Summary: This multicenter, double-blind, randomized, placebo-controlled trial evaluated the efficacy and safety of rituximab for preventing relapse in adults with frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS). A total of 72 patients were randomized in a 1:1 ratio; 66 received at least 1 dose of the study drug (rituximab or placebo) and were included in the final analysis. Rituximab 375 mg/m2 was administered at weeks 1, 2, and 25, alongside standardized corticosteroid tapering. The most common cause of FRNS and SDNS was minimal change disease (> 80% in both groups). The primary endpoint—the proportion of patients free from relapse at 49 weeks—was significantly higher in the rituximab group than in the placebo group (87.4% vs 38.0%; P < .001). Rituximab markedly reduced the risk of relapse (hazard ratio 0.16; 95% CI, 0.05–0.46). Similar results were observed in the per-protocol analysis. Secondary outcomes showed higher rates of corticosteroid discontinuation in the rituximab group, while kidney function parameters and proteinuria at week 49 were comparable between groups. Exploratory analyses demonstrated sustained peripheral B-cell depletion following rituximab administration, with repopulation occurring by week 49. Infection rates were higher among rituximab-treated patients with low immunoglobulin levels, although serious adverse events were infrequent overall.

In a post relapse open-label phase, rituximab effectively maintained remission following corticosteroid-induced remission, with relapse-free rates exceeding 95% at both 25 and 49 weeks.

Comment: The magnitude of the benefit of Rituximab was clinically substantial in this trial, with relapse-free survival more than doubling compared with placebo and enabling meaningful corticosteroid sparing.

The dosing strategy—repeated administration including a maintenance dose at week 25—likely explains the superior durability of remission compared with earlier pediatric trials and observational adult studies. These findings reinforce the concept that maintenance rituximab, rather than single-course therapy, is critical for sustained disease control in podocytopathies. The absence of severe rituximab-related toxicity supports its use as a steroid-sparing agent, particularly in patients with corticosteroid-related morbidity.

However, limitations include a modest sample size, cohort heterogeneity with respect to histological findings, short post-treatment follow-up, exclusion of patients who did not receive the study drug from the primary analysis, and lack of adjustment for multiple secondary comparisons. Importantly, the study was not powered to assess long-term safety or efficacy beyond one year, nor to clarify mechanistic links between B-cell depletion and relapse prevention.

Summary: The OPTIMIZE trial was an investigator-driven, multicentre, randomized, open-label study evaluating whether a calcineurin inhibitor–sparing immunosuppressive regimen improves outcomes in older kidney transplant recipients. A total of 379 de novo kidney transplant recipients aged ≥65 years were randomized 1:1 to receive either low-dose tacrolimus with everolimus and prednisolone (TEP) or standard-dose tacrolimus with mycophenolate mofetil and prednisolone (TMP). Participants were stratified by donor type: recipients of kidneys from older deceased donors (stratum A) and recipients of kidneys from younger deceased or living donors (stratum B).

The primary endpoint was “successful transplantation” at 2 years, defined as patient survival with a functioning allograft and an eGFR ≥30 mL/min/1.73 m² in stratum A or ≥45 mL/min/1.73 m² in stratum B. Secondary endpoints included patient survival, graft survival, death-censored graft survival, treated biopsy-proven acute rejection (tBPAR), kidney function trajectories, and safety outcomes.

At 2 years, successful transplantation occurred in 50% of patients in the TEP group and in 57% in the TMP group, with no statistically significant difference between the regimens. Patient survival (89% in both groups), graft survival, death-censored graft survival, and the incidence of tBPAR were also comparable. Kidney function remained stable over time in both groups, with no significant difference in mean eGFR or eGFR slope. Overall infection and serious adverse event rates were similar between groups. TEP was associated with more edema and higher lipid levels, while neurological adverse events tended to be less frequent. A nonsignificant trend toward fewer non-skin malignancies was observed in the TEP group.

Comment: This trial investigates an important clinical question in an increasingly common patient population: older kidney transplant recipients with distinct immunologic and nonimmunologic risk profiles. Contrary to the study hypothesis, reducing tacrolimus exposure by combining it with everolimus did not improve graft function, survival, or overall transplantation success at two years. The findings suggest that modest CNI reduction may be insufficient to significantly reduce CNI-related nephrotoxicity in this group, even when tacrolimus exposure is clearly separated between treatment arms.

Notably, outcomes in both groups were favorable, reflecting advances in transplant care over the past decade and reaffirming the safety and effectiveness of kidney transplantation in older patients. The lack of reduction in infectious complications with everolimus contrasts with earlier trials such as TRANSFORM, possibly due to lower MMF dosing, limited statistical power, or the confounding impact of the COVID-19 pandemic. The distinct adverse-effect profiles of the drugs highlight the importance of tailoring immunosuppressive regimens to individual comorbidities, tolerability, and metabolic risks. Future analyses with longer follow-up, frailty assessments, and quality-of-life measures may provide further guidance on personalized immunosuppression strategies in this growing patient population.

Summary: The Phase 3 VISIONARY trial enrolled 510 adults with biopsy-proven IgA nephropathy and persistent proteinuria despite maximally optimized supportive care (ACEi/ARB +/- SGLT2i). Participants were randomised to receive sibeprenlimab 400mg subcutaneously or placebo every four weeks for 100 weeks, with the primary endpoint being the change in 24-hour urine protein-creatinine ratio at nine months for the prespecified interim analysis. In this analysis of the first 320 patients (sibeprenlimab, n = 152; placebo, n = 168), the trial population was representative of IgA nephropathy, with 62.5% men, 59% Asian participants, and high rates of background use of ACEi/ARB (97.5%) and SGLT2i (40%). The median age was 42 years; mean eGFR was 63.4ml/min/1.73 m2; and median 24-hour uPCR was 1.25 g/day. At nine months, sibeprenlimab reduced 24-hour uPCR by 50.2% from baseline, whereas uPCR increased by 2.1% in the placebo group; corresponding to a 51.2% lower adjusted geometric least-squares mean uPCR with sibeprenlimab (96.5% CI, 42.9-58.2; P<0.001). Treatment led to substantial suppression of APRIL and galactose-deficient IgA1 (Gd-IgA1) levels, both central to the pathogenesis of IgA nephropathy, while maintaining an acceptable interim safety profile, with no excess serious adverse events.

Comment: The Phase 3 interim analysis of the VISIONARY trial positions APRIL inhibition with sibeprenlimab as a promising mechanism-based therapy for expanding the therapeutic repertoire in IgA nephropathy. While maximized supportive care with ACEi/ARBs and SGLT2is remains foundational and recommended for all patients with IgA nephropathy, the KDIGO 2025 guidelines now recommend additional targeted therapies to reduce pathogenic IgA formation and limit nephron injury, including targeted-release budesonide (Nefcon) for patients at risk of progression, and dual endothelin-angiotensin receptor antagonists such as sparsentan for hemodynamic and profibrotic modulation. Systemic steroids still have a role, but at reduced doses and with prophylaxis when budesonide is unavailable. Against this backdrop, sibeprenlimab directly inhibits upstream immune dysregulation by lowering pathogenic Gd-IgA1 production. In the interim analysis, sibeprenlimab produced approximately a 50% placebo-adjusted reduction in proteinuria at 9 months and reduced APRIL and Gd-IgA1 levels, suggesting additive benefits to the standard of care while avoiding systemic immunosuppressive toxicity. Notably, sibeprenlimab is not the only agent targeting this pathway, as other selective APRIL inhibitors and dual BAFF.APRIL antagonists also show early anti-proteinuric benefits, reinforcing the importance of the APRIL-axis in IgA nephropathy. Clinically, sibeprenlimab may be relevant for patients with persistent high-risk proteinuria despite supportive treatment and budesonide. However, long-term eGFR and kidney outcome data are still pending to confirm the disease-modifying benefit. Together, these findings demonstrate a shift towards precision, mechanism-based therapy in IgA nephropathy.

Summary: In this multi-center, double-blind, placebo-controlled trial, 1228 adults receiving maintenance hemodialysis were assigned to high-dose fish oil supplementation (4g daily of omega-3 fatty acids containing 1.6g EPA and 0.8g DHA) or placebo. The primary outcome was a composite of serious cardiovascular events, including cardiac death, myocardial infarction, stroke, and peripheral vascular disease requiring amputation. After a median follow-up of 3.5 years, fish-oil supplementation significantly reduced the rate of serious cardiovascular events compared with placebo (0.31 vs 0.61 per 1000 patient-days; hazard ratio [HR] 0.57; 95% CI 0.47 to 0.70; P<0.001), with consistent reductions across individual components. The composite outcome of first cardiovascular event or death from any cause was also lower in the fish-oil group (HR 0.73, 95% CI 0.61 to 0.87). There was no difference in adverse events or treatment discontinuation between the groups, including no increase in gastrointestinal or bleeding risk.

Comment: Cardiovascular disease remains the leading cause of death among patients receiving maintenance hemodialysis, yet efforts to reduce this risk have largely been unsuccessful. Many trials targeting traditional cardiovascular pathways, including lipid-lowering studies such as 4D, AURORA, and the dialysis subgroup in SHARP, have failed to deliver meaningful reductions in cardiovascular mortality. These results have highlighted the distinct pathophysiology of cardiovascular disease in end-stage kidney disease, where arrhythmia, chronic inflammation, vascular calcification and oxidative stress play a central role beyond atherosclerosis. As such, the PISCES trial provides evidence that high-dose omega-3 fatty acid supplementation significantly reduced cardiovascular events in hemodialysis patients, with benefits consistently observed across cardiac death, myocardial infarction, stroke, and peripheral vascular complications. The magnitude and consistency of benefit are uncommon in dialysis trials, suggesting an underlying biological mechanism for fish-oil benefits (e.g., anti-inflammatory, antiarrhythmic, antithrombotic). However, several limitations exist. The high dose used may limit real-world implementation, the durability of benefit over longer follow-up is unknown, and the optimal patient subgroup most likely to benefit remains unclear. Further studies are also needed to confirm generalizability and to better define the mechanisms underlying the observed effect. Nevertheless, this simple, inexpensive, and seemingly well-tolerated supplementation represents a potentially pragmatic strategy for reducing cardiovascular risk in a population with few proven preventive options.

Summary:

LIBERATE-D is a multicenter, unblinded, superiority trial conducted at four clinical sites from January 2020 to March 2025. The study enrolled 220 hospitalized adults with dialysis-requiring acute kidney injury (AKI-D) who were hemodynamically stable (not requiring vasopressor support at enrolment) and had a baseline estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m² prior to hospitalization. Participants were randomized to either a conservative dialysis strategy, in which dialysis was delivered only when predefined metabolic or clinical indications were met, or conventional thrice-weekly intermittent hemodialysis, continued until traditional recovery criteria were achieved. The primary outcome was recovery of kidney function at hospital discharge, defined as being alive and dialysis-free for at least 14 consecutive days. Secondary endpoints included dialysis frequency, dialysis-free days to day 28, time to recovery, and safety outcomes.

At discharge, kidney function had recovered in 64% of patients in the conservative dialysis group compared with 50% in the conventional dialysis group (difference 13.8%; 95% CI, 0.8–26.8; P = 0.04). Although this difference was attenuated and no longer statistically significant after prespecified adjustment, patients assigned to conservative dialysis received substantially fewer dialysis sessions (median 1.8 vs 3.1 per week, difference: −1.4 sessions, P < .001), achieved recovery earlier (2 days vs. 8.5 days in the conventional group, difference: −6.5 days, P < .001), and had significantly more dialysis-free days by day 28 (median 21 days in the conservative group vs. 5 days in the conventional group, difference: 16 days, P < .001). Dialysis-associated hypotension events were less frequent in the conservative group, with no increase in serious adverse events, mortality, or other safety signals.

Comment: The LIBERATE-D is one of the first randomized trials to directly test whether less intensive dialysis can promote kidney recovery once dialysis has begun. The rationale is compelling, as fixed dialysis can mask biochemical signs of recovery, reduce urine output through excessive ultrafiltration, and expose vulnerable kidneys to repeated episodes of intradialytic hypotension. The observed reduction in intradialytic hypotension provides a plausible mechanistic link between dialysis intensity and delayed kidney recovery. Although dialysis is used as supportive therapy, the findings suggest that it may be a modifiable risk factor for nonrecovery in selected patients with AKI-D. It should be noted that the trial population consisted of hemodynamically stable patients, and the results cannot be generalized to more commonly encountered hemodynamically unstable patients. From a practice perspective, LIBERATE-D supports a more individualized approach to dialysis delivery in AKI, rather than a fixed schedule borrowed from end-stage kidney disease.