Christelle Barbet

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.

Pathogenic Variants in Complement Genes and Risk of Atypical Hemolytic Uremic Syndrome Relapse after Eculizumab Discontinuation

BACKGROUND AND OBJECTIVES The complement inhibitor eculizumab has dramatically improved the outcome of atypical hemolytic uremic syndrome. However, the optimal duration of eculizumab treatment in atypical hemolytic uremic syndrome remains debated. We report on the French atypical hemolytic uremic syndrome working groups first 2-year experience with eculizumab discontinuation in patients with atypical hemolytic uremic syndrome. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS Using the French atypical hemolytic uremic syndrome registry database, we retrospectively identified all dialysis-free patients with atypical hemolytic uremic syndrome who discontinued eculizumab between 2010 and 2014 and reviewed their relevant clinical and biologic data. The decision to discontinue eculizumab was made by the clinician in charge of the patient. All patients were closely monitored by regular urine dipsticks and blood tests. Eculizumab was rapidly (24-48 hours) restarted in case of relapse. RESULTS Among 108 patients treated with eculizumab, 38 patients (nine children and 29 adults) discontinued eculizumab (median treatment duration of 17.5 months). Twenty-one patients (55%) carried novel or rare complement genes variants. Renal recovery under eculizumab was equally good in patients with and those without complement gene variants detected. After a median follow-up of 22 months, 12 patients (31%) experienced atypical hemolytic uremic syndrome relapse. Eight of 11 patients (72%) with complement factor H variants, four of eight patients (50%) with membrane cofactor protein variants, and zero of 16 patients with no rare variant detected relapsed. In relapsing patients, early reintroduction (≤48 hours) of eculizumab led to rapid (<7 days) hematologic remission and a return of serum creatinine to baseline level in a median time of 26 days. At last follow-up, renal function remained unchanged in nonrelapsing and relapsing patients compared with baseline values before eculizumab discontinuation. CONCLUSIONS Pathogenic variants in complement genes were associated with higher risk of atypical hemolytic uremic syndrome relapse after eculizumab discontinuation. Prospective studies are needed to identify biomarkers predictive of relapse and determine the best strategy of retreatment in relapsing patients.

Therapeutic drug monitoring of eculizumab: Rationale for an individualized dosing schedule.

The annual cost of eculizumab maintenance therapy in paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic–uremic syndrome (aHUS) exceeds

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

300,000 per patient. A better understanding of eculizumab pharmacokinetics and subsequent individual dose adjustment could reduce this cost. We measured the trough eculizumab concentration in 9 patients with maintenance therapy (aHUS, n = 7; PNH, n = 2) and determined: 1) the intra- and inter-individual variability; 2) the influence of weight on eculizumab pharmacokinetics; and 3) the rate of elimination of eculizumab following discontinuation. A one-compartment model was developed to describe the pharmacokinetics of eculizumab and predicted complement activity by body weight. Trough eculizumab concentrations were >50 µg/mL in 9/9, >100 µg/mL in 8/9, and >300 µg/mL in 5/9 of patients. Intra-individual variability was low but eculizumab concentrations, closely correlated with patient weight (R2 = 0.66, p = 0.034), varied broadly (55 ± 12 to 733 ± 164 µg/mL). Pharmacokinetic modeling showed that the elimination half-life varied greatly, with an increase from 7.8 d in a patient weighing 100 kg to 19.5 d in a 40 kg patient. We predicted that infusions of 1200 mg could be spaced every 4 or 6 weeks in patients weighing <90 and <70 kg, respectively. In this pilot study, the current recommended use of a fixed eculizumab dose for maintenance therapy is associated with excessively high trough concentrations in many patients. Further prospective larger studies are now required to support an individualized schedule adjusted for patient weight and based on the observed trough serum eculizumab concentration.

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

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.

Risk Factors for Autoimmune Diseases Development After Thrombotic Thrombocytopenic Purpura.

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.

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

Abstract Autoimmune thrombotic thrombocytopenic purpura (TTP) can be associated with other autoimmune disorders, but their prevalence following autoimmune TTP remains unknown. To assess the prevalence of autoimmune disorders associated with TTP and to determine risk factors for and the time course of the development of an autoimmune disorder after a TTP episode, we performed a cross sectional study. Two-hundred sixty-one cases of autoimmune TTP were included in the French Reference Center registry between October, 2000 and May, 2009. Clinical and laboratory data available at time of TTP diagnosis were recovered. Each center was contacted to collect the more recent data and diagnosis criteria for autoimmunity. Fifty-six patients presented an autoimmune disorder in association with TTP, 9 years before TTP (median; min: 2 yr, max: 32 yr) (26 cases), at the time of TTP diagnosis (17 cases) or during follow-up (17 cases), up to 12 years after TTP diagnosis (mean, 22 mo). The most frequent autoimmune disorder reported was systemic lupus erythematosus (SLE) (26 cases) and Sjögren syndrome (8 cases). The presence of additional autoimmune disorders had no impact on outcomes of an acute TTP or the occurrence of relapse. Two factors evaluated at TTP diagnosis were significantly associated with the development of an autoimmune disorder during follow-up: the presence of antidouble stranded (ds)DNA antibodies (hazard ratio (HR): 4.98; 95% confidence interval (CI) [1.64–15.14]) and anti-SSA antibodies (HR: 9.98; 95% CI [3.59–27.76]). A follow-up across many years is necessary after an acute TTP, especially when anti-SSA or anti-dsDNA antibodies are present on TTP diagnosis, to detect autoimmune disorders early before immunologic events spread to prevent disabling complications.

Routine Determination of GFR in Renal Transplant Recipients by HPLC Quantification of Plasma Iohexol Concentrations and Comparison With Estimated GFR

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.

Ultrastructural demonstration of a relationship between acquired cutis laxa and monoclonal gammopathy.

Estimated glomerular filtration rate (eGFR) methods are not sufficiently reliable in renal transplant recipients (RTR) and should be replaced by iohexol plasma clearance measurement. However, this method has poor availability in health centers. The aim of our study was to develop a high‐performance liquid chromatography (HPLC) method for plasma iohexol measurement in routine practice and to evaluate its plasma clearance as a reference of GFR. We developed an HPLC method using UV detection. We evaluated sample storage conditions to provide recommendations for routine practice. Then, we compared GFRbased on plasma iohexol clearance (GFR‐iohexol) to eGFR using modification of diet in renal disease, Cockcroft and Gault, and CDK‐EPIequations in 40 RTR. The method was validated over a concentration range of 15–300 μg/l. Excellent linearity (r > 0.998), inter‐ and intraday precision (CV < 3.3%), and accuracy (>96.8%) were complied with ICH guidelines. We also demonstrated excellent samples stability (9 days). Although eGFR methods are not references in RTR, we found a correct concordance between eGFR and GFR‐iohexol in our population. To conclude, our method is simple, rapid, accurate, and reliable for routine clinical and research use especially in RTR. J. Clin. Lab. Anal. 26:376‐383, 2012.