KEY POINTS: This study evaluated the safety and efficacy of B -cell maturation antigen-CD19 dual-targeted chimeric antigen receptor- T -cell therapy for patients with relapsed/refractory AL amyloidosis. B -cell maturatio...KEY POINTS: This study evaluated the safety and efficacy of B -cell maturation antigen-CD19 dual-targeted chimeric antigen receptor- T -cell therapy for patients with relapsed/refractory AL amyloidosis. B -cell maturation antigen-CD19 dual-targeted chimeric antigen receptor- T -cell therapy was well tolerated and no dose limiting toxicity occurred. Single-cell analysis confirmed B -cell maturation antigen-CD19 chimeric antigen receptor- T -cell enabled complete elimination of pathogenic plasma and B cells and promoted immune reconstitution. BACKGROUND: The potential efficacy of chimeric antigen receptor (CAR)- T cells for the treatment of relapsed/refractory systemic light chain (AL) amyloidosis remains elusive. This study aimed to investigate the efficacy and safety of B -cell maturation antigen (BCMA)-CD19 dual-targeted CAR- T -cell therapy in patients with refractory/relapsed AL amyloidosis in a single-center exploratory trial. METHODS: The key eligibility criteria of this trial were patients with AL amyloidosis and at least one major organ involvement who were refractory to or had relapsed from at least two lines of therapy. The primary outcome was the safety of CAR- T therapy. All eligible patients received a single infusion of 0.3×10 6 /kg the BCMA-CD19 dual-targeted CAR- T cells after preconditioning with fludarabine (30 mg/m 2 per day for 3 days) and cyclophosphamide (300 mg/m 2 per day for 3 days). RESULTS: Notably, six patients with refractory/relapsed AL amyloidosis were enrolled, all of whom had kidney involvement, and one of whom had cardiac involvement with Mayo stage 3a disease. After a median follow-up of 640 (range, 563-745) days, all six patients achieved hematologic complete response (100%, 95% confidence interval, 54% to 100%) and renal response (100%, 95% confidence interval, 54% to 100%). The median time to hematologic response and renal response were 9 (interquartile range, 6-11) and 75 (interquartile range, 18-180) days, respectively. One patient relapsed at month 6, while the other patients remained in remission. Grade 1 cytokine release syndrome occurred in two patients, and no immune effector cell-associated neurotoxicity syndrome was identified. Pneumonia occurred in two of the six patients. One patient had grade 3 urticaria and grade 2 AKI. One patient developed acute promyelocytic leukemia 15 months post-CAR- T -cell therapy. Single-cell RNA/ B -cell receptor sequencing confirmed that BCMA-CD19 dual-targeted CAR- T cells enabled the comprehensive clearance of pathogenic plasma cells and aberrant B cells, while also promoting endogenous immune reconstitution in AL amyloidosis. CONCLUSIONS: This study provides preliminary evidence for the feasibility and tolerability of BCMA-CD19 dual-targeting CAR- T -cell therapy, and it showed promising activity in patients with relapsed/refractory AL amyloidosis. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov, NCT05978661 .
Agarwal R, Correa-Rotter R, Navaneethan SD
… +14 more, Fukami K, Heerspink HJL, Mann JFE, McGill JB, Mottl AK, Nangaku M, Rosenstock J, Rossing P, Vaduganathan M, Scott C, Li L, Aldworth C, Green JB, Weir MR
J Am Soc Nephrol
· 2026 Mar · PMID 41905767
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KEY POINTS: We investigated the effect of empagliflozin, finerenone, and their combination on eGFR decline in people with type 2 diabetes and albuminuria. Acute declines in eGFR occurred more in those on combination ther...KEY POINTS: We investigated the effect of empagliflozin, finerenone, and their combination on eGFR decline in people with type 2 diabetes and albuminuria. Acute declines in eGFR occurred more in those on combination therapy, on diuretics, and with higher eGFR; eGFR changes were reversible. Finerenone's additive effect to empagliflozin on urinary albumin-to-creatinine ratio lowering is nonhemodynamic; empagliflozin lowers urinary albumin-to-creatinine ratio in part driven by eGFR change. BACKGROUND: eGFR decline is common with sodium-glucose cotransporter 2 inhibitors and renin-angiotensin system inhibitors, often prompting treatment interruption or cessation, limiting cardiorenal benefits. This mostly prespecified COmbinatioN effect of FInerenone anD EmpaglifloziN in participants with chronic kidney disease and type 2 diabetes using a UACR Endpoint (CONFIDENCE) trial analysis investigated the effect of empagliflozin, finerenone, and their combination on change from baseline in eGFR and its determinants and the relationship of change in eGFR with albuminuria reduction in people with type 2 diabetes and CKD. METHODS: Evaluable participants ( N =790) with type 2 diabetes, CKD, and albuminuria, receiving stable doses of renin-angiotensin system inhibitors, were randomized 1:1:1 to empagliflozin, finerenone, or both. The primary outcome was urinary albumin-to-creatinine ratio (UACR) change from baseline to day 180. We assessed mean eGFR change from baseline at day 14 (acute), determinants of acute eGFR decline, and acute eGFR change from baseline as a mediator of UACR reduction at day 180. RESULTS: The mean acute eGFR decline was greater with combination therapy (-6.6 ml/min per 1.73 m 2 ) than with finerenone (-2.1 ml/min per 1.73 m 2 ) or empagliflozin (-4.8 ml/min per 1.73 m 2 ) monotherapy; P < 0.001. Acute decline in eGFR was significantly more pronounced among participants with higher baseline eGFR and in those receiving diuretics at baseline ( P < 0.001 for both factors). Baseline values for systolic BP and UACR had no statistically significant effect on acute eGFR decline. Exploratory analysis showed that acute eGFR change mediated 28% of the effect of adding empagliflozin to finerenone on UACR reduction at day 180 but only 5.2% of the effect when adding finerenone to empagliflozin. AKI was uncommon in all treatment groups. CONCLUSIONS: Acute eGFR decline was significantly associated with combination therapy, higher baseline eGFR, and diuretic use at baseline. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov, NCT05254002 .
Heerspink HJL, Noronha IL, Górriz JL
… +15 more, Lim SK, Kotwal SS, Kirsztajn GM, Barros Neto J, Ryan J, Fu MS, Kim SG, Barratt J, Brahmbhatt Y, Housler GJ, Jiao R, Dahlke M, Lodha A, Mottl AK, Atrasentan and Sodium Glucose Cotransporter-2 Inhibitor Efficacy and Safety Trial (ASSIST) Investigator Group
J Am Soc Nephrol
· 2026 Mar · PMID 41904616
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KEY POINTS: Patients with IgA nephropathy and proteinuria are at risk of kidney failure despite use of guideline-recommended renin-angiotensin system and sodium-glucose cotransporter 2 (SGLT2) inhibition. Atrasentan redu...KEY POINTS: Patients with IgA nephropathy and proteinuria are at risk of kidney failure despite use of guideline-recommended renin-angiotensin system and sodium-glucose cotransporter 2 (SGLT2) inhibition. Atrasentan reduces proteinuria in IgA nephropathy, but its efficacy as adjunct to renin-angiotensin system and SGLT2 inhibition has not been rigorously tested. Atrasentan provided a clinically meaningful reduction in proteinuria in adults with IgA nephropathy treated with renin-angiotensin system and SGLT2 inhibitors. BACKGROUND: Atrasentan, a highly selective endothelin-A receptor antagonist, is approved for proteinuria reduction in adults with IgA nephropathy. Renin-angiotensin system inhibitors (RASi) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) are guideline recommended, yet the additional benefit of atrasentan has not been rigorously determined. METHODS: We performed a randomized, double-blind, placebo-controlled crossover study of atrasentan in adults with IgA nephropathy, eGFR ≥30 ml/min per 1.73 m 2 , and urinary protein >0.5 g/d while on maximal, stable RASi and SGLT2i. Participants were randomized 1:1 to either sequence AB or sequence BA (0.75 mg atrasentan [A] once daily during period 1 and matching placebo [B] during period 2, or vice versa), with a 12-week washout period in between. The primary end point was the change in urinary protein-to-creatinine ratio (UPCR) to week 12. The secondary end point was the change in UPCR to week 24. Safety end points included the type, incidence, severity, seriousness, and relatedness of adverse events (AEs). RESULTS: We recruited 54 participants with mean age 48 years (SD 12), 43% female, mean (SD) eGFR 63 (22) ml/min per 1.73 m 2 , and median UPCR 1.0 g/g (Q1-Q3, 0.7-1.4). Treatment with atrasentan versus placebo resulted in a difference in geometric mean percentage change in UPCR at week 12 of -25.3% (95% confidence interval, -36.8 to -11.7; P < 0.001). The treatment difference in UPCR between atrasentan versus placebo during treatment period 2 at week 24 was -26.4% (95% confidence interval, -45.8 to -0.0). There was one unrelated serious adverse event. Fluid retention events were uncommon, and none required hospitalization. There were no study drug discontinuations due to treatment-related adverse events and no deaths. CONCLUSIONS: Atrasentan provided a clinically meaningful reduction in proteinuria in adults with IgA nephropathy and proteinuria ≥0.5 g/d treated with RASi and SGLT2i therapy. Atrasentan was well tolerated, and no new safety signals emerged. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: NCT05834738 .
Zhao Z, Zhou Z, Cong A
… +14 more, Su C, Chen Q, Huang Z, Liu J, Yang Z, Zhu J, Hu Z, Yuan L, Li J, Zhou Z, Cai Y, Zhang W, Hou FF, Cao W
J Am Soc Nephrol
· 2026 Mar · PMID 41893892
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KEY POINTS: LARP7 suppresses TGF- β /SMAD3-driven fibrosis by sequestering CDK9, which inhibits SMAD3 T179 phosphorylation and profibrotic transcription. TGF- β 1 represses LARP7 expression in injured tubules, establishi...KEY POINTS: LARP7 suppresses TGF- β /SMAD3-driven fibrosis by sequestering CDK9, which inhibits SMAD3 T179 phosphorylation and profibrotic transcription. TGF- β 1 represses LARP7 expression in injured tubules, establishing a self-reinforcing loop that amplifies and sustains fibrogenic signaling. Tubule-specific LARP7 restoration interrupts this vicious cycle, attenuates SMAD3 activity, and confers protection against kidney fibrosis in vivo . BACKGROUND: TGF- β 1/SMAD3 signaling drives organ fibrosis, underscoring the need to identify its endogenous regulators for precision therapies. LARP7, a core component of the 7SK snRNP complex that sequesters cyclin-dependent kinase 9, has an unexplored role in kidney fibrosis and a potential interplay with TGF- β /SMAD3 signaling. METHODS: Single-cell and spatial transcriptomic analyses combined with immunostaining of human kidney biopsies were used to investigate the association between LARP7 and TGF- β /SMAD3 signaling in patients with CKD. In vivo and in vitro models evaluated the expression profile of LARP7 after insults and its contribution to TGF- β /SMAD3 signaling and fibrosis postinjury. RESULTS: We demonstrated that LARP7, abundantly expressed in normal tubules, was downregulated in CKD patients and inversely correlated with TGF- β /SMAD3 activation. This expression pattern was conserved across ischemic, toxic, and obstructive fibrosis models and recapitulated in TGF- β 1-treated tubular epithelial cells, indicating a general link between LARP7 downregulation and enhanced TGF- β /SMAD3 signaling. Further loss-of-function and gain-of-function in vitro studies confirmed that LARP7 acted as a specific disruptor of SMAD3 linker region (T179) phosphorylation-an event that coincided with C -terminal phosphorylation and amplified SMAD3 transcriptional activity. LARP7 mediated this by sequestering CDK9 within the 7SK snRNP, thereby preventing CDK9-SMAD3 interaction and consequently inhibiting SMAD3 T179 phosphorylation and profibrotic transcription. TGF- β 1 itself suppressed LARP7 expression, completing a self-reinforcing feedback loop that perpetuates TGF- β /SMAD3 signaling in injured tubular epithelial cells. Further in vivo studies showed that tubule-specific Larp7 deletion exacerbated kidney fibrosis after ischemic injury, whereas its overexpression, either preventatively (prefibrosis in an obstructive model) or therapeutically (postfibrosis in ischemic and toxic models), attenuated functional decline and halted fibrotic progression. CONCLUSIONS: Our findings revealed tubular LARP7 as a key negative regulator of TGF- β /SMAD3-driven kidney fibrogenesis. Targeted overexpression of LARP7 in injured tubular epithelial cells attenuated TGF- β 1/SMAD3 signaling and conferred protection against postinjury fibrosis.
Short KM, Tortelote GG, Jones LK
… +11 more, Diniz F, Edgington-Giordano F, Cullen-McEwen LA, Schröder J, Spencer A, Keniry A, Polo JM, Bertram JF, Blewitt ME, Smyth IM, El-Dahr SS
J Am Soc Nephrol
· 2026 Mar · PMID 41885952
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KEY POINTS: Maternal low protein diet reduced kidney size and altered branching without changing ureteric tip number, with fewer nephrons at birth and adulthood. Nephron progenitor proliferation and commitment were impai...KEY POINTS: Maternal low protein diet reduced kidney size and altered branching without changing ureteric tip number, with fewer nephrons at birth and adulthood. Nephron progenitor proliferation and commitment were impaired, pretubular aggregate formation decreased, consistent with a reduced nephron number. BACKGROUND: Low nephron number has a direct effect on the development of hypertension and CKD later in life. Although intrauterine growth restriction caused by maternal low-protein diet (LPD) is believed to be a significant cause of reduced nephron endowment in impoverished communities, its influence on the cellular and molecular processes that drive nephron formation are poorly understood. METHODS: We conducted a comprehensive characterization of the effect of LPD on kidney development using tomographic and confocal imaging to quantify changes in branching morphogenesis and the cellular and morphologic features of nephrogenic niches across development. These analyses were paired with single-cell RNA sequencing to dissect the transcriptional changes that LPD imposes during development of the kidneys to affect nephron number. RESULTS: Single-cell analysis revealed differential expression across metabolic, cell cycle, epigenetic, and reciprocal inductive signaling pathways in most cell types, shifting cellular energy production and developmental trajectories. In nephron progenitor cells, LPD impeded commitment and differentiation toward pretubular aggregates and renal vesicles, accompanied by downregulated Wnt signaling. Confocal microscopy showed fewer pretubular aggregates and reduced progenitor proliferation, consistent with impaired commitment. Critically, nephron progenitor cell proliferation remained reduced through P0, whereas ureteric tip proliferation, although reduced earlier, had normalized by P0. Branching morphology also changed, with optical projection tomography showing shorter tip and tip-parent lengths, consistent with subtle patterning defects. CONCLUSIONS: This study demonstrates that gestational LPD reduced nephron endowment by impairing nephron progenitor cell commitment, with concurrent alterations in branching morphogenesis.
Lake J, Mariniello M, Schiano G
… +6 more, Guo Q, Mabillard H, Sayer JA, Olinger E, Terzi F, Devuyst O
J Am Soc Nephrol
· 2026 Mar · PMID 41885939
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KEY POINTS: Lipocalin-2 upregulation paralleled intracellular uromodulin aggregates in mouse and cellular models of autosomal dominant tubulointerstitial kidney disease because of pathogenic uromodulin. The induction of...KEY POINTS: Lipocalin-2 upregulation paralleled intracellular uromodulin aggregates in mouse and cellular models of autosomal dominant tubulointerstitial kidney disease because of pathogenic uromodulin. The induction of lipocalin-2 was triggered by mutant uromodulin accumulation and endoplasmic reticulum stress in tubular cells. Genetic loss of lipocalin-2 reduced iron deposits in the kidney but did not affect kidney damage, indicating that lipocalin-2 was not driving disease progression. BACKGROUND: Autosomal dominant tubulointerstitial kidney disease due to pathogenic UMOD variants (ADTKD- UMOD ) is a toxic proteinopathy caused by intracellular accumulation of mutant uromodulin (UMOD) and endoplasmic reticulum (ER) stress. Lipocalin-2 (LCN2) is an acute phase protein induced by ER stress with context-dependent roles in kidney injury. METHODS: To examine the role of LCN2 in ADTKD- UMOD , we used Umod knock-in mouse models (C171Y, R186S, C125R), urine samples from affected patients, and mIMCD3 cells expressing wild-type or mutant UMOD. LCN2 expression was assessed by immunoblotting, immunostaining, and ELISA. Autophagy was stimulated with Torin1 to evaluate effects on LCN2 induction. UmodR186S/+ mice were crossed with Lcn2-/- mice to determine the impact of LCN2 deficiency on disease progression. RESULTS: Robust LCN2 induction was observed in kidneys and urine of UmodR186S/+ , UmodC125R/+ , and UmodC171Y/+ mice, correlating with UMOD aggregates and ER stress severity in thick ascending limb cells. In patients, specific UMOD variants were associated with elevated urinary LCN2. In mIMCD3 cells expressing mutant UMOD (C170Y, R185S), treatment with Torin1 reduced aggregates and attenuated LCN2 induction. Genetic deletion of Lcn2 in UmodR186S/+ mice decreased interstitial iron deposition but did not alter UMOD accumulation, interstitial inflammation, or fibrosis. CONCLUSIONS: LCN2 was induced by intracellular UMOD aggregates and ER stress in various models of ADTKD- UMOD . Although it influenced iron handling, LCN2 did not drive fibrosis or inflammation, supporting a role as a biomarker of toxic proteinopathy rather than a therapeutic target.
Molnar AO, Kang Y, Nash DM
… +6 more, Li L, Blake PG, Garg AX, Brimble KS, Young A, Jain AK
J Am Soc Nephrol
· 2026 Mar · PMID 41854725
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KEY POINTS: Multidisciplinary kidney care eligibility changed from eGFR ≤33.4 ml/min per 1.73 m 2 to 2-year kidney failure risk ≥10% (includes eGFR and proteinuria). After the change, we found no difference in outcomes s...KEY POINTS: Multidisciplinary kidney care eligibility changed from eGFR ≤33.4 ml/min per 1.73 m 2 to 2-year kidney failure risk ≥10% (includes eGFR and proteinuria). After the change, we found no difference in outcomes such as dialysis initiation, preparation for dialysis, and hospitalizations. The results of this study help guide decision making with respect to the care of patients with advanced CKD. BACKGROUND: We examined the effect of a change in the eligibility criteria for multidisciplinary kidney care implemented across Ontario, Canada, on April 1, 2016 (criteria moved from an eGFR ≤33.4 ml/min per 1.73 m 2 to 2-year kidney failure risk ≥10%, which incorporates assessment of proteinuria, or an eGFR <15). METHODS: Population-based, interrupted time series analysis using administrative health care databases that included adults with an outpatient eGFR ≤33.4 ml/min per 1.73 m 2 followed by a nephrologist ( N =97,299). We examined multidisciplinary clinic and nephrologist visits, dialysis-related outcomes, hospital encounters, and mortality by monthly interval between October 1, 2013, and February 1, 2020. Autoregressive integrated moving average models were tested for level (immediate) and slope (over time) changes in outcomes after the intervention and were fit on preintervention change data for projected trends. RESULTS: After intervention, there was a significant monthly decline in the multidisciplinary clinic visit rate of 1.49 visits per 100 person-years (95% confidence interval [CI], -2.83 to -0.14) and a significant monthly increase in the proportion of patients with a referral to multidisciplinary care within 1 year before starting dialysis ( i.e ., late referral; positive slope change, 0.67%; 95%, CI, 0.06 to 1.28). The intervention was not associated with significant changes in the proportion of patients initiating dialysis, initiating dialysis with a central venous catheter or during a hospitalization, using home dialysis, or in the rate of nephrologist visits. Immediately after intervention, there were small, significant increases in mortality and hospital encounters, but importantly, there was no monthly (slope) change in mortality and a significant negative monthly change in hospital encounters (-0.24 encounters per 100 person-years; 95% CI, -0.38 to -0.09). CONCLUSIONS: Changing the eligibility criteria for multidisciplinary kidney care from an eGFR ≤33.4 ml/min per 1.73 m 2 to a 2-year kidney failure risk ≥10% or an eGFR <15 ml/min per 1.73 m 2 resulted in significantly fewer patients receiving such care without negatively affecting important clinical outcomes.
Wong SPY, Schell JO, Bursic AE
… +13 more, Butler CR, Callahan MB, Corbett C, DeGraauw J, Gazaway S, Gelfand S, Hall R, Saeed F, Scherer JS, Shaban H, Stein EJ, Weiss JW, ASN Kidney Health Workgroup on Conservative Kidney Management
J Am Soc Nephrol
· 2026 Jun · PMID 41848800
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KEY POINTS: Conservative management is customized CKD care, symptom management, and support to navigate care across the CKD trajectory through end of life. Conservative management is defined by shared decision-making and...KEY POINTS: Conservative management is customized CKD care, symptom management, and support to navigate care across the CKD trajectory through end of life. Conservative management is defined by shared decision-making and interdisciplinary teamwork in alliance with patients and care partners. Implementation of conservative management hinges on each practice's logistical considerations and resource availability. UNLABELLED: Conservative management is holistic and whole-person care for people with kidney failure. This care pathway is often a good choice for patients who prioritize independence, quality of life, and avoidance of burdens associated with life-prolonging therapies such as dialysis. This Kidney Health Guidance aims to provide evidence-based clinical guidance to promote best practices in conservative management care delivery. Conservative management comprises three components, including customized CKD care, symptom management, and smooth navigation of care transitions. This Kidney Health Guidance describes the application of these three components across the illness trajectory, including the role of shared decision-making, care partner engagement, and interdisciplinary collaboration. Practical strategies are outlined for health care professionals to integrate conservative management care delivery into practice. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3//www.asn-online.org/media/podcast/JASN/2026_03_18_KTS_March2026.mp3.