Due to the multifaceted aspects of kidney function, the management of CKD not only requires knowledge of kidney physiology and pathophysiology but also a keen understanding of how to diagnose, treat, and monitor the metabolic derangements and complications of reduced kidney function. In this article, we provide questions that cover a broad range of clinical scenarios that may test the clinical acumen of a kidney health professional. Each question starts with a brief clinical scenario to guide the reader. Questions are followed by a selection of answers. As in most clinical situations, a variety of tests and/or interventions may be appropriate. As knowledge on the management of kidney diseases and associated complications evolve, the optimal choice for these questions may also evolve.

Resistant hypertension (RH) includes hypertensive patients with uncontrolled blood pressure (BP) while receiving ≥3 BP-lowering medications or with controlled BP while receiving ≥4 BP-lowering medications. The exact prevalence of RH is challenging to quantify. However, a reasonable estimate of true RH is around 5% of the hypertensive population. Patients with RH have higher cardiovascular risk as compared with hypertensive patients in general. Standardized office BP measurement, confirmation of medical adherence, search for drug- or substance-induced BP elevation, and ambulatory or home BP monitoring are mandatory to exclude pseudoresistance. Appropriate further investigations, guided by clinical data, should be pursued to exclude possible secondary causes of hypertension. The management of RH includes the intensification of lifestyle interventions and the modification of antihypertensive drug regimens. The essential aspects of lifestyle modification include sodium restriction, body weight control, regular exercise, and healthy sleep. Step-by-step adjustment of the BP-lowering drugs based on the available evidence is proposed. The suitable choice of diuretics according to patients' renal function is presented. Sacubitril/valsartan can be carefully substituted for the prior renin-angiotensin system blockers, especially in those with heart failure with preserved ejection fraction. If BP remains uncontrolled, device therapy such as renal nerve denervation should be considered. Since device-based treatment is an invasive and costly procedure, it should be used only after careful and appropriate case selection. In real-world practice, the management of RH should be individualized depending on each patient's characteristics.

Hypertension and diabetes mellitus (DM) are two of the leading lifestyle diseases in the Indian and South Asian populations that often co-exist due to overlapping pathophysiological factors. Obesity, insulin resistance, inflammation, and oxidative stress are thought to be some common pathways. Up to 50% of hypertensive cases in India are diagnosed with type 2 diabetes mellitus (T2DM), which defines the need for a comprehensive guideline for managing hypertension in diabetic patients. These RSSDI guidelines have been formulated based on consultation with expert endocrinologists in India and Southeast Asia, acknowledging the needs of the Indian population. Ambulatory blood pressure monitoring and office and home-based blood pressure (BP) monitoring are recommended for the early analysis of risks. Cardiovascular risks, end-organ damage, and renal disorders are the primary complications associated with diabetic hypertension that needs to be managed with the help of non-pharmacological and pharmacological interventions. The non-pharmacological interventions include the nutrition education of the patient to reduce the intake of salt, sodium, and trans fats and increase the consumption of nuts, fresh fruits, vegetables, and potassium-rich foods. It is also recommended to initiate 50 to 60 min of exercise three to four times a week since physical activity has shown to be more beneficial for hypertension control in Indian patients than dietary modulation. For the pharmacological management of hypertension in patients with T2DM, angiotensin II receptor blockers (ARBs) are recommended as the first line of therapy, demonstrating their superiority over other antihypertensive agents such as ACEi. However, most of the global hypertension guidelines recommend initiation with combination therapy to achieve better BP control in most patients and to reduce the risk of adverse events. For combination therapy, calcium channel blockers (CCBs) are recommended to be administered along with ARBs instead of beta-blockers or diuretics to avoid the risk of cardiovascular events and hyperglycaemia. Among the CCBs, novel molecules (e.g. cilnidipine) are recommended in combination with ARBs for better cardiovascular and reno-protection in diabetic hypertensive patients.

The term thiazide is universally understood to refer to diuretics that exert their principal action in the distal tubule. The thiazide class is heterogenous and can be further subdivided into compounds containing the benzothiadiazine ring structure-the thiazide-type (e.g., hydrochlorothiazide)-and those lacking the benzothiadiazine ring-the thiazide-like (e.g., chlorthalidone and indapamide) drugs. Thiazide-like agents are longer acting and constitute the diuretics used in most of the cardiovascular outcome trials that established benefits of treatment with diuretics, but pragmatic aspects, such as lack of availability in convenient formulations, limit their use. Regardless of class heterogeneity, thiazides have retained importance in the management of hypertension for over 60 years. They are reliably effective as monotherapy in a majority of hypertensive patients, and augment the efficacy of other classes of antihypertensives when used in combination. Importantly, a thiazide-based treatment regimen lowers cardiovascular events, and their sturdy effect reinforces their place among the recommended first-line agents to treat hypertension in major domestic and international hypertension guidelines. There are few head-to-head comparisons within the class, but potential differences have been explored indirectly as well as in non-blood pressure mechanisms and potential pleiotropic properties. Until proven otherwise, the importance of these differences remains speculative, and clinicians should assume that cardiovascular events will be lowered similarly across agents when equivalent blood pressure reduction occurs. Thiazides remain underutilized, with only about one-third of hypertensive patients receiving them. For many patients, however, a thiazide is an indispensable component of their regimen to achieve adequate blood pressure control.

Hypertension is a chronic condition leading to increased stress on the heart and blood vessels, a critical risk factor for clinically significant events such as myocardial infarction heart failure, stroke and death. Chlorthalidone and hydrochlorothiazide are first-line antihypertensive agents for most patients with hypertension. The aim of our meta-analysis was to compare the efficacy and safety of both therapies in patients with hypertension. Searches of electronic databases PubMed, MEDLINE, Scopus, PsycInfo and eLIBRARY.ru, were performed. We used network meta-analysis to combine direct and indirect evidence. Forest plots and closed loops depict estimated results from studies included in our meta-analysis. Of 1289 identified sources, only 37 were included in our meta-analysis. Our analysis has demonstrated a slight superiority for chlorthalidone regarding SBP and not statistically significant differences regarding DBP. Simultaneously, hydrochlorothiazide seems to be a safer choice of therapy, as evidenced by the levels of serum potassium. The two diuretics can be used interchangeably.

Resistant hypertension (RH) induces higher morbidity and mortality due to cardiovascular disease and stroke than hypertension without treatment resistance. New guidelines define RH as blood pressure (BP) ≥130/80 mmHg in a patient taking ≥3 antihypertensive agents of different classes or BP <130/80 mmHg in a patient taking ≥4 antihypertensive drugs. According to the new definition, pseudo-resistance due to error in BP measurement, white coat effect and medication nonadherence must be excluded to make the diagnosis of RH. This 2020 update focuses on the lifestyle and antihypertensive drug management of RH and includes recent proof-of-principle trials of renal nerve ablation in hypertension. Stepwise evidence-based pharmacologic treatment of RH includes optimization of the 3-drug regimen, substitution of a thiazide-like for a thiazide diuretic and addition of a mineralocorticoid receptor antagonist as the fourth drug. Non-evidence-based recommendations include addition of a β-blocker as the fifth drug and switching to a minoxidil-based regimen as the final step in achieving BP control.

Resistant hypertension (RHTN) is defined as uncontrolled blood pressure despite the use of ≥3 antihypertensive agents of different classes, including a diuretic, usually thiazide-like, a long-acting calcium channel blocker, and a blocker of the renin- angiotensin system, either an ACE (angiotensin-converting enzyme) inhibitor or an ARB (angiotensin receptor blocker), at maximal or maximally tolerated doses. Antihypertensive medication nonadherence and the white coat effect, defined as elevated blood pressure when measured in clinic but controlled when measured outside of clinic, must be excluded to make the diagnosis. RHTN is a high-risk phenotype, leading to increased all-cause mortality and cardiovascular disease outcomes. Healthy lifestyle habits are associated with reduced cardiovascular risk in patients with RHTN. Aldosterone excess is common in patients with RHTN, and addition of spironolactone or amiloride to the standard 3-drug antihypertensive regimen is effective at getting the blood pressure to goal in most of these patients. Refractory hypertension is defined as uncontrolled blood pressure despite use of ≥5 antihypertensive agents of different classes, including a long-acting thiazide-like diuretic and an MR (mineralocorticoid receptor) antagonist, at maximal or maximally tolerated doses. Fluid retention, mediated largely by aldosterone excess, is the predominant mechanism underlying RHTN, while patients with refractory hypertension typically exhibit increased sympathetic nervous system activity.

In 2018, the American Heart Association published a Scientific Statement on resistant hypertension. We compared the prevalence of apparent treatment-resistant hypertension (aTRH) among US adults as defined in the 2018 and 2008 American Heart Association Scientific Statements using data from 4158 participants with hypertension, taking antihypertensive medication in the 2009 to 2014 National Health and Nutrition Examination Survey. Blood pressure (BP) was measured 3 times, and antihypertensive medication classes were identified through a pill bottle review. In both Scientific Statements, aTRH was defined as uncontrolled BP while taking ≥3 classes of antihypertensive medication or taking ≥4 classes of antihypertensive medication regardless of BP level. Uncontrolled BP was defined as systolic/diastolic BP ≥140/90 mm Hg (≥130/80 mm Hg for those with diabetes mellitus or chronic kidney disease) in the 2008 Scientific Statement and systolic/diastolic BP ≥130/80 mm Hg (systolic BP ≥130 mm Hg only for low-risk adults ≥65 years of age) in the 2018 Scientific Statement. The prevalence of aTRH was 17.7% and 19.7% according to the 2008 and 2018 Scientific Statement definitions, respectively (Δ=2.0%; 95% CI, 1.5%-2.7%). Overall, 10.3 million US adults had aTRH according to the 2018 Scientific Statement. The most common 3-drug combination taken included an angiotensin-converting enzyme inhibitor, β-blocker, and thiazide diuretic. Using the 2018 definition, 3.2% of US adults with aTRH were taking a thiazide-like diuretic (chlorthalidone or indapamide), and 9.0% were taking a mineralocorticoid receptor blocker (spironolactone or eplerenone). In conclusion, the prevalence of aTRH is only modestly higher using the definition in the 2018 versus 2008 resistant hypertension Scientific Statement.

Resistant hypertension (RH) is defined as above-goal elevated blood pressure (BP) in a patient despite the concurrent use of 3 antihypertensive drug classes, commonly including a long-acting calcium channel blocker, a blocker of the renin-angiotensin system (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a diuretic. The antihypertensive drugs should be administered at maximum or maximally tolerated daily doses. RH also includes patients whose BP achieves target values on ≥4 antihypertensive medications. The diagnosis of RH requires assurance of antihypertensive medication adherence and exclusion of the "white-coat effect" (office BP above goal but out-of-office BP at or below target). The importance of RH is underscored by the associated risk of adverse outcomes compared with non-RH. This article is an updated American Heart Association scientific statement on the detection, evaluation, and management of RH. Once antihypertensive medication adherence is confirmed and out-of-office BP recordings exclude a white-coat effect, evaluation includes identification of contributing lifestyle issues, detection of drugs interfering with antihypertensive medication effectiveness, screening for secondary hypertension, and assessment of target organ damage. Management of RH includes maximization of lifestyle interventions, use of long-acting thiazide-like diuretics (chlorthalidone or indapamide), addition of a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and, if BP remains elevated, stepwise addition of antihypertensive drugs with complementary mechanisms of action to lower BP. If BP remains uncontrolled, referral to a hypertension specialist is advised.

Resistant hypertension defined as requiring 3 or more complementary antihypertensive drugs at maximally tolerated doses accounts for approximately 3% to 4% of all cases of hypertension. Its increased incidence over the past decade is related to the increase in obesity in the Western world. There are a number of dietary factors that affect sympathetic tone including sodium intake apart from increased body mass. This article discusses the mechanisms of sympathetic stimulation and activation in the context of animal models and human studies. In addition, there is a review of clinical trials with and without device therapy that summarizes the clinical findings. Effective management should be based on pathophysiologic principles and a focus on blood pressure reduction to levels well below 150/90 mm Hg because outcome trial evidence and Food and Drug Administration guidance supports this construct. The key to success of device-based therapy depends on identifying the cohort with true resistant hypertension that can benefit from therapies that are adjuncts to pharmacotherapy. Physicians need to concentrate on educating the patient on lifestyle modifications and themselves on use of proper combinations of antihypertensive medications. If this approach fails to result in a safe level of blood pressure then the patient should be referred to a board-certified clinical hypertension specialist.

Resistant or difficult to treat hypertension is defined as high blood pressure that remains uncontrolled with 3 or more different antihypertensive medications, including a diuretic. Recent definitions also include controlled blood pressure with use of 4 or more medications as also being resistant to treatment. Recently, refractory hypertension, an extreme phenotype of antihypertensive treatment failure has been defined as hypertension uncontrolled with use of 5 or more antihypertensive agents, including a long-acting thiazide diuretic and a mineralocorticoid receptor antagonist. Patients with resistant vs refractory hypertension share similar characteristics and comorbidities, including obesity, African American race, female sex, diabetes, coronary heart disease, chronic kidney disease, and obstructive sleep apnea. Patients with refractory vs resistant hypertension tend to be younger and are more likely to have been diagnosed with congestive heart failure. Refractory hypertension might also differ from resistant hypertension in terms of underlying cause. Preliminary evidence suggests that refractory hypertension is more likely to be neurogenic in etiology (ie, heightened sympathetic tone), vs a volume-dependent hypertension that is more characteristic of resistant hypertension in general.

Neither randomized controlled trials nor efforts to identify genetic markers have been helpful with regard to the goal of individualizing diuretic therapy in the treatment of hypertension, a goal that receives little clinical or research attention. This review will examine, and bring attention to, the considerable yet overlooked information relevant to individualizing diuretic therapy. It will bring attention to clinical, biochemical, and pharmacological clues that can be helpful in identifying who is likely to respond to a diuretic, who needs a stronger diuretic regimen, which diuretic to prescribe, and how to minimize adverse effects. New directions for clinical research aimed at individualizing use in hypertension will be explored. Research and clinical attention to the goal of individualizing diuretic treatment in hypertension need to be renewed, to help us achieve greater hypertension control with fewer adverse effects and lower costs.

Short-term effects of chlorthalidone are unknown in low kidney function. The effects of 8-week treatment with 25-mg chlorthalidone on the top of ongoing treatment were compared between control hypertensives and low kidney function hypertensives as assessed by estimated glomerular filtration rate <60 mL/min×1.73 m(2). Screening period consisted of 2 visits for patient selection and pretreatment laboratory evaluations (baseline). Inclusion criteria were uncontrolled hypertension on nondiuretic antihypertensive treatment. Exclusion criteria were chlorthalidone contraindications, refused consent, treatment with >3 antihypertensive drugs, severe hypertension, severe comorbidities, unreliable estimated glomerular filtration rate. Treatment period consisted of 5 visits (weeks 1, 2, 4, 6, and 8). Post-treatment laboratory evaluations were performed 3 to 4 days before week-8 visit. The 2 groups differed for baseline estimated glomerular filtration rate (low kidney function and control: n=60 and 60; mean, 39 and 76; range, 15-59 and 60-104) but not for sex, age, and baseline blood pressure. Week-8 blood pressure changes were a decrease in both groups (low kidney function and control: systolic pressure, -20 and -23; 95% confidence interval, -22/-18 and -26/-19; diastolic pressure, -9 and -10, -11/-7, and -13/-8) without significant between-group differences. Incidence of adverse events was similar in the 2 groups (15.0% and 16.7%). Baseline estimated glomerular filtration rate did not predict blood pressure changes and adverse events in either groups (P>0.6). In both groups, post-treatment changes were a decrease for estimated glomerular filtration rate and serum potassium, an increase for serum uric acid (P<0.01). Data show that short-term chlorthalidone effects were not reduced in hypertensives with low kidney function.

There are few data available examining the clinical impact of switching patients from hydrochlorothiazide (HCTZ) to chlorthalidone for blood pressure management.

The goal of this study was to compare within-patient clinic blood pressure readings, serum electrolyte levels, and renal function markers before and after a medication change from HCTZ to chlorthalidone in a veteran population.

This was a retrospective, pre- and postmeasure, self-controlled study. Veterans Affairs Ann Arbor Healthcare System patients switched from HCTZ to chlorthalidone between January 1, 2001, and January 31, 2012, who had at least 1 follow-up clinic blood pressure reading recorded between 2 and 8 weeks from the date of the medication change were included in the study. Mean pre- and postmeasure values for systolic and diastolic clinic blood pressures, serum potassium, serum sodium, serum calcium, serum creatinine, and blood urea nitrogen were compared by using a 2-tailed, paired t test with a significance level (α) of 0.05.

Of the 40 patients included in the study 95% were male, 65% were white, and the mean age was 64.9 (10.8) years. Both mean systolic (-15.8 mm Hg [95% CI, 8.9 to 22.6], P < 0.0001) and mean diastolic (-4.2 mm Hg [95% CI, 1.5 to 6.9], P = 0.0035) blood pressures showed statistically and clinically significant reductions after the medication change. A statistically significant decrease in mean sodium (-1.1 mmol/L [95% CI, 0.4 to 1.9], P = 0.003) and an increase in mean serum creatinine (0.06 mg/dL [95% CI, -0.09 to -0.02], P = 0.002) was observed; however, these changes may not be viewed as clinically significant by many practitioners. No statistically significant changes were observed in any of the other outcomes examined. Most patients (38 of 40) were taking at least 1 additional antihypertensive agent; 73% of patients were using ≥ 3 antihypertensive agents at the time of the medication change.

In patients with hypertension already taking HCTZ, switching to chlorthalidone seems to further reduce systolic and diastolic blood pressures without any clinically significant changes in renal function or electrolyte levels.

Obesity is a global pandemic and with its rise, its associated co-morbidities are increasing in prevalence, particularly uncontrolled hypertension. Lifestyle changes should be an anchor for the management of obesity-related hypertension; however, they are difficult to sustain. Drug therapy is often necessary to achieve blood pressure control. Diuretics, inhibitors of the renin-angiotensin system, and dihydropyridine calcium channel blockers are often used as first trio, with subsequent additions of mineralocorticoid receptor antagonists and/or dual alpha/beta blocking agents. While a number of agents are currently available, 50 % of hypertensive patients remain uncontrolled. A number of novel drug and invasive therapies are in development and hold significant potential for the effective management of obesity-related hypertension.

Resistant hypertension (RH), defined simply, is blood pressure (BP) requiring the use of four or more antihypertensive agents, whether controlled or uncontrolled. RH is an increasingly common problem in elderly patients and may affect as many as 20% of the hypertensive population. Unfortunately, at least 30% of patients evaluated for RH are actually adequately controlled when more carefully assessed by home BP monitoring or ambulatory BP monitoring, thus representing a white coat effect. It is also essential to exclude pseudoresistance resulting from improper BP recording techniques or failure of the patient to adhere to the prescribed treatment regimen. Concurrent use of drugs that may interfere with prescribed antihypertensive agents, including many over the counter herbal preparations, must also be excluded. The underlying mechanisms principally driving true RH include pathophysiologic abnormalities of aldosterone signaling, sodium and water retention, excessive sympathetic nervous system activity, and obstructive sleep apnea. Appropriate treatment regimens will usually include an inhibitor of the renin-angiotensin-aldosterone system, a calcium channel blocker, and a diuretic. An aldosterone receptor blocker can be instituted at any step, and is very effective as a fourth drug. Beta-blockers can also be integrated into these treatment plans and may be especially helpful when excessive sympathetic nervous system activity is suspected. Novel device therapies that interrupt sympathetic nerve stimulation at the carotid sinus and kidney are under investigation, and may add entirely new directions in the management of RH. What is most important is that treatment regimens should be targeted to specific patient profiles.

Diuretics are among the most commonly prescribed cardiovascular (CV) medications. The strength of evidence supporting the effectiveness of diuretics in lowering blood pressure and for preventing major adverse CV events in patients with hypertension varies considerably among diuretic classes and even among agents within the same class. Unfortunately, common prescribing habits among American physicians, including specialists in CV diseases, are not in line with the existing evidence regarding diuretic therapy for improving CV prognosis. In conclusion, although hydrochlorothiazide is the standard diuretic used for hypertension, the outcomes data suggest that chlorthalidone, indapamide, and possibly even the aldosterone receptor blockers (spironolactone and eplerenone) may be superior agents.

Resistant hypertension is a failure to achieve goal BP (<140/90 mm Hg for the overall population and <130/80 mm Hg for those with diabetes mellitus or chronic kidney disease) in a patient who adheres to maximum tolerated doses of 3 antihypertensive drugs including a diuretic. The kidneys play a critical role in long-term regulation of blood pressure. Blunted pressure natriuresis, with resultant increase in extracellular fluid volume, is an important cause of resistant hypertension. Activation of the renin-angiotensin-aldosterone system, increased renal sympathetic nervous system activity and increased sodium reabsorption are important renal mechanisms. Successful treatment requires identification and reversal of lifestyle factors or drugs contributing to treatment resistance, diagnosis and appropriate treatment of secondary causes of hypertension, use of effective multidrug regimens and optimization of diuretic therapy. Since inappropriate renal salt retention underlies most cases of drug-resistant hypertension, the therapeutic focus should be on improving salt depleting therapy by assessing and, if necessary, reducing dietary salt intake, optimizing diuretic therapy, and adding a mineralocorticoid antagonist if there are no contraindications.

Resistant hypertension is defined as blood pressure above the patient's goal despite the use of 3 or more antihypertensive agents from different classes at optimal doses, one of which should ideally be a diuretic. Evaluation of patients with resistive hypertension should first confirm that they have true resistant hypertension by ruling out or correcting factors associated with pseudoresistance such as white coat hypertension, suboptimal blood pressure measurement technique, poor adherence to prescribed medication, suboptimal dosing of antihypertensive agents or inappropriate combinations, the white coat effect, and clinical inertia. Management includes lifestyle and dietary modification, elimination of medications contributing to resistance, and evaluation of potential secondary causes of hypertension. Pharmacological treatment should be tailored to the patient's profile and focus on the causative pathway of resistance. Patients with uncontrolled hypertension despite receiving an optimal therapy are candidates for newer interventional therapies such as carotid baroreceptor stimulation and renal denervation.

There is an epidemic of chronic kidney disease in the Western world, with hypertension being the second most common cause. Blood pressure control rates, while improving, are still below 50% for the United States population. The following three challenges remain for the treatment of hypertension and associated prevention of end-stage kidney disease. First, a better understanding by the general medical community of how and in whom to use renin angiotensin aldosterone system blockers is needed. Second, the appropriate initiation of fixed-dose combination therapy to achieve blood-pressure goals needs to be clarified. Finally, the subgroup of patients with kidney disease needs more aggressive blood pressure lowering.

Resistant hypertension is defined as failure to achieve goal blood pressure (BP) when a patient adheres to the maximum tolerated doses of 3 antihypertensive drugs including a diuretic. Although the exact prevalence of resistant hypertension is currently unknown, indirect evidence from population studies and clinical trials suggests that it is a relatively common clinical problem. The prevalence of resistant hypertension is projected to increase, owing to the aging population and increasing trends in obesity, sleep apnea, and chronic kidney disease. Management of resistant hypertension must begin with a careful evaluation of the patient to confirm the diagnosis and exclude factors associated with "pseudo-resistance," such as improper BP measurement technique, the white-coat effect, and poor patient adherence to life-style and/or antihypertensive medications. Education and reinforcement of life-style issues that affect BP, such as sodium restriction, reduction of alcohol intake, and weight loss if obese, are critical in treating resistant hypertension. Exclusion of preparations that contribute to true BP treatment resistance, such as nonsteroidal anti-inflammatory agents, cold preparations, and certain herbs, is also important. Lastly, BP control can only be achieved if an antihypertensive treatment regimen is used that focuses on the genesis of the hypertension. An example is volume overload, a common but unappreciated cause of treatment resistance. Use of the appropriate dose and type of diuretic provides a solution to overcome treatment resistance in this instance.

The aims of this article are to review the current controversies related to the use of thiazide diuretics as first-line treatment of hypertension and to discuss the causal roles for hyperuricemia and hypokalemia on the adverse consequences of thiazide usage.

Thiazides significantly reduce morbidity and mortality in hypertensive subjects. There remains, however, debate about thiazide usage as first-line treatment of hypertension. This negative impact of thiazides may be partially attributed to the ability of thiazides to exacerbate features of metabolic syndrome or increase the risk for developing diabetes. Several clinical trials suggest that thiazide-induced hyperuricemia and hypokalemia may account for some of these negative effects. Thiazide treatment is also associated with a decline of renal function in spite of a lowering blood pressure. In this review, we discuss the clinical and experimental evidence supporting a potential role of hyperuricemia and hypokalemia on the development of renal injury and worsening of the metabolic syndrome.

Hyperuricemia and hypokalemia may have pivotal roles in the exacerbation of the metabolic syndrome in response to thiazides. We propose that controlling serum uric acid and serum potassium could improve thiazide efficacy and also reduce its risk for inducing metabolic syndrome or diabetes.

Resistant hypertension is an important clinical problem that is poorly studied and not well managed. The objective of this study was to identify factors associated with successful treatment of resistant hypertension in a specialty clinic.

This was a retrospective observational study examining the medical records of patients seen at a specialty hypertension clinic at the University of Rochester, Rochester, New York, USA, in the year 2005. The records of 68 patients were reviewed. Those presenting with resistant hypertension (defined as BP > or =140/90mm Hg and receiving at least three antihypertensive medications, including a diuretic) were identified. Change in medication type and dosage, BP reduction, and percentage of patients at Joint National Committee (JNC)-7 goal were noted.

Twenty-eight patients were included in the analysis. Mean age was 62.5 +/- 11.6 years, 54% were women, and mean presenting BP was 175.4 +/- 23.5/87.5 +/- 14.6mm Hg. After an average of 6.2 +/- 3.2 visits over a mean of 13.9 +/- 13.5 months, mean BP was reduced to 145.3 +/- 27.7/73.9 +/- 13.6mm Hg (paired t-test: p = 0.001 SBP, p = 0.0001 DBP), and 44.8% of the patients were at their JNC-7 goal. Change in the mean number of antihypertensive medications was not significantly different between the initial and final clinic visits (4.1 +/- 1.2 vs 4.2 +/- 1.0; p = 0.627). Combination pill use increased from four patients (14%) at initial visit to 19 (68%) at final visit. Numbers of patients treated with diuretics, beta-adrenoceptor antagonists, calcium channel antagonists (CCB), and minoxidil increased at the final clinic visit. Significant dose-related changes included the up-titration of CCBs to high doses, and the initiation of moderate doses of thiazide diuretics; mainly chlorthalidone (67% final visit vs 0% at initial visit).

Patients referred to a specialty clinic for the control of resistant hypertension achieved significant reductions in BP with frequent visits, combination pills, and greater use and higher doses of CCBs and thiazide diuretics.

Hypertension is a growing public health problem worldwide. Only 37% of American hypertensives currently have their blood pressures controlled. Hypertension is traditionally diagnosed in the medical office, but both home and ambulatory blood pressure monitoring can help. Lifestyle modifications are recommended for everyone who has higher than "normal" blood pressure (<120/80 mm Hg). Voluminous clinical trial data support beginning drug therapy with low-dose chlorthalidone, unless the patient has a specific indication for a different drug. Additional drugs (typically in the sequence, angiotensin converting-enzyme inhibitor or angiotensin receptor blocker, calcium antagonist, beta-blocker, alpha-blocker, aldosterone antagonist, direct vasodilator, and centrally acting alpha(2)-agonist) can be added to achieve the blood pressure goal (usually <140/90 mm Hg, but <130/80 mm Hg for diabetics and those with chronic kidney disease). Special circumstances exist for treatment of hypertension in pregnancy, in childhood, in the elderly, and in both extremes of blood pressure (pre-hypertension or hypertensive emergencies).

Low-dose thiazide-type diuretics are recommended as initial therapy for most hypertensive patients. Chlorthalidone has significantly reduced stroke and cardiovascular end points in several landmark trials; however, hydrochlorothiazide remains favored in practice. Most clinicians assume that the drugs are interchangeable, but their antihypertensive effects at lower doses have not been directly compared. We conducted a randomized, single-blinded, 8-week active treatment, crossover study comparing chlorthalidone 12.5 mg/day (force-titrated to 25 mg/day) and hydrochlorothiazide 25 mg/day (force-titrated to 50 mg/day) in untreated hypertensive patients. The main outcome, 24-hour ambulatory blood pressure (BP) monitoring, was assessed at baseline and week 8, along with standard office BP readings every 2 weeks. Thirty patients completed the first active treatment period, whereas 24 patients completed both. An order-drug-time interaction was observed with chlorthalidone; therefore, data from only the first active treatment period was considered. Week 8 ambulatory BPs indicated a greater reduction from baseline in systolic BP with chlorthalidone 25 mg/day compared with hydrochlorothiazide 50 mg/day (24-hour mean = -12.4+/-1.8 mm Hg versus -7.4+/-1.7 mm Hg; P=0.054; nighttime mean = -13.5+/-1.9 mm Hg versus -6.4+/-1.8 mm Hg; P=0.009). Office systolic BP reduction was lower at week 2 for chlorthalidone 12.5 mg/day versus hydrochlorothiazide 25 mg/day (-15.7+/-2.2 mm Hg versus -4.5+/-2.1 mm Hg; P=0.001); however, by week 8, reductions were statistically similar (-17.1+/-3.7 versus -10.8+/-3.5; P=0.84). Within recommended doses, chlorthalidone is more effective in lowering systolic BPs than hydrochlorothiazide, as evidenced by 24-hour ambulatory BPs. These differences were not apparent with office BP measurements.