Impact of Low-Dose Fluconazole on Tacrolimus Dosing in Renal Transplant.

BACKGROUND: The interaction between azole antifungal therapy and immunosuppressant tacrolimus (TAC) is a barrier to use. OBJECTIVE: This study quantified the drug interaction between low-dose fluconazole (LDF) and TAC to determine the appropriate TAC dose adjustment when used concurrently in renal transplant recipients. METHODS: We conducted a single-center retrospective chart review of renal transplant patients >18 years who received LDF or nystatin (NYS), and TAC. The primary outcome was the difference in tacrolimus total daily dose (TAC TDD) for LDF versus NYS groups. Secondary outcomes included days with supratherapeutic, therapeutic and subtherapeutic tacrolimus levels, time to therapeutic level, incidence of adverse drug reactions and graft rejection. RESULTS: We evaluated 94 patients and included 81. Low-dose fluconazole received a greater TAC TDD prior to post-operative day (POD) 10 (10.5 ± 4.7 mg vs. 7.1 ± 4.5 mg, p < 0.001), but a decreased TAC TDD POD 10 - 30 (8.6 ± 2.2 mg vs. 9.8 ± 0.8 mg, p < 0.001) and following LDF discontinuation (6.9 ± 0.1 mg vs. 9.0 ± 0.4 mg, p < 0.001). Low-dose fluconazole had more patient-days with supratherapeutic (17.9 ± 7.0 vs. 13.9 ± 8.5; p = 0.02) but fewer with subtherapeutic (6.7 ± 5.7 vs. 12.9 ± 7.2; p < 0.01) TAC levels. There was no difference in patient-days with therapeutic TAC levels (15.9 ± 5.8 vs. 14.4 ± 6.6, p = 0.28), meanwhile LDF required less patient-days to therapeutic TAC level (7.1 ± 2.7 vs. 11.5 ± 7.7; p < 0.01). There was no difference in adverse drug reactions between groups and no incidence of graft rejection. CONCLUSION: A 20% reduction in TAC TDD is warranted in renal transplant patients when used concomitantly with LDF to achieve therapeutic levels.

Evaluating the Impact and Rationale of Race-Specific Estimations of Kidney Function: Estimations from U.S. NHANES, 2015-2018.

BACKGROUND: Standard equations for estimating glomerular filtration rate (eGFR) employ race multipliers, systematically inflating eGFR for Black patients. Such inflation is clinically significant because eGFR thresholds of 60, 30, and 20 ml/min/1.73m2 guide kidney disease management. Racialized adjustment of eGFR in Black Americans may thereby affect their clinical care. In this study, we analyze and extrapolate national data to assess potential impacts of the eGFR race adjustment on qualification for kidney disease diagnosis, nephrologist referral, and transplantation listing. METHODS: Using population-representative cross-sectional data from the United States National Health and Nutrition Examination Survey (NHANES) from 2015-2018, eGFR values for Black Americans were calculated using the Modification of Diet in Renal Disease (MDRD) equation with and without the 1.21 race-specific coefficient using cohort data on age, sex, race, and serum creatinine. FINDINGS: Without the MDRD eGFR race adjustment, 3.3 million (10.4%) more Black Americans would reach a diagnostic threshold for Stage 3 Chronic Kidney Disease, 300,000 (0.7%) more would qualify for beneficial nephrologist referral, and 31,000 (0.1%) more would become eligible for transplant evaluation and waitlist inclusion. INTERPRETATION: These findings suggest eGFR race coefficients may contribute to racial differences in the management of kidney. We provide recommendations for addressing this issue at institutional and individual levels. FUNDING: No external funding was received for this study.

Identifying a Kidney Transplant Recipient COVID Phenotype to Aid Test Utilization in the Setting of Limited Testing Availability-Does One Exist?

The high morbidity and mortality of COVID-19 in immunocompetent patients raises significant concern for immunosuppressed kidney transplant recipients (KTRs). This level of concern, both on the part of the KTRs and transplant professionals, is heightened by a lack of prior knowledge on how Severe Acute Respiratory Syndrome 2 virus (SARS-CoV-2) may manifest differently in immunosuppressed patients. Characterizing how KTRs may present differently than the general population would allow for more targeted and timely evaluation and treatment of KTRs with COVID-19 infection. METHODS: Without prior knowledge of how this virus would affect our transplant center's delivery of care to KTRs who are SARS-CoV-2 positive or patients under investigation, and in the setting of limited testing availability, we initiated a quality assurance and improvement project (QAPI) to track KTRs followed at our transplant center through the SARS-CoV-2 testing process. RESULTS: Of the 53 symptomatic patients, 20 (38%) tested positive for SARS-CoV-2 either on presentation to the emergency department or referral to a designated outpatient testing center. In addition, 16 (80%) of the 20 patients who tested positive required inpatient treatment. Intriguingly, patients with a history of polyoma BK viremia (BKV) had a higher incidence of testing positive for SARS-CoV-2 compared to patients without a history of BKV (80% and 28%, respectively; P = .002). The Positive Predictive Value and Likelihood ratio was 80% and 6.6 for this association, respectively. Among our KTRs tested, those receiving belatacept had a lower likelihood of testing positive for SARS-CoV-2. This finding approached, but did not achieve, statistical significance (P = .06).

The Role of the General Nephrologist in Evaluating Patients for Kidney Transplantation: Core Curriculum 2020.

Transplantation is the preferred modality of replacement therapy for most patients with kidney failure. In the United States, more than 3,000 new patients are registered each month on the kidney transplant waiting list for this life-saving therapy. A potential kidney transplant recipient's evaluation typically begins with a referral by the general nephrologist to a transplantation center. In this installment in the Core Curriculum in Nephrology, we endeavor to achieve a shared understanding of the patient factors that contribute to optimal patient and allograft outcomes following kidney transplantation. In addition, we provide a primer on the routine listing, evaluation, testing, and candidate selection process in an effort to demystify the current criteria commonly used by transplantation centers. Issues common to a majority of candidates, including cardiovascular health, frailty as a measure of biological age, history of prior malignancy, and high body mass index are reviewed in detail. With this knowledge, we hope to facilitate improved communication between general and transplantation nephrologists.

Graft-Versus-Host Disease After Pancreatic Transplantation.

Graft-versus-host disease (GVHD) is a common complication of hematopoietic stem cell transplantation but can rarely occur after solid organ transplants. Small bowel and liver transplants are typically implicated, but solid organ transplant-associated GVHD has also been associated with other organs. We present a 40-year-old diabetic woman who underwent renal followed by pancreatic transplantation over a span of 21 months and ultimately developed acute classic GVHD. The diagnosis proved to be challenging in the context of confounding infections and inconclusive bone marrow and skin biopsy findings. She had multiorgan failure at the time of endoscopic confirmation and died after having minimal response to aggressive immunosuppression.

Delayed Graft Function Phenotypes and 12-Month Kidney Transplant Outcomes.

BACKGROUND: Ischemia-reperfusion injury (IRI) leading to delayed graft function (DGF), defined by the United Network for Organ Sharing as dialysis in the first week (UNOS-DGF), associates with poor kidney transplant outcomes. Controversies remain, however, about dialysis initiation thresholds and the utility for other criteria to denote less severe IRI, or slow graft function (SGF). METHODS: Multicenter, prospective study of deceased-donor kidney recipients to compare UNOS-DGF to a definition that combines impaired creatinine reduction in the first 48 hours or greater than 1 dialysis session for predicting 12-month estimated glomerular filtration rate (eGFR). We also assessed 10 creatinine and urine output-based SGF definitions relative to 12-month eGFR. RESULTS: In 560 recipients, 215 (38%) had UNOS-DGF, 330 (59%) met the combined definition, 14 (3%) died, and 23 (4%) had death-censored graft failure by 12 months. Both DGF definitions were associated with lower adjusted 12-month eGFR (95% confidence interval)-by 7.3 (3.6-10.9) and 7.4 (3.8-11.0) mL/min per 1.73 m, respectively. Adjusted relative risks for 12-month eGFR less than 30 mL/min per 1.73 m were 1.9 (1.2-3.1) and 2.1 (1.1-3.7), with unadjusted areas under the curve of 0.618 and 0.627, respectively. For SGF definitions, postoperative day (POD) 7 creatinine had the strongest association with 12-month eGFR, and POD5 creatinine and creatinine reduction between POD1 and POD2 demonstrated modest separations in 12-month eGFR. CONCLUSIONS: Although UNOS-DGF does not adequately predict 12-month function on its own, our findings do not support changing the definition. Postoperative day 7 creatinine is correlated with 12-month eGFR, but large translational studies are needed to understand the biological link between IRI severity at transplant and longer-term outcomes.

New Organ Allocation System for Combined Liver-Kidney Transplants and the Availability of Kidneys for Transplant to Patients with Stage 4-5 CKD.

A new proposal has been created for establishing medical criteria for organ allocation in recipients receiving simultaneous liver-kidney transplants. In this article, we describe the new policy, elaborate on the points of greatest controversy, and offer a perspective on the policy going forward. Although we applaud the fact that simultaneous liver-kidney transplant activity will now be monitored and appreciate the creation of medical criteria for allocation in simultaneous liver-kidney transplants, we argue that some of the criteria proposed, especially those for allocating a kidney to a liver recipient with AKI, are too liberal. We call on the nephrology community to follow the consequences of this new policy and push for a re-examination of the longstanding policy of allocating kidneys to multiorgan transplant recipients before all other candidates. The charge to protect our system of equitable organ allocation is very challenging, but it is a challenge that we must embrace.

Duration of prophylaxis against fungal infection in kidney transplant recipients.

OBJECTIVE: To compare the efficacy of 2 strategies that use nystatin to prevent thrush and Candida esophagitis in kidney transplant recipients. METHODS: A retrospective chart review was conducted of adult kidney transplant recipients at our center, where the protocol for prophylaxis against fungal infection was changed in March 2013. Before the protocol change, kidney transplant recipients received nystatin for 1 month (before group) and after the change they received nystatin for the duration of admission (after group). The primary outcome measure was the incidence of thrush and Candida esophagitis within 3 months after transplant. Analyses were conducted on all kidney transplant recipients (intention to treat) and on only those kidney transplant recipients who received at least 1 dose of nystatin (modified intention to treat). Additional data collected included the duration of nystatin and immunosuppression regimens. The Student t test and Fisher exact test were used to calculate P values for continuous and categorical data. RESULTS: A total of 84 kidney transplant recipients, 42 in each cohort, were included in the analysis. The groups did not differ significantly at baseline. Nystatin was administered for a mean of 29 days in the before group and 5.74 days in the after group. Overall, 3 kidney transplant recipients (4%), all from the after group, experienced an episode of thrush and no patients experienced Candida esophagitis. Two recipients who experienced thrush did not receive any nystatin. CONCLUSIONS: Limiting the administration of nystatin to the duration of admission after transplant may be sufficient for prophylaxis of fungal infections in kidney transplant recipients.

Oncologic issues and kidney transplantation: a review of frequency, mortality, and screening.

Kidney transplant recipients are at increased risk for development of malignancy compared with the general population, and malignancies occur at an earlier age. This increased risk, as expressed by the standard incidence ratio (SIR), varies widely, but it is highest in malignancies triggered by oncogenic viruses. For other cancers, this increased risk is the direct consequence of immunosuppressants promoting tumor growth and lowering immune system tumor surveillance. In this review, we briefly discuss the common malignancies with increased risk after kidney transplantation, explore the pros and cons associated with screening, and summarize current prevention and treatment recommendations.

A one-day centralized work-up for kidney transplant recipient candidates: a quality improvement report.

BACKGROUND: Waiting time for a kidney transplant is calculated from the date the patient is placed on the UNOS (United Network for Organ Sharing) waitlist to the date the patient undergoes transplant. Time from transplant evaluation to listing represents unaccounted waiting time, potentially resulting in longer dialysis exposure for some patients with prolonged evaluation times. There are established disparities demonstrating that groups of patients take longer to be placed on the waitlist and thus have less access to kidney transplant. STUDY DESIGN: Quality improvement report. SETTING & PARTICIPANTS: 905 patients from a university-based hospital were evaluated for kidney transplant candidacy, and analysis was performed from July 1, 2004, to January 31, 2010. QUALITY IMPROVEMENT PLAN: A 1-day centralized work-up was implemented on July 1, 2007, whereby the transplant center coordinated the necessary tests needed to fulfill minimal listing criteria. OUTCOME: Time from evaluation to UNOS listing was compared between the 2 cohorts. Multivariable Cox proportional hazards models were created to assess the relative hazards of waitlist placement comparing 1-day versus conventional work-up and were adjusted for age, sex, race, and education. RESULTS: Of 905 patients analyzed, 378 underwent conventional evaluation and 527 underwent a 1-day center-coordinated evaluation. Median time to listing in the 1-day center-coordinated evaluation compared with conventional was significantly less (46 vs 226 days, P < 0.001). On multivariable analysis controlling for age, sex, and education level, the 1-day in-center group was 3 times more likely to place patients on the wait list (adjusted HR, 3.08; 95% CI, 2.64-3.59). Listing time was significantly decreased across race, sex, education, and ethnicity. LIMITATIONS: Single center, retrospective. Variables that may influence transplant practitioners, such as comorbid conditions or functional status, were not assessed. CONCLUSIONS: A 1-day center-coordinated pretransplant work-up model significantly decreased time to listing for kidney transplant.

Kidney transplantation and HIV: does recipient privacy outweigh the donor's right to information?

BACKGROUND AND OBJECTIVES: There exists an inherent conflict between a kidney donor's right to know key aspects of a recipient's medical history and specific disease, such as HIV, where federal and state statues protect this information. The authors of the live organ donor consensus group expressly stated the principal of a donor's right to recipient information. This information includes the risks and benefits of not only the donation procedure, but also the risks, benefits, and alternative treatment options of the recipient. In this paper, a case will be presented highlighting this conflict and the ethical and legal reasoning used to resolve it. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A 22-year-old woman came forward as a directed kidney donor for an HIV-positive individual. The donor and recipient were medically appropriate for kidney donation and transplantation. During the donor advocacy panel review, there was disagreement regarding whether or not the potential donor had the right to know about the HIV status of the potential recipient. RESULTS: In living kidney transplantation to HIV-positive individuals, the recipient's right to privacy of information outweighs the donor's right to know. CONCLUSIONS: Although protecting the recipient's right to privacy is paramount, the donor is still entitled to consider factors a priori that could alter their decision to donate. This can be accomplished by informing the donor that they are not entitled to protected health information of the recipient and that their decision to donate should be based on knowing the recipient is medically appropriate for kidney transplantation.