Association of gender and access to cadaveric renal transplantation

The ofha,

lournai 0‘ the

National

Kidney

Foundation

American Journal ofKidney DiseasesVOL 30, NO 6, DECEMBER ORIGINAL

1997

INVESTIGATIONS

Association of Gender and Access to Cadaveric Renal Transplantation Wendy E. Bloembergen,

MD, Elizabeth A. Mauger, PhD, Robert A. Wolfe, PhD, and Friedrich K. Port, MD

0 Previous studies have revealed that females are less likely than males to receive a renal transplant, the most successful form of treatment of end-stage renal disease (ESRD). The purpose of this study was to determine whether the barrier is to inclusion on the transplant waiting list or to transplantation after being placed on the transplant waiting list. An existing data set was used that included data from the Michigan Kidney Registry, supplemented with data received from the Organ Procurement Agency of Michigan. White and black patients less than 65 years of age and starting ESRD treatment between January 1,1984, and December 31,1989, were included. Cox proportional hazards models were used to determine the effect of gender on (1) time to transplantation among all ESRD patients, (2) time from diagnosis of ESRD to inclusion on the transplant waiting list among all ESRD patients, and (3) time from inclusion on the waiting list to transplantation among those patients on the waiting list. Patients were censored at the time of living-related transplantation or death, and were monitored until December 31, 1989. In all, 5,026 incident ESRD patients were included in the study (44.3% female). Of these, 1,626 patients were included on the waiting list (40.1% female); 823 of these received a transplant (37.7% female). Adjusting for age, race, and diagnosis, females were 25% less likely to receive a cadaveric transplant than males (female to male relative rate ratio [RR], 0.75; P < 0.001). Females with ESRD aged 46 to 55 years and 56 to 65 years were 33% (RR, 0.67; P < 0.001) and 29% (RR, 0.71; P < 0.05) less likely to be included on the transplant waiting list, respectively, than their male counterparts. There was no difference in the rate of wait list inclusion among ESRD patients younger than 46 years. Females with ESRD who were included on the transplant waiting list were 26% (RR, 0.74; P < 0.001) less likely to receive a transplant than males on the waiting list. These results indicate that females are both less likely to be on the transplant waiting list (ages over 45 years) and, once on the list, less likely to receive a transplant (all ages) than males. Further study is necessary to determine the factors contributing to these important barriers to transplantation among females with ESRD. 0 1997 by the National Kidney Foundation, Inc. INDEX

WORDS:

Kidney

transplant;

recipient;

sex;

female.

R

ENAL transplantation is the most successful treatment of end-stage renal disease (ESRD) in terms of patient survival’ and quality of life.2-7 Despite this, previous studies have shown that females are consistently less likely than males to receive either a cadaveri?” or a living-related renal transplant.‘22’3 To receive a cadaveric renal transplant, patients in general must be included on a transplant waiting list and then subsequently be chosen from this list based on several factors. To be included on the waiting list, transplantation must first be considered by American

Journal

of Kidney

Diseases,

Vol 30, No 6 (December),

From the Department of Internal Medicine, School of Medicine, and the Departments of Epidemiology and Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI. Received January 17, 1997; accepted in revised,fonn July 8, 1997. Dr Bloembergen was supported by a fellowship award from the Kidney Foundation of Canada. Address reprint requests to Wendy E. Bloembergen, MD, MS, Kidney Epidemiology and Cost Center, 315 W Huron St, Suite 240, Ann Arbor, MI 48103. 0 1997 by the National Kidney Foundation, inc. 0272~6386/97/3006-0002$3.00/O 1997:

pp 733-738

733

734

BLOEMBERGEN

the physician and the patient as an option, and an evaluation to determine whether the patient is medically suitable must take place. Barriers to transplantation may exist for females at one or more of these steps. To define at what level the barrier to cadaveric renal transplantation occurs (before or after inclusion on the waiting list), we aimed (1) to confirm or refute the previously described relationship of gender and cadaveric transplantation in females among incident patients with ESRD treated in Michigan, (2) to determine whether females with ESRD are less likely to be included on the transplant waiting list than males with ESRD, and (3) to determine whether females included on the transplant waiting list are less likely to be transplanted than males on the waiting list. MATERIALS

AND

were adjusted for age (< 25 years, 26 to 45 years, 46 to 55 years, and 56 to 65 years), race (white and black), and primary cause of ESRD (diabetes, hypertension, glomerulonephritis, and other). The presence of an age by gender interaction was also tested for each model. To confirm or refute results of prior studies which indicate that females with ESRD are less likely than males with ESRD to receive a cadaveric renal transplant, the initial model included the entire study sample of incident ESRD patients and analyzed the effect of gender on time from diagnosis of ESRD to time of cadaveric renal transplantation. To determine whether, among incident ESRD patients, females are less likely to be included on the transplant waiting list than males, the effect of gender on time from diagnosis of ESRD to inclusion on the transplant waiting list was analyzed among the entire study sample in a second Cox model. To then determine whether females with ESRD who were on the transplant waiting list were less likely to receive a cadaveric transplant than their male counterparts, a third Cox proportional hazards was performed to determine the effect of gender on the time from inclusion on the waiting list to time of transplantation among those patients on the waiting list.

METHODS RESULTS

Data For a prior study aimed at comparing the mortality risk among dialysis patients and cadaveric renal transplant recipients,’ a data set was developed in which data from the Michigan Kidney Registry was supplemented with data on dates of first listing for a cadaveric transplant, which were provided by the Organ Procurement Agency of Michigan. The Michigan Kidney Registry database contains information on all patients treated for ESRD in the state of Michigan between 1973 to 1993. It contains detailed demographic information, the primary renal diagnosis, and longitudinal treatment information for each patient. Identification of cases and data collection are estimated to be over 99% complete and 97% accurate.14 For each patient, data on gender, race, age at onset of ESRD, and primary cause of ESRD, as well as dates of ESRD onset, inclusion on the transplant waiting list, transplantation, and death were included in this analysis file. The availability of this data set allowed the analyses presented in the current report.

Statistical

ET AL

Analysis

All white and black patients younger than 65 years who initiated ESRD therapy between January 1,1984, and December 31, 1989, were included (N = 5,026). Patients were excluded if their race was other than white or black due to small sample size (2.5%). For patients included on the waiting list before the start of dialysis, the date of ESRD onset was changed to 1 day prior to the date of inclusion on the waiting list. This occurred for 166 male and 132 female patients. Cox proportional hazards models were used for all analyses, as this method allowed the comparison of time to event (inclusion on the waiting list or transplantation). Patients were censored at the time of living-related transplantation or death, and were monitored until December 31, 1989. The independent variable of interest in all models was gender. All analyses

Of the entire incident study sample (N = 5,026), 44.3% were female. The mean age of the study patients at onset of ESRD was 46 years (range, 0 to 65 years); 59.5% of patients were white. The cause of ESRD was reported as diabetes in 36%, hypertension in 23%, glomerulonephritis in 17%, and other in 23%. Throughout the follow-up period, 1,626 (44.3%) of the patients initiating ESRD therapy from 1984 to 1989 were included on the transplant waiting list, of which 40.1% were female (Fig 1). Of these 1,626 patients who were included on the transplant waiting list, 823 received a cadaveric renal transplant during the time of follow-up. Of these patients receiving a transplant, 37.7% were female. Figure 2 shows the relative rate of transplantation among males and females initiating ESRD therapy in Michigan from 1984 to 1989, adjusted for age, race, and primary diagnosis. It indicates that females were 25% less likely than males to receive a cadaveric renal transplant (female to male relative rate ratio [RR], 0.75; P < 0.001). This ratio did not vary significantly by age (P < 0.05). Figure 3 shows the relative rate of inclusion on the transplant waiting list among males and females with ESRD, adjusted for race and primary cause of ESRD. These relative rates are shown by age groups because statistically sig-

GENDER

AND

CADAVERIC

RENAL

Incident

Relative

ESRD

N=5026 1 44.3%

1.25

female

Rate

T

]

I

I

Wait-listed

Not Wait-listed

N=1626 140.1%

735

TRANSPLANTATION

N=3400

0.00

female)

o-25 (N=380)

26-45 (N=1724)

46-55 (N=1130,

56-65 (N=17Y2,

&I~

Transplant

No Transplant

N=823 / 37.7%

Fig 3. Relative rate of inclusion waiting list for male (B) and female patients by age category, adjusted mary cause of ESRD.

N=803

female

/

Fig 1. Total number (and percentage of females) of new ESRD patients included in the study sample, as well as the number of patients included on the waiting list and then transplanted during the follow-up period.

nificant age interaction was found. There was no significant difference in time to inclusion on the waiting list between males and females with ESRD aged 45 years or younger (42% of the total population). However, in patients aged 46 to 55 years (22.5% of the total population), females were 33% less likely to be included on the transplant waiting list (RR, 0.67; P < 0.001) and in patients aged 56 to 65 years (36% of the total population), females were 29% less likely to be included (RR, 0.71; P < 0.05).

The adjusted relative rate of transplantation among males and females on the transplant waiting list is shown in Fig 4. Once on the transplant waiting list, females were 26% less likely than males to receive a transplant (RR, 0.74; P < 0.001). This analysis is adjusted for age, race, primary ESRD diagnosis, and date of ESRD onset. This ratio was not significantly different for the four age groups (P > 0.05). DISCUSSION

These results confirm other reports indicating that female patients starting ESRD therapy are less likely than their male counterparts to receive

Relative 1.50

Relative

on the transplant (0) incident ESRD for race and pri-

Rate

I.!50

Rate

pc0.001 p
/ 0.74

1

j

Males Fig 2. Relative rate of transplantation female incident ESRD patients, adjusted and primary diagnosis.

Females for male and for age, race,

Fig 4. Relative rate of transplantation female ESRD patients who were included plant waiting list, adjusted for age, race, diagnosis.

for male and on the transand primary

736

a cadaveric renal transplant. The results of this study suggest that barriers to cadaveric renal transplantation exist for females both at the level of becoming included on the waiting list (except for those in the younger age groups) and at receiving a transplant once having been included on the waiting list. The reason for the gender difference in cadaveric transplantation is therefore likely multifactorial. Potential barriers at the level of inclusion on the waiting list are numerous. The possibility of gender selection on the part of physicians and/ or other health care personnel is supported by the findings of a study of patients receiving dialysis in three US states, in which females were less likely to be considered transplant candidates by their medical caregivers than their male counterparts, after adjustment for other patient characteristics, including illness severity and certain comorbid conditions.” Consideration of the potential risk of exacerbation of steroid-induced osteoporosis, particularly in postmenopausal women, may be a possible explanation for this finding. However, it has been suggested that gender bias exists in the treatment of ESRD itself, as the age- and race-adjusted incidence rate for females starting ESRD therapy is consistently lower than that of males in the United States16; the difference is even larger in other countries.‘7,‘8 Based on a review of death certificates in the United States and Sweden, Kjellstrand and colleagueslg-z’ reported that females are more likely to die of uremia without renal replacement therapy than males in these countries, suggesting that the difference in incidence rates for treated ESRD does not simply reflect a greater incidence of diseases causing or contributing to ESRD among males. The results of this current Michigan study show a difference in incidence rates for males and females that is considerably larger than that seen nationally,16 but that is similar to the difference seen in other countries.17,18 Reports in other areas of medicine have found similar treatment differences by gender. For example, there is a growing literature suggesting less aggressive treatment of coronary artery disease in females.22-Z Gender bias also may be operational outside of the patient’s medical interactions, at the level of the patients’ families, friends, and colleagues, manifested perhaps by less encouragement to consider and proceed with cadaveric renal transplantation for females than males.

BLOEMBERGEN

ET AL

Another major factor that deserves consideration is that of possible differences in patient preference. Females may perceive greater risk of transplantation and/or be less willing to accept the side effects of immunosuppressants. They may be less assertive and motivated to pursue the process of transplant evaluation and eventual transplantation. On average, they may have beliefs and attitudes that cause them to be more accepting of treatment with dialysis than males. These possible behavioral differences have not been adequately considered in many of the reports of gender differences in medical care. That they may be important is supported by a recent study that found females with severe heart failure to be more likely to refuse to undergo a cardiac transplant than their male counterpartsz6 Another possible explanation is an economic one. Following renal transplantation, Medicare eligibility is eventually lost and expensive immunosuppressants must be paid for by other means. This may be a greater deterrent to transplantation for females than males due to the generally lower income and insurance status of females compared with males. This study has indicated that a barrier also seems to exist for females with ESRD in receiving a transplant once they are included on the transplant waiting list. Immunologic reasons may contribute to this finding. Females have been shown to have higher levels of preformed lymphocytotoxic antibodies,27 which may reduce the chance of immunologically matching with the donor kidney. It is not clear to what extent this higher degree of sensitization affects transplantation rates for females compared with males. Gender differences in patient preference or behavior may again play a role among patients on the waiting list. For example, females may be more likely to turn down the offer of a kidney when they are notified of their selection as the proposed recipient. Bias on the part of the health care professional selecting the recipient is also a potential, but likely remote, possibility. This study has shown that for the years 1984 to 1989, the lower cadaveric transplantation rates for females compared with males were a result of both a lower rate of inclusion on the transplantation waiting list for females and a lower rate of transplantation for females once they are included on the waiting list. Recent data included

GENDER AND CADAVERIC RENAL TRANSPLANTATION

737

in the 1997 US Renal Data System Annual Data Report” indicate that for the years 1992 to 1995, females continued to receive cadaveric transplants at a rate 34% lower than males overall (18% lower for ages 0 to 19 years, 6% lower for ages 20 to 44 years, 35% lower for ages 45 to 64 years, and 50% lower for ages > 65 years). We are not aware of any reasons to believe that the “levels” at which the barriers are present have changed since the years of the data used in this study (1984 to 1989). Epidemiological or prospective clinical studies that include data on insurance, income, matching, parity, preformed lymphocytotoxic antibody status, and patient preferences, health attitudes, and beliefs are necessary to further delineate the precise factors that contribute to the apparent barriers to inclusion on the waiting list and to transplantation for females. The data set used in these analyses did not include these variables. In the meantime, it is hoped that the simple awareness of these gender differences will lead to improvements in the factors that are modifiable and to an eventual reduction in this gender difference. In addition to eliminating any possible gender selection bias, this could include more encouragement on the part of nephrologists and other health care personnel for the patient to consider transplantation, given its superior patient outcome compared with dialysis.

5. Evans RW, Manninen DL, Garrison LP Jr, Hart LG, Blagg CR, Gutman RA, Hull AR, Lowrie EG: The quality of life of patients with end-stage renal disease. N Engl J Med 312:553-559, 1985 6. Russell JD, Beecroft ML, Ludwin D, Churchill DW: The quality of life in renal transplantation-A prospective study. Transplantation 54:656-660, 1992 7. Laupacis A, Keown PA, Pus N, Krueger H, Ferguson B, Wong C, Muirhead N: A study of the quality of life and cost utility of renal transplantation. Kidney Int 50:235-242, 1996 8. Held PJ, Pauly MY, Bovbjerg RR, Newmann J, Salvatierra 0: Access to kidney transplantation: Has the United States eliminated income and racial differences? Arch Intern Med 148:2594-2600, 1988 9. Gaylin DS, Held PJ, Port FK, Hunsicker LG, Wolfe RA, Kahan BD, Jones CA, Agodoa LYC: The impact of comorbid and sociodemographic factors on access to renal transplantation. JAMA 269:603-608, 1993 10. Kjellstrand CM: Age, sex, and race inequality in renal transplantation. Arch Intern Med 148: 1305-1309, 1988 11. Eggers PW: Effect of transplantation on the Medicare end-stage renal disease program. N Engl J Med 318:223-229, 1988 12. Ojo A, Port FK: Influence of race and gender on related donor renal transplantation rates. Am J Kidney Dis 2:835-841, 1993 13. Bloembergen WE, Port FK, Mauger EA, Briggs JP, Leichtman AB: Gender discrepancies in living related renal transplant donors and recipients. J Am Sot Nephro17: 11391144, 1996 14. Cowie CC, Port FK, Wolfe RA, Savage PJ, Moll PP, Hawthorne VM: Disparities in incidence of diabetic end-stage renal disease according to race and type of diabetes. N Engl J Med 321:1074-1079, 1989 15. Soucie JM, Neylan JF, McClellan W: Race and sex differences in the identification of candidates for renal transplantation. Am J Kidney Dis 19:414-419, 1992 16. US Renal Data System: USRDS 1996 Annual Data Report. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 1996. Am J Kidney Dis 28:Sl-S165, 1996 (suppl 2) 17. Canadian Organ Replacement Register: 1993 Annual Report. Don Mills, Ontario, Canada, Canadian Institute for Health Information, 1995 18. Disney APS (ed): Australia and New Zealand Dialysis and Transplant Registry: ANZDATA Report, 1993. Adelaide, South Australia, Australia and New Zealand Dialysis and Transplant Registry, 1994 19. Kjellstrand CM: Giving life-Giving death. Ethical problems of high technology medicine. Acta Med Stand 725:1-88, 1988 (suppl) 20. Kjellstrand CM, Logan GM: Racial, sexual and age inequalities in chronic dialysis. Nephron 5:257-263, 1987 21. Kjellstrand CM, Tyden G: Inequalities in chronic dialysis and transplantation in Sweden. Acta Med Stand 224: 149156, 1988 22. Ayanian JZ, Epstein AM: Differences in the use of procedures between women and men hospitalized for coronary heart disease. N Engl J Med 325:221-225, 1991 23. Maynard C, Litwin PE, Martin JS, Weaver WD: Gender

ACKNOWLEDGMENT The Organ Procurement Agency of Michigan and the Transplant Society of Michigan made this study possible by generously sharing their transplant waiting list data. The Michigan Kidney Registry was funded in part by the National Kidney Foundation (1969.1993) and by the Michigan Department of Public Health, Lansing (1973-1991). REFERENCES 1. Port FK, Wolfe RA, Mauger EA, Berling DP, Bang K: Comparison of survival probabilities for dialysis patients versus cadaveric renal transplant recipients. JAMA 270: 1339. 1343, 1993 2. Churchill DN, Torrance GW, Taylor DW, Barnes CC, Ludwin D, Shimizu A, Smith EK: Measurement of quality of life in end-stage renal disease. The time trade-off approach Clin Invest Med 10:14-20, 1987 3. Bremer BA, McCausley CR, Wrona RM, Johnson JP: Quality of life in end-stage renal disease. Am .I Kidney Dis 13:200-209, 1989 4. Hart LG, Evans RW: The functional status of ESRD patients as measured by the sickness impact profile. J Chron Dis 40:117S-13OS, 1987

738 differences in the treatment and outcome of acute myocardial infarction: Results from the Myocardial Infarction Triage and Intervention Registry. Arch Intern Med 152:972-976, 1992 24. Steingart RM, Packer M, Hamm P, Coglianese ME, Gersh B, Geltman EM, Sollano J, Katz S, Moye L, Basta LL: Sex differences in the management of coronary artery disease. N Engl J Med 325:226-230, 1991 25. Healy B: The Yentl syndrome. N Engl J Med 325:274276, 1991 26. Aaronson KD, Schwartz JS, Goin JE, Mancini DM:

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ET AL

Sex differences in patient acceptance of cardiac transplant candidacy. Circulation 91:2753-2761, 1995 27. Koka P, Cecka JM: Sensitization and crossmatching in renal transplantation, in Terasaki P (ed): Clinical Transplants 1989. Los Angeles, CA, UCLA Tissue Typing Laboratory, 1989, pp 379-390 28. US Renal Data System: USRDS 1997 Annual Data Report. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, Am J Kidney Dis 3O:Sl-S213, 1997 (suppl 1)