Multiple sites of calciphylaxis in a patient with chronic renal failure.

Calciphylaxis has seldom been reported in patients with acute renal failure or in pre-dialysis patients. It also has been reported at lower calcium phosphorous products and in patients with adynamic bone disease. We report a pre-hemodialysis (HD) patient with acute renal failure and biopsy-proven calciphylaxis involving multiple cutaneous sites with calcification of the perineal area resulting in dry gangrene of the penis that necessitated a partial penectomy. The patient had elevated serum calcium, phosphorous and parathyroid hormone level of 612 pg/mL. The same patient suffered subsequently from a calcium embolus that occluded his left ophthalmic artery and resulted in left eye blindness. Calciphylaxis is a devastating phenomenon and physicians should have a high clinical suspicion for it in HD patients as well as in patients with late stages of chronic kidney disease.

Cinacalcet HCl and concurrent low-dose vitamin D improves treatment of secondary hyperparathyroidism in dialysis patients compared with vitamin D alone: the ACHIEVE study results.

BACKGROUND AND OBJECTIVES: Patients with chronic kidney disease (CKD) receiving dialysis often develop secondary hyperparathyroidism with disturbed calcium and phosphorus metabolism. The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (KDOQI) was established to guide treatment practices for these disorders. The ACHIEVE study was designed to test two treatment strategies for achieving KDOQI goals. DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: Individuals on hemodialysis treated with vitamin D sterols were enrolled in this 33-week study. Subjects were randomly assigned to treatment with either cinacalcet and low-dose vitamin D (Cinacalcet-D) or flexible vitamin D alone (Flex-D) to achieve KDOQI-recommended bone mineral targets. ACHIEVE included a 6-week screening phase, including vitamin D washout, a 16-week dose-titration phase, and an 11-week assessment phase. RESULTS: Of 173 subjects enrolled, 83% of Cinacalcet-D and 67% of Flex-D subjects completed the study. A greater proportion of Cinacalcet-D versus Flex-D subjects had a >30% reduction in parathyroid hormone (PTH) (68% versus 36%, P < 0.001) as well as PTH <300 pg/ml (44% versus 23%, P = 0.006). The proportion of subjects simultaneously achieving targets for intact PTH (150-300 pg/ml) and calcium-phosphorus product (Ca x P) (<55 mg2/dl2) was also greater (21% versus 14%), but this was not statistically significant. This was attributable to 19% of Cinacalcet-D subjects with a PTH value below the KDOQI target range. CONCLUSIONS: Achievement of KDOQI targets was difficult, especially with Flex-D. Maintaining calcium and phosphorus target values precluded the use of vitamin D doses necessary to lower PTH to within the narrow target range and highlighted limitations inherent to the KDOQI treatment algorithm.

Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system.

BACKGROUND: Plasma uric acid has been associated with hypertension in a variety of disorders, and has been shown to be predictive of hypertension. The mechanistic role of uric acid in the development of hypertension is not known however. METHOD: We tested the hypothesis that uric acid stimulates vascular smooth muscle cell (VSMC) proliferation and oxidative stress by stimulating the vascular renin-angiotensin system (RAS). Rat VSMC were exposed to 0-300 micromol uric acid for 48 h. RESULTS: Uric acid (200 and 300 micromol) stimulated the proliferation of VSMC as measured by thymidine uptake. This effect was prevented by 10(-6) mol losartan or by 10(-6) mol captopril. Incubation of VSMC with uric acid for 48 h also increased angiotensinogen messenger RNA expression and intracellular concentrations of angiotensin II. These responses were also inhibited by losartan and captopril. Increased expression of angiotensinogen mRNA was also inhibited by co-incubation with PD 98059, a mitogen-activated protein (MAP) kinase inhibitor. Uric acid stimulated the production of hydrogen peroxide and 8-isoprostane in VSMC. These increases in oxidative stress indicators were significantly reduced by co-incubating the cells with captopril or losartan. Uric acid also decreased nitrite and nitrate concentrations in the culture medium, an effect that was prevented by losartan and captopril. CONCLUSION: These results demonstrate that uric acid stimulates proliferation, angiotensin II production, and oxidative stress in VSMC through tissue RAS. This suggests that uric acid causes cardiovascular disorders by stimulating the vascular RAS, and this stimulation may be mediated by the MAP kinase pathway.

Uric acid and the vasculature.

Hyperuricemia is a frequent finding in diseases in which the clinical manifestations are thought to be secondary to a state of generalized vascular endothelial dysfunction and related to the cardiovascular disease present in conditions associated with the metabolic syndrome, such as hypertension or diabetes. Traditionally, uric acid has not been given an active role in the pathologic process underlying these conditions. However, there is now a growing body of experimental and clinical evidence that points to a mechanistic role for uric acid in cardiovascular disease. The mechanisms that are most often thought to link uric acid and endothelial dysfunction involve inflammation and generation of oxidative stress in the vasculature. These observations allowed new clinical applications and formulations of therapies, such as the introduction of xanthine oxidase inhibitors in the management of congestive heart failure.

Insulin stimulates endogenous angiotensin II production via a mitogen-activated protein kinase pathway in vascular smooth muscle cells.

OBJECTIVE: The present study was designed to determine the effects of insulin on cytosolic angiotensin II production and proliferation in cultured rat vascular smooth muscle cells. DESIGN AND METHODS: Vascular smooth muscle cells were incubated with insulin for 48 h. Cytosolic angiotensin I and II were determined by radioimmunoassays of purified cell homogenates. Angiotensin II was also detected by immunohistochemistry of intact cells. Cell proliferation was determined by pulse labeling with radiolabeled thymidine. Angiotensinogen mRNA expression was determined by slot-blot analysis. RESULTS: Insulin significantly increased cytosolic angiotensin II concentration in vascular smooth muscle cells. Lisinopril, omapatrilat and irbesartan inhibited this increase of angiotensin II, but had no effect on angiotensin I levels. Immunohistochemical staining confirmed the presence of angiotensin II in control and insulin-treated vascular smooth muscle cells. Insulin increased cell proliferation, and addition of lisinopril, omapatrilat or irbesartan inhibited this effect. Insulin also increased expression of angiotensinogen mRNA in cultured vascular smooth muscle cells, but PD98059, a mitogen-activated protein kinase inhibitor, prevented the rise in angiotensinogen expression. CONCLUSION: These results support the concept that insulin stimulates angiotensin II production in cultured vascular smooth muscle cells through a mitogen-activated, protein kinase-dependent pathway that might be a factor in the progression of atherosclerosis. Agents that block the renin-angiotensin system have direct protective effects, reducing vascular angiotensin II and growth of vascular smooth muscle cells and are thus of cardiovascular benefit.

The effect of aldosterone on glucose metabolism.

There is an association of glucose intolerance and diabetes with primary aldosteronism, but the frequency and mechanisms are not clear. This paper reviews the possible mechanisms of impaired glucose metabolism in primary aldosteronism. Patients with primary aldosteronism can have impaired pancreatic insulin release and reduction in insulin sensitivity. These effects may be due to hypokalemia, but the evidence suggests other factors such as a direct impact of excess aldosterone on insulin action in contributing to the metabolic dysfunction. In general adrenal surgery in cases of aldosterone-producing adenoma will correct the metabolic abnormalities, but it is less sure if treatment with spironolactone in cases of idiopathic hyperplasia will correct impaired glucose tolerance.

Decreased erythrocyte insulin binding in hypertensive subjects with hyperinsulinemia.

BACKGROUND: This study investigates erythrocyte insulin receptor binding and affinity in subjects with hypertension and hyperinsulinemia. Insulin receptor-binding function has not been extensively studied in hypertensive subjects. METHODS: Insulin receptor density, binding affinity, and protein tyrosine kinase activity were measured in erythrocytes from 18 hypertensive and 16 normotensive subjects. Insulin sensitivity was measured by the fasting plasma insulin/glucose ratio and the homeostatic assessment model algorithm (HOMA) index. Erythrocyte insulin binding was determined by a competitive binding assay and protein tyrosine kinase activity was measured by an enzyme-linked immunoabsorbent assay technique. RESULTS: Fasting plasma insulin/glucose ratio and the insulin resistance index (HOMA) were significantly higher in the hypertensive versus normotensive subjects. Receptor saturation of the high affinity binding sites (Bmax) was reduced in the hypertensive versus control subjects. The Kd values were lower in the erythrocytes from hypertensive than control subjects. Insulin-induced protein tyrosine kinase activity was decreased in erythrocytes from hypertensive versus control subjects. CONCLUSIONS: A reduced erythrocyte insulin receptor density and tyrosine protein kinase activity may reflect insulin receptor dysfunction in hypertensive individuals who have insulin resistance and hyperinsulinemia. More information is needed examining insulin receptor function in other target tissues such as fat or skeletal muscle cells before defects in the insulin receptor can be firmly proposed as a cause of the metabolic syndrome.