Pablo Iñigo

Association between cytokine gene polymorphisms and outcomes in renal transplantation: a meta-analysis of individual patient data

BACKGROUND Cytokine gene polymorphisms have been associated with poor outcomes after renal transplantation such as chronic allograft nephropathy (CAN), graft rejection (GR) and graft failure (GF), but the effects of these polymorphisms are still controversial. We therefore conducted a systematic review, with individual patient data (IPD) where possible, to determine the association between cytokine polymorphisms (TGF-beta1, TNF-alpha and IL-10) and outcomes after renal transplantation. METHODS Five investigators were willing to participate and provided IPD. The outcomes of interest were GF, GR and CAN. Subjects with at least one of these were classified as having poor outcomes. Heterogeneity of gene effects was assessed. Multiple logistic regression was applied to assess gene effects, adjusting for clinical variables such as HLA matching and age. RESULTS One-thousand and eighty-seven subjects were included in the IPD meta-analysis. Pooled results showed no evidence of heterogeneity and indicated that the strongest variables determining poor outcomes are HLA mismatching (OR = 1.6-1.8 for >/=3 HLA-A, -B, -DR mismatches compared with those with <3 mismatches) and age (OR = 1.2-1.4 for age 45 years or more). Incremental information on risk of a poor outcome is provided by the TGF-beta1c10 polymorphism (OR = 1.5, P = 0.034, 95% CI: 1.0-2.2 for TC genotype compared to TT genotype). Haplotypes of TGF-beta1 at c10 and c25 were inferred and the C-C haplotype was a marker of a poor outcome (OR = 1.3, P = 0.177, 95% CI: 1.0-2.3). Three polymorphisms of the IL-10 gene at -1082, -819, -592 are in strong linkage disequilibrium with each other (correlation coefficients: 0.6-1) and inferred haplotypes between these three loci show some association, with ACC increasing the risk of poor events compared to GCC (OR = 1.3, P = 0.044, 95% CI: 0.9-1.6). CONCLUSION Pooled results to date suggest possible association between both the TGF-beta1 c10 polymorphism and a 3-SNP-haplotype of IL-10 and poor outcomes in renal transplantation, but this needs to be confirmed in larger studies.

Renoprotective Effects of Losartan in Renal Transplant Recipients

Background/Aims: Chronic allograft nephropathy is the main cause of late graft loss and nonimmunological factors, including hypertension and proteinuria, the principal etiological factors. In this context, blockage of the renin-angiotensin system could be helpful. The aim of the present study was to review the renoprotective efficacy of losartan in a large group of renal transplant patients undergoing long-term follow-up. Methods: A retrospective analysis of 276 renal transplant patients treated with losartan was performed. The indication for losartan was arterial hypertension in 163 patients, proteinuria in 37 patients and hypertension plus proteinuria in the remaining 76 patients. Clinical and biochemical parameters before starting losartan treatment (–6 months, –3 months and at baseline) and 3, 6, 9, 12, 18 and 24 months after the introduction of losartan were analyzed. Results: Arterial hypertension significantly decreased after the introduction of losartan (p = 0.000). Serum creatinine was significantly decreased by losartan therapy, and changes in the serum creatinine slope (1/sCr) before and after losartan were statistically significant. Proteinuria markedly decreased after the introduction of losartan. Clinical and biochemical tolerance of losartan was excellent in most patients and only 9 out of the 276 patients (3%) treated with losartan discontinued the drug because of an adverse event. During follow-up, only 3 patients required substitutive treatment with dialysis due to progressive deterioration of renal function in the context of chronic allograft nephropathy. Conclusion: Losartan demonstrated high efficacy as a renoprotective agent in renal transplant patients and could be useful in the treatment and prevention of chronic allograft nephropathy.

Expression of transforming growth factor-b1 and hypoxia-inducible factor-1a in an experimental model of kidney transplantation.

Background. Ischemia-reperfusion syndrome has been recognized as an important pathogenic factor in renal transplantation, not only in the development of delayed graft function but also in the development of acute and chronic rejection. Hypoxia-inducible factor (HIF)-1 activates transcription of several genes implicated in cell survival, such as vascular endothelial growth factor (VEGF), and in tissue repair transforming growth factor (TGF)-&bgr;. The purpose of this study was to characterize TGF-&bgr;1, VEGF, and HIF-1&agr; expression profiles during renal transplantation with heart-beating donors (HBD) and non-heart-beating donors (NHBD). Methods. An experimental model of renal transplantation using 40 pairs of large, white, Landrace pigs and including HBD and NHBD was used. Cold-ischemia time was the same in all groups (6 hr), and three groups of NHBD (30, 45, and 90 min) were studied. Immunosuppressive therapy consisted of cyclosporine, except in one HBD group, which was treated with azathioprine. TGF-&bgr;1, VEGF, and HIF-1&agr; expression profiles were performed in renal biopsies obtained at different times: after anesthetic induction (basal); 30, 45, and 90 min after warm ischemia; after cold ischemia; 1 hr after reperfusion; and 5 days after transplantation. Results. TGF-&bgr;1 expression increased after cold ischemia in HBD and remained unaltered during the surgical process in all NHBD groups. HIF-1&agr; and VEGF expression were not greatly modified during surgery in the HBD or NHBD groups. All groups showed a significant increase in TGF-&bgr;1 and HIF-1&agr; expression as well as down-regulation of VEGF 5 days after transplantation, and these effects were independent of immunosuppressive treatment. There were no statistically significant differences among the groups at 5 days after transplantation, although the increase in TGF-&bgr;1 was more pronounced in the HBD groups, especially in azathioprine-treated animals. Conclusions. The initial up-regulation of TGF-&bgr;1 observed in HBD immediately after cold ischemia could have a positive effect on epithelial-tubular regeneration. Warm ischemia has a detrimental effect on TGF-&bgr;1 expression during the early phases of renal transplantation and has no effect on VEGF and HIF-1&agr; expression. The up-regulation of TGF-&bgr;1 and HIF-1&agr; observed after transplantation could have a positive effect on tubular repair. TGF-&bgr;1 expression was lower in animals treated with cyclosporine, probably because of cellular toxicity.