De novo thrombotic microangiopathy after kidney transplantation in adults: Interplay between complement genetics and multiple endothelial injury.

De novo thrombotic microangiopathy (dnTMA), after renal transplantation may significantly alter graft outcomes. However, its pathogenesis and the role of complement alternative pathway dysregulation remain elusive. We studied all consecutive adult patients with a kidney allograft biopsy performed between January 2004 and March 2016 displaying dnTMA. Ninety-two patients were included. The median time of occurrence was 166 (IQR 25-811) days. The majority (82.6 %) had TMA localized only in the graft. Calcineurin inhibitor toxicity and antibody-mediated rejection (ABMR) were the 2 most frequent causes (54.3% and 37.0%, respectively). However, etiological factors were multiple in 37% patients. Interestingly, pathogenic variants in the genes of complement alternative pathway were significantly more frequent in the 42 tested patients than in healthy controls (16.7% vs 3.7% respectively, P < .008). The overall graft survival after biopsy was 66.0% at 5 years and 23.4% at 10 years, significantly worse than a matched cohort without TMA. Moreover, graft survival of patients with TMA and ABMR was worse than a matched cohort with ABMR without TMA. The 2 main prognostic factors were a positive C4d staining and a lower estimated glomerular filtration rate at diagnosis. DnTMA is a severe and multifactorial disease, induced by 1 or several endothelium-insulting conditions, mostly calcineurin inhibitor toxicity and ABMR.

Eculizumab dose tapering should take into account the nonlinearity of its pharmacokinetics.

AIMS: Eculizumab is a monoclonal antibody targeting complement protein C5 used in renal diseases. As recommended dosing regimen leads to unnecessarily high concentrations in some patients, tailored dosing therapeutic drug monitoring was proposed to reduce treatment cost. The objectives of the present work were (i) to investigate the target-mediated elimination of eculizumab and (ii) whether a pharmacokinetic model integrating a nonlinear elimination allows a better prediction of eculizumab concentrations than a linear model. METHODS: We analysed 377 eculizumab serum concentrations from 44 patients treated for atypical haemolytic uraemic syndrome and C3 glomerulopathy with a population pharmacokinetic approach. Critical concentrations (below which a non-log-linear decline of concentration over time is evidenced) were computed to estimate the relevance of the target-mediated elimination. Simulations of dosing regimens were then performed to predict probabilities of target attainment (i.e. trough >100 mg/L). RESULTS: Pharmacokinetics of eculizumab was nonlinear and followed a mixture of first-order (CL = 1.318 mL/day/kg) and Michaelis-Menten elimination (Vmax = 26.07 mg/day, Km = 24.06 mg/L). Volume of distribution (72.39 mL/kg) and clearance were weight-dependent. Critical concentrations (Vmax/CL) ranged from 144.7 to 759.7 mg/L and were inversely related to body weight (P = .013). Nonlinearity was thus noticeable at therapeutic concentrations. Simulations predicted that 1200 mg of eculizumab every 21 days would allow 85% and 76% of patients to maintain a therapeutic exposure, for 50 or 90 kg body weight, respectively. CONCLUSIONS: Our study investigates the nonlinear elimination of eculizumab and discusses the importance of accounting for eculizumab target-mediated elimination in therapeutic drug monitoring.

Conversion From Intravenous In-Hospital Belatacept Injection to Subcutaneous Abatacept Injection in Kidney Transplant Recipients During the First COVID-19 Stay-at-Home Order in France.

The first COVID-19 stay-at-home order came into effect in France on 17 March 2020. Immunocompromised patients were asked to isolate themselves, and outpatient clinic visits were dramatically reduced. In order to avoid visits to the hospital by belatacept-treated kidney transplant recipients (KTRs) during the initial period of the pandemic, we promptly converted 176 KTRs at two French transplant centers from once-monthly 5 mg/kg in-hospital belatacept infusion to once-weekly 125 mg subcutaneous abatacept injection. At the end of follow-up (3 months), 171 (97.16%) KTRs survived with a functioning graft, 2 (1.14%) had died, and 3 (1.70%) had experienced graft loss. Two patients (1.1%) experienced acute T cell-mediated rejection. Nineteen patients (10.80%) discontinued abatacept; 47% of the KTRs found the use of abatacept less restrictive than belatacept, and 38% would have preferred to continue abatacept. Mean eGFR remained stable compared to baseline. Seven patients (3.9%) had COVID-19; among these, two developed severe symptoms but survived. Only one patient had a de novo DSA. Side effects of abatacept injection were uncommon and non-severe. Our study reports for the first time in a large cohort that once-weekly injection of abatacept appears to be feasible and safe in KTRs previously treated with belatacept.

Complement-driven hemolytic uremic syndrome.

Overactivation of the complement alternative pathway drives the pathogenesis of primary atypical hemolytic uremic syndrome (aHUS). Genetically-determined or acquired dysregulation of the complement is frequently identified in patients with aHUS, pregnancy-related hemolytic uremic syndrome (HUS), and severe hypertension-associated HUS. In contrast, it is still unclear whether self-limited complement activation, which frequently occurs in other forms of HUS, provides key mechanistic clues or results from endothelial damage. Development of novel biomarkers is underway to firmly establish complement-driven pathogenesis. C5 blockade therapy has revolutionized the management of aHUS patients, resulting in a halving of the subpopulation under chronic dialysis over the course of a few years. On the other hand, the efficacy of C5 blockade in secondary forms of HUS, as assessed by small and uncontrolled case series, is less compelling and should be investigated through properly designed prospective clinical trials. The increased risk of meningococcal infection, related to C5 inhibition, must be rigorously addressed with suitable prophylaxis. Treatment duration should be determined based on an individualized benefit/risk assessment.

Nonskeletal and skeletal effects of high doses versus low doses of vitamin D3 in renal transplant recipients: Results of the VITALE (VITamin D supplementation in renAL transplant recipients) study, a randomized clinical trial.

Vitamin D sufficiency is associated with a reduced risk of fractures, diabetes mellitus, cardiovascular events, and cancers, which are frequent complications after renal transplantation. The VITALE (VITamin D supplementation in renAL transplant recipients) study is a multicenter double-blind randomized trial, including nondiabetic adult renal transplant recipients with serum 25-hydroxy vitamin D (25(OH) vitamin D) levels of <30 ng/mL, which is randomized 12 to 48 months after transplantation to receive high (100 000 IU) or low doses (12 000 IU) of cholecalciferol every 2 weeks for 2 months and then monthly for 22 months. The primary outcome was a composite endpoint, including diabetes mellitus, major cardiovascular events, cancer, and death. Of 536 inclusions (50.8 [13.7] years, 335 men), 269 and 267 inclusions were in the high-dose and low-dose groups, respectively. The serum 25(OH) vitamin D levels increased by 23 versus 6 ng/mL in the high-dose and low-dose groups, respectively (P < .0001). In the intent-to-treat analysis, 15% versus 16% of the patients in the high-dose and low-dose groups, respectively, experienced a first event of the composite endpoint (hazard ratio, 0.94 [0.60-1.48]; P = .78), whereas 1% and 4% of patients in the high-dose and low-dose groups, respectively, experienced an incident symptomatic fracture (odds ratio, 0.24 [0.07-0.86], P = .03). The incidence of adverse events was similar between the groups. After renal transplantation, high doses of cholecalciferol are safe but do not reduce extraskeletal complications (trial registration: ClinicalTrials.gov; identifier: NCT01431430).

Vasculitis and familial Mediterranean fever: Description of 22 French adults from the juvenile inflammatory rheumatism cohort.

Objective: The frequency of vasculitis may be increased in patients with Familial Mediterranean Fever (FMF), according to several studies. Our aim was to assess the characteristics of French adult patients with both diseases. Methods: Patients with vasculitis were selected from patients followed for FMF in the French JIR-cohort. Results: Twenty-two patients were included [polyarteritis nodosa (PAN) n = 10, IgA vasculitis n = 8, unclassified vasculitis n = 2, granulomatosis with polyangiitis n = 1, and microscopic polyangiitis n = 1]. Pathogenic mutations in exon 10 were found in all 21 patients (96%) for which MEFV testing results were available, and 18 (82%) had two pathogenic mutations. Histology showed vasculitis in 59% of patients. Most patients with FMF-associated PAN were HBV-negative and had an inactive FMF before PAN onset, and 40% had a peri-renal or central nervous system bleeding. Most patients with FMF-associated IgA vasculitis had an active FMF before vasculitis onset, and 25% had digestive bleeding. Both patients with unclassified vasculitis had ischemic and/or hemorrhagic complications. Conclusion: This study confirms the predominance of PAN and IgA vasculitis in patients with FMF and the high frequency of bleeding in FMF-associated PAN. FMF should be considered in case of persistent symptoms and/or inflammatory syndrome despite vasculitis treatment in Mediterranean patients.

Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients.

Cystinosis, a rare autosomal recessive lysosomal storage disorder, results in an abnormal accumulation of the amino acid cystine in multiple organs and tissues of the body. Renal symptoms typically develop in the first few months of life, with extra-renal manifestations becoming apparent over the next 10-20 years, which require coordinated multidisciplinary care. Here, we describe a consensus-based guidance to support the management of adolescents and adults living with cystinosis. The programme was led by a Steering Committee (SC) of six experts in the management of patients with cystinosis, who identified a list of 15 key questions reflecting the multi-organ effects of cystinosis. An Extended Faculty (EF) of eight additional specialists was invited to answer the questions via an online digital platform using a quasi-Delphi approach. The consolidated answers were summarized into recommendations. Where evidence was lacking, recommendations were developed using collective expert consensus. The EF was asked to agree/disagree with the clinical recommendations. The expert-agreed clinical recommendations provide guidance that considers both renal and extra-renal systems. The topics covered are advice on fertility and family planning, consideration of the nervous, muscular, ophthalmic, cardio-respiratory, endocrine, dermatological and gastrointestinal systems, as well as guidance on dental care, diet, lifestyle, and improving quality of life and psychological well-being. In summary, this work outlines recommendations and a checklist for clinicians with a vision for improving and standardizing the multidisciplinary care for patients with cystinosis.

Outcomes of kidney-transplanted patients with history of intestinal reconstruction of the urinary tract.

Background: Due to increased risk of pyelonephritis, patients with intestinal reconstruction of the lower urinary tract (IRLUT) have long been advised against kidney transplantation. The aim of this study was to compare the outcomes of transplantation between patients with IRLUT and patients with normal LUT (NLUT) using propensity score matching method. Methods: The study included 23 kidney recipients with IRLUT matched to 46 kidney recipients with NLUT using known allograft survival and pyelonephritis risk factors as covariates. One-, 5-, and 10-year graft survival, pyelonephritis, and surgical complications occurrence and graft function were compared. Results: One-, 5-, and 10-year graft survival were 96%, 91%, and 63% in the IRLUT group and 96%, 88%, and 70% in the NLUT group, respectively (p = 0.72). Patients with IRLUT had increased cumulative risk of pyelonephritis at 10 years (70% vs. 19%; log-rank < 0.01) without impacting graft function or rejection occurrence. There was no difference in overall surgical complication, but patients with IRLUT had more urological complications than patients with NLUT (62% vs. 28%; p < 0.01). Conclusions: Our case-control study consolidates the results regarding the safety of transplantation in patients with IRLUT using a strong validated matching method and provides new insights regarding graft function, pyelonephritis, and surgical complications in this population.

Weak antibody response to three doses of mRNA vaccine in kidney transplant recipients treated with belatacept.

Poor responses to mRNA COVID-19 vaccine have been reported after 2 vaccine injections in kidney transplant recipients (KTRs) treated with belatacept. We analyzed the humoral response in belatacept-treated KTRs without a history of SARS-CoV-2 infection who received three injections of BNT162b2-mRNA COVID-19 vaccine. We also investigated vaccine immunogenicity in belatacept-treated KTRs with prior COVID-19 and characterized symptomatic COVID-19 infections after the vaccine in belatacept-treated KTRs. Among the 62 belatacept-treated KTRs (36 [58%] males), the median age (63.5 years IQR [51-72]), without COVID-19 history, only four patients (6.4%) developed anti-SARS-CoV-2 IgG with low antibody titers (median 209, IQR [20-409] AU/ml). 71% were treated with mycophenolic acid and 100% with steroids in association with belatacept. In contrast, in all the 5 KTRs with prior COVID-19 history, mRNA vaccine induced a strong antibody response with high antibody titers (median 10 769 AU/ml, IQR [6410-20 069]) after two injections. Seroprevalence after three-vaccine doses in 35 non-belatacept-treated KTRs was 37.1%. Twelve KTRs developed symptomatic COVID-19 after vaccination, including severe forms (50% of mortality). Breakthrough COVID-19 occurred in 5% of fully vaccinated patients. Administration of a third dose of BNT162b2 mRNA COVID-19 vaccine did not improve immunogenicity in KTRs treated with belatacept without prior COVID-19. Other strategies aiming to improve patient protection are needed.

Feasibility and safety of tailored dosing schedule for eculizumab based on therapeutic drug monitoring: Lessons from a prospective multicentric study.

AIMS: Eculizumab is an anti-C5 monoclonal antibody approved for rare diseases including atypical haemolytic-uraemic syndrome. The maintenance phase dosing regimen is identical for all adult patients: 1200 mg every 2 weeks. Recent studies reported an overexposure in many patients when considering a target trough concentration range of 50-100 mg/L. The aim of the present work was to validate the feasibility of therapeutic drug monitoring of eculizumab in atypical haemolytic-uraemic syndrome patients. METHODS: We performed a 2-step prospective multicentre study. In the first phase, we developed a pharmacokinetic population model using data from 40 patients and identified patients for whom a 1-week lengthening of interval between infusions would lead to a trough concentration above 100 mg/L. In the second phase, selected patients were allocated a 1-week extension and eculizumab trough concentrations were monitored. RESULTS: The model confirmed the previously reported influence of bodyweight on elimination clearance and predicted that 36 (90%) patients would be eligible for interval extension. In the second phase of the study, a 1-week lengthening of interval between infusions was performed in 15 patients whose trough concentration at the next visit was predicted with a Bayesian model to be above 100 mg/L. After interval extension, 10 patients (67%) presented measured trough concentrations over 100 mg/L. No biological or clinical recurrence of disease was observed, even in the 5 patients with concentrations below 100 mg/L in whom the initial dosing regimen was resumed. CONCLUSION: Safe eculizumab interval adjustment is feasible with a PK monitoring.

COVID-19 severity in kidney transplant recipients is similar to nontransplant patients with similar comorbidities.

Higher rates of severe COVID-19 have been reported in kidney transplant recipients (KTRs) compared to nontransplant patients. We aimed to determine if poorer outcomes were specifically related to chronic immunosuppression or underlying comorbidities. We used a 1:1 propensity score-matching method to compare survival and severe disease-free survival (defined as death and/or need for intensive care unit [ICU]) incidence in hospitalized KTRs and nontransplant control patients between February 26 and May 22, 2020. Patients were matched for risk factors of severe COVID-19: age, sex, body mass index, diabetes mellitus, preexisting cardiopathy, chronic lung disease, and basal renal function. We included 100 KTRs (median age [interquartile range (IQR)]) 64.7 years (55.3-73.1) in three French transplant centers. After a median follow-up of 13 days (7-30), transfer to ICU was required for 34 patients (34%) and death occurred in 26 patients (26%). Overall, 43 patients (43%) developed a severe disease during a median follow-up of 8.5 days (2-14). Propensity score matching to a large French cohort of 2017 patients hospitalized in 24 centers, revealed that survival was similar between KTRs and matched nontransplant patients with respective 30-day survival of 62.9% and 71% (p = .38) and severe disease-free 30-day survival of 50.6% and 47.5% (p = .91). These findings suggest that severity of COVID-19 in KTRs is related to their associated comorbidities and not to chronic immunosuppression.

Dissociation of humoral and cellular immune responses in kidney transplant recipients with EBV mucocutaneous ulcer.

EBV-positive mucocutaneous ulcer (EBV-MCU) is a rare EBV-positive B-cell lymphoproliferative disorder occurring in immunocompromised patients such as patients with solid organ or hematopoietic stem cells transplantation. EBV-MCU often consists of an isolated and circumscribed cutaneous or mucosal ulcerative lesion with a self-limited growth potential and a high regression rate upon immunosuppressive treatment withdrawal or rituximab therapy. Nevertheless, the pathophysiology of this latent infection leading to clonal lymphoproliferation is not well established. We report here two cases of EBV-MCU in kidney transplant recipients with a dissociated immune response to EBV with the absence of EBV-related antibodies and a positive T-cell response to EBV suggesting a potential specific oncogenic mechanism in this lymphoproliferative disorder.

Increased incidence and unusual presentations of CMV disease in kidney transplant recipients after conversion to belatacept.

Belatacept may increase cytomegalovirus (CMV) disease risk after conversion from CNI-based therapy. We analyzed CMV disease characteristics after belatacept conversion. Propensity score matching was used to compare CMV disease incidence in belatacept- and CNI-treated kidney transplant recipients (KTRs). CMV disease characteristics and risk factors under belatacept were analyzed. In total, 223 KTRs (median age [IQR] 59.2 years [45.4-68.5]) were converted to belatacept (median of 11.5 months [2.5-37.0] post-transplantation); 40/223 (17.9%) developed CMV disease. Independent risk factors included increased age (p = .0164), D+/R- CMV serostatus (p = .0220), and low eGFR at conversion (p = .0355). Among 181 belatacept-treated patients matched to 181 controls, 32/181 (17.7%) experienced CMV disease (vs. 5/181 controls [2.8%]). CMV disease cumulative incidences were 6.33 and 0.91/100 person-years (p-y) in belatacept and control groups, respectively. CMV disease risk was particularly high in elderly patients (converted >70 years) and those with eGFR <30 ml/min; cumulative incidences were 18.4 and 5.2/100 p-y, respectively. CMV diseases under belatacept were atypical, with late-onset disease (24/40 patients [60%]), high CMV seropositivity (27/40, 67%), increased severe and tissue-invasive disease rates (gastrointestinal involvement in 32/40 [80%]) and life-threatening diseases (4/40 [10%]). These findings should stimulate further research to secure the use of belatacept as a valuable rescue therapy in KTRs.