Q J Med 2003; 96: 867-868
© 2003 Association of Physicians
Correspondence |
Familial juvenile hyperuricaemic nephropathy
Sir,We would like to take this opportunity to provide some updated information regarding the pathogenesis of familial juvenile hyperuricaemic nephropathy (FJHN). There has been discussion in recent months in QJM as to whether hyperuricaemia is a primary or secondary effect of the disease.1,2 In a Letter to the Editor from QJM, February 2003,1 it was stated by Drs Puig and Torres that an ‘ ... unresolved aspect of FJHN is the gene defect.’ In December 2002, we reported mutation in the uromodulin gene as a cause of FJHN in three kindreds.3 We then identified an additional family with a mutation in the uromodulin gene as a cause of FJHN.4 Two other groups have subsequently confirmed our original report.5,6 While there is speculation that other genes may be responsible for this condition, no other genes have as yet been identified.
Uromodulin, better known as Tamm-Horsfall glycoprotein, is produced in the thick ascending limb of Henle.7 Despite many years of study, the function of Tamm-Horsfall protein remains unclear. It has been postulated to be important in main-taining the integrity of the thick ascending loop of Henle,8 binding to various cytokines,9 or preventing urinary tract infections.10 It has not been postulated to be involved in uric acid transport, and this would seem unlikely, as most uric acid transport occurs in the proximal tubule, and Tamm-Horsfall glycoprotein is localized to later portions of the tubule.
Identification of uromodulin mutations associated with FJHN has permitted us to definitively identify all mutation carriers in a given family, allowing us to characterize the variability in clinical presentation of the disease. Through studies of genotype-phenotype correlations in families segregating FJHN causing uromodulin gene mutations, we have been able to determine that not all individuals suffering from FJHN have hyperuricaemia.11 Several of our patients carrying a uromodulin gene mutation have suffered from progressive renal failure, despite having normal serum uric acid levels. Several family members have also had progressive renal disease despite the usage of allopurinol.
These results suggest that the hyperuricemia associated with FJHN is secondary to functional changes brought about by the mutation in the uromodulin gene, and that hyperuricaemia is not the primary disorder. In our experience, allopurinol does not stop progression, but whether it slows progression is difficult to determine, due to small sample sizes in all groups studied so far.
It is possible that other mutations may result in a clinical phenotype presenting as FJHN. For this reason, in order to prevent confusion, we suggest the term ‘uromodulin-associated kidney disease’ for those families with a uromodulin gene mutation. With regard to allopurinol responsiveness, families with a mutation in the uromodulin gene may not be responsive to allopurinol, whereas families with a mutation in other genes may be responsive. To this end, it would be most useful to know if uromodulin mutations are responsible for FJHN in the families reported by Puig and Fairbanks.1,2
School of Dental Medicine Division of Oral Biology University of Pittsburgh Pittsburgh USA
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Section on Nephrology Wake Forest University School of Medicine Winston-Salem USA e-mail: ableyer{at}wfubmc.edu School of Dental Medicine Division of Oral Biology University of Pittsburgh Pittsburgh USA
References
1. Puig JG, Torres RJ. Familial juvenile hyperuricaemic nephropathy. Q J Med 2003; 96:172–3.
2. Fairbanks LD, Cameron JS, Venkat-Raman G, Rigden SPA, Rees L, Van’t Hoff W, Mansell M, Pattison J, Goldsmith DJA, Simmonds HA. Early treatment with allopurinol in familial juvenile hyperuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal disease. Q J Med 2002; 95:597–607.
3. Hart TC, Gorry MC, Hart PS, Woodard AS, Shihabi Z, Sandhu J, Shirts B, Xu L, Zhu H, Barmada MM, Bleyer AJ. Mutations of the UMOD gene are responsible for med-ullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet 2002; 39:882–92.
4. Bleyer AJ, Trachtman H, Sandhu J, Gorry MC, Hart TC. Renal Manifestations of a Mutation in the Uromodulin (Tamm Horsfall Protein) Gene. Am J Kidney Disease 2003; in press.
5. Turner JJ, Stacey JM, Harding B, Kotanko P, Lhotta K, Puig JG, Roberts I, Torres RJ, Thakker RV. Uromodulin mutations cause familial juvenile hyperuricemic nephropathy. J Clin Endocrinol Metab 2003; 88:1398–401.[Abstract]
6. Casari G, Amoroso A. Molecular analysis of uromodulin and SAH genes, positional candidates for autosomal dominant medullary cystic kidney disease linked to 16p12. J Nephrol 2003; 16:459.
7. Kumar S, Muchmore A. Tamm-Horsfall protein-uromodulin (1950-1990). Kidney Int 1990; 37:1395–401.[Web of Science][Medline]
8. Hoyer JR, Sisson SP, Vernier RL. Tamm-Horsfall glycoprotein: Ultrastructural immunoperoxidase localization in rat kidney. Lab Invest 1979; 41:168–73.[Web of Science][Medline]
9. Muchmore AM, Decker JM. Uromodulin: An immunosuppressive 85 kD glycoprotein isolated from human pregnancy urine is a high affinity ligand for recombinant Il-1 alph. J Biol Chem 1986; 261:13404–7.
10. Orskov I, Ferencz A, Orskov F. Tamm Horsfall protein or uromucoid is the normal urinary slime that traps type I fimbriated Escherichia coli. Lancet 1980; 1:887.[Web of Science][Medline]
11. Bleyer AJ, Woodard AS, Shihabi Z, Sandhu J, Zhu H, Satko SG, Weller N, Deterding E, McBride D, Gorry MC, Xu L, Ganier D, Hart TC. Clinical characterization of a family with a mutation in the uromodulin (Tamm-Horsfall glycoprotein) gene. Kidney Int 2003; 64:36–42.[CrossRef][Medline]
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