Living kidney Donations and Postdonation Risk Factors

Transcription

1 CLINICAL AND TRANSLATIONAL RESEARCH Associations of Recipient Illness History With Hypertension and Diabetes After Living Kidney Donation Krista L. Lentine, 1,2,7 Mark A. Schnitzler, 1 Huiling Xiao, 1 Connie L. Davis, 3 David Axelrod, 4 Kevin C. Abbott, 5 Paolo R. Salvalaggio, 1 Thomas E. Burroughs, 1 Georges Saab, 6 and Daniel C. Brennan 6 Background. Little is known about associations of family health history with outcomes after kidney donation. Methods. Using a database wherein Organ Procurement and Transplantation Network identifiers for 4650 living kidney donors in 1987 to 2007 were linked to administrative data of a US private health insurer ( claims), we examined associations of illness history as a measure of family history with postdonation diagnoses and drug-treatment for hypertension and diabetes. Cox regression with left and right censoring was applied to estimate associations (adjusted hazards ratios, ahr) of illness history with postnephrectomy donor diagnoses, stratified by donor- relationship. Results. Recipient end-stage renal disease from hypertension, as compared with other end-stage renal disease causes, was associated with modest, significant increases in the age- and gender-adjusted relative risks of hypertension diagnosis (ahr, 1.37%; 95% confidence interval [CI], ) after donor nephrectomy among related donors. After adjustment for age, gender, and race, type 2 diabetes compared with non-diabetic status was associated with twice the relative risk of postdonation diabetes (ahr, 2.14; 95% CI, ; P 0.003) among related donors. These patterns were significant among white but not among non-white related donors. Recipient type 1 diabetes was associated with postdonation diabetes only in black related donors (ahr, 3.22; 95% CI, ; P 0.04). Recipient illness did not correlate significantly with outcomes in unrelated donors. Conclusions. These data support a need for further study of family health history as a potential sociodemographic correlate of donor outcomes, including examination of potential mediating factors and variation in risk discrimination among donors of different racial groups. Keywords: Diabetes mellitus, Family health history, Hypertension, Kidney transplantation, Living donors. (Transplantation 2011;XX: ) As living kidney donation has become an increasingly common option to address the organ shortage, the standards of postdonation follow-up and risk discrimination assume even greater importance for the informed counseling This work was supported, in part, by the National Institute of Diabetes Digestive and Kidney Diseases (NIDDK) grants K08DK (K.L.L.) and P30DK (M.A.S., D.C.B.). Data reported here have been supplied by the United Network for Organ Sharing (UNOS) as the contractor for the Organ Procurement and Transplantation Network (OPTN). The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy of or interpretation by the OPTN, the US Government, the Department of Defense, the NIDDK or the National Institutes of Health. The authors declare no conflicts of interest. This work was performed at Saint Louis University, St. Louis, MO. 1 Center for Outcomes Research, Saint Louis University School of Medicine, St. Louis, MO. 2 Division of Nephrology, Saint Louis University School of Medicine, St. Louis, MO. 3 Kidney and Pancreas Transplant Program, University of Washington, Seattle, WA. 4 Department of Surgery, Dartmouth-Hitchcock Medical Center, Hanover, NH. 5 Nephrology Service, Walter Reed Army Medical Center, Washington, DC. and care of patients who undergo this altruistic procedure. Medical evaluation of the potential living kidney donor focuses on excluding patients with medical abnormalities at the time of assessment, including conditions that pose risk of accelerated kidney disease after donation such as diabetes and hypertension (1). In the context of selection and exclusion practices, kidney donation does not seem to increase the risk 6 Division of Nephrology, Washington University School of Medicine, St. Louis, MO. 7 Address correspondence to: Krista L. Lentine, M.D., M.S., Saint Louis University Center for Outcomes Research, Salus Center, 4th Floor, 3545 Lafayette Avenue, St. Louis, MO lentinek@slu.edu K.L.L. and M.A.S. participated in study design, data acquisition, data analysis, and writing of the manuscript; H.X. participated in study design, data analysis and writing of the manuscript; C.L.D., D.A., K.C.A., P.R.S., T.E.B., G.S., and D.C.B. participated in study design, interpretation, and writing of the manuscript; and K.L.L. wrote the first draft of the manuscript. Received 19 November 2010; Revision requested 6 December Accepted 31 January Copyright 2011 by Lippincott Williams & Wilkins ISSN /11/XX0XX-1 DOI: /TP.0b013e31821a1ae2 Transplantation Volume XX, Number XX, Month XXX,

2 2 Transplantation Volume XX, Number XX, Month XXX, 2011 TABLE 1. Distributions of living donor traits according relationship to their, and according to comorbidities among related donations Donor traits Full donor sample Related to (N 3776) Unrelated to (N 874) Recipient ESRD due to hypertension (N 455) Donors related to their Recipient ESRD not due to hypertension (N 3321) Type 1 diabetic (N 468) Type 2 diabetic (N 346) Non-diabetic (N 2962) Male gender (%) a Race (%) Non-Hispanic a b c white Non-Hispanic a b c black Hispanic a Other c OPTN-reported hypertension at donation (%) OPTN-reported Diabetes at donation (%) Age at donor 36.5 (9.8) 40.5 (10.1) a 35.1 (9.9) b 36.6 (9.8) 38.1 (9.8) 35.3 (9.5) 36.3 (9.9) c nephrectomy (yr); Mean (SD) Duration of insurance eligibility in the dataset (yr) (median) Percentages reflect proportions of the indicated column with the trait of interest ( column percents ). a P 0.05 for difference in distribution of traits at donation in donors related to their compared to unrelated to their. b Among donors related to their : P 0.05 for difference in distribution of traits at donation in donors whose s had ESRD from hypertension compared to ESRD from other causes. c Among donors related to their : P 0.05 for difference in distribution of donor traits according to diabetes status. ESRD, end-stage renal disease; OPTN, Organ Procurement and Transplantation Network; SD, standard deviation. of end-stage renal disease (ESRD) or death compared with outcomes in the general population (2 4). However, while normal predonation medical evaluation increases the overall likelihood of long-term good health, it should not be expected to ensure uniformly excellent outcomes over time. Rather, as in the general population, the risk of medical conditions after donation varies with baseline demographic factors including age and race (5 8). Family history is an established risk factor for hypertension and diabetes in the general population (9, 10), but little is known about the associations of family health history with medical outcomes after kidney donation. Currently, nationally mandated donor follow-up in the United States is limited in both duration and content. The Organ Procurement and Transplantation Network (OPTN) surveys transplant centers on donor vital status, renal function and other comorbidities only up to the second postdonation anniversary (11), and cost and inconvenience pose barriers to compliance even with such limited reporting requests (12). We recently linked administrative data from a private insurance provider to OPTN-supplied identifiers for previous living donors to enable longer term postdonation medical outcomes assessment independent of an individual s interaction with the transplant center (8). In this study, we used these integrated data to examine associations of illness history with postdonation diagnoses of hypertension and diabetes in living-related kidney donors. RESULTS Among 4650 living donors in the linked database, 81.2% (n 3776) were related to their including 3548 first-degree relatives. Donors related to their s were more commonly non-white race and were younger at donation than unrelated donors (Table 1). The racial distribution of related donors varied according to illness history, such that 37% of donors related to a with ESRD from hypertension were black, compared with 11.1% of related donors whose s had ESRD from other causes; 23% of donors related to a with type 2 diabetes were black, compared with 14.3% of related donors with non-diabetic s. The median time from donor nephrectomy to the end of insurance benefits was 7.7 years. The median duration of captured donor insurance eligibility in the study sample was 2.1 years, and did not differ significantly according to donor- relationship or according to illness among related donors.

3 2011 Lippincott Williams & Wilkins Lentine et al. 3 TABLE 2. Adjusted associations of illness history with postdonation hypertension and diabetes among living donors according to donor- relationship status a Predictor of interest: Recipient illness Donors related to Donors with first-degree relationship to Donors not related to ahr (95% CI) P ahr (95% CI) P ahr (95% CI) P Donor outcome: Hypertension diagnosis Model 1 b Recipient ESRD from hypertension 1.37 ( ) ( ) ( ) 0.18 Model 2 c Recipient ESRD from hypertension 1.26 ( ) ( ) ( ) 0.11 Donor outcome: Diabetes diagnosis Model 1 b Type 1 diabetic 0.96 ( ) ( ) ( ) 0.81 Type 2 diabetic 2.14 ( ) ( ) ( ) 0.78 Model 2 c Type 1 diabetic 1.02 ( ) ( ) ( ) 0.78 Type 2 diabetic 2.01 ( ) ( ) ( ) 0.75 a Donors (n 12) with pre-donation hypertension reported to the OPTN were excluded from the hypertension outcome analyses. One donor with pre-donation diabetes reported to the OPTN was excluded from the diabetes outcome analyses. b Adjusted for donor age and gender. c Adjusted for donor age, gender, and race. ahr, adjusted hazards ratio; CI, confidence interval; ESRD, end-stage renal disease. TABLE 3. Adjusted associations of illness history with post-donation hypertension and diabetes among related living donors according to donor race/ethnicity a Predictor of interest: Recipient illness Non-Hispanic white donors Non-Hispanic black donors Hispanic donors ahr (95% CI) P ahr (95% CI) P ahr (95% CI) P Donor outcome: Hypertension diagnosis Recipient ESRD from hypertension b 1.39 ( ) ( ) ( ) 0.41 Donor outcome: Diabetes diagnosis Type 1 diabetic b 0.91 ( ) ( ) ( ) 0.99 Type 2 diabetic b 2.56 ( ) ( ) ( ) 0.09 a Donors (n 8) with pre-donation hypertension reported to the OPTN were excluded from the hypertension outcome analyses among related donors. One donor with pre-donation diabetes reported to the OPTN was excluded from the diabetes outcome analyses among related donors. b Adjusted for donor age and gender. ahr, adjusted hazards ratio; CI, confidence interval; ESRD, end-stage renal disease. At 5 years postdonation, the cumulative prevalence of hypertension diagnosis was 24.0% among related donors with ESRD due to hypertension and 15.7% among related donors whose s had ESRD from other causes. After adjustment for age and gender, ESRD due to hypertension, as compared with other causes of ESRD, was associated with approximately 37% higher relative risks of hypertension diagnosis (adjusted hazards ratios [ahr], 1.37%; 95% confidence interval [CI], ; P 0.009) after donor nephrectomy among related donors (Table 2). Relative risk was similar and of near-significance after additional adjustment for donor race. Relative risks were also similar among first-degree relatives, but with wider confidence intervals, and statistical significance was limited to the age and gender-adjusted risk of hypertension diagnosis. In contrast, there were no significant associations of ESRD from hypertension with donor hypertension risk among unrelated donors, and the point estimates trended towards reduced (ahr 1.0) rather than increased risk. Recipient ESRD from hypertension was associated with significantly increased risk of postnephrectomy hypertension among white related donors (ahr, 1.39%; 95% CI, ; P 0.04) (Table 3). Hypertension was more common among black and Hispanic compared with white related donors (overall 5-year cumulative frequency by racial group: 25.8%, 23.0% vs. 14.8%, respectively), but hypertension risk did not differ significantly according to ESRD cause among black or Hispanic related donors (Table 3). The cumulative prevalence of diagnosed diabetes at 5 years after donation was 3.3% among related donors with type 1 diabetic s, 8.1% among related donors with type 2 diabetic s, and 3.7% among related donors

4 4 Transplantation Volume XX, Number XX, Month XXX, 2011 with nondiabetic s. Compared the absence of diabetes, type 2 diabetes was associated with approximately twice the relative risk of diabetes diagnosis (ahr, 2.14; 95% CI, ; P 0.003) among related living donors after adjustment for donor age and gender (Table 2). However, type 1 diabetes was not associated with the likelihood of postnephrectomy donor diabetes. The relative risks of donor diabetes associated with type 2 diabetes status among related donors were modestly attenuated but remained highly significant after additional adjustment for donor race. Associations of type 2 diabetes with subsequent donor diabetes were slightly stronger among donors with first-degree relationships to their. Among unrelated donors, neither type 1 nor type 2 diabetes were associated with the risk of subsequent living donor diabetes (P 0.7). The age- and gender-adjusted relative risk implications of type 2 diabetes for diabetes diagnosis in related donors was significant among white related donors (ahr, 2.56; 95% CI, ; P 0.003) and showed a nonsignificant trend among Hispanic donors (ahr, 3.14; 95% CI, ; P 0.09) but not among black donors (Table 3). In contrast, type 1 diabetes was associated with postdonation diabetes only in black related donors (ahr, 3.22; 95% CI, ; P 0.04). DISCUSSION Better understanding of postdonation medical outcomes among kidney donors selected for good health status at the time of donation may improve long-term prognostication and counseling before donor nephrectomy. We used administrative data collected in the course of clinical practice to study the association of illness history with postdonation hypertension and diabetes diagnoses in living kidney donors. After adjustment for age, gender, and race, type 2 diabetes compared with non-diabetic status was associated with more than twice relative risk of diabetes diagnosis in related donors. As compared with donors to related s with non-hypertensive ESRD, relatives of s with ESRD from hypertension had approximately 37% higher age and gender-adjusted relative risks of hypertension diagnosis after living kidney donation. Black donors were over-represented among related donors giving to s with hypertensive ESRD or with type 2 diabetes, and adjustment for race somewhat attenuated the associations of hypertensive ESRD and of type 2 diabetes with donor medical outcomes. However, the increased risk of postdonation hypertension and diabetes were not principally explained by race-related risk variation, as illness history was significantly correlated with the risk of postdonation medical outcomes among white related donors. To reduce the risk of future end-organ damage from medical comorbidities in living donors, the Amsterdam Forum medical guidelines for the live kidney donor assessment consider overt diabetes at the time of evaluation as an exclusion to donation (but not prediabetes or diabetes risk factors) (1). Hypertension at evaluation generally excludes kidney donation, except in hypertensive persons defined as particularly low risk (1, 13). In a cohort study of prior kidney donors at the University of Minnesota, drug-treated hypertension and diabetes were reported in 24.7% and 3.1%, respectively, of a subgroup of 255 dominantly white race (99.2%) donors assessed at an average of 12.2 years after donation (3). In contrast, among a cohort of 38 Canadian Aboriginal donors evaluated at an average of 14 years after donation, 42% were hypertensive and 19% were diabetic (7), and hypertension was recently identified in 41% of 39 African American donors studied at an average of 7 years after donation at the University of Maryland (6). Using administrative billing records, we recently found racial variation in medical outcomes after kidney donation similar to relative patterns in the general population (8). The results of the current study suggest that family history may be a sociodemographic correlate of medical outcomes after living kidney donation, particularly among white donors. Although black and Hispanic donors experience higher risk of hypertension and diabetes compared with whites, we did not find risk differences according to family history among non-white donors. A recent study of 211 black Americans in the general population similarly did not find an association of parental hypertension history with blood pressure levels (14). Although our data describe one of the largest cohorts of non-white kidney donors in the literature, the black and Hispanic sub-groups were substantially smaller than the group of white donors, and further study of risk discrimination among non-white donors is needed. Associations of family history with the risk of hypertension and diabetes have been extensively documented in the general population (9, 10, 15, 16). Seminal data from a US nationwide screening program found that paternal hypertension history was associated with twice the hypertension prevalence found in persons with negative family history, independent of body weight (9). In the Nurses Health Study, the age-adjusted relative risk of type 2 diabetes in participants with a family history of diabetes was twice the risk of participants without diabetes in the family (10). A portion of diabetes risk was explained by shared dietary habits and obesity (10). Genetic variants associated with increased risk of hypertension and diabetes have also been identified (17 19), but much of the mediation of family-history risk remains unexplained. Observed associations of type 2 diabetes history with risk of postdonation diabetes in our study appeared modestly stronger among donors with first-degree compared with any relationship to their. Further study is warranted to better define the importance of family history for living donor outcomes by gathering information from a more complete spectrum of family members beyond the related, and data on potential mediators such as obesity, lifestyle, environment, and genetics. To understand the clinical importance of hypertension and diabetes after kidney donation, future work should seek to quantify implications of these comorbidities for the risk of ESRD, cardiovascular disease, and other health outcomes that impact global health and quality of life. In the general population, each increase of 20 mm Hg usual systolic blood pressure (or, approximately equivalently, 10 mm Hg usual diastolic blood pressure) in mid-adulthood has been estimated to confer more than a twofold difference in strokerelated mortality, and twice the risk of death from ischemic heart disease and other vascular causes (20). Diabetes confers approximately twofold excess risk of an array vascular diseases in the general population, independently from other

5 2011 Lippincott Williams & Wilkins Lentine et al. 5 conventional risk factors (21). However, the end-organ impact of hypertension and diabetes may differ in kidney donors because closer surveillance and early intervention in otherwise healthy adults may mitigate consequences. Nonetheless, better understanding of the risk for hypertension and diabetes is relevant to counseling on possible financial risks from future prescriptions, medical treatment and associated insurance premiums, and may strengthen policy proposals for provision of universal health insurance to living donors. This study is limited by restriction of family history information to illness among related s. Recipient illness history was available per OPTN reports and misclassification is possible; in particular, patients classified as having ESRD from hypertension may have ESRD from other causes as clinical diagnoses of hypertensive nephropathy are often not confirmed by biopsy. The expected impact of such misclassification is bias towards a null result, such that the true association of primary hypertension with donor hypertension may be stronger than observed. Billing claims are surrogate measures for diagnoses but have been demonstrated to provide sensitive measures of diabetes and cardiovascular disease diagnoses in other populations (22, 23). We could not distinguish incident diagnoses definitively based on claims data that may be left-censored and limitation of OPTN collection of hypertension status at donation to recent years. Nonetheless, diabetes at evaluation should be a universal exclusion to donor candidacy and even in contemporary practice, hypertension at donation was reported in only 2.0% of US donors (24). Although a normal donor evaluation may reduce the risk of long-term health complications, donors are not exempt from epidemiologic determinants of medical comorbidities in the general population. Long-term tracking of health outcomes after living kidney donation is vital for discriminating the risk of lifetime morbidity, informed counseling, and donor protection and healthcare policy. These data support a need for further study of family health history as a potential sociodemographic correlate of donor outcomes, including examination of potential mediating factors and possible variation in the risk discrimination afforded by family history among donors of different racial groups. MATERIALS AND METHODS Data Sources and Participant Selection Study data were assembled by linking OPTN records for previous living kidney donors with administrative data from a national private health insurer. OPTN data include information on all donors and transplant s in the United States as submitted by OPTN member centers. After approval by the Health Resources and Services Administration and the Saint Louis University Institutional Review Board, beneficiary identifier numbers from the insurer s electronic databases were linked using names and birthdates to unique OPTN identifiers for living kidney donors. Because of the large sample size, the anonymity of the patients studied, and the nonintrusive nature of the research, a waiver of informed consent was granted per the Department of Health and Human Services Code of Federal Regulations (Title 45, Part 46, Paragraph ). Analyses were performed using Health Information Portability and Accountability Act-compliant, limited datasets with all direct identifiers removed. People were eligible if they had OPTN records of serving as a living kidney donor in October 1987 through July 2007 and benefits under the participating insurer after donor nephrectomy at some point in May 2000 to December 2007 (the period of available claims data). All study participants were simultaneously enrolled in medical and pharmacy benefits with this company exclusively during the study window. Study Measures Donor demographic data from the OPTN at donor nephrectomy included age, gender, race, and donor- relationship status as reported by the patient to the transplant center. First-degree donor- relationship was defined as parent, child, twin, or other sibling, whereas any biological relationship also included those defined as other blood-related relatives. Body mass index was reported for 5.3% of the linked donors and so was inadequate for inclusion in analytic models. The OPTN began collecting information on predonation hypertension and diabetes in June 2004, and this information was used to exclude donors with prevalent hypertension and diabetes, respectively, when available. Recipient cause of ESRD and other medical conditions were abstracted from the OPTN candidate registration forms. Recipient diabetes was classified as type 1 or type 2 per OPTN reporting. As use of antihypertensive agents is prevalent among patients with ESRD, ESRD due to hypertension was abstracted to define history of clinically significant hypertension. Diagnoses of medical conditions among prior kidney donors were ascertained by billing claims with corresponding International Classification of Disease, Ninth Revision, Clinical Modification diagnosis codes similar to algorithms described previously: hypertension, , ; diabetes, 250, 357.2, 362.0, , and (8). Statistical Analyses Datasets were merged and analyzed with SAS for Windows software, version 9.2 (SAS Institute Inc., Cary, NC). As windows of insurance benefits varied across the sample, Cox regression with left and right censoring was applied to model associations (ahr) of illness history with donor diagnoses after living donation, stratified by donor- relationship status. Separate parameters for type 1 and type 2 diabetes were included in the models of diabetes after living donation. Given previously demonstrated associations of donor race with medical outcomes after living donation and correlations of donor race with illness history, staged models were designed a priori with adjustment for donor age and gender, and then for donor, age, gender, and race. Analyses stratified according to non-hispanic white, non-hispanic black, and Hispanic donor race/ethnicity were also performed. Donors with reported hypertension (n 12 total) or diabetes (n 1 total) at donation were excluded from analyses of postdonation hypertension and diabetes, respectively. REFERENCES 1. Delmonico F. A report of the Amsterdam forum on the care of the live kidney donor: Data and medical guidelines. Transplantation 2005; 79(6 suppl): S Fehrman-Ekholm I, Elinder CG, Stenbeck M, et al. Kidney donors live longer. Transplantation 1997; 64: Ibrahim HN, Foley R, Tan L, et al. 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