allopurinol and Nephritis

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

Excess of uric acid is mainly treated with xanthine oxidase (XO) inhibitors, also called uricostatics because they block the conversion of hypoxanthine and xanthine into urate. Normally, accumulation of upstream metabolites is prevented by the hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme. The recycling pathway, however, is impaired in the presence of HPRT deficiency, as observed in Lesch-Nyhan disease. To gain insights into the consequences of purine accumulation with HPRT deficiency, we investigated the effects of the XO inhibitor allopurinol in Hprt-lacking (HPRT-/-) mice. Allopurinol was administered in the drinking water of E12-E14 pregnant mothers at dosages of 150 or 75 μg/ml, and mice sacrificed after weaning. The drug was well tolerated by wild-type animals and heterozygous HPRT+/- mice. Instead, a profound alteration of the renal function was observed in the HPRT-/- model. Increased hypoxanthine and xanthine concentrations were found in the blood. The kidneys showed a yellowish appearance, diffuse interstitial nephritis, with dilated tubules, inflammatory and fibrotic changes of the interstitium. There were numerous xanthine tubular crystals, as determined by HPLC analysis. Oil red O staining demonstrated lipid accumulation in the same location of xanthine deposits. mRNA analysis showed increased expression of adipogenesis-related molecules as well as profibrotic and proinflammatory pathways. Immunostaining showed numerous monocyte-macrophages and overexpression of alpha-smooth muscle actin in the tubulointerstitium. In vitro, addition of xanthine to tubular cells caused diffuse oil red O positivity and modification of the cell phenotype, with loss of epithelial features and appearance of mesenchymal characteristics, similarly to what was observed in vivo. Our results indicate that in the absence of HPRT, blockade of XO by allopurinol causes rapidly developing renal failure due to xanthine deposition within the mouse kidney. Xanthine seems to be directly involved in promoting lipid accumulation and subsequent phenotype changes of tubular cells, with activation of inflammation and fibrosis.

Topics: Allopurinol; Animals; Hypoxanthine Phosphoribosyltransferase; Lesch-Nyhan Syndrome; Mice; Mice, Knockout; Nephritis; Xanthine; Xanthine Oxidase

Deceased after cardiac death donors represent an important source of organs to reduce organ shortage in transplantation. However, these organs are subjected to more ischaemia-reperfusion injury (IRI). Reducing IRI by targeting coagulation is studied here in an experimental model.. The effect of an anti-Xa compound (fondaparinux) was evaluated using an autotransplanted kidney model in pigs. Kidneys were clamped for 60 min (warm ischaemia) and then preserved for 24 h at 4 °C in University of Wisconsin solution (UW). The anti-Xa compound was injected intravenously before warm ischaemia and used during cold storage, and its effects were compared with those of intravenous injection of unfractionated heparin (UFH) before warm ischaemia and use during cold storage, or use of UW alone during cold storage.. At 3 months after transplantation, anti-Xa treatment improved recovery of renal function and chronic serum creatinine levels compared with UW and UFH (mean(s.e.m.) 89(4), 250(4) and 217(8) µmol/l respectively). The anti-Xa treatment also reduced fibrosis, and decreased tissue expression of markers of the epithelial-mesenchymal transition compared with UW and UFH. Cleaved protease-activated receptor 2 was overexpressed in the UW group compared with the anti-Xa and UFH groups. Leucocyte infiltrates were decreased in the anti-Xa group compared with the UW and UFH groups. Macrophage invasion was also decreased by anticoagulation treatment.. Peritransplant anticoagulation therapy was beneficial to graft outcome, in both the acute and chronic phases. Moreover, specific inhibition of coagulation Xa protease further protected kidney grafts, with better recovery and decreased expression of chronic lesion markers. Surgical relevance The increasing use of marginal donors highlights the importance of organ quality in transplantation. Renal ischaemia-reperfusion injury (IRI), which includes a deleterious activation of coagulation, plays a central role in determining graft quality and outcome. Using an established porcine renal autotransplantation preclinical model with high clinical relevance, the benefits of anticoagulation therapy using an antifactor Xa molecule were evaluated. Peritransplantion anticoagulation treatment, specifically with an anti-Xa compound, protected marginal kidney grafts, improving functional recovery and reducing chronic lesions. This study demonstrates the benefits of anticoagulation therapy at the time of organ collection, particularly for marginal organs, encountered in cases of extended criteria and deceased after circulatory death donors. This anticoagulation strategy could be an important addition to current donor and organ management protocols in order to limit IRI and improve outcome.

Topics: Adenosine; Allopurinol; Animals; Anticoagulants; Constriction; Cytokines; Fondaparinux; Glutathione; Insulin; Kidney; Kidney Transplantation; Leukocytes; Nephritis; Organ Preservation Solutions; Polysaccharides; Raffinose; Reperfusion Injury; Swine; Transplantation, Autologous; Warm Ischemia

Hyperuricemia has recently been recognized to be a risk factor for nephropathy in the diabetic subject. We tested the hypothesis that lowering uric acid with a xanthine oxidase inhibitor might reduce renal injury in the diabetic mouse. Diabetic (db/db) mice were treated with allopurinol or no treatment for 8 wk. Serum uric acid, renal function, and histology were assessed at death. The direct effect of uric acid in human proximal tubular epithelial cells was also evaluated under normal or high glucose condition. We found that db/db mice developed hyperuricemia, albuminuria, mesangial matrix expansion, and mild tubulointerstitial disease. Allopurinol treatment significantly lowered uric acid levels, reduced albuminuria, and ameliorated tubulointerstitial injury, but it did not prevent mesangial expansion. The mechanism for protection was shown to be due to a reduction in inflammatory cells mediated by a reduction in ICAM-1 expression by tubular epithelial cells. Interestingly, allopurinol did not reduce oxidative stress in the kidney. An inflammatory role of uric acid on tubular cells was also confirmed by our in vitro evidence that uric acid directly induced ICAM-1 expression in the human proximal tubular cell. In conclusion, hyperuricemia has a pathogenic role in the mild tubulointerstitial injury associated with diabetic nephropathy but not glomerular damage in db/db mice. Lowering uric acid may reduce tubulointerstitial injury in diabetes.

Topics: Albuminuria; Allopurinol; Animals; Blood Pressure; Blood Urea Nitrogen; Cell Line; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Enzyme Inhibitors; Hyperuricemia; Intercellular Adhesion Molecule-1; Kidney; Male; Mice; Mice, Inbred C57BL; Nephritis; Oxidative Stress; Time Factors; Uric Acid; Xanthine Oxidase

Aristolochic acid (AA), a naturally occurring nephrotoxin and rodent carcinogen, has recently been associated with the development of urothelial cancer in humans. Understanding which enzymes are involved in AA activation and/or detoxication is important in the assessment of an individual susceptibility to this natural carcinogen. We examined the ability of enzymes of rat renal and hepatic cytosolic fractions to activate AA to metabolites forming DNA adducts by the nuclease P1-enhanced version of the (32)P-postlabeling assay. Cytosolic fractions of both these organs generated AA-DNA adduct patterns reproducing those found in renal tissues from humans exposed to AA. 7-(Deoxyadenosin-N(6)-yl)aristolactam I, 7-(deoxyguanosin-N(2)-yl)aristolactam I and 7-(deoxyadenosin-N(6)-yl)aristolactam II were identified as AA-DNA adducts formed from AAI and 7-(deoxyguanosin-N(2)-yl)aristolactam II and 7-(deoxyadenosin-N(6)-yl)aristolactam II were generated from AAII by hepatic cytosol. Qualitatively the same AA-DNA adduct patterns were observed, although at lower levels, upon incubation of AAs with renal cytosol. To define the role of cytosolic reductases in the reductive activation of AA, we investigated the modulation of AA-DNA adduct formation by cofactors, specific inducers or selective inhibitors of the cytosolic reductases, DT-diaphorase, xanthine oxidase (XO) and aldehyde oxidase. The role of the enzymes in AA activation was also investigated by correlating the DT-diaphorase- and XO-dependent catalytic activities in cytosolic sample with the levels of AA-DNA adducts formed by the same cytosolic sample. On the basis of these studies, we attribute most of the cytosolic activation of AA to DT-diaphorase, although a role of cytosolic XO cannot be ruled out. With purified DT-diaphorase, the participation of this enzyme in the formation of AA-DNA adducts was confirmed. The binding orientation of AAI in the active site of DT-diaphorase was predicted by computer modeling based on published X-ray structures. The results presented here are the first report demonstrating a reductive activation of carcinogenic AAs by DT-diaphorase.

Topics: Aldehyde Oxidase; Aldehyde Oxidoreductases; Animals; Antineoplastic Agents; Aristolochic Acids; Carcinogens; Cell Nucleus; Chromatography, High Pressure Liquid; Cytosol; DNA; DNA Adducts; DNA, Complementary; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Enzyme Activation; Liver; Models, Chemical; Models, Molecular; NAD(P)H Dehydrogenase (Quinone); Nephritis; Phenanthrenes; Rats; Rats, Wistar; Thymus Gland; Time Factors; Xanthine Oxidase

The superoxide radical plays major roles in the neutrophil-medicated acute inflammatory response and in postischemic tissue injury, although the sources and actions of the radical are quite different in these two pathological states. While neutrophils produce superoxide for the primary purpose of aiding in the killing of ingested microbes, a second useful function has evolved. The superoxide released from actively phagocytosing neutrophils serves to attract more neutrophils by reacting with, and activating, a latent chemotactic factor present in plasma. Superoxide dismutase, by preventing the activation of this superoxide-dependent chemotactic factor, exerts potent anti-inflammatory action. During ischemia, energy-starved tissues catabolize ATP to hypoxanthine. Calcium transients in these cells appear to activate a calmodulin regulated protease which attacks the enzyme xanthine dehydrogenase, converting it to a xanthine oxidase capable of superoxide generation. When the tissue is reperfused and reoxygenated, all the necessary components are present (xanthine oxidase, hypoxanthine, and oxygen) to produce a burst of superoxide which results in extensive tissue damage. Ischemic tissues are protected by superoxide dismutase or allupurinol, an inhibitor of xanthine oxidase.

Topics: Animals; Free Radicals; Humans; In Vitro Techniques; Inflammation; Ischemia; Nephritis; Neutrophils; Oxidation-Reduction; Oxygen; Superoxide Dismutase; Superoxides; Xanthine Oxidase

Topics: Adolescent; Allopurinol; Child; Child, Preschool; Drug Therapy, Combination; Humans; Nephritis; Purine-Pyrimidine Metabolism, Inborn Errors; Uric Acid; Uricosuric Agents

Topics: Adolescent; Adult; Alkaptonuria; Allopurinol; Amniotic Fluid; Athetosis; Carbohydrates; Chorea; Chromatography, Ion Exchange; Compulsive Behavior; Female; Gout; Humans; Hypertension; Infant; Infant, Newborn; Intellectual Disability; Male; Maple Syrup Urine Disease; Methods; Middle Aged; Nephritis; Nicotinic Acids; Phenols; Pregnancy; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Self Mutilation; Spectrophotometry; Sulfuric Acids; Ultraviolet Rays; Uric Acid; Xanthines

Topics: Animals; Chemical and Drug Induced Liver Injury; DNA; Kidney; Liver; Male; Nephritis; Proteins; Rats; RNA; Time Factors; Uranium; Xanthine Oxidase