Hypertension After Kidney Transplant

In Practice Hypertension After Kidney Transplant Mahendra Mangray, MD, and John P. Vella, MD, FRCP Hypertension in kidney transplant recipients is a major “traditional” risk factor for atherosclerotic cardiovascular disease. Importantly, atherosclerotic cardiovascular disease is the leading cause of premature death and a major factor in death-censored graft failure in transplant recipients. The blood pressure achieved after transplant is related inversely to postoperative glomerular filtration rate (GFR), with many patients experiencing a significant improvement in blood pressure control with fewer medications within months of surgery. However, the benefits of improved GFR and fluid status may be affected by the immunosuppression regimen. Immunosuppressive agents affect hypertension through a variety of mechanisms, including catechol- and endothelin-induced vasoconstriction, abrogation of nitric oxide–induced vasodilatation, and sodium retention. Most notable is the role of calcineurin inhibitors in promoting hypertension, cyclosporine more so than tacrolimus. Additionally, the combination of calcineurin- and mammalian target of rapamycin (mTOR)-inhibitor therapy is synergistically nephrotoxic and promotes hypertension, whereas steroid withdrawal and minimization strategies seem to have little or no impact on hypertension. Other important causes of hypertension after transplant, beyond a progressive decrease in GFR, include transplant renal artery stenosis and sequelae of antibody-mediated rejection. Calcium channel blockers may be the most useful medication for mitigating calcineurin inhibitor–induced vasoconstriction, and use of such agents may be associated with improvements in GFR. Use of inhibitors of the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, remains an attractive strategy for many transplant recipients, although some recipients may have significant adverse effects associated with these medications, including decreased GFR, hyperkalemia, and anemia. In conclusion, hypertension control affects both patient and long-term transplant survival, and its best management requires careful analysis of causes and close monitoring of therapies. Am J Kidney Dis. 57(2):331-341. © 2011 by the National Kidney Foundation, Inc. INDEX WORDS: Hypertension; human; kidney; transplantation; immunosuppression.

CASE PRESENTATION A 57-year-old white man with end-stage renal disease secondary to autosomal dominant polycystic kidney disease required 4 different antihypertensive medications while hemodialysis dependent to achieve moderate blood pressure (BP) control (mean BP, 149/94 mm Hg predialysis). After 3 years of hemodialysis therapy, he received a deceased donor kidney transplant. The transplant functioned promptly and the serum creatinine level reached a nadir of 1.42 mg/dL (125.5 ␮mol/L; estimated glomerular filtration rate [eGFR], 55 mL/min/1.73 m2 [0.92 mL/s/1.73 m2]) within 4 days of surgery. Immunosuppression included tacrolimus, mycophenolate mofetil, and low-dose prednisone. His requirement for antihypertensive medications decreased substantially, such that within 4 months of transplant, only a single agent was required to achieve BP readings consistently ⬍130/90 mm Hg. Three years after transplant, serum creatinine level increased to 2.9 mg/dL (256.3 ␮mol/L; eGFR, 22.8 mL/min/1.73 m2 [0.38 mL/s/1.73 m2]) after steroid therapy withdrawal, and BP control deteriorated, requiring the addition of 2 more antihypertensive agents. A transplant biopsy showed Banff grade Ia acute cellular rejection superimposed on grade II interstitial fibrosis and tubular atrophy. After rejection rescue therapy, creatinine level stabilized at 2.1 mg/dL (185.6 ␮mol/L; eGFR, 34.1 mL/min/1.73 m2 [0.57 mL/s/1.73 m2]). Despite alterations in immunotherapy, he continues to require 3 antihypertensive medications.

INTRODUCTION Atherosclerotic cardiovascular disease is a frequent cause of morbidity and the dominant cause of mortality after kidney transplant1,2 (Fig 1). Compared with dialysis, transplants decrease mortality, and recent Am J Kidney Dis. 2011;57(2):331-341

studies suggest that this effect is due largely to the decrease in cardiovascular disease complications.4 This review focuses on hypertension as one of the major “traditional” determinants for cardiovascular disease after kidney transplant. Posttransplant hypertension may be modulated by both kidney function and immunotherapy, as described in the vignette, and such factors are explored in greater detail in the ensuing text. The 2 major goals of antihypertensive therapy after transplant are preservation of kidney function (or slowing of kidney disease progression) and decreasing cardiovascular disease risk. It should be noted that most data pertaining to hypertension after transplant have accrued from clinical trials that focus on immunotherapeutic regimens, as well as analyses of registry databases, rather than studies that primarily focus on From the Maine Transplant Program, Maine Medical Center and Tufts University, Portland, ME. Received July 19, 2010. Accepted in revised form October 27, 2010. Address correspondence to John Vella, MD, FRCP, Maine Medical Center, Tufts University School of Medicine, 19 West St, Portland, ME 04102. E-mail: [email protected] © 2011 by the National Kidney Foundation, Inc. 0272-6386/$36.00 doi:10.1053/j.ajkd.2010.10.048 331

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Figure 1. Mortality after kidney transplant. Atherosclerotic disease is the most common cause of death after transplant (44%) and outweighs the contributions from infection and malignancy combined (33%). Abbreviations: CBVD, cerebrovascular disease; CVD, cardiovascular disease. Source: US Renal Data System.3

hypertension as an end point. The limited data pertaining to the outlined goals is discussed next.

DEFINITION Hypertension is defined by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) as systolic BP (SBP) ⬎140 mm Hg, diastolic BP ⬎90 mm Hg, or the need for antihypertensive therapy.5 The JNC 7 also recommends that treatment be provided to achieve BP ⬍140/90 mm Hg or ⬍130/80 mm Hg in patients with diabetes or chronic kidney disease. The National Kidney Foundation’s KDOQI (Kidney Disease Outcomes Quality Initiative) has similar treatment target recommendations that have been endorsed recently by the KDIGO (Kidney Disease: Improving Global Outcomes) working group.6,7 In patients with significant proteinuria (defined as spot urine protein-creatinine ratio ⬎500 mg/g), a European Best Practice Guideline suggests that the BP goal be decreased to ⬍125/75 mm Hg.8 The reader is reminded that the recently published ACCORD (Action to Control Cardiovascular Risk in Diabetes) Study shows no benefit to be gained in patients with diabetes from intensively decreasing their SBP to a goal ⬍120 mm Hg.9 EPIDEMIOLOGY Before the US Food and Drug Administration approval of cyclosporine in 1983, nearly half of all transplant recipients had hypertension, an observation attributed at the time to activation of the reninangiotensin system of either native kidney or transplant derivation.10 Presently, ⬎90% of calcineurininhibitor–treated kidney transplant recipients have hypertension,11-13 and in one study, only 5% of kidney transplant recipients were normotensive, defined 332

as ambulatory BP readings ⬍130/80 mm Hg without treatment.14 This change in the reported incidence of hypertension may reflect changing definitions of hypertension over time and thus direct comparison may be misleading. Hypertension negatively affects transplant and patient survival outcomes. In one report, the prevalence, treatment, control, and clinical correlates of hypertension and its association with outcomes were studied in a retrospective cohort of 1,666 kidney transplant recipients15 (Fig 2). After adjusting for the effects of acute rejection and transplant function (among other variables), each 10–mm Hg of SBP was associated with an ⬃5% increased risk of transplant failure and death (Fig 2). In another study of nearly 25,000 primary deceased donor kidney recipients, improved longterm transplant outcome was observed in patients with SBP ⬎150 mm Hg at 1 year posttransplant when SBP was controlled to ⬍140 mm Hg at 3 years versus those with sustained increases in SBP.17

DIAGNOSIS How should BP be measured after transplant, where, and by whom? Traditionally, BP measurements typically are performed in the office by either a medical assistant, nurse, or physician. Prasad et al18 reported results of a prospective study of more than 200 transplant recipients who had BP checked before, during, and after a physician visit. Using multivariate analysis, the presence of the physician at the time of BP measurement caused BP to increase by 3-4 mm Hg. The investigators commented that this observation occurred despite “adequate patient experience with posttransplant clinic visits and BP-altering medication.”18 Alternatives to office BP readings include self BP measurement (SBPM) at home, and ambulatory BP monitoring (ABPM).19 There are growing

Figure 2. Association of hypertension at 1 year with transplant survival. Kidney transplant survival is inversely proportional to blood pressure. Abbreviation: SBP, systolic blood pressure. Reproduced from Opelz et al16 with permission of Nature Publishing Group. Am J Kidney Dis. 2011;57(2):331-341

Hypertension/Transplant

data from studies of the general population that SBPM is associated with improved outcomes compared with clinic measurements.20,21 What about the transplant population? Stenehjem et al22 compared office, SBPM, and ABPM in 49 kidney transplant recipients. Mean office and 24-hour ABPM readings were similar (133/82 vs 133/80 mm Hg). However, SBPM values in the morning and evening were significantly higher than ABPM values. Adequate BP control was found in 53% of patients using office BP compared with 29% using home BP and 16% using mean 24-hour ambulatory BP. Haydar et al23 examined the relationship between BP measured using ABPM compared with daytime office BP and also observed predictors of diurnal variation in almost 200 kidney transplant recipients. The concordance rate between casual BP and ABPM was 80%, and using casual BP, only 15% of hypertensive kidney transplant patients would be given an erroneous diagnosis of normotension. They also found that SBP diurnal variation was predicted independently using age and GFR, although it correlated with cyclosporine level and ABPM-to-transplant interval. In addition, the investigators showed that ABPM is a more sensitive method for diagnosing hypertension than sole reliance on office BP in kidney transplant recipients.

DETERMINANTS AND PATHOGENESIS In contrast to the general and CKD populations, risk factors for hypertension after transplant include determinants of both donor and recipient origin and also factors that relate to the transplant process and immunosuppression, as summarized in Box 1 and Fig 3. Guidi et al24 showed the interplay of such factors in a prospective observational study of 85 transplant recipients with stable kidney function (without cyclosporine therapy) followed up for 8 years. Recipients without a family history of hypertension engrafted with a kidney derived from a hypertensive family developed hypertension more frequently than those with a kidney transplant derived from a normotensive family or recipients with familial hypertension (in whom the origin of the kidney did not influence the prevalence of posttransplant hypertension). In the follow-up study of these patients, recipients of kidneys derived from hypertensive families developed higher diastolic BPs and greater degrees of acute kidney injury during acute rejection than the other recipients.25 HYPERTENSION AND LEFT VENTRICULAR HYPERTROPHY Left ventricular hypertrophy (LVH) is an independent risk factor for death and cardiovascular disease in Am J Kidney Dis. 2011;57(2):331-341

Box 1. Factors Contributing to Hypertension After Transplant Recipient Factors ● Pre-existing hypertension & left ventricular hypertrophy ● Body mass index ● Native kidney disease Donor Factors ● Donor age ● Donor sex ● Donor hypertension Transplant Factors ●Cold ischemia time ● Warm ischemia time ● Delayed transplant function Immunotherapy ● Corticosteroids ● Calcineurin inhibitors (cyclosporine ⬎ tacrolimus) Transplant Dysfunction ● Acute rejection ● Antibody-mediated rejection ● Chronic allograft nephropathy ● Thrombotic microangiopathy ● Recurrent or de novo glomerular disease Transplant Renal Artery Stenosis Transplant obstruction ● Ureteric stenosis ● Lymphocele

the general population, dialysis patients, and after kidney transplant. As an example, in a retrospective study of almost 500 transplant patients, baseline LVH defined using electrocardiographic criteria was a risk factor for death (relative risk [RR], 1.9) and congestive heart failure (RR, 2.27) and was independent of other major prognostic variables.26 Anemia and diastolic BP were independent risk factors for increasing LVH between the first and fifth years. SBP was the only predictor of de novo LVH at 5 years. Midvedt et al27 presented a prospective study of 154 patients that compared the effect of an angiotensin-converting enzyme (ACE) inhibitor (lisinopril) with a calcium channel blocker (CCB; controlled-release nifedipine) in treatment of posttransplant hypertension, focusing on changes in LVH. Patients were randomly assigned in a double-blind fashion to receive 30 mg of nifedipine or 10 mg of lisinopril once daily. Hypertension was equally well controlled in the 2 groups throughout the study, and left ventricular mass index was decreased by 15% in both groups. The investigators concluded that hypertensive kidney transplant recipients with well-controlled BP experience regression of left ventricular mass after kidney transplant.

ROLE OF IMMUNOSUPPRESSIVE AGENTS Steroids Pharmacologic doses of steroids mediate hypertension through a variety of mechanisms that include mineralocorticoid-induced sodium retention, increased responsiveness to vasoconstrictors, and decreased va333

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Figure 3. Mechanisms by which hypertension after kidney transplant is mediated. A complex interplay exists resulting from decreased glomerular filtration rate (GFR), vasoconstriction, and sodium retention that are variously adversely affected by immunosuppressive agents. Abbreviation: RAS, renin-angiotensin system.

sodilator production. In addition, recent in vitro studies have shown a direct role of the glucocorticoid receptor on vascular smooth muscle.28 The estimated incidence of glucocorticoid-associated hypertension is ⬃15%,29 with the effect highest in those with pre-existing hypertension.30 Most patients in the United States continue to receive steroid therapy after transplant.1,4 However, steroid-avoidance or early-withdrawal protocols for non–African American recipients of primary allografts are gaining traction within the transplant community to minimize or avoid the predictable adverse consequences. The question is whether such protocols result in tangible improvements in primary outcomes. In a 12-month open-label multicenter study, de novo kidney transplant recipients were randomly assigned to receive no steroids, steroids to day 7 posttransplant (steroid withdrawal), or standard steroid therapy, all in combination with cyclosporine, enteric-coated mycophenolate, and basiliximab. No differences were observed in terms of SBP or diastolic BP between groups. Mean SBPs at study end were 133 ⫾ 20, 135 ⫾ 18, and 132 ⫾16 mm Hg in the steroid-free, steroid-withdrawal, and standard-steroid groups, respectively.31 There was a significantly higher incidence of rejection in the steroid-avoidance or -withdrawal groups. Most importantly, there were no differences in patient or transplant survival at the end of the study. Most likely we now are seeing an example of regression to the mean whereby steroidtreated patients receive much lower cumulative immunotherapy than their predecessors, and the consequent impact of steroids on BP is negligible. 334

Calcineurin Inhibitors Both cyclosporine and tacrolimus have induced or exacerbated hypertension in transplant recipients.32,33 Cyclosporine in particular activates the sympathetic nervous system, upregulates endothelin, and inhibits inducible nitric oxide, all of which cause potent vasoconstriction and systemic hypertension.34,35 The hypertensive effect of such therapy can be appreciated from studies of patients with bone marrow and cardiac transplant before and after the availability of cyclosporine. The incidence of hypertension increased from ⬍10% overall to 30%-60% in bone marrow patients and 70%-90% in heart transplant recipients.13,36 In kidney transplant recipients, decreasing the dose of cyclosporine by 50% at 1 year or longer post–kidney transplant has decreased the risk of hypertension in patients treated with steroids and mycophenolate mofetil without increasing rejection risk.37 It now is known that tacrolimus has less of an effect on BP than cyclosporine38 when used with prednisone and mycophenolate mofetil. However, when tacrolimus is used in combination with sirolimus, the combination exacerbates hypertension. Furthermore, registry data indicate that the latter combination is synergistically nephrotoxic and is associated with decreased long-term transplant survival.39,40

EFFECT OF GFR ON HYPERTENSION AFTER TRANSPLANT Hypertension and GFR are intimately interrelated after kidney transplant, as illustrated by the vignette at the beginning of this review. Karthikeyan et al41 Am J Kidney Dis. 2011;57(2):331-341

Hypertension/Transplant

showed increasing requirements of antihypertensive medications from 0.7 in kidney transplant recipients with chronic kidney disease stage 1 to 2.3 in those with stage 5 function. In another study, the progression rate of decreased kidney function was quantitated from the reciprocal of serum creatinine over time in patients with clinical and histologic evidence of chronic kidney transplant rejection. Mean BP significantly correlated with serum creatinine level at the time of the change in the slope showing more severe hypertension in patients with more severe decreased kidney function. The investigators concluded that higher BPs correlate with greater rates of progression of decreased kidney function.42 Kasiske et al43 also examined the impact of hypertension on transplant survival. After adjusting for effects of rejection, kidney function, and other variables, each 10 mm Hg of SBP was associated with an increased RR of transplant failure and death. In addition, early posttransplant systolic hypertension strongly and independently predicts poor long-term transplant survival in pediatric patients.44 Chronic allograft nephropathy is associated clinically with a gradual deterioration in transplant function, variable degrees of proteinuria, and, pertinent to this review, new or worsening hypertension.45,46 This syndrome is the second most common cause of transplant failure (after death with transplant function). The newly revised Banff classification system has renamed chronic allograft nephropathy “interstitial fibrosis and tubular atrophy (IF-TA), without evidence of any specific etiology.”47 It is defined as kidney transplant dysfunction occurring at least 3 months posttransplant in the absence of active acute rejection, calcineurin-inhibitor drug toxicity, or other diseases. Recurrent disease is the third most common cause of long-term transplant loss after death with function and chronic allograft nephropathy and often is associated with new-onset or worsening hypertension.48,49 For example, in a study of 3,998 transplant recipients reported to the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry, recurrent disease accounted for ⬃8% of patients with transplant loss at 10 years compared with 15% for death with transplant function and 20% for chronic allograft nephropathy.

ANTIBODY-MEDIATED REJECTION Antibody-mediated rejection is a specific type of rejection characterized by the development of acute transplant dysfunction associated with specific transplant morphologic changes, deposition of complement (C4d), and presence of donor-reactive antibody. A subset of patients with antibody-mediated rejection Am J Kidney Dis. 2011;57(2):331-341

exists who present with malignant hypertension.50 In a German study of 33 kidney transplant recipients with refractory vascular rejection, antibodies were found to target the angiotensin II type 1 (AT1) receptor in 16 recipients in the absence of anti-HLA antigen antibodies.50 Most patients did not have hypertension before vascular rejection occurred, implying that posttransplant hypertension was secondary to the rejection process. Most AT1 receptor–related vascular rejection occurred during the first week after transplant. Seven of 16 AT1 receptor patients were treated with combination therapy consisting of plasmapheresis, intravenous immune globulin infusions, and losartan. The treatment significantly prolonged transplant survival compared with AT1 receptor–positive patients who received conventional rescue therapy. This type of rejection seems to be very uncommon in the United States.

TRANSPLANT RENAL ARTERY STENOSIS Transplant renal artery stenosis typically presents 3-24 months after surgery, although it can present at any stage after transplant.51 It has been suggested that up to 12% of transplant recipients with hypertension may have functionally significant transplant renal artery stenosis.52 Risk factors for transplant renal artery stenosis development include cytomegalovirus infection,53 delayed transplant function,52 organ procurement complications, and surgical techniques.54 Suggestions that the incidence is higher in recipients of live donor compared with deceased donor allografts have been disputed, although it seems that a pediatric donor source is a major risk factor.55 Patients typically present in a fashion similar to native kidney renal artery stenosis with refractory hypertension, flash pulmonary edema,51 and acute kidney injury after ACE-inhibitor or angiotensin II receptor blocker (ARB) therapy initiation.56 The diagnosis of transplant renal artery stenosis also may be suggested if a new bruit is detected over the kidney transplant. Diagnosis Various reports over time have suggested a role for ultrasonography as a screening test for transplant renal artery stenosis.51,57-59 Such testing is advantageous because it is noninvasive and does not expose the patient to the risk of iodinated contrast media. However, sonography may be operator dependent and conventional angiography remains the gold-standard diagnostic test. Potential complications of angiography are predictable and include groin hematoma, renal artery dissection, thrombosis, perforation, and acute kidney injury caused by radiocontrast-induced nephropathy or, less commonly, atheroembolic disease.60 The transplant often is biopsied 335

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before revascularization, which is recommended to define and grade the presence of intercurrent conditions, such as chronic allograft nephropathy.55 Magnetic resonance angiography is of limited value in the diagnosis of transplant (compared with native) renal artery stenosis.61 Treatment The primary treatment for transplant renal artery stenosis involves percutaneous intervention (angioplasty with or without stent placement).51,52 The technical success rate of percutaneous intervention has been reported to be as high as 94%, with a clinical success rate of 82%.62 Recurrent stenosis may occur in ⬃10%, and transplant loss has been reported in up to 30% of cases.63 Audard et al52 performed a retrospective analysis of 29 kidney transplant recipients with transplant renal artery stenosis treated with percutaneous transluminal angioplasty. Interestingly, acute rejection occurred more frequently in patients with transplant renal artery stenosis (48%) compared with a control group (28%). Long-term transplant survival was significantly higher in the control group compared with the transplant renal artery stenosis group. Surgical revascularization generally has been reserved for patients with disease not amenable to percutaneous intervention.

MANAGEMENT OF HYPERTENSION The dual goals of posttransplant hypertension management are to prolong transplant survival and minimize cardiovascular risk (per JNC 7 guidelines, as described). Therapeutic lifestyle modification generally is recommended as first-line therapy for patients in the general population. In truth, there are remarkably few data in the transplant population that have rigorously examined this intervention. As an example, effects of a 12-month dietary regimen on nutritional status and metabolic outcome of kidney transplant recipients in the first posttransplant year recently were reported by Rike et al.64 Forty-six deceased donor kidney transplant recipients were enrolled during the first posttransplant year and followed up prospectively. Adherence to dietary recommendations was related to sex (male better than female) and associated with weight loss primarily due to a decrease in fat mass, with decreases in total cholesterol and plasma glucose levels and a concomitant increase in serum albumin level. No change in hypertension control was reported. Optimal management of hypertension after transplant includes manipulating immunotherapy when possible. For example, patients using cyclosporine often experience improved BP control after dose reduction or conversion to either tacrolimus or siroli336

mus.37-39 Despite such manipulations, most transplant recipients continue to require one or more agents to achieve adequate control of hypertension. Use of agents that favorably affect atherogenesis, such as antiplatelet and cholesterol-lowering medications, as well as glycemic control, are beyond the scope of this review.

SPECIFIC CLASSES OF ANTIHYPERTENSIVE AGENTS What is the optimal pharmacologic antihypertensive agent of choice for kidney transplant recipients? An ideal drug would be dosed once daily, be inexpensive, and provide other beneficial properties. Fortunately, many agents are now available that meet at least some of these criteria (Table 1). In truth, most patients require more than one agent to achieve BP control targets because of either lack of efficacy or dose-limiting adverse effects. The reader is reminded that ␤-blocker therapy decreases morbidity and mortality after myocardial infarction and also is of benefit in patients with congestive heart failure.65 Although specific data pertaining to ␤-blockade in transplant recipients are lacking, it seems sensible to recommend that such agents be used, especially in the perioperative period in high-risk patients. CCBs inhibit voltage-gated calcium channels in vascular smooth muscle and cardiac myocytes, reduce contractility, and induce vasodilatation. Such drugs fall into 2 major classes: dihydropyridine (eg, amlodipine and nifedipine) and nondihydropyridine (eg, diltiazem and verapamil), which show somewhat differing mechanisms of action and, importantly for transplant, pharmacokinetics. It has long been known that vasoconstriction is the dominant mechanism by which calcineurin inhibitors induce acute nephrotoxicity and hypertension. Thus, vasodilatory CCBs have been an attractive option at least for the early management of hypertension after transplant.66 Therefore, are data available that support the use of such agents from clinical trials? A large, prospective, randomized, comparative study found clear sustained improvement in kidney transplant function in patients treated with nifedipine compared with lisinopril67 (Fig 4). Despite equivalent initial GFRs and attainment of similar BP levels, the following benefits were observed with nifedipine: (1) At 1 year, GFR had significantly increased in those treated with nifedipine (56 vs 46 mL/min at baseline), but was unchanged with lisinopril (44 and 43 mL/min, respectively); (2) At 2 years, improvement in GFR with nifedipine was maintained (10.3 mL/min; confidence interval, 4.0-16.6); no such benefit was observed with lisinopril. Am J Kidney Dis. 2011;57(2):331-341

Class

Medication (examples)

Dihydropyridine Amlodipine, CCBs nifedipine Nondihydropyridine Diltiazem, CCBs verapamil

Mechanism of Action

Vasodilation

Pharmacokinetics

Cytochrome P450 3A4 substrate Cytochrome P450 3A4 substrate & inhibition

Drug Interactions With Immunotherapy

Beneficial Effect in Tx Recipients

Principal Adverse Effects

Positive

Mitigates CNI-induced HTN & Edema nephrotoxicity Vasodilation, rate control Strongly positive Decreased requirement for CNI/ Edema, CNI toxicity, mTOR inhibitor, mitigates CNIbradycardia induced HTN & nephrotoxicity ACEi Lisinopril, ramipril Prevents conversion of Lisinopril: 100% excreted No direct PK interactions, May reverse posttransplant Hyperkalemia, AKI, (many others) Ang I to Ang II unchanged, urine 29%, caution with concurrent erythrocytosis, mitigation of anemia feces 69%; ramipril: high-dose CNI proteinuria, may mitigate AMRurine 60%, feces 40% because of risk of mediated by antibody to AT1 as parent drug & hyperkalemia receptor metabolites ARBs Losartan, Selectively antagonizes AT1 Variable renal & fecal No direct PK interactions, Losartan may decrease uric acid Hyperkalemia, AKI, candesartan, and AT2 receptors with excretion (unchanged) caution with concurrent levels anemia irbesartan high-dose CNI 1,000⫻ higher affinity for AT1 because of risk of hyperkalemia Vasodilator Hydralazine Dilates peripheral vessels Liver metabolism/renal & Negative Useful in hospital posttransplant SLE, headache fecal excretion (short half-life) Minoxidil Renal excretion Negative May reverse tacrolimus-induced Edema, hirsutism alopecia, may exacerbate cyclosporine-induced hypertrichosis Diuretics Furosemide, Salt & water excretion Renal excretion Negative Useful in patients with edema and Volume depletion, HCTZ hyperkalemia, thiazides less hypokalemia useful in patients with decreased GFR Potassium-sparing Amiloride, Inhibits distal convoluted tubule Renal & fecal excretion Negative Useful in patients with Hyperkalemia (especially diuretics spironolactone aldosterone-induced sodium (unchanged), urine hypokalemia or if there is if used with CNI/ACEi) resorption, inhibits distal (unchanged) suspected hyperaldosteronism, convoluted tubule may mitigate proteinuria aldosterone receptor ␤-Blockers Metoprolol (many Antagonizes ␤1-adrenergic Cytochrome P450 2D6 Negative Decrease risk of perioperative MI Bradycardia, fatigue, others) receptors substrate hyperkalemia ␣-Blockers Doxazosin Antagonizes ␣1-adrenergic Cytochrome P450 Negative May mitigate BPH Orthostasis receptors metabolized

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Note: There is no discussion of centrally acting medication, such as clonidine, because such agents rarely are required in transplant recipients. There are no published data pertaining to eplerenone use in transplant recipients. Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; AMR, antibody-mediated rejection; Ang, angiotensin; ARB, angiotensin receptor blocker; AT1, angiotensin II type 1; BPH, benign prostatic hypertrophy; CCB, calcium channel blocker; CNI, calcineurin inhibitor; GFR, estimated glomerular filtration rate; HCTZ, hydrochlorothiazide; HTN, hypertension; MI, myocardial infarction; mTOR, mammalian target of rapamycin; PK, pharmacokinetics; Tx, transplant.

Hypertension/Transplant

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Table 1. Classes of Antihypertensive Medications Used After Transplant

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Figure 4. Kidney function and choice of antihypertensive agent. The achieved glomerular filtration rate (GFR) in patients treated with calcium channel blockers is greater than for those treated with angiotensin-converting enzyme inhibitors (measured at 3 weeks and 1 and 2 years after transplant). Reproduced from Midtvedt & Hartmann68 with permission of the European Renal Association–European Dialysis and Transplant Association.

1. ACE-inhibitor or ARB therapy can cause or exacerbate a decrease in GFR,77 and this property may mimic or mask early signs of acute transplant rejection. Consequently, these drugs are difficult to use early after transplant when patients are at the highest risk of developing complications. 2. Hyperkalemia is a frequent finding after kidney transplant that is associated commonly with delayed transplant function and is an adverse effect of calcineurin-inhibitor (particularly tacrolimus) therapy. ACE-inhibitor/ARB therapy can exacerbate the frequency and severity of hyperkalemia and sometimes is life-threatening. 3. ACE inhibitors can cause or exacerbate anemia in transplant recipients, decreasing hematocrit by as much as 5%-10%78 through a mechanism that may be potentiated by cyclosporine.79 This incompletely understood phenomenon is believed to be caused by inhibition of erythropoiesis and may be useful in the management of posttransplant erythrocytosis, a condition characterized by a progressive increase in hematocrit (⬎50%) and risk of atherothrombotic events.

Effects of CCBs on long-term kidney function in calcineurin-inhibitor–treated kidney transplant recipients have been reported with variable efficacy.69-71 A meta-analysis of 21 studies published in 1994 concluded that the proposed benefits of CCBs and calcineurin inhibitors (decrease in both delayed transplant function and acute rejection episodes and possibly also better long-term transplant function) were conflicting.70 Despite this, such drugs typically are thought of as first-line agents for management of hypertension after kidney transplant, especially when target calcineurin-inhibitor levels are highest. It is important to remember when choosing nondihydropyridine CCBs that pharmacokinetic drug interactions occur when used with cyclosporine, tacrolimus, or sirolimus.72 Verapamil and diltiazem are potent inhibitors of cytochrome P450 C3A4 and cause plasma levels of the latter immunosuppressive drugs to increase sharply soon after initiation.72 This is a transcriptional event and typically occurs during a 2- to 5-day period postinitiation. Likewise, when CCB therapy is discontinued, one can expect levels of immunotherapy to decrease; therefore, clinical acumen dictates that such drugs be used with caution and frequent monitoring. The dihydropyridine CCBs share these properties to a much lesser extent and therefore are easier to use in transplant recipients, although they are more likely to be associated with the development of edema.

Therefore, are ACE inhibitors and ARBs helpful or harmful posttransplant? A systematic review of 21 randomized trials performed in a total of 1,549 patients assessed the effect of ACE-inhibitor or ARB use after kidney transplant. The primary outcome measure was change in kidney function (creatinine level, creatinine clearance, or GFR), and secondary outcomes included change in BP, hemoglobin level or hematocrit, proteinuria, and potassium concentration. Median follow-up was 27 months. ACE-inhibitor or ARB use was associated with a significant decrease in GFR (⫺5.8 mL/min). ACE-inhibitor or ARB use resulted in a lower hematocrit (⫺3.5%) and decrease in proteinuria (protein excretion, ⫺0.47 g/d), but no change in serum potassium level. There were insufficient data to determine the effect on patient or transplant survival.80 It seems reasonable to recommend the use of renin-angiotension system blockers in kidney transplant recipients, especially those with proteinuria and higher levels of kidney function.

ACE INHIBITORS/ARBs

TREATMENT OF REFRACTORY HYPERTENSION

Use of ACE inhibitors/ARBs for treatment of hypertension and slowing the progression of chronic kidney disease has been well defined in the nontransplant population.73-76 Use of such agents in the transplant population is more complex. Several factors should be considered when choosing such medications for kidney recipients.

A subset of patients develops persistent or refractory hypertension after transplant. Although consideration should be given to the elucidation of potential causes as previously described, combination pharmacologic intervention generally is required for such individuals. The medications used most commonly are listed in Table 1, with specific reference to their

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potential beneficial and adverse effects in kidney transplant recipients. Except for CCBs and ACE inhibitors, there are few or no published data for each class of medication that is specific to transplant.

IMPACT OF HYPERTENSION TREATMENT ON PATIENT AND TRANSPLANT SURVIVAL Therefore, does treating hypertension affect patient and transplant survival after kidney transplant? Probably the best data that address the question of survival rates was provided by Opelz and Dohler,17 as briefly described previously. This was an analysis of the Collaborative Transplant Study (CTS) observational database that evaluated transplant outcomes in relation to recipient SBP for 24,404 first cadaver kidney recipients who underwent transplant between 1987 and 2000. Three-year transplant survival rates were better for hypertensive patients (defined as SBP ⬎140 mm Hg at 1 year posttransplant) who achieved control to ⬍140 mm Hg compared with patients with sustained hypertension (RR, 0.79). Additional examination at 5 years showed that SBP lowering after year 3 was associated with improved 10-year transplant survival (RR, 0.83), whereas even a temporary increase in SBP at 3 years was associated with worse survival (RR, 1.37). Changes in SBP were paralleled by changes in the incidence of cardiovascular death in recipients younger than 50 years, but not in older recipients. The investigators concluded that decreasing SBP, even after several years of posttransplant hypertension, is associated with improved transplant and patient survival in kidney transplant recipients. There are no randomized clinical trial data that specifically address the question of hypertension control and patient/ transplant survival after kidney transplant. SUMMARY Despite improvements in patient and transplant survival, cardiovascular disease remains the most common cause of death and transplant loss after kidney transplant. Hypertension is almost ubiquitous in kidney transplant recipients and is a risk factor for cardiovascular disease. ABPM is encouraged, as well as attainment of the respective target BPs quoted. Lifestyle modifications, such as weight loss, increasing regular exercise, and sodium restriction, may be helpful, although such a recommendation is not supported by clinical trial evidence after transplant. No single algorithm for the management of posttransplant hypertension has been developed and uniformly adopted. Patients with established atherosclerotic cardiovascular disease, heart failure, and diabetes should receive ␤-blockers in the perioperative period.81 Hydralazine is a very useful drug in hospitalized Am J Kidney Dis. 2011;57(2):331-341

patients because of its short duration of action, although it is less useful as a long-term agent for the same reason. It seems reasonable to recommend that CCBs be used early after transplant at a time when patients are most likely to experience the vasomotor adverse effects of calcineurin-inhibitor therapy. We tend to avoid using nondihydropyridine CCBs to prevent pharmacokinetic drug interactions, although acknowledge that such a strategy may be useful for some patients to reduce the dose requirement of their expensive calcineurin-inhibitor therapy. Loop diuretics are very useful when managing hypertensive patients with edema and/or hyperkalemia. We tend to avoid using ACE-inhibitor or ARB therapy until 3-6 months have elapsed from transplant to avoid hyperkalemia, acute kidney injury, and anemia. Minoxidil occasionally is useful in patients with tacrolimusinduced alopecia. Care should be tailored to the need of the individual, and therapy should be goal oriented.

ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.

REFERENCES 1. Vella JP, Danovitch GM. Transplantation NephSAP. J Am Soc Nephrol. 2008;7(1):6-54. 2. Vella JP, Danovitch GM. Transplantation NephSAP. J Am Soc Nephrol. 2006;5(4):201-274. 3. US Renal Data System. USRDS 2008 Annual Data Report. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2008. http:// www.usrds.org. Accessed January 5, 2010. 4. Vella JP, Cohen DJ. Transplantation NephSAP. J Am Soc Nephrol. 2009;8(6):424-492. 5. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-2572. 6. National Kidney Foundation. K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease. Am J Kidney Dis. 2004;43(5 suppl 1):S1-290. 7. Kasiske BL, Zeier MG, Chapman JR, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int. 2010;77(4):299-311. 8. EBPG Expert Group on Renal Transplantation. European best practice guidelines for renal transplantation. Section IV: long-term management of the transplant recipient. Nephrol Dial Transplant. 2002;17(suppl 4):1-67. 9. Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-1585. 10. Linas SL, Miller PD, McDonald KM, et al. Role of the renin-angiotensin system in post-transplantation hypertension in patients with multiple kidneys. N Engl J Med. 1978;298(26):1440-1444. 11. First MR, Neylan JF, Rocher LL, Tejani A. Hypertension after renal transplantation. J Am Soc Nephrol. 1994;4(8 suppl):S30-36. 12. van der Schaaf MR, Hene RJ, Floor M, Blankestijn PJ, Koomans HA. Hypertension after renal transplantation. Calcium channel or converting enzyme blockade? Hypertension. 1995;25(1): 77-81. 339

Mangray and Vella 13. Textor SC, Canzanello VJ, Taler SJ, et al. Cyclosporineinduced hypertension after transplantation. Mayo Clin Proc. 1994; 69(12):1182-1193. 14. Paoletti E, Gherzi M, Amidone M, Massarino F, Cannella G. Association of arterial hypertension with renal target organ damage in kidney transplant recipients: the predictive role of ambulatory blood pressure monitoring. Transplantation. 2009; 87(12):1864-1869. 15. Kasiske BL, Anjum S, Shah R, et al. Hypertension after kidney transplantation. Am J Kidney Dis. 2004;43(6):1071-1081. 16. Opelz G, Wujciak T, Ritz E. Association of chronic kidney graft failure with recipient blood pressure. Collaborative Transplant Study. Kidney Int. 1998;53(1):217-222. 17. Opelz G, Dohler B. Improved long-term outcomes after renal transplantation associated with blood pressure control. Am J Transplant. 2005;5(11):2725-2731. 18. Prasad GV, Nash MM, Zaltzman JS. A prospective study of the physician effect on blood pressure in renal-transplant recipients. Nephrol Dial Transplant. 2003;18(5):996-1000. 19. Myers MG, Tobe SW, McKay DW, Bolli P, Hemmelgarn BR, McAlister FA. New algorithm for the diagnosis of hypertension. Am J Hypertens. 2005;18(10):1369-1374. 20. Bobrie G, Chatellier G, Genes N, et al. Cardiovascular prognosis of ”masked hypertension” detected by blood pressure self-measurement in elderly treated hypertensive patients. JAMA. 2004;291(11):1342-1349. 21. Stergiou GS, Kalogeropoulos PG, Baibas NM. Prognostic value of home blood pressure measurement. Blood Press Monit. 2007;12(6):391-392. 22. Stenehjem AE, Gudmundsdottir H, Os I. Office blood pressure measurements overestimate blood pressure control in renal transplant patients. Blood Press Monit. 2006;11(3):125-133. 23. Haydar AA, Covic A, Jayawardene S, et al. Insights from ambulatory blood pressure monitoring: diagnosis of hypertension and diurnal blood pressure in renal transplant recipients. Transplantation. 2004;77(6):849-853. 24. Guidi E, Menghetti D, Milani S, Montagnino G, Palazzi P, Bianchi G. Hypertension may be transplanted with the kidney in humans: a long-term historical prospective follow-up of recipients grafted with kidneys coming from donors with or without hypertension in their families. J Am Soc Nephrol. 1996;7(8):1131-1138. 25. Guidi E, Cozzi MG, Minetti E, Bianchi G. Donor and recipient family histories of hypertension influence renal impairment and blood pressure during acute rejections. J Am Soc Nephrol. 1998;9(11):2102-2107. 26. Rigatto C, Foley R, Jeffery J, Negrijn C, Tribula C, Parfrey P. Electrocardiographic left ventricular hypertrophy in renal transplant recipients: prognostic value and impact of blood pressure and anemia. J Am Soc Nephrol. 2003;14(2):462-468. 27. Midtvedt K, Ihlen H, Hartmann A, et al. Reduction of left ventricular mass by lisinopril and nifedipine in hypertensive renal transplant recipients: a prospective randomized double-blind study. Transplantation. 2001;72(1):107-111. 28. Goodwin JE, Zhang J, Geller DS. A critical role for vascular smooth muscle in acute glucocorticoid-induced hypertension. J Am Soc Nephrol. 2008;19(7):1291-1299. 29. Veenstra DL, Best JH, Hornberger J, Sullivan SD, Hricik DE. Incidence and long-term cost of steroid-related side effects after renal transplantation. Am J Kidney Dis. 1999;33(5):829-839. 30. Hricik DE, Lautman J, Bartucci MR, Moir EJ, Mayes JT, Schulak JA. Variable effects of steroid withdrawal on blood pressure reduction in cyclosporine-treated renal transplant recipients. Transplantation. 1992;53(6):1232-1235. 31. Vincenti F, Schena FP, Paraskevas S, Hauser IA, Walker RG, Grinyo J. A randomized, multicenter study of steroid avoid340

ance, early steroid withdrawal or standard steroid therapy in kidney transplant recipients. Am J Transplant. 2008;8(2):307-316. 32. Luke RG. Pathophysiology and treatment of posttransplant hypertension. J Am Soc Nephrol. 1991;2(2 suppl 1):S37-S44. 33. Hohage H, Bruckner D, Arlt M, Buchholz B, Zidek W, Spieker C. Influence of cyclosporine A and FK506 on 24 h blood pressure monitoring in kidney transplant recipients. Clin Nephrol. 1996;45(5):342-344. 34. Van Buren DH, Burke JF, Lewis RM. Renal function in patients receiving long-term cyclosporine therapy. J Am Soc Nephrol. 1994;4(8 suppl):S17-S22. 35. Sander M, Lyson T, Thomas GD, Victor RG. Sympathetic neural mechanisms of cyclosporine-induced hypertension. Am J Hypertens. 1996;9(11):121S-138S. 36. Shiba N, Chan MC, Kwok BW, Valantine HA, Robbins RC, Hunt SA. Analysis of survivors more than 10 years after heart transplantation in the cyclosporine era: Stanford experience. J Heart Lung Transplant. 2004;23(2):155-164. 37. Pascual M, Curtis J, Delmonico FL, et al. A prospective, randomized clinical trial of cyclosporine reduction in stable patients greater than 12 months after renal transplantation. Transplantation. 2003;75(9):1501-1505. 38. Margreiter R. Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: a randomised multicentre study. Lancet. 2002;359(9308):741-746. 39. Gonwa T, Mendez R, Yang HC, Weinstein S, Jensik S, Steinberg S. Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6 months. Transplantation. 2003;75(8):1213-1220. 40. Meier-Kriesche HU, Schold JD, Srinivas TR, Howard RJ, Fujita S, Kaplan B. Sirolimus in combination with tacrolimus is associated with worse renal allograft survival compared to mycophenolate mofetil combined with tacrolimus. Am J Transplant. 2005;5(9):2273-2280. 41. Karthikeyan V, Karpinski J, Nair RC, Knoll G. The burden of chronic kidney disease in renal transplant recipients. Am J Transplant. 2004;4(2):262-269. 42. Modena FM, Hostetter TH, Salahudeen AK, Najarian JS, Matas AJ, Rosenberg ME. Progression of kidney disease in chronic renal transplant rejection. Transplantation. 1991;52(2):239-244. 43. Kasiske BL, Anjum S, Shah R, et al. Hypertension after kidney transplantation. Am J Kidney Dis. 2004;43(6):1071-1081. 44. Mitsnefes MM, Khoury PR, McEnery PT. Early posttransplantation hypertension and poor long-term renal allograft survival in pediatric patients. J Pediatr. 2003;143(1):98-103. 45. Monaco AP, Burke JF Jr, Ferguson RM, et al. Current thinking on chronic renal allograft rejection: issues, concerns, and recommendations from a 1997 roundtable discussion. Am J Kidney Dis. 1999;33(1):150-160. 46. Yakupoglu U, Baranowska-Daca E, Rosen D, Barrios R, Suki WN, Truong LD. Post-transplant nephrotic syndrome: a comprehensive clinicopathologic study. Kidney Int. 2004;65(6):2360-2370. 47. Solez K, Colvin RB, Racusen LC, et al. Banff ’05 meeting report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (’CAN’). Am J Transplant. 2007;7(3):518-526. 48. Briganti EM, Russ GR, McNeil JJ, Atkins RC, Chadban SJ. Risk of renal allograft loss from recurrent glomerulonephritis. N Engl J Med. 2002;347(2):103-109. 49. Hariharan S, Peddi VR, Savin VJ, et al. Recurrent and de novo renal diseases after renal transplantation: a report from the renal allograft disease registry. Am J Kidney Dis. 1998;31(6):928-931. 50. Dragun D, Muller DN, Brasen JH, et al. Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection. N Engl J Med. 2005;352(6):558-569. Am J Kidney Dis. 2011;57(2):331-341

Hypertension/Transplant 51. Bruno S, Remuzzi G, Ruggenenti P. Transplant renal artery stenosis. J Am Soc Nephrol. 2004;15(1):134-141. 52. Audard V, Matignon M, Hemery F, et al. Risk factors and long-term outcome of transplant renal artery stenosis in adult recipients after treatment by percutaneous transluminal angioplasty. Am J Transplant. 2006;6(1):95-99. 53. Pouria S, State OI, Wong W, Hendry BM. CMV infection is associated with transplant renal artery stenosis. QJM. 1998;91(3): 185-189. 54. Humar A, Matas AJ. Surgical complications after kidney transplantation. Semin Dial. 2005;18(6):505-510. 55. Sankari BR, Geisinger M, Zelch M, Brouhard B, Cunningham R, Novick AC. Post-transplant renal artery stenosis: impact of therapy on long-term kidney function and blood pressure control. J Urol. 1996;155(6):1860-1864. 56. Hricik DE, Browning PJ, Kopelman R, Goorno WE, Madias NE, Dzau VJ. Captopril-induced functional renal insufficiency in patients with bilateral renal-artery stenoses or renal-artery stenosis in a solitary kidney. N Engl J Med. 1983;308(7):373-376. 57. Ghazanfar A, Tavakoli A, Augustine T, Pararajasingam R, Riad H, Chalmers N. Management of transplant renal artery stenosis and its impact on long term allograft survival: a single centre experience [published online ahead of print July 2, 2010]. Nephrol Dial Transplant. doi:10.1093/ndt/gfq393. 58. O’Neill WC, Baumgarten DA. Ultrasonography in renal transplantation. Am J Kidney Dis. 2002;39(4):663-678. 59. Li JC, Ji ZG, Cai S, Jiang YX, Dai Q, Zhang JX. Evaluation of severe transplant renal artery stenosis with Doppler sonography. J Clin Ultrasound. 2005;33(6):261-269. 60. Rudnick MR, Berns JS, Cohen RM, Goldfarb S. Nephrotoxic risks of renal angiography: contrast media-associated nephrotoxicity and atheroembolism—a critical review. Am J Kidney Dis. 1994;24(4):713-727. 61. Loubeyre P, Cahen R, Grozel F, et al. Transplant renal artery stenosis. Evaluation of diagnosis with magnetic resonance angiography compared with color duplex sonography and arteriography. Transplantation. 1996;62(4):446-450. 62. Patel NH, Jindal RM, Wilkin T, et al. Renal arterial stenosis in renal allografts: retrospective study of predisposing factors and outcome after percutaneous transluminal angioplasty. Radiology. 2001;219(3):663-667. 63. Fervenza FC, Lafayette RA, Alfrey EJ, Petersen J. Renal artery stenosis in kidney transplants. Am J Kidney Dis. 1998;31(1):142-148. 64. Rike AH, Mogilishetty G, Alloway RR, et al. Cardiovascular risk, cardiovascular events, and metabolic syndrome in renal transplantation: comparison of early steroid withdrawal and chronic steroids. Clin Transplant. 2008;22(2):229-235. 65. Chan JD, Rea TD, Smith NL, et al. Association of betablocker use with mortality among patients with congestive heart failure in the Cardiovascular Health Study (CHS). Am Heart J. 2005;150(3):464-470. 66. Ruggenenti P, Perico N, Mosconi L, et al. Calcium channel blockers protect transplant patients from cyclosporine-induced daily renal hypoperfusion. Kidney Int. 1993;43(3):706-711. 67. Midtvedt K, Hartmann A, Foss A, et al. Sustained improvement of renal graft function for two years in hypertensive renal transplant recipients treated with nifedipine as compared to lisinopril. Transplantation. 2001;72(11):1787-1792. 68. Midtvedt K, Hartmann A. Hypertension after kidney transplantation: are treatment guidelines emerging? Nephrol Dial Transplant. 2002;17(7):1166-1169.

Am J Kidney Dis. 2011;57(2):331-341

69. McCulloch TA, Harper SJ, Donnelly PK, et al. Influence of nifedipine on interstitial fibrosis in renal transplant allografts treated with cyclosporin A. J Clin Pathol. 1994;47(9):839-842. 70. Ladefoged SD, Andersen CB. Calcium channel blockers in kidney transplantation. Clin Transplant. 1994;8(2 pt 1):128-133. 71. Mourad G, Ribstein J, Mimran A. Converting-enzyme inhibitor versus calcium antagonist in cyclosporine-treated renal transplants. Kidney Int. 1993;43(2):419-425. 72. Kovarik JM, Beyer D, Bizot MN, Jiang Q, Allison MJ, Schmouder RL. Pharmacokinetic interaction between verapamil and everolimus in healthy subjects. Br J Clin Pharmacol. 2005; 60(4):434-437. 73. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet. 1997;349(9069):1857-1863. 74. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329(20): 1456-1462. 75. Maschio G, Alberti D, Janin G, et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med. 1996;334(15):939-945. 76. Ruggenenti P, PernaA, Gherardi G, Gaspari F, Benini R, Remuzzi G. Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN). Ramipril Efficacy in Nephropathy. Lancet. 1998;352(9136):1252-1256. 77. Curtis JJ, Laskow DA, Jones PA, Julian BA, Gaston RS, Luke RG. Captopril-induced fall in glomerular filtration rate in cyclosporine-treated hypertensive patients. J Am Soc Nephrol. 1993;3(9):1570-1574. 78. Vlahakos DV, Canzanello VJ, Madaio MP, Madias NE. Enalapril-associated anemia in renal transplant recipients treated for hypertension. Am J Kidney Dis. 1991;17(2):199-205. 79. Gaston RS, Julian BA, Curtis JJ. Posttransplant erythrocytosis: an enigma revisited. Am J Kidney Dis. 1994;24(1):1-11. 80. Hiremath S, Fergusson D, Doucette S, Mulay AV, Knoll GA. Renin angiotensin system blockade in kidney transplantation: a systematic review of the evidence. Am J Transplant. 2007;7(10): 2350-2360. 81. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery: Executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery) developed in collaboration with the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. J Am Coll Cardiol. 2007;50(17):17071732.

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