Marilda Mazzali

Is There a Pathogenetic Role for Uric Acid in Hypertension and Cardiovascular and Renal Disease

Hyperuricemia is associated with hypertension, vascular disease, renal disease, and cardiovascular events. In this report, we review the epidemiologic evidence and potential mechanisms for this association. We also summarize experimental studies that demonstrate that uric acid is not inert but may have both beneficial functions (acting as an antioxidant) as well as detrimental actions (to stimulate vascular smooth muscle cell proliferation and induce endothelial dysfunction). A recently developed experimental model of mild hyperuricemia also provides the first provocative evidence that uric acid may have a pathogenic role in the development of hypertension, vascular disease, and renal disease. Thus, it is time to reevaluate the role of uric acid as a risk factor for cardiovascular disease and hypertension and to design human studies to address this controversy.

A Role for Uric Acid in the Progression of Renal Disease

Hyperuricemia is associated with renal disease, but it is usually considered a marker of renal dysfunction rather than a risk factor for progression. Recent studies have reported that mild hyperuricemia in normal rats induced by the uricase inhibitor, oxonic acid (OA), results in hypertension, intrarenal vascular disease, and renal injury. This led to the hypothesis that uric acid may contribute to progressive renal disease. To examine the effect of hyperuricemia on renal disease progression, rats were fed 2% OA for 6 wk after 5/6 remnant kidney (RK) surgery with or without the xanthine oxidase inhibitor, allopurinol, or the uricosuric agent, benziodarone. Renal function and histologic studies were performed at 6 wk. Given observations that uric acid induces vascular disease, the effect of uric acid on vascular smooth muscle cells in culture was also examined. RK rats developed transient hyperuricemia (2.7 mg/dl at week 2), but then levels returned to baseline by week 6 (1.4 mg/dl). In contrast, RK+OA rats developed higher and more persistent hyperuricemia (6 wk, 3.2 mg/dl). Hyperuricemic rats demonstrated higher BP, greater proteinuria, and higher serum creatinine than RK rats. Hyperuricemic RK rats had more renal hypertrophy and greater glomerulosclerosis (24.2 +/- 2.5 versus 17.5 +/- 3.4%; P < 0.05) and interstitial fibrosis (1.89 +/- 0.45 versus 1.52 +/- 0.47; P < 0.05). Hyperuricemic rats developed vascular disease consisting of thickening of the preglomerular arteries with smooth muscle cell proliferation; these changes were significantly more severe than a historical RK group with similar BP. Allopurinol significantly reduced uric acid levels and blocked the renal functional and histologic changes. Benziodarone reduced uric acid levels less effectively and only partially improved BP and renal function, with minimal effect on the vascular changes. To better understand the mechanism for the vascular disease, the expression of COX-2 and renin were examined. Hyperuricemic rats showed increased renal renin and COX-2 expression, the latter especially in preglomerular arterial vessels. In in vitro studies, cultured vascular smooth muscle cells incubated with uric acid also generated COX-2 with time-dependent proliferation, which was prevented by either a COX-2 or TXA-2 receptor inhibitor. Hyperuricemia accelerates renal progression in the RK model via a mechanism linked to high systemic BP and COX-2-mediated, thromboxane-induced vascular disease. These studies provide direct evidence that uric acid may be a true mediator of renal disease and progression.

Uric Acid, Hominoid Evolution, and the Pathogenesis of Salt-Sensitivity

Humans have elevated serum uric acid as a result of a mutation in the urate oxidase (uricase) gene that occurred during the Miocene. We hypothesize that the mutation provided a survival advantage because of the ability of hyperuricemia to maintain blood pressure under low-salt dietary conditions, such as prevailed during that period. Mild hyperuricemia in rats acutely increases blood pressure by a renin-dependent mechanism that is most manifest under low-salt dietary conditions. Chronic hyperuricemia also causes salt sensitivity, in part by inducing preglomerular vascular disease. The vascular disease is mediated in part by uric acid-induced smooth muscle cell proliferation with activation of mitogen-activated protein kinases and stimulation of cyclooxygenase-2 and platelet-derived growth factor. Although it provided a survival advantage to early hominoids, hyperuricemia may have a major role in the current cardiovascular disease epidemic.

Hyperuricemia Causes Glomerular Hypertrophy in the Rat

Background/Aims: Rats with mild hyperuricemia develop systemic hypertension, interstitial renal disease, afferent arteriolopathy, and increased renin expression [Mazzali et al.: Am J Physiol 2002;6:F991–F997]. We hypothesized that hyperuricemia might also induce glomerular changes. Methods: We reviewed renal biopsies of rats previously made hyperuricemic for 7 weeks with the uricase inhibitor, oxonic acid. Controls included normal rats and oxonic acid-treated rats administered allopurinol, benziodarone, hydrochlorothiazide, or enalapril. Glomeruli were examined for size (computer image analysis) and structure (histology). An additional group of rats were administered oxonic acid or control diet for 6 months. Results: Renal biopsies showed that hyperuricemic rats had a 30% increase in glomerular tuft area (p < 0.01); these changes were prevented by allopurinol and benziodarone. Control of blood pressure with hydrochlorothiazide did not prevent the development of glomerular hypertrophy, whereas enalapril partially reduced the glomerular hypertrophy. Prolonged hyperuricemia was associated with the development of microalbuminuria (p < 0.05) and glomerulosclerosis (22 vs. 10%, p < 0.05) compared to control rats. Conclusions: Hyperuricemic rats develop glomerular hypertrophy that can be prevented in part by ACE inhibitor therapy. Prolonged hyperuricemia is associated with the development of glomerulosclerosis in the rat.

Hyperuricemia exacerbates chronic cyclosporine nephropathy

BACKGROUNDnHyperuricemia frequently complicates cyclosporine (CSA) therapy. The observation that longstanding hyperuricemia is associated with chronic tubulointerstitial disease and intrarenal vasoconstriction raised the hypothesis that hyperuricemia might contribute to chronic CSA nephropathy.nnnMETHODSnCSA nephropathy was induced by the administration of CSA (15 mg/kg/day) for 5 and 7 weeks to rats on a low salt diet (CSA group). The effect of hyperuricemia on CSA nephropathy was determined by blocking the hepatic enzyme uricase with oxonic acid (CSA-OA). Control groups included rats treated with vehicle (VEH) and oxonic acid alone (OA). Histological and functional studies were determined at sacrifice.nnnRESULTSnCSA treated rats developed mild hyperuricemia with arteriolar hyalinosis, tubular injury and striped interstitial fibrosis. CSA-OA treated rats had higher uric acid levels in association with more severe arteriolar hyalinosis and tubulointerstitial damage. Intrarenal urate crystal deposition was absent in all groups. Both CSA and CSA-OA treated rats had increased renin and decreased NOS1 and NOS3 in their kidneys, and these changes are more evident in CSA-OA treated rats.nnnCONCLUSIONnAn increase in uric acid exacerbates CSA nephropathy in the rat. The mechanism does not involve intrarenal uric acid crystal deposition and appears to involve activation of the renin angiotensin system and inhibition of intrarenal nitric oxide production.

Serum Uric Acid: A Risk Factor and a Target for Treatment?

Serum uric acid was first noted to be associated with increased BP by Frederick Mohamed in the 1870s. Although the link was rediscovered periodically over the years, it generally was dismissed as a surrogate marker for decreased renal function that led to increased uric acid and increased risk for hypertension and cardiovascular (CV) disease. Recently, however, several lines of evidence suggest that increased serum uric acid may be a significant modifiable risk factor. Increased serum uric acid is associated with increased risk for future hypertension in several large longitudinal clinical trials as well as an independent risk factor for poor CV prognosis. Animal model experiments demonstrate that increased serum uric acid causes increased BP that initially is reversible but becomes irreversible, salt sensitive, and uric acid independent over time. The mechanisms include the direct action of uric acid on smooth muscle and vascular endothelial cells. Finally, in adolescents with new-onset essential hypertension, the prevalence of elevated serum uric acid is >90%, and preliminary clinical trial evidence suggests that agents that lower serum uric acid may lower BP in this select population. Although the investigations are still preliminary, serum uric acid represents a possible new and intriguing target for the reduction of morbidity and mortality associated with hypertension and CV disease.

Uric Acid – A Uremic Toxin?

Uric acid might often be regarded as a simple marker of renal disease. Although it is well known that hyperuricemia causes gout which is associated with renal insufficiency and cardiovascular disease, one might think that it could attribute to the intrarenal urate crystal, but not to uric acid per se. In order to clarify the role of uric acid in the kidney, we hypothesized that uric acid causes renal disease. To generate mild hyperuricemia without intrarenal crystal in rats, we used low doses of an uricase inhibitor (2% oxonic acid). Hyperuricemia induced systemic hypertension, glomerular hypertrophy/hypertension, afferent arteriolar sclerosis, and macrophage infiltration in normal rat kidney. In progressive renal disease, such as cyclosporine nephropathy and remnant kidney in rat, uric acid accelerated the progression of renal disease. Thus, we concluded that uric acid is not a simple marker, but a cause of renal disease.

What Are the Key Arguments Against Uric Acid as a True Risk Factor for Hypertension

On March 24, 1882, at a dinner held by the Berlin Physiological Society, Robert Koch presented evidence to prove that galloping consumption, or tuberculosis, was attributable to a bacteria. His evidence was based on identifying the organism from the lungs of infected patients, growing it in a cell culture dish, and then injecting the bacteria in rabbits where it replicated the disease with similar lung lesions containing the bacteria. This approach, which included observations in humans as well as animal models, became adopted as Koch’s postulates for proving the cause of disease.nnIn recent years, uric acid has been proposed to have a causal role in some forms of hypertension. Nevertheless, there are observations that have challenged this hypothesis. Here we discuss some of the arguments that weaken the uric acid story, and how they might be addressed.nnUric acid is produced during purine metabolism with the generation of oxidants (Figure 1). In humans uric acid is the final end product, whereas in most mammals uric acid is further degraded into 5-hydroxyisourate by uricase, eventually producing allantoin. Serum uric acid levels vary in humans, with the normal range being between 3 and 7 mg/dL in the blood. Serum uric acid levels are increased by diets high in purine-rich foods or fructose, or by conditions associated with high cell turnover. Reduced urinary excretion of uric acid also results in higher serum uric acid levels, such as occurs with reduced renal function, reduced renal blood flow, and insulin resistance.nnnnFigure 1. nUric acid metabolism.nnnnSerum uric acid was originally linked with hypertension in the 1870s. For years, this association was attributed to the effect of renal vasoconstriction to reduce urinary excretion of uric acid. More recently, uric acid has been proposed to have a causal role in hypertension.1 Hyperuricemia would seem to fulfill …

Use of aminophylline and enalapril in posttransplant polycythemia.

BACKGROUNDnPosttransplant polycythemia (PTP) affects 6-30% of renal transplant recipients and can result in thromboembolic disease. The pathogenesis of PTP remains unknown and may be multifactorial. Although phlebotomy has previously been the treatment for PTP, drugs such as adenosine receptor antagonists or angiotensin-converting enzyme inhibitors can be used to control PTP.nnnMETHODSnThe authors performed a prospective study of two different drugs to treat PTP: aminophylline and enalapril. Twenty-seven patients with PTP lasting more than 6 months were evaluated. During phase 1, aminophylline was compared with enalapril. The patients sequentially received aminophylline and enalapril during 12-week periods, intercalated by 12-week periods of no drugs. During phase 2, enalapril was administered for 12 weeks.nnnRESULTSnFrom January 1984 to December 1993, 110 of 333 patients with PTP lasting more than 6 months (33%) developed polycythemia, and 27 patients were included in the present study. In phase 1, aminophylline had no effect on PTP. Enalapril promoted an erythropoiesis inhibition, characterized by a decrease in hematocrit and an increase in iron stores and ferritin levels. After withdrawal of enalapril, the hematocrit increased and the iron stores decreased. In phase 2, there was a progressive reduction in hematocrit after the 4th week of therapy. The lowest hematocrit was observed in the 12th week and then enalapril was stopped, leading to a subsequent rise in hematocrit. Erythropoietin levels and renal function remained constant during all periods of both phases of the study.nnnCONCLUSIONnThe use of adenosine antagonists was ineffective to treat PTP in our series. However, treatment with enalapril promoted an erythropoiesis inhibition, demonstrated by a reduction in hematocrit, hemoglobin, red blood cell count, and reticulocyte count, associated with an increase in iron stores. This response occurred independently from erythropoietin levels or hemodynamic graft changes.

Guidelines for Maintenance of Adult Patients With Brain Death and Potential for Multiple Organ Donations: The Task Force of the Brazilian Association of Intensive Medicine the Brazilian Association of Organs Transplantation, and the Transplantation Center of Santa Catarina

INTRODUCTIONnThe organ shortage for transplantation, the principal factor that increases waiting lists, has become a serious public health problem. In this scenario, the intensivist occupies a prominent position as one of the professionals that first has a chance to identify brain death and to be responsible for the maintenance of the potential deceased donor.nnnOBJECTIVEnThis report attempts to establish guidelines for care and maintenance of adult deceased donor organs guiding and standardizing care provided to patients with brain death.nnnMETHODnThese guidelines were composed by intensivists, transplant coordinators, professionals from various transplant teams, and used transplant center. The formulated questions were forwarded to all members and recommendations were constructed after an extensive literature review selecting articles with the highest degree of evidence.nnnRESULTSnGuidelines were developed in the form of questions reflecting frequent experiences in clinical intensive care practices. The main questions were: Is there an optimal interval for keeping organs of deceased donors viable? What actions are considered essential for maintaining deceased donors in this period? What are the limits of body temperature? How should the patient be warmed? Which laboratory tests should be performed? What is the collection interval? What are the limits in the laboratory and the capture scenario? What are the limits of blood pressure? When and how should one use catecholamines?nnnCONCLUSIONSnThis pioneer project involved a multidisciplinary team working in organ transplantation seeking to provide treatment guidance to increase the number of viable organs from deceased adult donors.