Maintenance immunosuppression use and the associated risk of avascular necrosis after kidney transplantation in the United States.

BACKGROUND: Avascular necrosis (AVN) after renal transplantation has been largely attributed to the use of corticosteroids. However, other risk factors such as microvascular thrombosis and hyperlipidemia have been well described and may be of increased importance in the era of early steroid cessation and avoidance. We hypothesized that maintenance immunosuppressive medications known to be associated with these risk factors for AVN would also be associated with a higher risk of AVN. METHODS: By using the U.S. Renal Data System database, we studied 27,772 primary patients on Medicare who received a solitary kidney transplant between January 1, 1996, and July 31, 2000. Cox proportional hazards regression models were used to calculate adjusted hazard ratios (AHRs) for patient- and transplant-related factors (including allograft rejection) with Medicare claims for AVN. The intensity and duration of corticosteroid use could not be assessed. RESULTS: Among patients who were prescribed sirolimus at discharge, 3.5% of patients who received the combination of sirolimus-cyclosporine A (CsA) demonstrated AVN, compared with 1.4% of patients who received the combination of sirolimus-tacrolimus (P=0.06 by chi). In Cox regression, CsA use (vs. tacrolimus) (AHR 1.36, 95% confidence interval, 1.09-1.71) was independently associated with an increased risk of AVN. Sirolimus use showed a trend toward significance (AHR 1.59, 95% confidence interval, 0.99-2.56), with no significant interaction with CsA. CONCLUSIONS: Compared with other maintenance immunosuppression, AVN was significantly more common after use of CsA prescribed at the time of discharge for renal transplantation. Whether this increased risk of AVN was directly attributable to hyperlipidemia, microvascular thrombosis, or differences in corticosteroid dosing could not be determined.

Induction sirolimus and delayed graft function after deceased donor kidney transplantation in the United States.

BACKGROUND/AIMS: Previous studies have reported a link between the use of induction sirolimus (INDSRL) and delayed graft function (DGF) after kidney transplantation. However, none have had sufficient power to adjust for all factors known to be associated with DGF. METHODS: We conducted a retrospective cohort study of US deceased donor kidney transplantation recipients in the United States Renal Data System (USRDS) from January 1, 2000 to May 31, 2001. Logistic regression analysis was used to model adjusted odds ratios (AOR) for the development of DGF, adjusted for other factors previously reported to be associated with DGF. RESULTS: Among 8,319 patients meeting inclusion criteria, 361 patients received INDSRL, of whom 98 (27.1%) had DGF, compared to 22.5% among patients who did not receive INDSRL. In multivariate analysis, INDSRL was associated with an increased risk of DGF, with an adjusted odds ratio of 1.42 (95% CI: 1.07-1.90). Other factors associated with DGF were similar to those previously reported. INDSRL was not significantly associated with graft loss at 1 year in Cox regression. CONCLUSIONS: INDSRL was independently associated with DGF in US deceased donor kidney transplantation recipients, adjusted for all other factors previously shown to be associated with DGF.

Human immunodeficiency virus infection and kidney transplantation in the era of highly active antiretroviral therapy and modern immunosuppression.

Before the era of highly active antiretroviral therapy, kidney transplant recipients infected with HIV had increased risk of death compared with HIV-uninfected recipients. More recent single-center reports have indicated improved results, but this has not been assessed in a national population. Therefore, a retrospective cohort study of US adult deceased donor kidney transplant recipients from January 1, 1996, to May 31, 2001 was conducted; patients were followed until October 31, 2001. A total of 27,851 patients had valid recipient HIV serology. Cox regression analysis was used to model adjusted hazard ratios for mortality and graft loss, respectively, adjusted for other factors, including comorbid conditions from Centers for Medicare and Medicaid Studies Form 2728. Factors independently associated with HIV infection were also assessed by logistic regression analysis. Only 12.8% of HIV-infected recipients were black, compared with 27.6% in the entire study cohort. HIV-infected kidney transplant recipients were significantly less likely to be black in logistic regression analysis (adjusted OR, 0.29; 95% CI, 0.08 to 0.99; P = 0.049), which was the only factor independently associated with HIV infection. It was found that HIV-infected recipients had improved survival compared with HIV-uninfected recipients, although this was not statistically significant in adjusted analysis (adjusted HR, 0.36; 95% CI, 0.05 to 2.53; P = 0.31). Kidney transplantation in HIV-infected patients is plausible and ongoing, but HIV-infected candidates who underwent kidney transplantation in the United States during the course of the study were demographically unrepresentative of HIV-infected candidates generally.

Early renal insufficiency and late venous thromboembolism after renal transplantation in the United States.

BACKGROUND: Pulmonary embolism (PE) is the most common preventable cause of death in hospitalized patients. Patients with severe chronic kidney disease (CKD) may be at increased risk for PE in comparison to the general population. Whether severe CKD is associated with increased risk for late venous thromboembolism (VTE) in a population of renal transplant recipients has not been determined. METHODS: Using the US Renal Data System database, we studied 28,924 patients receiving a kidney transplant from January 1, 1996, to July 31, 2000, with Medicare as primary payer, followed up until December 31, 2000. Cox proportional hazards regression models were used to calculate the association of transplant recipient estimated glomerular filtration rate (eGFR; by the Modification of Diet in Renal Disease formula) less than 30 mL/min/1.73 m2 (versus >30 mL/min/1.73 m2) 1 year after renal transplantation with Medicare claims for VTE (either deep-venous thrombosis or PE/infarction) 1.5 to 3 years after renal transplantation. RESULTS: The rate of VTE occurring 1.5 to 3 years after transplantation was 2.9 episodes/1,000 person-years. eGFR less than 30 mL/min/1.73 m2 versus higher at the end of the first year after renal transplantation was associated with significantly increased risk for later VTE (adjusted hazard ratio, 2.05; 95% confidence interval, 1.08 to 3.89). CONCLUSION: Patients with severe CKD after renal transplantation should be regarded as high risk for late VTE, which is a potentially preventable cause of death in this population.

Hepatitis C and renal transplantation in the era of modern immunosuppression.

Kidneys from donors who are positive for hepatitis C virus (DHCV+) have recently been identified as an independent risk factor for mortality after renal transplantation. However, it has not been determined whether risk persists after adjustment for baseline cardiac comorbidity or applies in the era of modern immunosuppression. Therefore, a historical cohort study was conducted of US adult cadaveric renal transplant recipients from January 1, 1996, to May 31, 2001; followed until October 31, 2001. A total of 36,956 patients had valid donor and recipient HCV serology. Cox regression analysis was used to model adjusted hazard ratios for mortality and graft loss, respectively, adjusted for other factors, including comorbid conditions from Center for Medicare and Medicaid Studies Form 2728 and previous dialysis access-related complications. It was found that DHCV+ was independently associated with an increased risk of mortality (adjusted hazard ratio, 2.12, 95% confidence interval, 1.72 to 2.87; P < 0.001), primarily as a result of infection. Mycophenolate mofetil was associated with improved survival in DHCV+ patients, primarily related to fewer infectious deaths. Adjusted analyses limited to recipients who were HCV+, HCV negative, or age 65 and over, or by use of mycophenolate mofetil confirmed that DHCV+ was independently associated with mortality in each subgroup. It is concluded that DHCV+ is independently associated with an increased risk of mortality after renal transplantation adjusted for baseline comorbid conditions in all subgroups. Recipients of DHCV+ organs should be considered at high risk for excessive immunosuppression.

Early renal insufficiency and hospitalized heart disease after renal transplantation in the era of modern immunosuppression.

Renal insufficiency has been identified as a risk factor for graft loss and death after renal transplantation but has not been consistently linked to early, nonfatal, hospitalized heart disease (HHD). With the United States Renal Data System database, 29,597 patients who received a kidney transplant between January 1, 1996, and July 31, 2000, with Medicare as the primary payer, and were monitored until December 31, 2000, were studied. Cox proportional-hazards regression models were used to calculate the association of recipient estimated GFR (eGFR) at 1 yr after renal transplantation, as determined with the Modification of Diet in Renal Disease formula, with hospitalization for treatment of acute coronary syndromes (ACS) (International Classification of Diseases, version 9, code 410.x or 411.x) or congestive heart failure (CHF) (code 428.x) 1 to 3 yr after renal transplantation. Rates of ACS and CHF were 2.2 and 4.9%, respectively, for patients with eGFR of <44.8 ml/min per 1.73 m(2), compared with 1.2 and 1.4% for patients with eGFR of >69.7 ml/min per 1.73 m(2). Reduced eGFR (<44.8 ml/min per 1.73 m(2), compared with >69.7 ml/min per 1.73 m(2)) at the end of the first 1 yr after transplantation was independently associated with increased risks of both ACS (adjusted hazard ratio, 2.16; 95% confidence interval, 1.39 to 3.35) and CHF (adjusted hazard ratio, 2.95; 95% confidence interval, 2.24 to 3.90). It was concluded that early renal insufficiency (approximately stage 3 chronic kidney disease) was associated with higher rates of HHD 1 to 3 yr after kidney transplantation. Preservation of renal function after renal transplantation may reduce the rates of HHD, and renal transplant recipients with reduced eGFR should be considered at high risk of developing cardiovascular disease.

Impact of renal transplantation on survival in end-stage renal disease patients with elevated body mass index.

BACKGROUND: Cadaveric renal transplantation is associated with a survival advantage compared with dialysis patients remaining on the renal transplantation waiting list, but this advantage has not been confirmed in obese end-stage renal disease (ESRD) patients. METHODS: Using data from the USRDS, we studied 7521 patients who presented with ESRD from 1 April 1995 to 29 June 1999 and later enrolled on the renal transplantation waiting list with body mass indices (BMI) >or=30 kg/m(2) at the time of presentation to ESRD, and followed until 6 November 2000. Recipients of preemptive renal transplantation or organs other than kidneys were excluded. Cox non-proportional hazards regression models were used to calculate adjusted, time-dependent hazard ratios (HR) for time to death in a given patient during the study period, controlling for renal transplantation, demographics and comorbidities (Form 2728). RESULTS: The incidence of mortality was 3.3 episodes per 100 patient-years (PY) in cadaveric renal transplantation and 1.9/100 PY in living donor renal transplantation compared with 6.6 episodes/100 PY in all patients on the transplant waiting list. In comparison to maintenance dialysis, both recipients of solitary cadaveric kidneys (HR 0.39, 95% CI 0.33 to 0.47), and recipients of living donor kidneys (HR 0.23, 95% CI 0.16 to 0.34) had statistically significant improved survival. A benefit of cadaveric renal transplantation did not apply to patients with BMI >or=41 kg/m(2) (HR 0.47, 95% CI, 0.17 to 1.25, P = 0.13). CONCLUSIONS: Obese patients on the renal transplant waiting list had a significantly lower risk of mortality after renal transplantation compared with those remaining on dialysis.

Donor hepatitis C seropositivity: clinical correlates and effect on early graft and patient survival in adult cadaveric kidney transplantation.

The impact of hepatitis C virus-positive donor kidneys on patient survival has not been analyzed in a national study. This study analyzed 20,111 adult (age, > or =16 yr) recipients having solitary cadaveric kidney transplants from adult donors with valid donor hepatitis C serologies from July 1, 1994, to June 30, 1998, in an historical cohort study (the 2000 United States Kidney Data System) of patient survival. Analysis was by the Cox proportional hazards models, which corrected for characteristics thought to affect outcomes. Of 484 kidneys positive for hepatitis C virus serology, 165 (34%) were given to recipients with confirmed negative hepatitis C serologies. Unadjusted 3-yr patient survival was 93% in all recipients of donor hepatitis C-negative kidneys versus 85% in all recipients of donor hepatitis C-positive kidneys (P = 0.01). Among hepatitis C-positive recipients, those who received hepatitis C-positive kidneys had worse survival than recipients of hepatitis C-negative kidneys. Among elderly hepatitis C-negative recipients, those who received hepatitis C-positive kidneys also had worse survival; in fact, all recipients of donor hepatitis C-positive kidneys had increased risk of mortality (P = 0.028). There were no significant interactions between donor hepatitis C positivity and either recipient hepatitis C positivity or older recipient age. The use of hepatitis C-positive kidneys in recipients who were hepatitis C-negative was fairly common and contrary to some current recommendations. Recipients of donor hepatitis C-positive kidneys were at independently increased risk of mortality, with no evidence that any subgroups were less affected.

Graft loss and acute coronary syndromes after renal transplantation in the United States.

The impact of graft loss on acute coronary syndromes (ACS) after renal transplantation has not been studied in a national population. It was hypothesized that ACS might be more frequent after graft loss, as many of the benefits of a functioning allograft on metabolism and volume regulation would be lost. Data from the 2000 United States Renal Data System (USRDS) was used to conduct an historical cohort study of ACS in 14,237 patients who received renal transplants between April 1, 1995, and June 30, 1998, (followed until April 28, 2000) with valid information from CMS Form 2728, excluding patients with hospitalized ACS before renal transplant. Cox nonproportional regression models were used to calculate the time-dependent adjusted hazard ratio (AHR) of graft loss (censored for death) for time-to-first hospitalization for ACS (International Classification of Diseases 9th Modification Diagnosis Codes [ICD9] code 410.x or 411.x) occurring after transplant. The incidence of ACS was 12.1 per 1000 patient-years (PY) in patients after graft loss versus 6.5 per 1000 PY after transplantation (excluding patients with graft loss). As a time-dependent variable, graft loss had an AHR of 2.54 (95% confidence interval, 1.09 to 5.96; P = 0.031 by Cox regression). Other risk factors associated with ACS included diabetes, older recipient, and male recipient. Allograft rejection was NS. Renal transplant recipients share some of the risk factors for ACS with the general population. In addition, graft loss was identified as a unique risk factor for ACS in this population.

Scleroderma at end stage renal disease in the United States: patient characteristics and survival.

BACKGROUND: The patient characteristics and mortality associated with scleroderma have not been characterized for a national sample of end stage renal disease (ESRD) patients. METHODS: 364,317 patients in the United States Renal Data System initiated on ESRD therapy between 1 January 1992 and 30 June 1997 with valid causes of ESRD were analyzed in an historical cohort study of scleroderma. RESULTS: Of the study population, 820 (0.22%) had scleroderma. The mean age of patients with scleroderma was 56.38 +/- 13.93 years vs. 60.48 +/- 16.51 years for patients with other causes of ESRD (p<0.01 by Student's t-test). In histogram analysis, there were two age peaks: 45-49 and 65-69. In logistic regression, patients with scleroderma, compared to patients with other causes of ESRD, were significantly more likely to be women, Caucasian, younger, and more likely to have congestive heart failure but less likely to have ischemic heart disease, stroke, and receive predialysis erythropoietin. The unadjusted two-year survival of patients with scleroderma during the study period was 49.3% vs. 63.8% in all other patients (adjusted hazard ratio, 1.96, 95% CI 1.70-2.26, p=0.0001 by Cox Regression). CONCLUSIONS: Among patients with ESRD, the demographics of patients with scleroderma were similar to those of patients with scleroderma in the general population. Patients with scleroderma had decreased survival compared to patients with other causes of ESRD, despite being equally likely to be wait listed and receive renal transplantation adjusted for other factors.

Risk factors for pulmonary embolism in chronic dialysis patients.

BACKGROUND: Risk factors for pulmonary embolism (PE) in end stage renal disease (ESRD) patients have not been studied in a large population. METHODS: 375,152 patients in the United States Renal Data System initiated on dialysis between 1 January 1992 and 30 June 1997 were analyzed in an historical cohort study of hospitalized PE (ICD9 Code 415.1x) occurring prior to receipt of renal transplant. Cox regression models were used to analyze risk factors for PE in dialysis. Dialysis modality was analyzed in an intention to treat fashion, thus patients who changed modalities later were considered to have remained on the same modality. RESULTS: The incidence of pulmonary embolism did not increase over time. Independent risk factors for hospitalizations for PE were similar to those in the general population (older age, females, systemic lupus erythematosus, lower risk for Asians) with the addition of peritoneal dialysis (vs. hemodialysis, adjusted odds ratio 1.56, 95% CI 1.15-2.13), polycystic kidney disease, and congestive heart failure. Notably, in Cox regression analysis, no relation was seen with baseline laboratory results (hematocrit, serum albumin, serum creatinine) or comorbidity (except congestive heart failure) and PE risk. Dialysis patients with PE had increased mortality (hazard ratio 1.20, 95% confidence interval 1.08-1.33). CONCLUSIONS: The incidence of PE did not increase significantly in ESRD patients from 1992-1997. PE were associated with increased mortality. Peritoneal dialysis patients may have higher risk of PE than hemodialysis patients, and other high-risk groups were identified.

Hospitalizations for bacterial septicemia in patients with end stage renal disease due to diabetes on the renal transplant waiting list.

The incidence and risk factors for hospitalizations for bacterial septicemia, a serious cause of morbidity and mortality in end stage renal disease (ESRD), have been studied separately for patients on chronic dialysis and after renal transplantation, but have not been compared directly. Using data from the USRDS, we studied 11,369 patients with ESRD due to diabetes enrolled on the renal and renal-pancreas transplant waiting list from 1 July 1994-30 June 1997. Cox non-proportional hazards regression models were used to calculate adjusted, time-dependent hazard ratios (HR) for time to hospitalization for bacterial septicemia (ICD9 Code 038.x). In Cox Regression analysis, renal transplantation was independently associated with a shorter time to bacterial septicemia (HR 1.22, 95% confidence interval, 1.05-1.40). In addition, renal transplantation was associated with a higher rate of sepsis due to gram-negative organisms (HR 3.32, 95% CI 2.614.23) and urinary tract infection (10.43, 95% CI 6.72-16.17) compared with patients still on the renal transplant waiting list. The relative risk of sepsis increased with time after renal transplantation. Renal transplantation was associated with a significantly higher risk and different spectrum of bacterial septicemia than maintenance dialysis, and the risk of sepsis did not decrease over time.

Hospitalizations for bacterial pneumonia after renal transplantation in the United States.

PURPOSE: Bacterial pneumonia has been cited as the leading cause of infectious death in renal transplant recipients but has not been studied in a national transplant population. SUBJECT AND METHODS: Retrospective analysis of the incidence, risk factors and mortality of hospitalized bacterial pneumonia (ICD9 Code 481.x486.x) for 33,479 renal transplant recipients in the United States Renal Data System transplanted from 1 July 1994-30 June 1997. RESULTS: Among all transplant recipients, 4.7% were hospitalized for a primary discharge diagnosis of pneumonia in the study period (2.86 episodes per 100 person years). 9.9% had bronchoscopy and 4.8% had open lung biopsy. A specific etiology was not identified in 72.5% of patients. The hospitalization rate for pneumonia and hazard for mortality due to hospitalized pneumonia were both constant over time. In logistic regression analysis, pneumonia prior to transplant (odds ratio 1.73, 95% confidence interval, 1.32-2.26), older recipient age, diabetes, delayed graft function, rejection (occurring at any time after transplant during the time of the study), duration of pre-transplant dialysis, and positive recipient cytomegalovirus serology were associated with pneumonia. In Cox Regression, hospitalization for pneumonia was associated with greater risk of mortality (hazard ratio 1.64, 95% CI, 1.42-1.89). CONCLUSIONS: Renal transplant recipients with a previous history of pneumonia are at increased risk for subsequent pneumonia, which is associated with substantially decreased patient survival. Given the low rate of specific etiologies identified in this study, invasive diagnosis may be underutilized in this population.

Effect of donor factors on early graft survival in adult cadaveric renal transplantation.

Previous studies of the effect of donor factors on renal transplant outcomes have not tested the role of recipient body mass index, donor/recipient weight ratios and age matching, and other factors. We analyzed 20,309 adult (age 16 or older) recipients having solitary cadaveric renal transplants from adult donors from 1 July 1994 to 30 June 1998 in an historical cohort study (the 2000 United States Renal Data System) of death censored graft loss by the Cox proportional hazards models, which corrected for characteristics thought to affect outcomes. The only independently significant findings in Cox Regression analysis were a high donor/ recipient age ratio (> or = 1.10, e.g. a 55-year-old donor given to a recipient age 50years or younger, adjusted hazard ratio (AHR) 3.22, 95% confidence interval (CI) 2.36-4.39) and African American donor kidneys (AHR 1.64, 95% CI, 1.24-2.17). African American recipients and older donors were not at independently increased risk of graft failure in this model. Among donor factors, older donor kidneys given to younger recipients and donor African American kidneys were independently associated with graft loss in recipients of cadaver kidneys. The task for the transplant community should be to find the best means for managing all donor organs without discouraging organ donation.

Acute coronary syndromes after renal transplantation in patients with end-stage renal disease resulting from diabetes.

Coronary heart disease is the leading cause of death in both diabetes mellitus and end-stage renal disease. Although renal transplantation is known to reduce mortality in end-stage renal disease, its effect on the incidence of acute coronary syndromes is unknown. Using data from the United States Renal Data System, we studied 11,369 patients with end-stage renal disease due to diabetes enrolled on the renal and renal-pancreas transplant waiting list from 1 July 1994 to 30 June 1997. Cox nonproportional hazards regression models were used to calculate the adjusted, time-dependent relative risk for the most recent hospitalization for acute coronary syndromes (including acute myocardial infarction, unstable angina, or other acute coronary syndromes, ICD9 Code 410.x or 411.x) for a given patient in the study period. Demographics and comorbidities were controlled by using data from the medical evidence form (HCFA 2728). After renal transplantation, patients had an incidence of acute coronary syndromes of 0.79% per patient year, compared to 1.67% per patient year prior to transplantation. In comparison to maintenance dialysis, renal transplantation was independently associated with a lower risk for acute coronary syndromes (hazard ratio 0.38, 95% confidence interval, 0.30-0.49). Patients with end-stage renal disease due to diabetes on the renal transplant waiting list were much less likely to be hospitalized for acute coronary syndromes after renal transplantation. The reasons for this decreased risk should be the subject of further study.