Kidney360

Recent initiatives by the U.S. Food and Drug Administration and the National Institutes of Health to reduce animal testing in drug development have highlighted the need for in vitro platforms that better recapitulate human biology for preclinical safety assessment. Drug-induced nephrotoxicity remains a major cause of drug attrition, underscoring the need for human-relevant kidney models. To address this, a pump-free human patient-derived proximal tubule microphysiological system was developed by integrating human renal proximal tubular epithelial cells (hRPTECs), isolated from non-tumorous nephrectomy cortex, with a porous membrane-based microfluidic device. Expanded hRPTECs were cultured for 10 days under static conditions or rocker-driven shear stress approximating physiological proximal tubular flow. Shear stress increased epithelial density, enhanced proximal tubule marker expression (Na+/K+-ATPase and aquaporin-1), and improved Zonula occludens-1 and occludin localization. Bulk RNA sequencing demonstrated transcriptomic changes associated with enhanced apical maturation and epithelial signature. In cisplatin-induced injury assays, shear-conditioned epithelia exhibited reduced cell density and increased {gamma}H2AX staining, indicating greater sensitivity to nephrotoxicity. These findings demonstrate that rocker-driven shear stress promotes epithelial maturation in patient-derived hRPTECs. The pump-free human patient-derived proximal tubule microphysiological system offers a practical, scalable, and physiologically relevant platform for modeling flow-dependent proximal tubule biology and assessing human-relevant nephrotoxicity.

Background: Current understanding of acute kidney injury (AKI) risk factors remains largely descriptive, offering limited precision into how specific biomarker values or physiologic thresholds influence susceptibility. We aimed to synthesize knowledge from machine learning models trained across multiple health systems to identify generalizable, value-specific risk drivers and biomarker interactions contributing to AKI risk. Methods: We analyzed electronic health records (EHRs) from 785,497 adult inpatients between 2010 and 2019 across nine U.S. academic medical centers within PCORnet. Interpretable gradient boosting machine models were independently developed at each health system to quantify predictor-outcome associations. Meta-regression was applied to integrate these site-level results, characterize nonlinear value-risk relationships, and identify bivariate interactions between predictors. Results: Meta-analysis revealed consistent, value-specific risk drivers across health systems. An increase in glucose from 100 mg/dL to 140 mg/dL was associated with a 1.46-fold higher risk of AKI. Chloride and anion gap also demonstrated elevated AKI risk with risk increases overlapping portions of their reference ranges, with anion gap showing a 1.14-fold increase across 4-12 mmol/L and chloride a 1.28-fold increase across 96-100 mEq/L. Electrolytes including potassium, calcium, and sodium showed quadratic associations with AKI risk. Bivariate meta-regression identified interactions between key predictors, highlighting pathways that jointly modulate AKI risk. Conclusion: This cross-system meta-analysis synthesizes machine learning-derived evidence into clinically interpretable knowledge, revealing how specific biomarker ranges and interactions modulate AKI risk. By moving beyond surface-level associations to quantitative, generalizable physiologic thresholds, these findings provide actionable insights to enhance risk stratification and personalized prevention in hospital care.

Background: Fibrosis, characterised by excessive accumulation of collagen type I (COL1), is a common feature of chronic diseases, including liver diseases (LDs), chronic kidney disease (CKD) and heart failure (HF). COL1 degradation products can be detected in urine by proteomics/ peptidomics analyses and may serve as non-invasive biomarkers of fibrosis. We aimed to identify a common molecular signature of fibrosis across these diseases that may ultimately guide interventions to slow disease progression and prevent organ damage. Methods: Using capillary electrophoresis coupled to mass spectrometry (CE-MS), naturally occurring COL1 degradation products (peptides) in the urine of patients with fibrotic disease, LDs (n=127), CKD (n=263) or HF (n=187), were investigated and compared with the same number of matched controls. Disease-associated COL1 peptides were identified separately for each condition, and peptides showing consistent associations across the three diseases were selected to define a common fibrosis signature. A support vector machine model based on the selected peptides was developed and validated in independent cohorts of patients with LDs (n=110), CKD (n=93), HF (n=32) and controls (n=643). Results: We identified a common fibrotic signature consisting of 50 COL1 degradation products, mainly downregulated in fibrosis. A model based on these peptides achieved a strong performance, with an area under the receiver operating characteristic curve (AUC) of 0.935 (95% confidence interval (CI) 0.917-0.953, p<0.0001) in an external validation cohort comprising pooled disease groups (LDs, CKD, and HF) and controls. Performance was maintained in LDs, CKD and HF, with AUCs of 0.917 (95% CI 0.890-0.944, p<0.0001), 0.951 (95% CI 0.931-0.971, p<0.0001) and 0.950 (95% CI 0.903-0.997, p<0.0001), respectively. The model scores were significantly associated with fibrosis stage in LDs (p=0.0097) and with interstitial fibrosis and tubular atrophy in CKD (p=0.045). Conclusion: A model of urinary COL1 peptides captures a shared collagen degradation signature across organs and diseases, enabling the non-invasive assessment of fibrosis irrespective of its origin. As these peptides exclusively reflect collagen degradation, the findings suggest impaired collagen degradation as a driver in fibrosis. Future clinical studies are warranted to evaluate the utility of this model for early fibrosis detection and earlier implementation of anti-fibrotic interventions.

Background: Initiation of emergency dialysis, often requiring temporary catheter owing to unprepared definitive vascular access, is associated with infectious and vascular complications and suggests advanced chronic kidney disease (CKD) care gaps. Previous studies focused on kidney failure or dialysis timing. This study aimed to predict initiation of emergency dialysis using machine learning and baseline data. Methods: This retrospective cohort study used the Japan Medical Data Center claims data (2014-2022). Adults with an estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2 were included. The primary outcome was initiation of emergency dialysis (temporary catheter code without evidence of previous access preparation). Participants were randomly divided into derivation (80%) and validation (20%) cohorts. Logistic regression, support vector machine, XGBoost, LightGBM, and random forest models were evaluated using internal cross-validation, post-hoc calibration of the selected model, and bootstrap confidence intervals. Results: The cohort included 3,062 individuals (derivation; n=2,449, validation; n=613). Emergency dialysis was initiated in 237 participants (7.7%); 185 (7.6%) and 52 (8.5%) in the derivation and validation cohorts, respectively. Validation area under the receiver operating characteristic curve ranged from 0.781-0.799, with the highest value observed for random forest (0.799, 95% confidence interval; 0.740-0.850). Risk stratification showed clear event enrichment in higher predicted risk categories. SHAP analyses identified hemoglobin, proteinuria, baseline eGFR, diabetes history, and diuretic use as key predictors. Decision curve analysis showed greater net benefit than eGFR alone at lower threshold probabilities. Conclusions: Baseline machine learning models showed moderate discrimination for initiation of emergency dialysis and identified clinically plausible predictors. These findings support potential use for risk stratification, although external validation and evaluation within pre-specified care pathways are needed before implementation.

Introduction Acute interstitial nephritis is an important differential diagnosis in patients with deteriorating kidney function. Diagnosis currently requires kidney biopsy, an invasive procedure associated with risks. We hypothesized that urinary T cells may serve as a non-invasive biomarker for acute interstitial nephritis. Methods A total of 320 patients undergoing clinically indicated kidney biopsy were enrolled in a discovery cohort at Charite Berlin (n = 80), an internal validation cohort at Charite (n = 100), and an external validation cohort at The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou (n = 140). Urinary immune cells were assessed by flow cytometry. Renal T cell infiltration was evaluated by immunofluorescence in kidney biopsy specimens from the discovery and internal validation cohorts, including 16 patients with acute interstitial nephritis and 9 patients without acute interstitial nephritis. Additionally, CXCL9 was measured by ELISA in 102 urine samples from these cohorts. Results Across all cohorts, 27 patients (8.4%) were diagnosed with acute interstitial nephritis. In the discovery cohort, multiple urinary T cell subsets were increased in acute interstitial nephritis, with activated CD4+ effector memory T cells expressing CD38 and HLA-DR showing the strongest diagnostic performance. This marker outperformed urinary monocytes, eosinophils, and CXCL9 and was validated in both independent cohorts. Across all cohorts, the area under the receiver operating characteristic curve was 0.84 and increased to 0.91 after exclusion of 8 patients receiving corticosteroids. A cutoff of 211 activated CD4+ effector memory T cells per 100 mL urine yielded a sensitivity of 78% and a specificity of 81%. Urinary activated CD4+ effector memory T cell counts correlated with renal CD4+ and CD4+ CD38+ T cell infiltration in acute interstitial nephritis. Conclusions Urinary activated CD4+ effector memory T cells expressing CD38 and HLA-DR represent a promising non-invasive biomarker for the diagnosis of acute interstitial nephritis.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cysts from different nephron segments, yet their origin remains inaccessible to in vivo imaging. Building on ex vivo studies that cyst sodium concentration ([Na+]) may reflect tubular origin, we developed a non-invasive 23Na magnetic resonance imaging (MRI) approach at 7 Tesla to phenotype ADPKD cysts in vivo based on cyst sodium. In nephrectomized ADPKD kidneys, cyst fluid [Na+] closely matched 23Na MRI signal intensities, revealing two distinct cyst phenotypes: serum-like high-[Na+] cysts and low-[Na+] cysts. High-[Na+] cysts expressed the proximal tubular marker sodium-glucose cotransporter-2, whereas low-[Na+] cysts expressed markers of distal tubules and collecting ducts. The vasopressin V2 receptor (V2R), the therapeutic target of tolvaptan, was detected exclusively in low-[Na+] cysts, linking sodium phenotype to therapeutic target expression. In vivo, 23Na MRI enabled classification of 2,299 cysts in 20 ADPKD patients. High-[Na+] cysts were 1.8-fold more frequent overall. Anatomical cyst localization did not predict sodium phenotype, underscoring the need for functional imaging rather than structural inference. Patients exhibited marked interindividual variation in cyst composition, with low-[Na+] cysts comprising 4.6% to 83.9% of all cysts. Given the exclusive expression of V2R in low-[Na+] cysts, this heterogeneity may influence disease progression and therapeutic responsiveness. These findings establish 23Na MRI as a non-invasive method to phenotype ADPKD cysts in vivo and provide a functional imaging approach with potential relevance for stratifying patients and guiding future therapeutic interventions.

Introduction The hemoglobin, albumin, lymphocytes and platelets (HALP) score, a novel nutritional and inflammatory biomarker, has been used in various chronic disease studies. However, the relationship between the HALP score and chronic kidney disease (CKD) remains poorly elucidated. This study aimed to explore the possible association between the HALP score and CKD. Methods Our analysis encompassed 25,160 adult participants drawn from NHANES cycles spanning 2009 through 2018. Weighted multivariable logistic regression and generalized additive models (GAMs) were employed to evaluate the independent associations between the HALP score and CKD, albuminuria, and low-estimated glomerular filtration rate (eGFR). Threshold effects were examined using two-piecewise linear regression. Subgroup and sensitivity analyses were performed to assess robustness. Receiver operating characteristic (ROC) curve analyses were applied to compare the discriminative capacity of the HALP score with the prognostic nutritional index (PNI), systemic immune-inflammation index (SII), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR). The clinical findings were further validated in a 5/6 nephrectomy rat model. Results After adjustment for multiple confounders, higher HALP scores were inversely associated with the risk of CKD (OR = 0.97, 95% CI: 0.94-0.99) and albuminuria (OR = 0.97, 95% CI: 0.93-0.99). However, after full adjustment for demographic characteristics, physical examination indices and laboratory parameters (Model 3), the correlation between the HALP score and low-eGFR was no longer statistically significant. Non-linear analyses revealed a threshold effect, with CKD risk declining as the HALP score increased up to an inflection point of 52.43 (OR = 0.97, 95% CI: 0.95-0.99), beyond which no further protective effect was observed. A similar threshold effect was identified for albuminuria. Subgroup and interaction analyses indicated no meaningful effect modification by age, sex, BMI, hypertension, or diabetes. Sensitivity analyses confirmed the robustness of the results. ROC analysis demonstrated that the HALP score showed superior discriminative ability for CKD and albuminuria compared with PNI, SII, LMR, and PLR. In the animal experiment, CKD model rats exhibited significantly lower HALP scores than controls. Inverse correlations were observed between the HALP score and serum creatinine (Scr), blood urea nitrogen (BUN), and urinary albumin-to-creatinine ratio (UACR), with UACR showing the strongest correlation, which was consistent with the clinical findings. Conclusion Lower HALP scores are independently associated with increased prevalence of CKD and albuminuria. As an affordable and readily measurable biomarker, the HALP score may facilitate CKD risk assessment.

Background: Whether benchmark performance reflects robust clinical reasoning rather than surface-level pattern recognition remains uncertain. We evaluated the robustness of state-of-the-art large language models (LLMs) on nephrology board renewal questions using "None of the other answers" (NOTA) substitution. Methods: From 210 Japanese Society of Nephrology board renewal questions (2014-2023), two nephrologists independently reviewed all items. Questions in which NOTA became the sole correct answer after replacement were included, yielding 145 validated questions. GPT-5, GPT-4o, Gemini 2.5 Pro, and Gemini 2.0 Flash were evaluated via application programming interfaces under default settings. The primary endpoint was accuracy, and paired differences were assessed using the exact two-sided McNemar test. Results: Accuracy was significantly lower after NOTA substitution for all models: GPT-4o, 66.21% to 19.31% (drop, 46.90 percentage points [pp]); GPT-5, 87.59% to 73.10% (14.48 pp); Gemini 2.0 Flash, 58.62% to 31.03% (27.59 pp); and Gemini 2.5 Pro, 86.90% to 55.86% (31.03 pp); all P < .001. GPT-5 showed the smallest decline and the highest accuracy in both versions. Conclusions: All evaluated LLMs showed a significant robustness gap after NOTA replacement. Newer models may be more robust, but multiple-choice accuracy remains an incomplete measure of clinical reasoning robustness.

Introduction: Autosomal-dominant tubulointerstitial kidney disease (ADTKD) is characterized by chronic kidney disease (CKD) with an average age of end-stage renal disease (ESRD) of approximately 45 years, bland urinary sediment, the absence of proteinuria and autosomal dominant inheritance. While several causative genes have been found, there remain families in whom no molecular diagnosis has been identified (ADTKD-NMD). Methods: We identified BICC1 truncating variants in several families with ADTKD-NMD in the Wake Forest Rare Inherited Kidney Disease Registry and then screened families in our database and other referred families for BICC1 truncating variants. We performed segregation analysis and characterized affected individuals for clinical and histopathologic phenotypes. We analyzed oligomer formation of BICC1 mutants with wild-type BICC1-, ANKS3- and ANKS6 proteins through co-immunoprecipitation and Western blotting, and we tested for posttranscriptional regulation of the BICC1 target mRNA, Dand5, in a Luciferase reporter assay. Results: We found 6 heterozygous truncating mutations in BICC1 segregating with the ADTKD phenotype in 8 independent pedigrees worldwide. Affected individuals developed kidney failure in the 6th to 7th decade of life that was characterized pathologically by tubular atrophy and interstitial fibrosis. The truncated gene products localized to cytoplasmic bodies and demonstrated various degrees of self-association or binding to the known interaction partners, ANKS3 and ANKS6. While the wild-type BICC1 gene product acts as a posttranscriptional repressor of target mRNAs, all truncation variants exhibited increased expression of substrate mRNA. Conclusions: Truncating variants in BICC1 are a novel cause of ADTKD, segregating with the disease phenotype and upregulating BICC1 target gene expression through a dominant-negative- or a gain-of-function mode of action.

Background: Early renal function decline is often accompanied by bothersome urological symptoms, yet effective early-stage nutritional interventions remain limited. L-Ergothioneine (EGT), a diet-derived antioxidant concentrated in renal tissue via the OCTN1 transporter, has shown renoprotective potential preclinically, but human interventional data are sparse. Methods: In this single-center, open-label, self-controlled trial, 31 adults (aged 45-70 years) with early renal function decline and persistent urological symptoms ([&ge;]3 months) received oral EGT (120 mg/day) for 90 days; 27 completed the study. Participants served as their own controls. The primary outcome was the within-subject change in eGFR (CKD-EPI 2021 creatinine); secondary outcomes included cystatin C-based eGFR, serum creatinine, UACR, a 10-item voiding diary, and a low-back-pain visual analogue scale (VAS). Within-subject changes were assessed by paired t-test or Wilcoxon signed-rank test. Results: Creatinine-based eGFR increased from 86.04 {+/-} 17.89 to 93.25 {+/-} 19.00 mL/min/1.73 m2 (+8.4%; p = 0.0016) and serum creatinine fell by 7.0% (p = 0.015). However, cystatin C-based eGFR and serum cystatin C were unchanged (p = 0.31 and p = 0.99), so the filtration signal was not corroborated by an independent, muscle-mass-independent marker. UACR showed a non-significant downward trend. Patient-reported outcomes improved most robustly: the total voiding diary score decreased by 57.2% (p < 0.0001) and low-back-pain VAS by 67.2% (p = 0.0002), with significant relief of urgency, frequency, and voiding difficulty. No product-related adverse events occurred. Conclusions: In this uncontrolled study, 90-day EGT supplementation was associated with marked improvement in urological symptoms and in creatinine-based eGFR, although the latter was not confirmed by cystatin C. These changes cannot be attributed to EGT alone and may substantially reflect placebo and natural-history effects. The findings are hypothesis-generating and warrant confirmation in a randomized, placebo-controlled trial using validated symptom instruments. Trial Registration: ChiCTR2500108897; Prospectively registered on 2025-09-08.

Dysfunction of the tubulointerstitial compartment is a key driver of chronic kidney disease (CKD) progression. However, tubular function remains largely unaddressed by routine clinical assessment. Here, we show that the urine ammonium-pH index (uAPI), a composite of urinary ammonium and pH, reflects kidney tubular function and predicts kidney function decline. Using acid/base, dietary, and potassium perturbations, segmental disruption of tubular ammonium handling, mathematical modelling, and data from patients with renal tubular acidosis, we identified defective ammoniagenesis as the main uAPI determinant. The uAPI was suppressed across four kidney disease models and dissociated from GFR. Kidney proteomics and single-nucleus RNA sequencing indicated downregulation of ammoniagenesis in proteinuric and diabetic kidney disease. In type 2 diabetes patients with preserved GFR, a reduced uAPI was associated with faster kidney function decline. In three CKD cohorts, low uAPI predicted CKD progression and significantly improved risk prediction. Together, this positions the uAPI as a scalable, non-invasive measure of kidney tubular function.

Introduction: To investigate the epidemiological characteristics of chronic kidney diseases (CKD) in China in 2021 and its trends between 1990 and 2021, in the context of significant population growth and lifestyle changes over the past 30 years that have likely influenced the CKD spectrum. Methods: Data on CKD prevalence, mortality, disability-adjusted life-years (DALY), and risk factors were obtained from the Global Burden of Disease Study 2021. The estimated decadal percentage changes were calculated to evaluate changes in trends in prevalence, mortality and disease burden. Results: In 2021, an estimated 118.4 (95% UI 109.4 to 127.5) million people in China were affected by CKD, contributing to 204 230 (95% UI 164 736 to 246 372) deaths and 6.13 (95% UI 5.18 to 7.21) million DALY. Although CKD due to diabetes mellitus and hypertension accounted for less than a quarter of all cases, they were responsible for over 90% of CKD-related deaths. Over the past three decades, CKD mortality and DALY rates have steadily increased, although the prevalence has stabilized in the last decade. Diabetes mellitus type 2 and hypertension have emerged as key drivers of CKD burden in China. Conclusions: The CKD burden in China shows a dual pattern of rising incidence and high mortality from diabetes and hypertension-related chronic kidney disease, alongside persistently high years lived with disability from glomerulonephritis and other causes.

Recently, an observational study demonstrated that a lower fractional excretion of uric acid (FEUA) is significantly associated with a higher risk of kidney failure. This study aimed to assess the efficacy of switching from febuxostat to dotinurad, which increases FEUA, in patients with chronic kidney disease (CKD) and hyperuricemia (HUA).This was a non-randomized, open-label, single-center, prospective, single-arm study involving 60 patients with CKD and HUA who received febuxostat. Participants first underwent a 3-month observation period, followed by a 3-month intervention period, during which treatment was switched from febuxostat to dotinurad. The primary outcomes were changes from baseline to 3-months after switching in the estimated glomerular filtration rate (eGFR) calculated from serum creatinine (eGFRcreat) and serum cystatin C (eGFRcys), as well as the serum uric acid levels. The secondary outcome was defined as the correlation between{Delta}FEUA and the changes in both eGFRcreat({Delta}eGFRcreat) and eGFRcys({Delta}eGFRcys), respectively. During the observation period, mean eGFRcreat decreased significantly. The baseline eGFRcreat (mL/min/1.73 m{superscript 2}) was 36.0 {+/-} 15.2, and the serum urate level (mg/dL) was 5.5 {+/-} 1.2. During the intervention period, eGFRcreat increased in contrast to the significant decline observed in eGFRcys. After 3 months of switching to dotinurad, the mean serum UA levels increased significantly from 5.5 {+/-} 1.2 to 6.1 {+/-} 1.4 mg/dL, despite a significant elevation in FEUA. Both {Delta}eGFRcreat and {Delta}eGFRcys after switching to dotinurad were positively correlated with {Delta}FEUA. Switching from febuxostat to dotinurad resulted in discrepant changes in eGFRcreat and eGFRcys, suggesting that renal function should be assessed carefully after switch. Additionally, the risk of elevated serum UA levels should be considered when switching from febuxostat to dotinurad in patients with CKD.

ABSTRACT Importance: The prevalence of chronic kidney disease (CKD) is increasing, with aging being a major contributor. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are well established therapies for CKD; however, adults aged 80 years or older have been underrepresented in previous large-scale trials. Consequently, evidence regarding effects of SGLT2i therapy in this cohort remains limited. Objective: To evaluate the association of SGLT2i initiation with mortality, kidney outcomes and cardiovascular outcomes among patients over 80 years of age and CKD. Design, Setting, Participants: This retrospective cohort study used data from TriNetX Research Network, a multicenter electronic health record database. To ensure comparable standard of care and SGLT2i eligibility, the period for the occurrence of the index event was restricted to January 1, 2021, until January 1, 2025. Propensity score matching was performed to balance comorbidities, laboratory parameters, concomitant medications, and frailty-associated factors between groups. Exposures: Initiation of SGLT2i therapy vs. non-use Main Outcomes and Measures: Outcome analysis focused on all-cause mortality, major adverse kidney events (MAKE) and major adverse cardiovascular events (MACE). Cox proportional hazards models were used to estimate hazard ratios with 95% confidence intervals; following propensity score matching, results were considered as adjusted hazard ratios (aHR). Results: After propensity score matching, 5,038 patients were included in each group. During two years of follow-up, SGLT2i initiation was associated with lower all-cause mortality (aHR 0.818; 95% CI 0.746 - 0.896, p<0.0001) and fewer MAKE events (aHR 0.779; 95% CI 0.0.715 - 0.850, p<0.0001). No significant difference in MACE was observed (aHR 1.007; 95%CI 0.938 - 1.082, p=0.84). Results were generally consistent across subgroups. Risk of acute kidney injury was higher in the SGLT2i group, while incident dialysis and end-stage renal disease were significantly reduced. Acute myocardial infarction and acute heart failure were increased in the SGLT2i group. Conclusion and Relevance: Regarding survival and kidney endpoints, even the oldest CKD patients seem to benefit from SGLT2i treatment, which was associated with reduced mortality as well as improved long-term renal outcomes. MACE showed no significant differences, while specific cardiac events were increased, reflecting possible safety concerns requiring further investigation in this specific age group.

Rationale & Objective: People who live in rural areas with advanced chronic kidney disease (CKD) face well-documented structural barriers to receiving care, yet little is known about how they experience their illness or perceive interactions with their healthcare teams. We aimed to characterize the lived experiences and care perceptions of adults living in rural areas with advanced, pre-dialysis CKD. Study Design: We conducted semi-structured qualitative interviews with patients and care partners. Setting & Participants: We recruited patients with advanced CKD (stages 4-5, not on dialysis) and their care partners from a single hospital-based nephrology clinic in northern New England serving a predominantly rural population. Analytical Approach: We analyzed interview transcripts using participatory Practical Thematic Analysis (PTA), an inductive, stakeholder-engaged approach to qualitative analysis. Results: We interviewed 12 patients and 4 care partners. Four themes were identified: (1) logistical challenges of rural CKD care were pervasive but frequently normalized as an expected feature of rural life; (2) disease progression and future treatments were sources of uncertainty and concern, with expectations about dialysis often shaped by peer accounts rather than clinical discussion; (3) clinical conversations centered on laboratory results and medications, leaving emotional concerns and psychologic challenges unaddressed; and (4) physical symptoms and lifestyle changes were common but frequently attributed to comorbid conditions rather than to CKD. Limitations: Recruitment from a single clinic with a small, racially homogeneous sample limits transferability. While in-person recruitment may have excluded patients with greater transportation barriers, those who attended represent a population navigating substantial access challenges to receive care. Conclusions: Adults living in rural areas with advanced CKD experience logistical, emotional, and informational challenges broadly consistent with those reported in non-rural CKD populations. Patients normalized geographic barriers and did not consistently identify rurality as a source of disadvantage, even as structural barriers persisted. These findings support the development of structured communication approaches in nephrology care that invite discussion of disease trajectory, daily life impacts, and emotional concerns.

Vitamin D sterols, phosphorus binders and calcimimetics are used to treat chronic kidney disease mineral and bone disorder (CKD-MBD) in hemodialysis. With few randomized trials, providers may titrate agents differently reflecting equipoise and opportunities for clinical trials. We studied patients initiating in-center hemodialysis at Dialysis Clinic, Inc facilities from 2006-2015 and who remained on hemodialysis for [&ge;]90 days (n=23,549). Multinomial logit models assessed titration among users of each medication at the start of the month considering static and dynamic CKD-MBD laboratories. Similarly parameterized logistic models assessed treatment initiation. Differences across facilities were quantified as random effects and corresponding median odds ratios. We observed patterns of titration associated with CKD-MBD laboratories including albumin-corrected serum calcium (Ca), serum phosphorus and parathyroid hormone (PTH) and minimal impact of patient characteristics. Best fit models incorporated 3 months of lagged Ca and phosphorus values and linear splines for current Ca, phosphorus and PTH values. Absolute titration probabilities for vitamin D sterols and calcimimetics were influenced by all three CKD-MBD parameters, such that Ca and phosphorus values altered the threshold PTH at which escalation and de-escalation probabilities crossed. Median odds ratios indicated the greatest facility variation for vitamin D sterol titration. Providers titrate CKD-MBD medications based largely on the full CKD-MBD laboratory phenotype, including the recent serum Ca, phosphorus and PTH history. Facility variation suggests equipoise in titration of vitamin D sterols with opportunities for clinical trials.

Objective: To determine the absolute risk of starting dialysis versus mortality among adults with chronic kidney disease (CKD) treated at EsSalud from 2013 to 2022, utilizing data from the Renal Health Surveillance system (VISARE). Methods: This retrospective cohort study analyzed clinical records from the VISARE system (EsSalud). We estimated rates of dialysis initiation and death using Fine & Gray competitive risk models. Additionally, we calculated Restricted Mean Survival Time (RMST), adjusting for age, sex, clinical stage, and geographic region. Results: Among 142,770 adults with confirmed CKD and available glomerular filtration rate data, only 15.2% had albumin-to-creatinine ratio measurements, allowing KDIGO staging of 40,404 patients (28.3%). Mortality without having previously started dialysis exceeded the probability of starting renal replacement therapy (RRT) from G1, becoming more marked in G3 of chronic kidney disease (CKD); the possibility of dialysis is only greater, as expected, in G5. This outcome was most prevalent in regions with limited healthcare coverage. The combination of diabetes, hypertension, and age over 55 (the triad) was associated with reduced restricted mean survival time at both 5- and 10-year horizons across all enrollment cohorts. While Lima saw the highest rates of renal replacement therapy initiation, the Andean and Amazonian regions reported the lowest indicators. Conclusions Death without prior dialysis was the dominant outcome from G1 to G3 in this Peruvian cohort with national insurance, with direct implications for prognostic counseling, recalibration of renal failure risk equations, and equitable expansion of nephrology services in underserved regions. Keywords: Renal Insufficiency, Chronic; Competitive Risk; Diabetes Mellitus; Hypertension; Mortality; Mass Screening.

Background: Diabetic kidney disease (DKD) remains a leading cause of end-stage renal disease worldwide, characterized by progressive structural and metabolic alterations secondary to chronic hyperglycemia. While numerous type 1 and type 2 rodent models have been developed to study the pathophysiology of DKD, no single model perfectly recapitulates the full clinical spectrum of human disease. The selection of an optimal model depends deeply on the specific research objective, as phenotypic expression and histopathological severity vary significantly across different strains and induction methods. The present study provides a comparative analysis of the renal histological of three widely utilized murine models: the chemically induced streptozotocin (STZ) model and the genetic Akita (type 1) and db/db (type 2) models. Methods: Male STZ-induced (28 weeks post-induction), heterozygous Akita (28 weeks old), and db/db mice at two different age intervals (18-21 and 16-24 weeks old) were assessed. Renal injury was quantified using four light-microscopic parameters: glomerulomegaly, mesangial hypercellularity, tubular vacuolization and arteriolar hyalinosis. Due to observed discrepancies between metabolic and structural findings in the db/db strain, transmission electron microscopy (TEM) was employed for subcellular characterization. Results: All models exhibited significant hyperglycemia and albuminuria. At the light-microscopic level, STZ and Akita mice demonstrated consistent and pronounced renal lesions. In contrast, db/db mice despite increasing albuminuria and obesity, light microscopy revealed heterogeneous and inconsistent histopathological changes. However, TEM analysis of db/db mice kidneys successfully captured early ultrastructural injury, including irregular glomerular basement membrane (GBM) thickening and focal podocyte foot process effacement, which were undetectable by light microscopy. Conclusions: Our findings indicate that the Akita and STZ-induced models exhibit prominent structural alterations detectable by conventional light microscopy, whereas the db/db model requires ultrastructural evaluation by TEM to reliably confirm renal injury. This study underscores the limitation of routine histology in certain type 2 diabetes models and highlights the complementary value of TEM for accurate histopathological characterization. Collectively, the alternative histopathological markers identified herein offer sensitive and readily accessible indices for monitoring early-to-moderate DKD progression, providing a more robust framework for preclinical model selection and therapeutic evaluation in future studies.

Purpose: Autosomal Dominant Polycystic Kidney Disease is the most common monogenic kidney disease and largely due to variants in PKD1. We aimed to assess pathogenicity evidence for PKD1 missense variants in disease databases and evaluate in silico pathogenicity prediction tool performance. Methods: PKD1 missense variants reported as pathogenic, likely pathogenic or likely benign were extracted from ClinVar and PKDB. Variants were re-classified using ACMG/AMP criteria to identify "truth sets" of pathogenic and benign variants. In silico scores were obtained from five tools (SIFT, PolyPhen-2, CADD, REVEL, AlphaMissense) and evaluated using established thresholds. A Receiver Operating Characteristic curve analysis was performed using the PKD1 variant truth sets. Results: 346/389 (89%) reported disease-causing missense variants in PKD1 were downgraded to Variants of Unknown Significance (VUS) using current classification criteria. Based on current thresholds, REVEL achieved the highest sensitivity of 62%, with specificity of 79%. AlphaMissense was the only tool not to misclassify any truth set variants, but many of the variant scores were between the pathogenic and benign thresholds. Conclusion: A large majority of PKD1 missense variants are classified as VUS with current pathogenicity criteria. Commonly used in silico tools, applied with established genome-wide thresholds, do not reliably distinguish pathogenic and benign missense variants in PKD1.

Background: ALECT2 is the third most common cause of renal amyloidosis in the United States, with a strong predilection for Hispanic patients in the Southwest. (PMID:24522497) Despite its regional prevalence, the data on the trajectory of kidney function decline and post-transplant outcomes remain poorly characterized. Methods: This is a retrospective study of patients diagnosed with ALECT2 by kidney biopsy at UNM from January 2014 to April 2024. Pre- and post-biopsy eGFR trajectories and post-transplant allograft function were analyzed. Results: 12 patients had pre-biopsy data available, with the mean age at diagnosis 64 SD 12.0 years, 8(67%) were females, and 8 identified as Hispanic. Mean eGFR at diagnosis was 31 (SD 29) indicating advanced kidney disease with 67% diagnosed as CKD stage 4 or 5. Concomitant kidney pathology was identified in 50% with diabetic nephropathy being present in 2/3 of those. A significant change in the eGFR trajectory identified at the time of biopsy through change point analysis [Figures A,C,D] Among four patients who underwent kidney transplantation, allograft eGFR remained stable over more than 60 months of follow-up [Figure D] Conclusion: In this cohort of predominantly Hispanic patients, ALECT2 amyloidosis presented with advanced CKD and accelerated loss of kidney function, which prompted a biopsy that detected the disease. Post- transplant allograft function was well maintained, supporting kidney transplantation as a viable treatment strategy for ALECT2-associated kidney disease.