Sensitivity of erythrocytes to oxidant stress in uremia

The erythrocytes from 19 chronic hemodialysis patients were examined for Heinz bodies and their sensitivity to oxidant stress. Heinz bodies were found in 63% of patients and an elevated level of oxidized hemoglobin in 36%. When exposed to acetylphenhydrazine oxidant stress, 84% had a normal response and 95% had stable reduced glutathione levels. Ascorbic-acid-induced oxidant stress was tolerated by 84%. The activities of enzymes associated with the hexose monophosphate shunt were examined and found to be intact. This study demonstrates an increased number of Heinz bodies in hemodialysis patients. However, this is not due to an increased sensitivity to oxidant stress. Other mechanisms must be sought to explain the presence of Heinz bodies in these patients.     

Deficiencies of calcium-regulatory proteins in dialysis patients: a novel concept of cardiovascular calcification in uremia

Dialysis patients suffer a manifold increase in cardiovascular mortality when compared to a nonuremic population, while this phenomenon is not sufficiently explained by an increased prevalence of traditional risk factors, such as hypercholesterolemia and hypertension. The presence of hyperphosphatemia, of an increased calcium x phosphate product, as well as the magnitude of vascular and valvular calcifications, were recently identified as specific major risk factors of cardiovascular mortality in the uremic population. Furthermore, hyperphosphatemia and an increased calcium x phosphate product could be quantitatively linked to the burden of coronary artery calcification in young dialysis patients, suggesting the correction of hyperphosphatemia as the central target for preventive therapeutic intervention. Recent studies in knockout mice, however, point to the alternative possibility that deficiencies in calcium-regulatory proteins may represent important pathomechanisms leading to extraosseous calcifications. alpha 2-Heremans Schmid glycoprotein (Ahsg/fetuin) and matrix Gla protein (MGP) are strong inhibitors of calcification in vivo. Novel evidence that deficiencies of such proteins may be involved in the pathogenesis of cardiovascular calcifications in dialysis patients will be discussed.     

Albumin is the major plasma protein target of oxidant stress in uremia.

BACKGROUND: Patients with uremia are exposed to increased oxidative stress. Examination of the oxidation of individual plasma proteins may be useful in establishing specific pathways of oxidative stress in vivo and in determining functional consequences of oxidant stress exposure. We therefore examined oxidative modification of plasma proteins by carbonyl formation using Western blot immunoassay and enzyme-linked immunosorbent assay (ELISA) techniques in patients with chronic renal failure (CRF) and on chronic hemodialysis therapy (HD). METHODS: Plasma was obtained from 25 HD, 20 CRF, and 20 healthy volunteers, derivatized with 2,4 dinitrophenylhydrazine (DNP) and electrophoresed on duplicate 4 to 12% gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gels, transferred to nitrocellulose, and stained for DNP for carbonyls and amido black for protein content. Data are recorded as DNP area/protein area and are reported in densitometry units. Total plasma carbonyls were determined by ELISA. RESULTS: Plasma albumin is substantially more oxidized in HD than in healthy volunteers (1.22 +/- 0.14 densitometry units vs. 0.60 +/- 0.08, P = 0.002). There were no significant differences in oxidation of plasma transferrin, immunoglobulin, and fibrinogen in HD versus healthy volunteers. In CRF patients, plasma albumin is more oxidized compared with normal volunteers (1.36 +/- 0.20 densitometry units vs. 0.94 + 0.08, P = 0.09). There were no differences in oxidation of plasma transferrin, fibrinogen, and immunoglobulin in CRF patients versus healthy volunteers. An increased plasma protein carbonyl concentration in CRF patients compared with healthy volunteers was confirmed by ELISA (0.31 +/- 0.07 vs. 0.04 +/- 0.01 nmol/mg protein (P = 0.001). CONCLUSION: Albumin is the major plasma protein target of oxidant stress in CRF and HD patients.     

Arteriosclerosis, vascular calcifications and cardiovascular disease in uremia

PURPOSE OF REVIEW: Arterial calcification in chronic kidney disease (CKD) is associated with increased cardiovascular risk. The mechanisms responsible for arterial calcification include alterations of mineral metabolism and expression of mineral-regulating proteins. RECENT FINDINGS: Arterial calcification is similar to bone formation, involving differentiation of vascular smooth muscle cells (VSMCs) into phenotypically distinct osteoblast-like cells. Elevated phosphate and/or calcium trigger a concentration-dependent increase of calcium precipitates in VSMC in vitro. The calcification is initiated by VSMC release of membrane-bound matrix vesicles and formation of apoptotic bodies. The presence of serum prevents these changes, indicating the presence of calcification inhibitors. Arterial calcification occurs in two sites: the tunica intima and tunica media. Intimal calcification is a marker of atherosclerotic disease and is associated with arterial stenotic lesions. Medial calcification influences outcome by promoting arterial stiffening whose principal consequences are left-ventricular hypertrophy and altered coronary perfusion. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in CKD patients. Age, duration of dialysis, smoking and diabetes are risk factors for the development of arterial calcification in end-stage renal disease. Oversuppression of parathyroid hormone and low bone turnover potentiate the development of arterial calcification. SUMMARY: Arterial disease in CKD patients is characterized by extensive calcification. Evidence has accumulated pointing to the active and regulated nature of the calcification process. Elevated phosphate and calcium may stimulate sodium-dependent phosphate cotransport involving osteoblast-like changes in cellular gene expression. Arterial calcification is responsible for stiffening of the arteries with increased left-ventricular afterload and abnormal coronary perfusion as the principal clinical consequences.     

Hyperhomocysteinemia and cardiovascular disease in uremia: the newest evidence in epidemiology and mechanisms of action

In the general population, hyperhomocysteinemia is an independent risk factor for cardiovascular disease (ischemic disease, such as stroke and myocardial infarction, and arterial and venous thrombosis). We can presume that the association is causal, based on the example of homocystinuria, and on the evidence put forward by several basic science and epidemiologic studies. However, the results of large intervention trials, which may grant further support to this hypothesis, are not yet available. In chronic renal failure and in uremia, the evidence that is offered by carefully performed prospective studies also indicate the presence of an association, although some studies suggest reverse epidemiology. The mechanisms underlying the association, and able to explain the several toxic effects of homocysteine, related or not to cardiovascular disease, are unclear. Oxidation, nitrosylation, and hypomethylation are among the postulated mechanisms. In uremia, protein hypomethylation interferes with protein repair; DNA hypomethylation impairs regulation of gene expression, whereas folate treatment reverts such alterations. Acylation, another structural modification able to impair protein function, is a possible mediator of homocysteine toxicity.     

Metabolic stress and altered glucose transport: activation of AMP-activated protein kinase as a unifying coupling mechanism

5'AMP-activated protein kinase (AMPK) can be activated in response to cellular fuel depletion and leads to switching off ATP-consuming pathways and switching on ATP-regenerating pathways in many cell types. We have hypothesized that AMPK is a central mediator of insulin-independent glucose transport, which enables fuel-depleted muscle cells to take up glucose for ATP regeneration under conditions of metabolic stress. To test this hypothesis, rat epitrochlearis muscles were isolated and incubated in vitro under several conditions that evoke metabolic stress accompanied by intracellular fuel depletion. Rates of glucose transport in the isolated muscles were increased by all of these conditions, including contraction (5-fold above basal), hypoxia (8-fold), 2,4-dinotrophenol (11-fold), rotenone (7-fold), and hyperosmolarity (8-fold). All of these stimuli simultaneously increased both alpha1 and alpha2 isoform-specific AMPK activity. There was close correlation between alpha1 (r2 = 0.72) and alpha2 (r2 = 0.67) AMPK activities and the rate of glucose transport, irrespective of the metabolic stress used, all of which compromised muscle fuel status as judged by ATP, phosphocreatine, and glycogen content. 5-Aminoimidazole-4-carboxamide ribonucleoside, a pharmacological AMPK activator that is metabolized to an AMP-mimetic ZMP, also increased both glucose transport and AMPK activity but did not change fuel status. Insulin stimulated glucose transport by 6.5-fold above basal but did not affect AMPK activity. These results suggest that the activation of AMPK may be a common mechanism leading to insulin-independent glucose transport in skeletal muscle under conditions of metabolic stress.     

Arteriosclerosis, calcium phosphate deposition and cardiovascular disease in uremia: current concepts at the bench

PURPOSE OF REVIEW: Cardiovascular disease is the leading cause of death in patients with chronic kidney disease. A growing body of data points to nontraditional risk factors, including disturbances in mineral metabolism, as important determinants of the extremely high cardiovascular morbidity and mortality rates in these patients. Disturbances in mineral metabolism, especially elevated calcium and phosphate levels, have been linked to vascular and valvular calcification, both of which are associated with poor prognosis in chronic kidney disease patients. This review highlights important recent findings regarding the etiology of vascular calcification, with special emphasis on pathways that may be particularly relevant in chronic kidney disease patients. RECENT FINDINGS: New studies indicate that not only vascular intimal calcification (associated with atherosclerosis) but also vascular medial calcification are correlated with decreased survival in chronic kidney disease patients. With the relatively recent recognition of vascular calcification as an actively regulated process, a growing list of inducers (calcium, phosphate, inflammatory cytokines) and inhibitors (matrix Gla protein, fetuin, pyrophosphate, osteopontin) have been discovered. Interesting recent evidence suggests that they may contribute to the prevalence of this pathology in chronic kidney disease patients. SUMMARY: Vascular calcification is associated with decreased survival in chronic kidney disease patients. Understanding the causes and regulatory factors controlling vascular calcification will help refine therapeutic modalities currently in use, as well as develop novel therapeutics to abate and potentially reverse this deleterious process.     

Touraine Solente Gole syndrome: The elephant skin disease

Touraine Solente Gole syndrome is a rare hereditary syndrome of primary pachydermoperiostosis, with the characteristic triad of pachydermia (or elephant like skin), periostosis and acropachia. A 27-year-old patient presented with aesthetic deformity of forehead due to deep skin folds and coarsening of facial features due to progressive thickening of skin. Associated palmoplantar hyperkeratosis with broadened of finger and toe tips and digital clubbing were noticed. Dermatologic evaluation revealed cutis verticis gyrata of scalp, seborrhoeic hyperplasia of face and hyperhidrosis. Natural history of the disease and aetiopathogenesis were reviewed. Aesthetic correction of forehead through frontal rhytidectomy was attempted.KEY WORDS: Clubbing, cutis verticis gyrata, frontal rhytidectomy, hypertrophic osteoarthropathy, pachyderma, periostosis     

The changing concept of cardiovascular reactivity

Cardiovascular reactivity has long been measured in laboratory responses to a wide variety of cognitive and physical stressors, with the hypothesis that exaggerated reactivity plays a pathogenetic role in the development of essential hypertension. However there are few data to support the belief that behavioural differences of cognitive perception of stressors account for observed differences of reactivity. Cardiovascular reactivity in the laboratory does not predict hypertension or account for differences of blood pressure variability in the natural environment. Hypertensives do not exhibit increased blood pressure variability. Antihypertensive therapy consistently fails to lower cardiovascular reactivity in either the laboratory or natural milieu, supporting the dual and largely independent regulation of the basal and reactive blood pressures. It is concluded that there is little support for the use of laboratory stress testing to delineate either the pathogenesis of hypertension, the evaluation of hypertensive subjects, or the efficacy of antihypertensive therapy.     

Erectile dysfunction as a predictor of cardiovascular disease

Although it has been recognized that erectile dysfunction (ED) and coronary artery disease share many of the same risk factors--smoking, dyslipidemia, diabetes and hypertension--just in the past few years several new studies now suggest that ED is an important early marker of the presence of coronary artery disease. Recent analyses suggest that ED symptoms occur prior to coronary artery disease symptoms and may be a predictor of future major cardiovascular events. Some of these new studies also suggest that ED is an independent risk factor for predicting cardiovascular events--that is independent of other well-established risk factors. Taken together, these new studies suggest that when a patient presents with ED, the patient should be questioned about cardiac health and cardiovascular risk factors. If cardiovascular risk factors are identified, they should be worked up and aggressively treated--as treatment of these risk factors may be life-saving.