Abstract Introduction: Intradialytic hypotension (IDH) is common during hemodialysis and is associated with adverse outcomes. Although sertraline may improve autonomic dysfunction, which contributes to the pathogenesis of IDH, its efficacy in preventing IDH remains uncertain. Methods: We conducted a prospective, randomized, double-blind, placebo-controlled, crossover trial in maintenance hemodialysis patients with IDH in ≥25% of sessions. Participants received sertraline or placebo for 4 weeks, followed by a 4-week washout before crossover (total 12 weeks). Sertraline was initiated at 50 mg/day for 1 week and increased to 100 mg/day for weeks 2-4. Primary outcome was the incidence of IDH. Secondary outcomes included IDH incidence stratified by diabetes status, symptomatic IDH, therapeutic interventions, intradialytic blood pressure changes, and adverse events. Results: Thirty-seven patients were enrolled (mean age 64.0 years; 49% male; median dialysis vintage 24 months). In the intention-to-treat analysis, sertraline significantly reduced IDH episodes compared with placebo (2.5 vs 4.2 episodes per patient, p for treatment effect<0.001, period effect=0.607, sequence effect=0.577). Among diabetic patients, IDH incidence was lower with sertraline (2.5 vs 4.3 episodes per patient, p<0.001), whereas no difference was observed in non-diabetic patients. Sertraline also reduced symptomatic IDH (0.5% vs. 1.4%, p=0.036) and therapeutic interventions (5.2 vs. 8.4 events, p=0.001). Systolic blood pressure and mean arterial pressure at 1- and 3-hours during dialysis were significantly higher with sertraline. Adverse events were comparable. Conclusions: In maintenance hemodialysis patients with frequent IDH, sertraline significantly reduced IDH episodes, particularly among those with diabetes, decreased symptomatic events and rescue interventions, and improved intradialytic hemodynamic stability.
Abstract Introduction Antibody-mediated rejection (ABMR) remains a leading cause of late kidney allograft loss. Recently, microvascular inflammation in kidney biopsy without detectable donor-specific antibodies (DSA)—termed DSA-negative ABMR (DSAneg ABMR)—is increasingly recognized. Methods We used the nationwide Korean Transplantation Registry (KOTRY) to compare outcomes among biopsy-proven DSA-positive ABMR (DSApos ABMR), DSAneg ABMR, and T-cell–mediated rejection (TCMR). From 10,391 kidney transplant recipients, 740 patients met inclusion criteria (DSAneg ABMR 90; DSApos ABMR 124; TCMR 526). The primary outcome was kidney graft failure. Cause-specific competing risk models were applied. To elucidate mechanisms of DSAneg ABMR, we integrated KOTRY with an in-depth single-center data, enrolling 56 patients for serologic, genetic, and pathologic investigations using stored biospecimens. Results Over 2,610.1 person-years (median follow-up 3.10 years), the primary outcome occurred in 93 (12.6%) patients (14 in DSAneg ABMR, 15 in DSApos ABMR, and 64 in TCMR; incidence 3.56/100 person-years). Versus DSAneg ABMR, fully adjusted hazard ratios (HRs) for the kidney graft failure were 0.78 (95% CI, 0.36–1.69; P=0.52) for DSApos ABMR and 0.64 (0.35–1.18; P=0.15) for TCMR. In the etiologic cohort (n=56), frequent findings included MIC-A and MIC-B gene mismatches (16/19 [84.2%] and 15/19 [78.9%]), SIRPα B-to-A incompatibility (7/19 [36.8%]), kidney-relevant autoantibodies (21/52 [40.4%]), and missing self for NK cells (9/18 [50.0%]). Late-appearing DSAs, MIC-A mismatch, and missing self were associated with worse graft outcomes. While overall Banff scores were comparable between the ABMR groups, the DSAneg group exhibited higher tubulitis and lower microvascular inflammation scores. Conclusion Both DSApos ABMR and DSAneg ABMR confer higher risks of adverse outcomes than TCMR in a Korean national cohort. DSAneg ABMR is etiologically heterogeneous with different prognosis. Further prospective studies with systematic biospecimen collection are warranted.
Introduction: Epidemiological evidence suggests a strong association between osteoporosis (OP) and nephrolithiasis (NL), yet the causal direction of this relationship remains debated. This study aimed to elucidate the bidirectional causal relationship between OP and NL using a two-sample mendelian randomization (MR) approach. Methods: We utilized genome-wide association study summary statistics from Taiwan Biobank (TWB; OP: 14,507 cases/79,846 controls; NL: 6,318 cases/88,035 controls) and BioBank Japan (BBJ; OP: 9,794 cases/159,138 controls; NL: 11,699 cases/155,328 controls). Genetic instruments were selected using a suggestive genome-wide threshold of p value <1.0 × 10−5, followed by LD clumping and weak-instrument filtering. The primary causal estimates were calculated using the inverse variance-weighted (IVW) method. Sensitivity analyses, including weighted median, MR-Egger regression, and MR-PRESSO, were performed to evaluate the robustness of the results and assess pleiotropy. Results: In total, 46 single-nucleotide polymorphisms (SNPs) were used for OP-causing NL in the TWB-to-BBJ analysis, 10 SNPs for OP-causing NL in the BBJ-to-TWB analysis, 14 SNPs for NL-causing OP in the TWB-to-BBJ analysis, and 10 SNPs for NL-causing OP in the BBJ-to-TWB analysis. In the analysis assessing the effect of OP on NL, using genetic instruments from BBJ and outcome data from TWB, we observed a significant causal association (IVW β = 0.211, 95% CI: 0.039–0.384, p = 0.016). This finding was corroborated by the weighted median (p = 0.043) and robust MR-Egger (p = 0.025) analyses, with no evidence of directional pleiotropy (MR-Egger intercept p = 0.858). Conversely, in the reverse analysis, NL did not show a significant causal effect on OP risk in either cohort configuration (IVW p > 0.05). Conclusions: Our findings provide suggestive evidence that OP causally increases the risk of NL, whereas NL does not causally affect OP risk. Clinically, patients with OP may represent a high-risk population warranting screening for urinary tract stones.
Introduction: Diabetic kidney disease (DKD) is characterized by impairment of renal glomerular and tubular cells. Low plasma levels of ceramides and lactosylceramides containing very long-chain (VLC) fatty acid were found to be predictive of DKD development. Elongase 1 (Elovl1) is a ubiquitous elongase that elongates C20-C22 fatty acids to generate VLC C24 fatty acids. Using a novel transgenic (TG) mouse overexpressing Elovl1, we investigated whether modification to sphingolipid fatty acid composition averts DKD development. Methods: A TG mouse overexpressing Elovl1 was created at the Medical University of South Carolina/Transgenic Core. Elovl1 TG and wild type (WT) mice were rendered diabetic using serial streptozotocin injections. Plasma, kidney, liver, and urine sphingolipidomics of diabetic and non-diabetic TG and WT mice were analyzed using mass spectroscopy and matrix-assisted laser desorption/ionization-imaging mass spectrometry. Sphingolipid metabolizing enzymes were analyzed using immunohistochemical and multispectral imaging coupled with digital analysis. Results: Plasma sphingomyelins were higher, but lactosylceramides were lower in diabetic TG than in diabetic WT mice. Kidney lactosylceramides were also lower in diabetic TG mice. In urine, diabetic TG mice excreted more VLC lactosylceramides than diabetic WT mice, but less VLC sphingomyelins, VLC ceramides, sphingosine and sphingosine 1-phosphate. There was extensive damage to proximal tubules in kidneys of diabetic WT mice compared to diabetic TG mice. Glomeruli in diabetic WT kidneys appeared also abnormal, whereas no obvious abnormality of glomeruli in diabetic TG was observed. In diabetic TG, Elovl1 overexpression resulted in decreased kidneys levels of both ceramide synthase and acid sphingomyelinase, but increased acid ceramidase levels compared to non-diabetic TG mice. Conclusion: The diabetic Elovl1 TG mouse revealed interaction between Elovl1 overexpression and DKD development, and showed that distinct VLC sphingolipids could be involved in maintaining cell membrane integrity of renal cells.
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common inherited kidney disorders characterized by the progressive formation of renal cysts. It is a systemic disease with significant extra-renal manifestations. Among these, cardiac electrical abnormalities are increasingly recognized as clinically important yet underappreciated contributors to cardiovascular morbidity and mortality. Beyond cyst formation, pathogenic variants in PKD1 or PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively, interfere with calcium homeostasis, mechanotransduction, and mitochondrial function in both kidney and heart tissues. These molecular changes trigger a cascade of pathological events, including RAAS activation, TGF-driven fibrosis, and oxidative stress, leading to structural and electrical remodeling of the heart. These alterations contribute to cardiac electrical remodeling, manifesting clinically as QT interval and corrected QT (QT/QTc) prolongation, left ventricular hypertrophy, atrial fibrillation, ventricular arrhythmias, and other electrocardiographic abnormalities. Despite growing evidence, cardiac electrical abnormalities in ADPKD remain understudied in clinical practice. Early detection of subclinical cardiovascular abnormalities may be facilitated by electrocardiographic monitoring, cardiac imaging, and complementary biomarker assessment. Additionally, findings from iPSC-derived cardiomyocyte models support the translational potential of personalized drug-screening platforms. This review summarizes current evidence linking polycystin dysfunction to cardiac electrical abnormalities in ADPKD by integrating molecular mechanisms with experimental and clinical findings. It also highlights the need for integrated cardio-renal approaches to improve cardiovascular surveillance, risk stratification, and future therapeutic development in ADPKD.
