Progressive Loss Of Kidney Function Research Articles

Animal models to study cognitive impairment of chronic kidney disease.

Mild cognitive impairment (MCI) is common in people with chronic kidney disease (CKD) and its prevalence increases with progressive loss of kidney function. MCI is characterized by a decline in cognitive performance greater than expected for an individual age and education level but with minimal impairment of instrumental activities of daily living. Deterioration can affect one or several cognitive domains (attention, memory, executive functions, language, and perceptual motor or social cognition). Given the increasing prevalence of kidney disease, more and more people with CKD will also develop MCI causing an enormous disease burden for these individuals, their relatives and society. However, the underlying pathomechanisms are poorly understood and current therapies mostly aim at supporting patients in their daily life. This illustrates the urgent need to elucidate the pathogenesis, and potential therapeutic targets and test novel therapies in appropriate preclinical models. Here, we will outline the necessary criteria for experimental modelling of cognitive disorders in CKD. We discuss the use of mice, rats and zebrafish as model systems and present valuable techniques through which kidney function and cognitive impairment can be assessed in this setting. Our objective is to enable researchers to overcome hurdles and accelerate preclinical research aimed at improving therapy of people with CKD and MCI.

Urine tricarboxylic acid cycle metabolites and risk of end stage kidney disease in patients with type 2 diabetes.

Metabolites in tricarboxylic acid (TCA) pathway have pleiotropic functions. To study the association between urine TCA cycle metabolites and the risk for chronic kidney disease (CKD) progression in individuals with type 2 diabetes. A prospective study in a discovery (n = 1826) and a validation (n = 1235) cohort of type 2 diabetes in a regional hospital and a primary care facility. Urine lactate, pyruvate, citrate, alpha-ketoglutarate, succinate, fumarate and malate were measured by mass spectrometry. CKD progression was defined as a composite of sustained eGFR below 15 ml/min/1.73 m2 , dialysis, renal death or doubling of serum creatinine. During a median of 9.2 (IQR 8.1-9.7) and 4.0 (3.2-5.1) years of follow-up, 213 and 107 renal events were identified. Cox regression suggested that urine lactate, fumarate and malate were associated with an increased risk (adjusted hazard ratio, aHR [95% CI] 1.63 [1.16-2.28], 1.82 [1.17-2.82] and 1.49 [1.05-2.11], per SD), while citrate was associated with a low risk (aHR 0.83 [0.72-0.96] per SD) for the renal outcome after adjustment for cardio-renal risk factors. These findings were reproducible in the validation cohort. Noteworthy, fumarate and citrate were independently associated with the renal outcome after additional adjustment for other metabolites. Urine fumarate and citrate predict the risk for progression to ESKD independent of clinical risk factors and other urine metabolites. These two metabolites in TCA cycle pathway may play important roles in the pathophysiological network underpinning progressive loss of kidney function in patients with type 2 diabetes.

Arachidonic acid metabolism as a therapeutic target in AKI-to-CKD transition.

Arachidonic acid (AA) is a main component of cell membrane lipids. AA is mainly metabolized by three enzymes: cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP450). Esterified AA is hydrolysed by phospholipase A2 into a free form that is further metabolized by COX, LOX and CYP450 to a wide range of bioactive mediators, including prostaglandins, lipoxins, thromboxanes, leukotrienes, hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids. Increased mitochondrial oxidative stress is considered to be a central mechanism in the pathophysiology of the kidney. Along with increased oxidative stress, apoptosis, inflammation and tissue fibrosis drive the progressive loss of kidney function, affecting the glomerular filtration barrier and the tubulointerstitium. Recent studies have shown that AA and its active derivative eicosanoids play important roles in the regulation of physiological kidney function and the pathogenesis of kidney disease. These factors are potentially novel biomarkers, especially in the context of their involvement in inflammatory processes and oxidative stress. In this review, we introduce the three main metabolic pathways of AA and discuss the molecular mechanisms by which these pathways affect the progression of acute kidney injury (AKI), diabetic nephropathy (DN) and renal cell carcinoma (RCC). This review may provide new therapeutic targets for the identification of AKI to CKD continuum.

Change Over Time in Pre–End-Stage Renal Disease 24-Hour Urine Creatinine as Muscle Mass Surrogate and Post–End-Stage Renal Disease Mortality

Loss of muscle mass and sarcopenia are common in chronic kidney disease (CKD) and end-stage renal disease (ESRD), and sarcopenia can worsen insidiously in patients with advancing CKD. The temporal dynamics of sarcopenia in patients with progressive loss of kidney function, and its association with future outcomes, is unclear. In a contemporary national cohort of incident ESRD US veterans, we selected 661 patients who had at least 2 24-hour urine creatinine (24hrUC) measurements, a surrogate of muscle mass, performed during the 3-year prelude period prior to ESRD transition. We estimated 24hrUC slopes in mixed effects models. To assess the temporal dynamics of pre-ESRD changes in 24hrUC and its association with changing eGFR, we separately fitted in mixed effects models a penalized spline regression of 24hrUC on time and on eGFR. We examined the association of 24hrUC slopes with postdialysis all-cause mortality using Cox models adjusted for confounders. The mean slope of 24hrUC versus time was -78mg/year (95% confidence interval: -102 to -54), with a steeper decline noted in the last year prior to ESRD. More severe decreases in 24hrUC were associated with higher all-cause mortality: a 100mg/year decrease in 24hrUC was associated with a multivariable adjusted death hazard ratio of 1.41 (95% confidence interval: 1.00-1.98, P=.05). Patients with advanced CKD lose a substantial proportion of their muscle mass each year during pre-ESRD prelude. Loss of muscle mass accelerates near ESRD transition, and more loss of muscle mass is associated with higher mortality after ESRD transition.

The pathogenic role of succinate-SUCNR1: a critical function that induces renal fibrosis via M2 macrophage

BackgroundRenal fibrosis significantly contributes to the progressive loss of kidney function in chronic kidney disease (CKD), with alternatively activated M2 macrophages playing a crucial role in this progression. The serum succinate level is consistently elevated in individuals with diabetes and obesity, both of which are critical factors contributing to CKD. However, it remains unclear whether elevated succinate levels can mediate M2 polarization of macrophages and contribute to renal interstitial fibrosis.MethodsMale C57/BL6 mice were administered water supplemented with 4% succinate for 12 weeks to assess its impact on renal interstitial fibrosis. Additionally, the significance of macrophages was confirmed in vivo by using clodronate liposomes to deplete them. Furthermore, we employed RAW 264.7 and NRK-49F cells to investigate the underlying molecular mechanisms.ResultsSuccinate caused renal interstitial macrophage infiltration, activation of profibrotic M2 phenotype, upregulation of profibrotic factors, and interstitial fibrosis. Treatment of clodronate liposomes markedly depleted macrophages and prevented the succinate-induced increase in profibrotic factors and fibrosis. Mechanically, succinate promoted CTGF transcription via triggering SUCNR1-p-Akt/p-GSK3β/β-catenin signaling, which was inhibited by SUCNR1 siRNA. The knockdown of succinate receptor (SUCNR1) or pretreatment of anti-CTGF(connective tissue growth factor) antibody suppressed the stimulating effects of succinate on RAW 264.7 and NRK-49F cells.ConclusionsThe causative effects of succinate on renal interstitial fibrosis were mediated by the activation of profibrotic M2 macrophages. Succinate-SUCNR1 played a role in activating p-Akt/p-GSK3β/β-catenin, CTGF expression, and facilitating crosstalk between macrophages and fibroblasts. Our findings suggest a promising strategy to prevent the progression of metabolic CKD by promoting the excretion of succinate in urine and/or using selective antagonists for SUCNR1.

Renal involvement in Takayasu’s arteritis; a mini-review study

Takayasu’s arteritis is a chronic inflammatory disease affecting the aorta and its branches. It can also involve other organs, such as the kidneys. Inflammation of the renal artery can lead to hypertension, proteinuria, and progressive loss of kidney function over time. This condition is known as renovascular hypertension. The treatment for Takayasu’s arteritis involves managing symptoms with medications like corticosteroids, immunosuppressants, and antihypertensive drugs. Surgical intervention may be necessary if there are complications, such as aneurysms or blockages in the affected blood vessels. Lifestyle modifications such as maintaining a healthy weight, regular exercise, and smoking cessation can also help manage better disease management.

Validation of Townes As Mice As a Model of Chronic Kidney Disease and Venous Thrombosis Associated with Sickle Cell Trait

Individuals with sickle cell trait (SCT) are heterozygous carriers of the sickle beta-globin gene. Systematic analyses of large cohort studies over the past decade have established that SCT is a risk factor for a limited number of complications, most notably chronic kidney disease (CKD) and venous thrombosis (VT). SCT red blood cells (RBCs) can undergo sickling, although the degree and duration of hypoxia required to produce sickling are much greater than in sickle cell disease due to the lower intra-erythrocyte sickle hemoglobin beta (HbS) concentration of 25-45%. Hypoxia-mediated HbS polymerization can be enhanced by cellular dehydration, hyperosmolarity and/or acidosis that may be encountered in the renal inner medulla. Furthermore, prolonged exposure of SCT RBCs to profound hypoxia, such as in the nidus of a venous clot, will also result in sickling. The objective of this study was to determine if Townes AS mice manifest kidney dysfunction analogous to their SCT human counterparts. Furthermore, we evaluated whether VT was more pronounced in a well-described model of inferior vena cava (IVC) stasis. We used humanized male sickle cell trait (AS) and age-matched genetic control (AA) mice (n=7-16). Analysis of urinary renal biomarkers (albuminuria, proteinuria, kidney injury marker 1 (KIM-1), osmolality) and kidney function (transcutaneous measurement of glomerular filtration rate (GFR)) were conducted at 4-week intervals from 8 to 40 weeks of age. VT was induced by complete occlusion of the IVC in AA and AS mice. Sickling of RBCs was determined by histological and electron microscopy analysis of the IVC clot. Senicapoc, an oral Gardos channel inhibitor, was administered twice daily (20mg/kg, bid) for 2 weeks to prevent AS RBC dehydration and subsequent sickling. Human HbS accounts for 30.1% of total Hb expression in AS mice. Consistent with human SCT, peripheral blood counts did not differ from AA controls. Basal plasma thrombin-antithrombin complex levels were also not different between AA and AS mice. We performed a longitudinal study of renal structure and function in AA and AS mice over 40 weeks. At 8 weeks of age, AS mice exhibited no differences in any parameter compared to AA controls. However, AS mice subsequently developed albuminuria and a moderate but statistically significant increase in GFR (Figure 1). At 36 and 40 weeks of age, we observed progressive loss of kidney function demonstrated by statistically significant decreased GFR accompanied by a significant increase in albuminuria in AS mice (Figure 1). Over time, proteinuria gradually increased in AS mice, and had doubled by 40 weeks of age compared to AA controls (4.6 ±1.1 vs. 2.3 ±0.4 mg/24h, p<0.05). Increased levels of urinary KIM-1, a marker of tubular damage, were observed in AS mice throughout the duration of the study, with the highest levels at 16 weeks (228.3 ± 32.6 pg/24h vs. 53.8 ± 8.5 pg/24h, respectively, p˂0.05). Urine osmolality was not different at 8 weeks of age, but progressively declined in AS mice with statistically significant changes vs. controls starting at 24 weeks until the end of study (1946 ±63 vs. 2672 ±135 mOsm/kg at 40 weeks, p=0.002). Histologic analysis confirmed glomerular injury (congestion, glomerulosclerosis) and tubular injury (medullary congestion, interstitial fibrosis) in 40 week old AS mice. Following 24 hours of IVC stasis, thrombus weight was significantly increased (p<0.01) in AS mice (mean±SEM; 29.0 mg +/- 1.7; n=8) compared to AA controls (20.0 mg ± 1.7; n=7). Histologic and electron microscopic evaluation demonstrated that severe hypoxia (pO 2 ≈ 10 mm Hg) present in the nidus of venous thrombi was associated with extensive sickling of RBCs in AS mice. To determine if the enhancement of VT observed in AS mice was mediated by RBC sickling, mice were pretreated with Senicapoc or vehicle. Compared to vehicle-treated AS mice (27.3 mg ± 2.2 n=9) pre-treatment with Senicapoc significantly reduced (p<0.05) clot weight (18.1mg ± 1.1; n=7) to that observed in untreated AA controls. In aggregate, our data demonstrate that Townes AS murine nephropathy closely mimics the renal abnormalities (impaired urinary concentration and albuminuria with later onset loss of GFR) described in humans with SCT. Furthermore, we have established a mouse model of the venous thrombotic complications associated with SCT and have demonstrated that hypoxia-induced sickling of RBCs may contribute to enhanced VT observed in AS mice.

Elucidating the role of nicotinamide N-methyltransferase-p53 axis in the progression of chronic kidney disease.

Chronic kidney disease (CKD) is a significant global health issue characterized by progressive loss of kidney function. Renal interstitial fibrosis (TIF) is a common feature of CKD, but current treatments are seldom effective in reversing TIF. Nicotinamide N-methyltransferase (NNMT) has been found to increase in kidneys with TIF, but its role in renal fibrosis is unclear. Using mice with unilateral ureteral obstruction (UUO) and cultured renal interstitial fibroblast cells (NRK-49F) stimulated with transforming growth factor-β1 (TGF-β1), we investigated the function of NNMT in vivo and in vitro. We performed single-cell transcriptome sequencing (scRNA-seq) on the kidneys of mice and found that NNMT increased mainly in fibroblasts of UUO mice compared to sham mice. Additionally, NNMT was positively correlated with the expression of renal fibrosis-related genes after UUO injury. Knocking down NNMT expression reduced fibroblast activation and was accompanied by an increase in DNA methylation of p53 and a decrease in its phosphorylation. Our findings suggest that chronic kidney injury leads to an accumulation of NNMT, which might decrease p53 methylation, and increase the expression and activity of p53. We propose that NNMT promotes fibroblast activation and renal fibrosis, making NNMT a novel target for preventing and treating renal fibrosis.

A Current Landscape on Alport Syndrome Cases: Characterization, Therapy and Management Perspectives.

Alport syndrome (AS) is a rare genetic disorder categorized by the progressive loss of kidney function, sensorineural hearing loss and eye abnormalities. It occurs due to mutations in three genes that encode for the alpha chains of type IV collagen. Globally, the disease is classified based on the pattern of inheritance into X-linked AS (XLAS), which is caused by pathogenic variants in COL4A5, representing 80% of AS. Autosomal recessive AS (ARAS), caused by mutations in either COL4A3 or COL4A4, represents 15% of AS. Autosomal dominant AS (ADAS) is rare and has been recorded in 5% of all cases due to mutations in COL4A3 or COL4A4. This review provides updated knowledge about AS including its clinical and genetic characteristics in addition to available therapies that only slow the progression of the disease. It also focuses on reported cases in Saudi Arabia and their prevalence. Moreover, we shed light on advances in genetic technologies like gene editing using CRISPR/Cas9 technology, the need for an early diagnosis of AS and managing the progression of the disease. Eventually, we provide a few recommendations for disease management, particularly in regions like Saudi Arabia where consanguineous marriages increase the risk.

Plasma Tryptophan-Kynurenine Pathway Metabolites and Risk for Progression to End-Stage Kidney Disease in Patients With Type 2 Diabetes.

We sought to study the associations between plasma metabolites in the tryptophan-kynurenine pathway and the risk of progression to end-stage kidney disease (ESKD) in patients with type 2 diabetes. Plasma tryptophan, kynurenine, 3-hydroxykynurenine, kynurenic acid, and xanthurenic acid concentrations were measured in discovery (n = 1,915) and replication (n = 346) cohorts. External validation was performed in Chronic Renal Insufficiency Cohort (CRIC) participants with diabetes (n = 1,312). The primary outcome was a composite of incident ESKD (progression to estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m2, sustained dialysis, or renal death). The secondary outcome was annual eGFR decline. In the discovery cohort, tryptophan was inversely associated with risk for ESKD, and kynurenine-to-tryptophan ratio (KTR) was positively associated with risk for ESKD after adjustment for clinical risk factors, including baseline eGFR and albuminuria (adjusted hazard ratios [HRs] 0.62 [95% CI 0.51, 0.75] and 1.48 [1.20, 1.84] per 1 SD). High levels of kynurenic acid and xanthurenic acid were associated with low risks of ESKD (0.74 [0.60, 0.91] and 0.74 [0.60, 0.91]). Consistently, high levels of tryptophan, kynurenic acid, and xanthurenic acid were independently associated with a slower eGFR decline, while a high KTR was predictive of a faster eGFR decline. Similar outcomes were obtained in the replication cohort. Furthermore, the inverse association between kynurenic acid and risk of ESKD was externally validated in CRIC participants with diabetes (adjusted HR 0.78 [0.65, 0.93]). Accelerated catabolism of tryptophan in the kynurenine pathway may be involved in progressive loss of kidney function. However, shunting the kynurenine pathway toward the kynurenic acid branch may potentially slow renal progression.

Polycystic Kidney Disease Diet: What is Known and What is Safe.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by kidney cyst formation and progressive kidney function loss. Dietary interventions such as caloric restriction, intermittent fasting, and ketogenic diet have recently emerged as potential strategies to induce metabolic reprogramming and slow ADPKD progression. We review the available evidence supporting the efficacy and safety of these interventions in ADPKD. Dietary interventions show promise in managing ADPKD by improving metabolic health and reducing oxidative stress. However, while preclinical studies have shown favorable outcomes, limited clinical evidence supports their effectiveness. In addition, the long-term consequences of these dietary interventions, including their effect on adverse events in patients with ADPKD, remain uncertain. To optimize ADPKD management, patients are advised to follow a dietary regimen that aims to achieve or maintain an ideal body weight and includes high fluid intake, low sodium, and limited concentrated sweets. Caloric restriction seems particularly beneficial for patients with overweight or obesity because it promotes weight loss and improves metabolic parameters. Supplementation with curcumin, ginkgolide B, saponins, vitamin E, niacinamide, or triptolide has demonstrated uncertain clinical benefit in patients with ADPKD. Notably, β -hydroxybutyrate supplements have shown promise in animal models; however, their safety and efficacy in ADPKD require further evaluation through well-designed clinical trials. Therefore, the use of these supplements is not currently recommended for patients with ADPKD. In summary, dietary interventions such as caloric restriction, intermittent fasting, and ketogenic diet hold promise in ADPKD management by enhancing metabolic health. However, extensive clinical research is necessary to establish their effectiveness and long-term effects. Adhering to personalized dietary guidelines, including weight management and specific nutritional restrictions, can contribute to optimal ADPKD management. Future research should prioritize well-designed clinical trials to determine the benefits and safety of dietary interventions and supplementation in ADPKD.

Kidney disease progression in pediatric and adult posterior urethral valves (PUV) patients.

Posterior urethral valves (PUV) is the most common cause of obstructive uropathy in boys; approximately 15% develop kidney failure by early adulthood. However, rates of kidney function decline are poorly defined in PUV children and adults, as is the impact of potentially modifiable chronic kidney disease (CKD) progression risk factors. We conducted a retrospective review of all PUV patients followed at our institution from 1995 to 2018. Inclusion criteria were estimated glomerular filtration rate (eGFR) > 20ml/min/1.73 m2 after 1year of age, no dialysis or kidney transplant history, and ≥ 2 yearly serum creatinine values after age 1year. eGFRs were calculated using creatinine-based estimating formulas for children (CKID U25) or adults (CKD-EPI). The primary outcome was annualized change in eGFR, assessed with linear mixed effects models. We also examined the association of acute kidney injury (AKI), proteinuria, hypertension (HTN), and recurrent febrile urinary tract infections (UTIs) with eGFR decline. Fifty-two PUV patients met the inclusion criteria. Median (interquartile range) eGFR decline was 2.6 (2.1, 3.1) ml/min/1.73 m2/year. Children (n = 35) and adults (n = 17) demonstrated progressive decline. Proteinuria and recurrent UTIs were significantly associated with faster progression; AKI and HTN were also associated but did not reach significance. PUV patients show progressive loss of kidney function well into adulthood. Proteinuria and recurrent UTIs are associated with faster progression, suggesting potential modifiable risk factors. This is the first study to report annualized eGFR decline rates in PUV patients, which could help inform the design of clinical trials of CKD therapies.

No impact of a high-fat meal coupled with intermittent hypoxemia on acute kidney injury biomarkers in adults with and without obstructive sleep apnea.

Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxemia, which is associated with progressive loss of kidney function, where postprandial fluctuations in renal physiology may further compromise oxygen supply and kidney function. Therefore, we measured biomarkers of acute kidney injury (AKI) following a high-fat meal with and without intermittent hypoxemia. Eighteen healthy young men (mean age [SD]: 22.7 years [3.1]) and seven middle-aged to older individuals with OSA (54.4 years [6.4]) consumed a high-fat meal during normoxia or intermittent hypoxemia (~15 hypoxic cycles per hour, ~85% oxyhemoglobin saturation) for 6 h. We observed no changes in estimated glomerular filtration rate and plasma concentrations of creatinine, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) at any measured time points. In both groups, plasma concentrations of interleukin-18 (IL-18) increased after 6 h during normoxia only (p = 0.033, ηp 2 = 0.122), and plasma concentrations of liver-type fatty acid-binding protein (L-FABP) transiently decreased after 3 h in both conditions (p = 0.008, ηp 2 = 0.152). These findings indicate that AKI biomarkers are not acutely elevated during the postprandial state with or without intermittent hypoxemia, suggesting that other mechanisms may play more important roles in the progression of kidney disease in OSA.

Participation rate and yield of two home-based screening methods to detect increased albuminuria in the general population in the Netherlands (THOMAS): a prospective, randomised, open-label implementation study

Chronic kidney disease (CKD) has a rising global prevalence and is expected to become the fifth leading cause of death by 2030. Increased albuminuria defines the early stages of CKD and is among the strongest risk factors for progressive CKD and cardiovascular disease. The value of population screening for albuminuria to detect CKD in an early phase has yet to be studied. We aimed to evaluate the effectiveness of two home-based albuminuria population screening methods. Towards Home-based Albuminuria Screening (THOMAS) was a prospective, randomised, open-label implementation study that invited Dutch adults aged 45-80 years for albuminuria screening. Individuals were randomly assigned (1:1) to screening by applying either a urine collection device (UCD) that was sent by post to a central laboratory for measurement of the albumin-to-creatinine ratio (ACR) by immunoturbidimetry or to screening via a smartphone application that measures the ACR with a dipstick method at home. Randomisation was done with a four-block method via a web-based system and was stratified by age, sex, and socioeconomic status. If two or more individuals per household were invited to participate, these individuals were randomly assigned to the same group. In case of confirmed increased albuminuria at home, participants were invited for an elaborate screening in a regional hospital (Amphia Hospital, Breda, Netherlands) for CKD and cardiovascular risk factors. When abnormalities were found, participants were referred to their general practitioner for treatment. The primary outcomes were the participation rate and yield of the home-based screening and elaborate screening. Participation rate was assessed in the intention-to-screen population (ie, all participants who were invited for the home-based screening or elaborate screening). Yield was assessed in the per-protocol population (ie, all individuals who participated in the home-based screening or elaborate screening). An exploratory analysis assessed the sensitivity and specificity of both home-based screening methods. To this end, an additional quantitative ACR test was performed among people participating in the elaborate screening, and a substudy was performed among participants with a first negative home-based screening test, who were invited for an additional test. The study is registered with ClinicalTrials.gov, NCT04295889. 15 074 participants were enrolled between Nov 14, 2019, and March 19, 2021. 7552 (50·1%) were randomly assigned to home-based albuminuria screening by the UCD method and 7522 (49·9%) were assigned to albuminuria screening by the smartphone application method. The participation rate of the home-based screening was 4484 (59·4% [95% CI 58·3-60·5]) of the 7552 invited individuals for the UCD method and 3336 (44·3% [43·2-45·5]) of 7522 invited individuals for the smartphone application method (p<0·0001). Increased ACR was confirmed by home-based testing in 150 (3·3% [95% CI 2·9-3·9]) of 4484 individuals for the UCD method and 171 (5·1% [4·4-5·9]) of 3336 indivduals for the smartphone application method. 124 (82·7% [95% CI 75·8-87·9]) of 150 individuals assigned to the UCD method and 142 (83·0% [76·7-87·9]) of 171 participants assigned to the smartphone application method attended the elaborate screening. Sensitivity to detect increased ACR was 96·6% (95% CI 91·5-99·1) for the UCD method and 98·1% (89·9-99·9) for the smartphone application method, and specificity was 97·3% (94·7-98·8) for the UCD method and 67·9% (62·0-73·3) for the smartphone application method, indicating that the test characteristics of only the UCD method were sufficient for screening. Albuminuria, hypertension, hypercholesterolaemia, and decreased kidney function were newly diagnosed in 77 (62·1%), 44 (35·5%), 30 (24·2%), and 27 (21·8%) of 124 participants for the UCD method, respectively. Of the 124 participants assigned to the UCD method who completed elaborate screening, 111 (89·5%) were referred to their general practitioner for treatment because of newly diagnosed CKD or cardiovascular disease risk factors or known risk factors outside the target range. Home-based screening of the general population for increased ACR using a UCD had a high participation rate and correctly identified individuals with increased albuminuria and yet unknown or known but outside target range CKD and cardiovascular risk factors. By contrast, the smartphone application method had a lower at-home participation rate than the UCD method and the test specificity was too low to accurately assess individuals for risk factors during the elaborate screening. The UCD screening strategy could allow for an early start of treatment to prevent progressive kidney function loss and cardiovascular disease in patients with CKD. Dutch Kidney Foundation, Top Sector Life Sciences & Health of the Dutch Ministry of Economic Affairs.

Association of body mass index with the development of metabolic acidosis in patients with chronic kidney disease

AbstractAimsHigher body mass index (BMI) is associated with higher bone mass and bone serves as a buffer during the development of metabolic acidosis. The authors sought to examine the relationship between BMI and metabolic acidosis in patients with chronic kidney disease (CKD).Materials and MethodsThe study utilized a large US longitudinal data repository including over 103 million patients from healthcare provider organizations to evaluate the relationship between the exposure variable (BMI) and the prevalence and incidence of metabolic acidosis among patients with estimated glomerular filtration rate &lt;60 ml/min/1.73 m2. Incident metabolic acidosis was identified at the first of two consecutive post‐index serum bicarbonate values, 10–365 days apart, between 12 and &lt;22 mEq/L in patients with normal index serum bicarbonate. Cox proportional hazard models were adjusted for multiple variables including demographics, comorbidities, income, education, and kidney function.Results103,766 patients qualified for this study; 6472 (6.2%) had metabolic acidosis at index. An inverse association between BMI category and metabolic acidosis was observed for both baseline (prevalence) and new‐onset (incidence) metabolic acidosis. Compared to BMI category of 18.5 to &lt;25 kg/m2, each category of incrementally higher BMI was associated with a decreasing risk of incident metabolic acidosis; the adjusted hazard ratios (95% confidence interval) were 0.866 (0.824–0.911), 0.770 (0.729–0.813), 0.664 (0.622–0.709), and 0.612 (0.571–0.655) for BMI 25 to &lt;30, 30 to &lt;35, 35 to &lt;40, and 40+ kg/m2, respectively.ConclusionsAmong patients with CKD, an incremental increase in BMI was inversely associated with both the prevalence and incidence of metabolic acidosis. These associations suggest that increased body weight may protect against the development of metabolic acidosis, a risk factor for progressive loss of kidney function.

Performance Evaluation and Comparative Analysis of Several Machine Learning Classification Techniques Using a Data-driven Approach in Predicting Renal Failure

Abstract: Renal failure is characterized by progressive kidney function loss over time. It is a serious medical condition that affects millions of people worldwide. It is caused by the inability of the kidneys to properly filter waste and excess fluids from the blood. Renal failure can be a consequence of chronic kidney disease. Chronic kidney disease is a long-term condition that causes the kidneys to gradually lose function over time. If chronic kidney disease is not adequately managed, the kidney’s function may continue to decline, leading to renal failure. It is essential to monitor and manage chronic kidney disease to prevent renal failure from developing. This research paper presents an approach for predicting renal failure using several machine-learning classification techniques. The study evaluates the performance of various classifiers such as Decision Tree, Naive Bayes, Extreme Gradient Boosting, Logistic Regression, and Support Vector Machines using various evaluation metrics. The performance of these classifiers is evaluated using various metrics such as accuracy, precision, recall, and F1-score. This proposed method can be useful for early diagnosis and treatment of renal failure, thus reducing the complications and costs associated with the disease. By comparing and evaluating the performance of these models, we aim to identify the most effective approach for predicting renal failure and provide valuable insights for clinical practice.

#6841 IS NEPHRECTOMY ALWAYS USEFUL IN ADPKD? A CASE REPORT OF HEPATIC FIBROSIS WITH SPLENOMEGALY AND PANCYTOPENIA AS LATE CONSEQUENCE

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease. Its main feature is the progressive enlargement of both kidneys with progressive loss of kidney function. ADPKD is the 4th leading cause of dialysis in the world. The disease has systemic involvement. Liver cysts are the most common extrarenal manifestations of ADPKD and are often incidental findings. However the liver can reach considerable size but its function is always preserved. Cysts lead to structural changes of the biliary tree and determine discomfort related to mass effect when significant liver enlargement occurs. Few cases of Budd Chiari syndrome (BCS) or of hepatic fibrosis have been reported in ADPKD patients after nephrectomy. Probably the removal of the kidneys can lead to obstruction of inferior vena cava by liver cysts. Method We report a case of hepatic fibrosis with splenomegaly and severe pancytopenia as a tardive complication after bilateral nephrectomy. Case report A 47 years old man was admitted c/o Division of Nephrology of San Raffaele Hospital in August 2018 because of a high-grade fever, general malaise, nausea and abdominal pain. The patient had a previous diagnosis of ADPKD. Genetic test indicative of PKD1 truncating mutation. He was chronically attended in the outpatient clinic of the same Division. On admission in hospital his renal function was severely impaired (crea 10 mg/dl; urea 213 mg/dl). No abnormalities at the blood count. Reactive C protein was elevated (156 mg/l nv 0-6). Urine culture was found negative. Abdominal NMR showed an important volumetric increase (compared with a NMR performed in 2014) of both kidneys with diameters of about 30 cm, several cysts with hemorrhagic and infective features and numerical and dimensional increase of the hepatic cysts; spleen was reported with normal diameters. Multiple antibiotic treatments were performed unfortunately without benefit. Therefore considering the state of end stage renal disease, the persistent infection and the severe symptoms, in September 2018 the patient underwent bilateral nephrectomy and hemodialysis was started. During the following years imaging studies aimed at the preparation for transplantation were performed. In November 2020 an abdominal NMR showed for the first time splenomegaly with a bipolar diameter of 14 cm. A NMR follow up was started. In January 2021 a further increase was reported as spleen diameter resulted of 14.5 cm and a volumetric increase of hepatic cysts was shown. In September 2022 spleen reached to a diameter of 17 cm. Contextually in November 2020 patient started to present pancytopenia that had progressively been worsening with many concomitant infective and bleeding episodes. All hematologic causes were excluded. Just to explain the genesis of the splenomegaly in September 2022 a fibroscan was performed and a pathological liverstiffness was found. All hepatitis markers were negative and immunologic ones as well. Splenectomy was assumed, but patient clinical conditions so far do not allow it. Transplantation is currently contraindicated Conclusion These evidences underline the necessity of scrupolous evaluation of polycystic kidneys and their anatomic relationship with the liver before nephrectomy. Nephrectomy is frequently considered in the preparation for renal transplantation. In light of these possible complications, maybe removal of kidneys should be considered carefully in ADPKD patients with large involvement of the liver by cysts.

#5309 MODELLING LONG-TERM OUTCOMES FOR PATIENTS WITH IMMUNOGLOBULIN A NEPHROPATHY (IGAN) FROM SHORT-TERM PROTEINURIA DATA

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is rare kidney disease that leads to glomerular injury, progressive loss of kidney function and progression to kidney failure. Pre-specified interim proteinuria data from ongoing clinical trials is being used as the basis of regulatory approval of new therapies but little is known about the translation of these results to long-term patient outcomes; a topic of particular interest to heath technology assessment (HTA) groups looking to inform decisions on reimbursement before final renal outcome data are available. The objective of this study was to model long-term outcomes for patients with IgAN based on short-term proteinuria data. Method We developed a de novo model including a short-term (36-week) decision tree and a long-term Markov model to capture expected lifetime outcomes associated with treatment for IgAN. We used achievement of proteinuria &amp;lt;1 g/day as a clinically relevant treatment target. The short-term model included data on proteinuria level and distribution of chronic kidney disease (CKD) health states (CKD 1/2, 3, 4, and 5). At the end of 36 weeks of treatment, patients were categorized into groups based on their proteinuria level (&amp;lt;1g/day and ≥1 g/day) and CKD stage before transitioning to the long-term Markov model. In the long-term model, proteinuria level-based, CKD health state transition matrices derived from analysis of UK National Registry of Rare Kidney Disease (RaDaR) data, and transition matrices to dialysis and transplant derived from the US Renal Data System (USRDS) were used. Other included clinical inputs of complications and mortality were derived from extension of US Optum data analyses and literature. Health-related quality of life (HRQoL) was assessed as health state utilities and disutility associated with complications. Hypothetic scenarios of improvement in short-term proteinuria and impact on long term outcomes were tested. Model outputs included life years (LYs) and quality-adjusted life years (QALYs). Effectiveness was discounted at 3% annually. Deterministic sensitivity analysis was conducted. Results Over a lifetime, patients receiving treatment that increased the probability of achieving proteinuria &amp;lt;1 g/day by 10% in the short-term, were modelled to have gained an additional 0.388 LYs from reduced CKD/transplant/dialysis-related mortality and 0.633 QALYs from delaying CKD progression to kidney failure. As expected, results improved when the probability of achieving proteinuria &amp;lt;1 g/day increased; with a 30% increase in the probability of achieving proteinuria &amp;lt;1 g/day, LYs gained were 0.562 (Figure 1) and QALYs 0.968 (Figure 2). Results were most sensitive to time horizon and long-term extrapolation of CKD health state transition matrices. Conclusion Despite challenges inherent in the translation of surrogate endpoints to long-term outcomes, combining short-term proteinuria from clinical trials and long-term CKD data from real-world registry and claims-based data provides a solution. Based on modelling, treatments that increase the probability of achieving &amp;lt;1 g/day in the short-term, are expected to provide benefits to patients with IgAN in the long-term including less time with advanced kidney disease, less time on dialysis and avoiding the need for kidney transplant resulting in improved survival, and better quality of life. Refinement and customization of country-specific model inputs will help ensure outputs are relevant for different jurisdictions and as representative of anticipated real-world outcomes as possible.

#4333 A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF BION-1301 IN ADULTS WITH IGA NEPHROPATHY

Abstract Background and Aims IgA nephropathy (IgAN) is the leading cause of primary glomerulonephritis and has limited treatment options, especially for high-risk patients. Approximately 30-45% of IgAN patients progress to end-stage kidney disease over a period of 20-25 years and proteinuria is the strongest predictor of disease progression [1]. BION-1301 is a novel, humanized monoclonal antibody that blocks a proliferation-inducing ligand (APRIL), a cytokine that is elevated in patients with IgAN. APRIL promotes the production of pathogenic galactose-deficient IgA1 (Gd-IgA1), resulting in immune complex formation and subsequent glomerular deposition, leading to inflammation and kidney injury. Blocking APRIL with BION-1301 is a potential disease-modifying approach to treating IgAN. Interim results from a Phase 1/2 trial of BION-1301 in patients with IgAN (NCT03945318) demonstrate rapid and durable reductions in Gd-IgA1 and sustained, clinically meaningful reductions in proteinuria with an acceptable safety profile [2]. Methods CHK02-02 is a Phase 3, randomized, double-blind, placebo-controlled study to evaluate the effect of BION-1301 in adults with primary IgAN at risk of progressive kidney function loss. Approximately 272 patients will be enrolled across North America, South America, Europe and Asia-Pacific. Key eligibility criteria include biopsy-proven IgAN within the past 10 years (not due to secondary causes), eGFR ≥ 30 ml/min/1.73 m2 (CKD-EPI) and total urine protein ≥ 1.0 g/day at screening. Patients must be stable on a maximally tolerated dose of angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blocker (ARB) for at least 12 weeks prior to screening or intolerant to ACEi/ARB. Patients may also be on a stable dose of SGLT2i, mineralocorticoid receptor antagonists, and/or endothelin receptor antagonists for at least 12 weeks prior to screening. The study will be comprised of a screening period (6 weeks), a double-blind treatment period (104 weeks), and a safety follow-up period (24 weeks). Patients will be randomized 1:1 to receive subcutaneous 600 mg BION-1301 Q2W or placebo for 104 weeks. Randomization will be stratified by region (Asia vs. Rest of World), baseline proteinuria (≥ 2 g/day vs. &amp;lt; 2 g/day) and eGFR (≤ 45 ml/min/1.73 m2 vs. &amp;gt; 45 ml/min/1.73 m2). An additional ∼20 patients with eGFR 20 to &amp;lt; 30 mL/min/1.73 m2 will be enrolled into an exploratory cohort not included in the primary or secondary analyses. Results The primary endpoint is change in proteinuria (UPCR from a 24-hour urine collection) from baseline to week 36. The key secondary endpoint is change in eGFR from baseline to week 104. Additional secondary endpoints will evaluate the effect of BION-1301 vs. placebo on composite clinical outcomes including patients experiencing at least one of the following: 30% or 40% reduction in eGFR, eGFR &amp;lt; 15 mL/min/1.73 m2, dialysis, kidney transplantation or all-cause mortality. Safety endpoints include type, incidence, severity, and relatedness of adverse events (AEs) and serious AEs. Exploratory endpoints include impact of BION-1301 on disease biomarkers and health-related quality of life as well as analysis of BION-1301 pharmacokinetics and immunogenicity. Conclusion BION-1301 provides a potentially disease-modifying approach for the treatment of IgAN by directly targeting the disease pathogenesis. Interim results of the Phase 1/2 open-label trial demonstrated proof-of-concept for BION-1301 to reduce pathogenic Gd-IgA1 and provide sustained, clinically meaningful reductions in proteinuria while supporting SC dosing at 600 mg Q2W [2]. The Phase 3 trial will evaluate the effect of BION-1301 vs. placebo on proteinuria, eGFR and composite clinical endpoints and key safety measures in adult patients with IgAN at risk of progressive kidney function loss.

Patient-centric holistic integrative therapies as an adjuvant in checking the progression of chronic kidney disease: A case study.

Chronic kidney diseases (CKDs) characterized by progressive loss of kidney function impart significant burden on the patients. Besides physical disabilities, CKD affects the mental health and quality of life of the patients. Recent studies suggest the need for interdisciplinary patient-centric care in the management of CKD. The present study introduced patient-centric holistic integrative therapies (YNBLI) in a 64-year-old female diagnosed with CKD in 2021, who presented with breathlessness, fatigue, loss of appetite, and anxiety. She is a known case of type 2 diabetes, hypertension and osteoarthritis of knee. She was advised for dialysis by her nephrologists', however, she was reluctant to undergo dialysis due to anxiety about the side effects and lifelong dependency on dialysis. She initially underwent a 10-day YNBLI program at our inpatient setting followed by adhering to the home-based YNBLI for 16 weeks. She showed significant improvement in the kidney function, hemoglobin levels, quality of life and symptoms with no adverse events. The improvements were consistent throughout the 16 weeks after discharge. This study presents the effective use of patient-centric holistic integrative therapies (YNBLI) as an adjuvant in the management of CKD. Future studies are warranted to substantiate these findings.