Moving closer to understanding the risks of living kidney donation

Recent studies from the United States and Norway have suggested an unexpected 8‐ to 11‐fold relative risk of ESRD after kidney donation, but a low long‐term absolute risk. Abundant renal epidemiologic data predict that these studies have underestimated long‐term risk. The 1% lifetime post‐donation risk in the US study requires medical screening to predict ESRD in 96 of 100 candidates. This is particularly unlikely in the 30–35% of candidates under age 35, half of whose lifetime ESRD will occur after age 64. Many experts have attributed the increased relative risks in these studies to loss of GFR at donation, which ultimately means that high–normal pre‐donation GFRs will reduce absolute post‐donation risks. The 8‐ to 11‐fold relative risks predict implausible risks of uninephrectomy in the general population, but lower estimates still result in very high risks for black donors. Young vs. older age, low vs. high–normal pre‐donation GFRs, black race, and an increased relative risk of donation all predict highly variable individual risks, not a single “low” or “1%” risk as these studies suggest. A uniform, ethically defensible donor selection protocol would accept older donors with many minor medical abnormalities but protect from donation many currently acceptable younger, black, and/or low GFR candidates.     

‘Normal for Now’ or ‘At Future Risk’: A Double Standard for Selecting Young and Older Living Kidney Donors

Transplant centers medically evaluate potential living kidney donors in part to determine their baseline remaining lifetime risk for end stage renal disease (ESRD). If baseline risk is increased by the presence of a risk factor for ESRD, donation is often refused. However, as only about 13% of ESRD occurs in the general population by age 44, a normal medical evaluation cannot be expected to significantly reduce the 7% lifetime risk for a ‘normal’ 25‐year‐old black donor or the 2–3% risk for a similar white donor. About half of newly diagnosed ESRD in the United States occurs by age 65, and about half of that is from diabetic nephropathy, which takes about 25 years to develop. Therefore, the remaining baseline lifetime risk for ESRD is significantly lower in the normal, nondiabetic 55‐year‐old donor candidate. Some older donors with an isolated medical abnormality such as mild hypertension will be at lower or about the same overall baseline lifetime risk for ESRD as are young ‘normal’ donor candidates. Transplant centers use a ‘normal for now’ standard for accepting young donors, in place of the long‐term risk estimates that must guide selection of all donors.     

Recipient Outcomes Following Transplantation of Allografts From Live Kidney Donors Who Subsequently Developed End‐Stage Renal Disease

Live kidney donors have an increased risk of end‐stage renal disease (ESRD) compared with nondonors; however, it is unknown whether undetected, subclinical kidney disease exists at donation that subsequently contributes to this risk. To indirectly test this hypothesis, the authors followed the donated kidneys, by comparing the outcomes of 257 recipients whose donors subsequently developed ESRD with a matched cohort whose donors remained ESRD free. The compared recipients were matched on donor (age, sex, race/ethnicity, donor–recipient relationship), transplant (HLA mismatch, peak panel‐reactive antibody, previous transplantation, year of transplantation), and recipient (age, sex, race/ethnicity, body mass index, cause of ESRD, and time on dialysis) risk factors. Median recipient follow‐up was 12.5 years (interquartile range 7.4–17.9, maximum 20 years). Recipients of allografts from donors who developed ESRD had increased death‐censored graft loss (74% versus 56% at 20 years; adjusted hazard ratio [aHR] 1.7; 95% confidence interval [CI] 1.5–2.0; p < 0.001) and mortality (61% versus 46% at 20 years; aHR 1.5; 95% CI 1.2–1.8; p < 0.001) compared with matched recipients of allografts from donors who did not develop ESRD. This association was similar among related, spousal, and unrelated nonspousal donors. These findings support a novel view of the mechanisms underlying donor ESRD: that of pre‐donation kidney disease. However, biopsy data may be required to confirm this hypothesis.     

Long‐Term Non–End‐Stage Renal Disease Risks After Living Kidney Donation

Despite generally positive outcomes and high rates of satisfaction, living kidney donors are at risk for both medical and psychosocial problems. In this review, the authors summarize non–end‐stage renal disease (ESRD) risks for donors and describe limitations to the data. We review the evidence of medical risks (e.g. increased cardiovascular disease and mortality, preeclampsia) and psychosocial risks (e.g. mood disturbance, financial burden). We then discuss the evidence of differential risks among subsets and the impact of postdonation events (e.g. development of diabetes). Collectively, available evidence indicates the following. (1) Recognizing the importance of non‐ESRD risks has been overshadowed by analyses of the reported risk of ESRD. This imbalance should be remedied. (2) There is little quantification of the true contribution of donation to medical and psychosocial outcomes. (3) Most studies, to date, have been retrospective, with limited sample sizes and diversity and with less‐than‐ideal controls for comparison of outcomes. (4) Many postdonation events (diabetes and hypertension) can now be reasonably predicted, and their association with adverse outcomes can be quantified. (5) Mechanisms and systems need to be implemented to evaluate and care for donors who develop medical and/or psychosocial problems. (6) Costs to donors are a significant burden, and making donation financially neutral should be a priority.     

Causes and timing of end‐stage renal disease after living kidney donation

End‐stage renal disease (ESRD) is a risk after kidney donation. We sought, in a large cohort of kidney donors, to determine the causes of donor ESRD, the interval from donation to ESRD, the role of the donor/recipient relationship, and the trajectory of the estimated GFR (eGFR) from donation to ESRD. From 1/1/1963 thru 12/31/2015, 4030 individuals underwent living donor nephrectomy at our center, as well as ascertainment of ESRD status. Of these, 39 developed ESRD (mean age ± standard deviation [SD] at ESRD, 62.4 ± 14.1 years; mean interval between donation and ESRD, 27.1 ± 9.8 years). Donors developing ESRD were more likely to be male, as well as smokers, and younger at donation, and to have donated to a first‐degree relative. Of donors with a known cause of ESRD (n = 25), 48% was due to diabetes and/or hypertension; only 2 from a disease that would have affected 1 kidney (cancer). Of those 25 with an ascertainable ESRD cause, 4 shared a similar etiology of ESRD with their recipient. Almost universally, thechange of eGFR over time was stable, until new‐onset disease (kidney or systemic). Knowledge of factors contributing to ESRD after living kidney donation can improve donor selection and counseling, as well as long‐term postdonation care.     

Risk of End‐Stage Renal Disease in HIV‐Positive Potential Live Kidney Donors

New federal regulations allow HIV‐positive individuals to be live kidney donors; however, potential candidacy for donation is poorly understood given the increased risk of end‐stage renal disease (ESRD) associated with HIV infection. To better understand this risk, we compared the incidence of ESRD among 41 968 HIV‐positive participants of North America AIDS Cohort Collaboration on Research and Design followed for a median of 5 years with the incidence of ESRD among comparable HIV‐negative participants of National Health and Nutrition Examination III followed for a median of 14 years. We used risk associations from multivariable Cox proportional hazards regression to derive cumulative incidence estimates for selected HIV‐positive scenarios (no history of diabetes, hypertension, AIDS, or hepatitis C virus coinfection) and compared these estimates with those from similarly selected HIV‐negative scenarios. For 40‐year‐old HIV‐positive individuals with health characteristics that were similar to those of age‐matched kidney donors, viral load <400 copies/mL, and CD4⁺ count ≥500 cells/μL, the 9‐year cumulative incidence of ESRD was higher than that of their HIV‐negative peers, yet still low: 2.5 versus 1.1 per 10 000 among white women, 3.0 versus 1.3 per 10 000 among white men, 13.2 versus 3.6 per 10 000 among black women, and 15.8 versus 4.4 per 10 000 among black men. HIV‐positive individuals with no comorbidities and well‐controlled disease may be considered low‐risk kidney donor candidates.     

Lifetime risk of end‐stage kidney disease in living donors for paediatric kidney transplant recipients in Australia and New Zealand – a retrospective study

Living kidney donors (LKD) for paediatric kidney transplant recipients (KTR) have a heightened motivation to donate for emotional reasons and the clear health benefits to the KTR. We hypothesized that the cohort of LKD for paediatric KTR (LKD‐P) includes motivated young parents with a higher lifetime end‐stage kidney disease (ESKD) risk compared to adult KTR (LKD‐A). Data from the Australia and New Zealand Dialysis and Transplant LKD Registry (2004–2015) was analysed to compare baseline characteristics and predonation ESKD risk in LKD‐P (n = 315) versus LKD‐A (n = 3448). LKD‐P were younger (median age 42 vs. 50 years; P < 0.001) and had a marginally higher lifetime ESKD risk (median 0.44% vs. 0.40%; P < 0.01), with a similar proportion of LKD exceeding 1% risk threshold (5.4% vs. 5.6%; P = NS). Compared to grandparents as LKD‐P, parents (median age 41 vs. 59 years; P < 0.001) had a higher lifetime ESKD (0.44% vs. 0.25%; P < 0.001). Although unique benefits to paediatric KTR justify the minor increase in lifetime ESKD risk in young parents, carefully selected grandparents are an alternative LKD‐P option, allowing parents to donate for subsequent transplants.     

GFR ≤25 years postdonation in living kidney donors with (vs. without) a first‐degree relative with ESRD

An increased risk of ESRD has been reported for living kidney donors, and appears to be higher for those donating to a relative. The reasons for this are not clear. One possibility is that ESRD is due to the nephrectomy‐related reduction in GFR, followed by an age‐related decline that may be more rapid in related donors. Between 1/1/1990 and 12/31/2014, we did 2002 living donor nephrectomies. We compared long‐term postdonation eGFR trajectory for donors with (n = 1245) vs. without (n = 757) a first‐degree relative with ESRD. Linear mixed‐effects models were used to model the longitudinal trajectory of eGFR. With all other variables held constant, we noted a steady average increase in eGFR until donors reached age 70: 1.12 (95% CI: 0.92‐1.32) mL/min/1.73m^²/yr between 6 weeks and 5 years postdonation; 0.24 (0.00‐0.49) mL/min/1.73m^²/yr between 5 and 10 years; and 0.07 (?0.10 to +0.25) mL/min/1.73m^²/yr between 10 and 20 years for donors with attained age less than 70. After age 70, eGFR declined. After we adjusted for predonation factors, the difference in eGFR slopes between related and unrelated donors was 0.20 mL/min/1.753 m²/year (0.07‐0.33). Our data suggests that postdonation, kidney donor eGFR increases each year for a number of years and that eGFR trajectory does not explain any increase in ESRD after donation.     

Predicting End‐Stage Renal Disease After Liver Transplant

Few equations have been developed to predict end‐stage renal disease (ESRD) after deceased donor liver transplant. This retrospective observational cohort study analyzed all adult deceased donor liver transplant recipients in the Scientific Registry of Transplant Recipients (SRTR) database, 1995–2010. The prediction equation for ESRD was developed using candidate predictor variables available in SRTR after implementation of the allocation policy based on the model for end‐stage liver disease. ESRD was defined as initiation of maintenance dialysis therapy, kidney transplant or registration on the kidney transplant waiting list. We used Cox proportional hazard models to develop separate equations for assessing risk of ESRD by 6 months posttransplant and between 6 months and 5 years posttransplant. Variables in the 6‐month equation included recipient age, history of diabetes, history of dialysis before liver transplant, history of malignancy, body mass index, serum creatinine and liver donor risk index. Variables in the 6‐month to 5‐year equation included recipient race, history of diabetes, hepatitis C status, serum albumin, serum bilirubin and serum creatinine. The prediction equations have good calibration and discrimination (C statistics 0.74–0.78). We have produced risk prediction equations that can be used to aid in understanding the risk of ESRD after liver transplant.     

The Novel Application of Genomic Profiling Assays to Shorten Inactive Status for Potential Kidney Transplant Recipients With Breast Cancer

The concern about cancer recurrence has traditionally resulted in delaying kidney transplantation for 2–5 years after a cancer diagnosis in patients who are otherwise eligible for transplant. This period of inactive status to observe the tumor biology can result in significant morbidity and decreased quality of life for patients with end‐stage renal disease (ESRD). We reported the novel application of genomic profiling assays in breast cancer to identify low‐risk cancers in two patients with ESRD who were able to have the mandatory inactive status eliminated prior to kidney transplantation.     

Ethnic and Gender Related Differences in the Risk of End‐Stage Renal Disease After Living Kidney Donation

There is limited data pertaining to the risk of End Stage Renal Disease (ESRD) after living kidney donation. The Organ Procurement and Transplantation Network and the Center for Medicare and Medicaid Services databases were used to identify living kidney donors (LKDs) who subsequently developed ESRD and to calculate LKD ESRD rates. We found 126 cases of ESRD among 56 458 LKDs (0.22%) who donated during October 1, 1987–March 31, 2003. The overall LKD ESRD rate was 0.134 per 1000 years at risk, with an average duration of follow‐up of 9.8 years. ESRD rates for LKDs overall and for Black, White, male and female donors compared favorably to the ESRD incidence in the general population. The LKD ESRD rate was nearly five times higher for Blacks than for Whites and two times higher for males than females. However, these ethnic and gender‐related differences were similar to those previously reported for ESRD in the general population. Our findings do not show an increase in the risk of ESRD for LKDs and support the current practice of living kidney donation. Further research is needed to determine if improved donor screening or follow‐up will reduce the risk of postdonation ESRD.     

Left‐Sided Living Kidney Donation Leads to Transiently Reduced Adrenocortical Responsiveness

Living kidney donation is safe and established, but can lead to long‐term complications such as chronic fatigue. Since the adrenal vein is usually transected during left‐sided donor nephrectomy—which is not necessary on the right—we hypothesized that venous congestion might lead to an impairment of adrenal function, offering a possible explanation. In this prospective open label, monocentric cohort study, adrenal function was compared in left‐ and right‐sided living kidney donors. The primary endpoint was plasma cortisol response to low‐dose adrenocorticotropic hormone (ACTH) stimulation. Secondary endpoints included plasma renin and ACTH concentration as well as adrenal volume in response to donor nephrectomy. A total of 30 healthy donors—20 left‐ and 10 right‐sided donations—were included. On postoperative day 1, response to low‐dose ACTH stimulation was intact, but significantly lower after left‐sided donor nephrectomy. After 28 days, adrenal responsiveness to ACTH stimulation did not differ any longer. Magnetic resonance imaging volumetry showed no significant adrenal volume change over 4 weeks, neither after left‐ nor after right‐sided nephrectomy. In conclusion, left‐sided living kidney donation entails a transiently reduced adrenocortical responsiveness, which returns to baseline after 28 days.     

Inferior long‐term allograft and patient outcomes among recipients of offspring living donor kidneys

While offspring‐to‐parent living donor kidney transplantations may represent an ideal donor–recipient combination to optimize long‐term transplantation outcomes, the sex‐specific long‐term success of these transplantations remains unclear. We hypothesize that allograft and recipient survivals in offspring‐to‐parent living donor kidney transplantation differ between men and women due to donor‐specific alloimmunization during pregnancy. We retrospectively analyzed long‐term allograft and patient survival among men and women who received an offspring living donor kidney compared with those who received other haplotype‐matched living donor kidneys. Based on multivariable Cox proportional hazards modeling of Organ Procurement and Transplantation Network data from 2001 to 2015, we found that both men and women who received offspring living donor kidneys had significantly increased mortality compared with recipients who received nonoffspring living donor kidneys. While male recipients of any living donor kidney had greater risk of mortality and allograft failure than female recipients, there was no significant difference in all‐cause allograft failure or mortality in male versus female recipients of offspring living donor kidney transplantations. Our analysis demonstrated no significant interaction between recipient sex and donor offspring status. We conclude that nonoffspring living donors should be considered whenever feasible for both men and women with multiple donor options.     

Integrating APOL1 Gene Variants Into Renal Transplantation: Considerations Arising From the American Society of Transplantation Expert Conference

Thirteen percent of individuals of African ancestry express two variant copies of the gene encoding apolipoprotein 1 (APOL1) that has been associated with an increased risk of end‐stage renal disease (ESRD) in the general population. Limited studies suggest that the survival of transplanted kidneys from donors expressing two APOL1 risk alleles is inferior to that of kidneys from donors with zero or one risk allele. In living kidney donation, two case reports describe donors expressing two APOL1 risk alleles who developed ESRD. Given the potential impact of APOL1 variants on the utility and safety of kidney transplantation and living kidney donation, the American Society of Transplantation convened a meeting with the goals of summarizing the current state of knowledge with respect to transplantation and APOL1, identifying knowledge gaps and studies to address these gaps, and considering approaches to integrating APOL1 into clinical practice. The authors recognize that current data are not sufficient to support traditional evidence‐based guidelines but also recognize that it may require several years to generate the necessary data. Thus, approaches as to how APOL1 might currently be integrated into the clinical decision‐making process were considered. This report summarizes the group's deliberations.     

Population level outcomes and cost‐effectiveness of hepatitis C treatment pre‐ vs postkidney transplantation

Direct‐acting antivirals approved for use in patients with end‐stage renal disease (ESRD) now exist. HCV‐positive (HCV+) ESRD patients have the opportunity to decrease the waiting times for transplantation by accepting HCV‐infected kidneys. The optimal timing for HCV treatment (pre‐ vs posttransplant) among kidney transplant candidates is unknown. Monte Carlo microsimulation of 100 000 candidates was used to examine the cost‐effectiveness of HCV treatment pretransplant vs posttransplant by liver fibrosis stage and waiting time over a lifetime time horizon using 2 regimens approved for ESRD patients. Treatment pretransplant yielded higher quality‐adjusted life years (QALYs) compared with posttransplant treatment in all subgroups except those with Meta‐analysis of Histological Data in Viral Hepatitis stage F0 (pretransplant: 5.7 QALYs vs posttransplant: 5.8 QALYs). However, treatment posttransplant was cost‐saving due to decreased dialysis duration with the use of HCV‐infected kidneys (pretransplant: $735 700 vs posttransplant: $682 400). Using a willingness‐to‐pay threshold of $100 000, treatment pretransplant was not cost‐effective except for those with Meta‐analysis of Histological Data in Viral Hepatitis stage F3 whose fibrosis progression was halted. If HCV+ candidates had access to HCV‐infected donors and were transplanted ≥9 months sooner than HCV‐negative candidates, treatment pretransplant was no longer cost‐effective (incremental cost‐effectiveness ratio [ICER]: $107 100). In conclusion, optimal timing of treatment depends on fibrosis stage and access to HCV+ kidneys but generally favors posttransplant HCV eradication.     

Health outcomes among non‐Caucasian living kidney donors: knowns and unknowns

The growth in living kidney donation has been accompanied by greater racial diversity. Most information on post‐donation health comes from single‐center studies of dominantly Caucasian cohorts. Recent linkage of U.S. donor registration data with death records demonstrated higher mortality risks among African American donors, but importantly, no differences in death compared with demographically matched, healthy controls. Within the donor population, some recent studies have also identified higher likelihoods of post‐donation hypertension, diabetes mellitus and kidney failure in African American and Hispanic donors. Thus, based on concerns for higher risks of long‐term end‐organ damage, it may be reasonable to consider race within the living donor selection process, such as use of more stringent exclusion criteria among non‐Caucasian living donors with baseline elevated blood pressure. Recently identified associations of coding variants in the apolipoprotein L1 (APOL1) gene with nondiabetic renal failure in African Americans raise promise of APOL1 genotyping as a novel tool for risk stratifying African American potential donors, but more data are needed to understand implications for post‐donation outcomes. To tailor counseling and informed consent, focused attention to long‐term medical outcomes among non‐Caucasian living donors is needed, and should include assembly of healthy non‐donor controls for assessment of attributable risks of donation.     

Screening of Living Kidney Donors for Genetic Diseases Using a Comprehensive Genetic Testing Strategy

Related living kidney donors (LKDs) are at higher risk of end‐stage renal disease (ESRD) compared with unrelated LKDs. A genetic panel was developed to screen 115 genes associated with renal diseases. We used this panel to screen six negative controls, four transplant candidates with presumed genetic renal disease and six related LKDs. After removing common variants, pathogenicity was predicted using six algorithms to score genetic variants based on conservation and function. All variants were evaluated in the context of patient phenotype and clinical data. We identified causal variants in three of the four transplant candidates. Two patients with a family history of autosomal dominant polycystic kidney disease segregated variants in PKD1. These findings excluded genetic risk in three of four relatives accepted as potential LKDs. A third patient with an atypical history for Alport syndrome had a splice site mutation in COL4A5. This pathogenic variant was excluded in a sibling accepted as an LKD. In another patient with a strong family history of ESRD, a negative genetic screen combined with negative comparative genomic hybridization in the recipient facilitated counseling of the related donor. This genetic renal disease panel will allow rapid, efficient and cost‐effective evaluation of related LKDs.     

Oxalate retinopathy is irreversible despite early combined liver‐kidney transplantation in primary hyperoxaluria type 1

In primary hyperoxaluria type 1 (PH1), systemic oxalate deposition (oxalosis) in end‐stage renal disease (ESRD) is associated with high morbidity and mortality, particularly in children with infantile oxalosis (IO). Combined liver and kidney transplantation (CLKT) is the only curative treatment option in these patients. After CLKT, systemic oxalosis decreases continuously, although only insufficient data are available regarding oxalate retinopathy (ROx), leading to severe visual impairment. We analyzed long‐term follow‐up data of ROx in 13 patients undergoing CLKT for PH1 at our center between 1998 and 2018. Age at transplantation was 1.3‐14.2 years, including nine patients with IO. We performed visual acuity testing, slit lamp investigation, funduscopy, fundus photography, and spectral‐domain optical coherence tomography (SD‐OCT) imaging. Severe (grade 2‐4) ROx was present in all nine children with IO but not in the four patients developing ESRD in adolescence. A significant negative correlation was found between age at onset of ESRD and grade of ROx (r = ?0.66; P < .001). Notably, follow‐up assessment after CLKT demonstrated no regression of ROx after a median of 5.3 years (range 0.6‐14). The data show that despite early CLKT in IO, ROx is irreversible and the concomitant visual deterioration occurs prior to transplantation.     

Pre‐ and postdonation kidney function in donors of a kidney paired donation with unique criteria for donor glomerular filtration rate – a longitudinal cohort analysis

Baseline predonation estimated GFR (eGFR) appears to predict the risk of postdonation chronic kidney disease in live donors. New KIDGO guidelines recommend an eGFR ≥90 ml/min/1.73 m² as an acceptable level of glomerular filtration rate (GFR) for kidney donation. In the Australian Paired Kidney Exchange (AKX) program, all donors with a raw measured GFR (mGFR) ≥80 ml/min are deemed suitable for donation, but the significance of this selection indicator is unclear. We analysed the first 129 live donors in the AKX program with at least 1‐year follow‐up linking records in the AKX database and ANZDATA. There were 73 male and 56 female donors; mean (±SD) age was 53 ± 11 years. Predonation eGFR was 94 ± 13 ml/min/1.73 m², mGFR 99 ± 17 ml/min/1.73 m² and raw mGFR 108 ± 18 ml/min. Baseline eGFR was <80 ml/min/1.73 m² in 19 donors, and <90 ml/min/1.73 m² in 42 donors. At 1 year postdonation eGFR was 68 ± 15 ml/min/1.73 m² and the predicted eGFR at 30 years postdonation was on average 50 (29–83) ml/min/1.73 m². The hypothetical mean age at end‐stage kidney disease was estimated to be 145 (95% CI 120–263) years. Over 30% of AKX live donors would have been excluded from donation using KDIGO guidelines. Using AKX donor guidelines, the majority of donors with predicted eGFR <30 ml/min/1.73 m² 30‐year postdonation were aged ≥50 years. Long‐term outcome data on AKX donors with low eGFR will need careful monitoring.