Islet-after-kidney transplantation versus kidney alone in kidney transplant recipients with type 1 diabetes (KAIAK): a population-based target trial emulation in France.

BACKGROUND: Islet transplantation has been associated with better metabolic control and quality of life than insulin treatment alone, but direct evidence of its effect on hard clinical endpoints is scarce. We aimed to assess the effect of islet transplantation on patient-graft survival in kidney transplant recipients with type 1 diabetes. METHODS: In this retrospective cohort study, we enrolled all patients with type 1 diabetes who received a kidney graft in France during the study period, identified from the CRISTAL nationwide registry. Non-inclusion criteria included recipients from transplant centres that never proposed islet transplantation during the study period, recipients with a functional pancreas throughout the follow-up duration, recipients with more than two kidney transplants, HLA-sensitised recipients, recipients with less than 1 year of follow-up after kidney transplantation, misclassified recipients with type 2 diabetes, recipients aged over 65 years, recipients of kidney grafts from Donation after Circulatory Death donors, recipient with HIV or hepatitis, recipients with cancer, and recipients of combined liver-kidney transplants. Patients who also received islet-after-kidney (IAK) transplantation were compared with controls who received kidney transplantation alone according to a 1:2 matching method based on time-dependent propensity scores, ensuring patients comparability at the time of islet transplantation. The primary outcome was patient-graft survival, a composite outcome defined by death, re-transplantation, or return to dialysis. FINDINGS: Between Jan 1, 2000, and Dec 31, 2017, 2391 patients with type 1 diabetes were identified as having received a kidney transplant, 47 patients of whom also received an islet transplantation. 2002 patients were not eligible for islet transplantation and 62 were excluded due to missing data. 327 eligible recipients from 15 centres were included in the study dataset for the target trial emulation. 40 patients who received IAK transplantation were successfully matched to 80 patients who received kidney transplantation alone. 13 (33%) of 40 patients in the IAK transplantation group returned to dialysis or died, compared with 36 (45%) of 80 patients in the kidney transplantation alone group. We found a significant benefit of islet transplantation compared with kidney transplantation alone on patient-graft survival, with a hazard ratio (HR) of 0·44 (95% CI 0·23-0·88; p=0·022), mainly explained by a protective effect on the risk of death (HR 0·41, 0·13-0·91; p=0·042). There was no meaningful association between IAK and death-censored graft survival (0·73, 0·30-1·89; p=0·36). INTERPRETATION: In kidney transplant recipients with type 1 diabetes, IAK transplantation was associated with a significantly better patient-graft survival compared with kidney transplantation alone, mainly due to a protective effect on the risk of death. These results potentially serve as compelling grounds for advocating wider access to islet transplantation in patients with type 1 diabetes undergoing kidney transplant, as reimbursement of islet transplantation is provided in few countries worldwide. FUNDING: Programme Hospitalier de la Recherche Clinique, Fondation pour la Recherche Medicale, and Fonds de Dotation Line Renaud-Loulou Gasté.

Preclinical in vivo assessment of the activity of AZD7442 anti-SARS-CoV-2 monoclonal antibodies against Omicron sublineages.

Therapeutic monoclonal antibodies have been successful in protecting vulnerable populations against SARS-CoV-2. However, their effectiveness has been hampered by the emergence of new variants. To adapt the therapeutic landscape, health authorities have based their recommendations mostly on in vitro neutralization tests. However, these do not provide a reliable understanding of the changes in the dose-effect relationship and how they may translate into clinical efficacy. Taking the example of EvusheldTM (AZD7442), we aimed to investigate how in vivo data can provide critical quantitative results and project clinical effectiveness. We used the Golden Syrian hamster model to estimate 90 % effective concentrations (EC90) of AZD7442 in vivo against SARS-CoV-2 Omicron BA.1, BA.2 and BA.5 variants. While our in vivo results confirmed the partial loss of AZD7442 activity for BA.1 and BA.2, they showed a much greater loss of efficacy against BA.5 than that obtained in vitro. We analyzed in vivo EC90s in perspective with antibody levels measured in a cohort of immunocompromised patients who received 300 mg of AZD7442. We found that a substantial proportion of patients had serum levels of anti-SARS-CoV-2 spike protein IgG above the estimated in vivo EC90 for BA.1 and BA.2 (21 % and 92 % after 1 month, respectively), but not for BA.5. These findings suggest that AZD7442 is likely to retain clinical efficacy against BA.2 and BA.1, but not against BA.5. Overall, the present study illustrates the importance of complementing in vitro investigations by preclinical studies in animal models to help predict the efficacy of monoclonal antibodies in humans.

Prophylactic treatment of FSGS recurrence in patients who relapsed in a previous kidney graft.

BACKGROUND AND HYPOTHESIS: Recurrence of focal segmental glomerulosclerosis (FSGS) is common after kidney transplantation and is classically associated with a significant decrease in graft survival. A major risk factor is a prior history of FSGS recurrence on a previous graft. This analysis reports the impact of a prophylactic treatment of FSGS recurrence in very high-risk patients who experienced a recurrence on a previous graft. METHODS: We performed a retrospective multicentre observational study in 25 French transplantation centres. The inclusion criteria were patients aged more than 18 years who had undergone kidney transplant between December 31, 2004, and December 31, 2020, and who had a history of FSGS recurrence on a previous graft. RESULTS: We identified 66 patients: 40 received prophylactic treatment (PT+), including intravenous cyclosporine and/or rituximab and/or plasmapheresis, and 26 did not receive any prophylactic treatment (PT-). The time to progression to end-stage kidney disease was similar between groups. The PT + group was younger at FSGS diagnosis and at the time of kidney retransplantation and lost their previous graft faster. The overall recurrence rate was 72.7% (76.9% in the PT- group and 70.0% in the PT + group, P = 0.54). At least partial remission was achieved in 87.5% of patients. The 5-year graft survival was 67.7% (95% CI: 53.4 to 78.4%): 65.1% (95%CI: 48.7 to 77.4%) in patients with FSGS recurrence vs. 77.3% (95% CI: 43.8 to 92.3%) in patients without recurrence (P = 0.48). CONCLUSION: Our study suggests that prophylactic treatment should not be used routinely in patients receiving a second transplantation after recurrence of FSGS on a previous graft. The recurrence rate is high regardless of the use of prophylactic treatment. However, the 5-year graft survival remains satisfactory.

Intrinsic capacity and frailty in older adults with end-stage kidney disease undergoing pre-kidney transplant comprehensive geriatric assessment.

OBJECTIVE: Frailty has been extensively studied in end-stage kidney disease (ESKD) and kidney transplant (KT) patients. The identification of frailty is useful to predict adverse outcomes among ESKD and KT patients. The recent concept of intrinsic capacity (IC) appears as a good and easy-to-understand tool to screen for and monitor frailty in older adults with ESKD. This study aims to assess the relationships between frailty and IC in older adults with ESKD awaiting KT. DESIGN: Cross-sectional study SETTING AND PARTICIPANTS: 236 patients from a day-care geriatric unit undergoing pre-KT geriatric assessment between 2017 and 2022 were included in the main sample, and 151 patients in an independent multicentric replication sample. MEASUREMENTS: Frailty was evaluated using the physical frailty phenotype (PFP) and IC measures using the World Health Organization's screening (step 1) and diagnostic (step 2) tools for five IC domains (vitality, locomotion, audition, cognition, psychology). Multivariate regressions were run to assess relationships between PFP and IC domains, adjusted for age, sex, and comorbidities. Analyses were replicated using another independent multicenter cohort including 151 patients with ESKD to confirm the results. RESULTS: Impairments in the locomotion, psychology, and vitality IC domains according to WHO screening tools were associated with frailty (odds ratio 9.62 [95% CI 4.09-24.99], 3.19 [95% CI 1.11-8.88], and 3.11 [95% CI 1.32-7.29], respectively). When IC were measured linearly with z-scores, all IC domains except hearing were inversely associated with frailty. In the replication cohort, results were overall similar, with a greater association between psychology domain and frailty. CONCLUSION: This study highlights the relationship between frailty and IC in ESKD patients. We assume that IC may be assessed and monitored in ESKD patients, to predict and prevent future frailty, and post-KT adverse outcomes.

Assessment of epidemiology and outcomes of adult patients with kidney-limited thrombotic microangiopathies.

Thrombotic microangiopathies (TMA) are usually associated with hematological features (RH-TMA). The epidemiology of TMA limited to kidneys (RL-TMA) is unclear Therefore, patients with TMA and native kidney biopsies were identified during 2009-2022 in 20 French hospitals and results evaluated. RL-TMA was present in 341/757 (45%) patients and associated with lower creatinine levels (median 184 vs 346 µmol/L) than RH-TMA. RL-TMA resulted from virtually all identified causes, more frequently from anti-VEGF treatment and hematological malignancies but less frequently from shigatoxin-associated hemolytic uremic syndrome (HUS), systemic sclerosis, gemcitabine and bacterial infection, and even less frequently when three or more causes/triggers were combined (RL-TMA: 5%; RH-TMA: 12%). RL-TMA was associated with significantly lower major cardiovascular events (10% vs 20%), kidney replacement therapy (23% vs 43%) and death (12% vs 20%) than RH-TMA during follow-up (median 28 months). Atypical HUS (aHUS) was found in 326 patients (RL-TMA: 43%, RH-TMA: 44%). Among the 69 patients with proven complement-mediated aHUS, eculizumab (anti-C5 therapy) was used in 43 (62%) (RL-TMA: 35%; RH-TMA: 71%). Among the 257 other patients with aHUS, including 51% with RL-TMA, eculizumab was used in 29 but with unclear effects of this treatment. Thus, RL-TMA represents a very high proportion of patients with TMA and results from virtually all known causes of TMA and includes 25% of patients with complement-mediated aHUS. Adverse outcomes of RL-TMA are lower compared to RH-TMA but remain significant. Anti-C5 therapy was rarely used in RL-TMA, even in proven complement-mediated aHUS, and its effects remain to be assessed.

Living During COVID-19 While Immunocompromised: A Patient and Physician Perspective from France.

This article is co-authored by a kidney transplant recipient and her nephrologist. By sharing her personal experience of the coronavirus disease 2019 (COVID-19) pandemic, the patient illustrates the concerns of immunocompromised patients during this unprecedented health crisis. She describes the difficulties encountered at work, the omnipresent protective measures, and the need for appropriate information. The nephrologist, who follows a cohort of over 1700 kidney transplant recipients, recounts the medical team's struggle to protect their vulnerable patients against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as a veritable succession of hopes and disappointments. She describes the management of immunosuppression in kidney transplant recipients, the deployment of the COVID-19 vaccination program with the finding of poor immune responses in many patients including those receiving immunosuppressant drugs after kidney transplant, and the first use of prophylactic monoclonal antibodies. From both the patient's and the physician's perspectives, the COVID-19 pandemic has required continuous adaptation.

A kidney transplant patient and her physician describe their experiences during the coronavirus disease 2019 (COVID-19) pandemic in France. The patient outlines her ongoing challenges during the pandemic due to being on lifelong anti-rejection drugs; such treatment suppresses the immune system resulting in poor ability to fight infection and poor response to vaccination. She discusses anxieties regarding having to travel to and attend work as an individual vulnerable to COVID-19. In addition, she found it difficult to find appropriate information at the start of the pandemic. Once vaccinated, she did not develop antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). She subsequently received preventive antibody treatment which relieved her anxieties considerably. However, the pandemic is still very real for her, and she has gone from having an invisible disability­her kidney transplant­to having a visible disability because she always wears a mask. Thus far, she has not contracted COVID-19. The physician recounts her challenge to protect vulnerable kidney transplant patients against SARS-CoV-2, the initiation of the COVID-19 vaccination program, the finding of poor immune responses to vaccination in many patients, and the first use of antibody therapies to prevent against SARS-CoV-2 infection. In 2023­2024, the situation is much more manageable for physicians because COVID-19 is better controlled in terms of severity and management than it was in 2020­2021. The COVID-19 pandemic has required continuous adaptation from both the patient's and the physician's perspective.

Hot Spot of Complement Factor I Rare Variant p.Ile357Met in Patients With Hemolytic Uremic Syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a rare kidney disease due to a dysregulation of the complement alternative pathway. Complement factor I (CFI) negatively regulates the alternative pathway and CFI gene rare variants have been associated to aHUS with a low disease penetrance. We report 10 unrelated cases of HUS associated to a rare CFI variant, p.Ile357Met (c.1071T>G). All patients with isolated p.Ile357Met CFI missense variant were retrospectively identified among patients included between January 2007 and January 2022 in the French HUS Registry. We identified 10 unrelated patients (70% women; median age at HUS diagnosis, 36.5 years) who carry the same rare variant p.Ile357Met in the CFI gene. Seven patients (cases 1-7) presented with aHUS in the native kidney associated with malignant hypertension in 5 patients. None received a C5 inhibitor. Two of these cases occurred in the peripartum period with complete recovery of kidney function, while 5 of these patients reached kidney failure requiring replacement therapy (KFRT). Four patients with KFRT subsequently underwent kidney transplantation. Three later developed C3 glomerulopathy in their kidney graft, but none had aHUS recurrence. Three other patients (cases 8-10) experienced de novo thrombotic microangiopathy after kidney transplantation, precipitated by various triggers. The rare CFI variant p.Ile357Met appears to be a facilitating genetic factor for HUS and for some forms of secondary HUS.

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.

A Tubular Vena Cava Conduit Used to Lengthen a Kidney Transplant Renal Artery Injured During Organ Procurement.

Introduction: Organ transplantation is limited by the supply of transplantable organs, and the supply of organs cannot meet the needs of patients on the waiting list. Ensuring transplantation of any procured organ is therefore mandatory. Organ injury, mostly to the organ's vasculature, can occur during multi-organ procurement, preventing subsequent transplantation. In such a context, vascular reconstructions of arterial or venous organ injuries can be useful. Report: This report describes the case of an obese 64 year old female with a history of diabetic nephropathy who underwent a cadaveric kidney transplant (right kidney with one main renal artery, one inferior polar artery, one vein, and one ureter). The ex situ preparation of the graft revealed that the main renal artery was injured and cut close to the renal hilum (0.8 cm length, 6 mm diameter), not allowing graft implantation. In order to increase the length of the main renal artery, the donor inferior vena cava was used to create a tubular conduit, allowing subsequent graft implantation. Cold and warm ischaemic times were respectively 12 hours and 36 minutes, with immediate graft function. The patient was discharged on day 8 (serum creatinine level was 95 µmol/L). Twelve month follow up was uneventful (serum creatinine level was 108 µmol/L and duplex ultrasonography showed homogeneous blood flow throughout the graft). Discussion: This case report highlights the possibility of overcoming an injured kidney graft artery by creating a tubular vena cava conduit in order to allow subsequent transplantation. Vascular reconstructions of organs injured during procurement should be considered.

Aortobifemoral Bypass in Kidney Transplant Candidates: A Ten-Year Experience.

In patients with severe aorto-iliac calcifications, vascular reconstructions can be performed in order to allow kidney transplantation. The aim of this study was to analyze the outcomes of kidney transplant candidates who underwent an aortobifemoral bypass (ABFB) for aorto-iliac calcifications. A retrospective study including all kidney transplant candidates who underwent an ABFB between 2012 and 2022 was performed. Primary outcome was 30-day morbidity-mortality after ABFB. Secondary outcome was accessibility to kidney transplant waiting list. Twenty-two ABFBs were performed: 10 ABFBs in asymptomatic patients presenting severe aorto-iliac circumferential calcifications without hemodynamic consequences, and 12 ABFBs in symptomatic patients in whom aorto-iliac calcifications were responsible for claudication or critical limb threatening ischemia. Overall 30-day mortality was 0%. Overall 30-day morbidity was 22.7%: 1 femoral hematoma and 1 retroperitoneal hematoma requiring surgical drainage in the asymptomatic group, and 2 digestive ischemia requiring bowel resection and 1 femoral hematoma requiring surgical drainage in the symptomatic group. Among the 22 patients, 20 patients could access to kidney waiting list and 8 patients underwent a kidney transplantation, including 3 living-donor transplantations. Aorto-iliac revascularization can be an option to overcome severe calcifications contraindicating kidney transplantation.

Imlifidase for Kidney Transplantation of Highly Sensitized Patients With a Positive Crossmatch: The French Consensus Guidelines.

Imlifidase recently received early access authorization for highly sensitized adult kidney transplant candidates with a positive crossmatch against an ABO-compatible deceased donor. These French consensus guidelines have been generated by an expert working group, in order to homogenize patient selection, associated treatments and follow-up. This initiative is part of an international effort to analyze properly the benefits and tolerance of this new costly treatment in real-life. Eligible patients must meet the following screening criteria: cPRA ≥ 98%, ≤ 65-year of age, ≥ 3 years on the waiting list, and a low risk of biopsy-related complications. The final decision to use Imlifidase will be based on the two following criteria. First, the results of a virtual crossmatch on recent serum, which shall show a MFI for the immunodominant donor-specific antibodies (DSA) > 6,000 but the value of which does not exceed 5,000 after 1:10 dilution. Second, the post-Imlifidase complement-dependent cytotoxicity crossmatch must be negative. Patients treated with Imlifidase will receive an immunosuppressive regimen based on steroids, rATG, high dose IVIg, rituximab, tacrolimus and mycophenolic acid. Frequent post-transplant testing for DSA and systematic surveillance kidney biopsies are highly recommended to monitor post-transplant DSA rebound and subclinical rejection.

Torque teno virus viral load predicts SARS-CoV-2 vaccine response in kidney transplant recipients.

Transplant recipients display poor responses to SARS-CoV-2 mRNA vaccines. In this retrospective study, we investigate torque teno virus (TTV) viral load (VL), a ubiquitous virus reflecting global immune response levels, as a predictive factor of vaccine response in kidney transplant recipients (KTR). Four hundred and fifty-nine KTR having received two SARS-CoV-2 mRNA vaccine doses were enrolled, and 241 of them subsequently received a third vaccine dose. Antireceptor-binding domain (RBD) IgG response was assessed after each vaccine dose and TTV VL was measured in pre-vaccine samples. Prevaccine TTV VL > 6.2 log10 copies (cp)/mL was independently associated with nonresponse to two doses (odds ratio (OR) = 6.17, 95% confidence interval (CI95) = 2.42-15.78) as well as to three doses (OR = 3.62, 95% CI95 = 1.55-8.49). In nonresponders to the second dose, high TTV VL in prevaccine samples or measured before the third dose were equally predictive of lower seroconversion rates and antibody titers. High TTV VL before and during SARS-CoV-2 vaccination schedules are predictive of poor vaccine response in KTR. This biomarker should be further evaluated regarding other vaccine responses.

Urinary collagen peptides: Source of markers for bone metabolic processes in kidney transplant recipients.

INTRODUCTION: Kidney transplant recipients (KTRs) are at an increased risk of fractures. Total urinary hydroxyproline excretion served as marker for bone resorption (BR) but was replaced by ß-CrossLaps (CTX), a C-terminal collagen α-1(I) chain (COL1A1) telopeptide. We investigated the low-molecular-weight urinary proteome for peptides associated with changes in bone metabolism after kidney transplantation. METHODS: Clinical and laboratory data including serum levels of CTX in 96 KTR from two nephrology centers were correlated with signal intensities of urinary peptides identified by capillary electrophoresis mass spectrometry. RESULTS: Eighty-two urinary peptides were significantly correlated with serum CTX levels. COL1A1 was the predominant peptide source. Oral bisphosphonates were administered for decreased bone density in an independent group of 11 KTR and their effect was evaluated on the aforementioned peptides. Study of the peptides cleavage sites revealed a signature of Cathepsin K and MMP9. Seventeen of these peptides were significantly associated with bisphosphonate treatment, all showing a marked reduction in their excretion levels compared to baseline. DISCUSSION: This study provides strong evidence for the presence of collagen peptides in the urine of KTR that are associated with BR and that are sensitive to bisphosphonate treatment. Their assessment might become a valuable tool to monitor bone status in KTR.

The complement system in IgAN: mechanistic context for therapeutic opportunities.

The complement system plays a crucial role in innate immunity, providing essential defense against pathogens. However, uncontrolled or prolonged activation of the complement cascade can significantly contribute to kidney damage, especially in cases of glomerulonephritis. Immunoglobulin A nephropathy (IgAN), the most prevalent form of primary glomerulonephritis, has growing evidence supporting the involvement of complement alternative and lectin pathways. In fact, patients with IgAN experience complement activation within their kidney tissue, which may be involved in the development of glomerular damage and the progression of IgAN. Complement activation has emerged as a significant area of interest in IgAN, with numerous complement-targeting agents currently being explored within this field. Nevertheless, the exact mechanisms of complement activation and their role in IgAN progression require comprehensive elucidation. This review seeks to contextualize the proposed mechanisms of complement activation within the various stages ("hits") of IgAN pathogenesis, while also addressing the clinical implications and anticipated outcomes of complement inhibition in IgAN.