V. Sepe

Oxidative stress and inflammation: Implications in uremia and hemodialysis

Oxidative response and inflammation constitute a major defense against infections, but if not properly regulated they could also lead to a number of deleterious effects. Patients affected by different stages of acute and chronic kidney disease, particularly patients on hemodialysis, present a marked activation of oxidative and inflammatory processes. This condition exposes these patients to an elevated risk of morbidity and mortality. This Review is up to date and it analyses the newest notions about pathophysiological mechanisms of oxidative stress and inflammation in patients with renal diseases, also considering the different strategies studied to counterbalance this high risk state.

Toll‐like receptor 4 expression is increased in circulating mononuclear cells of patients with immunoglobulin A nephropathy

We investigated Toll‐like receptors (TLR‐3, ‐4 and ‐7) expression in circulating mononuclear cells of patients with immunoglobulin A nephropathy (IgAN), a disease with debated relationships with mucosal immunity. TLR‐4 expression (detected by fluorescence activated cell sorter) and mRNA transcriptional levels (Taqman) were significantly higher in patients with IgAN than in healthy controls (P = 0·00200 and P = 0·0200). TLR‐3 and TLR‐7 were not modified significantly. In IgAN patients proteinuria was correlated significantly with TLR‐4 expression (P = 0·0312). In a group of nephrotic syndromes, TLR‐3, ‐4 and ‐7 expression was similar to healthy controls. A significant difference in TLR‐4 expression and mRNA levels was found between very active IgAN patients (proteinuria > 1 g/1·73 m2/day in association with severe microscopic haematuria) and inactive patients (proteinuria < 0·5 g/1·73 m2/day, with absent or minimal haematuria). No correlation with levels of aberrantly glycosylated IgA1, age, renal biopsy features or therapy was found. This study shows for the first time an up‐regulation of TLR‐4 in circulating mononuclear cells of patients with IgAN, particularly in association with proteinuria and heavy microscopic haematuria.

Effects of hypercholesterolemia on renal hemodynamics : Study in patients with nephrotic syndrome

Experimental and clinical studies have demonstrated a positive relationship between hyperlipidemia and rate of progression of renal disease, suggesting that lipids can induce or aggravate glomerular injury mainly by interacting with mesangial cells. Nevertheless, recently has been demonstrated that increased cholesterol levels can also induce endothelial cell dysfunction. Thus, since endothelium is known to play a major role in modulating the vascular tone, we have tested the possibility that hypercholesterolemia impairs the renal hemodynamics in patients with active nephrotic syndrome and elevated serum cholesterol levels. In this single-blind, nonrandom study, 12 patients were treated with pravastatin (group T, treated, n = 12) and 8 with placebo (group C, controls, n = 8). The controls were studied after the pravastatin group had been completed. Before starting the treatment the patients underwent basal determinations including routine laboratory investigations and PAH and inulin clearances. The same determinations were repeated after 48 h, and 6 and 12 weeks from the beginning of the treatment. The study at 48 h was performed to see if pravastatin had a direct, cholesterol-independent effect on renal function. The following basal results were reported (mean +/- SEM; group T vs. group C): serum cholesterol (mmol/l) 9.7 +/- 0.4 vs. 9.1 +/- 0.3 (NS); proteinuria (g/24 h): 6.2 +/- 0.2 vs. 7.0 +/- 0.7 (NS); PAH clearance (ml/min): 353 +/- 21 vs. 385 +/- 31 (NS); inulin clearance (ml/min): 62.5 +/- 7.7 vs. 67 +/- 9.3 (NS). After 48 h, no changes were observed in both groups. Subsequently, in group T, the following percentage changes of basal levels were observed: serum cholesterol -21.4 +/- 3.2% at 6 weeks (p < 0.05) and -34.9 +/- 3.2% at 12 weeks (p < 0.01); inulin clearance +3 +/- 3.7% at 6 weeks (NS) and +9.3 +/- 2.9% at 12 weeks (p < 0.05); PAH clearance +7 +/- 3.1% at 6 weeks (p < 0.05) and +21.2 +/- 5.5% at 12 weeks (p < 0.01). By contrast, no significant changes of these parameters occurred in group C at any time, so that the percent changes of baseline values of CPAH were significantly greater in group T (at 6 weeks: p < 0.05; at 12 weeks p < 0.005). These results indicate that the reduction of cholesterol is associated with a significant increase in renal plasma flow, thus, suggesting that hypercholesterolemia may actually impair the renal hemodynamics. We speculate that this effect may contribute to increase the risk of ischemic acute renal failure in nephrotic patients and, along with changes induced in the mesangium by other mechanisms, to contribute to the progression of renal disease.

Trapianto renale e infezione da HCV: analisi retrospettiva dei dati relativi alla popolazione del Centro Trapianti di Pavia

La valutazione della storia naturale dell’infezione da HCV nei pazienti trapiantati di rene è complicata da alcune problematiche tra cui: la frequente asintomaticità dell’epatopatia; l’andamento delle transaminasi, espressione di danno epatocellulare, che sono fluttuanti e raramente elevati (1). Pertanto l’analisi istologica epatica rimane fondamentale per accertare l’entità delle alterazioni epatiche indotte da HCV (2). L’infezione da HCV sembra anche influenzare sia la sopravvivenza del paziente che del rene trapiantato, che negli studi a lungo termine, risultano essere più basse rispetto ai pazienti HCVnegativi, l’infezione rappresenta la causa di morte più frequente (3). Per tali ragioni è necessaria la messa a punto di protocolli specifici per definire le caratteristiche del candidato al trapianto renale con infezione da HCV. La biopsia epatica è indispensabile per accertare la severità del danno istologico epatico indotto da HCV nei pazienti con viremia (HCV Rna PCR) elevata, esame ormai essenziale per scrinare questa categoria di pazienti (2). Nei candidati con lesioni istologiche epatiche cirrotiche o pre-cirrotiche si consiglia di evitare il trapianto. Nei candidati con lesioni istologiche epatiche minime o con segni di epatite cronica (stadio I, II) e con documentata viremia HCV nel siero, va consigliata terapia antivirale. La limitata efficacia dell’Interferonnei pazienti trapiantati, associata all’elevato rischio di rigetto acuto e di effetti collaterali, suggerisce di trattare i pazienti dializzati con epatite cronica HCV correlata prima del trapianto (4). Le recenti evidenze suggeriscono che i pazienti uremici HCV+ con diagnosi istologica di epatopatia attiva dovrebbero essere sottoposti a trattamento antivirale specifico e protratto (Interferon+ ribavirina per 6-12 mesi) prima di valutare la possibilità di un trapianto renale (4). La nostra analisi retrospettiva ha lo scopo di valutare l’approccio clinico e la storia naturale dei pazienti HCV+ trapiantati di rene e in lista d’attesa afferenti al nostro Centro Trapianti.

Reversibility of Acute Cyclosporine Renal Impairment by Dopamine in Healthy Subjects

Up to now, no studies were designed to investigate the role of renal hemodynamic abnormalities in relation to acute Cyclosporine A (CsA) nephrotoxicity and to verify whether dopamine infusion could cuonteract this acute renal disfunction in healthy subjects.