Hyperuricemia refers to a condition where serum uric acid levels exceed 420 μmol/L in males and 360 μmol/L in females on two separate fasting tests under a normal purine diet. Hyperuricemic kidney damage is classified into acute hyperuricemic nephropathy, chronic hyperuricemic nephropathy, and uric acid kidney stones. Approximately 2/3 of uric acid is excreted by the kidneys, while the remaining 1/3 is excreted through the gastrointestinal tract.
Pathogenesis
Common causes of hyperuricemia include:
- Genetic Factors: Familial hyperuricemic nephropathy, hypoxanthine-guanine phosphoribosyltransferase deficiency, etc.
- Dietary Factors: High-purine diets, high-fructose diets, and long-term excessive alcohol consumption.
- Drug Factors: Thiazide diuretics, loop diuretics, cyclosporine, tacrolimus, pyrazinamide, etc.
- Volume Depletion
- Hypoxemia
- Myeloproliferative Disorders: Such as polycythemia vera.
- Other Factors: Including renal failure, obesity-induced metabolic syndrome, and intense physical activity.
Acute hyperuricemic nephropathy is often observed in patients undergoing chemotherapy or radiotherapy for malignant tumors. High concentrations of uric acid exceed the reabsorption capacity of the proximal tubules, leading to uric acid crystal formation in the tubular lumen, causing obstruction and acute kidney injury.
The mechanisms of chronic hyperuricemia-induced kidney damage include increased uric acid excretion causing tubular interstitial damage or kidney stone formation, uric acid crystals triggering inflammatory responses, preglomerular arteriole lesions, renal inflammation, and activation of the renin-angiotensin system and cyclooxygenase-2 (COX-2).
In patients with hyperuricosuria, insufficient solubility of uric acid in the urine results in precipitation and deposition, leading to stone formation.
Pathology
Light Microscopy
In the early stages, urate crystals are observed in the loops of Henle and collecting ducts. Subsequently, tubular epithelial cell damage and disintegration occur, with urate crystals depositing in the renal interstitium. This leads to secondary lymphocytic and mononuclear cell infiltration, multinucleated giant cell formation, and fibrosis. In polarized light microscopy, bright white spots are visible. With disease progression, thickening of renal arteriole walls, luminal narrowing, and glomerulosclerosis may develop. In routine sections, urate crystals dissolve, leaving only radiating, colorless, starburst-like structures. In frozen sections or tissue fixed with pure ethanol, blue needle-shaped crystals can be observed. Immunopathology shows no specific findings, while electron microscopy reveals starburst-like crystals within tubular epithelial cells and the renal interstitium.
Clinical Manifestations
Acute hyperuricemic nephropathy typically occurs 1–2 days after chemotherapy or radiotherapy for malignant tumors. The most common symptoms include nausea, emesis, lumbar pain, abdominal pain, oliguria, or even anuria. Features of tumor lysis syndrome, such as azotemia, hyperkalemia, and lactic acidosis, are often present simultaneously. Urinalysis frequently reveals uric acid crystals.
Patients with chronic hyperuricemic nephropathy usually have long-standing hyperuricemia and recurrent gout attacks. Early kidney damage is often insidious, presenting as decreased urine concentrating ability, with no formed elements in the urinary sediment and negative or trace proteinuria. Chronic kidney disease gradually develops over time. When glomerular filtration function remains normal, the fractional excretion of uric acid increases.
The most common symptoms of uric acid kidney stones are renal colic and hematuria, though they are also frequently detected incidentally during physical examinations. Physical examination may reveal tophi or gouty arthritis.
Diagnosis and Differential Diagnosis
Acute Hyperuricemic Nephropathy
This condition is commonly observed 1–2 days after chemotherapy or radiotherapy for tumors and presents as oliguric acute kidney injury accompanied by severe hyperuricemia, with serum uric acid levels often exceeding 893 μmol/L. Differentiation from drug-induced acute interstitial nephritis is often required.
Chronic Hyperuricemic Nephropathy
A history of typical gout, progressive kidney function impairment, and minimal changes in urinalysis may raise suspicion of chronic hyperuricemic nephropathy. Renal pathology, in light microscopy, can reveal urate deposition in the kidney, aiding in diagnosis. Differential diagnosis involves excluding other causes, such as lead poisoning, and distinguishing it from chronic kidney disease (CKD)-induced hyperuricemia. In CKD-induced hyperuricemia, kidney damage typically precedes hyperuricemia, and fractional excretion of uric acid is often reduced.
Uric Acid Kidney Stones
Diagnosis requires confirmation of kidney stones, followed by determining whether they are uric acid stones. Uric acid stones are radiolucent on X-rays and are referred to as "negative stones."
Treatment
Acute Hyperuricemic Nephropathy
Prevention is the primary approach. Xanthine oxidase inhibitors, such as allopurinol or febuxostat, can be administered 3–5 days prior to chemotherapy or radiotherapy to reduce uric acid production. Recombinant uricase (rasburicase) may also be used to convert uric acid into the more water-soluble end product allantoin, thereby lowering serum uric acid levels. In cases of hyperuricemia, the aforementioned drugs can be used, along with hydration, diuretics, and urine alkalization to reduce uric acid deposition. Severe cases may require hemodialysis.
Chronic Hyperuricemic Nephropathy
Uric acid-lowering therapy is necessary and includes:
- Reducing dietary purine intake.
- Inhibiting uric acid production with xanthine oxidase inhibitors, such as allopurinol and febuxostat. Allopurinol is primarily excreted by the kidneys, and its dosage should be adjusted based on GFR in cases of renal impairment. Severe drug rash is a serious adverse reaction to allopurinol, with a mortality rate of 20%–25%. The HLA-B*5801 allele is a high-risk genetic marker for this reaction. Febuxostat is metabolized via both hepatic and renal pathways.
- Promoting uric acid excretion with uricosuric agents such as benzbromarone, which is suitable for patients with significantly reduced fractional excretion of uric acid.
- Enhancing uric acid breakdown with agents such as uricase.
For patients with CKD and gout, treatment can follow the principles of gout management. Whether asymptomatic hyperuricemia in CKD requires uric acid-lowering therapy remains controversial.
Uric Acid Kidney Stones
The treatment aims to reduce the size of existing stones and prevent new stone formation. Management includes a low-purine diet, the use of allopurinol or febuxostat to lower serum uric acid levels, and urine alkalization.
Prognosis
Acute hyperuricemic nephropathy has a favorable prognosis with timely prevention and treatment. Chronic hyperuricemic nephropathy is closely associated with hypertension and cardiovascular and cerebrovascular diseases. Without timely intervention, it may progress to end-stage renal disease.
Prevention
In addition to controlling dietary purine intake and using medications to lower serum uric acid levels, comprehensive management of comorbid conditions such as hypertension, anemia, and electrolyte imbalances is essential. This approach can prevent or reverse the progression of hyperuricemic kidney damage and improve patient outcomes.