CME INDIA Presentation by Dr. N. K. Singh, MD, FICP, Diabetologist Physician, Director – Diabetes and Heart Research Centre (DHRC), Dhanbad, Chairman – RSSDI Jharkhand, Editor – CME INDIA.

Investigate Hyporuricemia?

Why is it strongly recommended that such individuals be considered for differential diagnosis of hypouricemia?

See this case scenario:

• 20-year-old previously healthy male .
• Developed exercise-induced acute kidney injury.
• A month before, he experienced multiple episodes of vomiting and severe back pain while participating in a 400-meter race.
• He was diagnosed with acute kidney injury.
• He reported a similar episode a few months before this.
• No history of any infectious illness, myalgias, seizures, hematuria, or illicit drug or alcohol use preceding this event.
• Initial laboratory assessment:
  • Blood urea nitrogen 28 mg/dL,
  • Creatinine 3.4 mg/dL, and
  • Serum uric acid (UA) 1.5 mg/dL;
  • Serum myoglobin, creatinine kinase, and aldolase were normal.
  • Urinalysis was unremarkable.
  • Renal function improved with fluid resuscitation, and creatinine returned to baseline, 1.0 mg/dL.
• What do you think about diagnosis of this case?

Why we are concerned?

• Uric acid (UA) is the final product of purine metabolism in humans.
• After reuptake in the renal proximal tubule, only 10% of filtered UA is eliminated in the urine. 
• Serum UA level is determined by the balance between the rate of purine metabolism and clearance.
• Hypouricemia can be caused by malnutrition or genetic predisposition.
• There are two forms of genetic predisposition:
  1. A functional disability in UA synthesis – Deficiencies of xanthine oxidase (XO), purine nucleoside phosphorylase (PNP), and 5-phosphoribosyl-pyrophosphate (PRPP) are related to the defects in UA synthesis.
  2. Defects in the UA reabsorption system.
• Inherited disorders of UA metabolism present as serious conditions. It can present as intellectual disability or immunodeficiency.
• Renal hypouricemia (RHUC) is asymptomatic Its identification is difficult in primary medical practice. Be careful if you get it presented as renal stone or exercised induced acute renal failure. The main cause is a defect in the UA reabsorption system.
• Differentiating between inherited and transient hypouricemia is challenging because a low level of UA reflects malnutrition status.

How we define hypouricemia?

• Hypouricemia is arbitrarily defined as a serum urate concentration of less than 2 mg/dL. 

What is RHUC?

• Renal hypouricemia (RHUC) is a pathological condition that is caused by faulty urate reabsorption transporters in the renal proximal tubular cells. It does not derive from congenital purine metabolism abnormalities or secondary hypouricemia.
• So far diagnostic guidance and guidelines for RHUC have been lacking, partly due to the low evidence level of studies on RHUC.

How common?

• Akaoka et al. from Japan first reported a case study of RHUC in 1975.
• It is known to be relatively common in the Japanese population.
• The prevalence of RHUC is estimated to be approximately 0.2% in males and 0.4% in females in Japan.
• RHUC is also reported in Jewish and Roma and East Asia populations.
• Recent genetic studies have identified faults in the URAT1/SLC22A12 and GLUT9/SLC2A9 urate transporter genes as causes of RHUC type 1 and type 2.

How presented?

• Mainly it is asymptomatic.
• One of its characteristics is a low serum uric acid (SUA) level.
• It is usually combined with increased renal excretion of uric acid.

How to approach Low Uric acid?

• If we detect a low serum uric acid (SUA) level, we should examine whether the patient’s SUA is lower than 2 mg/dl or not. It means we should reexamine the patient’s SUA level, because it sometimes varies according to their condition, and also test their urinary excretion of uric acid.
• Exclude drug-induced hypouricemia.
• If asymptomatic, think of only 2 conditions:
  1. RHUC. Most RHUC cases have been discovered by chance in health examinations that detect low SUA levels.
  2. Xanthinuria. A rare disease. It is distinguishable from other types of hypouricemia because it shows little urinary urate excretion.
• Clinical signs of urolithiasis and EIAKI often lead to an initial diagnosis of RHUC.

How to manage?

• EIAKI cases sometimes need hemodialysis treatment, but generally show transient and recurrent acute kidney injury (AKI), and receive the standard treatment for AKI.
• Allopurinol, a xanthine oxidoreductase (XOR) inhibiter, was administered in some case reports for preventive purposes, based on a hypothetic mechanism of its pathogenesis, although convincing evidence for its efficacy is lacking.(Ref. 2)
• For urinary stones, urinary alkalization using citrate compounds is an effective therapy , and drinking plenty of fluids is recommended for prevention.
• Should xanthine oxidoreductase (XOR) inhibitors be administered to prevent exercise-induced acute kidney injury (EIAKI) in patients with renal hypouricemia? Recommendation : It is not yet possible to make a hard-and-fast rule. However, XOR inhibitors might prevent the onset or relapse of EIAKI. Administration of XOR inhibitors should therefore be decided in the light of its potential benefits and harms, especially for athletes and high-risk patients with a past history of EIAKI attacks(2)

What are the main implications?

• The two key clinical issues:
  1. Diagnosis of RHUC.
  2. Prevention of exercise-induced acute kidney injury (EIAKI).

Diseases that cause hypouricemia

CME INDIA Learning Points

• Physicians should treat patients appropriately if they suffer complications of RHUC.
• RHUC complications are exercise-induced acute kidney injury (EIAKI) or urinary stones.
• In case RHUC patients do not have such complications, we should advise them that they are at risk of these complications and should therefore take action to prevent them.
• Remember that some mild RHUC patients show an SUA of 2.1–3.0 mg/dl, we should retest their SUA level and do ask if there is a familial history of RHUC.

Case Discussion (As per Ref 3)

• Clinical presentation in this case is strongly suggestive of hereditary renal hypouricemia.
• This is a genetic disorder.
• It is characterized by mutations in the human urate transporter 1 (hURAT1), encoded by SLC22A12 gene, or by impairment of the voltage urate transporter (URATv1), encoded by SLC2A9 (GLUT9) gene (3).
• Sanger sequencing of the most commonly implicated genes (SLC22A12 and SLC2A9), revealed only benign polymorphisms. In this patient only homozygous single nucleotide polymorphisms in SLC22A12 was found.
• Before his next race, he was prescribed allopurinol 300 mg daily for 3 days.
• He completed this race uneventfully.
• Allopurinol is better known for the management of hyperuricemia. The rationale for use of allopurinol in this hypouricemic patient was to decrease the generation of UA, thus, decreasing the filtered UA load and lowering the risk of precipitation of UA in the tubules.
• With this approach recurrence of renal injury was successfully prevented.

References:

1. Akaoka I, Nishizawa T, Yano E, Takeuchi A, Nishida Y. Familial hypouricaemia due to renal tubular defect of urate transport. Ann Clin Res. 1975;7(5):318–24
2. Akiyoshi Nakayama, Hirotaka Matsuo,Akira Ohtahara et al. Clinical practice guideline for renal hypouricemia (1st edition).Human Cell (2019) 32:83–87 https://doi.org/10.1007/s13577-019-00239-3
3. Bhasin B, Stiburkova B, De Castro-Pretelt M, Beck N, Bodurtha JN, Atta MG. Hereditary renal hypouricemia: a new role for allopurinol? Am J Med. 2014;127(1):e3–e4. https://doi. org/10.1016/j.amjmed.2013.08.025.

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