Q J Med 2003; 96: 172-173
© 2003 Association of Physicians
Correspondence |
Familial juvenile hyperuricaemic nephropathy
‘La Paz’ University Hospital, Madrid, Spain e-mail: jgarciapuig{at}navegalia.com
Sir,
Fairbanks et al.1 raise three contentious aspects concerning familial juvenile hyperuricaemic nephropathy (FJHN): (a) whether the reduced urinary uric acid excretion is the cause or the result of the renal disease; (b) whether allopurinol prevents renal deterioration; and (c) the gene defect underlying the disturbance of uric acid under-excretion. Our most recent studies may shed some light on these questions and clarify the basis of the pathogenic hypothesis that we have proposed.2
In their discussion, the authors criticize our hypothesis that FJHN may be a consequence of a primary disruption of renal hemodynamics because ‘it rests on the measurement of the filtration fraction which was obtained with the para-aminohippurate clearance to derive renal plasma flow and urate and hippurate share tubular transporters’. This is incorrect. We did not formulate our pathogenic hypothesis based on the results of the filtration fraction. In fact, as stated in our main publication,2 the filtration fraction was found to be normal. We elaborated this hypothesis on the basis of several findings, including histological, biochemical and radiological findings. Ischaemic changes were documented in the three kidney biopsies belonging to three patients from an affected kindred (collapse of the glomerular tufts, dilation of the capsular spaces eventually filled with hyaline material). A diminished renal plasma flow and increased renal vascular resistances was seen not only in the patients from five kindreds, but also in obligate carriers with normal serum urate concentrations and glomerular filtration rates.3 In addition, ultrasound imaging and colour Doppler studies among 24 subjects belonging to five kindreds clearly showed a disturbance of renal haemodynamics, evidenced by a pulsatility index and a velocity blood pressure index that had positive and negative predictive values of 82% and 87%, and 92% and 63%, respectively.4 These data do not allow the firm establishment of a pathogenic sequence of events but, in our opinion, do support a disturbance of renal haemodynamics as a cardinal event in FJHN.
Fairbanks et al. believe that allopurinol prevents renal deterioration by reducing serum urate levels. We respect their opinion, but our experience is just the opposite: among 12 patients from three kindreds followed over 1–6 years, half were treated and half were not treated with allopurinol,5 depending on whether they had gout or not. Mean baseline serum urate was similar in both groups (7.5 and 7.2 mg/dl). Mean serum urate in the six treated patients was 4.6 mg/dl, and remained below 6.0 mg/dl throughout the follow-up study (29 patient-years). Mean baseline serum creatinine was 2.0 mg/dl in allopurinol-treated patients and increased to 4.5 mg/dl. In non-treated patients, baseline serum creatinine was 1.4 mg/dl and increased to 2.1 mg/dl during the follow-up (15 patient-years).5 Thus, our experience does not support a nephroprotective effect of allopurinol in FJHN.
The third unresolved aspect of FJHN is the gene defect. A FJHN locus has been localized to chromosome 16p11–12 by linkage studies in European and Japanese families. By means of positional mapping studies, we have recently contributed to the finding of a peak LOD score of +4.93 between FJHN and the locus D16S417 at a recombination fraction of 0%.6 Analysis of the haplotypes located the disease to a 2 Mb interval flanked centromerically by D16S3113 and telomerically by D16S403, and containing more than 20 genes. None of the currently identified urate transporter genes map to this region. Thus, other urate transporters should be identified or, alternatively, it is possible that the FJHN gene defect may influence tubular urate transport.
References
1. 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.[Web of Science]
2. Puig JG, Miranda ME, Mateos FA, Picazo ML, Jiménez ML, Calvin TS, Gil AA. Hereditary nephropathy associated with hyperuricemia and gout. Arch Intern Med 1993; 153:357–65.
3. Mateos FA, Puig JG on behalf of the Spanish group for the study of FNAH. Rena hemodynamic in familial nephropathy associated with hyperuricemia (FNAH). Adv Exp Med Biol 1995; 370:31–4.
4. Prieto C, Berrocal T on behalf of the Spanish group for the study of FNAH. Ultrasound imaging and colour doppler studies in familial nephropathy associated with hyperuricemia (FNAH). Adv Exp Med Biol 1995; 370:65–8.
5. Miranda ME on behalf of the Spanish group for the study of FNAH. The influence of allopurinol on renal deterioration in familial nephropathy associated with hyperuricemia (FNAH). Adv Exp Med Biol 1995; 370:61–4.
6. Kamatani N, Moritani M, Yamanaka H, Takeuchi F, Hosaya T, Itakura M. Localisation of a gene for familial juvenile hyperuricaemic nephropathy causing underexcretion-type gout on Chromosome 16p12 by genome-wide linkage analysis of a large family. Arthritis Rheum 2000; 43:923–9.
7. Stiburková B, Majewski J, Sebesta I, Zhang W, Ott J, Kmoch S. Familial juvenile hyperuricaemic nephropathy: localisation of the gene on chromosome 16p11.2 and evidence for genetic heterogeneity. Am J Hum Genet 2000; 6:1989–94.
8. Stacey JM, Turner JJO, Harding B, Nesbit MA, Kotanko P, Lhotta Torres RJ, Puig JG, Thakker RV. Genetic mapping studies of familial juvenile hyperuricaemic nephropathy (FJHN) on chromosome 16p11-12. J Clin Endocrinol Metab 2003; in press.
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