Jean-Frédéric Marlière

Urinary albumin excretion and the risk of graft loss and death in proteinuric and non-proteinuric renal transplant recipients

Background: Microalbuminuria and macroalbuminuria constitute risk factors for ESRD and death in non‐transplanted populations. Whether microalbuminuria (especially in non‐proteinuric patients) and macroalbuminuria constitute risk factors for graft loss and death is presently unknown in renal transplantation.

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.

Early Pulse Pressure and Low-Grade Proteinuria as Independent Long-Term Risk Factors for New-Onset Diabetes Mellitus After Kidney Transplantation

Risk factors for new‐onset diabetes after transplantation (NODAT) need to be assessed in large cohorts.

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.

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 IFNγ 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.

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 IFNγ 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.

CMV Infection in the Donor and Increased Kidney Graft Loss: Impact of Full HLA-I Mismatch and Posttransplantation CD8+ Cell Reduction

Despite a large body of literature, the impact of chronic cytomegalovirus (CMV) infection in donor on long‐term graft survival remains unclear, and factors modulating the effect of CMV infection on graft survival are presently unknown. In this retrospective study of 1279 kidney transplant patients, we analyzed long‐term graft survival and evolution of CD8+ cell population in donors and recipients by CMV serology and antigenemia status. A positive CMV serology in the donor was an independent risk factor for graft loss, especially among CMV‐positive recipients (R+). Antigenemia was not a risk factor for graft loss and kidneys from CMV‐positive donors remained associated with poor graft survival among antigenemia‐free recipients. Detrimental impact of donors CMV seropositivity on graft survival was restricted to patients with full HLA‐I mismatch, suggesting a role of CD8+ cells. In R+ patients with positive CMV antigenemia during the first year, CD8+ cell count did not increase at 2 years posttransplantation, in contrast to R− recipients. In addition, marked CD8+‐cell decrease was a risk factor of graft failure in these patients. This study identifies HLA‐I full mismatch and a decrease of CD8+ cell count at 2 years as important determinants of CMV‐associated graft loss.

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: 5.7 years; 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 10 years, respectively, after transplantation. RI at 3 months 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 1 month [HR per 0.1:1.74 (1.33–2.27), P < 0.0001] and 12 months [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 DSCs 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 &mgr;mol/L: 3 months 2/6); ≥130 &mgr;mol/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.

[OP.2B.06] RENAL RESISTIVE INDEX AND PULSE PRESSURE AT 3 MONTHS HAVE A DIFFERENT IMPACT ON LONG-TERM RISK OF DEATH AND GRAFT LOSS IN RENAL TRANSPLANTATION

Objective: Some studies suggest that pulse pressure (PP) and renal resistive index (RI) could be predictive of the risk of death; however, whether they also predict graft loss is debated. It was recently demonstrated that RI reflects large artery arterial stiffness as PP does but RI is also affected by alteration in renal microcirculation alteration. Finally, the respective predictive value of these 2 parameters considered together on graft loss and death is unknown. Design and method: Cohort study of consecutive patients who received a renal graft in Tours from 1985 to 2014 in whom PP and RI were measured at 3 months. The long-term risk of death and graft loss was assessed. Results: 1237 renal transplant recipients were included (age: 49.3 ± 14.5; 61.8% men). At 3 months, RI was 0.68 ± 0.08 (RI > 0.75: 17.2%; RI > 0.80: 5.8%). Arterial pressure was 138 ± 16/79 ± 11 (PP: 59.6 ± 14.5 mmHg; médiane: 60 mmHg); 55.4% were uncontrolled (i.e. PA> = 140/90 mmHg). During follow-up (meidan: 5.9 years; range: 0.4–27.5; 9772 patients-years), 130 patients died and 216 lost their graft. In univariate analysis, RI (as well as PP) was associated with the risk of death (RI > 0.80: HR = 2.50 [1.63–3.83]; RI > 75: HR = 3.19 [2.32–4.39], both: P < 0.0001) and graft loss (RI > 0.80: HR = 1.71 [1.16–2.52], P = 0.0068; RI > 75: HR = 1.53 [1.15–2.03], P = 0.0035). RI significantly predicted death (RI > 0.80: HR = 2.98 [2.10–4.23]; RI > 75: HR = 3.63 [2.32–5.69], both: P < 0.0001) but not PP > 60 mmHg after adjustment on RI > 0.80 (HR = 1.07 [0.75–1.52], P = 0.7088) or RI > 0.75 (HR = 1.04 [0.74–1.48], P = 0.8109) when RI and PP were simultaneously considered in multivariate analyses. Similar results were observed when RI and PP were expressed as continuous parameters, and after adjustment on recipient age. In contrast, only PP > 60 mmHg was associated with the risk of graft loss after adjustment on RI (HR for adj. on RI > 0.80: HR = 1.31 [1.01–1.71], P = 0.0457; HR for adj. on RI > 0.75: HR = 1.30 [1.00–1.70], P = 0.0516), and adjustment on RI and age (HR = 1.32 [1.01–1.73], P = 0.0406; HR = 1.32 [1.01–1.72], P = 0.0441 respectively); RI was not (RI > 80: HR = 1.17 [0.68–2.01], P = 0.5765; RI > 75: HR = 1.20 [0.85–1.69], P = 0.2933). Conclusions: Pulse pressure and renal resistive index at 3 months differently impact the long-term risk of death and graft loss.