Introduction

Abstract

Forty years ago, studies on uric acid and purines were a major field in medical investigation, involving numerous scientists including several Chiefs of Medicine from American Universities. Purine bases were known to be part of the recently discovered DNA code, the metabolic pathways leading to urate synthesis were mostly delineated, and clinical conditions arising from disorders of purine metabolism were being discovered. Most importantly, therapies aimed at altering purine metabolism were introduced by Elion and Hitchings, for which they received the Nobel prize. Their work resulted in the introduction of synthesized purine analogues that were useful in the treatment of cancer and in suppressing the immune response after transplantation (azathioprine), and in the process resulted in the fortuitous discovery of allopurinol as a means to control urate concentrations by inhibiting the enzyme, xanthine oxidase. In the kidney, the role of crystalline uric acid/urate had been proposed as both a cause of acute renal failure (acute urate nephropathy) and chronic renal disease (gouty nephropathy), and investigations also were focused on the complex renal tubular handling of urate as a filterable anion. Again, new pharmacologic agents allowed manipulation of urate excretion by altering reabsorption and/or secretion. These were exciting times!However, studies on uric acid and purine metabolism fell out of vogue in the mid- to late 1970s because most of the questions seemed answered, at least within the limits of available techniques. However, one important area remained unresolved, that being the role of uric acid in patients with cardiovascular and/or chronic renal disease. Although the association of uric acid with cardiovascular and renal disease had been known since the 1800s, it remained—and still remains—controversial whether uric acid has a causal role in cardiovascular and renal disease, or whether the gouty phenotype simply is more common in patients who also develop cardiovascular disease. Indeed, it is known that an increased serum uric acid level (although only rarely clinical gout) is common in patients with renal disease, arising from decreased glomerular filtration, and also that both gout and hyperuricemia are common equally in the metabolic syndrome, which is characterized by obesity and insulin resistance (possibly secondary to insulin effects on tubular handling of uric acid), and in hypertension (possibly owing to decreased renal excretion secondary to increased renal vascular resistance). Because it has been possible to ascribe reasons why uric acid might be increased in patients at cardiovascular risk, many investigators have concluded that uric acid is not a true risk factor for cardiovascular disease, but simply marks those at increased risk. Consistent with this hypothesis are some studies that report that an increased serum uric acid level does not always predict risk for cardiovascular or renal disease, if one controls for the other cardiovascular risk factors that frequently are observed in these patients. However, other epidemiologic studies have found uric acid to be an independent risk factor after controlling for these factors, raising the question of whether a causal relationship may have been overlooked. Furthermore, a series of tantalizing experimental studies in animal models and in cell culture have provided potential mechanisms by which uric acid may cause cardiovascular and renal disease and, interestingly, none of the mechanisms involve crystal deposition but rather are mediated by increased serum levels of uric acid. In this issue of Seminars in Nephrology, these studies are reviewed.The first major question relates to whether uric acid may have a causal role in the development of hypertension. In the first article, Johnson et al examine the relationship between diet, uric acid, and hypertension, with emphasis on studies of native populations as well as an evolutionary perspective, and raise the interesting possibility that dietary changes may have influenced serum uric acid levels and that this correlates with the worldwide epidemic of hypertension and obesity. Studies then are presented by Sanchez-Lozada et al, showing that experimental hyperuricemia causes hypertension in animals and that it also causes intense renal vasoconstriction and glomerular hypertension. Feig then summarizes clinical studies in humans, providing strong suggestive evidence that uric acid may be involved in the initiation of hypertension in adolescents. A mechanistic approach is provided by Kanellis and Kang, who show that uric acid mediates endothelial dysfunction and the release of vasoconstrictive substances. Finally, a unique perspective as to the difficulties in interpretation of epidemiologic studies on uric acid and cardiovascular disease is provided by Short and Tuttle. In aggregate, these studies provide a challenging case for a true pathogenetic role of uric acid in the development of hypertension.The relationship of uric acid with renal disease also is discussed. Today we no longer see the gouty kidneys observed commonly until the 1960s, so that some investigators have proposed that the entity gouty nephropathy does not exist, but arose in the past from other factors such as lead poisoning. An alternative possibility that others have proposed for why gouty nephropathy may no longer be observed commonly could relate to the widespread use of allopurinol. However, most investigators had considered that gouty nephropathy (if indeed it existed) was mediated by intrarenal crystal deposition. However, this may not be the complete story. Experimental studies summarized by Kang and Nakagawa provide evidence that an increase in uric acid level in rats can cause renal disease via a crystal-independent pathway, and interesting data by Mazzali et al suggests that this may be a mechanism by which calcineurin inhibitors cause renal damage. Cameron and Simmonds also present a comprehensive review of the hereditary hyperuricemic conditions and their relationship with renal disease. Interestingly, familial juvenile hyperuricemic nephropathy is associated with renal damage without significant intrarenal crystal deposition, and although all do not agree with their conclusion, Cameron, as well as other investagators, have suggested that controlling uric acid levels early in this disease may help prevent progression of the renal disease. Interpretation of studies in this area remains problematic because we still have no comprehensive picture of urate handling in the renal tubule. Although the main proximal brush-border sodium-coupled urate reabsorptive carrier present in most mammals, including humans, has been cloned and localized, little is known of possible voltage-dependent secretory pathways, and, above all, almost no information exists on basolateral urate transport in human renal tubular cells.Finally, the interesting relationship of uric acid to preeclampsia is discussed by Lam et al, raising the possibility of a pathogenetic role of uric acid in this condition, and, similarly, the strong relationship between uric acid and overall outcomes in congestive heart failure is discussed by Doehner and Anker.Although all these studies provide tantalizing new evidence that uric acid may have a contributory role in hypertension and renal disease, there are numerous caveats one must recognize. One problem that has dogged experimental studies on urate in relation to human disease is that major species differences exist not only in the synthesis, but also in the metabolism and renal handling of urate. Thus, many of these studies were performed in rodents, in which uric acid metabolism is significantly different from that in humans. Rodents express uricase (a protein that is absent in humans owing to a genetic mutation), which degrades uric acid so that blood levels of uric acid in the rat are low, in the 1 to 2 mg/dL (60–120 μmol/L) range. Rodents also have more than 100 times the levels of xanthine oxidase.This may partially explain why most studies in humans suggest uric acid is only generated at certain sites (liver and intestine). Although xanthine oxidase mRNA and protein have been alleged to be present in trace amounts in other tissues, including vascular endothelium and smooth muscle, these probably represent homologous sequences of the closely related enzyme aldehyde oxidase. A further complication is that in humans, liver- or gut-derived xanthine oxidase circulates, and may bind to human vascular endothelium and produce urate in the local environment. Finally, although human blood vessels may not produce urate intracellularly as rat vascular cells do, urate-handling anion transporters are present on almost all human cells, which can import urate into the cells. Obviously, studies in which uricase inhibitors are administered to rats are of great interest, but these inhibitors may have effects independent of their ability to block uricase.Although such studies are of great interest, the ultimate proof as to whether uric acid has a causal role in hypertension and renal disease in humans can be obtained only by designing careful, prospective studies in which the effect of decreasing uric acid on blood pressure and renal function are determined. Nevertheless, the studies presented in this issue clearly show that this is an important and timely subject for investigation. Forty years ago, studies on uric acid and purines were a major field in medical investigation, involving numerous scientists including several Chiefs of Medicine from American Universities. Purine bases were known to be part of the recently discovered DNA code, the metabolic pathways leading to urate synthesis were mostly delineated, and clinical conditions arising from disorders of purine metabolism were being discovered. Most importantly, therapies aimed at altering purine metabolism were introduced by Elion and Hitchings, for which they received the Nobel prize. Their work resulted in the introduction of synthesized purine analogues that were useful in the treatment of cancer and in suppressing the immune response after transplantation (azathioprine), and in the process resulted in the fortuitous discovery of allopurinol as a means to control urate concentrations by inhibiting the enzyme, xanthine oxidase. In the kidney, the role of crystalline uric acid/urate had been proposed as both a cause of acute renal failure (acute urate nephropathy) and chronic renal disease (gouty nephropathy), and investigations also were focused on the complex renal tubular handling of urate as a filterable anion. Again, new pharmacologic agents allowed manipulation of urate excretion by altering reabsorption and/or secretion. These were exciting times! However, studies on uric acid and purine metabolism fell out of vogue in the mid- to late 1970s because most of the questions seemed answered, at least within the limits of available techniques. However, one important area remained unresolved, that being the role of uric acid in patients with cardiovascular and/or chronic renal disease. Although the association of uric acid with cardiovascular and renal disease had been known since the 1800s, it remained—and still remains—controversial whether uric acid has a causal role in cardiovascular and renal disease, or whether the gouty phenotype simply is more common in patients who also develop cardiovascular disease. Indeed, it is known that an increased serum uric acid level (although only rarely clinical gout) is common in patients with renal disease, arising from decreased glomerular filtration, and also that both gout and hyperuricemia are common equally in the metabolic syndrome, which is characterized by obesity and insulin resistance (possibly secondary to insulin effects on tubular handling of uric acid), and in hypertension (possibly owing to decreased renal excretion secondary to increased renal vascular resistance). Because it has been possible to ascribe reasons why uric acid might be increased in patients at cardiovascular risk, many investigators have concluded that uric acid is not a true risk factor for cardiovascular disease, but simply marks those at increased risk. Consistent with this hypothesis are some studies that report that an increased serum uric acid level does not always predict risk for cardiovascular or renal disease, if one controls for the other cardiovascular risk factors that frequently are observed in these patients. However, other epidemiologic studies have found uric acid to be an independent risk factor after controlling for these factors, raising the question of whether a causal relationship may have been overlooked. Furthermore, a series of tantalizing experimental studies in animal models and in cell culture have provided potential mechanisms by which uric acid may cause cardiovascular and renal disease and, interestingly, none of the mechanisms involve crystal deposition but rather are mediated by increased serum levels of uric acid. In this issue of Seminars in Nephrology, these studies are reviewed. The first major question relates to whether uric acid may have a causal role in the development of hypertension. In the first article, Johnson et al examine the relationship between diet, uric acid, and hypertension, with emphasis on studies of native populations as well as an evolutionary perspective, and raise the interesting possibility that dietary changes may have influenced serum uric acid levels and that this correlates with the worldwide epidemic of hypertension and obesity. Studies then are presented by Sanchez-Lozada et al, showing that experimental hyperuricemia causes hypertension in animals and that it also causes intense renal vasoconstriction and glomerular hypertension. Feig then summarizes clinical studies in humans, providing strong suggestive evidence that uric acid may be involved in the initiation of hypertension in adolescents. A mechanistic approach is provided by Kanellis and Kang, who show that uric acid mediates endothelial dysfunction and the release of vasoconstrictive substances. Finally, a unique perspective as to the difficulties in interpretation of epidemiologic studies on uric acid and cardiovascular disease is provided by Short and Tuttle. In aggregate, these studies provide a challenging case for a true pathogenetic role of uric acid in the development of hypertension. The relationship of uric acid with renal disease also is discussed. Today we no longer see the gouty kidneys observed commonly until the 1960s, so that some investigators have proposed that the entity gouty nephropathy does not exist, but arose in the past from other factors such as lead poisoning. An alternative possibility that others have proposed for why gouty nephropathy may no longer be observed commonly could relate to the widespread use of allopurinol. However, most investigators had considered that gouty nephropathy (if indeed it existed) was mediated by intrarenal crystal deposition. However, this may not be the complete story. Experimental studies summarized by Kang and Nakagawa provide evidence that an increase in uric acid level in rats can cause renal disease via a crystal-independent pathway, and interesting data by Mazzali et al suggests that this may be a mechanism by which calcineurin inhibitors cause renal damage. Cameron and Simmonds also present a comprehensive review of the hereditary hyperuricemic conditions and their relationship with renal disease. Interestingly, familial juvenile hyperuricemic nephropathy is associated with renal damage without significant intrarenal crystal deposition, and although all do not agree with their conclusion, Cameron, as well as other investagators, have suggested that controlling uric acid levels early in this disease may help prevent progression of the renal disease. Interpretation of studies in this area remains problematic because we still have no comprehensive picture of urate handling in the renal tubule. Although the main proximal brush-border sodium-coupled urate reabsorptive carrier present in most mammals, including humans, has been cloned and localized, little is known of possible voltage-dependent secretory pathways, and, above all, almost no information exists on basolateral urate transport in human renal tubular cells. Finally, the interesting relationship of uric acid to preeclampsia is discussed by Lam et al, raising the possibility of a pathogenetic role of uric acid in this condition, and, similarly, the strong relationship between uric acid and overall outcomes in congestive heart failure is discussed by Doehner and Anker. Although all these studies provide tantalizing new evidence that uric acid may have a contributory role in hypertension and renal disease, there are numerous caveats one must recognize. One problem that has dogged experimental studies on urate in relation to human disease is that major species differences exist not only in the synthesis, but also in the metabolism and renal handling of urate. Thus, many of these studies were performed in rodents, in which uric acid metabolism is significantly different from that in humans. Rodents express uricase (a protein that is absent in humans owing to a genetic mutation), which degrades uric acid so that blood levels of uric acid in the rat are low, in the 1 to 2 mg/dL (60–120 μmol/L) range. Rodents also have more than 100 times the levels of xanthine oxidase. This may partially explain why most studies in humans suggest uric acid is only generated at certain sites (liver and intestine). Although xanthine oxidase mRNA and protein have been alleged to be present in trace amounts in other tissues, including vascular endothelium and smooth muscle, these probably represent homologous sequences of the closely related enzyme aldehyde oxidase. A further complication is that in humans, liver- or gut-derived xanthine oxidase circulates, and may bind to human vascular endothelium and produce urate in the local environment. Finally, although human blood vessels may not produce urate intracellularly as rat vascular cells do, urate-handling anion transporters are present on almost all human cells, which can import urate into the cells. Obviously, studies in which uricase inhibitors are administered to rats are of great interest, but these inhibitors may have effects independent of their ability to block uricase. Although such studies are of great interest, the ultimate proof as to whether uric acid has a causal role in hypertension and renal disease in humans can be obtained only by designing careful, prospective studies in which the effect of decreasing uric acid on blood pressure and renal function are determined. Nevertheless, the studies presented in this issue clearly show that this is an important and timely subject for investigation.