Michele Di Dio

The NLRP3 inflammasome has emerged as a potential molecular link between cellular stress, sterile inflammation, and progressive kidney damage. This review critically examines canonical, non-canonical, and mitochondrial mechanisms of NLRP3 regulation across the acute kidney injury (AKI)–acute kidney disease (AKD)–chronic kidney disease (CKD) continuum, integrating their relationships with pyroptosis, maladaptive repair, fibrosis, and epigenetic regulation. Particular attention is given to endocrine–metabolic signals that may shape renal inflammasome activity. Hyperglycemia, advanced glycation end products, mitochondrial reactive oxygen species, TXNIP signaling, lipotoxicity, impaired tubular fatty-acid oxidation, podocyte insulin resistance, obesity-related adipokine imbalance, and aldosterone-mineralocorticoid receptor activation may converge on NLRP3. Conversely, inflammasome-dependent cytokine release and pyroptosis may amplify insulin resistance, metabolic dysfunction, and cardiorenal injury, establishing a bidirectional endocrine-renal inflammatory loop. Importantly, increased NLRP3 mRNA or protein abundance is distinguished from functional inflammasome activation, which is more strongly supported by downstream evidence such as ASC recruitment/oligomerization, caspase-1 activation, mature IL-1β/IL-18 production, GSDMD cleavage, or pyroptotic cell death. A central issue is whether NLRP3 is a causal driver of kidney disease or a marker of ongoing tissue injury. Although genetic and pharmacological studies support a pathogenic role in experimental models, clinical evidence remains largely associative and disease-dependent. NLRP3-related signals should therefore be regarded as candidate, rather than validated, biomarkers. SGLT2 inhibitors, GLP-1 receptor agonists and finerenone may indirectly attenuate NLRP3 signaling, but mechanistic mediation of their clinical benefits remains unproven. Defining cell-specific activation and clinical target engagement will be essential to establish NLRP3 as a biomarker and therapeutic target.

Male reproductive aging is increasingly recognized as a systemic process in which inflammaging drives progressive dysfunction of urogenital tissues. Key mechanisms include immune–metabolic alterations, activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, as well as epigenetic remodeling. Evidence from experimental and clinical studies suggests that these processes are often investigated independently, and integrative models in humans remain limited. Here, we propose a conceptual framework linking the prostate, testis, and skeletal muscle, in which oxidative stress may act as a mediator amplifying systemic dysregulation at different levels during the aging process. Lifestyle and metabolic interventions, including caloric restriction, resistance exercise, and selected nutraceuticals, may act as key modulators of inflammaging pathways, thus highlighting new potential targets for precision medicine approaches.

Introduction: Post-prostatectomy incontinence (PPI) remains a major functional concern after robot-assisted radical prostatectomy (RARP). Posterior musculofascial reconstruction (PMFR) has been shown to facilitate early urinary continence (EUC), but variations in technique may further improve outcomes. We evaluated whether a modified vesicourethral anastomosis (VUA) incorporating simultaneous PMFR with a single barbed suture [pontine VUA (P-VUA)] may facilitate continence recovery compared with the standard Van Velthoven anastomosis (ST-VUA). Materials and Methods: This prospective study included patients undergoing RARP between January 2021 and December 2023. Allocation was based on surgeon preference. UC was defined as the use of no pads or one dry safety pad per day and was assessed at 10, 30, 90, 180, and 365 days after catheter removal. Multivariable logistic regression was performed to evaluate factors associated with 30-day continence. Time to continence was additionally analyzed using Kaplan–Meier methods. Results: This prospective comparative study included 157 patients undergoing robot-assisted radical prostatectomy (RARP) between January 2021 and December 2023 (76 ST-VUA, 81 P-VUA). Baseline and pathological characteristics were comparable between groups. Catheterization time was significantly shorter in the P-VUA group (5.0 ± 1.1 vs. 6.7 ± 1.4 days, p < 0.001). Continence rates were higher in the P-VUA group at 10 days (72.8% vs. 55.3%, p = 0.03), 30 days (84.0% vs. 68.4%, p = 0.035), 90 days (92.6% vs. 76.3%, p = 0.007), 180 days (93.8% vs. 82.9%, p = 0.044), and 365 days (97.5% vs. 86.8%, p = 0.015). Kaplan–Meier analysis demonstrated a shorter time to continence in Group P (log-rank p = 0.0037). In multivariable analysis, P-VUA was independently associated with higher odds of 30-day continence (OR 6.38, 95% CI 2.08–19.63, p = 0.001). Conclusions: The study suggests that the P-VUA technique was associated with faster recovery of urinary continence compared with ST-VUA in this prospective, non-randomized cohort. These findings support the hypothesis that integrating anatomical reconstruction principles into the anastomotic step may enhance functional outcomes after RARP. However, the results should be interpreted with caution, given the study design and sample size, and require confirmation in larger, preferably randomized studies.

In recent decades, the rate of kidney transplantation has risen significantly, leading to better outcomes in terms of cardiovascular and overall mortality for patients with kidney failure. Although kidney transplantation represents the most effective therapeutic option, it is not devoid of the risk of failure. Immunological and non-immunological risk factors are involved. These factors often interact and may act synergistically, ultimately influencing graft longevity and patient survival. Both contribute to long-term transplant outcomes; however, non-immunological factors, representing a significant clinical challenge, will be the focus of our review. Of the numerous non-immunological risk factors, for clarity and to avoid overextending the discussion, only those most closely associated with chronic kidney disease have been considered: hypertension, anemia, diabetes mellitus, proteinuria, electrolyte and acid–base imbalances, and impaired bone mineralization. Hypertension is reported in approximately 90% of kidney transplant recipients, often related to immunosuppressive therapy and residual renal dysfunction, and it is strongly associated with reduced graft survival. Anemia affects approximately 20–51% of these patients, contributing to cardiovascular morbidity and a more rapid decline in graft function, as does pre-existing diabetes mellitus. Proteinuria has a prevalence ranging from 7.5% to 45%, depending on the established target, and is a significant negative prognostic factor. Metabolic complications are also frequent; for example, hyperkalemia has an incidence of 25–44%, and metabolic acidosis has a prevalence of 12–58%. In our review, each of these factors is analyzed in terms of clinical impact, etiopathogenic mechanism, and available therapeutic management.

Background/Objectives: The optimal surgical approach for kidney stones (KS) measuring 15–20 mm remains debated. RIRS and mini-PCNL are both effective options, but they differ in invasiveness, resource use, and cost. This study aimed to compare perioperative outcomes and hospital costs of RIRS and mini-PCNL using a micro-costing approach. Methods: This retrospective study included patients with KS > 15 mm in diameter who were treated between January 2021 and December 2023 at the Department of Urology, Sapienza University of Rome-Polo Pontino. Clinical parameters, operative time (OT), length of stay (LoS), complications, and stone-free rate (SFR) were compared. Costs were estimated using a micro-costing method, including disposable materials, operating room (OR) time (3.9 EUR/min), imaging, and hospitalization (334 EUR/day). The total cost per treated and per SF patient was calculated for both techniques. Results: A total of 119 patients were analyzed: 62 underwent RIRS, and 57 underwent mini-PCNL. Mean OT was shorter for RIRS (87 vs. 113 min; p < 0.001), and LoS was longer for mini-PCNL (2.24 vs. 1.22 days; p = 0.008). Final SFR was higher for mini-PCNL (94.7% vs. 88.7%; p = 0.043). Complication rates were comparable, with most events classified as Clavien–Dindo I–II. Disposable materials represented the main cost driver (EUR 1097 for RIRS vs. EUR 806 for mini-PCNL). The total cost per treated patient was EUR 3689 for RIRS and EUR 3154 for mini-PCNL (p = 0.009). The cost per SF patient was EUR 4159 for RIRS and EUR 3331 for mini-PCNL (p = 0.007). Conclusions: Both RIRS and mini-PCNL are safe and effective for the management of KS ≥ 15 mm. Mini-PCNL achieves higher SFR and greater cost-efficiency than RIRS. These findings support the use of mini-PCNL as the preferred option in centers with adequate expertise and resources.

Objectives: Upper urinary tract urothelial cell carcinoma (UTUC) in kidney transplant recipients (KTRs) presents distinct clinical challenges due to the complexities of managing both cancer and the long-term immunosuppressive therapy required to preserve graft function. UTUC in this population often presents at advanced stages, contributing to poorer outcomes compared to immunocompetent individuals. Methods: This systematic review (SR) evaluates the incidence, clinical presentation, treatment approaches, and survival outcomes of UTUC in KTRs, based on 16 retrospective studies including 526 patients. Results: The present study highlights a predominance of female patients (ranging from 50% to 91.6%) and significant variability in time to diagnosis (from 7 to 181 months post-transplant). Tumor characteristics also showed considerable heterogeneity, with high-grade and advanced-stage (T3–T4) tumors being more common. The standard treatment for UTUC in KTRs remains radical nephroureterectomy (RNU), with additional resection of the bladder (TURB) when bladder cancer (BC) coexists. Survival outcomes vary significantly, with 5-year overall survival (OS) rates ranging from 16.7% to 90.9%, strongly influenced by tumor stage at diagnosis. This SR further reports high rates of bladder recurrence (18.8% to 61.2%) and challenges in balancing effective cancer treatment with graft preservation. The variability in immunosuppressive regimens across studies complicates the assessment of their role in UTUC progression. The limitations of the current evidence include small sample sizes, retrospective designs, and inconsistent follow-up durations. Conclusions: This SR underscores the need for tailored treatment strategies and improved long-term surveillance. Future research should focus on prospective studies with larger cohorts, exploring the impact of immunosuppression and novel therapies on UTUC outcomes in KTRs.

Background: The Hugo™ Robotic-Assisted Surgery (Hugo™ RAS) system represents a novel advancement in robotic surgical technology. Despite this, there remains a scarcity of data regarding extraperitoneal robot-assisted radical prostatectomy (eRARP) using this system. Methods: We conducted a prospective study at Ospedale Regionale “F. Miulli” from June 2023 to January 2024, enrolling consecutive patients diagnosed with prostate cancer (PCa) undergoing eRARP ± lymph node dissection. All procedures employed a modular four-arm setup performed by two young surgeons with limited prior robotic surgery experience. This study aims to evaluate the safety and feasibility of eRARP using the Hugo™ RAS system, reporting comprehensive preoperative, intraoperative, and postoperative outcomes in the largest reported cohort to date. Results: A total of 50 cases were analyzed, with a mean patient age of 65.76 (±5.57) years. The median operative time was 275 min (Q1–Q3 150–345), and the console time was 240 min (Q1–Q3 150–300). The docking time averaged 10 min (Q1–Q3 6–20). There were no intraoperative complications recorded. Two major complications occurred within the first 90 days. At the 3-month mark, 36 patients (72%) achieved undetectable PSA levels (<0.1 ng/mL). Social continence was achieved by 66% of patients, while 40% maintained erectile function. Conclusions: eRARP utilizing the Hugo™ RAS system demonstrated effectiveness and safety in our study cohort. However, more extensive studies with larger cohorts and longer follow-up periods are necessary to thoroughly evaluate long-term outcomes.

Purpose: The accuracy of multiparametric magnetic resonance imaging (mpMRI) heavily relies on image quality, as evidenced by the evolution of the prostate imaging quality (PI-QUAL) scoring system for the evaluation of clinically significant prostate cancer (csPC). This study aims to evaluate the impact of PI-QUAL scores in detecting csPC within PI-RADS 4 and 5 lesions. Methods: We retrospectively selected from our database all mpMRI performed from January 2019 to March 2022. Inclusion criteria were as follows: (1) mpMRI acquired in our institution according to the technical requirements from the PI-RADS (v2.1) guidelines; (2) single lesion scored as PI-RADS (v2.1) 4 or 5; (3) MRI-TBx performed in our institution; (4) complete histology report; and (5) complete clinical record. Results: A total of 257 male patients, mean age 70.42 ± 7.6 years, with a single PI-RADS 4 or 5 lesion undergoing MRI-targeted biopsy, were retrospectively studied. Of these, 61.5% were PI-RADS 4, and 38.5% were PI-RADS 5, with 84% confirming neoplastic cells. In high-quality image lesions (PI-QUAL ≥ 4), all PI-RADS 5 lesions were accurately identified as positive at the final histological examination (100% of CDR). For PI-RADS 4 lesions, 37 (23%) were negative, resulting in a cancer detection rate of 77% (95% CI: 67.51–84.83). Conclusions: The accuracy of mpMRI, independently of the PI-RADS score, progressively decreased according to the decreasing PI-QUAL score. These findings emphasize the crucial role of the PI-QUAL scoring system in evaluating PI-RADS 4 and 5 lesions, influencing mpMRI accuracy.

Nephrology is an ever-evolving field of medicine. The importance of such a discipline is related to the high clinical impact of kidney disease. In fact, abnormalities of kidney function and/or structure are common in the general population, reaching an overall prevalence of about 10%. More importantly, the onset of kidney damage is related to a strikingly high risk of cardiovascular events, mortality, and progression to kidney failure which, in turn, compromises quality and duration of life. Attempts to comprehend the pathogenesis and molecular mechanisms involved in kidney disease occurrence have prompted the development and implementation of novel drugs in clinical practice with the aim of treating the ‘specific cause’ of kidney disease (including chronic kidney disease, glomerular disease, and genetic kidney disorders) and the main immunological complications following kidney transplantation. Herein, we provide an overview of the principal emerging drug classes with proved efficacy in the context of the aforementioned clinical conditions. This can represent a simplified guide for clinical nephrologists to remind them of the vast and heterogeneous armamentarium of drugs that should be used in the present and the future to improve the management of patients suffering from kidney disease.

Partial nephrectomy (PN) is the primary surgical method for renal tumor treatment, typically involving clamping the renal artery during tumor removal, leading to warm ischemia and potential renal function impairment. Off-clamp approaches have been explored to mitigate organ damage, yet few results have emerged about the possible effects on hemoglobin loss. Most evidence comes from retrospective studies using propensity score matching, known to be sensitive to PS model misspecification. The energy balancing weights (EBW) method offers an alternative method to address bias by focusing on balancing all the characteristics of covariate distribution. We aimed to compare on- vs. off-clamp techniques in PN using EB-weighted retrospective patient data. Out of 333 consecutive PNs (275/58 on/off-clamp ratio), the EBW method achieved balanced variables, notably tumor anatomy and staging. No significant differences were observed in the operative endpoints between on- and off-clamp techniques, although off-clamp PNs showed slight reductions in hemoglobin loss and renal function decline, albeit with slightly higher perioperative blood loss. Our findings support previous evidence, indicating comparable surgical outcomes between standard and off-clamp procedures, with the EBW method proving effective in balancing baseline variables in observational studies comparing interventions.