Focal C4d staining in peritubular capillaries and kidney graft survival: results of a retrospective study.

A diffuse positivity (>or=50%) of C4d in kidney graft peritubular capillaries (PTC) significantly correlates with the presence of acute or chronic antibody-mediated rejection. In contrast, significance of a "focal" deposit (10%-50%) is not yet completely defined. The purpose of this study was to assess the impact of focal positive C4d staining on graft survival. We retrospectively reviewed 63 renal biopsies in 54 kidney transplant recipients. They were performed between January 2005 and December 2008 because of graft impairement, namely, a significant increase in serum creatinine and/or urinary protein. C4d positivity was assessed by immunohistochemistry on paraffin-embedded sections, in combination with conventional histopathologic evaluation. Biopsies were classified as negative (<10%) versus with focal (10%-50%) or diffuse deposits (>50%). Cumulative survival was calculated by the Kaplan-Meier method, and Cox regression analysis was used for the multivariate analysis. Focal C4d staining in PTC significantly correlated with worse graft survival (P = .006), similarly to diffuse C4d staining. On multivariate analysis, focal C4d staining prognostically correlated with graft survival, but not recipient or donor age, prior transplantation, number of HLA mismatches or the presence of tubulitis in the sample. Focal C4d staining was associated with worse graft survival.

Bimodal distribution of major cardiovascular events in kidney allograft recipients.

Cardiovascular disease (CVD) is the major cause of death after renal transplantation. We have retrospectively analyzed the incidence and the time of appearance of CVD among 870 consecutive cadaveric kidney transplant recipients, including 143 patients (16.5%) who experienced a fatal or nonfatal event after transplantation. Seventy-four recipients (54%) showed a fatal CVD. Studying the various manifestations, we observed a higher frequency of cardiac events (59% of ischemic heart disease), with 15% cerebrovascular disease and 22% peripheral vascular or aortic disease. In our group, CVDs were distributed in a bimodal manner, with a higher incidence in the first posttransplantation year and a late cluster of CVD at 8 years posttransplantation. The risk of death (hazard function) for CVD increased dramatically during the 8th year after transplantation. This trend of CVD after kidney transplantation may be explained by inadequate evaluation and management of CVD risk factors during waiting list time and, after transplantation, by the cumulative effects of traditional and nontraditional risk factors.

Specific alloantigen self-control by regulatory T cells in organ transplantation: a review.

Multidrug immunosuppressive protocols have increased short-term patient and graft survival rates from 50% to 90% in the past two decades. Unfortunately, chronic graft rejection still remains the main cause of long-term failure and patients must undergo lifelong immunosuppression. The severe side effects such as life-threatening infections, secondary malignancies, and cardiovascular dysfunction all together include roughly 50% of deaths among kidney transplant patients with functioning grafts. Therefore, it should be of crucial importance to reduce immunosuppression and seek induction of specific tolerance to donor alloantigens. Several investigations have suggested that the acquisition of tolerance to self and/or foreign antigens is dependent on the number and function of naturally occurring and acquired regulatory T cells, which can control all aggressive T cells. The regulatory T cells together with their receptors, costimulatory molecules, cytokines, chemokines, and growth factors all contribute to maintain an equilibrium between aggressive and suppressive effector immune responses. As a consequence of increased knowledge, new immunosuppressive approaches based on either alloantigen-specific regulatory T-cell expansion in vivo or in vitro have been proposed to achieve donor-specific transplantation tolerance in kidney allograft recipients. This contribution attempted to summarize knowledge about regulatory T cells and developing methods to induce specific tolerance in kidney transplantation.

Monitoring of cellular immunity by interferon-gamma enzyme-linked immunosorbent spot assay in kidney allograft recipients: preliminary results of a longitudinal study.

Several efforts have been made in past years to identify markers for patients at heightened risk of acute and chronic immune-mediated allograft rejection. The ex vivo monitoring of cellular immunity by the enzyme-linked immunosorbent spot (ELISPOT) assay has recently emerged as a primary tool in predicting short- and long-term outcomes in kidney allograft recipients. Therefore, we started the systematic application of interferon-gamma (IFN-gamma) ELISPOT assay to measure the frequency of producing IFN-gamma in recipient peripheral blood lymphocytes (PBLs) stimulated with donor lymphocytes before and 7, 14, 21, 28, and 60 days after transplantation. Preliminary results in eight kidney transplant patients indicated that the number of HLA mismatches never correlated with the number of IFN-gamma spots. The frequencies of pretransplantation IFN-gamma spots were positively and significantly correlated with the number of posttransplantation IFN-gamma spots. Clinical outcomes were better among recipients with lower frequencies than those with higher frequencies of pre- and/or posttransplantation IFN-gamma spots. The highest pre- and posttransplantation number of IFN-gamma spots was observed in a patient who developed early acute rejection. Significant increases in the number of IFN-gamma spots preceded the onset of acute rejection events and were decreased by supplemental IV steroid administration. Considering the low number of observations, these preliminary results must be considered cautiously; nevertheless, we are encouraged to extend the systematic application of serial IFN-gamma ELISPOT assay measurements in a more consistent cohort of patients.

Modulation of incipient glomerular lesions in experimental diabetic nephropathy by hypotensive and subhypotensive dosages of an ACE inhibitor.

A glomerular permeability defect occurs early in the course of type 1 diabetes and precedes the onset of microalbuminuria and renal morphological changes. Recently, ACE inhibitors have been shown to prevent loss of glomerular membrane permselective function, but the mechanism of this nephroprotective effect is still being debated. The objective of the present study was to evaluate the effects of hypotensive and subhypotensive dosages of the ACE inhibitor quinapril ex vivo and of its active metabolite quinaprilat in vitro on the glomerular albumin permeability (P(alb)) defect in the early phases of experimental diabetes. For the ex vivo study, six groups of male Wistar rats were evaluated for 4 weeks. One group served as a nondiabetic control (C); the other five groups were rendered diabetic and included untreated diabetic rats (D) and diabetic rats receiving quinapril at the dosages of 5 (DQ1), 2.5 (DQ2), 1.25 (DQ3), and 0.625 (DQ4) mg. kg(-1). day(-1). Dosage-dependent effects of quinapril on systolic blood pressure and the glomerular filtration rate were observed. In contrast, control of P(alb) in isolated glomeruli exposed to oncotic gradients, proteinuria, and glomerular and tubular hypertrophy was obtained with subhypotensive dosages (DQ3 and DQ4 groups) of the ACE inhibitor. In the in vitro study, quinaprilat reduced P(alb) significantly in concentration ranges from 10(-6) to 10(-14) mol/l compared with results in control glomeruli. The effect on P(alb) may have occurred by mechanisms different from kidney ACE inhibitor. These study results indicated that ACE inhibitor treatment prevents the early onset of the P(alb) defect in experimental diabetes. This effect seemed to occur independently of systemic or glomerular hemodynamic changes and, at least partially, from kidney ACE inhibition.

Extraintestinal infection by group C Salmonella: a case report and review of the literature.

Infected or mycotic aneurysms of the aorta are not very frequent but they are associated with high morbidity and mortality rates. Vascular infections due to Salmonella are not very frequent, but in recent years the reports of infections of this type have been on the increase. The authors report their experience with a case of aneurysm of the abdominal aorta infected by group C Salmonella and go on to review the literature on the subject.