Because renal insufficiency can affect the excretion of serum uric acid, resulting in hyperuricemia, and severe renal pathological changes may interfere with the diagnosis of renal ischemic injury, we studied patients with IgAN and normal renal function. The results suggested that the prevalence or occurrence of glomerular ischemic lesions in patients with IgAN and hyperuricemia was significantly higher than in the normouricemia group. As serum uric acid levels increased, the prevalence or occurrence of glomerular ischemic lesions increased, and serum uric acid levels were an independent risk factor for glomerular ischemic lesions. In patients with IgAN, hyperuricemia may be associated with glomerular ischemia and participate in the process of renal injury.
There is evidence that persistent hyperuricemia can cause renal tissue changes, such as arteriolonephrosclerosis, glomerulosclerosis and renal tubular lesions, leading to chronic kidney disease [4, 5]. As Russo E et al. reported in a retrospective study, Serum uric levels are independently associated with AD and poor prognosis in patients with IgAN [6].One of the mechanisms serum uric acid aggravates renal ischemic injury may be the activation of the renin–angiotensin system. Renal artery stenosis is an important mediator of renal disease progression. It affects renal hemodynamics, increases glomerular perfusion pressure and promotes renal vascular smooth muscle hyperplasia, endothelial cell fibrosis and inflammatory cell infiltration [7, 8]. Uric acid can activate extracellular signal–regulated kinase (ERK1/2), accompanied by de novo induction of cyclooxygenase 2 (COX2) and local thromboxane synthesis. It can upregulate the mRNA levels of platelet-derived growth factor (PDGF) A and C chains and platelet-derived growth factor (PDGF)-α receptor. Uric acid can also stimulate monocytes to synthesise monocyte chemoattractant protein 1, which is a key chemotactic factor for vascular diseases and atherosclerosis. These inflammatory reactions may cause vascular smooth muscle damage and proliferation [9, 10]. Animal experiments have shown that hyperuricemia can directly promote vascular smooth muscle hyperplasia and thicken the afferent arterioles, and it can cause arterial contraction when serum uric acid levels are slightly elevated [11]. Other animal experiments show that In the kidney of hyperuricemic rats, endothelial staining in peritubular capillaries (PTC) was substantially decreased with de-novo expression of α-smooth muscle actin in endothelial cells of PTC. Serum uric induced a phenotypic transition of epithelial and endothelial cells via an induction of oxidative stress and glycocalyx shedding, which could be one of the mechanisms of uric acid-induced kidney disease [12]. Uric acid can damage the ability of endothelial cells to produce nitric oxide (NO), weakening vasodilation [13], enhancing endothelial cell oxidativ e stress and promoting endothelial cell apoptosis [14]. Changes in these blood vessels may cause stenosis or occlusion of small arteries, leading to glomerular ischemic pathological changes and further aggravating kidney injury. As Dong et al. reported in a study, Arterial-arteriolar sclerosis (AS) in patients with IgAN was independently associated with the poor prognosis, In the subgroup analysis, patients presenting with AS and higher uric acid had a significant trend for a shorter time to reach the end point [15].The narrowing of the lumen of small blood vessels can further enhance renin activity, resulting in a vicious cycle.
The incidence of hyperuricemia in the glomerular ischemic lesions group was significantly higher than in the non-glomerular ischemic lesions group. This may be because renal ischemia can lead to hypoxia in local tissues, increasing the production of lactic acid. Excessive lactic acid excretion competitively inhibits uric acid excretion, resulting in uric acid retention in the body and reducing urate clearance through the action of lactic acid [16]. Low renal blood flow perfusion stimulates the reabsorption of uric acid. Ischemia can also lead to increased uric acid synthesis; in an ischemic environment, ATP is decomposed into adenine and xanthine and more xanthine oxidase is generated.
This study has certain limitations. We only measured serum uric acid once; therefore, the assessment of the relationship between serum uric acid levels and IgAN glomerular ischemic lesions was not as accurate as possible. Furthermore, beside renal factors, excessive alcohol intake, a high-purine diet and the application of diuretics can also lead to hyperuricemia, and this study did not consider these factors. Finally, when serum uric acid concentration exceeds 410 µmol/L, uric acid in the plasma is saturated (at pH 7.4, temperature 37 °C and serum sodium under normal conditions). If serum uric acid concentration reaches saturation, these substances are prone to form crystals and accumulate in soft tissues. Therefore, some male patients may have hyperuricemia even if serum uric acid concentration is lower than 420 µmol/L.
In summary, serum uric acid levels of patients with IgAN are closely correlated with glomerular ischemic lesions, and the two may affect each other. Reducing the serum uric acid level may reduce the degree of glomerular ischemic injury.
