Dalila B. Corry

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 μmol uric acid for 48 h. Results Uric acid (200 and 300 μmol) 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.

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.

Efficacy and safety of sitagliptin in patients with type 2 diabetes and ESRD receiving dialysis: a 54-week randomized trial.

BACKGROUND Treatment with oral antihyperglycemic agents has not been well characterized in patients with type 2 diabetes and end-stage renal disease (ESRD). The efficacy and safety of sitagliptin and glipizide monotherapy in patients with type 2 diabetes and ESRD on dialysis therapy were assessed in this study. STUDY DESIGN 54-week, randomized, double-blind, parallel-arm study. SETTING & PARTICIPANTS From 31 clinical sites in 12 countries, 129 patients 30 years or older with type 2 diabetes and ESRD who were on dialysis therapy and had a hemoglobin A1c (HbA1c) level of 7%-9% were randomly assigned 1:1 to treatment. INTERVENTION Monotherapy with sitagliptin, 25 mg daily or glipizide (initiated with 2.5 mg daily and titrated up to a potential maximum dose of 10 mg twice daily or down to avoid hypoglycemia). OUTCOMES Primary end points were 54-week change in HbA1c level from baseline and tolerability with sitagliptin. A secondary end point was the comparison of sitagliptin versus glipizide on the incidence of symptomatic hypoglycemia. RESULTS Of 129 patients randomly assigned, 64 were in the sitagliptin group (mean baseline age, 61 years; HbA1c, 7.9%) and 65 were in the glipizide group (mean baseline age, 59 years; HbA1c, 7.8%). After 54 weeks, the least squares mean change from baseline in HbA1c level was -0.72% (95% CI, -0.95% to -0.48%) with sitagliptin and -0.87% (95% CI, -1.11% to -0.63%) with glipizide, for a difference of 0.15% (95% CI, -0.18% to 0.49%). The incidences of symptomatic hypoglycemia and severe hypoglycemia were 6.3% versus 10.8% (between-group difference, -4.8% [95% CI, -15.7% to 5.6%]) and 0% versus 7.7% (between-group difference, -7.8% [95% CI, -17.1% to -1.9%]) in the sitagliptin and glipizide groups, respectively. Higher incidences (ie, 95% CI around between-treatment difference excluded 0) of cellulitis and headache were found with sitagliptin compared to glipizide (6.3% vs 0%, respectively, for both). LIMITATIONS Small sample size limits between-group comparisons. CONCLUSIONS Treatment with sitagliptin or glipizide monotherapy was effective and well tolerated over 54 weeks in patients with type 2 diabetes and ESRD who were receiving dialysis.

Agreement between Central Venous and Arterial Blood Gas Measurements in the Intensive Care Unit

BACKGROUND AND OBJECTIVES Venous blood gas (VBG) analysis is a safer procedure than arterial blood gas (ABG) analysis and may be an alternative for determining acid-base status. The objective of this study was to examine the agreement between ABG and central VBG samples for all commonly used parameters in a medical intensive care unit (ICU) population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We performed a single-center, prospective trial to assess the agreement between arterial and central VBG measurements in a medical ICU. Adult patients who were admitted to the ICU and required both a central venous line and an arterial line were enrolled. When an ABG was performed, a central venous sample was obtained to examine the agreement among the pH, Pco(2), and bicarbonate. Data comparing central and peripheral VBG values were also obtained. RESULTS The mean arterial minus venous difference for pH, Pco(2), and bicarbonate was 0.027, -3.8, and -0.80, respectively. Bland-Altman plots for agreement of pH, Pco(2), and bicarbonate showed 95% limits of agreement of -0.028 to 0.081, -12.3 to 4.8, and -4.0 to 2.4, respectively. Regression equations were derived to predict arterial values from venous values as follows: Arterial pH = -0.307 + 1.05 x venous pH, arterial Pco(2) = 0.805 + 0.936 x venous Pco(2), and arterial bicarbonate = 0.513 + 0.945 x venous bicarbonate. The mean central minus peripheral differences for pH, Pco(2), and bicarbonate were not clinically important. CONCLUSIONS Peripheral or central venous pH, Pco(2), and bicarbonate can replace their arterial equivalents in many clinical contexts encountered in the ICU.

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.

Selective aspects of the insulin resistance syndrome.

There is increasing recognition of new features in the insulin resistance syndrome and its association with new disease states or treatment modalities. Recent additions to the list of features in the insulin resistance syndrome include elevated non-esterified fatty acids, abnormalities in visceral fat metabolism, elevated uric acid, elevated hematocrit, endothelial dysfunction, abnormalities in glucocorticoids, and differences in the phenotypic expression of the syndrome between men and women. A critical factor that may be inherent in the syndrome is the distribution and metabolism of visceral fat. This finding is also accompanied by the recognition of the role of non-esterified fatty acids as a cause of many of the risk factors in the insulin resistance syndrome. Elevated non-esterified fatty acids contribute to hypertension, glucose intolerance and increased arteriosclerosis. Elevated cortisol levels and disrupted metabolism, as well as abnormalities in the hypothalamic-pituitary-adrenal axis are seen in the insulin resistance syndrome. In women, adipose cells express fewer glucocorticoid receptors and less of the enzyme that metabolizes cortisol, 11β-hydroxysteroid dehydrogenase. Several inflammatory factors such as tumor necrosis factor-α may be an etiologic link in the risk found in the insulin resistance syndrome. Certain cases of the syndrome appear to be related to specific drug therapies (steroids, immunosuppressive agents and antiretroviral agents), as seen in transplant patients and HIV-infected individuals.

1,25-Dihydroxyvitamin D3 Stimulates Calcium and Phosphate Absorption by Different Mechanisms: Contrasting Requirements for Sodium

Previous studies from our laboratory have demonstrated that 1,25-dihydroxyvitamin D3 (1,25D) stimulates separate calcium (Ca) and inorganic phosphate (P) absorptive mechanisms in rat intestine (1,2). The proportion of Ca to P “pumps” varies in different regions of the intestine. Thus, there is a preponderance of Ca pumps in the duodenum, a preponderance of P pumps in the jejunum and an equal distribution of Ca and P pumps in the ileum (3). Interestingly, the colon has only 1,25D-responsive Ca pumps (2). The active Ca absorptive mechanisms in duodenum, ileum and colon appear to share certain characteristics, all exhibiting a Km of approximately 1 mM (2,3). The expression of this 1,25D-induced Ca absorption in colon does not appear to require the presence of extracellular sodium ions (4). In the present study we examined the sodium (Na) requirement of 1,25D-stimulated P transport processes in rat jejunum.

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.

Delayed clearance of hepatitis B surface antigen and development of hepatitis B surface antibody in a chronic hemodialysis patient

The introduction of hepatitis B vaccination and infection control in 1977 has greatly decreased the prevalence of hepatitis B. Currently, approximately 2.8% of the end-stage renal disease population is hepatitis B positive with a presence in 27.7% of the USA hemodialysis (HD) units according to the Dialysis Outcomes and Practice Patterns Study data. The behavior of hepatitis B infection differs significantly between immunocompetent and immunosuppressed hosts. Immunosuppressed hosts present more subtly with complications of chronic hepatitis B infection, being more challenging to detect. It is also well known that patients with chronic infection on HD have a small chance of clearing the virus. We report here a case of a hepatitis B positive HD patient who underwent spontaneous delayed serological clearance of hepatitis B surface antigen and development of immunity via appearance of hepatitis B surface antibody. This is a rare occurrence, and the few similar reported cases will be discussed.

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.