Eculizumab as a therapeutic approach for severe crescentic recurrence of immunoglobulin A nephropathy after kidney transplantation.

Crescentic forms of immunoglobulin A nephropathy (IgAN) are rare but can be associated with rapid kidney failure and a high rate of end-stage renal disease despite immunosuppression therapy. Complement activation has emerged as a key driver of glomerular injury in IgAN. Therefore, complement inhibitors may be a rational treatment option in patients unresponsive to first-line immunosuppressive therapy. Here, we describe the case of a 24-year-old woman presenting with crescentic IgAN recurrence a few months after living kidney transplantation. Considering the dramatic graft failure accompanied by malignant hypertension and thrombotic microangiopathy features worsening after a first-line of high-dose steroids and 3 sessions of plasma exchanges, eculizumab was started as a rescue therapy. For the first time, the clinical response to eculizumab was highly successful, with a complete graft recovery without any relapse after 1 year of treatment. Further clinical studies are strongly needed to specify which patients might benefit from terminal complement blockade.

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.

18F-Fluorocholine PET/CT Compared with Current Imaging Procedures for Preoperative Localization of Hyperfunctioning Parathyroids in Patients with Chronic Kidney Disease.

Hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) includes secondary (sHPT) and tertiary hyperparathyroidism (tHPT). Considering that the role of preoperative imaging in the clinical setting is controversial, in the present study we have retrospectively compared pre-surgical diagnostic performances of 18F-Fluorocholine (18F-FCH) PET/CT, cervical ultrasonography (US), parathyroid scintigraphy, and 4D-CT in a group of 30 patients with CKD and HPT (18/12 sHPT/tHPT), 21 CKD G5 including 18 in dialysis, and 9 kidney transplant recipients. All patients underwent 18F-FCH, and 22 had cervical US, 12 had parathyroid scintigraphy, and 11 had 4D-CT. Histopathology was the gold standard. Seventy-four parathyroids were removed: 65 hyperplasia, 6 adenomas, and 3 normal glands. In the whole population, in a per gland analysis, 18F-FCH PET/CT was significantly more sensitive and accurate (72%, 71%) than neck US (25%, 43%), parathyroid scintigraphy (35%, 47%), and 4D-CT (40%, 47%). The specificity of 18F-FCH PET/CT (69%) was lower than that of neck US (95%) and parathyroid scintigraphy (90%), without, however, achieving significance. 18F-FCH PET/CT was more accurate than all other diagnostic techniques when sHPT and tHPT patients were considered separately. 18F-FCH PET/CT sensitivity was significantly higher in tHPT (88%) than in sHPT (66%). Three ectopic hyperfunctioning glands (in three different patients) were all detected by 18F-FCH PET/CT, two by parathyroid scintigraphy, and none by cervical US and 4D-CT. Our study confirms that 18F-FCH PET/CT is an effective preoperative imaging option in patients with CKD and HPT. These findings may be of greater importance in patients with tHPT (who could benefit from minimally invasive parathyroidectomy) than in patients with sHPT, who often undergo bilateral cervicotomy. In these cases, preoperative 18F-FCH PET/CT may be helpful in locating ectopic glands and may guide the surgical choice for gland preservation.

Management and Outcome After Early Renal Transplant Vein Thrombosis: A French Multicentre Observational Study of Real-Life Practice Over 24 Years.

Early (<14 days) renal transplant vein thrombosis posttransplant (eRVTPT) is a rare but threatening complication. We aimed to assess eRVTPT management and the rate of functional renal transplantation. Of 11,172 adult patients who had undergone transplantation between 01/1997 and 12/2020 at 6 French centres, we identified 176 patients with eRVTPT (1.6%): 16 intraoperative (Group 1, G1) and 160 postoperative (Group 2, G2). All but one patient received surgical management. Patients in group G2 had at least one imaging test for diagnostic confirmation (N = 157, 98%). During the operative management of the G2 group, transplantectomy for graft necrosis was performed immediately in 59.1% of cases. In both groups, either of two techniques was preferred, namely, thrombectomy by renal venotomy or thrombectomy + venous anastomosis repair, with no difference in the functional graft rate (FGR) at hospital discharge (p = NS). The FGR was 62.5% in G1 and 8.1% in G2 (p < 0.001). Numerous complications occurred during the initial hospitalization: 38 patients had a postoperative infection (21.6%), 5 experienced haemorrhagic shock (2.8%), 29 exhibited a haematoma (16.5%), and 97 (55.1%) received a blood transfusion. Five patients died (2.8%). Our study confirms the very poor prognosis of early renal graft venous thrombosis.

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).

Prediction of Vaccine Response and Development of a Personalized Anti-SARS-CoV-2 Vaccination Strategy in Kidney Transplant Recipients: Results from a Large Single-Center Study.

Kidney transplant recipients (KTRs) displays marked inter-individual variations in magnitude of immune responses to anti-SARS-CoV-2 vaccination. The aim of this large single-center study was to identify the predictive factors for serological response to the mRNA-1273 vaccine in KTRs. We also devised a score to optimize prediction with the goal of implementing a personalized vaccination strategy. The study population consisted of 564 KTRs who received at least two doses of the mRNA-1273 vaccine. Anti-RBD IgG titers were quantified one month after each vaccine dose and until six months thereafter. A third dose vaccine was given when the antibody titer after the second dose was <143 BAU/mL. A score to optimize prediction of vaccine response was devised using the independent predictors identified in multivariate analysis. The seropositivity rate after the second dose was 46.6% and 22.2% of participants were classified as good responders (titers ≥ 143 BAU/mL). On analyzing the 477 patients for whom serology testing was available after the second or third dose, the global seropositivity rate was 69% (good responders: 46.3%). Immunosuppressive drugs, graft function, age, interval from transplantation, body mass index, and sex were associated with vaccine response. The devised score was strongly associated with the seropositivity rate (AUC = 0.752, p < 0.0001) and the occurrence of a good antibody response (AUC = 0.785, p < 0.0001). Notably, antibody titers declined over time both after the second and third vaccine doses. In summary, a high burden of comorbidities and immunosuppression was correlated with a weaker antibody response. A fourth vaccine dose and/or pre-exposure prophylaxis with monoclonal antibodies should be considered for KTRs who remain unprotected.

Breakthrough COVID-19 cases despite prophylaxis with 150 mg of tixagevimab and 150 mg of cilgavimab in kidney transplant recipients.

The cilgavimab-tixagevimab combination retains a partial in vitro neutralizing activity against the current SARS-CoV-2 variants of concern (omicron BA.1, BA.1.1, and BA.2). Here, we examined whether preexposure prophylaxis with cilgavimab-tixagevimab can effectively protect kidney transplant recipients (KTRs) against the omicron variant. Of the 416 KTRs who received intramuscular prophylactic injections of 150 mg tixagevimab and 150 mg cilgavimab, 39 (9.4%) developed COVID-19. With the exception of one case, all patients were symptomatic. Hospitalization and admission to an intensive care unit were required for 14 (35.9%) and three patients (7.7%), respectively. Two KTRs died of COVID-19-related acute respiratory distress syndrome. SARS-CoV-2 sequencing was carried out in 15 cases (BA.1, n = 5; BA.1.1, n = 9; BA.2, n = 1). Viral neutralizing activity of the serum against the BA.1 variant was negative in the 12 tested patients, suggesting that this prophylactic strategy does not provide sufficient protection against this variant of concern. In summary, preexposure prophylaxis with cilgavimab-tixagevimab at the dose of 150 mg of each antibody does not adequately protect KTRs against omicron. Further clarification of the optimal dosing can assist in our understanding of how best to harness its protective potential.

The MHC class I MICA gene is a histocompatibility antigen in kidney transplantation.

The identity of histocompatibility loci, besides human leukocyte antigen (HLA), remains elusive. The major histocompatibility complex (MHC) class I MICA gene is a candidate histocompatibility locus. Here, we investigate its role in a French multicenter cohort of 1,356 kidney transplants. MICA mismatches were associated with decreased graft survival (hazard ratio (HR), 2.12; 95% confidence interval (CI): 1.45-3.11; P < 0.001). Both before and after transplantation anti-MICA donor-specific antibodies (DSA) were strongly associated with increased antibody-mediated rejection (ABMR) (HR, 3.79; 95% CI: 1.94-7.39; P < 0.001; HR, 9.92; 95% CI: 7.43-13.20; P < 0.001, respectively). This effect was synergetic with that of anti-HLA DSA before and after transplantation (HR, 25.68; 95% CI: 3.31-199.41; P = 0.002; HR, 82.67; 95% CI: 33.67-202.97; P < 0.001, respectively). De novo-developed anti-MICA DSA were the most harmful because they were also associated with reduced graft survival (HR, 1.29; 95% CI: 1.05-1.58; P = 0.014). Finally, the damaging effect of anti-MICA DSA on graft survival was confirmed in an independent cohort of 168 patients with ABMR (HR, 1.71; 95% CI: 1.02-2.86; P = 0.041). In conclusion, assessment of MICA matching and immunization for the identification of patients at high risk for transplant rejection and loss is warranted.

Infection or a third dose of mRNA vaccine elicits neutralizing antibody responses against SARS-CoV-2 in kidney transplant recipients.

Transplant recipients, who receive therapeutic immunosuppression to prevent graft rejection, are characterized by high coronavirus disease 2019 (COVID-19)-related mortality and defective response to vaccines. We observed that previous infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but not the standard two-dose regimen of vaccination, provided protection against symptomatic COVID-19 in kidney transplant recipients. We therefore compared the cellular and humoral immune responses of these two groups of patients. Neutralizing anti-receptor-binding domain (RBD) immunoglobulin G (IgG) antibodies were identified as the primary correlate of protection for transplant recipients. Analysis of virus-specific B and T cell responses suggested that the generation of neutralizing anti-RBD IgG may have depended on cognate T-B cell interactions that took place in germinal center, potentially acting as a limiting checkpoint. High-dose mycophenolate mofetil, an immunosuppressive drug, was associated with fewer antigen-specific B and T follicular helper (TFH) cells after vaccination; this was not observed in patients recently infected with SARS-CoV-2. Last, we observed that, in two independent prospective cohorts, administration of a third dose of SARS-CoV-2 mRNA vaccine restored neutralizing titers of anti-RBD IgG in about 40% of individuals who had not previously responded to two doses of vaccine. Together, these findings suggest that a third dose of SARS-CoV-2 mRNA vaccine improves the RBD-specific responses of transplant patients treated with immunosuppressive drugs.