letter to the editor
Kidney donors at increased risk? Additional studies are needed To the Editor: The recent article by Mj en et al.1 reports that former kidney donors have increased long-term risk of death, cardiovascular death, and end-stage renal disease (ESRD). The authors note the increased risk to be small, and conclude that they will continue to promote living donation. Yet, we are already aware of insurance companies citing these data (in the United States) when denying or charging increased rates for life and health insurance. Despite its strengths (comparing donors with healthy controls), there are weaknesses in the analysis: (1) all postdonation ESRD is in related donors; relatives of those with ESRD are known to have increased ESRD rates.2–4 (2) Most ESRD was due to immunologic disease, which would have affected both kidneys. (3) The statistical analysis is a concern due to the following: (a) 1901 donors are compared with 32,621 controls with much of the data imputed; (b) the reported hazard ratio for ESRD in donors was 11.38, yet only 0.47% of donors developed ESRD; (c) the donors were 8 years older than controls and, in the analysis adjusted for age, cardiovascular death was nonsignificant; (d) there is uncertainty about the randomness of imputed data, especially on key determinants of survival such as smoking; and (e) 9512 potential controls were eliminated because of ‘reduced general health’. (4) Rather than the entire country, the matched controls were from a relatively small, genetically homogenous geographic area. (5) The difference in mortality was about 5% and only seen after 15 years; the number at risk at or beyond this time point was not stated. (6) The donor cohort originated in the 1970s, whereas controls began observation between 1984 and 1988; in the interval, average lifespan increased. Clearly, Mj en et al. make important observations and future candidates need to be informed of the results. However, additional studies, addressing the limitations noted, are needed to validate these findings. 1. 2.
3.
4.
Mj en G, Hallan S, Hartmann A et al. Long-term risks for kidney donors. Kidney Int 2014; 86: 162–167. Lei HH, Perneger TV, Klag MJ et al. Familial aggregation of renal disease in a population-based case-control study. J Am SocNephrol 1998; 9: 1270–1276. O’Dea DF, Murphy SW, Hefferton D et al. Higher risk for renal failure in firstdegree relatives of white patients with end-stage renal disease: a population-based study. Am J Kidney Dis 1998; 32: 794–801. McClellan WM, Satko SG, Gladstone E et al. Individuals with a family history of ESRD are a high-risk population for CKD: implications for targeted surveillance and intervention activities. Am J Kidney Dis 2009; 53(3 Suppl 3): S100–S106.
Arthur J. Matas1, E.S. Woodle2, Robert S. Gaston3, John L.R. Forsythe4, Jonas Wadstro¨ m5 and Mark D. Stegall6 1
Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA; 2Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; 3Department of Medicine, University of Alabama, Birmingham, Alabama, USA; 4Transplant
650
Unit, Royal Infirmary of Edinburgh, University of Edinburgh, Edinburgh, UK; Department of Transplantation, Karolinska University Hospital, Solna, Sweden and 6Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA Correspondence: Arthur J. Matas, Department of Surgery, University of Minnesota, 420 Delaware Street S.E., MMC 195, Minneapolis, Minnesota 55455, USA. E-mail: [email protected] 5
Kidney International (2014) 86, 650; doi:10.1038/ki.2014.146
The Authors Reply: We appreciate the comments from Matas et al.,1 and agree with their worry that insurance companies are citing these data when assessing rates for life or health insurance. They raise some statistical concerns, which we would like to address. First, the estimated hazard ratio (HR) for end-stage renal disease (ESRD) was 11.38 for living kidney donors versus controls. This increased risk has recently been confirmed in a large US study,2 although the corresponding absolute risk increase is low due to the rarity of ESRD among donors and controls. Second, different mean age between donors and controls was handled by adjusted analyses. Third, Matas et al.1 question the multiple imputation. HRs were relatively similar in complete case analyses and after multiple imputations for missing data, indicating that missing data were missing at random and strengthening the validity of our findings. Although the P-value for cardiovascular death was 0.08 in complete case analysis, this was related to fewer events in this analysis as HR was similar to that seen after multiple imputation. Fourth, the matched controls can be considered representative as the Norwegian population is relatively homogenous, and the HUNT study is regarded as characteristic of Norway as a whole. Fifth, even 20 years after donation, there were still 599 donors available for analysis, which is an adequate number for analyses. Also, we accounted for differences in year of donation/inclusion by statistical adjustment. Finally, repeating survival analyses by excluding those who donated before 1984 did not change results. Having made these points, we would like to stress that we agree on the need for further studies to validate our findings. 1. 2.
Matas AJ, Woodle ES, Gaston RS et al. Kidney donors at increased risk? Additional studies are needed. Kidney Int 2014; 86: 650. Muzaale AD, Massie AB, Wang MC et al. Risk of end-stage renal disease following live kidney donation. JAMA 2014; 311: 579.
Geir Mj en1, Stein Hallan2, Friedo W. Dekker3 and Hallvard Holdaas4 1
Oslo University Hospital, Department of Medicine, Oslo, Norway; Norwegian University of Science and Technology, Institute of Cancer Research and Molecular Biology, St Olav’s Hospital, Trondheim, Norway; 3 LUMC–Clinical Epidemiology, Leiden, The Netherlands and 4National Hospital, Oslo, Norway Correspondence: Geir Mj en, Oslo University Hospital, Department of Medicine, Kirkeveien, Oslo 0027, Norway. E-mail: [email protected] 2
Kidney International (2014) 86, 650; doi:10.1038/ki.2014.148
Kidney International (2014) 86, 649–653
Kidney donors at increased risk? Additional studies are needed To the Editor: The recent article by Mj en et al.1 reports that former kidney donors have increased long-term risk of death, cardiovascular death, and end-stage renal disease (ESRD). The authors note the increased risk to be small, and conclude that they will continue to promote living donation. Yet, we are already aware of insurance companies citing these data (in the United States) when denying or charging increased rates for life and health insurance. Despite its strengths (comparing donors with healthy controls), there are weaknesses in the analysis: (1) all postdonation ESRD is in related donors; relatives of those with ESRD are known to have increased ESRD rates.2–4 (2) Most ESRD was due to immunologic disease, which would have affected both kidneys. (3) The statistical analysis is a concern due to the following: (a) 1901 donors are compared with 32,621 controls with much of the data imputed; (b) the reported hazard ratio for ESRD in donors was 11.38, yet only 0.47% of donors developed ESRD; (c) the donors were 8 years older than controls and, in the analysis adjusted for age, cardiovascular death was nonsignificant; (d) there is uncertainty about the randomness of imputed data, especially on key determinants of survival such as smoking; and (e) 9512 potential controls were eliminated because of ‘reduced general health’. (4) Rather than the entire country, the matched controls were from a relatively small, genetically homogenous geographic area. (5) The difference in mortality was about 5% and only seen after 15 years; the number at risk at or beyond this time point was not stated. (6) The donor cohort originated in the 1970s, whereas controls began observation between 1984 and 1988; in the interval, average lifespan increased. Clearly, Mj en et al. make important observations and future candidates need to be informed of the results. However, additional studies, addressing the limitations noted, are needed to validate these findings. 1. 2.
3.
4.
Mj en G, Hallan S, Hartmann A et al. Long-term risks for kidney donors. Kidney Int 2014; 86: 162–167. Lei HH, Perneger TV, Klag MJ et al. Familial aggregation of renal disease in a population-based case-control study. J Am SocNephrol 1998; 9: 1270–1276. O’Dea DF, Murphy SW, Hefferton D et al. Higher risk for renal failure in firstdegree relatives of white patients with end-stage renal disease: a population-based study. Am J Kidney Dis 1998; 32: 794–801. McClellan WM, Satko SG, Gladstone E et al. Individuals with a family history of ESRD are a high-risk population for CKD: implications for targeted surveillance and intervention activities. Am J Kidney Dis 2009; 53(3 Suppl 3): S100–S106.
Arthur J. Matas1, E.S. Woodle2, Robert S. Gaston3, John L.R. Forsythe4, Jonas Wadstro¨ m5 and Mark D. Stegall6 1
Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA; 2Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; 3Department of Medicine, University of Alabama, Birmingham, Alabama, USA; 4Transplant
650
Unit, Royal Infirmary of Edinburgh, University of Edinburgh, Edinburgh, UK; Department of Transplantation, Karolinska University Hospital, Solna, Sweden and 6Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA Correspondence: Arthur J. Matas, Department of Surgery, University of Minnesota, 420 Delaware Street S.E., MMC 195, Minneapolis, Minnesota 55455, USA. E-mail: [email protected] 5
Kidney International (2014) 86, 650; doi:10.1038/ki.2014.146
The Authors Reply: We appreciate the comments from Matas et al.,1 and agree with their worry that insurance companies are citing these data when assessing rates for life or health insurance. They raise some statistical concerns, which we would like to address. First, the estimated hazard ratio (HR) for end-stage renal disease (ESRD) was 11.38 for living kidney donors versus controls. This increased risk has recently been confirmed in a large US study,2 although the corresponding absolute risk increase is low due to the rarity of ESRD among donors and controls. Second, different mean age between donors and controls was handled by adjusted analyses. Third, Matas et al.1 question the multiple imputation. HRs were relatively similar in complete case analyses and after multiple imputations for missing data, indicating that missing data were missing at random and strengthening the validity of our findings. Although the P-value for cardiovascular death was 0.08 in complete case analysis, this was related to fewer events in this analysis as HR was similar to that seen after multiple imputation. Fourth, the matched controls can be considered representative as the Norwegian population is relatively homogenous, and the HUNT study is regarded as characteristic of Norway as a whole. Fifth, even 20 years after donation, there were still 599 donors available for analysis, which is an adequate number for analyses. Also, we accounted for differences in year of donation/inclusion by statistical adjustment. Finally, repeating survival analyses by excluding those who donated before 1984 did not change results. Having made these points, we would like to stress that we agree on the need for further studies to validate our findings. 1. 2.
Matas AJ, Woodle ES, Gaston RS et al. Kidney donors at increased risk? Additional studies are needed. Kidney Int 2014; 86: 650. Muzaale AD, Massie AB, Wang MC et al. Risk of end-stage renal disease following live kidney donation. JAMA 2014; 311: 579.
Geir Mj en1, Stein Hallan2, Friedo W. Dekker3 and Hallvard Holdaas4 1
Oslo University Hospital, Department of Medicine, Oslo, Norway; Norwegian University of Science and Technology, Institute of Cancer Research and Molecular Biology, St Olav’s Hospital, Trondheim, Norway; 3 LUMC–Clinical Epidemiology, Leiden, The Netherlands and 4National Hospital, Oslo, Norway Correspondence: Geir Mj en, Oslo University Hospital, Department of Medicine, Kirkeveien, Oslo 0027, Norway. E-mail: [email protected] 2
Kidney International (2014) 86, 650; doi:10.1038/ki.2014.148
Kidney International (2014) 86, 649–653
