Transplant Hypertension

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.

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.