Novel indications for referral and care for simultaneous liver kidney transplant recipients.

PURPOSE OF REVIEW: Kidney dysfunction is challenging in liver transplant candidates to determine whether it is reversible or not. This review focuses on the pertinent data on how to best approach liver transplant candidates with kidney dysfunction in the current era after implementing the simultaneous liver kidney (SLK) allocation policy and safety net. RECENT FINDINGS: The implementation of the SLK policy inverted the steady rise in SLK transplants and improved the utilization of high-quality kidneys. Access to kidney transplantation following liver transplant alone (LTA) increased with favorable outcomes. Estimating GFR in liver transplant candidates remains challenging, and innovative methods are needed. SLK provided superior patient and graft survival compared to LTA only for patients with advanced CKD and dialysis at least 3 months. SLK can provide immunological protection against kidney rejection in highly sensitized candidates. Post-SLK transplant care is complex, with an increased risk of complications and hospitalization. SUMMARY: The SLK policy improved kidney access and utilization. Transplant centers are encouraged, under the safety net, to reserve SLK for liver transplant candidates with advanced CKD or dialysis at least 3 months while allowing lower thresholds for highly sensitized patients. Herein, we propose a practical approach to liver transplant candidates with kidney dysfunction.

A multicenter prospective study to define the natural history of BK viral infections in kidney transplantation.

BACKGROUND: BK polyomavirus (BKV) can cause permanent loss of allograft function due to BKV-associated nephropathy (BKVN) in kidney transplant recipients. Besides immunosuppression reduction, there are no consistently effective interventions for BKV infection. Study purpose was to define natural history of BKV infection, identify risk factors for BKV reactivation and BKVN in kidney transplant recipients, and inform the design/conduct of future clinical trials of BKV-targeted therapeutics. METHODS: We conducted a multicenter prospective observational study of incident kidney transplant recipients at six U.S. transplant centers. Participants were monitored every 4 weeks for BKV reactivation and followed for up to 24 months post-transplant. We used regression models (logistic, survival, mixed models) to study relationships between BK viremia/BKVN, clinical characteristics, and allograft function. RESULTS: We enrolled 335 participants. Fifty-eight (17%) developed BK viremia, 6 (2%) developed biopsy-proven BKVN, and 29 (9%) developed suspected/presumed BKVN (defined as BKV viral load > 10,000 copies/mL without biopsy). Male donor sex was associated with lower odds for BK viremia, whereas recipient Black race was associated with two-fold increased odds for BK viremia. Recipient female sex was associated with more rapid clearance of BK viremia. Persistent BK viremia/BKVN was associated with poorer allograft function by 24 months post-transplant. CONCLUSIONS: We identified multiple donor and recipient demographic factors associated with risk for BKV infection and poorer allograft function by 24 months post-transplant. This may help design future clinical trials of therapies to prevent or mitigate the deleterious impact of BKV reactivation on kidney transplant outcomes.

Understanding Delayed Graft Function to Improve Organ Utilization and Patient Outcomes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Delayed graft function (DGF) is a common complication after kidney transplant. Despite extensive literature on the topic, the extant definition of DGF has not been conducive to advancing the scientific understanding of the influences and mechanisms contributing to its onset, duration, resolution, or long-term prognostic implications. In 2022, the National Kidney Foundation sponsored a multidisciplinary scientific workshop to comprehensively review the current state of knowledge about the diagnosis, therapy, and management of DGF and conducted a survey of relevant stakeholders on topics of clinical and regulatory interest. In this Special Report, we propose and defend a novel taxonomy for the clinical and research definitions of DGF, address key regulatory and clinical practice issues surrounding DGF, review the current state of therapies to reduce and/or attenuate DGF, offer considerations for clinical practice related to the outpatient management of DGF, and outline a prospective research and policy agenda.

Survey of Salary and Job Satisfaction of Transplant Nephrologists in the United States.

BACKGROUND AND OBJECTIVES: There are no standardized benchmarks to measure productivity and compensation of transplant nephrologists in the United States, and consequently, criteria set for general nephrologists are often used. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A web-based survey was sent to 809 nephrologists who were members of the American Society of Transplantation to gather data on measures of productivity, compensation, and job satisfaction. Factors associated with higher total compensation and job satisfaction were examined. RESULTS: Of 365 respondents, 260 were actively practicing in the United States and provided data on compensation. Clinical productivity was assessed variably, and although 194 (76%) had their work relative value units (wRVUs) reported to them, only 107 (44%) had an established RVU target. Two hundred thirty-four respondents (90%) had fixed base compensation, and 172 (66%) received a bonus on the basis of clinical workload (68%), academic productivity (31%), service (32%), and/or teaching responsibility (31%). Only 127 respondents (49%) filled out time studies, and 92 (35%) received some compensation for nonbillable transplant activity. Mean total compensation (base salary and bonus) was $274,460±$91,509. The unadjusted mean total compensation was higher with older age and was higher for men; Hispanic and White respondents; adult care transplant nephrologists; residents of the western United States; US medical school graduates; nonuniversity hospital employees; and those with an administrative title, higher academic rank, and a higher number of years in practice. Two hundred and nine respondents (80%) thought their compensation was unfair, and 180 (70%) lacked a clear understanding of how they were compensated. One hundred forty-five respondents (55%) reported being satisfied or highly satisfied with their job. Job satisfaction was greater among those with higher amounts of compensation and US medical school graduates. CONCLUSIONS: We report significant heterogeneity in the assessment of productivity and compensation for transplant nephrologists and the association of compensation with job satisfaction.

CKD in Recipients of Nonkidney Solid Organ Transplants: A Review.

Chronic kidney disease (CKD) after solid organ transplant is a common clinical presentation, affecting 10% to 20% of liver, heart, and lung transplant recipients and accounting for approximately 5% of the kidney transplant waiting list. The causes of CKD are different for different types of transplants and are not all, or even predominantly, due to calcineurin inhibitor toxicity, with significant heterogeneity particularly in liver transplant recipients. Many solid organ transplant recipients with advanced CKD benefit from kidney transplantation but have a higher rate of death while waitlisted and higher mortality after transplant than the general kidney failure population. Recent organ allocation policies and proposals have attempted to address the appropriate identification and prioritization of candidates in need of a kidney transplant, either simultaneous with or after nonkidney transplant. Future research should focus on predictive factors for individuals identified as being at high risk for progression to kidney failure and death and on strategies to preserve kidney function and minimize the CKD burden in this unique patient population.

Risk of ESKD in Older Live Kidney Donors with Hypertension.

BACKGROUND AND OBJECTIVES: Hypertension in older kidney donor candidates is viewed as safe. However, hypertension guidelines have evolved and long-term outcomes have not been explored. We sought to quantify the 15-year risk of ESKD and mortality in older donors (≥50 years old) with versus those without hypertension. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A United States cohort of 24,533 older donors from 1999 to 2016, including 2265 with predonation hypertension, were linked to Centers for Medicare and Medicaid Services data and the Social Security Death Master File to ascertain ESKD development and mortality. The exposure of interest was predonation hypertension. From 2004 to 2016, hypertension was defined as documented predonation use of antihypertensive therapy, regardless of systolic BP or diastolic BP; from 1999 to 2003, when there was no documentation of antihypertensive therapy, hypertension was defined as predonation systolic BP ≥140 or diastolic BP ≥90 mm Hg. RESULTS: Older donors were 82% white, 6% black, 7% Hispanic, and 3% Asian. The median follow-up was 7.1 years (interquartile range, 3.4-11.1; maximum, 18). There were 24 ESKD and 252 death events during the study period. The 15-year risk of ESKD was 0.8% (95% confidence interval [95% CI], 0.4 to 1.6) for donors with hypertension (mean systolic BP, 138 mm Hg) versus 0.2% (95% CI, 0.1 to 0.4) for donors without hypertension (mean systolic BP, 123 mm Hg; adjusted hazard ratio, 3.04; 95% CI, 1.28 to 7.22; P=0.01). When predonation antihypertensive therapy was available, the risk of ESKD was 6.21-fold higher (95% CI, 1.20 to 32.17; P=0.03) for donors using antihypertensive therapy (mean systolic BP, 132 mm Hg) versus those not using antihypertensive therapy (mean systolic BP, 124 mm Hg). There was no significant association between donor hypertension and 15-year mortality (hazard ratio, 1.18; 95% CI, 0.84 to 1.66; P=0.34). CONCLUSIONS: Compared with older donors without hypertension, older donors with hypertension had higher risk of ESKD, but not mortality, for 15 years postdonation. However, the absolute risk of ESKD was small.

The changing landscape of live kidney donation in the United States from 2005 to 2017.

The number of live kidney donors has declined since 2005. This decline parallels the evolving knowledge of risk for biologically related, black, and younger donors. To responsibly promote donation, we sought to identify declining low-risk donor subgroups that might serve as targets for future interventions. We analyzed a national registry of 77 427 donors and quantified the change in number of donors per 5-year increment from 2005 to 2017 using Poisson regression stratified by donor-recipient relationship and race/ethnicity. Among related donors aged <35, 35 to 49, and ≥50 years, white donors declined by 21%, 29%, and 3%; black donors declined by 30%, 31%, and 12%; Hispanic donors aged <35 and 35 to 49 years declined by 18% and 15%, and those aged ≥50 increased by 10%. Conversely, among unrelated donors aged <35, 35 to 49, and ≥50 years, white donors increased by 12%, 4%, and 24%; black donors aged <35 and 35 to 49 years did not change but those aged ≥50 years increased by 34%; Hispanic donors increased by 16%, 21%, and 46%. Unlike unrelated donors, related donors were less likely to donate in recent years across race/ethnicity. Although this decline might be understandable for related younger donors, it is less understandable for lower-risk related older donors (≥50 years). Biologically related older individuals are potential targets for interventions to promote donation.

Academic achievement and employment in young adults with end-stage kidney disease.

BACKGROUND: Young adults with end-stage kidney disease (ESKD) are at a pivotal stage of life: progressing through education, seeking employment and developing relationships. We set out to explore how ESKD impacts education and employment attainment in a matched UK and USA patient cohort. Moreover, we aimed to determine if there were significant differences in reported perceptions of impact. DESIGN: A mixed methods design combining previously validated quantitative questionnaire surveys and qualitative semi-structured interviews. PARTICIPANTS: Young people with ESKD aged 18-30 years (N = 27), attending single-centre follow-up in Oxford, UK were matched with 27 comparable young people aged 19-30 years, under follow-up in Denver, USA. Twelve of these patients from Denver were selected for interview. MEASUREMENTS: Self-report questionnaires surveyed patient demographics, educational and employment achievement and experiences. Questionnaire categorical data for matched pairs were analysed using Bowker's test of symmetry. Sequential flow analyses of interview content delineated perception patterns through thematic coding. RESULTS: Sixty percent of non-student Oxford participants were employed compared with 41% in Denver (p = 0.023). Forty-four percent of Oxford patients compared with 52% in Denver, reported illness had made it difficult to gain employment (p = 0.88). In Oxford, 32% completed high school as their highest educational achievement, versus 68% in Denver (p = 0.22). Qualitative themes included fatigue, self-esteem loss, social isolation and low mood. The impact of dialysis and poor understanding from educators/employers resulted in lost work time, and/or limited educational attainment. CONCLUSION: ESKD profoundly impacts on education and employment of young adults in the United States and United Kingdom, generating substantial barriers. Poor understanding appears prevalent amongst educators and employers. Healthcare providers must recognise these problems and invest resources towards tailored support in order to improve associated psychosocial and clinical outcomes.

Defining kidney allograft benefit from successful pancreas transplant: separating fact from fiction.

PURPOSE OF REVIEW: To define the natural history of kidney allograft loss related to recurrent diabetes following transplant, and to understand the potential benefit of pancreas transplantation upon kidney allograft survival. RECENT FINDINGS: A postulated benefit of simultaneous pancreas kidney transplant is that, unlike kidney transplant alone, euglycemia from the added pancreas allograft may confer a nephroprotective benefit and prevent recurrent diabetic nephropathy in the renal allograft. Recent large database analyses and long-term histological assessments have been published that assist in quantifying the problem of recurrent diabetic nephropathy and answering the question of the potential benefits of euglycemia. Further data may be extrapolated from larger single-center series that follow the prognosis of early posttransplant diabetes mellitus as another barometer of risk from diabetic nephropathy and graft loss. SUMMARY: Recurrent diabetic nephropathy following kidney transplant is a relatively rare, late occurrence and its clinical significance is significantly diminished by the competing risks of death and chronic alloimmune injury. Although there are hints of a protective effect upon kidney graft survival with pancreas transplant, these improvements are small and may take decades to appreciate. Clinical decision-making regarding pancreas transplant solely based upon nephroprotective effects of the kidney allograft should be avoided.

De Novo Donor-Specific Antibody Formation in Tacrolimus-Based, Mycophenolate Versus Mammalian Target of Rapamycin Immunosuppressive Regimens.

OBJECTIVES: De novo donor-specific antibody formation posttransplant is associated with decreased graft survival. It is not known whether mammalian target of rapamycin inhibitors may be advantageous or detrimental compared with mycophenolate in the prevention of de novo donor-specific antibody formation. MATERIALS AND METHODS: We compared 66 kidney and kidney-pancreas transplant recipients who received tacrolimus, mammalian target of rapamycin inhibitor, and prednisone (group 1; 36 of whom received everolimus and 30 of whom received sirolimus) versus 132 patients who received tacrolimus, mycophenolate, and prednisone (group 2) matched for age, sex, race, and type/timing of transplant from 2007 to 2012. RESULTS: Rates of de novo donor-specific antibody formation were comparable between groups at 1, 6, and 12 months (16.7%, 25.8%, and 28.8% for group 1 vs 9.8%, 15.2%, and 22.0% for group 2). There were no significant differences in class (I, II, or mixed), strength (mean fluorescence intensity) of de novo donor-specific antibody, glomerular filtration rate, proteinuria levels, or acute rejection between the groups. In those with de novo donor-specific antibody by 6 months, acute rejection was more common versus those without de novo donor-specific antibody formation (24.3% vs 5.6% at 6 mo; P = .002), with rates of 27.0% versus 6.8% at 1 year (P = .001) and 40.7% versus 11.3% at 2 years (P < .001). An associated reduction in glomerular filtration rate also occurred. CONCLUSIONS: Mammalian target of rapamycin inhibitors were neither protective nor permissive for de novo donor-specific antibody formation versus mycophenolate when used with clinically relevant tacrolimus dosing regimens.

Live donor kidney - PAK versus SPK: how to decide?

PURPOSE OF REVIEW: Patients with type 1 diabetes and end stage renal disease face a complex choice when considering the relative risks and benefits of kidney transplant alone with or without subsequent pancreas after kidney transplant (PAK) or simultaneous kidney pancreas transplant (SPK). RECENT FINDINGS: SPK is considered the optimal treatment regarding long-term patient survival, but when also faced with the option of living donor kidney transplant with the potential for PAK later, the ideal option is less clear. SUMMARY: This review summarizes the current literature regarding SPK, living donor kidney transplant alone, and PAK transplant outcomes and examines the relative risks of pre- and posttransplant variables that impact patient and graft survival to help inform this complex treatment decision.

Current status of pancreas transplantation.

PURPOSE OF REVIEW: To review recent pancreas transplantation outcomes and indications and describe studies of the impact of pancreas transplant upon patient survival and secondary complications. RECENT FINDINGS: A number of surgical advances have occurred that have improved the early success rate of transplant, and modern immunosuppressive strategies have improved the rate of longer term allograft survival. Pancreas transplant is associated with a mortality benefit when performed in patients with end-stage renal disease in combination with kidney transplant, but questions regarding the impact upon secondary diabetic complications together with the risk assumed by the surgical procedure and the attendant immunosuppression in the nonuremic patient may have tempered enthusiasm for broader expansion of transplantation. Thus, despite these advances, the number of pancreas transplants performed annually is falling consistently. Efforts to define optimal donor and recipient characteristics and understand the pathophysiological impact of pancreas transplant are active areas of research that may lead to greater expansion of pancreas transplant in the future. SUMMARY: The review summarizes these advances, including the utilization patterns of pancreas transplant and current concepts of patient selection and graft monitoring, and places into perspective the current and future role of pancreas transplantation as a therapeutic option in diabetes.

Multiorgan transplantation.

Kidney transplantation has proven to be the gold standard therapy for severe chronic kidney disease (CKD) due to multiple etiologies in individuals deemed eligible from a surgical standpoint. While kidney transplantation is traditionally considered in conditions of native kidney disease such as diabetes and immunological or inherited causes of kidney disease, an increasing indication for kidney transplantation is kidney dysfunction in the setting of other severe organ dysfunction that requires transplant, such as severe liver or heart disease. In these settings, multiorgan transplantation is now commonly performed, with controversy regarding the appropriate utilization of kidneys transplanted both from a physiological perspective (distinguishing those who require a kidney transplant) and also from an ethical perspective (allocation of a scarce resource to a more morbid population). These issues persist in the setting of simultaneous pancreas-kidney transplant (SPK), in which utilization for patients with type 1 diabetes has been historically accepted. Questions of physiological benefit persist, and utilization is waning despite broader allocation policies that encourage SPK, including consideration for patients with type 2 diabetes. The purpose of this review will be to summarize the physiological data regarding multiorgan transplantation and place these into context while reviewing current allocation policy in the United States.

Immunosuppressive Medications.

Immunosuppressive agents are commonly used in the nephrologist's practice in the treatment of autoimmune and immune-mediated diseases and transplantation, and they are investigational in the treatment of AKI and ESRD. Drug development has been rapid over the past decades as mechanisms of the immune response have been better defined both by serendipity (the discovery of agents with immunosuppressive activity that led to greater understanding of the immune response) and through mechanistic study (the study of immune deficiencies and autoimmune diseases and the critical pathways or mutations that contribute to disease). Toxicities of early immunosuppressive agents, such as corticosteroids, azathioprine, and cyclophosphamide, stimulated intense investigation for agents with more specificity and less harmful effects. Because the mechanisms of the immune response were better delineated over the past 30 years, this specialty is now bestowed with a multitude of therapeutic options that have reduced rejection rates and improved graft survival in kidney transplantation, provided alternatives to cytotoxic therapy in immune-mediated diseases, and opened new opportunities for intervention in diseases both common (AKI) and rare (atypical hemolytic syndrome). Rather than summarizing clinical indications and clinical trials for all currently available immunosuppressive medications, the purpose of this review is to place these agents into mechanistic context together with a brief discussion of unique features of development and use that are of interest to the nephrologist.

Simultaneous Liver-Kidney Transplant: Too Many or Just Enough?

For liver transplant candidates with advanced kidney dysfunction, simultaneous liver-kidney (SLK) transplantation is an important option. As the incidence of severe kidney dysfunction has increased over the past decade, so have the numbers of SLK transplants. This has engendered controversy within the transplant community because SLK transplants draw deceased donor kidneys from the kidney transplant candidate pool. Because kidney recovery after liver transplant alone (LTA) is difficult to predict, indications for SLK are not precisely defined. Candidates with hepatorenal syndrome can have kidney recovery after as much as 12 weeks on dialysis, whereas those with CKD may have early ESRD after LTA because of perioperative events and calcineurin inhibitor exposure. Although large observational studies generally show slightly improved survival in SLK recipients compared with LTA, inferences from these studies are limited by selection biases. Therefore, a true survival benefit of SLK in candidates without ESRD is still unproved. Although selection practices vary, generally LTA candidates have more kidney dysfunction because of hepatorenal syndrome and acute kidney injury, whereas SLK candidates have less severe liver disease and more CKD or ESRD. The debate over appropriate SLK is primarily one of the optimal kidney utilization vs the best interests of individual liver transplant candidates.