Living Kidney Donation in Racial and Ethnic Minorities: Balancing Acuity of the Organ Shortage with Uncertainties for Long-Term Donor Risk

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1 Curr Transpl Rep (2014) 1:18 23 DOI /s LIVE KIDNEY DONATION (KL LENTINE, SECTION EDITOR) Living Kidney Donation in Racial and Ethnic Minorities: Balancing Acuity of the Organ Shortage with Uncertainties for Long-Term Donor Risk Mona D. Doshi Published online: 4 January 2014 # Springer International Publishing AG 2014 Abstract The overwhelmingly positive impact of kidney transplantation on recipient survival and quality of life makes it the treatment of choice for those requiring renal replacement therapy. Live kidney donation provides additional benefit of shorter wait time for receiving a transplant and improved graft survival. There are numerous studies demonstrating short- and long-term medical safety of live kidney donation, albeit with data dominantly derived from studies with Caucasian donors. Racial and ethnic minorities form a third of the general population but constitute over half of the dialysis population. The absolute rates of live donor kidney transplants in minorities remain low due to lack of knowledge about its benefits and reluctance to share this information with families and friends due to concerns regarding the potential donor s health after surgery. While attempts are being made to overcome these barriers, it is imperative we support these efforts with evidence-based knowledge regarding medical and psychosocial risks associated with this procedure. This review summarizes findings of studies addressing these issues in African American and Hispanic donors. Keywords Living donors. African American. Hispanics. Minorities. Kidney transplant. Kidney disease. Hypertension. End stage kidney disease. Living kidney donation. Organ shortage. Long-term donor risk Introduction Kidney transplant is the preferred form of renal replacement therapy, but its success is hindered by organ shortage, leading M. D. Doshi (*) Department of Medicine, Wayne State University, 4160 John R, HPOB, Suite 908, Detroit, MI 48201, USA mdoshi@med.wayne.edu to longer wait time and increasing patient deaths on the waitlist [1]. Efforts are being made to reduce barriers to live kidney donation to shorten wait time, improve graft outcomes and reduce the shortage. These efforts include advances in laparoscopic donor nephrectomy to minimize pain and hospital stay after surgery, liberalization of live kidney donor acceptance criteria and establishment of paired kidney exchange programs to overcome immunological barriers to live donor kidney transplants. The number of living donors had increased worldwide over the last decade but recently has stabilized, or even declined, possibly due to concerns about long-term safety in selected groups of donors [2]. Live kidney donation is widely accepted on the premise that it carries low or acceptable minimal risk to the donor and is offset by personal satisfaction associated with recipient well-being. There are numerous studies establishing the short- and long-term medical safety of live kidney donation in Caucasians, but this remains to be confirmed in Hispanic and African American donors [3, 4]. African Americans and Hispanics together constitute 30 % of the total population, but comprise 53 % of the kidney transplant waitlist and only 41 % of all kidney transplants in the United States [1]. The Organ Procurement Transplant Network (OPTN) annual data reports that 30 % of Caucasians received a kidney transplant within 2 years of wait listing, whereas only 20 % of African Americans and Hispanics received one within that time span. This may be partially explained by higher rates of live donor kidney transplants in Caucasians than in African Americans and Hispanics (43.8 %, 17.8 % and 31.2 % respectively per 2012 report). Increasing the number of live donor kidney transplants in nonwhite persons with end stage renal disease (ESRD) may help overcome some of the disparity in transplant rates. It is therefore imperative that both the short- and long-term risks associated with live kidney donation are better defined in nonwhite donors to enhance donor selection and counseling. The purpose of this review is to briefly describe the barriers to live

2 Curr Transpl Rep (2014) 1: donor kidney transplants and to summarize the results of studies regarding safety of live kidney donation in racial and ethnic minorities. Strategies to Reduce Barriers to Live Donor Kidney Transplants Studies suggest that racial and ethnic minorities may encounter barriers at several steps along the path to a successful live donor kidney transplant [5, 6]. These include knowledge gaps on benefits of live donor kidney transplant, difficulty in identifying and approaching potential donors due to fear about a potential future risk of kidney disease in the donor (frequently a family member), concerns about the financial burden of testing, and complications after surgery [7, 8]. Initiatives are needed to address these barriers at all levels including patients, potential donors, health-care providers, health systems, and the community at large. Some transplant centers have tried to bridge the knowledge gap by developing culturally sensitive transplant educational materials for distribution to patients and their families including brochures and videos that share recipient and live kidney donor stories [9]. Another approach has been making house calls, i.e., a transplant team member conducts a seminar at the home of dialysis patient to educate family and friends about recipient benefits associated with live kidney donation [10], or encouraging the patient to identify a champion who would seek a live kidney donor on their behalf [11]. The goals of these approaches are to better educate recipients regarding benefits of live donor kidney transplants, improve recipient comfort in sharing this knowledge with their family and friends, correct misconceptions, and lastly, reduce barriers to live kidney donation. Perioperative Morbidity and Mortality Segev et al. [12 ] studied perioperative morbidity and mortality in 80,347 live kidney donors that donated between April 1, 1994 and March 31, 2009 in the United States. The death rate in the first 90 days following live donor nephrectomy was 3.1 per 10,000 donors (95 % CI, ). This mortality rate has not changed during the past 15 years, despite changes in surgical practices of using laparoscopic procedures and growing medical complexities in the donors with regards to increasing age, body mass index, and prevalence of hypertension [13]. African American donors were reported to have a higher surgical mortality of 7.6 per 10,000 donors (95 % CI, ) versus 2.6 per 10,000 white donors (95 % CI, ) and 2.0 per 10,000 Hispanic donors (95 % CI, ); relative risk (RR) 3.1 (95 % CI ; p=0.01) versus nonblack donors. Of note, higher postsurgical mortality has been reported in African Americans for other surgeries too [14]. Recently Schold et al. [15] used the National Inpatient Sample to determine the perioperative morbidity and mortality among 69,117 donors undergoing donor nephrectomies between 1998 and 2010 (representing 89 % of all donors in the U.S during that time frame). The investigators reported a higher rate of perioperative complications among African Americans (10.4 %) and whites (8.7 %) compared with donors from other race groups (6.3 %; p<0.001); however, after multivariate analyses this difference for higher risk among African American donors was not present. The long-term deaths in the donor were ascertained by Segev et al. [12 ] via the Social Security Death Master File. Again, the African American donors had higher mortality than white donors, 2.8 % versus 1.7 % at 12 years; hazard ratio (HR) 1.3; 95 % CI The long-term survival among the Hispanic donors was similar to the white donors. The investigators compared the survival of the donors with a carefully matched cohort of 9,364 participants of the third National Health and Nutrition Examination Survey (NHANES III) conducted between 1988 and The records of controls were screened for medical conditions that would have excluded them from being a live kidney donor. The long-term survival of the donors was better than race-matched controls across all racial groups. While this was a large longitudinal study with a diverse group of donors, there are several limitations to the study. First, the investigators selected controls from NHANES III where the enrollment ended in 1994 but is the start of their donor cohort study period. Thus, the donor and controls were not contemporary. Secondly, according to the Human Mortality Database, the death rate for the US population aged years decreased from 1995 to 2006 by approximately 17 %, and therefore, it is reasonable to conclude that the donors live longer than, or similar to, race-matched individuals from the general population. In addition, the control group was only one-eighth the size of the live donor cohort, leading to repeated use of a control and perhaps compromising some of their results. Consistent with findings in the general population, African American donors have higher perioperative and long-term mortality than donors of other races. However, the longevity of the donors is similar or higher than non-donors of similar racial background. Risk of Hypertension One of the earliest studies evaluating the effect of kidney donation on blood pressure in African American donors hails from the University of Alabama and was published in 1991 [16]. The investigators compared blood pressure in 24 African American live kidney donors with that of age-, gender- and time to donation-matched 24 Caucasian donors. The authors

3 20 Curr Transpl Rep (2014) 1:18 23 report that the pre- and post-donation mean arterial blood pressure was higher in African American donors than the Caucasians (94±2 vs 89±1 mm of Hg; p=0.02 and 99±2 vs 91±2 mm of Hg; p=0.02 respectively); however, the rise in mean arterial pressure was not different between the two groups. Almost two decades later, Nogueira et al. [17 ] studied the prevalence of hypertension in 107 African American living donors that underwent unilateral nephrectomy at the University of Maryland. Of the 39 donors who participated in the study, 16 (41 %) had hypertension at 6 years post donation. Eight of these donors with hypertension were already on blood pressure lowering medications and eight others were diagnosed at the study visit. This was the first study reporting prevalence of hypertension in African American live kidney donors, however only 36.4 % of invited donors participated in the study. The prevalence of hypertension in this group of African American donors was much higher than that reported in Caucasians by Ibrahim et al. [3 ] (32.1 % at 12 years after donation). To overcome the issues of small sample size, Lentine et al. [18 ] linked the OPTN records of 86,107 live kidney donors from 1987 through July 2007 with administrative data from a national private U.S. health insurer to compare the prevalence of hypertension among donors by race. Of these, 4,650 living donors (5.4 %) had captured post-donation insurance claims data within the records from one private health insurer at some point between May 2000 and December The physician billing claims and pharmacy claims submitted to the insurance company were used to ascertain post-donation development of hypertension. The controls for this study were selected from NHANES survey, where race and illnesses were self-reported. African American live kidney donors were reported to be at a higher risk of developing hypertension than Caucasian donors (per medical claims RR 1.52; 95 % CI, and per pharmacy claims RR 1.31; 95 % CI, ) at 8 years post donation, but the prevalence of hypertension was similar to that seen in race matched controls from NHANES population. For the Hispanic donors, the risk of post-donation hypertension was higher only when diagnosis was ascertained via medical claims RR 1.36; 95 % CI While this is a large study with one-third of the donors being non-white, the study was limited to a small fraction of donors under a single private insurance provider. The accuracy of prevalence of hypertension in both groups is limited by dependency on participants seeking medical care. Lastly, while it is practical to use population-based estimates to compare the risk of hypertension, living donors go through a detailed selection process and therefore are inherently healthier than the general population. As noted by the authors, the study compares the frequency of diagnoses among donors to the general population and does not provide attributable risk of donation, which requires healthy and comparable controls. Lentine and Segev [19] have also discussed this topic, including the strengths and limitations of secondary data for understanding donor outcomes in a recent editorial. Doshi et al. [20 ] estimated the prevalence of hypertension in 103 African American live kidney donors from two transplant centers in Detroit, Michigan and compared them to a carefully selected group of African Americans who would have been suitable live kidney donors at most transplant centers. The controls were selected from the participants in the Coronary Artery Risk Development in Young Adults (CARDIA) prospective cohort study [21]. Twenty-six hundred CARDIA participants were screened vigorously for good health at baseline, and only 235 were considered suitable to serve as controls for the study. The controls were matched for race, gender, age and duration of follow-up. The blood pressure was measured uniformly in donors and controls in accordance to the seventh report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure [22]. At 6 years of follow-up, hypertension risk was higher in donors compared with controls (42/103 [40.8 %] vs 42/235 [17.9 %]), absolute risk difference 22.9 %; 95 % CI, %; and RR 2.4; 95 % CI, While the prevalence of hypertension in the donors for this study is similar to the one reported by Nogueira et al. [17 ], it is higher than that reported by Lentine et al. [18 ]. The difference can be attributed to high incidence of undiagnosed hypertension in donors. Both Nogueira et al. [17 ] and Doshi et al. [20 ] reported that half of the donors were diagnosed with hypertension at the time of their study visit, which may be a reflection of poor access and/or utilization of primary care services among African American donors. Gibney et al. [23] reported that minorities are less likely to have medical insurance and are less likely to follow-up after donation. Thus, it possible that the adverse donor outcomes may be related to lack of insurance. Recently, Lentine et al. [24] evaluated the risk of hypertension in donors by linking the OPTN registry data for 4007 living donors between 1987 to 2008 with Medicare Billing data claims. Although there were fewer African American donors in the study, the incidence of hypertension was higher in African American than white donors (RR 1.4; 95 % CI, ). The incidence of malignant hypertension was higher in Hispanic than white donors (RR 1.96; 95 % CI, ). To summarize, there are several reports suggesting a higher prevalence of hypertension in African American than Caucasian former live kidney donors. Again, this is analogous to the observations in general population. Risk of Kidney Disease Post-operative renal function has been studied in Caucasian and African American donors via a single-center retrospective

4 Curr Transpl Rep (2014) 1: chart review and OPTN database report review [25, 26]. Both studies reported that post-donation renal function and the ability to compensate for loss of renal mass after live kidney donation was similar between Caucasian and African Americanlivekidneydonors. Intermediate follow-up studies on renal function approximately 6 years post-donation are limited to retrospective single-center(s) and OPTN/private insurance database reports [17, 18, 20 ]. The single center(s) studies from Maryland and Detroit report that mean estimated glomerular filtration rate (egfr) in the African American live kidney donors was 72.1±16.4 and 77± 19 ml/min/1.73 m 2, respectively, and % of donors had egfr <60 ml/min/1.732 m 2 [17, 20 ]. The incidence of microalbuminuria in these studies was also low at %. The absence of significant urinary albumin excretion makes a case against progressive damage from hyperfiltration injury and suggests that low post-donation renal function may primarily reflect loss of renal mass at a single time point. The study by Lentine et al. [18 ] using merged information from the OPTN and private insurance company administrative databases reported higher risk of chronic kidney disease in African American and Hispanic population, HR 2.32; 95 % CI, and 1.90; 95 % CI, , respectively, than Caucasian donors. Among a group of 2,307 donors with information on the staging of chronic kidney disease, African American and Hispanic donors were reported to have increased risk of chronic kidney disease stage III or higher than white donors (HR 3.60; 95 % CI, ; p=0.009 and HR 4.23; 95 % CI, ; p=0.006, respectively). However, these estimates were similar to African American and Hispanic respondents in NHANES population. This racial variation in occurrence of chronic kidney disease in donors after unilateral nephrectomy, with African Americans carrying the greater burden, was recently demonstrated among publicly insured former living donors [24]. Gibney et al. [27] were first to use the OPTN database to evaluate the risk of end stage renal disease in former live kidney donors. They reported that the absolute risk of end stage renal disease was low in African American donors but was higher than white donors. Cherikh et al. [28 ] comprehensively studied development of end stage renal disease in former donors by using the OPTN and Centers of Medicare Services Database. Of 56,458 living donors who donated during October 1, 1987 and March 31, 2003, 126 donors had developed end stage renal disease (0.22 %). While African Americans formed 13 % of all live kidney donors during the study period, they constituted 46.8 % of donors developing end stage kidney disease. The overall rate of end stage renal disease in living donors was per 1,000 years at risk which is lower than that seen in the general population. The post donation end stage renal disease rate was five times higher in African Americans than white donors (0.423 versus per 1,000 years at risk, RR 4.92; 95 % CI, ). This risk is similar to that seen in the general population, which is 3.7-fold higher in African Americans than whites [29]. There are several studies evaluating risk of chronic kidney disease and end stage renal disease in former live kidney donors. A small fraction of donors have low egfr (<60 ml/min/1.73 m 2 ) and develop end stage renal disease post donation, which may be due to racial predisposition but cannot rule out improper donor selection. Cherikh et al. [28 ] reported that donors that donated to full siblings were more likely to develop end stage renal disease than others, suggesting a greater role of familial/ genetic predisposition than racial. Risk of Diabetes and Cardiovascular Disease The risk for diabetes and cardiovascular disease in living donors was studied by Lentine et al. [18, 24]. Both African American and Hispanic donors were reported to have a greater risk of diabetes than Caucasian donors but not different than that seen in the general population. However, the Hispanic donors were reported to be at the greatest risk of developing diabetes, up to twofold to threefold greater than white donors. This may be due to increasing prevalence of obesity in non-white donors [30] and their inherent predisposition to diabetes due to genetic, familial and dietary factors. The risk of cardiovascular disease did not differ by donor race. Future Directions The above-mentioned studies suggest an increased prevalence of hypertension and kidney disease in African American than Caucasian donors but similar to that seen in the general population. Few studies have tried to compare outcomes across race between donors and carefully matched nondonors with regard to age, gender, and medical comorbidities but not for familial/genetic predisposition and socio-economic status. The donors, by study design, are more likely to be related to the recipient and therefore are likely to have family history of hypertension and end stage kidney disease and share similar socioeconomic background. Lack of medical insurance, access to health care and receipt of quality care may also explain higher prevalence of chronic illnesses in these donors. As suggested by others [31], a well done observational study that matches for genetic, familial, and socioeconomic factors is needed to address if the risks of chronic

5 22 Curr Transpl Rep (2014) 1:18 23 kidney disease and hypertension are truly altered by live kidney donation. Conclusions African American and Hispanic live kidney donors have higher rates of perioperative deaths and are more likely to develop hypertension, kidney disease and diabetes than Caucasian donors, but the risk estimate is similar to that of other individuals of their race who did not donate. Such evidence provides a legitimate basis for racial ethnic minorities concerns about risks associated with live kidney donation. While we encourage pursuit of live kidney donation and efforts to reduce barriers to live donor kidney transplants in racial and ethnic minorities with kidney disease, we need to counsel willing and medically appropriate potential donors regarding their inherent increased risk of developing these chronic illnesses. They should be encouraged to adopt a healthy life-style to mitigate these risks and maintain close medical follow-up for early detection and treatment. The full disclosure of the best available scientific evidence on the benefits and potential risks associated with live kidney donation could help alleviate some of their concerns. We need additional studies on African American and Hispanic donors to confirm or refute the findings of the current retrospective studies. Compliance with Ethics Guidelines Conflict of Interest interest. Mona D. Doshi declares that she has no conflict of Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. References Papers of particular interest, recently published, have been highlighted as: Of importance Of major importance 1. Matas AJ, Smith JM, Skeans MA, Lamb KE, Gustafson SK, Samana CJ, et al. OPTN/SRTR 2011 Annual Data Report: kidney. 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