Hyperuricemia and Renal Disease

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Gout and renal disease exist with a bidirectional relationship: gout can cause renal disease and renal disease can cause gout. Numerous studies have found these 2 conditions to be linked; the symptomatic uric acid crystallization seen in gout likely increases the risk of renal disease. However, connecting asymptomatic hyperuricemia with an increased risk of renal disease is more controversial and studies evaluating this potential association have been limited and fraught with methodological inconsistencies. Even more controversial is whether clinicians should be treating asymptomatic hyperuricemia to reduce the risk of chronic kidney disease (CKD) and other associated comorbidities, such as cardiovascular disease and diabetes.

Iskei et al investigated the incidence of end-stage renal disease (ESRD) in more than 48,000 individuals with and without hyperuricemia from a cohort out of Japan. Results showed calculated incidences of ESRD of per 1000 individuals screened were:

  • 1.22 for men without hyperuricemia
  • 4.64 for men with hyperuricemia
  • 0.87 for women without hyperuricemia
  • 9.03 for women with hyperuricemia

When hazard ratio was adjusted for hyperuricemia, incidences were 2.004 in men and 5.770 in women. It was also found that hyperuricemia was an independent risk factor for ESRD in women.

There have been many other epidemiologic studies showing the association of high uric acid levels in patients who go on to develop CKD. Continuing debates center on whether hyperuricemia is an independent risk factor for CKD or a compounding risk factor along with other comorbidities such as hypertension and renal vascular damage.

The pathogenesis of renal damage from chronic hyperuricemia in humans includes the effects of oxidative stress, inflammation, endothelial dysfunction, and renal fibrosis. In rat studies, raising uric acid levels lead to elevated glomerular hypertension and renal disease by similar mechanisms. Some researchers argue that hyperuricemia is not the true cause of renal damage, but rather a precursor to hypertension by activating the renin-angiotensin pathway, decreasing endothelial nitric oxide, and increasing renal vascular oxidative stress. It also may be true that certain epigenetic factors—such as environment and diet—play a role in the development of CKD by affecting urate transport and production.

As stated above, treating asymptomatic hyperuricemia to the reduce risk of developing chronic renal disease is highly debated. A scientific workshop organized by the National Kidney Foundation in September 2016 reviewed current evidence on the topic. The report generated concluded that there was not enough reliable and strong clinical data to support treating asymptomatic hyperuricemia to prevent or slow progression of CKD in renal patients. Additionally, the American College of Rheumatology does not currently recommend treating hyperuricemia to prevent the development of CKD due to lack of concrete data. Further, the Gout, Hyperuricemia and Crystal-Associated Disease Network states that uricosuric agent efficacy and safety throughout the stages of renal function requires more study. Clearly, larger placebo-controlled studies are still needed to guide clinicians on whether to treat asymptomatic hyperuricemia in those genetically predisposed to, at high risk of developing, or currently being treated for CKD.

References
  • Iseki K, et al. Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort. Am J Kidney Dis 2004;44:642.
  • Johnson RJ, et al. Hyperuricemia, acute and chronic kidney disease, hypertension, and cardiovascular disease: Report of a scientific workshop organized by the National Kidney Foundation. Am J Kidney Dis. 2018;71:851.
  • Sanchez-Lozada LG, et al. Mild hyperuricemia induces vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats. Kidney Int. 2005;67:237.
  • Stamp LK, et al. Management of gout in chronic kidney disease: a G-CAN Consensus Statement on the research priorities. Nat Rev Rheum. 2021;17:633.
  • Su HY, et al. Research advances in the mechanisms of hyperuricemia-induced renal injury. Biomed Res Int. 2020;2020:5817348.

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Filed under: Curbside Consultations , Rheumatology

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