NEPHRONOPHTHISIS/MEDULLARY CYSTIC KIDNEY DISEASE COMPLEX
Nephronophthisis and medullary cystic kidney disease (MCKD) are both inherited diseases of the renal tubules. They share several clinical and pathologic features, including progressive renal insufﬁciency with a bland urine sediment, macroscopic cysts at the outer medulla and corticomedullary border, microscopic dilation and atrophy of the distal tubules and collecting ducts, lamellation and splitting of the tubular basement membranes, lymphocytic interstitial inﬁltrate, and interstitial ﬁbrosis.
Because of their similarities, nephronophthisis and MCKD are generally considered to be components of a single disease complex. Despite this association, however, they differ in several important respects, including mode of inheritance, age at onset of end-stage renal disease (ESRD), and presence of extrarenal manifestations.
Nephronophthisis is an autosomal recessive disorder that accounts for approximately 5% to 10% of childhood ESRD in North America. Three different forms have been described—known as infantile, juvenile, and adolescent—that differ based on the age when ESRD occurs. The juvenile form is most common, with ESRD occurring at a mean age of 13 years. The adolescent form leads to ESRD at a mean age of 19 years, while the infantile form leads to ESRD at a mean age of 2 years.
Mutations in at least nine different genes, known as NHPH1 through NHPH9, have been shown to cause nephronophthisis. Mutations in NHPH1 account for about 20% of overall cases and result in juvenile neph- ronophthisis. This gene, located at chromosome 2q12.3, encodes nephrocystin-1, a protein involved in the adhesion of tubular epithelial cells both to each other and to the tubular basement membrane. The remaining NHPH genes each account for only about 3% of cases. Thus a signiﬁcant number of cases result from mutations in as yet unidentiﬁed genes.
Affected patients usually ﬁrst have polyuria and polydipsia, which reﬂect sodium wasting and defective urine concentration. On further evaluation, the clinical picture is consistent with nephrogenic diabetes insipidus. Over subsequent years, renal insufﬁciency supervenes, even- tually progressing to ESRD. The urine sediment is typically benign. Extrarenal manifestations may be noted in some patients—including retinitis pigmentosa, hepatic ﬁbrosis, skeletal defects, and cerebellar aplasia— depending on the underlying gene that is mutated.
If nephronophthisis is suspected, genetic testing can establish the diagnosis. Contrast-enhanced axial imaging may reveal the presence of macroscopic, predominantly medullary cysts in small- or normal-sized kidneys, in contrast to the enlarged kidneys seen in ADPKD. Renal biopsy, although not necessary for diagnosis, reveals the characteristic ﬁndings described above.
There is no directed therapy available for nephronophthisis, and affected patients invariably progress to ESRD. When possible, renal transplantation is appropriate.
MEDULLARY CYSTIC KIDNEY DISEASE
MCKD is a rare autosomal dominant disorder that exists in two different forms. Type 1 results from mutations occurring at a locus on chromosome 1q21. The major clinical manifestation is renal insufﬁciency with a bland urine sediment, which appears during the third decade or later and is slowly progressive. Unlike in nephronophthisis, polyuria and polydipsia may not be prominent. Renal biopsy can suggest the diagnosis, which is then established with genetic testing. Treatment is supportive, and once ESRD occurs, renal transplantation is appropriate.
Type 2 MCKD (also known as familial juvenile hyperuricemic nephropathy) reﬂects mutations in the UMOD gene, located on chromosome 16p12. This gene encodes uromodulin, also known as Tamm- Horsfall mucoprotein, which is produced in the thick ascending limb (TAL). The mutations causing type 2 MCKD interfere with the export of uromodulin from the tubular epithelial cells into the tubular lumen. The accumulation of abnormal uromodulin results in cell death and tubular atrophy. An increase in proximal salt reabsorption is typically enough to offset the salt wasting that would otherwise result from TAL dysfunction. Patients develop progressive renal insufﬁciency, however, that typically becomes apparent during the second decade. For uncertain reasons, patients also develop hyperuricemia, generally before the onset of renal dysfunction, that leads to recurrent episodes of gout. The combination of renal insufﬁciency, gout, and a family history of both should raise suspicion of the diagnosis of type 2 MCKD, which is established with genetic testing. Although treatment is mostly supportive, patients beneﬁt from allopurinol, which reduces the incidence of gout attacks and, in some studies, has been shown to slow the progression to ESRD.