Q J Med 2004; 97: 106-107
© Association of Physicians 2004; all rights reserved.
Correspondence |
Familial juvenile hyperuricaemic nephropathy
Sir,The letter of Bleyer et al.1 raised two important questions regarding our families reported in QJM,2 with the syndrome termed familial juvenile hyperuricaemic nephropathy (FJHN). The first was the questionable efficacy of allopurinol, in view of its lack of effect in ameliorating the progression of the renal lesion in the single large kindred they reported recently,3 and second, whether similar uromodulin mutations are responsible for FJHN in our families in that report.
Our QJM paper reported our findings in our first eight kindreds, studied for from 10 to 36 years. The results stressed the importance of compliance with allopurinol treatment, and we note that the propositus in the kindred described by Bleyer et al.3 was a poor complier. The importance of compliance is illustrated by one of our families (K3) studied for 20 years, in which renal function actually improved on allopurinol—except for the one very poor complier whose renal function fell by 50% before being lost to further study. This family also provides an answer to their second question—do the mutations differ in our families? K3 has a proven mutation in hepatocyte nuclear factor-1ß on chromosome 17q.4
The two children of our UK kindred K1, studied since their Austrian mother (and uncle) presented with gout and died of renal disease in 1974, aged 36 years, have been on allopurinol since 1989. They were followed up annually, and with hindsight would have been treated from the start had we then recognised that the low FEur was the hallmark of FJHN, rather than a raised plasma urate as Bleyer et al. imply. Since taking allopurinol, both siblings have maintained a stable, if slightly reduced, renal function.2 This kindred does have a linkage to chromosome 16q,5 and interestingly is a branch in the UK of the Innsbruck family mentioned by Lhotta,6 and reported by Turner et al.7 as having a heterozygous 481T-C mutation in the uromodulin gene. The case history of this Austrian branch of our kindred—the sister and nephew of our propositus—also underlines the importance of early recognition and treatment with allopurinol. FJHN was unrecognized and untreated until the GFR had fallen to 38 ml/min in the mother, that of the son being 58 ml/min at diagnosis.3 A combination of benzbromarone and allopurinol has stabilized the renal function in both, despite the very low GFR in one.6 Importantly, none of the other members of our families in the QJM paper now studied for up to 36 years have, like the kindred of Bleyer et al.,3 progressed to ESRD.
Regarding mutations, only one other kindred in the QJM paper has shown linkage to 16q,5 but a similar linkage has also been found in two of our other kindreds not listed in QJM. It remains difficult to understand how a defect in a protein located only in the ascending limb of the renal tubule could affect urate tubular reabsorption directly, since this is believed to be complete by the end of the proximal tubule, principally via a sodium-coupled anion exchanger.8 One possibility is that the voltage-dependent secretory pathway, postulated as being defective in FJHN, might have a wider distribution, although all studies to date also confirm the proximal tubule as being the main site of urate secretion as well.8
In summary, we disagree with the statement that allopurinol does not stop the progression of the renal lesion in the syndrome of FJHN: although controlled evidence is inevitably lacking in such a rare disorder, none of our patients would now be parted from their tablets! The crucial factors are earliest possible recognition/treatment, rigorous compliance with that treatment, plus earliest possible control of hypertension should it develop, and in young women—another factor often overlooked—the avoidance of contraceptive therapy of a type aggravating the condition, as it did in our family K2. Genetic analysis of our kindreds also helps to answer the second question—there is no single gene defect responsible for the syndrome of FJHN.
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Purine Research Renal Unit Guy's Hospital London e-mail: lynette.fairbanks{at}kcl.ac.uk
References
1. Bleyer AJ, Hart TC. Familial juvenile hyperuricaemic nephropathy. Q J Med 2003; 96:867–8.
2. Fairbanks LD, Cameron JS, Venkat-Raman G, et al. Early treatment with allopurinol in familial juvenile hyperuricaemic nephropathy (FJHN) ameliorates progression of renal disease in long-term studies. Q J Med 2002; 95:597–607.
3. Bleyer AJ, Woodard AS, Shihari Z, et al. Clinical characterisation of a family with a mutation in the uromodulin (Tamm-Horsfall glycoprotein) gene. Kidney Int 2003; 64:36–42.[CrossRef][Medline]
4. Bingham C, Ellard S, van’t Hoff WG, Simmonds HA, Marinaki AM, Badman MK, Winocour PH, Stride A, Lockwood CR, Nicholls AJ, Owen KR, Spyer G, Pearson ER, Hattersley AT. Familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1ß gene mutation. Kidney Int 2003; 63:1645–51.[CrossRef][Web of Science][Medline]
5. Stiburkova B, Majewski J, Hodanova K, Ondrova L, Jerabkova M, Zikanova M, Vylet’al P, Sebesta I, Marinaki A, Simmonds HA, Matthijs G, Fryns JP, Torres R, Puig JG, Ott J, Kmoch S. Familial juvenile hyperuricaemic nephropathy (FJHN): linkage analysis in 15 families, physical and transcriptional characterisation of the FJHN critical region on chromosome 16p11.2 and the analysis of seven candidate genes. Eur J Hum Genet 2003; 11:145–54.[CrossRef][Medline]
6. Lhotta K. Stopping progression of familial juvenile hyperuricaemic nephropathy with benzbromarone? Kidney Int 2003; 64:1920–1.[Medline]
7. Turner JJO, Stacey JJO, Harding B, et al. Uromodulin mutations cause familial juvenile hyperuricaemic nephropathy. J Clin Endocrinol Metab 2003; 88:1398–401.[Abstract]
8. Roch-Ramel F. Renal transport of organic anions. Curr Opin Nephrol Hypertens 1998; 7:517–24.[Web of Science][Medline]
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