Summary: his phase 2 randomized, double-blind, placebo-controlled trial assessed the efficacy and safety of BI 764198, a selective oral inhibitor of the TRPC6 channel, in adults with biopsy-confirmed primary or TRPC6-related genetic focal segmental glomerulosclerosis (FSGS). Increased TRPC6 activity raises intracellular calcium levels in podocytes, disrupting the cytoskeleton and leading to podocyte loss, proteinuria, and glomerulosclerosis. A total of 62 patients received BI 764198 (20 mg, 40 mg, or 80 mg) or placebo over 12 weeks. Baseline characteristics varied: mean eGFR was 45.5 mL/min/1.73 m² (placebo), 72 (20 mg), 66 (40 mg), and 46 (80 mg). Similarly, baseline 24-hour UPCR was 3.7 g/g (placebo), 4.0 g/g (20 mg), 3.1 g/g (40 mg), and 1.9 g/g (80 mg). The primary endpoint—a ≥25% reduction in urine protein–creatinine ratio (UPCR)—was achieved in 35% of treated patients, compared to 7% in the placebo group. The corresponding odds ratios (ORs) versus placebo were 10.0 (95% CI, 1.6–118.1), 1.5 (0.2–19.5), and 6.0 (0.9– 73.6) for the three doses of BI 764198, respectively, and 4.9 (1.0–48.8) for all doses combined. The most notable effect was observed with the 20 mg dose, showing a placebo-corrected reduction in proteinuria of approximately 40%. Importantly, all patients with TRPC6 variants receiving BI 764198 responded to treatment. Estimated GFR and blood pressure remained stable, indicating a direct podocyte-protective mechanism rather than a haemodynamic effect. The drug demonstrated a favorable safety profile, with adverse events comparable to placebo and no significant safety concerns.

Comment: Focal segmental glomerulosclerosis (FSGS) is a glomerular disease marked by podocyte injury, proteinuria, and a high risk of progressing to kidney failure. Modern classification recognizes three main types based on cause: primary, secondary, and genetic. Current treatments for primary and genetic forms are still limited, emphasizing the need for targeted therapies. This study is important because it introduces a mechanistically targeted therapy that tackles podocyte dysfunction, a key factor in FSGS progression. The results support the biological significance of TRPC6 in both genetic and primary forms of the disease and suggest that even partial modulation of channel activity may provide clinical benefits. However, the study has notable limitations, including a small sample size, short follow-up period, variability across dose groups, and relatively normal (non-nephrotic) serum albumin levels in some patients, which raises questions about the true prevalence of primary FSGS in the cohort. The unexpected lack of a clear dose– response relationship, along with the superior outcomes of the lowest dose, raises further questions about optimal dosing and pharmacodynamics. Additionally, the short duration prevents conclusions about long-term renal outcomes and safety. Overall, while preliminary, these findings are promising and support the need for larger, longer phase 3 trials to confirm efficacy, determine optimal dosing, and evaluate impacts on kidney function decline.

Summary: Sodium zirconium cyclosilicate (SZC) is an effective potassium binder that normalizes serum K⁺ in nondialysis CKD patients and in earlier DIALIZE studies of hemodialysis patients. The phase 3, event-driven, DIALIZEOutcomes trial evaluated whether SZC reduces major arrhythmia-related cardiovascular events (sudden cardiac death, stroke, arrhythmia-related hospitalization/intervention/emergency department visit) in hemodialysis patients with recurrent pre-dialysis hyperkalemia (≥ 5,5 mmol/l). Over 2600 randomized participants received SZC or placebo on non-dialysis days, starting at 5 g orally and titrating to individualized doses. The mean age was 56.1 years (SD 13.4). Sixty-two percent were male, mainly White (50.6%) or Asian (29.0%). Baseline pre-dialysis serum potassium levels were similar between groups, averaging 6.0 mmol/l (SD 0.7). Dialysis parameters, including adequacy and interdialytic weight gain, were comparable. Most participants had hypertension; about one-third each had dyslipidemia and type 2 diabetes. The study was terminated by the sponsor early due to low event rates, only one-third of planned events had occurred, and high study medication discontinuation (particularly in the placebo arm). Mean durations of exposure were 12.4 and 11.3 months for the SZC and placebo groups, respectively. SZC did not reduce the primary composite cardiovascular outcome (HR 0.98; 95% CI 0.76 – 1.26). Secondary cardiovascular endpoints similarly showed no differences. However, SZC significantly improved biochemical control: more patients maintained normokalemia, fewer developed severe hyperkalemia, and fewer required rescue therapy. Safety was comparable to placebo, with similar rates of adverse and serious adverse events.

Comment: Patients with kidney failure often develop persistent hyperkalemia, even with thrice-weekly hemodialysis, and rapid potassium shifts during dialysis increase the risk of arrhythmias and sudden cardiac death. The trial confirms that SZC effectively manages serum potassium in hemodialysis patients but does not demonstrate a cardiovascular benefit, likely due to limited statistical power, low event rates, modest baseline K⁺ levels, and the complex, nonlinear relationship between potassium and arrhythmias. Early termination due to low event rate and high discontinuation rates further hindered interpretation. The study population was relatively young compared to the typical in-center dialysis population and had a short follow-up duration; therefore, the low event rate was not surprising. Thus, a more extended follow-up period could have yielded more events. Although SZC enhances biochemical stability, this study does not support its use to reduce the risk of arrhythmia-related cardiovascular events specifically.

Summary: Sodium zirconium cyclosilicate (SZC) is an effective potassium binder that normalizes serum K⁺ in nondialysis CKD patients and in earlier DIALIZE studies of hemodialysis patients. The phase 3, event-driven, DIALIZEOutcomes trial evaluated whether SZC reduces major arrhythmia-related cardiovascular events (sudden cardiac death, stroke, arrhythmia-related hospitalization/intervention/emergency department visit) in hemodialysis patients with recurrent pre-dialysis hyperkalemia (≥ 5,5 mmol/l). Over 2600 randomized participants received SZC or placebo on non-dialysis days, starting at 5 g orally and titrating to individualized doses. The mean age was 56.1 years (SD 13.4). Sixty-two percent were male, mainly White (50.6%) or Asian (29.0%). Baseline pre-dialysis serum potassium levels were similar between groups, averaging 6.0 mmol/l (SD 0.7). Dialysis parameters, including adequacy and interdialytic weight gain, were comparable. Most participants had hypertension; about one-third each had dyslipidemia and type 2 diabetes. The study was terminated by the sponsor early due to low event rates, only one-third of planned events had occurred, and high study medication discontinuation (particularly in the placebo arm). Mean durations of exposure were 12.4 and 11.3 months for the SZC and placebo groups, respectively. SZC did not reduce the primary composite cardiovascular outcome (HR 0.98; 95% CI 0.76 – 1.26). Secondary cardiovascular endpoints similarly showed no differences. However, SZC significantly improved biochemical control: more patients maintained normokalemia, fewer developed severe hyperkalemia, and fewer required rescue therapy. Safety was comparable to placebo, with similar rates of adverse and serious adverse events.

Comment: Patients with kidney failure often develop persistent hyperkalemia, even with thrice-weekly hemodialysis, and rapid potassium shifts during dialysis increase the risk of arrhythmias and sudden cardiac death. The trial confirms that SZC effectively manages serum potassium in hemodialysis patients but does not demonstrate a cardiovascular benefit, likely due to limited statistical power, low event rates, modest baseline K⁺ levels, and the complex, nonlinear relationship between potassium and arrhythmias. Early termination due to low event rate and high discontinuation rates further hindered interpretation. The study population was relatively young compared to the typical in-center dialysis population and had a short follow-up duration; therefore, the low event rate was not surprising. Thus, a more extended follow-up period could have yielded more events. Although SZC enhances biochemical stability, this study does not support its use to reduce the risk of arrhythmia-related cardiovascular events specifically.

Summary: In the present study, 150 patients were randomly assigned to receive 40 mg of pravastatin or a placebo for two years. The primary outcome was the annual percent change in height-adjusted total kidney volume (HtTKV), with secondary endpoints including changes in renal blood flow and GFR (mGFR) measured over the 2-year treatment period. Data from 138 participants were available for analysis. The annual rate of increase in HtTKV median (interquartile range) was 3.1% (1.4, 6.8) in the placebo group and 4.3% (3.0, 6.6) in the pravastatin group. The annual decline in RBF was -15.1 mL/min/1.73 m² (95% CI: -50.7, 14.4) for pravastatin vs. -32.7 mL/min/1.73 m² (95% CI: -62.1, -0.8) for placebo. Median mGFR decline was -1.4 (-6.4, 2.0) for pravastatin vs. -2.3 (-5.1, 1.6) for placebo. Statistical analysis confirmed that neither the primary nor secondary outcomes differed significantly between the treatment arms.

Comment: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder. Tolvaptan remains the only approved disease-modifying therapy, but its use is constrained by aquaretic adverse effects and cost. Preclinical data suggest that statins attenuate cyst growth, and earlier clinical studies have reported improvements in renal blood flow and endothelial function. In the present study, pravastatin did not reduce HtTKV or slow the decline in kidney function compared with placebo. However, several limitations may confound these findings. Data on urological complications—such as macrohematuria, cyst haemorrhage, and infection—are lacking, despite their established association with accelerated disease progression. Similarly, the absence of information on lifestyle measures limits interpretation, as these factors may influence renal outcomes. Furthermore, blood pressure targets were defined as <140/80 mm Hg, which is less stringent than currently recommended for ADPKD by the latest KDIGO ADPKD Guidelines, potentially attenuating detectable treatment effects. In addition, the lack of detailed reporting on antihypertensive therapy further restricts assessment of confounding. Future studies should incorporate comprehensive clinical phenotyping, including urological events, lifestyle factors, and detailed therapeutic data, to more accurately define the potential role of statins in ADPKD progression.

Summary: This secondary analysis of a randomized crossover trial evaluates Dialysate Sodium Removal (DSR) for dialysis adequacy in infants (<15 kg, n=15) with Acute Kidney Injury (AKI), comparing conventional Peritoneal Dialysis (PD) to Continuous Flow Peritoneal Dialysis (CFPD). CFPD utilized two 8.5-Fr catheters inserted via the Seldinger technique. Following an initial 20 mL/kg fill (2.5% lactate), continuous flow was established at 50 mL/min/1.73 m², with the outflow rate slightly higher (+2.5 mL/min/1.73 m²) to facilitate ultrafiltration (UF). Every 4 hours, the system was fully drained to calculate UF using the mass difference between the delivery and drainage bags. Findings reveal that while critically ill children receive a massive sodium burden of approximately 14 mmol/kg/day, conventional PD achieved a DSR of only 2.7 mmol/kg/day, significantly lower than the 11 mmol/kg/day previously reported in smaller cohorts. In contrast, CFPD demonstrated a significantly higher DSR, driven primarily by increased ultrafiltration (UF) volumes. Analysis of transport kinetics showed a Dialysate-to-Plasma (D/P) sodium ratio of 0.94 and a Small Pore Ultrafiltration (UFSP) to total UF ratio of 82% in conventional PD (dropping to 66% in CFPD).

Comment: Acute PD remains a crucial, often first-line treatment for AKI in paediatric ICU, especially in resource-limited areas like Africa where extracorporeal therapies may be scarce. This study quantifies a “sodium gap” in critically ill children: with sodium intake of around 14 mmol/kg/day and removal via conventional PD at only 2.7 mmol/kg/day, a significant positive sodium balance occurs, likely leading to extracellular fluid expansion and worse outcomes. The findings also reveal limitations of sodium removal during acute PD and explain them mechanistically. Sodium sieving during short dwell times removes free water via aquaporins with minimal sodium, lowering dialysate sodium concentration. Short cycles (e.g., 1-hour dwells) end before sodium equilibrates through small pores, so the drained fluid remains relatively sodium-poor. Ultrafiltration continues, but net sodium removal drops. CFPD primarily enhances sodium removal by maintaining continuous flow and higher ultrafiltration volumes. The constant dialysate refresh preserves a favourable concentration gradient for water and sodium removal, avoiding the early “sieving” effect of intermittent short dwells. This allows more time and surface area for sodium transport, leading to greater clearance. Despite limitations such as a small sample size and potential measurement inaccuracies from indirect ionselective electrodes in high-glucose dialysate, the study provides evidence supporting CFPD as a more effective modality for sodium and solute removal. Future research should link improved dialytic sodium removal to clinical outcomes like reduced fluid overload and serum sodium stabilization, to better guide acute PD use.