BACKGROUND AND OBJECTIVES: The histopathologic classification for ANCA-associated GN distinguishes four classes on the basis of patterns of injury. In the original validation study, these classes were ordered by severity of kidney function loss as follows: focal, crescentic, mixed, and sclerotic. Subsequent validation studies disagreed on outcomes in the crescentic and mixed classes. This study, driven by the original investigators, provides several analyses in order to determine the current position of the histopathologic classification of ANCA-associated GN. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A validation study was performed with newly collected data from 145 patients from ten centers worldwide, including an analysis of interobserver agreement on the histopathologic evaluation of the kidney biopsies. This study also included a meta-analysis on previous validation studies and a validation of the recently proposed ANCA kidney risk score. RESULTS: The validation study showed that kidney failure at 10-year follow-up was significantly different between the histopathologic classes (P<0.001). Kidney failure at 10-year follow-up was 14% in the crescentic class versus 20% in the mixed class (P=0.98). In the meta-analysis, no significant difference in kidney failure was also observed when crescentic class was compared with mixed class (relative risk, 1.15; 95% confidence interval, 0.94 to 1.41). When we applied the ANCA kidney risk score to our cohort, kidney survival at 3 years was 100%, 96%, and 77% in the low-, medium-, and high-risk groups, respectively (P<0.001). These survival percentages are higher compared with the percentages in the original study. CONCLUSIONS: The crescentic and mixed classes seem to have a similar prognosis, also after adjusting for differences in patient populations, treatment, and interobserver agreement. However, at this stage, we are not inclined to merge the crescentic and mixed classes because the reported confidence intervals do not exclude important differences in prognosis and because an important histopathologic distinction would be lost.

• Keywords
• ANCA, Antibodies, Antineutrophil Cytoplasmic, Biopsy, Cohort Studies, Confidence Intervals, Observer Variation, Prognosis, Renal Insufficiency, glomerulonephritis, kidney biopsy,
• MeSH
• Biopsy MeSH
• Time Factors MeSH
• Glomerulonephritis * classification   complications   immunology   pathology   MeSH
• Kidney * immunology   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Predictive Value of Tests MeSH
• Prognosis MeSH
• Disease Progression MeSH
• Antibodies, Antineutrophil Cytoplasmic * immunology   MeSH
• Renal Insufficiency * diagnosis   etiology   MeSH
• Reproducibility of Results MeSH
• Retrospective Studies MeSH
• Risk Factors MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Validation Study MeSH
• Names of Substances
• Antibodies, Antineutrophil Cytoplasmic * MeSH

BACKGROUND: A substantial fraction of familial colorectal cancer (CRC) and polyposis heritability remains unexplained. This study aimed to identify predisposing loci in patients with these disorders. METHODS: Homozygosity mapping was performed using 222 563 SNPs in 302 index patients with various colorectal neoplasms and 3367 controls. Linkage analysis, exome and whole-genome sequencing were performed in a family affected by microsatellite stable CRCs. Candidate variants were genotyped in 10 554 cases and 21 480 controls. Gene expression was assessed at the mRNA and protein level. RESULTS: Homozygosity mapping revealed a disease-associated region at 1q32.3 which was part of the linkage region 1q32.2-42.2 identified in the CRC family. This includes a region previously associated with risk of CRC. Sequencing identified the p.Asp1432Glu variant in the MIA3 gene (known as TANGO1 or TANGO) and 472 additional rare, shared variants within the linkage region. In both cases and controls the population frequency was 0.02% for this MIA3 variant. The MIA3 mutant allele showed predominant mRNA expression in normal, cancer and precancerous tissues. Furthermore, immunohistochemistry revealed increased expression of MIA3 in adenomatous tissues. CONCLUSIONS: Taken together, our two independent strategies associate genetic variations in chromosome 1q loci and predisposition to familial CRC and polyps, which warrants further investigation.

• MeSH
• Adenomatous Polyposis Coli genetics   MeSH
• Genetic Predisposition to Disease * MeSH
• Genetic Linkage MeSH
• Genotype MeSH
• Homozygote MeSH
• Polymorphism, Single Nucleotide MeSH
• Colorectal Neoplasms genetics   MeSH
• Humans MeSH
• Chromosomes, Human, Pair 1 genetics   MeSH
• Chromosome Mapping MeSH
• RNA, Messenger metabolism   MeSH
• Microsatellite Repeats MeSH
• Neoplasm Proteins genetics   metabolism   MeSH
• Precancerous Conditions genetics   metabolism   MeSH
• GTPase-Activating Proteins genetics   metabolism   MeSH
• Aryl Hydrocarbon Receptor Nuclear Translocator genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• ARNT protein, human MeSH Browser
• RNA, Messenger MeSH
• Neoplasm Proteins MeSH
• GTPase-Activating Proteins MeSH
• Aryl Hydrocarbon Receptor Nuclear Translocator MeSH