Matteo Marcello

Persistent uremic symptoms remain common among patients receiving maintenance hemodialysis, even when contemporary dialysis prescriptions are optimized. These symptoms are only partially captured by conventional adequacy metrics and represent a major determinant of health-related quality of life. A growing body of evidence suggests that incomplete removal of protein-bound uremic toxins and larger middle molecules contributes to persistent symptom burden. Hemoadsorption, when integrated into the extracorporeal circuit, provides an additional clearance mechanism that may enhance solute removal beyond diffusion and convection alone. The ICHARUS study is a prospective, multicenter, observational, real-world registry enrolling adult patients receiving hemodialysis with persistent uremic symptoms despite optimized conventional therapy. Hemoadsorption combined with hemodialysis will be prescribed according to routine clinical practice. Study visits are scheduled at baseline and at one, three, and six months. The primary endpoint is the change in patient-reported symptom burden, assessed using the Dialysis Symptom Index, from baseline to three months. Secondary endpoints include changes in symptom-specific patient-reported outcomes, health-related quality of life, selected biochemical markers, and safety. By focusing on patient-reported outcomes in a pragmatic setting, the ICHARUS study aims to generate structured real-world evidence on the feasibility, safety, and potential clinical relevance of hemoadsorption combined with hemodialysis, supporting patient phenotyping and informing future hypothesis-driven interventional studies. ClinicalTrial.gov ID: NCT07522008.

Introduction: Peritoneal dialysis (PD) is a home-based renal replacement therapy designed to preserve patient autonomy and enhance quality of life. The advent of telemedicine and e-health technologies has enabled the widespread adoption of remote patient monitoring (RPM), particularly in automated PD (APD). This study aimed to evaluate the impact of optimizing RPM strategies in clinical practice. Methods: This retrospective observational study compared two cohorts of patients treated with APD supported by RPM during different time periods: 35 patients monitored daily in 2019 and 62 patients managed in 2024 according to a personalized clinical surveillance protocol based on clinical stability stratification. Results: The new protocol implemented intermittent monitoring of key treatment parameters – ultrafiltration volume, alarms, bypass events, cycle times, and missed sessions – supported by an automated alert system to prompt timely clinical intervention. Both cohorts were comparable in demographic and baseline clinical characteristics. No statistically significant differences were observed between groups in terms of adverse events (peritonitis, hospitalizations) or dialysis adequacy. Conclusion: We transitioned from a daily monitoring model to a selective, stratified approach, thereby establishing a personalized strategy tailored to the needs of individual patients. The success of this selective model can be attributed to a robust digital infrastructure, targeted education for patients and caregivers, and well-defined shared operating protocols between nurses and physicians. These findings support the effectiveness and sustainability of a “less-is-more” approach to RPM in APD patients, paving the way for future integration of predictive algorithms and artificial intelligence to enable more personalized and efficient clinical surveillance.

Uremic toxicity extends beyond small solutes to include middle molecules and protein-bound uremic toxins (PBUTs), which are inadequately removed by conventional dialysis. These limitations arise from membrane-dependent transport mechanisms and the high-affinity binding of PBUTs to albumin, restricting their effective clearance. Hemoadsorption, when coupled with hemodialysis (HAHD), provides a complementary approach by enabling direct physicochemical interactions between circulating solutes and sorbent materials, thereby overcoming constraints related to molecular size and protein binding. The concept of residual uremic toxicity highlights the persistence of biologically active solutes despite optimized dialysis delivery. In this context, patient selection should follow a phenotype-based, toxin-domain approach. Four main phenotypes are proposed: inflammatory, PBUT-driven symptom, middle-molecule burden, and neurocognitive. Each phenotype reflects a dominant toxin profile and provides a rationale for targeted extracorporeal strategies beyond conventional adequacy metrics. HAHD should be considered in patients with persistent symptoms, inflammation, or biochemical abnormalities despite optimized therapy. Treatment prescription must be individualized, integrating frequency, duration, and blood flow to reduce cumulative toxin burden over time. Emerging evidence suggests that HAHD may improve inflammatory markers, patient-centered outcomes, and potentially survival. Overall, HAHD represents a phenotype-driven strategy to better align extracorporeal therapies with the complex biology of uremia.

Introduction: Myoglobin is a middle molecule protein released into the bloodstream during rhabdomyolysis, where it contributes to acute kidney injury through hemodynamic, oxidative, and obstructive mechanisms. High cutoff membranes may enhance myoglobin clearance but carry a risk of clinically relevant albumin and other protein losses. Hemoadsorption may overcome these limitations. This study aimed to assess the adsorption capacity of a neutral microporous styrene-divinylbenzene copolymer sorbent for myoglobin. Methods: We performed two ex vivo hemoadsorption experiments using mini-modules of the HA380 cartridge. Dialysis effluent from a patient with severe rhabdomyolysis was concentrated to 1 L and circulated in a closed loop at 200 mL/min for 240 min. Experiments differed in sorbent mass (32 g vs. 10.6 g). Myoglobin concentrations were measured at predefined time points using ELISA. Removal ratio (RR) and adsorbed mass were calculated to estimate adsorption kinetics and resin capacity. Results: In the first experiment (32 g sorbent), myoglobin decreased from 66,356 to 8,553 µg/L (RR 87%), with 57.8 mg adsorbed (1.8 mg/g). In the second experiment (10.6 g sorbent), concentration decreased from 76,455 to 7,043 µg/L (RR 91%), with 69.6 mg adsorbed (6.56 mg/g). In both experiments, >50% of total myoglobin was removed within the first 60 min, while adsorption plateaued during the last 3 h, suggesting near saturation without complete exhaustion of binding sites. Conclusions: This is the first study to evaluate the myoglobin adsorption capacity of a polystyrene-divinylbenzene sorbent, demonstrating a high affinity for myoglobin with near-complete removal in an ex vivo model. Although saturation was not fully reached, the maximal capacity of the resin is likely higher than measured. These findings provide quantitative insight into myoglobin adsorption kinetics and support further in vitro and clinical studies to optimize timing and duration of hemoadsorption in severe rhabdomyolysis.

Eryptosis is a programmed cellular death that leads to the removal of defective red blood cells (RBCs). It is driven by convergent intracellular pathways centered on cytosolic Ca²⁺ overload, ceramide formation, caspase and calpain activation, disruption of membrane phospholipid asymmetry, and the externalization of phosphatidylserine on the cell surface, which marks the cell for clearance by macrophages. In hemodialysis (HD), intermittent extracorporeal circulation exposes erythrocytes to mechanical stress, bio-incompatible membrane surfaces, and rapid osmotic and ionic shifts. Experimental evidence indicates that osmotic shock induces eryptosis through synergistic Ca²⁺ influx and sphingomyelinase-dependent ceramide generation, providing a mechanistic framework for intradialytic erythrocyte injury. Clinical studies report heterogeneous eryptotic responses during HD, reflecting the balance between toxin removal and procedure-related stress. In contrast, peritoneal dialysis (PD) imposes sustained exposure to hyperosmolar, glucose-based solutions and is strongly influenced by inflammation and residual kidney function. Clinical and experimental data consistently demonstrate increased eryptosis in PD patients, with marked amplification during peritonitis and close associations with inflammatory mediators. This review integrates mechanistic and clinical evidence on eryptosis in HD and PD, highlights modality-specific triggers converging on shared downstream pathways and discusses translational implications and research priorities for improving dialysis biocompatibility and anemia management.

Background/Objectives: Cell-free DNA (cfDNA) is released into the circulation during inflammation-driven cellular injury and regulated cell death. Elevated cfDNA concentrations have been reported in several clinical settings, including chronic kidney disease, hemodialysis, and peritoneal dialysis (PD). We previously demonstrated that PD-related peritonitis induces an increase in circulating cfDNA; however, the mechanisms underlying cfDNA generation remained unclear. This study aimed (i) to confirm peritoneal cfDNA variation following peritonitis in PD patients, and (ii) to elucidate the apoptotic pathways responsible for cfDNA release. Methods: Fifty-four PD patients were enrolled and stratified into the following groups: Group A—no history of peritonitis (n = 25); Group B—remote peritonitis > 3 months prior (n = 21); Group C—recent peritonitis < 3 months prior (n = 8). cfDNA was quantified by qPCR. Apoptosis was assessed qualitatively by DNA laddering and quantitatively using ELISA assays for Caspase-3, Caspase-8 and Caspase-9. Results: cfDNA levels were significantly higher in patients with recent peritonitis compared to both other groups (p < 0.01). DNA laddering showed enhanced nucleosomal fragmentation, consistent with apoptosis. Caspase-3 concentrations were markedly increased in recent peritonitis (p < 0.01). Both Caspase-8 and Caspase-9 correlated with Caspase-3 (ρ = 0.57 and ρ = 0.47, respectively), indicating engagement of both extrinsic and intrinsic apoptotic pathways. Conclusions: In conclusion, peritoneal cfDNA in PD patients with peritonitis originates primarily from apoptosis and reflects dual-pathway caspase activation. cfDNA and Caspase-3 progressively decline with longer time elapsed from peritonitis, supporting their potential use as biomarkers for inflammatory activity and membrane recovery.

Acute kidney injury (AKI) is a serious and common complication among patients undergoing major surgery. The underlying pathophysiologic mechanism includes ischemia-reperfusion injury, complement activation, oxidative stress, and heme toxicity. Among potential preventive measures, recombinant alpha-1 microglobulin (A1M) emerged as a promising therapeutic candidate to mitigate kidney injury in high-risk clinical settings. Preclinical studies have shown its protective effect in different in vitro models such as cellular damage induced by radiation, proteases, and oxidative stress. In animal models, pretreatment with A1M significantly attenuated glomerular permeability changes induced by free fetal hemoglobin, reduced markers of oxidative injury in radiation-induced kidney damage, and conferred protection in ischemia-reperfusion injury by stabilizing mitochondrial function. These promising results led to the use of A1M in human patients. In Phase 1 clinical trials, RMC-035 demonstrated a safety profile with predictable, dose-linear pharmacokinetics. Moreover, in a Phase 1 study involving cardiac surgery patients, RMC-035 showed early signals of renal protection as indicated by reductions of renal tubular stress and injury biomarkers. Although a Phase 2 trial in cardiac surgery patients did not meet its primary endpoint of reducing the rate of AKI within 72 hours after surgery, a significant decline in major adverse kidney events at 90 days was observed that was mainly driven by a reduced rate of persistent renal dysfunction. An ongoing Phase 2b study aims to refine dosing strategies and better delineate its long-term renoprotective efficacy. Collectively, these studies seek to answer whether RMC-035 may improve kidney outcomes in settings characterized by oxidative and ischemia-reperfusion injury.

Background: Removal of large uraemic toxins is still a challenge. Haemodiafiltration (HDF) has produced some results, although large convective volume, optimal vascular access to increase the blood flow rate and strict water quality management are required. Medium cut-off, high-retention-onset membranes have been recently developed, introducing the concept therapy called expanded haemodialysis (HDx). Furthermore, vitamin E-coated membrane has potential beneficial effects on inflammation and oxidative stress. Methods: A prospective longitudinal multicentre study was conducted for 3 months among 24 chronic haemodialysis patients. Patients were randomly assigned into either HDF with high-flux membrane or HDx with Theranova or ViE-X membrane. The primary goal was to assess albumin loss among the three types of dialyzers. Secondary goals included assessment of depurative efficacy for uraemic toxins and clinical outcomes. Results: Mean albumin loss was significantly higher in patients undergoing HDx with Theranova membrane, without any difference in serum albumin concentration among the three groups. Instantaneous clearance of small and middle molecules was significantly higher in patients undergoing HDF, but we did not find differences in removal ratio and Kt/V. Reduction in the erythropoietin resistance index was observed in patients treated with ViE-X membrane due to their lower dialysis vintage. Conclusions: The higher albumin loss during HDx has no effects on pre-dialysis serum albumin. HDx with Theranova in the presence of lower session length, lower Qb, lower convective dose, and lower instantaneous clearance reached the same dialysis efficacy compared to HDF.

Chronic kidney disease–associated pruritus (CKD-aP) is a common complication in dialysis patients which is not fully addressed by pharmacological and dialytic therapy. The objective was to review the literature on the effects of extracorporeal blood purification modalities on CKD-aP. The population comprised patients aged ≥18 years on chronic dialysis. PubMed, Embase, and Medline were systematically searched until February 2024 for clinical studies comparing the effect of different dialysis modalities on pruritus intensity. Two reviewers extracted data independently. Risk of bias for randomized controlled trials (RCTs) was assessed using the Cochrane tool. Any extracorporeal blood purification therapy for the treatment of CKD-aP was included. Outcome was quantitative change in pruritus intensity on a validated itching scale. This review included eight RCTs examining five different dialysis modalities, three observational studies examining three dialysis modalities, and six prospective clinical trials assessing four dialysis modalities. These treatments included peritoneal dialysis, low-flux and high-flux dialysis, hemodiafiltration, expanded hemodialysis, hemadsorption, hemodiafiltration with endogenous reinfusion and dialysis with polymethylmethacrylate membrane. Risk of bias was high in most studies. The largest body of evidence was found for the efficacy of hemadsorption. Limitations of evidence included heterogeneity in diagnostic tools and treatment, risk of selection bias, small sample sizes and short follow-up durations that made it challenging to perform a robust systematic review and meta-analysis. Despite the high prevalence of pruritus among dialysis patients, current evidence for efficacy of standard dialytic treatment is weak. The only technique that appears to be effective is hemoadsorption alone or coupled with hemodialysis. More high-quality studies are needed to confirm the long-term benefits.

Chronic kidney diseases-associated pruritus (CKD-aP) is a term that indicates the itching associated to end stage kidney disease without any apparent cause. This symptom leads to decreased quality of life and increased risk of long-term morbidities and mortality. The pathogenesis of uremic pruritus is still unknown, however, different theories have merged: uremic toxins deposition, immune system dysregulation, peripheral neuropathy, and opioid imbalance. While in the last decade, research focused prevalently on pharmaceutical treatment of CKD-aP, extracorporeal therapies have also evolved providing an alternative but efficient treatment option. In this review, we assess the role of different extracorporeal methods on the treatment of CKD-aP.