INTRODUCTION:The number of kidney biopsies performed in patients with diabetes has increased rapidly over the last two decades. However, the overall value of the biopsy has been questioned because any coexisting non-diabetic kidney disease (NDKD) is not identified in many patients. Here, we quantify the frequency of identifying NDKD and examine clinical indications, demographic factors, and histologic parameters that increase the odds of finding NDKD and the impact on developing end stage kidney disease. METHODS:A retrospective analysis of clinical and pathologic parameters of 49,075 biopsied patients with diabetes with and without diabetic nephropathy (DN) from 2001-2024 was performed. Data from the United States Renal Data Service were examined to determine the impact of a NDKD on disease progression to end stage kidney disease. RESULTS:NDKD was found in 58.8% of patients with diabetes who underwent kidney biopsy, including 35.9% without concurrent DN and 22.9% as a second diagnosis in DN. Acute kidney injury and acute nephritic syndrome had greater odds of a NDKD diagnosis in patients with DN. The youngest (under 30 years) and oldest (60 years and older) patients had a higher prevalence of NDKD. Higher chronicity on biopsy was associated with a lower prevalence of NDKD diagnosis. Patients with NDKD were 2.56-fold less likely to develop end stage kidney disease compared to patients with DN alone. CONCLUSIONS:This is the largest analysis examining prevalence of a NDKD in patients with diabetes and the impact of biopsy indication on finding a second diagnosis in biopsy-proven DN. The objective is to provide nephrologists with guidance in when to perform a biopsy based on the odds of finding a NDKD related to the patient's clinical indication. Given the high prevalence of NDKD, our study shows that kidney biopsy remains a critical tool in the care of diabetic patients.

Primary aldosteronism is characterized by excess aldosterone production leading to hypertension and hypokalemia. We report three cases of unilateral primary aldosteronism after kidney transplantation. Each patient presented with elevated blood pressure and hypokalemia early posttransplant. Diagnosis was established through elevated aldosterone-to-renin ratios and positive aldosterone suppression tests, and lateralization was determined with selective adrenal venous sampling. Ipsilateral adrenalectomy improved hypokalemia and blood pressure control for all. Notably, two patients with biopsy-confirmed glomerular pathology after kidney transplantation exhibited proteinuria reduction following adrenalectomy.

Many clinical risk scores are deployed as additive rules with nonnegative integer points assigned to relevant binary predictive features. These integer weights not only make the score easier to use in practice but also promote sparsity in the resulting prediction model. Such risk scores are often derived by first fitting a regression model and then rounding the estimated coefficients to the nearest integer after appropriate scaling. This approach is computationally fast but does not guarantee optimality of the resulting score. Alternatively, one may search over all possible integer weights to directly optimize a value function by posing the problem as an integer programming task. However, the associated computational burden can be substantial, especially when the value function is nonconcave or even discontinuous. In this paper, we develop new machine learning algorithms that employ a flexible greedy optimization strategy to learn such additive scoring directly under explicit and sensible optimality objectives. We apply the proposed method to a large electronic health record (EHR) cohort in Epic Cosmos to construct an integer-weighted comorbidity score for measuring the risk of post-discharge mortality. We also conduct a simulation study to examine the finite-sample operating characteristics.

Importance:Donor-recipient age mismatch is an established risk factor in adult liver transplants (LTs), yet its effect in adolescents, who require long-term graft durability, has not been fully characterized. Despite pediatric prioritization, some adolescent donor livers are allocated to adults, limiting access to age-matched grafts for adolescents. Objective:To assess whether a donor-recipient age difference of 10 or more years is associated with inferior graft survival in LTs among adolescents and to estimate the benefits of broader geographic sharing of adolescent donor livers. Design, Setting, and Participants:This retrospective, registry-based case-control study used data from the Organ Procurement & Transplantation Network database, a nationwide US transplant registry. Participants were adolescents aged 12 to 17 years who received liver-only grafts from donation after brain death between March 1, 2002, and December 31, 2024, with follow-up until April 4, 2025. Propensity score matching (1:1) was performed on graft type and size mismatch, donor sex, donor-recipient sex mismatch, transplant center volume, and recipient variables. Exposure:Donor-recipient age difference of 10 or more years (age-mismatched graft) vs less than 10 years (age-matched graft). Main Outcomes and Measures:The primary outcome was 10-year graft survival. The secondary outcome was 10-year overall survival. Waiting time to an age-matched graft offer under alternative donor-sharing radii (1500 nautical miles [NM], 1000 NM, or no limit vs 500 NM) were also estimated. Results:Among 2020 adolescents receiving LTs (median age, 15.0 [IQR, 13.0-16.0] years; 1081 [53.5%] female), 612 (30.3%) received age-mismatched grafts (median donor age, 36.0 [IQR, 29.0-45.0] years) and 1408 (69.7%) received age-matched grafts (median donor age, 16.0 [IQR, 13.0-17.0] years). The age-mismatched group had a higher proportion of recipient candidates in the intensive care unit at transplant (287 [46.9%] vs 250 [17.8%]; P < .001). After propensity score matching (n = 526 per group), 10-year graft survival was 61.5% in the age-mismatched group and 74.2% in the age-matched group (P < .001), with consistent results across recipients' pretransplant hospitalization status. A simulation estimated that expanding the adolescent allocation radius to 1000 NM would allow 90% of adolescent candidates to receive age-matched offers within 15 days, compared with 44 days under the current 500-NM limit. Conclusions and Relevance:In this case-control study of a US national cohort of adolescents receiving LT, donor-recipient age mismatch of 10 or more years was associated with inferior graft survival. Broader allocation of adolescent donors may improve access to age-matched grafts and long-term outcomes.

BACKGROUND:Clinical trials in rare glomerular disease may establish short-term treatment efficacy but are limited by small sample sizes and short study duration. Observational data are needed to assess longer-term outcomes and can provide insights into real-world prescribing practices. This study applied modern statistical methods to real-world data from the Cure Glomerulonephropathy (CureGN) network to compare the effectiveness of rituximab and calcineurin inhibitors on long-term primary membranous nephropathy outcomes. METHODS:CureGN participants with biopsy-confirmed primary membranous nephropathy who initiated either of the two treatments at least 6 months after any previous immunosuppressant exposure were eligible. Inverse-probability-of-treatment weighting balanced covariates at treatment initiation. Inverse-probability-of-censoring weights accounted for censoring individuals if another immunosuppressant was started during follow-up. Outcomes included time from treatment initiation to composite kidney disease progression (40% decline in eGFR, kidney replacement therapy, or eGFR <15), proteinuria remission, and relapse following remission. Hazard ratios and differences in restricted mean survival times were estimated. RESULTS:325 treatment initiations across 250 unique participants were eligible, with median follow-up 53 months (25th-75th percentile: 24-79). Participants on calcineurin inhibitors had significantly higher risks of disease progression (HR=2.81; 95% CI: 1.16, 6.80). Hazard ratios for proteinuria remission (HR=0.77; 95% CI: 0.50, 1.17) and relapse (HR=1.42, 95% CI: 0.69, 2.92) had wide confidence intervals. CONCLUSIONS:Rituximab was associated with better kidney function preservation than calcineurin inhibitors over long follow-up. Proteinuria remission and relapse results favored rituximab but did not reach statistical significance. Long-term treatment comparative effectiveness in rare diseases can be evaluated with real-world data.

Randomized controlled trials are the gold standard for estimating the average effect of a treatment in a target population, but the same treatment may benefit some patients while having no effect on or even harming others. This phenomenon, termed heterogeneous treatment effects, can be quantified by estimating treatment effects within subgroups of patients, defined by various combinations of baseline covariates. One approach for quantifying heterogeneous treatment effects is to develop "effect models" that directly model complex interactions between baseline covariates and treatment assignment. "Effect scores," derived from effect models, can then be used to rank patients based on their predicted treatment benefit, enabling targeted treatment regimens. In this article, we provide a rigorous general framework for developing and evaluating effect models to characterize heterogeneous treatment effects from a single randomized control trial. We address challenges in valid model development, such as overfitting, and illustrate our approach in a real-world dataset with time-to-event outcomes subject to right-censoring.

Introduction:For oncology patients with limited treatment options, clinical trials may be a critical lifesaving pathway. Identifying relevant trials, however, is a time-consuming and difficult task. Several patient-trial matching processes incorporating large language models (LLMs) have been proposed to alleviate the burden on patients and oncologists. We aim to explore the benefits and practical challenges of zero-shot LLM-assisted trial matching processes by analyzing the results for a single pancreatic cancer patient. Materials and Methods:The results of a simple zero-shot LLM-assisted clinical trial matching process for our patient were compared to those of a "human benchmark," which was developed manually by two of the authors interfacing directly with ClinicalTrials.gov . Performance metrics - sensitivity, specificity, precision, and accuracy - were calculated. In addition, a qualitative content analysis (QCA) of LLM reasoning text was done to identify patterns in "errors," which we define as a human-LLM discrepancy in final patient eligibility. Implications and severity of errors are discussed. Results:The zero-shot LLM-assisted process returned potential trials with a sensitivity, specificity, and precision of 81.1%, 89.3%, and 86.5% respectively compared to the human benchmark. Qualitative error analyses revealed that about 73% of errors could potentially be alleviated with improved prompting and information access. Overall performance seemed comparable to that of human reviewers. Conclusion:The results from this preliminary real-world case study provide additional evidence to the literature in support of the integration of LLMs in clinical trial matching to provide benefit to patients with metastatic cancer with limited options.

Diabetic nephropathy (DN) is a major cause of end-stage renal disease, yet the molecular mechanisms driving tubular injury and fibrosis remain poorly defined. Here, we integrated single-cell multiplexed protein imaging, spatial transcriptomics, single-nucleus and single-cell RNA sequencing and chromatin accessibility profiling to comprehensively characterize human DN pathology. Our multi-modal analysis precisely maps kidney cell types and their spatial distributions, immune-fibrotic interactions, and key transcriptional regulators. We identified eight distinct cellular neighborhoods defining the immune-fibrotic microenvironment and uncovered molecular networks driving tubular injury and fibrosis. JUN (encoding c-Jun) emerged as a central regulator of transcriptional reprogramming during tubular injury and fibrogenic remodeling. In a diabetic mouse model, c-Jun is activated in injured proximal tubules. Using an inducible c-Jun mouse model, we demonstrated that tubular-specific c-Jun activation alone is sufficient to induce tubular injury, chronic inflammation, progressive fibrosis, and systemic metabolic alterations, including impaired glucose homeostasis. We also observed reduced expression of SLC4A4, a bicarbonate transporter essential for proximal tubular function, in injured tubules. Together, our findings establish a spatially resolved framework for understanding DN pathogenesis and identify c-Jun as a key mediator of tubular injury and fibrosis in diabetic kidney disease.

BACKGROUND:We evaluated the immunogenicity and safety of fractional doses of SARS-CoV-2 booster vaccines compared to full doses in adults aged 18-60 primed with full series of Sinovac, AZD1222, or Natural Infection in Sindh, Pakistan. METHODS:This observer-blind, randomized phase IV non-inferiority trial (Feb 2023-Jan 2024) evaluated one-third, half, or full doses of BNT162b2, or full-dose Sinovac, in 10 arms based on primary vaccination. Participants were followed for 6 months with blood samples and safety assessments at days 0, 28, 84, and 182. The primary endpoint was a > 4-fold rise in anti-Spike IgG at day 28, comparing full and fractional doses using a 10% non-inferiority margin. FINDINGS:A total of 903 participants received boosters. In Sinovac-primed individuals, ½ and ⅓ dose BNT162b2 boosters showed non-inferior seroresponse at Day 28 compared to full-dose Sinovac (66.7% and 70.5% vs. 19.4%), with higher responses at Days 84 and 182. No other non-inferiority comparisons met the threshold. Antibody levels were similar between full and fractional BNT162b2 doses over six months. All boosters were well tolerated, with no serious adverse events. INTERPRETATION:Fractional BNT162b2 doses were non-inferior to the full Sinovac dose, but not to the full BNT162b2 dose in any priming group. Given these findings and considering the need for further research on antibody thresholds to fully understand the protection provided by fractional doses, we recommend using full BNT162b2 doses as boosters for those primed with Sinovac. If full BNT162b2 doses are not available, fractional BNT162b2 doses may be considered, but another Sinovac dose should be avoided.

Introduction:Transplant glomerulitis is a morphological lesion seen in kidney allograft rejection that is associated with poor outcomes; however, little is known about how immune cells infiltrate and organize specifically within glomeruli. Methods:We used Co-Detection by Indexing (CODEX) multifluorescent imaging to measure 52 protein markers in a retrospective cohort of 41 human allograft nephrectomies (ANs) and evaluated the immunological landscape of transplant glomerulitis. Results:Characterization of 18 cell types identified diverse immune cells within inflamed glomeruli, with unique phenotypes and compositions compared with the extraglomerular microenvironment. Immunological phenotypes were conserved across glomeruli within individuals and associated with the general state of injury, with M1 macrophages and effector CD8 T cells associated with mild inflammation. Distance-based spatial analysis further revealed a profibrotic community composed of M2 macrophages, memory CD8 T cells and exhausted CD8 T cells surrounding endothelial cell hubs. These interaction networks were associated with regions of adverse glomerular remodeling, expression of profibrotic proteins, and were more prevalent in individuals with C4d-positive rejection. Conclusion:These results implicate distinct cell-cell interactions as hallmarks of alloimmune injury and chronic remodeling during transplant glomerulitis and may give rise to new tools for histological risk assessment of clinical rejection syndromes.

Commercial healthcare claims datasets area nonrandom sample of the US population, affecting generalizability. Rigorous comparisons of claims-derived results to ground-truth data that quantify external validity bias are lacking. Our goal is to (1) quantify external validity of commercial healthcare claims data and (2) to evaluate how socioeconomic/demographic factors are related to the bias. We analyzed inpatient discharge records occurring between January 1, 2019 and December 31, 2019 in five states: California, Iowa, Maryland, Massachusetts, and New Jersey, and compared rates (per person-year) of the 250 most common inpatient procedures between claims and reference data for each target population. We used Merative MarketScan Commercial Database for the claims data and State Inpatient Databases and the US Census as reference. For a target population of all Americans, commercial healthcare claims underestimate the rate of overall inpatient discharges by 23.1%. The extent of bias varied across procedures, with the rates of ~25% of procedures being underestimated by a factor of 2. Socioeconomic factors were significantly associated with the magnitude of bias (${R}^2=69.4\%,$P < .001). When the target population was restricted to commercially insured Americans, the bias decreased substantially (1.4% of procedures were biased by more than factor of 2), but some variation across procedures remained.

Immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) is a rare pattern of kidney injury and a progressive nephropathy characterized by the glomerular deposition of immune complexes and complement proteins. The IC-MPGN pattern of injury exhibits a membranoproliferative glomerulonephritis appearance by light microscopy and occurs secondary to various conditions or, more rarely, idiopathically, when no underlying etiology can be determined. Kidney biopsy is the only method for identifying IC-MPGN, distinguishing between IC-MPGN and complement 3 glomerulopathy (C3G), and for providing critical pathologic insights that guide further clinical evaluation for underlying etiologies and inform patient management. Given the progressive nature of IC-MPGN, it is crucial to identify patients early and to define the underlying pathophysiology for timely and appropriate treatment. However, several challenges remain in the accurate interpretation of kidney biopsy specimens and the effective treatment of idiopathic disease. In this commentary, two nephrologists and a nephropathologist review best practices in the clinical and histopathologic evaluation of IC-MPGN and discuss the central role of kidney biopsy in the differentiation of IC-MPGN and C3G. The challenges and considerations discussed are explored through an illustrative case of idiopathic disease, drawn from the authors' clinical experiences. Finally, remaining unmet needs are highlighted, and future perspectives on targeted treatments under investigation for patients with idiopathic IC-MPGN are provided.