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Hospitalizations for Fractures after Renal Transplantation in the United States
Hospitalizations for Fractures after Renal Transplantation in the United States KEVIN C. ABBOTT, MD, ROBERT J. OGLESBY, MD, IMAN O. HYPOLITE, ALLAN D. KIRK, PhD, CHIA W. KO, PhD, PAUL G. WELCH, MD, LAWRENCE Y. AGODOA, MD, AND WILLIAM E. DUNCAN, MD, PhD
PURPOSE: To investigate the incidence, risk factors, and associated mortality of fractures in renal transplant recipients. METHODS: Retrospective registry study of 33,479 patients in the United States Renal Data System (USRDS) who received kidney transplants between 1 July 1994 and 30 June 1997. Associations with hospitalizations for a primary discharge diagnosis of fractures (all causes) were assessed. RESULTS: Renal transplant recipients had an adjusted incidence ratio for fractures of 4.59 (95% confidence interval 3.29 to 6.31). In multivariate analysis, recipients with prevalent fractures, as well as recipients who were Caucasian, women, in the lower quartiles of recipient weight (95.9 kg), had end stage renal disease caused by diabetes, and had prolonged pretransplant dialysis were at increased risk for hospitalization because of fractures after transplantation. Recipients hospitalized for hip fractures had decreased all-cause survival (hazard ratio for mortality 1.60, 95% CI 1.13 to 2.26) in Cox Regression analysis. CONCLUSIONS: In the early post-transplant course (3 years), renal transplant recipients had a greater incidence of fractures than the general population, which were associated with decreased patient survival. Preventive efforts should focus on recipients with the risk factors identified in this analysis, most of which can be easily obtained through history and physical examination. Ann Epidemiol 2001;11:450–457. © 2001 Elsevier Science Inc. All rights reserved. KEY WORDS:
Fracture, Osteoporosis, Renal Transplant, Weight, Dialysis Duration, Complication,
USRDS.
INTRODUCTION Fractures are significant causes of morbidity in both the general population and in recipients of renal transplants
From the Nephrology Service (K.C.A., P.G.W.), Walter Reed Army Medical Center, Washington, DC; and Uniformed Services University of the Health Sciences, Bethesda, MD; Rheumatology Service (R.J.O.), Walter Reed Army Medical Center, Washington, DC; and Uniformed Services University of the Health Sciences (R.J.O.), Bethesda, MD; Office of Minority Research Health Coordination (I.O.H.), National Institute for Diabetes, Digestive, and Kidney Disease (NIDDK), National Institutes of Health (NIH), Bethesda, MD; Organ Transplantation Service (A.D.K.), National Institutes of Health, Bethesda, MD; Epidemiology, Statistics, and Data System Branch (C.W.K.), National Institute on Deafness and Other Communication Disorders (NIDCD), NIH, Bethesda, MD; NIDDK, NIH, Bethesda, MD; and Endocrinology Service (W.E.D.), Walter Reed Army Medical Center, Washington, DC. The opinions expressed are solely those of the authors and do not represent an endorsement by the Department of Defense or the National Institutes of Health. This is a government work. There are no restrictions on its use. Portions of this article were presented at AST 2000 in Chicago, IL, 13-17 May, 2000. Address reprint requests to: Dr. Kevin C. Abbott, LTC, MC, Director, Dialysis, Nephrology Service, Walter Reed Army Medical Center, Washington, DC 20307-5001. Tel.: (202) 782-6462/6463/6288, Fax: (202) 7820185. E-mail: [email protected] Received September 18, 2000; revised January 8, 2001; accepted January 23, 2001. © 2001 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
(1–6). Although fractures are generally believed to be a late complication after renal transplantation, the rates of and risk factors for fractures occurring in the early postrenal transplant course have not been analyzed for a national population, and, therefore, the true scope of the problem is unknown. The reported prevalence of fractures in renal transplant recipients ranges from 5 to 21%, with an estimated incidence of 2% per year (7, 8). A study of the United States Renal Data System (USRDS) end stage renal disease population found a cumulative incidence of hip fractures significantly higher than in the general population (9). Several reports indicate bone demineralization in transplant patients is greatest in the first few years after transplant; (10– 13) although a more recent report indicated levels approach normal at 10 years post transplant (14). Risk factors for fractures in the general population include decreased bone mineral density, increasing age, Caucasian race, female gender, and low weight (15–18). Similar findings have recently been reported for end stage renal disease patients, although weight and a history of previous fracture were not assessed (19). To characterize better the incidence and risk factors for hospitalizations resulting from fractures in the renal transplant population, we analyzed national data from the 1999 USRDS report. Our objectives 1047-2797/01/$–see front matter PII S1047-2797(01)00226-5
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Selected Acronyms and Abbreviations USRDS United States Renal Data System ESRD End stage renal disease NCHS National Center For Health Statistics
were to determine the rate of and risk factors for hospitalizations for a primary diagnosis of fractures of all nonpathological causes in renal transplant recipients.
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the study period, and, therefore, a given patient had only one hospitalization counted during the study period. Hospitalization data for transplant recipients may be unreliable after a recipient has survived 3 years post transplant, when hospitalization reporting to Medicare is no longer required. However, Medicare reporting starts immediately after transplant. The present study limited analysis to the first kidney transplant occurring in an individual recipient from 1 July 1994 to 30 June 1997 to avoid exceeding the 3-year period. Hospitalizations for fractures occurring at any time after renal transplant, including after graft failure, were counted in analysis, in an intention to treat fashion.
METHODS Data Sources and Study Sample
Analytic Variables and Outcome Measures
We conducted a national retrospective registry study of the incidence and demographic risk factors for hospitalized cases of fractures as a primary diagnosis in renal transplant recipients. Hospitalizations were chosen for two reasons: (i) they were more accessible in the database and less subject to interpretation than outpatient cases of fractures, especially because the USRDS database has no information on radiographic studies; and (ii) they could be compared directly to the National Center for Health Statistics. The variables included in the USRDS data files, as well as data collection methods and validation studies, are listed at the USRDS website, under “Researcher’s Guide to the USRDS Database,” Section E, “Contents of all the SAFs” (Standard Analysis Files), (20) and published in the USRDS. The demographics of the renal transplant population have been previously described (1999 USRDS report). SAF.TXUNOS was used as the main file. SAF.HOSP was used for hospitalization information as reported to Medicare (from which primary discharge diagnoses of fractures were extracted), and SAF. PATIENTS was used to extract the primary cause of renal disease (PDIS) and cause and date of death. For calculation of incidence ratios, hospitalizations with a primary discharge diagnosis of fractures were extracted from SAF.HOSP and merged with the file SAF.TXUNOS, and only the first renal transplant occurring in a given patient from 1 July 1994 to 30 June 1997 was retained in the final file. Because the National Center for Health Statistics calculates its values based on hospitalizations, and not individual patients, incidence ratios in the present analysis did the same. Therefore, patients could have multiple hospitalizations for fractures. Only patients receiving a renal transplant in the years 1995 and 1996 were used in comparison with the National Hospital Discharge Survey. For multivariate analysis (comparing renal transplant patients hospitalized for fractures with all other renal transplant recipients), the above file was modified to include only the first hospitalization for a fracture occurring during
The outcome variables were based on International Classification of Diseases-9th Modification Diagnosis Codes (ICD9) at hospital discharge for Fractures: 800.x to 829.x, excluding pathologic fractures (the same definition as used in the National Hospital Discharge Survey) (21). Patient characteristics and treatment factors were those at the date of transplant. Information on use or results of calcium or vitamin D supplements, parathyroid hormone, calcium, phosphorous or other laboratory levels, alcohol, tobacco, bone mineral density, radiologic procedures, tobacco smoking status or alcohol intake, female menopausal status, or use of hormonal replacement therapy were not available. The USRDS information on immunosuppressive medications did not include total dose, and almost all recipients were on corticosteroid therapy (22). Furthermore, the clinical details for patients who were not on maintenance medications were not known, and, therefore, information on maintenance medications was included only in univariate analysis for descriptive purposes. Patient characteristics and treatment factors were those at the date of transplant. The USRDS Researcher’s Agreement specifically prohibits patient contact or chart review; therefore, episodes of fractures could not be independently verified. For the year 1995, adjusted incidence ratios for hospitalizations for fractures accounting for age, race, and sex were calculated using data from the 1995 National Hospital Discharge Survey, from the National Center for Health Statistics (NCHS), (21) similar to previous published reports. (23) In 1996, race was not used as a correcting factor by the NCHS, because racial characteristics were not considered reliable for that year. Confidence intervals for incidence ratios were generated using the normal approximation to the Poisson distribution. (24). Hospitalizations occurring in recipients during the first year after transplant in 1995 were compared with hospitalizations for fractures reported in the year 1995 in the general population. Total follow-up was, therefore, 1 year in each case. To determine the possible bias introduced by counting renal transplant recipients
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with multiple hospitalizations, another ratio was also used counting only the first hospitalization for fracture occurring in the study period and comparing this with the rate reported in the NCHS. Previous investigators have used a similar approach (23). All analyses were performed using the Statistical Product for Service Solutions (SPSS 9.0 TM (SPSS, Inc., Chicago, IL)) program. Files were merged and converted to SPSS files using DBMS/Copy (Conceptual Software, Houston, TX). Univariate analysis was performed with chisquare testing for categorical variables and Student’s t-test for continuous variables. Variables with p 0.10 in univariate analysis for a relationship with development of a first hospitalization for fractures were entered into multivariate analysis as covariates. The independent association between patient factors and hospitalizations for fractures was examined using multivariate analysis with stepwise logistic regression (25). Covariates, including age, race, gender, weight, body mass index (BMI) (kg/m2), duration of dialysis before transplantation, pretransplant dialysis as a categorical variable, previous transplant, allograft rejection, antibody induction therapy, kidney-pancreas recipient, and primary cause of renal disease (obtained from the PDIS field of SAF.PATIENTS), were first assessed in univariate analysis as above and entered into the multivariate model if significant. Location was assessed both by individual state and north and south regions (north region defined as ESRD Networks 1 to 5, 9 to 12, and 16, south region defined as ESRD Networks 6 to 8, 13, 14 to 18, ESRD Networks defined at http:// www.hcfa.gov/quality/5d1.htm). Transplant date was also divided into quartiles for analysis. Multiple adjusted odds ratios and their 95% confidence intervals were computed from the regression coefficients and their standard errors. The USRDS cannot reliably distinguish between types of diabetes. However, patients with end stage renal disease resulting from diabetes who were less than 40 years old at the time of transplant were consid-
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ered as presumed type I diabetics for the purpose of this analysis, and this method has been used in other reports (26). To adjust for differences in follow-up time, analysis using a model stratified for quartiles of transplant date was also performed using the same covariates as above, with the exception of transplant date. Time to hospitalization for fracture was calculated using Kaplan Meier analysis with recipients censored (removed from analysis) at time of death, graft failure, or loss to follow-up. The independent association of hospitalizations for fractures with patient mortality was analyzed as a segmented time-dependent covariate in Cox proportional hazards regression analysis using the same coefficients as for logistic regression, model 1, with patient survival as the outcome variable (defined as time from the date of transplant until the latest follow-up date or date of death, whichever occurred first, with patients censored after the latest follow-up date).
RESULTS There were 33,479 renal transplant recipients in the United States Renal Data System transplanted from 1 July 1994 to 30 June 1997. Of these, 379 recipients were hospitalized with a primary discharge diagnosis of fractures, with 468 total hospitalizations. Recipients had 7.2 episodes of hospitalizations for fractures per 1000 person years at risk (6.90 for men and 9.93 for women) in a total of 52,562 person years at risk since the date of transplant. Mean follow-up was 1.65 1.14 years (range up to 3 years post transplant), 7.5% of patients were lost to follow-up. Of all hospitalizations for fractures after transplant, the most common fractures were femur (34.8%), ankle-foot (17.7%), pelvis (8.3%), and vertebrae (5.3%). In comparison, the percentage of femoral neck fractures of total fractures in the general population in 1996 was 34.4% (21), and the remaining distribution was similar to that seen in the general popula-
TABLE 1. Incidence ratios for primary hospitalizations for fractures per year, 1995 and 1996 Fractures a
Year
Incidence in the general population
1995
0.38% (988) Single hospitalization per transplant recipient 0.38% (1012) Single hospitalization per transplant recipient
1996
Incidence in renal transplant recipients
Incidence ratio
0.7% (78) 0.6% (63) 0.8% (87) 0.6% (68)
4.59 (3.29–6.31)b 3.72 (2.66–5.11)b 5.29 (4.24–6.55)c 4.13 (3.31–5.10)c
95% CI 95% confidence interval. a From the National Hospital Discharge Survey (http://www.cdc.gov.nchs) The percentage and n (in thousands) of the entire population hospitalized for fractures, by year. For transplant recipients, n is the actual number. Data for transplant recipients are given both as total hospitalizations, in which each recipient could have more than one hospitalization for fracture, and as single hospitalizations for recipient, in which only the first hospitalization occurring after transplant was counted. The National Hospital Discharge Survey numbers are for total hospitalizations only. b Adjusted for age, race, and sex, with 95% confidence intervals. c Adjusted only for age and sex, with 95% confidence intervals.
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tion, except for a higher rate of vertebral fractures, although this could not be compared statistically (27). Incidence ratios of hospitalizations for fractures in transplant recipients from 1995 to 1996 compared to the general population are shown in Table 1. These numbers cannot be compared directly, because the year 1995 adjusted for age, race, and sex; whereas, in 1996, racial characteristics in the NCHS were considered unreliable, and correction could only be made for age and sex. Given the higher proportion of African Americans in the renal transplant population, the incidence ratio for 1996 likely represents an underestimate. Ratios are also given counting only one hospitalization for fracture for each renal transplant recipient, to exclude bias from overcounting multiple hospitalizations. Characteristics of the study population are shown in Table 2. In univariate analysis, recipient Caucasian race, female sex, weight, donor type, and years of pretransplant dialysis were significantly different between recipients hospitalized for fractures and recipients not hospitalized for fractures. Recipients with fractures were older than recipients without fractures. Of recipients hospitalized for fractures after transplant, 3.8% were hospitalized for fracture before transplant, compared to 0.8% of recipients who were not hospitalized for fractures after transplant. Looked at differently, 5.4% (32.2 episodes per 1000 person years at risk, total 465 person years at risk) of recipients with a previous history of fracture were hospitalized for fracture after renal transplantation, as compared to 1.1% (6.98 episodes per 1000 person years at risk, total 52,122 person years at risk) of all other renal transplant recipients. Results of multivariate analysis with logistic regression are shown in Table 3 Prevalent fractures were the leading risk factor for fractures in multivariate analysis of hospitalization for fractures after transplantation. In addition, recipients who were Caucasian, female, older, had diabetes of all causes and presumed type I diabetes, female recipients, and recipients with prolonged pretransplant dialysis and a categorical (yes/no) history of pretransplant dialysis were also at increased risk of hospitalizations for fractures. Recipients in the highest quartile of weight had significantly lower risk of hospitalization for fractures after transplantation compared to all other quartiles, as did recipients with end stage renal disease attributable to glomerulonephritis and recipients in the most recent quartile of transplant date (consistent with decreased follow-up time). Location (as measured by region or state), allograft rejection, antibody induction therapy, and kidney–pancreas transplantation were not significant in the model. Results of analysis stratified for transplant date are shown in Table 4. The only factors significant in all quartiles were diabetes (all causes) and recipient age. Duration of pretransplant dialysis was significant in three of the four quartiles, and, in general, the more recent quartiles had
TABLE 2. Univariate analysis of factors assessed in renal transplant recipients, 1 July 1994 to 30 June 1997
Factor n Hospitalization for fracture before transplant (prevalent fracture) Female recipient Caucasian African American Cadaveric donor Living donor Mean age (years) Recip 15–44 45–64 65 Cause of ESRD Diabetes (both type I and type II) Diabetes with recipient 40 years old (presumed type I) Hypertension Glomerulonephritis Systemic lupus erythematosus Recipient weight (in kg)b Quartiles of weight (lowest to highest) 1 ( 48.6 kg) 2 (48.6–72.3 kg) 3 (72.4–95.9 kg) 4 (95.9 kg) Body mass indexc Years of dialysis before transplantd Years of dialysis before transplant 4 Pretransplant dialysis Previous transplant Kidney–pancreas recipient Rejection Antibody induction therapy
Renal transplant recipients hospitalized for all-cause fractures
All other recipients
379
33,100
3.8% (15)* 48.5% (184)* 81.8% (310)* 16.4% (62)* 78.6% (298)* 21.4% (81)* 47.65 14.02a 36.4% (138)* 45.4% (172)* 10.6% (40)*
0.8% (265) 39.7% (13,142) 72.5% (24,987) 22.1% (7328) 70.8% (23,451) 29.2% (9649) 42.82 14.61 47.3% (15,659) 39.6% (13,110) 5.5% (1835)
49.9% (188)*
26.4% (8266)
18.2% (69)* 8.2% (31)* 13.8% (52)* 2.4% (9) 71.06 16.97a
8.6% (2859) 13.5% (4230) 26.5% (8274) 3.1% (959) 72.32 19.57
26.7% (81) 31.0% (94)* 25.7% (78) 16.5% (50)* 24.74 4.98
25.0% (6132) 25.0% (6132) 25.0% (6142) 24.9% (6116) 25.43 5.02
1.93 1.53a
1.57 1.46
17.7% (67) 92.7% (344)* 4.8% (18) 11.6% (44) 32.5% (123) 44.1% (167)*
15.1% (4930) 86.7% (27,051) 6.1% (1985) 7.4% (2456) 28.0% (9280) 35.4% (11,722)
Data given as the number (% of total) or mean one standard deviation for column one, for column two given as the number and percentage of patients with that factor who were hospitalized for fractures. * p 0.01 vs. recipients without fractures by chi-square test. a 0 0.01 vs. recipients without fractures by Student’s t-test. b 24,825 recipients with valid data. c 23,215 recipients with valid data. d 30,507 recipients with valid data. ESRD end stage renal disease.
fewer significant factors consistent with decreased followup time. The adjusted hazard function for hospitalizations for fractures by years post transplantation is shown in Figure 1.
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TABLE 3. Multivariate analysis (by logistic regression) of risk factors for hospitalization for all fractures after renal transplantation, 1 July 1994 to 30 June 1997 Factor Prevalent fracture Diabetes (both type I and type II)c Diabetes with recipient 40 years old (presumed type I)c Pretransplant dialysis (Y/N) Recipient Weight (Quartiles) 1 ( 48.6 kg) 2 (48.6–72.3 kg) 3 (72.4–95.9 kg) 4 (95.9 kg) (reference) Caucasian recipient Female recipient Years of pretransplant dialysis Recipient age Quartiles of transplant date (per increase in quartile) Kidney-Pancreas Recipient Glomerulonephritisc n in modelb Initial–2LL Final–2LL Nagelkerke r2
Adjusted odds ratioa 2.82 (1.06–5.14)* 1.97 (1.46–2.66)* 1.76 (1.21–2.56)* 1.74 (1.02–2.96)* 2.01 (1.38–2.94)* 1.86 (1.32–2.63)* 1.77 (1.26–2.49)* 1.00 () 1.66 (1.24–2.24)* 1.29 (1.02–1.64)* 1.18 (1.08–1.28)* 1.02 (1.03–1.04)* 0.82 (0.72–0.92)* 0.64 (0.41–1.01) 0.51 (0.32–0.82)* 21,725 3451 3200 0.078
95% CI 95% confidence interval. Continuous variable, per year. * p 0.05 in logistic regression analysis. NA Not performed in model. Only covariates significant in at least one model are shown. a For hospitalization resulting from fracture after renal transplantation. b Discrepancy from total n of 33,479 primarily because of missing weights in 26% of recipients. c As cause of end-stage renal disease.
The cumulative hazard for fractures increased linearly after renal transplantation, with no leveling off or early peak. Given the known relationship between hip fractures and mortality in the general population, analysis was performed on the association between hip fractures and patient survival in this population. The average age of recipients hospitalized for hip fractures was 51.57 12.82 years versus 42.83 14.61 years for all other recipients. The 1-year allcause mortality for recipients hospitalized for hip fractures was 14.7% versus 7.3% of all other recipients (p 0.01 by chi square), and corresponding 2-year mortality was 22.0% versus 12.2% of all other recipients (p 0.01 by chi square). Hip fractures were independently associated with decreased patient survival in Cox nonproportional hazards regression analysis with hip fractures as a time-dependent covariate, hazard ratio for mortality 1.60, 95% CI 1.13 to 2.26.
DISCUSSION Although fractures are generally considered a long-term complication after renal transplantation, the present study
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describes an increased incidence of hospitalizations for fractures in renal transplant recipients in the early post-transplant period (mean follow-up 1.65 years) as compared to the general population. The rates and incidence ratios presented are in fair agreement with previous studies on the risk of hip fractures in the end stage renal disease population (9). Risk factors for fractures in the general population, such as previous fracture, Caucasian race, female gender, diabetes, and lower weight (independent of body mass index) were also significant risk factors for fractures in the renal transplant population. This is in contrast to a prospective study of 57 adult kidney transplant recipients, with primary endpoints of bone density and histological markers, which concluded the effects of corticosteroid therapy on bone metabolism were so dominant that the effects of age, gender, cyclosporine, and hyperparathyroidism were not apparent (28). Diabetes has previously been reported as a risk factor for fractures after renal transplantation, (5) in contrast to reports of fracture risk in patients on maintenance dialysis (19) A study by Coco et al. showed fracture risk in end stage renal disease patients is inversely proportional to serum parathyroid hormone level (29). It was previously believed that severe secondary hyperparathyroidism might be associated with increased fracture risk in patients with end stage renal disease, as primary hyperparathyroidism is in the general population (30). Although the study of Coco et al. did not include diabetes in the multivariate model, diabetes has been associated with low serum parathyroid hormone levels and adynamic bone disease (31). The discrepancy between diabetes-associated fracture risk after renal transplantation, as opposed to maintenance dialysis, may relate to the synergistic action of factors associated with diabetes, such as decreased bone mineral density, (32) impaired osteoblast function, (33) and impaired responsiveness to parathyroid hormone, (34) with the known effects of corticosteroids on bone density (35, 36). Diabetes was a consistently significant factor in all quartiles of transplant dates. Type I diabetes was less consistent, and this may be because of the inability of the database to separate out type II diabetes for analysis. Previous fractures are established risk factors for future fractures (37–39). The relatively low odds ratio for prevalent fractures (less than 3.0) seen in the present study, and not consistently in all models, may be skewed by the short follow-up of the study. This factor may also be affected by the possibly higher fracture risk of recipients without previous fractures receiving high-dose immunosuppressive therapy, especially corticosteroid therapy (40). Although prevalent fractures and corticosteroid therapy are both known risk factors for subsequent fractures, no study, to our knowledge, has assessed the effect of corticosteroid therapy on patients with prevalent fractures (41). The association of recipient weight, independent of height (i.e., BMI), found in the present analysis confirms
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TABLE 4. Multivariate analysis (by logistic regression) of risk factors for hospitalization for all fractures after renal transplantation, 1 July 1994 to 30 June 1997, stratified by quartile of transplant date Adjusted Odds Ratioa Factor Transplant Date Prevalent fracture Diabetes (both type I and type II)c Diabetes with recipient 40 years old (presumed type I)c Pretransplant dialysis (Y/N) Recipient weight (quartiles) 1 (48.6 kg) 2 (48.6–72.3 kg) 3 (72.4–95.9 kg) 4 (95.9 kg) (Reference) Caucasian recipient Female recipient Years of pretransplant dialysis (per year) Recipient age (per year) n in modelb Initial–2LL Final–2LL Nagelkerke r2
1 July 1994 to 12 April 1995
13 April 1995 to 9 Jan. 1996
10 Jan. 1996 to 3 Oct. 1996
4 Oct. 1996 to 30 June 1997
0.01 (1) 1.50 (0.85–2.66)*
3.73 (1.03–13.59)* 2.86 (1.54–5.32)*
4.35 (0.96–19.68) 2.23 (1.30–3.82)*
1.83 (0.40–8.17) 2.08 (1.21–3.57)*
2.19 (0.95–5.03)* 1.39 (0.53–3.65)*
2.08 (0.87–5.00) 0.95 (0.35–2.57)
1.57 (0.74–3.35) 2.33 (0.81–6.71)
2.07 (0.94–4.55) 3.54 (0.84–14.94)
3.22 (1.39–7.48)* 2.81 (1.28–6.14)* 1.59 (0.69–3.66)* 1.00 () 2.02 (1.04–3.92)* 1.32 (0.79–2.17)
1.09 (0.40–2.99) 1.58 (0.68–3.68) 2.29 (1.03–5.07)* 1.00 () 2.07 (1.00–4.71)* 1.72 (0.97–3.03)
1.62 (0.76–3.47) 1.51 (0.76–3.00) 1.38 (0.71–2.72) 1.00 () 1.56 (0.85–2.86) 1.04 (0.63–1.72)
1.00 (0.55–1.83) 1.38 (0.71–2.68) 0.97 (0.48–1.96) 1.00 () 1.46 (0.82–2.61) 1.45 (0.88–2.38)
1.14 (0.96–1.35)* 1.04 (1.02–1.07)* 5322 771 702 0.095
1.25 (1.03–1.52)* 1.03 (1.00–1.06)* 5400 623 564 0.10
1.06 (0.88–1.26) 1.02 (1.00–1.04)* 5622 813 766 0.062
1.21 (1.03–1.42)* 1.03 (1.01–1.05)* 5309 796 739 0.77
95% CI 95% confidence interval. *p 0.05 in logistic regression analysis. Only covariates significant in at least one model are shown. a For hospitalization resulting from fracture after renal transplantation. b Discrepancy from total N of 33,479 primarily due to missing weights in 26% of recipients. c As cause of end stage renal disease.
work on high-risk groups in the general population. Margolis et al., in a prospective study of elderly postmenopausal females, showed that total body weight accurately predicted hip fracture risk, although this risk could be completely explained by differences in bone mineral density (18). Mortality in renal transplant recipients hospitalized for hip fractures (who had an average age of 52 years) was similar to mortality after hip fracture in the elderly population (65 years). Aharonoff et al. showed that the elderly had a 1-year mortality rate of 12.7% following hip fracture (42). The present study found the 1-year mortality rate following hip fracture in renal transplant recipients was 14.7%. There are several limitations to this retrospective study. This study could not independently verify radiologic findings of fractures. However, ICD-9 coding for determining rates of medical conditions has been used in other published studies, (43–46) as well as the National Center for Health Statistics (21). Another reason for underestimating the frequency of fractures in this population would be the use of hospitalized cases of fractures in the fracture cohort. Nevertheless, hospitalized fractures would be a marker for more severe and disabling fractures. Furthermore, most hip fractures, which were the most common fracture site in this analysis, are hospitalized (47). The short follow-up duration
of the study may also be a limitation, although previous studies have demonstrated the peak risk of bone demineralization (although not necessarily fracture risk) occurs early post transplant (14). Strengths of the present analysis include its large size and population-based character, and comparisons with a national, rather than local, sample. The substantially younger age of the transplant population compared to the general population has other important implications given the increased fracture risk shown in the present study. As patient survival in this population improves, it is likely that absolute rates of fractures will increase dramatically. The mortality associated with hip fracture in this population is disproportional to age and worthy of further investigation. The confirmation of commonly accepted risk factors for fractures in the general population as risk factors in the transplant population is important for screening and targeted intervention. In addition, patients with prolonged pretransplant dialysis, who are not currently considered a target group for intervention in recently published transplant practice guidelines, (48) were also identified as at risk. Most of these risk factors can easily be obtained from a history and physical examination, requiring no additional equipment or calculations, an important consideration in today’s medical environment.
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14. Carlini RG, Rojas E, Weisinger JR, Lopez M, Martinis R, Arminiio A, Bellorin-Font E. Bone disease in patients with long-term renal transplantation with normal renal function. Am J Kidney Dis (2000; 36:160–166. 15. Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, Cauley J,Black D, Vogt TM. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med. 1995;332:767–773. 16. Raisz LG. The osteoporosis revolution. Ann Intern Med. 1997; 126(6):458–462. 17. Kelepouris N, Harper KD, Gannon F, Kaplan FS, Haddad JG. Severe osteoporosis in men. Ann Intern Med. 1995;123:452–460. 18. Margolis KL, Ensrud KE, Schreiner PJ, Tabor HK. Body size and risk for clinical fractures in older women. Study of Osteoporotic Fractures Research Group. Ann Intern Med. 2000;133(2):123–127. 19. Stethman-Breen CO, Sherrard DJ, Alem AM, Gillen DL, Heckbert SR, Wong CS, Ball A, Weiss NS. Risk factors for hip fracture among patients with end stage renal disease. Kidney Int. 2000;58:2200–2205.
FIGURE 1. Adjusted hazard (by Cox regression) for hospitalization for fractures, U.S. renal transplant recipients, by years postrenal transplant, 1 July 1994 to 1930 June 1997.
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20. http://www.usrds.org 21. www.cdc.gov.nchs 22. Ojo AO, Meier-Kriesche HU, Hanson JA, Leichtman AB, Cibrik D, Magee JC, Wolfe RA, Agodoa LY, Kaplan B. Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection. Transplantation. 2000; 69:2405–2409. 23. Sheiner PA, Magliocca JF, Bodian CA, Kim-Schluger L, Altaca G, Guarrera JV,Emre S, Fishbein TM, Guy SR, Schwartz ME, Miller CM. Long-term medical complications in patients surviving or 5 years after liver transplant. Transplantation. 2000;69:781–789. 24. Fisher L, Vanbelle G. Biostatistics. New York: John Wiley & Sons; 1993, pp. 771. 25. Kleinbaum DG. Logistic Regression : A Self-Learning Text (Statistics in the Health Sciences). Berlin: Springer; 1994. 26. Ojo AO, Kaplan B, Hanson JA, Meier-Kriesche HU, Leichtman AB, Magee JC, Cibrik DM, Wolfe RA, Port FK, Agodoa LY, Kaufman DB. Impact of transplant types on long-term mortality in type 1 diabetics with end-stage nephropathy. Transplantation. 2000;69:S270 (Abstract 612). 27. Gomberg BF, Gruen GS, Smith WR, Spott M. Outcomes in acute orthopedic trauma: A review of 130,506 patients by age. Injury. 1999; 30:431–437. 28. Monier-Faugere MC, Mawad H, Qi Q, Friedler RM, Malluche HH. Prevalence of low bone turnover and occurrence of osteomalacia after kidney transplantation. J Am Soc Nephrol. 2000;11:1093–1099. 29. Coco M, Rush H. Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone. Am J Kidney Dis. 2000; 36:1115–1121. 30. Khosla S, Melton LJ, Wermers RA, Crowson CS, O’Fallon WM, Riggs BL. Primary hyperparathyroidism and the risk of fracture: A population-based study. J Bone Miner Res. 1999;14:1700–1707. 31. Carmen Sanchez M, Auxiliadora Bajo M, Selgas R, Mate A, Millan I, Eugenia Martinez M, Lopez-Barea F. Parathormone secretion in peritoneal dialysis patients with adynamic bone disease. Am J Kidney Dis. 2000;36(5):953–961.
11. Parker CR, Freemont AJ, Blackwell PJ, Grainge MJ, Hosking DJ. Cross-sectional analysis of renal transplantation osteoporosis. J Bone Miner Res. 1999;14:1943–1951.
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12. Almond MK, Kwan JT, Evans K, Cunningham J. Loss of regional bone mineral density in the first 12 months following renal transplantation. Nephron. 1994;66:52–57.
33. Verhaeghe J, Van Herck E, van Bree R, Moermans K, Bouillon R. Decreased osteoblast activity in spontaneously diabetic rats. In vivo studies on the pathogenesis. Endocrine. 1997;7:165–175.
13. Cueto-Manzano AM, Konel S, Freemont AJ, Adams JE, Mawer B, Gokal R, Hutchison AJ. Effect of 1,25-dihydroxyvitamin D3 and calcium carbonate on bone loss associated with long-term renal transplantation. Am J Kidney Dis. 2000;35:227–236.
34. Picton ML, Moore PR, Mawer EB, Houghton D, Freemont AJ, Hutchison AJ, Gokal R, Hoyland JA. Down-regulation of human osteoblast PTH/PTHrP receptor mRNA in end-stage renal failure. Kidney Int. 2000;58:1440–1449.
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35. Ramsey-Goldman R, Dunn JE, Dunlop DD, Stuart FP, Abecassis MM, Kaufman DB, Langman CB, Salinger MH, Sprague SM. Increased risk of fracture in patients receiving solid organ transplants. J Bone Miner Res. 1999;14(3:456–463. 36. Rodino MA, Shane E. Osteoporosis after organ transplantation. Am J Med. 1998;104:459–469. 37. Ensrud KE, Black DM, Pelarmo L, Bauer DC, Barrett-Connor E, Quandt SA, Thompson DE, Karpf DB. Treatment with alendronate prevents fractures in women at highest risk: Results from the Fracture Intervention Trial. Arch Intern Med. 1997;157:2617–2624. 38. Nevitt MC, Ross PD, Palermo L, Musliner T, Genant HK, Thompson DE. Association of prevalent vertebral fractures, bone Density, and alendronate treatment with incident vertebral fractures: Effect of number and spinal location of fractures. Bone. 1999;25:613–619. 39. Ross PD, Davis JW, Epstein RS, Wasnich RD. Pre-existing fractures and bone mass predict vertebral fracture incidence in women. Ann Intern Med. 1991;114:919–923. 40. Jehle PM, Jehle DR. Use of corticosteroids in nephrology—Risk and prevention of osteoporosis induction. Nephrol Dial Transplant. 2000;15(5):565–568. 41. Ross PD. Risk factors for osteoporotic fractures. Endocrinol Metab Clin N Am. 1998;27:289–301.
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42. Aharonoff GB, Koval KJ, Skovron ML, Zuckerman JD. Hip fractures in the elderly: Predictors of one year mortality. J Orthop Trauma. 1997;11(3):162–165. 43. Cowan DN, DeFraites RF, Gray GC, Goldenbaum MB, Wishik SM. The risk of birth defects among children of Persian Gulf War veterans. N Engl J Med. 1997;336:1650–1656. 44. Cassel CK, Vladeck BC. ICD-9 code for palliative or terminal care. N Engl J Med 1996;335:1232–1234. 45. Assaf AR, Lapane KL, McKenney JL, Carleton RA. Possible influence of the prospective payment system on the assignment of discharge diagnoses for coronary heart disease. N Engl J Med. 1993;329:931–935. 46. Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and 6-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med. 1989;320:904–910. 47. Fisher E, Baron J, Malenka D, Barrett J, Bubolz T. Overcoming potential pitfalls in the use of Medicare data for epidemiologic research. Am J Publ Health. 1990;80:1487–1490. 48. Kasiske BL, Vazquez MA, Harmon WE, Brown RS, Danovitch GM, Gaston RS, Roth D, Scandling JD Jr, Singer GG. Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation. J Am Soc Nephrol. 2000;11 Suppl 15:S1–S86.
PURPOSE: To investigate the incidence, risk factors, and associated mortality of fractures in renal transplant recipients. METHODS: Retrospective registry study of 33,479 patients in the United States Renal Data System (USRDS) who received kidney transplants between 1 July 1994 and 30 June 1997. Associations with hospitalizations for a primary discharge diagnosis of fractures (all causes) were assessed. RESULTS: Renal transplant recipients had an adjusted incidence ratio for fractures of 4.59 (95% confidence interval 3.29 to 6.31). In multivariate analysis, recipients with prevalent fractures, as well as recipients who were Caucasian, women, in the lower quartiles of recipient weight (95.9 kg), had end stage renal disease caused by diabetes, and had prolonged pretransplant dialysis were at increased risk for hospitalization because of fractures after transplantation. Recipients hospitalized for hip fractures had decreased all-cause survival (hazard ratio for mortality 1.60, 95% CI 1.13 to 2.26) in Cox Regression analysis. CONCLUSIONS: In the early post-transplant course (3 years), renal transplant recipients had a greater incidence of fractures than the general population, which were associated with decreased patient survival. Preventive efforts should focus on recipients with the risk factors identified in this analysis, most of which can be easily obtained through history and physical examination. Ann Epidemiol 2001;11:450–457. © 2001 Elsevier Science Inc. All rights reserved. KEY WORDS:
Fracture, Osteoporosis, Renal Transplant, Weight, Dialysis Duration, Complication,
USRDS.
INTRODUCTION Fractures are significant causes of morbidity in both the general population and in recipients of renal transplants
From the Nephrology Service (K.C.A., P.G.W.), Walter Reed Army Medical Center, Washington, DC; and Uniformed Services University of the Health Sciences, Bethesda, MD; Rheumatology Service (R.J.O.), Walter Reed Army Medical Center, Washington, DC; and Uniformed Services University of the Health Sciences (R.J.O.), Bethesda, MD; Office of Minority Research Health Coordination (I.O.H.), National Institute for Diabetes, Digestive, and Kidney Disease (NIDDK), National Institutes of Health (NIH), Bethesda, MD; Organ Transplantation Service (A.D.K.), National Institutes of Health, Bethesda, MD; Epidemiology, Statistics, and Data System Branch (C.W.K.), National Institute on Deafness and Other Communication Disorders (NIDCD), NIH, Bethesda, MD; NIDDK, NIH, Bethesda, MD; and Endocrinology Service (W.E.D.), Walter Reed Army Medical Center, Washington, DC. The opinions expressed are solely those of the authors and do not represent an endorsement by the Department of Defense or the National Institutes of Health. This is a government work. There are no restrictions on its use. Portions of this article were presented at AST 2000 in Chicago, IL, 13-17 May, 2000. Address reprint requests to: Dr. Kevin C. Abbott, LTC, MC, Director, Dialysis, Nephrology Service, Walter Reed Army Medical Center, Washington, DC 20307-5001. Tel.: (202) 782-6462/6463/6288, Fax: (202) 7820185. E-mail: [email protected] Received September 18, 2000; revised January 8, 2001; accepted January 23, 2001. © 2001 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
(1–6). Although fractures are generally believed to be a late complication after renal transplantation, the rates of and risk factors for fractures occurring in the early postrenal transplant course have not been analyzed for a national population, and, therefore, the true scope of the problem is unknown. The reported prevalence of fractures in renal transplant recipients ranges from 5 to 21%, with an estimated incidence of 2% per year (7, 8). A study of the United States Renal Data System (USRDS) end stage renal disease population found a cumulative incidence of hip fractures significantly higher than in the general population (9). Several reports indicate bone demineralization in transplant patients is greatest in the first few years after transplant; (10– 13) although a more recent report indicated levels approach normal at 10 years post transplant (14). Risk factors for fractures in the general population include decreased bone mineral density, increasing age, Caucasian race, female gender, and low weight (15–18). Similar findings have recently been reported for end stage renal disease patients, although weight and a history of previous fracture were not assessed (19). To characterize better the incidence and risk factors for hospitalizations resulting from fractures in the renal transplant population, we analyzed national data from the 1999 USRDS report. Our objectives 1047-2797/01/$–see front matter PII S1047-2797(01)00226-5
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Selected Acronyms and Abbreviations USRDS United States Renal Data System ESRD End stage renal disease NCHS National Center For Health Statistics
were to determine the rate of and risk factors for hospitalizations for a primary diagnosis of fractures of all nonpathological causes in renal transplant recipients.
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the study period, and, therefore, a given patient had only one hospitalization counted during the study period. Hospitalization data for transplant recipients may be unreliable after a recipient has survived 3 years post transplant, when hospitalization reporting to Medicare is no longer required. However, Medicare reporting starts immediately after transplant. The present study limited analysis to the first kidney transplant occurring in an individual recipient from 1 July 1994 to 30 June 1997 to avoid exceeding the 3-year period. Hospitalizations for fractures occurring at any time after renal transplant, including after graft failure, were counted in analysis, in an intention to treat fashion.
METHODS Data Sources and Study Sample
Analytic Variables and Outcome Measures
We conducted a national retrospective registry study of the incidence and demographic risk factors for hospitalized cases of fractures as a primary diagnosis in renal transplant recipients. Hospitalizations were chosen for two reasons: (i) they were more accessible in the database and less subject to interpretation than outpatient cases of fractures, especially because the USRDS database has no information on radiographic studies; and (ii) they could be compared directly to the National Center for Health Statistics. The variables included in the USRDS data files, as well as data collection methods and validation studies, are listed at the USRDS website, under “Researcher’s Guide to the USRDS Database,” Section E, “Contents of all the SAFs” (Standard Analysis Files), (20) and published in the USRDS. The demographics of the renal transplant population have been previously described (1999 USRDS report). SAF.TXUNOS was used as the main file. SAF.HOSP was used for hospitalization information as reported to Medicare (from which primary discharge diagnoses of fractures were extracted), and SAF. PATIENTS was used to extract the primary cause of renal disease (PDIS) and cause and date of death. For calculation of incidence ratios, hospitalizations with a primary discharge diagnosis of fractures were extracted from SAF.HOSP and merged with the file SAF.TXUNOS, and only the first renal transplant occurring in a given patient from 1 July 1994 to 30 June 1997 was retained in the final file. Because the National Center for Health Statistics calculates its values based on hospitalizations, and not individual patients, incidence ratios in the present analysis did the same. Therefore, patients could have multiple hospitalizations for fractures. Only patients receiving a renal transplant in the years 1995 and 1996 were used in comparison with the National Hospital Discharge Survey. For multivariate analysis (comparing renal transplant patients hospitalized for fractures with all other renal transplant recipients), the above file was modified to include only the first hospitalization for a fracture occurring during
The outcome variables were based on International Classification of Diseases-9th Modification Diagnosis Codes (ICD9) at hospital discharge for Fractures: 800.x to 829.x, excluding pathologic fractures (the same definition as used in the National Hospital Discharge Survey) (21). Patient characteristics and treatment factors were those at the date of transplant. Information on use or results of calcium or vitamin D supplements, parathyroid hormone, calcium, phosphorous or other laboratory levels, alcohol, tobacco, bone mineral density, radiologic procedures, tobacco smoking status or alcohol intake, female menopausal status, or use of hormonal replacement therapy were not available. The USRDS information on immunosuppressive medications did not include total dose, and almost all recipients were on corticosteroid therapy (22). Furthermore, the clinical details for patients who were not on maintenance medications were not known, and, therefore, information on maintenance medications was included only in univariate analysis for descriptive purposes. Patient characteristics and treatment factors were those at the date of transplant. The USRDS Researcher’s Agreement specifically prohibits patient contact or chart review; therefore, episodes of fractures could not be independently verified. For the year 1995, adjusted incidence ratios for hospitalizations for fractures accounting for age, race, and sex were calculated using data from the 1995 National Hospital Discharge Survey, from the National Center for Health Statistics (NCHS), (21) similar to previous published reports. (23) In 1996, race was not used as a correcting factor by the NCHS, because racial characteristics were not considered reliable for that year. Confidence intervals for incidence ratios were generated using the normal approximation to the Poisson distribution. (24). Hospitalizations occurring in recipients during the first year after transplant in 1995 were compared with hospitalizations for fractures reported in the year 1995 in the general population. Total follow-up was, therefore, 1 year in each case. To determine the possible bias introduced by counting renal transplant recipients
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with multiple hospitalizations, another ratio was also used counting only the first hospitalization for fracture occurring in the study period and comparing this with the rate reported in the NCHS. Previous investigators have used a similar approach (23). All analyses were performed using the Statistical Product for Service Solutions (SPSS 9.0 TM (SPSS, Inc., Chicago, IL)) program. Files were merged and converted to SPSS files using DBMS/Copy (Conceptual Software, Houston, TX). Univariate analysis was performed with chisquare testing for categorical variables and Student’s t-test for continuous variables. Variables with p 0.10 in univariate analysis for a relationship with development of a first hospitalization for fractures were entered into multivariate analysis as covariates. The independent association between patient factors and hospitalizations for fractures was examined using multivariate analysis with stepwise logistic regression (25). Covariates, including age, race, gender, weight, body mass index (BMI) (kg/m2), duration of dialysis before transplantation, pretransplant dialysis as a categorical variable, previous transplant, allograft rejection, antibody induction therapy, kidney-pancreas recipient, and primary cause of renal disease (obtained from the PDIS field of SAF.PATIENTS), were first assessed in univariate analysis as above and entered into the multivariate model if significant. Location was assessed both by individual state and north and south regions (north region defined as ESRD Networks 1 to 5, 9 to 12, and 16, south region defined as ESRD Networks 6 to 8, 13, 14 to 18, ESRD Networks defined at http:// www.hcfa.gov/quality/5d1.htm). Transplant date was also divided into quartiles for analysis. Multiple adjusted odds ratios and their 95% confidence intervals were computed from the regression coefficients and their standard errors. The USRDS cannot reliably distinguish between types of diabetes. However, patients with end stage renal disease resulting from diabetes who were less than 40 years old at the time of transplant were consid-
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ered as presumed type I diabetics for the purpose of this analysis, and this method has been used in other reports (26). To adjust for differences in follow-up time, analysis using a model stratified for quartiles of transplant date was also performed using the same covariates as above, with the exception of transplant date. Time to hospitalization for fracture was calculated using Kaplan Meier analysis with recipients censored (removed from analysis) at time of death, graft failure, or loss to follow-up. The independent association of hospitalizations for fractures with patient mortality was analyzed as a segmented time-dependent covariate in Cox proportional hazards regression analysis using the same coefficients as for logistic regression, model 1, with patient survival as the outcome variable (defined as time from the date of transplant until the latest follow-up date or date of death, whichever occurred first, with patients censored after the latest follow-up date).
RESULTS There were 33,479 renal transplant recipients in the United States Renal Data System transplanted from 1 July 1994 to 30 June 1997. Of these, 379 recipients were hospitalized with a primary discharge diagnosis of fractures, with 468 total hospitalizations. Recipients had 7.2 episodes of hospitalizations for fractures per 1000 person years at risk (6.90 for men and 9.93 for women) in a total of 52,562 person years at risk since the date of transplant. Mean follow-up was 1.65 1.14 years (range up to 3 years post transplant), 7.5% of patients were lost to follow-up. Of all hospitalizations for fractures after transplant, the most common fractures were femur (34.8%), ankle-foot (17.7%), pelvis (8.3%), and vertebrae (5.3%). In comparison, the percentage of femoral neck fractures of total fractures in the general population in 1996 was 34.4% (21), and the remaining distribution was similar to that seen in the general popula-
TABLE 1. Incidence ratios for primary hospitalizations for fractures per year, 1995 and 1996 Fractures a
Year
Incidence in the general population
1995
0.38% (988) Single hospitalization per transplant recipient 0.38% (1012) Single hospitalization per transplant recipient
1996
Incidence in renal transplant recipients
Incidence ratio
0.7% (78) 0.6% (63) 0.8% (87) 0.6% (68)
4.59 (3.29–6.31)b 3.72 (2.66–5.11)b 5.29 (4.24–6.55)c 4.13 (3.31–5.10)c
95% CI 95% confidence interval. a From the National Hospital Discharge Survey (http://www.cdc.gov.nchs) The percentage and n (in thousands) of the entire population hospitalized for fractures, by year. For transplant recipients, n is the actual number. Data for transplant recipients are given both as total hospitalizations, in which each recipient could have more than one hospitalization for fracture, and as single hospitalizations for recipient, in which only the first hospitalization occurring after transplant was counted. The National Hospital Discharge Survey numbers are for total hospitalizations only. b Adjusted for age, race, and sex, with 95% confidence intervals. c Adjusted only for age and sex, with 95% confidence intervals.
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tion, except for a higher rate of vertebral fractures, although this could not be compared statistically (27). Incidence ratios of hospitalizations for fractures in transplant recipients from 1995 to 1996 compared to the general population are shown in Table 1. These numbers cannot be compared directly, because the year 1995 adjusted for age, race, and sex; whereas, in 1996, racial characteristics in the NCHS were considered unreliable, and correction could only be made for age and sex. Given the higher proportion of African Americans in the renal transplant population, the incidence ratio for 1996 likely represents an underestimate. Ratios are also given counting only one hospitalization for fracture for each renal transplant recipient, to exclude bias from overcounting multiple hospitalizations. Characteristics of the study population are shown in Table 2. In univariate analysis, recipient Caucasian race, female sex, weight, donor type, and years of pretransplant dialysis were significantly different between recipients hospitalized for fractures and recipients not hospitalized for fractures. Recipients with fractures were older than recipients without fractures. Of recipients hospitalized for fractures after transplant, 3.8% were hospitalized for fracture before transplant, compared to 0.8% of recipients who were not hospitalized for fractures after transplant. Looked at differently, 5.4% (32.2 episodes per 1000 person years at risk, total 465 person years at risk) of recipients with a previous history of fracture were hospitalized for fracture after renal transplantation, as compared to 1.1% (6.98 episodes per 1000 person years at risk, total 52,122 person years at risk) of all other renal transplant recipients. Results of multivariate analysis with logistic regression are shown in Table 3 Prevalent fractures were the leading risk factor for fractures in multivariate analysis of hospitalization for fractures after transplantation. In addition, recipients who were Caucasian, female, older, had diabetes of all causes and presumed type I diabetes, female recipients, and recipients with prolonged pretransplant dialysis and a categorical (yes/no) history of pretransplant dialysis were also at increased risk of hospitalizations for fractures. Recipients in the highest quartile of weight had significantly lower risk of hospitalization for fractures after transplantation compared to all other quartiles, as did recipients with end stage renal disease attributable to glomerulonephritis and recipients in the most recent quartile of transplant date (consistent with decreased follow-up time). Location (as measured by region or state), allograft rejection, antibody induction therapy, and kidney–pancreas transplantation were not significant in the model. Results of analysis stratified for transplant date are shown in Table 4. The only factors significant in all quartiles were diabetes (all causes) and recipient age. Duration of pretransplant dialysis was significant in three of the four quartiles, and, in general, the more recent quartiles had
TABLE 2. Univariate analysis of factors assessed in renal transplant recipients, 1 July 1994 to 30 June 1997
Factor n Hospitalization for fracture before transplant (prevalent fracture) Female recipient Caucasian African American Cadaveric donor Living donor Mean age (years) Recip 15–44 45–64 65 Cause of ESRD Diabetes (both type I and type II) Diabetes with recipient 40 years old (presumed type I) Hypertension Glomerulonephritis Systemic lupus erythematosus Recipient weight (in kg)b Quartiles of weight (lowest to highest) 1 ( 48.6 kg) 2 (48.6–72.3 kg) 3 (72.4–95.9 kg) 4 (95.9 kg) Body mass indexc Years of dialysis before transplantd Years of dialysis before transplant 4 Pretransplant dialysis Previous transplant Kidney–pancreas recipient Rejection Antibody induction therapy
Renal transplant recipients hospitalized for all-cause fractures
All other recipients
379
33,100
3.8% (15)* 48.5% (184)* 81.8% (310)* 16.4% (62)* 78.6% (298)* 21.4% (81)* 47.65 14.02a 36.4% (138)* 45.4% (172)* 10.6% (40)*
0.8% (265) 39.7% (13,142) 72.5% (24,987) 22.1% (7328) 70.8% (23,451) 29.2% (9649) 42.82 14.61 47.3% (15,659) 39.6% (13,110) 5.5% (1835)
49.9% (188)*
26.4% (8266)
18.2% (69)* 8.2% (31)* 13.8% (52)* 2.4% (9) 71.06 16.97a
8.6% (2859) 13.5% (4230) 26.5% (8274) 3.1% (959) 72.32 19.57
26.7% (81) 31.0% (94)* 25.7% (78) 16.5% (50)* 24.74 4.98
25.0% (6132) 25.0% (6132) 25.0% (6142) 24.9% (6116) 25.43 5.02
1.93 1.53a
1.57 1.46
17.7% (67) 92.7% (344)* 4.8% (18) 11.6% (44) 32.5% (123) 44.1% (167)*
15.1% (4930) 86.7% (27,051) 6.1% (1985) 7.4% (2456) 28.0% (9280) 35.4% (11,722)
Data given as the number (% of total) or mean one standard deviation for column one, for column two given as the number and percentage of patients with that factor who were hospitalized for fractures. * p 0.01 vs. recipients without fractures by chi-square test. a 0 0.01 vs. recipients without fractures by Student’s t-test. b 24,825 recipients with valid data. c 23,215 recipients with valid data. d 30,507 recipients with valid data. ESRD end stage renal disease.
fewer significant factors consistent with decreased followup time. The adjusted hazard function for hospitalizations for fractures by years post transplantation is shown in Figure 1.
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TABLE 3. Multivariate analysis (by logistic regression) of risk factors for hospitalization for all fractures after renal transplantation, 1 July 1994 to 30 June 1997 Factor Prevalent fracture Diabetes (both type I and type II)c Diabetes with recipient 40 years old (presumed type I)c Pretransplant dialysis (Y/N) Recipient Weight (Quartiles) 1 ( 48.6 kg) 2 (48.6–72.3 kg) 3 (72.4–95.9 kg) 4 (95.9 kg) (reference) Caucasian recipient Female recipient Years of pretransplant dialysis Recipient age Quartiles of transplant date (per increase in quartile) Kidney-Pancreas Recipient Glomerulonephritisc n in modelb Initial–2LL Final–2LL Nagelkerke r2
Adjusted odds ratioa 2.82 (1.06–5.14)* 1.97 (1.46–2.66)* 1.76 (1.21–2.56)* 1.74 (1.02–2.96)* 2.01 (1.38–2.94)* 1.86 (1.32–2.63)* 1.77 (1.26–2.49)* 1.00 () 1.66 (1.24–2.24)* 1.29 (1.02–1.64)* 1.18 (1.08–1.28)* 1.02 (1.03–1.04)* 0.82 (0.72–0.92)* 0.64 (0.41–1.01) 0.51 (0.32–0.82)* 21,725 3451 3200 0.078
95% CI 95% confidence interval. Continuous variable, per year. * p 0.05 in logistic regression analysis. NA Not performed in model. Only covariates significant in at least one model are shown. a For hospitalization resulting from fracture after renal transplantation. b Discrepancy from total n of 33,479 primarily because of missing weights in 26% of recipients. c As cause of end-stage renal disease.
The cumulative hazard for fractures increased linearly after renal transplantation, with no leveling off or early peak. Given the known relationship between hip fractures and mortality in the general population, analysis was performed on the association between hip fractures and patient survival in this population. The average age of recipients hospitalized for hip fractures was 51.57 12.82 years versus 42.83 14.61 years for all other recipients. The 1-year allcause mortality for recipients hospitalized for hip fractures was 14.7% versus 7.3% of all other recipients (p 0.01 by chi square), and corresponding 2-year mortality was 22.0% versus 12.2% of all other recipients (p 0.01 by chi square). Hip fractures were independently associated with decreased patient survival in Cox nonproportional hazards regression analysis with hip fractures as a time-dependent covariate, hazard ratio for mortality 1.60, 95% CI 1.13 to 2.26.
DISCUSSION Although fractures are generally considered a long-term complication after renal transplantation, the present study
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describes an increased incidence of hospitalizations for fractures in renal transplant recipients in the early post-transplant period (mean follow-up 1.65 years) as compared to the general population. The rates and incidence ratios presented are in fair agreement with previous studies on the risk of hip fractures in the end stage renal disease population (9). Risk factors for fractures in the general population, such as previous fracture, Caucasian race, female gender, diabetes, and lower weight (independent of body mass index) were also significant risk factors for fractures in the renal transplant population. This is in contrast to a prospective study of 57 adult kidney transplant recipients, with primary endpoints of bone density and histological markers, which concluded the effects of corticosteroid therapy on bone metabolism were so dominant that the effects of age, gender, cyclosporine, and hyperparathyroidism were not apparent (28). Diabetes has previously been reported as a risk factor for fractures after renal transplantation, (5) in contrast to reports of fracture risk in patients on maintenance dialysis (19) A study by Coco et al. showed fracture risk in end stage renal disease patients is inversely proportional to serum parathyroid hormone level (29). It was previously believed that severe secondary hyperparathyroidism might be associated with increased fracture risk in patients with end stage renal disease, as primary hyperparathyroidism is in the general population (30). Although the study of Coco et al. did not include diabetes in the multivariate model, diabetes has been associated with low serum parathyroid hormone levels and adynamic bone disease (31). The discrepancy between diabetes-associated fracture risk after renal transplantation, as opposed to maintenance dialysis, may relate to the synergistic action of factors associated with diabetes, such as decreased bone mineral density, (32) impaired osteoblast function, (33) and impaired responsiveness to parathyroid hormone, (34) with the known effects of corticosteroids on bone density (35, 36). Diabetes was a consistently significant factor in all quartiles of transplant dates. Type I diabetes was less consistent, and this may be because of the inability of the database to separate out type II diabetes for analysis. Previous fractures are established risk factors for future fractures (37–39). The relatively low odds ratio for prevalent fractures (less than 3.0) seen in the present study, and not consistently in all models, may be skewed by the short follow-up of the study. This factor may also be affected by the possibly higher fracture risk of recipients without previous fractures receiving high-dose immunosuppressive therapy, especially corticosteroid therapy (40). Although prevalent fractures and corticosteroid therapy are both known risk factors for subsequent fractures, no study, to our knowledge, has assessed the effect of corticosteroid therapy on patients with prevalent fractures (41). The association of recipient weight, independent of height (i.e., BMI), found in the present analysis confirms
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TABLE 4. Multivariate analysis (by logistic regression) of risk factors for hospitalization for all fractures after renal transplantation, 1 July 1994 to 30 June 1997, stratified by quartile of transplant date Adjusted Odds Ratioa Factor Transplant Date Prevalent fracture Diabetes (both type I and type II)c Diabetes with recipient 40 years old (presumed type I)c Pretransplant dialysis (Y/N) Recipient weight (quartiles) 1 (48.6 kg) 2 (48.6–72.3 kg) 3 (72.4–95.9 kg) 4 (95.9 kg) (Reference) Caucasian recipient Female recipient Years of pretransplant dialysis (per year) Recipient age (per year) n in modelb Initial–2LL Final–2LL Nagelkerke r2
1 July 1994 to 12 April 1995
13 April 1995 to 9 Jan. 1996
10 Jan. 1996 to 3 Oct. 1996
4 Oct. 1996 to 30 June 1997
0.01 (1) 1.50 (0.85–2.66)*
3.73 (1.03–13.59)* 2.86 (1.54–5.32)*
4.35 (0.96–19.68) 2.23 (1.30–3.82)*
1.83 (0.40–8.17) 2.08 (1.21–3.57)*
2.19 (0.95–5.03)* 1.39 (0.53–3.65)*
2.08 (0.87–5.00) 0.95 (0.35–2.57)
1.57 (0.74–3.35) 2.33 (0.81–6.71)
2.07 (0.94–4.55) 3.54 (0.84–14.94)
3.22 (1.39–7.48)* 2.81 (1.28–6.14)* 1.59 (0.69–3.66)* 1.00 () 2.02 (1.04–3.92)* 1.32 (0.79–2.17)
1.09 (0.40–2.99) 1.58 (0.68–3.68) 2.29 (1.03–5.07)* 1.00 () 2.07 (1.00–4.71)* 1.72 (0.97–3.03)
1.62 (0.76–3.47) 1.51 (0.76–3.00) 1.38 (0.71–2.72) 1.00 () 1.56 (0.85–2.86) 1.04 (0.63–1.72)
1.00 (0.55–1.83) 1.38 (0.71–2.68) 0.97 (0.48–1.96) 1.00 () 1.46 (0.82–2.61) 1.45 (0.88–2.38)
1.14 (0.96–1.35)* 1.04 (1.02–1.07)* 5322 771 702 0.095
1.25 (1.03–1.52)* 1.03 (1.00–1.06)* 5400 623 564 0.10
1.06 (0.88–1.26) 1.02 (1.00–1.04)* 5622 813 766 0.062
1.21 (1.03–1.42)* 1.03 (1.01–1.05)* 5309 796 739 0.77
95% CI 95% confidence interval. *p 0.05 in logistic regression analysis. Only covariates significant in at least one model are shown. a For hospitalization resulting from fracture after renal transplantation. b Discrepancy from total N of 33,479 primarily due to missing weights in 26% of recipients. c As cause of end stage renal disease.
work on high-risk groups in the general population. Margolis et al., in a prospective study of elderly postmenopausal females, showed that total body weight accurately predicted hip fracture risk, although this risk could be completely explained by differences in bone mineral density (18). Mortality in renal transplant recipients hospitalized for hip fractures (who had an average age of 52 years) was similar to mortality after hip fracture in the elderly population (65 years). Aharonoff et al. showed that the elderly had a 1-year mortality rate of 12.7% following hip fracture (42). The present study found the 1-year mortality rate following hip fracture in renal transplant recipients was 14.7%. There are several limitations to this retrospective study. This study could not independently verify radiologic findings of fractures. However, ICD-9 coding for determining rates of medical conditions has been used in other published studies, (43–46) as well as the National Center for Health Statistics (21). Another reason for underestimating the frequency of fractures in this population would be the use of hospitalized cases of fractures in the fracture cohort. Nevertheless, hospitalized fractures would be a marker for more severe and disabling fractures. Furthermore, most hip fractures, which were the most common fracture site in this analysis, are hospitalized (47). The short follow-up duration
of the study may also be a limitation, although previous studies have demonstrated the peak risk of bone demineralization (although not necessarily fracture risk) occurs early post transplant (14). Strengths of the present analysis include its large size and population-based character, and comparisons with a national, rather than local, sample. The substantially younger age of the transplant population compared to the general population has other important implications given the increased fracture risk shown in the present study. As patient survival in this population improves, it is likely that absolute rates of fractures will increase dramatically. The mortality associated with hip fracture in this population is disproportional to age and worthy of further investigation. The confirmation of commonly accepted risk factors for fractures in the general population as risk factors in the transplant population is important for screening and targeted intervention. In addition, patients with prolonged pretransplant dialysis, who are not currently considered a target group for intervention in recently published transplant practice guidelines, (48) were also identified as at risk. Most of these risk factors can easily be obtained from a history and physical examination, requiring no additional equipment or calculations, an important consideration in today’s medical environment.
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14. Carlini RG, Rojas E, Weisinger JR, Lopez M, Martinis R, Arminiio A, Bellorin-Font E. Bone disease in patients with long-term renal transplantation with normal renal function. Am J Kidney Dis (2000; 36:160–166. 15. Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, Cauley J,Black D, Vogt TM. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med. 1995;332:767–773. 16. Raisz LG. The osteoporosis revolution. Ann Intern Med. 1997; 126(6):458–462. 17. Kelepouris N, Harper KD, Gannon F, Kaplan FS, Haddad JG. Severe osteoporosis in men. Ann Intern Med. 1995;123:452–460. 18. Margolis KL, Ensrud KE, Schreiner PJ, Tabor HK. Body size and risk for clinical fractures in older women. Study of Osteoporotic Fractures Research Group. Ann Intern Med. 2000;133(2):123–127. 19. Stethman-Breen CO, Sherrard DJ, Alem AM, Gillen DL, Heckbert SR, Wong CS, Ball A, Weiss NS. Risk factors for hip fracture among patients with end stage renal disease. Kidney Int. 2000;58:2200–2205.
FIGURE 1. Adjusted hazard (by Cox regression) for hospitalization for fractures, U.S. renal transplant recipients, by years postrenal transplant, 1 July 1994 to 1930 June 1997.
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