BACKGROUNDYouth with type 2 diabetes (T2D) and severe obesity face high risk of diabetic kidney disease, which metabolic bariatric surgery (MBS) can mitigate. This study explores structural and molecular changes in kidneys after vertical sleeve gastrectomy (VSG), a form of MBS.METHODSWe performed paired analyses, including metabolic profiling, kidney volume assessment, histological evaluation, and single-cell RNA sequencing (scRNA-seq), on kidney biopsies from 5 youth with T2D and obesity pre- and 12 months post-VSG in the IMPROVE-T2D (Impact of Metabolic surgery on Pancreatic, Renal and cardiOVascular hEalth in youth with T2D) cohort. Circulating proteomics with kidney transcriptomics were linked using data from an independent cohort of youth with obesity, with or without T2D, undergoing MBS in Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS, n = 64).RESULTSAfter VSG, participants lost weight and had improvements in insulin sensitivity and metabolic parameters. Kidney changes included reduced renal hyperfiltration, total kidney volume, mesangial matrix area, and microalbuminuria. scRNA-seq in proximal tubule (PT) and thick ascending limb cells indicated repression of glycolysis, gluconeogenesis, and tricarboxylic acid (TCA) cycle genes, with upregulation of AMP-activated protein kinase (AMPK) and forkhead box O3 (FOXO3). Decreased metabolic signaling aligned with reduced ribosomal phosphorylated S6K (pS6K), suggesting attenuated mTORC1 activity. Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation in PT was diminished, correlating with lower circulating ligands from Teen-LABS proteomic data.CONCLUSIONMBS/VSG prompts kidney molecular adaptations, providing potential targets for nonsurgical interventions against obesity- and diabetes-associated kidney disease.FUNDINGUniversity of Washington with the American Diabetes Association, University of Michigan with Chan Zuckerberg Initiative, and Breakthrough T1D.

Arterionephrosclerosis is characterized by focal global glomerulosclerosis (FGGS), which is a constant feature of aging and hypertension. FGGS begins as normal-appearing glomeruli that undergo tuft contraction (TC) and progress to global glomerulosclerosis (GGS). Kidney tissue from 26 hypertensive and 25 age-matched non-hypertensive patients was analyzed for glomerular volume and for podocyte number using a WT1 antibody. Immunohistochemistry (IHC) was employed to detect the senescence-related biomarkers p16, p21, β-galactosidase (GLB1), and 5-nucleotidase (CD73). Antibodies against annexin 3 (ANXA3), cytokeratin 7, and CD44 were used to evaluate parietal epithelial cell (PEC) activation. The relationships between biomarkers, hypertension, TC, and GGS were quantitatively analyzed. With TC, podocyte numbers decreased in association with increased glomerular p16, p21, GLB1, and CD73 expression. With TC, WT1, CK7, and CD44-expressing PEC increased. TC and GGS expressed senescent markers in hypertensive and non-hypertensive kidneys; however, the frequency of TC (p < 0.01) and GGS (p < 0.001) was greater in hypertensive kidneys, and glomerular expression of senescence markers was correspondingly higher. Additionally, greater p16 and p21 expression was observed in the tubular atrophy of hypertension. As FGGS developed, podocyte depletion, cellular senescence markers, and PEC activation were associated with TC and increased with hypertension.

The International IgA Nephropathy (IgAN) prediction tool provides reliable risk estimates for kidney outcomes using clinical and histopathological variables. However, additional structural biomarkers may further improve prognostic precision. This study investigated whether incorporating estimated nephron number enhances the predictive performance of the International IgAN prediction tool. We conducted a post hoc analysis of 218 adult patients with primary IgAN diagnosed with native kidney biopsy between 2007 and 2017. Nephron number per kidney was estimated by multiplying estimated kidney cortical volume derived from unenhanced computed tomography by nonsclerotic glomerular density obtained from kidney biopsy specimens. The 5 year risk of a composite kidney outcome (≥ 50

Abstract Background Single-nephron glomerular filtration rate (GFR) represents a nephron-level functional index that may reveal key pathophysiological mechanisms driving progression in patients with diabetic nephropathy. However, its clinical relevance remains incompletely understood. This cross-sectional study assessed single-nephron estimated GFR (eGFR) across different chronic kidney disease (CKD) stages in patients with advanced diabetic nephropathy. Methods Nephron number was estimated as the number of nonglobally sclerotic glomeruli per kidney using computed tomography-derived cortical volume combined with biopsy stereology. Single-nephron eGFR was calculated by dividing eGFR by the nephron number of both kidneys. Patients were stratified according to CKD stage at kidney biopsy. Associations between CKD stages and single-nephron eGFR were evaluated using multivariable linear regression models adjusted for age, sex, urinary protein excretion, and eGFR. Results The study included 105 patients with biopsy-proven diabetic nephropathy and overt proteinuria (median age 59 years, 83% male, HbA1c 6.6%, 57% had nephrotic range proteinuria). The percentage of globally sclerotic glomeruli, mesangial expansion score, and prevalence of nodular lesions increased significantly with advancing CKD stage. Median nephron number declined from 529,178 to 224,458 per kidney, whereas glomerular volume remained constant. Single-nephron eGFR decreased markedly with CKD stage and remained significantly inversely associated with CKD stage after adjustment for clinicopathologic covariates ( P for trend <0.001). Conclusion In overt diabetic nephropathy, single-nephron eGFR decreased with advancing CKD stage, despite relatively preserved glomerular volume. At this stage of disease, structural alterations specific to diabetic nephropathy may impair effective single-nephron filtration capacity.

BACKGROUND:We previously reported substantial variability in the number of nephrons in patients with IgA nephropathy (IgAN), even among patients with similar risk factor profiles. This retrospective cohort study aimed to evaluate the clinical significance of nephron number at diagnostic biopsy for subsequent kidney outcomes in patients with IgAN. METHODS:The number of nephrons, defined as the total number of non-globally sclerotic glomeruli per kidney, was estimated using computed tomography imaging and biopsy-based stereology. Kidney outcomes were compared based on tertiles of nephron number. The primary endpoint was the annual slope of the estimated glomerular filtration rate (eGFR), and the secondary endpoint was the initiation of kidney replacement therapy. RESULTS:A total of 222 Japanese adults with IgAN were included. Among the entire cohort, eGFR exhibited a gradual decline over time during a median follow-up of 7.6 years. Annual eGFR slopes, adjusted for baseline eGFR, baseline proteinuria, Oxford classification scores, and therapies during the first year after biopsy, were -1.35, -1.11, and -0.97 mL/min/1.73 m2/year for the lowest to highest nephron number tertiles, respectively (P for trend < 0.001). Kidney replacement therapy was initiated in 32.4%, 10.8%, and 0% of patients in the lowest, middle, and highest tertiles, respectively (P for trend < 0.001). A significantly higher risk of kidney replacement therapy initiation with decreasing number of nephrons was confirmed using multivariable adjusted Cox proportional hazards models. CONCLUSIONS:Lower number of non-globally sclerotic glomeruli per kidney identified at diagnostic biopsy was independently associated with increased rate of future kidney functional decline in IgAN patients, providing additional information beyond conventional clinical and histopathological risk factors. Incorporating this metric into routine evaluation may enhance risk stratification and inform more personalized, targeted treatment strategies for patients with IgAN.

No previous studies have examined the clinical significance of nephron number in patients with IgA nephropathy. In patients with IgA nephropathy, a lower number of nephrons per kidney was significantly associated with an increased rate of subsequent decline in kidney function. These findings highlight the utility of incorporating this metric into diagnostic evaluations to help assess risk and tailor treatment for IgA nephropathy. We previously reported substantial variability in the number of nephrons in patients with IgA nephropathy, even among patients with similar risk factor profiles. This retrospective cohort study aimed to evaluate the clinical significance of nephron number at diagnostic biopsy for subsequent kidney outcomes in patients with IgA nephropathy. The number of nephrons, defined as the total number of nonglobally sclerotic glomeruli per kidney, was estimated using computed tomography imaging and biopsy-based stereology. Kidney outcomes were compared based on tertiles of nephron number. The primary end point was the annual slope of the eGFR, and the secondary end point was the initiation of KRT. A total of 222 Japanese adults with IgA nephropathy were included. Among the entire cohort, eGFR exhibited a gradual decline over time during a median follow-up of 7.6 years. Annual eGFR slopes, adjusted for baseline eGFR, baseline proteinuria, Oxford classification scores, and therapies during the first year after biopsy, were −1.35, −1.11, and −0.97 ml/min per 1.73 m 2 per year for the lowest to highest nephron number tertiles, respectively ( P for trend <0.001). KRT was initiated in 32.4%, 10.8%, and 0% of patients in the lowest, middle, and highest tertiles, respectively ( P for trend <0.001). A significantly higher risk of KRT initiation with decreasing number of nephrons was confirmed using multivariable adjusted Cox proportional hazards models. Lower number of nonglobally sclerotic glomeruli per kidney identified at diagnostic biopsy was independently associated with increased rate of future kidney functional decline in patients with IgA nephropathy, providing additional information beyond conventional clinical and histopathologic risk factors. Incorporating this metric into routine evaluation may enhance risk stratification and inform more personalized, targeted treatment strategies for patients with IgA nephropathy.

KEY POINTS:Systematic review/meta-analysis of 23 studies (15,289 patients) quantified prognostic effect of low-grade proteinuria in IgA nephropathy. Low-grade proteinuria (0.5-1.0 g/d) linked to higher kidney risk (hazard ratio, 1.73-2.87) and faster eGFR decline (-1.02 ml/min per year). Long-term suppression below 0.5 g/d should be a key therapeutic goal, supporting current IgA nephropathy clinical guidelines. BACKGROUND:Overt proteinuria (>1.0 g/d) is a well-established risk factor for kidney disease progression in IgA nephropathy. However, recent evidence suggests that even low-grade proteinuria, typically defined as 0.5-1.0 g/d, may be clinically significant. The prognostic effect of low-grade proteinuria has not been systematically evaluated. METHODS:We conducted a systematic review and meta-analysis to evaluate the association between low-grade proteinuria and adverse kidney outcomes in patients with IgA nephropathy. A systematic literature search was performed on PubMed and Web of Science. Eligible studies included those reporting on kidney outcomes such as eGFR decline, kidney failure, or eGFR slope in relation to low-grade proteinuria measured either at baseline or during follow-up ( e.g ., time-averaged proteinuria). Data were synthesized using random-effects meta-analysis. The protocol was registered in the Open Science Framework REGISTRIES ( https://osf.io/5dfqr ). RESULTS:A total of 23 studies ( N =15,289) met the inclusion criteria, of which 15 contributed to at least one meta-analysis. Baseline low-grade proteinuria was significantly associated with an increased risk of adverse kidney outcomes compared with proteinuria below 0.5 g/d (pooled hazard ratio, 1.73; 95% confidence interval [CI], 1.36 to 2.20; nine studies). Similarly, low-grade time-averaged proteinuria was associated with a higher risk of kidney outcomes (pooled hazard ratio, 2.87; 95% CI, 1.48 to 5.56; seven studies) and a significantly steeper annual decline in eGFR (mean difference, -1.02 ml/min per 1.73 m 2 per year; 95% CI, -1.60 to -0.45; four studies). Subgroup analyses and leave-one-out sensitivity analyses were consistent with the overall findings. CONCLUSIONS:Low-grade proteinuria, whether assessed at baseline or over time, is an important predictor of kidney disease progression in patients with IgA nephropathy. These results reinforce recent clinical guidelines recommending proteinuria control under 0.5 g/d. Long-term suppression of proteinuria should be considered a key therapeutic goal in IgA nephropathy.

Glomerular hypertension is a critical factor in kidney disease progression. Traditionally, nephron number (Nglom) was considered a determinant of glomerular hemodynamics, but emerging evidence suggests a more substantial impact of renal structural factors. This cross‐sectional study aimed to evaluate the relationship between renal histopathological parameters and intraglomerular hydrostatic pressure (Pglo) in healthy donors. Retrospective analyses were conducted on 60 healthy living donors who donated a kidney between January 1, 2007, and September 30, 2022. The non‐sclerotic glomerular number (Nglom NSG ), glomerular volume, cortical volume, and other histopathological parameters were evaluated. Pglo was estimated using Gomez's equation. Pglo was positively associated with cortical volume (standardized regression coefficient [ β ] = 0.34, p = 0.04) but not with Nglom NSG ( β = 0.12, p = 0.44). Cortical volume was inversely associated with afferent arteriolar resistance ( β = −0.33, p < 0.01). These findings suggest that an increase in cortical volume, independent of nephron number, may contribute to an increase in Pglo through a reduction in afferent arteriolar resistance. These results refine current models of glomerular hemodynamics, highlighting the importance of structural renal evaluation, including cortical volume, in assessing early chronic kidney disease risk.