J Am Soc Nephrol
· 2026 Jun · PMID 42247265
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Lithium remains a mainstay of therapy for bipolar disease and refractory depression with future potential for expanded use on the basis of novel data demonstrating its immunomodulatory and neuroprotective effects. This d...Lithium remains a mainstay of therapy for bipolar disease and refractory depression with future potential for expanded use on the basis of novel data demonstrating its immunomodulatory and neuroprotective effects. This drug accumulates intracellularly via sodium transport pathways, and its effects on complex cellular signaling mechanisms, including glycogen synthase kinase-3 β inhibition, form the basis of its therapeutic efficacy and toxicity. Increased intracellular levels disrupt cellular processes and trigger injury via mitochondrial dysfunction and oxidative stress. Lithium has a narrow therapeutic index and causes dose-dependent nephrotoxicity. A tubulointerstitial pattern of kidney injury is typical; however, lithium can rarely cause glomerular injury as well. An acute rise in serum lithium levels can result in severe volume depletion from lithium-induced natriuresis and aquaresis and cause AKI. Changes in kidney function and various drug interactions can acutely affect serum lithium levels further increasing the risk of toxicity. Arginine vasopressin resistance is the most common complication of chronic lithium use and can be an early manifestation. CKD occurs after a longer latency of over 10 years with a variable slope of GFR decline. Progression to ESKD is relatively low but is affected by the presence of other nephrotoxic risk factors. Epithelial sodium channel blockers such as amiloride can be helpful in mitigating lithium nephrotoxicity by reducing cellular accumulation. Hypercalcemia secondary to lithium-induced hyperparathyroidism is associated with a higher risk of nephrolithiasis and CKD progression. Kidney microcystic changes are common in lithium-induced CKD, and distal renal tubular acidosis can also be seen. Using the lowest effective lithium dose, close monitoring of kidney function and serum lithium levels and early diagnosis of lithium nephrotoxicity is critical in preventing irreversible kidney injury. The decision to discontinue lithium is challenging, and the benefits versus risks must be carefully weighed. This comprehensive review provides a pathogenetic basis and practical clinical framework for diagnosis and management of lithium nephrotoxicity.
Wilkie M, Heimbürger O, de Leon C
… +10 more, Carlsson O, Davenport A, Fan SL, Allen J, Castellano G, Daenen K, Dick J, Kamesh L, Cornacchia F, Hegbrant J
J Am Soc Nephrol
· 2026 Jun · PMID 42240452
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KEY POINTS: The study assessed the efficacy and safety of steady concentration peritoneal dialysis using the Carry Life UF system in the home setting over 4 weeks. Treatment with the Carry Life UF system resulted in high...KEY POINTS: The study assessed the efficacy and safety of steady concentration peritoneal dialysis using the Carry Life UF system in the home setting over 4 weeks. Treatment with the Carry Life UF system resulted in higher ultrafiltration volume, sodium removal, and glucose ultrafiltration efficiency compared with a 2.5% dextrose control exchange. The use of Carry Life UF in the home setting was well tolerated and safe, with no unexpected adverse events. BACKGROUND: Steady concentration peritoneal dialysis (PD) is a novel therapy for improved fluid management. We compared the efficacy and safety of steady concentration PD using the Carry Life UF system with a standard 2.5% dextrose continuous ambulatory peritoneal dialysis (CAPD) exchange in the home setting. METHODS: This is a prospective, multicenter, randomized, crossover study of adult patients on CAPD using 2-4 exchanges per day, with at least one daily 2.5% dextrose exchange. The home phase lasted 4 weeks for each study arm. During the Carry Life UF arm, one daily 2.5% dextrose exchange was replaced with a Carry Life UF treatment 3 days/wk (1.5% dextrose solution for PD fill, 11 or 15 g/h glucose dose) and a 1.5% dextrose exchange 4 days/wk. The primary outcome was difference in ultrafiltration (UF) volume with 5-hour Carry Life UF treatment versus 5-hour 2.5% dextrose exchange (control). Secondary outcomes included adverse events, peritoneal sodium removal, and glucose UF efficiency. RESULTS: A total of 19 participants (mean [SD] age 56 [15] years, six women, seven with diabetes) completed the study. Peritoneal solute transfer rate categories were fast four, average 12, and slow three. The UF volume primary outcome was met as Carry Life UF was superior to control in a prespecified superiority margin of 250 ml, mean increase 381 ml, 95% confidence interval (CI, 285 to 477). For the Carry Life UF total group (11 and 15 g/h cohorts analyzed together), mean (SD) UF volume was 513 (251) versus 132 (172) ml for the control. The secondary outcome peritoneal sodium removal was greater with Carry Life UF versus control (mean increase 43 mmol/exchange, 95% CI, 32 to 54). The secondary outcome glucose UF efficiency (UF volume in relation to glucose absorption) was enhanced with Carry Life UF versus control (mean increase 6.4 ml/g, 95% CI, 3.7 to 9.1). Two serious adverse events (peritonitis) occurred in the home phase, one episode in each study arm. CONCLUSIONS: This 4-week home study of steady concentration PD using the Carry Life UF system demonstrated efficacy and safety. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: NCT05874804 .
Lv L, Xin W, Lan Q
… +12 more, Li F, Xiong J, Huang Y, Nie L, Li Y, Wang S, Wang Y, Yao M, Gong S, Xin Q, Qin S, Zhao J
J Am Soc Nephrol
· 2026 May · PMID 42201776
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BACKGROUND: Acute kidney injury (AKI) represents a critical clinical complication with a high propensity of progression to chronic kidney disease (CKD), yet effective therapies remain limited. G protein-coupled receptors...BACKGROUND: Acute kidney injury (AKI) represents a critical clinical complication with a high propensity of progression to chronic kidney disease (CKD), yet effective therapies remain limited. G protein-coupled receptors (GPCRs) mediate diverse pathophysiological processes and are promising therapeutic targets. Here, we investigated the role of platelet activating factor receptor (PTAFR), a lipophilic GPCR, in AKI-to-CKD transition. METHODS: A mouse model of ischemia-reperfusion injury (IRI) induced AKI was built by bilateral renal artery clamping. The phenotypic role of PTAFR in renal tubular cells(RTECs) after AKI was investigated in tubule-specific Ptafr deficiency mice. The functional and molecular mechanisms were determined by transcriptomic profiling, flow cytometry, co-immunoprecipitation, western blotting and immunofluorescence. Lipidomic analysis and biological experiments were employed to identify the endogenous ligand of PTAFR. The translational potential of PTAFR was evaluated by structure based high throughput virtual screening(HTVS) of a small-molecule inhibitor in vivo and in vitro assays. RESULTS: The expression of PTAFR was upregulated in RTECs after AKI in vivo and in vitro. Tubule-specific depletion of PTAFR alleviated IRI-induced RTEC injury and kidney fibrosis after AKI. Mechanistically, PTAFR promoted RTECs G2/M arrest via suppressing MDM2-mediated p53 ubiquitin degradation. Phosphatidylethanolamine (PE) (18:0/18:1) was identified as a novel PTAFR endogenous ligand inducing RTECs G2/M arrest. Urinary PE (18:0/18:1) was correlated with kidney dysfunction and was able to effectively distinguish AKI patients from healthy controls. HTVS identified WAY-639497, a small-molecule PTAFR antagonist, that was able to mitigate IRI-induced RTEC injury and kidney fibrosis after AKI. CONCLUSIONS: PTAFR promoted tubular epithelial cell G2/M arrest by inhibiting MDM2-mediated p53 ubiquitin degradation and further contributed AKI-to-CKD transition.
Rao IR, Paramasivam G, Acharya S
… +4 more, R S, Shanbhag V, Jeedigunta M, Prabhu AR
J Am Soc Nephrol
· 2026 May · PMID 42201768
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BACKGROUND: Remote ischemic preconditioning may prevent contrast-associated acute kidney injury (AKI) and have cardioprotective effects in patients undergoing coronary angiographic procedures; however, results have been...BACKGROUND: Remote ischemic preconditioning may prevent contrast-associated acute kidney injury (AKI) and have cardioprotective effects in patients undergoing coronary angiographic procedures; however, results have been inconsistent. The aim of this systematic review and meta-analysis was to evaluate whether remote ischemic preconditioning lowers the risk of contrast-associated AKI and improves short-term kidney and cardiac outcomes in patients undergoing coronary angiography or percutaneous coronary intervention (PCI). METHODS: We performed a comprehensive literature search using PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception through December 6, 2025. Randomized controlled trials (RCTs) comparing remote ischemic preconditioning with either sham remote ischemic preconditioning or usual care for kidney and/or cardiac outcomes in patients undergoing coronary angiography or PCI were included. Two independent reviewers screened studies, extracted data, and assessed risk of bias using the Cochrane Risk of Bias 2.0 tool. Outcomes studied were contrast-associated AKI, need for dialysis, in-hospital mortality, in-hospital major adverse cardiovascular events (MACE), 30-day mortality, 30-day MACE, and major adverse kidney events at 30 days (MAKE30). Data were pooled using a random-effects model and expressed as risk ratios with 95% confidence intervals. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: Of the 5532 records identified, 36 RCTs encompassing 10,923 patients were included in this systematic review. Compared to sham remote ischemic preconditioning or usual care, remote ischemic preconditioning significantly reduced contrast-associated AKI (RR 0.54, 95% CI: 0.45-0.65; 30 RCTs, 5078 participants; high-certainty evidence). Remote ischemic preconditioning probably reduces in-hospital MACE (RR 0.51, 95% CI: 0.26-0.98; 4 RCTs, 1266 participants; moderate-certainty evidence). There were no differences in the need for dialysis, in-hospital mortality, 30-day mortality and 30-day MACE. CONCLUSIONS: Remote ischemic preconditioning reduces the risk of contrast-associated AKI and in-hospital MACE in patients undergoing coronary angiography or PCI, supporting its use as a simple adjunctive preventive strategy in clinical practice.
Han XY, Li ZY, Chen SF
… +3 more, Zhao MH, Little MA, Chen M
J Am Soc Nephrol
· 2026 May · PMID 42189612
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BACKGROUND: The nephroprotective role of sodium-glucose cotransporter 2 (SGLT2) inhibitors has been well-established by several randomized controlled trials (RCTs) involving patients with diabetic and non-diabetic chroni...BACKGROUND: The nephroprotective role of sodium-glucose cotransporter 2 (SGLT2) inhibitors has been well-established by several randomized controlled trials (RCTs) involving patients with diabetic and non-diabetic chronic kidney disease. However, the impact of SGLT2 inhibitors on antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and the underlying mechanisms remain unclear. METHODS: The therapeutic effects of canagliflozin were evaluated in a rat model of experimental AAV. RNA sequencing was performed on the kidney and lymph nodes. In parallel, mechanistic studies were conducted in mouse models. Myeloperoxidase (MPO) deficient (Mpo-/-) mice were immunized with mouse MPO and treated with canagliflozin. Splenocytes from these donors were then adoptively transferred into recombinase-activating gene-1 deficient (Rag1-/-) mice. Comprehensive immune phenotyping by flow cytometry, enzyme-linked immunospot (ELISpot) assays, and in vitro differentiation of human T cells were employed to dissect the immunomodulatory effects and underlying mechanisms. RESULTS: Canagliflozin alleviated kidney injury, pulmonary hemorrhage and T lymphocyte infiltration in AAV rats. Renal transcriptomic analysis showed a suppression of adaptive immunity pathways. In the adoptive transfer model, canagliflozin treatment of donor mice led to a significant reduction in splenic Th1, Th17, and CD8+ T cells, accompanied by a markedly diminished capacity of splenocytes to secrete IFN-γ and IL-17A upon restimulation. Transfer of these modulated splenocytes conferred significant nephroprotection to recipient mice. In vitro, canagliflozin suppressed the differentiation of primary CD4+ T cells from patients with AAV into both Th1 and Th17 lineages, but did not directly affect B cell activation or antibody production. Mechanistically, canagliflozin inhibited the phosphorylation of both p38 and ERK MAPKs in activated T cells, and the suppressive effect on cytokine production was partially reversed by activation of the p38 MAPK pathway. CONCLUSIONS: Canagliflozin alleviated experimental AAV by suppressing pathogenic T cell effector responses-an effect mechanistically linked to inhibition of the p38 signaling pathway.
J Am Soc Nephrol
· 2026 May · PMID 42172079
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Autosomal dominant Alport syndrome results from heterozygous pathogenic variants in COL4A3 or COL4A4 and is the most common monogenic kidney disease, affecting approximately 1% of the population. It is characterized by p...Autosomal dominant Alport syndrome results from heterozygous pathogenic variants in COL4A3 or COL4A4 and is the most common monogenic kidney disease, affecting approximately 1% of the population. It is characterized by persistent glomerular hematuria, a thinned glomerular basement membrane, and a family history of kidney disease. The typical Alport hearing loss and ocular abnormalities are not present. Autosomal dominant Alport syndrome is common in cohorts with hematuria, proteinuria, steroid-resistant nephrotic syndrome, kidney cysts, or kidney failure. Clinical features vary even in family members with the same genetic change. Overall, only two thirds of people with a heterozygous pathogenic COL4A3 or COL4A4 variant have hematuria because of incomplete penetrance. Missense variants that result in Gly substitutions are associated with proteinuria more often than truncating changes, which is different from X-linked disease. However missense variants are not consistently associated with kidney failure or the age at kidney failure. Sometimes, genetic testing is negative even where clinicians strongly suspect autosomal dominant Alport syndrome. Genetic testing distinguishes autosomal dominant Alport syndrome from X-linked disease, which is less common but has a higher risk of kidney failure. Autosomal dominant Alport syndrome with more severe features must also be distinguished from digenic disease especially where only one of the two causative variants is identified. People with autosomal dominant Alport syndrome should be monitored for increased albuminuria and treated from its onset with angiotensin-converting enzyme inhibitors and, if necessary, sodium-glucose cotransporter 2 inhibitors. Genetic testing is currently recommended for all first-degree family members whether or not they have hematuria.
Etemadi A, Liu S, Winkelmayer WC
… +2 more, Montez-Rath ME, Chang TI
J Am Soc Nephrol
· 2026 May · PMID 42160184
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BACKGROUND: How beta-blocker dialyzability affects cardiovascular outcomes in patients receiving hemodialysis remains unclear. Previous observational studies show conflicting results, and conducting clinical trials in th...BACKGROUND: How beta-blocker dialyzability affects cardiovascular outcomes in patients receiving hemodialysis remains unclear. Previous observational studies show conflicting results, and conducting clinical trials in this population has proven challenging. This uncertainty has contributed to substantial variation in beta-blocker prescribing patterns across regions and clinicians. METHODS: Using data from the United States (US) Renal Data System, we identified patients receiving beta-blockers on the day of starting hemodialysis and classified them into nondialyzable and dialyzable exposure groups. Geographical variations in nondialyzable and dialyzable beta-blocker prescription rates across neighboring regions in each state were leveraged as an instrumental variable. The treatment effect of nondialyzable vs dialyzable beta-blockers on major adverse cardiovascular events (MACE) at 6 months, 1 year, and 3 years was evaluated using instrumental variable g-estimation methods for survival outcomes. MACE comprised myocardial infarction, stroke, and all-cause mortality. RESULTS: The cohort of 40,313 participants from 41 US states experienced 25,720 MACE over the 3-year follow-up period (median years [interquartile range]: 1.4 [0.4 to 3.0]), with more than 42% occurring during the first 6 months after hemodialysis initiation. The instrumental variable met all statistical assumptions. Nondialyzable beta-blockers were associated with significantly lower risk of MACE at all three follow-up timepoints compared to dialyzable beta-blockers (hazard ratios [95% confidence intervals]: 0.82 [0.74 to 0.90], 0.85 [0.79 to 0.92] and 0.90 [0.85 to 0.96]). Similar patterns were observed for each separate component of MACE. CONCLUSIONS: The use of nondialyzable beta-blockers compared to dialyzable beta-blockers was associated with lower risk of MACE during all time points, including the early, high-risk period in the 6 months following hemodialysis initiation.