Management of hypertension in solid-organ transplantation

Posttransplant hypertension is a major risk factor for cardiovascular disease and chronic renal allograft dysfunction. A significant number of transplant recipients suffer from posttransplant hypertension in part because of corticosteroid and calcineurin inhibitor use. Although the optimal blood pressure range and the antihypertensive agents of choice in the transplant population have not been determined, the guidelines for blood pressure control in the general population can be extrapolated to the transplant population. The choice of an antihypertensive regimen should be tailored on the basis of the individual patient's risk factors and comorbidities.     

Hypertension and survival in chronic hemodialysis patients--past lessons and future opportunities

There is substantial controversy surrounding the benefits of control of hypertension in hemodialysis patients. Unlike the general population, some studies suggest that higher blood pressure in hemodialysis patients offers a survival advantage, what is termed as "reverse epidemiology." To critically analyze the relationship between total and cardiovascular mortality and blood pressure, peer-reviewed, published studies in hemodialysis patients were analyzed. Consideration of the world-wide experience suggests that analysis of incident cohorts reveal a clear link between elevated blood pressure and mortality. Increased pulse pressure, which is primarily due to increased systolic pressure, is also associated with cardiovascular morbidity and mortality. The counterintuitive relationship between blood pressure and mortality appears, in part, to be due to methods of data analysis. When data are analyzed with systolic or diastolic blood pressure as separate models, not conjointly, inverse relationship between blood pressure and total and cardiovascular mortality is generally seen. When both systolic and diastolic blood pressure are considered together, systolic blood pressure or increased pulse pressure assumes a major importance in predicting cardiovascular events whereas diastolic blood pressure retains the inverse relationship. Control of hypertension in hypertensive dialysis patients is associated with improved survival. Furthermore, the use of antihypertensive drug treatment is associated with improved survival regardless of blood pressure control. Low predialysis blood pressure is associated with increased cardiovascular deaths and deaths within 2 years from malignancy or withdrawal from dialysis. These data suggest that hypertension needs to be better controlled in hypertensive hemodialysis patients. Better methods of assessment of blood pressure control, consideration of cardiac structure and function, and performance of randomized controlled trials of pharmacologic and nonpharmacologic strategies are needed to establish benefits and determining goal blood pressure in hemodialysis patients.     

Which drug should be used to treat patients with uncomplicated essential hypertension?

PURPOSE OF REVIEW: To review recent data and guidelines on selecting the initial antihypertensive drug. RECENT FINDINGS: The main driver of benefit from blood pressure-lowering therapy is blood pressure reduction, and there is little evidence supporting additional drug class-specific benefits in primary prevention of major cardiovascular outcomes. The results also confirm that in the patient with uncomplicated hypertension as well as in those patients with diabetes without nephropathy, initial therapy with 'newer therapies' (i.e. angiotensin-converting enzyme inhibitors, calcium channel blockers, and angiotensin receptor blockers) are effective, but not more effective than thiazide diuretics, at reducing stroke, coronary heart disease, morbidity or mortality, or all-cause mortality. SUMMARY: While compelling indications may exist for specific drug classes in those with specific target organ damage (i.e. heart failure, renal insufficiency, and coronary artery disease), thiazide diuretics remain unsurpassed in lowering blood pressure and in preventing hypertension-related clinical outcomes. Despite a more favorable metabolic profile, alpha-blockers are less effective in preventing cardiovascular disease, especially heart failure and stroke. Calcium channel blockers produce a similar reduction in blood pressure and cardiovascular disease outcomes compared with thiazide-type diuretics, although they are consistently less effective in preventing heart failure. In the absence of heart failure or renal disease, angiotensin-converting enzyme inhibitors have shown little advantage in clinical trials over diuretics in preventing cardiovascular disease and are not indicated as an initial therapy in Blacks.     

Are calcium antagonists effective in preventing complications of hypertension and progression of renal disease?

Long-acting calcium antagonists have been shown to be safe and effective in lowering blood pressure, both as first-line agents and in combination with other classes of antihypertensive drug. They have also been shown to reduce the incidence of cerebrovascular and cardiovascular events in elderly patients with predominantly systolic hypertension. It is clear that reduced morbidity and mortality in hypertension is related to the degree to which blood pressure is reduced, regardless of the therapy used. This is the single most important conclusion of all recent trials, especially in the sub-group of hypertensive patients with diabetes. The World Health Organization-International Society of Hypertension guidelines acknowledge this and do not make specific recommendations as to initial therapy in the absence of other medical factors. However the use of thiazide diuretics and beta-blockers has strong support from large placebo-controlled trials in patients with mild-moderate essential hypertension. The British Hypertension Society and JNC VI guidelines restrict their recommendations for the use of calcium antagonists to isolated systolic hypertension and angina, or when other agents have failed, are contraindicated or are not tolerated. However, their efficacy in lowering blood pressure, their tolerability and potentially beneficial secondary effect on proteinuria, especially in combination with an angiotensin-converting enzyme inhibitor, still make them attractive antihypertensive agents. The results of further long-term outcome trials that make direct comparisons between calcium antagonists and other classes of antihypertensive drug are still awaited. Unlike angiotensin-converting enzyme inhibitors, the antiproteinuric effect of calcium antagonists, even that of the non-dihydropyridine type, seems to depend on an adequate and stable reduction in blood pressure.     

Clinical pharmacology of antihypertensive therapy

Adequate control of blood pressure poses challenges for hypertensive patients and their physicians. Success rates of greater than 80% in reducing blood pressure to target values among high-risk hypertensive patients reported by several recent clinical trials argue that effective medications currently are available. Yet, only 34% of hypertensive patients in the United States are at their goal blood pressure according to the most recent national survey. Rational selection of antihypertensive drugs that target both the patient's blood pressure and comorbid conditions coupled with more frequent use of low-dose drug combinations that have additive efficacy and low adverse-effect profiles could improve significantly US blood pressure control rates and have a positive impact on hypertension-related cardiovascular and renal mortality and morbidity. This article reviews the pharmacokinetic and pharmacodynamic principles that underlie the actions of drugs in each of the classes of antihypertensive agents when used alone and in combination, provides practical pharmacologic information about the drugs most frequently prescribed for treatment of hypertension in the outpatient setting, and summarizes the current data influencing the selection of drugs that might be used most effectively in combination for the majority of hypertensive patients whose blood pressures are not controlled adequately by single-drug therapy.     

Angiotensin converting enzyme insertion/deletion polymorphism does not influence postcardiac transplantation hypertension onset or progression.

BACKGROUND: The angiotensin converting enzyme insertion deletion polymorphism (ACE I/D) has been associated with much cardiovascular pathology, including posttransplantation hypertension. Hypertension is a significant cause of morbidity and mortality after cardiac transplantation. We investigated the influence of the ACE I/D polymorphism on posttransplantation hypertension. METHODS: A total of 211 heart transplant recipients and 154 corresponding donors were genotyped for the ACE I/D polymorphism by polymerase chain reaction. ACE enzymatic activity was measured by spectrophotometric kinetic analysis. Sitting systolic and diastolic blood pressures were recorded at 3 consecutive visits, and the mean was calculated. Clinical data, including demographics and medication, were collected for all recipients. Results were analyzed by the chi-square test and analysis of variance, taking a p value of <0.05 to be significant. RESULTS: A total of 41.7% of the subjects were hypertensive (diastolic blood pressure >90 mm Hg) at the time of the study, with 79.6% taking at least one antihypertensive agent. We found no difference between the number of antihypertensive agents, cyclosporin dose and level, renal function, or systolic blood pressure for the different recipient or donor genotypes. We also found no significant correlation between ACE enzymatic activity and systolic or diastolic blood pressure. CONCLUSIONS: Our study of 211 recipients and 154 corresponding donors is the largest investigation of this polymorphism in a cardiac transplantation population. We found no apparent relationship between the ACE genotype (of either donor or recipient) and systemic hypertension (absolute measurements and the number or dose of antihypertensive agents used).     

Malignant hypertension in a patient with end of stage renal disease (ESRD) treated by renal transplant

Control of hypertension is often a problem in the management of end stage renal disease (ESRD). Multiple modalities of treatment are required to prevent cardiovascular and cerebrovascular mortality and morbidity. These include fluid and salt restriction, multidrug regimes and dialysis. We report a case of young 25 years old patient, admitted with chronic renal failure, complicated by malignant and refractory hypertension, not responding to hemodialysis and antihypertensive agent. During stay in hospital, patient also had intracerebral hemorrhage, fits due to uncontrolled hypertension requiring ventilatory support followed. Renal transplant was considered to be the final therapeutic modality. After gradual recovery, a successful live-related renal transplant was performed. As soon as good graft was established, the blood pressure settled and 4 of the 5 antihypertensives were withdrawn. After 2 weeks, patient was discharged in a stable condition with a total stay of about 2 months.     

Treating hypertension in the patient with overt diabetic nephropathy

Arterial blood pressure is a major determinant of renal and cardiovascular outcomes in diabetic nephropathy. There is a proportional relationship between the systolic blood pressure and renal and mortality outcomes. Decreasing the diastolic pressure does not significantly decrease these outcomes. Irrespective of the magnitude of pretreatment systolic hypertension in the patient with type 2 diabetic nephropathy, the systolic pressure achieved with antihypertensive therapy is the important determinant of renal and cardiovascular risk. Achieving a lower systolic pressure down to 120 mm Hg is associated with substantial risk reduction. Although the data are limited, systolic blood pressure less than 120 mm Hg may be associated with increased all-cause mortality in this patient population, increasing the possibility of a J-curve response. A marked decrease in diastolic pressure, which is a danger when undertaking aggressive therapy with the goal of decreasing the systolic pressure to 130 mm Hg, can be associated with an increased risk of cardiac events. The renoprotective and proteinuria-decreasing effects of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers recommend these agents as the standard of care in type 2 diabetic nephropathy. In addition to angiotensin-converting enzyme inhibitor and angiotensin-receptor blocker therapy, controlling the systolic blood pressure in this difficult to control patient population may require the use of 3 or more antihypertensive agents.     

Isolated systolic hypertension is associated with adverse outcomes from coronary artery bypass grafting surgery

Isolated systolic blood pressure has not been sufficiently studied in the perioperative setting and may contribute to morbidity and mortality after coronary artery bypass grafting (CABG) surgery. Our objective was to determine the prevalence of isolated systolic hypertension among patients who had CABG surgery and to assess whether isolated systolic hypertension is associated with perioperative and postoperative in-hospital morbidity or mortality. Patients who underwent CABG were selected from a prospective epidemiological study involving 2417 patients in 24 medical centers. Patients were classified as having normal preoperative blood pressure, isolated systolic hypertension (systolic blood pressure >140 mm Hg), diastolic hypertension (diastolic blood pressure >90 mm Hg), or a combination of these. Demographic risk factors (age, sex, and ethnicity), clinical risk factors (diabetes mellitus, increased cholesterol, antihypertensive medications, history of congestive heart failure, myocardial infarction, hypertension, and neurological deficits), and behavioral risk factors (smoking and heavy drinking) were controlled for statistically. Adverse outcomes included left ventricular dysfunction, cerebral vascular dysfunction or events, renal insufficiency or failure, and all-cause mortality. Isolated systolic hypertension was found in 29.6% of patients. Unadjusted isolated systolic hypertension was associated with a 40% increased risk of adverse outcomes (odds ratio, 1.4; confidence interval, 1.1-1.7). After adjusting for other potential risk factors, the increased risk of adverse outcomes with isolated systolic hypertension was 30%. We conclude that isolated systolic hypertension is associated with a 40% increase in the likelihood of cardiovascular morbidity perioperatively in CABG patients. This increase remains present regardless of antihypertensive medications, anesthetic techniques, and other perioperative cardiovascular risk factors (e.g., age older than 60 yr or history of congestive heart failure, myocardial infarction, or diabetes). IMPLICATIONS: Isolated systolic hypertension is associated with a 40% increase in the likelihood of perioperative cardiovascular morbidity in coronary artery surgery patients.     

Critical review of treatment trials in hypertension

Summary: Despite numerous deficiencies in some antihypertensive drug treatment trials, and some questionable selections of studies for inclusion in several meta-analyses, undoubtedly such trials have shown treatment benefits from reducing hypertension. Complications that can be corrected or prevented include malignant hypertension, hypertensive heart failure, stroke and coronary artery morbidity. the all-cause mortality has been lowered in several trials. the benefits have been seen in subjects aged over 60 years, in women and men, and in patients with isolated systolic hypertension. the benefits have been achieved using a wide range of drugs, not only with beta-blockers or diuretics. Non-pharmacological means of lowering blood pressure have not been evaluated in relation to morbidity.     

Ambulatory blood pressure monitoring: from old concepts to novel insights

Ambulatory blood pressure monitoring (ABPM) is an out-of-office technique for the assessment of 24-h blood pressure measurements. ABPM is indicated to diagnose many conditions, including white-coat hypertension, resistant hypertension, episodic hypertension, nocturnal hypertension, autonomic dysfunction, hypotension secondary to excessive usage of antihypertensive medication, and masked hypertension. ABPM gives a better prediction of clinical outcomes in patients with hypertension and cardiovascular diseases when compared to office blood pressure measurements. Recently, several new indices have been introduced with the aim of predicting various clinical end-points in several patient populations. In this review, we aimed to determine the clinical utility of 24-h ABPM and its potential implications for the management of hypertension in patients with a high risk of cardiovascular mortality and morbidity, as well as various novel indices that can predict clinical end-points in different patient populations.     

Cardiovascular changes during chronic hypertensive states

It is well established that elevated blood pressure constitutes a major risk factor for coronary heart disease, arrythmias, heart failure, cerebrovascular disease, peripheral artery disease and renal failure. Blood pressure level and the duration of arterial hypertension (HTN) impact target organ damage. Many studies in adults have demonstrated the role of antihypertensive therapy in preventing cardiovascular (CV) events. The so-called hard end-points, such as death, myocardial infarction (MI) or stroke, are rarely seen in children, but intermediate target organ damage, including left ventricular hypertrophy, increased intima-media thickness and microalbuminuria, is already detectable during childhood. The goal of antihypertensive treatment is to reduce the global risk of CV events. In the adult population stratification of CV risk is based on blood pressure level, risk factors, subclinical target organ damage and established CV and kidney disease. Increased CV risk begins early in the course of kidney disease, and CV diseases are the most frequent cause of morbidity and mortality in patients with chronic kidney disease (CKD). Children with CKD are especially prone to the long-term effects of CV risk factors, which result in high morbidity and mortality in young adults. To improve the outcome, pediatric and adult CKD patients require nephro- and cardioprotection.     

Hypertension in the kidney transplant recipient

Elevated arterial blood pressure is common after kidney transplantation and contributes to shortened patient and allograft survivals and increased fatal and nonfatal cardiovascular events. Unfortunately, current evidence indicates that arterial blood pressure remains poorly controlled in kidney transplant recipients. One concern is how best to evaluate treated levels of arterial pressure in transplant recipients as office and clinic measurements often differ from blood pressure readings obtained using ambulatory blood pressure monitoring. Some antihypertensive drugs interact with immunosuppressive medications and adversely affect electrolyte balance and kidney function, which complicates the management of kidney transplant patients. Target blood pressure readings have been suggested by different guidelines, but patient-specific management plan is still lacking. Understanding the basic mechanisms responsible for the persistent hypertension after kidney transplantation is helpful in drafting patient-directed management plan that includes both pharmacologic and nonpharmacologic interventions to achieve target blood pressure control. In this review, we propose a multilayered treatment plan that addresses hypertension in both the early and late posttransplant periods, bearing in mind complications of antihypertensive medications, interactions with immunosuppressive drugs, patient comorbidities, and patient-specific cardiovascular risk factors in the posttransplant period.     

Anaesthesia and isolated systolic hypertension--pathophysiology and anaesthesia risk

This review examines the pathophysiology of isolated systolic hypertension, changing medical perspectives on this condition as a cardiovascular risk factor in the community and evolving evidence of it being an independent risk factor for perioperative morbidity and mortality. Hypertension is regarded as an added risk in anaesthesia. Continuation of antihypertensive medication through the perioperative period is an established principle. Studies supporting this practice have demonstrated greater perioperative haemodynamic stability in association with general anaesthesia and surgery in patients with treated hypertension compared to untreated hypertension. Therapy has historically focused on control of diastolic blood pressure, rather than systolic blood pressure. Recent clinical trial data and data from large observational studies show a closer association of systolic hypertension with both coronary heart disease and stroke compared with diastolic hypertension. This has led to recommendations for aggressive treatment of isolated systolic hypertension, especially in patients over 65 years old. The association between decreased compliance of the central systemic arteries and isolated systolic hypertension is well understood. The fact that this same pathology, lack of compliance of central arteries, can cause a decrease in diastolic blood pressure is not so well recognised. This means that, in patients with isolated systolic hypertension, decreasing diastolic blood pressure can be associated with worsening arterial disease and that systolic minus diastolic blood pressure may give a better indication of the problem. Anaesthetic assessment and technique should be studied and potentially revised in the light of these changes in perspective on isolated systolic hypertension.     

Hypertension and hemodialysis: pathophysiology and outcomes in adult and pediatric populations

Hypertension is prevalent in adult and pediatric end-stage renal disease patients on hemodialysis. Volume overload is a primary factor contributing to hypertension, and attaining true dry weight remains a priority for nephrologists. Other contributing factors to hypertension include activation of the sympathetic and renin–angiotensin–aldosterone systems, endothelial cell dysfunction, arterial stiffness, exposure to hypertensinogenic drugs, and electrolyte imbalances during hemodialysis. Epidemiologic studies in adults show that uncontrolled hypertension results in cardiovascular morbidity, but reveal increased mortality risk at low blood pressure, so that it remains unclear what the target blood pressure should be. Despite the lack of a definitive BP target, gradual dry weight reduction should be the first intervention for BP control. Renin–angiotensin–aldosterone system inhibitors have been shown to improve cardiovascular morbidity and mortality and are recommended as the initial pharmacologic therapy for hypertensive hemodialysis patients. Short-daily or nocturnal hemodialysis are also good therapeutic options for these patients. It is already established that hypertension in pediatric hemodialysis patients is associated with adverse cardiovascular outcomes, and there is emerging evidence that the mechanisms causing hypertension are similar to adults. Hypertension in adult and pediatric hemodialysis patients warrants aggressive management, although clinical trial evidence of a target BP that improves mortality does not currently exist.     

Analysis of hypertension in children post renal transplantation —a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS)

Hypertension is common in children after renal transplantation and is associated with multiple factors. Data regarding the prevalence of post-transplant hypertension and the relationship between immunosuppressive drugs and the presistence of hypertension in a large population of North American children have not been available. This study was designed by the North American Pediatric Renal Transplant Cooperative Study to evaluate in a large diverse multicenter population of children the prevalence of hypertension post transplantation, the type of antihypertensive medication used to treat this hypertension and to determinc the relationship between the blood pressure control and the immunosuppressive therapy. Analysis of 277 patients showed the following: (1) 70% of recipients required antihypertensive medications 1 month post transplant compared with 48% pre transplant; the incidence decreased to 59% at 24 months; (2) the majority of children received multiple drug therpay to control blood pressure; (3) hypertension can be controlled effectively despite inherent etiological factors, such as allograft source, prior hypertension and immunosuppressive therapy.     

Association Between Pulse Pressure and Cardiovascular Disease in Renal Transplant Patients

Elevated pulse pressure in general population has been shown to be associated with cardiovascular disease, which is the main cause of death in renal transplant patients. We investigated the effect that a wider pulse pressure range may have on cardiovascular disease after renal transplantation in 532 transplant patients with functioning graft for more than 1 year. Patients were classified into two groups depending on 1-year pulse pressure (< or >/=65 mmHg) and we analyzed patient and graft survival, post-transplant cardiovascular disease and main causes of death. Higher pulse pressure was associated with older recipient age (40.8 +/- 10.8 vs. 50 +/- 11.3), higher systolic blood pressure (132.7 +/- 16.1 vs. 164.5 +/- 16), lower blood diastolic pressure (84.5 +/- 11.6 vs. 84.4 +/- 11.2), higher prevalence of diabetes (12% vs. 23%) and total cardiovascular disease (20.9% vs. 33.6%). Five- and 10-year patient survivals were lower in the group with higher pulse pressure, being vascular disease the main cause of death in both groups. In a Cox regression model increased pulse pressure was associated with higher cardiovascular disease (RR = 1.73, 95% CI: 1.13-2.32 p < 0.01). In conclusion, pulse pressure was an independent risk factor for increased cardiovascular morbidity and mortality in renal transplant patients.     

Blood pressure control in dialysis patients: importance of the lag phenomenon

Failure by the world dialysis community to understand and use the dry-weight method of blood pressure (BP) control has resulted in an increasing incidence of treatment-resistant hypertension, which remains the principal cause of cardiovascular morbidity and mortality. This failure may in part be because the relationship between the extracellular volume (ECV) and BP is not simple and linear, but complex, because of a lag of several weeks between the normalization of the time-averaged ECV and the decrease in BP. Another cause for this failure may be the unwillingness to taper and stop all antihypertensive medications during the transition from hypertension to normotension. In this report, we describe in detail the lag phenomenon, document its presence during treatment in other populations, and describe how this knowledge is used in the application of the dry-weight method of drug-free BP control in the dialysis population.     

Influence of hypertension on cardiovascular outcomes in hemodialysis patients

Cardiovascular disease is a leading cause of morbidity and mortality in chronic hemodialysis patients. Most patients with chronic kidney disease have hypertension and its prevalence remains high following renal replacement therapy. Early studies suggested that hypertension was a risk factor for total and cardiovascular mortality in chronic hemodialysis patients, but the results of more recent studies have caused experts to question these assertions. Systolic hypertension, widened pulse pressure, and nondipping may be better predictors of mortality compared to diastolic hypertension or increased mean arterial pressure. Hypertension in hemodialysis patients is a risk factor for left ventricular hypertrophy (LVH), diastolic dysfunction, and congestive heart failure; good blood pressure control may promote its regression. Atherosclerosis and ventricular arrhythmias may also be linked to hypertension. Thus blood pressure control with a focus on systolic pressure appears to be a prudent strategy to improve cardiovascular outcomes in hemodialysis patients.