Clin J Am Soc Nephrol 3: S29-S37, 2008
© 2008 American Society of Nephrology
doi: 10.2215/CJN.02690707
Cardiovascular Disease in Transplant Recipients: Current and Future Treatment Strategies
John S. Gill
Division of Nephrology, University of British Columbia, St. Paul’s Hospital, Vancouver, British Columbia, Canada
Correspondence: Dr. John S. Gill, Division of Nephrology, University of British Columbia, St. Paul’s Hospital, Providence Building, Ward 6a, 1081 Burrard Street, Vancouver, BC, Canada, V6Z 1Y6. Phone: 604-806-9048; Fax: 604-806-8076; E-mail: jgill{at}providencehealth.bc.ca
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Abstract
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A cardiovascular disease event in a transplant recipient may be the result of a pretransplantation disease process, a direct effect of immunosuppressant medications, or the result of exposure to a variety of traditional and nontraditional risk factors after transplantation. Although the understanding of posttransplantation cardiovascular disease remains incomplete, there is evidence that the impact of posttransplantation cardiovascular disease has been decreased, through increased attention to this problem. In the absence of controlled studies to guide therapy, this review summarizes treatment of cardiovascular disease risk factors for which there is strong evidence of benefit in the nontransplantation setting, observational evidence of a similar risk in transplant recipients, and evidence that treatment can be safely administered to transplant recipients. Putative risk factors for posttransplantation cardiovascular disease for which the current level of evidence is insufficient to support specific treatment recommendations are also discussed. Potential new strategies to decrease the risk for cardiovascular disease events after transplantation in the future, including aggressive pretransplantation risk reduction, individualized treatments to prevent different types of cardiovascular disease, dedicated efforts to reduce cardiovascular disease events during transitions between dialysis and transplantation, and manipulation of immunosuppressant protocols, are also introduced.
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Introduction
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Although increased awareness of cardiovascular disease (CVD) has resulted in a reduction in CVD-related deaths over time (1,2), CVD remains the major known cause of death in transplant recipients (3) and is a significant barrier to improving long-term outcomes in kidney transplantation. The high risk for CVD in transplant recipients is in part explained by the high prevalence of conventional CVD risk factors (e.g., diabetes, hypertension, dyslipidemia) in this patient population; however, a significant portion of CVD risk in transplant recipients is unexplained by these factors (4) and may be related to pretransplantation exposure to chronic kidney disease (CKD)-related risk factors, ongoing exposure to CKD-related risk factors as a result of impaired allograft function, or to transplant-specific risk factors including those related to the use of immunosuppressant medications or infection. Given the relative absence of randomized, controlled trials in transplant recipients, this review summarizes treatments for which there is strong evidence of benefit in the nontransplantation setting, observational evidence of a similar risk in transplant recipients, and evidence that treatment can be safely administered to transplant recipients. The review also summarizes putative risk factors for posttransplantation CVD, for which the current level of evidence is insufficient to support specific treatment recommendations. Finally, the review introduces new strategies to decrease the risk for CVD events after transplantation.
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Definitions and Approach
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There are two major and overlapping categories of CVD: (1) Disorders of cardiovascular perfusion including atherosclerotic CVD (ischemic heart disease [IHD], cerebrovascular disease, and peripheral vascular disease) and (2) disorders of cardiac function including congestive heart failure (CHF) and left ventricular hypertrophy. Whereas some risk factors are unique to each type of CVD, many risk factors are common to the various types of CVD. Because our understanding of the relative contribution of individual risk factors to the different types of CVD is limited, no attempt to define specific treatment strategies for the different types of CVD is made in this review.
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CVD Risk Factors for Which There Is an Evidentiary Basis for Treatment
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Hypertension
Hypertension (HTN), defined as a systemic BP >140/90 (5), is prevalent in >70% of transplant recipients (6). HTN is a risk factor for allograft failure, death with a functioning allograft, atherosclerotic CVD, and disorders of cardiac function. The pathogenesis of HTN in transplant recipients is linked to pretransplant factors including pretransplant HTN, the type of primary kidney disease, and excess renin output from native kidneys. Posttransplantation factors include the quality of the donor organ, delayed graft function, acute rejection, transplant renal artery stenosis, the level of allograft function (GFR), chronic immune and nonimmune injury, recurrent or de novo glomerulonephritis in the allograft, and excessive weight gain (6,7). Both calcineurin inhibitors (CNI) and glucocorticoids contribute to HTN. HTN was significantly lower before the introduction of CNI (8,9). CNI cause afferent arteriolar vasoconstriction by sympathetic stimulation and by upregulation of the local renin-angiotensin-aldosterone system. (10,11) CNI also decrease vasodilator prostaglandins and nitric oxide and increase vasoconstrictor cytokines (12,13). Glucocorticoids contribute to HTN by causing sodium and water retention.
There are no randomized, controlled trials of antihypertensive drugs or optimal BP goals in transplant recipients. On the basis of large clinical trials in nontransplantation patients with and without kidney disease, the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines recommend BP goals of 125/75 mmHg for transplant recipients with proteinuria and 130/85 in the absence of proteinuria (14). Treatment should include nonpharmacologic interventions, but simultaneous initiation of nonpharmacologic and pharmacologic treatment should be considered when the BP is 
15 mmHg higher than target (15). Weight reduction, exercise, and dietary sodium restriction are the main nonpharmacologic considerations (5). Pharmacologic management should consider the potential for drug interactions; drug efficacy; and coexisting factors, including diabetes, IHD, CHF, and proteinuria. Specific indications such as proteinuria or a preexisting history of CVD may warrant the use of angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARB), or β blockers as initial agents (16). Loop diuretics should be used in the presence of fluid retention and may be particularly useful in the early posttransplantation period or when allograft function is reduced.
Dihydropyridine calcium channel blockers (DHP-CCB) are widely used because they counteract the vasoconstrictive effects of CNI (17). DHP-CCB were unexpectedly associated with an increased risk for IHD in a single-center, retrospective analysis (4). The use of DHP-CCB in proteinuric patients with CKD is associated with an increased risk for kidney function decline and death unless used with ARB (18–20). The mechanism for the potential adverse effect of DHP-CCB is not clear, however; these drugs are associated with increased catecholamine levels (21). Of note, the long-term CVD risk in patients who were treated with DHP-CCB was similar to that in patients who were treated with ACEi and diuretics in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (22). Non-DHP-CCB are used frequently in the early posttransplantation period because they also prevent renal vasoconstriction. CNI dosage reduction is required with the use of these agents. When used with ACEi, non-DHP-CCB have a synergistic antiproteinuric effect (23).
ACEi and ARB have well-documented antiproteinuric and cardioprotective effects. Use of these drugs may be complicated by hyperkalemia and anemia. A >30% reduction in kidney function should trigger suspicion of transplant renal artery stenosis (24–27). A recent systematic review concluded that ACEi and ARB were associated with a clinically significant reduction in proteinuria, GFR, and hematocrit, but there was insufficient evidence to determine the effect of these agents on patient or graft survival (28). A Canadian multicenter, randomized, controlled trial to determine the impact of ramipril on allograft function is ongoing (29).
Dyslipidemia
Dyslipidemia is present in 50 to 60% of kidney transplant recipients (30). Table 1 summarizes the current thresholds for the diagnosis of dyslipidemia as defined by the KDOQI guidelines (30). Dyslipidemia is strongly associated with atherosclerotic CVD in CKD and non-CKD populations (30,31).
Dyslipidemia is clearly linked to the use of corticosteroids, CNI, and sirolimus. Compared with cyclosporine, tacrolimus has been associated with better lipid profiles, whereas sirolimus has been associated with a greater incidence and severity of dyslipidemia. Other factors that contribute to dyslipidemia include weight gain, decreased kidney function, proteinuria, β blockers, and diuretics (32).
The KDOQI guidelines recommend that all adult and adolescent transplant recipients be tested for dyslipidemia (complete fasting lipid profile including total cholesterol, LDL, HDL, and triglycerides) (30). Testing should be done when patients are stable after transplantation and at least annually thereafter. In addition, testing should be done 2 to 3 mo after a change in immunosuppressant medications or conditions that are known to cause dyslipidemia (e.g., change in proteinuria or GFR).
The Assessment of Lescol in Renal Transplantation (ALERT) study randomly assigned 2102 prevalent transplant recipients with total cholesterol 4.0 to 9.0 mmol/L to fluvastatin 40 to 80 mg/d versus placebo (33). Fluvastatin lowered LDL cholesterol by 32%. The primary composite end point (cardiac death, nonfatal myocardial infarction, or coronary revascularization) was not different between the treatment and control groups; however, there was a significant difference in cardiac death and nonfatal myocardial infarction. Further analyses demonstrated that earlier initiation of therapy resulted in a greater reduction in CVD events. Patients who enrolled in ALERT within the first 4 yr of transplantation had a 64% risk reduction compared with 19% in patients who received a transplant 10 yr before enrollment.
Key differences between the KDOQI recommendations for treatment of dyslipidemia in transplant recipients (30) and the Adult Treatment Panel III (ATP III) (31) guidelines written for the general population are the inclusion of transplant recipients in the highest risk category for treatment, the requirement for at least annual evaluation for dyslipidemia (versus every 5 yr in ATP III), initiation of pharmacologic treatment at lower thresholds (drug therapy to treat an LDL of 100 to 129 mg/dl after 3 mo of lifestyle and dietary modifications), the use of statins as the initial pharmacologic treatment, and recommendations for patients who are younger than 20 yr (there is no recommendation for treatment of patients who are younger than 20 yr in ATP III).
The use of statins in the presence of CNI can lead to a significant increase in statin blood levels and increased risk for rhabdomyolysis. Recommended dosages specific for transplant recipients are available (30), and monitoring of creatinine phosphokinase levels may be prudent. Bile acid sequestrants may interfere with absorption of immunosuppressant drugs. When used, these drugs should be taken 1 h before or 4 h after a CNI. Ezetimibe blocks intestinal absorption of dietary cholesterol and is a useful adjuvant to statin therapy. No reports of interactions between ezetimibe, CNI, or sirolimus have been published.
New-Onset Diabetes
The reported incidence of new-onset diabetes (NOD) is highly variable and may be related to the variable criteria used define NOD in the literature. Despite the probable high incidence of NOD, patients may not be routinely screened and the incidence of NOD may be underestimated. Similar to mature-onset diabetes in the nontransplantation setting, patients who develop NOD can have glucose intolerance and may be asymptomatic for years before diagnosis. NOD may not be permanent, and glucose abnormalities may normalize without treatment, thereby making the condition difficult to diagnose. NOD seems to develop in two patterns: It either appears abruptly during the first 6 mo after transplantation or slowly develops over years (coincident with aging). For example, in a study of >2000 transplant recipients, the cumulative incidence of NOD was 5.9% at 6 mo and 7.1, 10.4, 13.2, 20.5, and 29.8% at 1, 3, 5, 10, and 15 yrs.
NOD has been associated with both allograft loss and death with a functioning allograft (35,36). A number of studies have shown that patients who develop NOD have a two to three times increased risk for fatal and nonfatal CVD events (37,38). Risk factors for development of NOD include transplantation from a deceased donor, older age, male gender, family history of diabetes, black race, Hispanic ethnicity, obesity, posttransplantation weight gain, hypertriglyceridemia, low HDL, hypertension, hyperuricemia, hepatitis C infection, CNI, glucocorticoids, and possibly sirolimus (36,39,40). Tacrolimus is associated with an increased risk for NOD compared with cyclosporine, and this risk may be magnified in black patients (41).
Published guidelines recommend that NOD be defined according to current American Diabetes Association and World Health Organization criteria (42). A complete history to identify risk factors for NOD before transplantation should be performed and used to individualize therapy to reduce the risk for NOD. Patients should also be screened for metabolic syndrome before transplantation (increased waist circumference, hypertriglyceridemia, low HDL, BP >130/85, and serum glucose of at least 110 mg/dl or 6.1 mmol) because this syndrome is associated with an increased risk for diabetes and CVD. Fasting plasma glucose should be monitored routinely after transplantation according to the following schedule: At least weekly during the first posttransplantation month; at 3, 6, and 12 mo; and then annually. Plasma glucose should also be randomly monitored at regular intervals. Oral glucose tolerance tests may be more predictive of CVD events than fasting plasma glucose, particularly in patients with impaired glucose tolerance. The 2003 international consensus guidelines recommend a stepwise approach to treatment unless patients develop symptomatic hyperglycemia or ketosis, in which case insulin monotherapy is required (42). The first step is nonpharmacologic therapy including lifestyle modification and patient education. In patients who require pharmacologic therapy, monotherapy with an oral agent (
glucoside reductase inhibitor, biguanides, meglitinides, sulfonylureas, and thiazolidinediones) is recommended. The choice of agent depends on individual patient needs, comorbid conditions, and safety considerations. In patients with impaired kidney function, the risk for lactic acidosis with metformin and for hypoglycemia with sulfonylureas are important considerations. Elderly patients may be at increased risk for hypoglycemia and should be treated initially with lower dosages of oral agents. Patients whose NOD does not respond to oral monotherapy can be treated with combined use of oral agents; no one combination of medications is more efficacious, and combinations should be tailored to individual patient needs. Failure of combination therapy requires insulin therapy, either alone or with combined use of oral agents. Co-administration of rosiglitazone and insulin is not recommended. Patients who require insulin should be referred to an endocrinologist.
Cigarette Smoking
Smoking clearly increases the risk for CVD death in kidney transplant recipients, and there is evidence that the smoking-related risk for death dissipates 5 yr after smoking cessation (43). Transplantation represents an opportunity to initiate smoking cessation successfully. The combined use of pharmacologic and nonpharmacologic strategies may be most effective, and there are no significant interactions between the commonly used drugs for smoking cessation and immunosuppressant medications.
Obesity
Obesity is a frequent posttransplantation complication. An analysis of US Renal Data System data showed that a surprising 60% of American transplant recipients between 1987 and 2001 were overweight or obese at the time of transplantation (44). Obesity is an established risk factor for atherosclerotic heart disease, and obesity increases the risk for diabetes, dyslipidemia, and hypertension. The risk for obesity is increased in steroid-treated patients. Removal of dietary restrictions after transplantation and physical inactivity are other important contributors to posttransplantation obesity.
Management of posttransplantation obesity includes lifestyle and dietary modifications. Rapid steroid elimination or steroid avoidance protocols are associated with a lower incidence of obesity (45,46). The benefit of late steroid withdrawal (3 mo after transplantation) on weight gain is less clear (47). The potential benefit of steroid reduction or withdrawal must be balanced against the risk for allograft rejection. There is limited experience with pharmacologic agents to promote weight loss in transplant recipients. The published experience with bariatric surgery in transplant recipients is limited; both gastric bypass surgery (48) and laparoscopic gastric banding (49) have been used to treat obesity in transplant recipients.
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CVD Risk Factors for Which There Is Insufficient Evidence for Treatment
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Proteinuria
Proteinuria is prevalent in 20 to 40% of transplant recipients (50,51). The evidence to treat proteinuria specifically to reduce CVD risk is lacking. Proteinuria is believed to be a marker of endothelial dysfunction, and there are ample observational data showing that proteinuria is clearly associated with an increased risk for CVD in transplant and nontransplant patients (51–53); however, there are limited data from controlled studies demonstrating that treatment of proteinuria decreases the risk for CVD (54). Controlled trials in the nontransplantation setting clearly demonstrate that proteinuria reduction is renoprotective; therefore, there is a stronger rationale to treat proteinuria to preserve allograft function. To date, no controlled trials in transplant recipients have demonstrated that proteinuria reduction preserves allograft function.
Anemia
The recent KDOQI guidelines on anemia management contain a dedicated discussion of posttransplantation anemia (55). Although anemia is associated with CVD in both transplant and nontransplant patients (56–58), there is no clear evidence that correction of anemia reduces the risk for CVD events. The main proven benefit of anemia treatment with erythropoiesis-stimulating agents in dialysis-treated and non–dialysis-treated patients with CKD is avoidance of transfusions and improved quality of life (59). There are no controlled studies demonstrating improvement in CVD, quality of life, or the need for transfusions in transplant recipients. Prospective interventional studies are needed to define the benefits of anemia treatment on posttransplantation CVD and other clinically meaningful outcomes.
Hyperhomocysteinemia
Several studies have documented that hyperhomocysteinemia is an independent risk factor for CVD in transplant recipients (60). Controlled trials in the nontransplantation setting have shown no benefit to treatment of hyperhomocysteinemia (61). Results of the ongoing Folic Acid for Vascular Outcome Reduction in Renal Transplantation (FAVORIT) study will provide definitive evidence regarding the benefit of treatment in transplant recipients (62).
C-Reactive Protein
An elevated concentration of C-reactive protein (CRP) is independently associated with increased risk for CVD events in transplant recipients (63). This finding is consistent with studies in the general population demonstrating an association between CRP and ischemic heart disease. CRP levels were lowered with the use of statins, and this reduction in CRP was associated with a reduced risk for CVD independent of the lipid-lowering effect (64). Further studies are warranted to determine the role of targeted therapies to lower the levels of inflammatory markers to reduce CVD risk.
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Future Strategies to Decrease the Risk for CVD Events after Transplantation
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This remainder of this review focuses on new potential strategies to decrease the risk for CVD events after transplantation.
Aggressive Pretransplantation Management of CVD
The concept that posttransplantation CVD is in part due to pretransplantation exposures has gained momentum with the inclusion of kidney transplant recipients in the CKD classification (65,66). This issue has significant therapeutic implications. If pretransplantation exposures portend an increased risk for CVD after transplantation, then a paradigm shift in our current waiting list management strategy would be indicated to minimize the impact of uremia in the setting of increased waiting times for transplantation. Our current waiting list management strategies are focused on identifying and excluding from transplantation patients who are at high risk for posttransplantation complications or who develop contraindications to transplantation, and are not necessarily focused on prevention of CVD.
There is evidence to suggest that pretransplantation exposures have a significant impact on posttransplantation CVD risk. A number of observational studies have demonstrated that patients with either no or short durations of dialysis exposure before transplantation have a lower risk for death than patients with longer durations of pretransplantation dialysis exposure (67–70); however, these observations may be confounded by the fact that patients who are likely to do well after transplantation may also be more likely to obtain transplants more rapidly. For example, patients with strong social supports, favorable sociodemographic characteristics, and predialysis nephrology care may be more likely to receive preemptive transplants and to pursue transplantation as a treatment option (68,71–73).
In contrast, findings from other studies have shown that the rates of death and nonfatal CVD events decrease dramatically after transplantation and that this change seems to occur in patients with both short and long durations of pretransplantation dialysis exposure. One study demonstrated that transplantation seems to halt the progression of CVD (74). Another study demonstrated relatively similar death rates after transplantation among patients who received transplants with waiting times of <12, 12 to 24, and 24 to 36 mo duration (75). These findings are particularly noteworthy, because the death rate among transplant candidates who remained on the waiting list increased dramatically with waiting time.
For better understanding of the impact of pretransplantation exposures on posttransplantation outcomes, a better method to determine the pretransplantation CVD burden is needed. The duration of pretransplantation dialysis exposure is likely a poor indicator of the pretransplantation CVD burden. Patients who receive a transplant after long durations of dialysis exposure may represent a surviving population who have a low burden of CVD because they are biologically protected from developing disease for reasons that we do not understand. Similarly, reliance on a history of overt clinical events (e.g., myocardial infarction, stroke, CHF) before transplantation is likely inadequate if the physiologic changes that occur with uremia do not result in overt clinical events before transplantation. A number of studies have shown that physiologic abnormalities such as coronary calcification, left ventricular hypertrophy, impaired arterial compliance, abnormalities of diurnal BP rhythm, elevated markers of oxidative stress, systemic inflammation, and endothelial dysfunction (63,76–82) are prevalent in kidney transplant recipients. Further studies to determine the natural history of these abnormalities after transplantation and their association with posttransplantation events are needed.
Develop Specific Treatment Strategies for Different Types of CVD
As discussed previously, our understanding of the risk factors that contribute to the different forms of CVD is limited. Recent analyses from the US Renal Data System demonstrated significant differences in the risk for specific CVD events after transplantation (Figure 1) (83). For example, the rates of myocardial infarction and cerebrovascular disease seem to be only minimally increased in transplant recipients compared with Medicare recipients without a known diagnosis of CKD (Figure 1). In contrast, the rates of CHF and peripheral vascular disease were higher in transplant recipients (Figure 1). These findings are consistent with observations from a retrospective study of more than 600 Canadian transplant recipients that found the incidence of CHF to be significantly higher than that in the Framingham cohort, whereas the incidence of IHD was not different from that in Framingham, leading the authors to conclude that transplantation should be considered a "state of accelerated heart failure" (56). The observations clearly suggest the need to identify patients who are at risk for specific types of CVD and to identify unique disease-specific risk factors for therapeutic intervention.
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Figure 1. Cardiovascular disease event rates in adult dialysis (n = 191,278), transplant (n = 22,673), chronic kidney disease (CKD; n = 44,941), and non-CKD (n = 1378,122) Medicare-insured prevalent patients on January 1, 2002. Rates are adjusted for gender, race, and diabetes status. Adapted from reference (83), with permission.
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Intensified Surveillance and Risk Reduction during Transitions between Dialysis and Transplantation
Recent publications have emphasized that there seems to be a distinct time course during which CVD events develop after transplantation (84,85). Most fatal CVD events are clustered around the time of transplantation and during the return to dialysis after transplant failure (Figure 2). Between these transition periods, CVD events seem to be relatively infrequent and slowly progressive over time. These findings suggest the need for well-defined prophylactic strategies during these high-risk transition periods. Research is needed to understand better the mechanisms underlying the high CVD event rates during transitions between dialysis and transplantation. Increased inflammation during the peritransplantation period may lead to an increase in atherosclerotic disease events during this time. Alternatively, peritransplantation events may be related to rapid administration of large volumes of fluid to patients with abnormal ventricular function. Similarly, the high mortality in patients with transplant failure may in part be related to graft loss’s being a proximal event in the disease course of a dying patient. Alternatively, other mechanisms, such as sepsis, may precipitate CVD events in patients with transplant failure (86).
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Figure 2. Death rates among 89,2002 adult patients (>18 yr of age) who began dialysis treatment between April 1995 and December 2003 and who were subsequently activated to the kidney-only transplant waiting list. Event rates are shown for a period of 3 yr during three distinct time periods: (1) Wait-listing, (2) during allograft function, and (3) during dialysis after allograft failure. Adapted from reference (29), with permission.
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Individualized Use of Immunosuppressant Medications and Immunosuppressant Withdrawal Strategies
Immunosuppressant medications have variable effects on the incidence and severity of different CVD risk factors. This suggests that individualized use of immunosuppressant medications in patients may be useful in minimizing CVD risk. For example, patients who are at high risk for NOD could be identified before transplantation and treated with cyclosporine rather than tacrolimus or with a rapid steroid elimination protocol. There are a number of considerations with this approach. We do not have a clear understanding of the net impact of different immunosuppressant medications on CVD. Specifically, we do not know the relative importance of different CVD risk factors (e.g., is NOD more important than dyslipidemia?); neither do we understand all of the mechanisms by which immunosuppressant medications may increase CVD risk. To date, there is no clear evidence that any one immunosuppressant medication provides a survival advantage over another. Similarly, the metabolic benefits of rapid steroid elimination or CNI avoidance/reduction protocols must be weighed against the increased risk for acute rejection and uncertainty about the long-term safety of these regimens. Nonetheless, the increased availability of new immunosuppressant agents provides an important new opportunity to decrease CVD risk and should be further developed. New trials testing these strategies should use standardized methods and definitions to permit assessment of all relevant CVD risk factors. For example, diabetes should be defined using standardized criteria, and kidney function should be measured or estimated by an agreed-on standard method. Further long-term outcomes from these trials should be provided to determine the safety of these approaches.
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Conclusions
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Although we lack complete understanding of posttransplantation CVD, there is evidence that we have decreased the impact of CVD on transplant outcomes through increased attention to risk factor reduction. There is sufficient evidence to recommend aggressive treatment of traditional CVD risk factors (hypertension, dyslipidemia, diabetes, smoking, and obesity). There is less evidence to support treatment of nontraditional CVD risk factors, including anemia, hyperhomocysteinemia, and CRP. New strategies that may decrease posttransplantation CVD in the future include aggressive management of CVD risk factors before transplantation, identification of patients who are at risk for different types of CVD and treatment of unique disease-specific risk factors, increased attention to CVD risk reduction during transitions between dialysis and transplantation, and individualized use of immunosuppressant medications in patients with different CVD risk profiles or reduced exposure to immunosuppressant medications with the use of minimization or avoidance protocols.
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Disclosures
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None.
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Acknowledgments
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J.S.G. is funded by the Michael Smith Foundation for Health Research.
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References
|
|---|
- Meier-Kriesche HU, Ojo AO, Port FK, Arndorfer JA, Cibrik DM, Kaplan B: Survival improvement among patients with end-stage renal disease: Trends over time for transplant recipients and wait-listed patients.
J Am Soc Nephrol12
:1293
–1296,2001[Abstract/Free Full Text]
- ANZDATA Registry Report 2006: Australia and New Zealand Dialysis and Transplant Registry, Adelaide, South Australia,2006
- USRDS:
Annual Data Report: Atlas of End Stage Renal Disease in the United States, Bethesda, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases,2005
- Kasiske BL, Chakkera HA, Roel J: Explained and unexplained ischemic heart disease risk after renal transplantation: Epidemiology of cardiovascular disease after renal transplantation.
J Am Soc Nephrol11
:1735
–1743,2000[Abstract/Free Full Text]
- Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ: Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
Hypertension42
:1206
–1252,2004[CrossRef]
- Kasiske BL, Anjum S, Shah R, Skogen J, Kandaswamy C, Danielson B, O’Shaughnessy EA, Dahl DC, Silkensen JR, Sahadevan M, Snyder JJ: Hypertension after kidney transplantation.
Am J Kidney Dis43
:1071
–1081,2004[CrossRef][Medline]
- Cosio FG, Dillon JJ, Falkenhain ME, Tesi RJ, Henry ML, Elkhammas EA, Davies EA, Bumgardner GL, Ferguson RM: Racial differences in renal allograft survival: The role of systemic hypertension.
Kidney Int47
:1136
–1141,1995[Medline]
- First MR, Neylan JF, Rocher LL, Tejani A: Hypertension after renal transplantation.
J Am Soc Nephrol4[Suppl]
:S30
–S36,1994[Abstract]
- Curtis JJ: Cyclosporine and posttransplant hypertension.
J Am Soc Nephrol2[Suppl]
:S243
–S245,1992[Abstract]
- Bantle JP, Nath KA, Sutherland DE, Najarian JS, Ferris TF: Effects of cyclosporine on the renin-angiotensin-aldosterone system and potassium excretion in renal transplant recipients.
Arch Intern Med145
:505
–508,1985[Abstract/Free Full Text]
- Bennett WM: Insights into chronic cyclosporine nephrotoxicity.
Int J Clin Pharmacol Ther34
:515
–519,1996[Medline]
- Lanese DM, Conger JD: Effects of endothelin receptor antagonist on cyclosporine-induced vasoconstriction in isolated rat renal arterioles.
J Clin Invest91
:2144
–2149,1993[Medline]
- Zhang R, Leslie B, Boudreaux JP, Frey D, Reisin E: Hypertension after kidney transplantation: Impact, pathogenesis and therapy.
Am J Med Sci325
:202
–208,2003[CrossRef][Medline]
- Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, Tuttle K, Douglas J, Hsueh W, Sowers J: Preserving renal function in adults with hypertension and diabetes: A consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group.
Am J Kidney Dis36
:646
–661,2000[Medline]
- European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV. 5.2. Cardiovascular risks. Arterial hypertension.
Nephrol Dial Transplant17
:25
–26,2002[Abstract]
- Kasiske BL, Vazquez MA, Harmon WE, Brown RS, Danovitch GM, Gaston RS, Roth D, Scandling JD, Singer GG: Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation.
J Am Soc Nephrol11[Suppl 15]
:S1
–S86,2000
- Midtvedt K, Hartmann A, Foss A, Fauchald P, Nordal KP, Rootwelt K, Holdaas H: Sustained improvement of renal graft function for two years in hypertensive renal transplant recipients treated with nifedipine as compared to lisinopril.
Transplantation72
:1787
–1792,2001[CrossRef][Medline]
- Brenner B, Garcia D, Anderson S: Glomeruli and blood pressure, less of one, more of the other.
Am J Hypertens1
:335
–347,1988[Medline]
- Wright JT Jr, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, Cheek D, Douglas-Baltimore JG, Gassman J, Glassock R, Hebert L, Jamerson K, Lewis J, Phillips RA, Toto RD, Middleton JP, Rostand SG: Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: Results from the AASK trial.
JAMA288
:2421
–2431,2002[Abstract/Free Full Text]
- Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, Briggs JP, Charleston J, Cheek D, Cleveland W, Douglas JG, Douglas M, Dowie D, Faulkner M, Gabriel A, Gassman J, Greene T, Hall Y, Hebert L, Hiremath L, Jamerson K, Johnson CJ, Kopple J, Kusek J, Lash J, Lea J, Lewis JB, Lipkowitz M, Massry S, Middleton J, Miller ER 3rd, Norris K, O’Connor D, Ojo A, Phillips RA, Pogue V, Rahman M, Randall OS, Rostand S, Schulman G, Smith W, Thornley-Brown D, Tisher CC, Toto RD, Wright JT Jr, Xu S: Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: A randomized controlled trial.
JAMA285
:2719
–2728,2001[Abstract/Free Full Text]
- de Champlain J, Karas M, Nguyen P, Cartier P, Wistaff R, Toal CB, Nadeau R, Larochelle P: Different effects of nifedipine and amlodipine on circulating catecholamine levels in essential hypertensive patients.
J Hypertens16
:1357
–1369,1998[CrossRef][Medline]
- Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT Collaborative Research Group.
JAMA283
:1967
,2000[Abstract/Free Full Text]
- Bakris G, Weir M, DeQuatro V, McMahon F: Effects of ACE inhibitor/calcium antagonist combination on proteinuria in diabetic nephropathy.
Kidney Int54
:1283
–1289,1998[CrossRef][Medline]
- Omoto K, Tanabe K, Tokumoto T, Shimmura H, Ishida H, Toma H: Use of candesartan cilexetil decreases proteinuria in renal transplant patients with chronic allograft dysfunction.
Transplantation76
:1170
–1174,2003[CrossRef][Medline]
- Inigo P, Campistol JM, Saracho R, Del Castillo D, Anaya F, Esforzado N, Navarro MD, Oppenheimer F: Renoprotective effects of losartan in renal transplant recipients. Results of a retrospective study.
Nephron Clin Pract95
:c84
–c90,2003[CrossRef][Medline]
- Campistol JM, Inigo P, Jimenez W, Lario S, Clesca PH, Oppenheimer F, Rivera F: Losartan decreases plasma levels of TGF-beta1 in transplant patients with chronic allograft nephropathy.
Kidney Int56
:714
–719,1999[CrossRef][Medline]
- del Castillo D, Campistol JM, Guirado L, Capdevilla L, Martinez JG, Pereira P, Bravo J, Perez R: Efficacy and safety of losartan in the treatment of hypertension in renal transplant recipients.
Kidney Int Suppl68
:S135
–S139,1998[Medline]
- Hiremath S, Fergusson D, Doucette S, Mulay AV, Knoll GA: Renin angiotensin system blockade in kidney transplantation: A systematic review of the evidence.
Am J Transplant7
:2350
–2360,2007[CrossRef][Medline]
- Knoll GA, Cantarovitch M, Cole E, Gill J, Gourishankar S, Holland D, Kiberd B, Muirhead N, Prasad R, Tibbles LA, Treleaven D, Fergusson D: The Canadian ACE-inhibitor trial to improve renal outcomes and patient survival in kidney transplantation study design.
Nephrol Dial Transplant September 10, 2007 [epub ahead of print]
- Kasiske BL: Clinical practice guidelines for managing dyslipidemias in kidney transplant patients.
Am J Transplant5
:1576
,2005[CrossRef][Medline]
- Executive Summary of the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
JAMA285
:2486
–2497,2001[Free Full Text]
- Pham PT, Pham PC, Danovitch GM: Cardiovascular disease posttransplant.
Semin Nephrol27
:430
–444,2007[CrossRef][Medline]
- Holdaas H, Fellstrom B, Jardine AG, Holme I, Nyberg G, Fauchald P, Gronhagen-Riska C, Madsen S, Neumayer HH, Cole E, Maes B, Ambuhl P, Olsson AG, Hartmann A, Solbu DO, Pedersen TR: Effect of fluvastatin on cardiac outcomes in renal transplant recipients: A multicentre, randomised, placebo-controlled trial.
Lancet,361
:2024
–2031,2003[CrossRef][Medline]
- Cosio FG, Pesavento TE, Osei K, Henry ML, Ferguson RM: Post-transplant diabetes mellitus: Increasing incidence in renal allograft recipients transplanted in recent years.
Kidney Int59
:732
–737,2001[CrossRef][Medline]
- Cosio FG, Pesavento TE, Kim S, Osei K, Henry M, Ferguson RM: Patient survival after renal transplantation: IV. Impact of post-transplant diabetes.
Kidney Int62
:1440
–1446,2002[CrossRef][Medline]
- Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ: Diabetes mellitus after kidney transplantation in the United States.
Am J Transplant3
:178
–185,2003[CrossRef][Medline]
- Lindholm A, Albrechtsen D, Frodin L: Ischemic heart disease: Major cause of death and graft loss after renal transplantation in Scandinavia.
Transplantation60
:451
–457,1995[Medline]
- Fernandez-Fresnedo G, Escallada R, de Francisco AL, Rodrigo E, Zubimendi JA, Ruiz JC, Pinera C, Herraez I, Arias M: Posttransplant diabetes is a cardiovascular risk factor in renal transplant patients.
Transplant Proc35
:700
,2003[CrossRef][Medline]
- Reisaeter AV, Hartmann, A: Risk factors and incidence of posttransplant diabetes mellitus.
Transplant Proc33[Suppl]
:8S
–18S,2001[CrossRef][Medline]
- Bloom RD, Rao V, Weng F, Grossman RA, Cohen D, Mange KC: Association of hepatitis C with posttransplant diabetes in renal transplant patients on tacrolimus.
J Am Soc Nephrol13
:1374
–1380,2002[Abstract/Free Full Text]
- Vincenti F, Friman S, Scheuermann E, Rostaing L, Jenssen T, Campistol JM, Uchida K, Pescovitz MD, Marchetti P, Tuncer M, Citterio F, Wiecek A, Chadban S, El-Shahawy M, Budde K, Goto N: Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus.
Am J Transplant7
:1506
–1514
- Davidson J, Wilkinson A, Dantal J, Dotta F, Haller H, Hernandez D, Kasiske BL, Kiberd B, Krentz A, Legendre C, Marchetti P, Markell M, van der Woude FJ, Wheeler DC: New-onset diabetes after transplantation: 2003 international consensus guidelines. Proceedings of an international expert panel meeting. Barcelona, Spain, 19 February 2003.
Transplantation75[Suppl]
:SS3
–SS24,2003[CrossRef][Medline]
- Kasiske BL, Klinger D: Cigarette smoking in renal transplant recipients.
J Am Soc Nephrol11
:753
–759,2000[Abstract/Free Full Text]
- Friedman AN, Miskulin DC, Rosenberg IH, Levey AS: Demographics and trends in overweight and obesity in patients at time of kidney transplantation.
Am J Kidney Dis41
:480
–487,2003[CrossRef][Medline]
- Matas AJ, Kandaswamy R, Gillingham KJ, McHugh L, Ibrahim H, Kasiske B, Humar A: Prednisone-free maintenance immunosuppression: A 5-year experience.
Am J Transplant5
:2473
–2478,2005[CrossRef][Medline]
- Cole E, Landsberg D, Russell D, Zaltzman J, Kiberd B, Caravaggio C, Vasquez AR, Halloran P: A pilot study of steroid-free immunosuppression in the prevention of acute rejection in renal allograft recipients.
Transplantation72
:845
–850,2001[CrossRef][Medline]
- Sivaraman P, Nussbaumer G, Landsberg D: Lack of long-term benefits of steroid withdrawal in renal transplant recipients.
Am J Kidney Dis37
:1162
–1169,2001[Medline]
- Alexander JW, Goodman HR, Gersin K, Cardi M, Austin J, Goel S, Safdar S, Huang S, Woodle ES: Gastric bypass in morbidly obese patients with chronic renal failure and kidney transplant.
Transplantation78
:469
–474,2004[Medline]
- Newcombe V, Blanch A, Slater GH, Szold A, Fielding GA: Laparoscopic adjustable gastric banding prior to renal transplantation.
Obes Surg15
:567
–570,2005[CrossRef][Medline]
- Fernandez-Fresnedo G, Plaza JJ, Sanchez-Plumed J, Sanz-Guajardo A, Palomar-Fontanet R, Arias M: Proteinuria: A new marker of long-term graft and patient survival in kidney transplantation.
Nephrol Dial Transplant19
:III47
–III51,2004[CrossRef][Medline]
- Roodnat JI, Mulder PG, Rischen-Vos J, van Riemsdijk IC, van Gelder T, Zietse R, IJzermans JN, Weimar W: Proteinuria after renal transplantation affects not only graft survival but also patient survival.
Transplantation72
:438
–444,2001[CrossRef][Medline]
- Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS: Urinary albumin excretion: An independent predictor of ischemic heart disease.
Arterioscler Thromb Vasc Biol19
:1992
–1997,1999[Abstract/Free Full Text]
- Wachtell K, Ibsen H, Olsen MH, Borch-Johnsen K, Lindholm LH, Mogensen CE, Dahlof B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristianson K, Lederballe-Pedersen O, Nieminen MS, Okin PM, Omvik P, Oparil S, Wedel H, Snapinn SM, Aurup P: Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: The LIFE study.
Ann Intern Med139
:901
–906,2003[Abstract/Free Full Text]
- Ibsen H, Olsen MH, Wachtell K, Borch-Johnsen K, Lindholm LH, Mogensen CE, Dahlof B, Devereux RB, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wan Y: Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: Losartan intervention for endpoint reduction in hypertension study.
Hypertension45
:198
–202,2005[Abstract/Free Full Text]
- IV. Clinical practice recommendations for anemia in chronic kidney disease in transplant recipients.
Am J Kidney Dis47[Suppl]
:S109
–S116,2006[CrossRef][Medline]
- Rigatto C, Parfrey P, Foley R, Negrijn C, Tribula C, Jeffery J: Congestive heart failure in renal transplant recipients: Risk factors, outcomes, and relationship with ischemic heart disease.
J Am Soc Nephrol13
:1084
–1090,2002[Abstract/Free Full Text]
- Rigatto C, Foley R, Jeffery J, Negrijn C, Tribula C, Parfrey P: Electrocardiographic left ventricular hypertrophy in renal transplant recipients: Prognostic value and impact of blood pressure and anemia relationship with ischemic heart disease.
J Am Soc Nephrol14
:462
–468,2003[Abstract/Free Full Text]
- Imoagene-Oyedeji AE, Rosas SE, Doyle AM, Goral S, Bloom RD: Posttransplantation anemia at 12 months in kidney recipients treated with mycophenolate mofetil: Risk factors and implications for mortality.
J Am Soc Nephrol17
:3240
–3247,2006[Abstract/Free Full Text]
- KDOQI clinical practice guideline and clinical practice recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target.
Am J Kidney Dis50
:471
–530,2007[CrossRef][Medline]
- Ducloux D, Motte G, Massy ZA: Hyperhomocyst(e)inemia as a risk factor after renal transplantation.
Ann Transplant6
:40
–42,2001[Medline]
- Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, Wang H, Nordrehaug JE, Arnesen E, Rasmussen K: Homocysteine lowering and cardiovascular events after acute myocardial infarction.
N Engl J Med354
:1578
–1588,2006[Abstract/Free Full Text]
- Bostom AG, Carpenter MA, Kusek JW, Hunsicker LG, Pfeffer MA, Levey AS, Jacques PF, McKenney J: Rationale and design of the Folic Acid for Vascular Outcome Reduction In Transplantation (FAVORIT) trial.
Am Heart J152
:448.e1
–448.e7,2006
- Winkelmayer WC, Lorenz M, Kramar R, Fodinger M, Horl WH, Sunder-Plassmann G: C-reactive protein and body mass index independently predict mortality in kidney transplant recipients.
Am J Transplant4
:1148
–1154,2004[CrossRef][Medline]
- Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, Pfeffer MA, Braunwald E: C-reactive protein levels and outcomes after statin therapy.
N Engl J Med352
:20
–28,2005[Abstract/Free Full Text]
- Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert J, Zeeuw D, Hostetter TH, Lameire N, Eknoyan G: Definition and classification of chronic kidney disease: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO).
Kidney Int67
:2089
–2100,2005[CrossRef][Medline]
- Abbud-Filho M, Adams PL, Alberu J, Cardella C, Chapman J, Cochat P, Cosio F, Danovitch G, Davis C, Gaston RS, Humar A, Hunsicker LG, Josephson MA, Kasiske B, Kirste G, Leichtman A, Munn S, Obrador GT, Tibell A, Wadstrom J, Zeier M, Delmonico FL: A report of the Lisbon Conference on the care of the kidney transplant recipient.
Transplantation83[Suppl]
:S1
–S22,2007[CrossRef][Medline]
- Cosio FG, Alamir A, Yim S, Pesavento TE, Falkenhain ME, Henry ML, Elkhammas EA, Davies EA, Bumgardner GL, Ferguson RM: Patient survival after renal transplantation: I. The impact of dialysis pre-transplant.
Kidney Int53
:767
–772,1998[CrossRef][Medline]
- Kasiske BL, Snyder JJ, Matas AJ, Ellison MD, Gill JS, Kausz AT: Preemptive kidney transplantation: The advantage and the advantaged.
J Am Soc Nephrol13
:1358
–1364,2002[Abstract/Free Full Text]
- Meier-Kriesche HU, Port FK, Ojo AO, Rudich SM, Hanson JA, Cibrik DM, Leichtman AB, Kaplan B: Effect of waiting time on renal transplant outcome.
Kidney Int58
:1311
–1317,2000[CrossRef][Medline]
- Mange KC, Joffe MM, Feldman HI: Effect of the use or nonuse of long-term dialysis on the subsequent survival of renal transplants from living donors.
N Engl J Med344
:726
–731,2001[Abstract/Free Full Text]
- Kasiske B, London W, Ellison M: Race and socioeconomic factors influencing early placement on the kidney transplant waiting list.
J Am Soc Nephrol9
:2142
–2147,1998[Abstract]
- Cass A, Cunningham J, Snelling P, Ayanian JZ: Late referral to a nephrologist reduces access to renal transplantation.
Am J Kidney Dis42
:1043
–1049,2003[CrossRef][Medline]
- Weng FL, Mange KC: A comparison of persons who present for preemptive and nonpreemptive kidney transplantation.
Am J Kidney Dis42
:1050
–1057,2003[Medline]
- Meier-Kriesche HU, Schold JD, Srinivas TR, Reed A, Kaplan B: Kidney transplantation halts cardiovascular disease progression in patients with end-stage renal disease.
Am J Transplant4
:1662
–1668,2004[CrossRef][Medline]
- Gill JS, Tonelli M, Johnson N, Kiberd B, Landsberg D, Pereira BJ: The impact of waiting time and comorbid conditions on the survival benefit of kidney transplantation.
Kidney Int68
:2345
–2351,2005[CrossRef][Medline]
- Covic A, Gusbeth-Tatomir P, Mardare N, Buhaescu I, Goldsmith DJ: Dynamics of the circadian blood pressure profiles after renal transplantation.
Transplantation80
:1168
–1173,2005[CrossRef][Medline]
- Riess K, GS, Oreopoulos A, Jones LW, McGavock J, Lewanczuk R, Haykowsky M: Impaired arterial compliance and aerobic endurance in kidney transplant recipients.
Transplantation82
:920
–923,2006[Medline]
- Simmons EM, Langone A, Sezer MT, Vella JP, Recupero P, Morrow JD, Ikizler TA, Himmelfarb J: Effect of renal transplantation on biomarkers of inflammation and oxidative stress in end-stage renal disease patients.
Transplantation79
:914
–919,2005[CrossRef][Medline]
- Cueto-Manzano AM, Morales-Buenrostro LE, Gonzalez-Espinoza L, Gonzalez-Tableros N, Martin-del-Campo F, Correa-Rotter R, Valera I, Alberu J: Markers of inflammation before and after renal transplantation.
Transplantation80
:47
–51,2005[CrossRef][Medline]
- Rosas SE, Mensah K, Weinstein RB, Bellamy SL, Rader DJ: Coronary artery calcification in renal transplant recipients.
Am J Transplant5
:1942
–1947,2005[CrossRef][Medline]
- Hernandez D, Gonzalez A, Rufino M, Laynez I, Rosa AD, Porrini E, Lacalzada J, Barragan A, Lorenzo V, Torres A: Time-dependent changes in cardiac growth after kidney transplantation: The impact of pre-dialysis ventricular mass.
Nephrol Dial Transplant22
:2678
–2685,2007[Abstract/Free Full Text]
- Montanaro D, Gropuzzo M, Tulissi P, Vallone C, Boscutti G, Mioni R, Risaliti A, Baccarani U, Adani GL, Sainz M, Lorenzin D, Bresadola F, Mioni G: Effects of successful renal transplantation on left ventricular mass.
Transplant Proc37
:2485
–2487,2005[CrossRef][Medline]
- USRDS:
Annual Data Report: Atlas of End Stage Renal Disease in the United States, Bethesda, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2005. Available at: http://www.usrds.org/2005/slides/html/06_morb_morte_05_files/v3_document.htm. Accessed November 25,2007
- Gill JS, Rose C, Pereira BJ, Tonelli M: The importance of transitions between dialysis and transplantation in the care of end-stage renal disease patients.
Kidney Int71
:442
–447,2007[CrossRef][Medline]
- Kasiske BL, Maclean JR, Snyder JJ: Acute myocardial infarction and kidney transplantation.
J Am Soc Nephrol17
:900
–907,2006[Abstract/Free Full Text]
- Johnston O, Zalunardo N, Rose C, Gill JS: Prevention of sepsis during the transition to dialysis may improve the survival of transplant failure patients.
J Am Soc Nephrol18
:1331
–1337,2007[Abstract/Free Full Text]
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Abstract
Introduction
