Biochemical Mechanisms beyond Glycosphingolipid Accumulation in Fabry Disease: Might They Provide Additional Therapeutic Treatments?

Fabry disease is a rare X-linked disease characterized by deficient expression and activity of alpha-galactosidase A (α-GalA) with consequent lysosomal accumulation of glycosphingolipid in various organs. Currently, enzyme replacement therapy is the cornerstone of the treatment of all Fabry patients, although in the long-term it fails to completely halt the disease's progression. This suggests on one hand that the adverse outcomes cannot be justified only by the lysosomal accumulation of glycosphingolipids and on the other that additional therapies targeted at specific secondary mechanisms might contribute to halt the progression of cardiac, cerebrovascular, and renal disease that occur in Fabry patients. Several studies reported how secondary biochemical processes beyond Gb3 and lyso-Gb3 accumulation-such as oxidative stress, compromised energy metabolism, altered membrane lipid, disturbed cellular trafficking, and impaired autophagy-might exacerbate Fabry disease adverse outcomes. This review aims to summarize the current knowledge of these pathogenetic intracellular mechanisms in Fabry disease, which might suggest novel additional strategies for its treatment.

Calcineurin-Inhibitor-Induced Hypomagnesemia in Kidney Transplant Patients: A Monocentric Comparative Study between Sucrosomial Magnesium and Magnesium Pidolate Supplementation.

Magnesium (Mg) contributes to DNA stability, protein synthesis and cardiac excitability, while Mg deficiency leads to increased cardiovascular mortality, diabetes, hyperparathyroidism and risk of fractures. In kidney transplant patients, calcineurin inhibitors (CNIs) downregulating Mg channel TRPM6 in the distal collecting tubule induce early hypomagnesemia (HypoMg), which is associated with a faster decline in allograft function. A new formulation, sucrosomial Mg (SucrMg), for oral supplements encapsulates Mg oxide in a phospholipid membrane covered by a sucrester matrix, enhancing gastric and intestinal Mg absorption. This study has evaluated Mg bioavailability, effectiveness and tolerance of SucrMg compared to the conventional preparation of Mg pidolate (PidMg). The association of blood Mg with risk of post-transplant dysglycemia and hyperparathyroidism has also been investigated. Forty hypomagnesemic adult single, double or combined kidney-pancreas or kidney-liver transplant recipients within 2 years from transplantation were recruited. In total, 16 patients received PidMg and 27 received SucrMg. Blood Mg was measured at baseline (T0), after 15 days (T1) and after 6 months (T2) of treatment. PTH, fasting glucose and calcium were measured at baseline and after 6 months of treatment. The tolerance was evaluated at the ambulatory visits. SucrMg compared to PidMg was more efficient at increasing Mg bioavailability at T1: p < 0.0001 vs. p = 0.72 ns, respectively, with a ∆% increase of 12.4% vs. 5.4%, p = 0.04. Both preparations increased blood Mg at T2, p < 0.0001 and p = 0.002, respectively. SucrMg was better tolerated. No difference was observed for fasting plasma glucose, PTH and calcium. On one hand, our study is the first among transplant patients to evaluate the efficacy of SucrMg in the correction of HypoMg, which might justify the limited number of patients enrolled and the short observation time; on the other hand, our results could serve as a useful working hypothesis for further studies with a larger number of transplant patients and an extended study duration to confirm the benefits observed with SucrMg.

The Supporting Role of Combined and Sequential Extracorporeal Blood Purification Therapies in COVID-19 Patients in Intensive Care Unit.

Critical clinical forms of COVID-19 infection often include Acute Kidney Injury (AKI), requiring kidney replacement therapy (KRT) in up to 20% of patients, further worsening the outcome of the disease. No specific medical therapies are available for the treatment of COVID-19, while supportive care remains the standard treatment with the control of systemic inflammation playing a pivotal role, avoiding the disease progression and improving organ function. Extracorporeal blood purification (EBP) has been proposed for cytokines removal in sepsis and could be beneficial in COVID-19, preventing the cytokines release syndrome (CRS) and providing Extra-corporeal organ support (ECOS) in critical patients. Different EBP procedures for COVID-19 patients have been proposed including hemoperfusion (HP) on sorbent, continuous kidney replacement therapy (CRRT) with adsorbing capacity, or the use of high cut-off (HCO) membranes. Depending on the local experience, the multidisciplinary capabilities, the hardware, and the available devices, EBP can be combined sequentially or in parallel. The purpose of this paper is to illustrate how to perform EBPs, providing practical support to extracorporeal therapies in COVID-19 patients with AKI.

The Effect of Green Tea as an Adjuvant to Enzyme Replacement Therapy on Oxidative Stress in Fabry Disease: A Pilot Study.

Enzymatic replacement therapy (ERT) is not very effective in halting the progression of Fabry disease (FD) toward cardiovascular (CV)-renal remodeling, particularly in case of late diagnosis. FD patients have increased oxidative stress (OS), critical for the induction of CV-renal remodeling. We investigated the effects of an adjuvant antioxidant treatment to ERT on OS and the possible advantages for related complications. OS was evaluated in 10 patients with FD before ERT, after 12 months of ERT, and after 6 months of adjuvant green tea (GT) to ERT by the following experiments: expression of p22phox; phosphorylation state of MYPT-1 and ERK 1/2 (by western blotting); and quantification of malondialdehyde (MDA) and heme oxygenase (HO)-1 levels (by ELISA). p22 phox and MYPT-1 phosphorylation decreased after ERT and significantly further decreased after GT. ERK 1/2 phosphorylation and MDA levels remained unchanged after ERT, but significantly decreased after GT. HO-1 significantly increased after ERT and further increased after GT. This study provides preliminary data highlighting the antioxidant effect exerted by ERT itself, further amplified by the adjuvant antioxidant treatment with GT. The results of this study provide evidence of the positive effect of early additive antioxidant treatment to reduce OS and prevent/alleviate cardio and cerebrovascular-renal complications related to OS.

[Tolvaptan in ADPKD patients at the University of Padova Nephrology Unit: impact on quality of life, efficacy and safety].

Autosomal dominant polycystic kidney disease (ADPKD) is responsible of the 10% of the dialysis patients. Tolvaptan is a consolidate option for treatment of ADPKD patients; it slows renal deterioration rate and cysts' growth, although its acquaretic effects often impact on quality of life (QoL) and treatment adherence. Few studies have documented the tolvaptan long term efficacy and safeness profiles and, mostly, the impact of treatment with tolvaptan on patients' QoL. Our study aimed to investigate in 13 ADPKD patients of our cohort the differences in terms of QoL before and after the start of treatment via a questionnaire based on SF-36 and PSQI tests, integrated with other original questions. In addition we have also examined the tolvaptan long term efficacy and safeness profiles. The results of our study show that tolvaptan does not significantly reduce patients QoL notwithstanding its expected acquaretic effects, the only reported side effects. Finally, the average annual renal deterioration rate was lower in patients treated with tolvaptan than in the others. Relevant limits of our study are the small number of selected patients and the relative short study duration. However, on one hand, the results of our study provide further information to the few data available in literature; on the other hand, they may serve as a useful working hypothesis for further studies with a larger number of patients enrolled and an extended study duration. They would demonstrate the absence of significant impact of tolvaptan on patients' QoL.

[Reduced oxidative stress in ADPKD patients treated with tolvaptan].

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent monogenic kidney disease. It causes hypertension and progressive renal failure, both strictly linked to oxidative stress (OxSt). Treatment with tolvaptan is a consolidate option which slows renal deterioration rate, although the molecular mechanisms involved are not fully clarified. We evaluated the OxSt state in tolvaptan-treated ADPKD patients, untreated patients and healthy subjects. OxSt was assessed in 9 patients for each group as mononuclear cell protein expression, MYPT-1 phosphorylation state (Western blot) and heme oxygenase (HO-1) (ELISA). p22 phox protein expression was lower in tolvaptan treated ADPKD and controls compared to untreated patients: 0.86 ±0.15 d.u. p=0.015; 0.53 ±0.11, p<0.001; 1.42 ±0.11 respectively. The same was observed for phosphorylated MYPT-1: 0.68 ±0.09, p=0.013 and vs 0.47 ±0.13, p<0.001, 0.96 ±0.28, while HO-1 of untreated patients was significantly lower compared to treated and controls: 5.33 ±3.34 ng/mL, 2.08 ±0.79, p=0.012, 1.97 ±1.22, p=0.012. Tolvaptan-treated ADPKD patients have reduced OxSt, which might contribute to slowing down the loss of renal function.

Effects of Tolvaptan on Oxidative Stress in ADPKD: A Molecular Biological Approach.

Autosomal dominant polycystic disease (ADPKD) is the most frequent monogenic kidney disease. It causes progressive renal failure, endothelial dysfunction, and hypertension, all of which are strictly linked to oxidative stress (OxSt). Treatment with tolvaptan is known to slow the renal deterioration rate, but not all the molecular mechanisms involved in this effect are well-established. We evaluated the OxSt state in untreated ADPKD patients compared to that in tolvaptan-treated ADPKD patients and healthy subjects. OxSt was assessed in nine patients for each group in terms of mononuclear cell p22phox protein expression, NADPH oxidase key subunit, MYPT-1 phosphorylation state, marker of Rho kinase activity (Western blot) and heme oxygenase (HO)-1, induced and protective against OxSt (ELISA). p22phox protein expression was higher in untreated ADPKD patients compared to treated patients and controls: 1.42 ± 0.11 vs. 0.86 ± 0.15 d.u., p = 0.015, vs. 0.53 ± 0.11 d.u., p < 0.001, respectively. The same was observed for phosphorylated MYPT-1: 0.96 ± 0.28 vs. 0.68 ± 0.09 d.u., p = 0.013 and vs. 0.47 ± 0.13 d.u., p < 0.001, respectively, while the HO-1 expression of untreated patients was significantly lower compared to that of treated patients and controls: 5.33 ± 3.34 vs. 2.08 ± 0.79 ng/mL, p = 0.012, vs. 1.97 ± 1.22 ng/mL, p = 0.012, respectively. Tolvaptan-treated ADPKD patients have reduced OxSt levels compared to untreated patients. This effect may contribute to the slowing of renal function loss observed with tolvaptan treatment.

The patient safety in extracorporeal blood purification treatments of critical patients.

Today, health systems are complex due to both the technological development in diagnostic and therapeutic procedures and the complexity of the patients that are increasingly older with several comorbidities. In any care setting, latent, organizational, and systematic errors can occur causing critical incident harmful for patients. Management of patients with acute kidney injury (AKI) requires a multidisciplinary approach for the diagnostic-therapeutic-rehabilitative path that can also require an extracorporeal blood purification treatment (EBPT). The complexity of these patients and EBPT require a clinical risk analysis and the introduction of protocols, procedures, operating instructions, and checklists to reduce clinical risk through promotion of the safety culture for all care providers. Caregivers must acquire a series of tools to evaluate the clinical risk in their reality to prevent incidents and customize patient safety in a proactive and reactive way. Established procedures that are made more needed by the COVID-19 pandemic can help to better manage patients in critical care area with intrinsic higher clinical risk. This review analyzes the communication and organizational aspects that need to be taken into consideration in the management of EBPT in a critical care setting by providing tools that can be used to reduce the clinical risk. This review is mostly addressed to all the caregivers involved in the EBPT in Critical Care Nephrology and in the Intensive Care Units.