COVID-19 and renal allograft rejection: insight from controlled and non-controlled studies.

AIM: Kidney transplant recipients (KTRs), due to their immunosuppressed status, are potentially more susceptible to both the severe effects of COVID-19 and complications in their transplanted organ. The aim of this study is to investigate whether COVID-19 infection increases the risk of rejection in kidney transplant recipients (KTRs). METHODS: This study involved a detailed literature review, conducted using PubMed, with the search being completed by September 7th, 2023. The search strategy incorporated a combination of relevant keywords: 'COVID', 'Renal', 'Kidney', 'Transplant', and 'Rejection'. The results from controlled and uncontrolled studies were separately collated and analyzed. RESULTS: A total of 11 studies were identified, encompassing 1,179 patients. Among these, two controlled studies reported the incidence of rejection in KTRs infected with COVID-19. Pooling data from these studies revealed no significant statistical correlation between COVID-19 infection and biopsy-proven rejection (p = 0.26). In addition, nine non-controlled studies were found, with rejection incidences ranging from 0% to 66.7%. The majority of these studies (eight out of nine) had small sample sizes, ranging from 3 to 75 KTRs, while the largest included 372 KTRs. The combined rejection rate across these studies was calculated to be 11.8%. CONCLUSION: In conclusion, the limited number of published controlled studies revealed no statistically significant association between COVID-19 infection and biopsy-proven rejection among KTRs. However, the broader analysis of non-controlled studies showed a variable rejection incidence with a pooled rejection rate of 11.8%. There is insufficient high-quality data to explore the association of COVID-19 infection and rejection.

BK viral infection: A review of management and treatment.

BK viral infection remains to be a challenging post-transplant infection, which can result in kidney dysfunction. The mainstay approach to BK infection is reduction of immunosuppression. Alterations in immunosuppressive regimen with minimization of calcineurin inhibitors, use of mechanistic target of rapamycin inhibitors, and leflunomide have been attempted with variable outcomes. Over the past few years, investigators have explored potential therapeutic options for BK infection. Fluoroquinolone prophylaxis and treatment was found to have no benefit in kidney transplant recipients. The utility of cidofovir is limited by its nephrotoxicity. Intravenous immunoglobulin is becoming a popular option for treatment and prophylaxis for BK infection, as it increases the neutralizing antibody titers against the most common BK virus serotypes. Virus-specific T cell therapy is an emerging treatment option for BK viremia. In this review, we will explore management and therapeutic options for BK infection and recent evidence available in literature.

A Critical Analysis of the Specific Pharmacist Interventions and Risk Assessments During the 12-Month TRANSAFE Rx Randomized Controlled Trial.

BACKGROUND: Medication safety issues have detrimental implications on long-term outcomes in the high-risk kidney transplant (KTX) population. Medication errors, adverse drug events, and medication nonadherence are important and modifiable mechanisms of graft loss. OBJECTIVE: To describe the frequency and types of interventions made during a pharmacist-led, mobile health-based intervention in KTX recipients and the impact on patient risk levels. METHODS: This was a secondary analysis of data collected during a 12-month, parallel-arm, 1:1 randomized clinical controlled trial including 136 KTX recipients. Participants were randomized to receive either usual care or supplemental, pharmacist-driven medication therapy monitoring and management using a smartphone-enabled app integrated with telemonitoring of blood pressure and glucose (when applicable) and risk-based televisits. The primary outcome was pharmacist intervention type. Secondary outcomes included frequency of interventions and changes in risk levels. RESULTS: A total of 68 patients were randomized to the intervention and included in this analysis. The mean age at baseline was 50.2 years; 51.5% of participants were male, and 58.8% were black. Primary pharmacist intervention types were medication reconciliation and patient education, followed by medication changes. Medication reconciliation remained high throughout the study period, whereas education and medication changes trended downward. From baseline to month 12, we observed an approximately 15% decrease in high-risk patients and a corresponding 15% increase in medium- or low-risk patients. CONCLUSION AND RELEVANCE: A pharmacist-led mHealth intervention may enhance opportunities for pharmacological and nonpharmacological interventions and mitigate risk levels in KTX recipients.

Non-Adherence to Appointments is a Strong Predictor of Medication Non-Adherence and Outcomes in Kidney Transplant Recipients.

BACKGROUND: Non-adherence is an important aspect of transplantation that affect outcomes. This study aims to investigate the impact of non-adherence to laboratory and clinic appointments on medication non-adherence and outcomes in kidney transplant (KT) recipients. METHODS: We analyzed KT recipients between 2005-14 with a detailed review of the medical records for non-adherence to laboratory and clinic appointments, as well as medication regimens. Baseline characteristics and clinical outcomes were compared between adherent and non-adherent groups. RESULTS: A total of 1413 KT recipients were included: 754 who were adherent and 659 who were non-adherent. Non-adherent recipients tend to be younger, African American, and have private insurance. Adherent patients tend to have a history of DM, heart disease, and receive an ECD kidney. Non-adherence to appointments was a strong predictor of medication non-adherence (OR 3.1), acute rejection (OR 1.4), and subsequent rejection episodes (OR 3.3 and 8.1 respectively for ≥ 1 and ≥ 2 rejection episodes). Subset analysis of patients who had early non-adherence within 1-year post-transplant showed predominance of younger, African American patients. The same patients had higher prevalence of medication non-compliance, overall and ≥ 1-year post-transplant, and mean number of readmissions. Kaplan-Meier analysis showed a trend towards lower graft survival in this group. CONCLUSIONS: Early non-adherence to laboratory and clinic appointments is a strong predictor of late medication non-adherence, acute rejection, and graft loss. Targeting patients that demonstrate early non-adherence to appointments with focused interventions may help improve kidney transplant outcomes in this high risk group.

Pharmacist-Led Mobile Health Intervention and Transplant Medication Safety: A Randomized Controlled Clinical Trial.

BACKGROUND AND OBJECTIVES: Medication safety events are predominant contributors to suboptimal graft outcomes in kidney transplant recipients. The goal of this study was to examine the efficacy of improving medication safety through a pharmacist-led, mobile health-based intervention. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a 12-month, single-center, prospective, parallel, two-arm, single-blind, randomized controlled trial. Adult kidney recipients 6-36 months post-transplant were eligible. Participants randomized to intervention received supplemental clinical pharmacist-led medication therapy monitoring and management via a mobile health-based application, integrated with risk-guided televisits and home-based BP and glucose monitoring. The application provided an accurate medication regimen, timely reminders, and side effect surveys. Both the control and intervention arms received usual care, including serial laboratory monitoring and regular clinic visits. The coprimary outcomes were to assess the incidence and severity of medication errors and adverse events. RESULTS: In total, 136 kidney transplant recipients were included, 68 in each arm. The mean age was 51 years, 57% were male, and 64% were Black individuals. Participants receiving the intervention experienced a significant reduction in medication errors (61% reduction in the risk rate; incident risk ratio, 0.39; 95% confidence interval, 0.28 to 0.55; P<0.001) and a significantly lower incidence risk of Grade 3 or higher adverse events (incident risk ratio, 0.55, 95% confidence interval, 0.30 to 0.99; P=0.05). For the secondary outcome of hospitalizations, the intervention arm demonstrated significantly lower rates of hospitalizations (incident risk ratio, 0.46; 95% confidence interval, 0.27 to 0.77; P=0.005). CONCLUSIONS: We demonstrated a significant reduction in medication errors, adverse events, and hospitalizations using a pharmacist-led, mobile health-based intervention.

Immunosuppression in kidney transplant recipients with COVID-19 infection - where do we stand and where are we heading?

The appropriate immunosuppressive regimen in kidney transplant recipients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2/COVID-19) infection remains unclear. The impact of direct virus injury complicated by dysregulated hyperimmune response with overwhelming release of various cytokines in COVID-19 infected subjects contributes to the complexity of management. The largest concern of the practicing clinicians at current time is how to tailor maintenance immune-modulating therapy during active viral infection and the efficacy of the soon-to-be upcoming immunization for COVID-19. This targeted review aims to cover most of the current evidence on the effect of key maintenance immunosuppressive agents in COVID-19 infection and proposes a line of management to specific scenarios on this very rapidly evolving subject.

Phenotype of immunosuppression reduction after kidney transplantation.

BACKGROUND: Immunosuppressive regimens are delivered without direct measure of the net state of immunosuppression. Besides therapeutic drug monitoring, adjustments in immunosuppressive medications are largely event-driven. METHODS: We studied the clinical phenotype of immunosuppression reduction (ISR) among kidney transplant recipients from 2005 to 2012. Patients were grouped into: no ISR, ISR for infection, or ISR for intolerance. Outcome measures were rejection, rejection-free survival, and IFTA-free survival. RESULTS: 1114 adult kidney transplant recipients were included: 57% had no ISR, 16% had ISR for infection, and 27% had ISR for intolerance. ISR for infection was mainly on MMF, while ISR for intolerance was mainly on FK. ISR was associated with higher rates of acute rejection. The Kaplan-Meier analysis showed increased prevalence of rejection among patients with ISR due to infection (P = .003) or intolerance (P = .05). The risk of interstitial fibrosis and tubular atrophy was increased in patients with ISR due to infection (P = .001) or intolerance (P = .018). CONCLUSION: Immunosuppression reduction is associated with increased prevalence of rejection. The clinical phenotype of ISR is dominated by IFTA remote from the onset of ISR. Solely focusing on acute rejection may underestimate effects of ISR on long-term graft function and survival.

Cytomegalovirus renal infection: Rare manifestation of a common post-transplant viral infection-A case series.

Cytomegalovirus is the most common viral infection in organ transplant recipients that usually affects the brain, lungs, liver, and gastrointestinal tract. Renal involvement of Cytomegalovirus (CMV) is otherwise rare. We present six cases of biopsy-proven CMV renal infection. Five out of the six patients had detectable CMV viremia. Kidney biopsy revealed glomerulopathy in four cases and tubulointerstitial involvement in two cases. All patients exhibited decline in renal function at the onset of infection. Four out of six patients had improvement of renal function following treatment of CMV disease. To date, this is the largest case series of pure biopsy-proven CMV renal infection described in a single center.

Tacrolimus confers lower acute rejection rates and better renal allograft survival compared to cyclosporine.

AIM: To compare the impact of tacrolimus (FK) and cyclosporine (CYA) on acute rejection and graft survival and to assess the predominant causes of graft loss between patients receiving these two calcineurin inhibitors (CNIs). METHODS: Retrospective review of 1835 patients who received a kidney transplant (KTX) between 1999-2012. Patients were grouped based on initial CNI utilized: 1195 in FK group, 640 in CYA group. Data on baseline characteristics, clinical outcomes, and causes of graft loss in both groups were analyzed. RESULTS: Cumulative acute rejection rates were 14% in the FK vs 24% in the CYA group. Despite more marginal donor characteristics in the FK group, these patients had better graft survival rates compared to the CYA group. Three and five year graft survival rates were 88% and 84% respectively in the FK group compared to 79% and 70% respectively in the CYA group (P < 0.001). After multivariate analysis, which controlled for confounders, FK use was a strong predictor for lower acute rejection rates [odds ratio (OR) 0.60, 95%CI: 0.45-0.79] and better renal allograft survival (OR 0.740, 95%CI: 0.58-0.94). Death with a functioning graft was the most common cause of graft loss in both groups. Common causes of death included cardiovascular disease, infections, and malignancies. Chronic allograft nephropathy was also found to be an important cause of graft loss, being more prevalent in the CYA group. CONCLUSION: The use of FK-based maintenance immunosuppression therapy is associated with a significantly lower rate of acute rejection and better graft survival compared to CYA-based regimen. Individualizing immunosuppression through risk-stratified CNI choice may lead to improved outcomes across all spectra of KTX patients.

Update on the clinical utility of once-daily tacrolimus in the management of transplantation.

Adherence to immunosuppression and minimizing variability in drug exposure are important considerations in preventing rejection and maximizing overall transplant outcomes. The availability of once-daily tacrolimus may confer potential benefit by simplifying immunosuppressive regimens, thereby improving medication adherence among transplant recipients. Pharmacokinetic studies in healthy normal volunteers and stable transplant recipients suggest that once-daily tacrolimus is bioequivalent to twice-daily tacrolimus. Efficacy studies suggest that once-daily tacrolimus is noninferior to twice-daily tacrolimus with a concentration-dependent rejection risk. The incidence of biopsy-proven acute rejection, graft survival, and patient survival are more or less comparable between the two tacrolimus formulations. Once-daily tacrolimus has also been reported to have favorable effects on blood pressure, lipid profile, and glucose tolerance. Once-daily tacrolimus may be a viable option to consider for de novo immunosuppression or for conversion from conventional tacrolimus.