Therapeutic Drug Monitoring of Ganciclovir in Cytomegalovirus-Infected Patients With Solid Organ Transplants and Its Correlation to Efficacy and Toxicity

Background:Cytomegalovirus causes morbidity and mortality, especially in immunocompromised patients, and is treated with (val)ganciclovir. Therapeutic drug monitoring of ganciclovir is often performed; however, clinically established target trough levels corresponding to efficacy are lacking. In 2021, our clinic increased the target trough level for ganciclovir from 1 to 2 mg/L to 2-4 mg/L. This study aims to compare both target trough levels in efficacy, toxicity, and occurrence of resistance.Methods:A retrospective cohort study was performed in adult solid organ recipients treated for cytomegalovirus infection with (val)ganciclovir. Clinical efficacy was defined as the absence of treatment failure, defined as > 1 log10increase in viral load within 2 weeks of treatment initiation, therapy switch to foscarnet, and/or request for resistance analysis.Results:A total of 46 patients were involved in the study, with 200 ganciclovir trough levels obtained. The composite endpoint was recorded in 23 (69.7%) and 10 (76.9%) patients in the 1-2 mg/L and the 2-4 mg/L group, respectively (P = 0.18). No association was found between ganciclovir trough levels and the composite endpoint (P = 1.0). However, a correlation was found between ganciclovir trough levels and the occurrence of lymphopenia (P = 0.02).Conclusions:Our study could not establish a difference in clinical efficacy or toxicity between target trough levels of 1-2 mg/L or 2-4 mg/L because of the lack of clinical differences between the compared groups. However, a correlation was found between ganciclovir trough levels and lymphopenia, which warrants further investigation

Complement component C3 and C5b-9 deposition on hypoxia reperfused endothelial cells by non-HLA antibodies against RhoGDI2: A player involved in graft failure?

Antibodies against Rho GDP-dissociation inhibitor 2 (RhoGDI2) are associated with inferior graft survival in transplant patients receiving a kidney from deceased donors. Although this suggests that these antibodies contribute to graft injury because of ischemia, it remains unknown whether they are also pathogenically involved in the process of graft loss. To study this, we firstly analyzed the IgG subclass profile of anti-RhoGDI2 antibodies in kidney transplant recipients, and whether antibody titers change over time or because of acute rejection. Next, we investigated the expression of RhoGDI2 on primary kidney and lung endothelial cells (ECs) upon hypoxia reperfusion. In addition, the complement-fixing properties of anti-RhoGDI2 antibodies were studied using imaging flow cytometry. Anti-RhoGDI2 antibodies in patients are mainly IgG1, and titers remained stable and seemed not be changed because of rejection. Antibodies against RhoGDI2, which surface expression seemed to increase upon hypoxia reperfusion, co-localized with C3 on ECs. Binding of human IgG1 monoclonal anti-RhoGDI2 antibodies as well as patient derived antibodies, resulted in complement activation, suggesting that these antibodies are complement fixing. This study suggested a potential pathogenic role of anti-RhoGDI2 antibodies in kidney graft loss. During ischemia reperfusion, the ability of these antibodies to fix complement could be one of the mechanisms resulting in tissue injury

Can We Predict Graft Intolerance Syndrome After Kidney Transplant Failure?: External Validation of a Previously Developed Model

Previously we established a prediction model for graft intolerance syndrome requiring graft nephrectomy in patients with late kidney graft failure. The aim of this study is to determine generalizability of this model in an independent cohort. The validation cohort included patients with late kidney graft failure between 2008 and 2018. Primary outcome is the prognostic performance of our model, expressed as the area under the receiver operating characteristic curve (ROC-AUC), in the validation cohort. In 63 of 580 patients (10.9%) a graft nephrectomy was performed because of graft intolerance. The original model, which included donor age, graft survival and number of acute rejections, performed poorly in the validation cohort (ROC-AUC 0.61). After retraining of the model using recipient age at graft failure instead of donor age, the model had an average ROC-AUC of 0.70 in the original cohort and of 0.69 in the validation cohort. Our original model did not accurately predict the graft intolerance syndrome in a validation cohort. However, a retrained model including recipient age at graft failure instead of donor age performed moderately well in both the development and validation cohort enabling identification of patients with the highest and lowest risk of graft intolerance syndrome

A systematic review and meta-analysis of COVID-19 in kidney transplant recipients:Lessons to be learned

Kidney transplant recipients (KTR) may be at increased risk of adverse COVID-19 outcomes, due to prevalent comorbidities and immunosuppressed status. Given the global differences in COVID-19 policies and treatments, a robust assessment of all evidence is necessary to evaluate the clinical course of COVID-19 in KTR. Studies on mortality and acute kidney injury (AKI) in KTR in the World Health Organization COVID-19 database were systematically reviewed. We selected studies published between March 2020 and January 18th 2021, including at least five KTR with COVID-19. Random-effects meta-analyses were performed to calculate overall proportions, including 95% confidence intervals (95% CI). Subgroup analyses were performed on time of submission, geographical region, sex, age, time after transplantation, comorbidities, and treatments. We included 74 studies with 5559 KTR with COVID-19 (64.0% males, mean age 58.2 years, mean 73 months after transplantation) in total. The risk of mortality, 23% (95% CI: 21%-27%), and AKI, 50% (95% CI: 44%-56%), is high among KTR with COVID-19, regardless of sex, age and comorbidities, underlining the call to accelerate vaccination programs for KTR. Given the suboptimal reporting across the identified studies, we urge researchers to consistently report anthropometrics, kidney function at baseline and discharge, (changes in) immunosuppressive therapy, AKI, and renal outcome among KTR

Early Estimation of Renal Function After Transplantation to Enable Appropriate Dosing of Critical Drugs: Retrospective Analysis of 103 Patients in a Single Center

BACKGROUND: Immediately after renal transplantation (RTX), estimation of renal function (eGFR) is important for drug dosing and the detection of potential complications. Conventional formulas cannot be used since the serum creatinine concentration is not at steady-state. In this study, we evaluated different dynamic renal function formulas (DRFFs) to estimate eGFR immediately after RTX. METHODS: We retrospectively included 154 RTX patients, of whom 45 had delayed graft function (DGF) and required dialysis, and 6 had unstable graft function without the need for dialysis; 103 patients had early, and thereafter stable, graft function (EGF). DRFFs were evaluated to calculate eGFR 1 day after transplantation (T1) using a new dynamic creatinine clearance calculation (D3C), two previously published formulas (Jelliffe, and the kinetic eGFR [KeGFR]), and a naive predictor (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] at T1). The estimated DRFF-based renal functions at T1 were compared with the CKD-EPI after stabilization of renal function 3 days after transplantation (eGFR-T3), which was considered the underlying renal function immediately after RTX. RESULTS: The D3C showed low bias (mean prediction error [MPE] - 4.5 ml/min/1.73 m2) and performed well on other outcome measures (R2 = 0.82, root mean squared error [RMSE] = 11.8 ml/min/1.73 m2, percentage of predictions within 30% of the reference value [p30%] = 76%). In addition, the D3C outperformed the KeGFR (MPE 20.5 ml/min/1.73 m2, R2 = 0.79, RMSE = 26.9 ml/min/1.73 m2, p30% = 29%), Jelliffe (MPE - 13.3 ml/min/1.73 m2, R2 = 0.76, RMSE = 19.1 ml/min/1.73 m2, p30% = 53%), and the naive predictor (bias - 24.8 ml/min/1.73 m2, R2 = 0.60, RMSE = 30.2 ml/min/1.73 m2, p30% = 21%). CONCLUSIONS: The newly developed D3C enables reliable assessment of renal function immediately after RTX, provides crucial information for drug dosing, and might also advance the detection of functional decline, potentially improving treatment and renal outcome

Modeling complement activation on human glomerular microvascular endothelial cells

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare kidney disease caused by dysregulation of the complement alternative pathway. The complement dysregulation specifically leads to damage to the glomerular endothelium. To further understand aHUS pathophysiology, we validated an ex vivo model for measuring complement deposition on both control and patient human glomerular microvascular endothelial cells (GMVECs). Methods: Endothelial cells were incubated with human test sera and stained with an anti-C5b-9 antibody to visualize and quantify complement depositions on the cells with immunofluorescence microscopy.Results: First, we showed that zymosan-activated sera resulted in increased endothelial C5b-9 depositions compared to normal human serum (NHS). The levels of C5b-9 depositions were similar between conditionally immortalized (ci)GMVECs and primary control GMVECs. The protocol with ciGMVECs was further validated and we additionally generated ciGMVECs from an aHUS patient. The increased C5b-9 deposition on control ciGMVECs by zymosan-activated serum could be dose-dependently inhibited by adding the C5 inhibitor eculizumab. Next, sera from five aHUS patients were tested on control ciGMVECs. Sera from acute disease phases of all patients showed increased endothelial C5b-9 deposition levels compared to NHS. The remission samples showed normalized C5b-9 depositions, whether remission was reached with or without complement blockage by eculizumab. We also monitored the glomerular endothelial complement deposition of an aHUS patient with a hybrid complement factor H (CFH)/CFH-related 1 gene during follow-up. This patient had already chronic kidney failure and an ongoing deterioration of kidney function despite absence of markers indicating an aHUS flare. Increased C5b-9 depositions on ciGMVECs were observed in all samples obtained throughout different diseases phases, except for the samples with eculizumab levels above target. We then tested the samples on the patient’s own ciGMVECs. The C5b-9 deposition pattern was comparable and these aHUS patient ciGMVECs also responded similar to NHS as control ciGMVECs. Discussion: In conclusion, we demonstrate a robust and reliable model to adequately measure C5b-9-based complement deposition on human control and patient ciGMVECs. This model can be used to study the pathophysiological mechanisms of aHUS or other diseases associated with endothelial complement activation ex vivo.</p

Considerable Variability Among Transplant Nephrologists in Judging Deceased Donor Kidney Offers

Introduction: Transplant clinicians may disagree on whether or not to accept a deceased donor kidney offer. We investigated the interobserver variability between transplant nephrologists regarding organ acceptance and whether the use of a prediction model impacted their decisions.Methods: We developed an observational online survey with 6 real-life cases of deceased donor kidneys offered to a waitlisted recipient. Per case, nephrologists were asked to estimate the risk of adverse outcome and whether they would accept the offer for this patient, or for a patient of their own choice, and how certain they felt. These questions were repeated after revealing the risk of adverse outcome, calculated by a validated prediction model. Results: Sixty Dutch nephrologists completed the survey. The intraclass correlation coefficient of their estimated risk of adverse outcome was poor (0.20, 95% confidence interval [CI] 0.08–0.62). Interobserver agreement of the decision on whether or not to accept the kidney offer was also poor (Fleiss kappa 0.13, 95% CI 0.129–0.130). The acceptance rate before and after providing the outcome of the prediction model was significantly influenced in 2 of 6 cases. Acceptance rates varied considerably among transplant centers. Conclusion: In this study, the estimated risk of adverse outcome and subsequent decision to accept a suboptimal donor kidney varied greatly among transplant nephrologists. The use of a prediction model could influence this decision and may enhance nephrologists’ certainty about their decision.</p

A nationwide evaluation of deceased donor kidney transplantation indicates detrimental consequences of early graft loss

Early graft loss (EGL) is a feared outcome of kidney transplantation. Consequently, kidneys with an anticipated risk of EGL are declined for transplantation. In the most favorable scenario, with optimal use of available donor kidneys, the donor pool size is balanced by the risk of EGL, with a tradeoff dictated by the consequences of EGL. To gauge the consequence of EGL we systematically evaluated its impact in an observational study that included all 10,307 deceased-donor kidney transplantations performed in The Netherlands between 1990 and 2018. Incidence of EGL, defined as graft loss within 90 days, in primary transplantation was 8.2% (699/8,511). The main causes were graft rejection (30%), primary nonfunction (25%), and thrombosis or infarction (20%). EGL profoundly impacted short- and long-term patient survival (adjusted hazard ratio; 95% confidence interval: 8.2; 5.1-13.2 and 1.7; 1.3-2.1, respectively). Of the EGL recipients who survived 90 days after transplantation (617/699) only 440 of the 617 were relisted for re-transplantation. Of those relisted, only 298 were ultimately re-transplanted leading to an actual re-transplantation rate of 43%. Noticeably, re-transplantation was associated with a doubled incidence of EGL, but similar long-term graft survival (adjusted hazard ratio 1.1; 0.6-1.8). Thus, EGL after kidney transplantation is a medical catastrophe with high mortality rates, low relisting rates, and increased risk of recurrent EGL following re-transplantation. This implies that detrimental outcomes also involve convergence of risk factors in recipients with EGL. The 8.2% incidence of EGL minimally impacted population mortality, indicating this incidence is acceptable

Tumor Ulceration Does Not Fully Explain Sex Disparities in Melanoma Survival among Adolescents and Young Adults

Hypertension in kidney transplant recipients (KTRs) is a risk factor for cardiovascular mortality and graft loss. Data on the prevalence of hypertension and uncontrolled hypertension (uHT) in paediatric and young adult KTRs are scarce. Also, it is unknown whether 'transition' (the transfer from paediatric to adult care) influences control of hypertension. We assessed the prevalence of hypertension and uHT among Dutch paediatric and young adult KTRs and analysed the effects of transition. Additionally, we made an inventory of variations in treatment policies in Dutch transplant centres. Cross-sectional and longitudinal national data from living KTRs a parts per thousand currency sign30 years of age (a parts per thousand yen1-year post-transplant, eGFR > 20 mL/min) were extracted from the 'RICH Q' database, which comprises information about all Dutch KTRs <19 years of age, and the Netherlands Organ Transplant Registry database for adult KTRs (a parts per thousand yen18-30 years of age). We used both upper-limit blood pressure (BP) thresholds for treatment according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. uHT was defined as a BP above the threshold. A questionnaire on treatment policies was sent to paediatric and adult nephrologists at eight Dutch transplant centres. Hypertension and uHT were more prevalent in young adult KTRs (86.4 and 75.8%) than in paediatric KTRs (62.7 and 38.3%) according to the KDIGO definition. Time after transplantation was comparable between these groups. Longitudinal analysis showed no evidence of effect of transition on systolic BP or prevalence of uHT. Policies vary considerably between and within centres on the definition of hypertension, BP measurement and antihypertensive treatment. Average BP in KTRs increases continuously with age between 6 and 30 years. Young adult KTRs have significantly more uHT than paediatric KTRs according to KDIGO guidelines. Transition does not influence the prevalence of uHT

ABO-incompatible kidney transplantation in perspective of deceased donor transplantation and induction strategies:a propensity-matched analysis

BACKGROUND: Kidney transplant candidates are blood group incompatible with roughly one out of three potential living donors. We compared outcomes after ABO-incompatible (ABOi) kidney transplantation with matched ABO-compatible (ABOc) living and deceased donor transplantation and analyzed different induction regimens. METHODS: We performed a retrospective study with propensity matching and compared patient and death-censored graft survival after ABOi versus ABOc living donor and deceased donor kidney transplantation in a nationwide registry from 2006 till 2019. RESULTS: 296 ABOi were compared to 1184 center and propensity matched ABOc living donor and 1184 deceased donor recipients (matching: recipient age, sex, blood group and PRA). Patient survival was better compared to deceased donor (hazard ratio (HR) for death of HR 0.69 [0.49-0.96], and not-significantly different from ABOc living donor recipients (HR 1.28 [0.90-1.81]). Rate of graft failure was higher compared to ABOc living donor transplantation (HR 2.63 [1.72-4.01]). Rejection occurred in 47% of 140 rituximab versus 22% of 50 rituximab/basiliximab, and 4% of 92 alemtuzumab treated recipients (p <0.001). CONCLUSIONS: ABOi kidney transplantation is superior to deceased donor transplantation. Rejection rate and graft failure are higher compared to matched ABOc living donor transplantation, underscoring the need for further studies into risk stratification and induction therapy