Medullary cystic kidney disease (MCKD) is an autosomal dominant form of tubulointerstitial nephropathy characterized by formation of renal cysts at the corticomedullary junction. It is characterized by adult onset of impaired renal function and salt wasting resulting in ... Medullary cystic kidney disease (MCKD) is an autosomal dominant form of tubulointerstitial nephropathy characterized by formation of renal cysts at the corticomedullary junction. It is characterized by adult onset of impaired renal function and salt wasting resulting in end-stage renal failure by the sixth decade (Wolf et al., 2004). For a general phenotypic description and a discussion of genetic heterogeneity of medullary cystic kidney disease, see MCKD1 (174000).
Hart et al. (2002) showed that MCKD2 and familial juvenile hyperuricemic nephropathy can be caused by mutation in the UMOD gene (see, e.g., 191845.0001 and 191845.0004), which maps to chromosome 16p13.11-p12.3, and are thus allelic disorders. Noting that ... Hart et al. (2002) showed that MCKD2 and familial juvenile hyperuricemic nephropathy can be caused by mutation in the UMOD gene (see, e.g., 191845.0001 and 191845.0004), which maps to chromosome 16p13.11-p12.3, and are thus allelic disorders. Noting that hyperuricemia is not always present in HNFJ1 and medullary cysts are not always present in MCKD2, and that the 2 conditions result from mutations of the same gene, the authors suggested that it would be appropriate to designate these 2 conditions 'uromodulin-associated kidney disease.' Rampoldi et al. (2003) described missense mutations in the UMOD gene in 3 families with MCKD2/HNJF1 and demonstrated allelism (191845.0010) in 1 family with a glomerulocystic kidney disease variant (609886), showing association of cyst dilatation and collapse of glomeruli with some clinical features similar to MCKD2/HNJF1 such as hyperuricemia and impairment of urine-concentrating ability. Experiments in transfected cells showed that all uromodulin mutations caused a delay in protein export to the plasma membrane due to a longer retention time in the endoplasmic reticulum. Immunohistochemistry on GCKD and MCKD2/HNJF1 kidney biopsies revealed dense intracellular accumulation of uromodulin in tubular epithelia of the thick ascending limb of Henle loop. Electron microscopy demonstrated accumulation of dense fibrillar material within the endoplasmic reticulum. Patient urine samples showed a severe reduction of excreted uromodulin. The maturation impairment was consistent with the clinical findings and suggested a pathogenetic mechanism leading to these kidney diseases.