Early treatment with allopurinol in familial juvenile hyerpuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal disease

Fairbanks, L. D.; Cameron, J. S.; Venkat‐Raman, Gopalakrishnan; Rigden, Susan P. A.; Rees, Leslie; Hoff, William van’t; Mansell, M. A.; Pattison, James M.; Goldsmith, David; Simmonds, H. Anne

doi:10.1093/qjmed/95.9.597

Cited by 67 publications

(29 citation statements)

References 16 publications

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“…Some reports indicate that allopurinol can slow down progression of kidney disease (24,25), whereas others state that it will treat only hyperuricemia and gout, without any effect on renal diagnosis (26). Because drug therapy has been reported in only a few patients, our data cannot answer the central question of whether allopurinol helps prevent or delay ESRD.…”

Section: Discussionmentioning

confidence: 69%

Association between Genotype and Phenotype in Uromodulin-Associated Kidney Disease

Moskowitz

Piret

Lhotta³

et al. 2013

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Uromodulin-associated kidney disease (UAKD) is an autosomal dominant disease caused by uromodulin (UMOD) gene mutations. This study explored genotype-phenotype correlations by examining the relationship between the type of UMOD mutation and the age at onset of ESRD.Design, setting, participants & measurements Extensive bibliographic research was used to ascertain patient-level data of all patients with UAKD published up to October 2011. Data included sex; ages at onset of hyperuricemia, gout, and ESRD; and UMOD genotype. Kaplan-Meier analysis and Cox proportional hazards models fitted with shared gamma frailty terms to adjust for within-family correlations were used to model time to event.Results Thirty-one peer-reviewed publications reporting on 202 patients from 74 families with 59 different UMOD mutations were included. Median ages at onset of hyperuricemia, gout, and ESRD were 24, 40, and 56 years, respectively. Men developed gout and ESRD significantly earlier than did women (age at ESRD was 50 years for men and 60 for women; P=0.04, shared frailty model). Median ages at ESRD development were lowest with Cys77Tyr (37.5 years) and highest with Gln316Pro (65.5 years) UMOD mutations. Onset of ESRD was significantly earlier with UMOD mutations located within the epidermal growth factor domains 2 and 3 (range, 45-52 years; P,0.01 and 0.04, respectively) compared with the cysteine-rich domains (range, 60-65 years; by shared frailty model). ConclusionsThe UMOD genotype is related to the clinical phenotype of UAKD. This finding may assist in counseling of patients.

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Section: Discussionmentioning

confidence: 69%

Association between Genotype and Phenotype in Uromodulin-Associated Kidney Disease

Moskowitz

Piret

Lhotta³

et al. 2013

Clinical Journal of the American Society of Nephrology

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“…With anecdotal evidence that it is useful, it has been proposed that allopurinol, a urate-lowering agent, should be offered to all those affected by UAKD, to slow progression (29,30). There is a need for proper, controlled trials of this and/or other potential therapies, to which end accurate genotypic as well as phenotypic characterization are important.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a Recurrent In-frame UMOD Indel Mutation Causing Late-onset Autosomal Dominant End-Stage Renal Failure

Smith

Robinson

Stewart

et al. 2011

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives In a single-center renal clinic, we have established routine mutation testing to diagnose UMOD-associated kidney disease (UAKD), an autosomal dominant disorder typically characterized by gout, hyperuricemia, and renal failure in the third to sixth decades.Design, setting, participants, & measurements Four probands and their multigeneration kindreds were assessed by clinical, historical, and biochemical means. Diagnostic UMOD sequencing was performed, and mutant uromodulin was characterized in vitro.Results All available affected members of the four kindreds harbored the same complex indel change in UMOD, which was associated with almost complete absence of gout and a later onset of CKD; the youngest age at ESRD or death was 38 years (range, 38 to 68 years) compared with 3 to 70 years in other reports. Three mutation carriers (all Յ35 years) are currently asymptomatic. The indel sequence (c.278_289del TCTGCCCCGAAGinsCCGCCTCCT; p.V93_G97del/ins AASC) results in the replacement of five amino acids, including one cysteine, by four novel residues, also including a cysteine. Uromodulin staining of the only available patient biopsy suggested disorganized intracellular trafficking with cellular accumulation. Functional characterization of the mutant isoform revealed retarded intracellular trafficking associated with endoplasmic reticulum (ER) retention and reduced secretion into cell culture media, but to a lesser extent than we observed with the previously reported C150S mutation. ConclusionsThe indel mutation is associated with a relatively mild clinical UAKD phenotype, consistent with our in vitro analysis. UAKD should be routinely considered as a causative gene for ESRD of unknown cause, especially where there is an associated family history or where biopsy reveals interstitial fibrosis.

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“…Clinical and biochemical data of the GB and Spanish patients have been described in detail previously. 2,7,20,24,27,28 In family BE1, the first symptoms in the affected individuals were mild anaemia (Hb levels 10 g %), slowly progressive renal failure and hyperuricaemia from the age of 10 years. The patients had small, echogenic kidneys on renal echography.…”

Section: Patientsmentioning

confidence: 99%

“…Importantly, members of all three GB kindreds showing linkage in this report and identified prior to the onset of severe renal disease have been treated successfully with allopurinol -in the case of GB2 and three for from 20 to 37 years. 27,28 Further gene mapping efforts must be focused on both refining the 16p11.2 locus and discover other FJHN loci in families not linked to 16p11.2. In this regard, it is of interest that kindred GB4, with a history of cysts at biopsy and phenotypically identical with MCKD2, has been found recently (following the onset of diabetes type 2) to have a defect on 17q involving the hepatocyte nuclear factor 1b gene (Bingham et al, personal communication).…”

Section: Candidate Gene Analysesmentioning

confidence: 99%

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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

et al. 2003

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Familial juvenile hyperuricaemic nephropathy (FJHN) is an autosomal dominant renal disease characterised by juvenile onset of hyperuricaemia, gouty arthritis, and progressive renal failure at an early age. Recent studies in four kindreds showed linkage of a gene for FJHN to the same genomic interval on chromosome 16p11.2, where the gene for the phenotypically similar medullary cystic disease type 2 (MCKD2) has been localised. In this study we performed linkage analysis in additional 15 FJHN families. Linkage of FJHN to 16p11.2 was confirmed in six families, which suggests that, in a large proportion of FJHN kindreds, the disease is likely to be caused by a gene or genes located outside of 16p11.2. Haplotype analysis of the new and previously analysed families provided two non-overlapping critical regions on 16p11.2 -FJHN1, delimited by markers D16S499-D16S3036 and FJHN2, delimited by markers D16S412-D16S3116. Considering MCKD2 to be a distinct molecular entity, the analysis suggests that as many as three kidney disease genes may be located in close proximity on 16p11.2. From genomic databases we compiled integrated physical and transcription maps of whole critical genomic region in which 45 known genes and 129 predicted loci have been localised. We selected, analysed and found no pathogenic mutations in seven candidate genes. The linkage and haplotype analysis reported here demonstrates the genetic heterogeneity of FJHN. The report of integrated physical and mostly in-silico predicted transcription maps of the FJHN critical region provides a basis for precise experimental annotation of the current transcript map, which is essential for final identification of the FJHN gene(s).

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Early treatment with allopurinol in familial juvenile hyerpuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal disease

Abstract: 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.

Cited by 67 publications

References 16 publications

Association between Genotype and Phenotype in Uromodulin-Associated Kidney Disease

Association between Genotype and Phenotype in Uromodulin-Associated Kidney Disease

Characterization of a Recurrent In-frame UMOD Indel Mutation Causing Late-onset Autosomal Dominant End-Stage Renal Failure

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

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