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Introduction

  1. Top of page
  2. Introduction
  3. Adult Kidney and Kidney–pancreas Recipients
  4. Heart Recipients
  5. Lung and Heart–lung Recipients
  6. Liver Recipients
  7. Pediatric Recipients
  8. Acknowledgments
  9. References

Kidney, heart, liver, and, to a lesser extent, pancreas and lung transplants have become routine treatments for end-stage organ failure. The short-term success rate is high. Graft loss from allograft rejection, the traditional enemy of transplantation, has been greatly reduced. These improved results have yielded patient survival rates at 1 and 3 years that exceed 90%.

However, emerging data indicate that accelerated cardiovascular disease (CVD) is a leading cause of death and graft loss in long-term survivors, ranking first in heart and kidney recipients and second only to malignancy in liver recipients. Pathogenesis may differ. Patients with end-stage renal disease (ESRD) are already at increased risk for CVD; heart recipients face the risk of a particularly aggressive form of coronary artery disease (CAD). In contrast, liver transplant candidates typically have a low prevalence of CVD risk factors and therefore are at low risk for CVD complications perioperatively.

Elevated blood pressure and elevated lipid levels have each been directly linked to increased CVD risk. Guidelines have been established for the general population. Importantly, for both, the aggressiveness of the intervention is determined not only by the absolute level of the risk factor but also by the presence of coexisting risk factors. Important cofactors for determining the aggressiveness of intervention for blood pressure control are shown in Table 1, and those for lipid level control are shown in Table 2 (1,2).

Table 1. : Risk factors modifying aggressiveness of antihypertensive treatment to prevent cardiovascular disease (modified from 1)
Smoking
Dyslipidemia
Diabetes
Age > 60 years
Postmenopause
Male gender
Family history of cardiovascular disease (men < 55 years,  women < 65 years)
Target organ damage
 Nephropathy
 Peripheral artery disease
 Retinopathy
Clinical cardiovascular disease
 Left ventricular hypertrophy
 Angina or prior myocardial infarction
 Prior coronary revascularization
 Heart failure
 Stroke or transient ischemic attack
Table 2. : Coexisting risk factors for cardiovascular disease (CVD) in nontransplant patients with elevated lipid levels (modified from 2)
  • a

    Note that an HDL cholesterol level of 60 mg/dL (1.6 mol/L) is associated with a decreased risk for CVD.

Age
 ≥?45 years (men)
 ≥?55 years (women)
Premature menopause without estrogen replacement therapy  (women)
Family history of premature coronary heart disease
Hypertension
HDL cholesterol levels < 35 mg/dL (0.9 mmol/L)a
Diabetes

The pathophysiology of CVD risk factors in transplant recipients is related, in part, to the effects of immunosuppressive drugs. Therefore, it is not clear whether the natural history of these drug-induced risk factors conforms to that observed in the general population. Moreover, drug–drug interactions – common in transplant recipients on numerous, lifelong immunosuppressants – may necessitate modifications in conventional therapy for hypertension or hyperlipidemia. In addition, risk factors unique to transplant recipients, such as the atherogenic effects of cytomegalovirus (CMV), may have additive effects and further influence treatment algorithms.

To discuss this problem, an ad hoc group of transplant care personnel recently met. We hereby summarize their discussions and recommendations.

Adult Kidney and Kidney–pancreas Recipients

  1. Top of page
  2. Introduction
  3. Adult Kidney and Kidney–pancreas Recipients
  4. Heart Recipients
  5. Lung and Heart–lung Recipients
  6. Liver Recipients
  7. Pediatric Recipients
  8. Acknowledgments
  9. References

Compared with age- and gender-matched general population controls, kidney and kidney–pancreas recipients face a markedly increased CVD risk post-transplant (3).

Risk factors

Pretransplant CVD

In many cases, kidney and kidney–pancreas recipients have already acquired CVD pretransplant. Mortality is higher among candidates on the transplant waiting list who are on dialysis, compared with waiting list recipients who are transplanted (4). Much of this increased mortality is due to CVD.

Diabetes

Diabetes is an increasingly common cause of ESRD. In addition, the use of calcineurin inhibitors and corticosteroids is associated with the development of new-onset, post-transplant diabetes. The incidence of post-transplant glucose intolerance not requiring treatment with insulin is even higher. Diabetes is a strong risk factor for CVD, both pre- and post-transplant (5).

Hypertension

Hypertension is present in 50–80% of kidney recipients and is associated with decreased patient and graft survival (6,7). Hypertension likely has at least the same adverse effect on CVD in kidney and kidney–pancreas recipients that it has in the general population (5).

Hyperlipidemia

About 60% of kidney and kidney–pancreas recipients have elevated plasma cholesterol levels (> 240 mg/dL). Several studies have found correlations between hyperlipidemia and CVD in transplant recipients (5,8–10).

Cigarette smoking

In retrospective, observational studies in kidney recipients, cigarette smoking has been linked to CVD (11,12), decreased patient survival (11,13), and decreased graft survival (14).

Obesity and sedentary lifestyle

Obesity is common post-transplant, in large part because of the weight gain from corticosteroid use. Anecdotal evidence suggests that kidney and kidney–pancreas recipients rarely exercise.

Systemic inflammation

Recent evidence suggests that atherosclerotic CVD is a systemic disease characterized by inflammation (15). A number of systemic inflammatory markers, such as C-reactive protein and fibrinogen, have been correlated with CVD events. In kidney recipients, CVD events have been associated with low serum albumin, a marker of systemic inflammation (5).

Infection

Another theory links infections to the pathogenesis of atherosclerosis. CMV infections are more common in transplant recipients than in the general population. Some studies associate CMV with CVD in transplant recipients (16); other studies do not.

Hyperhomocysteinemia

Elevated homocysteine levels are associated with CVD in the general population (17). Homocysteine levels are higher in kidney recipients than in the general population, and levels correlate inversely with renal function (18,19).

Oxidative stress

Trials of antioxidant vitamins in the primary prevention of CVD have generally been negative. In hemodialysis patients, vitamin E supplementation has, however, been shown to reduce CVD events in patients with known CAD (20).

Abnormal renal function and proteinuria

Elevated serum creatinine levels, microalbuminuria, and proteinuria have been linked to CVD in different populations (21–23). Recently, post-transplant proteinuria has been associated with increased mortality (24).

Management recommendations

In the absence of adequate clinical trial data in transplant recipients, we think it is reasonable to apply interventions that have been proven to reduce CVD in the general population or in other relevant high-risk populations, if two conditions are met: (i) the risk factor must also be associated with CVD in transplant recipients, and (ii) the intervention must be safe and must effectively modify the risk factor.

Pretransplant CVD

Transplant candidates should be screened for CVD as part of the pretransplant evaluation (25). High-risk candidates should be screened annually while on the transplant waiting list. Aggressively managing CVD risk factors before the transplant will likely play a critical role in preventing CVD after the transplant.

Diabetes

Glycemic control should be maximized by using all available measures (26). If possible, the use of calcineurin inhibitors and corticosteroids should be minimized to prevent the development of post-transplant diabetes, especially in high-risk groups.

Hypertension

Large randomized controlled trials in the general population have established that treating hypertension reduces the risk for CVD; these trials have led to the development of guidelines for the treatment of hypertension (1). Modifications for those with ESRD have been recommended by the National Kidney Foundation Task Force on Cardiovascular Disease (27). The blood pressure goal should be ≤ 135/85 mmHg, except for patients with diabetes, patients with more than 500 mg/d of urine protein excretion, patients with ≥ two risk factors for CVD, or patients with target organ damage. For these high-risk patients, the goal should be a blood pressure reading of ≤ 125/75 mmHg.

In general, there are no absolute contraindications to the use of any antihypertensive agent in kidney recipients. Calcium antagonists may improve renal function in recipients treated with cyclosporine. However, recent data have raised concerns about the safety of dihydropyridine calcium antagonists, at least as monotherapy (5). Angiotensin-converting enzyme (ACE) inhibitors (or angiotensin II receptor blockers) may have the added advantage of helping to reduce proteinuria and favorably influencing CVD events and possibly hyperlipidemia in some recipients. However, ACE inhibitors have been associated with hyperkalemia, anemia, and elevated serum creatinine levels after transplantation.

Hyperlipidemia

Kidney recipients should be screened for hyperlipidemia at least once during the first 6 months, at 1 year post-transplant, and then annually (28). Hyperlipidemia should be managed according to the Adult Treatment Panel II of the National Cholesterol Education Program (NCEP) (2). Hydrophilic HMG-CoA reductase inhibitors (e.g. pravastatin) are preferred for patients on calcineurin inhibitors. In addition, for recipients on calcineurin inhibitors, doses of lipophilic HMG-CoA reductase inhibitors should be reduced by 25%. In some recipients at high risk for CVD, consideration should be given to tailoring immunosuppressive protocols to minimize post-transplant lipid increases.

Smoking

Pre- and post-transplant, all patients should be strongly encouraged to quit smoking (29). Given the significant associations between cigarette smoking and both decreased patient survival and decreased death-censored graft survival (13), consideration should be given to not transplanting candidates who plan to continue to smoke post-transplant.

Exercise

A regular program of exercise should be strongly encouraged. Transplant centers should establish exercise guidelines and a follow-up program to help recipients stay on an exercise program.

Aspirin prophylaxis

Studies in the general population have shown that low-dose aspirin is effective in secondary prevention of recurrent CVD (30,31). A low dose of aspirin, e.g. 65–85 mg, appears to be as effective as higher doses.

Proteinuria

Microalbuminuria and proteinuria are common post-transplant. A mild degree of proteinuria has been identified as an independent risk factor for CVD (22–24). Measures that lower proteinuria, namely ACE inhibitors or angiotensin II receptor blockers (even in normotensive patients), should be strongly considered. However, close follow-up is necessary: ACE inhibitors have been associated with graft dysfunction, anemia, and hyperkalemia.

Research recommendations

Prospective risk factor cohort study

A large prospective, multicenter, cohort study would be very helpful to determine whether the relationship between traditional risk factors and CVD in kidney and kidney–pancreas recipients is similar to that in the general population. In addition, the role of newer, putative risk factors could be prospectively studied.

Pretransplant screening

How best to screen patients for CVD at the time they are listed for a transplant is a fertile area for clinical trials. Similarly, how to evaluate and care for transplant candidates on the cadaver waiting list is another crucial area that requires study.

Antihypertensive agents

Large multicenter, randomized, controlled trials are urgently needed to define which of several options for treating blood pressure would be most efficacious in reducing CVD events and preserving renal function in kidney and kidney–pancreas recipients.

Lipid-lowering strategies

The correct threshold for treating hyperlipidemia is a legitimate research question. Indeed, a strong argument can be made for testing the hypothesis that every kidney and kidney–pancreas recipient should be treated with an HMG-CoA reductase inhibitor, regardless of cholesterol level. In addition, recent animal studies have indicated that such agents have immunosuppressive properties independent of their lipid-lowering effect (32).

Homocysteine reduction

The transplant population is ideally suited for a randomized, controlled trial to determine whether combination vitamin therapy to reduce homocysteine levels can effectively reduce CVD.

Aspirin prophylaxis

Aspirin is already indicated for patients with known CVD. Its role in the primary prevention of CVD is less certain. The transplant population is well suited for a randomized, controlled trial to determine whether prophylactic aspirin can effectively reduce CVD morbidity and mortality in patients without known CVD.

Heart Recipients

  1. Top of page
  2. Introduction
  3. Adult Kidney and Kidney–pancreas Recipients
  4. Heart Recipients
  5. Lung and Heart–lung Recipients
  6. Liver Recipients
  7. Pediatric Recipients
  8. Acknowledgments
  9. References

An accelerated form of CAD is the leading cause of death for heart recipients (33,34). Both donor and recipient risk factors (several of them treatable) are associated with increased risks for this disease.

Donor risk factors

Donor age

A significant accumulation of data from autopsy studies during the Korean and Gulf Wars showed that the risk of atherosclerosis increased with age, even in men under the age of 40 (33,35).

Total ischemic time

Registry data (36) have shown that an ischemic time longer than 4 h is associated with an increased risk of death and CAD, and that this risk increases proportionally with increasing donor age (33,36). With increasing age, the endothelium may not tolerate cold and ischemic injury as well. The total ischemic time can be estimated prospectively; the increased risk of CAD can be avoided by only using older donors when ischemic times will be shorter than 4 h.

Other

Other donor factors associated with an increased risk of CAD post-transplant are black race; a history of hypertension, smoking, diabetes, hyperlipidemia, or obesity (33,37,38); and gender mismatch with the recipient (36). These risk factors are all additive. No one risk factor may influence the decision to use a donor heart, but the composite risk may warrant avoidance of a given donor.

Recipient risk factors

Both antigen-dependent and antigen-independent risk factors have been associated with the risk of CAD in the heart allograft. In the past, ‘CAD’ and ‘chronic rejection’ were used interchangeably. Currently, ‘allograft CAD’ is the preferred phrase.

Antigen-dependent factors

Acute rejection. Kobashigawa et al. (39) used intravascular ultrasound to directly measure changes in intimal thickening in the heart allograft over time. None of three factors – time to first rejection, number of rejection episodes, or severity of rejection – correlated with intimal thickening. However, when the biopsy grade was converted into a numeric grade and averaged over certain intervals post-transplant, the average score for the first 3 months post-transplant was associated with an increase in coronary intimal thickness. This finding suggests that a lower threshold for treating rejection should be used during the first 3 months.

Suppression of the indirect pathway of allorecognition may be particularly important (40,41).

Antibody-mediated rejection. A strong correlation has been shown between episodes of antibody-mediated (humoral) rejection and development of CAD. The inflammation and arteritis that are integral parts of this type of rejection lead to expansion of the intima. Even one episode of hemodynamically compromising rejection significantly increases mortality (42). There are some data demonstrating that such an episode of vascular (antibody-mediated) rejection also correlates with CAD (43,44).

Positive panel-reactive antibody (PRA). A positive PRA pretransplant has been associated with increased risk of death and rejection as well as CAD. Many centers now attempt to reduce the titer of PRA pretransplant (45,46).

Immunosuppression. The role of immunosuppression in the development of CAD is unclear. Cyclosporine (CSA) has been associated with significant improvement in graft and patient survival, but not a reduction in the incidence of CAD (47). The increase in survival time over the last two decades may have led to an increased opportunity to develop CAD. However, there seems to be a critical threshold dose of CSA. When examined by cut point analysis (rather than as a continuous variable), an average CSA dose of < 4 mg/kg/d during the first year post-transplant was associated with increased intimal thickening by intravascular ultrasound, compared with a higher dose (48). The CSA level correlated less well. Data from randomized trials suggest that lipid levels with tacrolimus (TAC) may be lower than with CSA (49); however, the incidence of glucose intolerance is higher with TAC. Other immunosuppressive agents such as corticosteroids may also influence the development of CAD.

Antigen-independent factors

Most of the attention to risk factors associated with the development of CAD after heart transplants focuses on antigen-independent factors (50). These include demographic factors such as older donor age, black donor race, male recipient gender, and gender mismatch between the recipient and donor (36), as well as risk factors associated with development of atherosclerosis in the nontransplant population (e.g. hyperlipidemia, diabetes, smoking, hypertension).

Hyperlipidemia. This was one of the first risk factors identified for development of CAD after heart transplants (51). An elevated LDL fraction of total cholesterol correlates with an increased risk of CAD, but a stronger correlation exists with both a low HDL fraction and an elevated triglyceride level (52). Intervention with lipid-lowering therapy after the disease becomes evident does not seem to alter its progression. However, the use of an HMG-CoA reductase inhibitor – from the time of the transplant, regardless of whether hyperlipidemia is present – has been associated with a reduction in the amount of intimal thickening (as measured by intravascular ultrasound at 1 year post-transplant) (52). This benefit has been shown with both pravastatin and simvastatin (53) and therefore may well represent a class effect rather than a benefit limited to a single agent (54). In one series, fenofibrate lowered CSA levels and increased the incidence of rejection; thus, CSA levels should be monitored closely in patients treated with fibric acid derivatives.

Hypertension and smoking. These risk factors for nontransplant CAD are likely important risk factors after heart transplantation.

Increased body mass index and diabetes. Increased body mass index (37) and diabetes (55) have been correlated with development of CAD.

CMV infection. CMV infection is a risk factor for CAD that appears to be unique to heart recipients (56,57). The risk of developing clinical CMV infections is a function of the CMV serology of the donor and recipient. The highest risk involves a CMV-negative recipient and a CMV-positive donor. CMV may cause up-regulation of MHC antigens (58) on the endothelium as well as increased lipid incorporation (59).

Homocysteine. In both transplant recipients and nontransplant patients, an elevated homocysteine level is associated with the combined endpoint of atherosclerosis and vascular disease (60). Most heart transplant programs begin folate therapy for recipients with a homocysteine level > 14 ng/dL.

Management recommendations

Hyperlipidemia

Most heart transplant programs now begin all recipients on a statin from the time of the transplant. Studies with intravascular ultrasound have shown that, although intimal thickening continues over time, the greatest increase occurs during the first year post-transplant (61). It is unclear what the target lipid levels should be post-transplant, or whether the targets should change with time. Current recommendations are to follow the NCEP guidelines for long-term risk reduction (2). Specifically, minimum goals should be an LDL cholesterol level < 100, HDL level > 35, and triglyceride level < 200/mg/dL.

Hypertension

The current guidelines from the Joint National Committee are recommended for all heart recipients (1).

CMV infection. Given the high correlation between CMV infection and development of CAD, most heart transplant programs now use aggressive prophylaxis: at least 2 weeks of intravenous ganciclovir, followed by up to 3 months of oral ganciclovir.

Lung and Heart–lung Recipients

  1. Top of page
  2. Introduction
  3. Adult Kidney and Kidney–pancreas Recipients
  4. Heart Recipients
  5. Lung and Heart–lung Recipients
  6. Liver Recipients
  7. Pediatric Recipients
  8. Acknowledgments
  9. References

Lung transplant recipients are at risk for two types of coronary vascular disease: progression of native CAD in single and bilateral single lung transplant recipients and de novo coronary disease in heart–lung transplant recipients. Interestingly, while graft CAD clearly occurs in heart–lung transplant recipients, its incidence is much lower than that seen in heart transplant recipients (62,63). When graft coronary vascular disease occurs, it is usually seen in conjunction with chronic lung rejection (obliterative bronchiolitis) (64,65). Risk factors for and management of graft coronary vascular disease are similar to those detailed for heart transplant recipients and will not be discussed further.

Risk factors

The most significant risk factor for native CAD after lung transplantation is pre-existing coronary vascular disease. In this regard, lung transplant recipients are a heterogeneous group, spanning the entire spectrum of risk for CAD. This relates to differences in the known major cardiovascular risk factors, including age, smoking history, and lipid abnormalities, rather than to effects of their underlying pulmonary disease per se. For example, young patients transplanted for cystic fibrosis have a very low incidence of coronary disease, while older patients with chronic obstructive pulmonary disease (COPD) have a much higher incidence. Because cigarette smoking is a major risk factor for both COPD and CAD, COPD patients referred for lung transplantation comprise a particularly high-risk group.

Management recommendations

Most lung transplant programs include comprehensive screening for coronary vascular disease, usually including coronary arteriography, in the pre-lung transplant evaluation of patients over the age of 40–45 years. In the largest study published to date, Snell et al. identified CAD in 32 of 85 lung transplant candidates over age 50 years; more than half of those 32 had significant stenoses and eight patients required intervention before or during their lung transplant surgery (66). Although most programs consider CAD of any degree to be at least a relative contraindication for lung transplantation, the point at which it becomes an absolute contraindication is not clear (67). In addition, the optimal strategy for periodic reevaluation of lung recipients with known CAD has not been defined. The approach to prevention of new or progressive coronary vascular disease after lung transplantation is similar to that used for kidney and liver recipients: control of hypertension, diabetes, and hyperlipidemia are central.

Liver Recipients

  1. Top of page
  2. Introduction
  3. Adult Kidney and Kidney–pancreas Recipients
  4. Heart Recipients
  5. Lung and Heart–lung Recipients
  6. Liver Recipients
  7. Pediatric Recipients
  8. Acknowledgments
  9. References

Cardiovascular risk for liver recipients differs substantially from that for kidney and heart recipients. The primary difference is related to hemodynamic and metabolic changes associated with chronic liver disease, which lead to peripheral vasodilatation, low arterial blood pressure, and reduced serum cholesterol levels (68,69). A number of autopsy studies have shown less pathologic evidence of atherosclerosis and a decreased incidence of vascular diseases (70,71). In addition to lower blood pressure and decreased serum lipid levels, patients with chronic liver disease have higher estrogen levels, which may help to prevent atherosclerosis, compared with kidney and heart recipients. Finally, since alcoholic cirrhosis is the most common cause of end-stage liver disease, the protective effect of moderate alcohol consumption, which is associated with elevated HDL levels and decreased cardiovascular mortality, may also explain the lower rates of CAD in cirrhotic patients (72,73). Thus, at the time of their liver transplant, patients with end-stage liver disease appear to have a lower degree of atherosclerotic disease, compared with patients undergoing kidney or heart transplants.

Risk factors

Immunosuppression

After a liver transplant, immunosuppressive therapy based on calcineurin inhibitors causes hemodynamic changes that lead to vasoconstriction, a rise in systemic blood pressure, and an increase in serum lipid levels. In addition, a number of liver recipients become obese and develop various degrees of glucose intolerance; a substantial number require insulin for hyperglycemic control (74,75).

Despite a high cardiovascular risk index, a number of series have shown that the risk of heart disease in liver recipients appears to be similar to that in the age-matched general population (76,77). However, a recent series with 10 years of follow-up demonstrated an 18% incidence of CVD deaths among liver recipients (78), suggesting that with follow-up ≥ 5 years, an increased incidence of CVD may exist.

Recent reports suggest that TAC-based immunosuppression is associated with less cardiovascular risk than CSA-based immunosuppression (75). In those reports, TAC-treated recipients gained less weight and had lower lipid levels and lower blood pressure. Trying to compare these two immunosuppressive regimens directly, however, was complicated by the fact that the CSA-treated recipients generally received higher doses of corticosteroids than did the TAC-treated recipients. Furthermore, a recent study suggests that steroid-free CSA protocols are associated with a decreased incidence of hypertension, diabetes, and hyperlipidemia; this finding supports the role of corticosteroids in causing cardiovascular risk (79). An additional caveat is that TAC is more diabetogenic than CSA.

Management recommendations

Hypertension – defined as a systolic blood pressure rise of 20–30 mmHg within the first weeks post-transplant, as a sustained systolic blood pressure > 140, or as a sustained diastolic blood pressure > 80 – should be aggressively treated. In addition, diabetes mellitus should be closely managed. Hyperlipidemia should be managed using HMG-CoA reductase inhibitors (2). Furthermore, when hyperlipidemia is found, consideration should be given to changing the immunosuppressive regimen. Steroid withdrawal after 3 months is associated with a minimal risk of inducing liver rejection, but can have profound effects on hypertension, diabetes mellitus, and hyperlipidemia (80). For liver recipients on CSA who have hypertension or hyperlipidemia, conversion to TAC improves those CVD risk factors (81). Liver recipients should be encouraged to lead an active life with regular exercise and should be encouraged to abstain from smoking (82).

Research recommendations

The relative cardioprotective role of liver disease provides a unique opportunity to prospectively identify development of CVD in liver recipients. The onset of CVD risk can be accurately defined, and the rate of progression can thus be studied very closely. Clinical research is needed regarding the optimal management of hyperlipidemia and the definition of which level warrants therapeutic intervention.

Pediatric Recipients

  1. Top of page
  2. Introduction
  3. Adult Kidney and Kidney–pancreas Recipients
  4. Heart Recipients
  5. Lung and Heart–lung Recipients
  6. Liver Recipients
  7. Pediatric Recipients
  8. Acknowledgments
  9. References

Little information is available regarding long-term cardiac morbidity and mortality in pediatric solid organ recipients. Most available data pertain only to pediatric kidney recipients, because once recipients reach adulthood, they are no longer followed by the pediatric registry. A single-center analysis showed that, of children dying with graft function, cardiac events accounted for four (11%) of 36 deaths (83); in another series, deaths occurring 10 or more years post-transplant were all due to cardiovascular causes (84). Risk factors associated with increased CVD in adult kidney recipients (85) have also been reported in pediatric kidney recipients.

Risk factors

Pretransplant CVD

Patient mortality is higher for pediatric patients on chronic dialysis awaiting a transplant than for pediatric kidney recipients (86). Much of the increased mortality is due to CVD.

Hypertension

Hypertension prevalence greater than 80% has been reported in children after kidney transplants (87–90). In a small study of pediatric kidney recipients followed 7–86 months post-transplant, systolic hypertension was associated with development of left ventricular hypertrophy – a risk factor for cardiac mortality in adults with chronic kidney disease (85,91).

Race is also a factor: 73% of black (compared with 56% of white) pediatric kidney recipients are on antihypertensive medication 5 years post-transplant (Tejani, Westchester County Medical Center, personal communication 2000).

Hyperlipidemia

Silverstein et al. (92) reported that 32 of 62 pediatric kidney recipients – roughly half – followed for a mean of 6.7 years post-transplant had elevated cholesterol (> 200 mg/dL) and triglyceride (> 200 mg/dL) levels. Similarly, Sharma et al. (93) noted that 17 (51.5%) of 33 pediatric kidney recipients followed for a mean of 7.4 years post-transplant had hypercholesterolemia. A third of them warranted dietary intervention and 10% were considered candidates for treatment with lipid-lowering medications. Hypertension was also present in 53% of the patients with hypercholesterolemia. In a longitudinal cohort study of 102 pediatric liver recipients, 50% had cholesterol levels above 170 mg/dL and 56% had triglyceride levels above 140 mg/dL (94).

Obesity and sedentary lifestyle

Excessive weight gain post-transplant occurs in a large number of pediatric solid organ recipients; however, the natural history of obesity in this population has not been addressed (95). In a study by McDiarmid et al., only 10% of pediatric liver recipients with hyperlipidemia engaged in routine exercise (McDiarmid, UCLA, personal communication 2000).

Diabetes

The incidence of new-onset insulin-dependent diabetes post-transplant in children on TAC has been reported in small series: two (4%) of 50 heart recipients (96), 12 (43%) of 28 heart–lung recipients, three (16%) of 19 kidney recipients (97), and three (2%) of 152 liver recipients (98). Insulin dependence, in most patients, resolves with lowered doses of prednisone and TAC.

Hyperhomocysteinemia

Homocysteine levels have been noted to be elevated in pediatric and adolescent recipients (99,100). Homocysteine levels were inversely related to GFR.

Management recommendations

Pretransplant CVD

Children should be screened for CVD as part of the pretransplant evaluation.

Hypertension

Blood pressure standards, including definitions and a classification of hypertension, have been published for children (101). Blood pressure should be measured at every clinic visit. For pediatric solid organ recipients with documented hypertension, home blood pressure monitoring equipment should be available. Treatment is considered successful if blood pressure is reduced to a level below the 90th percentile in diabetic children and below the 95th percentile in other children (102,103).

Hyperlipidemia

Levels in pediatric recipients should be screened pretransplant, at least once during the first 6 months post-transplant, at 1 year post-transplant, and then annually. Dietary modification should be the first approach to treat hyperlipidemia; children who do not respond to diet changes should be referred to a lipid specialist. Guidelines have been published for managing hypercholesterolemia in the general pediatric population (104). As with adults, modification of immunosuppression should also be considered.

Obesity and sedentary lifestyle

Height, weight, and body mass index should be recorded at least every 6 months. A program of regular exercise should be encouraged. Recipients with rapid weight gain or obesity should receive nutritional counseling.

Diabetes

Pediatric kidney recipients with diabetes should see a pediatric diabetes specialist. When possible, the dosage of immunosuppressive agents that are associated with development of post-transplant diabetes should be minimized.

Research recommendations

Physicians caring for pediatric solid organ recipients need to address the issue of CVD risk factors, because atherosclerotic CVD risk likely begins in childhood. We recommend the following:

  • 1
    Establishment of continuity between pediatric and adult databases, so long-term follow-up can be done for pediatric recipients;
  • 2
    A large prospective, multicenter study to determine the relationship between traditional risk factors and CVD in pediatric recipients;
  • 3
    Formulation of guidelines to identify and manage hyperlipidemia in pediatric recipients;
  • 4
    A large prospective, multicenter study of the effects of maintenance immunosuppressive agents on CVD risk factors in children;
  • 5
    A study of the pharmacokinetics, safety, and efficacy of statins in pediatric recipients;
  • 6
    Inclusion of pediatric recipients in clinical trials of pharmacogenetics.

Acknowledgments

  1. Top of page
  2. Introduction
  3. Adult Kidney and Kidney–pancreas Recipients
  4. Heart Recipients
  5. Lung and Heart–lung Recipients
  6. Liver Recipients
  7. Pediatric Recipients
  8. Acknowledgments
  9. References

Sponsored by grants from Bayer Pharma International, Fujisawa Healthcare, Inc., Merck & Company, Novartis Pharmaceuticals Corp., Roche Pharmaceuticals, SangStat Medical Corp., and Wyeth-Ayerst Pharmaceuticals.

References

  1. Top of page
  2. Introduction
  3. Adult Kidney and Kidney–pancreas Recipients
  4. Heart Recipients
  5. Lung and Heart–lung Recipients
  6. Liver Recipients
  7. Pediatric Recipients
  8. Acknowledgments
  9. References
  • 1
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  • 2
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  • 4
    Wolfe RA, Ashby VB, Milford EL et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999; 341: 17251730.
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    Kasiske BL, Chakkera H, Roel J. Explained and unexplained ischemic heart disease risk after renal transplantation. J Am Soc Nephrol 2000; 11: 17351743.
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    Kasiske BL, Klinger D. Cigarette smoking in renal transplant recipients. J Am Soc Nephrol 2000; 11: 753759.
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    Kasiske BL. Risk factors for accelerated atherosclerosis in renal transplant recipients. Am J Medical 1988; 84: 985992.
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