Oxidative stress and its role in Fabry disease.

Fabry disease is a rare X-linked disease characterized by deficient expression and activity of alpha-galactosidase A with consequent lysosomal accumulation of glycosphingolipids, particularly globotriaosylceramide in various organs. Currently, enzyme replacement therapy with recombinant human α-galactosidase is the cornerstone of the treatment of Fabry patients, although in the long term enzyme replacement therapy fails to halt disease progression, in particular in case of late diagnosis. This suggests that the adverse outcomes cannot be justified by the lysosomal accumulation of glycosphingolipids alone, and that additional therapies targeted at further pathophysiologic mechanisms might contribute to halting the progression of cardiac, cerebrovascular and kidney disease in Fabry patients. Recent evidence points toward the involvement of oxidative stress, oxidative stress signaling and inflammation in the pathophysiology of cardio cerebrovascular and kidney damage in Fabry patients. This review reports the current knowledge of the involvement of oxidative stress in Fabry disease, which clearly points toward the involvement of oxidative stress in the pathophysiology of the medium to long-term cardio-cerebrovascular-kidney damage of Fabry patients and summarizes the antioxidant therapeutic approaches currently available in the literature. This important role played by oxidative stress suggests potential novel additional therapeutic interventions by either pharmacologic or nutritional measures, on top of enzyme replacement therapy, aimed at improving/halting the progression of cardio-cerebrovascular disease and nephropathy that occur in Fabry patients.

Oxidative stress reduction by icodextrin-based glucose-free solutions in peritoneal dialysis: Support for new promising approaches.

BACKGROUND: Oxidative stress (OxSt) and inflammation are common in CKD and are known CV and mortality risk factors. In peritoneal dialysis (PD) OxSt and Inflammation even increase due to the use of glucose-based solutions. PATIENTS AND METHODS: This study analyzed in 15 PD patients the effect of 3 and 6 months of treatment with icodextrin-based glucose-free solutions on OxSt and inflammation, evaluating p22phox protein expression (Western blot), NADPH oxidase subunit, essential for OxSt activation, MYPT-1 phosphorylation state, marker of RhoA/Rho kinase pathway (ROCK) activity, involved in the induction of OxSt (Western blot) and Malondialdehyde (MDA) production (fluorimetric assay). Interleukin (IL)-6 blood level (chemiluminescence assay) has been measured and used as a marker of inflammation. RESULTS: p22phox protein expression, MYPT 1 phosphorylation, and MDA were reduced after 3 months from the start of icodextrin (1.28 ± 0.18 d.u. vs. 1.50 ± 0.19, p = 0.049; 0.89 ± 0.03 vs. 0.98 ± 0.03, p = 0.004; 4.20 ± 0.18 nmol/mL vs. 4.84 ± 0.32 nmol/mL, p = 0.045, respectively). In a subgroup of 9 patients who continued the treatment up to 6 months, MYPT-1 phosphorylation was further reduced at 6 months compared to baseline (0.84 ± 0.06 vs. 0.99 ± 0.04, p = 0.043), while p22phox protein expression was reduced only at 6 months versus baseline (1.03 ± 0.05 vs. 1.68 ± 0.22, p = 0.021). In this subgroup, MDA was reduced at 6 months versus baseline (4.03 ± 0.24 nmol/mL vs. 4.68 ± 0,32, p = 0.024) and also versus 3 months (4.03 ± 0.24 vs. 4.35 ± 0.21, p = 0.008). IL-6 level although reduced both at 3 and 6 months, did not reach statistical significance. CONCLUSIONS: The reduction of OxSt with icodextrin-based PD solutions, although obtained in a small patients cohort and in a limited time duration study, strongly supports the rationale of using osmo-metabolic agents-based fluids replacing glucose-based fluids. Ongoing studies with these agents will provide information regarding preservation of peritoneal membrane integrity, residual renal function, and reduction of CVD risk factors such as OxSt and inflammation.

Low-Protein Diet in Elderly Patients with Chronic Kidney Disease Stage 4 and 5 in Conservative Management: Focus on Sarcopenia Development.

INTRODUCTION: Chronic kidney disease is a degenerative and increasingly prevalent condition that includes metabolic abnormalities and is associated with a higher risk of sarcopenia. The conservative approach points primarily to controlling metabolic issues and reducing the risk of malnutrition and sarcopenia, slowing the progression of kidney disease. The present study aims to evaluate the effect of a low-protein diet on malnutrition and sarcopenia. METHODS: A total of 45 patients (33 male and 12 female) aged over 70 with chronic kidney disease stage 4-5 in conservative management were considered. All patients had a dietary assessment and prescription of personalized low-protein dietary plans (≤0.6 g protein/kg) and a follow-up control between 4 and 6 months. In preliminary and follow-up evaluations, anthropometric data, blood examinations, body composition results, muscle strength, physical performance, and a 3-day food diary were collected. RESULTS: In the follow-up period, a significant weight loss (p = 0.001) and a decrease in body mass index (p = 0.002) were recorded. Food diaries revealed a significant reduction in protein, sodium, potassium, and phosphorus intake (p < 0.001), with a significant reduction in urea (p < 0.001) and proteinuria (p = 0.01) without any impact on lean mass (p = 0.66). Considerable variations in adherence between food diaries and the prescribed diet were also noted. CONCLUSIONS: Providing a personalized low-protein diet led to significant benefits in a short period without worsening the patient's nutritional status.

"Every Cloud Has a Silver Lining": How Three Rare Diseases Defend Themselves from COVID-19 and What We Have Learnt from It.

The process of SARS-CoV-2 infection, responsible for the COVID-19 pandemic, is carried out through different steps, with the interaction between ACE2 and Spike protein (S) being crucial. Besides of that, the acidic environment of endosomes seems to play a relevant role in the virus uptake into cells and its intracellular replication. Patients affected by two rare genetic tubulopathies, Gitelman's and Bartter's Syndromes, and a rare genetic metabolic disease, Fabry Disease, have shown intrinsic protection from SARS-CoV-2 infection and COVID-19 on account of specific intrinsic features that interfere with the virus uptake into cells and its intracellular replication, which will be reported and discussed in this paper, providing interesting insights for present and future research.

EBV Reactivation in Transplant Recipients following SARS-CoV-2 Infection: A Retrospective Study.

Reactivation and primary infection with a high Epstein Barr Virus (EBV) DNA level in kidney transplant patients could cause severe complications, including the development of Post-Transplantation Lymphoproliferative Disease (PTLD). While in the general population the reactivation of EBV after SARS-CoV-2 infection has been reported, very few data are available in transplant recipients. Our retrospective study aimed to evaluate a possible EBV reactivation in kidney transplant patients following SARS-CoV-2 infection and a possible impairment of the immune system. In addition, the effects of changes in immunosuppressive therapy on EBV DNA reactivation and vaccination were also evaluated. A total of 166 kidney transplant patients followed at the Kidney-Pancreas Transplant Ambulatory Nephrology Unit at Padova University Hospital were retrospectively considered for an observation period of 6 months from January 2020 to April 2023. EBV DNA level was measured by Rt-PCR and evaluated 6 months before and after SARS-CoV-2 infection. Patients' serological states were established via quantification of anti-VCA and anti-EBNA (chemiluminescence). Patients' immune systems were characterized by CD4+/CD8+ lymphocyte ratio (flow cytometry). EBV DNA was reactivated in 50% of the 166 patients with COVID-19 who completed the study. Older patients with more severe forms of COVID-19 had higher EBV reactivation (p < 0.05). EBV reactivation significantly increased in patients with severe SARS-CoV-2 infection requiring hospitalization compared to patients managed at home (p < 0.001). CD4+/CD8+ lymphocyte ratio was reduced in patients with a younger age of transplant (p < 0.01) and on a higher dose of steroids (p < 0.01). The results of our study confirm the role of immunodepression, especially in recent transplant patients and those on high steroids, in EBV reactivation. These results combined with the few available in the literature might contribute to providing an optimal management of immunosuppressive treatment for these patients in order to obtain an immune state unfavorable to the activation of latent viruses, including EBV.

The RAAS Goodfellas in Cardiovascular System.

In the last two decades, the study of the renin-angiotensin-aldosterone system (RAAS) has revealed a counterregulatory protective axis. This protective arm is characterized by ACE2/Ang 1-7/MasR and Ang 1-9 that largely counteracts the classic arm of the RAAS mediated by ACE/Ang II/AT1R/aldosterone and plays an important role in the prevention of inflammation, oxidative stress, hypertension, and cardiovascular remodeling. A growing body of evidence suggests that enhancement of this counterregulatory arm of RAAS represents an important therapeutic approach to facing cardiovascular comorbidities. In this review, we provide an overview of the beneficial effects of ACE2, Ang 1-7/MasR, and Ang 1-9 in the context of oxidative stress, vascular dysfunction, and organ damage.

Safety of Citrate Anticoagulation in CKRT: Monocentric Experience of a Dynamic Protocol of Calcium Monitoring.

Regional Citrate Anticoagulation (RCA) is considered the first-line anticoagulation for Continuous Kidney Replacement Therapy (CKRT). The RCA requires strict protocols and trained staff to avoid unsafe use and ensure its benefit. We have analyzed all our CKRT prescriptions from December 2020 to April 2022 anonymously, collecting data on CKRT, lab tests, clinical conditions, and complications of RCA. In addition, in order to better detect citrate accumulation, we have performed an RCA protocol by reducing the CaTot/Ca2+ ratio cut-off from 2.50 to 2.40 and increasing the number of calcium checks according to its trend. Among the 374 patients in CKRT, 104 received RCA prescriptions, of which 11 (10.6%) were discontinued: 4 for the suspicion of citrate accumulation, 1 for the development of metabolic alkalosis, 1 for the shift to a different CKRT procedure due to the need for a higher bicarbonate dose, 4 for the elevation of hepatocytolysis indexes, and 1 due to a preemptive discontinuation following massive post-surgery bleeding. None of the patients have had citrate toxicity as indicated by a CaTot/Ca2+ greater than 2.50, and our protocol has allowed the early identification of patients who might develop clinical citrate toxicity.

Oxidants and Cardiorenal Vascular Remodeling-Insights from Rare Genetic Tubulopathies: Bartter's and Gitelman's Syndromes.

Two human genetic tubulopathies, Bartter's (BS) and Gitelman's (GS) syndromes, have normo/hypotension and absent cardiac remodeling despite their apparent angiotensin system (RAS) activation. This seeming contradiction has led to an extensive investigation of BSGS patients, the result of which is that BSGS represents a mirror image of hypertension. BSGS's unique set of properties has then permitted their use as a human model to probe and characterize RAS system pathways and oxidative stress in cardiovascular and renal remodeling and pathophysiology. This review details the results using GSBS patients that provide a deeper understanding of Ang II signaling and its associated oxidants/oxidative stress in humans. By providing a more complete and complex picture of cardiovascular and renal remodeling pathways and processes, studies of GSBS can inform the identification and selection of new targets and therapies to treat these and other oxidant-related disorders.

Slow Continuous Ultrafiltration in Regional Citrate Anticoagulation Performed with a Standard Fluid Infusion Central Venous Catheter in Intensive Care Unit for Fluid Overload in Acute on Chronic Heart Failure: A Case Report.

Slow continuous ultrafiltration (SCUF) is an extracorporeal therapy able to reduce fluid overload in chronic or acute heart failure resistant to diuretics. An in-vitro study demonstrated the SCUF feasibility using a standard fluid infusion central venous catheter (CVC). We describe the clinical application of this SCUF in regional citrate anticoagulation (SCUF-RCA) in a patient admitted to the Intensive Care Unit for acute decompensate heart failure with severe systemic fluid overload resistant to diuretics. To avoid risks deriving from a new catheterization, we used a pre-existing multi-lumen CVC for drug administration to provide 10 h of SCUF-RCA with a blood flow of 35 mL/min and 100 mL/h of ultrafiltration with a final weight loss of 1 Kilogram without technical and clinical complications. The patient had a hemodynamics improvement with the diuresis recovery from the previous oliguria after the SCUF-RCA. This clinical case can open the use of the SCUF-RCA in the clinical practice to treat the fluid overload unresponsive to maximal diuretic therapy not exposing the patient to the risks and complications related to the use of SCUF with CVC for dialysis and systemic anticoagulation with heparin. Accordingly, this technique may be useful in the treatment of fluid overload in outpatients.