INTRODUCTION — Hypertension is prevalent in most patients with end-stage kidney disease (ESKD)/advanced chronic kidney disease (CKD). The blood pressure frequently often rises early after kidney transplantation after saline loading interacts with initial high-dose immunosuppression. Long-term blood pressure is often easier to control after transplantation, as long as the individual achieves a good glomerular filtration rate (GFR). However, poorly controlled blood pressure is common among kidney transplant recipients [1-4]. In a single-center study, for example, only 5 percent of kidney transplant patients were normotensive, as defined by blood pressures less than 130/80 mmHg, as measured by ambulatory blood pressure monitoring [2].
Elevated blood pressure and pulse pressure can result in decreased allograft survival and left ventricular hypertrophy, with the latter being an independent risk factor for heart failure and death in the general population and kidney transplant recipients [5-9].
RISK FACTORS AND PATHOGENESIS — The following risk factors have been associated with a higher incidence of posttransplant hypertension [6,10-14]:
●Delayed and/or chronic allograft dysfunction
●Deceased-donor allografts, especially from a donor with a family history of hypertension
●Presence of native kidneys
●Cyclosporine, tacrolimus, and/or glucocorticoid therapy
●Increased body weight
●Renal artery stenosis
There is suggestive evidence that the transplanted kidney may have prohypertensive or antihypertensive properties. Multiple cross-transplantation studies in experimental models of genetic hypertension have shown that the inherited tendency to hypertension resides primarily in the kidney [15]. A similar relationship may exist in humans. In one report, transplantation of a kidney from normotensive donors with a negative family history of hypertension led to prolonged normotension in six recipients with a prior history of end-stage kidney disease (ESKD) due to benign nephrosclerosis and resistant hypertension while on dialysis [16].
A larger study of 85 patients found that elevations in blood pressure and increased antihypertensive drug requirements occurred much more frequently in recipients from "normotensive" families who received a kidney from a donor with a "hypertensive family"; a family history of hypertension in the recipient blunted the effect of a "hypertensive" kidney [17]. A follow-up study found that a "hypertensive" kidney transplanted into a recipient from a "normotensive" family had a greater hypertensive response during an acute rejection episode than did all other donor-recipient combinations [18].
The mechanism by which genetic factors affect kidney function and predispose to the development of hypertension are not known. (See "Genetic factors in the pathogenesis of hypertension".)
The importance of other factors that promote the development of hypertension varies at different times after transplantation. In the immediate posttransplant period, for example, an acute elevation in blood pressure usually reflects volume overload, graft dysfunction due to rejection, ischemia, or calcineurin inhibitor toxicity. Reversal of rejection or removal of excess fluid with diuretics or dialysis will lower the blood pressure in many cases [10].
Studies in cardiac transplants suggest that sympathetic activation may be an additional factor that can raise the blood pressure [19]. An alternate hypothesis is that the increase in vascular resistance results in inadequate relaxation rather than active vasoconstriction [20].
Role of glucocorticoids — Most patients need maintenance antihypertensive therapy, especially if pulse or high-dose daily glucocorticoids and/or cyclosporine/tacrolimus are given. Glucocorticoids are usually not a major risk factor for chronic hypertension in transplant recipients because of rapid dose reduction. They may, however, play a contributory role since gradual withdrawal of glucocorticoid therapy from stable kidney transplant recipients results in a fall in blood pressure in most patients; this effect is greatest in those with preexisting hypertension [21]. However, in a randomized trial of steroid avoidance or continuation with 5 mg daily from three months, there was no difference in the incidence of hypertension or number of drugs needed to manage hypertension [22].
Role of calcineurin inhibitors — Prior to the introduction of cyclosporine for maintenance immunosuppressive therapy, posttransplant hypertension was most often mediated by activation of the renin-angiotensin system, either in the native kidneys or in the rejecting allograft [23]. Although these factors may still contribute, calcineurin inhibitors play a predominant role if administered, raising the blood pressure in almost all patients and producing overt hypertension in many cases [11,12,24].
The importance of cyclosporine can be appreciated from results in bone marrow and cardiac transplantation, settings in which kidney dysfunction is less likely to be present. The incidence of hypertension after these procedures was below 10 percent prior to the availability of cyclosporine, but is approximately 30 to 60 percent after bone marrow transplantation and 70 to 100 percent after cardiac transplantation [12,25]. Although blood pressure is reportedly lower with tacrolimus than with cyclosporine [26], the combination of sirolimus and tacrolimus can exacerbate underlying hypertension [27]. (See "Cyclosporine and tacrolimus nephrotoxicity".)
Cyclosporine acts by increasing both systemic and renal vascular (primarily affecting the afferent arteriole) resistance. How this occurs is incompletely understood. Increased release of vasoconstrictors, particularly endothelin, has been thought to play an important role [28-30]. As an example, cyclosporine continues to induce transient renal vasoconstriction with prolonged therapy in humans; this response is temporally related to an elevation in urinary endothelin excretion [30]. A pathogenetic role for endothelin in this setting is suggested by the observation in rats that the administration of an endothelin receptor antagonist blunts the rise in blood pressure induced by cyclosporine [28,29]. Additional factors may include increased sodium transport in the loop of Henle [31].
RENAL ARTERY STENOSIS — Posttransplant hypertension due to kidney transplant artery stenosis is important to identify because it is a correctable form of hypertension. Although it can present at any time, renal artery stenosis usually becomes evident between three months and two years posttransplant [24].
The risk factors for kidney transplant artery stenosis include difficulties in organ procurement and operative techniques (such as improper suturing and trauma), atherosclerotic disease, cytomegalovirus (CMV) infection, and delayed allograft function [14,32,33]. In a retrospective study of 29 recipients with stenosis and a case-control group of 58 patients, an increased risk of stenosis was significantly associated with CMV infection (41 versus 12 percent) and delayed function (48 versus 16 percent) [14].
The prevalence of anastomotic kidney transplant artery stenosis is difficult to assess. This is due in part to discrepancies in the definition of hemodynamically significant lesions and the use of different diagnostic modalities. It has been suggested that functionally significant stenosis occurs in up to 12 percent of transplant recipients with hypertension, with a range of incidence from 1 to 23 percent [14].
As with other causes of bilateral renal artery stenosis or unilateral stenosis in a solitary kidney, the administration of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) to a patient with transplant renal artery stenosis can lead to a reversible decline in glomerular filtration rate (GFR) [24,34] (see "Renal effects of ACE inhibitors in hypertension"). Thus, an elevation in plasma creatinine concentration in this setting is suggestive but not diagnostic of renovascular disease in the graft. Persistent uncontrolled hypertension, flash pulmonary edema, and an acute elevation in blood pressure are other common features of this disorder [35].
Diagnosis — Although various different imaging techniques may be utilized to diagnose renal artery stenosis, arteriography is the preferred modality. However, since arteriography is invasive, magnetic resonance (MR) arteriography or computed tomography (CT) angiography are increasingly utilized techniques to screen and/or diagnose transplant recipients for the presence of renovascular disease [24,33].
Arteriography — Renal arteriography remains the procedure of choice for establishing the diagnosis of renal artery stenosis in the solitary transplanted kidney. A kidney allograft biopsy is generally performed prior to angiography to rule out chronic rejection or other form of kidney parenchymal disease. These findings decrease the likelihood of a successful response to correction of a stenosis and therefore are relative contraindications to intervention [10,36].
As previously mentioned, however, given the invasiveness of arteriography, several alternatives for the diagnosis of renal artery stenosis have been evaluated. These include ultrasonography, MR imaging, spiral CT angiography, and radioisotope renography. (See "Establishing the diagnosis of renovascular hypertension".)
Ultrasonography — In some centers, Doppler ultrasonography is the preferred screening modality for stenosis of the transplanted renal artery [33,37-39]. Data suggest that this technique is highly accurate, but is highly dependent upon the experience of the ultrasonographer. In one prospective study of 109 patients, the detection of stenosis with color Doppler ultrasonography was compared with intra-arterial digital subtraction angiography [38]. When renal artery stenosis was defined as more than a 50 percent reduction in vessel diameter, the finding of a peak systolic velocity of ≥2.5 m/second was associated with a sensitivity and specificity of 100 and 95 percent for the detection of stenosis, respectively. In general, reported sensitivities have ranged from 58 to 100 percent, while specificity ranges from 87 to 100 percent [39].
Magnetic resonance imaging — As in the nontransplant population, magnetic resonance angiography (MRA) can be utilized to screen for renal artery stenosis among transplant recipients. Technical improvements have resulted in enhanced detection of significant renal artery disease. In one study of nine transplant patients, for example, combined analysis using gadolinium-enhanced MRA and three-dimensional phase contrast postgadolinium had a sensitivity and specificity of 100 percent in detecting stenosis [40].
However, the administration of gadolinium during MR imaging has been strongly linked to an often-severe disease called nephrogenic systemic fibrosis among patients with moderate to severe kidney disease, particularly those requiring dialysis. As a result, it is recommended that gadolinium-based imaging be avoided, if possible, in patients with an estimated GFR (eGFR) less than 30 mL/min. There is no consensus among experts concerning the decision to administer gadolinium among patients with an eGFR between 30 and 60 mL/min. (See "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease".)
Spiral computed tomography angiography — Spiral CT angiography may be a useful noninvasive alternative to arteriography [33,41]. Most of the available published data have evaluated this technique in native kidneys. (See "Establishing the diagnosis of renovascular hypertension".)
Radioisotope renography — Radioisotope renography, performed before and after an ACE inhibitor, is not sufficiently sensitive if the history is very suggestive for renal artery stenosis [42,43]. Evaluation of a small number of patients suggests that renography may be more useful in predicting the physiologic significance of a moderately severe stenotic lesion as patients with a negative renogram are unlikely to respond to correction of the stenosis [43].
Treatment — The options available to correct stenosis of the renal artery include angioplasty (with or without stenting) and surgery.
Angioplasty — Percutaneous balloon angioplasty may be technically successful in up to 80 percent of cases, although 20 percent will develop recurrent stenosis [36,44]. This technique is also less successful in the patient with arterial kinking, anastomotic structures, and long lesions [45]. Repeat angioplasty is usually not successful in such patients.
The success of stent placement used in combination with angioplasty for a wide variety of vascular lesions suggests that deployment of metallic stents may be useful [46,47], particularly in those with recurrent stenosis of the transplant renal artery [48,49]. Stent deployment in six consecutive patients with recurrent stenosis was evaluated in a retrospective study [48]. At almost three years postprocedure, all arteries were patent without significant stenosis, and no additional interventions were required.
Surgery — The extensive fibrosis and scarring around the transplanted kidney makes surgical correction of a transplant artery stenosis difficult. Surgery should therefore be considered only in patients with resistant hypertension or with proximal recipient arteriosclerotic disease. Success rates have ranged from 60 to 90 percent. However, recurrent stenosis may occur in approximately 10 percent, and graft loss has been reported in up to 30 percent of cases [45,50].
DEFINITIONS AND GOALS OF THERAPY — Goal blood pressure is based in part upon the presence or absence of proteinuria and/or additional comorbid conditions, such as diabetes mellitus and/or atherosclerotic cardiovascular disease [3,51]. For transplant recipients who do not have proteinuria, a reasonable target blood pressure is <140/90 mmHg. This differs from the Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, which recommend that the target blood pressure should be less than 130/80 mmHg [52,53], but is in agreement with the Canadian Society of Nephrology recommendations [54]. For patients with significant proteinuria (greater than a spot urine total protein to creatinine ratio of 500 to 1000 mg/g), the target blood pressure should be <130/80 mmHg. The KDOQI work group suggests that a lower systolic blood pressure goal should be considered. The European Best Practice Guidelines recommend a blood pressure goal of less than 125/75 mmHg for proteinuric patients [55]. (See "Treatment of hypertension in patients with diabetes mellitus".)
The Systolic Blood Pressure Intervention Trial (SPRINT) concluded that, for patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of less than 120 mmHg as compared with less than 140 mmHg resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group. The applicability of this finding to kidney transplant recipients remains unclear as such patients were not included in the study groups. The SPRINT trial is discussed elsewhere. (See "Goal blood pressure in adults with hypertension".)
TREATMENT
Overview — Posttransplant hypertension should be treated to protect against cardiovascular disease and against possible hypertensive injury to the graft. It has been suggested that long-term kidney allograft survival may be negatively influenced by posttransplant hypertension [56,57]. There is experimental evidence to support this hypothesis. In an animal model of chronic kidney allograft rejection, antihypertensive therapy improved graft survival and function, diminished glomerular injury, and reduced proteinuria [58].
There are also clinical data showing benefits with blood pressure control. This was best shown in a study of nearly 25,000 first deceased-donor kidney recipients [59]. Among patients with systolic blood pressures >140 mmHg at one year posttransplant, improved long-term allograft outcome was observed among patients with systolic pressures controlled to less than 140 mmHg at three years versus those with sustained increases in systolic pressure (relative risk [RR] 0.79, 95% CI 0.73-0.86).
We use the following approach to the treatment of hypertension in the kidney transplant recipient; this approach assumes that acute rejection is not thought to contribute to the elevation in blood pressure [10-12]. It also assumes that the glucocorticoid dose is being reduced to a low maintenance level both to reduce the blood pressure and to minimize other metabolic complications, which might have adverse cardiovascular effects, such as glucose intolerance and hyperlipidemia.
Patient is taking a calcineurin inhibitor — Calcineurin inhibitor therapy levels are to be maintained within the desired target range. Target levels are generally dictated by time posttransplant, rejection risk, and use (or non-use) of concurrent other maintenance immunosuppression and not by the presence or absence of hypertension. A study that randomly assigned stable transplant recipients to late withdrawal of either a calcineurin inhibitor or mycophenolate mofetil (MMF) showed a reduction in blood pressure at three years among patients who had the calcineurin inhibitor withdrawn, but not among those who had MMF withdrawn [60]. Such an approach is generally not recommended, however, due to the risk of late acute rejection.
If the patient remains hypertensive, therapy with a calcium channel blocker (taking into account the drug interactions noted above) or a diuretic (with concurrent salt restriction) should be started. In general, dihydropyridine calcium channel blockers should be considered the first line treatment of choice [3,4]. Diuretics are useful for those with edema and hyperkalemia. Angiotensin-converting enzyme (ACE) and angiotensin II receptor blocker (ARB) therapy is generally deferred until the patient is six or more months posttransplant, has stable allograft function, and is not hyperkalemic.
Calcium channel blockers — Many physicians prefer a calcium channel blocker [11,12] because, in addition to proven antihypertensive efficacy, it minimizes cyclosporine-induced renal vasoconstriction. A large number of studies have evaluated the efficacy of calcium channel blockers in kidney transplant patients [61-68]. A 2009 systematic review of 29 studies with 2262 patients that compared calcium channel blockers with placebo or no treatment as well as seven studies with 405 patients that compared calcium channel blockers with ACE inhibitors found that calcium channel blockers were the most effective antihypertensive agent [68]:
●Compared with placebo or no treatment, calcium channel blockers were associated with a significant decrease in allograft loss (RR 0.75, 95% CI 0.59-0.99) and improvement in glomerular filtration rate (GFR; mean difference of 4.45 mL/min, 95% CI 2.22-6.68).
●Compared with calcium channel blockers, ACE inhibitors were associated with a decrease in GFR (mean difference of 11.48 mL/min, 95% CI -5.75 to -7.21) and increased incidence of hyperkalemia (RR 3.76, 95% CI 1.89-7.43).
This systematic review included studies in which patients were not taking a calcineurin inhibitor.
The non-dihydropyridine calcium channel blockers (diltiazem and verapamil) are cytochrome inhibitors (CYP3A/4). Thus, concurrent use with calcineurin and mammalian (mechanistic) target of rapamycin (mTOR) inhibitors (cyclosporine, tacrolimus, sirolimus, and everolimus) will lead to elevated immunosuppressive drug levels. This is a transcriptional event that takes 48 to 72 hours to impact. There is both an "on" effect when the calcium channel blocker is started and an "off" effect when the calcium channel blocker is stopped. Thus, frequently measuring calcineurin inhibitor or mTOR inhibitor levels before and after such medication transitions are necessary.
Some clinicians preferentially use these agents to reduce the dosing requirement of expensive immunosuppressives. Others avoid concurrent use to minimize disruptions in pharmacokinetics that can lead to labile levels and risk both toxicity and rejection unless immunosuppressive dose requirements are excessive. The impact of the dihydropyridine calcium channel blockers (amlodipine, nifedipine, isradipine) on cytochrome metabolism is much lower, and these agents are often preferred in solid organ transplant recipients based on their known impact on mitigating nephrotoxicity.
Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and other agents — Other antihypertensive drugs can be added if the blood pressure is not controlled with a calcium channel blocker. The role of ACE inhibitors/ARBs in the transplant patient is incompletely defined. These drugs effectively lower the blood pressure, and experiments in animals suggest that they may partially protect against cyclosporine nephrotoxicity when compared with similar blood pressure control with hydrochlorothiazide, reserpine, minoxidil, hydralazine, or furosemide [69,70].
However, there are several potential risks with ACE inhibitors/ARBs in calcineurin inhibitor-treated patients.
●The combination of ACE inhibition and cyclosporine-induced vascular disease can induce a modest decline in GFR via the same mechanism described above for renal artery stenosis [71]. Early after transplantation (within three to six months posttransplantation), the increase in serum creatinine concentration may confound the ability to accurately detect acute rejection.
●Cyclosporine/tacrolimus tends to raise the plasma potassium concentration, primarily by decreasing urinary potassium excretion (see "Cyclosporine and tacrolimus nephrotoxicity"). This effect can be exacerbated by an ACE inhibitor, which reduces angiotensin II production and subsequent aldosterone secretion. Thus, ACE inhibitors should be avoided in patients who already have a plasma potassium concentration above 5.0 mEq/L.
●ACE inhibitors can induce anemia in transplant recipients, lowering the hematocrit by as much as 5 to 10 percent [72] via an effect that may be enhanced by cyclosporine [73]. Why this occurs is incompletely understood, but a similar phenomenon probably accounts for the efficacy of ACE inhibition in posttransplant erythrocytosis. (See "Kidney transplantation in adults: Posttransplant erythrocytosis".)
To assess the safety and efficacy of ACE inhibitors and ARBs in kidney transplant recipients, a large number of retrospective and prospective studies have been performed [65,68,74-78]. The magnitude of these effects was evaluated in a 2009 systematic review of 10 studies with 445 patients that compared ACE inhibitors with placebo or no treatment, and of seven studies with 405 patients that compared ACE inhibitors with calcium channel blockers [68]. The following results were reported:
●Compared with calcium channel blockers, ACE inhibitors were associated with a decrease in GFR (mean difference of 11.48 mL/min, 95% CI -5.75 to -7.21); proteinuria level (mean difference of -0.28 g/24 hours, 95% CI -0.47 to -0.10); and hemoglobin value (mean difference of -1.3 g/dL, 95% CI -.57 to -1.02) and an increased incidence of hyperkalemia (RR 3.76, 95% CI 1.89-7.43).
●No definitive conclusions with respect to GFR and allograft loss could be reached when ACE inhibitors were compared with placebo or no treatment.
Several retrospective studies in patients with chronic allograft nephropathy have reported benefits with these agents in terms of slowing the progression of kidney failure and possibly mortality. This is discussed separately. (See "Kidney transplantation in adults: Chronic allograft nephropathy".)
A double-blind, randomized, placebo-controlled trial compared the effect of losartan, 100 mg (n = 77), or placebo (n = 76) initiated within three months of transplantation and continuing for five years [79]. The composite outcome included doubling of the fraction of renal cortical volume occupied by interstitium (or "interstitial expansion," which is a measure of interstitial fibrosis and tubular atrophy [IF/TA]) at five years, or end-stage kidney disease (ESKD) from IF/TA [79]. Use of losartan tended to be protective, with an odds ratio (OR) of 0.39 (95% CI 0.13–1.15, p = 0.08). However, losartan had no significant effect on time to a composite of ESKD, death, or doubling of creatinine level. The mean time to doubling of serum creatinine was longer in the losartan group, compared with placebo (1065 versus 450 days [hazard ratio (HR) 7.28, 95% CI 2.22–32.78]). In a secondary analysis, losartan appeared to reduce the risk of a composite endpoint, including of doubling of interstitial volume or all-cause ESKD (OR 0.36, 95% CI 0.13–0.99). Blood pressure, GFR, and serum creatinines did not differ between groups, possibly due to the small number of patients enrolled.
As with ACE inhibitors, ARBs may also be used in the treatment of posttransplant erythrocytosis and can cause anemia in some patients (see "Kidney transplantation in adults: Posttransplant erythrocytosis"). For patients with gout, ARBs have the additional advantage of modestly lowering the plasma uric acid concentration. (See "Kidney transplantation in adults: Hyperuricemia and gout in kidney transplant recipients".)
Given these issues, we prefer to wait three to six months posttransplantation for the institution of an ACE inhibitor or an ARB, if indicated. After this period, the risk of rejection is minimal, and significant anemia has likely resolved.
Patient is not taking a calcineurin inhibitor — Hypertensive patients not taking cyclosporine/tacrolimus should be started on antihypertensive medications. Calcium channel blockers, ACE inhibitors, and beta-blockers all may be effective in this setting. A diuretic may also be necessary in patients with allograft dysfunction in whom volume expansion often contributes to the rise in blood pressure.
Resistant hypertension — Patients with resistant hypertension should undergo renal arteriography to exclude renal artery stenosis, unless there are findings (such as kidney function impairment and an active urine sediment) suggesting possible recurrence of the primary disease. Angioplasty (with or without stenting) or surgery is indicated if a significant stenosis is found. In the absence of renovascular disease, recurrent disease, or rejection, consideration should be given to removal of the native kidneys if there is no other way to control the hypertension [80,81].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)
SUMMARY AND RECOMMENDATIONS
●Posttransplant hypertension occurs in up to 80 percent of kidney transplant recipients. (See 'Introduction' above.)
●Posttransplant hypertension may be due to recipient or donor factors, to immunosuppressive medications such as calcineurin inhibitors and steroids, or to renal artery stenosis, which can occur in up to 20 percent of kidney transplant recipients. (See 'Risk factors and pathogenesis' above and 'Renal artery stenosis' above.)
●Kidney transplant artery stenosis is important to identify because it is a correctable form of hypertension. Risk factors include difficulties in harvesting and operative techniques, atherosclerotic disease, cytomegalovirus (CMV) infection, and delayed allograft function. Persistent uncontrolled hypertension, flash pulmonary edema, and an acute elevation in blood pressure are common features of this disorder. Arteriography is the preferred diagnostic modality, but Doppler ultrasonography, computed tomography (CT) angiography, or magnetic resonance (MR) arteriography may also be used to diagnose renal artery stenosis.
However, the administration of gadolinium during MR imaging has been strongly linked to nephrogenic systemic fibrosis among patients with moderate to severe kidney disease. Gadolinium-based imaging should be avoided, if possible, in patients with an estimated glomerular filtration rate (eGFR) less than 30 mL/min. There is no consensus among experts concerning the decision to administer gadolinium among patients with an eGFR between 30 and 60 mL/min. (See 'Renal artery stenosis' above and "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease".)
●Goal blood pressure is 140/90 mmHg in patients without diabetes or proteinuria, and 130/80 mmHg in those with diabetes or proteinuria.
●Calcium channel blockers, particularly including verapamil and diltiazem, may increase the serum concentration of cyclosporine, tacrolimus, sirolimus and everolimus. (See 'Calcium channel blockers' above.)
If possible, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) should be avoided initially in order to avoid confusion in interpretation of a rise in serum creatinine that may suggest acute rejection or hyperkalemia. However, the use of such agents after three months may be beneficial. (See 'Treatment' above.)
