Often persisting for years after transplantation, the condition increases the risk of graft failure
 
By Warren L. Kupin, MD
 
HYPERTENSION is a common clinical problem in renal transplant patients, and it has important consequences for patient and graft survival. At five years after transplantation, more than 50% of patients have Stage I or Stage II hypertension and nearly 40% of patients have prehypertension. The proportion of patients receiving two or more antihypertensive agents after renal transplantation has increased steadily to about 55% during the past few decades (Am J Kidney Dis. 2004; 43:1071-1081). Despite the intensive clinical monitoring that follows renal transplantation, post-transplant hy-pertension often persists for years.

Etiologic factors

The etiology of hypertension in these patients is complex and includes a range of host, donor, allograft, and immunologic factors. Comorbidities are common in patients with end-stage renal disease awaiting transplantation, and these patients have increased rates of diabetes, hypertension, obesity, and glomerulonephritis. In normotensive patients, transplantation of a kidney from a donor with a family history of hypertension is associated with a 10-fold increase in the risk of post-transplant hypertension (J Am Soc Nephrol. 1996;7:1131-1138). Similarly, pre-existing hypertension in the recipient may be reversed by transplant of a kidney from a normotensive donor. Transplantation of a kidney from a hypertensive donor can worsen pre-existing hypertension in the recipient. The expansion of donor criteria has resulted in an increasing number of patients receiving kidneys from donors with hypertension and other risk factors.


Renal artery stenosis (RAS) is an important cause of post-transplant hypertension, and it occurs more frequently with the transplant of a kidney from a living donor than from a cadaver. Other risk factors for post-transplant RAS include pre-existing atherosclerotic disease or fibromuscular dysplasia in the donor, intimal damage during procurement or perfusion, and an end-to-end surgical anastomosis. RAS should be considered in any renal transplant patient with severe uncontrolled hypertension, an abdominal bruit over the anastomosis, and in recipients of kidneys from younger, Caucasian women.
The risk of hypertension is about 20% in patients receiving exogenous corticosteroid therapy, compared with 70% in those with Cushing’s disease (Blood Press. 1994;3:24-32). Steroid-induced hypertension is characterized by volume expansion, sodium retention, and increased sensitivity to catecholamines. In renal transplant patients receiving low-dose or alternate-day steroids, the risk of steroid-induced hypertension is minimal.

The incidence of post-transplant hypertension has increased concurrently with more widespread use of immunosuppression with calcineurin inhibitors. Nephrotoxicity is almost universal after 10 years of treatment with calcineurin inhibitors and may be accompanied by arterial hyalinosis, striped fibrosis, and tubular calcification (New Engl J Med. 2003;349:2326-2333). The risk of hypertension is lower in transplant recipients treated with tacrolimus than in those treated with cyclosporine A. Immunosuppression with rapamycin or mycophenolate mofetil is not associated with an increased risk of posttransplant hypertension.


Another important cause of posttransplant hypertension is CKD. The majority of renal transplant recipients have stage 3 or higher CKD and the risk and severity of hypertension increases in proportion to the degree of CKD in the allograft.

Patient, graft outcomes

CVD is the major cause of death in renal transplant recipients, and hypertension is a major risk factor for new-onset CVD following transplantation. CVD accounts for about 46% of overall mortality in patients with functioning renal allografts, followed by infection, malignancy, and other causes. An elevated pulse pressure one year after transplantation is associated with an increased risk for cardiovascular morbidity and mortality in renal transplant patients.

Hypertension directly influences graft survival after renal transplantation. The yearly rate of graft loss is 1.5% in patients who remain normotensive without antihypertensive treatment following transplantation, 2.1% in those who are normotensive with antihypertensive treatment, and 2.9% in those with hypertension despite antihypertensive treatment (Clin Transplant. 2005;19:181-192). A year after transplantation, BP is an independent risk factor for graft failure during the following six years.

Post-transplant BP predicts the rate of acute rejection in renal allograft recipients independently of graft function (Kidney Int. 2001; 59:1158-1164). For every level of post-transplant hypertension, the use of antihypertensive medications decreases the risk of acute allograft rejection. Graft survival following an episode of acute rejection is also negatively influenced by post-transplant hypertension. The mech-anisms by which post-transplant hypertension influence renal allo-graft function and survival are complex and may include direct effects on microvascular architecture and an independent effect on mediators of acute and chronic allograft nephropathy, including growth factors and major histocompatibility complex II antigens (Kidney Int. 2003;63:2302-2308).

Treatment

The American Society of Transplantation (AST) defines hypertension in adult renal transplant recipients who are not receiving antihypertensive medications as systolic BP of 140 mm Hg or higher or diastolic BP of 90 mm Hg or higher (J Am Soc Nephrol. 2000;11[Suppl 15]:S1-S86). The National Kidney Foundation recommends target BP values of 135/85 mm Hg for renal transplant recipients without proteinuria and 125/75 mm Hg for patients with proteinuria. Fewer than 30% of renal transplant recipients meet these goals.


BP may fluctuate during the early post-transplant period due to allograft dysfunction, changes in extracellular volume, administration of bolus corticosteroid therapy, and other factors. The BP target for avoiding graft ischemia during the early postoperative period is 160/90 mm Hg. Treatment recommendations for the control of immediate post-transplant hypertension include continued use of beta blockers, the use of a nicardipene drip if hypertension is uncontrolled, and initiation of calcium channel blocker (CCB) therapy if needed.

Dihydropyridine CCBs have been a mainstay of therapy for long-term control of post-transplant hypertension. Compared with ACE in-hibitors, these CCBs improve renal function, may reduce the incidence and severity of organ rejection, increase renal blood flow, and de-crease the risk of calcineurin in-hibitor-induced nephrotoxicity in renal transplant patients (Transplantation 2001;72:1787-1792). However, the consequences of the increase in renal blood flow on the chronic progression of allograft dysfunction have not been defined. Dihydropyridine CCBs also increase the degree of proteinuria and this may have a detrimental effect on long term allograft function. Treatment with dihydropyridine CCBs is associated with higher risks of peripheral edema, but less impairment of the hepatic cyto-chrome P-450 enzyme system, than is treatment with other types of CCBs. This is important because the pharmacokinetics of calcineurin inhibitors will be affected by drugs that alter the P-450 system, which in turn affects the degree of immunosuppression and toxicity of these agents.
Treatment with ACE inhibitors has traditionally been avoided during the early post-transplant period until serum creatinine levels have stabilized. However, recent studies have shown that these drugs can be introduced safely as early as four days post-transplant without affect-ing graft function. Compared with CCBs, ACE inhibitors are more often associated with graft rejection and hyperkalemia. Hyper-
tension control is similar with both drug classes, but post-transplant renal function at two-year follow-up is better with CCBs than with ACE inhibitors.

Angiotensin receptor blockers (ARBs) in the early post-transplant period have also been avoided
to prevent possible detrimental ef-fects on graft function. BP control is similar in hypertensive patients treated with CCBs or ARBs early after renal transplantation (Nephrol Dial Transplant. 2006;21:1389-1394). Hyperkalemia and anemia are more common in transplant patients treated with ARBs than in those treated with CCBs.

ACE inhibitors, CCBs and beta blockers all decrease left ventricular (LV) hypertrophy and improve LV diastolic function in renal transplant patients (Am J Cardiol. 2000;86:583-585). It appears that control of blood pressure is more important than inhibition of a specific biologic pathway. In patients with chronic allograft nephropathy, treatment with ACE inhibitors or ARBs is generally well tolerated
and may slow the progression of renal insufficiency and improve allograft survival. These agents would be of particular benefit in patients with proteinuria. 

Diuretic therapy is associated with an increased risk of volume depletion and worsening of calcineurin inhibitor-induced nephrotoxicity and is not a major initial component of the management of post-transplant hypertension.

In summary, hypertension is ubiq-uitous in renal transplant patients and similar to any patient with Stage 1 or Stage 2 hypertension.These patients often require two or three medications to achieve adequate BP control. Although subtle differences exist in side effects and benefits between the different classes of agents, most renal transplant recipients will usually benefit from a combination of a beta blocker, CCB, and ACEI/ARB. The most important post-transplant objective is to attain target blood pressure goals above all else. This will ultimately translate into improved allograft and patient survival. 
 
Dr. Kupin is associate professor of medicine and associate director of transplant nephrology at the University of Miami Jackson Memorial Medical Center in Florida.