From 《T & T GIM》：Clinical Case Studies
32. Polycystic Kidney Disease
(PKD1 and PKD2 Mutations)
Autosomal Dominant
PRINCIPLES
• Variable expressivity
• Genetic heterogeneity
• Two-hit hypothesis
MAJOR PHENOTYPIC FEATURES
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Age at onset: childhood through adulthood
Progressive renal failure
Renal and hepatic cysts
Intracranial saccular aneurysms
Mitral valve prolapse
Colonic diverticula
HISTORY AND PHYSICAL FINDINGS
Four months ago, P.J., a 35-year-old man with a history of mitral valve prolapse, developed
intermittent flank pain. He eventually presented to his local emergency department with severe
pain and hematuria. A renal ultrasound scan showed nephrolithiasis and polycystic kidneys
consistent with polycystic kidney disease. The findings from his physical examination were
normal except for a systolic murmur consistent with mitral valve prolapse, mild hypertension,
and a slight elevation of serum creatinine concentration. His father and his sister had died of
ruptured intracranial aneurysms, and P.J.’s son had died at 1 year of age from polycystic kidney
disease. At the time of his son’s death, the physicians had suggested that P.J. and his wife should
be evaluated to see whether either of them had polycystic kidney disease; however, the parents
elected not to pursue this evaluation because of guilt and grief about their son’s death. P.J. was
admitted for management of his nephrolithiasis. During this admission, the nephrologists told
P.J. that he had autosomal dominant polycystic kidney disease.
BACKGROUND
Disease Etiology and Incidence
Autosomal dominant polycystic kidney disease (ADPKD, MIM# 173900) is genetically
heterogeneous. Approximately 85% of patients have ADPKD-1 caused by mutations in the PKD1
gene; most of the remainder have ADPKD-2 due to mutations of PKD2. A few families have not
shown linkage to either of these loci, suggesting that there is at least one additional, as yet
unidentified locus.
ADPKD is one of the most common genetic disorders and has a prevalence of 1 in 300 to 1 in
1
1000 in all ethnic groups studied. In the United States, it accounts for 8% to 10% of end-stage renal
disease.
Pathogenesis
PKD1 encodes polycystin 1, a transmembrane receptor–like protein of unknown function. PKD2
encodes polycystin 2, an integral membrane protein with homology to the voltage-activated sodium
and calcium 1 channels. Polycystin 1 and polycystin 2 interact as part of a heteromultimeric
complex.
Cyst formation in ADPKD appears to follow a “two-hit” mechanism such as that observed with
tumor-suppressor genes and neoplasia (see Chapter 16); that is, both alleles of either PDK1 or
PDK2 must lose function for cysts to form. The mechanism by which loss of either polycystin 1 or
polycystin 2 function causes cyst formation has not been defined but involves mislocalization of cell
surface proteins that are normally restricted either to basolateral or epithelial surfaces of developing
renal tubular cells (see Chapter 14).
Phenotype and Natural History
ADPKD may manifest at any age but symptoms or signs most frequently appear in the third or
fourth decade. Patients present with urinary tract infections, hematuria, urinary tract obstruction
(clots or nephrolithiasis), nocturia, hemorrhage into a renal cyst, or complaints of flank pain from
the mass effect of the enlarged kidneys (Fig. C-32). Hypertension affects 20% to 30% of children
and nearly 75% of adults with ADPKD. The hypertension is a secondary effect of intrarenal
ischemia and activation of the renin-angiotensin system. Nearly half of patients have end-stage
renal disease by 60 years of age. Hypertension, recurrent urinary tract infections, male sex, and early
age of clinical onset are most predictive of early renal failure. Approximately 43% of patients
presenting with ADPKD before or shortly after birth die of renal failure within the first year of life;
end-stage renal disease, hypertension, or both develop in the survivors by 30 years of age.
ADPKD exhibits both interfamilial and intrafamilial variation in the age at onset and severity.
Part of the interfamilial variation is secondary to locus heterogeneity because patients with
ADPKD-2 have milder disease than patients with ADPKD-1. Intrafamilial variation appears to
result from a combination of environment and genetic background because the variability is more
marked between generations than among siblings.
In addition to renal cysts, patients with ADPKD develop hepatic, pancreatic, ovarian, and
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splenic cysts as well as intracranial aneurysms, mitral valve prolapse, and colonic diverticula.
Hepatic cysts are common in both ADPKD-1 and ADPKD-2, whereas pancreatic cysts are
generally observed with ADPKD-1. Intracranial saccular aneurysms develop in 5% to 10% of
patients with ADPKD; however, not all patients have an equal risk for development of aneurysms
because they exhibit familial clustering. Patients with ADPKD have an increased risk of aortic and
tricuspid valve insufficiency, and approximately 25% develop mitral valve prolapse. Colonic
diverticula are the most common extrarenal abnormality; the diverticula associated with ADPKD
are more likely to perforate than are those observed in the general population.
Management
In general, ADPKD is diagnosed by family history and renal ultrasound examination. The detection
of renal cysts by ultrasound examination increases with age such that 80% to 90% of patients have
detectable cysts by 20 years, and nearly 100% have them by 30 years. If necessary for prenatal
diagnosis or identification of a related kidney donor, the diagnosis can be confirmed by linkage or
mutation detection, or both, in some families.
The management and treatment of patients with ADPKD focus on slowing the progression of
renal disease and minimizing its symptoms. Hypertension and urinary tract infections are treated
aggressively to preserve renal function. Pain from the mass effect of the enlarged kidneys is
managed by drainage and sclerosis of the cysts.
INHERITANCE RISK
Approximately 90% of patients have a family history of ADPKD; only 10% of ADPKD results
from de novo mutations of either PDK1 or PDK2. Parents with ADPKD have a 50% risk of having
an affected child in each pregnancy. If the parents have had a child with onset of disease in utero, the
risk of having another severely affected child is approximately 25%. In general, however, the
severity of disease cannot be predicted because of variable expressivity. For families in which the
mutation is known or in which linkage analysis is possible, the recurrence risk can be modified by
analysis of fetal DNA.
Siblings and parents of patients with ADPKD also have an increased risk of disease. Renal
ultrasonography is the recommended method for the screening of family members.
Questions for Small Group Discussion
1. Compare the molecular mechanism of cyst development in ADPKD with the development of
neurofibromas in neurofibromatosis type 1.
2. Many mendelian diseases have variable expressivity that might be accounted for by modifier
loci. How would one identify such loci?
3. Why is ADPKD frequently associated with tuberous sclerosis? How might this illustrate a
contiguous gene deletion syndrome?
4. How can ADPKD be distinguished from autosomal recessive polycystic kidney disease?
5. Linkage analysis of families segregating ADPKD requires the participation of family
members in addition to the patient. What should be done if individuals crucial to the study do
not want to participate?
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REFERENCES
GeneTests. Medical genetics information resource [database online]. University of Washington,
Seattle, 1993-2006. Updated weekly. http://www.genetests.org
OMIM: Online Mendelian Inheritance in Man. McKusick-Nathans Institute for Genetic Medicine,
Johns Hopkins University, and National Center for Biotechnology Information, National Library
of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
Wilson PD: Polycystic kidney disease. N Engl J Med 350:151-164, 2004.
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