Epidemiology of Uromodulin-Associated Kidney Disease – Results from a Nation-Wide Survey

BACKGROUND/AIMS: Uromodulin-associated kidney disease (UAKD) is caused by uromodulin mutations and leads to end-stage renal disease. Our objective was to examine the epidemiology of UAKD. METHODS: Data from all UAKD families in Austria were collected. Patients included in the Austrian Dialysis and Transplantation Registry (OEDTR) with unclear diagnoses or genetic diseases were asked whether they had (1) a family history of kidney disease or (2) had suffered from gout. Patients with gout and autosomal dominant renal disease underwent mutational analysis. Kaplan-Meier and Cox analysis was employed to estimate time to renal failure. RESULTS: Of the 6,210 patients in the OEDTR, 541 were approached with a questionnaire; 353 patients answered the questionnaire. Nineteen of them gave two affirmative answers. In 7 patients, an autosomal dominant renal disease was found; in 1 patient a UMOD mutation was identified. One family was diagnosed through increased awareness as a consequence of the study. At present, 14 UAKD patients from 5 families are living in Austria (1.67 cases per million), and 6 of them require renal replacement therapy (0.73 per 1,000 patients). Progression to renal failure was significantly associated with UMOD genotype. CONCLUSION: UAKD patients can be identified by a simple questionnaire. UMOD genotype may affect disease progression

Effects of common haplotypes of the ileal sodium dependent bile acid transporter gene on the development of sporadic and familial colorectal cancer: A case control study

<p>Abstract</p> <p>Background</p> <p>The genetics of sporadic and non-syndromic familial colorectal cancer (CRC) is not well defined. However, genetic factors that promote the development of precursor lesions, i.e. adenomas, might also predispose to CRC. Recently, an association of colorectal adenoma with two variants (c.507C>T;p.L169L and c.511G>T;p.A171S) of the ileal sodium dependent bile acid transporter gene (<it>SLC10A2</it>) has been reported. Here, we reconstructed haplotypes of the <it>SLC10A2 </it>gene locus and tested for association with non-syndromic familial and sporadic CRC compared to 'hyper-normal' controls who displayed no colorectal polyps on screening colonoscopy.</p> <p>Methods</p> <p>We included 150 patients with sporadic CRC, 93 patients with familial CRC but exclusion of familial adenomatous polyposis and Lynch's syndrome, and 204 'hyper-normal' controls. Haplotype-tagging <it>SLC10A2 </it>gene variants were identified in the Hapmap database and genotyped using PCR-based 5' exonuclease assays with fluorescent dye-labelled probes. Haplotypes were reconstructed using the PHASE algorithm. Association testing was performed with both SNPs and reconstructed haplotypes.</p> <p>Results</p> <p>Minor allele frequencies of all <it>SLC10A2 </it>polymorphisms are within previously reported ranges, and no deviations from Hardy-Weinberg equilibrium are observed. However, we found no association with any of the <it>SLC10A2 </it>haplotypes with sporadic or familial CRC in our samples (all P values > 0.05).</p> <p>Conclusion</p> <p>Common variants of the <it>SLC10A2 </it>gene are not associated with sporadic or familial CRC. Hence, albeit this gene might be associated with early stages of colorectal neoplasia, it appears not to represent a major risk factor for progression to CRC.</p

Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat Med 14

Pauci-immune focal necrotizing glomerulonephritis (FNGN) is a severe inflammatory disease associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA). Here we characterize autoantibodies to lysosomal membrane protein-2 (LAMP-2) and show that they are a new ANCA subtype present in almost all individuals with FNGN. Consequently, its prevalence is nearly twice that of the classical ANCAs that recognize myeloperoxidase or proteinase-3. Furthermore, antibodies to LAMP-2 cause pauci-immune FNGN when injected into rats, and a monoclonal antibody to human LAMP-2 (H4B4) induces apoptosis of human microvascular endothelium in vitro. The autoantibodies in individuals with pauci-immune FNGN commonly recognize a human LAMP-2 epitope (designated P 41-49 ) with 100% homology to the bacterial adhesin FimH, with which they cross-react. Rats immunized with FimH develop pauci-immune FNGN and also develop antibodies to rat and human LAMP-2. Finally, we show that infections with fimbriated pathogens are common before the onset of FNGN. Thus, FimH-triggered autoimmunity to LAMP-2 provides a previously undescribed clinically relevant molecular mechanism for the development of pauci-immune FNGN