Gout is a painful inflammatory arthritis that affects the general population. However its morbidity and consequences of its treatment poses a greater healthcare burden on patients with chronic kidney disease. Numerous studies have demonstrated that hyperuricemia is associated with a reduced estimated GFR and one study has suggested that adults with eGFR < 60ml/kg/1.73 m2 are at 2-fold increased risk of developing hyperuricemia. Animal and human studies suggest that urate may play a significant role in cardiovascular disease [1], hypertension [2], and progression of renal disease [3]. The latter is controversial. Murray and Goldberg [4] suggested that 11% of the cases of chronic interstitial nephritis were primarily due to disorders of uric acid metabolism. However, Yu and Berger [5] could not demonstrate that there was such an association and felt that chronic interstitial nephritis could be attributed to hypertension, stones, aging and vascular disease. Whether chronic hyperuricemia alone can lead to interstitial disease is controversial. This is important as so many patients with chronic kidney disease have serum uric acid levels above 10 mg/dl. This is attributed to either declining glomerular filtration rate or to diuretics. The 2007-2008 data from NHANES revealed that 8.3 million Americans are affected by gout, of which 71% had CKD stage greater than stage 2 (GFR < 60). The prevalence of CKD stage 3 or greater in gout was 19.9%. Inclusion of proteinuria in the definition of CKD has led to investigation of prevalence of gout in patients with proteinuria. Juraschek et al. [6] found a graded positive relationship between gout and albuminuria and Krishnan et al. [7] stated that proteinuria is independently associated with increased risk of gout. Studies have shown that 5% of dialysis patients develop gout in the first year of dialysis and 15.4% will develop gout within the first 5 years of dialysis. Although reduced kidney function can precede the development of gout [8], gout may also adversely impact renal function. This has prompted several studies that have evaluated the adequacy of treatment of gout [9]. Many have found that the treatment of gout within the CKD population to be sub-optimal. For example, the German CKD study [9] reported about 30% of CKD patients with gout received no uric acid lowering medications. Here we will review the mechanism of renal urate handling and management of gout in the CKD population.

The kidney is responsible for more than 70% of urate excretion. It has an enormous capacity for urate secretion and the hyperuricemia in gout most commonly results from an undersecretion rather than overproduction of uric acid. Multiple studies have evaluated the transporters involved in the renal handling of urate, and genome-wide association studies have now provided a better understanding of the molecular mechanism of urate handling. Human studies have shown that urate in plasma is minimally bound to proteins and almost 100% freely filterable at the glomerulus into the renal tubule. In steady state only 5% to 10% of filtered urate is excreted in the urine. Interestingly, the kidney maintains this excretion rate in the face of an increased urate concentration, which underscores the remarkable capacity of the kidney to increase its urate reabsorption. Moreover, 99% of the filtered urate can be reabsorbed even if the filtered load is increased fourfold [10].

Renal Urate Reabsorption: Sodium dependent absorption of lactate and other monocarboxylate anions increases the intracellular concentration of anions that exchange with luminal urate. High levels of circulating levels of lactate, ketones, nicotinate and pyrazinoate result in increased uptake at the apical membrane and a secondary increase in apical urate-anion exchange, which results in hyperuricemia. URAT1 is the predominate urate-anion exchanger in the luminal membrane of the proximal tubule. It is localized to the brush border membranes of renal proximal tubule cells. URAT1 is inhibited by uricosuric agents such as probenecid and benzbromarone as well as by losartan. GLUT 9 is a voltage-dependent urate transporter located on the basolateral membrane of proximal tubule. Both URAT1 and GLUT9 are inhibited by losartan in vitro. It has been observed clinically that this effect is not a drug class effect but is specific to losartan, as the oocyte studies have shown that URAT1 and GLUT9 are inhibited by losartan and not by valsartan [11].

Renal Urate Secretion: ABCG2, adenosine triphosphate binding cassette transporter 2, is a multidrug resistant transporter that is localized in the apical membrane of the proximal tubular cells and mediates urate secretion across the apical membrane [12]. NPT1 (Sodium phosphate transporter 1) is located in the proximal tubule apical membrane and has been shown to transport both phosphate and urate. The NPT4 (Sodium phosphate transporter 4) has also been shown to be localized in the apical membrane of renal proximal tubule cells, and to transport urate. Diuretics interact with NPT4 and alter renal urate handling. Both thiazide and loop diuretics can directly inhibit NPT4-mediated urate secretion.

Factors that affect serum urate level: Exposure to high altitude increases serum urate levels. Alcohol intake increases serum lactate and beta-hydroxy butyrate levels causing indirect activation of renal urate reabsorption, increasing serum urate levels. Volume depleted state causes hyperuricemia. Both short term and long term salt restriction in humans causes significant hyperuricemia, which is dramatically reversed by salt loading. Excessive parathyroid hormone levels reduce urate excretion in primary hyperparathyroidism, and urate excretion is also reduced during the pharmacological treatment of osteoporosis [13].

Gouty arthritis patients have multiple co-morbidities. For example, review of the Veterans Affairs medical database showed that 47% had chronic kidney disease [13]. The National Health and Nutrition Examination Survey [13] revealed that 9% of patients with gouty arthritis had renal impairment. As noted previously, it is not clear if hyperuricemia plays a role in the pathogenesis of CKD or if it is simply a marker of the disease. Nevertheless the management of gouty arthritis requires a dual approach: management of inflammation and management of hyperuricemia. Typically treatment of inflammation is reserved for acute gouty attacks, but anti-inflammatory therapy may also be needed to control chronic low grade inflammation during inter-attack periods. Urate lowering therapy is necessary to maintain uric acid levels below its solubility level (< 6 mg/dl) in order to prevent acute gout attacks. Treatment choices in the management of acute gout are as follows.

EULAR (European League Against Rheumatism) guide-lines [16] and recommendations for NSAIDs are as follows for the different stages of chronic kidney disease: NSAIDs are relatively contraindicated in CKD stage I-II. If they are used, the suggested dose is indomethacin 50 mg three times a day or an equivalent NSAID until pain becomes tolerable. It is not to be used for more than a week, and the dose should be rapidly reduced to zero. Caution is advised in CKD stage III. Creatinine levels should be monitored carefully. NSAIDS are generally not recommended in stage IV-V because of the adverse effect they can have on renal function.

Lowering serum uric acid levels to less than 6mg/dl in CKD patients with gout has a tendency to reduce acute gouty flares. The presence of CKD does not alter the need to reach this goal; however, levels less than 5 mg/dl may be more appropriate in advance disease. Treatment options in the treatment of chronic gouty arthritis for lowering serum uric acid levels are as follows:

The authors confirm that this article content has no conflict of interest.