Polycystic kidney disease, or PKD, is a genetic disease in which the kidneys become filled
with hundreds of cysts, or fluid-filled sacs, causing them to be larger than normal and
to quit functioning over time.
These cysts develop in the outer layer—the cortex, as well as the inner layer—the medulla—of
both kidneys.
These cysts, which are lined with renal tubular epithelium, fill up with fluid and get larger
and larger over time, making the kidneys much larger than normal.
The blood vessels that feed neighboring healthy nephrons can get compressed by growing cysts,
which literally starves them of oxygen.
Poorly perfused kidneys respond by activating the renin-angiotensin-aldosterone system,
which facilitates fluid retention and leads to hypertension.
Also, expanding cysts can compress the collecting system, causing urinary stasis, and in some
cases this can lead to kidney stones.
Additionally, destruction of the normal renal architecture can cause symptoms like flank
pain and hematuria, or blood in the urine.
Over time, as enough nephrons are affected, it leads to renal insufficiency and eventually
renal failure.
Now the first type of PKD is autosomal dominant PKD or ADPKD, which used to be called adult
PKD, since symptoms usually manifest in adulthood.
The first gene responsible for ADPKD is PKD1, which when mutated causes the more severe
and earlier onset variety, and PKD2, which when mutated causes less severe disease and
is also later in onset.
PKD1 and PKD2 code for the polycystin 1 and polycystin 2 proteins, respectively, which
are components of the primary cilium.
Now, the primary cilium is an appendage that sticks out from most cells in the body and
receives developmentally important signals.
More specifically, in the nephron, as the urinary filtrate flows by and cause it to
bend, polycystin 1 and polycystin 2 respond by allowing calcium influx, which activates
pathways in the cell that inhibit cell proliferation.
If either component is absent, that signal to inhibit growth isn’t received, and so
cells proliferate abnormally and start to express proteins that cause water to be transported
into the lumen of the cyst, which makes them get larger and larger, compressing the surrounding
tissue more and more, and this is how the cysts develop and grow.
As expected for a dominant disease, a person who develops ADPKD would have inherited a
single, heterozygous mutation in PKD1 or PKD2.
This leaves one functional copy of the gene in every cell, and this turns out to actually
produce enough polycystin 1 or polycystin 2 to prevent cyst formation.
So how do cysts occur then?
Well it turns out that a random mutation in the remaining good copy of the gene is almost
guaranteed to happen in some of the tubular cells as the kidney develops.
This ‘second hit’ causes polycystin 1 or 2 to be absent and is what impairs normal
signalling through the cilium and leads to cyst formation.
So on the level of the person as a whole, ADPKD shows a pattern of dominant inheritance,
but on the cellular level it’s technically a recessive trait.
Polycystins are important in the kidney, but are developmentally important in other places
of the body, too.
Patients can have cysts that are typically benign pop up in the liver, seminal vesicles,
and pancreas.
The vasculature can also be affected, for example individuals might develop aortic root
dilation which can lead to heart failure, and have berry aneurysms of the cerebral arteries,
usually in the Circle of Willis.
These aneurysms can have a thin wall, allowing them to rupture and develop into a subarachnoid
hemorrhage.
Autosomal recessive PKD or ARPKD used to be called infantile PKD, since symptoms usually
manifest in infancy.
ARPKD happens when someone inherits a mutation on both copies of the PKHD1 gene, which codes
for the fibrocystin protein.
Fibrocystin co-localizes with polycystin 2, where, although largely unclear, it might
be involved in the regulation pathway and calcium signaling described with ADPKD, and
therefore it’s thought that a similar mechanism might cause cyst formation in ARPKD.
In any case, with ARPKD, this cyst formation can lead to renal failure even before birth,
which means the fetus has trouble producing urine, and since amniotic fluid comes from
fetal urine, fetuses with ARPKD can develop oligohydramnios, or low amniotic fluid.
In fact, if enough amniotic fluid is missing, it can can cause Potter sequence.
Without the amniotic fluid, the uterine walls actually compress the fetus, which causes
physical developmental abnormalities, like club feet and a flattened nose.
Also as a part of Potter sequence, is pulmonary hypoplasia, or underdeveloped lungs since
the amniotic fluid is important in helping the lungs expand and develop normally.
Underdeveloped lungs can cause respiratory insufficiency after birth, which ends up being
fatal in a lot of cases of ARPKD.
For diagnosis, ARPKD is one of the many conditions that can be picked up via prenatal ultrasound,
which could show bilaterally large kidneys with cysts and oligohydramnios.
ARPKD also causes congenital hepatic fibrosis, which over time can cause portal hypertension,
or compromised blood flow through the portal venous system.
Portal hypertension can cause esophageal varices, upper GI bleeds, hemorrhoids, and splenomegaly
from blood being shunted through collateral veins.
Since cholangiocytes, or the epithelial cells that line the bile ducts, also have primary
cilia that express fibrocystin, ARPKD can also cause defects in the bile ducts which
leads to dilation.
Dilated intrahepatic ducts, which can cause cholestasis or poor bile secretion, and dilation
of the common bile duct can lead to ascending cholangitis.
The treatment of PKD is usually directed at specific symptoms and organ dysfunction.
For example, for hypertension, medications like angiotensin converting enzyme inhibitors
or angiotensin receptor blockers can be used to counteract activation of the renin-angiotensin-aldosterone
system.
Also, ursodiol is sometimes taken to help treat cholestasis since it slows down the
rate at which cholesterol is absorbed by the intestines.
In cases of kidney failure, dialysis or kidney transplant are sometimes needed.
For individuals with portal hypertension, a portocaval shunt, which bypasses the liver
by connecting the portal vein to the inferior vena cava, or again a liver transplant might
be needed.
Alright, as a quick recap, polycystic kidney disease is a genetic disorder in which the
kidneys become filled with hundreds of cysts, causing them to be larger than normal and
to fail over time.
PKD comes in two varieties: autosomal dominant, which presents in adulthood, and autosomal
recessive, which presents in infancy or even before birth.
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