Valérie Chatelet

Eculizumab for Atypical Hemolytic Uremic Syndrome Recurrence in Renal Transplantation

Eculizumab (anti‐C5) has been sporadically reported as an efficient therapy for atypical hemolytic uremic syndrome (aHUS). However, the lack of series precludes any firm conclusion about the optimal use of anti‐C5 for preventing or treating aHUS posttransplant aHUS recurrence. We thoroughly studied 22 renal transplant recipients with aHUS who received off‐label therapy with anti‐C5, including 12 cases, which have not been reported yet. Nine patients, all carrying a complement genetic abnormality associated with a high risk of aHUS recurrence, received prophylactic anti‐C5 therapy to prevent posttransplant recurrence. Eight of them had a successful recurrence‐free posttransplant course and achieved a satisfactory graft function, while the remaining patient experienced early arterial thrombosis of the graft. Thirteen renal transplant recipients were given anti‐C5 for posttransplant aHUS recurrence. A complete reversal of aHUS activity was obtained in all of them. Importantly, the delay of anti‐C5 initiation after the onset of the aHUS episode inversely correlated with the degree of renal function improvement. Three patients in whom anti‐C5 was subsequently stopped experienced a relapse. Altogether these data suggest that long‐term eculizumab is highly effective for preventing and treating posttransplant aHUS recurrence. Our study also indicates that anti‐C5 should be promptly started if a recurrence occurs.

Complement Genes Strongly Predict Recurrence and Graft Outcome in Adult Renal Transplant Recipients with Atypical Hemolytic and Uremic Syndrome

Atypical hemolytic and uremic syndrome (aHUS) is a severe disease strongly associated with genetic abnormalities in the complement alternative pathway. In renal posttransplantation, few data are available on recurrence risk and graft outcome according to genetic background in aHUS patients. The aim of this study was to identify risk factors for recurrence and transplant outcome and, in particular, the role of complement gene abnormalities. We retrospectively studied 57 aHUS patients who had received 71 renal transplants. A mutation in complement gene was identified in 39 (68%), in factor H (CFH), factor I (CFI), membrane cofactor‐protein (MCP), C3 and factor B (CFB). At 5 years, death‐censored graft survival was 51%. Disease recurrence was associated with graft loss (p = 0.001). Mutations in complement genes were associated with higher risk of recurrence (p = 0.009). Patients with CFH or gain of function (C3, CFB) mutations had a highest risk of recurrence. M‐TOR inhibitor was associated with significant risk of recurrence (p = 0.043) but not calcineurin inhibitor immunosuppressive treatment (p = 0.29). Preemptive plasmatherapy was associated with a trend to decrease recurrence (p = 0.07). Our study highlights that characterization of complement genetic abnormalities predicts the risk of recurrence‐related graft loss and paves the way for future genetically based individualized prophylactic therapeutic strategies.

Early Low-Grade Proteinuria: Causes, Short-Term Evolution and Long-Term Consequences in Renal Transplantation

Proteinuria 1 year after transplantation is associated with poor renal outcome. It is unclear whether low‐grade (<1 g/24 h) proteinuria earlier after transplantation and its short‐term change affect long‐term graft survival. The effects of proteinuria and its change on long‐term graft survival were retrospectively assessed in 484 renal transplant recipients. One‐ and 3‐month proteinuria correlated with donor age, donor cardiovascular death, prolonged cold and warm ischemia times and acute rejection. One‐ and 3‐month proteinuria (per 0.1 g/24 h, hazard ratio (HR): 1.07 and 1.15, p < 0.0001)—especially low‐grade proteinuria (HR: 1.20 and 1.26, p < 0.0001)—were powerful, independent predictors of graft loss. Its short‐term reduction correlated with arterial pressure (AP) (the lower the 3‐month diastolic and 12‐month systolic AP, the lower the risk of increasing proteinuria during 1–3 months and 3–12 months periods, respectively: Odds ratio (OR) per 10 MmHg: 0.78, p = 0.01 and 0.85, respectively, p = 0.02), and was associated with decreased long‐term graft loss (per 0.1 g/24 h: HR: 0.88 and 0.98, respectively, p < 0.0001), independently of initial proteinuria. Early low‐grade proteinuria due to pre‐transplant renal lesions, ischemia‐reperfusion and immunologic injuries is a potent predictor of graft loss. Short‐term reduction in proteinuria is associated with improved long‐term graft survival.

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.

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.

Kidney transplantation in patients with systemic sclerosis: a nationwide multicenter study

Kidney transplantation is one of the therapeutic options for end‐stage renal disease (ESRD) in systemic sclerosis (SS). Current evidence demonstrates poorer patient and graft survival after transplantation in SS than in other primary kidney diseases. All the patients presenting ESRD associated with SS who had received a kidney allograft between 1987 and 2013 were systematically included from 20 French kidney transplantation centres. Thirty‐four patients received 36 kidney transplants during the study period. Initial kidney disease was scleroderma renal crisis in 76.4%. Extrarenal involvement of SS was generally stable, except cardiac and gastrointestinal involvements, which worsened after kidney transplantation in 45% and 26% of cases, respectively. Patient survival was 100%, 90.3% and 82.5% at 1, 3 and 5 years post‐transplant, respectively. Pulmonary involvement of SS was an independent risk factor of death after transplantation. Death‐censored graft survival was 97.2% after 1 and 3 years, and 92.8% after 5 years. Recurrence of scleroderma renal crisis was diagnosed in three cases. In our study, patient and graft survivals after kidney transplantation can be considered as excellent. On this basis, we propose that in the absence of extrarenal contraindication, SS patients presenting with ESRD should be considered for kidney transplantation.