Continuing Education Activity

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of end-stage renal disease (ESRD) worldwide, affecting approximately 500,000 people in the United States alone. ADPKD is characterized by clusters of fluid-filled cysts in both kidneys, associated with a gradual decline in renal function. PKD can be categorized into 2 forms based on inheritance patterns: autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). ADPKD is more prevalent, affecting 1 in 500 to 1,000 people, while ARPKD occurs less frequently, with an estimated prevalence of 1 in 20,000 to 40,000 people.

ADPKD is a multisystem and progressive disease with bilateral renal cyst formation associated with kidney enlargement and other organ involvement, such as the heart, liver, pancreas, spleen, and arachnoid membranes. This activity describes the epidemiology, genetics, clinical presentation, and management of ADPKD, providing healthcare professionals with the knowledge and tools to improve patient care for this complex and prevalent condition.

Objectives:

• Implement a systematic screening protocol for ADPKD, including regular imaging studies and genetic testing, in patients with a family history of the disease.

• Initiate appropriate management strategies, including lifestyle modifications and pharmacological interventions, in patients diagnosed with ADPKD to slow disease progression and manage associated complications.

• Apply evidence-based guidelines for the management of ADPKD, including the use of tolvaptan when indicated, to optimize patient outcomes.

• Facilitate coordinated care among healthcare providers to ensure seamless transitions between primary care, nephrology, and other subspecialties, optimizing the management of ADPKD patients' complex healthcare needs.

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of renal failure worldwide. ADPKD is a multisystem and progressive disease with cyst formation, kidney enlargement, and extrarenal organ involvement (eg, liver, pancreas, spleen, and arachnoid membranes). In the adult population, ADPK occurs in all races and is responsible for 6% to 10% of patients on dialysis in the United States. Cysts may be detected in childhood or in utero, but clinical manifestations appear in the third or fourth decade of life.

Autosomal recessive polycystic kidney disease (ARPKD) is rare and affects 1 in 20,000 births. ARPKD has a much more severe clinical course and is caused by mutations in polycystic kidney and hepatic disease 1 (PKHD1), which encodes fibrocystin. ARPKD usually presents in childhood and often causes death in childhood or perinatally. Please see StatPearl's companion article, Autosomal Recessive Polycystic Kidney Disease.[1]

Etiology

ADPKD involves mutations in various genes, 3 of which are identified. PKD1 (chromosome 16p13.3) accounts for 85% of ADPKD cases, and PKD2 (4q21) contributes to 15% of cases. Mutations in GANAB are thought to contribute to 1% of ADPKD patients with more variable polycystic liver disease.[2] Mutations in PKD1 and PKD2 express similar phenotypes. In the PKD1 form, about 50% of patients need renal replacement therapy by 60 years. PKD2 mutations are seen in older individuals and present with a milder disease with fewer kidney cysts, late-onset hypertension, and less ESRD than PKD1.[3] 

Epidemiology

ADPKD is a worldwide condition affecting all races with a prevalence rate of diagnosed cases ranging from 1 in 400 to 1 in 1000 with variable ages of diagnosis. Some patients remain asymptomatic their whole lives. ESRD caused by ADPKD in African Americans is less common than in White Americans. ESRD caused by ADPKD in men and women are respectively 8.7 and 6.9 per 1 million in the United States using data from 1998 to 2001. Corresponding data for the same time frame are 7.8 and 6.0 per million in Europe and 5.6 and 4.0 per million in Japan. The worldwide incidence is about 12.5 million individuals.[4][5] 

Due to increased awareness, early detection, and hypertension (HTN) treatment, the age of onset of ESRD has increased, and all-cause mortality has decreased. Renal disease is more severe in males; however, polycystic liver disease is noted to be much more prominent in females, suggesting there may be an element of hormonal regulation.[6]

Pathophysiology

Eighty-five percent of patients with ADPKD have PKD1 mutations, 15% have the PKD2 gene mutation, and about 1% have GANAB gene mutations. Other mutations leading to PKD are unidentified, and 10% to 15% of patients with ADPKD have no known family history, suggesting a high de novo mutation rate.[6] PKD1 and PKD2 mutations have the same phenotype, but patients with PKD2 have a milder disease with fewer kidney cysts, later onset of HTN, and less ESRD than patients with PKD1. Patients with GANAB mutations also have a milder phenotype than PKD1 but have more associated hepatic disease. 

PKD1 codes for polycystin-1 (PC1), an integral membrane protein with a long, extracellular N-terminal, 11 transmembrane regions, and a short, intracellular C-terminal. PC1 is present in focal adhesions, primary cilia, tight junctions, desmosomes, and adherens junctions and plays a vital role in cell-to-cell and cell-to-matrix interactions.

PKD2 codes for polycystin-2 (PC2), which has a short cytoplasmic N-terminal, 6 transmembrane regions, and a short cytoplasmic C-terminal. PC2 is present in the endoplasmic reticulum, plasma membrane, primary cilia, centrosomes, and mitotic spindles in dividing cells. PC2 is also involved in intracellular calcium regulation.

Both PCI and PC2 are present in the primary cilia of renal epithelial cells and play a role in producing transmembrane calcium currents in the presence of stretch or luminal flow and increasing intracellular calcium.[7][8][9] PC1 and PC2 play a crucial role in cell proliferation, differentiation, and fluid secretion through G protein-mediated or JAK-STAT-mediated signaling pathways, which results in increased intracellular concentrations of cyclic adenosine monophosphate (cAMP), leading to an increase in chloride secretion across the luminal membrane.[10] Chloride-rich fluid secretion is an essential component of cystogenesis, leading to the expansion of cysts, even after the detachment from their parent nephron. The accumulation of cyst fluid, rich in chloride and sodium, relies on the active luminal excretion of chloride primarily through the cystic fibrosis transmembrane conductor regulator (CFTR).[11][12][13]

Increased levels of cAMP are found in animal models of ADPKD in the kidneys, liver, and vascular smooth muscle cells, and this plays a vital role in the proliferation of different cell types.[14][15] Cyclic AMP increases the proliferative pathways in cells derived from PKD kidneys while at the same time inhibiting the proliferation of cells from normal human kidneys. 

Each kidney cyst is believed to originate from a single, genetically transformed clonal hyperproliferative epithelial cell. A somatic mutation, known as the "second hit," in either the PKD1 or PKD2 gene leads to cyst growth and development. The continuous proliferation of epithelial cells, fluid secretion, and alterations in the extracellular matrix result in focal outpouching from the parent nephron. Cyst formation can occur in proximal and distal tubules but is most common in the distal nephron and collecting duct.[6] Cysts become separate from the parent nephron when their size exceeds 2 cm and continue to autonomously secrete fluid, leading to cyst expansion and kidney enlargement, which, in turn, results in a reduction in functional nephrons. The continuous expansion of cysts compresses renal vessels, leading to intrarenal ischemia, which activates the renin-angiotensin-aldosterone system (RAAS). The cysts trigger an inflammatory response in the surrounding renal parenchyma and promote renal fibrosis. Progressive cyst expansion, increased systemic vascular resistance, sodium retention, and renal fibrosis ultimately lead to ESRD.[9]

Liver cysts are a common manifestation of ADPKD and are more prevalent in women than men. They are shown to increase in size and number in response to high estrogen states such as pregnancy and oral contraceptive use. In the hepatic system, the absence of polycystin leads to cyst formation, increased cell proliferation and apoptosis, enhanced fluid secretion, abnormal cell–matrix interactions, and alterations in cell polarity. Proliferative and secretive activities of cystic epithelium are regulated by estrogens either directly or by increasing growth signals, such as nerve growth factor, IGF1, FSH, and VEGF.[16]

Hypertension in ADPKD is postulated to be related to local areas of kidney ischemia, which develop due to cyst expansion. This results in increased renin release and a rise in blood pressure.[17][18] It is worth mentioning that attenuated arteries in the walls of cysts and cells in the connective tissue surrounding cysts contain cells with renin and active renin, so there may be a feedback loop where the increased hypertension leads to increased cyst size.[19] Moreover, higher cyst burden, as reflected by increased total kidney volume, even with normal creatinine, is considered a risk factor for the development of hypertension.[20][21]

Histopathology

Histologic samples show epithelial cell proliferation, abnormal fluid secretion, and abnormal extracellular matrix deposition of the cystic epithelial cells. Alterations in the pericystic blood and lymphatic microvasculature accompany these changes. Tubular dilation, microcysts, and tubular atrophy are common. Tubular dilation is also associated with an enlarged Bowman's space. There is extensive interstitial fibrosis in the peritubular area, especially near cysts. Cyst enlargement also compresses the surrounding nephrons, interstitium, and vasculature. Vascular changes include fibrosclerosis and lumen narrowing. Inflammatory cells are prominent, especially fibroblasts and monocytes.[6][22]

History and Physical

Patients with ADPKD can present with a variety of clinical conditions. Kidney function can remain normal for decades. However, once GFR starts to decline, renal impairment is usually rapid, with an average GFR loss of 4.0 to 5.0 ml/min/year. Male sex, early age of onset of HTN, PKD1 genotype, and presence of proteinuria are worse prognostic indicators. Total kidney volume (TKV) is the primary predictive biomarker of future GFR loss. ADPKD is a disorder involving many organ systems. The most common clinical presentations are HTN, anemia, liver cysts, hematuria, flank pain, abdominal masses, urinary tract infections, renal failure, nephrolithiasis, and renal cancers. 

Hypertension is the most universal and earliest clinical presentation in most patients with ADPKD.[17][18][23] Microalbuminuria, proteinuria, and hematuria are also more prevalent in patients with hypertension and ADPKD. Episodes of acute flank pain are often seen due to cyst bleeding, infection, stones, and, rarely, tumors. Visible hematuria may be the initial presenting symptom.[24] Cyst hemorrhage is a frequent complication causing gross hematuria when the cyst communicates with the collecting system. It can manifest as fever, raising the possibility of cyst infection. Occasionally, a hemorrhagic cyst will rupture, resulting in a retroperitoneal bleed. Urinary tract infection (UTI) is common in ADPKD. UTI presents as cystitis, acute pyelonephritis, cyst infection, and perinephric abscesses. Escherichia coli, Klebsiella, Proteus species, and other Enterobacteriaceae are the most common infectious causes. 

Renal stone disease occurs in about 20% of patients with ADPKD. Most stones are composed of uric acid, calcium oxalate, or both. Stones can be challenging to diagnose on imaging in ADPKD because of cyst wall and parenchymal calcification. CT urography can be helpful.

Prevalence of hepatic cysts increases with age, and polycystic liver disease should be suspected when four or more cysts are present in the hepatic parenchyma.[25][26] Patients may remain asymptomatic or present with liver impairment or pain secondary to infection or rupture of the cyst. About 7% to 36% of patients also have pancreatic cysts, which are more common with PKD2 mutations than with PKD1.[27]

Mitral valve prolapse and aortic regurgitation are the most common cardiovascular abnormalities.[28] ADPKD is also associated with increased coronary aneurysms, asymptomatic pericardial effusions, congenital heart malformations, and atrial fibrillation. Gastrointestinal abnormalities are also common; up to 50% of patients with ADPKD will also have diverticulosis.[6]

Although children do not generally have renal impairment (as opposed to ARPKD), they have higher rates of HTN and proteinuria than children without ADPKD, which requires close monitoring and treatment. It is also suggested that in children, the presence of early-onset ADPKD is equivalent to the incidence of ARPKD, so differentiation between these two may be difficult.[6]

Evaluation

ADPKD is suspected in patients with renal impairment associated with multiple bilateral cysts on renal imaging by CT or renal ultrasound, with or without a family history of ADPKD (see Image. Polycystic Kidneys (ADPKD) and Liver Cysts). Ultrasound is usually sufficient for asymptomatic patients with normal renal function (see Image. Polycystic Kidney). CT or MRI can help estimate the height-adjusted total kidney volume for risk stratification of disease progression and may be beneficial for management (see Image. Autosomal Polycystic Kidney Disease). In patients with a strong family history and palpable kidneys, a baseline CT or MRI can be helpful in the management of possible future complications. 

As per the Renal Association Clinical Practice Guidelines, parents or carers of individuals with ADPKD should receive education regarding the risk of inheriting ADPKD. Blood pressure should be checked every 2 years for at-risk children older than 2 years and young adults. The decision to undergo genetic testing or kidney ultrasound for asymptomatic children should be collaborative, involving caretakers and healthcare professionals. In children, if the initial ultrasound findings are negative for kidney cysts, follow-up ultrasounds should be deferred until adolescence (between ages 15 and 18).[29]

Ultrasound Criteria: Original Ravine PKD1 Diagnostic Criteria

• Ages 15 to 29 years: 2 or more cysts, unilateral or bilateral
• Ages 30 to 59 years: 2 or more cysts in each kidney
• Ages 60 years or older: 4 or more cysts in each kidney [30]

These criteria are also used for diagnosing PKD2 but are less accurate. Two notable characteristics of these criteria are as follows:

• Three or more total cysts in those aged 15 to 39 years have a positive predictive value of 100%.
• Two or fewer cysts in those older than 40 years have a negative predictive value of 100%.[31] 

Treatment / Management

The Mayo classification system (classes 1A, 1B, 1C, 1D, and 1E) can be ranked from lowest to highest risk for worse disease outcomes. Of these criteria, TKV is the most diagnostic.[32][33] The last 3 stages are associated with a higher risk for ESRD, and these criteria help to identify high-risk patients who would benefit from more aggressive management. 

Life Style and Dietary Modifications

Although not definitively proven to prevent ADPKD progression, patients are instructed to drink three liters daily to suppress vasopressin, thereby decreasing cAMP production and inhibiting cyst production.[34][35]  All ADPKD patients are advised to limit their sodium intake to less than 2 grams per day. The CRISP study showed a positive correlation between the increase in TKV and 24-hour urine sodium excretion. Restricted sodium intake can also improve blood pressure. 

Flank Pain

Causes of flank pain that may require intervention, such as infection, stone, and tumor, should be excluded. Tricyclic antidepressants are useful, as in other chronic pain syndromes, and are well tolerated. Cyst aspiration, under ultrasound or CT guidance, can be done if distortion of the kidney by a large cyst is considered the cause of the pain. If multiple cysts are contributing to pain, laparoscopic or surgical cyst fenestration may be of benefit. 

Cyst Hemorrhage

Cyst hemorrhage episodes are usually self-limited, and patients respond well to conservative management with bed rest, analgesics, and increased fluid intake to prevent obstructing clots. Rarely, bleeding is more severe, leading to hemodynamic instability; this requires hospitalization and transfusions.

Cyst and Urinary Tract Infection

Immediate treatment of symptomatic cystitis and asymptomatic bacteriuria is indicated to prevent retrograde seeding of the renal parenchyma.[36] Agents of choice include trimethoprim-sulfamethoxazole or fluoroquinolones with good cyst penetration. If fever persists after 1 to 2 weeks of appropriate antimicrobial therapy, infected cysts should be drained percutaneously or surgically. In the case of end-stage polycystic kidneys, nephrectomy should be considered.

Nephrolithiasis

Potassium citrate is the treatment of choice in stone-forming conditions associated with ADPKD, such as distal acidification disorders, uric acid stones, and hypocitraturic calcium oxalate stones.

Management of Blood Pressure

Management of hypertension is essential in reducing cardiovascular mortality and the progression of renal failure. As per the HALT-PKD study, the goal blood pressure range is less than 120 to 125/80 mm Hg, similar to other patients with chronic kidney disease. However, in patients with preserved or nearly preserved GFR, a lower blood pressure goal of less than 110/75 mm Hg is associated with a decreased incidence of cardiovascular events and a slower rate of cyst growth.[37] Angiotensin inhibitors are preferred agents if there is no contraindication. ACE inhibition also protects the glomeruli by decreasing intraglomerular pressure and reducing the rate of GFR decline in those with proteinuria. Beta-blockers and calcium-channel blockers are second-line treatments. Thiazides are preferred in patients with normal renal function as a third-line, while loop diuretics are recommended in patients with impaired renal function as an alternative to thiazide diuretics.[38][39] 

Tolvaptan slows the progression of kidney disease by blocking the reception of vasopressin signaling at the V2 receptor, lowering the intracellular cyclic AMP that would otherwise stimulate cystic proliferation and growth.[34][35] It is the only FDA-approved medicine for ADPKD at high risk for disease progression; however, due to its high cost and adverse effects, its use is recommended only in patients at high risk of disease progression. Modified guidelines have shifted from using a patient's historical GFR to total kidney volume (TKV), which precedes declining GFR. It is thought that in older patients with a greater number of comorbidities, these comorbidities contribute to declining GFR as much or more than the ADPKD disease; therefore, preference for tolvaptan use is geared towards patients younger than 55 years with declining GFR and fewer comorbidities, but there is no definite age cutoff. A current guideline for tolvaptan use is a yearly decline in GFR of ≥3.0 mL/min, primarily attributed to ADPKD. Loss estimation should be derived from at least 5 measurements over 4 years. Indicators that the GFR decline could be due to factors other than ADPKD include known vascular disease, uncontrolled HTN, diabetes mellitus, and severe proteinuria (>1 g/d). Tolvaptan use has not been studied in patients younger than 18.[40]

The Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease (TEMPO) and Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) are two landmark trials showing efficacy of tolvaptan in preventing GFR decline. However, tolvaptan comes with a black box warning due to the potential for liver failure. Baseline measurements of AST, ALT, and bilirubin should be taken, and subsequent measurements should occur at 2 weeks and 4 weeks after initiation, followed by monthly measurements for the first 18 months and then every 3 months after that. Due to the risks of liver injury, tolvaptan is only available through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS). Tolvaptan is contraindicated in patients taking CYP3A4 inhibitors, and these patients were excluded from the TEMPO and REPRISE trials. Common adverse effects among patients taking tolvaptan include increased thirst, polyuria, nocturia, polydipsia, and hypernatremia, common causes of drug discontinuation.[40][41]

Statins are used in chronic kidney disease patients as renal failure is equivalent to coronary heart disease. Their evidence for slowing disease progress in ADPKD is conflicting.[42]

Mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, have been studied but have not shown any benefit on renal outcomes. Significant adverse effects also preclude their use.[43][41]

Somatostatin and somatostatin analogs such as octreotide, lanreotide, and pasireotide have not been shown to affect the disease progression of ADPKD.[44]

Nephrectomy is indicated in patients with ADPKD with unbearable abdominal discomfort, anorexia, renal cell carcinoma, renal hemorrhage, kidney infection with gas-forming agents, and staghorn calculi in nonfunctioning kidneys with persistent urinary tract infections. Nephrectomy for large, cystic kidneys can be considered for ESRD patients on renal replacement therapy to increase the abdominal capacity for a future kidney transplant.  

ADPKD with ESRD requires renal replacement therapy by kidney transplant, hemodialysis, or peritoneal dialysis. Survival of ADPKD patients on hemodialysis is higher (10-15% at 5-year mortality) than patients on hemodialysis due to other causes, mainly due to a lower incidence of coronary artery disease in this population group.[45]  

Treatments on the Horizon

There are many possibilities for future treatments for ADPKD. Lixivaptan, a V2 antagonist without known liver toxicity, is being studied in the large-scale randomized control trial ACTION. Another drug class currently being investigated is glucosylceramide synthase inhibitors. This class of drugs is involved in building complex glycosphingolipids and has been shown to reduce cyst formation in animal models, although the exact mechanism of action is unknown.[41] 

Transepithelial chloride secretion is a key mechanism behind cystogenesis and is mediated through the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR  inhibitors are being studied for possible inhibition of cyst formation, but studies are currently preclinical. Metformin is a well-established drug that blocks the aerobic glycolysis pathway, linked to cell proliferation that leads to cyst formation and growth. Studies found that metformin was safe and well-tolerated in adults with ADPKD and may reduce renal function decline.[41][46]

Curcumin, produced by the spice turmeric, activates the transcription of antioxidants, suppresses inflammation, and reduces cell proliferation. It is currently under study for various diseases, and researchers are investigating its potential positive effects on reducing cell growth and improving the function of arteries in ADPKD.[46][47]

Differential Diagnosis

Renal cysts can be seen in other systemic diseases, and the differential diagnosis includes simple renal cysts, tuberous sclerosis, renal cysts and diabetes from hepatocyte nuclear factor 1-beta (HNF1B) deficiency, von Hippel-Lindau disease, medullary sponge kidney disease, Oro-facial-digital syndrome type I, and Bardet-Biedl syndrome.

Renal cysts can be seen in tuberous sclerosis, but this condition is usually associated with characteristic skin lesions, facial angiofibroma, connective tissue nevi, and cardiac, renal, and pulmonary manifestations.[48] HNF1B mutations can lead to renal cysts, often associated with various other systemic disorders such as early-onset diabetes, early-onset gout, pancreatic hypoplasia, abnormal liver function, and genital tract malformations.[49] 

Medullary sponge kidney disease is a rare congenital disorder that can cause the formation of cysts or dilations in the renal tubules. While it can lead to renal cyst-like structures, it is also highly associated with nephrocalcinosis and nephrolithiasis.

Orofaciodigital syndrome type I is a genetic disorder characterized by various abnormalities in the face, oral cavity, and digits. While kidney abnormalities, including cysts, can occur, it is not typically the primary diagnostic criterion.

Bardet-Biedl syndrome is a complex genetic disorder characterized by various symptoms, including vision problems, obesity, and kidney abnormalities. Renal cysts can be one of the kidney manifestations in this syndrome but are not the sole defining feature.

Prognosis

Up to 75% of patients with ADPKD will develop ESRD by 70 years. A Canadian study reported that 25% of patients with ADPKD had ESRD by 47 years, 50% by 59 years, and 75% by 70 years. A French study showed that 22% of patients with ADPKD had ESRD by 50 years, 42% by 58 years, and 72% by 73 years.[6]

Complications

A ruptured cerebral aneurysm is the most serious extrarenal complication of PKD and has a four times higher prevalence in PKD patients compared to the general population. The risk for a cerebral aneurysm increases with a personal or family history of cerebral aneurysm or subarachnoid hemorrhage, female sex, and older age. Smoking, hypertension, and excess alcohol intake are modifiable risk factors. Hepatic cysts are also a complication of ADPKD, and incidence increases with age, with an approximate prevalence of 10% to 20% up to the age of 30 years and reaching up to 50% to 70% in those older than 60.

Liver cysts may be associated with hepatic pain from cyst hemorrhage or hepatic cyst infection but rarely cause hepatic function impairment. ADPKD is often associated with diverticular disease and abdominal wall or inguinal hernias.

Deterrence and Patient Education

Patients should regularly follow up with nephrologists after diagnosis. Early diagnosis, risk assessment, and proper management of hypertension or proteinuria can help slow the progression of disease severity. Lifestyle modifications like increased oral intake of water, restricted salt intake, and avoidance of NSAIDs are associated with long-term benefits.

Enhancing Healthcare Team Outcomes

Polycystic kidney disease is a systemic disorder that affects many organs; hence, a multidisciplinary management approach is necessary. A nephrologist, surgeon, interventional radiologist, cardiologist, social worker, and dialysis nurse are key professionals required to care for these patients. The patient must educated on optimal blood pressure control and regular blood testing to assess renal function. Patients need to be educated about the complications that may include cerebral aneurysms, kidney stones, and end-stage renal disease.[50][51]

The PRO-PKD score has been developed to predict the prognosis of ADPKD. As uncontrolled hypertension accelerates renal function decline, it is essential to control blood pressure properly. Pain control and early treatment of cysts or urinary tract infections can improve the quality of life in ADPKD patients. Education of patients about the condition can also reduce the number of hospitalizations.[52][53]