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
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.
