Akinlolu O. Ojo By the time of renal transplantation, end-stage renal disease patients have a huge burden of cardiovascular disease (CVD) andare heavily saturatedwithatherosclerotic risk factors. Worsening of preexisting risk factors or newCVDrisk factors may develop in the posttransplant period consequent in part to the diabetogenic and atherogenic potential of immunosuppressive drugs. The annual risk of a fatal or non-fatal CVD event of 3.5 to 5% in kidney transplant recipients is 50-fold higher than the general population. Renal allograft dysfunction, proteinuria, anemia, moderate hyperhomocysteinemia and elevated serum C-reactive protein concentrations, each dependently confer greater risk of CVD morbidity and mortality in the posttransplant period. Long-term care of renal transplant recipients should programmatically incorporate the recommendations of the National Kidney Foundation Working Groups and Euro- pean Best Practice Guidelines Expert Group on Renal Transplantations into the management of hypertension, dyslip- idemia, smoking, and posttransplant diabetes mellitus. Timely utilization of coronary revascularization procedures should be undertaken as these treatments are equally effective in the kidney transplant population. (Transplantation 2006;82: 603611) A lthough successful renal transplantation is accompanied by a 10- to 20-year increase in life expectancy (1, 2), the survival of kidney transplant recipients is significantly short- ened by atherosclerotic cardiovascular disease (CVD) (3, 4). The annual risk of a CVD death is 3.5% to 5% in renal trans- plant recipients, which is 50-fold higher thanthe general pop- ulation (57). Similarly, the incident cases of congestive heart failure are three times more likely after kidney transplanta- tion compared to the general population (8). Stroke accounts for nearly half of posttransplant CVDdeaths and extracranial cerebrovascular atherosclerosis occurs four times more fre- quently in renal transplant recipients compared to controls (24.5% vs. 6.2%, P0.001) (911). Acute coronary syn- drome is highly prevalent in the early posttransplant period and on the average, CVD mortality accounts for 30% and 75% of early and late posttransplant deaths, respectively (6, 12, 13). The durable improvement in allograft survival fol- lowing the introduction of calcineurin inhibitors has been accompanied by longer life expectancy, which presents the opportunity for renal transplant recipients to face a greater prospect of premature CVD death with a functioning graft rather than immunologic graft failure and resumption of di- alysis, which was more prevalent in the early eras (14). Pa- tients undergoing renal transplantation are already heavily burdened by a high risk of CVD and they encounter several factors in the posttransplant period that further accentuate the prevalence and severity of several CVD risk factors. The probability of CVD mortality is only modestly reduced in kidney transplant recipients when compared to dialysis pa- tients on the kidney transplant waiting list (15, 16). This re- view focuses on the role of traditional and novel CVD risk factors and on the primary and secondary preventative strat- egies available for the management of posttransplant cardio- vascular disease in the renal transplant population. Risk Factors for Cardiovascular Disease Table 1 shows the prevalence of traditional CVDrisk fac- tors in all dialysis patients, end-stage renal disease (ESRD) pa- tients eligible for kidney transplantation, and kidney transplant recipients. Although many of these risk factors may have con- tributed to the development and progression of the underlying renal disease, these predisposing factors do not remit following the successful treatment of the uremic state with kidney trans- plantation in part because posttransplant immunosuppression, comorbid conditions, intercurrent illnesses, level of renal allo- graft function, and patient behavior contribute variously to the acquisition of new CVD risk factors and/or the aggravation of existing ones (1723). In addition, novel CVD factors such as hyperhomocysteinemia, oxidative stress, lupus anticoagulant antibodies, systemic inflammation, proteinuria, and advanced glycosylation end products (AGES) have been implicated in the pathogenesis of CVDin kidney transplant recipients (7, 2429). The current understanding of the epidemiology, pathophysiol- ogy, and management of major risk factors for CVD are now described. Hypertension Hypertension, defined as systemic blood pressure (BP) 140/90 (JNC VII) (30), is the most prevalent CVD risk fac- tor inkidney transplant recipients, affecting 7590%of recip- ients (20, 3133). Three recent observational studies suggest a 12% increase risk of fatal or nonfatal CVD event for every 1 mm Hg increase in systolic blood pressure (6, 31, 34). Multi- ple factors contribute to the pathogenesis of posttransplant hypertension including pretransplant hypertension, high body mass index, primary kidney disease, quality of donor organ, delayed graft function, acute rejection, calcineurin in- hibitor therapy, glucocorticoids, transplant renal artery ste- nosis and chronic allograft nephropathy (3437). Indirect evidence suggests that the most potent etiologic factors for posttransplant hypertension are pretransplant hypertension and calcineurin inhibitor therapy. Up to half of the patients had hypertension prior to transplantation either as primary Department of Medicine, University of Michigan, Ann Arbor, MI. Address correspondence to: Akinlolu O. Ojo, M.D., Ph.D., University of Michigan Medical Center, Division of Nephrology, 3914 Taubman Cen- ter, Box 0364, Ann Arbor, MI 48109-0364. E-mail: aojo@umich.edu Received 12 May 2006. Revision requested 26 May 2006. Accepted 2 June 2006. Copyright 2006 by Lippincott Williams & Wilkins ISSN 0041-1337/06/8205-603 DOI: 10.1097/01.tp.0000235527.81917.fe Transplantation Volume 82, Number 5, September 15, 2006 603 cause of kidney failure or secondary to chronic kidney disease (5). The prevalence of posttransplant hypertension was sig- nificantly lower (5060%) prior to the introduction of cal- cineurin inhibitors in 1983 (33, 38). Calcineurin inhibitors promote intense afferent arteriolar vasoconstriction via stim- ulation of the sympathetic nervous system and by upregulat- ing the local rennin angiotension aldosterone system(39, 40). Furthermore, calcineurin inhibitors mediates a reduction in vasodilator prostaglandin, nitric oxide, and increased elabo- ration of other vasoconstrictor cytokines including adenosine, thromboxane A2, cysteinyl leukotrienes, platelet-derived growth factor, and endothelin-1 (4143). Sodium and water reten- tion mediated by glucocorticoid therapy also contribute to posttransplant hypertension and may account for 15% of the risk of posttransplant hypertension in kidney recipients (44). The etiologic roles of calcineurin inhibitors and glucocorti- coids present an attractive therapeutic target for the manage- ment of CVD risk factors as recent clinical trials of transplant immunosuppression demonstrate significant improvement in systemic blood pressure control and reduction in the number of required antihypertensive drugs following the elimination of calcineurin inhibitor or glucocorticoid from the maintenance immunosuppressive regimen (4547). There are no randomized clinical trials of antihyperten- sive drugs andoptimal bloodpressure goals inkidney transplant recipients. Basedonlargeclinical trials inthenontransplant pop- ulation with and without significant renal disease, the National Kidney Foundation (NKF) KDOQI guidelines include recom- mended blood pressure goals of 125/75 mmHg for renal trans- plant recipients with proteinuria and 130/85 mm Hg in the ab- sence of proteinuria (48). The management plan for hypertension in the transplant population should include simultaneous initiation of nonphar- macologic strategies along with drug therapy. An initial trial of nonpharmacologic therapy alone may be successful only if the level of systolic blood pressure is within 10 mm Hg of target BP and simultaneous initiation of multiple drug therapy should be considered if the presenting blood pressure readings are 15 mm Hg higher than target BP (4951). Weight reduction, regular moderate exercise, dietary sodium, and restriction are essential (51, 52). The pharmacologic management of hypertension in renal transplant population presents several unique issues re- lated to potential drug interactions, drug efficacy, and concur- rent medical problems. Patients should be stratified by the pres- enceof proteinuriaanddiabetes mellitus toguidetheselectionof antihypertensivedrugs (53). Thedihydropyridinecalciumchan- nel blockers (DHP-CCB) are the most widely utilized class of drugs, in part because of their putative beneficial effect on cal- cineurin inhibitor-induced vasoconstriction (5456). DHP-CCB are potent antihypertensive agents withdocumentedevidence of CVDprotection in the nontransplant population (57) and have been demonstrated to be effective in controlling blood pressure and in preserving graft function in kidney transplant recipients (55). DHP-CCB are associated with improved renal allograft functioncomparedtoangiotensinconvertingenzyme inhibitors (ACEI) in the short and medium terms (56, 58). The use of DHP-CCB in proteinuric chronic kidney disease patients is as- sociated with increased risk of renal disease progression and death except when used in conjunction with angiotensin II blockade therapy (5961). Long-term cardiovascular protec- tionappeared to be comparable betweenDHP-CCB, ACEI, and diuretics in the ALLHAT trial of approximately 40,000 patients with no significant renal disease or proteinuria (57). The nondi- hydropyridine calcium channel blockers (non-DHP CCB) are synergistic withACEI intheir antiproteinuric effect (62, 63). Sig- nificant dose reductionof the calcineurininhibitors is uniformly necessary with the non-DHP-CCB. Angiotensin receptors blockers (ARBs) and ACEI may be particularly attractive in the kidney transplant population because of their antiproteinuric, renoprotective, and cardioprotective benefits (6467) but ane- mia and hyperkalemia may limit the use of optimal dosages of these drugs ACEI andARB(49). Beta blockers anddiuretics may be indicated for preexisting CVD and fluid retention respec- tively, but they both harbor increased potential for metabolic abnormalities. Bradycardia and blunting of hypoglycemic un- awareness are serious limiting factor for beta blockers. The larg- est clinical trial of antihypertensive therapy suggests that thiazide diuretics should be the preferred initial antihypertensive drug and this is reinforced by the JNC VII guidelines (51, 57). How- ever, this recommendation does not apply to renal transplant recipients, whoareremarkablydifferent fromtheALLHATpop- ulation (68). In absence of any large clinical trial specifically fo- cused on kidney transplant recipients, the high prevalence of proteinuria, diminishedglomerular filtrationrate (GFR), diabe- tes mellitus, and preexisting CVD should guide the selection of antihypertensive medication. Specific indications such as pro- teinuria, graft vasculopathy, or preexisting CVD may warrant the use of ACEI (or ARB) or beta blockers, respectively, as the initial agents. Loop diuretics should be added in the presence of fluid and water retention and poor allograft function. The NKF working group recommends the use of the JNC VII guidelines for the management of hypertension in kidney recipients (69). Cigarette Smoking Approximately 2530%of kidney transplant recipients continue to use inhalation tobacco products habitually (17, 70). Smoking increases the risk of CVD death in kidney re- cipients. The relative risk (RR) of death ranges from 1.56 in recipients with cumulative smoking history of 1125 pack- years to a RR of 2.14 for recipients with 25 pack-years (71 74). In the immediate period after allograft implantation, smoking increased the risk of an acute coronary syndrome by three- to fourfold (75). In one study, the adverse effects of smoking dissipated five years after smoking cessation (73). The immediate postoperative period presents a unique op- portunity to introduce a smoking cessationprogram. Because TABLE 1. Prevalence of CVD risk factors in ESRD patient groups (5, 18, 20, 31, 34, 70, 79, 156158) Risk factor Dialysis patients (%) Transplant candidates (%) Transplant recipients (%) Systemic hypertension 80 75 80 Diabetes mellitus 40 35 55 Hypercholesterolemia 25 25 60 Obesity (BMI 30) 14 20 32 Tobacco use 18 24 20 LVH 75 75 52 Anemia (HCT 30%) 32 25 40 604 Transplantation Volume 82, Number 5, September 15, 2006 tobacco use is necessarily terminated during the initial trans- plant hospitalization, incorporation of smoking cessation into the early posttransplant care should be essential compo- nent of the critical pathway preceding discharge. Multifaceted programs with both behavioral and pharmacologic compo- nents have been proven to be more effective (76, 77). There are no documented significant pharmacokinetic interac- tions between the commonly used immunosuppressants and tobacco-dissuading drugs. Dyslipidemia Hypercholesterolemia is present in 5060% of kidney transplant recipients (20, 7880). Lipid-lowering therapy de- crease the risk of cardiovascular events in both primary and secondary preventions studies in wide range of population groups (81, 82). The potential benefit of lipid reduction in renal transplant recipients was demonstrated in the ALERT study (Assessment of LEscol in Renal Transplantation) in which 2,102 renal transplant recipients with total cholesterol 4-0-9.0 mmol/L were randomized to fluvastatin 4080 mg/dL versus placebo (83). Fluvastatin lowered low-density lipoprotein (LDL) cholesterol by 32%. The fluvastatin- treated patients had a 35% reduction in the incidence of cardiac death or nonfatal acute myocardial infarction (84). Figure 1 shows the Kaplan-Meier curves for CVD event rates between the study groups. In concert with the modified guidelines of the Adult Treatment Panel III, kidney transplant recipients should be considered as a high-risk group for ini- tiation of lipid-lowering treatment and treatment goals. The recommendation of the NKF Working Group on the man- agement of dyslipidemia in kidney transplant recipients (Ta- ble 2) are consistent with the ATP III Panel guidelines and its recent modifications (85, 86). The NKF working group rec- ommendations was based on the most comprehensive evalu- ation of evidence available in the literature and expert opin- ions and should be considered as main guidelines for clinical management of dyslipidemia in the kidney transplantation population. The NKF recommendations cautions against the use of bile acid sequestrants because of potential interference with the absorption of immunosuppressive drugs. When bile acid sequestrants are used as adjunctive therapy, it should be administered one hour before to four hours after the dose of calcineurin inhibitors (85). The safety of statins in organ re- cipients receiving calcinuerin inhibitors and other drugs me- tabolized in the P450 system is well documented (83, 8791). Ezetimibe is a newadjunctive agent for lowering LDL choles- terol that was found to be safe and effective and safe in kidney transplant recipients in one study of 40 stable kidney trans- plant recipients (92). Renal Allograft Dysfunction DiminishedGFRis anindependent risk for CVDevents (9395). A 10 ml/min/1.73 m 2 decrease in GFR is associated with a 610% increase in the risk of a CVD event (93, 95). This observation is similarly true in renal transplant recipi- ents (21, 23, 96). Table 3 shows the relationship betweenbase- line renal allograft function and the risk of CVD event in kidney transplant recipients in the ALERT study. Strategies designed to preserve renal allograft functionare likely to ame- liorate the risk of de novo or recurrent cardiovascular events. Anemia It is well established that anemia worsens the severity of many CVD disorders (congestive heart failure coronary ar- tery disease and peripheral vascular disease) in the general population, in patients with chronic kidney disease, and evidence now showsin kidney transplant recipients (97 99). Anemia is a common problem in kidney transplant recipients (100102) and it is an independent risk factor for posttransplant LVH and CVD events (98). Cardiovas- cular events (myocardial infarction, cardiovascular death, angina, congestive heart failure) is 35% less likely (RR0.65, P0.022) in the first six months after transplantation in dia- betic transplant recipients with hematocrit 30% compared to those with lower hematocrit levels (103). Single-center and large multi-institutional studies report anemia prevalence of 3040% at various times after transplantation (101, 104, 105). The Transplant European Survey on Anemia Manage- ment (TRESAM) survey found a prevalence rate of 38.6% in 4263 kidney transplant recipients from 72 European centers FIGURE 1. From Andany et al (78). Mean (95% con- fidence interval) levels of total cholesterol (TC), LDL- cholesterol, HDL-cholesterol and triglycerides (TG, all in mmol/L) during the study follow-up period. Placebo (square) and fluvastatin (circle) groups. TABLE 2. Management of dyslipidemia in adult kidney transplant recipients (86) Dyslipidemia Goal Initiate Increase Alternative TG 500 mg/dL TG 500 mg/dL TLC TLC Fibrate or niacin Fibrate or niacin LDL 100129 mg/dL LDL 100 mg/dL TLC TLC low dose statin Bile acid seq. or niacin LDL 130 mg/dL LDL 100 mg/dL TLC low dose statin TLC max. dose statin Bile acid seq. or niacin TG 200 mg/dL and non-HDL 130 mg/dL Non-HDL 130 mg/dL TLC low dose statin TLC max. dose statin Fibrate or niacin To convert mg/dL to mmol/L, multiply triglycerides by 0.01129 and cholesterol by 0.02586. TG, triglycerides; LDL, low-density lipoprotein cholesterol; TLC, therapeutic lifestyle changes; seq., sequestrant; max., maximum. 2006 Lippincott Williams & Wilkins 605 Ojo (100). The high prevalence of posttransplant anemia can- not be attributed to to uncorrected pretransplant anemia of CKD as the prevalence five years after kidney transplan- tation range from 3035% in recipients with functioning allograft (104). The etiology of posttransplant anemia is multifactorial: female gender; calcineurin inhibitors, azathioprine, myco- phenolate mofetil, sirolimus; poor graft function; older age group; acute rejection episodes; iron, folate, and vitamin B12 deficiency; recent infection; and angiotensin (II) interrupting drugs (100, 104, 106, 107). The management of posttransplant anemia appears to be suboptimal despite the fact that the major causes of posttransplant anemia are remediable and the availability of recombinant Human Erythropoietin (rHuEPO) as an effective drug therapy. According to studies, only 36% of anemic transplant recipients (Hct 30%) un- dergo iron studies and less than half of anemic patients are receiving iron supplementation or rHuEPO (107). Al- though a significant fraction of posttransplant anemia cases are due to persistent iron deficiency and immunosuppressive drug therapy, up to one third of anemia cases in kidney recip- ients living in developing countries have macrocytic anemia due to folate and vitamin B12 deficiencies (106). Because of the link between CVD and posttransplant anemia, effective management of anemia with supplementation of iron, folate, vitamin B12, and rHuEPO when indicated is likely to have a salutary effect on posttransplant CVD. However, caution is warranted against liberal use of rHuEPO. In kidney trans- plant recipients with anemia, the use of rHuEPO shortened the time to achieve target hematocrit but did not have a sig- nificant impact on the achieved level of hematocrit compared to non-rHuEPO treated randomized controls (108) and ran- domized clinical trials in anemic patients with chronic kidney disease but without kidney transplantation did not demon- strate improvement in LVH with rHUEPO therapy (109). Thus, epidemiologic association between LVH and anemia may not translate into direct benefits inthis conditionfollow- ing successful treatment of anemia. For these reasons, pro- spective intervention studies of posttransplant anemia man- agement would be invaluable to determine the optimal use of rHuEPO and the potential benefits of anemia treatment on posttransplant CVD. The role of particularly aggressive pre- ventative management of posttransplant anemia should also be tested in high-risk groups such as diabetics and those un- willing to receive blood transfusions (103, 110). Hyperhomocysteinemia, Inflammatory Cytokines, and CD4 Lymphopenia In parallel with the prevalence of diminished GFR, mod- erate hyperhomocysteinemia is prevalent in kidney transplant recipients (25, 28, 111113). Homocysteine is an atherogenic amino acid that is associated with increased risk of ischemic heart disease. Several studies have documented that moderate hyperhomocysteinemia is anindependent riskfactor for CVDin renal transplant recipients inwhomthe riskof CVDincreasedby 6%for every 1 mol/L increase in total homocysteine level (24, 28, 114). The etiology of hyperhomocysteinemia in renal trans- plant recipients is not well understood but there is an inverse relationship between renal allograft function and serumhomo- cysteine levels (111). Supraphysiologic doses of B-vitamins can reduce hyperhomocysteinemia in kidney recipients but it is unclear whether reduction in serum homocysteine concentra- tionis accompaniedby a reductioninCVDrates (115, 116). The Folic Acid for Vascular Outcome Reduction in Renal Trans- plantation study (FAVORIT) is an ongoing clinical trial of 3,000 renal transplant recipients with moderate hyperhomo- cysteinanemia that should provide a definitive evidence of potential benefit of CVD reduction with supraphysiologic doses of vitamin B6 and folic acids in this population. Until the results of FAVORIT become available in 2008, there is no basis to treat moderate hyperhomocysteinemia with B-vitamins as a means to reduce the risk of CVD. Elevated serum concentrations of C-reactive protein and sialic acid are independently associated with increased risk of CVDevents, all-cause mortality, and cardiac mortality in kidney transplant recipients (26, 117). Bakri et al. found significantly higher serum concentrations of sialic acid, C- reactive protein, and fibrinogen in kidney recipients with CVD compared to those without CVD (117). Single-center retrospective studies performed by Varagunamet al. revealed that elevated levels of C-reactive protein was the single most important predictor of CVD mortality in a series of 115 renal transplant recipients (26). In this series, CVD death are was 0%, 10%, and22%inkidney recipients withserumC-reactive protein concentrations of 0 to 5 mg/dL, 5 to 10 mg/dL, and 10 mg/dL, respectively (P0.05). These findings are con- sistent with recent studies in the general population showing C-reactive protein and other inflammatory markers as robust biomarkers andpredictors of ischemic heart disease (27, 118). Although specific therapies to lower the serum levels of in- flammatory markers are not yet warranted for preventing CVD, lowering of serumconcentrations of C-reactive protein in patients treated with statin for hyperlipidemia is associated with an independent beneficial effect on the risk of CVD events (119). Evidence in HIV patients indicate that intense immu- nodeficiency states may accelerate atherosclerosis and data from experimental studies suggest that impairment in T-cell mediated immunity may contribute to the development and progression of atherosclerosis (120, 121). Transplant registry data showed an increased risk of cardiovascular death in renal transplant recipients treated with T-cell depleting polyclonal antithymocyte globulins (122). Dulcoux et al. examined the relationship between peripheral CD4 cell counts and TABLE 3. Incidences of the endpoints in 1,052 placebo- treated patients divided into quartiles on the basis of their baseline creatinine levels (mol/L) (21) First (%) Second (%) Third (%) Fourth (%) Serum creatinine (mol/L) 111 111134 134167 167 Major adverse cardiac event 11.5 12.1 11.6 16.0 Cardiac death 4.2 5.1 3.5 8.0 Noncardiovascular death 5.4 5.1 4.3 10.1 All-cause mortality 11.2 10.9 8.5 22.7 P values have been calculated using univariate Cox regression. 606 Transplantation Volume 82, Number 5, September 15, 2006 atherosclerotic events in 302 renal transplant recipients and found a linear increase in the risk of CVD events with decreasing CD4 cell count (123). Multivariate analysis confirmed that CD4 lymphopenia is an independent risk factor for cardiovascular complications in renal transplant recipients. If these findings are confirmed in larger studies, the use of immunosuppressive drugs with prolonged T-cell depletion may warrant a reassessment of the risk-benefit profile of these agents. Posttransplant Diabetes Mellitus Diabetes mellitus is a major cause of premature athero- sclerosis and increased CVD morbidity and mortality. New- onset insulin resistance and chronic hyperglycemia requiring treatment with insulin and/or oral hypoglycemic agents is a common complication affecting 25% of renal transplant re- cipients (22, 79, 124). A plethora of studies have shown that kidney transplant recipients who develop posttransplant dia- betes mellitus (PTDM) are at two- to threefold increased of fatal and nonfatal CVD events (13, 22, 75, 125127). Risk factors for development of PTDM include African American race, posttransplant weight gain, hepatitis C infection, cal- cineurin inhibitors, glucocorticoid therapy, and hypertension (22, 79, 128). Tacrolimus is significantly more diabetogenic compared to cyclosporine with PTDM developing in 20% of tacrolimus-treated patients compared to 4%in cyclosporine- treated patients (129). African Americans treated with ta- crolimus have a 39%risk of PTDMinthe first three years after transplantation (130, 131). Because many of the risk factors for PTDM are modifi- able, excess CVD due to PTDM can be mitigated by: 1) early diagnosis and treatment with periodic screening of recipients using fasting serum glucose; 2) behavior management to mini- mize posttransplant weight gain; 3) use of steroidavoidance reg- imeninpatients whoare at increasedriskof PTDM; 4) judicious calcineurin inhibitor minimization and use of calcineurin-free regimen; 5) aggressive glycemic control including the of multi- drug hypoglycemic regimen; and 6) periodic surveillance for CVDin patients with PTDMusing appropriate cardiac imaging and exercise modalities. Proteinuria Proteinuria is prevalent in 2040% of kidney trans- plant recipients with a functioning allograft (132, 133). It is nowwell established that abnormal urinary protein excretion is an independent risk factor for ischemic heart disease in bothdiabetic andnondiabetic populations (134136). Epide- miologic studies implicate proteinuria as a more potent pre- dictor of CVD compared to hypertension, hyperlipidemia, and male gender (134). Several studies directly implicate pro- teinuria as an independent predictor of cardiovascular death in renal transplant recipients (132, 137, 138). Roodnat et al. found a twofold risk of death in renal transplant recipients with functioning graft and proteinuria compared to recipi- ents without proteinuria (137). The 10-year risk of posttrans- plant CVDis 39.4%vs. 20.9%(P0.001) in proteinuric renal transplant recipients compared to those without proteinuria (29). Table 4 shows the prevalence of posttransplant CVD by proteinuria status (29). Proteinuria appears to be a biomarker of systemic endothelial dysfunction inherent to the atheroscle- rotic process (139). Angiotensin converting enzyme inhibitors and ARBproduce significant reduction in proteinuria in kidney transplant recipients (67, 140), and the inclusion of these agents in the antihypertensive regimen of transplant recipients may be beneficial beyond blood pressure reduction alone. Other Risk Factors Left ventricular hypertrophy is present in 5070% of kidney transplant recipients and is associated with increased risk of CVD events (141, 142). Obesity is a potent risk factor for CVD event and death in kidney transplant recipients (16, 71). An increasing fraction of patients on the kidney trans- plant waiting list have body mass index (BMI) 30. The average weight gain in the first transplant year posttransplan- tation range from 2230 pounds with a threefold increase in the fraction of recipients who attained BMI 30 (from 10% pretransplant to 30%) (143). Comprehensive weight reduc- tion program should be undertaken when excessive weight gain is observed in the posttransplant period as data shows an independent increased risk of both glucose intolerance and cardiovascular disease in recipients with high BMI (124, 144). High pulse pressure is an independent risk factor for CVD morbidity and mortality (145). Atherothrombotic lesions are more likely in patients with pretransplant hypercoagulable states (146). Approximately 28%kidney transplant recipients have antiphospholipid antibodies (APA) (7). Kidney trans- plant recipients with APAhave a 33%risk of a CVDevent com- pared to 9% in kidney recipients without APA (P0.0003, RR 2.82) (7, 147) It is prudent to include screening for APA and other hypercoagulable states as part of the diagnosis and man- agement of CVD in the posttransplant period. Ambulatory blood pressure monitoring may provide insight into the diurnal variability and efficacy of antihypertensive regimen but there are no specific indications for its use in the renal transplant population (148150). Secondary Prevention Results of coronary revascularization procedures in kidney transplant recipients with ischemic heart disease are comparable to that of the general population, although long-term results appear to favor surgical revasculariza- tion (151, 152). In a report on 83 kidney transplant recipi- ents who underwent percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG), Ferguson et al. found actuarial patient survival of 89%, 77%, and 65% at one, three, and five years with graft loss or wors- ening of renal function after the procedure (151). In this se- ries, two patients lost their graft due to chronic rejection 16 TABLE 4. Prevalence of cardiovascular disease according to the presence of proteinuria in kidney transplant recipients in recipients without pretransplant CVD (29) RTR with proteinuria RTR without proteinuria P value Posttransplant CVD 35.3.4% 14.6 0.001 Mean time a (years) 4.284.3 3.53.23 NS RTR renal transplant recipients. a Mean time SD from transplantation to the development of a cardio- vascular event. 2006 Lippincott Williams & Wilkins 607 Ojo and 19 months after PTCA (151). Among 31 kidney recipi- ents who underwent CABGin Hannover, Germany, early (30 days) postoperative mortality was low(3%, one patient death due to necrotizing enterocolitis) and there was no perioperative impairment ingraft functionor graft loss (153). Incontrast, of 13 kidney transplant recipients who underwent cardiac operations (mostly CABG) in a series from Pittsburgh, seven patients (54%) developed postoperative acute renal failure and three patients (23%) did not recover graft function but the overall early andlate mortality inthis groupwas also low(154). Thus, coronary revascularization in kidney transplant recipients appears to confer significant patient survival benefits with minimal risk to the allograft in most series. Conclusion More than 7580% of kidney transplant recipients have one or more cardiovascular risk factors. Cardiovascular events develop at annual rate of 3.5% to 5%, putting kidney recipients at a 50-fold excess compared to the general population. Treat- ment guidelines for the management of CVDrisk factors should be incorporated at a programmatic level into the long-termcare of kidney transplant recipients. Multidimensional strategies aimed at preserving good allograft function should also been seen as preventative treatment for cardiovascular disease. Statins, ezetimibe, calcium channel blockers angiotensin recep- tor blockade, andthiazolidine are safe andeffective intransplant recipients and should be used for the same indication as in the general population. Management of posttransplant anemia is suboptimal in most series despite a strong link between CVD and anemia. Additional studies of lipid lowering therapy are needed to address questions not yet answered by the ALERT study. Management of novel risk factors such as elevated serum C-reactive proteinandhyperhomocysteinemia shouldawait ad- ditional data from ongoing clinical trials, although lifestyle changes shown to have beneficial effect on these novel risk fac- tors should be adopted. Coronary revascularization procedures confer survival benefits in kidney transplant recipients with low risk of impairment in allograft function. 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Decreased renal function is a strong risk factor for cardiovascular death after renal transplantation. Transplantation 2003; 75(8): 1291. 24. Massy ZA, Chadefaux-Vekemans B, Chevalier A, et al. Hyperhomocys- teinaemia: a significant risk factor for cardiovascular disease in renal transplant recipients. Nephrol Dial Transplant 1994; 9(8): 1103. 25. Ducloux D, Ruedin C, Gibey R, et al. Prevalence, determinants, and clinical significance of hyperhomocyst(e) inaemia in renal-transplant recipients. Nephrol Dial Transplant 1998; 13(11): 2890. 26. Varagunam M, Finney H, Trevitt R, et al. Pretransplantation levels of C-reactive protein predict all-cause and cardiovascular mortality, but not graft outcome, in kidney transplant recipients. Am J Kidney Dis 2004; 43(3): 502. 27. Pai JK, Pischon T, Ma J, et al. Inflammatory Markers and the Risk of Coronary Heart Disease in Men and Women. N Engl J Med 2004; 351(25): 2599. 28. Franke S, Muller A, Sommer M, et al. 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Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and ne- phropathy. N Engl J Med 2001; 345(12): 861. 60. Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized con- trolled trial. JAMA 2001; 285(21): 2719. 61. Wright JT Jr., Bakris G, Greene T, et al. Effect of blood pressure lower- ing and antihypertensive drug class on progression of hypertensive kid- ney disease: results from the AASK trial. JAMA 2002; 288(19): 2421. 62. Bakris G, Weir M, DeQuattro V, McMahon F. Effects of an ACE inhib- itor/calcium antagonist combination on proteinuria in diabetic ne- phropathy. Kidney Int 1998; 54: 1283. 63. Smith AC, Toto R, Bakris GL. Differential effects of calcium channel blockers on size selectivity of proteinuria in diabetic glomerulopathy. Kidney International 1998; 54: 889. 64. Omoto K, Tanabe K, Tokumoto T, et al. Use of candesartan cilexetil decreases proteinuria in renal transplant patients with chronic allograft dysfunction. Transplantation 2003; 76(8): 1170. 65. Inigo P, Campistol JM, Saracho R, et al. Renoprotective effects of lo- sartan in renal transplant recipients. Results of a retrospective study. Nephron Clin Pract 2003; 95(3): c84. 66. del Castillo D, Campistol JM, Guirado L, et al. Efficacy and safety of losartan in the treatment of hypertension in renal transplant recipients. Kidney Int 1998; 68: S135. 67. Campistol JM, Inigo P, Jimenez W, et al. Losartan decreases plasma levels of TGF-beta1 in transplant patients with chronic allograft ne- phropathy. Kidney Int 1999; 56(2): 714. 68. Houston MC. ALLHAT debate: diuretics are not preferred, first-line initial therapy for hypertension. Arch Intern Med 2004; 164(5): 570. 69. Kasiske BL, Vazquez MA, HarmonWE, et al. Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation. 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Enhancing Provider Education and Improving Healthcare Disparities in Chronic Myeloid Leukemia (CML) and Multiple Myeloma (MM) Through A Rural Regional North Carolina Hospital Network