Long-term risks for kidney donors
2013; Elsevier BV; Volume: 86; Issue: 1 Linguagem: Inglês
10.1038/ki.2013.460
ISSN1523-1755
AutoresGeir Mjøen, Stein Hallan, Anders Hartmann, Aksel Foss, Karsten Midtvedt, Ole Øyen, Anna Varberg Reisæter, Per Pfeffer, Trond Jenssen, Torbjørn Leivestad, Pål‐Dag Line, Magnus Øvrehus, Dag Olav Dale, Hege Pihlstrøm, Ingar Holme, Friedo W. Dekker, Hallvard Holdaas,
Tópico(s)Dialysis and Renal Disease Management
ResumoPrevious studies have suggested that living kidney donors maintain long-term renal function and experience no increase in cardiovascular or all-cause mortality. However, most analyses have included control groups less healthy than the living donor population and have had relatively short follow-up periods. Here we compared long-term renal function and cardiovascular and all-cause mortality in living kidney donors compared with a control group of individuals who would have been eligible for donation. All-cause mortality, cardiovascular mortality, and end-stage renal disease (ESRD) was identified in 1901 individuals who donated a kidney during 1963 through 2007 with a median follow-up of 15.1 years. A control group of 32,621 potentially eligible kidney donors was selected, with a median follow-up of 24.9 years. Hazard ratio for all-cause death was significantly increased to 1.30 (95% confidence interval 1.11–1.52) for donors compared with controls. There was a significant corresponding increase in cardiovascular death to 1.40 (1.03–1.91), while the risk of ESRD was greatly and significantly increased to 11.38 (4.37–29.6). The overall incidence of ESRD among donors was 302 cases per million and might have been influenced by hereditary factors. Immunological renal disease was the cause of ESRD in the donors. Thus, kidney donors are at increased long-term risk for ESRD, cardiovascular, and all-cause mortality compared with a control group of non-donors who would have been eligible for donation. Previous studies have suggested that living kidney donors maintain long-term renal function and experience no increase in cardiovascular or all-cause mortality. However, most analyses have included control groups less healthy than the living donor population and have had relatively short follow-up periods. Here we compared long-term renal function and cardiovascular and all-cause mortality in living kidney donors compared with a control group of individuals who would have been eligible for donation. All-cause mortality, cardiovascular mortality, and end-stage renal disease (ESRD) was identified in 1901 individuals who donated a kidney during 1963 through 2007 with a median follow-up of 15.1 years. A control group of 32,621 potentially eligible kidney donors was selected, with a median follow-up of 24.9 years. Hazard ratio for all-cause death was significantly increased to 1.30 (95% confidence interval 1.11–1.52) for donors compared with controls. There was a significant corresponding increase in cardiovascular death to 1.40 (1.03–1.91), while the risk of ESRD was greatly and significantly increased to 11.38 (4.37–29.6). The overall incidence of ESRD among donors was 302 cases per million and might have been influenced by hereditary factors. Immunological renal disease was the cause of ESRD in the donors. Thus, kidney donors are at increased long-term risk for ESRD, cardiovascular, and all-cause mortality compared with a control group of non-donors who would have been eligible for donation. Living donor kidney transplantation is the preferred treatment for end-stage renal disease (ESRD), because it is associated with improved graft and patient survival compared with transplantation from a deceased donor.1.Cohen D.J. St Martin L. Christensen L.L. et al.Kidney and pancreas transplantation in the United States, 1995–2004.Am J Transplant. 2006; 6: 1153-1169Crossref PubMed Scopus (128) Google Scholar Living kidney donation, however, requires that healthy individuals voluntarily undergo major surgery with no physical health benefit to themselves. Although rare, perioperative mortality does occur during organ retrieval from living donors and have been estimated to occur in 0.2% of liver donors and 0.03% of kidney donors.2.Middleton P.F. Duffield M. Lynch S.V. et al.Living donor liver transplantation—adult donor outcomes: a systematic review.Liver Transpl. 2006; 12: 24-30Crossref PubMed Scopus (224) Google Scholar,3.Segev D.L. Muzaale A.D. Caffo B.S. et al.Perioperative mortality and long-term survival following live kidney donation.JAMA. 2010; 303: 959-966Crossref PubMed Scopus (552) Google Scholar Less serious perioperative risks are accepted and well documented.3.Segev D.L. Muzaale A.D. Caffo B.S. et al.Perioperative mortality and long-term survival following live kidney donation.JAMA. 2010; 303: 959-966Crossref PubMed Scopus (552) Google Scholar,4.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: 1273-1279Crossref PubMed Scopus (85) Google Scholar Kidney donation inevitably leads to reduced renal function and is associated with an increase in proteinuria, as well as a rise in blood pressure (BP) greater than that attributable to normal aging.5.Boudville N. Prasad G.V. Knoll G. et al.Meta-analysis: risk for hypertension in living kidney donors.Ann Intern Med. 2006; 145: 185-196Crossref PubMed Scopus (314) Google Scholar,6.Garg A.X. 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: 1801-1810Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar These factors are associated with an increased risk for cardiovascular and all-cause mortality in the general population.7.Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (8986) Google Scholar, 8.Matsushita K. van d V. Astor B.C. 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: 2073-2081Abstract Full Text Full Text PDF PubMed Scopus (2832) Google Scholar, 9.Tonelli M. Wiebe N. Culleton B. et al.Chronic kidney disease and mortality risk: a systematic review.J Am Soc Nephrol. 2006; 17: 2034-2047Crossref PubMed Scopus (1204) Google Scholar Follow-up studies of living organ donors have not reported increased cardiovascular and all-cause mortality, but results may have been confounded by selection bias in the control groups. In most studies, controls were selected from the general population, which includes adults with medical conditions that would make them ineligible for kidney donation.10.Fehrman-Ekholm I. Elinder C.G. Stenbeck M. et al.Kidney donors live longer.Transplantation. 1997; 64: 976-978Crossref PubMed Scopus (328) Google Scholar, 11.Ibrahim H.N. Foley R. Tan L. et al.Long-term consequences of kidney donation.N Engl J Med. 2009; 360: 459-469Crossref PubMed Scopus (819) Google Scholar, 12.Mjoen G. Reisaeter A. Hallan S. et al.Overall and cardiovascular mortality in Norwegian kidney donors compared to the background population.Nephrol Dial Transplant. 2012; 27: 443-447Crossref PubMed Scopus (55) Google Scholar As a result, these controls would have been less healthy than the living donors and an effect of organ donation on all-cause and cardiovascular mortality could have been underestimated. Three studies have included control groups selected to have comparable health status to the living donors, and each of these demonstrated no increase in cardiovascular disease or mortality over a follow-up time of approximately 6 years.3.Segev D.L. Muzaale A.D. Caffo B.S. et al.Perioperative mortality and long-term survival following live kidney donation.JAMA. 2010; 303: 959-966Crossref PubMed Scopus (552) Google Scholar,13.Garg A.X. Prasad G.V. Thiessen-Philbrook H.R. et al.Cardiovascular disease and hypertension risk in living kidney donors: an analysis of health administrative data in Ontario, Canada.Transplantation. 2008; 86: 399-406Crossref PubMed Scopus (111) Google Scholar,14.Garg A.X. Meirambayeva A. Huang A. et al.Cardiovascular disease in kidney donors: matched cohort study.BMJ. 2012; 344: e1203Crossref PubMed Scopus (154) Google Scholar It is possible, however, that living donors may be at increased risk of death for many years beyond the period that has been investigated to date. Thus an analysis with a longer follow-up time may be necessary to examine the possible impact of living donor nephrectomy. Occurrence of ESRD in living donors has also been observed long term after kidney donation although the absolute number of cases presented has been very low, and it is uncertain whether the statistical assessment used has been sufficient. The aim of the present study was to estimate long-term all-cause mortality, cardiovascular mortality, and risk for ESRD in kidney donors compared with a selected control group screened for eligibility for live-kidney donation. During 1963–2007, 2269 live-kidney donations were performed at Oslo University Hospital. After excluding marginal donors, 1901 donors were included (Figure 1). Among these, 1519 were first-degree relatives, 89 were other relatives, and 293 were unrelated. Median follow-up time was 15.1 (1.5–43.9) years. Mean estimated glomerular filtration rate (eGFR) at donation was 104.7ml/minper1.73m2 (n=1766, s.d. 13.7). All donors were Caucasians. Controls were included from the Health Study of Nord-Trøndelag (HUNT) population study. Out of the 74,991 individuals participating in this population-based survey, a control group of 32,621 was constructed to fit criteria for kidney donation (Table 1). Median follow-up time for the control group was 24.9 (0.1–26.0) years.Table 1Baseline characteristics of kidney donors and controlsKidney donorsControlsAge, years46.0±11.5n=190137.6±11.7n=32,621Male gender, %41.0n=190146.9n=32,621Current smoking, %41.5n=137539.5n=25,993Systolic BP, mmHg123.3±10.0n=1768121.4±10.4n=31,398Diastolic BP, mmHg77.4±7.2n=176877.2± 7.9n=31,394BMI, kg/m224.2± 2.8n=155823.5± 2.6n=31,421Abbreviations: BMI, body mass index; BP, blood pressure. Open table in a new tab Abbreviations: BMI, body mass index; BP, blood pressure. For donors, outcome data on all-cause mortality and renal replacement therapy were ascertained as of January 2010 and cardiovascular mortality as of January 2008. For controls, all outcome data were ascertained as of January 2010. During the observation period, there were 224 deaths among 1901 kidney donors from the initial inclusion group, 68 (30.4%) of which were due to cardiovascular disease. There were 2425 deaths among the 32,621 controls, 688 (28.4%) of which were due to cardiovascular disease. No donors died during or immediately after the surgical procedure. Figure 2 shows the survival data for donors and controls. The survival curves were significantly different (P<0.001). Table 2a shows the hazard ratio (HR) for death by any cause in kidney donors compared with controls. The unadjusted risk associated with kidney donation was 2.49 (95% confidence interval (CI), 2.13–2.91, P<0.001). In adjusted complete case analysis, the HR for kidney donors was 1.48 (95% CI, 1.17–1.88, P=0.001). After multiple imputation, HR was 1.30 (95% CI, 1.11–1.52, P=0.001). There was a corresponding increase in cardiovascular mortality (HR 1.40, 95% CI 1.03–1.91, P=0.03) (Table 2b).Table 2aHazard ratio for death by any cause in kidney donors versus controlsUnadjusted (n=27,368–34,522)Adjusted 1aAdjusted for age, gender, year of inclusion, systolic BP, smoking, and BMI. (n=2038/27,144)Adjusted 2bAfter multiple imputation. (n=2649/34,522)Kidney donation2.49 (2.13–2.91, P<0.001)1.48 (1.17–1.88, P=0.001)1.30 (1.11–1.52, P=0.001)Inclusion year0.95 (0.93–0.97, P<0.001)0.95 (0.93–0.98, P<0.001)0.97 (0.95–0.98, P<0.001)Age, years1.10 (1.10–1.11, P<0.001)1.10 (1.10–1.11, P<0.001)1.10 (1.10–1.11, P<0.001)Male1.62 (1.49–1.73, P<0.001)1.44 (1.32–1.58, P<0.001)1.52 (1.41–1.65, P<0.001)Systolic BP1.04 (1.03–1.04, P<0.001)1.00 (1.00–1.01, P=0.45)1.00 (1.00–1.01, P<0.24)Smoking1.64 (1.50–1.79, P<0.001)1.97 (1.80–2.15, P<0.001)1.91 (1.74–2.10, P<0.001)BMI1.12 (1.11–1.14, P<0.001)1.02 (1.00–1.04, P=0.06)1.01 (0.99–1.03, P=0.21)Abbreviations: BMI, body mass index; BP, blood pressure.a Adjusted for age, gender, year of inclusion, systolic BP, smoking, and BMI.b After multiple imputation. Open table in a new tab Table 2bHazard ratio for cardiovascular death in kidney donors versus controlsUnadjusted (n=27,368–34,522)Adjusted 1aAdjusted for age, gender, year of inclusion, systolic BP, smoking, and BMI. (n=568/27,144)Adjusted 2bAfter multiple imputation. (n=756/34,522)Kidney donation3.18 (2.39–4.23, P<0.001)1.52 (0.95–2.43, P=0.08)1.40 (1.03–1.91, P=0.03)Inclusion year0.90 (0.87–0.94, P<0.001)0.92 (0.87–0.98, P=0.005)0.95 (0.92–0.98, P=0.004)Age, years1.13 (1.13–1.14, P<0.001)1.13 (1.12–1.14, P<0.001)1.13 (1.13–1.14, P<0.001)Male2.23 (1.92–2.60, P<0.001)2.04 (1.71–2.44, P<0.001)2.04 (1.75–2.38, P<0.001)Systolic BP1.05 (1.05–1.06, P<0.001)1.01 (1.00–1.02, P=0.15)1.01 (1.00–1.02, P=0.05)Smoking1.82 (1.55–2.14, P<0.001)2.30 (1.94–2.72, P<0.001)2.10 (1.75–2.51, P<0.001)BMI1.17 (1.14–1.21, P<0.001)1.05 (1.01–1.08, P=0.006)1.03 (1.00–1.07, P=0.03)Abbreviations: BMI, body mass index; BP, blood pressure.a Adjusted for age, gender, year of inclusion, systolic BP, smoking, and BMI.b After multiple imputation. Open table in a new tab Abbreviations: BMI, body mass index; BP, blood pressure. Abbreviations: BMI, body mass index; BP, blood pressure. A total of nine donors (0.47%) developed ESRD. All were family members. Median time from donation was 18.7 (10.3–24.3) years. Renal failure in donors was mainly caused by immunological diseases: glomerulonephritis (n=3), systemic lupus erythematosus (n=1), Wegener’s granulomatosis (n=1), ANCA (anti-neutrophil cytoplasmic antibodies)-positive vasculitis (n=1), sarcoidosis (n=1), and diabetes/nephrosclerosis (n=2). In the control group, 22 individuals developed ESRD. Reported causes were glomerulonephritis (n=5), pyelonephritis (n=4), polycystic kidney disease (n=4), hypertension (n=3), diabetes (n=1), amyloidosis (n=1), systemic lupus erythematosus (n=1), drug induced nephropathy (n=1), medullary cystic disease (n=1), and unknown (n=1). The crude incidence of ESRD in donors was 302 per million person-years. The overall incidence rate for development of ESRD in Norway is about 100 per million per person-year. After multiple imputation of missing values, the estimated HR for ESRD in kidney donors was 11.38 (4.37–29.63, P<0.001) (Table 2c).Table 2cCox regression analysis for risk of end-stage renal disease in kidney donors versus controlsUnadjusted (n=25,063–35,222)Adjusted 1aAdjusted for age, gender, and year of inclusion. (n=31/34,522)Adjusted 2bAfter multiple imputation and further adjustments for blood pressure, BMI, and smoking. (n=31/34,522)Kidney donation18.99 (8.63–41.76, P<0.001)11.42 (4.43–29.40, P<0.001)11.38 (4.37–29.63, P<0.001)Inclusion year0.76 (0.70–0.83, P<0.001)0.91 (0.83–1.00, P=0.04)0.90 (0.82–0.99, P=0.03)Age, years1.04 (1.01–1.07, P=0.003)1.03 (1.00–1.06, P=0.04)1.02 (0.99–1.05, P=0.13)Male0.94 (0.46–1.91, P=0.86)1.04 (0.51–2.11, P=0.10)0.90 (0.43–1.88, P=0.77)Systolic BP1.03 (1.00–1.07, P=0.14)—1.01 (1.00–1.06, P=0.03)Smoking1.09 (0.48–2.46, P=0.83)—1.19 (0.51–2.76, P=0.68)BMI1.19 (1.02–1.38, P=0.03)—1.13 (0.96–1.32, P=0.14)Abbreviations: BMI, body mass index; BP, blood pressure.a Adjusted for age, gender, and year of inclusion.b After multiple imputation and further adjustments for blood pressure, BMI, and smoking. Open table in a new tab Abbreviations: BMI, body mass index; BP, blood pressure. Assessing competing risks for the outcomes of cardiovascular death and ESRD did not change our findings. Neither did repeating analyses after excluding donors with eGFR 140/90mmHg, BMI>30kg/m2, >70 years or <20 years of age, macroalbuminuria, or eGFR <70ml/minper1.73m2 (Figure 1). eGFR was calculated using the chronic kidney disease Epidemiology Collaboration equation.23.Levey A.S. Stevens L.A. Estimating GFR using the CKD Epidemiology Collaboration (CKD-EPI) creatinine equation: more accurate GFR estimates, lower CKD prevalence estimates, and better risk predictions.Am J Kidney Dis. 2010; 55: 622-627Abstract Full Text Full Text PDF PubMed Scopus (605) Google Scholar Healthy matched controls were included from the HUNT 1, a population-based survey carried out between 1984 and 1987. This cohort was selected to allow for sufficient follow-up time. All residents of Nord-Trøndelag county, aged ≥20 years, were eligible, out of which 74,991 (88.1%) took part in the survey. A more comprehensive description of the survey is available at the HUNT study’s website (www.medisin.ntnu.no/hunt/). To achieve appropriate controls for kidney donors, only subjects with BP≤140/90mmHg and BMI≤30kg/m2 were included. Furthermore, only those who rated their own health as ‘good’ or ‘excellent’ were selected. Individuals with diabetes, cardiovascular disease, or using BP-lowering medication were excluded. Data on renal function and albuminuria were not available for controls. No donors were lost to follow-up. Information on mortality and cause of death was obtained from Statistics Norway, through a unique 11-digit identification number given to all Norwegian inhabitants at birth. Causes of death were based on International Statistical Classification of Diseases and Related Health Problems (ICD), versions 8–10. Cardiovascular death was defined by ICD-10 codes ranging from I00 through I99. Sudden death (ICD 10 code R99) was not included as cardiovascular death. All donors and controls with ESRD receiving chronic dialysis treatment or kidney transplantation were identified by cross-linking the identity of donors to the Norwegian Renal Registry. This registry includes all Norwegians receiving renal replacement therapy. The annual report can be accessed at www.nephro.no Statistical analyses were performed using Stata version 11SE (StataCorp, 4905, StataCorp, College Station, TX). Parametric and non-parametric tests were chosen as appropriate for descriptive comparisons. Cox regression was used to investigate the outcomes of all-cause mortality, cardiovascular mortality, and renal replacement therapy. The proportional hazards assumption was tested using observed versus expected plots and Schoenfeld residuals. Survival analyses were adjusted for age, gender, year of inclusion (donation), systolic BP, smoking status, and BMI. Due to missing data for smoking (27.4%), systolic BP (6.3%), and BMI (17.3%), survival analyses were repeated after replacing missing data using multiple imputations.24.Sterne J.A. White I.R. Carlin J.B. et al.Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls.BMJ. 2009; 338: b2393Crossref PubMed Scopus (3984) Google Scholar Missing values were estimated based on known covariates and outcome variables; 20 sets were created and pooled for analysis. Final multivariate analyses after multiple imputations, shown in the tables as ‘adjusted 2’, were considered the main analyses. To enable construction of a survival curve, matching on age, gender, systolic BP, BMI, and smoking was done using coarsened exact matching.25.Blackwell M. Iacus S. King G. et al.CEM: coarsened exact matching in Stata.Stata J Nephrol. 2009; 9: 524-546Google Scholar After multiple imputations and matching, survival curves were constructed adjusted for year of inclusion. For the outcomes of ESRD and cardiovascular mortality, competing risks were assessed by sensitivity analysis and competing risk regression.26.Fine J.P. Gray R.J. A proportion hazards model for the subdistribution of a competing risk.J Am Stat Ass. 1999; 94: 496-509Crossref Scopus (9182) Google Scholar,27.Kleinbaum D.G. Klein M. Survival analysis: A Self-learning Text. Springer, New York, Dordrecht, Heideberg, London2012Crossref Google Scholar In accordance with some center’s practice for pre-donation renal function, Cox regression analyses were repeated with a cutoff for eGFR of 80ml/min per1.73m2, which did not change our results. This project was supported by a grant from the Norwegian Extrafoundation. Correction to "Long-term risks for kidney donors"Kidney InternationalVol. 88Issue 6PreviewCorrection to:Kidney International (2014) 86, 162–167; doi:10.1038/ki.2013.460 Full-Text PDF Open ArchiveKidney International 60th anniversary edition: transplantation—the chosen 5Kidney InternationalVol. 98Issue 5PreviewKidney International, as the flagship journal of the International Society of Nephrology, has witnessed the transition of kidney transplantation from a highly experimental procedure in the 1960s some 6 years after the first successful living donor transplant in Boston and contributed to the evolution of transplantation to the preferred treatment for patients with kidney failure. As a journal that grew up and came of age in golden age of physiology and pathology, seminal papers in the transplant field were published in its pages. Full-Text PDF
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