A multicentre, patient- and assessor-blinded, non-inferiority, randomised and controlled phase II trial to compare standard and torque teno virus-guided immunosuppression in kidney transplant recipients in the first year after transplantation: TTVguideIT.

BACKGROUND: Immunosuppression after kidney transplantation is mainly guided via plasma tacrolimus trough level, which cannot sufficiently predict allograft rejection and infection. The plasma load of the non-pathogenic and highly prevalent torque teno virus (TTV) is associated with the immunosuppression of its host. Non-interventional studies suggest the use of TTV load to predict allograft rejection and infection. The primary objective of the current trial is to demonstrate the safety, tolerability and preliminary efficacy of TTV-guided immunosuppression. METHODS: For this purpose, a randomised, controlled, interventional, two-arm, non-inferiority, patient- and assessor-blinded, investigator-driven phase II trial was designed. A total of 260 stable, low-immunological-risk adult recipients of a kidney graft with tacrolimus-based immunosuppression and TTV infection after month 3 post-transplantation will be recruited in 13 academic centres in six European countries. Subjects will be randomised in a 1:1 ratio (allocation concealment) to receive tacrolimus either guided by TTV load or according to the local centre standard for 9 months. The primary composite endpoint includes the occurrence of infections, biopsy-proven allograft rejection, graft loss, or death. The main secondary endpoints include estimated glomerular filtration rate, graft rejection detected by protocol biopsy at month 12 post-transplantation (including molecular microscopy), development of de novo donor-specific antibodies, health-related quality of life, and drug adherence. In parallel, a comprehensive biobank will be established including plasma, serum, urine and whole blood. The date of the first enrolment was August 2022 and the planned end is April 2025. DISCUSSION: The assessment of individual kidney transplant recipient immune function might enable clinicians to personalise immunosuppression, thereby reducing infection and rejection. Moreover, the trial might act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical applications, including as guidance for immune modulators or disease-modifying agents. TRIAL REGISTRATION: EU CT-Number: 2022-500024-30-00.

Serum and Urinary Biomarkers in COVID-19 Patients with or without Baseline Chronic Kidney Disease.

In a prospective, observational, non-interventional, single-center study, we assessed various plasma and urinary biomarkers of kidney injury (neutrophil gelatinase-associated Lipocain [NGAL], kidney-injury molecule-1 [KIM-1], and interleukin-18 [IL-18]); inflammation (IL-6, C-reactive protein [CRP]); plus angiotensin converting enzyme 2 (ACE2) in 120 COVID-19 patients (of whom 70 had chronic kidney disease (CKD) at emergency-department (ED) admission). Our aim was to correlate the biomarkers with the outcomes (death, acute kidney injury [AKI]). All patients had received a chest-CT scan at admission to calculate the severity score (0-5). Biomarkers were also assessed in healthy volunteers and non-COVID-19-CKD patients. These biomarkers statistically differed across subgroups, i.e., they were significantly increased in COVID-19 patients, except for urinary (u)KIM1 and uIL-18. Amongst the biomarkers, only IL-6 was independently associated with mortality, along with AKI and not using remdesivir. Regarding the prediction of AKI, only IL-6 and uKIM1 were significantly elevated in patients presenting with AKI. However, AKI could not be predicted. Having high baseline IL-6 levels was associated with subsequent ventilation requirement and death. The mortality rate was almost 90% when the chest CT-scan severity score was 3 or 4 vs. 6.8% when the severity score was 0-2 (p < 0.0001).

Renin-angiotensin-aldosterone system blockers in Bulgarian COVID-19 patients with or without chronic kidney disease.

When angiotensin-converting enzyme inhibitor/angiotensin receptor blocker-treated patients present with SARS-CoV-2 infection there is a debate to know whether renin-angiotensin-aldosterone (RAAS) blockers should be stopped or not. We conducted a prospective observational study in Bulgarian COVID-19-infected patients with or without chronic kidney disease (CKD) to assess whether maintenance RAAS blocker therapy has an impact on SARS-CoV-2 infection and its complications. We included 120 in-patient COVID-19 subjects, of whom 70 had CKD and 50 had normal renal function. A total of 30% of the patients (total number of 36 patients, 21 females) were receiving RAAS therapy at admission and it was maintained throughout hospitalization. The overall mortality was 19.2% (23 patients); there was no significant difference across the 2 groups (P-value = .21), except in RAAS blockers-treated hypertensive patients who had a significantly lower mortality as compared to non-RAAS-blockers-treated hypertensive patients (P = .04). Regarding subsequent intensive-care unit admission, there were 50% less patients in the RAAS group (4 out of 36, i.e., 11%) as compared to 19 out of 84 from the non-RAAS group, that is, 22.6% (P = .29). Overall, 37 patients developed acute kidney injury (any stage by KDIGO); of them 14 (37.8%) were receiving RAAS blockers. Acute kidney injury was not significantly associated with the use of RAAS blockers (P-value = .28). Likewise, both in non-CKD and in CKD patients the use of RAAS blockers did not have an impact on renal function recovery after SARS-CoV-2 infection. Finally, regarding RAAS blockers and the biological parameters outcome only D-dimers were significantly lower at the follow-up as compared to that in non-RAAS blocker treated patients. RAAS blockers benefited patients with hypertension by lowering mortality rate. Other than that, RAAS blocker therapy continuation during SARS-CoV-2 infection in CKD and non-CKD patients had no significant impact upon major outcomes.

COVID-19 Infection in Chronic Kidney Disease Patients in Bulgaria: Risk Factors for Death and Acute Kidney Injury.

Regarding COVID-19 infection, Bulgaria has one of the lowest rates of vaccination in Europe, and its COVID-19-related mortality rate has been one of the highest in the European Union. Chronic kidney disease (CKD)-COVID-19 patients are at higher risk of developing acute kidney injury (AKI) and death after hospital admission. This single-center prospective cohort study from Bulgaria included 120 in-patient COVID-19 subjects of whom 70 had CKD and 50 normal renal function. Diabetes mellitus, hypertension, obesity, and cardiovascular disease were statistically more prevalent in the CKD group as compared to the non-CKD group. At admission, D-dimer, creatinine, and urea levels were significantly higher in the CKD group, whereas estimated glomerular-filtration rate was significantly lower as compared to the non-CKD patients. During hospitalization, 23 patients (19.1%) died, of which 19 were in the CKD group (p-value = 0.0096); in addition, 38 developed AKI (31.6%), of which 31 were in the CKD group (p-value = 0.0006). Using binary logistic regression, being male, having experienced AKI, and not having been treated with remdesivir were independent risk factors for COVID-19-induced mortality. Regarding risk of AKI, having had COVID-19-related symptoms for more than 6 days before admission, having CKD at baseline, and having not received remdesivir therapy were independent predictive factors for developing AKI after admission.

SARS-CoV-2 anti-spike antibodies after a fourth dose of COVID-19 vaccine in adult solid-organ transplant recipients.

BACKGROUND: A fourth dose of SARS-CoV-2 vaccine is recommended in solid-organ transplant (SOT) recipients, but the immunogenicity is poorly known. METHODS: We conducted a retrospective, observational, monocentric study between the 1st January 2021 and 31st March 2022 of the anti-Spike antibody titers after one to four doses of vaccine in SOT. RESULTS: 825 SOT were included. Median age at first vaccine injection was 61.2 (IQR 50.9-69.3) years; 66.7 % were male; 63.4 % had received four vaccine doses. The proportion of participants with a strong humoral response (>260 BAU/mL) increased with the number of vaccine doses: 10.6 % after the 1st dose (D1), 35.1 % after the 2nd (D2), 48.5 % after the 3rd (D3), and 65.1 % after the 4th (D4) (p < 0.001). Among the tested patients, the proportion with a detectable humoral response was significantly higher after D4 than after D3 (47 % vs 22 %, p = 0.01). Liver transplant recipients had more frequently a strong humoral response after D2, D3 and D4 (OR = 5.3, 3.7 and 6.6 respectively when compared with other organ transplant recipients, p < 0.001). In kidney transplant recipients, belatacept-containing regimen was associated with a lower rate of detectable humoral (9 % vs 40 %, p = 0.025) after D3, but there was no statistical difference after D4. CONCLUSION: A fourth dose should be proposed to SOT recipients who did not developed an immune response after 3 doses. Kidney transplant recipients receiving belatacept have a poorer, although frequently detectable response.

Very Early Severe Posttransplant Recurrent Antineutrophil Cytoplasmic Antibody-Associated Glomerulonephritis after Kidney Transplantation: Two Case Reports.

Successful kidney transplantation (KTx) in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) has been reported with excellent patient and graft survival rates. The recurrence of AAV in transplant recipients is rare, and its mechanisms of action are not clearly known. The optimum time for KTx and the relevance of ANCA titer at the time of transplantation remain controversial. We report two cases of extremely rapid recurrent AAV after renal transplantation; both were still ANCA-positive at the time of transplantation, which led us to question the pathogenesis of ANCA antibodies in recurrence in a kidney allograft. Apheresis plus immunosuppressive therapies were ineffective in the first case and the patient became dialysis-dependent, whereas in the second case methylprednisone pulses plus rituximab infusions resulted in long-lasting remission.

Belatacept Use after Kidney Transplantation and Its Effects on Risk of Infection and COVID-19 Vaccine Response.

INTRODUCTION: Belatacept is a common immunosuppressive therapy used after kidney transplantation (KT) to avoid calcineurin-inhibitor (CNI) use and its related toxicities. It is unclear whether its use exposes KT recipients (KTx) to a greater risk of infection or a poorer response to vaccines. Areas covered: We reviewed PubMed and the Cochrane database. We then summarized the mechanisms and impacts of belatacept use on the risk of infection, particularly opportunistic, in two settings, i.e., de novo KTx and conversion from CNIs. We also focused on COVID-19 infection risk and response to SARS-CoV-2 vaccination in patients whose maintenance immunosuppression relies on belatacept. Expert opinion: When belatacept is used de novo, or after drug conversion the safety profile regarding the risk of infection remains good. However, there is an increased risk of opportunistic infections, mainly CMV disease and Pneumocystis pneumonia, particularly in those with a low eGFR, in older people, in those receiving steroid-based therapy, or those that have an early conversion from CNI to belatacept (i.e.,

Impact of Circulating SARS-CoV-2 Mutant G614 on the COVID-19 Pandemic.

Coronavirus family has caused several human illnesses, the latest caused by SARS-CoV-2, has led to COVID-19 pandemic posing serious threat to global health. A SARS-CoV-2 variant encoding a D614G mutation in the viral spike (S) protein has now become the most prevalent form of the virus worldwide, suggesting a fitness advantage for the mutant. The G614 variant is associated with higher upper respiratory tract viral load, higher infectivity, increased total S protein incorporation into the virion, reduced S1 shedding and a conformational change leading to a more ACE2- binding and fusion- competent state. However, it does not seem to be correlated to increased disease severity or escape neutralizing antibodies.

Transplantation in the era of the Covid-19 pandemic: How should transplant patients and programs be handled?

Due to the Covid-19 pandemic caused by SARS-CoV-2, transplant programs worldwide have been severely impacted with dwindling numbers of transplantations performed and a complete halt in several areas. In this review we examine whether SARS-CoV-2 infection presents differently in transplant recipients, whom and how we should test, how susceptible the transplant population is to overt infection and describe the range of outcomes. From retrieved published reports on SARS-CoV-2infections in 389solid organ transplant recipients reported in the literature, the overall mortality rate was 16.7% (n = 65); however for those with mild or moderate Covid-19 disease this was 2.9% and 2.3% respectively; conversely, for those with severe infection the mortality rate was 52.2%.We then address questions regarding halting transplantation programs during this pandemic, whether all human tissues being considered for transplantation are capable of transmitting the infection, and if we should alter immunosuppressive medications during the pandemic.