Guillaume Claisse

Significance Statement Although complement blockade is highly effective for preventing recurrence of atypical hemolytic uremic syndrome (HUS) after kidney transplant, debates regarding the use of eculizumab prophylaxis continue because of its very high cost. An individualized strategy—using eculizumab prophylaxis specifically in patients with moderate- to high-risk kidney transplants, determined by complement analysis and a medical history of a previous recurrence—was implemented in France in 2011 and subsequently adopted more widely. In the authors’ retrospective study of patients with atypical HUS in France, they found that prophylactic use of eculizumab almost abolished the risk of recurrence and significantly increased graft survival, especially in high-risk transplants. It also led to a substantial expansion after 2012 of the transplanted population among patients with atypical HUS and ESKD. These findings support use of eculizumab prophylaxis based on pretransplant risk stratification. Background Atypical hemolytic uremic syndrome (HUS) is associated with high recurrence rates after kidney transplant, with devastating outcomes. In late 2011, experts in France recommended the use of highly individualized complement blockade–based prophylaxis with eculizumab to prevent post-transplant atypical HUS recurrence throughout the country. Methods To evaluate this strategy’s effect on kidney transplant prognosis, we conducted a retrospective multicenter study from a large French nationwide registry, enrolling all adult patients with atypical HUS who had undergone complement analysis and a kidney transplant since January 1, 2007. To assess how atypical HUS epidemiology in France in the eculizumab era evolved, we undertook a population-based cohort study that included all adult patients with atypical HUS ( n =397) between 2007 and 2016. Results The first study included 126 kidney transplants performed in 116 patients, 58.7% and 34.1% of which were considered to be at a high and moderate risk of atypical HUS recurrence, respectively. Eculizumab prophylaxis was used in 52 kidney transplants, including 39 at high risk of recurrence. Atypical HUS recurred after 43 (34.1%) of the transplants; in four cases, patients had received eculizumab prophylaxis and in 39 cases they did not. Use of prophylactic eculizumab was independently associated with a significantly reduced risk of recurrence and with significantly longer graft survival. In the second, population-based cohort study, the proportion of transplant recipients among patients with ESKD and atypical HUS sharply increased between 2012 and 2016, from 46.2% to 72.3%, and showed a close correlation with increasing eculizumab use among the transplant recipients. Conclusions Results from this observational study are consistent with benefit from eculizumab prophylaxis based on pretransplant risk stratification and support the need for a rigorous randomized trial.

BACKGROUND: Detecting impaired glomerular filtration rate (GFR) is important in intensive care units (ICU) in order to diagnose acute kidney injuries and adjust the dose of renally excreted drugs. Whether serum Cystatin C (SCysC) may better reflect glomerular filtration rate than serum creatinine (SCr) in the context of intensive care medicine is uncertain. METHODS: We compared the performance of SCysC and SCr as biomarkers of GFR in 47 critically ill patients (median SOFA (Sepsis-related Organ Failure Assessment) score of 5) for whom GFR was measured by a reference method (urinary clearance of iohexol). RESULTS: Mean Iohexol clearance averaged 96 ± 54 mL/min and was under 60 mL/min in 28% of patients. Mean SCr and SCysC concentrations were 0.70 ± 0.33 mg/dL and 1.26 ± 0.61 mg/L, respectively. Area under the ROC curve for a GFR threshold of 60 mL/min was 0.799 and 0.942 for SCr and SCysC, respectively (p = 0.014). CONCLUSIONS: We conclude that ScysC significantly outperfoms SCr for the detection of an impaired GFR in critically ill patients. TRIAL REGISTRATION: ClinicalTrials.gov: B7072006347.

Export Activation of complement through the alternative pathway has a key role in the pathogenesis of IgA nephropathy (IgAN). Large, international, genome-wide association studies have shown that deletion of complement factor H–related genes 1 and 3 (CFHR3,1Δ) is associated with a reduced risk of developing IgAN, although the prognostic value of these deletions in IgAN remains unknown. Here, we compared the renal outcomes of patients with IgAN according to their CFHR3,1Δ genotype. This retrospective, monocentric cohort study included 639 white patients with biopsy-proven IgAN since 1979 (mean age at diagnosis, 40.1 years; median follow-up, 132 months). We determined the number of CFHR3 and CFHR1 gene copies by quantitative PCR and collected clinical and biologic data by reviewing the patients’ medical records. In all, 30.5% of the patients were heterozygous and 4% were homozygous for CFHR3,1Δ. We did not detect an association between CFHR3,1Δ and age, eGFR, urinary protein excretion rate, or the presence of hypertension or hematuria at the time of diagnosis. The mean intensities of immune IgA, IgG, and C3 deposits were lower in the group with heterozygous or homozygous gene deletions than in those with no deletion. However, CFHR3,1Δ did not associate with progression to stage 3 CKD or renal death. In conclusion, the CFHR3,1Δ genotype did not associate with progression toward CKD stages 3 and 5 in our white population of patients with IgAN, although it did associate with a reduced level of glomerular immune deposits.

Long-term safety of living kidney donation (LKD), especially for young donors, has become a real matter of concern in the transplant community and may contribute to creating resistance to LKD. In this context, the criteria that govern living donor donations must live up to very demanding standards as well as adjust to this novel reality. In the first part, we review the existing guidelines published after 2010 and critically examine their recommendations to see how they do not necessarily lead to consistent and universal practices in the choice of specific thresholds for a parameter used to accept or reject a living donor candidate. In the second part, we present the emergence of a new paradigm for LKD developed in the 2017 Kidney Disease: Improving Global Outcomes guidelines with the introduction of an integrative risk-based approach. Finally, we focus on predonation renal function evaluation, a criteria that remain central in the selection process, and discuss several issues surrounding the donor candidate's glomerular filtration rate assessment.

BACKGROUND: The prognosis of IgA nephropathy (IgAN) is very heterogeneous. Predicting the nature and the rate of the disease progression is crucial for refining patient treatment. The aim of this study was to evaluate the prognostic impact of an Oxford classification-based repeat kidney tissue evaluation to predict end-stage renal disease (ESRD). METHODS: Patients with biopsy-proven primary IgAN who underwent two renal biopsies at our centre were analyzed retrospectively. Renal biopsies were scored by two pathologists blinded to the clinical data and according to the updated Oxford classification. Cox models were generated to evaluate the prognostic impact considering the Oxford classification elementary lesions from the first (Model 1) or the second (Model 2) biopsy, adjusted on clinical data at time of reevaluation. The prognostic impacts of the dynamic evolution of each elementary lesion between biopsies were also assessed through univariate and multivariate evaluation. RESULTS: A total of 168 adult patients were included, with a median follow-up duration of 18 (range 11-24) years. The second biopsy was performed either systematically (n = 112) of for-cause (n = 56), after a median time of 5.4 years. The prognostic performances of Model 2 (second biopsy) were significantly better than Model 1 (first biopsy, analysis of deviance P < 0.0001). The dynamic changes of C and T lesions were significantly associated with the progression toward ESRD after adjustment on variables from Model 2. CONCLUSION: Both static and dynamic Oxford-based histological evaluation offered by a repeat biopsy improves the prediction of ESRD in patients with IgAN.