allopurinol and Hypertension--Renal

Numerous experimental and clinical studies suggest that uric acid might have pathobiologic implications in the development and progression of hypertension, kidney disease, and coronary heart disease, among others, resulting in renewed interest in uric acid as a potential pathogenic mediator in these clinical conditions. Despite encouraging animal studies showing beneficial roles of allopurinol, clinical studies and randomized controlled trials remain scarce, and, despite available clinical evidence supporting a therapeutic role for allopurinol, multiple issues remain before routine use of allopurinol can be recommended for use in patients with hyperuricemia and hypertension, kidney disease, or coronary heart disease. These include a need for more robust clinical trial data that evaluate efficacy on hard clinical outcomes, optimal dose, duration of treatment, and the potential for serious allergic reactions. In this article we review the current available evidence describing the effects of allopurinol in hypertension, kidney disease, and coronary heart disease, highlighting unresolved issues surrounding allopurinol use for uric acid lowering in individuals without gout.

Topics: Allopurinol; Antihypertensive Agents; Cardiotonic Agents; Chronic Disease; Coronary Disease; Gout Suppressants; Humans; Hypertension, Renal; Randomized Controlled Trials as Topic; Uric Acid

The relationship between hypertension and chronic kidney disease (CKD) has long been the subject of controversy. The pathogenetic mechanisms of nephropathy in non-diabetic individuals with hypertension, as well as optimal hypertension treatment targets in populations with nephropathy remain important clinical concerns. This manuscript reviews breakthroughs in molecular genetics that have clarified the complex relationship between hypertension and kidney disease, answering the question of which factor comes first. An overview of the potential roles that hyperuricemia plays in the pathogenesis of hypertension and CKD and current blood pressure treatment guidelines in populations with CKD are discussed. The ongoing National Institutes of Health-sponsored Systolic Blood Pressure Intervention Trial (SPRINT) is underway to help answer these important questions. Enrollment of 9250 hypertensive SPRINT participants will be completed in 2013; important results on ideal blood pressure control targets for reducing nephropathy progression, cardiovascular disease end-points, and preserving cognitive function are expected. As such, many of the controversial aspects of hypertension management will likely be clarified in the near future.

Topics: Allopurinol; Animals; Antihypertensive Agents; Apolipoprotein L1; Apolipoproteins; Black People; Causality; Chronic Disease; Diabetic Angiopathies; Diabetic Nephropathies; Disease Management; Disease Models, Animal; Genetic Predisposition to Disease; Glomerulosclerosis, Focal Segmental; Goals; Humans; Hypertension; Hypertension, Renal; Hyperuricemia; Kidney Diseases; Lipoproteins, HDL; Multicenter Studies as Topic; Polymorphism, Genetic; Randomized Controlled Trials as Topic; Rats

Topics: Acidosis; Acute Kidney Injury; Allopurinol; Aluminum Hydroxide; Burkitt Lymphoma; Child; Humans; Hypercalcemia; Hyperlipidemias; Hypertension, Renal; Hypoglycemia; Lymphoma; Male; Mannitol; Metabolic Diseases; Phosphorus Metabolism Disorders; Uric Acid; Xanthines

Topics: Adrenal Cortex Hormones; Adult; Allopurinol; Autoimmune Diseases; Azathioprine; Bone Diseases; Diabetes Mellitus; Drug Synergism; Duodenal Ulcer; Embolism, Fat; Glomerulonephritis; Histocompatibility; Humans; Hypertension, Renal; Immunosuppressive Agents; Infections; Kidney Glomerulus; Kidney Transplantation; Malabsorption Syndromes; Male; Mercaptopurine; Neoplasm Transplantation; Neoplasms; Obesity; Osteoporosis; Pancreatitis; Peptic Ulcer Hemorrhage; Phenylbutazone; Postoperative Complications; Proteinuria; Transplantation, Homologous

The aim of this study was to observe the effects of uric acid lowering therapy (UALT), febuxostat and allopurinol, on blood pressure (BP) and serum creatinine level. Post-hoc data were derived from a phase-III, randomised, double-blind, 4-week trial of male gouty patients that compared the safety and efficacy of febuxostat and allopurinol in adults with gout. The subjects were randomly assigned to one of five groups, 35-37 in each group (febuxostat: 40, 80, 120 mg/d; allopurinol: 300 mg/d; control group: placebo). Blood pressure and serum creatinine level were measured at baseline and at weeks 2 and 4. Diastolic BP and creatinine level had decreased significantly in the UALT groups compared to the control group at week 4. Diastolic BP had decreased significantly in the allopurinol group and serum creatinine level had decreased significantly in the febuxostat groups at week 4. After adjusting for confounding variables, serum uric acid changes were found to be significantly correlated with changes in serum creatinine level but were not associated with changes in systolic or diastolic BP. UALT in gouty subjects significantly decreased diastolic BP and serum creatinine level. Changes in uric acid were significantly correlated with those in serum creatinine level, suggesting the feasibility of renal function improvement through UALT in gouty men.

Topics: Allopurinol; Biomarkers; Blood Pressure; Creatinine; Dose-Response Relationship, Drug; Febuxostat; Gout; Gout Suppressants; Humans; Hypertension, Renal; Male; Middle Aged; Reproducibility of Results; Sensitivity and Specificity; Thiazoles; Treatment Outcome

The present study aimed to clarify the beneficial effect of allopurinol on cardiovascular morbidity and mortality in a cohort of hypertensive nephropathy patients with impaired kidney function.. One hundred and seventy-eight patients diagnosed with hypertensive nephropathy and presenting with impaired kidney function (estimated glomerular filtration rate <45 mL/min/1.73 m(2)) were recruited from nephrology clinics. Oral allopurinol was prescribed in 67 of these patients. The effects of allopurinol use on the development of cardiovascular disease (i.e. ischemic heart disease, congestive heart failure, and stroke) and all-cause death was analyzed using the Cox proportional hazard model.. During the follow-up of 18.4 months (mean), 28 primary events occurred. Basal use of allopurinol was a significant beneficial factor (hazard ratio = 0.342, p = 0.0434, standard error = 0.53058) after adjusting for confounding factors.. The use of allopurinol in hypertensive subjects with impaired kidney function appears to be beneficial in preventing cardiovascular morbidity and all-cause mortality, indicating that this xanthine oxidase inhibitor protects the vascular system, at least in this specific group.

Topics: Aged; Allopurinol; Cardiovascular Diseases; Disease-Free Survival; Female; Humans; Hypertension, Renal; Incidence; Japan; Male; Middle Aged; Nephritis

Oxidative stress is considered a central pathophysiological event in cardiovascular disease, including hypertension. Early age reduction in renal mass is associated with hypertension and oxidative stress in later life, which is aggravated by increased salt intake. The aim of the present study was to examine if renal sympathetic denervation can exert blood pressure lowering effects in uninephrectomized (UNX) rats (3-week old) fed with high salt (HS, 4%; w/w) diet for 4 weeks. Moreover, we investigated if renal denervation is associated with changes in NADPH and xanthine oxidase-derived reactive oxygen species. Rats with UNX + HS had reduced renal function, elevated systolic and diastolic arterial pressures, which was accompanied by increased heart weight, and cardiac superoxide production compared to sham operated Controls. UNX + HS was also associated with higher expression and activity of NADPH and xanthine oxidase in the kidney. Renal denervation in rats with UNX + HS attenuated the development of hypertension and cardiac hypertrophy, but also improved glomerular filtration rate and reduced proteinuria. Mechanistically, renal denervation was associated with lower expression and activity of both NADPH oxidase and xanthine oxidase in the kidney, but also reduced superoxide production in the heart. In conclusion, our study shows for the first time that renal denervation has anti-hypertensive, cardio- and reno-protective effects in the UNX + HS model, which can be associated with decreased NADPH oxidase- and xanthine oxidase-derived reactive oxygen species (i.e., superoxide and hydrogen peroxide) in the kidney.

Topics: Animals; Blood Pressure; Cardiomegaly; Denervation; Glomerular Filtration Rate; Heart; Hypertension, Renal; Kidney; Myocardium; NADP; Rats; Reactive Oxygen Species; Xanthine Oxidase

Experimentally-induced hyperuricaemia [due to inhibition of uricase with oxonic acid (OA)] in rats causes hypertension and renal alterations which can be prevented by lowering uric acid (UA) with allopurinol. Febuxostat (Fx), an investigational, nonpurine and selective xanthine oxidase inhibitor, is a more effective UA-lowering agent than allopurinol. We therefore tested the hypothesis that Fx might be useful in treating hyperuricemia-induced hypertension and renal damage.. Four groups of male rats were studied: OA (750 mg/kg by daily gavage) was given for 8 weeks and Fx (5-6 mg/kg/day in drinking water; OA+Fx: n = 10) or placebo (OA+P: n = 11) were administered for 4 weeks beginning at 4 weeks after initiation of the study. Two groups of normal (N) rats were studied as controls (N+P and N+Fx: n = 10/group). Systolic blood pressure (SBP) and fasting plasma UA were measured in all animals at baseline and at 4 and 8 weeks. Glomerular haemodynamics by micropuncture techniques were determined at 8 weeks followed by histological evaluation of glomerular and afferent arteriole morphologies.. In OA-induced hyperuricaemic rats, Fx lowered UA and ameliorated systemic and glomerular hypertension as well as mesangial matrix expansion and the development of preglomerular arteriolar disease as indicated by a reduction of the arteriolar area and media-to-lumen ratio. In normal rats, Fx tended to lower UA and had no effect on blood pressure, renal hemodynamics and afferent arteriole morphology.. These results suggest that Fx merits further evaluation for the treatment of hypertension and renal alterations induced by hyperuricaemia.

Topics: Animals; Blood Pressure; Febuxostat; Follow-Up Studies; Gout Suppressants; Hypertension, Renal; Hyperuricemia; Kidney Glomerulus; Male; Oxonic Acid; Rats; Rats, Sprague-Dawley; Renal Circulation; Thiazoles; Uric Acid; Xanthine Oxidase

Hyperuricaemia and reactive oxygen species have recently been associated with essential hypertension. Xanthine oxidoreductase (XOR) produces urate and, in its oxidase isoform, reactive oxygen species also. Our previous studies indicated that hypertension-prone rat strains have greater renal XOR activity than their normotensive counterparts, and that dietary sodium modifies renal XOR activity.. To clarify whether renal XOR induction precedes or follows the development of hypertension.. Five-week-old spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were kept for 3-8 weeks on low sodium (0.3% salt w/w) or high sodium (6.0% salt w/w) intakes, with or without allopurinol, an inhibitor of XOR, to study the possible pathogenetic role of XOR in hypertension. Systolic blood pressure (SBP), renal XOR activity and mRNA expression were measured.. Regardless of sodium intake, renal XOR activity increased twofold during growth in SHRs, but not in WKY rats. SBP increased from 122 +/- 4 to 241 +/- 13 mmHg in SHRs kept on the high-sodium diet and to 204 +/- 11 mmHg in those on the low-sodium diet. At the end of the experiment, renal XOR activity correlated with SBP in SHRs. Allopurinol prevented hypertension-induced left ventricular and renal hypertrophy in SHRs, but had negligible effect on blood pressure.. Renal XOR induction in SHRs does not precede the development of hypertension, but progress concomitantly with an increase in SBP. The results indicate a role for locally synthesized XOR in the development of hypertension-associated end-organ damage, but no major role in the development of hypertension.

Topics: Allopurinol; Animals; Enzyme Inhibitors; Hypertension, Renal; Hypertrophy, Left Ventricular; Kidney; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium Chloride, Dietary; Xanthine Dehydrogenase; Xanthine Oxidase

Chronic renal failure (CRF) is associated with oxidative stress, the mechanism of which remains uncertain. Superoxide is the primary oxygen free radical produced in the body, NAD(P)H oxidase is the major source of superoxide production and superoxide dismutase (SOD) is responsible for removal of superoxide. We hypothesized that CRF-induced oxidative stress may be due to increased production and/or decreased dismutation of superoxide.. Immunodetectable superoxide dismutase isoforms (Cu Zn SOD and Mn SOD), as well as, NAD(P)H oxidase (gp91 phox subunit) proteins and xanthine oxidase (XO) activity were determined in the kidney and liver of CRF (5/6 nephrectomized) and sham-operated control rats. Subgroups of animals were treated with SOD-mimetic drug, tempol and blood pressure and urinary nitric oxide metabolites (NOx) were monitored.. The CRF group showed marked down-regulations of CuZn SOD and Mn SOD and significant up-regulation of gp91 phox in the liver and kidney, which are among the metabolically most active tissues. In contrast, XO activity was depressed in both tissues. Arterial pressure and nitrotyrosine abundance were elevated while urinary NOx excretion was depressed, pointing to increased NO inactivation by superoxide and decreased NO availability in CRF animals. Administration of SOD-mimetic agent, tempol, for one week, ameliorated hypertension, reduced nitrotyrosine abundance and increased urinary NOx excretion in the CRF animals.. CRF is associated with depressed SOD and elevated NAD(P)H oxidase expression, which can contribute to oxidative stress by increasing superoxide. This is evidenced by favorable response to administration of SOD-mimetic drug, tempol, and increased nitrotyrosine that is the footprint of NO interaction with superoxide.

Topics: Animals; Antioxidants; Cyclic N-Oxides; Down-Regulation; Hypertension, Renal; Kidney; Kidney Failure, Chronic; Male; Membrane Glycoproteins; NADPH Oxidase 2; NADPH Oxidases; Oxidative Stress; Rats; Rats, Sprague-Dawley; Spin Labels; Superoxide Dismutase; Up-Regulation; Xanthine Oxidase

The thick ascending limb of the loop of Henle (THAL) plays an important role in the regulation of NaCl and water reabsorption. In vivo studies have shown that the free radical superoxide (O) stimulates Na and water reabsorption by the kidney. However, it is not known whether O regulates transport along the nephron in general or in the THAL specifically. We hypothesized that O stimulates THAL NaCl reabsorption. Cl absorption was measured in isolated, perfused THALs from Sprague-Dawley rats. First, we tested whether extracellular O stimulates Cl absorption. Addition of the O-generating system xanthine oxidase/hypoxanthine increased Cl absorption from 112.7 +/- 12.0 to 146.2 +/- 13.9 pmol. mm(-1). min(-1), a 33% increase (P < 0.03). When superoxide dismutase (300 U/ml) was present in the bath, addition of xanthine oxidase/hypoxanthine did not significantly increase Cl absorption (116.9 +/- 13.8 vs. 102.5 +/- 8.5 pmol. mm(-1). min(-1)). Furthermore, adding 200 nM H(2)O(2) to the bath did not significantly affect Cl absorption (from 130.3 +/- 13.7 to 125.3 +/- 19.6 pmol. mm(-1). min(-1)). Because extracellular O stimulated Cl absorption, we next tested whether endogenously produced O could stimulate transport. Under basal conditions, THALs produced detectable amounts of O, as measured by lucigenin-enhanced chemiluminescence. Adding the O scavenger tempol to the bath decreased Cl absorption from 198.1 +/- 35.4 to 132.4 +/- 23.5 pmol. mm(-1). min(-1), a 31% decrease (P < 0.02). To make sure tempol was not exerting cytotoxic effects, we tested whether its effect was reversible. With tempol in the bath, Cl absorption was 117.2 +/- 9.3 pmol. mm(-1). min(-1). Sixty minutes after tempol was removed from the bath, Cl absorption had increased to 149.2 +/- 9.1 pmol. mm(-1). min(-1) (P < 0.05). We concluded that both exogenous and endogenous O stimulate THAL NaCl absorption. To our knowledge, these are the first data showing a direct effect of O on nephron transport.

Topics: Animals; Biological Transport; Cyclic N-Oxides; Free Radical Scavengers; Hydrogen Peroxide; Hypertension, Renal; Hypoxanthine; In Vitro Techniques; Loop of Henle; Male; Nephrons; Oxidants; Rats; Rats, Sprague-Dawley; Sodium Chloride; Sodium-Potassium-Chloride Symporters; Spin Labels; Superoxide Dismutase; Superoxides; Xanthine Oxidase

Shichimotsu-koka-to (SKT) has been prescribed to treat patients with essential and renal hypertension. We investigated the effects of SKT on renal lesions in stroke-prone spontaneously hypertensive rats (SHRSPs). SHRSPs were given an extract of SKT by mixing it with drinking water, from 8 through 29 weeks of age, so that the average intake of SKT extract was about 1.5 g/kg/d. At 29 weeks of age, the kidneys of SHRSPs exhibited proliferative arteritis characterized by the proliferation of smooth muscle cells in the interlobular arteries, dilation and degeneration of renal tubules, infiltration of inflammatory cells and hemorrhage, with partial swelling or necrotizing of glomeruli. In particular, arteritis and periarteritis were noted. The treatment of SHRSPs with SKT ameliorated this morphological damage in the kidney and significantly decreased urea nitrogen in the serum. Treatment with SKT also strongly decreased the xanthine oxidase (XOD) activity and significantly increased the superoxide dismutase (SOD) activity in the kidney of SHRSPs; consequently, these values became close to those in normotensive Wistar Kyoto rats (WKYs). These results indicate that treatment with SKT ameliorated the histopathological damage and change in activity of enzymes related to free radicals in the kidney of SHRSPs, which may be important mechanisms for SKT for protecting SHRSPs from renal dysfunction.

Topics: Animals; Antihypertensive Agents; Creatinine; Drinking; Drugs, Chinese Herbal; Eating; Free Radical Scavengers; Free Radicals; Hypertension; Hypertension, Renal; Japan; Kidney; Male; Nitrogen; Pharmaceutical Preparations; Plant Extracts; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Superoxide Dismutase; Urea; Xanthine Oxidase

Recent research suggests the involvement of hydroxyl and superoxide free radicals in the development of gentamicin-induced acute renal tubular necrosis. Xanthine oxidase has been implicated as an important source of superoxide free radicals. Spontaneously hypertensive (Wistar-Kyoto) rats (SHR) have excessive oxidant stress which may render them more sensitive to the proported oxygen free radical producing effects of gentamicin. This study was undertaken to determine if the xanthine oxidase inhibitor allopurinol will ameliorate the effects of gentamicin. Normotensive Wistar-Kyoto (WKY) rats and SHR were administered allopurinol (40 mg/kg twice daily) orally 4 days before and throughout a 12-day gentamicin treatment period. The allopurinol only treatment group demonstrated no noticeable histological or functional changes considered to be indicative of nephrotoxicity. Gentamicin-injected WKY rats and SHR equally demonstrated extensive proximal tubular and glomerular damage characteristic of aminoglycoside-induced kidney damage. Allopurinol failed to protect either rat strain against the histological damage caused by gentamicin. Equivalent alterations in serum creatinine, serum gentamicin, urinary N-acetyl-beta-D-glucosaminidase excretion, body weight, urinary output, and blood pressure occurred in the gentamicin with allopurinol and gentamicin only treatment groups. Our results demonstrate allopurinol does not ameliorate the pathogenesis of gentamicin. SHR do not appear to be more sensitive to the effects of gentamicin induced kidney damage with or without allopurinol as compared with WKY rats.

Topics: Allopurinol; Animals; Gentamicins; Hypertension, Renal; Kidney Diseases; Male; Oxygen; Rats; Rats, Inbred SHR; Rats, Inbred WKY