likely to experience progressive decline in kidney function than those not receiving biologic treatment (hazard ratios {HRs] [95% CI], 0,84 [0,68-1,02]}. Conclusion In all patients with RA, renal function should be monitored and in the case of pathologic results, renal biopsy should be performed. In RA patients with renal disorder, suspected causal drug should be removed from the treatment and specific immunosuppressive therapy initiated. Improved pain management associated with biologic treatment may help to reduce the need for potentially nephrotoxic anti-inflammatory agents such as NSAIDs and certain types of non-biologic DMARDs, which could consequently reduce the risk of drug-induced nephrotoxicity and thereby contribute to the lower risk of renal diseases.

#3632 CHARACTERIZATION AND REGULATION OF THE PATHOGENIC MUCIN 1 FRAMESHIFT PROTEIN IN PATIENT DERIVED CELLS AFFECTED BY ADTKD-MUC1

Abstract Background and Aims Autosomal Dominant Tubulointerstitial Kidney Diseases (ADTKD) are caused by mutations in one of at least five genes (UMOD, MUC1, HNF1B, REN and SEC61A1) and are characterized by progressive decline in kidney function, reaching end-stage renal disease (ESRD) usually in mid adulthood. ADTKD-MUC1 is one of the most frequent subforms, exclusively caused by a characteristic frameshift mutation, leading to the de novo protein MUC1-fs. MUC1-fs is believed to play the distinct pathogenic role in terms of a toxic proteinopathy, accumulating in the early secretory pathway. The substance BRD4780 is reported to re-route MUC1-fs towards lysosomal degradation (Dvela-Levitt et al., Cell 2019), with interventional trials being in preparation. Therefore, we aimed to gain more insights into MUC1-fs temporal and spacial regulative characteristics, comparing pharmacological intervention vs. RNA interference in patient derived tubular cells. Methods Cell culture (HKC-8 cells and patient derived human urinary Primary Tubular Cells, huPTC); siRNA knockdown; Transient transfection; Immunofluorescence; immunogold electron microscopy (EM); Immunoblotting (IB); Lentiviral SV40/Large-T antigen immortalization of huPTC; Generation of a novel polyclonal MUC1-fs antibody with an independent antigen downstream of the VNTR. Results To analyze MUC1-fs protein in more detail, we generated iTCs (immortalized tubular cells) from huPTC of patients with ADTKD-MUC1. Clonal selection of cells was performed to gain immortalized clones with MUC1-fs expression. MUC1-fs mainly localizes to the secretory pathway. Co-localization was only partially observed with TMED9, which localizes to COP vesicles, being involved in protein trafficking within the early secretory pathway. TMED9 negative components of this pathway also showed MUC1-fs staining, such as the Golgi apparatus and Early Endosomes. Immunogold EM of huPTC reveals MUC1-fs expression within the ER and (secretory) vesicles. Ultrastructural analyses of biopsies by EM from ADTKD-MUC1 patients did not show specific protein accumulation, as previously described in ADTKD-UMOD. RNA interference for MUC1 and pharmacological application of BRD4780 was performed in huPTC and iTCs, with detailed description of MUC1-fs regulation kinetics. Both approaches led to strongly reduced MUC1-fs protein levels. MUC1-fs protein revealed a significantly shorter half life than wildtype mucin 1, possibly due to its different cellular distribution. Conclusion Our data confirm and extend previously published information on intracellular MUC1-fs localization and regulation (Dvela-Levitt et al., Cell 2019). The protein kinetics of MUC1-fs appear quite dynamic in terms of synthesis and decay, which should argue for it being a suitable pharmacological target. Both, BRD4780 and RNA interference potently downregulate MUC1-fs. Interestingly, in primary and immortalized patient derived cells MUC1-fs localization is not confined to the early secretory pathway. Should the effect of BRD4780 be restricted to TMED9 positive COP vesicles, this may implicate reduced effectivenes. Therefore, RNA interference may be more efficient, since it reduces MUC1-fs at an earlier stage and is not dependent on intracellular processing.

#5661 EARLY COMPENSATORY INCREASE IN SINGLE-KIDNEY EGFR AFTER UNILATERAL NEPHRECTOMY IS ASSOCIATED WITH A LOWER LONG-TERM RISK OF EGFR DECLINE

Abstract Background and Aims The healthy kidney has reserve capacity, allowing for an increase in single-kidney GFR (ΔskGFR) in the remaining kidney after nephrectomy. We evaluated whether higher ΔskGFR, as a reflection of renal resilience, is associated with a lower long-term risk of eGFR decline in individuals undergoing unilateral nephrectomy. Method We included 1777 participants from the observational SCREAM project who underwent radical unilateral nephrectomy in Stockholm during 2006–2021. We calculated the ΔskGFR using the eGFR (CKD-EPI 2009) at 3 months post-nephrectomy eGFR minus 50% of the pre-nephrectomy eGFR and evaluated its pre-nephrectomy determinants (age, sex, eGFR, comorbidities) with multivariable linear regression. Follow-up started at 3-months post-nephrectomy, and Cox regression was used to explore the association between Δsk-GFR and the subsequent risk of CKD progression (defined as composite of a decline &amp;gt;30% relative to three months post-nephrectomy eGFR or initiation of kidney replacement therapy), adjusting for age, sex and pre-nephrectomy eGFR. Results Mean (SD) age was 68 ± 11 years, 40% of patients were female, 92% had a kidney cancer diagnosis and mean (SD) pre-nephrectomy eGFR was 75 ± 19 mL/min/1.73m2. Median (IQR) Δsk-GFR was 11 (7–20) mL/min/1.73m2. Pre-nephrectomy determinants of Δsk-GFR were age (St.Β = −0.20, P≪0.001) and pre-nephrectomy eGFR (St.Β = 0.14, P&amp;lt;0.001). During a median follow-up of 4 years (maximum 15 years), 178 participants developed CKD progression. The group with a Δsk-GFR above the median value (11 mL/min/1.73m2) had a 42% lower risk of CKD progression (adjusted HR: 0.58, 95% CI: 0.42 – 0.80), compared to those with a lower Δsk-GFR (Figure). Conclusion A larger compensatory increase in single-kidney eGFR early after unilateral nephrectomy, suggesting better renal resilience, was associated with a lower risk of CKD progression during long-term follow-up. Evaluation of Δsk-GFR could help identify patients at higher risk of progressive kidney function decline.

Diagnostic and prognostic biomarkers for tubulointerstitial fibrosis.

Renal fibrosis is the final common pathophysiological pathway in chronic kidney disease (CKD) regardless of the underlying cause of kidney injury. Tubulointerstitial fibrosis (TIF) is considered to be the key pathological predictor of CKD progression. Currently, the gold standard tool to identify TIF is kidney biopsy, an invasive method that carries risks. Non-invasive diagnostics rely on an estimation of glomerular filtration rate (eGFR) and albuminuria that assess kidney function, but these fail to accurately diagnose early CKD, and predict progressive decline in kidney function. In this review we summarize the current and emerging molecular biomarkers which have been studied in various clinical settings and in animal models of kidney disease and which correlate with the degree of TIF. We examine the potential of these biomarkers to non-invasively diagnose TIF and predict disease progression. We also examine the potential of novel technologies and non-invasive diagnostic approaches in assessing TIF. Limitations of current and potential biomarkers are discussed, and knowledge gaps are identified. Abstract figure legend The best predictor of chronic kidney disease (CKD) is tubulointerstitial fibrosis (TIF). Kidney biopsy is the gold standard diagnostic method for TIF, which is invasive. Non-invasive methods might involve assessing kidney function, identifying potential urinary and blood biomarkers, and using novel technologies. Assessing kidney function by measuring glomerular filtration rate and albuminuria has poor diagnostic and prognostic accuracy for TIF. In this review, we present current and potential soluble biomarkers and novel technologies and discuss their diagnostic and prognostic accuracies. This article is protected by copyright. All rights reserved.

Independent Prognostic and Predictive Role of Interstitial Macrophages in Kidney Biopsies of IgA Nephropathy Patients.

A relevant percentage of IgAN patients experience a progressive decline in kidney function. According to the KDIGO guidelines, proteinuria and eGFR are the only validated prognostic markers. The role of interstitial macrophages in kidney biopsies of IgAN patients and the outcome of patients treated with renin-angiotensin system inhibitors (RASBs) alone or combined with glucocorticoids were evaluated. Clinical and laboratory records (age, gender, hypertension, hematuria, proteinuria, eGFR, serum creatinine, and therapy), MEST-C parameters of the Oxford classification, C4d deposition, peritubular capillaries, and glomerular and interstitial macrophages in 47 IgAN patients undergoing kidney biopsy consecutively between 2003 and 2016 were examined. A high number of interstitial macrophages significantly correlated with peritubular capillary rarefaction and impairment of kidney function. Cox's multivariable regression analysis revealed that a value > 19.5 macrophages/HPF behaved as an independent marker of an unfavorable outcome. Patients exhibiting > 19.5 macrophages/HPF treated at the time of diagnosis with RASBs combined with methylprednisolone had an estimated probability of a favorable outcome higher than patients treated with RASBs alone. Thus, a value > 19.5 macrophages/HPF in IgAN biopsies can predict an unfavorable outcome and endorse a well-timed administration of glucocorticoids. Studies evaluating urine biomarkers associated with peritubular capillary rarefaction in patients with marked macrophage infiltration may help personalized treatment decisions.