Uric acid and preeclampsia

Increased uric acid level is a key clinical feature of preeclampsia; higher levels correlate with significant maternal and fetal morbidity and mortality. The cause of hyperuricemia and its specific role in the pathogenesis of preeclampsia, however, remain unclear. Although uric acid has been shown to roughly parallel the severity of the maternal syndrome, it has not been useful in predicting the development of preeclampsia. Nevertheless, there have been recent data supporting a pathogenic role potentially in the hypertension and endothelial cell dysfunction of preeclampsia. This article reviews our current understanding of hyperuricemia in the setting of preeclampsia, and highlights the hypothesis that hyperuricemia may contribute to vascular damage in preeclampsia.     

Uric acid nephrolithiasis

Uric acid nephrolithiasis may be the final manifestation of various pathophysiological processes. Recent advances in renal urate transport have elucidated mechanisms by which hyperuricosuria occurs. However, in most uric acid stone formers the primary pathophysiologic defect is an excessively acidic urine pH rather than hyperuricosuria. Insulin resistance may contribute to the development of acidic urine by augmenting endogenous acid production and decreasing renal ammonium excretion. Medical management strategies focus primarily on alkali treatment or decreasing hyperuricosuria.     

Uric acid and transplantation

Hyperuricemia is a common complication in organ transplant recipients, with a higher incidence in kidney and heart recipients. Risk factors for post-transplant hyperuricemia include reduced glomerular filtration rate, diuretic use, cyclosporine therapy, increasing age at transplant, obesity, and metabolic syndrome, as well as the presence of pretransplant hyperuricemia. The impact of hyperuricemia in patient and graft survival is unclear because uric acid only recently has been considered a risk factor for cardiovascular disease and graft survival. The effect of uric acid on graft function remains controversial, with studies suggesting that uric acid is an independent risk factor for chronic allograft dysfunction, contrasting with other studies suggesting that hyperuricemia is only a marker of reduced glomerular filtration rate. Strategies to reduce uric acid levels include reduction or avoidance of cyclosporine treatment, adequacy of antihypertension treatment, avoidance of diuretics, nutritional management, and use of uric acid–lowering agents. In this article, we review the incidence and risk factors for the development of post-transplant hyperuricemia, the effect of different immunosuppressive regimens in uric acid handling, and recent results from studies comparing uric acid levels and renal function in organ transplant recipients that try to identify which comes first: hyperuricemia or chronic allograft dysfunction?     

Uric acid and transplantation

Hyperuricemia is a common complication in organ transplant recipients, and frequently is associated with chronic cyclosporine immunosuppressive therapy. Kidney and heart transplant recipients are prone to develop posttransplant hyperuricemia. Risk factors for hyperuricemia include decreased glomerular filtration rate (GFR), diuretic use, and preexistent history of hyperuricemia. The influence of hyperuricemia in patient and graft survival is unclear because uric acid is not usually considered a common risk factor for cardiovascular disease that affects graft and patient survival. However, there have been small studies that have suggested that control of uric acid levels contributes to recovery of renal function (in heart and liver transplant recipients) and in an improvement in GFR in renal transplant recipients. Despite controversies in the need for hyperuricemia treatment in transplant patients, strategies to decrease uric acid levels includes a decrease or avoidance of cyclosporine treatment, adequacy of antihypertension treatment, avoidance of diuretics, nutritional management, and use of uric acid-decreasing agents. In this article we review the incidence and risk factors for the development of posttransplant hyperuricemia, discuss the influence of different immunosuppressive agents on uric acid metabolism, and suggest some alternative treatments for posttransplant hyperuricemia. We also consider that uric acid should be considered as a potential risk factor for renal allograft nephropathy or for renal dysfunction in nonrenal transplant recipients, as well as a comorbid factor for a decrease in patient and graft survival.     

Uric acid and hypertension

A link between serum uric acid and the development of hypertension was first hypothesized in the 1870s. Although numerous epidemiologic studies in the 1980s and 1990s suggested an association, relatively little attention was paid to it until recently. Animal models have suggested a two-step pathogenesis by which uric acid initially activates the renin angiotensin system and suppresses nitric oxide, leading to uric acid–dependent increase in systemic vascular resistance, followed by a uric acid–mediated vasculopathy, involving renal afferent arterioles, resulting in a late sodium-sensitive hypertension. Initial clinical trials in young patients have supported these mechanisms in young patients but do not yet support pharmacologic reduction of serum uric acid as first-line therapy for hypertension.     

Uric acid in chronic heart failure

The pathophysiologic understanding of chronic heart failure (CHF) has shifted from a mere hemodynamic disorder to a much more complex approach including changes and imbalances in neurohormonal, immune, and metabolic functions. Among metabolic abnormalities, hyperuricemia is a constant finding in CHF. The xanthine oxidase metabolic pathway increasingly is appreciated as an important contributor to both symptoms of CHF as well as progression of the disease. Recent data suggest hyperuricemia to be an independent marker of impaired prognosis in CHF. In this article, the significance of the xanthine oxidase metabolic pathway in CHF is discussed. Data on xanthine oxidase inhibition are reviewed, which suggest a beneficial effect of therapeutically targeting this enzymatic pathway.     

Uric acid and hypertension in adolescents

Hypertension is the most common form of cardiovascular disease. Although it is less common in adolescents than in adults, hypertension and the associated organ damage can and often does begin early in life. Consequently, for many with high blood pressure (BP), measures directed at the long-term prevention of cardiovascular morbidity may need to be started in adolescence to achieve maximal effectiveness. This article discusses some of the problems unique to hypertension in the young, as well as recent discoveries regarding the likely role played by increases in serum uric acid level in the development of adolescent-onset essential hypertension.     

Uric acid and the kidney

Uric acid, the end product of purine metabolism, is excreted predominantly by the proximal tubules. Abnormal serum levels of uric acid are due to alterations in production or excretion. Fractional excretion of uric acid is helpful in determining the underlying etiology of hypouricemia or hyperuricemia in children. Abnormalities in the molecular mechanisms that control renal uric acid tubular transport are implicated in various disorders associated with abnormal uric acid levels. Gout is rare in children; yet its presence necessitates evaluation for enzymatic defects in purine metabolism. Well-known effects of uric acid on the kidney include nephrolithiasis and acute kidney injury (AKI) in the setting of tumor lysis. However, recent data suggest that uric acid may be an important factor in the pathogenesis of AKI in general, as well as of chronic kidney disease (CKD) and hypertension. Hence, uric acid may not only be a marker but also a potential therapeutic target in kidney disease. Nonetheless, because of confounders, more studies are needed to clarify the association between uric acid and multifactorial disorders of the kidney.     

Uric acid urolithiasis and crystallization inhibitors

An in vitro study of the inhibitory effects that some substances occasionally present in urine can provoke on the crystallization of uric acid has been performed. The most remarkable crystallization inhibitory effects were produced by mucine at concentrations of >0.5 mg/l. Pentosan polysulfate and chondroitin sulfate also clearly increased the uric acid crystallization times at concentrations of >100 mg/l. Saponins, such as escin and glycyrrhizic acid, also produced a notable delay in uric acid crystallization times at concentrations of >10 mg/l. Similar effects were observed in the presence of a surfactant substance, lauryl sulfate. N-Acetyl-L-cysteine caused crystallization perturbations only when it was present at concentrations of >50 mg/l. Citric acid and phytic acid caused no effects on uric acid crystallization even at the highest concentrations assayed (1,000 and 5 mg/l, respectively). From the results obtained it can be deduced that mainly glycoproteins, glycosaminoglycans and surfactant substances can exert protective effects against uric acid crystallization.     

Uric acid stones following hepatic transplantation

We report the case of a 52 year old man with a history of insulin-requiring diabetes and hepatitis B with cirrhosis who received an orthotopic liver transplant. One year later he developed renal colic and was found to have a 3 mm stone at the left ureterovesical junction. Numerous other stones formed and infrared spectroscopy analysis demonstrated all to be composed of 100% uric acid. Urine collections demonstrated a low urine pH of 5.1 without hyperuricosuria. His stones were effectively prevented with potassium citrate therapy. Few incidence data are available for uric acid stone occurrence in solid organ recipients. Calcineurin inhibitors are thought to often cause hyperuricemia on the basis of decreased urate excretion. However, this effect would not be expected to cause hyperuricosuria nor uric acid stones. This class of drugs may also be associated with low urine pH, perhaps on the basis of hypoaldosteronism, but the contribution of such a syndrome to uric acid stone formation is not established.