Letters
P values and confidence intervals fully account for the technique we used. Matas and colleagues also misinterpreted our lifetime risk calculation, inferring that the lifetime ESRD risk of “healthy controls younger than 30 years was 0 per 10 000” rather than that ESRD risk by age 30 was 0 per 10 000 controls who entered the risk set prior to that age. Drs Kiberd and Tennankore suggest that our method of splicing together early follow-up intervals to estimate lifetime risks might have resulted in underestimation of risk. We agree that estimating lifetime risk of ESRD based on 15-year follow-up in different age cohorts is an approximation; unfortunately, it will be decades before we have follow-up long enough for better lifetime estimates. We also agree that cumulative risk will vary by donor characteristics; our cumulative risk estimates should only be interpreted as averages. Of 3 groups of researchers, 2 believe we have overestimated and 1 believes we have underestimated donor risk of ESRD. We disagree with several concerns raised about our methods, and we hope we have clarified these. We agree that our findings should not discourage kidney donation because the risks remain very low. However, better understanding and quantifying risk associated with donation remain a priority. Abimereki D. Muzaale, MD, MPH Allan B. Massie, PhD, MHS Dorry L. Segev, MD, PhD Author Affiliations: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. Corresponding Author: Dorry L. Segev, MD, PhD, Department of Surgery, Johns Hopkins Medical Institutions, 720 Rutland Ave, Baltimore, MD 21205 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Segev reported receiving institutional grant support from the National Institutes of Health. No other disclosures were reported. 1. Segev DL, Muzaale AD, Caffo BS, et al. Perioperative mortality and long-term survival following live kidney donation. JAMA. 2010;303(10):959-966. 2. Rust KF, Rao JN. Variance estimation for complex surveys using replication techniques. Stat Methods Med Res. 1996;5(3):283-310.
Outcomes After Kidney Donation To the Editor Dr Muzaale and colleagues1 reported the estimated lifetime risk of end-stage renal disease (ESRD) in donors as 0.9% compared with 0.14% in healthy nondonors and 3.26% in unscreened nondonors (general population), an 8-fold higher cumulative incidence of ESRD in donors compared with healthy nondonor controls. These data are important for discussions with prospective donors, especially donors of African American descent who have the highest relative risk. The Editorial by Drs Gill and Tonelli that accompanied this study has 2 inaccuracies that should temper the conclusion that “the low absolute risk of ESRD should reassure future donors of the safety of living kidney donation.”2 First, Gill and Tonelli celebrated the 56-year postdonation survival of Ron Herrick as proof that a person can live with a solitary kidney. Although Herrick lived to the age of 79 years (not 81 years) after donating at the age of 23 years, he spent most 94
of his last decade requiring dialysis, a fact rarely mentioned.3 Whether living with a single kidney accelerated his development of ESRD, cardiovascular disease, and death is not known, an uncertainty that also exists for others who donate and develop ESRD after donation. Second, Gill and Tonelli stated that the increased risk of ESRD should lead to closer follow-up: “donors should have kidney function, albuminuria, blood glucose, and blood pressure assessed annually by their primary care physician,” which is unchanged from the current recommendation. Because 18% of living donors do not have health insurance at the time of donation,4 these donors are unlikely to get routine yearly follow-up past that required for transplant centers to perform for the first 2 years following donation. Additionally, many donors with insurance will not obtain follow-up. To do everything possible to ensure and improve the safety of living donation, the transplant community should be more stringent about follow-up, support a longitudinal registry, and maintain the ability to contact previous donors to obtain blood samples as needed for subsequent testing. Living kidney donation is an important strategy for treating ESRD. The transplant community has a moral obligation to ensure that it is as safe as possible and that donors know the actual risks they face.5 Gill and Tonelli suggested that donation is safe, but the data presented by Muzaale et al1 convincingly show an increased risk of renal failure after donation that has not been fully appreciated previously. Lainie Friedman Ross, MD, PhD J. Richard Thistlethwaite Jr, MD, PhD Author Affiliations: Department of Pediatrics, University of Chicago, Chicago, Illinois (Ross); Department of Surgery, University of Chicago, Chicago, Illinois (Thistlethwaite). Corresponding Author: Lainie Friedman Ross, MD, PhD, Department of Pediatrics, University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving a Robert Wood Johnson Investigator Award in Health Policy grant to write a book studying the ethical and policy issues raised by living donor transplantation. 1. Muzaale AD, Massie AB, Wang M-C, et al. Risk of end-stage renal disease following live kidney donation. JAMA. 2014;311(6):579-586. 2. Gill JS, Tonelli M. Understanding rare adverse outcomes following living kidney donation. JAMA. 2014;311(6):577-578. 3. Crosby C. Transplant just one chapter of first organ donor's life. http://www .kjonline.com/news/transplant-just-one-chapter-of-first-organ-donors-life _2011-01-01.html?pagenum=full. Accessed February 24, 2014. 4. Gibney EM, Doshi MD, Hartmann EL, Parikh CR, Garg AX. Health insurance status of US living kidney donors. Clin J Am Soc Nephrol. 2010;5(5):912-916. 5. Davis CL, Cooper M. The state of US living kidney donors. Clin J Am Soc Nephrol. 2010;5(10):1873-1880.
To the Editor The recent Editorial by Drs Gill and Tonelli1 accompanying our study2 of ESRD risk following kidney donation raised several methodological questions that we believe merit response. Gill and Tonelli suggested that “repeated inclusion of controls with long event-free survival … may have underestimated the risk of ESRD in nondonors.” We fail to see how re-
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peated sampling could lead to bias, but it does affect variance. We conducted a bootstrap specifically designed to account for the variance of repeated sampling on rare outcomes. Using this bootstrap and other appropriate statistical tests, we reported our findings as statistically significant. Furthermore, any differences in follow-up (or duration of event-free survival) were accounted for by our use of survival analysis. Gill and Tonelli mention the “competing risk of death” which may be higher in nondonors. However, failure to account for higher death rates in nondonors would cause our study to overestimate ESRD incidence in nondonors, producing bias in the opposite direction from that posited by the Editorial, as has been described both theoretically 3 and empirically.4 Our ESRD ascertainment captured outcomes in donors who listed preemptively (before dialysis onset), but not preemptive listings by nondonors. However, as Gill and Tonelli point out, our follow-up time was longer for nondonors. Most nondonors who listed preemptively would either receive a transplant or initiate dialysis shortly thereafter, both of which are captured by our algorithm. Regardless, a slight delay in ESRD ascertainment of nondonors would hardly be sufficient to account for our observations. Gill and Tonelli contrast our findings with the higher crude ESRD incidence in the screened (but unmatched) NHANES population. This is an inappropriate comparison that suffers from considerable confounding because NHANES purposefully oversampled older, black, and Hispanic persons.5 Because we show that these 3 subgroups have much higher ESRD risk, only the matched analysis gives an unbiased estimate of absolute risk increase of ESRD in donors compared with nondonors. We believe that the purported limitations raised by Gill and Tonelli do not diminish confidence in our findings, including our relative risk estimates. We agree, however, that our findings show “low absolute risk” of donation, and also that “progressive kidney disease may be more likely to cause ESRD in donors, who have less renal reserve following donation, than in nondonors.” We hope that our study will guide counseling of kidney donors and inform future research. Allan B. Massie, PhD Abimereki D. Muzaale, MD, MPH Dorry L. Segev, MD, PhD Author Affiliations: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. Corresponding Author: Dorry L. Segev, MD, PhD, Department of Surgery, Johns Hopkins University School of Medicine, 720 Rutland Ave, Baltimore, MD 21205 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Segev reported receiving institutional grant support from the National Institutes of Health. No other disclosures were reported. 1. Gill JS, Tonelli M. Understanding rare adverse outcomes following living kidney donation. JAMA. 2014;311(6):577-578. 2. Muzaale AD, Massie AB, Wang M-C, et al. Risk of end-stage renal disease following live kidney donation. JAMA. 2014;311(6):579-586. 3. Putter H, Fiocco M, Geskus RB. Tutorial in biostatistics: competing risks and multi-state models. Stat Med. 2007;26(11):2389-2430.
4. Turin TC, Tonelli M, Manns BJ, et al. Lifetime risk of ESRD. J Am Soc Nephrol. 2012;23(9):1569-1578. 5. Centers for Disease Control and Prevention. NHANES III Web Tutorial. http: //www.cdc.gov/nchs/tutorials/NHANES/SurveyDesign/SampleDesign/Info1_III .htm. Accessed March 17, 2014.
In Reply: We apologize for the error regarding Mr Herrick’s age and health status and a correction accompanies this letter. Of course, whether a specific individual did or did not experience complications from a procedure is not useful for evaluating that procedure’s safety; this is why large clinical studies are needed. Drs Ross and Thistlethwaite state that 18% of living donors do not have health insurance at the time of donation. Nearly all developed countries outside the United States provide universal insurance coverage for such follow-up, so this statistic does not reflect a general failure to attend to the needs of kidney donors. Instead, it is evidence of the need for health care reform in the United States. As Muzaale et al1 have shown, the absolute risk of kidney failure following living donation is extremely low in the United States despite the shortcomings of the current system of followup. Given the absence of evidence that kidney failure is causally linked to donation, we agree that long-term donor follow-up may be best justified as a moral obligation rather than an evidence-based requirement. With respect, we believe that the letter from Dr Massie and colleagues has missed the forest for the trees. Their study was rigorously conducted but does have significant limitations that reduce confidence in the relative risk estimates. Their results were based on a complex bootstrapped model that represented the experience of 96 217 individuals, but only 17 actual (compared with simulated) nondonor controls who actually developed kidney failure. We do not believe that statistical methods (no matter how sophisticated) ensure the generalizability of these controls to the entire population of potential living donors. Massie and colleagues claim that their study showed that the cumulative incidence of kidney failure was higher among older black and Hispanic participants than whites. The number of actual individuals who developed kidney failure was not presented by age or race, but because there were only 17 cases across all age and race categories, these results are even less reliable. Muzaale et al1 should have provided the actual number of ESRD cases by age and race to substantiate their claim that unmatched comparisons of crude ESRD incidence are biased. Last, Massie and colleagues misunderstood our comment about competing risks. It is true that using a formal competing risk framework would have led to higher relative risk estimates than those from the Kaplan-Meier estimates presented in the study. We do not dispute this statement, which is not the real issue. Instead, we were highlighting that selecting an inappropriate control group can lead to biased relative risk estimates. Specifically, because people cannot be initiated on dialysis after they die, selecting controls who are at higher risk of death than the comparator group of kidney donors will spuriously increase the apparent risk of kidney fail-
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ure associated with kidney donation. We hope Massie and colleagues will present analyses comparing the risk of the composite outcome of kidney failure or death between donors and matched nondonors. We maintain that the relative risk estimates presented by Muzaale et al1 have significant limitations and should be used with caution when counseling potential donors. However, their absolute risk estimates of kidney failure following living kidney donation are the best available and will be useful to potential donors.
cellation is open surgery, risks and benefits of the procedures must be compared. However, it has been demonstrated that power morcellation of a uterus can be performed inside of an insufflated bag within the peritoneal cavity.4 This technique affords the advantages of morcellation while avoiding tissue dissemination, thus obviating the choice between the benefits of minimally invasive surgery and the oncological risks of tissue dispersion. Although not currently in common practice, this solution should be adopted or improved to appropriately and safely care for patients. Alexander Melamed, MD, MPH
John S. Gill, MD Marcello Tonelli, MD
Author Affiliation: Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Boston, Massachusetts.
Author Affiliations: Division of Nephrology, University of British Columbia, Vancouver, Canada (Gill); Department of Medicine, University of Alberta, Edmonton, Alberta, Canada (Tonelli).
Corresponding Author: Alexander Melamed, MD, MPH, Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, 75 Francis St, Boston, MA 02115 ([email protected]).
Corresponding Author: John S. Gill, MD, Division of Nephrology, University of British Columbia, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada ([email protected]).
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
1. Kho KA, Nezhat CH. Evaluating the risks of electric uterine morcellation. JAMA. 2014;311(9):905-906.
1. Muzaale AD, Massie AB, Wang M-C, et al. Risk of end-stage renal disease following live kidney donation. JAMA. 2014;311(6):579-586.
2. Park JY, Park SK, Kim DY, et al. The impact of tumor morcellation during surgery on the prognosis of patients with apparently early uterine leiomyosarcoma. Gynecol Oncol. 2011;122(2):255-259.
Electric Uterine Morcellation
3. Schwingl PJ, Ory HW, Visness CM. Estimates of the risk of cardiovascular death attributable to low-dose oral contraceptives in the United States. Am J Obstet Gynecol. 1999;180(1 pt 1):241-249.
To the Editor Drs Kho and Nezhat1 discussed the risks associated with electric morcellation of uterine tissue within a patient’s abdomen, a practice that is common in minimally invasive gynecologic surgery. The authors suggested that current evidence is insufficient to estimate the harm that results from dissemination of an occult uterine leiomyosarcoma when morcellation is used for presumed fibroids. The authors also stated that devices that allow surgeons to perform electric morcellation inside an endoscopic bag are “being developed.” I would like to discuss both points. Published studies, small as they are, do allow for the calculation of harm associated with morcellation of an occult leiomyosarcoma. In a series of 56 consecutive patients with earlystage leiomyosarcomas treated at a South Korean tertiary care center between 1989 and 2010, Park et al2 found that recurrencefree and overall survival were significantly reduced among patients with a history of uterine tissue morcellation. Five-year survival was 46% among patients who underwent morcellation compared with 73% when uteri were removed intact. Based on these data, inadvertent morcellation of a leiomyosarcoma in 100 patients may result in 27 excess deaths. Assuming conservatively that among 1000 patients undergoing surgery for uterine fibroids, 1 patient will have an occult leiomyosarcoma, the rate of death from leiomyosarcoma attributable to morcellation could be 27 deaths per 100 000 procedures. To contextualize this risk in terms familiar to gynecologists, a cardiovascular mortality rate of 19 deaths per 100 000 women is considered sufficiently high as to contraindicate estrogen-progestin contraceptive use among smokers older than 35 years.3 The benefits of minimally invasive surgery in gynecology are well known; however, the risks of uncontrolled tissue dispersion from morcellation are not theoretical. If the alternative to mor96
4. Shibley KA. Enclosed morcellation using a large bowel isolation bag [published on January 30, 2014]. http://www.youtube.com/watch? v=xs9Wj6ou8CE. Accessed February 25, 2014.
In Reply In our Viewpoint, we highlighted the following issues: (1) bringing attention to the risks associated with intracorporeal morcellation, (2) using alternatives to unprotected or unenclosed intracorporeal morcellation, (3) developing safer techniques and instruments, and (4) encouraging improvements in surgical procedure and device monitoring. We reiterate our concern that appropriate and safe use of medical technology is paramount, yet we must disagree with Dr Melamed’s suggestion that the current understanding and instrumentation will suffice. Much work remains to be done to address concerns regarding intracorporeal morcellation, including quantifying the risks of both benign and occult malignant tissue dissemination, as well as risks of iatrogenic tissue injury. Increased scrutiny on the topic stresses the importance of discussing these issues, which have been a concern for the past several years.1,2 We respectfully disagree with his assessment of our article based on the study by Park et al.3 Even though a significant contribution to the literature regarding morcellation and the effects of disseminating leiomyosarcoma, the study—a retrospective cohort of 56 patients at a single center—does have limitations. Although valuable, small descriptive studies are limited by various issues and are not adequate to describe all concerns about morcellation and, in our view, do not negate the need to better characterize the rates, sequelae, and subpopulations of women who experience these various complications, as well as those who may have benefited. We applaud innovators who are actively searching for solutions to problems that arise in practice. In fact, we too are seek-
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P values and confidence intervals fully account for the technique we used. Matas and colleagues also misinterpreted our lifetime risk calculation, inferring that the lifetime ESRD risk of “healthy controls younger than 30 years was 0 per 10 000” rather than that ESRD risk by age 30 was 0 per 10 000 controls who entered the risk set prior to that age. Drs Kiberd and Tennankore suggest that our method of splicing together early follow-up intervals to estimate lifetime risks might have resulted in underestimation of risk. We agree that estimating lifetime risk of ESRD based on 15-year follow-up in different age cohorts is an approximation; unfortunately, it will be decades before we have follow-up long enough for better lifetime estimates. We also agree that cumulative risk will vary by donor characteristics; our cumulative risk estimates should only be interpreted as averages. Of 3 groups of researchers, 2 believe we have overestimated and 1 believes we have underestimated donor risk of ESRD. We disagree with several concerns raised about our methods, and we hope we have clarified these. We agree that our findings should not discourage kidney donation because the risks remain very low. However, better understanding and quantifying risk associated with donation remain a priority. Abimereki D. Muzaale, MD, MPH Allan B. Massie, PhD, MHS Dorry L. Segev, MD, PhD Author Affiliations: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. Corresponding Author: Dorry L. Segev, MD, PhD, Department of Surgery, Johns Hopkins Medical Institutions, 720 Rutland Ave, Baltimore, MD 21205 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Segev reported receiving institutional grant support from the National Institutes of Health. No other disclosures were reported. 1. Segev DL, Muzaale AD, Caffo BS, et al. Perioperative mortality and long-term survival following live kidney donation. JAMA. 2010;303(10):959-966. 2. Rust KF, Rao JN. Variance estimation for complex surveys using replication techniques. Stat Methods Med Res. 1996;5(3):283-310.
Outcomes After Kidney Donation To the Editor Dr Muzaale and colleagues1 reported the estimated lifetime risk of end-stage renal disease (ESRD) in donors as 0.9% compared with 0.14% in healthy nondonors and 3.26% in unscreened nondonors (general population), an 8-fold higher cumulative incidence of ESRD in donors compared with healthy nondonor controls. These data are important for discussions with prospective donors, especially donors of African American descent who have the highest relative risk. The Editorial by Drs Gill and Tonelli that accompanied this study has 2 inaccuracies that should temper the conclusion that “the low absolute risk of ESRD should reassure future donors of the safety of living kidney donation.”2 First, Gill and Tonelli celebrated the 56-year postdonation survival of Ron Herrick as proof that a person can live with a solitary kidney. Although Herrick lived to the age of 79 years (not 81 years) after donating at the age of 23 years, he spent most 94
of his last decade requiring dialysis, a fact rarely mentioned.3 Whether living with a single kidney accelerated his development of ESRD, cardiovascular disease, and death is not known, an uncertainty that also exists for others who donate and develop ESRD after donation. Second, Gill and Tonelli stated that the increased risk of ESRD should lead to closer follow-up: “donors should have kidney function, albuminuria, blood glucose, and blood pressure assessed annually by their primary care physician,” which is unchanged from the current recommendation. Because 18% of living donors do not have health insurance at the time of donation,4 these donors are unlikely to get routine yearly follow-up past that required for transplant centers to perform for the first 2 years following donation. Additionally, many donors with insurance will not obtain follow-up. To do everything possible to ensure and improve the safety of living donation, the transplant community should be more stringent about follow-up, support a longitudinal registry, and maintain the ability to contact previous donors to obtain blood samples as needed for subsequent testing. Living kidney donation is an important strategy for treating ESRD. The transplant community has a moral obligation to ensure that it is as safe as possible and that donors know the actual risks they face.5 Gill and Tonelli suggested that donation is safe, but the data presented by Muzaale et al1 convincingly show an increased risk of renal failure after donation that has not been fully appreciated previously. Lainie Friedman Ross, MD, PhD J. Richard Thistlethwaite Jr, MD, PhD Author Affiliations: Department of Pediatrics, University of Chicago, Chicago, Illinois (Ross); Department of Surgery, University of Chicago, Chicago, Illinois (Thistlethwaite). Corresponding Author: Lainie Friedman Ross, MD, PhD, Department of Pediatrics, University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving a Robert Wood Johnson Investigator Award in Health Policy grant to write a book studying the ethical and policy issues raised by living donor transplantation. 1. Muzaale AD, Massie AB, Wang M-C, et al. Risk of end-stage renal disease following live kidney donation. JAMA. 2014;311(6):579-586. 2. Gill JS, Tonelli M. Understanding rare adverse outcomes following living kidney donation. JAMA. 2014;311(6):577-578. 3. Crosby C. Transplant just one chapter of first organ donor's life. http://www .kjonline.com/news/transplant-just-one-chapter-of-first-organ-donors-life _2011-01-01.html?pagenum=full. Accessed February 24, 2014. 4. Gibney EM, Doshi MD, Hartmann EL, Parikh CR, Garg AX. Health insurance status of US living kidney donors. Clin J Am Soc Nephrol. 2010;5(5):912-916. 5. Davis CL, Cooper M. The state of US living kidney donors. Clin J Am Soc Nephrol. 2010;5(10):1873-1880.
To the Editor The recent Editorial by Drs Gill and Tonelli1 accompanying our study2 of ESRD risk following kidney donation raised several methodological questions that we believe merit response. Gill and Tonelli suggested that “repeated inclusion of controls with long event-free survival … may have underestimated the risk of ESRD in nondonors.” We fail to see how re-
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Copyright 2014 American Medical Association. All rights reserved.
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peated sampling could lead to bias, but it does affect variance. We conducted a bootstrap specifically designed to account for the variance of repeated sampling on rare outcomes. Using this bootstrap and other appropriate statistical tests, we reported our findings as statistically significant. Furthermore, any differences in follow-up (or duration of event-free survival) were accounted for by our use of survival analysis. Gill and Tonelli mention the “competing risk of death” which may be higher in nondonors. However, failure to account for higher death rates in nondonors would cause our study to overestimate ESRD incidence in nondonors, producing bias in the opposite direction from that posited by the Editorial, as has been described both theoretically 3 and empirically.4 Our ESRD ascertainment captured outcomes in donors who listed preemptively (before dialysis onset), but not preemptive listings by nondonors. However, as Gill and Tonelli point out, our follow-up time was longer for nondonors. Most nondonors who listed preemptively would either receive a transplant or initiate dialysis shortly thereafter, both of which are captured by our algorithm. Regardless, a slight delay in ESRD ascertainment of nondonors would hardly be sufficient to account for our observations. Gill and Tonelli contrast our findings with the higher crude ESRD incidence in the screened (but unmatched) NHANES population. This is an inappropriate comparison that suffers from considerable confounding because NHANES purposefully oversampled older, black, and Hispanic persons.5 Because we show that these 3 subgroups have much higher ESRD risk, only the matched analysis gives an unbiased estimate of absolute risk increase of ESRD in donors compared with nondonors. We believe that the purported limitations raised by Gill and Tonelli do not diminish confidence in our findings, including our relative risk estimates. We agree, however, that our findings show “low absolute risk” of donation, and also that “progressive kidney disease may be more likely to cause ESRD in donors, who have less renal reserve following donation, than in nondonors.” We hope that our study will guide counseling of kidney donors and inform future research. Allan B. Massie, PhD Abimereki D. Muzaale, MD, MPH Dorry L. Segev, MD, PhD Author Affiliations: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. Corresponding Author: Dorry L. Segev, MD, PhD, Department of Surgery, Johns Hopkins University School of Medicine, 720 Rutland Ave, Baltimore, MD 21205 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Segev reported receiving institutional grant support from the National Institutes of Health. No other disclosures were reported. 1. Gill JS, Tonelli M. Understanding rare adverse outcomes following living kidney donation. JAMA. 2014;311(6):577-578. 2. Muzaale AD, Massie AB, Wang M-C, et al. Risk of end-stage renal disease following live kidney donation. JAMA. 2014;311(6):579-586. 3. Putter H, Fiocco M, Geskus RB. Tutorial in biostatistics: competing risks and multi-state models. Stat Med. 2007;26(11):2389-2430.
4. Turin TC, Tonelli M, Manns BJ, et al. Lifetime risk of ESRD. J Am Soc Nephrol. 2012;23(9):1569-1578. 5. Centers for Disease Control and Prevention. NHANES III Web Tutorial. http: //www.cdc.gov/nchs/tutorials/NHANES/SurveyDesign/SampleDesign/Info1_III .htm. Accessed March 17, 2014.
In Reply: We apologize for the error regarding Mr Herrick’s age and health status and a correction accompanies this letter. Of course, whether a specific individual did or did not experience complications from a procedure is not useful for evaluating that procedure’s safety; this is why large clinical studies are needed. Drs Ross and Thistlethwaite state that 18% of living donors do not have health insurance at the time of donation. Nearly all developed countries outside the United States provide universal insurance coverage for such follow-up, so this statistic does not reflect a general failure to attend to the needs of kidney donors. Instead, it is evidence of the need for health care reform in the United States. As Muzaale et al1 have shown, the absolute risk of kidney failure following living donation is extremely low in the United States despite the shortcomings of the current system of followup. Given the absence of evidence that kidney failure is causally linked to donation, we agree that long-term donor follow-up may be best justified as a moral obligation rather than an evidence-based requirement. With respect, we believe that the letter from Dr Massie and colleagues has missed the forest for the trees. Their study was rigorously conducted but does have significant limitations that reduce confidence in the relative risk estimates. Their results were based on a complex bootstrapped model that represented the experience of 96 217 individuals, but only 17 actual (compared with simulated) nondonor controls who actually developed kidney failure. We do not believe that statistical methods (no matter how sophisticated) ensure the generalizability of these controls to the entire population of potential living donors. Massie and colleagues claim that their study showed that the cumulative incidence of kidney failure was higher among older black and Hispanic participants than whites. The number of actual individuals who developed kidney failure was not presented by age or race, but because there were only 17 cases across all age and race categories, these results are even less reliable. Muzaale et al1 should have provided the actual number of ESRD cases by age and race to substantiate their claim that unmatched comparisons of crude ESRD incidence are biased. Last, Massie and colleagues misunderstood our comment about competing risks. It is true that using a formal competing risk framework would have led to higher relative risk estimates than those from the Kaplan-Meier estimates presented in the study. We do not dispute this statement, which is not the real issue. Instead, we were highlighting that selecting an inappropriate control group can lead to biased relative risk estimates. Specifically, because people cannot be initiated on dialysis after they die, selecting controls who are at higher risk of death than the comparator group of kidney donors will spuriously increase the apparent risk of kidney fail-
jama.com
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Copyright 2014 American Medical Association. All rights reserved.
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Letters
ure associated with kidney donation. We hope Massie and colleagues will present analyses comparing the risk of the composite outcome of kidney failure or death between donors and matched nondonors. We maintain that the relative risk estimates presented by Muzaale et al1 have significant limitations and should be used with caution when counseling potential donors. However, their absolute risk estimates of kidney failure following living kidney donation are the best available and will be useful to potential donors.
cellation is open surgery, risks and benefits of the procedures must be compared. However, it has been demonstrated that power morcellation of a uterus can be performed inside of an insufflated bag within the peritoneal cavity.4 This technique affords the advantages of morcellation while avoiding tissue dissemination, thus obviating the choice between the benefits of minimally invasive surgery and the oncological risks of tissue dispersion. Although not currently in common practice, this solution should be adopted or improved to appropriately and safely care for patients. Alexander Melamed, MD, MPH
John S. Gill, MD Marcello Tonelli, MD
Author Affiliation: Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Boston, Massachusetts.
Author Affiliations: Division of Nephrology, University of British Columbia, Vancouver, Canada (Gill); Department of Medicine, University of Alberta, Edmonton, Alberta, Canada (Tonelli).
Corresponding Author: Alexander Melamed, MD, MPH, Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, 75 Francis St, Boston, MA 02115 ([email protected]).
Corresponding Author: John S. Gill, MD, Division of Nephrology, University of British Columbia, 1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada ([email protected]).
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
1. Kho KA, Nezhat CH. Evaluating the risks of electric uterine morcellation. JAMA. 2014;311(9):905-906.
1. Muzaale AD, Massie AB, Wang M-C, et al. Risk of end-stage renal disease following live kidney donation. JAMA. 2014;311(6):579-586.
2. Park JY, Park SK, Kim DY, et al. The impact of tumor morcellation during surgery on the prognosis of patients with apparently early uterine leiomyosarcoma. Gynecol Oncol. 2011;122(2):255-259.
Electric Uterine Morcellation
3. Schwingl PJ, Ory HW, Visness CM. Estimates of the risk of cardiovascular death attributable to low-dose oral contraceptives in the United States. Am J Obstet Gynecol. 1999;180(1 pt 1):241-249.
To the Editor Drs Kho and Nezhat1 discussed the risks associated with electric morcellation of uterine tissue within a patient’s abdomen, a practice that is common in minimally invasive gynecologic surgery. The authors suggested that current evidence is insufficient to estimate the harm that results from dissemination of an occult uterine leiomyosarcoma when morcellation is used for presumed fibroids. The authors also stated that devices that allow surgeons to perform electric morcellation inside an endoscopic bag are “being developed.” I would like to discuss both points. Published studies, small as they are, do allow for the calculation of harm associated with morcellation of an occult leiomyosarcoma. In a series of 56 consecutive patients with earlystage leiomyosarcomas treated at a South Korean tertiary care center between 1989 and 2010, Park et al2 found that recurrencefree and overall survival were significantly reduced among patients with a history of uterine tissue morcellation. Five-year survival was 46% among patients who underwent morcellation compared with 73% when uteri were removed intact. Based on these data, inadvertent morcellation of a leiomyosarcoma in 100 patients may result in 27 excess deaths. Assuming conservatively that among 1000 patients undergoing surgery for uterine fibroids, 1 patient will have an occult leiomyosarcoma, the rate of death from leiomyosarcoma attributable to morcellation could be 27 deaths per 100 000 procedures. To contextualize this risk in terms familiar to gynecologists, a cardiovascular mortality rate of 19 deaths per 100 000 women is considered sufficiently high as to contraindicate estrogen-progestin contraceptive use among smokers older than 35 years.3 The benefits of minimally invasive surgery in gynecology are well known; however, the risks of uncontrolled tissue dispersion from morcellation are not theoretical. If the alternative to mor96
4. Shibley KA. Enclosed morcellation using a large bowel isolation bag [published on January 30, 2014]. http://www.youtube.com/watch? v=xs9Wj6ou8CE. Accessed February 25, 2014.
In Reply In our Viewpoint, we highlighted the following issues: (1) bringing attention to the risks associated with intracorporeal morcellation, (2) using alternatives to unprotected or unenclosed intracorporeal morcellation, (3) developing safer techniques and instruments, and (4) encouraging improvements in surgical procedure and device monitoring. We reiterate our concern that appropriate and safe use of medical technology is paramount, yet we must disagree with Dr Melamed’s suggestion that the current understanding and instrumentation will suffice. Much work remains to be done to address concerns regarding intracorporeal morcellation, including quantifying the risks of both benign and occult malignant tissue dissemination, as well as risks of iatrogenic tissue injury. Increased scrutiny on the topic stresses the importance of discussing these issues, which have been a concern for the past several years.1,2 We respectfully disagree with his assessment of our article based on the study by Park et al.3 Even though a significant contribution to the literature regarding morcellation and the effects of disseminating leiomyosarcoma, the study—a retrospective cohort of 56 patients at a single center—does have limitations. Although valuable, small descriptive studies are limited by various issues and are not adequate to describe all concerns about morcellation and, in our view, do not negate the need to better characterize the rates, sequelae, and subpopulations of women who experience these various complications, as well as those who may have benefited. We applaud innovators who are actively searching for solutions to problems that arise in practice. In fact, we too are seek-
JAMA July 2, 2014 Volume 312, Number 1
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