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Hereditary Renal Hypouricemia: A New Role for Allopurinol?
CLINICAL COMMUNICATION TO THE EDITOR
Hereditary Renal Hypouricemia: A New Role for Allopurinol? To the Editor: Hereditary renal hypouricemia is a genetic disorder characterized by defective renal handling of uric acid. The affected individuals are predisposed to recurrent episodes of exercise-induced non-myoglobinuric acute kidney injury and nephrolithiasis.
CASE REPORT An 18-year-old white, previously healthy male presented to the Nephrology clinic for evaluation of exercise-induced acute kidney injury. A month before presentation, he experienced multiple episodes of vomiting and severe back pain while participating in a 400-meter race. He was taken to the Emergency Department and diagnosed with acute kidney injury. He reported a similar episode a few months before this. There was no history of any infectious illness, myalgias, seizures, hematuria, or illicit drug or alcohol use preceding this event. Initial laboratory assessment in the Emergency Department showed: 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.
DISCUSSION The clinical presentation in this case is strongly suggestive of hereditary renal hypouricemia. This is a genetic disorder 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.1-5 This leads to excessive urinary Funding: The genetic analysis was performed by BS in her laboratory in the Czech Republic. This work was supported by a grant from the Czech Republic, The Ministry of Education, Youth and Sports (LH13245) and a grant from the Czech Republic, Ministry of Health (IGA MZ NT/11322–4/ 2010). Conflict of Interest: None. Authorship: All authors had access to the data and contributed to this manuscript. Requests for reprints should be addressed to Mohamed G. Atta, MD, MPH, Division of Nephrology, 1830 E. Monument Street, Suite 416, Baltimore, MD 21287. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2014 Elsevier Inc. All rights reserved.
wasting of UA and hypouricemia (serum UA levels <2.0 mg/dL).3 Potential mechanisms of acute kidney injury include increased UA production during exercise causing urate nephropathy, renal vasoconstriction following depletion of free radical scavengers including urate, or increased free radicals with ischemia reperfusion injury.2-4 During episodes of acute kidney injury, serum UA levels are inappropriately normal or low, as in this case. We performed Sanger sequencing of the most commonly implicated genes (SLC22A12 and SLC2A9), which revealed only benign polymorphisms. Additionally, sequencing of 11 other genes including ABCG2, MRP4, PDZK1, SLC22A13 (OAT10), and SLC22A11 (OAT4) was unrevealing. It is interesting to note that our patient had only homozygous single nucleotide polymorphisms in SLC22A12; thus, a partial deletion of the gene could not be ruled out. Urine hypoxanthine and xanthine levels were normal. We hypothesize that this patient might have a novel unknown mutation(s) in a urate transporter. Before his next race, we prescribed allopurinol 300 mg daily for 3 days. We measured pre- and postexercise labs (Table), and 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, we successfully prevented recurrence of renal injury. The patient was able to resume his athletic lifestyle without apprehension of repeat symptoms or recurrent acute kidney injury. Table Laboratory Values at Baseline and Pre- and Postexercise with Allopurinol Treatment Baseline Pre-exercise Postexercise Blood urea nitrogen, mg/dL 14 1.1 Serum creatinine (Scr), mg/dL Serum uric acid (SUA), mg/dL 1.3 Spot urine uric acid 104.5 (UUA), mg/dL Spot urine creatinine 241 (Ucr), mg/dL Fractional excretion of UA 38 (FEUA*), %
11 1.2 1.4 84
14 1.0 0.9 22
325
165
22
15
Normal FEUA at the patient’s age group is 15%. UA ¼ uric acid. *FEUA: (UUA X Scr)/ (SUA x Ucr).
e4
The American Journal of Medicine, Vol 127, No 1, January 2014 Bhavna Bhasin, MDa Blanka Stiburkova, PhDb Mauricio De Castro-Pretelt, MDc Natalie Beck, MGC, CGCc Joann N. Bodurtha, MD, MPHc Mohamed G. Atta, MD, MPHa a
Division of Nephrology Johns Hopkins University School of Medicine Baltimore, Md b Institute of Inherited Metabolic Disorders First Faculty of Medicine Charles University in Prague General University Hospital in Prague Prague, Czech Republic c McKusick-Nathans Institute of Genetic Medicine Johns Hopkins University School of Medicine Baltimore, Md
http://dx.doi.org/10.1016/j.amjmed.2013.08.025
ACKNOWLEDGEMENT We would like to acknowledge the contribution of Professor Kimiyoshi Ichida, Department of Pathophysiology, Tokyo
University of Pharmacy and Life Sciences, Tokyo, Japan and Division of Kidney and Hypertension, Jikei University School of Medicine, Tokyo, Japan. Prof. Ichida performed additional DNA sequencing analysis in his laboratory in Japan.
References 1. Sebesta I, Stiburkova B, Bartl J, et al. Diagnostic tests for primary renal hypouricemia. Nucleosides Nucleotides Nucleic Acids. 2011;30(12): 1112-1116. 2. Yan MT, Cheng CJ, Chen JS, Lin SH. The case: a young man with acute kidney injury after exercise. The diagnosis: exercise induced acute kidney injury in hereditary renal hypouricemia. Kidney Int. 2010;77(10): 935-936. 3. Ochi A, Takei T, Ichikawa A, et al. A case of acute renal failure after exercise with renal hypouricemia demonstrated compound heterozygous mutations of uric acid transporter 1. Clin Exp Nephrol. 2012;16(2): 316-319. 4. Dinour D, Gray NK, Campbell S, et al. Homozygous SLC2A9 mutations cause severe renal hypouricemia. J Am Soc Nephrol. 2010;21(1): 64-72. 5. Stiburkova B, Ichida K, Sebesta I. Novel homozygous insertion in SLC2A9 gene caused renal hypouricemia. Mol Genet Metab. 2011;102(4):430-435.
Hereditary Renal Hypouricemia: A New Role for Allopurinol? To the Editor: Hereditary renal hypouricemia is a genetic disorder characterized by defective renal handling of uric acid. The affected individuals are predisposed to recurrent episodes of exercise-induced non-myoglobinuric acute kidney injury and nephrolithiasis.
CASE REPORT An 18-year-old white, previously healthy male presented to the Nephrology clinic for evaluation of exercise-induced acute kidney injury. A month before presentation, he experienced multiple episodes of vomiting and severe back pain while participating in a 400-meter race. He was taken to the Emergency Department and diagnosed with acute kidney injury. He reported a similar episode a few months before this. There was no history of any infectious illness, myalgias, seizures, hematuria, or illicit drug or alcohol use preceding this event. Initial laboratory assessment in the Emergency Department showed: 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.
DISCUSSION The clinical presentation in this case is strongly suggestive of hereditary renal hypouricemia. This is a genetic disorder 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.1-5 This leads to excessive urinary Funding: The genetic analysis was performed by BS in her laboratory in the Czech Republic. This work was supported by a grant from the Czech Republic, The Ministry of Education, Youth and Sports (LH13245) and a grant from the Czech Republic, Ministry of Health (IGA MZ NT/11322–4/ 2010). Conflict of Interest: None. Authorship: All authors had access to the data and contributed to this manuscript. Requests for reprints should be addressed to Mohamed G. Atta, MD, MPH, Division of Nephrology, 1830 E. Monument Street, Suite 416, Baltimore, MD 21287. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2014 Elsevier Inc. All rights reserved.
wasting of UA and hypouricemia (serum UA levels <2.0 mg/dL).3 Potential mechanisms of acute kidney injury include increased UA production during exercise causing urate nephropathy, renal vasoconstriction following depletion of free radical scavengers including urate, or increased free radicals with ischemia reperfusion injury.2-4 During episodes of acute kidney injury, serum UA levels are inappropriately normal or low, as in this case. We performed Sanger sequencing of the most commonly implicated genes (SLC22A12 and SLC2A9), which revealed only benign polymorphisms. Additionally, sequencing of 11 other genes including ABCG2, MRP4, PDZK1, SLC22A13 (OAT10), and SLC22A11 (OAT4) was unrevealing. It is interesting to note that our patient had only homozygous single nucleotide polymorphisms in SLC22A12; thus, a partial deletion of the gene could not be ruled out. Urine hypoxanthine and xanthine levels were normal. We hypothesize that this patient might have a novel unknown mutation(s) in a urate transporter. Before his next race, we prescribed allopurinol 300 mg daily for 3 days. We measured pre- and postexercise labs (Table), and 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, we successfully prevented recurrence of renal injury. The patient was able to resume his athletic lifestyle without apprehension of repeat symptoms or recurrent acute kidney injury. Table Laboratory Values at Baseline and Pre- and Postexercise with Allopurinol Treatment Baseline Pre-exercise Postexercise Blood urea nitrogen, mg/dL 14 1.1 Serum creatinine (Scr), mg/dL Serum uric acid (SUA), mg/dL 1.3 Spot urine uric acid 104.5 (UUA), mg/dL Spot urine creatinine 241 (Ucr), mg/dL Fractional excretion of UA 38 (FEUA*), %
11 1.2 1.4 84
14 1.0 0.9 22
325
165
22
15
Normal FEUA at the patient’s age group is 15%. UA ¼ uric acid. *FEUA: (UUA X Scr)/ (SUA x Ucr).
e4
The American Journal of Medicine, Vol 127, No 1, January 2014 Bhavna Bhasin, MDa Blanka Stiburkova, PhDb Mauricio De Castro-Pretelt, MDc Natalie Beck, MGC, CGCc Joann N. Bodurtha, MD, MPHc Mohamed G. Atta, MD, MPHa a
Division of Nephrology Johns Hopkins University School of Medicine Baltimore, Md b Institute of Inherited Metabolic Disorders First Faculty of Medicine Charles University in Prague General University Hospital in Prague Prague, Czech Republic c McKusick-Nathans Institute of Genetic Medicine Johns Hopkins University School of Medicine Baltimore, Md
http://dx.doi.org/10.1016/j.amjmed.2013.08.025
ACKNOWLEDGEMENT We would like to acknowledge the contribution of Professor Kimiyoshi Ichida, Department of Pathophysiology, Tokyo
University of Pharmacy and Life Sciences, Tokyo, Japan and Division of Kidney and Hypertension, Jikei University School of Medicine, Tokyo, Japan. Prof. Ichida performed additional DNA sequencing analysis in his laboratory in Japan.
References 1. Sebesta I, Stiburkova B, Bartl J, et al. Diagnostic tests for primary renal hypouricemia. Nucleosides Nucleotides Nucleic Acids. 2011;30(12): 1112-1116. 2. Yan MT, Cheng CJ, Chen JS, Lin SH. The case: a young man with acute kidney injury after exercise. The diagnosis: exercise induced acute kidney injury in hereditary renal hypouricemia. Kidney Int. 2010;77(10): 935-936. 3. Ochi A, Takei T, Ichikawa A, et al. A case of acute renal failure after exercise with renal hypouricemia demonstrated compound heterozygous mutations of uric acid transporter 1. Clin Exp Nephrol. 2012;16(2): 316-319. 4. Dinour D, Gray NK, Campbell S, et al. Homozygous SLC2A9 mutations cause severe renal hypouricemia. J Am Soc Nephrol. 2010;21(1): 64-72. 5. Stiburkova B, Ichida K, Sebesta I. Novel homozygous insertion in SLC2A9 gene caused renal hypouricemia. Mol Genet Metab. 2011;102(4):430-435.