Rigas Kalaitzidis

Predictors of Hyperkalemia Risk following Hypertension Control with Aldosterone Blockade

Background: Aldosterone antagonists have proven efficacy for management of resistant hypertension and proteinuria reduction; however, they are not widely used due to risk of hyperkalemia. This study assesses the risk factors for hyperkalemia in patients with chronic kidney disease (CKD) and resistant hypertension whose blood pressure (BP) is reduced to a guideline goal. Methods: This is a two-center study conducted in university-based hypertension clinics directed by clinical hypertension specialists. Forty-six patients with resistant hypertension and stages 2 or 3 CKD (mean estimated glomerular filtration rate (eGFR) 56.5 ± 16.2 ml/min/1.73 m2) were evaluated for safety and efficacy of aldosterone blockade added to preexisting BP-lowering regimens. All patients were on three mechanistically complementary antihypertensive agents including a diuretic and a renin-angiotensin system blocker. Patients were evaluated after a median of 45 treatment days. The primary endpoint was change in systolic BP. Secondary endpoints included change in serum potassium, creatinine, eGFR, diastolic BP and tolerability. Results: The mean age of the patients studied was 64.9 ± 10.7 years, all were obese and 86% had type 2 diabetes, with 82% being African-American. Addition of aldosterone antagonism yielded a further mean reduction in systolic BP of 14.7 ± 5.1 mm Hg (p = 0.001). Females with BMI >30 and those with a baseline systolic BP >160 mm Hg were more likely to have a greater BP reduction to aldosterone antagonism. In total, 39% of the patients had a >30% decrease in eGFR when the BP goal was achieved. The mean increase in serum potassium was 0.4 mEq/l above baseline (p = 0.001), with 17.3% manifesting hyperkalemia, i.e. serum potassium >5.5 mEq/l. Predictors of hyperkalemia included a baseline eGFR of ≤45 ml/min/1.73 m2 in whom serum potassium was >4.5 mEq/l on appropriately dosed diuretics. Contributing risks in this subgroup included a systolic BP reduction of >15 mm Hg associated with an eGFR fall of >30%. Conclusion: Aldosterone antagonism is effective and safe for achieving a BP goal among people with diabetic nephropathy when added to a triple antihypertensive regimen that includes a blocker of the renin-angiotensin system and an appropriately selected and dosed diuretic. Caution is advised when using aldosterone blockade for BP control in people with advanced stage 3 nephropathy with a serum potassium of >4.5 mEq/l for safety reasons.

The Kidney, Hypertension, and Remaining Challenges

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.

Effects of Thiazolidinediones Beyond Glycaemic Control

The incidence of type 2 diabetes continues to increase in the western world over the past decade. Consequently, complications of this disease have reached crisis proportions. In addition to the classical oral hypoglycaemic agents, i.e. sulfonylureas, newer classes have emerged that work by different mechanisms such as insulin sensitizers. One such class are the thiazolidinediones (rosiglitazone and pioglitazone). These agents act as ligands for the gamma peroxisome proliferator-activated receptors (PPARs) and result in a lower glucose. Data from animal and human studies supports the concept that thiazolidinediones exert several other beneficial metabolic and vascular effects, in addition to glycaemic control, including improvement in lipid profile, blood pressure lowering, redistribution of body fat away from the central compartment, anti-inflammatory effects such as reduction in hs-CRP and microalbuminuria as well as subclinical vascular inflammation, improvement in endothelial function. Conversely, thiazolidinediones have well-established side effects, most important of which are fluid retention leading to weight gain and development of heart failure as well as an increased incidence of bone fractures. Moreover, evidence from clinical trials suggests that these agents do not reduce cardiovascular risk. This article discusses the pleiotropic effects of thiazolidinediones focusing on clinical cardiovascular outcomes as well as other potential therapeutic uses in the context of their side-effect profile.

Novel therapies of diabetic nephropathy.

Purpose of reviewCurrent therapies proven to slow the progression of diabetic nephropathy include blockade of the renin–angiotensin system (RAS) with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Given our better understanding of the pathophysiology of diabetic nephropathy, newer therapies to treat this condition are slowly emerging. Recent findingsAnimal studies and a single clinical trial demonstrate efficacy of the renin inhibitor, aliskiren, to decrease a marker of nephropathy progression, that is albuminuria. On the basis of animal study results, pyridoxamine, an inhibitor of advanced glycation and ruboxistaurin, a protein kinase C inhibitor showed promise as new agent to treat nephropathy. The clinical trial results were less than gratifying, however. Sulodexide, a glycosaminoglycan, works to reduce proteinuria presumably by restoring the already reduced glycoproteins present in the glomerular basement membrane. Like other agents, sulodexide also looked promising in animal studies, but failed to demonstrate albuminuria reduction in a large multicentre clinical trial (SUN-Micro-Trial). SummaryThis review summarizes newer therapies for slowing the progression of diabetic nephropathy. Aliskiren shows promise from small clinical studies, but we await the results of the multicentre, international ALTITUDE trial in about 2012. On the basis of the results of trials only, pyridoxamine may have a chance at further evaluation, but that is also unclear.

Effects of angiotensin Ii receptor blockers on diabetic nephropathy

Impaired kidney function increases the risk of cardiovascular morbidity and mortality. Coexistence of hypertension and type 2 diabetes increases the risk of kidney damage, hypertension being an independent risk factor for kidney disease progression. Angiotensin II, through its inflammatory, proliferative, and thrombotic effects, adversely affects renal perfusion and increases oxidative stress, thus playing a pivotal role in kidney disease progression. Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors improve markers of kidney disease and slow kidney disease progression in diabetic and nondiabetic patients; this kidney protection may be in addition to their antihypertensive activity in those with advanced proteinuric nephropathy. Key beneficial effects of ARBs and ACE inhibitors throughout the kidney disease continuum are primarily explained by blood pressure lowering effects and partially by their direct blockade of angiotensin II. Recent studies have shown that telmisartan, an ARB with high lipophilicity and the longest half-life compared with other ARBs, provides benefits on markers of cardiovascular risk, that is, microalbuminuria and slowing of early-stage nephropathy.

Pathogenesis and Treatment of Microalbuminuria in Patients With Diabetes: The Road Ahead

The incidence of type 2 diabetes is increasing in the United States, which is expected to result in an increased prevalence of microalbuminuria and higher cardiovascular risk. Microalbuminuria is an indication that a low‐level inflammatory process is ongoing. In patients with hypertension, with or without diabetes, increasing urinary albumin excretion (UAE) is associated with elevated levels of inflammatory markers, endothelial dysfunction, and platelet activation. Microalbuminuria is associated with an increased incidence of cardiovascular disease (CVD) morbidity and mortality in patients with hypertension and in those with diabetes with or without hypertension. Antihypertensive agents that modulate the renin‐angiotensin‐aldosterone system (RAAS) can delay the onset and reduce progression of microalbuminuria and decrease CVD morbidity and mortality in patients with diabetes. Clinical trials provide a spectrum of results regarding the protective effects of RAAS‐blocking agents. Consideration of baseline blood pressure (BP), UAE and CVD risk, and the extent of BP lowering with treatment is necessary when interpreting clinical trial results in patients with microalbuminuria. It remains to be determined whether targeting the underlying inflammatory process can retard or prevent microalbuminuria progression or whether treatment of microalbuminuria can prevent end‐stage renal disease or death.

Hypertension in Early-Stage Kidney Disease: An Update From the Kidney Early Evaluation Program (KEEP)

BACKGROUND Chronic kidney disease (CKD) is a worldwide public health problem. Systolic blood pressure as an associated feature of CKD has not been fully explored in community volunteer and nationally representative samples of the US population. METHODS This cross-sectional analysis evaluated hypertension and early-stage CKD in participants in the Kidney Early Evaluation Program (KEEP), a voluntary community-based health screening program administered by the National Kidney Foundation, and the National Health and Nutrition Examination Survey (NHANES) data to assess similarities and differences between these populations. Participants in both databases were 18 years or older. RESULTS The KEEP database included 88,559 participants and the NHANES included 20,095. Hypertension prevalence was greater in KEEP (69.6%) than NHANES (38.1%; P < 0.001). Compared with NHANES participants, KEEP participants had greater rates of obesity (79.5% versus 51.5%; P < 0.001) and diabetes (28.0% versus 8.9%; P < 0.001). In participants with diabetes, KEEP had slightly greater rates of prevalent hypertension (88.5% versus 85.7%; P = 0.03). In participants with hypertension, CKD stages 3 and 4 were more prevalent in KEEP than NHANES (79.1% versus 69.3%; P < 0.001). Rates of CKD stages 3 and 4 were greater in KEEP than NHANES for the following subgroups: African Americans (72.4% versus 57.4%; P < 0.001), smokers (69.1% versus 55.6%; P = 0.002), and participants with hypercholesterolemia (80.2% versus 71.9%; P < 0.001). CONCLUSIONS In the volunteer KEEP population, rates of hypertension and CKD were greater than in NHANES, most prominently in African Americans and participants with increased cardiovascular risk.

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.

Should nephrologists use beta-blockers? A perspective

Given the high prevalence of cardiovascular disease in people with chronic kidney disease (CKD) and the clear benefits of mortality reduction observed for most β−blockers in clinical trials, they are relatively underused in CKD patients [1,2]. The rationale for use of β-blockers in patients with CKD is reviewed in detail elsewhere [2,3] but is summarized in this editorial. Alterations in β- and α-receptor responsiveness are associated with sympathetic over-activity in CKD. This increased sympathetic activity is involved in the genesis of hypertension, and contributes to cardiac complications seen in CKD [2,3]. The contribution of the sympathetic nervous system to nephropathy progression is documented in sub-totally nephrectomized rats where non-hypotensive doses of β-blockers ameliorate development of glomerulosclerosis and cardiac injury [4]. In men, sympathetic over-activity, as assessed by sural nerve microneurography, was present in patients on haemodialysis [5], stage 4 nephropathy [6] and in early stage 2 nephropathy among patients with polycystic kidney disease [7]. The role of the damaged kidney in causing sympathetic over-activity is illustrated by normalization of sympathetic over-activity in haemodialysis patients following bilateral nephrectomy [5] and in renal allograft recipients when their shrunken native kidneys are removed [8]. The most common cause of death in stage 3 and higher CKD results from complications of cardiovascular disease. This may be due, in part, to inadequate treatment of blood pressure, where blood pressure goals were not attained and agents known to reduce mortality secondary to cardiovascular causes, i.e. aspirin, ACE inhibitors and β-blockers were not used [9]. In a separate study, β-blockers were used in fewer than 30% of haemodialysis patients [10]. This is surprising, since β-blockers are well-established, evidence-based therapy for reducing cardiovascular risk in hypertension associated with diabetes and after myocardial infarction [11,12]. Observational studies support definite survival benefits derived from β-blocker use in patients with advanced CKD [13,14]. Furthermore, a prospective,

Should proteinuria reduction be the criterion for antihypertensive drug selection for patients with kidney disease

Purpose of reviewProteinuria, that is, more than 200 mg/day of urinary albumin, is associated with the presence of kidney disease. Its increase over time is strongly correlated with progression of nephropathy. Retrospective analyses of nephropathy outcome trials show that proteinuria reduction of 30% or more after initiation of blood pressure (BP)-lowering therapy is associated with slower nephropathy progression than lowering BP without its reduction. Recent findingsRetrospective analyses of five large nephropathy outcome trials demonstrate that nephropathy progression slowed by an additional 28–39% over the control or placebo group when proteinuria was reduced in concert with BP. Two separate trials demonstrate that nephropathy progression was slowed to a lesser degree when BP was reduced to a similar degree, but proteinuria reduced less than 30%. These associations do not hold for those with microalbuminuria, in which BP reduction is the key element to slowing nephropathy progression. Recent cardiovascular outcome trials fail to show a relationship between reductions in proteinuria and nephropathy outcomes. This large cardiovascular endpoint trial, however, was not only powered for nephropathy outcomes but also failed to show a benefit between proteinuria reduction and cardiovascular events, a previously established observation. SummaryAll patients with a history of hypertension and either kidney disease or diabetes should have an annual check for albuminuria. If albumin is present in amounts of more than 200 mg/day, strategies for BP-lowering therapy should also focus on a reduction of more than 30% of urinary protein.