Renal resistive index as a new independent risk factor for new-onset diabetes mellitus after kidney transplantation.

Pulse pressure and urinary albumin excretion were recently identified as risk factors of new-onset diabetes after renal transplantation (NODAT), suggesting that microvascular injury may be implicated in NODAT. However, the relationship between of microvascular injury and NODAT is unknown. In the present long-term (median follow-up: 5.7years; observation period: 4908 patient-years) retrospective study in 656 renal transplant recipients, the association between baseline renal resistance index (RI, used as a marker of widespread microvascular damage) and the incidence of NODAT was assessed. The incidence of NODAT was 11.2% and 14.6% at 5 and 10years, respectively, after transplantation. RI at 3months was a risk factor for NODAT [hazard ratio (HR) per 0.1: 2.19 (1.55-3.09), P<0.0001]. RI >0.75 (vs. 0≤0.75) was a potent a predictor of NODAT [HR: 3.29 (1.91-5.67), P<0.0001], even after adjustments [HR: 3.29 (1.50-7.24), P=0.0030] on age, weight, glucose, nephropathy, and arterial pressure. Similar results were observed when RI was measured at 1month [HR per 0.1:1.74 (1.33-2.27), P<0.0001] and 12months [HR per 0.1:1.74 (1.33-2.27), P<0.0001] after transplantation. High RI early after renal transplantation is a long-term risk factor for NODAT, and could be used to refine the individual risk of NODAT.

Doubling of serum creatinine in clinical trials, cost-effectiveness studies, and individual patients: adequate use in renal transplantation.

BACKGROUND: The predictive value of doubling of serum creatinine (DSC) has never been assessed in renal transplantation. We evaluated it in terms of its use for clinical trials, cost-effectiveness studies, and individual patients. METHODS: Retrospective longitudinal study in 896 renal transplant recipients. RESULTS: Death-censored graft loss occurred in 133 patients, during follow-up (up to 21 years). DSC was a risk factor for graft loss; however, the relative risk was different in patients with glomerular filtration rate less than 40 vs. more than or equal to 40 mL/min (hazard ratio: 14.5 [95% confidence interval: 7.4-28.4] vs. 47.8 [28.4-80.6], P=0.0051). Parameters influencing creatinine value (weight, age, sex) did not modify DSC's predictive value. The use of the composite endpoint DSC or death-censored graft loss instead of death-censored graft loss alone in clinical trials would reduce sample size by 7.1% to 9.0%. The annual probability of DSC to graft loss transition decreased from 76% (follow-up <1 year) to 5% (follow-up ≥10 years). Median graft half-life after DSC was 10 months [95% confidence interval: 6-18] but varied with increasing time to DSC (<1 year: 1 month [0.5-6]; 3-4.9 years: 15 months 5/67) and reference creatinine (<130 µmol/L: 3 months 2/6); ≥130 µmol/L: 25 months 15/37). CONCLUSIONS: DSC may be adequately used to refine the risk of death-censored graft loss for individual patients. However, the use of DSC as an endpoint in clinical trials marginally affects sample size, and the probability of DSC to graft loss transition is not constant, which limits the use of DSC in cost-effectiveness analyses of renal transplantation.

Autosomal dominant polycystic kidney disease: risk factor for nonmelanoma skin cancer following kidney transplantation.

Nonmelanoma skin cancers (NMSC) are the most common malignant tumors following solid organ transplantation. Risk factors for NMSC mainly include immunosuppression, age, sun exposure and patient phototype. Recent findings have suggested that autosomal dominant polycystic kidney disease (ADPKD) may increase the risk of developing NMSC. We performed a monocenter retrospective study including all kidney recipients between 1985 and 2006 (n = 1019). We studied the incidence of NMSC, solid cancers and post-transplantation lymphoproliferative disease (PTLD), and analyzed the following parameters: age, gender, phototype, time on dialysis, graft rank, immunosuppressive regimen, history of cancer and kidney disease (ADPKD versus others). Median follow-up was 5.5 years (range: 0.02-20.6; 79 838 patient-years). The cumulated incidence of NMSC 10 years after transplantation was 12.7% (9.3% for solid cancers and 3.5% for PTLD). Autosomal dominant polycystic kidney disease and age were risk factors for NMSC (HR 2.63; P < 0.0001 and HR 2.21; P < 0.001, respectively) using univariate analysis. The association between ADPKD and NMSC remained significant after adjustments for age, gender and phototype using multivariate analysis (HR 1.71; P = 0.0145) and for immunosuppressive regimens (P < 0.0001). Autosomal dominant polycystic kidney disease was not a risk factor for the occurrence of solid cancers after transplantation (HR 0.96; P = 0.89). Our findings suggest that ADPKD is an independent risk factor for developing NMSC after kidney transplantation.

Association between a polymorphism in the human programmed death-1 (PD-1) gene and cytomegalovirus infection after kidney transplantation.

BACKGROUND: Cytomegalovirus (CMV) infection is the most frequent infectious disease following organ transplantation. Strategies to prevent this infection remain a matter for debate, and discovering genetic risk factors might assist in adapting preventive strategies. By inhibiting IFNgamma production, programmed death 1 (PD-1) has a crucial role in anti-CMV immune response. A single nucleotide polymorphism (SNP) within intron 4 of the gene (rs11568821), called PD-1.3, has recently been reported to be clinically relevant in several immune disorders. However, its association with CMV infection has never been reported. METHODS: In this study, the risk of CMV infection according to PD-1.3 genotype was investigated in 469 kidney graft recipients transplanted between 1995 and 2005. RESULTS: It was found that the A allele was associated with the risk of CMV infection in seropositive patients who did not receive CMV prophylaxis (OR=2.60, p=0.006). Multivariate analysis including other risk factors for CMV infection showed that this allele was independently associated with CMV infection (OR=2.54; p=0.010). Interestingly, combined analysis of PD-1.3 with the IL12B 3'UTR SNPs (previously shown to be associated with CMV infection) revealed that patients with the PD-1.3 A allele had a much higher risk of CMV infection compared to those having neither risk allele (OR=3.76; p=0.0003). CONCLUSION: This study identified a new genetic risk factor for CMV infection after kidney transplantation and suggests that an adjustment of CMV prophylaxis based on genetic markers would merit further investigation.

Association between a polymorphism in the IL-12p40 gene and cytomegalovirus reactivation after kidney transplantation.

BACKGROUND: Cytomegalovirus (CMV) infection is associated with a significant rate of morbidity after organ transplantation. The genetic factors influencing its occurrence have been little investigated. IL-12 plays a crucial role in anti-infectious immune responses, especially by stimulating IFNgamma production. An A-to-C single nucleotide polymorphism (SNP) within the 3'-untranslated region of the IL-12p40 gene has been characterized and was reported to be both functionally and clinically relevant. However, the impact of this single nucleotide polymorphism on events after organ transplantation has never been reported. METHODS: In this study, we investigated the impact of the 3'-untranslated region polymorphism on the occurrence of CMV infection in 469 kidney recipients transplanted at the University Hospital of Tours between 1995 and 2005. The polymorphism was genotyped using the restriction fragment length polymorphism method and CMV infection was determined by pp65 antigenemia. RESULTS: Multifactorial Cox regression analysis demonstrated that the presence of the C allele was an independent risk factor for CMV infection (OR=1.52, P=0.043), the risk being even higher when study was restricted to patients with positive CMV serological status before the graft and who did not receive any CMV prophylaxis (OR=1.88, P=0.028). CONCLUSIONS: This study identified a new genetic risk factor for CMV reactivation after kidney transplantation. The results of our study suggest that C carriers might especially benefit from CMV prophylaxis.

Immunosuppressive medications, clinical and metabolic parameters in new-onset diabetes mellitus after kidney transplantation.

New-onset diabetes after transplantation (NODAT) is a growing concern in transplantation. All modifiable risk factors are not yet identified. We assessed the relationship between baseline clinical and biochemical parameters and NODAT. Eight-hundred and fifty-seven in-Caucasian renal transplant recipients were included. Charts were individually reviewed. The follow-up was 5.3 years (ranges: 0.25-20.8; 5613 patient-years). The incidence of NODAT was 15.0%, 18.4% and 22.0% at 10, 15 and 20 years following transplantation. Age, body mass index (BMI), glucose (all P < 0.0001) and triglycerides [hazard ratio (HR) per 1 mmol/l: 1.44 [1.17-1.77], P = 0.0006] were potent risk factors whereas steroid withdrawal (HR: 0.69 [0.47-1.01], P = 0.0601) reduced the risk. As compared to cyclosporine, sirolimus (HR: 3.26 [1.63-6.49], P = 0.0008) and tacrolimus (HR: 3.04 [2.02-4.59], P < 0.0001) were risk factors for NODAT. The risk of NODAT was comparable for sirolimus (HR: 2.35 [1.06-5.19], P = 0.0350) and tacrolimus (HR: 2.34 [1.46-3.75], P = 0.0004) after adjustments on age, BMI, glucose and steroid withdrawal; however, unlike sirolimus, tacrolimus remained significant after adjustment on triglycerides. The risk of NODAT appeared similar, but its pathophysiology seemed different in sirolimus- and tacrolimus-treated patients; this observation needs confirmation. However, main independent risk factors were age, BMI, initial glucose and triglycerides.

Respective predictive role of urinary albumin excretion and nonalbumin proteinuria on graft loss and death in renal transplant recipients.

Proteinuria is constituted by urinary albumin (UAE) and nonalbumin proteins (NAP). UAE was shown to predict ESRD and death. Whether NAP predicts graft or patient outcome is unknown in renal transplantation. We retrospectively analyzed the impact of UAE and NAP respectively on end-stage renal disease (ESRD) and death in 616 renal transplant recipients. In subjects with proteinuria <0.25 g/day, 76% of urine proteins were NAP; in those with >1 g/day, 44% of the urine proteins were NAP. Determinants of UAE and NAP were partly different: fasting glucose, body weight, donor cause of death and cyclosporine were significantly associated with NAP (but not UAE); panel reactive antibodies (PRA) and rapamycine were significantly associated with UAE (but not with NAP). NAP expressed as a continuous (HR: per g/day: 4.00 [2.85-5.63], p < 0.0001) or a categorical (presence vs. absence, HR = 29.09[8.80-96.20], p < 0.0001) parameter and UAE (per g/day, HR = 1.86 [1.24-2.78], p < 0.0001) were risk factors for graft loss in univariate analyses. NAP remained significant even after adjustment on UAE. The presence of NAP (HR: 5.37 [2.55-11.34], p < 0.0001) and macroalbuminuria (HR: 4.12 [1.65-10.29], p = 0.0024) were risk factors for death. Proteinuria is made of various proportions of UAE and NAP in renal transplantation; these two parameters provide different information on graft/patient survival.