CMV and renal allograft rejection 443 Nephrol Dial Transplant (2012) 27: 443 447 doi: 10.1093/ndt/gfr303 Advance Access publication 2 June 2011 Overall and cardiovascular mortality in Norwegian kidney donors compared to the background population Geir Mjøen 1, Anna Reisaeter 1, Stein Hallan 2, Pål-Dag Line 3, Anders Hartmann 1, Karsten Midtvedt 1, Aksel Foss 3, Dag Olav Dahle 4 and Hallvard Holdaas 1 1 Medical Department, Oslo University Hospital Rikshospitalet, Oslo, Norway, 2 Medical Department, St Olavs Hospital, Trondheim, Norway, 3 Surgical Department, Oslo University Hospital, Oslo, Norway and 4 Cardiology Department, Oslo University Hospital Ulleval, Oslo, Norway Correspondence and offprint requests to: Geir Mjøen; E-mail: geir.mjoen@rikshospitalet.no Abstract Background. There are concerns regarding potential longterm risks to the living kidney donor. Cardiovascular mortality has not been evaluated. The aim of this study was to assess overall and cardiovascular mortality in previous kidney donors compared with a general population sample. Methods. All live kidney donors in Norway in the period 1963 2007 were included. Controls matched 3:1 for age, gender and year of birth were provided by Statistics, Norway. Cause of death was retrieved from the death master file. Vital status as of 1 January 2010 was provided for all participants, and cause of death was available until 1 January 2008. Comparative survival analyses were performed by Kaplan Meier curves and log-rank test. Age-stratified death rates were calculated and compared with a selected group with a health status hypothetically allowing donation. Results. There were 2269 living kidney donors in the study period. At donation, mean age was 47.6 1 12.6 years, Ó The Author 2011. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com
444 G. Mjøen et al. 41.3% were male. Median observation time was 14.3 years. A total of 324 donors died during the study period. Causes of death were similar for donors and controls. By Kaplan Meier analysis, overall and cardiovascular mortality was lower for previous kidney donors than for matched controls (P < 0.001 and P ¼ 0.004, respectively). Age-stratified death rates were elevated for the oldest group of donors. Conclusions. Overall and cardiovascular mortality results are partially reassuring. However, the seemingly elevated mortality rate among the oldest donors requires further study. Keywords: cardiovascular; kidney donors; living donation; mortality Introduction Live donor nephrectomy is a special procedure with healthy people voluntarily undergoing major surgery without any personal health benefit. Although previous studies show an acceptable quality of life after donation [1, 2], this raises several ethical and medical concerns. The practice is based on the assumption that carefully selected donors, being offered qualified medical follow-up, are not exposed to future medical risks. However, data supporting this view is rather scarce and hampered with methodological problems. As a potential consequence of reduced renal mass following donor nephrectomy, some studies have indicated a small increase in proteinuria [3] and a slight increase in blood pressure [4]. In the general population, such modest increases in proteinuria and blood pressure have been associated with an increased risk of premature cardiac death and all-cause mortality [5, 6]. However, life expectancy following kidney donation has been described as similar or superior to that of the general background population [7, 8]. Such studies do not take into account that kidney donors are extremely healthy and clearly supposed to have a substantially longer life with less medical complications than the general population. Therefore, a few studies have compared kidney donors with selected control groups with a health status qualifying to be a potential kidney donor [9, 10]. Data have been encouraging, but studies with longer follow-up and from different populations are needed to fully justify the live donor nephrectomy practice. Our aim was to study long-term overall and cardiovascular mortality in kidney donors compared to a matched background population. Norway has run an extensive programme for live donor nephrectomy for >30 years and has adequate systems for follow-up. We also wanted to evaluate age-specific death rates in our donor population. Methods In Norway, all kidney transplantations are centralized to one centre. As previously described, workup of potential donors is performed by the local nephrology departments [11, 12]. Renal function has been evaluated with creatinine clearance but, in later years, we have used isotope measurements of glomerular filtration rate. Urine analysis included dipstick, microscopy and albumin creatinine ratio. Blood pressure was based on two office measurements, using 24-h ambulatory blood pressure measurements in cases of doubt. Donors with isolated medical abnormalities have been evaluated according to international consensus, allowing in some cases donation from donors with uncomplicated hypertension treated with one antihypertensive medication, donors with isolated microalbuminuria, donors with low-normal renal function or obese donors [13]. Although donors are nowadays considered hypertensive with a blood pressure >140/ 90 mmhg, those who donated three and four decades ago were allowed to have higher blood pressures as this was considered normal. Donors are offered free lifelong follow-up, and the Norwegian health system is based on universal health care with reimbursements of all necessary costs. All kidney donors are registered in the Norwegian Living Donor registry, and baseline demographic data were collected from the registry as well as from patient files. Using the unique personal identification numbers given to all Norwegians at birth (Section of Health Statistics at Statistics Norway), we were able to identify deaths and causes of death in all Norwegian kidney donors. In addition, Statistics Norway provided a control group from the general Norwegian background population. The control group was generated at random from previous Norwegian population censuses. Controls were matched 3:1 to donors for age at donation, year of birth and gender; consequently, these variables were similar for donors and their respective controls. Causes of death were described using the International Statistical Classification of Diseases and Related Health Problems (ICD) versions 8 10. We defined cardiovascular death as described by the block I00-I99 in ICD-10. Sudden death was not included as cardiovascular death. Death from kidney disease was defined as the diagnoses within the block N00- N19, N25-29 and I12. Furthermore, to facilitate comparison with previously published material [14], we calculated age-stratified death rates for those donating in the period 1980 2002. Statistical analyses were performed using SPSS version 17. Mortality rates were described with Kaplan Meier curves and significance was tested with the log-rank test. The study was approved by the regional ethics committee. Results From January 1963 to December 2007, a total of 2269 kidney donor nephrectomies were performed at our centre. Mean age at donation was 47.7 years and 41.3% were males. Further baseline data are displayed in Table 1. Statistics Norway provided three controls with the same age, gender and year of birth for each kidney donor (6807 controls). The median observation time was 14.7 years. Vital status as of 1 January 2010 was provided for all participants, and cause of death was available until 1 January 2008. A total of 324 donors died within the study period, and cause of death was available for the first 274 (consecutive) of these. Table 1. Baseline data on live kidney donors (n ¼ 2269) Variable Median (range), mean (SD), frequencies (%) Age (years) 47.6 (18.4 81.4) Male gender (%) 938 (41.9) Median observation time (years) 14.7 (1.5 43.9) Mean body mass index (kg/m 2 ) 24.8 (3.3) Mean blood pressure (mmhg) 125.3/78.4 (11.6/7.8) S-creatinine (lmol/l) 80.6 (13.5) Relation to recipient (%) Sibling 859 (38.3) Parent 758 (33.4) Offspring 213 (9.5) Other relative 81 (3.6) Unrelated 348 (15.3)
Overall and cardiovascular mortality in kidney donors 445 Figure 1 shows that, by Kaplan Meier analysis, kidney donors had significantly lower mortality rates than the matched Norwegian background population sample (logrank test, P < 0.001). For example, after 20 years, 83.3% of donors were alive compared to 78.9% of controls. Table 2 shows causes of death in donors and controls. Cardiovascular disease was the most common cause of death, and Figure 2 displays cardiovascular mortality over time. Kidney donors had slightly lower cardiovascular mortality (log-rank test, P ¼ 0.004). As shown in Table 2, the proportion of donors dying from other causes was also lower compared to the controls. Six previous kidney donors had kidney disease as the primary diagnosis on the death certificate (five chronic renal failure, one glomerulonephritis) and nine of the controls (six chronic renal failure, one glomerulonephritis and two hypertensive kidney disease). A comparison of age-specific death rates between a subgroup (n ¼ 1594) of our donors and a previously published [14] sample of individuals who would hypothetically be eligible for kidney donation are shown in Table 3. Discussion The main finding in this long-term follow-up study was that kidney donors had lower overall and cardiovascular mortality when compared to a matched background population. Two studies [7, 8] have indicated better survival in kidney donors, however, they were not able to test for statistical significance. Garg et al. [9] matched donors and controls using health administrative data and evaluated a composite end point of death and cardiovascular events also without detecting any differences. Segev et al. [10] compared donors with a selected healthy sample from NHANES 3, demonstrating superior donor survival. However, followup in these two studies was limited to ~6 years. Evaluating cardiovascular mortality among previous kidney donors is important not only in relation to donor safety but also whether decreased renal function per se increases cardiovascular morbidity and mortality [15]. A recent study by Prasad et al. [16, 17] did not demonstrate any increase in traditional cardiovascular risk factors shortly after donation, but this study may have been underpowered to detect true differences. The finding of lower cardiovascular mortality in kidney donors compared to the background population has to our knowledge not been reported previously. Garg et al. [9] did not find any statistically significant difference in the rate of major cardiovascular events or death between previous donors and controls, although the low number of events in each group and relatively short time of observation (6.2 years) may have decreased the possibilities of detecting a true difference. Furthermore, we demonstrated donors to have similar causes of death as the background population, with cardiovascular disease and cancer being the most common. This seems to be a universal finding in survival studies of previous kidney donors [7, 8, 18, 19]. Kidney disease as cause of death was slightly more frequent among kidney donors, though overall a rare outcome. Lin et al. [14] demonstrated that applying donor health criteria to an unselected population yielded a group with a lower age-stratified death rate than the population it was selected from. In general, the age-stratified death rates for the selected sample from the study by Lin et al. were quite similar to those observed for previous Norwegian kidney donors. However, within the oldest age group (70 79 years), the death rate was markedly higher for previous Norwegian donors than for the selected group published by Lin et al. (44.32 6.53 versus 27.83 5.01 deaths per 1000 years). Though there were fewer individuals in this group, with fewer person-years of observation time in the analysis allowing for more uncertain estimates, this Fig. 1. Kaplan Meier analysis of all-cause mortality for previous kidney donors (green) compared with general background population (blue) (P < 0.001).
446 G. Mjøen et al. Fig. 2. Kaplan Meier analysis of cardiovascular mortality for previous kidney donors (green) compared with general background population (blue) (P ¼ 0.004). Table 2. Causes of death Variable Kidney donors (%) (n ¼ 2269) Background population sample (%) (n ¼ 6807) Overall mortality 324 (14.3) 1230 (18.1) Information on cause of 274 1054 death Cardiovascular disease 105 (38.3) 412 (39.1) Cancer 84 (30.7) 339 (32.2) Infectious disease 9 (3.3) 47 (4.5) Trauma 15 (5.5) 50 (4.7) Other 61 (22.3) 206 (19.5) Table 3. Age-specific crude death rates Age Norwegian kidney donors donating 1980 2002 (n ¼ 1594) n Death rate per 1000 person-years Healthy sample [14] from Lin et al. examined 1988 94 (n ¼ 6053) n Death rate per 1000 person-years 20 29 122 0.88 6 0.62 2348 0.95 6 0.26 30 39 318 1.49 6 0.53 1705 1.25 6 0.31 40 49 437 2.76 6 0.62 977 2.72 6 0.77 50 59 393 7.27 6 1.08 481 6.98 6 1.72 60 69 249 22.07 6 2.45 350 17.02 6 3.72 70 79 75 44.32 6 6.53 192 27.83 6 5.01 were minor differences regarding body mass index (24.7 kg/m 2 for Norwegian donors versus 23.7 kg/m 2 for Lin et al.), male gender (41 versus 46%) and Caucasian race (100 versus 78%). Information on blood pressure and renal function was not available for the NHANES sample, but as these values were within the predetermined selection criteria [14], they should be less likely to affect the results. The current study has some limitations. Making comparisons with the background population may decrease the possibilities of detecting a true increase in mortality among kidney donors as these are healthier than the ageand gender-matched background population at the time of donation [14]. Such comparisons should preferably be done against a comparable control group satisfying the donation criteria at the start of follow-up. Further, we had no means of controlling for potential genetic components of kidney disease and/or cardiovascular risk, as many of our donors are first-degree relatives of a kidney transplant recipient. The strengths of this study are a complete mortality data set with a long follow-up time since donation and available information on cause of death. However, there is a need for further long-term studies on mortality and cardiovascular outcomes in previous donors, preferably with control groups that satisfy the criteria for kidney donation at baseline. Also, the seemingly elevated death rate among the oldest donors requires further study. difference is troubling and requires further investigation. This is especially important in relation to accepting more and more kidney donation from older donors. Also, there Acknowledgements. Funding. This project was supported by funds from the Norwegian Extrafoundation for health and rehabilitation. Conflict of interest statement. None declared.
Overall and cardiovascular mortality in kidney donors 447 References 1. Clemens K, Boudville N, Dew MA et al. The long-term quality of life of living kidney donors: a multicenter cohort study. Am J Transplant 2011; 11: 463 469 2. Clemens KK, Thiessen-Philbrook H, Parikh CR et al. Psychosocial health of living kidney donors: a systematic review. Am J Transplant 2006; 6: 2965 2977 3. Garg AX, Muirhead N, Knoll G et al. Proteinuria and reduced kidney function in living kidney donors: a systematic review, meta-analysis, and meta-regression. Kidney Int 2006; 70: 1801 1810 4. Boudville N, Prasad GV, Knoll G et al. Meta-analysis: risk for hypertension in living kidney donors. Ann Intern Med 2006; 145: 185 196 5. Matsushita K, van der Velde M, Astor BC et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010; 375: 2073 2081 6. Lewington S, Clarke R, Qizilbash N et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360: 1903 1913 7. Ibrahim HN, Foley R, Tan L et al. Long-term consequences of kidney donation. N Engl J Med 2009; 360: 459 469 8. Fehrman-Ekholm I, Elinder CG, Stenbeck M et al. Kidney donors live longer. Transplantation 1997; 64: 976 978 9. Garg AX, Prasad GV, Thiessen-Philbrook HR et al. Cardiovascular disease and hypertension risk in living kidney donors: an analysis of health administrative data in Ontario, Canada. Transplantation 2008; 86: 399 406 10. Segev DL, Muzaale AD, Caffo BS et al. Perioperative mortality and long-term survival following live kidney donation. JAMA 2010; 303: 959 966 11. Mjoen G, Oyen O, Holdaas H et al. Morbidity and mortality in 1022 consecutive living donor nephrectomies: benefits of a living donor registry. Transplantation 2009; 88: 1273 1279 12. Mjoen G, Midtvedt K, Holme I et al. One- and five-year follow-ups on blood pressure and renal function in kidney donors. Transpl Int 2010; 24: 73 77 13. Delmonico FA. Report of the Amsterdam forum on the care of the live kidney donor: data and medical guidelines. Transplantation 2005; 79 (6 Suppl): S53 S66 14. Lin J, Kramer H, Chandraker AK. Mortality among living kidney donors and comparison populations. N Engl J Med 2010; 363: 797 798 15. Foley RN, Ibrahim HN. Long-term outcomes of kidney donors. Curr Opin Nephrol Hypertens 2010; 19: 129 133 16. Prasad GV, Lipszyc D, Huang M et al. A prospective observational study of changes in renal function and cardiovascular risk following living kidney donation. Transplantation 2008; 86: 1315 1318 17. Ramesh Prasad GV, Lipszyc D, Sarker S et al. Twenty four-hour ambulatory blood pressure profiles 12 months post living kidney donation. Transpl Int 2010; 23: 771 776 18. Rizvi SA, Naqvi SA, Jawad F et al. Living kidney donor follow-up in a dedicated clinic. Transplantation 2005; 79: 1247 1251 19. Ramcharan T, Matas AJ. Long-term (20-37 years) follow-up of living kidney donors. Am J Transplant 2002; 2: 959 964 Received for publication: 3.3.11; Accepted in revised form: 29.4.11