Introduction
Familial juvenile hyperuricemic nephropathy was first described by Duncan and Dixon in the year 1960. It is reported to be one of the rare hereditary conditions affecting the kidney, with only 50 families reported so far in the literature as affected by this condition. It is characterized by abnormally high uric acid levels in the blood. The symptoms of the disease manifest during childhood and the progression of the disease would result in renal failure. The majority of patients undergo dialysis or even die at around 30 to 40 years of age due to the advent of kidney failure.
What Is Familial Juvenile Hyperuricemic Nephropathy?
It is a rare disorder affecting the kidneys with an autosomal dominant inheritance pattern. It is characterized by high levels of uric acid in the blood and decreased excretion of uric acid in the urine. Mainly caused due to the mutations in the genes responsible for maintaining the uric acid balance. It is one among the group of disorders called familial urate-associated nephropathies (FUAN).
What Is an Autosomal Dominant Inheritance Pattern?
Autosomal dominant inheritance pattern, in which one copy of a mutated gene from either parent is enough to cause the disease. A parent with a mutated gene has a 50 % chance of passing the disease to their children.
What Is the Etiology of Familial Juvenile Hyperuricemic Nephropathy?
Studies report that the mutation in the UMOD gene is responsible for the causation of the disease. The locus for that gene is located on chromosome 16p12.
What Is the Pathogenesis of Familial Juvenile Hyperuricemic Nephropathy?
The UMOD gene provides instructions for producing a protein called uromodulin, also known as Tamm-Horsefall protein (glycosylphosphatidylinositol (GPI) -anchored protein). It is a glycoprotein produced by the renal tubular epithelial cells in the thick ascending limb of the loop of Henle in the kidneys. Urate is filtered by the glomerulus and reabsorbed in the renal tubules, with only ten percent of it being excreted in the urine. The mutation occurring in this gene will affect the uromodulin synthesis, thereby causing retention of the protein in Henle's loop. This results in improper filtration of waste products leading to increased levels of uric acid in the blood (hyperuricemia) and decreased excretion of uric acid in the urine. The increased uric acid levels in the blood will lead to the deposition of the urate crystals in the interstitial tubules of the kidney, causing tubulointerstitial nephritis. As the disease progresses, it develops into a fulminant end-stage renal disease.
What Is Hyperuricemia?
Hyperuricemia is the increased uric acid level in the blood with a level of more than 6.8 mg/dl. It may occur due to two reasons either due to increased production or decreased excretion of uric acid in the urine.
What Are the Symptoms of Familial Juvenile Hyperuricemic Nephropathy?
The symptoms of this condition include;
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Hyperuricemia - Increased uric acid levels in the blood, above 6.8 mg/dl.
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Chronic Tophaceous Gout - Is caused due to the chronic deposition of uric acid crystals around the joints forming white growths or mass.
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Joint Pain - Severe joint pain may occur as a result of gout affecting the joints.
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Swelling - Maybe due to tophus formation in the joint and the skin secondary to gout.
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Hypertension - As a result of impaired kidney function and the disrupted mechanisms that maintain the blood pressure in hypertension.
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Hyperuricosuria - Decreased urinary excretion of uric acid.
What Are the Criteria Followed to Diagnose This Disorder?
According to Dahan et al., the following three criteria are necessary to diagnose the condition and includes,
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The affected patient shows an autosomal dominant inheritance pattern of the disease, with two related family members suffering from chronic renal failure.
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Other hereditary conditions causing nephropathy should be excluded.
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There should be a history of hyperuricemia and chronic gout in patients affected by the disease.
How Is Familial Juvenile Hyperuricemic Nephropathy Diagnosed?
1. Blood Test
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Hyperuricemia - Increased uric acid levels in the blood.
2. 24-Hour Urine Examination - This would reveal less excretion of uric acid in the urine.
3. Plain X-ray - This would reveal the presence of white tophaceous mass around the joints.
4. Fluid Aspiration - Aspirated fluid from the joint space would reveal the presence of monosodium urate crystals and inflammatory cells.
5. Ultrasound of the Kidney - May reveal the presence of cysts of varying sizes in a few cases.
6. Microscopic Examination - Would reveal the features of chronic tubulointerstitial nephropathy with focal fibrosis of the interstitium, atrophy of the tubules, and the presence of chronic inflammatory cell infiltrate with irregular membrane thickening.
7. Genetic Testing - To confirm the gene mutation in the UMOD gene located at the locus 16p12.
What Are the Differential Diagnosis of Familial Juvenile Hyperuricemic Nephropathy?
The other conditions which also show hyperuricemia and other related symptoms to familial juvenile hyperuricemic nephropathy include:
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Lesch Nyhan Syndrome - It is characterized by overproduction of uric acid and neurological abnormalities.
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Kelley Seegmiller Syndrome - It is caused due to the partial deficiency of an enzyme called hypoxanthine-guanine phosphoribosyltransferase. This enzyme is involved in the purine metabolism; deficiency of this would result in increased urate levels in the blood.
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Medullary Cystic Disease - It is characterized by the formation of numerous fluid-filled cysts in the kidneys, thereby affecting the filtering capacity of the kidneys. This, in turn, causes improper excretion of uric acid in the blood leading to hyperuricemia.
What Are the Complications of Familial Juvenile Hyperuricemic Nephropathy?
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Chronic Gouty Nephropathy - It may occur due to chronic deposition of urate crystals in the joint.
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Chronic Renal Failure - Chronic renal failure develops around middle age as a consequence of the prolonged increase in serum uric acid levels. Their deposition in the interstitial tubules, thereby reducing the glomerular filtration rate, deteriorating kidney function, and progressing to end-stage renal disease.
How Is Familial Juvenile Hyperuricemic Nephropathy Treated?
There is no specific treatment for juvenile hyperuricemic nephropathy; treatment is aimed at reducing the symptoms, the steps in management include,
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Allopurinol - It is given to treat the symptoms of gout and reduces the progression of the disease.
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Colchicine - It is used to reduce the build-up of uric acid crystals in the body.
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Paracetamol - It is given to decrease the pain; NSAIDs should be avoided to reduce the chance of renal failure.
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Intramuscular Steroids - Are given to reduce the pain and swelling in the joints.
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Antibiotics - Are given to reduce the risk of infection secondary to the infected tophi.
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General Measures - Patients are advised to take plenty of fluids and have a diet low in proteins.
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Antihypertensives - Are prescribed to treat increased blood pressure.
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Dialysis or Renal Transplantation - It is indicated in patients who have progressed to renal failure.
Conclusion
Familial juvenile hyperuricemic nephropathy is a rare hereditary disorder associated with increased uric acid levels in the blood. The symptoms start to appear in childhood, and the prognosis is bad as it progresses to end-stage renal disease in middle age. Most patients affected with this disease undergo dialysis at around 30 to 40 years of age as a consequence of renal failure. Early diagnosis and symptomatic treatment would help in better survival.
