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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 cardiovascu-
lar 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 minimi-
zation 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
Am J Kidney Dis. 57(2):331-341. © 2011 by the National Kidney Foundation, Inc.

INDEX WORDS: Hypertension; human; kidney; transplantation; immunosuppression.

CASE PRESENTATION studies suggest that this effect is due largely to the
A 57-year-old white man with end-stage renal disease secondary decrease in cardiovascular disease complications.4
to autosomal dominant polycystic kidney disease required 4 differ- This review focuses on hypertension as one of the
ent antihypertensive medications while hemodialysis dependent to major “traditional” determinants for cardiovascular
achieve moderate blood pressure (BP) control (mean BP, 149/94 disease after kidney transplant. Posttransplant hyper-
mm Hg predialysis). After 3 years of hemodialysis therapy, he
received a deceased donor kidney transplant. The transplant func- tension may be modulated by both kidney function
tioned promptly and the serum creatinine level reached a nadir of and immunotherapy, as described in the vignette, and
1.42 mg/dL (125.5 ␮mol/L; estimated glomerular filtration rate such factors are explored in greater detail in the
[eGFR], 55 mL/min/1.73 m2 [0.92 mL/s/1.73 m2]) within 4 days of ensuing text.
surgery. Immunosuppression included tacrolimus, mycophenolate
mofetil, and low-dose prednisone. His requirement for antihyper-
The 2 major goals of antihypertensive therapy after
tensive medications decreased substantially, such that within 4 transplant are preservation of kidney function (or
months of transplant, only a single agent was required to achieve slowing of kidney disease progression) and decreas-
BP readings consistently ⬍130/90 mm Hg. Three years after ing cardiovascular disease risk. It should be noted that
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
most data pertaining to hypertension after transplant
steroid therapy withdrawal, and BP control deteriorated, requiring have accrued from clinical trials that focus on immu-
the addition of 2 more antihypertensive agents. A transplant biopsy notherapeutic regimens, as well as analyses of registry
showed Banff grade Ia acute cellular rejection superimposed on databases, rather than studies that primarily focus 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 From the Maine Transplant Program, Maine Medical Center
antihypertensive medications. and Tufts University, Portland, ME.
Received July 19, 2010. Accepted in revised form October 27,
INTRODUCTION Address correspondence to John Vella, MD, FRCP, Maine
Atherosclerotic cardiovascular disease is a frequent Medical Center, Tufts University School of Medicine, 19 West St,
Portland, ME 04102. E-mail:
cause of morbidity and the dominant cause of mortal- © 2011 by the National Kidney Foundation, Inc.
ity after kidney transplant1,2 (Fig 1). Compared with 0272-6386/$36.00
dialysis, transplants decrease mortality, and recent doi:10.1053/j.ajkd.2010.10.048

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

improved long- System. The investigators commented that this observa- tive) has similar treatment target recommendations tion occurred despite “adequate patient experience that have been endorsed recently by the KDIGO with posttransplant clinic visits and BP-altering medi- (Kidney Disease: Improving Global Outcomes) work. cally are performed in the office by either a medical sure (JNC 7) as systolic BP (SBP) ⬎140 mm Hg.5 The JNC 7 also recommends that treat. the presence of the physician at the time of kidney disease.19 There are growing mg/g).666 kidney transplant recipi- ents15 (Fig 2). nearly half of all transplant recipients had hypertension. ⬎90% of calcineurin.9 EPIDEMIOLOGY Before the US Food and Drug Administration ap- proval of cyclosporine in 1983. Figure 2. results of a prospective study of more than 200 sive therapy. defined ing Group. the prevalence. 332 Am J Kidney Dis. BP measurements typi- tion.7 In patients with significant proteinuria self BP measurement (SBPM) at home. and after a physician visit. In one report. and clinical correlates of hyperten- sion and its association with outcomes were studied in a retrospective cohort of 1. cerebrovascular (Fig 2). The National Kidney Foundation’s BP measurement caused BP to increase by 3-4 mm KDOQI (Kidney Disease Outcomes Quality Initia. Abbreviations: CBVD. treatment. Atherosclerotic ables). and by whom? Traditionally. Source: US Renal Data deceased donor kidney recipients.57(2):331-341 . CVD. where.10 Presently. The limited data pertain. In another study of nearly 25. SBP was controlled to ⬍140 mm Hg at 3 years versus ing to the outlined goals is discussed next. Hypertension negatively affects transplant and pa- tient survival outcomes. control. Using multivariate ⬍130/80 mm Hg in patients with diabetes or chronic analysis. only 5% of kid.6. or physician. Kidney transplant survival is inversely proportional to blood pressure. and Treatment of High Blood Pres.11-13 and in one study. Prasad et al18 reported diastolic BP ⬎90 mm Hg. ment be provided to achieve BP ⬍140/90 mm Hg or during. Detec. or the need for antihyperten. Hg. Abbreviation: SBP. each 10–mm Hg of SBP was associated with disease is the most common cause of death after transplant an ⬃5% increased risk of transplant failure and death (44%) and outweighs the contributions from infection and malig- nancy combined (33%). cation. Evaluation. nurse. assistant. an observation attributed at the time to activation of the renin- angiotensin system of either native kidney or trans- plant derivation. Association of hypertension at 1 year with trans- inhibitor–treated kidney transplant recipients have plant survival. the Joint National Committee on Prevention. systolic blood pressure. 2011. After adjusting for the effects of acute rejection and transplant function (among other vari- Figure 1.000 primary disease. hypertension. Reproduced from Opelz et al16 with permission of Nature Publish- ney transplant recipients were normotensive. Mangray and Vella as ambulatory BP readings ⬍130/80 mm Hg without treatment.17 DEFINITION DIAGNOSIS Hypertension is defined by the Seventh Report of How should BP be measured after transplant.”18 Alternatives to office BP readings include ing group.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.3 term transplant outcome was observed in patients with SBP ⬎150 mm Hg at 1 year posttransplant when hypertension as an end point. transplant recipients who had BP checked before. cardiovascular disease. and ambula- (defined as spot urine protein-creatinine ratio ⬎500 tory BP monitoring (ABPM).14 This change in the reported incidence of hypertension may reflect changing definitions of hy- pertension over time and thus direct comparison may be misleading. Mortality after kidney transplant. those with sustained increases in SBP. a European Best Practice Guideline suggests that the BP goal be decreased to ⬍125/75 mm Hg.

As an example. In addition. Patients were randomly assigned developed hypertension more frequently than those in a double-blind fashion to receive 30 mg of nifedi- with a kidney transplant derived from a normotensive pine or 10 mg of lisinopril once daily. 1. Recipients channel blocker (CCB.27) and was independent of risk factors for hypertension after transplant include other major prognostic variables. 2011. They ● Recurrent or de novo glomerular disease also found that SBP diurnal variation was predicted Transplant Renal Artery Stenosis Transplant obstruction independently using age and GFR. ● Delayed transplant function tory BP. and decreased va- Am J Kidney Dis. Hypertension family or recipients with familial hypertension (in was equally well controlled in the 2 groups through- whom the origin of the kidney did not influence the out the study. In the decreased by 15% in both groups. Midvedt et 3. tive heart failure (RR. mineralocorticoid-induced sodium retention.26 Anemia and dia- determinants of both donor and recipient origin and stolic BP were independent risk factors for increasing also factors that relate to the transplant process and LVH between the first and fifth years. 2.9) and conges- In contrast to the general and CKD populations.57(2):331-341 333 .20.Hypertension/Transplant data from studies of the general population that SBPM Box 1. kidney transplant. and left ventricular mass index was prevalence of posttransplant hypertension). concluded that hypertensive kidney transplant recipi- neys derived from hypertensive families developed ents with well-controlled BP experience regression of higher diastolic BPs and greater degrees of acute left ventricular mass after kidney transplant. baseline LVH DETERMINANTS AND PATHOGENESIS defined using electrocardiographic criteria was a risk factor for death (relative risk [RR]. Haydar et al23 examined the relationship Immunotherapy between BP measured using ABPM compared with ● Corticosteroids daytime office BP and also observed predictors of ● Calcineurin inhibitors (cyclosporine ⬎ tacrolimus) diurnal variation in almost 200 kidney transplant Transplant Dysfunction ● Acute rejection recipients. as summarized in Box 1 and Fig only predictor of de novo LVH at 5 years. SBPM values ● Donor sex in the morning and evening were significantly higher ● Donor hypertension than ABPM values. the investigators showed that ABPM is a more sensitive method for diagnosing hypertension than sole reliance on office BP in kidney the general population. Guidi et al24 showed the interplay of such factors in al27 presented a prospective study of 154 patients that a prospective observational study of 85 transplant compared the effect of an angiotensin-converting en- recipients with stable kidney function (without cyclo.21 What about the transplant ● Pre-existing hypertension & left ventricular hypertrophy population? Stenehjem et al22 compared office. only 15% ● Chronic allograft nephropathy of hypertensive kidney transplant patients would be ● Thrombotic microangiopathy given an erroneous diagnosis of normotension. zyme (ACE) inhibitor (lisinopril) with a calcium sporine therapy) followed up for 8 years. and using casual BP. kidney injury during acute rejection than the other recipients. SBP was the immunosuppression. dialysis patients. Mean ● Native kidney disease Donor Factors office and 24-hour ABPM readings were similar ● Donor age (133/82 vs 133/80 mm Hg). Adequate BP control was found in Transplant Factors 53% of patients using office BP compared with 29% ●Cold ischemia time ● Warm ischemia time using home BP and 16% using mean 24-hour ambula. Factors Contributing to Hypertension After Transplant is associated with improved outcomes compared with Recipient Factors clinic measurements. although it corre. However. in a retrospective study of almost 500 transplant patients. recipients of kid. SBPM. ● Body mass index and ABPM in 49 kidney transplant recipients. The investigators follow-up study of these patients.25 ROLE OF IMMUNOSUPPRESSIVE AGENTS Steroids HYPERTENSION AND LEFT Pharmacologic doses of steroids mediate hyperten- VENTRICULAR HYPERTROPHY sion through a variety of mechanisms that include Left ventricular hypertrophy (LVH) is an indepen. and after transplant recipients. The concordance rate between casual BP ● Antibody-mediated rejection and ABPM was 80%. increased dent risk factor for death and cardiovascular disease in responsiveness to vasoconstrictors. ● Ureteric stenosis lated with cyclosporine level and ABPM-to-transplant ● Lymphocele interval. controlled-release nifedipine) without a family history of hypertension engrafted in treatment of posttransplant hypertension. focusing with a kidney derived from a hypertensive family on changes in LVH.

renin-angiotensin system. and standard-steroid groups. as illustrated by the vignette at impact of steroids on BP is negligible. A complex interplay exists resulting from decreased glomerular filtration rate (GFR). Mean SBPs at study end were 133 ⫾ 20.30 inducible nitric oxide. Abbreviation: RAS.13. Most importantly. Karthikeyan et al41 334 Am J Kidney Dis. Calcineurin Inhibitors ies have shown a direct role of the glucocorticoid Both cyclosporine and tacrolimus have induced or receptor on vascular smooth muscle. upregulates endothelin.39. kidney transplant recipients. Furthermore.4 However. In addition.29 with the effect highest in those with nervous system. ine. The incidence of hypertension increased from munity to minimize or avoid the predictable adverse ⬍10% overall to 30%-60% in bone marrow patients consequences. transplant survival. when tacrolimus is used groups.57(2):331-341 . in combination with sirolimus. recent in vitro stud. and 132 ⫾16 mm Hg in the steroid-free. and the consequent after kidney transplant. de novo cyclosporine by 50% at 1 year or longer post–kidney kidney transplant recipients were randomly assigned transplant has decreased the risk of hypertension in to receive no steroids.35 The hy- receive steroid therapy after transplant. or standard steroid therapy. Hypertension and GFR are intimately interrelated notherapy than their predecessors. Mechanisms by which hypertension after kidney transplant is mediated. AFTER TRANSPLANT treated patients receive much lower cumulative immu. and basiliximab. transplant before and after the availability of cyclospor- grafts are gaining traction within the transplant com. pertensive effect of such therapy can be appreciated steroid-avoidance or early-withdrawal protocols for from studies of patients with bone marrow and cardiac non–African American recipients of primary allo. all of which cause potent vaso- Most patients in the United States continue to constriction and systemic hypertension. rotoxic and is associated with decreased long-term dence of rejection in the steroid-avoidance or -with. there were no differences in patient or transplant survival at the end EFFECT OF GFR ON HYPERTENSION of the study. re. erbates hypertension. the beginning of this review.1. and inhibits pre-existing hypertension. enteric-coated my. the combination exac- 135 ⫾ 18. Mangray and Vella Figure 3. However. The question is whether such protocols and 70%-90% in heart transplant recipients. No differences were cyclosporine38 when used with prednisone and myco- observed in terms of SBP or diastolic BP between phenolate mofetil. decreasing the dose of In a 12-month open-label multicenter study. known that tacrolimus has less of an effect on BP than cophenolate.40 drawal groups.28 The estimated exacerbated hypertension in transplant recipients.33 incidence of glucocorticoid-associated hypertension Cyclosporine in particular activates the sympathetic is ⬃15%. and sodium retention that are variously adversely affected by immunosup- pressive agents. cate that the latter combination is synergistically neph- spectively.36 In result in tangible improvements in primary outcomes. all mofetil without increasing rejection risk. vasoconstriction. Most likely we now are seeing an example of regression to the mean whereby steroid. 2011.34. steroids to day 7 posttransplant patients treated with steroids and mycophenolate (steroid withdrawal). registry data indi- steroid-withdrawal.37 It now is in combination with cyclosporine.31 There was a significantly higher inci.32. sodilator production.

Hypertension/Transplant showed increasing requirements of antihypertensive exists who present with malignant hypertension. less commonly.51 and acute kidney Recurrent disease is the third most common cause injury after ACE-inhibitor or angiotensin II receptor of long-term transplant loss after death with function blocker (ARB) therapy initiation. new or worsening hypertension. compared with AT1 receptor–positive patients who vival.50 In medications from 0. artery stenosis development include cytomegalovirus plant failure (after death with transplant function). In another study. perforation. transplant renal artery stenosis also may be suggested ated with new-onset or worsening hypertension.55 Pa- months posttransplant in the absence of active acute tients typically present in a fashion similar to native rejection.51 It has been suggested that cally with a gradual deterioration in transplant func.56 The diagnosis of and chronic allograft nephropathy and often is associ.42 Kasiske et al43 also exam. the progres. atheroem- A subset of patients with antibody-mediated rejection bolic disease. of live donor compared with deceased donor allo- dence of any specific etiology. renal artery dissection. In addition. antibodies were with stage 5 function.45.57(2):331-341 335 . flash pulmonary edema.48. treatment significantly prolonged transplant survival ined the impact of hypertension on transplant sur.49 if a new bruit is detected over the kidney transplant. variable degrees of proteinuria.53 delayed transplant function.51. without evi. calcineurin-inhibitor drug toxicity. and plant morphologic changes. or other kidney renal artery stenosis with refractory hyperten- diseases. implying that post- kidney transplant rejection. Potential complications of angiogra- rejection characterized by the development of acute phy are predictable and include groin hematoma.50 Most patients did not have hypertension patients with clinical and histologic evidence of chronic before vascular rejection occurred.3 in those with refractory vascular rejection.998 transplant recipients reported to the Australia and New Zealand Dialysis Diagnosis and Transplant (ANZDATA) Registry.44 3-24 months after surgery. Mean BP significantly transplant hypertension was secondary to the rejection correlated with serum creatinine level at the time of process. thrombosis. failure and death. sion. intrave- correlate with greater rates of progression of de. acute kidney injury caused by radiocontrast-in- ment (C4d). up to 12% of transplant recipients with hypertension tion. sonography may be operator dependent and ANTIBODY-MEDIATED REJECTION conventional angiography remains the gold-standard Antibody-mediated rejection is a specific type of diagnostic test. After adjusting for effects of rejection. duced nephropathy or.7 in kidney transplant recipients a German study of 33 kidney transplant recipients with chronic kidney disease stage 1 to 2. Most AT1 receptor–related vascular rejection the change in the slope showing more severe hyperten. and. For example. 2011.”47 It is defined as grafts have been disputed. although it can present at Chronic allograft nephropathy is associated clini. This type of function. the patient to the risk of iodinated contrast media. recurrent dis. and surgical techniques.52 Risk factors for transplant renal syndrome is the second most common cause of trans. and other variables.52 organ pro- The newly revised Banff classification system has curement complications.57-59 Such testing is advanta- transplant function and 20% for chronic allograft geous because it is noninvasive and does not expose nephropathy. The creased kidney function. However. in a study of 3. infection. kidney received conventional rescue therapy. The investigators concluded that higher BPs tion therapy consisting of plasmapheresis. Various reports over time have suggested a role for ease accounted for ⬃8% of patients with transplant ultrasonography as a screening test for transplant loss at 10 years compared with 15% for death with renal artery stenosis. although it seems that a kidney transplant dysfunction occurring at least 3 pediatric donor source is a major risk factor. and presence of donor-reactive antibody. occurred during the first week after transplant. any stage after transplant. and losartan.54 renamed chronic allograft nephropathy “interstitial Suggestions that the incidence is higher in recipients fibrosis and tubular atrophy (IF-TA). pertinent to may have functionally significant transplant renal this review.60 The transplant often is biopsied Am J Kidney Dis. deposition of comple. TRANSPLANT RENAL ARTERY STENOSIS dicts poor long-term transplant survival in pediatric Transplant renal artery stenosis typically presents patients.46 This artery stenosis. transplant dysfunction associated with specific trans. nous immune globulin infusions. Seven sion in patients with more severe decreased kidney of 16 AT1 receptor patients were treated with combina- function. each 10 mm Hg of SBP rejection seems to be very uncommon in the United was associated with an increased RR of transplant States. early posttransplant systolic hypertension strongly and independently pre. found to target the angiotensin II type 1 (AT1) recep- sion rate of decreased kidney function was quantitated tor in 16 recipients in the absence of anti-HLA antigen from the reciprocal of serum creatinine over time in antibodies.

37-39 Despite such manipulations.6). importantly for transplant.62 Recurrent stenosis may occur An ideal drug would be dosed once daily. as renal artery stenosis.3 mL/min. such as the diagnosis of transplant (compared with native) antiplatelet and cholesterol-lowering medications. served with lisinopril. Despite equivalent mass. fall into 2 major classes: dihydropyridine (eg. in patients with congestive heart failure. nately. dence interval. Interestingly. randomized. most with transplant renal artery stenosis treated with percu. but was unchanged with lisinopril (44 and 43 mL/min.61 well as glycemic control.51. dilti- described). The reader is reminded transplant renal artery stenosis (48%) compared with that ␤-blocker therapy decreases morbidity and mor- a control group (28%). such as chronic allograft nephropathy. acute control targets because of either lack of efficacy or rejection occurred more frequently in patients with dose-limiting adverse effects. with decreases in total cholesterol and plasma initial GFRs and attainment of similar BP levels. recipients are lacking. In truth. contractility. confi- often experience improved BP control after dose reduc. 336 Am J Kidney Dis. there are remark.65 Although pared with the transplant renal artery stenosis group. It has long been known that vaso- ably few data in the transplant population that have constriction is the dominant mechanism by which rigorously examined this intervention. improvement in GFR possible. which show somewhat differing ally is recommended as first-line therapy for patients mechanisms of action and. many agents are now available that meet at spective analysis of 29 kidney transplant recipients least some of these criteria (Table 1). and transplant loss has been reported in up sive. recipients continue to require one or more agents to tions. Use of netic resonance angiography is of limited value in agents that favorably affect atherogenesis. For example. Mangray and Vella before revascularization.57(2):331-341 . be inexpen- in ⬃10%. specific data pertaining to ␤-blockade in transplant Surgical revascularization generally has been re. patients using cyclosporine with nifedipine was maintained (10. tive period in high-risk patients. especially in the periopera- percutaneous intervention. ANTIHYPERTENSIVE AGENTS plasty with or without stent placement). Therapeutic lifestyle modification gener. and provide other beneficial properties. pharmacokinetics. achieve adequate control of hypertension. reduce The dual goals of posttransplant hypertension man.55 Mag.66 Therefore. GFR had significantly increased in those reported. no such benefit was ob- tion or conversion to either tacrolimus or siroli. with a clinical sive agent of choice for kidney transplant recipients? success rate of 82%. amlodip- mize cardiovascular risk (per JNC 7 guidelines. CCBs inhibit voltage-gated calcium channels in MANAGEMENT OF HYPERTENSION vascular smooth muscle and cardiac myocytes.52 The tech- nical success rate of percutaneous intervention has What is the optimal pharmacologic antihyperten- been reported to be as high as 94%. patients require more than one agent to achieve BP taneous transluminal angioplasty. which is recommended to mus. prospective. (2) At 2 years. Long-term transplant survival tality after myocardial infarction and also is of benefit was significantly higher in the control group com. A large. calcineurin inhibitors induce acute nephrotoxicity and effects of a 12-month dietary regimen on nutritional hypertension. are data reported by Rike et al. 4. Fortu- to 30% of cases. Such drugs agement are to prolong transplant survival and mini. comparative study tively. vasodilatory CCBs have been an status and metabolic outcome of kidney transplant attractive option at least for the early management of recipients in the first posttransplant year recently were hypertension after transplant. treated with nifedipine (56 vs 46 mL/min at baseline). 2011. and induce vasodilatation. are beyond the scope of this review. the glucose levels and a concomitant increase in serum following benefits were observed with nifedipine: albumin level. No change in hypertension control was (1) At 1 year. Adherence to dietary recommendations was found clear sustained improvement in kidney trans- related to sex (male better than female) and associated plant function in patients treated with nifedipine com- with weight loss primarily due to a decrease in fat pared with lisinopril67 (Fig 4). In truth. it seems sensible to recommend served for patients with disease not amenable to that such agents be used.0-16. plant includes manipulating immunotherapy when respectively).63 Audard et al52 performed a retro. Thus. as ine and nifedipine) and nondihydropyridine (eg. in the general population.64 Forty-six deceased donor available that support the use of such agents from kidney transplant recipients were enrolled during the clinical trials? first posttransplant year and followed up prospec. azem and verapamil). most transplant define and grade the presence of intercurrent condi. As an example. Treatment The primary treatment for transplant renal artery SPECIFIC CLASSES OF stenosis involves percutaneous intervention (angio. Optimal management of hypertension after trans.

bradycardia induced HTN & nephrotoxicity ACEi Lisinopril. 337 hypertension. may mitigate AMR- urine 60%. feces 40% because of risk of mediated by antibody to AT1 as parent drug & hyperkalemia receptor metabolites ARBs Losartan. urine 29%. mTOR. angiotensin. AT1. AKI. HCTZ. AKI. . mitigates CNI. mitigation of anemia feces 69%. ramipril: high-dose CNI proteinuria. others) receptors substrate hyperkalemia ␣-Blockers Doxazosin Antagonizes ␣1-adrenergic Cytochrome P450 Negative May mitigate BPH Orthostasis receptors metabolized Note: There is no discussion of centrally acting medication. acute kidney injury. mammalian target of rapamycin. Vasodilation. AMR.57(2):331-341 Hypertension/Transplant Table 1. There are no published data pertaining to eplerenone use in transplant recipients. GFR. HTN. angiotensin-converting enzyme inhibitor. calcineurin inhibitor. angiotensin II type 1. Ang. convoluted tubule may mitigate proteinuria aldosterone receptor ␤-Blockers Metoprolol (many Antagonizes ␤1-adrenergic Cytochrome P450 2D6 Negative Decrease risk of perioperative MI Bradycardia. benign prostatic hypertrophy. candesartan.000⫻ higher affinity for AT1 high-dose CNI because of risk of hyperkalemia Vasodilator Hydralazine Dilates peripheral vessels Liver metabolism/renal & Negative Useful in hospital posttransplant SLE. BPH. Vasodilation Cytochrome P450 3A4 Positive Mitigates CNI-induced HTN & Edema CCBs nifedipine substrate nephrotoxicity Nondihydropyridine Diltiazem. rate control Cytochrome P450 3A4 Strongly positive Decreased requirement for CNI/ Edema. ramipril Prevents conversion of Lisinopril: 100% excreted No direct PK interactions. such as clonidine. Tx. headache fecal excretion (short half-life) Minoxidil Renal excretion Negative May reverse tacrolimus-induced Edema. MI. HCTZ hyperkalemia. CCBs verapamil substrate & inhibition mTOR inhibitor. 2011. Selectively antagonizes AT1 Variable renal & fecal No direct PK interactions. inhibits distal (unchanged) suspected hyperaldosteronism. pharmacokinetics. thiazides less hypokalemia useful in patients with decreased GFR Potassium-sparing Amiloride. Abbreviations: ACEi. caution with concurrent erythrocytosis. ARB. Inhibits distal convoluted tubule Renal & fecal excretion Negative Useful in patients with Hyperkalemia (especially diuretics spironolactone aldosterone-induced sodium (unchanged). myocardial infarction. hirsutism alopecia. Losartan may decrease uric acid Hyperkalemia. fatigue. AKI. and AT2 receptors with excretion (unchanged) caution with concurrent levels anemia irbesartan 1. may exacerbate cyclosporine-induced hypertrichosis Diuretics Furosemide. because such agents rarely are required in transplant recipients. CNI. May reverse posttransplant Hyperkalemia. PK.Am J Kidney Dis. hydrochlorothiazide. calcium channel blocker. angiotensin receptor blocker. Salt & water excretion Renal excretion Negative Useful in patients with edema and Volume depletion. antibody-mediated rejection. transplant. CNI toxicity. CCB. urine hypokalemia or if there is if used with CNI/ACEi) resorption. Classes of Antihypertensive Medications Used After Transplant Medication Drug Interactions With Class (examples) Mechanism of Action Pharmacokinetics Immunotherapy Beneficial Effect in Tx Recipients Principal Adverse Effects Dihydropyridine Amlodipine. estimated glomerular filtration rate. (many others) Ang I to Ang II unchanged.

decreasing hematocrit calcineurin-inhibitor–treated kidney transplant recipi. ACE inhibitors can cause or exacerbate anemia Effects of CCBs on long-term kidney function in in transplant recipients. therefore. combination pharma- population is more complex. and potassium concentration. crolimus) therapy. The dihydropyridine CCBs share determine the effect on patient or transplant sur- these properties to a much lesser extent and therefore vival.72 This is a dian follow-up was 27 months. individuals. are thought of as first-line agents for management of Therefore.79 This meta-analysis of 21 studies published in 1994 con. ⫺ 5-day period postinitiation. ACE-inhibitor or ARB transcriptional event and typically occurs during a use was associated with a significant decrease in GFR 2. Although consider- disease has been well defined in the nontransplant ation should be given to the elucidation of potential population. tacroli.5%) and decrease in protein- immunotherapy to decrease. creat- mus. Hyperkalemia is a frequent finding after kidney Figure 4.69-71 A that may be potentiated by cyclosporine. 2. ACE-inhibitor or ARB use resulted CCB therapy is discontinued. a condition char- possibly also better long-term transplant function) acterized by a progressive increase in hemato- were conflicting. hyperkalemia and sometimes is life-threaten- ing. Kidney function and choice of antihypertensive transplant that is associated commonly with agent. are listed in Table 1. The primary outcome measure actions occur when used with cyclosporine.80 It seems reasonable to recommend the use of are easier to use in transplant recipients. such drugs typically crit (⬎50%) and risk of atherothrombotic events. ACE-inhibitor or ARB therapy can cause or exacerbate a decrease in GFR. especially when harmful posttransplant? A systematic review of 21 target calcineurin-inhibitor levels are highest. or sirolimus. esis and may be useful in the management of plant function and acute rejection episodes and posttransplant erythrocytosis. can exacerbate the frequency and severity of pean Renal Association–European Dialysis and Transplant Association.8 mL/min). lieved to be caused by inhibition of erythropoi- cineurin inhibitors (decrease in both delayed trans. hemoglobin level or hemato- plasma levels of the latter immunosuppressive drugs crit. Me- to increase sharply soon after initiation. Likewise.72 Verapamil and diltiazem are inine clearance. Several factors should be cologic intervention generally is required for such considered when choosing such medications for kid. incompletely understood phenomenon is be- cluded that the proposed benefits of CCBs and cal. after kidney transplant. Consequently. The achieved glomerular filtration rate (GFR) in patients delayed transplant function and is an adverse treated with calcium channel blockers is greater than for those effect of calcineurin-inhibitor (particularly ta- treated with angiotensin-converting enzyme inhibitors (mea- sured at 3 weeks and 1 and 2 years after transplant). but no change in men dictates that such drugs be used with caution and serum potassium level.73-76 Use of such agents in the transplant causes as previously described. A subset of patients develops persistent or refrac- tension and slowing the progression of chronic kidney tory hypertension after transplant. with specific reference to their 338 Am J Kidney Dis. higher levels of kidney function. ACE INHIBITORS/ARBs TREATMENT OF REFRACTORY HYPERTENSION Use of ACE inhibitors/ARBs for treatment of hyper. Mangray and Vella 1.77 and this prop- erty may mimic or mask early signs of acute transplant rejection. randomized trials performed in a total of 1. was change in kidney function (creatinine level. tients assessed the effect of ACE-inhibitor or ARB use hydropyridine CCBs that pharmacokinetic drug inter. one can expect levels of in a lower hematocrit (⫺3. especially those with proteinuria and of edema. uria (protein excretion. The medications used most commonly ney recipients. when (⫺5. and secondary outcomes potent inhibitors of cytochrome P450 C3A4 and cause included change in BP. 2011. Repro. proteinuria.70 Despite this. by as much as 5%-10%78 through a mechanism ents have been reported with variable efficacy. There were insufficient data to frequent monitoring.57(2):331-341 . are ACE inhibitors and ARBs helpful or hypertension after kidney transplant.47 g/d). 3. or GFR).549 pa- It is important to remember when choosing nondi. although they renin-angiotension system blockers in kidney trans- are more likely to be associated with the development plant recipients. ACE-inhibitor/ARB therapy duced from Midtvedt & Hartmann68 with permission of the Euro. clinical acu. these drugs are difficult to use early after transplant when patients are at the highest risk of developing complications.

ABPM is encouraged. 0. cardiovascular disease remains the most 7. and therapy should be goal oriented. 1978. Vella JP. 2004. Patients with established atheroscle. Transplant. 1. heart failure. in the incidence of cardiovascular death in recipients 2.25(1): Hydralazine is a very useful drug in hospitalized 77-81. Bakris GL. Detection. The Seventh Report of the Joint National Committee on Prevention. such as weight loss. KDIGO clinical common cause of death and transplant loss after practice guideline for the care of kidney transplant recipients: a kidney transplant. but not in older recipients. Zeier MG. Vella JP. 2011. MD: National Institutes of Health. Tejani A. vival in kidney transplant recipients. 2010. McDonald KM. Three-year transplant survival rates were induced alopecia. Chapman JR. renin-angiotensin system in post-transplantation hypertension in pa- No single algorithm for the management of post. Cushman WC. 2003. survival. J Am Soc Nephrol. Nephrol Dial as attainment of the respective target BPs quoted.83). Vella JP. CCBs be used early after transplant at a time when patients are most likely to experience the vasomotor IMPACT OF HYPERTENSION TREATMENT ON adverse effects of calcineurin-inhibitor therapy. Calcium should receive ␤-blockers in the perioperative period. Am J Kidney Dis.17(suppl 4):1-67. 10. Linas SL. tients with multiple kidneys. National Kidney Foundation.17 as briefly ics are very useful when managing hypertensive pa- described previously. 12. Danovitch GM.57(2):331-341 339 . Loop diuret- rates was provided by Opelz and Dohler.77(4):299-311. and anemia. transplant hypertension has been developed and uni. www. the question of hypertension control and patient/ 5. helpful. We tend to Collaborative Transplant Study (CTS) observational avoid using ACE-inhibitor or ARB therapy until 3-6 database that evaluated transplant outcomes in rela. Kidney Int.37). Effects of ing regular exercise. Cohen DJ. even 3. Care should be tailored to the need better for hypertensive patients (defined as SBP ⬎140 of the individual. Changes in SBP were paralleled by changes Soc Nephrol. It seems reasonable to recommend that of medication that is specific to transplant.usrds. 0. Am J Kidney Dis. investigators concluded that decreasing SBP.5(4):201-274. Floor M. US Renal Data System. 8.79). 2010. although such a recommendation is not sup. Bethesda. 2006. al- transplant recipients. as well long-term management of the transplant recipient.8(6):424-492.81 channel or converting enzyme blockade? Hypertension. Support: None. Hene RJ. tion at 5 years showed that SBP lowering after year 3 Financial Disclosure: The authors declare that they have no was associated with improved 10-year transplant sur. http:// associated with improved transplant and patient sur. Section IV: cardiovascular disease. Hypertension is almost ubiquitous summary. and Treatment of High Blood Pressure: the JNC 7 report. J Am (RR. although Therefore. Evaluation. JAMA. 2010. European in kidney transplant recipients and is a risk factor for best practice guidelines for renal transplantation. EBPG Expert Group on Renal Transplantation. Except for CCBs and ACE inhibi. and sodium restriction. Neylan JF.362(17):1575-1585. Rocher LL. et al. Miller PD. Hypertension after renal transplantation. Blankestijn PJ. et al. renal transplantation. may be intensive blood-pressure control in type 2 diabetes mellitus. First MR. transplant survival after kidney transplant. 1995.4(8 suppl):S30-36. J Am Soc randomized clinical trial data that specifically address Nephrol. Kasiske BL.404 first cadaver kidney lemia. 9. Transplantation NephSAP. National Institute of after several years of posttransplant hypertension.298(26):1440-1444. N Engl J Med. vival (RR. Transplantation NephSAP. some patients to reduce the dose requirement of their ably the best data that address the question of survival expensive calcineurin-inhibitor therapy. K/DOQI Clinical Practice Guide- lines on Hypertension and Antihypertensive Agents in Chronic Kid- Despite improvements in patient and transplant ney Disease. Additional examina. acute kidney injury. increas. Accessed January 5. There are no 4. there are few or no published data for each class same reason. and diabetes Koomans HA. 2009. relevant financial interests. et al. 2008. van der Schaaf MR. Hypertension after formly adopted.Hypertension/Transplant potential beneficial and adverse effects in kidney patients because of its short duration of action. 1994. is Diabetes and Digestive and Kidney Diseases. Role of the ported by clinical trial evidence after transplant. Danovitch GM. though it is less useful as a long-term agent for the tors. Evans GW.43(5 suppl 1):S1-290. ACKNOWLEDGEMENTS tained hypertension (RR. J Am younger than 50 years. 2002. SUMMARY 6. Chobanian AV. We PATIENT AND TRANSPLANT SURVIVAL tend to avoid using nondihydropyridine CCBs to prevent pharmacokinetic drug interactions. This was an analysis of the tients with edema and/or hyperkalemia. Black HR.289(19):2560-2572. 11. The Soc Nephrol. USRDS 2008 Annual Data Report. 2008.7(1):6-54. Transplantation NephSAP. et al. mm Hg at 1 year posttransplant) who achieved control to ⬍140 mm Hg compared with patients with rotic cardiovascular disease. does treating hypertension affect patient acknowledge that such a strategy may be useful for and transplant survival after kidney transplant? Prob. whereas even a temporary increase REFERENCES in SBP at 3 years was associated with worse survival 1. Lifestyle modifications. Byington RP. Minoxidil recipients who underwent transplant between 1987 occasionally is useful in patients with tacrolimus- and 2000. months have elapsed from transplant to avoid hyperka- tion to recipient SBP for 24. 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