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. Thanks for watching, you can help support
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