Ivana Lazich

Prediction and Management of Hyperkalemia Across the Spectrum of Chronic Kidney Disease

Hyperkalemia commonly limits optimizing treatment to slow stage 3 or higher chronic kidney disease (CKD) progression. The risk of hyperkalemia is linked to dietary potassium intake, level of kidney function, concomitant diseases that may affect potassium balance such as diabetes, and use of medications that influence potassium excretion. The risk predictors for developing hyperkalemia are an estimated glomerular filtration rate of less than 45 mL/min/1.73 m(2) and a serum potassium level greater than 4.5 mEq/L in the absence of blockers of the renin-angiotensin-aldosterone system (RAAS). Generally, monotherapy with RAAS blockers does not increase risk substantially unless hypotension or volume depletion occur. Dual RAAS blockade involving any combination of an angiotensin-converting enzyme inhibitor, angiotensin-receptor blocker, renin inhibition, or aldosterone-receptor blocker markedly increases the risk of hyperkalemia in patients with stage 3 or higher CKD. Moreover, dual RAAS blockade further reduces albuminuria by 25% to 30% compared with monotherapy, it has failed to show a benefit on CKD progression or cardiovascular outcome, and thus is not indicated in such patients because of its marked increase in hyperkalemia potential. Although sodium polystyrene resins exist to manage hyperkalemia in patients requiring therapy that increases serum potassium levels, they are not well tolerated. Newer, more predictable, better-tolerated polymers to bind potassium are on the horizon and may be approved within the next 1 to 2 years.

Epidemiology of hypertensive kidney disease

The prevalence of hypertension, chronic kidney disease (CKD) and end-stage renal disease (ESRD) attributable to hypertension continues to rise worldwide. Identifying the precise prevalence of CKD attributable to hypertension is difficult owing to the absence of uniform criteria to establish a diagnosis of hypertensive nephropathy. Despite the increasing prevalence of CKD-associated hypertension, awareness of hypertension among individuals with CKD remains suboptimal and rates of blood-pressure control remain poor. Targeted subgroups involved in studies of CKD seem to reach better rates of blood-pressure control, suggesting that this therapeutic goal can be achieved in patients with CKD. Elevated blood-pressure levels are associated with CKD progression. However, the optimal blood-pressure level and pharmacological agent remains unclear. Physicians treating patients with CKD must recognize the importance of maintaining optimal salt and volume balance to achieve blood-pressure goals. Furthermore, agents that modify the renin–angiotensin–aldosterone axis can be an important adjunct to therapy and physicians must monitor expected changes in serum creatinine and electrolyte levels after their administration. Hypertension remains a common factor complicating CKD. Future investigations identifying early signs of hypertension-related CKD, increasing awareness of the effects of hypertension in CKD and determining optimal therapeutic interventions might help reduce the incidence of hypertensive nephropathy.

Effects of combining simvastatin with rosiglitazone on inflammation, oxidant stress and ambulatory blood pressure in patients with the metabolic syndrome: the SIROCO study

Aim: Individually, statins and thiazolidinediones (TZDs) show positive effects on atherosclerosis progression in cellular and animal models as well as patients with diabetes; however, their combined effects have not been studied. This study examines the effects of simvastatin combined with rosiglitazone on vascular inflammation, oxidant stress, ambulatory blood pressure (BP) and other atherosclerotic factors in patients with the metabolic syndrome.

Effects of nebivolol on aortic compliance in patients with diabetes and maximal renin angiotensin system blockade: the EFFORT study.

The beneficial effects of nebivolol on arterial stiffness and endothelial dysfunction are well documented in untreated hypertensive patients and differ from nonvasodilatory β‐blockers. This study tests the hypothesis that the addition of nebivolol in predominantly African American patients with type 2 diabetes already receiving maximally tolerated doses of renin‐angiotensin system (RAS) blockers will further improve large artery compliance. Patients with type 2 diabetes and hypertension on maximal RAS blockade (n=70) were randomized to nebivolol or metoprolol succinate daily. Doses were titrated until systolic blood pressure (SBP) was <130 mm Hg. Radial artery applanation tonometry and pulse wave velocity (PWV) analysis were used to derive central aortic pressures and hemodynamic indices at repeated visits at intervals during a 6‐month period. Both metoprolol succinate and nebivolol groups demonstrated reductions in brachial SBP (−8.2±4.3 mm Hg [P=.01] and −7.8±3.7 [P=.002], respectively) and aortic DBP (−2.4±1.8 [P=.039] and −4.0±2.9 mm Hg [P=.013], respectively). Aortic SBP decreased in the nebivolol group only (125.3±8 to 121.6±8.2, P=.025). There were no between group differences in aortic SBP, DBP, augmentation index, or PWV reduction. A significant increase in hemoglobin A1c was observed only in the metoprolol group. In patients with well‐controlled type 2 diabetes and hypertension treated with maximally tolerated RAS blockade, nebivolol does not offer significant reductions in aortic BP over metoprolol succinate but maintains a stable metabolic profile.

Endothelin Antagonism in Patients with Resistant Hypertension and Hypertension Nephropathy

Resistant hypertension is a failure to achieve a blood pressure (BP) goal of < 140/90 mm Hg despite treatment with at least three different antihypertensive medications classes at a maximally tolerated dose and including a diuretic. The most important systems that require alteration include the renin-angiotensin-aldosterone system, sympathetic nervous system, and (more recently) the endothelin (ET) system. To date, several clinical trials have assessed the effects of ET antagonism, both selective and nonselective, on BP control in humans. The nonselective ET antagonist bosentan was evaluated in patients with mild-to-moderate hypertension. Bosentan was able to lower diastolic BP when compared to placebo and, similarly, to enalapril. Similar findings have been published for darusentan, an ET receptor antagonist with higher affinity for the type A receptor. More recent research has focused on the impact of ET in the setting of resistant hypertension. Studies with darusentan as an add-on therapy in patients with resistant hypertension found a significant BP-lowering effect of 17/10 mm Hg compared to placebo. This BP-lowering effect was similar at higher doses. In a similar patient cohort, darusentan also lowered mean 24-hour BP to a greater extent than the central α₂-agonist guanfacine. Another selective ET(A) antagonist, atrasentan, provided other benefits on metabolism in addition to its antihypertensive effect. Atrasentan significantly decreased glucose in diabetes and improved lipid profiles while slowing coronary artery disease progression. Selective ET receptor blockade also has dose-dependent side effects. In a large number of trials, almost one third of the patients suffered excessive fluid retention and edema that was significantly higher than in the placebo groups. One trial, ASCEND, was terminated early due to an increased incidence of fluid retention and increased episodes of heart failure. Thus, this class of agents is effective in resistant hypertension, but lower doses with fewer side effects need to be developed.

Newer renin-angiotensin-aldosterone system blocker combinations: is there an advantage?

Purpose of reviewThe necessity for new and more effective management approaches to achieve blood pressure goals is still present in spite of the number of antihypertensive medications available. One of the cornerstones of successful therapy is implementation of drug combinations that act on complementary biological pathways. This review article focuses on the evaluation of recent data supporting newer combinations involving inhibition of the renin–angiotensin–aldosterone system (RAAS) with other drug classes such as calcium channel blockers (CCBs) and diuretics. Recent findingsNew angiotensin receptor blockers as well as renin inhibitors, with a more robust blood pressure-lowering effect than their predecessors, have emerged recently. The data presented in this text also strongly supports a combination therapy approach as initial therapy to achieve blood pressure goals in a timely fashion. Additionally, the blood pressure-lowering effect is more robust with lower-dose, single-pill combinations than with highest doses of single agents alone. Therefore, using combination agents is less prone to side effects. The challenges for such single-pill combinations remain affordability. For this reason, payers and patients have traditionally not preferred such agents in spite of better blood pressure control and adherence rates. SummaryThe new combinations of renin inhibitors and the new angiotensin receptor blocker combinations add to the armamentarium of agents to control blood pressure. Whereas the new angiotensin receptor blocker offers greater efficacy on blood pressure control over other agents in the class and the availability of the only chlorthalidone combination, no outcome data exist yet with any of the new agents.

Morphometric and histological parameters in veins of diabetic patients undergoing brachiocephalic fistula placement

Diabetic patients with end‐stage renal failure have higher rates of arteriovenous failures when compared with nondiabetics. The aim was to compare differences in indicators of vascular remodeling and endothelial dysfunction in veins of patients with or without diabetes at the time of surgical placement. In this prospective observational trial, vein samples were collected from patients when a brachiocephalic fistula was created. Morphometric measurements and extent of fibrosis were determined using Image J software. Histological analysis, for the presence of myofibroblasts and level of endothelial nitric oxide synthase, was performed by immunohistochemical staining and scored in semi‐quantitative manner. Asymmetric dimethylarginine was determined at the time of access placement. Comparison of diabetics and nondiabetics was performed using Wilcoxon rank sum and Fishers exact tests. Eighteen patients were included; 10 were diabetics. There was a significant difference in the measurement of vein area between groups, with diabetic vein samples having larger luminal area of average 832,001.18 μm2 (317,582.17–3,695,670.36, P = 0.04). The maximal intimal to medial thickness ratio was higher in diabetic vein samples (0.71 vs. 0.24, P = 0.03) along with statistically significant higher maximal intimal thickness (312.12 vs. 115.14 μm, P = 0.03). There is a significant difference in vascular wall remodeling between diabetics and nondiabetics at the level of the cephalic vein at the time of brachiocephalic placement. The unexpected finding of significantly larger luminal area in diabetic veins could be a major factor positively affecting brachiocephalic outcomes in otherwise impaired remodeling in this patient population.

Antihypertensive Therapy and New-Onset Diabetes

Numerous analyses demonstrate that antihypertensive therapies promote development of type-2 diabetes mellitus. This is particularly true in obesity patients with impaired glucose tolerance. Numerous randomized studies provide evidence that the use of diuretics and β blockers produces the highest risk for conversion to diabetes, whereas angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARB) lead to less new-onset diabetes compared to placebo. β Blockers worsen glycemic control through worsening of insulin resistance and reduced flow to muscle whereas diuretics impair glucose metabolism, in part, through reducing potassium. Thus, diuretics and β blockers not only increase glucose in those with diabetes but also promote the development of new-onset diabetes in those with glucose intolerance. Given the latest guidelines, β blockers are not indicated for routine use to treat hypertension and diuretics should be reserved for second- or third-line agents. Data from the NICE guidelines in the United Kingdom put diuretics as third-line agents after blockers of the renin–angiotensin system and calcium antagonists. One must keep in mind, however, that in multiple trials where diuretics were shown to worsen glycemic control, there was a mortality benefit as increasing doses of oral hypoglycemic medications were used. In short, while these agents can be avoided as initial agents for treatment of hypertension, many patients with heart or kidney disease, i.e., eGFR < 60 mL/min, will require diuretic therapy to control blood pressure.