Didier Ducloux

CD4 lymphocytopenia as a risk factor for skin cancers in renal transplant recipients

BACKGROUND Renal transplant recipients are at increased risk of developing skin cancer. It remains difficult to establish the actual influence of overimmunosuppression in the development of skin cancers. We investigated whether lymphocyte subset count may predict the risk of developing skin cancer in long-term renal transplant recipients. METHODS One hundred fifty long-term renal transplant recipients were followed for a mean period of 26 months. Each patient was examined at least annually by a dermatologist. Lymphocyte subsets were measured annually. RESULTS Fifteen patients exhibited skin cancers. Patients with and without skin cancer did not differ in age, gender, transplant duration, hemodialysis duration before transplantation, immunosuppressive regimen, and serum creatinine concentration. CD4 cell counts were significantly lower in patients with skin cancers (330+/-179/mm3 vs. 503+/-338/mm3; P<0.01), whereas total lymphocyte and CD8 and CD19 cell counts were similar between the two groups. CONCLUSIONS CD4 cell depletion is associated with skin cancer in long-term renal transplant recipients.

One-Year Post-Transplant Weight Gain is a Risk Factor for Graft Loss

Metabolic syndrome (MS) and obesity participate in the pathogenesis of kidney disease. We explored the impact of MS and post‐transplant weight gain on graft survival. Two hundred ninety‐two renal transplant recipients (RTRs) were included in the study. Various parameters (e.g. anthropometric, biological) were measured at the time of transplantation as well as 1 year post‐transplant. The proportion of patients with overweight or obesity significantly increased during the first year post‐transplant (p = 0.04). Mean weight gain was 2.7 ± 5.8 kg. Thirty patients (10.3%) lost their graft during follow‐up. In multivariate analysis, patients with an increase in body mass index (BMI) of more than 5% at 1 year post‐transplant had an increased risk of graft loss with (HR: 2.82 [95% CI: 1.11–7.44], p = 0.015) or without death censoring (HR: 2.31 [95% CI: 1.06–5.04], p = 0.035). Low creatinine clearance (HR: 4.72 [95% CI: 1.63–13.69], p = 0.004), high urinary protein excretion (HR: 3.21 [95% CI: 1.27–8.18], p = 0.014) and delayed graft function (DGF) (HR: 2.621 [95% CI: 1.07–6.39], p = 0.036) were also independent risk factors for graft loss. MS did not independently predict graft loss, partly due to significant interactions with low‐grade inflammation. We conclude that post‐transplant weight gain significantly reduces graft survival.

Mycophenolate mofetil in renal transplant recipients with cyclosporine-associated nephrotoxicity: a preliminary report.

BACKGROUND There is a great concern over cyclosporine (CsA) nephrotoxicity in renal transplant recipients, and the effects of conversion from CsA to azathioprine (AZA) remain controversial. Large studies have demonstrated that mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid, is superior to AZA as a posttransplant immunosuppressant. METHODS Six patients with isolated biopsy-proven CsA nephrotoxicity were converted from CsA-AZA to MMF. RESULTS Mean follow-up was 12+/-2 months. No patient experienced acute rejection. The mean serum creatinine concentration decreased from 225+/-58 to 159+/-66 micromol/L (P<0.0005). Hyperlipidemia and blood pressure improved after CsA withdrawal. CONCLUSION In a selected transplant population with biopsy-proven CsA nephrotoxicity, CsA withdrawal with a concomitant switch from AZA to MMF seems to be safe and allows a significant improvement of renal function.

Mycophenolate mofetil-induced villous atrophy

Mycophenolate mofetil (MMF) is a new immunosuppressant developed for the prevention and treatment of acute renal rejection after transplantation. Diarrhea is the most frequent side effect observed during treatment with MMF. Its pathogenic mechanisms remain unknown. We describe a case of severe diarrhea due to villous atrophy in a renal transplant recipient during treatment with MMF. The patient was free of symptoms before MMF. Villous atrophy disappeared a few months after MMF withdrawal.

Recurrence of hemolytic-uremic syndrome in renal transplant recipients: a meta-analysis.

BACKGROUND Recurrence of hemolytic-uremic syndrome (HUS) in the allograft is associated with a very poor renal prognosis. Meta-analysis of previous trials may allow us to better estimate its real frequency, to identify risk factors for recurrence, and to predict the outcome of patients with definite recurrence. METHODS An exhaustive search was conducted of HUS recurrence in renal transplantation from January 1977 to June 1997 using MEDLINE. RESULTS Ten studies comprising 159 grafts in 127 patients were identified. The rate of recurrence was 27.8%. One-year graft survival was 76.6% in patients without recurrence and 33.3% in patients with recurrence (P<0.001). Older age at onset of HUS (16.96+/-7.6 years vs. 9.95+/-6.55 years; P<0.02), shorter mean interval between HUS and transplantation (2.51+/-2.7 years vs. 6.03+/-6.4 years; P<0.01), shorter mean interval between HUS and end-stage renal disease (0.79+/-0.39 years vs. 2.78+/-2.47 years; P<0.01), living-related donors, and the use of calcineurin inhibitors were associated with recurrence. CONCLUSION Risk factors for HUS recurrence in renal transplantation could be identified through this meta-analysis.

CD4 Cell Lymphopenia and Atherosclerosis in Renal Transplant Recipients

Several animal studies suggest that T cell-mediated immunodeficiency may play a role in the progression of atherosclerosis. This study examined the association between lymphocyte subsets and atherosclerotic events in renal transplant recipients. A total of 302 consecutive renal transplant recipients were enrolled in this prospective study. Peripheral blood lymphocyte subsets were quantified and analyzed with respect to other known cardiovascular risk factors. The patients were followed for a mean duration of 23.5 +/- 4.5 mo. Mean CD4, CD8, and CD19 cell levels were 511 +/- 290/mm(3), 553 +/- 596/mm(3), and 66 +/- 62/mm(3), respectively. CD4 levels were positively related to transplant duration (r = 0.32; P = 0.02) and inversely related to age (r = 0.35; P = 0.01). Twenty-five atherosclerotic events (AE) occurred in 25 patients (8.3%). CD4 levels were lower in patients who experienced CVE (288 +/- 170/mm(3) versus 531 +/- 290/mm(3); P < 0.0001). Cox regression analysis showed that patients in the three upper quartiles of CD4 cell count had a decreased risk of CVE compared with those in the lowest quartile. There was a linear increase in risk of CVE with decreasing CD4 cell count (P < 0.0001). A CD4 cell count in the highest quartile (>663/mm(3)) divided the risk of CVE by 10 as compared with the lowest quartile. In conclusion, CD4 lymphocytopenia is an independent risk factor for the development of cardiovascular complications in renal transplant recipients, suggesting that impaired immune response promotes accelerated atherogenesis in this population.

Urinary cytotoxic molecular markers for a noninvasive diagnosis in acute renal transplant rejection

Perforin (P), Granzyme B (GB) and Fas‐Ligand (FAS‐L) are cytotoxic molecules involved in acute rejection (AR) after renal transplantation. A noninvasive diagnostic test to monitor AR and other complications could improve clinical management. We investigated the predictive and diagnostic interest of target mRNA measurements, with a quantitative PCR assay, in AR, as well as in other clinical complications recurrent in kidney transplantation. One hundred and sixty‐two urine specimens from 37 allograft recipients were investigated. Clinical settings were AR, urinary tract infection (UTI), cytomegalovirus infection (CMVi) or disease (CMVd), chronic allograft nephropathy (CAN), delayed graft function (DGF) and stable graft course (controls). In the case of AR, mRNA levels of all three molecules were significantly higher than in recipients not showing any clinically evident signs of complication. Indeed, it was observed that expression levels of P, GB and Fas‐L mRNA also increase in other clinical situations such as UTI, CMV and DGF. Finally, kinetic studies in three patients with AR revealed that increased P, GB and Fas‐L mRNA levels could precede or were concomitant with increased serum creatinin levels. P, GB and Fas‐L gene expression in urine specimens were upregulated in AR episodes but also in UTI, CMV infection and DGF. Therefore, this technique would appear to be of limited clinical value as a noninvasive method of diagnosing AR.

Metabolic syndrome and atherosclerotic events in renal transplant recipients.

Background. Metabolic syndrome (MS) is a known cardiovascular risk factor in the general population. We explored the influence of MS on the occurrence of atherosclerotic events (AEs) after renal transplantation. Methods. Three hundred thirty-seven renal transplant recipients were included in the study. Various parameters (e.g., anthropometric and biological) were measured 1 year after transplant. Results. One year after transplant, 32% of the study population met criteria for MS. Older age, male gender, pretransplant high body mass index, and an increase in body mass index ≥5% in the first year after transplant were predictive factors for development of MS at 1 year after transplant. Forty-two patients (12.4%) experienced AEs during the 8 years of follow-up. The cumulated incidence of AEs was greater in patients with MS compared with others without MS (25% vs. 7%; P<0.001). In multivariate analysis, patients with MS at 1 year after transplant had an increased risk of AE (hazard ratio 3.40, 95% confidence interval 1.58−7.32, P=0.002). Older age, low creatinine clearance, high C-reactive protein level, and a past history of cardiovascular disease were other independent risk factors for AE. Conclusions. Similar to the general population, MS is an independent risk factor for AE after renal transplantation. Relevant preventive measures targeting different aspects of MS would then have a potential impact on prevalence of AE in this population.

IL-6 Promoter Polymorphism −174 Is Associated with New-Onset Diabetes after Transplantation

New-onset diabetes after transplantation (NODAT) is a serious complication of transplantation. This study tested whether IL-6 production capacity may influence the development of NODAT in two different groups of patients. The occurrence of NODAT was analyzed with respect to IL-6 gene promoter polymorphism at position -174 (G-->C) and other relevant risk factors retrospectively in 217 renal transplant recipients and prospectively in 132. A linear increase in both circulating IL-6 (P = 0.09) and C-reactive protein (an indicator of basal IL-6 secretion; P = 0.03) concentrations from the CC genotype to the GG genotype was observed. In the multivariate model, the CC genotype was associated with a decreased risk for NODAT compared with the GG genotype in the two cohorts. Homeostasis Model Assessment for Insulin Resistance also revealed lesser insulin sensitivity in the GG carriers than in the CC carriers (2.15 +/- 2 versus 1.32 +/- 1.03; P = 0.03). Subgroup analysis showed that the influence of IL-6 gene promoter polymorphism on the development of NODAT was restricted mostly to overweight patients. These results highly suggest that IL-6 production capacity influences the development of NODAT and that diabetes-inducing drug administration should be limited in overweight patients who carry the GG genotype.

Impact of Cyclosporine Reduction With MMF: A Randomized Trial in Chronic Allograft Dysfunction. The ‘Reference’ Study

Long‐term use of calcineurine inhibitors (CNIs) may contribute to the development of chronic allograft dysfunction (CAD). We investigate the impact of the introduction of MMF combined with cyclosporine (CsA) 50% dose reduction. An open, randomized, controlled, multicenter, prospective study was conducted in 103 patients, receiving a CsA‐based therapy with a serum creatinine between 1.7–3.4 mg/dL, more than 1 year after transplantation. They were randomized to receive MMF with half dose of CsA (MMF group) or to continue their maintenance CsA dose (control group). A total of 96 weeks after randomization, the evolution of renal function assessed by regression line analysis of 1/SeCr improved in the MMF group (positive slope) vs. the control group (negative slope), 4.2 × 10−4 vs. −3.0 × 10−4, respectively (p < 0.001). Concurrently, the absolute renal function improved significantly in the MMF group. No episode of biopsy‐proven acute rejection occurred. One patient in each group lost his graft because of biopsy‐proven chronic allograft nephropathy. There was a significant decrease of triglycerides level in the MMF group. Anemia and diarrhea were statistically more frequent in the MMF group.