The interplay of NAD+, hyperuricemia, and renal damage: A scientific review

Abstract

Identifying potential mechanisms by which hyperuricemia might cause kidney diseases is important, as it may help identify new therapies. Nicotinamide adenine dinucleotide (NAD⁺) is a coenzyme involved in hundreds of metabolic reactions, including bioenergetics, DNA repair, and gene expression. Hyperuricemia (HU) is a common metabolic disorder associated with the development of chronic kidney disease (CKD), beyond its well-established links to gout and kidney stones. Here, we review the complex relationship between NAD⁺ levels, HU, and renal damage. Uric acid (UA) crystal deposition induces a local inflammatory response linked to Toll-like receptor and inflammasome activation, while soluble UA drives mitochondrial and endothelial dysfunction, activation of the renin-angiotensin system, inflammation, and epithelial and endothelial-to-mesenchymal transition. Here we discuss how oxidative stress, mitochondrial dysfunction, and inflammation from HU can indirectly deplete intracellular NAD⁺ by increasing the activity of NAD⁺-consuming enzymes. Given NAD⁺´s critical role in kidney health, therapeutically increasing NAD⁺ levels through precursor supplementation (e.g., nicotinamide, nicotinamide riboside, nicotinamide mononucleotide) or inhibiting NAD⁺ consuming enzymes shows promise for preventing or treating HU-associated kidney damage. We recommend clinical trials to determine if increasing NAD⁺ levels can improve the management of HU-induced kidney disease.