Hyperuricemia may be the result of uric acid overproduction or diminished renal uric acid excretion (and as recently suggested apart from renal perhaps also non-renal urate excretion) (1).
Overproduction may be the result of genetic disease, e.g. HGPRT mutation (hypoxanthine-guanine phosphoribosyltransferase) or PRPPS mutations (phosphoribosyl-pyrophosphate synthase). Acquired conditions are myeloproliferative or lymphopoliferative disease and most frequently dietary causes interacting with genetic background.
Diminished renal excretion of urate may be caused by primary nephropathies causing renal failure or be caused by genetic variants of urate transporters; recent genome-wide association analyses (Köttgen, Nature Genetics, in press) had identified a number of loci coding for tubular reabsorption which are associated with elevated serum urate concentrations.
In the past lead intoxication was an important cause of elevated urate concentration, but this has virtually disappeared in Mid Europe.
Cases of familial hereditary disease causing hyperuricemia, e.g. familial juvenile hyperuricemic nephropathy type 1 (FJHN2), medullary cystic renal disease type 2 (MCKD2) or glomerulocystic renal disease are associated with progressive renal failure. There is currently uncertainty whether in these genetic diseases caused by urate transporter mutations Allopurinol causes less progression of renal function by reducing serum uric acid concentration (2, 3).
In the past, there had been discussions whether elevated serum uric acid concentration in chronic kidney disease (CKD) is pathogenetically irrelevant or whether it contributes to progressive reduction of renal function. The causal function of uric acid in mediating progression of CKD had been clearly documented in the remnant kidney model by Kang (4). One recently identified mechanism is uric acid induced epithelial to mesenchymal transition (Ryu, Am. J. Physiol. Renal, 2013 (e-pub).
Today, there is also increasing clinical evidence that uric acid concentrations (even within the range of normal concentrations) actively promote loss of renal function. Therefore current studies evaluate whether uric acid is a novel target for therapeutic intervention. On the one hand there is strong observational evidence that urate is a factor contributing to onset and progression of CKD: for instance in a recent 10.2 year follow-up study uric acid was a significant risk factor for CKD, at least in males, for individuals in the fourth quartile of serum uric acid concentration the risk of CKD was significantly (p < 0.0001) increased by a factor of 2.1 (5). Similarly a study in Taiwan (6) – confirmed in Thailand (Satirapoj, Nephrology, Carlton; in press) – showed that the risk of onset of chronic kidney disease is significantly increased by a factor of 1.03 (95% CI 1.1-1.6) per > 1 mg/dl higher serum uric acid concentration. In a health check-up study by Yamada (7) the onset of CKD was progressively higher from the first to the fourth quartile of serum urate concentration (1.00; 1.85; 2.57; 3.54) in males and in females as well. In cross-sectional studies, uric acid concentration is also correlated to the presence of CKD (8) and furthermore an increase of plasma uric acid concentration is correlated to the decrease of renal function, i.e. progression of CKD as shown in a prospective cohort study; in the 4th quartile, the adjusted odds ratio was higher by a factor of 2.86 and uric acid increase > 1 mg/dl was associated with a risk of CKD higher by 1.63 (CI 1.25-2.12) (9).
Apart from all-cause CKD, hyperuricemia has also been identified as a risk factor for progression of primary kidney diseases, e.g. IgA glomerulonephritis (10). The role of uric acid concentration in the progression of IgA-GN was underlined by a biopsy study: no deterioration of renal function was seen in the patients with a serum uric acid concentration < 7.5 mg/dl (11). In line with this observation indirect evidence suggests renal vasoconstriction triggered by uric acid in patients with IgA glomerulonephritis (12).
Furthermore a recent kidney biopsy study in 167 patients with CKD documented a significant correlation between tertiles of serum uric acid concentration and hyalinosis as well as wall thickening (13).
Similarly, serum uric acid concentration has been shown to predict the onset of diabetic nephropathy in individuals with type 1 diabetes (14) and was even a predictor of the onset type 2 diabetes in the off-spring cohort of the Framingham heart study (15). This has also been documented in a 15-year follow-up study (1986-2001) by Krishnan (16): individuals with a serum uric acid concentration > 7 mg/dl had a hazard ratio (HR) of 1.94 to develop diabetes, HR 1.46 to develop insulin resistance, and HR 2.15 to develop pre-diabetes. In a 5-year follow-up study on 449 type 2 – diabetic individuals with normal renal function and no proteinuria at baseline Zoppini (17) documented that hyperuricemia, defined as > 7 mg/dl in men and > 6.5 mg/dl in women, increased the odds ratio of developing kidney disease by a factor of 2.55 (CI 1.71-3.85; p < 0.001).
An adverse effect of serum uric acid on kidney damage has also been documented in recipients of kidney transplants (18) and in patients at risk of acute kidney injury: Lapsia (19) found that progressively higher serum uric acid concentrations were associated with a progressively higher incidence of AKI.
It deserves mentioning that recent evidence documents that elevated uric acid concentration increases the risk of acute kidney injury (19, 20).
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