Donor-Derived Hereditary Renal Hypouricemia

Renal hypouricemia (RHUC) results from mutations in urate transporter genes, notably URAT1/SLC22A12 and GLUT9 /SLC2A9, impairing tubular uric acid transport1Kikuchi Y. Koga H. Yasutomo Y. Kawabata Y. Shimizu E. Naruse M. et al.Patients with renal hypouricemia with exercise-induced acute renal failure and chronic renal dysfunction.Clin Nephrol. 2000 Jun; 53: 467-472Google Scholar. While mostly asymptomatic, 10% of patients are susceptible to exercise-induced acute kidney injury (EI-AKI) and/or nephrolithiasis2Ichida K. Hosoyamada M. Hisatome I. Enomoto A. Hikita M. Endou H. 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 JASN. 2004 Jan; 15: 164-173Google Scholar. Diagnosis relies on two biochemical parameters - serum uric acid (SUA) <2 mg/dl and FeUA >10%. We report the first case of donor-derived SCL2A9 mutation (RHUC 2) 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 0.3mg/dl) with high FeUA (95%), suggesting RHUC. She was born of non-consanguineous marriage and had no history of EI-AKI or nephrolithiasis (Figure S1). Whole exome sequencing (WES) in donor revealed compound heterozygous mutation in SLC2A9 gene associated with RHUC2, with R380W classified as pathogenic and I335N classified as variant of uncertain significance (Table S1). In silico prediction tools indicate that I335N variant is probably deleterious due to its conservation across different species. No pathogenic mutation attributable to etiology of end-stage kidney disease or RHUC was detected in recipient. After detailed counseling, kidney transplantation proceeded uneventfully. Patient was discharged with nadir creatinine of 0.8mg/dl with advice to avoid strenuous physical activity and dehydration. Post-transplant, recipient exhibited persistently low SUA (0.6mg/dl) and high FeUA (38%). Both donor and recipient have normal renal function at three-months post-transplant with no clinical manifestations of RHUC. Few successful kidney transplants from donors having RHUC 1 (URAT1 mutation) have been documented mostly from Japanese population3Tsuji K. Kitamura M. Muta K. Mochizuki Y. Mori T. Sohara E. et al.Transplantation of a kidney with a heterozygous mutation in the SLC22A12 (URAT1) gene causing renal hypouricemia: a case report.BMC Nephrol. 2020 Dec; 21: 282Google Scholar, 4Teng L. Zhang Y. Ye L. Lv J. Mao Y. Schneider R. et al.Donor-derived hypouricemia in irrelevant recipients caused by kidney transplantation.Ann Transl Med. 2020 Mar; 8 (330–330)Google Scholar, 5Miyauchi T. Terashita M. Ogata M. Murata M. Osako K. Imai N. et al.Renal hypouricemia in a recipient of living-donor kidney transplantation: a case report and literature review.CEN Case Rep. 2022 May; 11: 177-183Google Scholar (Table 1). Most of the recipients developed hypouricemia post-transplant with high FeUA levels, however none had EI-AKI or nephrolithiasis.Table 1Previous cases of donor-derived RHUCAuthor, yearSerum uric acid (mg/dl)FeUADonor mutated GeneVariantOutcomeKiyokazu Tsuji et al, 20203Tsuji K. Kitamura M. Muta K. Mochizuki Y. Mori T. Sohara E. et al.Transplantation of a kidney with a heterozygous mutation in the SLC22A12 (URAT1) gene causing renal hypouricemia: a case report.BMC Nephrol. 2020 Dec; 21: 282Google Scholar2.520.8%SLC22A12(NM_144585.4:c.269G > A (p.Arg90His)2 years post-transplant, creatinine is normal, serum uric acid 3.8mg/dl, FeUA 12.4%. No exercise induced AKI or urolithiasisLisha Teng et al, 20204Teng L. Zhang Y. Ye L. Lv J. Mao Y. Schneider R. et al.Donor-derived hypouricemia in irrelevant recipients caused by kidney transplantation.Ann Transl Med. 2020 Mar; 8 (330–330)Google Scholar0.8NASLC22A12p.R89H(c.G266A) and p.L181V(c.C541G)2 recipients – Patient 1 maintains Cr 0.9mg/dl, uric acid 1.1mg/dl, FeUA 44%Patient 2 Cr 0.9mg/dl, Cr 0.8, FeUA 75%Takamasa Miyauchi et al, 20215Miyauchi T. Terashita M. Ogata M. Murata M. Osako K. Imai N. et al.Renal hypouricemia in a recipient of living-donor kidney transplantation: a case report and literature review.CEN Case Rep. 2022 May; 11: 177-183Google Scholar0.659.7%SCL22A12Homozygous mutation W258XNo exercise induced AKIAt 9 months, Cr 0.95, serum UA is 1mg/dl and FEUA is 55Index case0.395%SLC2A9Compound heterozygous mutation c.1004T>A (p.Ile335Asn) in Exon 8 (VUS)c.1138C>T (p.Arg380Trp) in Exon 9 (Pathogenic)At 3-months post-transplant, serum uric acid is 0.6mg/dl and FeUA is 38%, no EI-AKI or urolithiasisDonor Cr 0.8mg/dl and SUA is 0.4mg/dl Open table in a new tab The R380W pathogenic variant, previously reported in heterozygous state in symptomatic individuals, typically maintains SUA between 1-3mg/dlS1,S2. Further studies at functional and molecular level are warranted to elucidate combined effect of the two variants which may have resulted in unusually low SUA levels in our patient. In conclusion, RHUC 1/2 should be suspected in hypouricemic patients with high FeUA. Prospective recipients from affected donors should be informed of potential risks. While sporadic reports exist, more research is needed on the implications of RHUC in transplantation. Consent We have obtained detailed informed consent from the patient and donor Financial support None Conflict of interest None Download .pdf (.11 MB) Help with pdf files