Elias V. Balaskas

Mineralocorticoid Receptor Antagonism for Cardiovascular Protection in End-Stage Renal Disease: New Data But the Controversy Continues.

Patients with end-stage renal disease (ESRD) have one of the highest rates of cardiovascular morbidity and mortality. Unlike in the general population where ischemic atherosclerotic events are the most common causes of cardiovascular death, among people with ESRD, serious arrhythmias and cardiac arrests make up the bulk of cardiovascular mortality. The huge burden of sudden cardiac deaths in these individuals is attributable to a number of pathophysiological alterations related to ESRD, including left ventricular (LV) hypertrophy, intermyocardiocytic fibrosis, and disturbances in electrolyte balance. Notably, prospective observational studies have demonstrated that among ESRD patients, LV hypertrophy represents a strong and independent predictor of future cardiovascular events, particularly sudden cardiac death. In the setting of ESRD, overactivity of the reninangiotensin-aldosterone axis is proposed to be a prominent player in the complex mechanistic background of LV hypertrophy. Experimental studies have shown that excessive aldosterone is directly involved in the process of intermyocardiocytic fibrosis. Initially, aldosterone triggers an inflammatory response mediated through monocyte and macrophage infiltration and increased expression of proinflammatory cytokines. This inflammatory reaction is followed by fibroblast proliferation and increased collagen deposition, resulting in perivascular and, lastly, interstitial fibrosis. In most experimental models, mineralocorticoid receptor antagonists (MRAs) were shown to downregulate the proinflammatory and profibrotic actions of aldosterone, reversing in this way the adverse myocardial remodeling. On the basis of the aforementioned background data, clinical studies have provided evidence that small doses of MRAs alone or in combination with angiotensinconverting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) caused regression of LV mass in patients with essential hypertension and LV hypertrophy or in patients with primary hyperaldosteronism. An evolution around the potential cardioprotective properties of MRAs began with the publication of the Randomized Aldactone Evaluation Study (RALES). This trial and the subsequent Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) clearly demonstrated that among patients with heart failure and reduced LV ejection fraction, add-on MRA therapy on top of background treatment with ACE inhibitors or ARBs and/or b-blockers effectively and safely reduced cardiovascular morbidity and mortality. However, patients with severely impaired renal function (ie, estimated glomerular filtration rate <30 mL/min/ 1.73 m) were excluded from these studies; thus, it remains unclear whether MRAs carry the ability to offer cardiovascular risk reduction in patients with advanced kidney disease, including those receiving maintenance dialysis. This question is further complicated by the fact that the increased use of MRAs in heart failure patients after the publication of the RALES trial was associated with a 4.5-fold increase in incidence of hospitalizations caused by hyperkalemia and a 6.6-fold increase in hyperkalemia-associated mortality, along with the propensity of patients with advanced chronic kidney disease towards hyperkalemia. Among ESRD patients, the efficacy of MRAs is largely understudied. This is because of the concerns that any advantages of these agents in causing regression of LV hypertrophy may be compensated by excess risk of life-threatening hyperkalemia, since MRAs could theoretically decrease potassium removal through the intestine, which comprises an important route for ESRD patients. However, a systematic review of 10 small studies evaluating the safety profile of the MRA spironolactone in dialysis patients suggested that administration of this compound at low doses (up to 50 mg daily) is accompanied by relevant small increases in serum potassium levels (on average 0.3–0.5 mmol/L); thus, it appears that the overall risk of incident hyperkalemia with MRA therapy may be lower than originally thought. A recent randomized study compared the safety profile of eplerenone relative to placebo in 146 hemodialysis patients. Administration of eplerenone up to a maximal dose of 50 mg/d for 13 weeks was, indeed, associated with significantly higher incidence of hyperkalemia, defined as serum Address for correspondence: Panagiotis I. Georgianos, MD, PhD, Section of Nephrology and Hypertension, 1st Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, St. Kyriakidi 1, Thessaloniki, Greece E-mail: pangeorgi@yahoo.gr

Arterial stiffness in end-stage renal disease—pathogenesis, clinical epidemiology, and therapeutic potentials

Arterial stiffness is an important risk factor for cardiovascular morbidity and mortality in patients with end-stage renal disease (ESRD). Arterial stiffness aggravates cardiovascular risk via multiple pathways, such as augmentation of aortic systolic pressure, subendocardial hypoperfusion, and excess pulsatile energy transmission from macro- to microcirculation. Pathogenesis of the arteriosclerotic process in ESRD is complex and not yet fully understood. Several factors unique to ESRD, such as mineral metabolism disturbances, vascular calcifications, formation of advanced glycation end-products, and acute and chronic volume overload, are proposed to play a particular role in the progression of arteriosclerosis in ESRD. As these and other mechanistic pathways of arterial stiffening in ESRD are elucidated, there is hope that this knowledge will be translated into novel therapeutic interventions targeting arterial stiffness. In the meantime, blood pressure (BP) lowering via strict volume control and appropriate use of antihypertensive drugs is a fundamental step in reversing accelerated arterial stiffening and modifying the cardiovascular risk profile of ESRD patients. In this article, we review the pathogenesis, clinical epidemiology, and therapies targeting arterial stiffness in ESRD, discussing recent advances and high-priority goals of future research in these important areas.

Levels of Endocan, Angiopoietin-2, and Hypoxia-Inducible Factor-1a in Patients with Autosomal Dominant Polycystic Kidney Disease and Different Levels of Renal Function

Background: Endothelial dysfunction leading to unbalanced vasoconstriction and ischemia of renal parenchyma is increasingly proposed as an alternative pathway of renal damage in autosomal dominant polycystic kidney disease (ADPKD). However, human studies investigating the evolution of such phenomena are limited. This study investigated the levels of emerging biomarkers of endothelial function, angiogenesis and hypoxia, in ADPKD patients with different renal function. Methods: The study population consisted of three groups: 26 ADPKD patients with impaired renal function (Group A; estimated glomerular filtration rate [eGFR] 45–70 mL/min/1.73 m2), 26 ADPKD patients with preserved renal function (Group B; eGFR >70 mL/min/1.73 m2), and 26 age- and sex-matched controls with no history of renal disease. Circulating levels of endocan (endothelial cell-specific molecule-1) angiopoietin-2, and hypoxia-inducible factor-1a (HIF-1a) were determined by enzyme-linked immunosorbent assay techniques. Results: Patients in Group A had significantly higher levels of endocan (7.17 ± 0.43 ng/mL), angiopoietin-2 (5,595.43 ± 3,390), and HIF-1a (163.68 ± 37.84 pg/mL) compared to patients in Group B (6.86 ± 0.59 ng/mL, p = 0.017, 3,854.41 ± 3,014.30, p = 0.018, 136.84 ± 42.10 pg/mL, p = 0.019 respectively) or controls (4.83 ± 0.69 ng/mL, 1,069 ± 427.88 pg/mL, 70.20 ± 17.49 pg/mL, p < 0.001 for all comparisons). Of note, patients in Group B had also higher levels of all markers compared to controls (p < 0.001) despite having similar renal function. In correlation analyses within ADPKD patients, we noted strong correlations of all studied markers with asymmetric dimethylarginine (ADMA; endocan r = 0.908, p < 0.001, angiopoietin-2 r = 0.983, p < 0.001 and HIF-1a r = 0.998, p < 0.001), and only weak or modest correlations with eGFR. Conclusions: This study suggests that endothelial dysfunction causing microcirculatory changes, linked to angiogenesis and hypoxia, may come early in the course of ADPKD and could be a key regulator of renal injury progression.

Serum Fas Ligand, Serum Myostatin and Urine TGF-β1 Are Elevated in Autosomal Dominant Polycystic Kidney Disease Patients with Impaired and Preserved Renal Function

Background/Aims: The pathophysiology of renal disease progression in autosomal dominant polycystic disease (ADPKD) is largely unknown. Recent evidence suggests microvascular dysfunction leading to renal ischemia, as an additional pathway for renal function decline. This study examined the levels of serum Fas ligand (FasL), serum myostatin and urine transforming growth factor-beta 1 (TGF-β1) and their association with markers of endothelial dysfunction, in ADPKD patients with preserved or impaired renal function. Methods: Seventy-eight participants were enrolled in the study, divided in three groups: Group A consisted of 26 ADPKD patients with impaired renal function (eGFR 45-70 ml/min/1.73m2), Group B of 26 ADPKD patients with preserved renal function (eGFR > 70 ml/min/1.73m2), and Group C of 26 age- and sex- matched controls with no history of renal disease. Serum FasL, myostatin and urine levels of TGF-β1 were measured as biomarkers of vascular dysfunction, apoptosis and fibrosis with ELISA techniques. Results: Group A patients had significantly higher levels of FasL (13.12±1.69 ng/mL), myostatin (4.62±0.59 ng/mL) and urine logTGF-β1 (3.56±0.49 ng/24h) compared to Group B (9.6±1.28 ng/mL, 3.06±0.35, and 2.09±0.37, respectively, p< 0.001 for all comparisons) or controls (6.59±1.17 ng/mL, 2.18±0.45 ng/ml, and 1.58±0.21, respectively, p< 0.001 for all comparisons). Patients in Group B had also higher levels of all markers compared to controls (p< 0.001), despite having similar renal function. In ADKPD patients negative associations of eGFR with FasL (r=-0.799, p< 0.001), myostatin (r=-0.856, p< 0.001) and TGF-β1 (r=-0.476, p< 0.001) but positive correlations of these markers with asymmetric dimethylarginine (ADMA) (r=0.825; r=0.749; and r=0.599, respectively p< 0.001) were noted. Multivariate analysis demonstrated that FasL was independently associated with high urine TGF-β1 (OR 3.774, 95%CI 1.180-12.072, p=0.025). Conclusions: ADPKD patients with moderately preserved renal function have higher levels of FasL, myostatin and urine TGF-β1 than controls. These results indicate that an interplay between endothelial dysfunction and renal ischemia with mechanisms linked to apoptosis and fibrosis may be present even in early stages of ADPKD.

Treating Hypertension in Diabetic Patients With Advanced Chronic Kidney Disease: What Should We Have in Mind?

To the Editor: We have read with interest the study by Weinrauch and colleagues, which investigated the prevalence of multidrug antihypertensive therapy in diabetic patients with and without impaired renal function. In a retrospective cohort of 10,151 diabetic outpatients collected during a 5-year period in the Joslin Diabetes Center, Weinrauch and coworkers showed that the mean number of prescribed antihypertensive drugs increased from 1.5 agents daily in those with an estimated glomerular filtration rate (eGFR) >90 mL/min/1.73 m to 3.1 antihypertensive agents daily in those with eGFR <30 mL/min/1.73 m. The prevalence of multidrug antihypertensive therapy (defined as the use of at least three antihypertensive agents, one of which had to be a diuretic) was 17% in those with an eGFR of >90 mL/ min/1.73 m and increased to 67% in those with eGFR <30 mL/min/1.73 m. The proportion of patients treated with multidrug antihypertensive regimens was shown to increase with advancing stage of chronic kidney disease (CKD), even when the alternative definition of use of at least four antihypertensive drugs, including a diuretic, was applied. These findings are clinically relevant because the study emphasizes the necessity for multidrug therapy in a high proportion of hypertensive patients with advanced CKD, incorporating real-world data from a huge sample of US diabetic outpatients. However, the estimates of the prevalence of multidrug antihypertensive therapy provided in this analysis should not be interpreted as a proxy for the prevalence of resistant hypertension, as falsely suggested in the paper. Undoubtedly, hypertension is often difficult to control in patients with advanced CKD. However, the term “resistant hypertension” reflects a particular category of hypertensive patients and the diagnosis of this clinical entity should follow the currently available definitions. One patient is considered to have resistant hypertension when the blood pressure (BP) remains uncontrolled despite the concomitant use of three or more antihypertensive drugs at maximally tolerated doses, including a diuretic, or when four or more antihypertensive agents are used regardless of BP levels. Even if we consider that those patients who met the second definition of multidrug antihypertensive therapy used in this study truly had resistant hypertension, there may be several others with resistant hypertension who remained misclassified without properly performed BP recordings to assess BP control status. Even in that case, we need to know whether these patients had controlled or uncontrolled resistant hypertension, because uncontrolled resistant hypertension has been associated with worse clinical outcomes. Apart from the issue of multidrug antihypertensive regimens, several other modifications may be necessary when treating hypertension in diabetic patients with advanced CKD. The authors nicely present in Table I of their paper the categories of antidiabetic compounds prescribed to the study participants according to stage of CKD. In a similar manner, it would be valuable to know the most commonly prescribed antihypertensive drug classes in diabetic patients with varying levels of renal function. For example, hydrochlorothiazide and thiazide-like diuretics are generally inactive in patients with eGFR <30 mL/min/1.73 m and should be replaced by the more potent loop diuretics. Further, although agents that block the renin-angiotensin-aldosterone system (RAAS) are recommended as first-line antihypertensive therapy in patients with diabetes, particularly when albuminuria is present, it is not so rare in daily clinical practice to discontinue RAAS inhibitor use in patients with eGFR as low as 20 to 25 mL/min/1.73 m; this commonly occurs because of fear of acute renal injury and hyperkalemia that may result in the need for earlier initiation of hemodialysis in such patients. We encourage the authors to provide this valuable information either in their response to this letter or in a separate paper. We believe that these data would be informative for clinicians who manage hypertension in patients with advanced CKD.

Long-term Efficacy and Safety of Atorvastatin in Dyslipidemic Patients Undergoing Continuous Ambulatory Peritoneal Dialysis

Objective Lipid abnormalities are common in patients on continuous ambulatory peritoneal dialysis (CAPD) and they are risk factors for atherosclerosis. In this prospective uncontrolled study, the aim was to evaluate the efficacy and safety of atorvastatin, a new statin, in hypercholesterolemic CAPD patients with or without hypertriglyceridemia who failed to respond to diet control. Methods Following a hypolipidemic diet for 2 months, atorvastatin was administered at a dose of 10 mg/day once daily in 24 patients (14 males, 10 females). Mean age was 59.9 years (range, 19-74 years) and average time on CAPD was 16.6 months (range, 4-52 months). The results were evaluated at 0, 1, 3, 6, 12, 18, 24, 30, 36, 42, and 48 months. A total of three patients received atorvastatin for longer than 48 months, eight patients received it for longer than 42 months, 10 patients for longer than 36 months, 17 patients for longer than 24 months, 20 patients for longer than 18 months, and all (24) patients for longer than 12 months. Results Highly significant decreases were noted in total cholesterol (from 282 ± 28 to 178 ± 22 mg/dL, 20-50%, mean, 34%; p p p p Conclusions Our data indicate that atorvastatin, even at a low dose of 10 mg/day, is an effective, safe, and well-tolerated drug for the long-term treatment of hyperlipidemia in CAPD patients. [ Hong Kong J Nephrol 2003;5(2):78-83]