HPE Grunenthal handbook - Page 20

comorbidities Gout and chronic kidney disease: An emerging risk factor An increasing body of evidence has linked gout and hyperuricaemia to the development and progression of chronic kidney disease, and it is suggested that urate lowering therapy might not only reduce flares and chronic tophaceous gout but also protect kidney function and prevent deterioration Austin G Stack MD MSc FRCPI Department of Nephrology, University Hospital Limerick, Limerick, Ireland Gout is a common chronic polyarthritis that affects between 2% and 4% of the adult population and which causes significant pain and disability due to its effects on joints, tendons and bone. 1 The principal cause of gout is hyperuricaemia, a disorder of purine metabolism, which results in deposition of urate crystal in joints and initiates a chronic inflammatory response that is responsible for the phenotypic presentations. 2 A large body of evidence now incriminates both gout and its precursor, hyperuricaemia, in the pathogenesis of chronic kidney disease (CKD), a major chronic disease that contributes substantially to adverse clinical outcomes and considerably reduced life expectancies. 3–9 The definition of CKD, now well established in the wider clinical community, is the presence of pathologic abnormalities of kidney structure or function that persist for at least three months, usually a glomerular filtration rate (GFR) <60ml/min/1.73m 2 , or a urinary albumin-to- creatinine ratio (ACR) of >30mg/g. 10 For almost 60 years, it has been known that gout and hyperuricaemia are linked to the development of CKD and end-stage kidney disease (ESKD). Autopsy studies by Talbot and Terplan found pathological evidence of chronic kidney damage in almost all gout patients. 11,12 Prospective observational studies over the past decade have confirmed strong independent associations of uric acid with the development of new-onset CKD, progression of existing CKD, and rapid development of ESKD. 3–9 Other studies have also yielded strong relationships between gout and the risk of ESKD. 13,14 Even more compelling evidence is now available from clinical trials and quasi-experimental studies that demonstrate a slowing in the rate of kidney function decline and reduction in risk of ESKD following treatment with urate-lowering therapies. 15–20 Together these provide compelling evidence that uric acid and gout per se are major risk factors for CKD. Effective treatment of hyperuricaemia and gout treatment may afford protection and reduce the risk of ESKD. Pathophysiology of hyperuricaemia Hyperuricaemia is a byproduct of purine metabolism, and is the principal driver of gout. 2 Unlike most mammals, humans lack the enzyme uricase, and are unable to convert uric acid to an inactive metabolic for excretion. The degradation of the purine nucleotides to purine bases, guanine and hypoxanthine, and their subsequent metabolism results in the generation of uric acid. 21 This last step is under the enzymatic control of the oxidising enzyme, xanthine oxidase. 20 | 2018 | hospitalpharmacyeurope.com Under normal circumstances, the excretion of uric acid is through the gut and the kidney in order to maintain homeostasis. By far the greatest contributor to the excretion of uric acid is the kidney, which is responsible for two-thirds of the excretion, whereas the gut eliminates a third. These physiologic mechanisms are inadequate to eliminate the normal daily urate production and, consequently, serum uric acid levels have risen in human populations over time with substantial global variation. 22 Indeed, the average serum concentration of uric acid in normal populations is 400µmol/l (6.8mg/dl), which approaches the solubility threshold of urate in blood. Uric acid levels above this threshold precipitate out of serum and may deposit in tissues. The kidney is by far the most important regulator of uric acid excretion, excreting approximately 60% of daily production. 23 Transporters, such as URAT 1 and GLUT 9 in the proximal tubule are key regulators of urate movement into and out of the cell. Uric acid filters freely through the glomerulus and approximately 90% if the filtered load is reabsorbed through the proximal tubule. Tubular secretion in the S2 segment of the proximal tubule returns 50% of the filtered load back into the urinary space for excretion. Role of hyperuricaemia and gout in CKD Experimental evidence The contribution of hyperuricaemia to the development of kidney disease has been demonstrated in a series of elegant animal models. 24–26 In most animals, uric acid is degraded by uricase to allantoin and excreted. Unfortunately, this is not the case in humans, who lost the uricase enzyme over 15 million years ago due to mutation. In experimental rat models, hyperuricaemia induces the development of hypertension and the development of a specific afferent arteriopathy. Compared with controls, animals with experimentally induced hyperuricaemia experienced significant increases in afferent arteriolar wall thickness. 25 The severity of the arteriolar wall thickness correlated with systolic blood pressure and the degree of hyperuricaemia. Moreover, these models proved that hyperuricaemia led to activation of the renin–aldosterone system and a variety of pathological kidney abnormalities including: arteriolarsclerosis of the afferent arteriolar system, glomerular hypertrophy, and interstitial fibrosis. 24 The impact of hyperuricaemia in animals with pre-existing kidney disease was even more striking with acceleration of kidney disease,