Polycystic Kidney Disease 

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited disorders in humans. It is the most frequent genetic cause of renal failure in adults, accounting for 6-8% of patients on dialysis in the United States.

ADPKD is a multisystemic and progressive disorder characterized by the formation and enlargement of cysts in the kidney (as seen in the image below) and other organs (eg, liver, pancreas, spleen). Clinical features usually begin in the third to fourth decade of life, but cysts may be detectable in childhood and in utero.^[1]

Pain—in the abdomen, flank, or back—is the most common initial complaint, and it is almost universally present in patients with ADPKD (see Clinical). Ultrasonography is the diagnostic procedure of choice (see Workup). Medical therapy is needed to control problems such as hypertension, urinary tract infections, hematuria, and pain. Surgical drainage of cysts may be indicated. Patients who progress to end-stage renal disease (ESRD) may require dialysis or renal transplantation. (see Treatment).

For a discussion of ADPKD in children, see the Medscape Reference article Pediatric Polycystic Kidney Disease.

The main feature of ADPKD is a bilateral progressive increase in the number of cysts, which may lead to ESRD. Hepatic cysts, cerebral aneurysms, and cardiac valvular abnormalities also may occur.^{[2, 3]}

Although ADPKD is a systemic disease, it shows a focal expression because less than 1% of nephrons become cystic. In ADPKD, each epithelial cell within a renal tubule harbors a germ-line mutation, yet only a tiny fraction of the tubules develop renal cysts.

It is currently held that the cells are protected by the allele inherited from the parent without ADPKD. When this allele is inactivated by a somatic event (mutation or otherwise) within a solitary renal tubule cell, the cell divides repeatedly until a cyst develops, with an aberrant growth program causing endless expansion. The severity of ADPKD is thought to be a direct consequence of the number of times and the frequency with which this cystogenic process occurs within the kidneys over the life of the patient. However this hypothesis is hard to understand in neonatal cases.

The hyperplastic cells cause an out-pocketing of the tubule wall, with the formation of a saccular cyst that fills with fluid derived from glomerular filtrate that enters from the afferent tubule segment. Progressive expansion eventually causes most of the emerging cysts to separate from the parent tubule, leaving an isolated sac that fills with fluid by transepithelial secretion. This isolated cyst expands relentlessly as a result of continued proliferation of the mural epithelium together with the transepithelial secretion of sodium chloride and water into the lumen.

The expanding fluid-filled tumor masses elicit secondary and tertiary changes within the renal interstitium evinced by thickening and lamination of the tubule basement membranes, infiltration of macrophages, and neovascularization. Fibrosis within the interstitium begins early in the course of the disease.

Cellular proliferation and fluid secretion may be accelerated by cyclic adenosine monophosphate (cAMP) and growth factors, such as epidermal growth factor (EGF). In summary, cysts function as autonomous structures and are responsible for progressive kidney enlargement in ADPKD.

Approximately 85-90% of patients with ADPKD have an abnormality on the short arm of chromosome 16 (ie, ADPKD type 1 [ADPKD1]). A second defect, termed ADPKD type 2 (ADPKD2), is responsible for 10-15% of ADPKD cases and is found on the long arm of chromosome 4. A third genotype may exist, but no genomic locus is assigned.

PKD1 and PKD2 are expressed in most organs and tissues of the human body. The proteins that are encoded by PKD1 and PKD2, polycystin 1 and polycystin 2, seem to function together to regulate the morphologic configuration of epithelial cells. The polycystins are expressed in development as early as the blastocyst stage and are expressed in a broad array of terminally differentiated tissues. The functions of the polycystins have been scrutinized to the greatest extent in epithelial tissues of the kidneys and liver and in vascular smooth muscle (see Etiology).

A decrease in urine-concentrating ability is an early manifestation of ADPKD. The cause is not known. Plasma vasopressin levels are increased; this increase may represent the body's attempt to compensate for the reduced concentrating capacity of the kidneys and could contribute to the development of renal cysts, hypertension, and renal insufficiency.^[4]

Bleeding

Renal cysts in ADPKD are associated with excessive angiogenesis evinced by fragile vessels stretched across their distended walls. When traumatized, these vessels may leak blood into the cyst, causing it to expand rapidly, resulting in excruciating pain. If bleeding continues, then the cyst may rupture into the collecting system, causing gross hematuria. Alternatively, the cyst may rupture into the subcapsular compartment and eventually dissect through the renal capsule to fill the retroperitoneal space.

ADPKD is a hereditary disorder. The pattern of inheritance is autosomal dominant. Because the disorder occurs equally in males and females, each offspring has a 50% chance of inheriting the responsible mutation and, hence, the disease.

ADPKD is a genetically heterogeneous condition that involves at least 2 genes. PKD1 is located on 16p13.3 and accounts for most ADPKD cases. PKD2 is located on 4q21-q22 and accounts for 15% of ADPKD cases.

Polycystin 1 and 2

PKD1 codes for a 4304–amino acid protein (polycystin 1). The function of polycystin 1 is not yet fully defined, but this protein interacts with polycystin 2 and is involved in cell cycle regulation and intracellular calcium transport. Polycystin 1 localizes in the primary cilia of renal epithelial cells, which function as mechanosensors and chemosensors.

PKD2 codes for a 968–amino acid protein (polycystin 2) that is structurally similar to polycystin 1 and co-localizes to the primary cilia of renal epithelial cells. It is a member of the family of voltage-activated calcium channels.

Polycystin 1 and polycystin 2 are highly conserved ubiquitous transmembrane proteins. In the kidney, they are located in the epithelial cells of the renal tubules—in particular, in the primary cilia at the luminal side of the tubules, as well as in other areas of the renal cell epithelium.

Polycystin 1 is a large protein with a long extracellular N-terminal region, 11 transmembrane domains, and a short intracellular C-terminal tail. Polycystin 2 is structurally related to the transient receptor potential (TRP) channel family, and it is known to function as a nonselective cation channel permeable to Ca²⁺.

Polycystin 1 and polycystin 2 form heteromeric complexes and colocalize in the primary cilium of renal epithelial cells. The primary cilium is a long, nonmotile tubular structure located in the apical surface of the epithelial cells in the renal tubules. Its function was unknown for a long time. However, studies now indicate that the primary cilium may be a mechanoreceptor that senses changes in apical fluid flow and that transduces them into an intracellular Ca²⁺ signaling response.

This model involves the participation of polycystin 1 as a mechanical sensor of ciliary bending induced by luminal fluid flow. Bending of the cilium would cause a conformational change in polycystin 1 that would, in turn, activate the polycystin 2–associated Ca²⁺ channel, increasing the intracellular Ca²⁺ concentration and triggering intracellular signaling pathways leading to normal kidney development.^[5]

A good genotype-phenotype correlation has not been well established for ADPKD1 and ADPKD2.^[6]

ADPKD1 is more severe than ADPKD2. The mean age of ESRD for patients with ADPKD1 is 53 years. The mean age of ESRD for patients with ADPKD2 is 74 years.

The genetic heterogeneity of ADKPD, and the possible contribution of modifier genes, may explain the wide clinical variability in this disease, both within and between families.^[7]

ADPKD is responsible for 6-10% of ESRD cases in North America and Europe. Approximately 1 per 800-1000 population carries a mutation for this condition. Approximately 85-90% of patients with ADPKD have ADPKD1; most of the remaining patients have ADPKD2.^[8]

ADPKD is slightly more severe in males than in females, but the difference is not statistically significant.

Symptoms generally increase with age. Children very rarely present with renal failure from ADPKD.

The prognosis in patients with ADPKD covers a wide spectrum. Renal failure has been reported in children; conversely, individuals with ADPKD may live a normal lifespan without knowing that they have the disease. More typically, however, ADPKD causes progressive renal dysfunction, resulting in grossly enlarged kidneys and kidney failure by the fourth to sixth decade of life. There is an inverse association between the size of polycystic kidneys and the level of glomerular filtration.^{[9, 10]}

An early study estimated that approximately 70% of patients with ADPKD would develop renal insufficiency if they survived to age 65 years. Currently, half of all patients with ADPKD require renal replacement therapy by age 60 years. Risk factors for progression include the following:

• PKD1 genotype
• Large kidneys
• Several episodes of gross hematuria^[11]
• Severe and frequent kidney infections
• Hypertension
• Multiple pregnancies
• Black racial background^[8]
• Male sex

The presence of more than one risk factor increases the risk of progression to ESRD.

The 2 forms of ADPKD are ADPKD1 and ADPKD2.^[12] Although they share similar clinical features, renal prognosis is strikingly different.^[13] ADPKD2 is a milder disease, based on the age of onset of ESRD. The median age of renal survival for individuals with ADPKD2 is 68 years, which is significantly older than for those with ADPKD1, in whom the median age of renal survival is 53 years. Although ADPKD2 is milder than ADPKD1, it has an overall impact on survival and shortens life expectancy.

A study of 180 patients with ADPK by Idrizi et al found that recurrent episodes of gross hematuria may increase the risk for more severe renal disease.^[11] In the 43 study patients who experienced at least one episode of gross hematuria before age 30 years, renal survival was worse than in the other patients with ADPKD (a 10-year difference in survival). Although 60% of the study patients experienced urinary tract infections (UTIs), appropriate treatment of UTI decreased its frequency and slowed the rate of progression to renal failure.

Cardiovascular pathology and infections account for approximately 90% of deaths of those patients treated by hemodialysis or peritoneal dialysis and after renal transplantation.

Another cause of mortality is in ADPKD is subarachnoid hemorrhage from intracranial aneurysms.^[14] This complication is rare and severe.

In a retrospective, observational study of 88 patients with ADPKD who died between 1981 and 1999, Rahman et al determined that almost half of the patients died of cardiovascular problems.^[15] The median age of death was 60.5 years.

Causes of death included the following:

• Cardiovascular problems - 46.6% of patients
• Infection - 15.9% of patients, with 42% of these deaths resulting from septicemia
• Central nervous system disorders - 11.36% of patients, with 60% of these deaths caused by cerebrovascular events
• Uremia - 2.2% of patients
• Other, miscellaneous causes - 11.36%

Ensure that patients are aware that this disease is hereditary and that their children have a 50% chance of acquiring the disease. Patients should also understand that although several treatments are being tested, this disease currently has no cure. Only interventions that slow the progression of renal disease (eg, adequate blood pressure control) are of benefit. Hopefully, effective specific therapy will be available in a few years.

Prenatal diagnosis is available through DNA linkage studies, if enough family members cooperate, or through a mutation search. Suggest that family members who are not screened for ADPKD have annual blood pressure checks and urine screenings for hematuria.