eMedicine Specialties > Nephrology > Cystic Diseases of the Kidney

Polycystic Kidney Disease

Author: Roser Torra, MD, PhD, Consulting Staff, Hereditary Renal Diseases, Department of Nephrology, Fundacio Puigvert, Spain
Contributor Information and Disclosures

Updated: Mar 15, 2010

Introduction

Background

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.

Pathophysiology

The main feature of ADPKD is bilateral progressive cystic dilation of the renal tubules, which may lead to end-stage renal disease (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.

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 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 5-15% 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.

Frequency

International

ADPKD is responsible for 6-10% of ESRD cases in North America and Europe. Approximately 1 per 800-1000 people carries the mutation for this condition. Approximately 85-90% of patients with ADPKD have ADPKD1; most of the remaining patients have ADPKD2.⁴

Mortality/Morbidity

• The major cause of morbidity is progressive renal dysfunction, resulting in grossly enlarged kidneys and kidney failure. In general, half of patients with ADPKD undergo renal replacement therapy by age 60 years. 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 subarachnoidal hemorrhage from intracranial aneurysms (ICAs). This complication is rare and severe.
• In a retrospective, observational study of 88 patients with ADPKD who died sometime between 1981 and 1999, Rahman et al determined that almost half of the patients died of cardiovascular problems.⁵ More specifically, the investigators found, using data from the Sheffield Kidney Institute, in the United Kingdom, and clinical notes, that the 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%
• 
  The median age of the nonsurviving patients was 60.5 years.

Sex

• ADPKD is slightly more severe in males than in females, but it is not statistically significant.

Age

• Symptoms generally increase with age. Children very rarely present with renal failure from ADPKD.
• The mean age of onset of ESRD in patients with ADPKD1 is 53 years; in patients with ADPKD2, it is 74 years.

Clinical

History

• Renal manifestations
  • A decrease in urine-concentrating ability is an early manifestation of the disease.
  • Microalbuminuria occurs in 35% of patients with ADPKD. However, nephrotic-range proteinuria is uncommon.
  • Patients may develop renal failure, usually in the fourth to sixth decade of life. The development of renal insufficiency is highly variable in ADPKD. Renal failure has been reported in children, and, conversely, individuals with the condition may live a normal life expectancy without knowing that they have the disease. An early study estimated that approximately 70% of patients with ADPKD would develop renal insufficiency if they survived to age 65 years. There is an inverse association between the size of polycystic kidneys and the level of glomerular filtration.
• Hypertension^6,7
  • Hypertension is one of the most common early manifestations of ADPKD. Even when renal function is normal, hypertension has been found in 50-75% of patients. In fact, the clinical course of hypertension in ADPKD is very unlike that of hypertension in chronic glomerulonephritis or tubulointerstitial nephropathies. In ADPKD, the hypertension is usually more severe early in the course of the disease and becomes less problematic with the progression of the renal insufficiency. Studies of the renin-angiotensin-aldosterone system have not convincingly demonstrated that they play an important role in its pathogenesis. A rise in diastolic blood pressure is the rule in ADPKD.
  • Doulton and colleagues have demonstrated that activation of the classic circulating renin-angiotensin system (RAS) is no greater in patients with hypertensive ADPKD than in individuals with essential hypertension.⁸ In spite of this evidence, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers are still the most indicated drugs to treat hypertension in patients with ADPKD.
• Pain
  • Pain, located in the abdomen, the flank, or the back, is the most common initial complaint, and it is almost universally present in patients with ADPKD. The pain can be caused by enlargement of one or more cysts, bleeding, either confined inside the cyst or leading to gross hematuria with passage of clots, or a perinephric hematoma; urinary tract infection (eg, acute pyelonephritis, infected cysts, perinephric abscess); nephrolithiasis and renal colic; and, rarely, a coincidental hypernephroma.
  • In addition, patients with ADPKD may have abdominal pain related to definitively or presumably associated conditions. Dull aching and an uncomfortable sensation of heaviness may result from a large polycystic liver. Although rare, hepatic cysts may become infected, especially after renal transplantation. Abdominal pain can also result from diverticulitis, which has been reported to occur with increased frequency in patients with ADPKD maintained on dialysis.
  • Patients with ADPKD may be at a higher risk of developing thoracic aortic aneurysms. Abdominal aortic aneurysms are not increased among these patients.
  • These patients may also develop pain for reasons completely unrelated to their underlying disease; thus, abdominal pain in patients with ADPKD may be a diagnostic challenge.
• Hematuria
  • Hematuria frequently is the presenting manifestation and usually is self-limited (lasting less than or equal to 1 wk).
  • Polycystic kidneys are unusually susceptible to traumatic injury, with hemorrhage occurring in approximately 60% of individuals. Mild trauma can lead to intrarenal hemorrhage or bleeding into the retroperitoneal space accompanied by intense pain that often requires narcotics for relief. The cysts 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, it may rupture into the subcapsular compartment and eventually dissect through the renal capsule to fill the retroperitoneal space.
• Stroke - A family history of stroke (or cerebrovascular accident), the presence of symptoms that may be related to an aneurysm, or a job or hobby in which a loss of consciousness may be lethal indicates the need for aneurysm screening with magnetic resonance angiography.

Physical

• Palpable, bilateral flank masses occur in patients with advanced ADPKD.
• Nodular hepatomegaly occurs in those with severe polycystic liver disease.
• Symptoms related to renal failure (eg, pallor, uremic fetor, dry skin, edema) are rare upon presentation.

Causes

• ADPKD is a hereditary disorder. The pattern of inheritance is autosomal dominant. Because the disorder occurs equally in both sexes, each offspring has a 50% chance of inheriting the affected chromosome 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.
  • PKD1 codes for a 4304–amino acid protein (polycystin 1) with as yet undefined function but 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 colocalizes 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 that, in the kidney, 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.
  • A good genotype-phenotype correlation has not been well established for ADPKD1 and ADPKD2.
  • 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.

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