Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease.

ADPKD is a systemic, inherited disorder due to mutations in the majority (approximately 93%) in either the PKD1 or PKD2 genes.

These mutations lead to fluid-filled cyst formation, proliferation, and growth in multiple organs including the kidneys, liver, and pancreas.

ADPKD is also associated with multiple gastrointestinal, connective tissue, and cardiovascular abnormalities.

Synonyms

Polycystic Kidney Disease
ADPKD
PKD
Hereditary Polycystic Kidney Disease

Epidemiology & Demographics

•Most common genetic cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD)
•Mendelian autosomal dominant disorder
•Each child of an affected parent has a 50% chance of inheriting the mutated gene
•Affects all ethnic groups equally worldwide
•Autosomal dominant polycystic kidney disease type 1: Approximately 78% of affected individuals with genetically resolved cases have a gene mutation on chromosome 16 (PKD1 gene)
•Autosomal dominant polycystic kidney disease type 2: Approximately 15% of affected individuals with genetically resolved cases have a gene mutation located on chromosome 4 (PKD2 gene)
•Autosomal dominant polycystic kidney disease type 3: Increasing number of cases (nearly 7%) linked to mutations of the alpha glucosidase II gene (GANAB) located on chromosome 11q12.3
•Disease has 100% penetrance and does not skip generations

Incidence

ADPKD prevalence has been reported to be between 1 in 400 and 1 in 1000 live births, based on earlier studies from Denmark.

The U.S. ADPKD prevalence has been reported in subsequent studies from Europe and Japan between 1 in 2525 and 1 in 4000.

Genetics

The majority of ADPKD cases stem from a mutation in the PKD1 gene, located on the short arm of chromosome 16. The gene encoding polycystin-1 (PC1) plays a vital role in cell-cell and cell-matrix interactions and primary ciliary function. Mutations in the PKD1 gene lead to altered differentiation of epithelial cells and the abnormal phenotypic expression that characterizes ADPKD. ADPKD is less commonly (approximately 17%) caused by a mutation in the PKD2 gene, located on chromosome 4. The PKD2 gene encodes the protein polycystin-2 (PC2) that is involved in intracellular calcium signaling. PKD2 patients typically have milder disease with later onset of hypertension, ESRD, and death. PC1 and PC2 form a single functional protein complex via interactions of their intracellular carboxy termini. Consequently, mutation of either the PKD1 or PKD2 gene produces a similar phenotype that cannot be distinguished clinically.

ADPKD is also caused by mutations in the GANAB gene, which is located on chromosome 11q12.3 and expressed in kidney and liver. The gene product plays an important role in PC1 maturation. Typically, ADPKD patients with GANAB gene mutations have mild PKD and mild-to-severe polycystic liver disease.

Clinical Presentation

ADPKD is a systemic disorder, and symptoms relate primarily to kidney cyst burden or total kidney volume (TKV) and extrarenal involvement, including polycystic liver disease and vascular complications. TKV and kidney cyst volume increases exponentially with time and follow a patient-specific curvilinear increase.

Renal Manifestations

Most patients with ADPKD are relatively asymptomatic, particularly in the first three decades of life. A diagnosis of ADPKD is typically established by identification of an affected family member with asymptomatic screening (approximately 40% of cases), or renal imaging performed for clinical indications. 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. Typically, more than half of patients will experience one of these complications by age 30. All of these complications represent manifestations of increased cyst burden or TKV.

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, unilaterally or bilaterally. Gross hematuria occurs in 35% to 50% of patients and associates with greater TKV. Gross hematuria may also result from spontaneous or traumatic cyst rupture into the collecting system. Less often microscopic hematuria secondary to nephrolithiasis occurs. Nephrolithiasis occurs in approximately 27% of ADPKD patients, due in part to low levels of urinary citrate, increased serum uric acid concentrations, and alterations in calcium oxalate and calcium phosphate supersaturation. Nephrolithiasis may present with acute flank pain with radiation to the groin, often with fever and hematuria, which is often microscopic.

Polyuria, nocturia, and increased thirst in ADPKD are manifestations of impaired urinary concentrating ability. Proteinuria is not a common feature of ADPKD (approximately 18% of adults and 27% of children) and is usually less than 1 gram per day. However, detectable proteinuria and microalbuminuria correlate with increased TKV and more severe kidney disease.

Lower urinary tract infections are common in ADPKD and may not occur more frequently 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.

Cardiac Manifestations

Hypertension occurs in 60% of patients with ADPKD before any substantial decline in kidney function, and it appears earlier in men than in women. Hypertension in ADPKD is due primarily to upregulation of the renin-angiotensin-aldosterone system (RAAS).

Hypertension strongly associates with increased cyst burden or TKV. Hypertension is a predictor of worse renal outcomes and is associated with cardiovascular morbidity and mortality. Cardiac valvular abnormalities occur in 25% to 30% of ADPKD patients and include mitral valve prolapse and aortic regurgitation.

Extrarenal Manifestations

•The prevalence of intracranial aneurysms (ICAs) in ADPKD is approximately 5% and increases to as high as 20% in patients who have a first-degree relative with a known intracranial aneurysm rupture.
•ICA rupture is a serious complication and may produce significant permanent morbidity or death. Routine ICA screening is recommended for patients with a family history of ICA or intracerebral bleed. Recently, smoking exposure and concurrent hypertension have been shown to associate with ICA in ADPKD. Screening is also recommended for ADPKD patients before major elective surgery, patients employed in high-risk occupations that would potentially place the lives of others at risk from a ruptured aneurysm (e.g., pilots, heavy machine operators), or 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 the most common extrarenal manifestation and occur in nearly 85% of ADPKD patients by age 30. 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 even after ESRD occurs.
•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 reduced fertility.
•Patients with ADPKD may be at an increased risk of developing liver, colon, and kidney cancer. However, there is sparse evidence on which to recommend any changein current cancer-screening guidelines for ADPKD patients.

Natural History

•Patients with PKD1 gene mutations typically have more severe disease progression than patients with PKD2 gene mutations. The median age of onset of ESRD is 54 yr in PKD1 gene patients and 74 yr in PKD2 patients.
•Patients with truncating PKD1 gene mutations experience more severe disease progression than patients with nontruncating PKD1 gene mutations. The median age of onset of ESRD is 55 yr in PKD1 patients with truncating mutations and 67 yr with nontruncating mutations.
•Other clinical risk factors associated with progressive kidney disease in ADPKD include male gender, onset of hypertension before 35 yr of age, gross hematuria before age 40 yr, proteinuria or microalbuminuria, increased urinary sodium excretion, and increased circulatory 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 of TKV and cyst volume are strong predictors of future renal functional decline and progression to CKD stage 3. A baseline height-adjusted TKV (htTKV) of 600 ml/min predicts the risk of developing CKD stage 3 within 8 yr. Patients with ADPKD may be classified as 1A-1E based on the Mayo Clinic Imaging Classification of ADPKD that helps physicians identify patients with severe disease (www.mayo.edu/research/documents/pkd-center-adpkd-classification/doc-20094754). This classification is based on annual growth rates estimated from age-based htTKV (<1.5% (1A), 1.5% to 3% (1B), 3% to 4.5% (1C), 4.5% to 6% (1D), >6%/year (1E)). This classification should only be applied in cases of ADPKD classified as typical ADPKD (i.e., large kidneys with extensive cysts scattered throughout both kidneys at ages 15 to 80 yr). 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.

Diagnosis

•Ultrasound of the kidneys is the most commonly used imaging modality for screening and diagnosis. It 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 and MRI are more sensitive than ultrasound, with cyst detection at <1 cm in size.
•The following diagnostic criteria are used for diagnosis of ADPKD in asymptomatic individuals at risk for development of disease (i.e., positive family history of ADPKD):
•Individuals 15 to 39 yr of age: At least three unilateral or bilateral kidney cysts.
•Individuals 40 to 59 yr of age: At least two cysts in each kidney.
•Individuals older than 60 yr 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. Currently, more than 20 cysts distributed bilaterally with a consistent phenotype is considered reliable for making a diagnosis.
•Genetic testing can be done to diagnose ADPKD when imaging results are equivocal and when a definitive diagnosis is required in a young at-risk individual, e.g., potential living kidney donor or family planning.

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
•The below table compares clinical features of cystic kidney diseases

Comparison of Clinical Features of Cystic Kidney Diseases

From Goldman L, Shafer AI: Goldman-Cecil medicine, ed 26, Philadelphia, 2020, Elsevier.

Disease	Inheritance	Frequency	Gene Product	Age of Onset	Cyst Origin	Renomegaly	Cause of ESRD	Other Manifestations
ADPKD	AD	1: 400-1000	Polycystin-1(PC1); Polycystin-2(PC2); Glucosidase II alpha subunit (GIIα); DnaJB11	20s and 30s	Anywhere (including Bowman capsule)	Yes	Yes (for PC1, PC2, or DnaJB11) No (for GIIα)	Liver cysts Cerebral aneurysms Hypertension Mitral valve prolapse Kidney stones UTIs
ARPKD	AR	1: 10,000-40,000	Fibrocystin/polyductin	First year of life	Distal nephron, CD	Yes	Yes	Hepatic fibrosis Pulmonary hypoplasia
ACKD	No	90% of ESRD patients at 8 yr	None ∗	Years after onset of ESRD	Proximal and distal tubules	Rarely	No	None
Simple cysts	No	50% in those older than 40 yr	None ∗	Adulthood	Anywhere (usually cortical)	No	No	None
NPHP	AR	1: 80,000	Nephrocystins (NPHP1–20)	Childhood or adolescence	Medullary DCT	No	Yes	Retinal degeneration; neurologic, skeletal, hepatic, cardiac malformations
ADTKD-UMOD	AD	Rare	Uromodulin	Adults	Cortico-medullary	No	Yes	Gout
ADTKD-MUC1	AD	Rare	Mucin-1	Adults	Cortico-medullary	No	Yes	None
ADTKD-REN	AD	Rare	Renin	Childhood	Cortico-medullary	No	Yes	Anemia, gout, hyperkalemia
ADTKD-HNF1B	AD; spontaneous	Rare	HNF1β	Childhood or adulthood	Cortico-medullary	Rarely	Variable	Early-onset diabetes, pancreatic hypoplasia, hypomagnesemia, hyperthyroidism, liver function abnormalities, gout, renal and urogenital anomalies, mental retardation, risk of renal cell carcinoma
MSK	No	1: 5000-20,000	None ∗	30s	Medullary CD	No	No	Kidney stones
Tuberous sclerosis	AD	1: 10,000	Hamartin (TSC1), tuberin (TSC2)	Childhood	Loop of Henle, DCT	Rarely	Rarely	Renal cell carcinoma, tubers, seizures, angiomyolipoma, hypertension
VHL syndrome	AD	1: 40,000	VHL protein	20s	Cortical nephrons	Rarely	Rarely	Retinal angioma, CNS hemangioblastoma, renal cell carcinoma, pheochromocytoma
Oral-facial-digital syndrome-1	XD	1: 250,000	OFD1 protein	Childhood or adulthood	Renal glomeruli	Rarely	Yes	Malformation of the face, oral cavity, and digits; liver cysts; mental retardation
HIPKD	AR	Rare	Phospho-mannomutase 2	Childhood	Renal glomeruli	Yes	Yes	Hypoglycemic seizures; occasional liver cysts
BBS	AR	1: 65,000-160,000	BBS 1-18	Adulthood	Renal calyces	Rarely	Yes	Syndactyly and polydactyly, obesity, retinal dystrophy, male hypogenitalism, hypertension, mental retardation

ACKD, acquired cystic kidney disease; AD, autosomal dominant; ADPKD, autosomal dominant polycystic kidney disease; DnaJB11, DnaJ homolog subfamily B member 11; AR, autosomal recessive; ARPKD, autosomal recessive polycystic kidney disease; BBS, Bardet-Biedl syndrome; CD, collecting duct; CNS, central nervous system; DCT, distal convoluted tubule; ESRD, end-stage renal disease; ADTKD, autosomal dominant tubulointerstitial kidney disease; UMOD, uromodulin; MUC1, mucin-1; REN, renin; HNF1β, hepatocyte nuclear factor 1 β; MSK, medullary

Laboratory Tests

•Hemoglobin and hematocrit may be elevated because of increased erythropoietin production; however, these levels are usually similar to levels in other CKD patients.
•Urinalysis can show microscopic hematuria and proteinuria (rarely >1 g per 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 from splenic sequestration.
•Metabolic acidosis, hyperparathyroidism, and hyperphosphatemia are associated with CKD in ADPKD.

Treatment

Nonpharmacologic Therapy

Dietary intervention is prescribed to all ADPKD patients.

•Restriction of dietary salt (<2 grams sodium per 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 per day) showed that greater urine sodium excretion was associated with kidney growth or increase in htTKV and more rapid renal function decline.
•Intracellular cyclic adenosine monophosphate (cAMP) contributes to cyst formation and growth in ADPKD. Circulating vasopressin stimulates renal cAMP production. Increasing water intake to greater than 3 L per day can suppress circulating vasopressin levels. Consequently, increasing water intake is recommended for all ADPKD patients with preserved kidney function. However, serum sodium should be monitored carefully in advanced CKD because patients are vulnerable for development of hyponatremia.

Chronic General Treatment

•In young individuals with preserved kidney function, the HALT-PKD trial showed that strict BP control of <110/75 mm Hg was associated with a slower increase of TKV (15% slower over 5 yr), reduced urinary albumin excretion, and greater reduction of left ventricular mass index.
•For ADPKD patients over the age of 35 yr or with renal dysfunction, 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.
•Angiotensin–converting-enzyme inhibitors or angiotensin II type 1 receptor blockers are the drug of choice as first-line treatment for hypertension.
•Hyperlipidemia should be aggressively treated, and the LDL-cholesterol target is <80 mg/dl.
•Pravastatin has been found to have a beneficial effect on htTKV, left ventricular mass index, and urinary albumin excretion in a randomized, double-blind, placebo-controlled phase 2 trial involving 91 children and young adults with ADPKD. Over a 3-year period, a 23% increase 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 this study.
•Currently, statin use in the management of ADPKD is by physician choice. A larger, randomized controlled trial is required to study the effect of statins on cyst growth.
•Patients who progress to ESRD require renal replacement therapy. Both peritoneal dialysis and hemodialysis can be used as a bridge to kidney transplantation, but preemptive transplantation is preferred.

The complication rates after nephrectomy are higher with pre-kidney transplant nephrectomy compared with posttransplant nephrectomy. Blood transfusion during pre-kidney transplant nephrectomy may cause allosensitization and delay transplantation evaluation. Consequently, routine pre-kidney transplant nephrectomy is not recommended. Pre-kidney transplant unilateral or bilateral nephrectomy is recommended only in select patients with recurrent infections, recurrent or severe bleeding, renal cell carcinoma, and significant kidney enlargement causing limitation of daily activities, and malnutrition.

Acute General Treatment

•The treatment of gross hematuria is typically supportive with bed rest (compressbleeding cyst), hydration, and analgesics without nonsteroidal antiinflammatory drugs. 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. There is some concern that residual stone fragments cause renal dysfunction. Percutaneous nephrolithotomy is a potentially safer option in certain cases.
•Infections are treated with antibiotics that penetrate cysts, including fluoroquinolones, trimethoprim/sulfamethoxazole, vancomycin, and rarely, chloramphenicol.
•New therapies affecting cyst growth.

Tolvaptan

•In a phase 3, double-blind, placebo-controlled, randomized trial (TEMPO 3:4 trial) involving 1450 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 rate of increase and decline of kidney function are greater in patients with increased albuminuria. The benefits of tolvaptan on TKV were seen across CKD stages 1 to 3.
•The effect of tolvaptan on delaying renal function decline was maintained for an additional 2 yr in the extension study, TEMPO 4:4 trial, in which all participants were offered tolvaptan treatment for an additional 2 yr.
•A second tolvaptan trial (REPRISE) examined the safety and efficacy of tolvaptan in more advanced ADPKD. This was a 12-month, phase III, randomized withdrawal, multicenter, placebo-controlled, and double-blind trial that included 1370 patients with eGFRs between 25 and 65 ml/min/1.73 m². Tolvaptan-treated patients demonstrated a reduction in eGFR decline of 35% compared to placebo. Those receiving placebo lost 3.61 ml/min per 1.73 m² per year. Tolvaptan-treated patients demonstrated an eGFR decline of 2.34 ml/min per 1.73 m² per year, a statistically significant difference of 1.27 ml/min per 1.73 m² per year. The beneficial effect of tolvaptan on renal function decline was established in all subgroups (<55 yr age, men and women, and patients with CKD stages 3A, 3B, and 4). Beneficial effects were not present in subjects older than 55 yr. Firm conclusions cannot be made in this subgroup due to relatively smaller numbers.
•Based on the above studies, on April 24, 2018, the FDA approved tolvaptan for treatment of ADPKD in adult patients at risk for rapidly progressing ADPKD.
•Patients at Mayo classes 1C-1E levels of cyst burden (faster rates of cyst growth) likely have rapidly progressive disease and should be considered for treatment with tolvaptan. Treated individuals may experience polyuria, nocturia, abnormally frequent urination, and polydipsia. Post-hoc analyses of TEMPO 3:4 and TEMPO 4:4 trials suggest that drug effects are more pronounced early on following drug initiation and in subjects with better kidney function. Appropriate hydration is essential to prevent thirst, dehydration, and hypernatremia.
•A minor eGFR reduction of 5% to 10% is anticipated after initiation of tolvaptan and reversible upon drug discontinuation. Tolvaptan dose reduction or withholding of the agent is recommended if a significant decline of eGFR of >20% is observed. Renal function testing should be carried out 2 and 4 weeks after initiation of therapy, then monthly for the next 18 months, and every 3 months afterward. To ensure that patients are maintaining hydration while on tolvaptan, plasma sodium concentration measurements must be obtained. Urinary osmolality can be used to assess treatment response and target drug dosing.
•Another important adverse event associated with tolvaptan is liver toxicity. Two patients in the TEMPO 3:4 trial (https://pubmed.ncbi.nlm.nih.gov/23121377/) and 1 patient in the TEMPO 4:4 trial (https://pubmed.ncbi.nlm.nih.gov/28379536/) developed serious drug-induced liver injury. In the REPRISE trial, liver adverse effects were greater in the tolvaptan group compared to placebo (5.6% vs. 1.2%). Because of the risks of serious liver injury, tolvaptan prescriptions are only available through a restricted distribution program called the Risk Evaluation and Mitigation Strategy (REMS). Under this program, liver function testing is done before initiation of treatment, at 2 wk and 4 wk after initiation, then monthly for the first 18 mo and every 3 mo afterward.

Other Therapies Affecting Cyst Growth

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. Another randomized phase III trial involving 100 ADPKD patients with eGFRs between 15 and 40 ml/min per 1.73 m² demonstrated that a 3-year treatment with octreotide long-acting release (octreotide LAR) significantly slowed kidney volume growth. Octreotide LAR did not affect GFR decline compared with placebo. However, fewer patients in the octreotide group progressed to the combined end point of doubling of serum creatinine or ESRD compared to placebo (19% vs. 43%). A 1-year, randomized, placebo-controlled study of another somatostatin analogue, pasireotide long-acting release, demonstrated slow rates of increase of total liver and volumes.

•In a phase 2, randomized, double-blind, placebo-controlled study, the oral tyrosine kinase inhibitor bosutinib reduced kidney growth and preserved kidney function. However, medication-related adverse events (diarrhea, rash, and pancreatitis) and acute declines in kidney function have limited development of this agent. A phase II trial of another tyrosine kinase inhibitor, tesevatinib is ongoing.
•Two randomized, double-blind trials investigating mammalian target of rapamycin inhibitors, sirolimus and everolimus, did not show any effect on renal function in ADPKD subjects. The shorter duration of these trials and inadequate dosing of the medications may have affected the outcome.
•Renal cyst formation and growth over time results in increased interstitial inflammation, oxidative stress, and fibrosis. Bardoxolone has antiinflammatory and antioxidant properties and is undergoing investigation as treatment of ADPKD in a phase III randomized trial.

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 of nephrectomy pre-kidney transplantation.
•Genetic counseling should be offered if patients plan to start a family or are considering kidney screening examinations for children. Individuals at risk for ADPKD should undergo pretest and posttest counseling if ADPKD is discovered.

Pearls & Considerations

•ADPKD is the most common, single, genetic cause of CKD.
•TKV increases exponentially over time, and the increase of TKV is a strong predictor of future kidney functional decline.
•Increasing water intake to >3 L per day is recommended in patients with ADPKD and preserved kidney function.
•Tolvaptan is recommended for patients with rapidly progressing ADPKD.
•Strict blood pressure control is recommended for all ADPKD patients.

Autosomal Dominant Polycystic Kidney Disease