620
U N I T 7
Kidney and Urinary Tract Function
for diagnosis of ADPKD, but are usually reserved for
cases in which radiographic imaging is negative and the
need for a definitive diagnosis is essential, such as when
screening family members for potential kidney dona-
tion. Magnetic resonance angiography is recommended
for persons who have a family history of cerebral aneu-
rysm or stroke and for those with new-onset or severe
headache.
The treatment of ADPKD is largely supportive and
aimed at delaying progression of the disease. Control
of hypertension and prevention of ascending UTIs are
important. Pain is a common complaint of persons with
ADPKD, and a systematic approach is needed to differ-
entiate the etiology of the pain and define an approach
for management.
Cyclic adenosine monophosphate (cAMP) has been
shown to increase proliferation of epithelial cells in cyst
walls and the rate of fluid secretion into cysts. One of
the prime mediators of cell proliferation, acting through
cAMP, is
arginine vasopressin
(AVP), also known as the
antidiuretic hormone
. In studies using genetically pro-
duced polycystic animals, the use of vasopressin V2
receptor inhibitors reduced cyst growth and preserved
renal function. Because an increase in urine osmolality
serves to increase vasopressin levels, it is often recom-
mended that persons with ADPKD drink approximately
3000 L of water throughout the waking hours to reduce
plasma AVP levels.
6,7
Normally cAMP is broken down by
phosphodiesterases. Because caffeine raises cAMP levels
by interfering with phosphodiesterase activity, it is also
recommended that caffeinated beverages be avoided.
6,7
In addition to increasing water intake to decrease
vasopressin levels, the angiotensin-converting enzyme
(ACE) inhibitors or angiotensin II receptor blockers
(ARBs) may be used to interrupt the renin-angiotensin-
aldosterone system as a means of reducing intraglomer-
ular pressure and renal vasoconstriction. Although not
approved by the Food and Drug Administration (FDA),
there has been recent interest in the use of vasopressin
receptor antagonists (vaptans) to decrease cyst develop-
ment.
9
Dialysis and kidney transplantation are reserved
for those who progress to kidney failure.
Autosomal Recessive Polycystic Kidney
Disease
Autosomal recessive (childhood) polycystic kidney disease
(ARPKD) is characterized by cystic dilation of the cortical
and medullary collecting tubules
3–5
(see Fig. 25-2B). It is
rare compared with ADPKD, occurring in 1 to 20,000 live
births. Autosomal recessive (childhood) polycystic kidney
disease is caused by mutations in the
PKHD1
gene. The
gene product, fibrocystin, is found in the collecting ducts
of the kidney, biliary ducts of the liver, and exocrine
ducts of the pancreas, and appears to be involved in the
regulation of cell proliferation and adhesion. Perinatal,
neonatal, infantile, and juvenile subcategories have been
defined, dependent on time of presentation. The perinatal
and infantile types are most common. Serious manifes-
tations are usually present at birth, with the infant pro-
gressing rapidly into renal failure.
The typical infant with ARPKD presents with bilat-
eral flank masses, accompanied by severe renal fail-
ure, signs of impaired lung development, and variable
degrees of liver fibrosis and portal hypertension. Potter
facies and other defects associated with oligohydram-
nios may be present. Hypertension is usually noted
within the first few weeks of life and is often severe.
Approximately 75% of infants die during the perinatal
period, often of pulmonary hypoplasia.
3
Children and
juveniles who survive infancy develop a distinctive type
of liver fibrosis. In older children, liver disease is the pre-
dominant clinical concern.
The treatment of ARPKD is largely supportive.
Aggressive ventilatory support is often necessary in the
neonatal period because of pulmonary hypoplasia and
hypoventilation. Modern neonatal respiratory technol-
ogy and renal replacement therapy (e.g., dialysis and
kidney transplant) have increased the 10-year survival
rate of children surviving beyond the 1st year of life.
Morbidity and mortality in the older child is related to
complications of kidney failure and liver disease.
Nephronophthisis and Medullary Cystic
Kidney Disease
Nephronophthisis and adult-onset medullary cystic kid-
ney disease both produce progressive medullary tubu-
lointerstitial cystic disease, but vary in terms of genetic
causes and patterns of inheritance.
4,5
Nephronophthisis
has an autosomal recessive pattern of inheritance with
onset in infancy, childhood, or adolescence. It is caused
by mutations in NPHP genes, whose gene products are
located on the primary cilia, similar to those of ADPKD
and ARPKD. Medullary cystic kidney disease has an
autosomal dominant pattern of inheritance, with onset in
adolescence and progression to renal failure in adulthood
that is caused by a mutation in the MCKD 1 or 2 genes.
4
Common characteristics of the two cystic diseases
are small and shrunken kidneys and the presence of a
variable number of cysts, usually concentrated at the
corticomedullary junction area of the kidney. The ini-
tial insult involves the distal tubules, with tubular base-
ment membrane disruption followed by chronic and
progressive tubular atrophy involving both the medulla
and cortex. Although the presence of medullary cysts is
important, the cortical tubulointerstitial damage is the
eventual cause of chronic kidney disease and failure.
5
Nephronophthisis can present as three clinical vari-
ants: infantile, juvenile, or adolescent.
4
The juvenile
form is most common and accounts for 5% to 10%
of chronic kidney disease in children. Symptoms begin
between 4 to 6 years of age, and progress to chronic
kidney disease within 10 years. Some juvenile forms of
nephronophthisis have extrarenal complications, includ-
ing ocular motor abnormalities, retinitis pigmentosa,
liver fibrosis, and cerebellar abnormalities. The onset
and progression of the adolescent form causes chronic
kidney failure at 10 to 20 years of age, and the infantile
form before 2 years of age.
Children with nephronophthisis and adults with med-
ullary cystic kidney disease present first with polyuria,
