Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Bharathi V. Reddy, M.D.
Arlene Chapman, M.D.

Basic Information

Definition

Autosomal dominant polycystic kidney disease (ADPKD) is a systemic inherited disorder due to mutations in either the PKD1 or PKD2 gene. These mutations lead to cyst formation and growth in multiple organs including kidneys, liver, and pancreas. ADPKD is also associated with multiple gastrointestinal and cardiovascular abnormalities. It is the most common inherited kidney disease, and its prevalence is greater than Huntington’s disease, hemophilia, sickle cell disease, cystic fibrosis, myotonic dystrophy, and Down syndrome combined.

Synonyms

Adult polycystic kidney disease
Polycystic kidney disease
ADPKD

ICD-10CM CODES
Q61.3	Polycystic kidney, unspecified
Q61.2	Polycystic kidney, adult type
Q61.19	Other polycystic kidney, infantile type
Z82.71	Family history of polycystic kidney

Epidemiology & Demographics

Most common, single, genetic cause of chronic kidney disease (CKD).
Mendelian dominant disorder.
Affects all ethnic groups equally worldwide.
Approximately 85 percent of ADPKD individuals have a mutation on chromosome 16 (PKD1 locus), and 15% have a mutation located on chromosome 4 in the PKD2 gene. A growing number of the ADPKD population has mutations in the glucosidase, alpha, neutral AB form (GANAB) gene located on chromosome 11q12.3.
Each child of an affected parent has a 50% chance of inheriting the mutated gene.
The disease has 100% penetrance and does not skip generations.

Incidence

Between 1 in 400 and 1000 live births in the U.S.

Genetics

ADPKD is caused by a mutation in the PKD1 gene, located on the short arm of chromosome 16, which lies next to the tuberous sclerosis complex 2 gene (TSC2). The gene encoding polycystin-1 (PC1) plays a vital role in cell-cell and cell-matrix interactions, and primary ciliary function. Mutations in PKD1 lead to an alteration in the differentiation of epithelial cells and the abnormal phenotypic expressions characteristic of ADPKD. ADPKD is less commonly caused by a mutation in the PKD2 gene located on chromosome 4. PKD2 encodes the protein polycystin-2 (PC2), which is involved in intracellular calcium signaling. PKD2 patients typically have milder disease with later onset of end-stage renal disease (ESRD), death, and hypertension. Polycystin 1 and 2 form a single functional complex through interactions of their intracellular carboxy termini. Consequently, a mutation of either PKD1 or PKD2 results in a similar phenotype.

ADPKD is also caused by mutations in the GANAB gene in up to 3% of ADPKD patients. This gene is located on chromosome 11q12.3 and is expressed in the kidney and liver. The GANAB gene encodes the catalytic subunit of glucosidase II (GIIα). GII is thought to play an important role in PC1 maturation. Cystogenesis is likely caused by defects in protein maturation and cell surface localization of polycystin 1 and polycystin 2. Usually patients with ADPKD who have mutations in GANAB have mild PKD and mild to severe polycystic liver disease.

Clinical Presentation

ADPKD is a systemic disorder, and symptoms relate primarily to the kidney cyst burden and extrarenal involvement, including polycystic liver disease and vascular complications (Fig. 1). Total kidney volume (TKV) and cyst volume in ADPKD increase exponentially over time in patients with ADPKD.

FIG.1

A, Axial contrast-enhanced computed tomography (CT) image and B, coronal T2-weighted single-shot fast spin echo magnetic resonance imaging (MRI) in a 39-year-old woman with autosomal polycystic kidney disease. Contrast administration is necessary to differentiate the cystic tissue from preserved parenchyma and detect small cysts using CT, but it is not necessary using MRI.

From Chebib FT, et al.: Autosomal dominant polycystic kidney disease: core curriculum 2016, *Am J Kidney Dis* 67(5):792–810, 2016.

Renal Manifestations

Many patients with ADPKD are asymptomatic. The diagnosis is established by either the identification of an afflicted family member, asymptomatic screening (approximately 40%), or renal imaging performed for another reason. Patients may present with gross hematuria, flank mass/pain, polyuria/nocturia, fever due to a kidney or lower urinary tract infection, nephrolithiasis, or blood pressure elevation. All of these complications are manifested through increased cyst burden or TKV.

Gross hematuria occurs in 35% to 50% of patients with ADPKD, and associated with increased TKV. Hematuria is also caused by rupture of a cyst into the collecting system or secondary to nephrolithiasis. Nephrolithiasis occurs in approximately 27% of ADPKD patients, due in part to low levels of urinary citrate. Kidney stones may present as flank pain or hematuria, commonly microscopic.

Polyuria, nocturia, and increased thirst in ADPKD occur from impaired urinary concentrating ability and increases in circulating vasopressin levels.

Proteinuria is not a common feature of ADPKD and is usually less than 1 g/day. However, the presence of detectable proteinuria and microalbuminuria is correlated with increased TKV and more severe kidney disease.

Urinary tract infections are common in patients with PKD but do not appear to be more common than in the general population. Renal cyst infections are specific to ADPKD, and patients typically present with localized flank pain, fevers, and nausea and vomiting, similar to pyelonephritis.

Acute flank pain can be caused by a kidney stone, kidney, or liver cyst rupture or hemorrhage. Chronic pain is typically due to enlarged kidneys, either unilaterally or bilaterally.

Cardiac Manifestations

Hypertension occurs in 60% of patients with ADPKD prior to any substantial decline in kidney function, and appears earlier in males than in females. Hypertension in ADPKD is due to upregulation of renin-angiotensin-aldosterone system (RAAS). Hypertension is a predictor of worse renal outcome and is associated with cardiovascular morbidity and mortality. Cardiac valvular abnormalities occur in 25% to 30% of patients, and include mitral valve prolapse and aortic regurgitation.

Extrarenal Manifestations

The prevalence of intracranial aneurysms (ICA) in ADPKD is approximately 5% and increases to as high as 20% in patients with a first-degree relative with a known intracranial aneurysm rupture.
Rupture of an ICA is a serious complication of PKD, and may produce significant permanent morbidity or death. Routine screening for ICA is recommended for patients with a family history of ICA or intracerebral bleed, or for patients with warning symptoms such as a sentinel headache.
In addition to kidney cysts, cysts can develop in the liver, pancreas, and seminal vesicles. Hepatic cysts are common and occur in up to ∼85% of ADPKD patients by the age of 30 years. Hepatic cysts represent the most common extrarenal manifestation of ADPKD. Liver cystic disease is typically asymptomatic and develops slightly later than kidney cysts in ADPKD. However, hepatic cysts can cause serious complications including pain, infection, bleeding, and biliary obstruction. Liver cysts continue to grow and expand after patients reach ESRD.
Colonic diverticula and abdominal or inguinal hernias occur more frequently in ADPKD patients.
Seminal vesical cysts have been reported to occur in up to 40% of men with ADPKD, but are not associated with changes in fertility.
Patients with ADPKD may be at an increased risk of developing liver, colon, and kidney cancer. However, there is sparse evidence upon which to recommend any change in current cancer-screening guidelines for patients with PKD.

Natural History

Patients with PKD1 mutations have faster disease progression than patients with PKD2 mutations. The median age of onset of ESRD is 54 years in PKD1 patients and 74 years in PKD2 patients.
Other clinical risk factors associated with progressive kidney disease in ADPKD include male sex, onset of hypertension before 35 years of age, early onset of gross hematuria, presence of proteinuria or microalbuminuria, increased urinary sodium excretion, and increased low-density lipoprotein cholesterol levels. However, all of these risk factors are mediated through cyst burden or TKV.
Data from the Consortium of Radiologic Imaging studies of Polycystic Kidney Disease (CRISP) indicate that a decline in renal blood flow and increases in TKV and cyst volume are strong predictors of future renal functional decline and progression to CKD stage 3. Baseline height-adjusted TKV (htTKV) of 600 ml/m predicts the risk of developing stage 3 CKD within 8 years. Patients with ADPKD can be classified into categories 1A-1E based on htTKV limits for their ages. Patients in class 1A are at a low risk for renal function decline. Patients in classes 1C-1E are at a high risk for progressive disease. This classification helps physicians identify patients with severe disease.

Diagnosis

Ultrasound of the kidneys is the most commonly used imaging modality for screening and diagnosis and is inexpensive, readily available, noninvasive, and free of radiation. CT and MRI are also used, but typically in the setting of acute complications. CT scans (Fig. E2) and MRI are more sensitive than ultrasound, with cyst detection at <1 cm in size.

FIG.E2

Autosomal dominant polycystic kidney disease: computed tomographic (CT) scan without contrast material. This CT image demonstrates the markedly enlarged kidney bilaterally with multiple low-density cysts throughout both kidneys. The little remaining renal parenchyma is noted by the sparse, higher density material squeezed by the cysts.

From Skorecki K, Chertow GM, Marsden PA, et al.: *Brenner & Rector’s the kidney*, ed 10, Philadelphia, 2016, Elsevier.

The following diagnostic criteria are used for diagnosis of ADPKD in asymptomatic individuals at risk for development of ADPKD (i.e., those with positive family history of ADPKD):

Individuals 15 to 39 years of age: At least three unilateral or bilateral kidney cysts.
Individuals 40 to 59 years of age: At least two cysts in each kidney.
Individuals older than 60 years of age: At least four cysts in each kidney.

With no family history of ADPKD, there is no definitive number of cysts and/or cyst location that provides an unequivocal diagnosis. The diagnosis is strongly suspected when multiple and bilateral kidney cysts are present along with hepatic cysts.

Genetic testing can be done to diagnose ADPKD when imaging results are equivocal and when a definitive diagnosis is required in a young individual such as a potential living donor.

Differential Diagnosis

Multiple benign simple cysts
Autosomal-recessive PKD
Familial juvenile nephronophthisis
Medullary cystic or UMOD (uromodulin) disease
Medullary sponge kidney
Tuberous sclerosis
von Hippel-Lindau syndrome
Acquired cystic kidney disease (Fig. 3)

FIG.3

Adulthood-acquired polycystic kidney disease: computed tomographic scan, axial image without contrast material (A) and axial image after administration of contrast material (B). The kidneys are small bilaterally with multiple 1-cm cysts primarily in the cortex.

From Skorecki K, Chertow GM, Marsden PA, et al: Brenner & Rector’s The Kidney, ed 10, Philadelphia, 2016, Elsevier.

Laboratory Tests

Hemoglobin and hematocrit may be elevated because of increased erythropoietin production but are typically similar to levels in other patients with CKD.
Urinalysis can show microscopic hematuria and proteinuria (seldom >1 g/day).
With decreased kidney function, blood urea nitrogen and creatinine are elevated.
Platelet counts can be mildly reduced in patients with extensive polycystic liver disease.
Metabolic acidosis, hyperparathyroidism, and hyperphosphatemia are all associated with CKD in ADPKD.

Treatment

Nonpharmacologic Therapy

Dietary intervention should be prescribed to all patients with ADPKD.

Restriction of dietary salt (<2 g sodium/day) and calories is recommended. Post hoc analysis of the HALT-PKD trial in which all patients were instructed to follow a sodium-restricted diet (2.4 g/day) showed that the urine sodium excretion is associated with kidney growth and faster renal function decline.
Cyclic adenosine monophosphate (cAMP) contributes to cyst formation and growth in ADPKD. Vasopressin stimulates the production of cAMP. Increasing water intake to greater than 3 L/day can suppress vasopressin. Increasing water intake is recommended in all ADPKD patients with preserved renal function. However, serum sodium should be monitored carefully in patients with advanced renal dysfunction as they are prone to developing hyponatremia.

Chronic General Rx

Data from the HALT-PKD trial showed that in young individuals with preserved kidney function, strict BP control of <110/75 mm Hg was associated with slower increase in TKV, reduced urinary albumin excretion, and a greater reduction of left ventricular mass index.
For all ADPKD patients, the goal BP is <130/80 mm Hg. For young, healthy patients with ADPKD and with intact kidney function, the goal BP target can be <110/75 mm Hg.
ACE inhibitors or angiotensin receptor blockers are the first drug of choice for treatment of hypertension.
Hyperlipidemia should be aggressively treated with LDL-cholesterol targets <80 mg/dl.
Pravastatin was found to have a beneficial effect on htTKV, LVMI, and urinary albumin excretion in a randomized, double-blind placebo-controlled phase II trial involving 91 children and young adults with ADPKD. A 23% change in htTKV was observed in the pravastatin group compared to 31% in the placebo group.
Statin therapy did not show any benefit in a post hoc analysis of the HALT PKD trials. However, this study was not randomized, different statin drugs and doses were used, and only a small number of statin users were in that study.
Use of statins in the management of patients with ADPKD is a personal physician choice. A larger randomized study is needed to study the effect of statins on cyst growth.
Patients who progress to ESRD require renal replacement therapy. Both peritoneal dialysis or hemodialysis can be used as a bridge to kidney transplantation.
Pretransplant unilateral or bilateral nephrectomy is recommended only in select patients with recurrent infections, renal cell carcinoma, and significant kidney enlargement causing limitation of daily activities, and malnutrition.

Acute General Rx

The treatment of gross hematuria is typically supportive with bed rest, hydration, and analgesics. Antihypertensive medications should be stopped during this time.
Extracorporeal shock wave lithotripsy (ESWL) has been used in patients with small obstructing kidney stones (<2 cm diameter) in the renal pelvis or calyces. Percutaneous nephrolithotomy is another potential option.
Infections are treated with antibiotics that penetrate cysts, such as fluoroquinolones, trimethoprim/sulfamethoxazole, vancomycin, and chloramphenicol.
New therapies impacting cyst growth
Several compounds that impact the cyst growth are being tested in ADPKD.
In a phase 3 double-blind, placebo-controlled, randomized trial involving 1,450 patients with PKD and preserved kidney function, the vasopressin-receptor 2 antagonist, tolvaptan, significantly decreased kidney volume and slowed the decline in kidney function. The benefits of tolvaptan on TKV increase and decline of kidney function is stronger in patients with increased albuminuria. The benefits of tolvaptan on TKV were seen across different stages of chronic kidney disease stages 1–3. The results of another confirmatory trial (REPRISE) are pending.
A small trial involving the somatostatin analogue octreotide long-acting repeatable depot showed that there was significantly less increase in TKV in the octreotide group compared to placebo.
In a phase 2, randomized, double-blind, placebo-controlled study, the oral src/bcr-abl tyrosine kinase inhibitor, bosutinib, reduced kidney growth in patients with ADPKD and preserved renal function. However, side effects of the medication (diarrhea, rash, and pancreatitis) and acute declines in kidney function have limited development of this agent.
Two randomized, double-blind trials involving mammalian target of rapamycin inhibitors, sirolimus and everolimus, did not show any effect on renal function in these patients. The shorter duration of these trials and inadequate dosing of the medications may have affected the outcome.

Referral

Patients with ADPKD should be referred at time of diagnosis to a nephrologist for ongoing care. Urology can also be consulted in patients with nephrolithiasis for recurrent episodes of gross hematuria, or consideration for nephrectomy before transplantation.

Genetic counseling should be offered if patients plan to start a family or are considering having their children screened. Individuals at risk for ADPKD should undergo pretest and posttest counseling if they are found to have ADPKD.

Pearls & Considerations

ADPKD is the most common, single, genetic cause of chronic kidney disease.
TKV increases exponentially over time, and the increase in TKV is a strong predictor of future renal function decline.
Increasing water intake to >3 L/day is recommended in patients with ADPKD and preserved renal function.
Strict blood pressure control is recommended in all patients with ADPKD.

Ferri – Autosomal Dominant Polycystic Kidney Disease (ADPKD)