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). Although early reports suggested that medullary cystic kidney disease and familial juvenile nephronophthisis (NPHP1; 256100) represented the same disease entity because of the overlapping phenotype (Chamberlin et al., 1977), they are now considered to be distinct disorders. MCKD has adult onset and shows autosomal dominant inheritance, whereas NPHP1 has juvenile onset and shows autosomal recessive inheritance (Christodoulou et al., 1998). NPHP1 is caused by mutation in the nephrocystin gene (NPHP1; 607100) on chromosome 2q13. - Genetic Heterogeneity of Medullary Cystic Kidney Disease See also MCKD2 (603860), which is caused by mutation in the UMOD gene (191845) on chromosome 16p.
Thorn et al. (1944) are credited with the first description of medullary cystic renal disease under the designation 'salt-losing nephritis.' They noted an association with red and blond hair. Rayfield and McDonald (1972) also recognized the association between ... Thorn et al. (1944) are credited with the first description of medullary cystic renal disease under the designation 'salt-losing nephritis.' They noted an association with red and blond hair. Rayfield and McDonald (1972) also recognized the association between medullary cystic disease and red and blond hair. Smith and Graham (1945) reported an isolated case. Goldman et al. (1966) described a kindred with 17 affected members spanning 5 generations. Fifteen had died in the second decade of life with rapid clinical deterioration after the onset of symptoms. The kidneys showed thin cortices, prominent glomerular hyalinization, numerous corticomedullary and intramedullary cysts lined by low cuboidal epithelium, and increase in medullary connective tissue. The authors noted differences from polycystic kidney disease (see 173900), such as the absence of flank pain, and the presence of hypertension and small kidneys. Gardner (1971) reported 2 extensively affected sibships. The average age of onset of symptoms was 23 years in one and 35 years in the second. The average duration of illness was only 2.2 years. Wrigley et al. (1973) described a family with somewhat later onset of medullary cystic kidney disease. Whelton et al. (1974) reported another affected family. Giangiacomo et al. (1975) presented a family in which the onset of autosomal dominant MCKD was unusually early. Stavrou et al. (1998) reported a large Cypriot family in which at least 23 members spanning 4 generations had interstitial nephropathy inherited in an autosomal dominant pattern. Ten patients were deceased. Clinical features were variable and included renal medullary cysts, hypertension, hyperuricemia, and gout. Urinalysis of 10 patients showed no hematuria, pyuria, or casts. The mean age at onset of end-stage renal disease (ESRD) was 62 years. Two renal biopsies showed interstitial fibrosis and severe tubular atrophy consistent with a primary tubulointerstitial process. There was also periglomerular fibrosis with a few sclerotic glomeruli. Linkage analysis excluded the NPHP1 locus on 2q13 and the PKD1 locus (601313) on 16p. Ala-Mello et al. (1999) used the term 'nephronophthisis' for both the dominant disorder called medullary cystic disease and recessive juvenile nephronophthisis (NPHP1). The dominant form was characterized by later age at onset of first symptoms, at start of dialysis, and at transplantation. In a survey of 59 cases ascertained in Finland, 17 came from 4 families showing dominant inheritance and 37 came from apparently recessive families; 2 were considered new dominant mutations, and 3 sporadic cases could not be classified. Parvari et al. (2001) studied a family of Jewish ancestry in which 15 members spanning 4 generations had chronic renal failure with onset between 18 and 38 years of age. Hypertension was often the presenting sign, followed by progressive renal insufficiency. No polyuria, anemia, gout, hematuria, or proteinuria were seen. An average of 4.5 years elapsed between diagnosis and end-stage renal disease. Renal pathology at early stages of the disease showed extensive tubulointerstitial fibrosis and global glomerulosclerosis. Wolf et al. (2004) reported a Belgian kindred with MCKD. Age at presentation ranged from 29 to 53 years, and age at ESRD varied between 34 and 49 years. First symptoms included polyuria, polydipsia, and anemia. One patient had hypertension and 2 had hyperuricemia. Gout was not reported. Variable ultrasound findings included small kidneys and small medullary cysts. Kiser et al. (2004) reported a large Native American kindred in which 12 living members had MCKD1 confirmed by linkage analysis. Age at onset of renal insufficiency ranged from 34 to 65 years and age at development of ESRD ranged from 35 to 66 years. No patient presented with polyuria, polydipsia, or urinary salt wasting; most presented with abnormal laboratory data obtained for other reasons. Other features included gout (61%), hypertension (55%), and anemia (39%). Ultrasound detected renal cysts in 44% of patients, and renal biopsies of 4 patients showed interstitial fibrosis, interstitial inflammation, tubular atrophy, and glomerulosclerosis. Only 2 patients had significant proteinuria on urinalysis. Kirby et al. (2013) reported 6 unrelated families with MCKD1, including the families previously reported by Kiser et al. (2004) and Kimmel et al. (2005). Affected individuals had slowly progressive kidney dysfunction beginning in adulthood, absent or low grade proteinuria with bland urinary sediments, decreased glomerular filtration rate, and absence of other association signs or symptoms of systemic disease. Hypertension tended to occur only after onset of chronic renal failure. Hematuria was typically not present. Renal biopsies showed tubulointerstitial fibrosis and tubular atrophy, and renal ultrasounds occasionally showed cortical cysts, but cysts were often not present.
In 16 kindreds with MCKD, Wolf et al. (2006) failed to identify pathogenic sequence changes in 37 genes within the MCKD1 critical region.
In affected members of 6 unrelated families with autosomal dominant medullary cystic kidney ... In 16 kindreds with MCKD, Wolf et al. (2006) failed to identify pathogenic sequence changes in 37 genes within the MCKD1 critical region. In affected members of 6 unrelated families with autosomal dominant medullary cystic kidney disease-1, Kirby et al. (2013) identified a heterozygous 1-bp insertion of a cytosine in 1 copy of an extremely long (1.5-5.0 kb) GC-rich coding variable number tandem repeat (VNTR) sequence in the MUC1 gene (158340.0001). The insertion was within a stretch of 7 cytosines occurring at positions 53-59 in a single copy of the canonical 60-mer repeat. The insertion of cytosine occurred in a different VNTR size in each family, indicating independent occurrence of the mutations. Some of the families had previously been reported (e.g., by Kiser et al., 2004). The insertion was predicted to cause a frameshift, resulting in a mutant protein with many copies of a novel repeat sequence, but lacking a downstream self-cleavage module and both the transmembrane and intracellular domains characteristic of the wildtype MUC1 precursor protein. Full genotyping of this region showed that the mutation segregated with the risk-associated haplotype in each family, but was not found in over 500 controls from various populations. A similar cytosine insertion was found in 13 of 21 additional families with the disorder who were studied, consistent with it being a fully penetrant cause of disease. Antibodies against a peptide synthesized to correspond to the predicted mutant VNTR sequence showed specific intracellular staining in epithelial cells from the loop of Henle, distal tubule, and collecting duct of patients that was not seen in controls. The mutant MUC1 showed partial colcalization with wildtype MUC1 in the collecting duct of a patient. Kirby et al. (2013) emphasized that the mutation was missed by massively parallel sequencing and was found only by diligent analysis of the linked region using cloning, Southern blot analysis, long-range PCR, and reconstruction of the VNTR allele in patients and controls.