Health care transition from pediatric-focused to adult-focused nephrology care comes with significant challenges for adolescents/young adults with kidney disease, their caregivers, and the pediatric-focused and adult-foc...Health care transition from pediatric-focused to adult-focused nephrology care comes with significant challenges for adolescents/young adults with kidney disease, their caregivers, and the pediatric-focused and adult-focused practitioners. As younger generations enter this period, transition preparation strategies need to better align with their preferences for autonomy and digital fluency. This scoping review focused on several structured protocols, such as the Recognition, Insight, Self-Reliance, and Establishment of Healthy Habits to Transition model; Self-Management and Transition to Adulthood with R x ; ON Taking Responsibility for Adolescent/Adult Care; Ready Steady Go/Plain Language, Engagement, Empathy, Empowerment, Respect; and others, evaluating their adaptability to younger generations' preferences. This review also highlights barriers posed by emerging technological tools, such as limitations of resources and inconsistent physician coordination. Finally, the role of caregivers is explored, underscoring the importance of early preparation to foster independence and address transition preparation needs. Ultimately, successful preparation and transfer of care require the development of thoughtful and equitable digital tools. Adjusting protocols to meet the expectations of adolescents and young adults may improve adherence and long-term outcomes after their transfer to adult-focused health care.
J Am Soc Nephrol
· 2026 Feb · PMID 41739578
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KEY POINTS: Many kidney transplant noninferiority trials used unjustified or overly generous margins, risking adoption of inferior therapies. Inadequate analyses, poor missing data handling, and weak Consolidated Standar...KEY POINTS: Many kidney transplant noninferiority trials used unjustified or overly generous margins, risking adoption of inferior therapies. Inadequate analyses, poor missing data handling, and weak Consolidated Standards of Reporting Trials (CONSORT) adherence limit trial interpretation. Stronger noninferiority trial design and reporting are needed to improve evidence quality in kidney transplantation. BACKGROUND: Noninferiority trials are essential in kidney transplantation, where established standard-of-care treatments make placebo-controlled designs infeasible, and their use is increasing. We aimed to assess the design and reporting quality of noninferiority trials in kidney transplantation, specifically assessing adherence to existing guidelines. METHODS: We searched medical literature analysis and retrieval system online, Embase, and Cochrane Central Register of Controlled Trials for randomized controlled noninferiority trials in kidney transplantation published up to February 2025. Two investigators reviewed and extracted data. Study quality was assessed regarding design and reporting quality using key noninferiority design criteria and the Consolidated Standards of Reporting Trials 2012 extension, respectively. RESULTS: We identified 43 unique trials: 36 (84%) compared a novel immunosuppressive regimen to standard of care and 26 (60%) were industry sponsored. The noninferiority margin (the worst-case loss in efficacy considered clinically acceptable) was not justified in 28 (65%) studies and poorly justified in seven (16%). Of 32 studies with a categorical primary outcome, 30 (94%) assessed absolute risk reduction rather than relative risk. Most studies had high withdrawal and dropout rates, yet 33 (77%) did not specify methods for handling missing data. Intention-to-treat analysis alone was used to determine primary efficacy in 24 (56%) studies. Twelve studies (28%) provided an incorrect conclusion, most claiming equivalence when noninferiority had not been adequately demonstrated. Both design and reporting quality have improved over time ( P = 0.02, P = 0.002, respectively). No association was evident between design or reporting quality and journal impact factor or sponsor type. CONCLUSIONS: We found major deficiencies in the design, conduct, and reporting of noninferiority trials in kidney transplantation.
Bolas G, Borza CM, Bock F
… +11 more, Dong X, Hanson O, Chiusa M, Cao S, Tsai MT, Fogo AB, Zhang MZ, Harris RC, Brooks CR, Zent R, Pozzi A
J Am Soc Nephrol
· 2026 Feb · PMID 41734039
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KEY POINTS: Discoidin domain receptor 1 (DDR1) translocated to the mitochondria of proximal tubule cells after AKI. DDR1 contributed to AKI by promoting the production of mitochondrial reactive oxygen species and cell ap...KEY POINTS: Discoidin domain receptor 1 (DDR1) translocated to the mitochondria of proximal tubule cells after AKI. DDR1 contributed to AKI by promoting the production of mitochondrial reactive oxygen species and cell apoptosis. Mechanistically, DDR1 translocated to mitochondria by interacting with Hsp60 and promoted oxidative stress by regulating phosphorylation of p66Shc. BACKGROUND: Mitochondrial damage with overproduction of mitochondrial reactive oxygen species (mtROS) and apoptosis is a hallmark of AKI. Discoidin domain receptor 1 (DDR1) is a collagen receptor tyrosine kinase that contributes to AKI. Mass spectrometry analysis of DDR1-interacting proteins identified several mitochondrial proteins, suggesting that DDR1 associated with mitochondria. Thus, we analyzed whether DDR1 translocated to mitochondria and promoted mitochondrial dysfunction after AKI. METHODS: We analyzed DDR1 localization in kidneys of patients with AKI and mice after ischemia/reperfusion-induced AKI. To determine whether mitochondrial DDR1 (mtDDR1) regulated mitochondrial functions, we generated kidney cells expressing wild-type or a kinase dead DDR1. Then, we investigated the location of wild-type or mutated DDR1 on collagen stimulation, the steps involved in DDR1 mitochondrial translocation, and the contribution of mtDDR1 in regulating mtROS production and apoptosis. RESULTS: mtDDR1 was detected in injured human and mice kidneys, and collagen-activated DDR1 translocated to the mitochondria where it increased mtROS production and tubule cell apoptosis. Collagen-activated DDR1 translocated to the outer membrane of mitochondria through its association with the chaperone mtHsp60 and induced oxidative stress and apoptosis by promoting tyrosine phosphorylation of p66Shc, a regulator of the cellular redox state and apoptosis. Moreover, cells expressing a kinase dead DDR1, treated with a DDR1 inhibitor, or expressing p66Shc mutated in the DDR1-targeted phosphorylation sites had reduced mtROS and apoptosis. CONCLUSIONS: We describe a novel noncanonical pathway whereby activated DDR1 translocates to the mitochondria to promote oxidative stress and cell apoptosis.
Lee HH, Cho SMJ, McCarthy CP
… +4 more, Yoo TH, Wadhera RK, Secemsky EA, Natarajan P
J Am Soc Nephrol
· 2026 Feb · PMID 41719070
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BACKGROUND: The real-world uptake of the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) blood pressure (BP) guideline, which lowered the systolic BP target to <120 mmHg for patients with chronic kidney disease (C...BACKGROUND: The real-world uptake of the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) blood pressure (BP) guideline, which lowered the systolic BP target to <120 mmHg for patients with chronic kidney disease (CKD), is poorly understood. We examined the adoption of the 2021 KDIGO systolic BP target in clinical practice and its association with clinical outcomes. METHODS: The study was based on data from the Mass General Brigham healthcare network, an integrated healthcare system spanning primary to tertiary care in New England. In serial cross-sectional analysis, we identified ∼50 000 patients with CKD stage 3-4 in each year from 2020 to 2024 and assessed the annual proportion of patients within the 2021 KDIGO systolic BP target. In longitudinal analysis, we identified 18 996 patients with incident CKD stage 3-4 in 2014-2019 and evaluated the association between systolic BP above vs. within the target and clinical outcomes. RESULTS: In serial cross-sectional analysis, 18.3% of patients with CKD had systolic BP within the 2021 KDIGO target in 2020 (pre-guideline). The proportion changed only marginally after the guideline's publication-18.0% in 2021 (absolute difference, -0.3% [95% CI, -1.2 to 1.3]), 19.3% in 2022 (absolute difference, 1.0% [95% CI, -0.1 to 2.0]), 20.0% in 2023 (absolute difference, 1.7% [95% CI, 0.2 to 3.1]), and 21.9% in 2024 (absolute difference, 3.6% [95% CI, 1.9 to 5.3]). In longitudinal analysis, patients with systolic BP above the 2021 KDIGO target exhibited higher risks of cardio-kidney end points, lower risk of hypotension, and no differences in other safety end points compared to those within the target. CONCLUSIONS: Adoption of the 2021 KDIGO BP guideline remained limited in real-world practice. As of 2024, nearly 4 in 5 patients with CKD had systolic BP above the new guideline target.
Hundemer GL, Desbiens LC, Agharazii M
… +12 more, Madore F, Vaidya A, Leung AA, Kline GA, Sood MM, Akbari A, White C, Glassman I, Shaw JLV, Colantonio DA, Ramsay T, Goupil R
J Am Soc Nephrol
· 2026 Feb · PMID 41686513
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KEY POINTS: This prospective study of 976 adults measured the association between subclinical primary aldosteronism and kidney outcomes. Among a general healthy adult population, subclinical primary aldosteronism was ass...KEY POINTS: This prospective study of 976 adults measured the association between subclinical primary aldosteronism and kidney outcomes. Among a general healthy adult population, subclinical primary aldosteronism was associated with steeper decline in eGFR over time. Primary aldosteronism pathophysiology spans a wide unrecognized continuum that parallels the risk for kidney disease. BACKGROUND: Primary aldosteronism, an overt form of renin-independent aldosterone production, leads to steeper eGFR decline compared with primary hypertension. Mounting evidence suggests that milder forms of renin-independent aldosterone production (subclinical primary aldosteronism) are highly prevalent; however, the link between subclinical primary aldosteronism and eGFR decline remains unknown. METHODS: This prospective cohort study included 976 Canadian adults aged 40-69 years, with predominantly normal BP or mild untreated hypertension, from the randomly sampled, population-based CARTaGENE cohort. Aldosterone and renin concentrations were measured at enrollment (2009-2010). Creatinine and cystatin C were measured at enrollment and 5-7 years postenrollment. Multivariable linear mixed regression models were used to measure the associations of aldosterone, renin, and the aldosterone-to-renin ratio (ARR) with eGFR decline over time. RESULTS: The mean (SD) age of participants was 53 (7) years; 51% were female. Mean BP was 121 (15)/72 (10) mm Hg, and 11% had BP ≥140/90 mm Hg. Mean eGFR CrCysC was 109 (16) ml/min per 1.73 m 2 . At higher ARR levels, there was steeper mean eGFR decline over time (Tertile 1 [ARR, ≤0.49 ng/dl per mU/L]: -1.40 [1.77] ml/min per 1.73 m 2 /yr, Tertile 2 [ARR, 0.50-0.87 ng/dl per mU/L]: -1.48 [1.75] ml/min per 1.73 m 2 /yr, Tertile 3 [ARR, >0.87 ng/dl per mU/L]: -1.57 [1.79] ml/min per 1.73 m 2 /yr; P = 0.01), representing 11% steeper decline in the highest versus lowest ARR tertile. At lower renin levels, there was steeper mean eGFR decline over time (Tertile 1 [renin, ≤9.2 mU/L]: -1.59 [1.80] ml/min per 1.73 m 2 /yr, Tertile 2 [renin, 9.3-15.9 mU/L]: -1.53 [1.77] ml/min per 1.73 m 2 /yr, Tertile 3 [renin, >15.9 mU/L]: -1.33 [1.72] ml/min per 1.73 m 2 /yr; P = 0.04), representing 16% steeper eGFR decline in the lowest versus highest renin tertile. There was no significant association between aldosterone and eGFR change over time ( P = 0.50). All aforementioned associations were independent of BP and were consistent among participants with normal BP in isolation. CONCLUSIONS: Independent of BP, elevated ARR and suppressed renin were associated with steeper eGFR decline over time.
Ha K, Loeb GB, Park M
… +11 more, Gupta M, Akiyama Y, Argiris J, Pinedo A, Park CH, Brandes N, Ritu F, Ye CJ, Coyote-Maestas W, Reiter JF, Delling M
J Am Soc Nephrol
· 2026 Feb · PMID 41665965
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KEY POINTS: We developed assays to measure genetic variant effects on polycystin-1, the protein mutated in most autosomal dominant polycystic kidney disease. All tested pathogenic variants disrupted either polycystin-1 c...KEY POINTS: We developed assays to measure genetic variant effects on polycystin-1, the protein mutated in most autosomal dominant polycystic kidney disease. All tested pathogenic variants disrupted either polycystin-1 ciliary trafficking or channel function. Trafficking and channel function of some pathogenic variants was restored by low temperature culture to promote polycystin folding. BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the leading monogenic cause of kidney failure and affects millions of people worldwide. Despite the prevalence of ADPKD, limited mechanistic understanding has hindered therapeutic development. Most ADPKD is caused by loss-of-function variants in polycystin-1 (PC1). METHODS: We developed assays that quantify the effect of nontruncating variants on PC1 ciliary localization, membrane trafficking, and polycystin channel function. RESULTS: We evaluated 29 nontruncating variants in PC1 and found that pathogenic variants disrupt two molecular phenotypes: ( 1 ) localization of PC1 at the primary cilium or ( 2 ) polycystin ion channel activity. Ciliary localization of a subset of polycystin variants was restored when cells were cultured at low temperature. A subset of variants with localization restored by low temperature formed functional channels. CONCLUSIONS: This study demonstrated that disruptions in polycystin ciliary trafficking and channel function are common causes of ADPKD. Defects in ciliary trafficking and channel function can be rescued for a subset of pathogenic variants, establishing a foundation for polycystin-targeted therapies in ADPKD.
Li Z, Haycraft CJ, Croyle MJ
… +20 more, Hudson D, Yuan Y, Simanyi K, Vendrame HC, Wang J, Kachwala AI, Ma Y, Parant JM, Chumley P, Zhou J, Mrug M, Parnell SC, Tran PV, Gao H, Qian F, Outeda P, Wallace DP, Watnick TJ, Yoder BK, PKD Research Resource Consortium
J Am Soc Nephrol
· 2026 Feb · PMID 41665947
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KEY POINTS: A HaloTag knock-in resource allows direct visualization of endogenous polycystin-2 (PC2), enabling quantitative analysis of its localization, turnover, and transport dynamics. PC2-HaloTag labeling establishes...KEY POINTS: A HaloTag knock-in resource allows direct visualization of endogenous polycystin-2 (PC2), enabling quantitative analysis of its localization, turnover, and transport dynamics. PC2-HaloTag labeling establishes PC1-dependent and Tulp3-dependent control of PC2 ciliary targeting in vivo and in cells. BACKGROUND: Polycystin-2, encoded by PKD2 , is a cation channel essential for kidney physiology. Dysfunction of Pkd2 causes autosomal dominant polycystic kidney disease. Currently, our understanding of cystogenesis in the kidney is limited by the difficulty of visualizing the localization and molecular functions of endogenous polycystin proteins. METHODS: Using clustered regularly interspaced short palindromic repeats/Cas9, we engineered a Pkd2 HaloTag knock-in mouse (referred to as Pkd2c-Halo ) and derived tsSV40-immortalized Pkd2c-Halo renal epithelial cell lines. We optimized HaloTag labeling for in vivo and in vitro applications, demonstrating its use in confocal and live cell microscopy, pulse-chase assays, affinity isolation, and in vivo imaging of Pkd2 protein localization after kidney injury and in disease-relevant Tulp3R400W/R400W and Pkd1null mutant backgrounds. RESULTS: Homozygous Pkd2c-Halo mice were viable, fertile, and phenotypically normal, confirming that the C-terminal HaloTag did not disrupt Pkd2 function. Pkd2-c-Halo was detected by Western blotting and localized to endoplasmic reticulum and the primary cilium. Labeling occurred within 30 minutes and plateaued by 3 hours at doses of ≥2 nmol/mouse and ≥25 nM in vivo and in cultured cells, respectively. Pulse-chase analysis showed complete Pkd2-c-Halo turnover within 48 hours in the cilia of the choroid plexus in vivo and 24 hours in cultured renal epithelial cells. HaloTrap affinity resin purified the endogenous Pkd2-c-Halo from cells and tissues efficiently for protein complex analysis. While kidney injury is known to accelerate cyst formation, unilateral ureteral obstruction did not alter Pkd2-c-Halo expression or distribution. Finally, in a Pkd1 null background or in mice homozygous for Tulp3R400W , an allele identified in a patient with hepatorenal cystic disease, Pkd2-c-Halo failed to localize in cilia in kidney tubule epithelium. CONCLUSIONS: The Pkd2-c-Halo mouse and derived renal epithelial cell lines enable detection of endogenous polycystin-2 in vivo and in vitro , allowing analysis of its localization, turnover under homeostatic conditions, after kidney injury, and in disease-relevant genetic backgrounds.
Cratere MG, Perrone B, Canciani B
… +2 more, Schaeffer C, Rampoldi L
J Am Soc Nephrol
· 2026 Feb · PMID 41632531
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KEY POINTS: Calorie restriction stimulated autophagy and degradation of mutant uromodulin, leading to amelioration of cell stress and tubular damage. At early disease stage, calorie restriction largely reverted autosomal...KEY POINTS: Calorie restriction stimulated autophagy and degradation of mutant uromodulin, leading to amelioration of cell stress and tubular damage. At early disease stage, calorie restriction largely reverted autosomal dominant tubulointerstitial kidney disease (ADTKD)- UMOD phenotype, preventing inflammation, fibrosis, and kidney function decline. At advanced disease stage, calorie restriction significantly delayed disease progression and worsening of kidney function. BACKGROUND: Mutations in UMOD , encoding uromodulin, lead to autosomal dominant tubulointerstitial kidney disease (ADTKD), a genetic cause of kidney failure. UMOD mutations have a common gain-of-toxic-function effect, causing mutant uromodulin retention in the endoplasmic reticulum (ER). This leads to ER stress, alteration of protein homeostasis and mitochondrial dynamics, defective autophagy, and increased cell death. Calorie restriction exerts a beneficial role in diseases characterized by accumulation of pathogenic protein and inflammation, by modulating several pathways, including autophagy induction and suppression of inflammation and fibrosis. Given the relevance of these features in ADTKD, we investigated the effect of calorie restriction on disease onset and progression. METHODS: Transgenic mice expressing C147W uromodulin (Tg Umod C147W ) were subjected to a moderate (30%) calorie restriction regimen for 15 or 24 weeks, starting at different stages of disease progression. RESULTS: Calorie restriction restored autophagy, as shown by decreased P62 punctae and quenched mammalian target of rapamycin (mTOR) activation specifically in mutant uromodulin-expressing cells, and it recovered expression of key ER-phagy receptor genes, with a concomitant, striking reduction of mutant uromodulin ER retention. In presymptomatic Tg Umod C147W mice, calorie restriction alleviated epithelial cell stress. This, likely along with a direct anti-inflammatory effect of calorie restriction, prevented inflammation and progressive decline of kidney function. At this early disease stage, calorie restriction ameliorated the already established kidney damage and reduced fibrosis, suggesting reversal of ADTKD phenotype. Calorie restriction was also effective in significantly delaying disease progression in Tg Umod C147W mice with advanced disease and already compromised kidney function. CONCLUSIONS: Calorie restriction enhanced autophagy and uromodulin degradation, counteracting the primary effect of UMOD mutations, and significantly ameliorated kidney disease onset and progression.
J Am Soc Nephrol
· 2026 Feb · PMID 41632529
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KEY POINTS: The Medicare Secondary Payer Act modestly reduced federal dialysis spending when accounting for the effect on forgone tax revenue. The policy saved money only when private prices were <3.05 times Medicare rat...KEY POINTS: The Medicare Secondary Payer Act modestly reduced federal dialysis spending when accounting for the effect on forgone tax revenue. The policy saved money only when private prices were <3.05 times Medicare rates. Medicare assuming primary payer status for all dialysis care would have saved the government $1 billion annually. BACKGROUND: The Medicare Secondary Payer Act (MSPA) requires that employer group health plans serve as the primary payer for individuals with ESRD for 30 months, with Medicare serving as the secondary payer. After 30 months, Medicare becomes the primary payer. The net fiscal consequences of this policy for the federal government are unknown. METHODS: We estimated the net federal fiscal effect of the MSPA for patients receiving dialysis and identified the private-to-Medicare spending ratio ( R ) at which the policy breaks even, accounting for the forgone tax revenue associated with tax-deductible private health care spending. We conducted an economic evaluation using published data on spending and utilization for ESRD, private-to-Medicare spending ratios for dialysis, dialysis chain financials, and federal tax parameters. Primary outcomes were expressed per privately insured dialysis patient-year, with a national aggregate calculated from incident ESRD counts. RESULTS: At current tax rates, the break-even spending ratio was R <3.05. Using central price ratio estimates of R =2.99, the MSPA reduced federal outlays by $2217 per privately insured dialysis patient-year, or $75 million annually, relative to Medicare being the primary payer for dialysis patients without a coordination period. Ignoring the effect of the MSPA on tax revenue overstated the estimated savings from the MSPA by 4500%. Altering the MSPA so Medicare became the primary payer for dialysis treatments while retaining the coordination period for other services for dialysis patients would have increased federal savings to $29,981 per privately insured dialysis patient-year or $1 billion annually. CONCLUSIONS: Under current prices and tax rates, the MSPA modestly reduced federal spending, while counterfactual policy changes would result in larger savings.