Kostas C. Siamopoulos

Outcomes in subgroups of hypertensive patients treated with regimens based on valsartan and amlodipine: An analysis of findings from the VALUE trial.

Background In the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial the primary outcome (cardiac morbidity and mortality) did not differ between valsartan and amlodipine-based treatment groups, although systolic blood pressure (SBP) and diastolic blood pressure reductions were significantly more pronounced with amlodipine. Stroke incidence was non-significantly, and myocardial infarction was significantly lower in the amlodipine-based regimen, whereas cardiac failure was non-significantly lower on valsartan. Objectives The study protocol specified additional analyses of the primary endpoint according to: sex; age; race; geographical region; smoking status; type 2 diabetes; total cholesterol; left ventricular hypertrophy; proteinuria; serum creatinine; a history of coronary heart disease; a history of stroke or transient ischemic attack; and a history of peripheral artery disease. Additional subgroups were isolated systolic hypertension and classes of antihypertensive agents used immediately before randomization. Methods The 15 245 hypertensive patients participating in VALUE were divided into subgroups according to baseline characteristics. Treatment by subgroup interaction analyses were carried out by a Cox proportional hazard model. Within each subgroup, treatment effects were assessed by hazard ratios and 95% confidence intervals. Results For cardiac mortality and morbidity, the only significant subgroup by treatment interaction was of sex (P = 0.016), with the hazard ratio indicating a relative excess of cardiac events with valsartan treatment in women but not in men, but SBP differences in favour of amlodipine were distinctly greater in women. No other subgroup showed a significant difference in the composite cardiac outcome between valsartan and amlodipine-based treatments. For secondary endpoints, a sex-related significant interaction was found for heart failure (P < 0.0001), with men but not women having a lower incidence of heart failure with valsartan. Conclusion As in the whole VALUE cohort, in no subgroup of patients were there differences in the incidence of the composite cardiac endpoint with valsartan and amlodipine-based treatments, despite a greater blood pressure decrease in the amlodipine group. The only exception was sex, in which the amlodipine-based regimen was more effective than valsartan in women, but not in men, whereas the valsartan regimen was more effective in preventing cardiac failure in men than in women.

Dyslipidemia in chronic kidney disease: an approach to pathogenesis and treatment.

BACKGROUND/AIMS Cardiovascular disease (CVD) is a major cause of mortality in patients with mild to moderate chronic kidney disease (CKD) and end-stage renal disease (ESRD). Dyslipidemia has been established as a well-known traditional risk factor for CVD in the general population and it is well known that patients with CKD exhibit significant alterations in lipoprotein metabolism. In this review the pathogenesis and treatment of renal dyslipidemia are discussed. METHODS Studies on lipid abnormalities in CKD stages 1-4, in nephrotic syndrome, and in hemodialysis and peritoneal dialysis patients are analyzed, as well as the lipid profile of kidney graft recipients. Also, the results of the effects of epoietin treatment and hypolipidemic drugs in CKD patients are reported. RESULTS Disturbances in lipoprotein metabolism are evident even at the early stages of CKD and usually follow a downhill course that parallels the decline of renal function. However, several intrinsic or exogenous factors can influence the phenotypic expression of these alterations. According to the literature, current evidence suggests that unlike dialysis patients, mild to moderate CKD patients could be benefit from the use of statins. CONCLUSION The use of statins is indicated in patients with mild to moderate CKD, while in subjects with ESRD lipid-lowering therapy should be individualized.

C.E.R.A. Corrects Anemia in Patients with Chronic Kidney Disease not on Dialysis: Results of a Randomized Clinical Trial

BACKGROUND AND OBJECTIVES This study examined the efficacy of C.E.R.A., a continuous erythropoietin receptor activator, for correcting anemia in patients who had chronic kidney disease (CKD) and were not on dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In this open-label, randomized, parallel-group, Phase III study, 324 adult patients with CKD not on dialysis nor receiving treatment with erythropoiesis-stimulating agents (ESAs) were randomly assigned (1:1) to receive subcutaneous C.E.R.A. once every 2 wk or darbepoetin alfa once weekly during an 18-wk correction period and a 10-wk evaluation period. Thereafter, patients receiving C.E.R.A. were randomly assigned to C.E.R.A. once every 2 wk or once monthly, and patients receiving darbepoetin alfa could receive darbepoetin alfa once weekly or once every 2 wk for a 24-wk extension period. Dosage was adjusted to achieve a hemoglobin (Hb) response and to maintain Hb +/-1 g/dl of the response level and 11 to 13 g/dl. Primary end points were Hb response rate during correction and evaluation and change in Hb concentration between baseline and evaluation. RESULTS Hb response rates were 97.5% for C.E.R.A. and 96.3% for darbepoetin alfa. Adjusted mean changes in Hb from baseline to evaluation were 2.15 g/dl (C.E.R.A.) and 2.00 g/dl (darbepoetin alfa). Analysis showed that C.E.R.A. once every 2 wk was as effective as darbepoetin alfa once weekly for correcting anemia. Hb levels remained stable in all groups during the extension period. C.E.R.A. and darbepoetin alfa were well tolerated. CONCLUSIONS Subcutaneous C.E.R.A. once every 2 wk corrects anemia in ESA-naïve patients who are not on dialysis.

Pathogenetic mechanisms of hypomagnesemia in alcoholic patients.

The aim of our study was to describe the possible pathophysiologic mechanisms of hypomagnesemia in alcoholic patients. A total of 127 chronic alcoholic patients admitted to our university hospital for causes related to alcohol abuse were studied. Hypomagnesemia was the most common electrolyte disturbance observed in 38 patients (29.9%). In 18 of them inappropriate magnesiuria was evident, possibly due to hypophosphatemia, to metabolic acidosis or to a direct magnesiuric effect of acute alcohol consumption. The causes of hypomagnesemia in the remaining 20 patients were alcohol withdrawal syndrome and diarrhea. Respiratory alkalosis was evident in 10 hypomagnesemic patients and could have played a role in the development of hypomagnesemia. A decreased magnesium intake could also have contributed to the hypomagnesemia, especially in malnourished alcoholic patients. Hypomagnesemic patients more frequently had other acid-base and electrolyte abnormalities, such as hypophosphatemia, hypokalemia, hypocalcemia, and respiratory alkalosis, as compared with the normomagnesemic patients. Moreover, in hypomagnesemic patients serum magnesium levels were correlated with the indices of potassium and phosphorus excretion, suggesting that serum magnesium levels play a central role in the homeostasis of the other electrolytes. In conclusion, hypomagnesemia is the most common electrolyte abnormality observed in alcoholic patients, as a result of various pathophysiologic mechanisms.

Increased activity of platelet-activating factor acetylhydrolase in low-density lipoprotein subfractions induces enhanced lysophosphatidylcholine production during oxidation in patients with heterozygous familial hypercholesterolaemia

Patients with heterozygous familial hypercholesterolaemia (FH) have elevated plasma concentrations of low‐density lipoprotein (LDL) and develop premature atherosclerosis. There is increasing evidence that oxidative modification of LDL is important for the pathogenesis of atherosclerosis, and the LDL‐associated platelet‐activating factor acetylhydrolase (PAF‐AH) seems to play a key role in LDL oxidation by hydrolysing the oxidized phospholipids of phosphatidylcholine (PC) and producing lysophosphatidylcholine (lyso‐PC). We measured the total serum and high‐density lipoprotein (HDL) levels of PAF‐AH activity and studied the distribution of PAF‐AH activity among three LDL subfractions isolated by gradient ultracentrifugation in 15 patients with heterozygous FH and 13 normolipidaemic control subjects. We also determined the lyso‐PC production in each LDL subfraction during Cu2+‐induced oxidation in vitro. The total serum PAF‐AH activity in heterozygous FH patients was significantly higher than in control subjects, whereas the HDL‐associated PAF‐AH activity, expressed as a percentage of total serum PAF‐AH activity, was significantly lower in the FH patients than in control subjects (13.9 ± 6.6% vs. 30.6 ± 4.4%, P < 0.001). Among the LDL subfractions, the PAF‐AH activity in both normolipidaemic control subjects and FH patients, expressed as nmol mg−1 protein min−1, was significantly higher in the LDL3 subfraction (33.1 ± 4.8 and 53.4 ± 11.5 respectively) than in the LDL2 (18.6 ± 5.3 and 26.8 ± 10.4 respectively, P < 0.0001 for both comparisons) and LDL1 subfractions (5.1 ± 1.5 and 7.8 ± 2.6, respectively, P < 0.0001 for both comparisons). Additionally, the enzyme activity in each LDL subfraction of the heterozygous FH patients was significantly higher than in control subjects (P < 0.02 for LDL1, P < 0.03 for LDL2 and P < 0.0001 for LDL3). No difference was observed in the susceptibility to oxidation of each LDL subfraction among the heterozygous FH patients and the normolipidaemic control subjects. During oxidation, the PAF‐AH activity decreased, whereas the lyso‐PC levels significantly increased in all subfractions of both groups. The lyso‐PC/sphingomyelin molar ratio in each LDL subfraction of the FH patients 3 h after the onset of the oxidation was significantly higher than in control subjects [0.38 ± 0.05 and 0.27 ± 0.04, respectively, for LDL1 (P < 0.006), 0.47 ± 0.08 and 0.39 ± 0.03, respectively, for LDL2 (P < 0.04), 0.55 ± 0.11 and 0.42 ± 0.06, respectively, for LDL3 (P < 0.02)]. Our results show that heterozygous FH patients exhibit higher PAF‐AH activity than control subjects in all LDL subfractions, resulting in higher lyso‐PC production during oxidation, which confers on these subfractions higher biological potency. This phenomenon, in combination with the diminished anti‐atherogenic and antioxidant capability of HDL in these patients due to the relatively low HDL‐cholesterol levels compared with LDL‐cholesterol levels and, consequently, the relatively low HDL‐associated PAF‐AH activity, could contribute to the higher atherogenicity and incidence of coronary artery disease observed in FH patients.

Effect of micronized fenofibrate and losartan combination on uric acid metabolism in hypertensive patients with hyperuricemia

It has been reported that micronized fenofibrate and losartan can significantly decrease serum uric acid levels by augmenting uric acid excretion. We undertook this study to evaluate the effects of the combination treatment with micronized fenofibrate and losartan in nondiabetic hypertensive dyslipidemic patients with hyperuricemia (serum uric acid, >7 mg/ dl). A total of 25 patients (15 men, 10 women) aged 21-66 years was studied. In all patients, serum lipid parameters, including Lp(a), fibrinogen, and uric acid levels, as well as fractional excretion of uric acid (FEUA) were obtained before treatment, 8 weeks after micronized fenofibrate treatment (200 mg daily), and 8 weeks after combination therapy with micronized fenofibrate (200 mg daily) and losartan (50 mg daily). Fenofibrate alone significantly decreased total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, Apo B, Lp(a), fibrinogen, and uric acid levels (from 7.6+/-0.55 to 5.6 +/-0.5 mg/dl; p < 0.0001) and increased high-density lipoprotein (HDL) cholesterol, Apo A1, and FEUA (from 6.5+/-1.8% to 12.2+/-4%; p < 0.0001). The addition of losartan beyond the decrease in blood pressure values did not significantly alter serum metabolic parameters. However, a small additional decrease in serum uric acid levels (from 5.6+/-0.5 to 4.9+/-1 mg/dl; p < 0.05) was found because of a further increase in FEUA (from 12.2+/-4% to 14+/-5.5%; p < 0.05). It is concluded that the combination of micronized fenofibrate and losartan is useful for the management of patients with multiple metabolic abnormalities, including hyperuricemia.

Cyclosporin-associated nephropathy in patients with autoimmune diseases

SummaryRenal biopsy specimens were evaluated from patients with different autoimmune diseases treated with cyclosporin (CyA). Ten biopsies were done before CyA, 10 biopsies after low-dose (<7.5 mg/kg/day, initial dose or mean daily dose within the first month, respectively), and 9 after high-dose (>7.5 mg/kg/day) treatment. Definite chronic CyA nephrotoxicity (cyclosporin-associated arteriolopathy and/or interstitial fibrosis striped form with tubular atrophy) was only present in the initial high-dose group. In this group a significant serum creatinine increase was noted and 8 of the 9 patients were hypertensive. No significant correlation was found between the severity of morphologic lesions and the mean daily dose during total treatment, cumulative dose, and duration of therapy. The morphologic changes in the low-dose group did not differ from the control biopsy specimens before CyA treatment. Based on these results, it can be concluded that major nephrotoxicity can be avoided by initial low CyA doses.

PAF-acetylhydrolase activity on Lp(a) before and during Cu2+-induced oxidative modification in vitro

In human plasma with no detectable lipoprotein (a) (Lp(a)) levels, platelet-activating factor acetylhydrolase (PAF-AH) is associated with low density lipoprotein (LDL) and high density lipoprotein (HDL) with a distribution of 70 and 30%, respectively. We used a density gradient ultracentrifugation procedure to study the distribution of PAF-AH among lipoproteins in plasma containing Lp(a). Lp(a) was migrated as a broad band in the density region of d = 1.050-1.100 g/ml, independently of its isoform size. In plasma with Lp(a) levels 30-40 mg/dl or 80-100 mg/dl the PAF-AH activity migrated in this density region was 4 or 9% higher as compared to plasma having Lp(a) levels < 8 mg/dl (P < 0.05 or P < 0.02, respectively). Enrichment of plasma with the dense LDL5 subfraction, significantly increased the enzyme activity distributed in this density region. The physicochemical properties of the Lp(a)-associated PAF-AH activity were similar to those reported for the LDL-associated enzyme. However, the kinetic constants in small Lp(a) isoforms were significantly higher compared to large ones. Isoform F had apparent Km = 117 +/- 9 mumol/l and Vmax = 94 +/- 5 nmol/mg protein per min, and isoform S2/S3 had apparent Km = 36 +/- 9 mumol/l and Vmax = 25 +/- 5 nmol/mg protein per min. Removal of apolipoprotein (a) (apo(a)) from Lp(a) by reductive cleavage with dithiothreitol, slightly affected the amount of PAF-AH existing on Lp(a) since, only 15 +/- 5% of the total enzyme activity dissociated from its particle after density gradient ultracentrifugation. During Cu(2+)-induced Lp(a) oxidation, the PAF-AH activity decreased from 10.90 +/- 2.30 nmol/mg per min to 2.57 +/- 0.56 nmol/mg per min 4 h after the initiation of the oxidation (P < 0.001). The apparent Km of the enzyme remained essentially unchanged during oxidation, whereas Vmax was significantly decreased from 58.6 +/- 7.8 nmol/mg protein per min to 38.2 +/- 8.7 nmol/mg protein per min (P < 0.03). An extensive hydrolysis of the endogenous phosphatidylcholine (PC) to lysophosphatidylcholine (lyso-PC) was observed during Lp(a) oxidation, since the Lyso-PC/sphingomyelin molar ratio at the end of oxidation (0.55 +/- 0.09) was significantly higher than that before oxidation (0.19 +/- 0.01, P < 0.001). Our results show that the existence of Lp(a) in plasma alters the distribution of PAF-AH among the other lipoproteins. Apo(a) seems to affect the association of the enzyme with Lp(a) but does not bind itself to PAF-AH. During Lp(a) oxidation, the PAF-AH activity decreases whereas an extensive hydrolysis of the endogenous PC to Lyso-PC is observed which is possibly due to the PAF-AH activity.

Apolipoprotein(a) phenotypes and lipoprotein(a) concentrations in patients with renal failure

Patients with renal failure have an increased incidence of atherosclerotic disease. Numerous studies have shown that these patients show increased serum lipoprotein(a) [Lp(a)] concentrations compared with the control population. However, variable alleles at the apolipoprotein(a) [apo(a)] gene locus determine to a large extent the Lp(a) concentration in the general population. We therefore undertook the present study to evaluate apo(a) phenotypes and Lp(a) serum concentrations in a large number of patients with renal disease. Seventy-nine patients treated by hemodialysis (HD), 47 patients treated by continuous ambulatory peritoneal dialysis (CAPD), 68 patients with mild/moderate chronic renal failure (CRF) and serum creatinine levels of 1.8 to 8 mg/dL, and 73 healthy controls were studied. All patients showed significantly elevated median serum Lp(a) concentrations in comparison with controls: HD patients, 15.7 mg/dL (P < 0.01); CAPD patients, 20 mg/dL (P < 0. 005); CRF patients, 15.1 mg/dL (P < 0.01) versus controls, 7 mg/dL. The greater Lp(a) values in all groups were not explained by differences in isoform frequencies, whereas their increase was apo(a)-type specific. Thus, patients in all groups with high-molecular-weight (HMW) apo(a) isoforms showed a significant elevation of Lp(a) levels, whereas serum Lp(a) concentrations in patients with low-molecular-weight (LMW) isoforms were not significantly different from controls, except for CAPD patients, who presented increased serum Lp(a) concentrations. We conclude that in patients with renal failure, even of mild/moderate degree, as well as in patients with end-stage renal disease undergoing HD or CAPD, elevated Lp(a) concentrations are mainly observed in those with HMW apo(a) phenotypes.

The role of obesity in kidney disease: recent findings and potential mechanisms

Obesity epidemic is in rise in almost every industrialized country and continues to be a growing problem worldwide. In fact, obesity per se has been recognized as a chronic disease. Consequently, there has been a cascade of metabolic changes initiated by the markedly risen prevalence that contributes to the increased incidence of diabetes, hypertension, and cardiovascular disease. Moreover, obesity is also associated with an increased risk of chronic kidney disease (CKD). The majority of the studies indicate a direct relationship between body mass index (BMI) and CKD risk. Moreover, current evidence emphasized the fact that central obesity measurements, such as waist circumference, could be a better predictor of CKD progression and mortality than BMI. The detrimental effects of obesity on kidney outcome have been recognized in nondialysis-dependent (NDD)-CKD patients. However, survival in overweight or obese CKD patients undergoing maintenance hemodialysis is paradoxically opposed compared with the general population. This “reverse epidemiology,” however, is valid mainly for the inflammated end-stage renal disease (ESRD) patients. In fact, renal transplant recipients with higher BMI have inferior patient and graft survival compared to patients with lower BMI. This review also provides perspectives concerning the mechanisms associated with obesity, such as the renin–angiotensin–aldosterone system (RAAS) activation, and the role of leptin, adiponectin, fetuin-A, and adipose tissue, as factors that contribute to the development of CKD. Prevention strategies for CKD patients are also discussed and should be considered by clinicians.