Case 4: cardiovascular risk in renal transplantation (2003)

INTRODUCTION After 2 years of dialysis, KL, a 50-year-old white male, underwent cadaveric renal transplantation. The donor was a 58 year old male with a history of hypertension. The immunosuppressive regimen following transplantation consisted of CsA, MMF, and prednisone. KL’s renal function improved slowly and a calcium channel blocker was introduced to control his elevated blood pressure. At 8 weeks posttransplant, the patient developed acute rejection that was treated with corticosteroids. Lipid values at this time were elevated: total cholesterol and LDL-cholesterol levels were 260 and 142 mg/dL, respectively. At 7 months KL presented with acute chest pain. EKG changes indicated inferior wall ischemia and his stress test was positive. Coronary angiography revealed right coronary disease with proximal stenosis. He underwent angioplasty with stent placement. KL’s antihypertensive medication was changed to an ACE-inhibitor (ramipril) and pravastatin was started to control hyperlipidemia. At 2 years, KL’s serum creatinine was 3.0 mg/dl with proteinuria (3g/day). Biopsy revealed chronic allograft nephropathy. The doses of pravastatin and ramipril were increased to control lipid levels and blood pressure, respectively. Results of non-invasive cardiac testing were normal at this time. The following year, moderate hypercalcemia and an inappropriately elevated PTH level were detected—subtotal parathyroidectomy was performed. Five years after transplantation, KL presented with chest pain and coronary angiography revealed triple vessel disease. Following angiography KL developed acute renal failure and required dialysis therapy. Triple vessel coronary bypass surgery was performed. KL experienced postoperative hypotension and his fluids were difficult to manage within the normal range. Immunosuppression was withdrawn. Currently KL is 55 years old and is maintained on dialysis treatment. He is being considered for retransplantation. DISCUSSION The American Society of Transplantation defines cardiovascular disease (CVD) as ischemic heart disease, cerebral vascular disease and peripheral vascular disease (1). CVD is the major cause of death and graft loss following renal transplantation (2). Between 1988 and 1997, 36% of deaths with graft function were due to cardiovascular causes, half of which followed myocardial infarction (2). The present case provides an opportunity to discuss the identification and management of cardiovascular risk factors as a critical component of posttransplant care. We will outline the key steps to identify, prevent and manage CVD risk factors among renal allograft recipients. Pretransplant Risk for CVD Identifying cardiovascular risk in the renal transplant candidate is an important first step in managing CVD. The National Kidney Foundation Task Force on CVD advises that all renal transplant recipients be considered at risk for CVD because of their exposure to risk factors such as chronic renal insufficiency and treatment with hemodialysis or peritoneal dialysis during their pretransplant course (3). Some patients may be at increased risk for posttransplant CVD because of predisposing donor factors. For example, in our clinical case, KL has received a kidney from a donor with a history of hypertension. Some studies suggest this increases his risk of developing CVD following transplantation (4). Among the general population, older age, hypertension, hyperlipidemia, diabetes, smoking and physical inactivity are conditions associated with increased risk of CVD. There is a higher prevalence of these risk factors in patients with chronic renal disease (3). Prolonged duration of time on dialysis is associated with a higher prevalence of CVD (5). This may be related to accelerated atherosclerosis from hypertension, hyperparathyroidism and uremia. Increased coronary calcification may also result from prolonged dialysis treatment (6)Thus, pretransplant CVD and the presence of CVD risk factors before transplantation are critical in the development of posttransplant CVD (Table 1) (3). Table 1: Table 1. Pre-transplant risk factors for CVDBecause the risks associated with surgery are higher for potential renal transplant recipients than for the general population, preoperative evaluation of CVD is recommended (1,3). This screening may help to prevent perioperative morbidity and mortality and avoid subsequent development and progression of CVD with a functioning graft (3). Cardiac Evaluation Prior to Transplantation The purpose of cardiac evaluation prior to transplantation is to assess both the surgical risk of cardiac complications and to predict the long-term cardiovascular health of the patient receiving a renal allograft. Nevertheless, cardiac evaluation of ESRD patients remains a challenge. The American Society of Transplantation (AST) recommends use of the American College of Physicians’ cardiac risk index to identify patients’ CVD status and risk prior to renal replacement surgery (1). The recommendations for screening guidelines, developed by the National Kidney Foundation Task Force on CVD, appear in reference 3. Exercise testing, shown to reliably predict patients at high risk for surgical failure, may be difficult for many renal transplant candidates (1,3). Tests such as dipyridamole thallium and dobutamine stress echocardiography are recommended and may better estimate the probability of adverse cardiac events for renal transplant recipients compared to the general population (1). At the time of transplantation, KL presented with a low-risk profile for perioperative cardiac events, facilitating the decision to proceed with surgery. However, long-term patient and graft survival depend upon continued evaluation and control of CVD risk factors at regular intervals throughout the posttransplant course. Cardiovascular Risk Following Transplantation Following transplantation, CVD compromises both patient and graft survival. The relationship between CVD and patient mortality following transplantation is well-documented. Approximately one-third of all deaths among renal allograft recipients are due to cardiac events; cerebrovascular accidents are responsible for an additional 5% (7). Furthermore, cardiovascular disease and stroke account for over 40% of death with graft function (2). Smoking (8), age at transplant (4,5,8), male gender (4,8,9), diabetes at transplant (4), and pretransplant ischemic heart disease (4,5,8) have all been identified as significant risk factors for posttransplant CVD. Ponticelli and colleagues also found that time on dialysis and pretransplant hypertension and hyperlipidemia increased the risk for cardiovascular events following transplantation (5). Multiple studies have examined risk factors for posttransplant death due to CVD. Diabetes, acute rejection and delayed graft function have been significantly associated with death due to ischemic heart disease (9). Kasiske and colleagues determined that renal transplant recipients experiencing two or more acute rejection episodes, or serum cholesterol levels >200 mg/dL, or triglycerides >350 mg/dL were at significantly increased risk for ischemic heart disease beyond the first year posttransplant (10). Table 2 summarizes the risk factors for ischemic heart disease in renal transplant recipients described in the literature (4,8,9,11). Table 2: Table 2. Post-transplant risk factors for CVDThe contribution of cardiovascular risk factors to renal allograft dysfunction is less frequently described. However, the relationship is becoming more obvious as long-term patient survival improves (12). We now recognize associations between hypertension, renal insufficiency, hyperlipidemia, graft loss and patient mortality. In one study, hypertensive renal transplant recipients (blood pressure >160/95 mmHg or patients receiving antihypertensive medications) had significantly higher serum creatinine levels at 1,3 and 5 years following transplantation. More importantly, at 10 years posttransplant, graft survival was compromised among the hypertensive patients (13). An independent investigation found that the risk of graft failure increased significantly with incremental increases in systolic and diastolic blood pressure (14). Finally, analysis of the USRDS database has revealed significant association between the loss of a primary renal allograft and mortality, particularly among patients with Type 1 diabetes mellitus (15). Elevated lipid levels also contribute to renal allograft dysfunction. The probability of doubling serum creatinine was significantly greater in patients with triglycerides ≥200 mg/dL (16). The same study showed that hypercholesterolemic patients experienced a non-statistically significant increase in renal dysfunction compared to patients without hypercholesterolemia. Two additional studies have shown that hypercholesterolemia in patients who experience previous acute rejection increases the risk for graft loss (17,18). The relationship between hyperhomocysteinemia, endothelial dysfunction and atherosclerosis is currently under investigation (19,20). Further study is required to establish target homocysteine levels in kidney transplant patients. The present clinical case illustrates the risk factors for developing CVD in transplant recipients. The case also demonstrates the rapid progression of this disease in the presence of CVD risk factors. Modifying Cardiovascular Risk: The Role of Immunosuppression The outcome of KL’s primary transplant emphasizes the need to minimize cardiovascular risk among renal allograft recipients starting at the time of transplantation, and continuing through the patient’s lifetime. In addition to diet and exercise, pharmacotherapy is essential to manage CVD risk factors. Clearly, antihypertensive agents and antihyperlipidemics are important targeted therapies. However, the choice of immunosuppressive agents also influences many of the posttransplant risk factors for CVD. Diabetes. Historically, the incidence of posttransplant diabetes mellitus (PTDM) has been reported to occur in 3.6% to 18% of renal transplant recipients (1). Results of current clinical trials reveal that between 3.6 and 18% of kidney transplant patients develop posttransplant diabetes mellitus (21–23). The incidence is slightly but not statistically significantly higher in patients maintained on tacrolimus therapy (21–23). High trough concentrations of cyclosporine or tacrolimus and African American recipient race have been associated with an increased incidence of PTDM (22). Similarly, sustained exposure to corticosteroids has been associated with the development of PTDM, while regimens that avoid corticosteroid use or taper corticosteroid doses reduce the risk of diabetes (24). There is also a strong association between hepatitis C infection and PTDM (25,26). Hypertension. Over three-quarters of renal transplant recipients have hypertension (3). Clinical trials comparing calcineurin inhibitors rarely reveal significant differences in blood pressure among patients maintained on cyclosporine or tacrolimus. This is primarily due to tight management of blood pressure levels using antihypertensive medications. However, many trials that have monitored the use of antihypertensives reveal that Prograf-treated patients require fewer medications to control blood pressure (18,21,27). One study compared the influence of cyclosporine and tacrolimus on blood pressure in a population in which antihypertensive medications were withheld (28). Systolic and diastolic blood pressures decreased significantly when patients were crossed over from cyclosporine to tacrolimus, and returned to elevated levels when conversion back to cyclosporine therapy occurred. In healthy subjects, cyclosporine was shown to increase mean arterial pressure significantly, while administration of tacrolimus had minimal impact (29). Corticosteroids negatively affect blood pressure. Patients receiving high dose prednisone were twice as likely to develop hypertension compared to patients maintained on low dose corticosteroids (63% vs. 32%, respectively;P <0.05) (30). As expected, withdrawal of corticosteroids has been shown to reduce hypertension in renal transplant recipients (31). Similarly, lower mean blood pressure has been achieved in patients maintained on a cyclosporine-free immunosuppressive regimen (32). Hyperlipidemia. Immunosuppressive agents may also modify patients’ lipid profiles. Hilbrands and colleagues observed elevations in LDL-cholesterol and triglycerides in patients maintained on cyclosporine monotherapy (33). Compared to renal transplant recipients receiving tacrolimus combination therapy, patients maintained on cyclosporine-based immunosuppression for 5 years had a significantly greater requirement for antihyperlipidemic agents (20.0% vs. 58.8%, P <0.001) (18). In addition, conversion from cyclosporine to tacrolimus has been shown to result in significant reductions in total serum cholesterol, LDL-cholesterol and triglyceride levels (28). Corticosteroid dose has also been associated with hyperlipidemia. Investigators have reported that total cholesterol and LDL-cholesterol levels decrease with withdrawal of corticosteroids (34). There has been increased attention to posttransplant hyperlipidemia with the introduction of the adjunct agent sirolimus. Despite the use of statins and fibrates, elevations in total cholesterol, LDL-cholesterol and triglycerides have been observed in renal transplant recipients receiving sirolimus (35). Careful monitoring of serum lipid levels is recommended in patients receiving sirolimus therapy. Preliminary findings suggest that tacrolimus-treated renal transplant recipients exhibit lower homocysteine levels compared to patients maintained on cyclosporine (36,37). A prospective study is underway to determine the impact of homocysteine levels on cardiovascular events. Acute rejection. We have discussed how immunosuppressive agents can modify cardiovascular risk through their effects on glucose tolerance, blood pressure and lipid levels. Prevention of acute rejection also reduces cardiovascular risk, possibly by reducing the requirement for corticosteroids to treat acute rejection (10). Compared to cyclosporine therapy, treatment with tacrolimus improves protection against acute rejection and may help facilitate control of hypertension and hyperlipidemia (21,23,38). With increasing interest in ways to minimize maintenance immunosuppression posttransplant, consideration must be given to the impact of increasing acute rejection rates on graft and patient survival (39). With reduction in acute rejection rates and improvement in short-term graft survival, our focus has shifted to long-term survival. Death with a functioning graft is an important cause of late graft failure. Immunosuppressive therapies have not been shown to reduce mortality from CVD. However, withdrawal of corticosteroids and administration of tacrolimus over cyclosporine has been shown to reduce CVD risk factors. Therefore, it is reasonable to consider altering immunosuppressive therapy to alter the major risk factors for CVD. Prevention and management of CVD is critical to enhance long-term transplant outcomes. Identification of CVD prior to transplantation is important to prevent morbidity and mortality after transplantation. Pharmacotherapy to reduce the risk of CVD events is critical. This can be done through the use of antihypertensives (ACE inhibitors; angiotensin receptor blockers), antihyperlipidemics (HMG-CoA reductase inhibitors) and agents that reduce the levels of homocysteine. Regimens that allow avoidance or tapering of corticosteroids help to improve glucose tolerance, blood pressure and lipid control. Choosing a calcineurin inhibitor such as tacrolimus with a lower CVD risk profile may benefit renal transplant recipients. Currently, we are unable to provide evidence that improved management of cardiovascular risk factors translates to improved long-term outcomes for renal transplant recipients. Studies that investigate the relationship between altered cardiovascular risk and transplant outcomes will be extremely valuable.