Observations on Autosomal Dominant Polycystic Kidney Disease

Kidneys are amazing. These two fist-sized organs have a big job; they filter all the blood in the body and regulate the amount of fluid in the bloodstream. Kidneys filter around a gallon of blood every 4 minutes, all day, every day, forever. Problems with the kidneys can be severe. One problem that can arise with kidneys is autosomal dominant polycystic kidney disease (ADPKD). Research studies on animals (primarily rats) have helped us understand some of the mechanisms behind autosomal dominant polycystic kidney disease. However, we still don’t know a lot about it, including its prevalence. This genetic condition seems to affect less than 1% of the population but is associated with severe problems that can lead to dialysis, kidney transplants, and death. It affects women and men equally and takes time to develop. An early sign is high blood pressure, but most people develop no symptoms until their 30s and 40s. Typical signs and symptoms include:

• High blood pressure
• Pain in the back and side
• Blood in the urine
• Rapidly lowering filtration rate (GFR or eGFR)
• Enlargement of the kidneys due to fluid-filled cysts

By the time a person is 70, there is a 50% chance that someone with ADPKD will need dialysis or a transplant. 

The kidneys have tons of tubular blood vessels that filter fluids. The epithelial cells lining these vessels have a long antenna-like protein that sticks out into the blood flow. Scientists think this protein, called the primary cilium (plural cilia), senses the blood flow rate through the vessels. The primary cilium attaches to signaling pathways in the cell, which determines many of the cell’s functions, such as how to grow and reproduce. Figuring this out has been a long and challenging process requiring decades of research.

With ADPKD, some of the primary cilia are not built correctly. They send the wrong signals to the cell, and big problems emerge. Cells might turn upside-down, grow abnormally large, or form fluid-filled growths called cysts. These cysts can grow extremely large and replace kidney cells. Erratic signals from the primary cilia are also implicated in fibrosis (thickening or scarring), enlarged kidneys (because of cysts), and kidney failure. 

So, how do we get ADPKD? The name autosomal dominant polycystic kidney disease gives clues, especially if you’re familiar with genetics. Each of our cells (except red blood cells) contains DNA, the genetic code that makes us unique. This code is organized into an X or Y sex chromosome and one of 22 autosomal (non-sex) chromosomes. On each chromosome, we have genes, which are cohesive pieces of DNA that comprise a single inheritable trait, like eye color or freckles. A lot of the time, these genes contain the genetic code required to make a single protein. The DNA sequence of that gene determines the form of the protein. In ADPKD, one of two genes, PDK1 or PDK2, have a mutation that makes the corresponding proteins malfunction. These proteins are involved with the primary cilium and result in the problems we see with ADPKD. Interestingly, though every cell in a person with ADPKD has the defective gene, only around 5% of an affected person’s kidney cells change. Scientists think a secondary effect causes some cells to start going rogue, a phenomenon they call the “second hit.”

So, what can be done about ADPKD? Unfortunately, there are no cures for this disease yet. Management consists of treating high blood pressure, pain, cyst and urinary tract infections. Additionally, patients may be told to avoid things that may stress the kidneys, like caffeine and estrogens. To really treat autosomal dominant polycystic kidney disease we need more knowledge. Scientists are working on ways to fix single-gene errors for diseases like ADPKD, but they need to know more about the genes and who has them. Animal analysis can help us with the mechanisms, but observational studies that look at people’s genes are needed to know what to target and how to do so safely. These studies typically don’t involve an investigational medication but are necessary to develop them. With the help of clinical research volunteers, we may be able to make our knowledge about ADPKD as amazing as our kidneys!

Staff Writer / Editor Benton Lowey-Ball, BS, BFA

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