Patrick Affeldt

Background: Cytomegalovirus (CMV) infections are a common complication after kidney transplantation (KTx) and negatively affecting patient outcome. Valganciclovir (VGC) prophylaxis is often limited by drug‐induced side effects and dose reduction due to decline in kidney function.Method: In the present study, episodes of CMV viremia in the first year after KTx in a cohort of 316 recipients were analyzed retrospectively to identify risk factors linked to persistent infections.Results: In the studied cohort, 18.7% of patients showed a high‐risk (HR) constellation (D+/R–) for CMV infections. CMV viremia affected 22% of our cohort, with HR patients being the most affected cohort (44.1%). Within this group, most viremic events (65.3%) occurred while patients were still on prophylactic therapy, showing significantly higher viral loads and a longer duration compared to seropositive recipients.Conclusion: The analysis at hand revealed that detection of viremia under ongoing antiviral prophylaxis bears an increased risk for sustained viral replication and antiviral drug resistance in HR patients. We identified low estimated glomerular filtration rate (eGFR) and lower dose VGC prophylaxis post‐KTx as a risk factor for breakthrough infections in HR patients in our single center cohort. These patients might benefit from a closer CMV monitoring or novel prophylactic agents as letermovir. image

Cytomegalovirus (CMV) represents one of the most common infectious complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, a common diagnostic test used to stratify the risk for CMV infection in allo-HSCT recipients is the qualitative CMV serology of donor and recipient. A positive serostatus of the recipient is the most important risk factor for CMV reactivation and associated with reduced overall survival post-transplantation (TX). Direct and indirect effects of CMV are involved in the poorer survival outcome. The present study investigated if the quantitative interpretation of anti-CMV IgG before allo-HSCT might serve as a novel parameter for the identification of patients at risk for CMV reactivation and worse outcome post-TX. For this purpose, a cohort of 440 allo-HSCT recipients over a period of 10 years was retrospectively analyzed. Our findings indicated that patients with high CMV IgG pre-allo-HSCT had a higher risk to develop CMV reactivation, including clinically relevant infections, and a worse prognosis 36 months post-allo-HSCT as compared to recipients with low CMV IgG values. In the letermovir (LMV) era, this group of patients might benefit from a closer CMV monitoring, and hence, earlier intervention if needed, especially after discontinuation of prophylaxis.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a serious hazard for hemodialysis (HD) patients and kidney transplant (KTX) recipients as they suffer from an impaired immune response to SARS-CoV-2 vaccination. In addition, a definition of SARS-CoV-2 IgG titer that indicates a sufficient immune response, especially against new omicron variants, is urgently needed. In the present study, the immune response to either a third or a fourth dose of a mRNA vaccine was investigated in 309 dialysis and 36 KTX patients. SARS-CoV-2 IgG titer thresholds indicating neutralizing activity against wild type (WT) and the omicron variant BA.1 were quantified. After four vaccine doses, a high-neutralizing activity against WT was evidenced in HD patients, whereas the neutralizing rate against BA.1 was significant lower. Concerning KTX recipients, humoral and cellular immune responses after a third vaccination were still highly impaired. This calls for modified omicron-targeting vaccines.

Dialysis patients and kidney transplant (KTX) recipients suffer from an impaired immune system and show a decreased response to the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccination. We performed a retrospective analysis of 1505 serological SARS-CoV-2 measurements obtained from 887 dialysis patients and 86 KTX recipients. The results were separated by patient subgroups (dialysis/KTX) as well as SARS-CoV-2 status. The latter criterion included SARS-CoV-2-naïve patients with or without COVID-19 vaccination and convalescent patients receiving a booster shot. Serologies of 27 vaccinated healthy individuals served as the reference group. Vaccine-induced cellular immune response was quantified by an interferon-γ release assay in 32 KTX recipients. We determined seroconversion rates of 92.6%, 93.4%, and 71.4% in dialysis patients vaccinated with either BNT162b2, mRNA-1273, or AZD1222, respectively. Vaccination-induced anti-SARS-CoV-2 antibody titers were lower in dialysis patients compared to healthy individuals, and vaccination with mRNA-1273 induced higher titers than BNT162b2. The initial seroconversion rate was 39.5% in KTX recipients vaccinated with BNT162b2. A linear regression model identified medication with mycophenolate-mofetil/mycophenolic acid as an independent risk factor for missing seroconversion. Within a cohort of 32 KTX recipients, cellular and humoral immune reactivity to SARS-CoV-2 was detectable in three patients only. Conclusively, vaccine-induced seroconversion rates were similar in dialysis patients compared to healthy individuals but were strongly impaired in KTX recipients. Anti-SARS-CoV-2 IgG titers elicited by double active immunization were significantly lower in both cohorts compared to healthy individuals, and immune responses to vaccination vanished quickly.

The treatment options for cytomegalovirus (CMV) infections in immunosuppressed patients are limited, mainly consisting of (val-)ganciclovir (VGC/GCV) as the first-line treatment. We report on three transplant recipients, one stem cell transplant (allo-HSCT) patient and two kidney transplant (KTx) recipients, with prolonged CMV viremia treated with a combined therapy based on letermovir (LMV), CMV-specific intravenous immunoglobulins (IVIg), and VGC/GCV, which led to the sustained control of CMV viremia in all patients.

Chronic kidney disease (CKD) is still a major health concern. Kidney transplantation is the gold standard in the event of kidney failure. However, long-term transplant survival is limited by allograft rejection. Consequently, optimal diagnostic strategies to detect rejection as early as possible are urgently required. The current standard of care for detecting rejection is the measurement of eGFR and changes in proteinuria. These parameters are unspecific and their sensitivity is limited, on the one hand. Donor-specific antibodies (DSA) have been a more recent addition to the diagnostic armamentarium. On the other hand, kidney biopsies as the gold standard come with the intrinsic risk of an invasive procedure and are thus frequently only used when the clinical parameters become conspicuous {1}. Consequently, there is a great interest in sensitive and specific non-invasive markers of immunological activation and rejection risk (“liquid biopsy”). As an example, these efforts have resulted in studies on donor-derived cell-free DNA in kidney transplantation {2}. However, none of the newly identified markers have made their way to routine clinical diagnostics so far. Small urinary extracellular vesicles, or more specifically, exosomes, have gained increasing attention during the last years due to their active secretion from all cells lining the nephron {3,4}. Exosomes are nanometer-sized vesicles which serve as mediators of cell communication. Furthermore, their content - e.g. mRNA - is protected from degradation, making them an optimal source of stable biomarkers. Fekih et al. were now able to make a major step ahead using urinary vesicles as a tool to detect transplant rejections. This study collected 192 urine samples from 175 kidney transplant patients who received a transplant biopsy at the same time because of suspected acute rejection. Exosomal mRNA content of these samples was determined using a qPCR inflammation panel containing assays for 586 genes. Multigene signatures were then clinically validated for their diagnostic suitability. The exosomal mRNA signature was able to differentiate between biopsies from patients with rejection (all causes) and those without rejection. The ability to discriminate between these groups was significantly better (AUC 0.93) than using eGFR increase (AUC 0.57). The negative predictive value of the exosome signature was 93.3%, the positive predictive value 86.2%. Following the same principle, another gene signature was identified to differentiate between T-cell-mediated and antibody-mediated rejection (AUC 0.87, negative and positive predictive values 90.6% and 77.8%). The diagnostic capacity of these panels is quite unique for a non-invasive tool in kidney transplantation and outperformed the presence of DSA, as well as the combination of DSA and urinary protein-creatinine ratio. The study did not collect serial samples; consequently, a judgement on a potential predictive nature of the mRNA panels regarding rejection episodes is not possible at this point. Besides, it is not clear yet to what extent other inflammatory events such as BKV nephropathy or urinary tract infections may influence the results in clinical practice. Nonetheless, this work may indeed be the crucial step towards the first non-invasive assay for clinical routine that allows for targeted decision-making regarding the need for transplant biopsies in individual patients.

Background: Recently, chronic hepatitis E virus (HEV) infections gained increasing attention as a possible cause for elevated liver enzymes of unknown origin and liver cirrhosis in solid organ transplant recipients. Reduction of immunosuppressive therapy and/or use of antiviral drug ribavirin have been established as possible treatment strategies.Methods: The efficacy of dose reduction of mycophenolic acid (MPA) and ribavirin therapy was retrospectively analyzed in eight renal transplant patients of our outpatient clinic who were diagnosed with HEV infection by detection of specific antibodies (immunoglobulin M and immunoglobulin G) and/or positive RNA in blood and stool. In four patients serial HEV viral loads in blood were measured.Results: Only one patient reached HEV clearance after reduction of immunosuppressive therapy (predominantly reduction of MPA daily dose) alone, whereas six patients were treated with ribavirin after reduction of immunosuppressive therapy due to persistent virus replication. Four of six patients reached HEV clearance after 3 months of ribavirin therapy. HEV clearance was observed after 34–42 days. Two patients, both treated with rituximab within the last 12 months before diagnosis of HEV infection, needed prolonged ribavirin therapy due to persistent viral replication.Conclusion: Reduction of daily dose of MPA therapy alone in transplant patients with chronic HEV infection may not be sufficient to control viral replication. HEV clearance under ribavirin therapy shows interindividual variability. Therefore, serial viral monitoring may be useful to personalize treatment duration. Rituximab therapy is a risk factor for complicated‐to‐treat chronic HEV infection.