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.

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.

SARS-Cov-2 Seroprevalence in a French Kidney Transplant Center Located Within a "High-risk" Zone.

BACKGROUND: Data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence in kidney transplant recipients (KTRs) remain rare. We sought to shed further light on this issue by conducting a single-center study in a kidney transplant center located in one of the France's highest risk zone (Grand Est) for coronavirus disease 2019 (Covid-19) during the initial disease outbreak. METHODS: To this aim, we used a survey approach coupled with systematic investigation of SARS-CoV-2 serology in a cohort of 1390 KTRs. RESULTS: SARS-CoV-2 serologies were available for 780 survey respondents, among whom 48 had anti-SARS-CoV-2 antibodies (total seroprevalence: 6.2%). Thirty-five of the 48 seropositive KTRs had previously received a diagnosis of Covid-19, whereas the remaining 13 patients were not known to be infected (8 asymptomatic cases). Specifically, 18.7% of seropositive KTRs and 1.1% of the entire cohort were asymptomatic. Household exposure was found to markedly increase the risk of SARS-CoV-2 transmission. CONCLUSIONS: Our findings demonstrate that the overall SARS-CoV-2 seroprevalence in KTRs living in one of the France's highest risk zone for Covid-19 during the first French lockdown was as low as 6.3%. Rapid and strict implementation of protective measures could have significantly mitigated virus spread even in an area of high virus circulation.

Biomarkers of Cytokine Release Syndrome Predict Disease Severity and Mortality From COVID-19 in Kidney Transplant Recipients.

BACKGROUND: Data on coronavirus disease 2019 (COVID-19) in immunocompromised kidney transplant recipients (KTR) remain scanty. Although markers of inflammation, cardiac injury, and coagulopathy have been previously associated with mortality in the general population of patients with COVID-19, their prognostic impact amongst KTR with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has not been specifically investigated. METHODS: We conducted a cohort study of 49 KTR who presented with COVID-19. Clinical and laboratory risk factors for severe disease and mortality were prospectively collected and analyzed with respect to outcomes. The study participants were divided into 3 groups: (1) mild disease manageable in an outpatient setting (n = 8), (2) nonsevere disease requiring hospitalization (n = 21), and (3) severe disease (n = 20). RESULTS: Gastrointestinal manifestations were common at diagnosis. The 30-day mortality rate in hospitalized patients was 19.5%. Early elevations of C-reactive protein (>100 mg/L) and interleukin-6 (>65 ng/L) followed by increases in high-sensitivity troponin I (>30 ng/L) and D-dimer (>960 ng/mL) were significantly associated with severe disease and mortality. Viral load did not have prognostic significance in our sample, suggesting that outcomes were chiefly driven by a cytokine release syndrome (CRS). CONCLUSIONS: Regular monitoring of CRS biomarkers in KTR with COVID-19 is paramount to improve clinical outcomes.

In-depth virological assessment of kidney transplant recipients with COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread widely, causing coronavirus disease 2019 (COVID-19) and significant mortality. However, data on viral loads and antibody kinetics in immunocompromised populations are lacking. We aimed to determine nasopharyngeal and plasma viral loads via reverse transcription-polymerase chain reaction and SARS-CoV-2 serology via enzyme-linked immunosorbent assay and study their association with severe forms of COVID-19 and death in kidney transplant recipients. In this study, we examined hospitalized kidney transplant recipients with nonsevere (n = 21) and severe (n = 19) COVID-19. SARS-CoV-2 nasopharyngeal and plasma viral load and serological response were evaluated based on outcomes and disease severity. Ten recipients (25%) displayed persistent viral shedding 30 days after symptom onset. The SARS-CoV-2 viral load of the upper respiratory tract was not associated with severe COVID-19, whereas the plasma viral load was associated with COVID-19 severity (P = .010) and mortality (P = .010). All patients harbored antibodies during the second week after symptom onset that persisted for 2 months. We conclude that plasma viral load is associated with COVID-19 morbidity and mortality, whereas nasopharyngeal viral load is not. SARS-CoV-2 shedding is prolonged in kidney transplant recipients and the humoral response to SARS-CoV-2 does not show significant impairment in this series of transplant recipients.

Pre-existing donor-specific antibodies are detrimental to kidney allograft only when persistent after transplantation.

Donor-specific antibodies (DSA) increase the risk of allograft rejection and graft failure. They may be present before transplant or develop de novo after transplantation. Here, we studied the evolution of preformed DSA and their impact on graft outcome in kidney transplant recipients. Using the Luminex Single Antigen assay, we analyzed the sera on the day of transplantation of 239 patients who received a kidney transplant. Thirty-seven patients (15.5%) had pre-existing DSA detected the day of transplantation. After 5 years, the pre-existing DSA disappeared in 22 patients whereas they persisted in 12. Variables associated with DSA persistence were age <50 years (P = 0.009), a history of previous transplantation (P = 0.039), the presence of class II DSA (P = 0.009), an MFI of preformed DSA >3500 (P < 0.001), and the presence of two or more DSA (P < 0.001). DSA persistence was associated with a higher risk of graft loss and antibody-mediated rejection. Previously undetected preformed DSA are deleterious to graft survival only when they persist after transplantation.

Recent Changes in Chronic Kidney Disease-Mineral and Bone Disorders and Associated Fractures After Kidney Transplantation.

BACKGROUND: The management of chronic kidney disease-mineral and bone disorders has recently changed. We investigated the modifications of chronic kidney disease-mineral and bone disorder with a special focus on the incidence of fractures in the first year after kidney transplantation (KT). METHODS: We retrospectively compared 2 groups of patients who consecutively underwent transplantation at our center 5 years from each other. Group 1 consisted of patients (n = 152) transplanted between 2004 and 2006, whereas patients in group 2 (n = 137) underwent KT between 2009 and 2011. RESULTS: During the end-stage renal disease phase at the time of transplant, cinacalcet, and native vitamin D were used significantly more frequently in group 2. Median intact parathyroid hormone levels were lower and severe hyperparathyroidism decreased significantly. Vitamin D deficiency dropped from 64% to 20%. After transplantation, persistent hyperparathyroidism (parathyroid hormone > 130 ng/L) and bone turnover markers were significantly reduced in group 2. Native vitamin D supplementation increased over time, whereas the use of active vitamin D was unchanged. The 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were significantly higher. The fracture incidence at 1 year decreased significantly (3.1% vs 9.1%; P = 0.047). No steroid sparing was observed in group 2. Bisphosphonates after KT were more frequently used in group 2. CONCLUSIONS: Recent changes in clinical practice are associated with reductions in pretransplant and posttransplant hyperparathyroidism, vitamin D deficiency, and fracture risk after KT.

Risk factors for BK virus infection in the era of therapeutic drug monitoring.

BACKGROUND: Overimmunosuppression is a widely recognized risk factor for BK virus (BKV) infection, particularly with the combination of tacrolimus, mycophenolate mofetil (MMF), and steroids. Nevertheless, the exact impact of exposure to tacrolimus and MMF is not well understood. METHODS: We examined 240 kidney recipients between 2006 and 2008. BKV was monitored every 2 months in the urine or blood. A kidney biopsy was performed when viremia exceeded 10 copies/mL. RESULTS: Ninety-five (40%) patients had sustained viruria, 48 (20%) sustained viremia, and 17 (7%) biopsy-proven polyomavirus-associated nephropathy. The mean time-to-occurrence was 7.6, 7.9, and 9.7 months for viruria, viremia, and polyomavirus-associated nephropathy. Risk factors associated with BKV infection in univariate analyses were retransplantation, panel-reactive antibody more than 0%, cytomegalovirus D+/R-, cold ischemia time, delayed graft function, induction with antithymocyte globulins, acute rejection before month 3 (M3), tacrolimus trough levels more than 10 ng/mL, and M3 AUC0-12 hr more than 50 hr mg/L. Multivariate analyses showed that cytomegalovirus D+/R- (adjusted hazard ratio [AHR], 2.03; P=0.05), acute rejection (AHR, 5.4; P<0.001), and mycophenolic acid AUC0-12 hr more than 50 hr mg/L (AHR, 3.6; P=0.001) were risk factors for BKV. CONCLUSIONS: This study identified a link between a state of increased immunosuppression and BKV infection, especially in patients with higher MMF exposure and elevated tacrolimus trough levels at M3.

LMX1B mutations cause hereditary FSGS without extrarenal involvement.

LMX1B encodes a homeodomain-containing transcription factor that is essential during development. Mutations in LMX1B cause nail-patella syndrome, characterized by dysplasia of the patellae, nails, and elbows and FSGS with specific ultrastructural lesions of the glomerular basement membrane (GBM). By linkage analysis and exome sequencing, we unexpectedly identified an LMX1B mutation segregating with disease in a pedigree of five patients with autosomal dominant FSGS but without either extrarenal features or ultrastructural abnormalities of the GBM suggestive of nail-patella-like renal disease. Subsequently, we screened 73 additional unrelated families with FSGS and found mutations involving the same amino acid (R246) in 2 families. An LMX1B in silico homology model suggested that the mutated residue plays an important role in strengthening the interaction between the LMX1B homeodomain and DNA; both identified mutations would be expected to diminish such interactions. In summary, these results suggest that isolated FSGS could result from mutations in genes that are also involved in syndromic forms of FSGS. This highlights the need to include these genes in all diagnostic approaches to FSGS that involve next-generation sequencing.

Incidence and risk factors of glucose metabolism disorders in kidney transplant recipients: role of systematic screening by oral glucose tolerance test.

BACKGROUND: New-onset diabetes after transplantation (NODAT) increases infectious and cardiovascular complications and reduces patient and graft survival. We assessed the incidence and the risk factors for glucose metabolism abnormalities before and after kidney transplantation using an oral glucose tolerance test (OGTT). The purpose of the study was to better identify patients at risk for NODAT to adapt their immunosuppressive treatment and their management after transplantation. METHODS: OGTT was performed before transplantation in 243 patients placed on the kidney waiting list between January 1, 2005, and December 31, 2008. Of these 243 patients, 120 received a kidney transplant and also had an OGTT after transplantation. RESULTS: Impaired glucose tolerance (IGT) was identified in 22 of 120 patients (18%) before transplantation. After transplantation, diabetes developed in 31 patients and 16 patients had IGT. According to univariate analyses, risk factors for NODAT were age more than 50 years, body mass index more than 25 kg/m, pretransplant IGT, autosomal dominant polycystic kidney disease, and acute rejection. According to multivariate analyses, pretransplant IGT (relative risk=2.4), autosomal dominant polycystic kidney disease (relative risk=3), and acute rejection (RR, 2.8) remained significantly associated with NODAT. Patients were stratified by age, primary kidney disease, and pretransplant OGTT. The risk of developing NODAT increased 2.4-, 5-, and 14-fold, depending on the number of risk factors. CONCLUSION: Pretransplant OGTT, together with age and nephropathy, is a helpful tool for identifying patients at risk for NODAT. For patients with two or three of these risk factors, the adjustment of immunosuppression may be recommended.