Hypertension is a common feature after solid organ transplantation, related to preexisting disease, the vascular effects of immunosuppressive medications, and in the setting of renal transplantation, the presence of acute or chronic allograft morbidity. Transplant patients frequently carry a heavy burden of atherosclerotic disease involving multiple vascular beds and thus are at increased risk for cardiovascular events including myocardial infarction, congestive heart failure, and stroke. Hypertension may be a cause or a complication of native kidney disease or renal allograft injury. Regardless of which presents first, hypertension may accelerate further renal decline, particularly when proteinuria is present. Thus transplant recipients require meticulous attention to blood pressure (BP) control.
Hypertension following solid organ transplantation affects not only kidney recipients, but also heart, liver, and bone marrow recipients. Its presence after transplantation may be a continuation of pretransplant hypertension; a result of immunosuppressive medication effects, particularly of calcineurin inhibitors (CNIs) and corticosteroids; or a result of sodium and volume retention. The severity and persistence of this condition relate to the type of organ transplanted, primarily a result of the immunosuppression regimen used in that setting, and the level of native and/or allograft renal function. Although there are nuances for management that relate to the type of solid organ transplanted, most concepts salient to renal transplantation, which has been subject to more studies, also apply to the other posttransplant settings. The subsequent discussion will focus on renal transplant recipients.
Historically, the incidence of hypertension after renal transplant increased from between 45% and 55% to between 70% and 90% with the adoption of CNI-based (cyclosporine, then tacrolimus) immunosuppression. In this setting, worsening or de novo hypertension may result from reduced renal function caused by CNI agents, rejection, chronic allograft injury, or hypoperfusion resulting from transplant renal artery stenosis (RAS). As immunosuppressive medication doses are reduced with time after transplant, hypertension severity often declines, resulting in improved control. Even so, current control rates are suboptimal, and treatment can be challenging.
Concern has been raised within the transplant community regarding the flat survival rates for renal transplant recipients in recent years. Premature death of a patient with a functioning graft, often resulting from cardiovascular (CV) disease, has become a major cause of transplant failure. Nonimmunologic factors such as hypertension, are major determinants of long-term kidney graft survival. Observational studies have shown hypertension to be an independent risk factor for CV disease after kidney transplantation, suggesting that transplant recipients would benefit from improved BP control. Levels of BP 1 year after renal transplant predict allograft survival over subsequent years. Even so, improved BP control can reduce ongoing renal allograft injury and improve long-term graft survival. Thus it is essential that clinicians caring for transplant patients focus on hypertension control to improve CV risk, minimize renal dysfunction, and promote long-term success of the renal allograft.
Pathogenesis
Immunosuppressive Therapy
Posttransplant hypertension is directly related to administration of CNI agents in combination with corticosteroids. It is less common when CNIs are used without corticosteroids in the liver transplant setting, although prevalence rates did not differ in steroid minimization trials following renal transplantation. The rate of rise in BP and accelerated CV risk are more prominent with cyclosporine; however, prevalence rates of posttransplant hypertension with cyclosporine and tacrolimus are similar by 1 year after transplant. With the higher doses of corticosteroids used for induction, BP may be particularly elevated during the first weeks to months following transplantation. Vasoconstriction in the kidney results in decreased renal blood flow and glomerular filtration rate (GFR) within hours of CNI administration, leading to reduction in sodium excretion. These changes may reverse if treatment is discontinued or the dosage is reduced. Sustained administration of CNIs results in vascular and interstitial changes that eventually become irreversible.
The primary hemodynamic consequence of CNI is an increase in systemic vascular resistance caused by widespread vasoconstriction. Calcineurin inhibitors activate the renin-angiotensin system through a direct effect on the juxtaglomerular cells and indirectly via renal vasoconstriction, with high intrarenal renin activity, yet low systemic circulating levels. Cyclosporine augments the vasoconstrictive effects of angiotensin II. CNI-induced imbalance in circulating vasoconstrictor (endothelin and thromboxane) and vasodilatory (prostacyclin and nitric oxide) compounds results in impaired vasodilation. It is likely that CNIs alter function of the endothelium by shifting the relative balance of vasoconstrictive and vasodilatory pathways. Direct aggravation of hypertension by CNIs has been confirmed by the reduction in BP that occurs with later conversion to a non–CNI-based immunosuppressive regimen. This happens despite equally severe renal dysfunction in patients whose hypertension improves.
Azathioprine and mycophenolate mofetil have not been associated with hypertension. Effects of sirolimus on BP are less clear, but reports of BP-lowering with conversion from cyclosporine to sirolimus support either fewer or no hypertensive effects. Belatacept-based immunosuppression is associated with higher GFR and preservation of renal function. As reported from the long-term extension of the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT) Study, hypertension is still present in the majority of patients, although fewer agents were needed to achieve BP goals and reported BP levels were lower with Belatacept than for cyclosporine-treated control subjects.
Glucocorticoids can cause or worsen hypertension, even in the absence of a mineralocorticoid effect, and may explain up to 15% of posttransplant hypertension. At the higher doses used early after transplantation, some activation of mineralocorticoid receptors occurs, manifested by potassium wasting, especially with high sodium intake. Glucocorticoid effects include increased cardiac output and enhanced pressor responses to epinephrine, angiotensin II, and other pressure stimuli. The role of corticosteroids in CNI-induced hypertension is complex. Although glucocorticoids alone rarely have major effects on BP in normal subjects, corticosteroids administered in immunosuppressive doses to patients with impaired renal function commonly elevate BP and aggravate hypertension. Hence, it is likely that both CNIs, corticosteroids, and their combination are major elements in the prevalence and severity of posttransplant hypertension.
Renal Allograft Factors
Blood pressure alterations may provide clues to subclinical acute rejection, hypoperfusion, or chronic allograft nephropathy. Causes of posttransplant hypertension occurring within the first 3 months after transplant generally differ from those causing late or persistent hypertension ( Box 34.1 ). This distinction is useful when considering possible causes and choosing appropriate treatment. Transplant complications such as rejection, organ preservation injury, and transplant RAS can impair renal function and worsen hypertension. Severe hypertension during the early postoperative period is more common in those with severe hypertension before transplant, in African Americans, and in patients with delayed graft function. Primary mediators include hypervolemia, high CNI and glucocorticoid doses, withdrawal of preoperative antihypertensive medications, and postoperative pain. Beyond the first 3 months, hypertension may relate to donor variables, as donor age and donor hypertension are strongly associated with graft function. A well-functioning renal allograft frequently improves and may even normalize BP in the recipient.
Within the First 3 Months
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Pretransplant hypertension
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African-American race/ethnicity
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Renal allograft dysfunction
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Renal outflow obstruction
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Hypervolemia
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High-dose calcineurin inhibitors
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High-dose corticosteroids
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Postoperative pain
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Discontinuation of pretransplant antihypertensive medications
During Long-Term Care
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Donor variables
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Increased donor age
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African-American donor
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Hypertensive donor
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Recipient variables
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Older age
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African-American race/ethnicity
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Male gender
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Obesity
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Diabetes mellitus
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Pretransplant hypertension
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Native kidney disease
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Renal allograft dysfunction
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Recurrent primary renal disease
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Immunosuppressive medications
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Calcineurin inhibitors
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Corticosteroids
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Transplant renal artery stenosis
Hypertension after transplantation is both a sign of kidney disease and a cause of kidney dysfunction. Renal transplant recipients with lower renal function (creatinine clearance <60 mL/min) in the first year are more likely to develop posttransplant hypertension. Alternatively, hypertension is associated with reduced renal allograft survival, independent of renal function. In a retrospective series of 1600 renal transplant recipients, for each 10 mm Hg rise in systolic BP, the risk for allograft loss increased by 12% to 15%. Worsening hypertension suggests acute or chronic graft pathology that may be otherwise clinically silent. Hypertension is likely to worsen with declining allograft function and may be particularly severe in those with chronic transplant glomerulopathy or focal segmental glomerulosclerosis developing late after transplant.
Transplant RAS may present as de novo or worsening hypertension, or a decline in renal function precipitated by BP treatment, particularly with use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Although it may manifest at any time, it is most commonly diagnosed between 3 months and 2 years posttransplant. Anastomotic stenosis is more likely in recipients of pediatric deceased donor kidneys related to smaller donor vessels, and in recipients of living donor kidneys related to the nature of the anastomotic technique without use of a donor aortic patch. Risk factors include older recipient age, male gender, smoking, and preexisting diabetes. Stenosis of the iliac artery is likely to be as a result of atherosclerotic disease and may be associated with other symptoms of peripheral vascular disease. A critical iliac artery stenosis may present with classic features of renovascular hypertension including sudden circulatory congestion or flash pulmonary edema. Stenosis of the allograft artery may result from atherosclerotic disease of donor origin or, more often, progressive stenosis at the surgical anastomotic site.
Clinical Features
Many features of posttransplant hypertension are similar to those of the general population with hypertension, including higher prevalence in African Americans, males, and those at higher weight or body mass index. Recipients with preexisting diabetes are more likely to be hypertensive, with primarily systolic hypertension and widened pulse pressures. Studies in nontransplant populations implicate arterial stiffening as the cause for this pattern, which is associated with greater CV risk.
Hypertension developing after organ transplantation is characterized by abnormal circadian BP rhythm ( Fig. 34.1 ), with absence or reversal of the 10% to 20% nocturnal fall commonly seen in normal subjects and those with primary hypertension. The magnitude of this fall is often blunted after transplantation, and some patients develop a paradoxical rise, with their highest pressures in the overnight hours. In the nontransplant setting, loss of nocturnal BP fall is associated with accelerated target organ damage, including left ventricular hypertrophy (LVH), lacunar stroke, and microalbuminuria. Similarly, nocturnal BP elevations may predispose transplant recipients to renal allograft injury and accelerated atherosclerotic complications. This phenomenon is best documented using overnight ambulatory BP monitoring (ABPM). Circadian reversal has been observed following heart, liver, and kidney transplantation, most commonly in the first year. Serial studies suggest that some patients will regain more normal circadian BP patterns within the first year after transplantation. In a study of 241 renal transplant recipients at a median ABPM to transplant interval of 14 weeks, abnormal systolic diurnal variation correlated positively with age, serum creatinine, and blood cyclosporine trough level, and negatively with GFR and the time interval from transplantation. In this series, 21% of patients had isolated nocturnal hypertension with normal daytime pressures. Only age and GFR were independent predictors of abnormal systolic diurnal variation.
Evaluation
The diagnosis of hypertension in transplant recipients follows criteria published in national guidelines, currently from the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7). BP should be measured at every clinic visit and home self-measurement should be encouraged. Elevated office BP measurements should be verified by standardized nurse or serial device measurements, ABPM, or home self-measurement. In recent years, growing recognition of the importance of nocturnal BP levels and the presence of white coat and masked hypertension in transplant recipients has led to greater use of out-of-office measurements, particularly ABPM.
Renal function must be closely followed, as a decline in GFR may indicate rejection or hemodynamic compromise. A renal allograft biopsy often provides clinically useful information, including the presence of subclinical acute rejection, recurrent or de novo glomerulopathies, CNI toxicity, viral infections, or other pathologic changes that require modifications in treatment. Transplant RAS may be difficult to diagnose. Low-pitched systolic bruits are common over the surgical anastomotic site without stenosis; even systolic-diastolic bruits may occur as a result of arteriovenous fistulas caused by allograft biopsy. Several Doppler ultrasound series report arterial stenosis prevalence rates of 9% to 12%, but the technique requires operator expertise because of variability in the angles required to visualize the transplant renal artery. Magnetic resonance angiography has been reported to give a high proportion of false-positive results, although visualization is superior. Treatment by endovascular repair with angioplasty or stenting can provide recovery of blood flow with improvement or stabilization of renal function. Restenosis is common and may require surgical correction of the stenotic segment.
Treatment
Treatment goals for posttransplant hypertension are theoretical, based on limited trial data and patterned after goals advised for the general population and particularly those designed for patients with chronic kidney disease. Some transplant guidelines continue to advise BP target levels less than 130/80 mm Hg, especially for high-risk subpopulations, including those with diabetes or proteinuric renal disease. In the initial days after transplantation, renal perfusion is critical and blood pressure may be maintained above ideal targets to ensure optimal blood flow. During the first several weeks after transplant, rapid changes in immunosuppression, volume shifts, and changes in renal function require close monitoring of serum creatinine as a marker of renal function. Concurrent rapid changes in antihypertensive treatment may affect serum creatinine levels and implicate antihypertensive agents as the cause of renal function loss, resulting in dose reductions and inadequate control long-term. Thus, early after transplantation, BP should be lowered gradually to less than 150/90 mm Hg, with intensification of therapy later. By one month after transplant, targets should be tightened to less than 140/90 mm Hg as immunosuppression targets are reduced including corticosteroid dose for those maintained on corticosteroids long-term. Beyond the first 3 months, increasing evidence supports more aggressive efforts to achieve lower BP targets to prevent CV disease progression and kidney allograft injury. These targets are currently in evolution for the general and CKD population related to results of recent trials indicating better outcomes with targets as low as 120 mm Hg systolic. Whether or not the same targets are optimal for transplant recipients are uncertain as these patients were not included in the trials. Patients should be provided with their current BP readings, along with specific BP goals.
Control of BP after transplantation can be challenging for many reasons, including polypharmacy, impaired graft function, older age, and comorbidities. Clinical inertia, defined as failure to initiate or intensify therapy when warranted, is increasingly recognized in the general population, but also occurs in the transplant setting. Use of an automated device (e.g., BPTRU, Conquitlam, British Columbia, Canada, Omron Healthcare, Lake Forest, Illinois) and ABPM provide standardized, repeated measurements that more closely reflect out-of-office readings and thereby reduce measurement uncertainty for the provider and reassure the patient that changes need to be made. Use of home measurements provides essential feedback to transplant recipients, and clear targets facilitate improved and appropriate communication with providers. If there is a discrepancy between home and automated office readings, check the accuracy of the home monitor and the patient’s measurement technique.
Nonpharmacologic Therapy
Although efficacy has not been demonstrated in the renal transplant population, lifestyle modification has documented value for BP-lowering in primary hypertensives, patients with chronic kidney disease (CKD), and elderly populations. These interventions are generally not harmful and may provide other health benefits; thus they should be recommended to transplant recipients as well. As in the general population, obesity is increasingly common, with most recipients gaining weight after transplantation. Weight gain is often associated with worsening hypertension, and even modest weight loss may produce measurable BP reductions.
Increased plasma volume occurs commonly as a compensatory response to antihypertensive therapy and may manifest as fluid retention (weight gain, edema) or a poor response to increased antihypertensive medications. High sodium intake and obesity contribute to increased plasma volume. Hence, sodium restriction enhances the antihypertensive efficacy of most BP medications and will minimize diuretic-induced potassium wasting. Because renal transplant recipients are more sensitive to polyuria and hypovolemia over the first several months after transplantation, extreme sodium restriction should be avoided. For chronic management, restricted sodium intake may be an effective ancillary treatment. Regular exercise decreases BP primarily by facilitating weight loss. The use of the Dietary Approaches to Stop Hypertension (DASH) diet may benefit transplant patients but should be introduced with caution, given that its emphasis on vegetable-based foods may worsen hyperkalemia in patients receiving CNIs.
Pharmacologic Therapy
General Concepts
Most treatment principles relevant to treating primary hypertension apply to transplant recipients as well. Treatment may require two or more antihypertensive agents to achieve recommended BP targets.
Transplant recipients are exposed to complex drug regimens with a high potential for serious drug interactions. Particular attention should be paid to selection of calcium channel blockers (CCBs) metabolized through the cytochrome P450 pathways because their effects of enhancement or blunting of CNI metabolism may induce major changes in CNI levels and trigger rejection or drug toxicity. Transplant recipients may develop unique side effects and have a higher incidence of known side effects that occur less commonly in other populations of patients with hypertension. Antihypertensive agents may affect kidney function, and agent and dose changes should be introduced gradually and require close monitoring.
Lacking prospective data testing the efficacy and safety of each agent in transplant recipients, treatment recommendations are based on clinical experience. Advantages and disadvantages of specific agents and recommendations for the transplant setting are listed in Table 34.1 . Several principles merit emphasis. The choice of antihypertensive agent should take into account the reduced GFR and renal vasoconstriction universally present. Uric acid levels are elevated, sometimes profoundly. Calcineurin inhibitors partially inhibit renal potassium and hydrogen ion excretion, predisposing patients to hyperkalemic metabolic acidosis. Diuretic therapy is often avoided to prevent worsening of azotemia and hyperuricemia. Aldosterone antagonists and other potassium-sparing agents must be used with caution. ACE inhibitors and ARBs, when used alone, may have limited efficacy early posttransplant and may aggravate both hyperkalemia and acidosis.
