How The Kidneys Are Destroyed Step By Step By High Uric Acid

The harm of high uric acid to the kidney

Hyperuricemia (HUA) causes kidney damage and is divided into the following three types:

1. Acute uric acid nephropathy is due to the deposition of a large number of uric acid crystals in the renal interstitium and renal tubules, and the renal tubules are filled and blocked by uric acid, resulting in oliguric acute renal failure. It is common in secondary gouty nephropathy, such as lytic tumor syndrome.

2. Chronic uric acid nephropathy is caused by the deposition of urate crystals in the renal medulla, which is common in primary gouty nephropathy, and Lao Li belongs to this type.

3. Uric acid kidney stones can be seen in both primary and secondary gouty nephropathy.

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At present, it is believed that the mechanism of HUA causing kidney damage is as follows:

Activation of the renin-angiotensin system (RAS) and cyclooxygenase 2 (COX-2) systems

High uric acid activates RAS, leading to systemic hypertension and glomerular high pressure, hyperperfusion, and renal fibrosis. Angiotensin Ⅱ (Ang Ⅱ) can regulate the expression of COX-2 and the production of prostaglandins through the mitogen-activated protein kinase (MAPK) signal transduction pathway, and then induce the proliferation, hypertrophy, and Inflammatory cell infiltration of the vessel wall.

Dysfunction of endothelial cells

Uric acid inhibits the production of nitric oxide (NO) in endothelial cells and reduces its activity through a series of complex mechanisms. As the most abundant antioxidant in the body, it directly consumes a large amount of NO and produces 6-aminouracil, resulting in abnormal endothelial cell function, weakening the vasodilation effect, and slowing down the proliferation of endothelial cells, thereby causing hypertension and vascular disease.

The role of inflammatory factors

As a pro-inflammatory factor, uric acid can stimulate the synthesis of platelet-derived growth factor (PDGF) and promote monocytes to produce monocyte chemoattractant (MCP-1), interleukin-1 (lL-1) and tumor necrosis factor (TNF-ɑ) and other inflammatory factors, and these inflammatory factors are directly or indirectly involved in kidney damage.

obesity

The incidence of gout in obese patients is 2 times higher than that of the general population. The adipocytokines secreted by fat in the human body can activate the sympathetic nervous system, weaken urinary sodium excretion through RAS and the physiological concentration of the kidneys, and enhance renal tubular sodium reweighting. Absorption leads to sodium and water retention leading to high blood pressure, leading to a glomerular hyperfiltration state. In addition, Leptin, TNF-α, and IL-6 secreted by adipose tissue directly promote inflammation and cause kidney damage.

lipid metabolism disorder

Lipid deposition in epithelial cells stimulates the production and release of cytokines, directly stimulates epithelial cells to produce extracellular matrix, and participates in the damage of renal tubular epithelium through oxidation, prompting epithelial cells to synthesize a variety of cytokines related to inflammation and fibrosis, or Indirect involvement in chronic progressive lesions of the renal tubules and interstitium.

In addition, the study also found that lead exposure in the environment, changes in urate transporter activity, and genetic factors are also related to the development of gouty nephropathy.

HUA can not only cause kidney damage through the above-mentioned mechanism but also be an independent progression factor of IgA nephropathy, diabetic nephropathy, chronic kidney disease, acute kidney injury, etc., which will accelerate the progress of kidney damage in the above diseases[3].

Treatment of Gouty Nephropathy

lifestyle therapy

Lose weight, limit purine-rich meats, and seafood, limit foods high in fructose, don't eat too much low-fat or nonfat dairy, and limit alcohol to control HUA. Clinical studies have shown that only lifestyle changes can reduce SUA levels by 10% to 18%[3,4].

medical treatment

Drugs that inhibit the uric acid synthesis

Allopurinol

At present, it is still the first-line drug for the treatment of hyperuricemia, with a strong uric acid-lowering effect, good tolerance, and high-cost performance. Its metabolite oscypurine is the main component of reducing uric acid, and it is mainly excreted by the kidneys. When renal function declines, the dose should be appropriately reduced to avoid serious side effects caused by accumulation in the body. In recent years, allopurinol has been reported case of fatal drug eruption. Studies have shown that the occurrence of this adverse reaction is related to those with positive HLA-B*5801 alleles. It is recommended to perform genetic testing on patients before medication, which largely limits its application.

febuxostat

Also known as febuxostat, it can reduce blood uric acid by inhibiting the activity of xanthine oxidase, preventing and reducing the synthesis of uric acid from hypoxanthine and xanthine. Unlike allopurinol, febuxostat is mainly metabolized in the liver, and a small part is excreted by the kidneys. For mild to moderate renal insufficiency, there is no need to adjust the dosage. It is suitable for those who are allergic to allopurinol or who cannot tolerate it or are ineffective in treatment. Recommended for the treatment of chronic hyperuricemia with a history of gout.

Drugs that promote uric acid excretion

These drugs increase the excretion of uric acid by inhibiting the reabsorption of urate ions by the proximal renal tubule, thereby reducing the concentration of urate in the blood, alleviating or preventing the formation of urate crystals, reducing joint damage, and Promoting the dissolution of urate crystals that have formed.

Representative drugs are benzbromarone and probenecid. These drugs increase the risk of urinary tract stones. When using these drugs, pay attention to drinking more water and using drugs that alkalize urine. Before using such drugs, the excretion of urinary uric acid should be measured. If the patient’s 24-hour urinary uric acid excretion is >3.54 mmol or has urinary calculi, such drugs should be contraindicated, and should be used with caution in patients with ulcer disease or renal insufficiency. In addition, benzbromarone has liver toxicity, and attention should be paid to monitoring the patient's liver function during application.

Uricase drugs

Uricase can oxidize and degrade uric acid into allantoin, which may reduce the blood uric acid level and achieve the purpose of treating hyperuricemia. At present, recombinant uricase has gradually improved in terms of antigenicity and half-life, and it will become a new way to reduce uric acid. The biosynthetic uric acid oxidase mainly includes:

Recombinant Aspergillus flavus urate oxidase (rasburicase)

For the treatment and prevention of acute hyperuricemia in patients with hematological malignancies with high-risk tumor lysis syndrome, especially for patients with chemotherapy-induced hyperuricemia. The level of blood uric acid in patients treated with this drug decreased rapidly and remained at a low level throughout the induction chemotherapy period.

Pegylated recombinant urate oxidase (PEG-uricase)

Intravenous injection can quickly and powerfully reduce blood uric acid. It is mainly used for severe HUA, and refractory gout, especially for patients with tumor lysis syndrome. The representative drug is pegloticase, which is a pegylated uric acid-specific enzyme. Uricase is bound to polyethylene glycol through a monomethyl ether covalent bond and is mainly excreted by the kidneys.

other

In addition, drugs such as colchicine, losartan, fenofibrate, and cilnidipine also have the effect of lowering uric acid.

The increase in serum creatinine also made Lao Li realize the importance of actively controlling diet and cooperating with physicians in the treatment of gouty nephropathy. Since then, his gout attacks have decreased, and his renal function has also recovered and has stabilized at around 160 μmol/L.

for more information:ali.ma@wecistanche.com