Asymptomatic Hyperuricemia and the Kidney: Lessons from the URRAH Study

Abstract

Chronic kidney disease (CKD) is a prevalent global health concern affecting approximately 850 million people worldwide, with a significant and rising mortality rate. CKD often coexists with hyperuricemia (HSUA), which is also increasingly common due to its association with hypertension, obesity, and diabetes. The interplay between hyperuricemia and CKD is complex; while in vitro studies and animal models support a role for uric acid mediating glomerular and tubule-interstitial damage, and HSUA has been shown to predict the onset and progression of CKD, the expectations of renal protection by the use of urate lowering treatment (ULT) are inconsistent. A significant challenge in managing asymptomatic HSUA in CKD patients lies in determining the appropriate SUA threshold values. Recent research, including the URRAH project, has sought to identify SUA cut-offs predictive of cardiovascular mortality, but these thresholds may vary depending on the severity of CKD. This variability complicates the establishment of universal guidelines for treating asymptomatic HSUA, leading to a lack of specific recommendations in clinical practice. In conclusion, while hyperuricemia is recognized as a prognostic factor for CKD and cardiovascular risk, more research is needed to refine the threshold values for SUA and to identify which patients may benefit from ULT. Stratification based on glomerular filtration rate may be necessary to tailor the treatments and improve outcomes in this population.

Keywords: cardiovascular risk; cut-offs; kidney disease; uric acid.

Figure 1

Kidney involvement in hyperuricemia. In the context of symptomatic hyperuricemia (left side of the figure), the etiological role of HSUA levels in developing kidney diseases is related to urate monosodium crystals deposition, which can lead to urate nephropathy and nephrolithiasis. In this setting, the crystallized form of uric acid works as an activator of immune responses, triggering inflammation and ultimately causing chronic kidney disease. It has been proposed that the asymptomatic form of hyperuricemia has relevant clinical implications for the kidneys as well (right side of the figure). One hypothesis is that HSUA levels may directly affect the kidneys through the pro-oxidative and pro-inflammatory effects of soluble urate, which activates the innate immune system. Moreover, UA can induce endothelial dysfunction and increase the activity of the renin-angiotensin system; these proposed mechanisms might eventually lead to arteriosclerosis, glomerulosclerosis, and interstitial fibrosis. In addition to that, UA may have an indirect effect on renal function, i.e., by inducing hypertension and CV disease, which subsequently cause CKD. Abbreviations. RAS: renin-angiotensin system; ROS: reactive oxygen species; HSUA: high serum uric acid; UA: uric acid; CV: cardiovascular; CKD: chronic kidney disease.