Diseases of the “nephronophthisis/medullary cystic
kidney disease (NPHP/MCKD) complex” are renal
cystic diseases that share a virtually identical renal histology15 characterized
by thickening and disintegration of the tubular basement membrane,
interstitial lymphocytic infiltrations with fibrosis, and distal
tubular atrophy with cysts (Fig. 470-3A).
Over time, chronic sclerosing tubulointerstitial nephropathy develops.
In contrast to polycystic kidney disease, cysts occur primarily
at the corticomedullary junction of the kidneys, and kidney size
remains normal or is slightly diminished (Fig.
470-3B). Although histology is similar in all forms of the
disease, the two different disease groups of recessive nephronophthisis
(NPHP) and dominant medullary cystic kidney disease (MCKD) can be
clearly distinguished by age of onset or pattern of inheritance.
Autosomal recessive nephronophthisis (NPHP) leads to ESKD at
a median age of 13 years. In NPHP, a history of polyuria, polydipsia,
anemia, and growth retardation is common. Patients often describe
nighttime fluid intake starting at about 6 years of age. Partially
due to excessive salt loss, these children do not develop the usually
typical symptoms of chronic renal disease (hematuria, proteinuria,
hypertension, or edema). Therefore, the diagnosis is usually only
made late in the course of the disease. Renal ultrasound is an important
aid in diagnosing NPHP (Fig. 470-3B) and
is integrated into the diagnostic algorithm (Fig.
470-1). The ultrasonographic characteristics of NPHP are normal
or slightly reduced kidney size; increased echogenicity; a lack
of corticomedullary differentiation; and, beyond the age of 9 years, cysts
at the corticomedullary border of the kidneys. A history of similar
disease in preceding generations suggests a diagnosis of dominant
MCKD, whereas a lack of family history suggests recessive NPHP (Fig. 470-1).
Extrarenal manifestations may occur in all forms of recessive
NPHP, so ophthalmologic examination and brain MRI are warranted.
Recessive NPHP can be associated with extrarenal organ involvement.
Retinitis pigmentosa is associated with NPHP in Senior-Løken
syndrome (SLSN)20 and cerebellar vermis aplasia and coloboma
of the eye in Joubert syndrome.21 The inability to perform
horizontal eye movements (ocular motor apraxia type Cogan) was found
in infants and toddlers with homozygous deletions in the NPHP1 gene. An
association of NPHP with hepatic fibrosis or cone-shaped epiphyses
has also been described. In addition, truncating mutations in NPHP3,
NPHP6, and NPHP8 can lead to Meckel-Gruber syndrome (Fig.
470-1). If obesity, diabetes mellitus, infertility, or polydactyly
are present, Bardet-Biedl syndrome should be considered (Fig. 470-1) and may be confirmed by mutation
analysis. In addition, Jeune syndrome (asphyxiating thoracic dysplasia)22 and
Ellis-van Creveld syndrome can be part of the differential diagnosis.
Mutations in nine different recessive genes have been identified
as causing NPHP.15 These are NPHP1, NPHP2/inversin,
NPHP3, NPHP4, NPHP5, NPHP6/CEP290, NPHP7/GLIS2, NPHP8/RPGRIP1L,
and NPHP9/NEK8, defining NPHP types 1 through 9, respectively
(Table 470-1).2 Gene identification
generated new insights into disease mechanisms of NPHP, as described
above and shown in eFigure 470.1. Gene identification
has made definite molecular genetic diagnostics possible for approximately
30% of cases. Deletions of the NPHP1 gene on both parental
chromosomes account for approximately 21% of all NPHP cases,
whereas the other genes NPHP2-9 (Table
470-1) contribute about 1% each. The causative genes
are still unknown in about 70% of cases. Following genetic
counseling, mutation analysis will first be performed in the most
frequent form, NPHP1. Mutation analysis will unequivocally confirm
the diagnosis of NPHP in approximately 30% of children with
NPHP. If changes on renal ultrasound are seen before the age of 4
years, mutation analysis is warranted in NPHP2/INVS (Fig. 470-1).
Medullary Cystic Kidney
MCKD is characterized by autosomal dominant inheritance, adult-onset
of ESKD. The extrarenal involvement seen in NPHP is absent. However, MCKD
can be associated with hyperuricemia and gouty arthritis in most
affected individuals. A gene locus (MCKD1) for MCKD type 1 has been mapped
to chromosome 1q21, but the gene is unknown. Mutations of the UMOD
gene encoding uromodulin/Tamm-Horsfall protein were detected
as the cause of MCKD type 2. Histology of MCKD is indistinguishable
from the one seen in NPHP (Fig. 470-3A).
Definitive molecular genetic diagnostics is possible by UMOD mutation
analysis. Mutations in UMOD my also cause the clinical picture of
glomerulocystic kidney disease (GCKD; see the following section).