ABSTRACT
BACKGROUND: Autosomal dominant tubulointerstitial kidney disease caused by mucin-1 gene (MUC1) mutations (ADTKD-MUC1) is characterized by progressive kidney failure. Genetic evaluation for ADTKD-MUC1 specifically tests for a cytosine duplication that creates a unique frameshift protein (MUC1fs). Our goal was to develop immunohistochemical methods to detect the MUC1fs created by the cytosine duplication and, possibly, by other similar frameshift mutations and to identify novel MUC1 mutations in individuals with positive immunohistochemical staining for the MUC1fs protein. METHODS: We performed MUC1fs immunostaining on urinary cell smears and various tissues from ADTKD-MUC1-positive and -negative controls as well as in individuals from 37 ADTKD families that were negative for mutations in known ADTKD genes. We used novel analytic methods to identify MUC1 frameshift mutations. RESULTS: After technique refinement, the sensitivity and specificity for MUC1fs immunostaining of urinary cell smears were 94.2% and 88.6%, respectively. Further genetic testing on 17 families with positive MUC1fs immunostaining revealed six families with five novel MUC1 frameshift mutations that all predict production of the identical MUC1fs protein. CONCLUSIONS: We developed a noninvasive immunohistochemical method to detect MUC1fs that, after further validation, may be useful in the future for diagnostic testing. Production of the MUC1fs protein may be central to the pathogenesis of ADTKD-MUC1.
Subject(s)
Genetic Predisposition to Disease/epidemiology , Mucin-1/genetics , Polycystic Kidney, Autosomal Dominant/genetics , Polycystic Kidney, Autosomal Dominant/pathology , Biopsy, Needle , Case-Control Studies , Female , Humans , Immunohistochemistry , Incidence , Male , Mutation/genetics , Pedigree , Polycystic Kidney, Autosomal Dominant/mortality , Prognosis , Registries , Retrospective Studies , Risk AssessmentABSTRACT
BACKGROUND: Medullary cystic kidney disease (MCKD) is an inherited interstitial nephritis, leading to end-stage renal disease (ESRD) between the fourth and seventh decade of life. MCKD shares clinical and morphological features with nephronophthisis, although advances in molecular genetics have distinguished these 2 entities. Data regarding graft survival after kidney transplantation in MCKD patients are extremely limited. The aim of this study was to compare renal graft survival in transplanted MCKD1 and non-MCKD1 patients, to discover whether renal transplantation can be considered as an acceptable treatment for MCKD. METHODS: Thirty-three transplanted patients with MCKD1 and 33 controls (transplanted due to other causes) were included in the study. Graft losses were considered censored for death. Graft survival was evaluated with the Kaplan-Meier method, and comparisons between groups were made by log-rank test. Cox regression analysis was used to estimate the effect of several variables on graft survival, and the chi-square test was used to compare groups of categorical data. RESULTS: The 1-year cumulative graft survival rate for the MCKD1 group was 97%, while at 5 and 10 years it was 94% and 86%, respectively. For the control group, the respective values at years 1, 5 and 10 were 97%, 97% and 90%. Comparisons of graft survival rates between the 2 groups revealed no significant differences. CONCLUSIONS: Renal graft survival of transplanted MCKD1 patients was not shown to be inferior in comparison with that for patients undergoing transplants due to other causes. Therefore, it may represent a treatment of choice in MCKD1 patients with ESRD.
