Pasquale Esposito

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.

The Syndrome of Inappropriate Antidiuresis: Pathophysiology, Clinical Management and New Therapeutic Options

Hyponatremia is a marker of different underlying diseases and it can be a cause of morbidity itself; this implies the importance of a correct approach to the problem. The syndrome of inappropriate antidiuresis (SIAD) is one of the most common causes of hyponatremia: it is a disorder of sodium and water balance characterized by urinary dilution impairment and hypotonic hyponatremia, in the absence of renal disease or any identifiable non-osmotic stimulus able to induce antidiuretic hormone (ADH) release; according to its definition, it is diagnosed through an exclusion algorithm. SIAD is usually observed in hospitalized patients and its prevalence may be as high as 35%. The understanding of the syndrome has notably evolved over the last years, as reflected by the significant change in the name, once the syndrome of inappropriate secretion of ADH (SIADH), today SIAD. This review is up to date and it analyses the newest notions about pathophysiological mechanisms, classification, management and therapy of SIAD, including vaptans.

Downregulation of cell survival signalling pathways and increased cell damage in hydrogen peroxide‐treated human renal proximal tubular cells by alpha‐erythropoietin

Objective:  Erythropoietin has been shown to have a protective effect in certain models of ischaemia‐reperfusion, and in some cases the protection has been correlated with activation of signalling pathways known to play a role in cell survival and proliferation. We have studied whether erythropoietin would overcome direct toxic effects of hydrogen peroxide (H2O2) treatment to human renal proximal tubular (HK‐2) cells.

Kinetics of T-Lymphocyte Subsets and Posttransplant Opportunistic Infections in Heart and Kidney Transplant Recipients

Background. The potential use of T-lymphocyte measurements as infection risk markers after solid organ transplant has not been fully investigated. We analyzed the kinetics of T-lymphocyte subsets within the first 8 months posttransplant and their correlation with opportunistic infections (OIs) in solid organ transplant recipients. Methods. Serial measurement of CD4 and CD8 T cells was performed retrospectively in 48 heart transplant recipients (HTR) and 42 kidney transplant recipients (KTR). Generalized estimating equation models were used to analyze longitudinal data separately for HTR and KTR. Results. An initial CD4 T-cell drop (at months 1 and 2, in HTR and KTR, respectively) coincided with the peak of OIs. HTR with a low nadir CD4 T-cell count (≤200/&mgr;L) showed poor CD4 T-cell recovery (175±277 cells/&mgr;L at baseline vs 242±99 cells/&mgr;L at month 8) and their CD8 T cells increased from 153±194 cells/&mgr;L at baseline to 601±399 cells/&mgr;L at month 8. KTR with a low nadir CD4 T-cell count (≤200/&mgr;L) showed a modest CD4 T-cell recovery (138±46 cells/&mgr;L at baseline vs. 440±448 cells/&mgr;L at month 8), and their CD8 T cells increased from 90±41 cells/&mgr;L at baseline to 450±242 cells/&mgr;L at month 8. HTR developing OIs had lower CD4 (P<0.001) and CD8 T cells (P=0.001) than those without infections, whereas in KTR the risk for OIs seemed restricted to patients with low CD8 T cells. HTR with OIs had a low CD4/CD8 T-cell ratio, whereas KTR had a high CD4/CD8 T-cell ratio. Conclusions. Determination of T-lymphocyte subsets is a simple and effective parameter to identify patients at risk of developing OIs.

Anaemia management in non-dialysis chronic kidney disease (CKD) patients: a multicentre prospective study in renal clinics

BACKGROUND Knowledge on anaemia management in non-dialysis chronic kidney disease (ND-CKD) patients regularly followed in renal clinics is scarce although being essential to identifying areas of therapeutic improvement. METHODS We prospectively evaluated anaemia management in two visits, performed 6 months apart, in 755 prevalent ND-CKD stage 3b-5 patients followed in 19 nephrology clinics from ≥6 months. Anaemia was defined as severe (Hb <11 g/dL) or mild (Hb: 11-13.5 in males and 11-12 g/dL in females); iron deficiency (ID) was defined as transferrin saturation (TSAT) <20% and/or ferritin <100 ng/mL. Primary endpoint was the change of anaemia and ID prevalence between baseline and 6-month visit. Secondary endpoint was the prevalence of clinical inertia to either ESA or iron supplementation, that is, the lack of ESA or iron prescription despite Hb <11 g/dL or ID. RESULTS Age was 69 ± 13 years and GFR 27.5 ± 10.0 mL/min/1.73 m(2); male gender, diabetes and prior cardiovascular disease were 57.2, 30.1 and 30.1%, respectively. Prevalence of severe and mild anaemia was 18.0 and 44.0% at baseline and remained unchanged at Month 6 (19.3 and 43.2%). ID was prevalent at both visits (60.1 and 60.9%). Clinical inertia to ESA was similar at baseline and at Month 6 (39.6 and 34.2%, respectively, P = 0.487) and it was less frequent than clinical inertia to iron therapy (75.7 and 72.0%, respectively). CONCLUSIONS This study shows that anaemia prevalence is unexpectedly high in the setting of tertiary nephrology care. This was due to a persistent clinical inertia in the anaemia management, remarkable for iron supplementation and less critical, but still significant, for ESA treatment.

Interleukin-6 release from peripheral mononuclear cells is associated to disease activity and treatment response in patients with lupus nephritis.

Sir, We read with great interest the article by De La Torre, et al. recently published in Lupus. The authors, through clinical and flow cytometric evaluations, demonstrate that there is an increased expression of interleukin-6 (IL-6) agonistic receptor gp130 on peripheral lymphocytes, drawn from patients with systemic lupus erythematosus (SLE). In addition, they interestingly report a significant association between gp130 expression and disease activity score, suggesting that gp130 could provide a useful tool for monitoring patients with SLE. In agreement with these findings, we report the results of a small longitudinal study, which we performed in patients with lupus nephritis, in order to evaluate the relationship among IL-6 release from peripheral blood mononuclear cells (PBMCs), proteinuria and disease activity. In this study, we demonstrate a strong correlation between IL-6 spontaneous release and both systemic and renal disease activity. Moreover, we supply evidence that an effective treatment results in decreasing clinical disease activity and IL-6 production by PBMCs. Fourteen patients (36.5 10.7 year, 12 women) affected by SLE, as defined by American Rheumatism Association criteria, with renal involvement (histological findings:WHO class III for six patients, class IV for five patients and class V for three patients) were enrolled. These patients underwent induction therapy with intravenousmethylprednisolone, followed by oral prednisone, and 6-monthly boluses of intravenous cyclophosphamide. After the induction, patients started the maintenance therapy with oral prednisone combined with either cyclosporine A (eight patients) or mycophenolate mofetil (six patients). A 12-month follow-up was performed. SLE disease activity index 2000 (SLEDAI-2K) was calculated every 3 months, as previously reported. Similarly, urine protein/creatinine (P/C) ratio and creatinine clearance on 24-h urine collection were calculated. IL-6 spontaneous production by PBMCs was evaluated before the initiation of the induction treatment (basal condition) and after 12 months. PBMCs were isolated from blood samples by lymphoprep gradient density centrifugation and were cultured for 24 h. At the end of the incubation period, cell-free supernatants were collected, and IL-6 concentration was evaluated by ELISA, as described elsewhere. IL-6 release by cultured PBMCs was significantly higher in basal condition when compared with posttreatment values (443.0 84.1 vs. 27.4 17.8 pg/mL; P< 0.001) (Figure 1A), whereas there was no significant difference in IL-6 levels between patients treated with mycophenolate or cyclosporine (20.2 10.5 vs. 32.7 20.9 pg/mL, ns). At 12month check-up, patients showed a significant decrease of both proteinuria and SLEDAI-2K, when compared with basal values (P/C ratio 1.76 1.25 vs. 0.69 0.38, P< 0.05, and 8.4 2.2 vs. 4.9 2.4, P< 0.01, respectively). Creatinine clearance did not significantly change (basal value 81.4 18.8 vs. 12-month value 81.3 17.2). IL-6 production resulted significantly associated to both SLEDAI-2K and P/C ratio (rs1⁄4 0.4180, P1⁄4 0.0002 and rs1⁄4 0.2670, P1⁄4 0.0049, respectively) (Figure 1B). However, this association could be due, at least in part, to the fact that an effective treatment may independently decrease both SLEDAI and IL-6 levels, acting as a confounding factor. High serum and urinary IL-6 levels have already been reported in lupus nephritis, but the relationship between IL-6 production and disease activity is still debated. Showing a close correlation between IL-6 spontaneous release and SLE activity, our data, in addition to those reported by De La Torre, could contribute to better define the important role of IL-6 activation in lupus nephritis. Longitudinal and bigger studies are required to confirm these findings and to discriminate the effects of different treatments on inflammatory status in patients with lupus nephritis.

Saquinavir in steroid-dependent and -resistant nephrotic syndrome: a pilot study

BACKGROUND Some difficult cases of idiopathic nephrotic syndrome (NS) have been treated with a HIV protease inhibitor provided with proteasome-inhibiting activity. The objective of this study was to limit nuclear factor κB (NF-κB) activation which is up-regulated in these patients, aiming at decreasing proteinuria and prednisone need. METHODS Ten cases with long-lasting (up to 15 years) history of NS with steroid dependence (six cases, of which three with secondary steroid resistance) or resistance to steroids (four cases) unsuccessfully treated with multiple immunosuppressive drugs, accepted a treatment with the protease inhibitor saquinavir. p50/p65 NF-κB nuclear localization and immunoproteasome/proteasome messenger RNA (mRNA) were monitored in peripheral blood mononuclear cells (PBMCs). The effects of saquinavir on NF-κB nuclear localization in cultured PBMCs and in immortalized human podocytes were assessed. RESULTS After a median follow-up of 14.7 months (6-68.7), 1/4 primary steroid-resistant NS (SRNS) and 5/6 steroid-dependent NS or secondary SRNS became infrequent (5) or frequent (1) relapsers, with 63% prednisone reduction (from 25.3 to 8.4 mg/kg/month, P = 0.015). Saquinavir was effective in association with low doses of calcineurin inhibitors (cyclosporine 2 mg/kg/day or tacrolimus 0.01-0.06 mg/kg/day). No side effects were observed apart from transitory mild diarrhoea. In PBMCs, NF-κB was down-regulated, while MECL-1 immunoproteasome/beta2 proteasome mRNA ratio was reversed to normal values. In culture, saquinavir blunted NF-κB activation in human podocytes and in PBMCs. CONCLUSIONS In this pilot study, a HIV antiprotease drug reduced proteinuria and had a steroid-sparing effect in some multidrug-resistant/-dependent NS. This observation warrants further investigation.

Mesenchymal stromal cells improve renal injury in anti-Thy 1 nephritis by modulating inflammatory cytokines and scatter factors

MSC (mesenchymal stromal cells) can differentiate into renal adult cells, and have anti-inflammatory and immune-modulating activity. In the present study, we investigated whether MSC have protective/reparative effects in anti-Thy1 disease, an Ab (antibody)-induced mesangiolysis resulting in mesangioproliferative nephritis. We studied five groups of rats: (i) rats injected with anti-Thy1.1 Ab on day 0 (group A); (ii) rats injected with anti-Thy1.1 Ab on day 0+MSC on day 3 (group B); (iii) rats injected with anti-Thy1.1 Ab on day 0+mesangial cells on day 3 (group C); (iv) rats injected with saline on day 0+MSC on day 3 (group D); and (v) rats injected with saline on day 0 (group E). Rats were killed on days 1, 3, 7 and 14. MSC prevented the increase in serum creatinine, proteinuria, glomerular monocyte influx and glomerular histopathological injury. Furthermore, MSC suppressed the release of IL-6 (interleukin-6) and TGF-β (transforming growth factor-β), modulated glomerular PDGF-β (platelet-derived growth factor-β), and reset the scatter factors and their receptors, potentiating HGF (hepatocyte growth factor)/Met and inactivating MSP (macrophage-stimulating protein)/Ron (receptor origin nantaise). Few MSC were found in the kidney. These results indicate that MSC improve anti-Thy 1 disease not by replacing injured cells, but by preventing cytokine-driven inflammation and modulating PDGF-β and the scatter factors, i.e. systems that regulate movement and proliferation of monocytes and mesangial cells.

Severe Symptomatic Hyponatremia During Sibutramine Therapy: A Case Report

Sibutramine, a serotonin reuptake inhibitor, currently is used in treatment of obesity. The known side effects of sibutramine, ie, hypertension and tachycardia, depend on its adrenergic and serotoninergic effects. We describe a case of life-threatening hyponatremia associated with sibutramine use in an obese woman. We hypothesize that sibutramine, through its effect on neurotransmitters, may induce antidiuretic hormone secretion and lead to a syndrome of inappropriate antidiuretic hormone secretion. We advise careful monitoring of water-electrolytic balance during sibutramine therapy.

The role of therapeutic drug monitoring in the treatment of cytomegalovirus disease in kidney transplantation

Cytomegalovirus (CMV) infection is a common complication following solid organ transplantation that may severely affect the outcome of transplantation. Ganciclovir (GCV) and its prodrug valganciclovir are successfully used to prevent and treat CMV infection; however, in a small percentage of patients, CMV gene mutations may lead to drug resistance. GCV resistance is defined as increasing CMV viremia or progressive clinical disease during prolonged antiviral therapy, due to CMV gene mutation. This has emerged as a new challenge, especially because alternative drugs such as cidofovir and foscarnet have a number of important side effects. Here we report the case of a kidney transplanted patient who experienced life-threatening CMV disease, which initially appeared to be GCV-resistant, but was instead found to be associated with inadequate antiviral drug levels. The patient was then successfully treated by monitoring plasma GCV levels. We suggest using plasma GCV monitoring in the management of all cases of critical CMV disease, in which GCV resistance is suspected.