Background.: Focal segmental glomerulosclerosis (FSGS) recurrence after kidney transplantation is a leading cause of allograft failure and remains difficult to treat. Standard therapies, including plasma exchange (PEX) and rituximab, are often ineffective and poorly tolerated. Growing evidence implicates immune-mediated circulating factors, such as IgG and IgM autoantibodies, in disease pathogenesis. Given the central role of memory B cells and plasma cells in antibody production, we tested the safety/efficacy profile of a combined B-cell and plasma cell–depleting approach with rituximab and daratumumab in patients with posttransplant FSGS recurrence. Methods.: This is a retrospective analysis of a multicenter, international cohort of sixteen patients (median age 37 y) with biopsy-proven FSGS recurrence posttransplant who received anti-CD20 plus anti-CD38 monoclonal antibodies or anti-CD38 alone. The majority of patients were resistant to common therapies, including rituximab and PEX. Results.: The treatment achieved complete or partial remission in 5 and 11 patients, respectively. Five experienced proteinuria relapse, and 4 responded to repeated daratumumab alone. At the last follow-up (median 11 [2–18] mo), 13 patients are still in remission and PEX was discontinued in all but 3 cases. Overall, kidney function improved after treatment, and no severe acute or chronic adverse events were reported. Serological analysis revealed a significant decline in IgM, but not in IgG, after treatment. Conclusions.: Despite the retrospective, nonrandomized design, the temporal association between treatment and remission supports an effect of anti-CD38 monoclonal antibody alone or in combination with anti-CD20. Treatment is safe and may confer enhanced efficacy over standard approaches. Prospective, mechanistic studies are warranted to validate these findings and delineate the immunopathogenesis of FSGS recurrence.

Patients with autosomal dominant polycystic kidney disease (ADPKD), a genetic disease due to mutations of the PKD1 or PKD2 gene, show signs of complement activation in the urine and cystic fluid, but their pathogenic role in cystogenesis is unclear. We tested the causal relationship between complement activation and cyst growth using a Pkd1 ^KO renal tubular cell line and newly generated conditional Pkd1 ^–/– C3 ^–/– mice. Pkd1 -deficient tubular cells have increased expression of complement-related genes ( C3 , C5 , CfB , C3ar , and C5ar1 ), while the gene and protein expression of complement regulators DAF, CD59, and Crry is decreased. Pkd1 ^–/– C3 ^–/– mice are unable to fully activate the complement cascade and are characterized by a significantly slower kidney cystogenesis, preserved renal function, and reduced intrarenal inflammation compared with Pkd1 ^–/– C3 ^+/+ controls. Transgenic expression of the cytoplasmic C-terminal tail of Pkd1 in Pkd1 ^KO cells lowered C5ar1 expression, restored Daf levels, and reduced cell proliferation. Consistently, both DAF overexpression and pharmacological inhibition of C5aR1 (but not C3aR) reduced Pkd1 ^KO cell proliferation. In conclusion, the loss of Pkd1 promotes unleashed activation of locally produced complement by downregulating DAF expression in renal tubular cells. Increased C5a formation and C5aR1 activation in tubular cells promotes cyst growth, offering a new therapeutic target.

Microplastics (MPs) are widespread environmental contaminants, but their potential effects on kidney health remain poorly defined. As an organ continuously exposed to circulating particles and involved in their urinary elimination, the kidney may represent both a target of MP toxicity and a route of excretion. In this narrative review, we examine current evidence linking MPs to kidney injury, integrating experimental, mechanistic, and human data. Particular attention is given to the early events governing particle–cell interactions. After exposure, micro- and nanoplastics acquire an eco- and biomolecular corona that modifies their surface properties, cellular recognition, uptake, and biodistribution. Following internalization through phagocytic and endocytic pathways, particles may accumulate within endolysosomal compartments and interact with intracellular structures, disrupting cellular homeostasis. In renal cells, these events converge on mitochondrial dysfunction, reactive oxygen species generation, endoplasmic reticulum stress, inflammatory signaling, altered autophagy, and regulated cell death. Several interconnected pathways have been implicated, including Keap1–Nrf2/ARE and NF-κB signaling, MAPK and IRE1/XBP1-mediated stress responses, ACSL4–GPX4-related ferroptosis, and TGF-β1-related profibrotic signaling. Human studies have detected MPs in urine and kidney tissue and provide preliminary evidence linking MP burden with early markers of kidney damage, although current findings remain limited by small study populations and substantial methodological heterogeneity. Patients with chronic kidney disease, particularly those receiving dialysis, may represent a population of special interest because potentially altered renal handling may coexist with repeated exposure to polymer-based medical devices and dialysis fluids. Despite this potential relevance, data on MP exposure and accumulation in CKD and dialysis patients remain remarkably scarce. We finally discuss the limitations of current experimental models and analytical methods and the need for standardized biomonitoring, more environmentally relevant particles and exposure concentrations, and detection strategies capable of reaching the nanoscale, including artificial intelligence-assisted analysis. Overall, available evidence provides a mechanistic basis for MP-induced kidney injury, but its clinical relevance and contribution to human kidney disease remain to be established.

The complement system include soluble and cell surface proteins and it is an important arm of the innate immune system. Once activated, the complement system rapidly gener-ates proteins with inflammatory and vasoactive activities. Although complement is crucial to host defense and homeostasis, its inappropriate or uncontrolled activation can also drive tissue injury. Glomerulopathy encompasses a spectrum of diseases with diverse eti-ologies, clinical presentations, and outcomes. Among the intricate web of factors contrib-uting to glomerulopathies pathogenesis, the role of complement activation has emerged as a focal point of research interest and therapeutic intervention. The pioneer drug was eculizumab, which made it possible to drastically change the prognosis of atypical hemo-lytic uremic syndrome, an otherwise fatal disease. This comprehensive review aims to elu-cidate the multifaceted interplay between complement pathways and glomerulopathy, shedding light on potential pathway for targeted therapies and improved patient care.