Polycystic kidney disease (PKD) is one of the most common inherited genetic diseases in humans. It is a chronic, progressive disease and is associated with substantial morbidity and mortality. In PKD, gene mutations cause the formation of numerous cysts, sometimes numbering in the thousands, in the kidneys, the liver and other organs. PKD cysts can be observed even before birth and grow and enlarge throughout a patient’s life.  This is particularly problematic in the kidneys, where cyst growth can disrupt the normal renal architecture, replace much of the normal kidney structure and cause a progressive decline in kidney function. As compared to a normal size kidney, which is about the size of a human fist, polycystic kidneys can grow as a large as a football and weigh up to 38 pounds each.  This can lead to kidney failure and the need for dialysis or kidney transplantation.  In the United States, approximately 2,500 new people with PKD require dialysis or a kidney transplant every year.  PKD exists around the world and in all races, occurring equally in women and men.

There are two major forms of PKD:  autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common form of PKD. A person who has the autosomal dominant genetic mutation has a 50% chance of passing ADPKD onto each of his/her children.  A child can get ADPKD by inheriting the mutation from only one parent. Two major sites of genetic mutation have been identified for ADPKD.  About 85% of families with ADPKD have a mutation in the PKD1 gene, sometimes referred to as PKD1 disease.  A mutation can also occur in the PKD2 gene, resulting in PKD2 disease.  PKD2 patients usually have a milder form of ADPKD, being diagnosed at a later age and with a slower rate of progression to kidney failure. The diagnosis of ADPKD is usually established by imaging the kidney with ultrasonography, although other imaging tests such as CT scans or MRIs may be used.  Family history is also important and genetic testing may be required in certain settings.  There are an estimated 140,000 diagnosed ADPKD patients in the US with about 6,000 new patients being diagnosed each year. Although a diagnosis can occur at any age, most  patients receive an ADPKD diagnosis between the ages of 30 and 50.   Patients often present with hypertension, which occurs prior to loss of kidney function in 2/3 of patients, hematuria (blood in the urine), renal insufficiency, flank pain, calculi, or urinary tract infection, regardless of whether they carry mutations in the PKD1 or PKD2 gene.  

The picture below illustrates a typical pattern of disease progression and associated signs and symptoms in ADPKD. 

Cysts may also form in other organs, such as the liver or pancreas.  Of note, polycystic liver disease is the major extrarenal complication in patients with ADPKD.  In some ADPKD patients, liver enlargement as a result of continuous cyst growth is associated with clinical symptoms such as pain, abdominal fullness and, in advanced stages, leg edema and portal hypertension.

ADPKD is a progressive disease.  The likelihood of requiring dialysis is estimated at less than 2% in people under age 40, increasing to 50 to 75% by age 70 to 75.  By the age of 60, half of all ADPKD patients require dialysis or transplantation, with kidney failure occurring at an average age of 74 years for PKD2 patients vs. 55 years for PKD1 patients.  

Treatment of patients with ADPKD includes specific, non-specific and supportive measures.  Non-specific medications are prescribed for blood pressure control, pain management, and treatment of infections.  Non-pharmacological approaches are also used, including cyst decompression surgeries, dietary modifications and, later in the progression of disease, dialysis and/or transplantation.  Physicians have identified the need for a drug that could be administered safely over many years to delay disease progression in ADPKD patients. The FDA granted approval to the first drug developed specifically for the treatment of ADPKD, the vasopressin antagonist tolvaptan, in April, 2018.  Despite this noteworthy progress, additional agents are needed to address the many additional unmet patient needs.  Lixivaptan is being developed to help address some of those needs (see Lixivaptan discussion).

Autosomal recessive polycystic kidney disease (ARPKD) is an uncommon genetic disease with an estimated incidence of approximately 1 in 20,000 live births.  It is due to mutations in a related but distinct gene to the genes that cause ADPKD.  As an autosomal recessive disorder, the child must inherit the gene mutation from both parents who each must have a gene mutation.   ARPKD affects not only kidneys, but also other organ systems, especially the liver.  The severity and progression of ARPKD can vary greatly from one person to another, even among members of the same family.  The outcome is dependent on the degree of renal and hepatic involvement, which is usually related to the age of presentation.  Babies with the most severe cases of ARPKD often die hours or days after birth because their lungs did not develop prior to birth and pressure from enlarged kidneys can contribute to breathing problems. Twenty years ago, only half the children born with ARPKD survived to their 10th birthday.  ARPKD is still a disease that devastates families and dramatically affects quality of life for children who have it. But now babies who survive the first month have a greater than 80% chance of survival beyond 15 years, even though they often develop kidney failure before reaching adulthood.  Liver scarring, usually present at birth, can lead to progressive liver dysfunction and other problems.  Although some people with ARPKD do not develop signs or symptoms until later in childhood, the diagnosis of ARPKD may occur before a child is born.  Severe cases of ARPKD can be detected by routine ultrasound after 18 weeks of gestation. 

Treatment of patients with ARPKD is focused on specific symptoms and includes consideration of possible growth problems, breathing problems and liver disease.  There is no curative intervention for ARPKD.

UNMET TREATMENT NEEDS.   The combination of PKD being an inherited disease that can manifest early in life and the long duration of medical treatment, which often includes costly dialysis or transplantation for many patients, results in significant financial and emotional burden associated with the disease.  Current specific treatment options are limited. Certain patient populations are not likely to be eligible for treatment and patients receiving the only approved agent for ADPKD will need to be monitored for possible liver toxicity.  Thus there continues to be a need for more treatment options and a safe drug that could be taken chronically by a broad group of patients to slow the progression of the disease.   

Lixivaptan is being developed as a possible drug therapy with a differentiated safety and efficacy profile to prevent progression and avoid the need for dialysis and transplantation in many PKD patients.