End-stage renal disease (ESRD) is a major cause of morbidity and mortality in the United States and worldwide (1). When compared with dialysis, kidney transplantation has been shown to be more cost effective and associated with longer survival and superior quality of life; and it is considered the treatment of choice for patients with ESRD (2, 3).
With a limited supply of available organs for transplantation and an increasing ESRD population requiring renal transplantation, the transplant community faces a challenge to establish equipoise between “equity” (fairness in renal transplantation, such that every person likely to benefit from renal transplantation has a comparable opportunity to receive one) and “utility” (the notion that organs are transplanted in people with the maximum expected graft survival) in renal transplantation. The goal to maximize potential benefit from the scarce available resources, however, is riddled with ethical implications.
Pretransplant evaluation is one of the most vital aspects of the transplant process and underscores the significance of evaluating a patient's transplant candidacy using objective medical criteria. However, previous studies have demonstrated that African Americans (4–7), elderly (8), and women (9) are less likely to receive a renal transplant, and there exists a difference in listing practices for transplant among centers (10, 11). Substance abuse and compliance are some of the vital issues that are addressed during the pretransplant evaluation. Previous studies have demonstrated the association between substance abuse and inferior renal transplant outcomes (12–15). However, it is not clear to what extent substance abuse is related to transplant access. We hypothesized that active substance abuse should lead to reduced transplant access and aimed to evaluate the association between substance abuse and transplant access and to demonstrate the association between substance abuse and transplant outcome in a nationally representative sample of US dialysis patients.
The study population was identified in United States Renal Data System (USRDS) on the basis of existence of relevant data and inclusion and exclusion criteria described in the Materials and Methods. The study population had a mean age of ESRD onset of 62.9±15.5. Of the study population, 64.2% were white, 54.1% were male, 55.2% had diabetes, and with mean comorbidity index of 6.8±2.4. It is interesting to note that the proportion of whites and females, mean age of ESRD onset, calculated comorbidity index, and the proportion of living donors were significantly higher in patients with no substance abuse when compared with patients who were current smokers and abusing alcohol and drugs. Of the patients who were abusing a single substance, that substance was found to be tobacco in 78%, alcohol in 13%, and illicit drug use in 9%. In addition, we found that of the 1,002,924 patients who did not indulge in any kind of substance abuse, a total of 168,538 were wait listed, and 109,200 eventually received a transplant. Distribution of other baseline characteristics of the study population is presented in Table 1. Figure 1 further depicts the prevalence of individual substances of abuse at the time of ESRD onset in population subsets.
Transplant Access in the Entire Study Population
Compared with no substance abuse, abusing tobacco, alcohol, and drugs was found to be significantly associated with reduced transplant access (hazard ratio [HR] 0.39, P<0.001 for being placed on the waiting list/transplanted; HR 0.67, P=0.019 for transplant; Table 2). Individual substances of abuse were also found to be associated with transplant access. Because we lacked data regarding patient income, we used patient insurance status (public or private insurance) as a proxy for income level. We repeated the analysis after including recipient insurance status in the model and found the results to be essentially unchanged. When we added patient's hepatitis C status in the model, we found the effect size to be marginally reduced but still statistically significant for listing or transplant. However, the association lost significance for access to transplant in patients who were placed on the waiting list. Further, we also separately looked at patients younger than 18 years and found the association between substance abuse and access to renal transplantation to be insignificant. In addition, to better elucidate the dose-response relationship of substance abuse with transplant access, we also analyzed substance abuse as a continuous variable (ranging from 0 to 3, with one additional point given for each substance of abuse; Table 3). Poly substance abuse was found to be associated with diminished transplant access (HR 0.73, P<0.001 for being placed on the waiting list/transplanted; HR 0.90, [95% confidence interval 0.88–0.93], P<0.001 for transplant).
The contribution of smoking, alcohol, and drugs toward potentially limited access to transplantation might not be equal (e.g., smoking may be acceptable for candidacy at most renal transplant centers, which is not always the case with active alcohol or drug abuse). This is further supported by the Cox model results that demonstrate different effect size attributed to these individual factors (Table 2). To address this issue and to validate our approach of using substance abuse as a continuous variable, we performed sensitivity analysis. In this approach, instead of a uniform addition of a single point for each additional substance, we assigned different magnitudes of points to smoking (1.3), alcohol (1.6), and drug abuse (2.4) based on inverse HR values for the respective substances of abuse. Using this approach did not significantly change the results. In particular, for the entire study population, we found substance abuse to be associated with listing or transplanted (HR 0.81, P<0.001) and for transplant postlisting (HR 0.94, P<0.001).
Transplant Access in Subgroups
For subgroup analysis, we treated substance abuse as a continuous variable and evaluated its association with transplant access (Table 3). The results indicate a strong association of substance abuse with transplant access in most of the subgroups studied. In particular, substance abuse was associated with diminished transplant access in both males (HR 0.71 for listing/transplant) and females (HR 0.72 for listing/transplant) and in patients with diabetes (HR 0.72 for listing/transplant) and without diabetes (HR 0.71 for listing/transplant).
Graft Loss/Mortality Analysis After Renal Transplantation
As demonstrated in this report, substance abuse might be associated with lower likelihood and delayed listing and transplantation. One of the potential ways to explain the results might be worst outcomes posttransplantation in patients with substance abuse issues (12–15). If that is the case, one might wonder how many kidneys would be “lost” if patients with substance abuse issues were to be transplanted equally. We found that substance abuse (abusing alcohol, drugs, or being current smoker) is associated with accelerated graft loss or mortality (HR 1.19, P<0.001 for combined outcome of mortality or graft loss; Table 4). By using these results, we calculated that if subjects with substance abuse were to be transplanted at an equal rate to those not abusing substances, it would cost an additional 0.34% (i.e., loss of 3.4 kidneys for every 1000 transplanted) of renal allograft loss.
Our results confirmed the primary hypothesis that patients indulging in substance abuse have reduced access to renal transplantation. Polysubstance abuse was associated with a further reduction in the likelihood of being placed on the waiting list for renal transplantation and receiving a transplant. In addition, this report reinforces the findings of past studies that there exists a bias in terms of kidney allocation to patients, so that females (9), African Americans (4–7), and elderly (8) were found to be less likely to receive a renal transplant.
As this is a retrospective analysis, we can only speculate on the causal mechanisms of the observed association. Predicted graft and recipient survival are important elements of the decision-making process in pretransplant evaluation. There exists a reasonable concern among transplant professionals that a recipient's substance abuse might lead to accelerated graft loss (12–15) because of physiologic consequences, and also because of noncompliance, and as a result, many transplant programs listing and transplant criteria exclude patients with active substance abuse. Indeed, recipient's active smoking status before transplant has been shown to be associated with allograft loss (12). In a study by Kasiske et al. in renal transplant patients, the authors demonstrated that smoking more than 25 pack years at the time of transplantation (when compared with having smoked less than 25 packs years or having never smoked) was associated with a 30% additional risk of graft failure that was mostly related to increased recipient mortality. However, quitting smoking 5 years before the transplant seemed to dissipate the adverse effect of heavy smoking on patient and graft survival (13). Intravenous drug use has been shown to be a risk factor for hepatitis C and renal failure in nontransplant populations (16). Hepatitis C in turn has an adverse affect on allograft and recipient survival (17). In a previous study by our group, we demonstrated that alcohol dependency at the time of ESRD onset is a risk for renal graft failure and recipient death (18).
Another potential way to explain the association between substance abuse and reduced access to transplantation could be perceived association between substance abuse and noncompliance by healthcare professionals that can adversely effect outcomes. Active substance abuse, mental illness, and noncompliance can potentially be considered to be intertwined and affect transplant access. The importance of compliance has been demonstrated in the past and poor compliance is a well-recognized cause of organ rejection and graft loss (19–23), particularly in adolescent and pediatric patients (24). Patient's compliance may be improved by offering supportive psychologic assistance, especially in those patients coping with substance abuse, who potentially have a higher risk of being noncompliant (19).
Furthermore, substance abuse has been associated with psychiatric disorders, specifically higher rates of depression and maladaptive symptomatology (25) were identified in subjects with substance abuse. The lifetime prevalence of psychiatric comorbidities (e.g., depression, anxiety, and stress) has been shown to be higher in patients with alcohol abuse or dependence (26, 27). Smoking has been found to be associated with common psychiatric problems and mental disorders (28, 29). In turn, psychiatric disorders have been shown to independently limit patient's access to the transplant waiting list (5) as this population of patients may be identified by health professionals as having compliance difficulties. Indeed, studies in heart and bone marrow transplant recipients have demonstrated that pretransplant psychiatric illnesses, including symptoms of anxiety or depression, lead to higher posttransplant morbidity and mortality (30), hospitalization, and cost (31).
To address the issue of substance abuse and noncompliance, many transplant programs require a period of abstinence from substance abuse before a patient is placed on the waiting list, thereby identifying motivated patients who are more likely to be compliant after transplantation. However, this proposal is not without its limitations, as discussed by Bramstedt et al. (32): A scenario can be imagined where the patient has not entirely relapsed but had a single slip. These patients who voluntary admit the incident should be helped and encouraged, and a single event should not necessarily constitute a violation of the abstinence period. The authors believe that if applied, abstinence rule should not be followed rigidly and should be evaluated on a case by case basis.
In view of the scarcity of available kidneys for transplantation, it has been argued that because substance abuse might be associated with noncompliance and inferior outcomes after renal transplantation, it might be in the public interest to deny renal transplantation to patients who continue with substance abuse. Economists would agree that such an approach will use the available resources to the maximum, leading to increased graft survival and eventually making more kidneys available for transplantation. Potential donors can similarly make the case against donating to recipients with active substance abuse, which may jeopardize the long-term survival of their donated organ. The current national allocation system of zero antigen mismatched kidneys typifies the utilitarian approach where a zero mismatched kidney is transplanted to the individual regardless of the standing on the wait list (33).
Conversely, ethics would dictate that every individual who could potentially benefit from renal transplant be provided a comparable opportunity to receive one. An example of the equitable approach is when human leukocyte antigen-based matching was removed to reduce the disparity between whites and African Americans in terms of access to renal transplantation, with only a small increase in the rate of graft loss (34). These two seemingly conflicting ideologies lead to a dilemma in terms of policy development and implementation for renal transplant centers.
In light of the aforementioned discussion, pertaining to the current report, the following question arises—Is it reasonable to exclude all patients who are active smokers, abuse alcohol or drugs from being considered for renal transplant? To address this issue, we calculated “utility cost” if patients with substance abuse issues were transplanted at an equal rate to those with no substance abuse (an additional renal allograft loss of 0.34%). The authors believe that clinicians need to find a more optimal middle ground, where decisions regarding exclusion of patients from transplant are based on severity (e.g., possibly excluding patients with more than 25 pack years of smoking ) and type (e.g., patients with moderate alcohol consumption perhaps need not be excluded ) of substance abuse and assessment of compliance by pretransplant psychologic evaluation of the patient. With an ever-increasing demand for kidneys and limited supply pool, it is essential that a balance be maintained between equity and utility in transplant access.
The importance of facilitating and incentivizing patients to abstain from substance use cannot be overemphasized. Indeed, there is evidence to suggest that with appropriate and timely intervention, many patients can in fact quit abusing substances (36, 37). Long-term follow-up for transplant evaluation provides an excellent and rare opportunity for healthcare professionals to identify, diagnose, and treat substance abuse. Every effort should be made in both primary care and transplant center settings to encourage patients to address and treat their substance abuse.
There are few potential limitations to this study that deserve mentioning. First, because our study was a retrospective analysis, we could not assess causality, but only the association between substance abuse and transplant access. A second potential limitation could be misclassification bias as many patients might choose not to disclose their abusing drugs, alcohol, or tobacco. However, in that scenario, the effect size of association between substance abuse and access to transplantation would be decreased, whereas in this analysis, we demonstrated high level of statistical significance despite this limitation. A third limitation may have been our inability to stratify by severity of substance abuse (as opposed to simple binary designation of presence or absence of substance abuse) because of limitations of the data. However, we did perform stratified analysis on the basis of polysubstance abuse. Another limitation could be examining the data collected at the single time point (the onset of ESRD) and not a longitudinal analysis. However, the data collection happened at the same time point in the course of the kidney disease for all study participants. Finally, the perspective of referring nephrologists and transplant physicians regarding recipient substance abuse could not be assessed because of lack of data.
To summarize, the findings of this project indicate a strong negative association between tobacco, alcohol, or drug abuse and the likelihood of being placed on the waiting list for kidney transplant; and once on the waiting list the likelihood of receiving a transplant. It is vital that patients with ESRD be made aware of factors associated with successful listing and transplantation and that every attempt be made, both by the patients and healthcare professionals, to minimize substance abuse.
MATERIALS AND METHODS
We used data from the USRDS including the data directly provided to USRDS by United Network for Organ Sharing. Data were used from the Txunos_ki, Waitlist_ki, Rxhist60, DMMS waves 1–4, Case mix Severity, Case mix Adequacy, and Medevid files. The information regarding substance abuse was derived from Centers for Medicare & Medicaid Service (CMS) form 2728, filled and submitted by the dialysis units or transplant centers. Patient records with missing information regarding the main exposure variables (abuse of tobacco, alcohol, or drugs) were excluded from the study. In addition, patients with acute kidney failure who were on dialysis initially, but then recovered kidney function, and patients younger than 18 years were excluded from analysis. Incident and prevalent ESRD patients only from January 1, 1990 were included and follow-up ended on September 1, 2007. For recipients of multiple transplants, the first procedure was considered to be the transplant of interest. Of 1,866,627 patients available in the USRDS dataset, we initially excluded patients with lack of information regarding substance abuse. This led us to a figure of 1,192,500. Of this number, patients were excluded or included based on criteria described earlier, which left us with a figure of 1,077,699 ESRD patients who were eligible for our analysis.
We analyzed three outcomes in this project: (1) being placed on the waiting list for renal transplantation or transplanted, whichever occurred first (the time between dialysis start and being placed on the waiting list or first transplant); (2) first transplant in patients who were placed on the waiting list (time between dialysis start and transplantation); and (3) graft loss or patient death after transplant. For graft failure or mortality analysis, we used first date of return to dialysis, death, or retransplantation after the first transplant as the date of graft loss.
Primary Variables of Interest
Primary variables of interest included the following three variables measured at the time of onset of ESRD: (1) alcohol dependence; (2) active smoking; (3) drug dependence. In the data available to us, alcohol, smoking, and illicit drug use were categorized as binary variables (yes/no). To assess whether there exists a dose-response relationship (in terms of abusing more than one substance), we also analyzed substance abuse as a continuous variable graded as follows: 0, no substance abuse; 1, abusing one substance (alcohol, tobacco, or drugs); 2, using two out of three substances; and 3, abusing alcohol, tobacco, and drugs.
We used the following potential confounding factors in multivariate analysis: age at ESRD onset, sex, race, history of diabetes, comorbidity index (described later), body mass index, hemoglobin, serum creatinine, serum albumin, cause of ESRD, education, employment, donor type, vascular access, and dialysis type. As donor type might be associated with access to transplantation (because of differences of social network or donor choice to donate based on recipient's substance abuse), we decided to include it in the model.
To adjust for patient comorbidities, we formed a comorbidity coefficient similar to the Charlson comorbidity index (38). Each of the comorbid conditions available in the dataset contributed one point toward the composite index with additional points given for older age. We previously used similar approaches to describe comorbidities using abbreviated comorbidity indices of Davies et al. (39) and Charlson et al. (38) using information available in the data. These abbreviated indices were validated by strong association with clinical outcomes (40, 41).
Means and standard deviations were used to summarize continuous variables with normal distribution. Categorical variables were summarized as percent of total. To compare between groups, we used analysis of variance for continuous variables and chi-square for the categorical variables. Cox model was used for time to outcome analysis. We included potential confounding factors in the multivariate analysis. As measures of association between substance abuse and outcome variables, we estimated HRs and 95% confidence intervals. The data collected were analyzed using the SAS software version 9.2 (SAS Institute, Cary, NC).
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