HPE Grunenthal handbook - Page 21

ratio 3.12; 95% CI 2.29–4.25) among 21,457 healthy volunteers from the Vienna Health Screening Project followed for a period of seven years. 28 The strength of the relationship between uric acid and risk of CKD has been demonstrated in healthy subjects, both men and women, patients with and without diabetes, and in kidney transplant recipients. The results of these individual observational studies have been pooled together in recent meta-analysis. Sedaghat and colleagues systematically reviewed and analysed data from 11 prospective cohort studies. The pooled relative risk for incident CKD, defined as occurrence of GFR <60ml/min was 1.18, 95% CI 1.15–1.22) for every 1µmol/l increase in uric acid. 29 Some patients might be exposed to persistent hyperuricaemia over time while others may have a very time limited exposure. The uric acid trajectory that an individual is exposed to may determine their future risk of events. Tsai and colleagues analysed data from over 5000 CKD patients who were followed for a median of 31 months. CKD patients with the highest trajectories of uric acid experienced the greatest risk of kidney failure. Compared with patients in the low uric acid trajectory (average uric acid 5.6mg/dl), those in the highest trajectory (average uric acid 9.8mg/dl) had a 2.8-fold higher risk of progression to dialysis. 30 Collectively, this body of evidence links elevations in uric acid to the development of CKD and provides credible evidence that individuals with the highest levels incur the greatest risk. proteinuria and worsening glomerulosclerosis and tubulointerstitial disease. The causal association between hyperuricaemia and de novo kidney disease was further established when these animals were treated with urate lowering drugs, either allopurinol or febuxostat. 24–26 In these series of experiments, treatment with either allopurinol or febuxostat resulted in a lowering of uric acid, normalisation of systemic blood pressure and a reduction in the severity of the kidney damage. These series of biological experiments prove a strong independent association between hyperuricaemia and the development of hypertension and kidney disease, which can be mitigated or prevented by treatment with ULT. Epidemiological evidence The link between hyperuricaemia and gout and kidney disease has been carefully explored through several large epidemiological studies. Cross-sectional studies conducted in the general population have identified strong correlations between rising levels of uric acid and the prevalence of CKD (stage 2 or higher). 27 The prevalence of CKD stage 2 or higher was 52.5% for patients with sUA levels of 357–410µmol/l and increased to 86% among subjects with levels of 595µmol/l or higher. These studies suggested that, at the very least, CKD is very common among subjects with elevated levels of uric acid. Several large prospective studies have identified strong independent associations of elevated uric acid and risk of new-onset CKD or progression to ESKD. Obermayr et al found that a slightly elevated uric acid level (416–529µmol/l (7.0–8.9mg/dl)) was associated with a nearly doubled risk for incident kidney disease (odds ratio 1.74; 95% CI 1.45–2.09), and an elevated uric acid (>535µmol/l or ≥9.0mg/dl) was associated with a tripled risk (odds Novel insights to gout and risk of CKD Gout represents the cumulative burden of hyperuricaemia that has developed over many years. It is speculated that gout might further increase the risk of CKD compared with hyperuricemia alone, potentially mediated by higher urate burden, longer periods of exposure, repeated cycles of systemic inflammation from acute gout flares, and indeed greater exposure to non-steroidal anti-inflammatory drugs (NSAIDs). 14 Dissecting out the individual contribution of gout to the development of CKD is difficulty as gout patients tend to have several chronic diseases including higher prevalence of hypertension (68%), diabetes mellitus (15%), metabolic syndrome and cardiovascular risk factors, which are also risk factors for kidney disease. 31 The impact of gout on risk of kidney failure was explored in two recent large studies. Yu et al evaluated the association of gout with risk of ESKD using data from the National Taiwanese Insurance Database. 13 Adjusting for demographic factors, hypertension and diabetes, patients with gout experienced a 57% higher risk of ESKD compared to those without. A study by Stack et al analysed data from the UK Clinical Practice Research Database. 14 In this prospective cohort, adjusting for confounders, they found that patients with gout experienced a 29% higher risk of advanced CKD, where advanced CKD was defined as a composite of: doubling of serum creatinine, progression to eGFR <10ml/min, ESKD need for dialysis or kidney transplantation, and death associated with CKD. However, the strongest association was between gout and risk of ESKD, where patients experienced a 213% higher risk. These new data provide a more compelling argument that patients with gout experience significantly higher risks of kidney disease and progression to kidney failure. Does urate-lowering therapy reduce the risk of CKD? The benefits of lowering serum uric acid levels in hospitalpharmacyeurope.com | 2018 | 21