As posttransplant longevity has increased, nonimmune complications related to the transplant and posttransplant course have emerged as important factors in defining long-term outcomes. The incidence of, and risk factors for these complications may vary by transplanted organ based on immunosuppressive protocols and preexisting risk factors. This article discusses the relevant nonimmune complications associated with posttransplant care, with a focus on risk factors and management strategies.
In the 1980s the introduction of the drug cyclosporine changed the face of solid organ transplantation, decreasing acute allograft rejection and early graft loss, and dramatically improving 1-year patient and graft survival. For the first time in history, organ transplantation became standard of care rather than an experimental procedure. However, as posttransplant longevity has increased, nonimmune complications related to the transplant and posttransplant course have emerged as important factors in defining long-term outcomes. The incidence of, and risk factors for these complications may vary by transplanted organ based on immunosuppressive protocols and preexisting risk factors. This article discusses the relevant nonimmune complications associated with posttransplant care, with a focus on risk factors and management strategies.
Renal dysfunction
Renal dysfunction is one of the most common and well-described complications following solid organ transplantation. In their defining study on the topic, which included more than 69,000 predominantly adult nonrenal solid organ transplant recipients, Ojo and colleagues found that the cumulative 5-year risk of chronic renal failure, defined as the need for either chronic dialysis or kidney transplantation, was 6.9% to 21.3% depending on type of organ transplanted. The onset of chronic renal failure was found to increase the risk of posttransplant death by more than 4-fold, and progression to end-stage renal disease (ESRD) dramatically increased posttransplant cost of care. The relative morbidity and mortality of renal complications in pediatric solid organ recipients are potentially greater, as children have a longer life span following transplantation, with greater cumulative exposure to nephrotoxic medications and other renal insults.
Although the development of renal dysfunction following solid organ transplantation is a multifactorial process, the calcineurin inhibitors (CNI), cyclosporine and tacrolimus, constitute a major contributing factor. The nephrotoxic side effects of these medications have been well recognized since the introduction of cyclosporine in the 1980s. The CNI cause both acute and chronic nephrotoxicity. Acute nephrotoxicity involves afferent arteriolar vasoconstriction and reduced renal plasma flow, and is predictably associated with high trough levels. In contrast, chronic CNI-induced nephrotoxicity is not predicted by individual trough levels, and is characterized by potentially irreversible structural changes including arteriolopathy, tubulointerstitial fibrosis and, eventually, glomerulosclerosis.
Estimates of the incidence of posttransplant renal dysfunction in pediatric solid organ recipients have varied depending on the definition of renal dysfunction employed, the population examined, and the time frame post transplant ( Table 1 ). Given that most published studies are single-center ones and do not allow for multivariate analysis, the identification of specific risk factors for posttransplant renal dysfunction has been difficult. However, based on the current data from a few large single-center or database studies, several risk factors have been suggested. In pediatric liver transplant patients, older age at transplant, decreased glomerular filtration rate (GFR) at 1 year post transplant, use of cyclosporine (vs tacrolimus), arterial hypertension, and primary disease with known renal involvement have all been associated with long-term posttransplant renal dysfunction. In pediatric heart transplant recipients, higher CNI doses early post transplant, female sex, older age at transplant, early transplant era, pretransplant dialysis, longer duration of transplant listing, primary diagnosis of hypertrophic cardiomyopathy, African American race, renal dysfunction at 6 months post transplant, and previous transplant have emerged as risk factors. In pediatric lung transplant patients, older age at transplant and the diagnosis of cystic fibrosis have been implicated, whereas in a mixed population of pediatric (66%) and adult (34%) intestinal transplant patients pretransplant renal impairment, pretransplant intensive care unit hospitalization, and high-dose tacrolimus therapy emerged as risk factors. The drivers of posttransplant renal dysfunction in pediatric kidney graft recipients are more complicated and diverse. In this population, “chronic allograft nephropathy” may reflect chronic rejection, polyoma (BK virus) and other viral infections, and recurrent primary disease in addition to CNI nephrotoxicity.
| Organ (Number of Patients) | Posttransplant Follow-Up Period | Definition of Renal Failure/Dysfunction | Incidence of Renal Dysfunction | References |
|---|---|---|---|---|
| Heart (2032) | Mean 7 y | Serum creatinine >2.5 mg/dL | 11.8% | |
| Heart (91) | Median 5 y | mGFR <90 mL/min/1.73 m 2 | Cumulative incidence of 67% at 5 y, 8% with mGFR <30 mL/min/1.73 m 2 by 7 y post transplant | |
| Heart (77) | Median 5.1 y | cGFR <90 mL/min/1.73 m 2 | 17% at 1 y, 38.7% at 5 y | |
| Lung (125) | Mean 4.9 y | cGFR with National Kidney Foundation Chronic Kidney Disease staging | 38% cGFR <60 | |
| Lung (19) | Mean 5.36 y | cGFR <80 mL/min/1.73 m 2 | 63% | |
| Liver (352) | At 5-y visit | cGFR <90 mL/min/1.73 m 2 | 13% | |
| Liver (117) | Mean 7.6 y | mGFR <70 mL/min/1.73 m 2 | 32% | |
| Liver (101) | Median 6 y | mGFR <90 mL/min/1.73 m 2 | 28.7% | |
| Intestinal (62 total, 45 pediatric) | Mean 30 mo | cGFR <75% of normal | 16% |
Additional, genetic susceptibility factors to CNI nephrotoxicity have been hypothesized for some time, and may be related to the pharmacokinetic pathway of CNI absorption and metabolism. The complex pharmacokinetics of these drugs are affected by the biologic activity of the p -glycoprotein cellular efflux pump (coded for by the gene ABCB1) and the cytochrome P450 enzyme system. The protein product of ABCB1, multidrug resistance protein 1 (MDR1), pumps a variety of compounds, including the CNI, from the cytoplasm to the cell exterior, while CYP3A4 is responsible for the oxidative metabolism of the drugs. The combined activity of these proteins in the intestinal epithelial cell creates an absorptive barrier, limiting CNI bioavailability and, thus, drug contact. In addition, these proteins are present in the kidney (MDR1) and the liver (CYP3A4), thus both donor and recipient genetic variation may be relevant. Genetic polymorphisms, some of which influence the level of protein expression or activity, have been identified in both genes, and have been correlated with differing CNI dose requirements in adult renal and adult liver transplant recipients. In addition, single reports have found associations between single nucleotide polymorphisms (SNPs) in ABCB1 and nephrotoxicity in adult liver and renal transplant recipients.
In the complex pathway leading to CNI-induced nephrotoxicity, one of the final common mediators of the long-term structural kidney damage is the multifunctional, profibrogenic cytokine transforming growth factor (TGF)-β1. The CNI induce transcription of TGF-β1 in cultured renal tubular cells, rodent models, and human transplant recipients, and intrarenal levels of TGF-β1 RNA and protein correlate with the histologic findings of CNI-induced nephrotoxicity. Reports in a predominantly adult population of cardiac transplant recipients have identified an SNP in codon 10 of the signal sequence of TGF-β1 that is associated with posttransplant renal dysfunction. Polymorphisms of the renin-angiotensin system have also been implicated as genetic risk factors for posttransplant renal dysfunction in adult kidney transplant recipients.
Strategies for management of posttransplant renal dysfunction have largely focused on CNI minimization, replacement, or avoidance. Delayed introduction of CNI post transplant via use of induction immunosuppression with either antithymocyte globulin or anti-CD25 monoclonal antibody has been postulated to preserve renal function (and protect kidney grafts from delayed graft function) by protecting the kidney from acute CNI-induced injury during the vulnerable immediate posttransplant period, when rapid fluid shifts, blood pressure instability, and multiple potentially nephrotoxic medications may impact renal function.
Introduction of adjuvant immunosuppression with mycophenolate mofetil (MMF) in combination with decreased CNI dose is a widely employed method for preventing or managing renal dysfunction. CNI minimization with MMF has resulted in improvements in renal function (defined by either serum creatinine, calculated GFR, or measured GFR) in pediatric liver and heart transplant patients. In addition, studies in pediatric renal transplant recipients have shown improved renal function with addition of MMF to a CNI-based regimen, with or without simultaneous decreases in CNI dosing. This finding suggests that the benefit in these patients may be related to a combination of more effective immunosuppression and decreased CNI exposure.
Although less frequent, combination therapy with low-dose CNI and the non-nephrotoxic mTor inhibitor sirolimus has been associated with improved short-term renal function in pediatric heart transplant recipients. However, this strategy may hold some risk. Although sirolimus alone is not nephrotoxic, there are concerns about its use in combination with CNI, in which instance potentiation of CNI nephrotoxicity has been reported. There are also concerns regarding early posttransplant use of sirolimus associated with delayed graft function in renal transplant patients and hepatic artery thrombosis in liver transplant patients. Although these associations have not been confirmed in large, multicenter studies these concerns, in addition to the delayed wound healing seen with sirolimus, have limited its use early post transplant. In contrast, late replacement of CNI with sirolimus may be a promising strategy, and has been associated with improvements in serum creatinine and calculated GFR in pediatric and adult solid organ recipients.
The best combination of immunosuppressive agents for maintenance of excellent graft function while minimizing nephrotoxicity is unclear, and may need to be individualized based on patient- and organ-specific factors. In addition, the ideal timing of changes in immunosuppression is unknown. There are likely to be thresholds of renal function or time since transplant, beyond which changes in regimen are not effective at reversing renal disease. Identification of these thresholds is an area that requires further investigation.
The use of antihypertensive medications is another mechanism for renal protection. Calcium channel blockers and angiotensin-converting enzyme (ACE) inhibitors have both been associated with retained renal function post transplant; this is certainly related, in part, to the impact on blood pressure, chronic elevation of which can exacerbate kidney damage. However, these medications, particularly ACE inhibitors and angiotensin receptor blockers (ARBs), may have additional, direct beneficial effects on the pathway of CNI-induced nephrotoxicity, which involves activation of the renin-angiotensin system and downstream production of proinflammatory cytokines.
Attempts to minimize the impact of renal dysfunction on long-term posttransplant health and quality of life would be furthered by identification of easily available, noninvasive mechanisms for accurately assessing renal function, or biomarkers of early renal insufficiency. Formulas for estimating GFR based on serum creatinine are notoriously inaccurate in children following solid organ transplantation, routinely overestimating renal function. Estimation of GFR using cystatin-C–based equations may hold some promise in this area. In limited reports to date, cystatin C, a serum protein produced by all nucleated cells, independent of muscle mass, and freely filtered across the renal glomerular membrane, appears to be more accurate than serum creatinine at identifying mild and moderate degrees of renal dysfunction.
Additional renal complications following solid organ transplantation include proteinuria and renal tubular dysfunction leading to hyperkalemia, hypomagnesemia, and metabolic acidosis. Proteinuria has been reported both in association with, and independent of decreased GFR, and is additionally a side effect of sirolimus. In fact, proteinuria can be a limiting factor in the use of this otherwise renal sparing medication. Proteinuria is a harbinger of later renal dysfunction in diabetic nephropathy, although its prognostic importance in the nondiabetic population is less clear.
Role of the Primary Care Provider
As in many aspects of chronic care, the primary care provider (PCP) is an essential member of the management team. In providing routine well-child care, management of acute illness, anticipatory guidance, and standard monitoring, the pediatrician often acts as the first line of defense against posttransplant complications. Detection and management of renal dysfunction is no exception. Heightened attention on the part of the PCP with regard to blood pressure monitoring is essential. Ensuring that a blood pressure is obtained with the appropriately sized cuff at each visit (acute care in addition to well child), and that abnormal blood pressures (≥95% systolic or diastolic for age, sex, and height) is repeated expeditiously, is paramount. Close communication with the transplant center regarding the use of commonly prescribed antibiotics (which may impact CNI metabolism, leading to toxic levels and subsequent renal damage) and attention to the increased risk of dehydration in pediatric transplant patients, whose kidneys may already be compromised, are additional responsibilities.
Cardiovascular complications
Several epidemiologic studies have shown that solid organ transplant recipients have an increased prevalence of risk factors for cardiovascular disease, often resulting from preexisting disease as well as the consequences of the transplant procedure and posttransplant regime. Immunosuppressive agents are the primary culprits of cardiovascular toxicity, increasing the likelihood of hypertension, hyperlipidemia, hypercholesterolemia, and diabetes mellitus. For example, glucocorticoids and CNI are well-known precipitants of posttransplant hypertension, which has been documented in 62% to 75% of pediatric patients ( Table 2 ).
| Organ | Prevalence | References | ||
|---|---|---|---|---|
| 2 years | 5 years | 7 years | ||
| Kidney | 75% | 70% | North American Pediatric Renal Transplant Cooperative Study | |
| Liver | 14.5%/15.7% | Studies in Pediatric Liver Transplantation | ||
| Heart | 64.7% | International Society for Heart and Lung Transplantation | ||
| Lung | 71.6% | |||
Although both tacrolimus and cyclosporine can cause significant hypertension, cyclosporine appears to have a more dramatic impact on blood pressure. A retrospective study of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database revealed that patients receiving tacrolimus/mycophenolate mofetil/steroids were less likely to require antihypertensive medications at 1 and 2 years post transplant compared with patients receiving cyclosporine/MMF/steroids. A similar result was documented by Jain and colleagues in pediatric liver transplant patients, in which there was a significant reduction in the incidence and severity of hypertension in patients treated with tacrolimus compared with those on cyclosporine.
The mechanism of drug-induced hypertension in solid organ transplant recipients likely involves renal and peripheral vasoconstriction via the renin-angiotensin system and the sympathetic nervous system, as well as release of various vasoconstrictors into the bloodstream. Glucocorticoid therapy is hypothesized to precipitate activation of the renin-angiotensin system, increase vasopressor responses to norepinephrine and angiotensin II, and reduce activity of vasodepressor systems such as the endothelial-derived vasodilator nitric oxide. The pathogenesis of CNI-dependent hypertension is comparatively complex. Acute administration of CNI induces sympathetic neural activity, and prolonged therapy often precipitates chronic sympathetic overactivity. Similar to treatment with glucocorticoids, CNI also stimulate the renin-angiotensin system while additionally up-regulating angiotensin II receptors in vascular smooth muscle.
Although rare, hypertrophic cardiomyopathy is a serious complication associated with tacrolimus therapy. A study by Nakata and colleagues found a relationship between high blood levels of tacrolimus and increased myocardial hypertrophy in a predominantly pediatric population. Specifically, the patients whose blood levels of tacrolimus were above 15 ng/mL had a higher percentage of left ventricular wall thickness than that of patients whose blood levels were less than 15 ng/mL. This life-threatening complication is specific to tacrolimus and mandates immediate discontinuation of that medication.
Treatment of vascular risk factors may reduce the incidence of cardiovascular disease in solid organ transplant recipients, further improving long-term survival. Specific management protocols for risk reduction include therapeutic lifestyle changes, alteration of immunosuppressive regimen, or addition of specific medications to address each risk factor or complication. As the mainstays of posttransplant immunosuppressive therapy, glucocorticoid and CNI-free protocols may be unrealistic. Adjustments of immunosuppressive regimens, however, may be feasible and more reasonable. Glucocorticoid withdrawal or reduction as well as choice of CNI may reduce the prevalence of cardiovascular risk factors and disease by decreasing rates of hypertension, dyslipidemia, or diabetes mellitus. All classes of antihypertensive medications, including calcium-channel blockers, β-blockers, ACE inhibitors, ARBs, and diuretics, have been implemented effectively based on risk profile and therapeutic category. In addition to surveillance of tacrolimus levels and other parameters, long-term monitoring of cardiac function may also be warranted in high-risk populations.
Novel strategies for identification of high-risk populations include potential biomarkers such as B-type natriuretic peptide (BNP) or endothelin-1 (ET), which are elevated in pediatric liver transplant patients with early cardiac damage. Because cardiovascular damage typically occurs decades before clinical outcomes become apparent, BNP and ET levels and trends may help identify patients to target for more intensive monitoring or novel interventions to reduce the risk of cardiovascular disease.
Role of the Primary Care Provider
Once again, the PCP plays a critical role in monitoring and identification of risk factors and disease. Aggressive blood pressure monitoring, determination of familial risk factors, and anticipatory guidance regarding lifestyle choices should be routine components of care, and can be reinforced between the transplant team and the PCP. In addition, the PCP may be presented with acute cardiac complications after transplant, including hypertensive crisis, vascular thromboses, and cardiomyopathy, all of which may present with vague symptoms not obviously related to the transplanted organ. Evaluation of the pediatric transplant recipient must include the potential for these complications, and prompt communication with the transplant team will help to ensure the best possible outcomes.
Cardiovascular complications
Several epidemiologic studies have shown that solid organ transplant recipients have an increased prevalence of risk factors for cardiovascular disease, often resulting from preexisting disease as well as the consequences of the transplant procedure and posttransplant regime. Immunosuppressive agents are the primary culprits of cardiovascular toxicity, increasing the likelihood of hypertension, hyperlipidemia, hypercholesterolemia, and diabetes mellitus. For example, glucocorticoids and CNI are well-known precipitants of posttransplant hypertension, which has been documented in 62% to 75% of pediatric patients ( Table 2 ).
| Organ | Prevalence | References | ||
|---|---|---|---|---|
| 2 years | 5 years | 7 years | ||
| Kidney | 75% | 70% | North American Pediatric Renal Transplant Cooperative Study | |
| Liver | 14.5%/15.7% | Studies in Pediatric Liver Transplantation | ||
| Heart | 64.7% | International Society for Heart and Lung Transplantation | ||
| Lung | 71.6% | |||
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