Q J Med 2002; 95: 597-607
© 2002 Association of Physicians
Early treatment with allopurinol in familial juvenile hyerpuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal disease
From the 1 Purine Research Unit GKT, Departments of 2 Renal Medicine and 3 Paediatric Nephrology, Guy's Hospital, London, 4 Department of Paediatric Nephrology, Great Ormond Street Children's Hospital, London, 5 Middlesex Hospital, London, and 6 Renal Unit, St Mary's Hospital, Portsmouth, UK
Received 18 December 2001 and in revised form 2 May 2002
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Background: The efficacy of allopurinol in autosomal dominant familial juvenile hyperuricaemic nephropathy (FJHN) has been disputed.
Aim: To address this question, in the absence of controlled trials.
Design: Retrospective long-term follow-up study.
Methods: All kindreds were biochemically screened. Measurements included uric acid clearance, creatinine clearance, serum creatinine, and glomerular filtration rate (GFR). We used five siblings who had died or progressed to transplantation, ten other deceased relatives, and two index cases (one untreated, one non-compliant) as controls to assess the effects of allopurinol.
Results: Of eight families with FJHN, six had a strong history of renal disease and early parental death (mean age 41 years, n=10). Of 27 patients started immediately on allopurinol and treated uninterruptedly, 21 responded well, including three children born subsequently. Eight siblings (mean age 19 years) with a normal plasma creatinine at start (<120 µmol/l, mean GFR 80 ml/min/1.73 m2) retained stable renal function (mean 14.5 years, mean age 34 years, GFR 85 ml/min/1.73 m2). Of the 13 other responders, treated for up to 34 years, 10 with a creatinine <200 µmol/l at diagnosis (mean age 28 years, mean creatinine 137 µmol/l at start) now have a mean creatinine of 210 µmol/l. In contrast, five patients (mean age 26 years) with a creatinine >200 µmol/l (GFR <35 ml/min/1.73 m2) when allopurinol commenced, plus one untreated index case, all progressed rapidly (mean 6 years) to end-stage renal failure. In two others (one non-compliant, one initially untreated), GFR fell by >50% in 7 years. Introduction of allopurinol in the latter has stabilized GFR.
Discussion: Allopurinol reduced the morbidity and mortality from renal failure seen in untreated siblings and previous generations of these families. Early diagnosis of FJHN is important, so that treatment can begin before irreversible renal damage has developed.
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Introduction |
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The syndrome of familial juvenile hyperuricaemic nephropathy (FJHN)—a dominant disorder with high penetrance and progressive renal disease—was first described in 1960 in a family with gout, hyperuricaemia and renal disease.1 However, presentation is not always with gout, and unusually for gout, FJHN affects young men, women and children equally. The main diagnostic criterion is a universally reduced fractional excretion of urate (FEur, uric acid clearance factored by creatinine clearancex100) of 5.1±1.6%, irrespective of age or gender;2 FEur in healthy UK children being 18.4±5.1%, much higher than in either adult females 12.8±2.9% or males 8.1±3.2%.2 Although well-defined, FJHN is still not well-recognized clinically (reviewed in reference 3). The hallmark of this disease is dominantly inherited hyperuricaemia resulting from the grossly reduced FEur—even lower than that seen in the predominant type of gouty patient, the middle-aged male.2–7 The association of this reduced FEur with very early onset of renal disease is another feature which distinguishes FJHN, not only from ‘primary gout’, where renal function is generally normal for age,7 but also from other autosomal dominant nephropathies, which generally present in early middle age.3,8,9 Previous generations in our FJHN kindreds were considered to have ‘familial renal disease’ of unknown aetiology, and were treated only for this. More recently, an attack of gout,2–6 an equally unusual event in renal disease, and especially in young women and children,2 has drawn attention to such kindreds, enabling correct diagnosis and offering the opportunity of treatment with allopurinol.2–6
There are three main contentious points relating to FJHN. One is whether the reduced FEur and resultant hyperuricaemia are the cause, or the result, of the renal disease.3,10 The second is whether there is any beneficial effect of allopurinol treatment on renal function.10–13 The third is what gene(s) may be responsible for the low FEur.3,9 Miranda et al. could detect no beneficial effect of allopurinol in three kindreds followed at intervals over one to 9 years.10,12,13 Our previous follow-up studies, in a larger number of kindreds and at intervals ranging from 5 to 29 years, questioned this.14–17
Studies in children in these families showed that hyperuricaemia plus a reduced FEur is found in 50% of apparently healthy siblings still with normal renal function, which suggests uric acid as a causative agent in this nephropathy.2 If hyperuricaemia is the primary event, it would explain the beneficial effect of allopurinol suggested in our first report in 198014 and confirmed in three subsequent follow-up studies in 1991, 1997 and 1998.15–17
Since the publication of those reports, we have diagnosed many more families, now numbering nearly 50, and instigated allopurinol therapy. However, the period of study for these kindreds is of necessity short (1–9 years);2 consequently, they are not included in the present report. Nevertheless, allopurinol is proving equally beneficial. We focus here on eight of the first kindreds, because they have now been studied regularly for a median of 17.2 years (range 10–34). One patient, allergic to allopurinol, has been treated successfully with benzbromarone—a potent uricosuric10,11 while another is now on a combination of allopurinol and benzbromarone.
Because of the rarity of FJHN, there are no prospective randomized controlled trials examining the role of allopurinol in prevention of renal functional decline. In order to try to answer this question we have compared the fate of subjects given long-term allopurinol therapy with that of their relatives, either untreated, or non-compliant with allopurinol, stratifying the outcome data for renal function at commencement of treatment.
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The subjects reported here include eight index cases (5 female, 3 male, Table 1a), plus five siblings never treated with allopurinol, two deceased, two with severe renal disease and progressing rapidly to transplantation, one already transplanted: (1 female, 4 male, Table 1b). Biochemical screening of all other available family members revealed a further 17 siblings with the hallmark of FJHN, and identified the defect in the daughter of the index case K 16 I, plus 3/5 children born subsequently to K3 (2 male, 1 female) (Tables 2
and 3). Full details of these kindreds are given in previous publications; two (K14 and K16) having no previous family history (FH) of gout or renal disease (2–6,13–17).
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Only the details relevant to this report are summarized in Tables 1
–3. Data on 10 parents/relatives in the previous generation in six kindreds, with a strong family history are also included (Table 1c). These 10, together with the five siblings already on dialysis, transplanted or deceased (Table 1b), highlight the early progression to end stage renal disease (ESRD) in all family members considered to have a ‘familial renal disease’ of unknown aetiology and treated only for this.2–6
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Biochemical and renal function studies
All subjects studied were on low-purine caffeine-free diets. At the end of a 24-h urine collection (thymol preservative), 10 ml venous blood was collected into heparin or EDTA. Urines were examined for crystals, shaken and warmed before measuring the volume. Aliquots were taken and frozen at -20 °C if not processed immediately for uric acid and other purines by methods adapted to HPLC as described.2 Uric acid was measured by a uricase method.2 Renal clearances were corrected for body surface area. A normal creatinine is defined here as <120 µmol/l in adults, but varies within the range from 35–120 µmol/l in children between 1 and 17 years, increasing with age and height. GFR was measured by single-injection techniques, using inulin for children and 51Cr-EDTA for adults.
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Clinical studies
Gout in six of the eight index cases originally drew attention to a kindred with a history of ‘familial renal disease’2,4–6 (Table 1
). The other two kindreds, K14 and K16, had no previous family history, but the index case in K14 developed gout at 14 years (Tables 1a–c). K16 presented only with renal disease, but had a disproportionately high plasma uric acid (PUA) for age/sex. Hypertension was not a feature in four of the index cases prior to the start of contraceptive therapy in one, and the rapid onset of renal disease in the other three, nor in 19 of the siblings identified only during the family study (Tables 1 and 2).3 In the six kindreds with a family history of renal disease, the mean age at death of the affected parent, aunt or uncle (never treated with allopurinol) was 41 years, many having been on dialysis for up to 10 years (Table 1c).
All affected siblings identified as having FJHN were found through biochemical screening (Tables 2 and 3). All the other known causes of hyperuricaemia associated with familial renal disease were excluded on clinical grounds. Of the three siblings either on dialysis or transplanted when the index case was diagnosed, there is only one long-term survivor (now on allopurinol following successful transplantation) (Table 1b). Mild proteinuria (<0.7 g/l) was noted only in five of the six patients with a plasma creatinine >200 µmol/l (Table 2), who progressed rapidly to dialysis and transplantation. Full details of these six patients, including blood pressure readings, are reported in references 2–6.
Since commencing allopurinol, 26 of these patients have been followed at regular intervals (every 2–3 years) for 10–34 years for the adults, and 4–10 years for the children (Tables 2 and 3).13–16 The daily allopurinol dose has varied from 100 to 300 mg, sometimes on alternate days, depending on age and the degree of renal function.3 One patient proved to be non-compliant (K3 II3); another (K14 I) was switched to benzbromarone because of an allergic reaction to allopurinol.10 Benzbromarone (100 mg/day) has also been added to the allopurinol (150 mg/day), in another case (K4 II 1) because of intractable hyperuricaemia. (Table 2).
Plasma uric acid concentrations (PUA) and FEur
Hyperuricaemia (normal PUA <300 µmol/l in women, <340 µmol/l in men, <260 µmol/l for children in the UK) was present in the eight index cases (mean PUA 547 µmol/l) and all but one of the 20 adult siblings at diagnosis. PUA was also grossly elevated in the teenage daughter of K16 I (Table 2b) and the three children in Table 3 born subsequently to affected parents. Of the 10 patients with mildly reduced renal function at diagnosis (creatinine<200 µmol/l), hyperuricaemia in the three K4 kindred members has proved relatively intractable (although K4 II 1 was on allopurinol at diagnosis) and benzbromarone has been added to the allopurinol in K4 II 1, while K4 II 2 is now also on losartan. The reason for the low initial PUA in K7 II 4 is unknown. The important result in the other five long-term compliers in this cohort with mild renal disease (on allopurinol for a mean 17.2 years), is that PUA has fallen by a mean 30%.
In the eight subjects (all good compliers) who have retained stable or normal renal function on allopurinol over a mean 14.5 years, PUA has been reduced by a mean 23% (Table 3b). Mean PUA in the three children (on allopurinol for a mean of 6 years) has been reduced, similarly by 25% (Table 3c).
Mean FEur was 10.6% in the six with severe renal disease at diagnosis (Table 2), 6.2% in 10 with milder renal disease (creatinine <200 µmol/l at diagnosis) and 5.2% in the eight with normal plasma creatinine (Table 3a and b). FEur in the three children (11.4%, Table 3c) was also low. Bearing in mind that a third of the siblings were children also and 50% were female, these results are very low for age, sex and severity of renal disease. (mean plus range for FEur: healthy UK children (18.4±5.1%), adult females (12.8±2.9%), adult males (8.1±3.2%).2
Effect of allopurinol on renal function
Patients with plasma creatinine >200 µmol/l at diagnosis
Plasma creatinine (Table 2a and b) was elevated above 200 µmol/l in four of the index cases at diagnosis and in two siblings/relatives found during family screening, one aged 12 years being supposedly healthy.2 Progression in this group to ESRD, dialysis and transplantation was rapid despite allopurinol in 5/6 (mean 6 years, range 2–10 years). Such rapid progression, as well as the young age at ESRD (mean 31 years) in those unrecognized and untreated (Table 2a and b), or treated only after onset of severe renal impairment, highlights the importance of allopurinol. These results, together with the absence of hypertension in all those diagnosed before the onset of severe renal disease, clearly distinguish our patients with FJHN from those with other autosomal dominant renal diseases. Figure 1 illustrates this rapid rise in plasma creatinine in the index case in two kindreds, K2 and K5, treated only for renal disease until an attack of gout stimulated studies in all other family members. As found for the index case (K2 III 4) and her twin (K2 III 3), the cousin of the index case, K2 III 1 (Figure 1), treated originally only for renal disease (which was already severe when allopurinol started), creatinine also showed a sharp increase following oestrogen therapy with a linear rise thereafter, which paralleled that in the index case, despite allopurinol in both. However, following successful renal transplantation, creatinine fell in the former to a level now sustained on allopurinol for >16 years. The index case K2 III 4 died at 36 years after two failed transplants followed by 9 years on dialysis.2,16 The index case, K5 II 3, considered to have familial renal disease and treated only for this, progressed to ESRD in 8 years (Figure 2). Both K5 II 3 and her nephew K5 III 2 have remained on dialysis following failed transplants. An initially successful transplant lowered the plasma creatinine transiently in K5 III 2, which rose rapidly following rejection (Figure 2).
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Patients with raised plasma creatinine, but <200 µmol/l at diagnosis
The rapid decline in renal function in the above patients with a creatinine>200 µmol/l at start (Table 2a and b), contrasts sharply with the relative stability of renal function (Table 3a) in 10 patients (8 from the above kindreds, 2 with no family history). Although plasma creatinine was elevated in all, the concentration was <200 µmol/l when commenced on allopurinol (or switched to benzbromarone in K14). These 10 subjects (three being index cases) with a GFR>46 ml/min/1.73 m2 have maintained relatively stable renal function for from 10 to 34 years (Table 3b). However as in the index case K2 III 3 (Table 2a), plasma creatinine in the non-identical twin K2 III 4 remained stable for 6 years on allopurinol, but also increased (Figure 1) following the instigation of contraceptive therapy and onset of hypertension, which has required aggressive control.2,17
Patients with normal plasma creatinine at diagnosis
Eight seemingly healthy siblings in these kindreds, with only the hyperuricaemia and low FEur characteristic of FJHN, had a normal plasma creatinine for age when identified (Table 3b). Nevertheless, in four of them, a mild reduction in renal function was already evident (GFR 52–71 ml/min/1.73 m2), confirming that creatinine is a poor indicator of renal disease until the GFR has fallen below 50.6 Following commencement of allopurinol, renal function has remained unchanged throughout for up to 20 years, or even returned to normal in two instances (Table 3b, Figure 1).
A similar return of renal function toward normal has been evident in three affected children, born subsequently to K3 and treated for up to 10 years since first diagnosed when aged 4–5 years (Table 3c and Figure 2).
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Discussion |
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Assessing the effect of any treatment from a prospective study in a rare disease such as FJHN is difficult when an agent, allopurinol, is available which so clearly ameliorates the biochemical and clinical aspects. In FJHN patients with clinical gout, it could be considered unethical not to treat this. However, in the kindreds reported here, a suitable untreated group with which to compare outcomes in the allopurinol-treated group already existed.
Until now opinion had varied as to whether allopurinol has a beneficial effect on the evolution of renal disease in FJHN.2–6,10–17 Data other than our own have been based largely on studies of single families, or even of single patients. The present paper presents the largest number of patients studied, with the longest follow-up reported to date, and in our opinion contains persuasive evidence of a beneficial effect of allopurinol. It is clear (from Table 3) that patients with abnormal renal function but plasma creatinine <200 µmol/l had a higher pre-treatment, and post-treatment, plasma uric acid level (450 µmol/l then 386 µmol/l; 86% reduction from group baseline) than the group where renal function was entirely normal (366 µmol/l then 282 µmol/l; 77% reduction from group baseline). It would have been interesting to see whether very aggressive attempts to normalize plasma uric acid levels in all patients, regardless of starting renal function and plasma uric acid levels, would have proved a more efficacious strategy. However this would inevitably mean either very high doses of allopurinol, with the attendant risk of severe side-effects, or the use of combinations of uricosuric drugs relatively untested in uraemia.
Some of the apparent disparities between the published data on treatment of FJHN may arise also from heterogeneity in patients studied, and the timing and the duration of the treatment. As data in our study of these eight early kindreds have accumulated (Tables 1–3, Figures 1–3), it has become progressively clearer that early allopurinol treatment when renal function is still normal, or only mildly reduced, is likely to result in continued stable renal function for a decade or more, or even improvement (Table 3). Treatment started later, especially after renal damage has reduced function to half normal or less, is almost always accompanied by rapid progression to dialysis and transplantation or early death (Table 2), although even in these patients, the time to end-stage renal failure may be postponed. Some of those authors who failed to note any improvement, or even progression of renal failure in the presence of allopurinol,10–13 treated patients late, for relatively short periods, and their data are consistent with our own data from this subgroup of patients.
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Successful long-term prevention of renal damage in FJHN requires therefore not only early diagnosis and treatment, but long-term patient compliance. This is demonstrated by family K1, the index case and poor complier in K3 and the untreated daughter in K16. Both of these latter subjects suffered a 50% fall over 8 years in an originally normal GFR. Stabilization of declining renal function (
50 ml/min/1.73 m2) was noted in two index cases following allopurinol (given for gout prior to recognition of FJHN).
The importance of early recognition and allopurinol treatment of FJHN is reinforced by K1, where two siblings (K1 II 1,3, Figure 3) who developed gout and died in their thirties, drew attention to a family considered to have ‘familial renal disease’.14 The index case K1 II 3 was Austrian, but only a niece, K1 III 3, could be traced, who tested normal (Figure 3). A 1998 report from Austria18 revealed a female sibling K1 II 5 of the propositus plus her son KI III 4, both unrecognized and untreated, but already with severe and mild renal disease, respectively (Figure 3). In contrast, K1 III 1 and 2, now studied by us for over 20 years, have retained essentially normal renal function on allopurinol (Table 2b), reinforcing the importance of early recognition and allopurinol treatment in FJHN.
If, as we believe, allopurinol treatment is nephroprotective in FJHN, this suggests that some aspect of the concentration or traffic of uric acid in the tubular cells plays a major role in the renal damage. A putative gain-in-function mutation in the luminal urate anion exchanger, leading to apoptosis of proximal tubular epithelial cells, was proposed in the Austrian study to explain the hyperuricaemia, low FEur, and renal disease in FJHN.18 The exact source of the very low FEur in FJHN is not yet clear, but superactivity or deficiency in one or other of the luminal anion exchangers and/or the luminal or basolateral voltage-dependent pathways of urate transport (recently described and/or cloned3,19,20) could result in a net decrease in FEur. FEur is not, of course, altered by allopurinol, but the absolute amount of uric acid transiting through the proximal tubular cells will be reduced as plasma, and hence filtered, urate falls. Our study also supports the suggestion that agents which increase FEur, such as benzbromarone, will help normalize the FEur by blunting urate reabsorption18 and may be of value in FJHN, together with allopurinol, as previously suggested.10,18 Hyperuricemia per se, with increased filtration of urate but unchanged FEur and no increase in urate reabsorption, does not necessarily lead to renal damage, unless extreme and acute, as in Lesch-Nyhan disease, or partial hypoxanthine-guanine phosphoribosyltransferase deficiency.3 In the other rare uric acid overproduction disorder, phosphoribosylpyrophosphate superactivity, we have observed chronic untreated hyperuricaemia in a female carrier of this X-linked defect, with a normal FEur not associated with any loss of renal function for over 20 years.21
Thus some function of intracellular urate may be a crucial factor in determining renal damage in situations of low FEur, even though frank deposits of interstitial urate are rare in (mainly cortical) renal biopsies in FJHN. The latter is not too surprising in view of the medullary site of urate deposits, and their fugitive presence in many circumstances.22–24 Analogies can also be drawn between renal cholesterol embolization; this is much more commonly found histologically at post mortem than in native renal biopsy specimens. This possibility is supported by animal studies, which demonstrated that the absence of crystals at biopsy does not necessarily exclude a crystal nephropathy as the original cause of the renal lesion.21–24 The alternative hypothesis proposed, that FJHN arises from a primary renal vasoconstriction with secondary reduction in FEur,13 has a major weakness in that measurements of filtration fraction (upon which this hypothesis depends) rest crucially in turn upon the assumption of normal tubular handling of the para-aminohippurate (PAH) used to derive renal plasma flow indirectly. This is an unsafe assumption in FJHN, when urate and PAH share renal tubular transporters, and renal tubular transport is grossly disturbed.
The gene defect underlying the low FEur in our FJHN kindreds remains elusive. Other autosomal dominant renal diseases have been excluded,8,9,25,26 as has a linkage to chromosome 16q11.2, found so far only in three FJHN kindreds: one in Japan, and 2 of 3 in the Czech Republic.27–29 Our families would thus appear to refute the latest suggestion from a Belgian study that FJHN and autosomal dominant medullary cystic kidney disease type 2 (gene locus 16p12) are two facets of the same disease.30 Recently, a defect in hepatocyte nuclear factor-1ß on chromosome 17q was established in our family K3 following development of late-onset diabetes in three members (Bingham et al., submitted). This mutation is associated with autosomal dominant polycystic kidney disease and abnormal nephron development, but can affect many organ systems.31 The latter is not a feature of our other kindreds, but the different gene defect in this family raises the question of further heterogeneity in our cohort of patients.
The early onset and rapid progression of renal disease when unrecognized or untreated in our FJHN kindreds also contrasts with previous reports of other autosomal dominant kidney disease.8,9 Importantly, hypertension is not an early feature, but nevertheless its aggressive control when manifest has been equally vital, especially in K4, where control of plasma urate has proved difficult.3,14 The importance of using non-thiazide diuretics in FJHN is evident. Losartan, the first of the angiotensin-2-receptor antagonists, is a logical choice of anti-hypertensive, since it confers nephroprotection while, uniquely for this class of drug, its active metabolite (EXP3174) is a potent inhibitor of urate reabsorption in the proximal tubule, thereby lowering PUA and increasing FEur.32–34 Benzbromarone alone, or with allopurinol, has proved effective in lowering plasma urate in two patients on hypotensive agents.10,18
In the absence of a suitable genetic probe, the problem of diagnosis arises, especially since in renal disease FEur increases dramatically, sometimes up to 80%.2,3 The mean FEur of 11.4% in the three young affected children highlights the problem of diagnosis using one parameter alone. Plasma urate and renal function must also be considered, especially in children in FJHN kindreds. Importantly, even those seemingly normal at first screening should be evaluated every few years up to, as well as at least once post puberty.
In summary, this long-term study in eight FJHN kindreds, now over 34 years, has confirmed the importance of early diagnosis and instigation of uric-acid-lowering therapy using allopurinol, possibly together with benzbromarone. Importantly, this beneficial effect was seen only in the 21 subjects diagnosed before the onset of severe renal disease, and who were good compliers. The combined results highlight the importance of frequent screening and follow-up of children born into FJHN families. Whether the reduced FEur in FJHN has a separate genetic basis to the renal disease, or whether a different allele involving the same gene(s) controlling urate transport is implicated in FJHN, must await the location of the defective genes in our other kindreds. Clearly genetic heterogeneity is involved. Nevertheless, the efficacy of allopurinol in those patients recognized sufficiently early (especially in family K3) emphasizes the importance of both clinical vigilance and allopurinol and/or benzbromarone treatment, irrespective of the underlying gene defect.
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Acknowledgments |
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We are indebted to many organizations for support during this study: the Arthritis & Rheumatism Council, the Medical Research Council, the Wellcome Trust, the NKRF, the Special Trustees of Guy's Hospital, EC Grant BMH4-CT98-3079 and The Hadwen Trust for Humane Research. It would not have been possible without the interest and cooperation of all patients with FJHN and their doctors, and the many clinical and scientific investigators involved previously in different phases of this study. In particular, the vital and long-standing contribution of Drs Chisholm Ogg, Mary McBride, and Fernando Moro is evident from references 2–7, 9, 10, 16–21, 26.
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Address correspondence to Dr D.J.A. Goldsmith, 4th Floor TGH, Guy's Hospital, London Bridge SE1 9RT. e-mail: david.goldsmith{at}gstt.sthames.nhs.uk
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References |
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1. Duncan H, Dixon St J. Gout, familial hyperuricaemia and renal disease. Q J Med1960; 29:127–35.[Web of Science][Medline]
2. McBride MB, Simmonds HA, Ogg CS, Cameron JS, Rigden S, Rees L, Van't Hoff W, Moro F, Raman GV. Presymptomatic detection of familial juvenile hyperuricaemic nephropathy in children. Paediatr Nephrol1998; 12:359–64.
3. Cameron JS, Moro F, McBride MB, Simmonds HA: Inherited disorders of purine metabolism and transport. In: Davidson AM, et al., eds. Oxford Textbook of Clinical Nephrology, 2nd edn, vol. 3. Oxford, Oxford University Press, 1997: ch. 16.5.3, 2469–83.
4. Warren DJ, Simmonds HA, Gibson T, Naik RB. Familial gout and renal failure. Arch Dis Child1981; 56:699–704.
5. Calabrese G, Simmonds HA, Cameron JS. Precocious familial gout with reduced fractional urate clearance and normal purine enzymes. Q J Med1990; 75:441–50.[Web of Science][Medline]
6. Moro F, Ogg CS, Cameron JS, Simmonds HA, Duley JA, McBride MB, Davies PM. Familial juvenile gouty nephropathy with renal urate hypoexcretion preceding renal disease. Clin Nephrol1991; 35:263–9.[Web of Science][Medline]
7. Gibson T, Simmonds HA, Potter CF, Jeyarajah N, Highton J. Sequential studies of renal function in gout. Eur J Rheum Inflamm1979; l:79–85.
8. Christodolou K, Tsingis M, Stavrou C, Eleftheriou A, Papavlou P, Patsalis PC, Lonnou P, Pierides A, Deltas CC. Chromosome 1 localisation of a gene for autosomal dominant medullary cystic kidney disease (ADMCKD). Hum Mol Genet1998; 7:905–11.
9. Marinaki AM, Greener M, Fischer S, Lewis C, Town MM, Moro F, Simmonds HA, Cameron JS, Duley JA, Mathew CGP. Exclusion of five candidate disease loci by linkage analysis in familial juvenile hyperuricaemic nephropathy. J Inher Metab Dis2000; 23(Suppl 1):194.
10. Grahame R, Simmonds HA, McBride MB, Marsh FP. How should we treat tophaceous gout in patients with allopurinol sensitivity? Adv Exp Med Biol1998; 431:19–23.[Web of Science][Medline]
11. Zürcher RM, Bock HA, Thiel G. Excellent uricosuric efficacy of benzbromarone in cyclosporine-A-treated renal transplant patients: a prospective study. Nephrol Dial Transplant1994; 9:548–51.
12. Miranda ME, Puig JG, Mateos FA, Herranz I, Martinez Ara J, Berrocal T, Prieto C, Picazo ML. The influence of allopurinol on renal deterioration in familial nephropathy associated with hyperuricaemia. Adv Exp Med Biol1994; 370:61–4.[Medline]
13. Puig JG, Mateos FA, Sancho T, Torres RJ, Buno A, de Miguel E, Gil A. Gout: new questions for an ancient disease. Adv Exp Med Biol1998; 431:1–5.[Web of Science][Medline]
14. Simmonds HA, Cameron JS, Potter CF, Warren D, Gibson T, Farebrother D. Renal failure in young subjects with familial gout. Adv Exp Med Biol1980; 122A:15–20.[Medline]
15. Moro F, Simmonds HA, Mc Bride MB, Cameron JS, Williams DG, Ogg CS. Does allopurinol affect the progression in familial juvenile gouty nephropathy? Adv Exp Med Biol1992; 309A:199–203.
16. McBride MB, Simmonds HA, Moro F. Genetic gout in childhood: familial juvenile hyperuricaemic nephropathy, or ‘familial renal disease’? J Inher Metab Dis1997; 20:351–3.[Web of Science][Medline]
17. McBride MB, Simmonds HA, Ogg CS, Cameron JS, Rigden SPA, Rees L, Van't Hoff W, Moro F, Raman GV. Efficacy of allopurinol in ameliorating the progression in familial juvenile hyperuricaemic nephropathy (FJHN): a six year update. Adv Exp Med Biol1998; 431:7–11.[Web of Science][Medline]
18. Lhotta K, Gruber J, Sgonc R, Falko F, K
nig P. Apoptosis of tubular epithelial cells in familial juvenile gouty nephropathy. Nephron1998; 79:340–4.[Web of Science][Medline]
19. Roch-Ramel F, Werner D, Guisan B. Urate transport in brush-border membrane of human kidney. Am J Physiol1994; 266:F797–F805.
20. Lipowitz MS, Leal Pinto E, Rappaport JZ, Najfeld V, Abramson RG. Functional reconstitution, membrane targeting, genomic structure and chromosomal localization of a human urate transporter. J Clin Invest2001; 107:1103–15.[Web of Science][Medline]
21. Simmonds HA. Urate and uric acid crystal reactions within the kidney. In: Gresser U, Zöllner N, eds. Urate Deposition in Man and its Clinical Consequences. Heidelberg, Springer Verlag, 1991; 62–3.
22. Farebrother DA, Hatfield PJ, Simmonds HA, Cameron JS, Jones AS, Cadenhead A. Experimental crystal nephropathy: one year study in the pig. Clin Nephrol1975; 4:243–50.
23. Conger JD, Falk SA, Guggenheim SJ, Burke TJ. A micropuncture study of the early phase of acute urate nephropathy. J Clin Invest1976; 58:681–9.[Web of Science][Medline]
24. Farebrother DA, Simmonds HA, Warren D, Pincott J, Cameron JS. Uric acid crystal induced nephropathy: evidence of a specific renal lesion in a gouty family. J Pathol1981; 135:159–68.[Web of Science][Medline]
25. Moro F, Cameron JS, Simmonds HA, Duley JA, McBride MB, Mathew CGP, Ogg CS, Puig JG, Miranda ME, Mateos FA. Mapping the gene for familial juvenile hyperuricaemic nephropathy. Pharm World Sci1993; 15:F23.
26. Greener M, Marinaki AM, Town M, Moro F, Simmonds HA, Cameron JS, Duley JA, Mathew CGP. Exclusion of four candidate disease loci by linkage analysis in familial juvenile hyperuricaemic nephropathy (FJHN). Cell Mol Biol Lett1999; 4:371.
27. 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 Rheum2000; 43:925–9.[Web of Science][Medline]
28. Striburkova 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 Genet2000; 66:1989–94.[Web of Science][Medline]
29. Sebesta I, Krijt J, Pavelka K, Maly J, Simmonds HA, McBride MB. Familial juvenile hyperuricaemic nephropathy in adolescents. Adv Exp Med Biol1995; 370:73–7.
30. Dahan K, Fuchshuber A, Adamis S, Smaers M, Kroiss S, Loute G, Cosyns JP, Hildebrandt F, Verellen-Dumoulin C, Pirson Y. Familial juvenile hyperuricaemic nephropathy and autosomal dominant medullary cystic kidney disease type 2: two facets of the same disease? J Am Soc Nephrol2001; 12:2348–57.
31. Bingham C, Bulham MP, Ellard S, Allen LIS, Lipkin GW, van't Hoff WG, Woolf AS, R Tizzoni G, Novelli G, Nicholls AJ, Hattersley AT. Mutations in the hepatocyte nuclear factor-1ß gene are associated with familial hypoplastic glomerulocystic kidney disease. Am J Hum Genet2001; 68:219–24.[Web of Science][Medline]
32. Burnier M, Roch-Ramel F, Brunner HR. Renal effects of angiotensin II receptor blockade in normotensive subjects. Kidney Int1996; 49:1787–90.[Web of Science][Medline]
33. Kamper AL, Nielsen AH. Uricosuric effect of losartan in patients with renal transplants. Transplantation2001; 72:671–4.[Web of Science][Medline]
34. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med2001; 45:861–9.
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