Medullary Cystic Disease

Publisher Summary This chapter sheds light on the epidemiology, genetics, pathophysiology, and clinical manifestations of medullary cystic kidney disease (MCKD). MCKD segregates in families as a genetically heterogeneous autosomal dominant condition. Two nonallelic loci for MCKD were identified, the first, MCKD1 on chromosome 1q21, and the second, MCKD2 on chromosome 16p12. Mutations of the uromodulin gene, which encodes uromodulin (Tamm-Horsfall protein) are responsible for MCKD2. The uromodulin gene consists of 16,663 base pairs located on chromosome 16p12.3. The gene encodes 12 exons, although the translation initiation site (ATG) is located in exon 3. The two untranslated exons may play a role in the restricted tissue expression of the gene. The mutations in the UMOD gene are substitutions resulting in an exchange of a cysteine residue in most cases of MCKD2. The cysteine residues are important in intra-chain disulfide bonding to form the tertiary structure of uromodulin. The cardinal manifestation of MCKD2 is the development of progressive kidney failure over time. The renal disease in these patients is very slowly progressive and is variable both within families and between families. Renal insufficiency may manifest itself in childhood with a mildly to moderately increased blood urea nitrogen or serum creatinine. Patients with MCKD2 usually have bland urinary sediment, as the disease is tubulo-interstitial in origin and only affects the glomerulus secondarily. Mild proteinuria may develop later in the course of the disease, perhaps reflecting hyperfiltration changes. Individuals with MCKD2 and normal renal function typically have a reduced fractional excretion of uric acid, usually less than 5%.