Hybrid and SARS-CoV-2-vaccine immunity in kidney transplant recipients.

BACKGROUND: Kidney transplant recipients (KTR) are at high risk for severe COVID-19 and have demonstrated poor response to vaccination, making it unclear whether successive vaccinations offer immunity and protection. METHODS: We conducted a serologically guided interventional study where KTR patients that failed to seroconvert were revaccinated and also monitored seroconversion of KTR following the Norwegian vaccination program. We analysed IgG anti-RBD Spike responses from dose 2 (n = 432) up to after the 6th (n = 37) mRNA vaccine dose. The frequency and phenotype of Spike-specific T and B cell responses were assessed in the interventional cohort after 3-4 vaccine doses (n = 30). Additionally, we evaluated the Specific T and B cell response to breakthrough infection (n = 32), measured inflammatory cytokines and broadly cross-neutralizing antibodies, and defined the incidence of COVID-19-related hospitalizations and deaths. The Norwegian KTR cohort has a male dominance (2323 males, 1297 females), PBMC were collected from 114 male and 78 female donors. FINDINGS: After vaccine dose 3, most KTR developed Spike-specific T cell responses but had significantly reduced Spike-binding B cells and few memory cells. The B cell response included a cross-reactive subset that could bind Omicron VOC, which expanded after breakthrough infection (BTI) and gave rise to a memory IgG+ B cell response. After BTI, KTR had increased Spike-specific T cells, emergent non-Spike T and B cell responses, and a systemic inflammatory signature. Late seroconversion occurred after doses 5-6, but 38% (14/37) of KTR had no detectable immunity even after multiple vaccine doses. INTERPRETATION: Boosting vaccination can induce Spike-specific immunity that may expand in breakthrough infections highlighting the benefit of vaccination to protect this vulnerable population. FUNDING: CEPI and internal funds.

Optimizing medication adherence with home-monitoring - A feasibility study using capillary microsampling and mHealth in solid organ-transplanted adolescents.

BACKGROUND: Reliable methods to detect and reduce medication nonadherence in solid organ-transplanted (SOT) adolescents are warranted. We aimed to evaluate the feasibility of combining a medication-manager application (TusenTac®-app) with home-sampling of tacrolimus (Tac) in young SOT recipients. METHODS: Kidney and combined SOT recipients between 14 and 25 years were included. During an 8-week intervention period, the participants were instructed to use the transplant-specific, age-adapted TusenTac®-app daily and to perform weekly at-home Tac trough finger-prick microsampling. Microsample Tac concentrations were controlled against timed venous samples twice. Medication implementation and persistence adherence were measured with BAASIS© questionnaires, TusenTac®-registrations, Tac trough concentration coefficient of variation (CV%) and self-reporting by interview. For comparison, venous Tac trough CV% were obtained from the year before and after the short-term intervention. RESULTS: Twenty-two recipients were included, two withdrawals, leaving 20; median age 17.9 (14.5-24.8) years, 12 females (60%). The participants registered their dosage intake 88% (1502/1703) of the expected times, and 90% (106/118) of the microsamples were obtained correctly. At inclusion, 11 recipients (55%) were nonadherent assessed with BAASIS© questionnaire, four of these (36%) turned adherent during the intervention period. At the end, 70% reported improved timing-adherence at the interview. There was no significant change in TacCV% from the year before to the year after the short-term intervention. Home-sampling was reliable and measured Tac concentrations accurately. CONCLUSIONS: Home-monitoring, combining Tac finger-prick microsampling and a medication-manager app, is feasible in adolescent SOT recipients with 70% perceived improvement in medication timing-adherence. There were no significant long-term changes in TacCV% confirming the need for continuous use and individualized interventions.

Clinical performance of volumetric finger-prick sampling for the monitoring of tacrolimus, creatinine and haemoglobin in kidney transplant recipients.

AIMS: Finger-prick sampling has emerged as an attractive tool for therapeutic drug monitoring and associated diagnostics. We aimed to validate the clinical performance of using two volumetric devices (Capitainer® qDBS and Mitra®) for monitoring tacrolimus, creatinine and haemoglobin in kidney transplant (KTx) recipients. Secondarily, we evaluated potential differences between finger-prick sampling performed by healthcare professionals vs. self-sampling, and differences between the two devices. METHODS: We compared finger-prick and venous sampling in three settings: microsampling performed by healthcare personnel, self-sampling under supervision, unsupervised self-sampling. The finger-prick samples were analysed with adapted methods and results compared to routine method analysis of the venous blood samples. RESULTS: Twenty-five KTx recipients completed the main study and 12 KTx recipients completed a post hoc validation study. For tacrolimus measurements and predicted area under the curve, the proportions within ±20% difference were 79%-96% for Capitainer and 77%-95% for Mitra. For creatinine and haemoglobin, the proportions within ±15% were 92%-100% and 93%-100% for Capitainer and 79%-96% and 67%-92% for Mitra, respectively. Comparing sampling situations, the success rate was consistent for Capitainer (92%-96%), whereas Mitra showed 72%-88% and 52%-72% success rates with samples collected by healthcare personnel and the patients themselves. CONCLUSIONS: Capitainer and Mitra are technically feasible for measuring tacrolimus, creatinine and haemoglobin. In the context of self-sampling, Capitainer maintained consistent sampling success and analytical quality. Implementing volumetric finger-prick self-sampling for the monitoring of tacrolimus, creatinine and haemoglobin may simplify and improve the follow-up of KTx recipients.

Humoral vaccine response and breakthrough infections in kidney transplant recipients during the COVID-19 pandemic: a nationwide cohort study.

Background: Kidney transplant recipients (KTRs) experienced reduced SARS-CoV-2 vaccine response and were at increased risk of severe COVID-19. It is unknown if level of vaccine induced anti-receptor binding domain IgG (anti-RBD IgG) correlates with protection from and survival following COVID-19. We aimed to evaluate the effect of vaccine response on risk of breakthrough infections (BTI) and COVID-19 death in KTRs. Methods: We performed a nationwide study, examining the competing risk of SARS-CoV-2 infection, COVID-19 related/unrelated death, and vaccine efficacy as assessed by level of anti-RBD IgG response 4-10 weeks after each vaccination. The study included all KTR in Norway alive and with a functioning graft on February 20th, 2020, and events after November 11th, 2022 were right-censored. A pre-pandemic reference-cohort from January 1st 2019 to January 1st 2020 was included to evaluate excess mortality. The study was conducted at Oslo University Hospital, Rikshospitalet, Norway. Findings: The study included 3607 KTRs (59 [48-70] years) with a functioning graft at February 20th, 2020, who received (median [IQR]) 4 [3-4] vaccines (range 2-6, 99% mRNA). Anti-RBD IgG was measured in 12 701 serum samples provided by 3213 KTRs. Vaccine response was assessed 41 [31-57] days after vaccination. A total of 1090 KTRs were infected with SARS-CoV-2, 1005 (92%) were BTI, and vaccine response did not protect against BTI. The hazard ratio for COVID-19 related death 40 days post-infection was 1.71 (95% CI: 1.14, 2.56) comparing vaccine response levels (≥5 vs. ≥5000 BAU/mL). No excess non-COVID-19 mortality was registered in KTRs surviving SARS-CoV-2 infection compared to a 2019 pre-pandemic reference. Interpretation: Our findings suggested that SARS-CoV-2 mRNA vaccine response did not predict protection against infection, but prevention of fatal disease progression in KTRs and greater vaccine response further reduced the risk of COVID-19 death. No excess non-COVID-19 mortality was seen during the pandemic. Funding: CEPI and internal funds.

Cytomegalovirus High-risk Kidney Transplant Recipients Show No Difference in Long-term Outcomes Following Preemptive Versus Prophylactic Management.

BACKGROUND: Following kidney transplantation (KT), cytomegalovirus (CMV) infection remains an important challenge. Both prophylactic and preemptive antiviral protocols are used for CMV high-risk kidney recipients (donor seropositive/recipient seronegative; D+/R-). We performed a nationwide comparison of the 2 strategies in de novo D+/R- KT recipients accessing long-term outcomes. METHODS: A nationwide retrospective study was conducted from 2007 to 2018, with follow-up until February 1, 2022. All adult D+/R- and R+ KT recipients were included. During the first 4 y, D+/R- recipients were managed preemptively, changing to 6 mo of valganciclovir prophylaxis from 2011. To adjust for the 2 time eras, de novo intermediate-risk (R+) recipients, who received preemptive CMV therapy throughout the study period, served as longitudinal controls for possible confounders. RESULTS: A total of 2198 KT recipients (D+/R-, n = 428; R+, n = 1770) were included with a median follow-up of 9.4 (range, 3.1-15.1) y. As expected, a greater proportion experienced a CMV infection in the preemptive era compared with the prophylactic era and with a shorter time from KT to CMV infection ( P < 0.001). However, there were no differences in long-term outcomes such as patient death (47/146 [32%] versus 57/282 [20%]; P = 0.3), graft loss (64/146 [44%] versus 71/282 [25%]; P = 0.5), or death censored graft loss (26/146 [18%] versus 26/282 [9%]; P = 0.9) in the preemptive versus prophylactic era. Long-term outcomes in R+ recipients showed no signs of sequential era-related bias. CONCLUSIONS: There were no significant differences in relevant long-term outcomes between preemptive and prophylactic CMV-preventive strategies in D+/R- kidney transplant recipients.

Impact of Fasting Status and Circadian Variation on the Pharmacokinetics of Mycophenolate Mofetil and the Glucuronide Metabolite in Renal Transplant Recipients.

Mycophenolate mofetil (MMF) is an immunosuppressive prodrug often used to prevent allograft rejection following solid organ transplantation. After oral administration, MMF is rapidly hydrolyzed to the active metabolite mycophenolate acid (MPA), which is inactivated by glucuronosyltransferase to the mycophenolic acid glucuronide metabolite (MPAG). The aim was 2-fold: to investigate the impact of circadian variation and fasting versus nonfasting status on MPA and MPAG pharmacokinetics in renal transplant recipients (RTRs). Methods: RTRs with stable graft function treated with tacrolimus, prednisolone, and MMF (750 mg BID) were included in this open, nonrandomized study. Two 12-h pharmacokinetic investigations were conducted in succession following morning and evening doses, both in a fasting and in a real-life nonfasting condition. Results: A total of 30 (22 men) RTRs performed one 24-h investigation, and 16 repeated the investigation within 1 mo. In a real-life nonfasting state, MPA area under the curve (AUC)0-12 and C 0 failed to meet the bioequivalence criteria. Following the evening dose, mean MPA AUC12-24 was 16% lower (P < 0.001) compared with AUC0-12, and a shorter T max was observed (P = 0.09). Under fasting conditions, MPA AUC12-24 was 13% lower than AUC0-12, and the absorption rate was slower after the evening dose (P < 0.05). MPAG displayed circadian variation only under real-life conditions with lower AUC0-12 following the evening dose (P < 0.001). Conclusions: Both MPA and MPAG showed circadian variation with somewhat lower systemic exposures following the evening dose with limited clinical relevance in the dosing of MMF in RTRs. Fasting status affects MMF absorption rate differently, but with similar results in systemic exposure.

Kidney-transplanted Adolescents-Nonadherence and Graft Outcomes During the Transition Phase: A Nationwide Analysis, 2000-2020.

BACKGROUND: The transition from pediatric to young adult care is a vulnerable period for the renal transplant patient. We aimed to identify medication nonadherence (noninitiation, nonimplementation, and nonpersistence) and graft loss rates among adolescents and young adults and elucidate the influence of the transition phase on transplant outcomes. METHODS: A retrospective nationwide cohort analysis of all renal transplantations in Norway from 2000 to 2020 was performed. Data were retrieved from the Norwegian Renal Registry, and adherence data from hospital charts. Patients transplanted aged <50 y, with functioning graft at 6 mo, were included. Recipients transplanted aged <26 y were compared with recipients transplanted aged 26-50 y. Graft loss, acute rejection, and development of de novo donor-specific antibodies were assessed in relation to the transition phase, defined as 14-26 y. RESULTS: Data from 1830 kidney recipients were included: 371 (20%) transplanted <26 y (64% male, 68% living donor) versus 1459 transplanted 26-50 y (63% male, 44% living donor). There were 298 graft losses, 78 (21%) in the <26-y group versus 220 (15%) in the 26- to 50-y group. During the transition phase, 36 grafts were lost, 29 (81%) after transfer to the adult service. Medication nonadherence was the reason for 58% (21 of 36) of the losses during the transition phase, versus 12% (27 of 220) in the 26- to 50-y group ( P < 0.001). The 5-y graft survival rate was 89% (95% confidence interval, 85%-92%) and 94% (92%-95%), respectively ( P = 0.01). CONCLUSIONS: Nonadherence was verified as the main cause of kidney graft loss in the transition phase.

Titers of antibodies against ancestral SARS-CoV-2 correlate with levels of neutralizing antibodies to multiple variants.

Diagnostic assays currently used to monitor the efficacy of COVID-19 vaccines measure levels of antibodies to the receptor-binding domain of ancestral SARS-CoV-2 (RBDwt). However, the predictive value for protection against new variants of concern (VOCs) has not been firmly established. Here, we used bead-based arrays and flow cytometry to measure binding of antibodies to spike proteins and receptor-binding domains (RBDs) from VOCs in 12,000 serum samples. Effects of sera on RBD-ACE2 interactions were measured as a proxy for neutralizing antibodies. The samples were obtained from healthy individuals or patients on immunosuppressive therapy who had received two to four doses of COVID-19 vaccines and from COVID-19 convalescents. The results show that anti-RBDwt titers correlate with the levels of binding- and neutralizing antibodies against the Alpha, Beta, Gamma, Delta, Epsilon and Omicron variants. The benefit of multiplexed analysis lies in the ability to measure a wide range of anti-RBD titers using a single dilution of serum for each assay. The reactivity patterns also yield an internal reference for neutralizing activity and binding antibody units per milliliter (BAU/ml). Results obtained with sera from vaccinated healthy individuals and patients confirmed and extended results from previous studies on time-dependent waning of antibody levels and effects of immunosuppressive agents. We conclude that anti-RBDwt titers correlate with levels of neutralizing antibodies against VOCs and propose that our method may be implemented to enhance the precision and throughput of immunomonitoring.

Regression of a venous malformation during angiotensin-converting enzyme inhibitor treatment for hypertension.

Recent studies have reported that components of the renin-angiotensin system (RAS) are expressed in venous malformations by embryonic stem cell-like subpopulations. It has been hypothesized that these cells are sustained by the RAS and, therefore, could be a novel therapeutic target, using medications such as angiotensin-converting enzyme inhibitors. A young man with a symptomatic intramuscular venous malformation of the upper limb, and hypertension was treated with an angiotensin-converting enzyme inhibitor. After 8 months of treatment, we registered a considerable volume reduction of the venous malformation and a reduction in pain. Our observation warrants further research on the link between the RAS and venous malformations.

Poor Physical Function Trajectory Predicts Impaired Patient Survival in Older Recipients of Deceased Donor Kidneys: A Prospective Cohort Study.

Optimized health-related quality of life (HRQOL) at the time of kidney transplantation (KT) is associated with improved survival. In older KT recipients, we aimed to prospectively evaluate if HRQOL evolution during the first posttransplant year was associated with long-term patient survival. Methods: Recipients older than 65 y at KT who received an organ from a deceased brain-dead donor and survived >12 mo posttransplant were eligible. HRQOL was assessed pre-KT, at 10 wk, 6 mo, and 12 mo post-KT, using the Kidney Disease Quality of Life Short Form version 1.3 survey. A mixed-effect model was used to explore HRQOL evolution during the first posttransplant year in long-term survivors compared with nonsurvivors. Distinct HRQOL clusters were identified using a group-based trajectory modeling and their association with patient survival was investigated with Cox proportional hazard regression models. Results: We included 192 elderly recipients of deceased brain-dead donor kidneys who were transplanted from 2013 to 2020. Eleven died during the first year leaving 181 for evaluation (male, 125; mean age at KT, 72 y [65-84 y]). During a median observation time post-KT of 4.9 y (11.1-8.5 y), 57 recipients died. In survivors, all the generic and kidney-specific HRQOL domains substantially improved during the first year, whereas in nonsurvivors HRQOL deteriorated. Three longitudinal HRQOL trajectories indicating poor, fair, and good HRQOL evolution were identified. Poor physical function trajectory was significantly associated with higher mortality risk independent of covariates, as compared with good physical trajectory (hazard ratio, 2.38; 95% confidence interval, 1.15-5.01). Conclusions: In elderly KT recipients, detection of declining posttransplant physical function may imply impaired survival. Systematic HRQOL monitoring following KT provides added value when evaluating mortality and may guide therapeutic decisions.

Prolonged-Release Once-Daily Formulation of Tacrolimus Versus Standard-of-Care Tacrolimus in de novo Kidney Transplant Patients Across Europe.

Background: Tacrolimus is the calcineurin inhibitor of choice for preventing acute rejection episodes in kidney transplant patients. However, tacrolimus has a narrow therapeutic range that requires regular monitoring of blood concentrations to minimize toxicity. A new once-daily tacrolimus formulation, LCP-tacrolimus (LCPT), has been developed, which uses MeltDose™ drug-delivery technology to control drug release and enhance overall bioavailability. Our study compared dosing of LCPT with current standard-of-care tacrolimus [immediate-release tacrolimus (IR-Tac) or prolonged-release tacrolimus (PR-Tac)] during the 6 months following de novo kidney transplantation. Comparisons of graft function, clinical outcomes, safety, and tolerability for LCPT versus IR-Tac/PR-Tac were also performed. Methods: Standard immunological risk patients with end-stage renal disease who had received a de novo kidney transplant were randomized (1:1) to LCPT (N = 200) or IR-Tac/PR-Tac (N = 201). Results: Least squares (LS) mean tacrolimus total daily dose from Week 3 to Month 6 was significantly lower for LCPT than for IR-Tac/PR-Tac. Although LS mean tacrolimus trough levels were significantly higher for LCPT than IR-Tac/PR-Tac, tacrolimus trough levels remained within the standard reference range for most patients. There were no differences between the groups in treatment failure measures or safety profile. Conclusion: LCPT can achieve similar clinical outcomes to other tacrolimus formulations, with a lower daily dose. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT02432833.

Case Report: Let Us Not Forget the Treatment That Some Patients Have Received-The Brief 50-Year History of a Kidney Transplant Survivor.

Background: There has been a considerable improvement in post-transplant care since the early 1960s. Some patients we meet in the clinic have personally experienced this progress and have histories to tell that one must not forget. This is the brief history of a long-time "transplant survivor." Case Presentation: In 1970, a young woman developed acute oedema, proteinuria, hypertension and oliguria during pregnancy. Labor was induced, but neither the child nor the kidney function could be saved. Our patient started dialysis, and 4 years later received a kidney transplant donated by her father (then 55 years of age). Maintenance immunosuppression consisted of prednisolone and azathioprine until 2011, when azathioprine was switched to everolimus due to skin cancer. Before this, our patient was highly satisfied with prednisolone/azathioprine, despite discussions regarding newer immunosuppressive drugs, and always reminded the treating physician that one should "never change a winning team." Retrospectively, the avoidance of calcineurin inhibitors might have been beneficial for this patient who still has preserved an excellent renal function with s-creatinine levels around 100 µmol/L and just had sparse fibrosis detected in a recently performed transplant biopsy. The transplanted kidney is now 101 years old and is still working 24/7. Conclusions: Our patient received a kidney transplant for 46 years ago and still has a remarkably stable transplant function with s-creatinine levels around 100 µmol/L. This case report illustrates the potential endurance of the kidneys and is a reminder to keep taking individualized treatment decisions even though new treatment alternatives promise superiority.

Case Report: Pure Red Cell Aplasia Caused by Refractory Parvovirus B19 Infection After Pancreas Transplantation Alone.

A multidisciplinary team of doctors is in charge or is involved in the follow-up of patients who undergo solid organ transplantation (SOT). Immunosuppressive drugs are required after SOT, some potential unwanted side effects can be difficult to detect, and physicians must be aware of potential pitfalls. We report a case of a recipient with brittle type 1 diabetes who experienced severe and refractory anemia after pancreas transplantation alone (PTA). Despite a broad diagnostic approach for anemia, the diagnosis was delayed. The patient had normocytic normochromic anemia with severe reticulocytopenia and marked reduction or absence of erythroid precursors in the bone marrow, compatible with pure red cell aplasia (PRCA). Analyses of serological parvovirus B19 anti-IgM and anti-IgG antibodies, including PCR, were initially inconclusive/negative. The diagnosis of parvovirus B19 infection was confirmed after bone marrow biopsy with immunohistochemical staining for parvovirus B19. A retrospective analysis revealed an early post-transplant primary parvovirus B19 infection. The patient was successfully treated with intravenous immunoglobulin (IVIg) therapy. There is a risk of diagnostic delay for the less common types of anemia following SOT. Parvovirus B19 infection-associated PRCA is curable in SOT recipients and should be actively considered in patients with persistent anemia and low reticulocytes.

A Comorbidity Index and Pretransplant Physical Status Predict Survival in Older Kidney Transplant Recipients: A National Prospective Study.

Kidney transplantation (KT) is considered the best treatment for end-stage kidney disease (ESKD). In the increasing elderly ESKD population, KT should be reserved for carefully selected candidates who are expected to experience favorable outcomes. We aimed to prospectively evaluate pretransplant recipient factors that may predict patient survival and can eventually guide therapeutic decisions in elderly with ESKD. Methods: Recipient factors were evaluated in KT candidates aged ≥65 y. Comorbidity was assessed at waitlisting according to the Liu comorbidity index (LCI). Health-related quality of life outcomes were measured using the Kidney Disease Quality of Life Short Form, version 1.3. The Cox proportional hazard regression was used to evaluate predictors of patient survival. Results: We included 192 recipients, with a mean age of 72.1 (4.1) y, who were transplanted with kidneys from deceased brain-dead donors. During a median observation period of 4.6 (3.2-6.3) y, 66 recipients died. Elevated LCI consistently predicted poor patient survival. In recipients with LCI ≥4, dialysis >2 y comprised a 2.5-fold increase in mortality risk compared with recipients on dialysis ≤2 y. Self-reported pretransplant physical function was also proven to be a significant positive predictor of survival. Conclusion: The implementation of LCI and a physical function score during the evaluation of older kidney transplant candidates may improve the selection and thereby optimize posttransplant outcomes.

Use of Statins in Kidney Transplant Recipients in Norway.

Kidney transplant recipients (KTRs) experience increased risk of cardiovascular disease. Guidelines recommend HMG-CoA reductase inhibitor (statin) therapy when tolerated. We aimed to study changes in the prescription of statins and patients' adherence to treatment over time. A population-based observational study utilizing linked data from the Norwegian Renal Registry (national coverage of 99.9%) and the Norwegian Prescription Database was performed. Data from a total of 2250 first KTRs were included (mean age-54 years, 69% men). Dispensed prescriptions of statins and immunosuppressants for the period 2004-2016 for all first KTRs engrafted in the period 2005-2015 were analyzed. Seventy-two percent received statins the first year after kidney transplantation and the proportion increased with age. The proportion receiving a statin varied according to the time frame of transplantation (77% in 2005-2010 vs. 66% in 2012-2015). Among new users of statins, 82% of the patients were adherent both the second and third year after kidney transplantation, while the corresponding figure for those already receiving statins before transplantation was 97%. Statin continuation rates in KTRs were high. In conclusion, our findings show a slightly lower overall proportion of patients receiving statins after kidney transplants than the national target level of 80%. The proportion of statin users increased with the age of the KTRs but showed a decreasing trend as time progressed.