Autosomal Dominant Polycystic Kidney Disease: A Review

Abstract

Importance

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive development of kidney cysts and is the most common inherited kidney disorder worldwide. ADPKD accounts for 5–10% of kidney failure in the US and Europe, and its prevalence in the US is 9.3 per 10,000 individuals.

Observations

ADPKD is typically diagnosed in individuals aged 27 to 42 years and is primarily caused by pathogenic variants in the PKD1 (78%) or PKD2 (15%) genes. Most persons with ADPKD have an affected parent, but de novo disease is suggested in 10–25% of families. More than 90% of patients older than age 35 years have hepatic cysts, which may cause abdominal discomfort and occasionally require medical or surgical intervention. Hypertension affects 70–80% of patients with ADPKD, and approximately 9–14% develop intracranial aneurysms, which have a rupture rate of 0.57 per 1000 patient-years. Approximately 50% of individuals with ADPKD require kidney replacement therapy by age 62 years. The severity of kidney disease can be quantified using the Mayo Imaging Classification (MIC), which stratifies patients based on total kidney volume (TKV) adjusted for height and age, and ranges from MIC 1A to MIC 1E. Patients with MIC classes 1C to MIC 1E have larger kidneys because of more rapid growth (6–10%/year), compared to MIC 1A and 1B (1–5%/year) and have earlier progression to kidney replacement therapy, which occurs at a mean age of 58.4 years for MIC 1C; 52.5 years for MIC 1D; and 43.4 years for MIC 1E. Optimal management of ADPKD includes systolic blood pressure < 120 mm Hg for most patients, but < 110/75 mm Hg for patients with classes MIC 1C-1E who have an eGFR > 60 ml/min/1.73² and are younger than age 50 years; dietary sodium restriction (< 2000 mg/day); weight management; and adequate hydration (>2.5L daily). The vasopressin V2 receptor antagonist, tolvaptan reduces the annual rate of eGFR decline by 0.98–1.27 ml/min/1.73 m² and is indicated for patients with classes MIC 1C-1E or an eGFR decline > 3ml/min/year to slow disease progression and delay the onset of kidney failure.

Conclusion

ADPKD is the most common genetic kidney disease worldwide and is characterized by progressive development of kidney cysts. Patients typically have hypertension and liver cysts, and 9–14% develop intracranial aneurysms. First-line treatment includes blood pressure control, dietary and weight management, and adequate hydration. Tolvaptan reduces the rate of eGFR decline for those at high risk of rapid progression to kidney failure.

Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent monogenic kidney disease, and fourth leading cause of kidney failure worldwide. Mean age at diagnosis is typically between ages 27 and 42 years.^{1, 2} Across predominantly US sequencing databases (123,136 whole-exome and 78,280 whole-genome sequences), the prevalence of gene variants causing ADPKD is 9.3 in 10,000.³ However, the estimated number of persons with clinically recognized ADPKD in the US is 140,000 – 240,000, which is lower than predicted from the genetic variant prevalence.^4–5 Approximately 50% of individuals with ADPKD develop kidney failure, requiring kidney replacement therapy (KRT), by age 62 years.⁶ Patients with ADPKD may also have liver and pancreatic cysts⁷; intracranial ⁸ and other vascular aneurysms; aortic root dilatation, pericardial effusion, or cardiac valvular abnormalities⁹; abdominal hernias; diverticulosis; and male infertility. This review focuses on the pathophysiology, clinical presentation, diagnosis, treatment, and prognosis of ADPKD diagnosed in adulthood (BOX).

Methods

A PubMed review was performed for articles about ADPKD published between October 1, 1994, and January 20, 2025. In addition, we reviewed the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Evaluation, Management and Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) which was published online on January 20, 2025.¹⁰ Of the 193 retrieved articles, 105 were included in this Review, comprising 11 randomized clinical trials, 14 prospective and 37 retrospective cohort studies, 6 practice guidelines, 16 narrative reviews, 2 cross sectional studies, and 5 meta-analyses and 14 genetic or physiology studies.

Genetics and Pathophysiology

ADPKD is caused by a single pathogenic genetic variant in PKD1 (78% of screened families), PKD2 (15%)¹¹ or one of several minor genes including IFT140¹², GANAB¹³, DNAJB11¹⁴, ALG9¹⁵, ALG8¹⁶, ALG5¹⁷ and NEK8¹⁸ which affect polycystin maturation or function of primary (non-mobile) cilia. Primary cilia, present on most cells in the body, sense changes in fluid flow or pressure leading to signal transduction.¹⁹ Impaired primary cilia function in renal tubular epithelium, hepatic bile ducts and vascular endothelial and smooth muscle cells likely lead to the characteristic features of ADPKD: kidney and liver cysts, and intracranial aneurysms. The proteins polycystin-1 and polycystin-2 encoded by PKD1 and PKD2 genes, respectively, localize to the primary cilium. Loss of polycystin function leads to reduced intracellular calcium, increased cyclic adenosine monophosphate (cAMP) signaling, and activation of protein kinase A (PKA) which increases proliferation of cyst cells and increase cyst fluid secretion, and can cause interstitial inflammation and fibrosis that lead to cyst formation, destruction of non-cystic kidney parenchyma, and kidney failure (Figure 1).^{20, 21} Enlarging cysts within the kidney compress the renal vasculature, causing ischemia and chronic activation of the renin-angiotensin aldosterone system (RAAS),²² resulting in hypertension, an independent risk factor for loss of kidney function.²³ Polycystin-1 also affects mitochondrial function²⁴ shifting energy production from oxidative phosphorylation to glycolysis.^{25, 26}

Figure 1: Cellular pathways in ADPKD pathogenesis and targeted therapeutic strategies explored in clinical trials:

A) This panel illustrates the molecular mechanisms contributing to fluid secretion and cell proliferation in ADPKD. Central to this process is the activity of Protein Kinase A (PKA), which is influenced by cyclic AMP (cAMP) levels. B) This panel maps the points of intervention within the same cellular pathways that are targeted by various therapeutic agents.

PKD (Polycystic Kidney Disease), PKA (Protein Kinase A), cAMP (Cyclic Adenosine Monophosphate), CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), TMEM16A (Transmembrane Protein 16A), AMPK (AMP-activated Protein Kinase), mTOR (Mammalian Target of Rapamycin), HIF (Hypoxia-Inducible Factor), NRF2 (Nuclear Factor Erythroid 2–Related Factor 2), PPARα (Peroxisome Proliferator-Activated Receptor Alpha), SIRT1 (Sirtuin 1), p53 (Tumor Protein p53), STATs (Signal Transducer and Activator of Transcription proteins), PCREB (Phospho-Cyclic AMP Response Element-Binding Protein), V2-R (Vasopressin Type 2 Receptor), AC6 (Adenylyl Cyclase 6), AVP (Arginine Vasopressin), SSTR (Somatostatin Receptor), SGLT2 (Sodium-Glucose Transport Protein 2), IGFBP4 (Insulin-like Growth Factor Binding Protein 4), IGF1 (Insulin-like Growth Factor 1), IGFR (Insulin-like Growth Factor Receptor), ERK (Extracellular Signal-Regulated Kinase), TKIs (Tyrosine Kinase Inhibitors), IP3 (Inositol 1,4,5-Trisphosphate), IP3-R (IP3 Receptor), PDE1 (Phosphodiesterase 1), GPCR (G Protein-Coupled Receptor).

Kidney cysts

ADPKD is characterized by numerous bilateral kidney cysts (> 10 per kidney) and kidney enlargement (kidney length > 13 cm; normal, 10–12 cm in adults), and is distinct from acquired cystic kidney disease, which typically occurs after onset of kidney failure and is associated with small or atrophic kidneys (< 10 cm)²⁷. A study of a cohort of 1948 potential living kidney donors ²⁸ found that the presence of bilateral kidney cysts in healthy individuals without kidney disease increased with age, from 2.3% (age 18–49 years) to 11% (age 50–75 years). However, abdominal imaging with incidental findings of multiple bilateral kidney cysts should raise suspicion for ADPKD (Figure 2 right).

Figure 2: Diagnostic algorithm for evaluating individuals with numerous bilateral renal cysts, integrating family history, genetic testing, kidney function and cystic burden on imaging to guide the differentiation of ADPKD from other cystic kidney diseases.

While ADPKD is usually diagnosed clinically based on history and imaging, genetic testing can be pivotal not only for confirming the diagnosis but also for stratifying disease severity. In ambiguous cases, such as potential ADPKD without a family history or where ADPKD is suspected, genetic testing can provide definitive confirmation of the diagnosis.

ADPKD: Autosomal Dominant Polycystic Kidney Disease, GFR: Glomerular Filtration Rate, PLD: Polycystic Liver Disease, TKV: Total Kidney Volume, GU: Genitourinary, Mg: Magnesium, DM: Diabetes Mellitus, ADTKD: Autosomal Dominant Tubulointerstitial Kidney Disease, ADPLD: Autosomal Dominant Polycystic Liver Disease, OFD31 syndrome: Orofaciodigital syndrome 1, CKD: Chronic Kidney Disease, AML: Angiomyolipoma, pheo: Pheochromocytoma, RCC: Renal Cell Carcinoma

Liver cysts

Approximately 90% of patients with ADPKD older than age 35 years have liver cysts. Polycystic liver disease, defined as 10 or more hepatic fluid-filled cysts,²⁹ is typically associated with preserved liver synthetic function, and leads to moderate liver enlargement with height-adjusted total liver volume (htTLV) of 1000–1800 ml/m (normal 900 ml/m) in 50% of cases, with severe enlargement, exceeding 1800 ml/m in 5.3% of 558 patients.³⁰ In a study of 558 patients with ADPKD, more than 80% of patients with severe PLD were female;³⁰ women aged 16 to over 50 years were more likely than men to have greater than 15 liver cysts.³¹ Post-menopausal hormone replacement may be associated with increased liver cyst growth in persons with ADPKD. In a study of 19 women with ADPKD, 1 year of estrogen treatment was associated with a 7% increase (standard deviation (sd) 12%; n=11) in liver volume, compared to a 2% decrease (sd 8%) among 8 women not treated with estrogen (p<0.03).³²

Intracranial aneurysms

The prevalence of intracranial aneurysms is 9% to 14%³³ in individuals with ADPKD, with higher prevalence rates (21% to 27%) in those with a family history of intracranial aneurysm or subarachnoid hemmorhage³³, compared with 3.2%⁸ in an age-matched general population. In ADPKD, most intracranial aneurysms are small (<5 mm) and predominantly located in the anterior circulation, with 15–25% of affected individuals having multiple aneurysms.³⁴ A study that performed systematic screening brain MRAs for 83 patients with ADPKD revealed the prevalence of intracranial aneurysms was 16.9%, and 6% required neurosurgical intervention.³⁵ In a cross-sectional study of a multicenter cohort of 2449 patients in Europe, 44 were identified as having aneurysms prior to enrollment and an additional 66 were identified through screening those with a family history of aneurysms, those with at-risk occupations, or patients requesting screening after comprehensive information; risk factors for an aneurysm were female sex (1.47 fold higher in women vs men, p=0.012), older age [cumulative probability at age 40 years, 1.3% (CI 0.9–1.7%), vs age 70 years, 8.1% (CI 6.5–9.7)]³⁴, and a family history of intracranial aneurysm or subarachnoid hemorrhage. The risk of intracranial aneurysms also increases with higher total kidney volume (≥ 1000 ml, OR=2.81) or Mayo Imaging Class (MIC) 1C, 1D or 1E (OR=2.52), and advanced CKD (stages G3-G5, OR=2.31) as described in a series with 94 intracranial aneurysms diagnosed in 519 patients with ADPKD.³⁶

Epidemiology and Clinical Presentation

ADPKD is an autosomal dominant disease, so children of a parent with ADPKD have a 50% risk of ADPKD. Although most patients have a parent with ADPKD, 10–25% of cases occur in individuals with no prior family history of ADPKD.³⁷ In a cohort of 1044 patients, mean age at diagnosis of ADPKD was 27 to 33 years and the diagnosis was established in 39.8% during screening of asymptomatic individuals with a known family history, 14.8% during evaluation for abdominal or flank pain; 13% were incidentally detected on imaging; 12.7% were identified during work-up of hypertension and 7.1% during evaluation of hematuria or urinary tract infection (UTI).¹ In an international prospective cohort study³⁸ of 3400 patients with ADPKD aged 2–70 years, of unknown genotype, mean ages were 34.2 years (SD, 10.8) for patients with eGFR >90 ml/min/1.73 m² (SD, 10.8); 45.6 years (SD, 10.7) for eGFR 60–90 ml/min/1.73 m² and 55.3 years (SD, 9.7) years for eGFR < 30 ml/min/1.73 m². By the mean age 45 years, 67% had hypertension, 23% had proteinuria, and 29% had hematuria. Other associated conditions included nephrolithiasis (17.7%)³⁹, UTI (27.5%), and abdominal wall hernias (12%).³⁸

In a study of 230 patients with ADPKD, hepatic cysts were present on abdominal MRI in 57–60% at age 15–24 years, and 93–95% at age 35–46 years.⁴⁰ Although many patients with ADPKD do not experience symptoms related to liver cysts, 38/49 (77.6%) patients with polycystic liver disease had abdominal distention, fullness and discomfort, early satiety, back pain or dyspnea.⁴¹ Patients with ADPKD and polycystic liver disease typically have more symptoms with increasing liver volume due to cyst growth⁴². In a study of 137 patients, complications of polycystic liver disease include liver cyst hemorrhage (14%), cyst infection (6%), cyst rupture (4%), ascites (4%), portal hypertension (5%), IVC compression (3%), and esophageal varices (1.5%).²⁹

Additional extrarenal manifestations of ADPKD include pancreatic cysts (19%)⁴³, bronchiectasis (up to 37%)⁴⁴, seminal vesicle cysts (up to 40%),⁷ and abdominal wall hernias (10%)⁷. Less commonly, ADPKD is associated with aortic root or thoracic aortic aneurysms (0.92%)⁴⁵, coronary artery dissection (rare)⁴⁶, mitral valve prolapse (0–26%)⁹, mitral regurgitation (7.45%)⁴⁷, primary cardiomyopathy (8.3%)⁴⁸, and pericardial effusion (35%)⁴⁹.

Assessment and Diagnosis

The diagnosis of ADPKD is usually made by evaluation of kidney imaging, often in consultation with a nephrologist (Figure 2). Bilaterally enlarged kidneys (> 13 cm or 97.5^th percentile for age and sex) with more than 10 cysts per kidney are diagnostic of likely ADPKD⁵⁰, even in patients without a family history. Age-stratified cyst number criteria in those with a family history of ADPKD allow a clinical diagnosis without genotyping (Figure 2 left). For example, an ultrasound-based total kidney cyst count of more than 3 in a 31-year-old individual with a family history of ADPKD has a positive predictive value of 94.7% for the diagnosis of ADPKD, compared to criterion standard of genotyping. For patients aged 30 years or younger with a family history of ADPKD who are being evaluated for ADPKD, magnetic resonance imaging (MRI) is preferred over ultrasound due to its superior resolution for detecting smaller cysts. In patients with family history of ADPKD aged 16 to 40 years, detection of a total of 10 kidney cysts or more on MRI has a sensitivity and specificity of 100% to diagnose ADPKD, compared with a confirmed genetic diagnosis. Conversely, presence of 5 or fewer cysts on MRI in patients aged 16–40 years with a family history of ADPKD effectively rules out the disease.⁵¹ Genetic testing of the familial disease-causing variant in a young at-risk individual can also provide a definitive diagnosis.⁵²

Individuals with incidentally detected multiple kidney cysts who have atypical imaging findings such as unilateral, asymmetric, segmental, lopsided cysts or bilateral cysts with unilateral or bilateral kidney atrophy⁵³, or other features inconsistent with ADPKD, such as liver fibrosis, benefit from genetic testing to obtain a definitive diagnosis (Figure 2).⁵⁴ Although genetic testing is not necessary to diagnose ADPKD, particularly in a patient with a family history and classic imaging findings, it is now more commonly offered because genetic testing has become more affordable and reliable. A targeted polycystic kidney disease or kidney gene panel, or analysis of these genes in whole exome or whole genome sequencing are common testing approaches.⁵⁴

Risk of Decline in Kidney Function

Between ages 30–40 years, the annual decline in eGFR among patients with ADPKD ranges from 0.63 to 4.65 ml/min/1.73 m².⁵⁵ Kidney growth in ADPKD also varies widely, with annual TKV growth rates ranging from 1.5% to over 20%.⁵³ Kidney enlargement due to cyst development and growth starts at birth. However, kidney function typically remains stable until the TKV is ~1500 ml,⁵⁶ at which point kidney function declines. TKV continues to increase until kidney replacement therapy is required.⁵⁷ For individuals with ADPKD younger than 45 years and a creatinine clearance >70 ml/min/1.73 m², an ultrasound kidney length of 16.5 cm or greater predicts the development of stage 3 CKD within 8 years.⁵⁸

Overweight and obesity are also associated with increased TKV growth and eGFR decline. In a phase 3 study of patients with ADPKD, 670 with a normal BMI of 18.5–24.9 kg/m², 429 with a BMI of 25–29.9 kg/m² (overweight) and 213 with a BMI ≥30 kg/m² (obese), overweight and obesity were associated with a 1.52- and 2.91-fold greater TKV growth over 3 years, respectively.⁵⁹ A cohort study of 441 patients with early ADPKD reported each 5 unit increase in BMI was associated with an eGFR decline of 1.71 ml/min/1.73 m² over 60 months (p=0.03).⁶⁰

Preferred imaging for TKV includes abdominal MRI with or without IV gadolinium, or contrast-enhanced abdominal CT. Ultrasound measurements underestimate TKV by 9–11% compared to MRI measurements.⁶¹ Mayo Imaging Classification (MIC) stratifies patients with ADPKD who have symmetric, bilaterally enlarged kidneys with uniform distribution of cysts into 5 imaging classes based on age- and height-adjusted TKV. Each class is defined by a theoretical growth rate from a baseline height-adjusted volume of 150 ml/m: 1A (< 1.5% growth/year), 1B (1.5–3%), 1C (3–4.5%), 1D (4.5–6%), and 1E (> 6%). Transitions between adjacent MICs are observed in 11.5–15.6% of patients over a 7-year follow-up period.⁵³ A single imaging scan is typically sufficient to establish the MIC class, unless the patient’s height-adjusted TKV is between MIC 1B and 1C, which is the threshold for specific medical therapies such as tolvaptan (see below).

Approximately 50% of patients with ADPKD require kidney replacement therapy by age 62 years.⁶ Persons with MIC 1C, 1D and 1E are at high risk of early kidney failure, with mean ages of kidney replacement therapy of 58.4 years (sd 7.9), 52.5 years (sd 8.6), and 43.4 years (sd 7.0) years, respectively.⁶² Presence of the gene variant PKD1 is associated with more severe kidney disease than PKD2 (mean age at requiring kidney replacement therapy, 58.0 vs. 74.8 years, respectively).⁶ The PROgnosis of Polycystic Kidney Disease score (PROPKD) incorporates polycystic kidney disease genotype, sex, and two clinical risk factors (hypertension and a urologic complication, such as gross hematuria, flank pain or kidney cyst infection, before age 35 years). A PROPKD score of more than 6 correlates with a median kidney failure onset at 49 years and a 91% probability of kidney failure by age 60 years.⁶³

About 30–36% of patients with ADPKD are classified at low risk of progression,⁵³ including those with MIC 1A or 1B⁵³, or those with atypical features (focal cystic disease, MIC 2A)⁶⁴, or those with a PROPKD score less than 4.⁶³ Patients with MIC 1B develop kidney failure at a median age of 71.2 years⁶. Patients predicted to have slow progression based on MIC or PROPKD score who develop rapid or early loss of kidney function should be evaluated for other causes of kidney disease.²

Treatment

All patients with ADPKD benefit from dietary modifications⁶⁵, adequate hydration and weight and blood pressure (BP) control to preserve kidney function (Table 1). Patients should follow a low-salt diet (2.0 g or 90 mEq of sodium daily).⁶⁶ In an observational cohort of 589 patients with baseline mean salt intake of 9.1 g/day, each 1 gram of salt intake increase correlated with an annual eGFR loss of 0.11 ml/min/m².⁶⁷ Because ADPKD is associated with uric acid and calcium oxalate kidney stones, daily water intake of 2.5L is recommended.¹⁰ A randomized clinical trial of 184 patients with ADPKD did not demonstrate additional benefit in slowing TKV growth in those randomized to increased oral fluid intake to maintain a urine osmolarity of 270ml/kg, versus ad libitum water intake.⁶⁸

Table 1:

Current clinical practice recommendations and available therapies for kidney-related manifestations in ADPKD:

Disease-modifying treatment
	Indication, benefits, and risks	Recommended practice guidance	Adverse effects
Tolvaptan74	-Adults with ADPKD at risk of rapid progression (MIC 1C, 1D, or 1E; or eGFR decline ≥ 3 ml/min/year) -Benefits: Reduces GFR decline by 30%, and may delay KF onset -Risks: Aquaresis; potential liver injury (requires LFT monitoring)	Age 18–55: GFR ≥25 ml/min/1.73m2, with MIC 1C-1E Age 56–6575: CKD G3 or G4, eGFR decline ≥ 3 ml/min/year and MIC 1C-1E - Starting dose 45 mg AM, 15 mg PM, titrate to tolerability. - Monitor liver function monthly (first 18 months), then quarterly -Long-term treatment until reaching KF76	Thirst: 4–55% Polyuria: 5–38% Nocturia: 5–29% Polydipsia: 2–10% Hypernatremia: 1–4% Increased liver enzymes (ALT> 2.5-fold ULN): 1–6%; reversible after stopping tolvaptan
Optimized basic management
	Indication, benefits, and risks	Recommended practice guidance	Adverse effects
Blood pressure control10	All patients with BP >130/85 mm Hg -Benefits: decrease cardiovascular complications, prevent worsening renal function -Risks: dizziness, side effects related to antihypertensives, increased pill burden	- Target BP ≤110/75 mm Hg for ages 18–49 with CKD G1-G2 - SBP target of <120 mm Hg if ≥50 years old First-line: ACEIs or ARBs; second line options: alpha and beta dual blocker, beta blockers, diuretics (if not on tolvaptan), dihydropyridine calcium channel blockers - Reduce dietary sodium (<2.0 g/day)	ACEI: Hyperkalemia 1.8%, 4% with ARB; Angioedema (<1%); cough (up to 11%) ARB: hyperkalemia Dihydropyridine CCB: limb edema (10%) Alpha/Beta dual blockers: bradycardia, bronchospasm, diarrhea (2–12%), fatigue (24%), hyperglycemia (5–12%)
Weight management65	Patients with BMI >25 Kg/m2 - Overweight or obese have faster TKV growth and eGFR decline - Benefit: weight loss associated with slower TKV rate of growth - Risks/Safety: Requires medical supervision and dietitian consultation.	- Target or maintain BMI ≤25 Kg/m2 - Restrict caloric intake by 30%, or intermittent fasting and time-restricted eating (long-term efficacy and safety to be determined)	Caloric restriction: no major concerns. Monitor for anemia, bone loss. Intermittent fasting: fatigue, cold intolerance, irritability, insomnia, Ketogenic diet: hypercholesteremia (17%), increased risk of uric acid stones.
Lifestyle, dietary changes, and other CKD management65, 66	All patients with ADPKD Benefit: reducing osmolar intake and increased hydration can suppress vasopressin, which plays a central role in ADPKD pathophysiology.	-Sodium restriction <2.0 g/day (< 5 g salt/day) -Hydration: target morning urine osmolality ≤280 mOsm/kg by drinking > 2.5 liter of water per day -Physical activity: > 150 min per week - Lifestyle: Avoid tobacco, limit alcohol to <1 drink/day for women and <2/day for men - Phosphate restriction: moderate (800 mg/d) - Bicarbonate levels: target >22 mEq/L -Protein intake: 0.8–1.0 g/kg of ideal body weight, not exceeding 1.3 g/Kg/day - Assess for other renal processes if acute drop in GFR	N/A
Severe flank pain95	Evaluate pain in all patients: assess eligibility for interventions; refer to centers of expertise. - Benefits of interventions: pain control - Risks: failure to reduce pain; intervention-specific risks	Cyst aspiration with sclerosing agent, surgical fenestration, spinal cord stimulation, celiac plexus block, renal denervation, nephrectomy	-Cyst aspiration with sodium tetradecyl sulfate sclerotherapy: Hematoma (<1%), hematuria (1%), pain (6%), infection (3%). Nephrectomy complications: hemorrhage, infection, pneumonia, wound infection, bowel perforation
Urinary stone disease39	Evaluate risk factors and complications, particularly if acute pain or recurrent stones	- Hydration: fluid intake >2.5 L/d unless contraindicated - Medications: potassium citrate if hypocitraturia or uric acid stones - Lifestyle: control weight, diabetes mellitus, and metabolic syndrome - Urology referral	-Hydration: risk of hyponatremia if excessive -Potassium citrate: GI upset, hyperkalemia, particularly if combined with amiloride

ADPKD: Autosomal Dominant Polycystic Kidney Disease, KF: Kidney failure MIC: Mayo Imaging Classification, KF: Kidney Failure, LFT: Liver Function Test, eGFR: Estimated Glomerular Filtration Rate, AM: Morning, PM: Afternoon, ULN: Upper Limit of Normal, BP: Blood Pressure, SBP: Systolic Blood Pressure, CKD: Chronic Kidney Disease, ACEI: Angiotensin-Converting Enzyme Inhibitor, ARB: Angiotensin II Receptor Blocker, BMI: Body Mass Index, N/A: Not Available, GI: Gastrointestinal, KDIGO: Kidney Disease: Improving Global Outcomes, LDL: Low-Density Lipoprotein, V2R: Vasopressin V2 Receptor, mTOR: Mechanistic Target of Rapamycin.

Hypertension treatment

ACE inhibitors or Angiotensin Receptor Antagonists (ARBs) were recommended as first-line treatment for hypertension in ADPKD by KDIGO guidelines in 2025¹⁰. The recommendation for a systolic BP <120 mmHg for patients with ADPKD aged >50 years, or with an eGFR <60 ml/min/1.73 m² was based on CKD management guidelines.⁶⁶ The recommendation of a BP goal of ≤ 110/75 for patients with ADPKD younger than aged 50 years with eGFR >60 ml/min was based on the HALT-PKD study which included 558 patients with early stage ADPKD (mean age 36 years, baseline BP 125/79 mm Hg, mean eGFR 90–93 ml/min/1.73 m²).⁶⁹ Patients randomized to a lower BP target (95/60 to 110/75 mm Hg) vs a higher BP target (120/70 to 130/80 mm Hg) with either lisinopril and telmisartan or lisinopril with placebo had smaller increases in TKV (5.6% vs 6.6%, P=0.006) and significant decreases in urinary albumin (3.77% vs 2.43%, P < 0.0001).⁶⁹ However, symptoms of dizziness and lightheadedness were more common in the low BP group (80.7% vs 69.4%, P=0.002).⁶⁹

Tolvaptan

Patients at high risk for rapid eGFR decline (MIC 1C, 1D, 1E or PROPKD score > 6) may benefit from tolvaptan, a vasopressin (V2)-receptor antagonist that reduces cAMP-mediated cyst fluid secretion and cell proliferation (Figure 3).⁷⁰ A study of 1445 patients with ADPKD aged 18–50 years with a TKV >750 ml and an estimated creatinine clearance >60 ml/min reported that compared with placebo, those randomized to tolvaptan at the highest tolerable dose (45mg/15mg, 60mg/30mg, or 90mg/30mg) for 3 years had lower TKV yearly growth (2.8% vs 5.5% in the placebo group, P < 0.0001) and a slower decline in kidney function (difference of 0.98 ml/min/1.73m²/year compared to placebo, P<0.001).⁷¹ Another trial of 1370 patients with ADPKD aged 18–55 years with an eGFR of 25–65 ml/min/1.73m² or aged 56–65 years with an eGFR of 25–44 ml/min/1.73m², reported that those treated with tolvaptan for 1 year had a 1.27 ml/min/1.73m² slower loss of eGFR compared with placebo, P<0.001.⁷²

Figure 3: Risk stratification for ADPKD Patients.

The severity of kidney cystic disease in ADPKD patients can be predicted through a) age- and height-adjusted total kidney volume (Mayo Imaging Classification, MIC), b) a scoring system that includes PKD genotype, sex, and clinical complications (PROPKD score), c) PKD genotype alone, or d) GFR rate of decline

Abbreviations: MIC, Mayo Imaging Classification; GFR, Glomerular Filtration Rate; BP, Blood Pressure; BMI, Body Mass Index; ESKD, End-Stage Kidney Disease; CKD, Chronic Kidney Disease.

Pooled analyses of 8 clinical trials of tolvaptan and 5 cohort studies in which patients did not receive tolvaptan showed a sustained benefit of tolvaptan over 5.5 years of treatment⁷³, with an extrapolated cumulative delay in the onset of ESKD of 1.5–7 years⁷⁴, depending on kidney function at treatment initiation. Tolvaptan may benefit patients aged 56–65 with CKD stage G3 or G4 and greater than 3ml/min/1.73 m²/year eGFR decline⁷⁵. Benefit continues for patients with an eGFR of 29 to15 ml/min/1.73 m².⁷⁶ Excessive thirst (55%), polyuria (38%), nocturia (29%) and increased urinary frequency (23%) are common adverse effects of tolvaptan,⁷¹ leading to a discontinuation rate of 15.4% vs 5.0% in the placebo group. Because about 5% of patients treated with tolvaptan develop liver function test abnormalities,⁷¹ a Risk Evaluation and Mitigation Strategy (REMS) is mandated in the US, consisting of routine monitoring of liver function tests prior to initiation of tolvaptan, at 2 and 4 weeks, monthly for 18 months, and then every 3 months while taking tolvaptan. This monitoring has resulted in a low risk (0.9%) of severe liver injury with tolvaptan.⁷⁷ Chronic use of a diuretic was not permitted in the tolvaptan trials^{71, 72}, thus diuretics should be avoided in patients taking tolvaptan. The role of hydrochlorothiazide in decreasing treatment-associated polyuria in patients with ADPKD taking tolvaptan is currently being investigated.⁷⁸

Dialysis, Nephrectomy and Kidney Transplant

Patients with ADPKD who have late stage 4–5 CKD (eGFR of 15–20 ml/min/1.73m²) should be referred for dialysis and/or kidney transplant evaluation, with transplant prior to dialysis initiation preferred if feasible, consistent with guidelines for CKD.⁶⁶ A study from 2000–2018 that included 41,485 US patients with ADPKD, reported that at the time of the first need for kidney replacement therapy, 63–80% started hemodialysis, 15–18% started peritoneal dialysis, and 5–19% underwent transplant.⁷⁹ ADPKD does not recur in transplanted kidneys. In a retrospective study from a large single transplant center in the UK, among 126 patients with ADPKD, median dialysis-free survival was 18.2 years, and the rate of transplant failure or death was 2.5% per year.⁸⁰ After kidney transplant, ongoing surveillance of patients with ADPKD for intracranial aneurysm, symptomatic liver enlargement and cardiac complications is necessary. Unilateral or bilateral nephrectomy may be performed for patients with ADPKD and kidney failure who have recurrent kidney infections, bleeding from ruptured cysts, intractable abdominal pain, or massively enlarged kidneys that do not allow space for placement of a donor kidney.⁸¹

Hepatic cyst aspiration, sclerotherapy, somatostatins and liver transplant

Treatment options for symptomatic ADPKD-associated hepatomegaly include cyst aspiration and sclerotherapy (17–19% reduction in liver volume)⁸², partial liver resection⁸³ (Figure 4), and treatment with somatostatin analogs^84–86 (Table 2). Somatostatin analogs, such as long-acting octreotide, inhibit secretin-induced cAMP-mediated fluid secretion in cholangiocytes⁸⁷ and lower insulin-like growth factor (IGF) levels⁸⁸. A meta-analysis of 7 randomized clinical trials including 652 patients with polycystic kidney and liver disease reported that long-acting octreotide or lanreotide decreased TLV growth rate by 6.37% compared with control, (mean difference, −3.66%; 95% CI −5.35 to −1.97, p<0.0001) without reducing eGFR decline.⁸⁶ Liver transplantation for patients with ADPKD and polycystic liver disease is reserved for those with severe portal hypertension, hepatic decompensation, malnutrition or severe sarcopenia,⁸⁹ and accounted for 1.4% (51/3560) of liver transplants at two large transplant centers in Canada.⁹⁰ Although there are currently no published randomized clinical trials of hormonal treatments on liver cyst growth, a study of anti-estrogen therapy and liver cyst growth is ongoing.⁹¹ Use of hormone-containing birth control or hormone replacement therapy should be avoided in women at high risk of developing symptomatic hepatomegaly due to rapid liver cyst growth⁹², or established hepatomegaly (height-adjusted liver volume > 1000 ml/m).³⁰

Figure 4:

Representative radiological images from a 49-year-old female with ADPKD and severe polycystic liver disease due to a PKD1 truncating pathogenic variant and eGFR of 19 ml/min/1.73m². MRI images (A, B, C) illustrate a total kidney volume of 3220 mL and a MIC of 1D. The total liver volume is 5581 mL. Gross images of the removed cystic liver (D) and kidney (E) with a kidney length of 30 cm. Images courtesy of Dr. Fouad Chebib, Mayo Clinic.

Table 2:

Current clinical practice recommendations and available therapies for extrarenal manifestations in ADPKD

Management of extrarenal manifestations
	Indication, benefits, and risks	Recommended practice guidance	Adverse effects
Intracranial aneurysm (IA33)	- Inform patients about IA prevalence and the risks/benefits of screening. - Screening: Every 5 years for high-risk patients (family history of subarachnoid hemorrhage, IA, or sudden death).	- If IA detected, refer to multidisciplinary team - Immediate emergency department visit if thunderclap headache - Strict BP control (<100/75 mm Hg), smoking cessation, limit alcohol, avoid stimulant medications	Surgical vs endovascular treatment (no prior SAH): morbidity and mortality 10.1% vs 7.1%105
Mild – moderate polycystic liver disease (PLD)30	-Evaluate liver cysts and symptoms. -PLD defined as > 10 liver cysts.	Asymptomatic PLD: usually no treatment is needed. Symptomatic PLD: Treatment to improve quality of life. -Aspiration sclerotherapy: reduce liver volume by 17–19% reduction in liver volume82; 41% achieve partial/full regression, 36% experience recurrence83	Cyst aspiration and sclerotherapy: pain with procedure, cyst regrowth, variable symptom improvement
Severe PLD	- Definition: height adjusted total liver volume >1800 ml/m with severe symptoms.	- Somatostatin analogue (e.g., Long-acting octreotide): reduce liver growth and symptoms84. - Partial hepatectomy with cyst fenestration - Liver or combined liver-kidney transplantation -Transarterial embolization	-Somatostatin analogue: Hyperglycemia (pasireotide), abdominal cramping, diarrhea, bradycardia, cholelithiasis. -Hepatic Resection: ascites, pleural effusion, bile leak, hemorrhage83 -Liver transplant: 30-day mortality 3%, 1 yr. and 5 yr. survival 93%, 92%83.

Treatment of intracranial aneurysms

Management options for identified intracranial aneurysms including observation, endovascular coiling, microsurgical clipping, stent-supported coiling, or flow-diverter therapy. Treatment decisions should be individualized based on aneurysm size, location, and likelihood of rupture⁹³ (Table 2). The complication rate for endovascular repair of intracranial aneurysms is low (4–6%), however, this rate may exceed the likelihood of rupture of an untreated aneurysm, particularly for small asymptomatic intracranial aneurysms that tend to have slow or no growth.

Symptom Management

Some patients with ADPKD have substantial abdominal or flank pain and discomfort from enlarging kidney or liver cysts. In a two-round Delphi survey involving 1014 participants (60% patients or caregivers), kidney-cyst related pain was identified as the most important patient-reported outcome⁹⁴. Consensus-based KDIGO recommendations for conservative pain management include non-pharmacologic approaches, such as heat, light exercise, ice massage, and medications, including acetaminophen (no increased risk of toxicity with liver cysts), tricyclic antidepressants or gabapentin, and avoidance of NSAIDs.¹⁰ In select patients with severe pain, celiac plexus nerve block or renal denervation may be considered.⁹⁵

For some patients with ADPKD and large cysts, aspiration coupled with injection of a foaming and sclerosing agent such as sodium tetradecyl sulfate,⁹⁶ or surgical cyst fenestration may provide pain relief. In a prospective cohort study of 66 patients with ADPKD, foam sclerotherapy was associated with reduced pain in 70% of patients, and a decrease in TKV of 21.8% (median, 1138 [IQR, 801–1582] mL before vs 891 [IQR, 548–1450] mL after sclerotherapy; P< 0.001) in the treated kidney vs a 3.4% increase the untreated kidney at 13 months followup.⁹⁶ Cyst fenestration, which involves combined surgical deroofing and aspiration, provided symptom relief in 92% (286/311 patients) but was associated with adverse effects, including ascites, pleural effusion, bleeding, bile leak (23%), and mortality (2%).⁸³

Screening for intracranial aneurysms

The American Heart Association/American Stroke Association recommends screening with brain MRA or CTA for adults with ADPKD, particularly those with a family history of intracranial aneurysms. However, negative screening by CTA or MRA does not exclude development and rupture of a subsequent de novo aneurysm. KDIGO suggests tailoring screening recommendations to individual patients with ADPKD, considering factors such as family history, timing relative to major surgery such as a kidney transplant, patient occupation (with greater likelihood of harm for a pilot or bus driver, for instance), and personal preferences.¹⁰

Prognosis

A study utilizing the United States Renal Data System (USRDS) data from 2014 to 2016 reported that all-cause mortality among 1936 patients with ADPKD and non-ESRD CKD was approximately 18.4 deaths per 1,000 patient-years, compared with 37.4 deaths per 1,000 patient-years among 37,461 patients with ADPKD and ESRD.⁹⁷ However, ADPKD-related ESRD mortality in patients aged ≥ 65 years (99.8 per 1,000 patient-years) was lower than the general ESRD mortality in the US (216 per 1,000 patient-years).⁹⁷

In a retrospective analysis of 9% (75 of 812) persons with ADPKD with an intracranial aneurysm detected on pre-symptomatic screening, over a median follow up of 9 years, intracranial aneurysms remained stable in 83% (62/75), increased in size without rupturing in 10.6% (8/75), or new aneurysms formed 6.7% (5/75) or ruptured after prior negative imaging 0.27% (2/737).⁹⁸ Intracranial aneurysm rupture in patients with ADPKD occurs at a median age of 41 years, which is 11 years younger than in the general population.³⁴

Screening of family members

Asymptomatic at-risk family members such as children of an affected parent, can delay screening for ADPKD until early adulthood even if affected relatives have high-risk features such as early-onset kidney failure. However, individuals at risk of ADPKD, including those younger than 18 years, should have regular blood pressure screening because hypertension occurs in 20%⁹⁹ to 31%¹⁰⁰ of affected children and adolescents. Although a new diagnosis of a genetic condition does not currently affect medical insurance eligibility in the US, it may affect future employment, life insurance and disability insurance coverage;¹⁰¹ therefore screening is sometimes deferred. Screening may also be performed in a young asymptomatic family member who is considering donating a kidney to an affected relative. Screening for ADPKD may be performed by abdominal ultrasound imaging for those older than age 40 years. Abdominal MRI or genetic testing may be used in younger individuals.⁵²

Pregnancy

Pregnant individuals with ADPKD have similar live birth rates as the general population,¹⁰² but higher rates of new-onset hypertension (16% vs. 6%), worsening of pre-existing hypertension (7% vs. 1%), increased peripheral edema (25% vs. 15%) and higher rates of pre-eclampsia (11% vs. 4%) during pregnancy compared with individuals without ADPKD.¹⁰³ Individuals with ADPKD can undergo pre-implantation genetic testing performed after in vitro fertilization (IVF), to select embryos for implantation that do not carry the ADPKD genetic variant.¹⁰⁴

Practical Considerations and Application of Evidence:

All patients with ADPKD should be treated by a kidney specialist, and engage in shared decision-making about genetic testing, disease-modifying treatments, frequency of eGFR measurements and imaging, and intracranial aneurysm screening. Persons with ADPKD should be informed that ruptured intracranial aneurysms may present with thunderclap headaches, characterized by sudden, severe onset that reach maximum intensity within seconds to a minute, and require emergency medical attention.¹⁰

Limitations

This review has limitations. First, the quality of the literature included was not formally evaluated. Second, some relevant studies may have been missed. Third, due to the limited number of randomized clinical studies on ADPKD, data were often derived from pooled results of clinical practice instead of clinical trials.

Conclusion

ADPKD is the most common genetic kidney disease worldwide and is characterized by progressive development of kidney cysts. Patients typically have hypertension and liver cysts, and 9–14% develop intracranial aneurysms. First-line treatment includes blood pressure control, dietary and weight management, and adequate hydration. Tolvaptan reduces the rate of eGFR decline for those at high risk of rapid progression to kidney failure.

TEXT BOX: 3. Commonly Asked Questions:

1). What is the role of genetic testing in diagnosing or treating ADPKD?

The diagnosis of ADPKD can be made in patients with bilaterally enlarged (> 13 cm kidney length) kidneys and symmetric cyst distribution on kidney imaging (ultrasound, CT, or MRI). However, genetic testing is helpful to diagnose ADPKD in patients with an atypical imaging study or unusual clinical presentation, and in those without a family history of ADPKD. Genetic testing can also help inform prognosis because the risk of progression to kidney failure may depend on the specific gene variant causing ADPKD.

2). What are appropriate first steps after an initial diagnosis of ADPKD?

Patients diagnosed with ADPKD should undergo blood pressure assessment, blood testing to assess kidney function (serum creatinine), and urinalysis to evaluate for hematuria and/or proteinuria, and should be referred to a nephrologist. Family history of kidney failure, hemorrhagic stroke and intracranial aneurysm rupture should be obtained. If the diagnosis of ADPKD was made with a kidney ultrasound, an abdominal MRI without contrast or a contrast-enhanced abdominal CT may be helpful to provide a more accurate measurement of total kidney volume and evaluate for liver cysts.

3). Which patients are at high risk of early loss of kidney function?

In patients with ADPKD, total kidney volume and genotyping can help inform the predicted rate of progression to kidney failure. Patients with the largest height- and age-adjusted total kidney volume measurements are at highest risk of early kidney failure. Patients with PKD1 gene variants develop kidney failure at an earlier age than those with PKD2 gene variants, or other pathogenic gene variants associated with ADPKD.