OVERVIEW
Depression and Kidney Transplantation Joseph Chilcot,1,4 Benjamin Walter Jack Spencer,2 Hannah Maple,3 and Nizam Mamode3 While kidney transplantation offers several advantages in terms of improved clinical outcomes and quality of life compared to dialysis modalities, depressive symptoms are still present in approximately 25% of patients, rates comparable to that of the hemodialysis population. Correlates of depressive symptoms include marital status, income, kidney function, history of affective illness, malnutrition, and inflammation. Depressive symptoms are also associated with poor outcomes following kidney transplantation including nonadherence to immunosuppressant medication, graft failure, and all-cause mortality. Efforts to detect and treat depression should be a priority if one is to improve treatment adherence, quality of life, and outcomes in transplant recipients. Keywords: Depression, Kidney transplantation, Renal transplantation, Kidney transplant, Transplant, Outcomes. (Transplantation 2014;97: 717Y721)
t is well documented that end-stage renal disease (ESRD) patients experience high levels of depression with approximately 20% to 30% suffering from depressive symptoms (1Y3). When compared with dialysis modalities, kidney transplantation is associated with improved clinical outcomes (4), better quality of life (5), and lower rates of psychiatric morbidity (6, 7). Despite this, transplantation requires psychological adjustment and comes with its own treatment challenges. This can produce problematic feelings such as fear, guilt, and global distress. Depression is likely to be the most common psychological complaint in kidney transplant recipients and is the focus of this review. Specifically, this article describes the estimated prevalence, correlates, and consequences of depression in this setting, and evaluates treatment options.
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Prevalence Rates of Depression in Kidney Transplant Patients Prevalence rates for depression in renal patients vary as a product of the assessment undertaken (1, 8). As discussed elsewhere, the assessment of depression is complicated in kidney disease patients, partly as a result of overlapping physical symptoms between renal insufficiency and the features of The authors declare no funding or conflicts of interest. 1 Health Psychology Section, Psychology Department, Institute of Psychiatry, King’s College London, UK. 2 Department of Psychological Medicine, Institute of Psychiatry, King’s College London, UK. 3 Department of Transplantation, Guy’s Hospital, London, UK. 4 Address correspondence to: Joseph Chilcot, Ph.D., Health Psychology Section, Psychology Department, Institute of Psychiatry, King’s College London, 5th floor Bermondsey Wing, Guy’s Hospital Campus, London Bridge, London, SE1 9RT, UK. E-mail: [email protected] All authors contributed to the reviewing of references, and the writing and editing of this article. Received 30 August 2013. Revision requested 3 October 2013. Accepted 21 October 2013. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9707-717 DOI: 10.1097/01.TP.0000438212.72960.ae
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depression, such as lethargy (2, 9, 10). Screening approaches that utilize standardized questionnaires with predetermined cutoff scores often inflate estimated prevalence rates, with diagnostic approaches (i.e., clinical interviews) often attenuating these estimates (8). Several screening and severity measures have been used to evaluate depression symptoms in kidney transplant patients, and these include the Hospital Anxiety Depression Scale (11), Beck Depression Inventory (BDI) (12, 13), the Symptom Checklist (SCL-90) (14), and the Centre for Epidemiologic Studies Depression Scale (CES-D) (15). It is important to recognize that screening tools are not diagnostic measures; rather they are helpful indicators of those who have significant symptoms that might require further enquiry. It should therefore be noted that throughout this article when studies have adopted such measures, the term depression used does not refer to a diagnosed condition, rather high levels of depressive symptoms. Within the context of renal transplantation, the relative accuracy of screening and severity measures in relation to a clinical diagnosis of depression requires attention in suitably large studies. In one of the earliest studies looking at distress in kidney transplant patients, 46% were found to be distressed as defined by a General Health Questionnaire-30 score greater than 5 (16). More recently, Novak et al. (17) reported a 22% point prevalence of depression (CES-D score Q18) among 840 kidney transplant patients and Zelle et al. (18) reported a 31% prevalence using the SCL-90 (925). Use of the BDI has led to estimates between 13% and 39% (19Y24) with variability partly being attributable to methodological differences, such as differences in BDI cutoff scores used. Few studies have examined the incidence of depression over time among kidney transplant recipients. An analysis of Medicare claims in 47,899 kidney recipients revealed a cumulative yearly depression incidence of 5.05%, 7.29%, and 9.1% 3 years posttransplantation (25). Comparing the prevalence of depression symptoms between dialysis and transplant populations has led to mixed findings, which are often www.transplantjournal.com
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hard to interpret because of methodological limits and the potential for confounding. While it is generally recognized that transplantation confers a quality-of-life benefit, there is still significant variation within transplant patients (26, 27). One of the first studies to compare dialysis and transplant modalities revealed similar levels of distress (16), while others suggested that psychiatric morbidity or emotional distress is lower in transplanted patients (6, 7, 21, 28). For example, Szeifert et al. (29) found that the prevalence of depression is lower in transplant patients compared to dialysis patients (22% vs. 33%, respectively), and in multivariate analysis dialysis modality predicted higher depression scores. In a recent meta-analysis, Palmer et al. (8) found that the prevalence of depression, according to self-report or clinician rated tools, was lower in kidney transplant patients (26.6%, 95% CI, 20.9Y33.1) compared to ESRD patients (39.3%, 95% CI 36.8Y42.0). Although variation is evident in the literature with confidence intervals for point prevalence estimates large, it appears that approximately one in four patients screen positive for depression across the spectrum of advanced kidney disease, making it one of the more common comorbidities encountered in renal transplant candidates and recipients. Nevertheless, it is also clear that studies are needed to establish the trajectory of depression symptoms over time (30), following up a suitably large sample of patients from dialysis to transplantation and beyond. This will allow researchers and clinicians to observe the natural history of symptomatology, identify correlates, and possibly highlight optimal points for intervention. Factors Associated With Depression Following Kidney Transplantation Multiple studies have examined possible clinical, social, and psychological factors associated with depression in kidney transplant patients (Table 1). Demographic correlates of depression include age (25, 31), female gender (17, 25, 32, 33), race (25), employment status and financial situation (18, 29, 31, 32), education (17, 32), and marital status (17, 29). With regards to clinical factors, studies have shown a negative association between renal function (estimated glomerular filtration rate, eGFR) and depression in transplant patients (17, 29, 32). Zelle et al. (18) report significantly lower creatinine clearance and a higher proportion of proteinuria in depressed transplant patients compared with non-depressed patients. Lower hemoglobin (18, 32) and serum albumin levels (17, 20) have also been associated with depression in kidney transplant patients. Dobbels et al. reported a positive association between
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Medicare claimYidentified depression and having six HLA mismatches, rapamycin use, antithymocyte and antilymphocyte globulin for antibody induction therapy, and having diabetic nephropathy as a primary cause of kidney disease (25). Most of these clinical factors are related to graft function; therefore, these findings may reflect depression symptoms resulting from impending graft loss and the associated physical symptoms resulting from low eGFR. However, prospective evaluations are needed to better understand the casual pathways between depression and clinical factors in kidney transplant recipients. Others report that higher C-reactive protein (20), interleukin-6, and longer dialysis vintage (18, 25) are associated with heightened depression symptoms (32), although again there are conflicting data with respect to these findings (17, 29). There is little evidence that the duration of transplant graft survival is associated with depression in kidney recipients (18, 29, 31). More consistent findings suggest an association between the severity of comorbidity (including obesity) (17, 25, 29, 32) and heightened depression symptoms in kidney recipients. Regarding psychological factors, having a history of depression predicts concurrent mood following kidney transplantation (6, 20), which is also the case for hemodialysis patients (34). While psychological predictors of depression have been examined in some detail among dialysis patients (1, 35) with particular emphasis on patients’ illness beliefs (30, 36, 37), fewer data exists in kidney transplant patients. Poor psychological adjustment and coping are likely perpetuating contributors. A small study found that age, general life stress, and transplant-related stress were all related to levels of adjustment in transplant patients, although interestingly, moderate to high feelings of indebtedness towards to donor was unrelated to adjustment (38). A strong correlation has been observed between depression symptoms (BDI) with perceptions of illness and social support in renal transplant patients, although a small sample size and failure to control for potential confounding factors are limitations (39). Others have shown that posttransplantation emotional well-being is moderated by the coping preferences of the patient (40). Specifically, patients with a more active coping style (i.e., seeking health-related information) have a reduction in depression symptoms following transplantation compared to those who have a low preference for health-related information seeking, who tend to show increases in depression over time (40). This work has some relevance regarding extended criteria for donation because more patients are receiving less than ideal grafts therefore increasing the potential for clinical
TABLE 1. Summary of common demographic, clinical, and psychosocial correlates of depression in kidney transplant patients Demographic Age (25, 31) Marital Status (17, 29) Lower income/employment (18, 29, 31, 32) Gender (17, 25, 32, 33) White race (25), Education (17, 32)
Clinical
Psychological
Renal function (17, 29, 32) Inflammation (20) Comorbidity (17, 25, 29, 32) Serum hemoglobin (18, 32) Serum albumin (17, 20)
Past history of depression (20) Perceived stress (82) Coping style (40) Illness beliefs (39) Social support (39)
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complications and events. Managing the expectations of such recipients is likely to be an important factor related to adjustment in the months proceeding transplantation. Depression Predicts Poor Clinical Outcomes Not only does depression impact severely on quality of life in ESRD patients (41), it is associated with poor clinical outcomes, particularly mortality (42Y45). Among kidney transplant patients, depression also appears to play an important prognostic role in terms of kidney graft survival and patient mortality (17, 18, 24, 25, 46). In a large analysis of US Medicare claims, Dobbels et al. (25) found that depression was associated with a twofold increase in risk of graft failure, return to dialysis, and death with a functioning graft, after controlling for several demographic and clinical factors. Novak et al. (17) studied 840 kidney transplant patients and found that those defined as depressed (based upon a CES-D score Q18) were at greater risk of death over the study follow-up compared to non-depressed patients (HR=1.66, 95% CI 1.12Y2.47). Furthermore, baseline depression scores were also associated with death-censored graft survival (HR=1.03, 95% CI 1.01Y1.05), albeit failing to utilize competing risk survival models in their analysis. A recent study reported that depression, as assessed by the depression subscales of the SCL-90, predicted both all-cause and cardiovascular diseaseYrelated mortality (18). These findings support the work of others who have also found that depression predicts survival following heart (47) and liver transplantation (48), although taken together the evidence that depression is associated with clinical outcomes in solid organ transplant recipients is mixed (49). The association between depression and poor clinical outcomes in kidney transplant patients might be explained by several factors, with nonadherence to treatment regimens a strong explanatory factor. Nonadherence to immunosuppressant medicines is estimated to be approximately 22% to 28%, with around 16% to 36% of failed grafts thought to be the result of nonadherence behavior (50, 51). Depression has been found to increase the risk of treatment nonadherence threefold among patient populations (52). Both retrospective (53) and prospective studies (54, 55) of kidney graft recipients report an association between nonadherence and depression [see (56)]. In a recent study of kidney transplant patients, intentional nonadherence (i.e., choosing not to take them, or skip/adjusting a dose) to immunosuppressant medications was associated with depression symptoms (19). Furthermore, depression in kidney transplant patients is associated with unhealthy behaviors including lower activity levels and higher alcohol use, which may in turn impact upon transplant-related outcomes (18). Other suggested mechanisms that might explain poor outcomes in depressed patients include the well-established association between depression and cardiovascular disease (CVD) (57, 58) where malnutrition, inflammation, and immune function are all implicating factors (17, 32, 59Y62). In dialysis patients, depression has been found to correlate positively with pro-inflammatory cytokines (60, 62), which are also an important factor in the pathogenesis of CVD (63). As described previously, depression symptoms have be shown to have a small yet significant association with IL-6 among kidney transplant recipients (32). Nevertheless, the
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apparent relationship between depression and inflammation is complex and causal assumptions are difficult to infer because pro-inflammatory cytokines can cause symptoms similar to those observed in depression (64, 65). Taken together, the potential mechanisms linking depression with transplant-related outcomes are unduly complex, involving direct and indirect factors, which likely interact to increase the propensity for a poor outcome. Interventional Approaches for Treating Depression Given that depression is a prevalent and costly comorbidity in kidney transplant patients, efforts to detect symptoms and intervene with appropriate treatments are critical. Unfortunately, across the spectrum of advanced kidney disease, little research has been conducted evaluating treatments for depression in robust clinical trials. Group cognitive behavioral therapy has been shown to be effective at reducing depression symptoms among hemodialysis patients (66). Among renal transplant recipients, 12 weeks of psychotherapy (individual and group) has been shown to reduce depression symptoms over 12 months, although it should be noted that the control arm of this trial had significantly fewer depression symptoms at baseline, and the analysis failed to adequately consider the interaction between group and time (67). A small study of an intervention designed to improve quality of life and reduce distress in ESRD patients awaiting transplantation also demonstrated benefit to well-being (68), suggesting that targeting symptoms before transplantation might be one effective treatment model. Taken together, there is a need to further develop specific psychological-based interventions that target maladjustment and distress in renal transplant patients, which are tested in trials using robust methodologies. Renal transplant recipients are a heterogeneous population, with a range of baseline renal function, comorbidities, and immunosuppressive regimens, which are factors that need to be considered when treating depression with antidepressants. When considering treatment with an antidepressant, similar issues are raised as with treating depression in patients with CKD. The authors found no published trials of pharmacological treatments for depression purely in the renal graft recipient population. Further, the evidence for the pharmacological treatment of depression in CKD is very limited, with no robust randomized controlled trials published. As a result, most guidance imports evidence from the treatment of otherwise healthy individuals (69Y75), which may not be appropriate given the potential effects of impaired renal function, multiple medications, and comorbidities on existing agents. There is a clear need for high-quality trials, and the authors await the first data (76). There are reasons to be cautious when prescribing an antidepressant. The most widely used antidepressants, the selective serotonin reuptake inhibitors (SSRIs), all have an antiplatelet effect (77, 78). Renal graft recipients already have a theoretically associated increased risk of gastrointestinal bleeding through use of antiplatelet agents (79, 80) and immunosuppressants, such as steroids, as well as impaired platelet function in renal impairment. However, caution needs to be given to the use of gastroprotective agents if an
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SSRI is to be prescribed because some combinations interact to produce QTc prolongation. Detailed reviews of the pharmacological treatment options and pharmacokinetic considerations have been reported elsewhere (69Y72, 74, 75, 81). The authors recommend the careful consideration of non-pharmacological and pharmacological treatments for depression to ensure the most appropriate treatment be offered, particularly because untreated depression is a significant risk to well-being and outcome. Given concerns regarding harm in the form of gastrointestinal bleeding, the decision to treat depression pharmacologically is one best made following a discussion between the renal transplant team, specialist psychiatric liaison services, and renal pharmacists to ensure the safest and most effective agent is selected.
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CONCLUSIONS Despite advances in renal transplantation, depression is still a prevalent and problematic comorbidity that remains mostly overlooked. Depression in this setting predicts poor outcomes, including inferior graft survival. While the mechanisms underlying this relationship require further empirical attention, nonadherence is a significant explanatory factor. Efforts to support the adjustment process are critical and when mood symptoms require specific attention, psychological therapies show promise but do require further research into their acceptability and efficacy in this setting. Evidence regarding pharmacological interventions for clinically diagnosed depression in renal transplant patients also requires further investigation, specifically the concerns around safety. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
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Depression and Kidney Transplantation Joseph Chilcot,1,4 Benjamin Walter Jack Spencer,2 Hannah Maple,3 and Nizam Mamode3 While kidney transplantation offers several advantages in terms of improved clinical outcomes and quality of life compared to dialysis modalities, depressive symptoms are still present in approximately 25% of patients, rates comparable to that of the hemodialysis population. Correlates of depressive symptoms include marital status, income, kidney function, history of affective illness, malnutrition, and inflammation. Depressive symptoms are also associated with poor outcomes following kidney transplantation including nonadherence to immunosuppressant medication, graft failure, and all-cause mortality. Efforts to detect and treat depression should be a priority if one is to improve treatment adherence, quality of life, and outcomes in transplant recipients. Keywords: Depression, Kidney transplantation, Renal transplantation, Kidney transplant, Transplant, Outcomes. (Transplantation 2014;97: 717Y721)
t is well documented that end-stage renal disease (ESRD) patients experience high levels of depression with approximately 20% to 30% suffering from depressive symptoms (1Y3). When compared with dialysis modalities, kidney transplantation is associated with improved clinical outcomes (4), better quality of life (5), and lower rates of psychiatric morbidity (6, 7). Despite this, transplantation requires psychological adjustment and comes with its own treatment challenges. This can produce problematic feelings such as fear, guilt, and global distress. Depression is likely to be the most common psychological complaint in kidney transplant recipients and is the focus of this review. Specifically, this article describes the estimated prevalence, correlates, and consequences of depression in this setting, and evaluates treatment options.
I
Prevalence Rates of Depression in Kidney Transplant Patients Prevalence rates for depression in renal patients vary as a product of the assessment undertaken (1, 8). As discussed elsewhere, the assessment of depression is complicated in kidney disease patients, partly as a result of overlapping physical symptoms between renal insufficiency and the features of The authors declare no funding or conflicts of interest. 1 Health Psychology Section, Psychology Department, Institute of Psychiatry, King’s College London, UK. 2 Department of Psychological Medicine, Institute of Psychiatry, King’s College London, UK. 3 Department of Transplantation, Guy’s Hospital, London, UK. 4 Address correspondence to: Joseph Chilcot, Ph.D., Health Psychology Section, Psychology Department, Institute of Psychiatry, King’s College London, 5th floor Bermondsey Wing, Guy’s Hospital Campus, London Bridge, London, SE1 9RT, UK. E-mail: [email protected] All authors contributed to the reviewing of references, and the writing and editing of this article. Received 30 August 2013. Revision requested 3 October 2013. Accepted 21 October 2013. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9707-717 DOI: 10.1097/01.TP.0000438212.72960.ae
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depression, such as lethargy (2, 9, 10). Screening approaches that utilize standardized questionnaires with predetermined cutoff scores often inflate estimated prevalence rates, with diagnostic approaches (i.e., clinical interviews) often attenuating these estimates (8). Several screening and severity measures have been used to evaluate depression symptoms in kidney transplant patients, and these include the Hospital Anxiety Depression Scale (11), Beck Depression Inventory (BDI) (12, 13), the Symptom Checklist (SCL-90) (14), and the Centre for Epidemiologic Studies Depression Scale (CES-D) (15). It is important to recognize that screening tools are not diagnostic measures; rather they are helpful indicators of those who have significant symptoms that might require further enquiry. It should therefore be noted that throughout this article when studies have adopted such measures, the term depression used does not refer to a diagnosed condition, rather high levels of depressive symptoms. Within the context of renal transplantation, the relative accuracy of screening and severity measures in relation to a clinical diagnosis of depression requires attention in suitably large studies. In one of the earliest studies looking at distress in kidney transplant patients, 46% were found to be distressed as defined by a General Health Questionnaire-30 score greater than 5 (16). More recently, Novak et al. (17) reported a 22% point prevalence of depression (CES-D score Q18) among 840 kidney transplant patients and Zelle et al. (18) reported a 31% prevalence using the SCL-90 (925). Use of the BDI has led to estimates between 13% and 39% (19Y24) with variability partly being attributable to methodological differences, such as differences in BDI cutoff scores used. Few studies have examined the incidence of depression over time among kidney transplant recipients. An analysis of Medicare claims in 47,899 kidney recipients revealed a cumulative yearly depression incidence of 5.05%, 7.29%, and 9.1% 3 years posttransplantation (25). Comparing the prevalence of depression symptoms between dialysis and transplant populations has led to mixed findings, which are often www.transplantjournal.com
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hard to interpret because of methodological limits and the potential for confounding. While it is generally recognized that transplantation confers a quality-of-life benefit, there is still significant variation within transplant patients (26, 27). One of the first studies to compare dialysis and transplant modalities revealed similar levels of distress (16), while others suggested that psychiatric morbidity or emotional distress is lower in transplanted patients (6, 7, 21, 28). For example, Szeifert et al. (29) found that the prevalence of depression is lower in transplant patients compared to dialysis patients (22% vs. 33%, respectively), and in multivariate analysis dialysis modality predicted higher depression scores. In a recent meta-analysis, Palmer et al. (8) found that the prevalence of depression, according to self-report or clinician rated tools, was lower in kidney transplant patients (26.6%, 95% CI, 20.9Y33.1) compared to ESRD patients (39.3%, 95% CI 36.8Y42.0). Although variation is evident in the literature with confidence intervals for point prevalence estimates large, it appears that approximately one in four patients screen positive for depression across the spectrum of advanced kidney disease, making it one of the more common comorbidities encountered in renal transplant candidates and recipients. Nevertheless, it is also clear that studies are needed to establish the trajectory of depression symptoms over time (30), following up a suitably large sample of patients from dialysis to transplantation and beyond. This will allow researchers and clinicians to observe the natural history of symptomatology, identify correlates, and possibly highlight optimal points for intervention. Factors Associated With Depression Following Kidney Transplantation Multiple studies have examined possible clinical, social, and psychological factors associated with depression in kidney transplant patients (Table 1). Demographic correlates of depression include age (25, 31), female gender (17, 25, 32, 33), race (25), employment status and financial situation (18, 29, 31, 32), education (17, 32), and marital status (17, 29). With regards to clinical factors, studies have shown a negative association between renal function (estimated glomerular filtration rate, eGFR) and depression in transplant patients (17, 29, 32). Zelle et al. (18) report significantly lower creatinine clearance and a higher proportion of proteinuria in depressed transplant patients compared with non-depressed patients. Lower hemoglobin (18, 32) and serum albumin levels (17, 20) have also been associated with depression in kidney transplant patients. Dobbels et al. reported a positive association between
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Medicare claimYidentified depression and having six HLA mismatches, rapamycin use, antithymocyte and antilymphocyte globulin for antibody induction therapy, and having diabetic nephropathy as a primary cause of kidney disease (25). Most of these clinical factors are related to graft function; therefore, these findings may reflect depression symptoms resulting from impending graft loss and the associated physical symptoms resulting from low eGFR. However, prospective evaluations are needed to better understand the casual pathways between depression and clinical factors in kidney transplant recipients. Others report that higher C-reactive protein (20), interleukin-6, and longer dialysis vintage (18, 25) are associated with heightened depression symptoms (32), although again there are conflicting data with respect to these findings (17, 29). There is little evidence that the duration of transplant graft survival is associated with depression in kidney recipients (18, 29, 31). More consistent findings suggest an association between the severity of comorbidity (including obesity) (17, 25, 29, 32) and heightened depression symptoms in kidney recipients. Regarding psychological factors, having a history of depression predicts concurrent mood following kidney transplantation (6, 20), which is also the case for hemodialysis patients (34). While psychological predictors of depression have been examined in some detail among dialysis patients (1, 35) with particular emphasis on patients’ illness beliefs (30, 36, 37), fewer data exists in kidney transplant patients. Poor psychological adjustment and coping are likely perpetuating contributors. A small study found that age, general life stress, and transplant-related stress were all related to levels of adjustment in transplant patients, although interestingly, moderate to high feelings of indebtedness towards to donor was unrelated to adjustment (38). A strong correlation has been observed between depression symptoms (BDI) with perceptions of illness and social support in renal transplant patients, although a small sample size and failure to control for potential confounding factors are limitations (39). Others have shown that posttransplantation emotional well-being is moderated by the coping preferences of the patient (40). Specifically, patients with a more active coping style (i.e., seeking health-related information) have a reduction in depression symptoms following transplantation compared to those who have a low preference for health-related information seeking, who tend to show increases in depression over time (40). This work has some relevance regarding extended criteria for donation because more patients are receiving less than ideal grafts therefore increasing the potential for clinical
TABLE 1. Summary of common demographic, clinical, and psychosocial correlates of depression in kidney transplant patients Demographic Age (25, 31) Marital Status (17, 29) Lower income/employment (18, 29, 31, 32) Gender (17, 25, 32, 33) White race (25), Education (17, 32)
Clinical
Psychological
Renal function (17, 29, 32) Inflammation (20) Comorbidity (17, 25, 29, 32) Serum hemoglobin (18, 32) Serum albumin (17, 20)
Past history of depression (20) Perceived stress (82) Coping style (40) Illness beliefs (39) Social support (39)
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complications and events. Managing the expectations of such recipients is likely to be an important factor related to adjustment in the months proceeding transplantation. Depression Predicts Poor Clinical Outcomes Not only does depression impact severely on quality of life in ESRD patients (41), it is associated with poor clinical outcomes, particularly mortality (42Y45). Among kidney transplant patients, depression also appears to play an important prognostic role in terms of kidney graft survival and patient mortality (17, 18, 24, 25, 46). In a large analysis of US Medicare claims, Dobbels et al. (25) found that depression was associated with a twofold increase in risk of graft failure, return to dialysis, and death with a functioning graft, after controlling for several demographic and clinical factors. Novak et al. (17) studied 840 kidney transplant patients and found that those defined as depressed (based upon a CES-D score Q18) were at greater risk of death over the study follow-up compared to non-depressed patients (HR=1.66, 95% CI 1.12Y2.47). Furthermore, baseline depression scores were also associated with death-censored graft survival (HR=1.03, 95% CI 1.01Y1.05), albeit failing to utilize competing risk survival models in their analysis. A recent study reported that depression, as assessed by the depression subscales of the SCL-90, predicted both all-cause and cardiovascular diseaseYrelated mortality (18). These findings support the work of others who have also found that depression predicts survival following heart (47) and liver transplantation (48), although taken together the evidence that depression is associated with clinical outcomes in solid organ transplant recipients is mixed (49). The association between depression and poor clinical outcomes in kidney transplant patients might be explained by several factors, with nonadherence to treatment regimens a strong explanatory factor. Nonadherence to immunosuppressant medicines is estimated to be approximately 22% to 28%, with around 16% to 36% of failed grafts thought to be the result of nonadherence behavior (50, 51). Depression has been found to increase the risk of treatment nonadherence threefold among patient populations (52). Both retrospective (53) and prospective studies (54, 55) of kidney graft recipients report an association between nonadherence and depression [see (56)]. In a recent study of kidney transplant patients, intentional nonadherence (i.e., choosing not to take them, or skip/adjusting a dose) to immunosuppressant medications was associated with depression symptoms (19). Furthermore, depression in kidney transplant patients is associated with unhealthy behaviors including lower activity levels and higher alcohol use, which may in turn impact upon transplant-related outcomes (18). Other suggested mechanisms that might explain poor outcomes in depressed patients include the well-established association between depression and cardiovascular disease (CVD) (57, 58) where malnutrition, inflammation, and immune function are all implicating factors (17, 32, 59Y62). In dialysis patients, depression has been found to correlate positively with pro-inflammatory cytokines (60, 62), which are also an important factor in the pathogenesis of CVD (63). As described previously, depression symptoms have be shown to have a small yet significant association with IL-6 among kidney transplant recipients (32). Nevertheless, the
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apparent relationship between depression and inflammation is complex and causal assumptions are difficult to infer because pro-inflammatory cytokines can cause symptoms similar to those observed in depression (64, 65). Taken together, the potential mechanisms linking depression with transplant-related outcomes are unduly complex, involving direct and indirect factors, which likely interact to increase the propensity for a poor outcome. Interventional Approaches for Treating Depression Given that depression is a prevalent and costly comorbidity in kidney transplant patients, efforts to detect symptoms and intervene with appropriate treatments are critical. Unfortunately, across the spectrum of advanced kidney disease, little research has been conducted evaluating treatments for depression in robust clinical trials. Group cognitive behavioral therapy has been shown to be effective at reducing depression symptoms among hemodialysis patients (66). Among renal transplant recipients, 12 weeks of psychotherapy (individual and group) has been shown to reduce depression symptoms over 12 months, although it should be noted that the control arm of this trial had significantly fewer depression symptoms at baseline, and the analysis failed to adequately consider the interaction between group and time (67). A small study of an intervention designed to improve quality of life and reduce distress in ESRD patients awaiting transplantation also demonstrated benefit to well-being (68), suggesting that targeting symptoms before transplantation might be one effective treatment model. Taken together, there is a need to further develop specific psychological-based interventions that target maladjustment and distress in renal transplant patients, which are tested in trials using robust methodologies. Renal transplant recipients are a heterogeneous population, with a range of baseline renal function, comorbidities, and immunosuppressive regimens, which are factors that need to be considered when treating depression with antidepressants. When considering treatment with an antidepressant, similar issues are raised as with treating depression in patients with CKD. The authors found no published trials of pharmacological treatments for depression purely in the renal graft recipient population. Further, the evidence for the pharmacological treatment of depression in CKD is very limited, with no robust randomized controlled trials published. As a result, most guidance imports evidence from the treatment of otherwise healthy individuals (69Y75), which may not be appropriate given the potential effects of impaired renal function, multiple medications, and comorbidities on existing agents. There is a clear need for high-quality trials, and the authors await the first data (76). There are reasons to be cautious when prescribing an antidepressant. The most widely used antidepressants, the selective serotonin reuptake inhibitors (SSRIs), all have an antiplatelet effect (77, 78). Renal graft recipients already have a theoretically associated increased risk of gastrointestinal bleeding through use of antiplatelet agents (79, 80) and immunosuppressants, such as steroids, as well as impaired platelet function in renal impairment. However, caution needs to be given to the use of gastroprotective agents if an
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SSRI is to be prescribed because some combinations interact to produce QTc prolongation. Detailed reviews of the pharmacological treatment options and pharmacokinetic considerations have been reported elsewhere (69Y72, 74, 75, 81). The authors recommend the careful consideration of non-pharmacological and pharmacological treatments for depression to ensure the most appropriate treatment be offered, particularly because untreated depression is a significant risk to well-being and outcome. Given concerns regarding harm in the form of gastrointestinal bleeding, the decision to treat depression pharmacologically is one best made following a discussion between the renal transplant team, specialist psychiatric liaison services, and renal pharmacists to ensure the safest and most effective agent is selected.
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CONCLUSIONS Despite advances in renal transplantation, depression is still a prevalent and problematic comorbidity that remains mostly overlooked. Depression in this setting predicts poor outcomes, including inferior graft survival. While the mechanisms underlying this relationship require further empirical attention, nonadherence is a significant explanatory factor. Efforts to support the adjustment process are critical and when mood symptoms require specific attention, psychological therapies show promise but do require further research into their acceptability and efficacy in this setting. Evidence regarding pharmacological interventions for clinically diagnosed depression in renal transplant patients also requires further investigation, specifically the concerns around safety. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
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