To the Editor:
Renal hypouricemia (RHUC) results from disease causing variations in urate transporter genes, notably URAT1/SLC22A12 and GLUT9 /SLC2A9, impairing tubular uric acid transport.1 Although mostly asymptomatic, 10% of patients are susceptible to exercise-induced acute kidney injury and/or nephrolithiasis.2 Diagnosis relies on 2 biochemical parameters, serum uric acid (SUA) <2 mg/dl and fractional excretion of uric acid (FeUA) >10%. We report the first case of donor-derived RHUC due to a single nucleotide change in SLC2A9 gene in a kidney transplant recipient.
A 29-year-old Indian male with advanced kidney disease due to chronic glomerulonephritis presented seeking kidney transplantation. During evaluation for donation, his mother exhibited severe hypouricemia (SUA of 0.3 mg/dl) with high FeUA (95%), suggesting RHUC. She was born of nonconsanguineous marriage and had no history of exercise-induced acute kidney injury or nephrolithiasis (Supplementary Figure S1).
Clinical exome sequencing in the donor revealed compound heterozygous variant in SLC2A9 gene associated with RHUC 2, with R380W classified as pathogenic and I335N classified as variant of uncertain significance (Supplementary Figure S1 and Supplementary Table S1). In silico prediction tools indicate that the I335N variant is probably deleterious due to its conservation across different species. No pathogenic or likely pathogenic mutation attributable to the etiology of end-stage kidney disease or RHUC was detected in the recipient. However, the variant of uncertain significance (VUS) is inherited from the mother.
After detailed counseling, kidney transplantation proceeded uneventfully. The patient was discharged with nadir creatinine of 0.8 mg/dl with advice to avoid strenuous physical activity and dehydration. Posttransplant, the recipient exhibited persistently low SUA (0.6 mg/dl) and high FeUA (38%). Both the donor and the recipient have normal renal function at 3 months posttransplant with no clinical manifestations of RHUC.
Few successful kidney transplants from donors having RHUC 1 (URAT1 mutation) have been documented mostly from Japanese population3, 4, 5 (Table 1). Most of the recipients developed hypouricemia posttransplant with high FeUA levels; however, none had exercise-induced acute kidney injury or nephrolithiasis.
Table 1.
Previous cases of donor-derived RHUC
| Author, yr of publication | Serum uric acid (mg/dl) | FeUA | Donor mutated Gene | Variant details | Outcome |
|---|---|---|---|---|---|
| Tsuji et al.3, 2020 | 2.5 | 20.8% | SLC22A12 | c.269G > A (p.Arg90His) in heterozygous state | 2 yr posttransplant, creatinine is normal, serum uric acid 3.8mg/dl, FeUA 12.4%. No exercise induced AKI or urolithiasis |
| Lisha Teng et al.4, 2020 | 0.8 | NA | SLC22A12 | c.266G>A; (p.Arg89His) and c.541C>G; (p.Leu181Val) in compound heterozygous state | 2 recipients – patient 1 maintains Cr 0.9 mg/dl, uric acid 1.1 mg/dl, FeUA 44% patient 2 Cr 0.9 mg/dl, Cr 0.8, FeUA 75% |
| Takamasa Miyauchi et al.5, 2021 | 0.6 | 59.7% | SCL22A12 | A homozygous variant resulting in Tyr258∗ (variant details not mentioned) | No exercise induced AKI At 9 mo, Cr 0.95, serum UA is 1 mg/dl and FEUA is 55% |
| Index case | 0.3 | 95% | SLC2A9 | c.1004T>A; (p.Ile335Asn) and c.1138C>T; (p.Arg380Trp) in compound heterozygous state |
At 3 mo posttransplant, serum uric acid is 0.6 mg/dl and FeUA is 38%, no EI-AKI or urolithiasis Donor Cr 0.8 mg/dl and SUA is 0.4 mg/dl |
AKI, acute kidney injury; Cr, creatinine; EI, exercise-induced; FeUA, fractional excretion of uric acid; RHUC, renal hypouricemia; SUA, serum uric acid; UA, uric acid.
The R380W pathogenic variant, previously reported in heterozygous state in symptomatic individuals, typically maintains SUA between 1 to 3 mg/dl.S1,S2 Further studies at functional and molecular levels are warranted to elucidate combined effect of the 2 variants, which may have resulted in unusually low SUA levels in our patient.
In conclusion, RHUC 1 or 2 should be suspected in hypouricemic patients with high FeUA. Prospective recipients from affected donors should be informed of potential risks. Although sporadic reports exist, more research is needed on the implications of RHUC in transplantation.
Patient Consent
We have obtained detailed informed consent from the patient and donor.
Footnotes
Supplementary References.
Figure S1. Pedigree chart.
Table S1. Whole exome sequencing report of donor and patient.
Supplementary Material
Supplementary References. Figure S1. Pedigree chart. Table S1. Whole exome sequencing report of donor and patient.
References
- 1.Kikuchi Y., Koga H., Yasutomo Y., et al. Patients with renal hypouricemia with exercise-induced acute renal failure and chronic renal dysfunction. Clin Nephrol. 2000;53:467–472. [PubMed] [Google Scholar]
- 2.Ichida K., Hosoyamada M., Hisatome I., et al. Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol. 2004;15:164–173. doi: 10.1097/01.asn.0000105320.04395.d0. [DOI] [PubMed] [Google Scholar]
- 3.Tsuji K., Kitamura M., Muta K., et al. Transplantation of a kidney with a heterozygous mutation in the SLC22A12 (URAT1) gene causing renal hypouricemia: a case report. BMC Nephrol. 2020;21:282. doi: 10.1186/s12882-020-01940-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Teng L., Zhang Y., Ye L., et al. Donor-derived hypouricemia in irrelevant recipients caused by kidney transplantation. Ann Transl Med. 2020;8:330. doi: 10.21037/atm.2020.02.140. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Miyauchi T., Terashita M., Ogata M., et al. Renal hypouricemia in a recipient of living-donor kidney transplantation: a case report and literature review. CEN Case Rep. 2022;11:177–183. doi: 10.1007/s13730-021-00647-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
Supplementary References. Figure S1. Pedigree chart. Table S1. Whole exome sequencing report of donor and patient.