Hypertension After Transplantation

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What is the definition of hypertension in transplant recipients?

The definition of hypertension in transplant recipients follows that of the general population. Most guidelines for the general population define hypertension as a persistent systolic blood pressure on two separate days of 140 mm Hg or higher and/or diastolic blood pressure of 90 mm Hg or higher if age is 18 years or older. More recent hypertension guidelines have established a definition of 130/85 mm Hg, but the applicability to transplant patients is unclear.

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What is the incidence and prevalence of hypertension after transplantation?

The reported incidence of hypertension varies among different solid organ transplants. In kidney transplant recipients, it ranges from 50% to 80% in adult recipients and from 47% to 82% in pediatric recipients. According to the International Society of Heart and Lung Transplantation registry, among heart transplant survivors with a 10-year follow-up between April 1994 and June 2006, hypertension was present in 98% of patients. In liver transplant recipients, the range has been reported to be from 50% to almost 100% in some series.

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What is the clinical importance of hypertension in kidney transplant recipients?

Hypertension in kidney transplant recipients is associated with an increased risk of cardiovascular death (CVD), increased risk of allograft failure and mortality, and increased risk of hospitalization.

• Increased risk of cardiovascular disease

  • Hypertension is a traditional risk factor for CVD, which is the leading cause of death in patients with a functional kidney transplant. The annual rate of fatal or nonfatal CVD events is 3.5% to 5.0% in kidney transplant recipients, 50-fold higher than in the general population. Uncontrolled systolic and diastolic blood pressures are associated with worsening left ventricular hypertrophy at 5 years posttransplant, which is also associated with increased CVD.

  • In addition, it has been reported that for every 20-mm Hg increase in systolic blood pressure, there is an associated 32% increase in the risk for cardiovascular events. Of note, each 10-mm Hg decrease in diastolic blood pressure below the 70-mm Hg level was found to be associated with a 31% increase in cardiovascular risk, but no such association emerged for diastolic blood pressure levels less than 70 mm Hg.

• Increased risk of allograft failure and mortality

  • Hypertension is a potent nonimmunological risk factor and is independently associated with an increased risk of both allograft failure and mortality. The Collaborative Transplant Study, a large cohort study of nearly 30,000 kidney transplant recipients showed a graded association between both systolic and diastolic blood pressure and allograft failure. Moreover, increasing systolic pressure was associated with decreased graft survival at any level of diastolic blood pressure. In addition to decreased allograft survival, hypertension after transplant was associated with decreased patient survival. Each 10-mm Hg increase in systolic blood pressure above 140 mm Hg was associated with a hazard ratio (HR) of death of 1.18 (95% confidence interval [CI], 1.12–1.23). This risk persisted after adjusting for allograft function.

• Increased risk of hospitalization

  • Among kidney transplant recipients, hypertension is the second most common cause of cardiovascular- related hospitalization in the first year after transplantation, accounting for approximately 13% of admissions after heart failure. It is the fourth leading cause of hospitalization (approximately 7%) in the second year after transplantation.

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What is the pathogenesis of hypertension after kidney transplantation?

The pathogenesis of hypertension after kidney transplantation is related to several factors which are discussed below and are summarized in Fig. 19.1 .

• Endothelial dysfunction

  Endothelial dysfunction is associated with hypertension, and it predicts atherosclerosis progression and cardiovascular events in the general population. This is related to one or more of the following factors:

  • The imbalance between vasoconstrictive molecules (endothelin, thromboxane, and prostaglandins) and vasodilatory nitric oxide. This can be caused by calcineurin inhibitors (CNIs).

  • Increased generation of reactive oxygen species which can be seen in chronic inflammation, ischemia-reperfusion injury (which can manifest as delayed graft function after transplant), and increased angiotensin II (Ang II).

  • Acute rejection episodes, whether T-cell or antibody-mediated, leading to endothelial injury. This can alter renal blood flow, impair kidney function, and increase the risk of fibrosis and loss of kidney function.

• Arterial stiffness

  Arterial stiffness is a manifestation of hypertension but may also represent a cause of hypertension. Some studies have shown that CNIs accelerate the arterial stiffness process, whereas belatacept-based regimens seem to offer better vascular protection compared with CNIs.

• Renin-angiotensin-aldosterone system (RAAS) activation

  Activation of the RAAS leads to the production of Ang II, and acting through angiotensin II type 1 (AT ₁ ) receptors on cell membranes, leads to potent vasoconstriction of all blood vessels. It also causes the adrenal glands to release aldosterone, which increases reabsorption of salt and water, thereby leading to an increase in blood volume and elevated blood pressure. Increased activity of RAAS is seen in the presence of remaining ischemic native kidneys, transplant renal artery stenosis, increased sympathetic stimulation, and CNIs, among others.

• Sodium and water retention

  Sodium and water retention can be seen in those with low nephron mass and low glomerular filtration rate (GFR), due to the kidney’s reduced capacity to excrete sodium. CNIs cause increased sodium reabsorption via the increased activity of the thiazide-sensitive sodium-chloride cotransporter (NCC) and Na-K-2Cl cotransporter (NKCC2). As mentioned previously, upregulation of RAAS increases Ang II, leading to stimulation of aldosterone release. This induces the upregulation of Na ⁺ /K ⁺ -ATPase and epithelial sodium channel (ENaC) in the distal convoluted tubule and collecting duct. Ang II also stimulates the production of arginine vasopressin (AVP), which also modulates NCC function.

• Sympathetic nervous system activation

  Increased sympathetic nervous system activity has been implicated in the initiation, maintenance, and progression of posttransplant hypertension. Several factors can increase the activity of the sympathetic nervous system such as conditions that increase Ang II, comorbidities such as obesity and obstructive sleep apnea, and drugs such as CNIs.

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