Updated National Study of Functional Graft Renal Cell Carcinomas: Are They a Different Entity?

OBJECTIVE: To analyze de novo graft carcinoma characteristics from our updated national multicentric retrospective cohort. METHODS: Thirty-two transplant centers have retrospectively completed the database. This database concerns all kidney graft tumors including urothelial, and others type but excludes renal lymphomas over 31 years. RESULTS: One hundred and fifty twokidney graft carcinomas were diagnosed in functional grafts. Among them 130 tumors were Renal Cell Carcinomas. The calculated incidence was 0.18%. Median age of the allograft at diagnosis was 45.4 years old. The median time between transplantation and diagnosis was 147.1 months. 60 tumors were papillary carcinomas and 64 were clear cell carcinomas. Median tumor size was 25 mm. 18, 64, 21 and 1 tumors were respectively Fuhrman grade 1, 2, 3 and 4. Nephron sparing surgery (NSS) was performed on 68 (52.3%) recipients. Ablative therapy was performed in 23 cases (17.7%). Specific survival rate was 96.8%. CONCLUSION: This study confirmed that renal graft carcinomas are a different entity: with a younger age of diagnosis; a lower stage at diagnosis; a higher incidence of papillary subtypes.

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.

High-flow arteriovenous fistula and hemodynamic consequences at 1 year after kidney transplantation.

INTRODUCTION: There are only scarce data regarding the cardiovascular impact of arteriovenous fistula after kidney transplantation depending on fistula flow. METHODS: We performed a single-center, prospective, cohort study including 49 patients with a functional fistula at 1 year from kidney transplantation. Patients were convened for a clinical work-up, a biological analysis, a fistula's Doppler ultrasonography and an echocardiography. Main judgment criterion was comparison of echocardiography parameters between patients with relative (fistula flow >1 L/min and a fistula flow/cardiac output ratio >20%), absolute high-flow fistula (fistula flow >2 L/min) and normal-flow fistula. RESULTS: High-flow fistula frequency was 69%. Significantly higher left ventricular end-diastolic and systolic diameters were observed in this group compared with the normal-flow fistula group (53 ± 6 vs. 48 ± 7 mm; p = 0.04 and 33 ± 6 vs. 28 ± 8 mm; p = 0.02) and between the absolute and relative high-flow fistula subgroups (56 ± 6 vs. 51 ± 6 mm; p = 0.009 and 35 ± 6 vs. 31 ± 5 mm; p = 0.01). The study showed no other significant differences. CONCLUSIONS: This study showed a significantly higher but not pathological left ventricular end-diastolic and systolic diameters values in patients with high-flow fistula compared with patients with normal-flow fistula and between patients with respectively absolute and relative high-flow fistula.

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.

Intravenous immunoglobulin as a preventive strategy against BK virus viremia and BKV-associated nephropathy in kidney transplant recipients-Results from a proof-of-concept study.

BK virus (BKV) replication occurs frequently in kidney transplant recipients (KTR), potentially leading to BKV-associated nephropathy (BKVAN) and graft loss. Patients with high titers of BKV-neutralizing antibodies (NAbs) are protected against BKV replication, and intravenous immunoglobulin (IVIg) infusion can increase NAb titers. We investigated whether early IVIg administration prevents BKV replication in patients with low NAb titers (<4 log10 against the BKV-specific genotype). Based on NAb titers on the day of transplantation, KTR followed in the Strasbourg University Hospital (n = 174) were retrospectively divided into the following 3 risk categories for BKV replication: (1) patients with low NAb titers ("high-risk") who received IVIg for the first 3 posttransplant months (n = 44), (2) patients with low NAb titers ("high-risk") who did not undergo IVIg treatment (n = 41), and (3) patients with high NAb titers ("low-risk") who did not receive IVIg (n = 89). At 12 posttransplant months, the incidence of BKV viremia in the high-risk group treated with IVIg (6.8%) was similar to that observed in the low-risk group (10.1%) and markedly lower than that of the untreated high-risk group (36.6%; P < .001). Similar results were observed with regard to BKVAN. We conclude that IVIg may be a valuable strategy for preventing BKV replication.

Does a Useful Test Exist to Properly Evaluate the Pathogenicity of Donor-specific Antibodies? Lessons From a Comprehensive Analysis in a Well-studied Single-center Kidney Transplant Cohort.

BACKGROUND: Donor-specific antibodies (DSA) play a major role in antibody-mediated rejection (AMR) and graft dysfunction. However, the clinical relevance of complement-binding anti-HLA antibodies remains unclear. METHODS: Here, we analyzed DSA detected in the serum (sDSA) using single antigen bead, C1q, and C3d assays combined with the study of intragraft DSA (gDSA) in 86 patients who had DSA and underwent a kidney biopsy for cause (n = 58) or without evidence of kidney dysfunction (n = 28). DSA characteristics were collected and related to the presence of AMR, graft histological features, and allograft survival. RESULTS: Forty-five patients (52%) had C1q DSA, and 42 (51%) had C3d DSA. Allograft biopsies revealed AMR in 63 cases (73%), regardless of kidney function. gDSA were identified in 74% of biopsies. We observed a strong correlation among single antigen bead mean fluorescence intensity and complement assays positivity, presence of gDSA, and AMR occurrence. CONCLUSIONS: Complement-binding DSA per se were not significantly associated with allograft survival in the entire study sample. Finally, gDSA predicted subsequent graft loss in patients who showed a stable renal function at the day of biopsy. Our data suggest that DSA mean fluorescence intensity and presence of gDSA might provide prognostic information during posttransplant monitoring.

Eculizumab for Thrombotic Microangiopathy Associated with Antibody-Mediated Rejection after ABO-Incompatible Kidney Transplantation.

Thrombotic microangiopathy is a form of antibody-mediated rejection (ABMR): it is the main complication of ABO-incompatible (ABOi) kidney transplantation (KT). Herein, we report on two cases of ABMR with biological and histological features of thrombotic microangiopathy (TMA) that were treated by eculizumab after ABOi KT. The first patient presented with features of TMA at postoperative day (POD) 13. Because of worsening biological parameters and no recovery of kidney function, despite seven sessions of immunoadsorption, a salvage therapy of eculizumab was started on POD 23. Kidney function slightly improved during the first 4 months after transplantation. Eculizumab was stopped at month 4. However, kidney function worsened progressively, leading to dialysis at month 13 after transplantation. The second patient presented with features of TMA at POD 1. In addition to immunoadsorption therapy, eculizumab was started on POD 6. Kidney function improved. Eculizumab was stopped on POD 64 and immunoadsorption sessions were stopped on POD 102. At the last follow-up (after 9 months), eGFR was at 43 mL/min/1.73 m2. Our case reports show the beneficial effect of eculizumab to treat ABMR after ABOi KT. However, it should be given early after diagnosing TMA associated with ABMR.