What are the management and treatment options for Autosomal Dominant Polycystic Kidney Disease (ADPKD)?

Management and Treatment of ADPKD

Blood Pressure Control

For patients aged 18-49 years with early-stage ADPKD (eGFR >60 mL/min/1.73 m²), target blood pressure should be 110/75 mmHg measured by home monitoring, while patients ≥50 years or with eGFR <60 mL/min/1.73 m² should target systolic BP <120 mmHg measured in clinic. 1

• ACE inhibitors or ARBs are the first-line antihypertensive agents for all ADPKD patients with hypertension 1, 2, 3
• Never combine ACE inhibitors with ARBs or direct renin inhibitors due to increased risk of adverse events 2
• Standardized office BP measurements should be complemented with home or ambulatory monitoring for all patients regardless of kidney function 2, 3
• Resistant hypertension requiring ≥3 medications warrants investigation for medication non-adherence or secondary causes 2
• Monitor for isolated nighttime hypertension, which occurs in 16-18% of ADPKD patients and may be missed by office measurements alone 3

Disease-Modifying Therapy with Tolvaptan

Tolvaptan is indicated for patients with rapidly progressive disease (Mayo Imaging Classification 1C-1E or eGFR decline >3 mL/min/1.73 m² per year) to slow kidney function decline and delay kidney failure. 1, 4

• Tolvaptan reduces annual eGFR decline by 0.98-1.27 mL/min/1.73 m² compared to placebo 4
• Critical safety requirement: Monitor liver function tests before initiation and regularly during treatment, as tolvaptan can cause severe and potentially fatal hepatotoxicity 1
• Discontinue immediately if ALT or AST exceed 3 times the upper limit of normal without alternative explanation 1
• Expect copious aquaresis with increased thirst and polyuria, which significantly impacts quality of life and requires patient counseling 1
• Additional side effects include hyperuricemia and rarely gout 1
• Currently not recommended for children and adolescents outside of clinical trials due to lack of safety data 1

Lifestyle and Dietary Modifications

All ADPKD patients should engage in moderate-intensity physical activity for at least 150 minutes weekly plus strength training twice weekly, while maintaining awareness of potential kidney/liver injury risk with contact sports. 1, 2

• Water intake: Consume 2-3 liters of water daily (spread throughout the day) if eGFR ≥30 mL/min/1.73 m² and no contraindications exist 1
• Contraindications to high water intake include medications that increase hyponatremia risk (SSRIs, tricyclic antidepressants, thiazide diuretics) 1
• Dietary sodium restriction to <2000 mg/day 2, 4
• Avoid all tobacco products completely 1, 2
• Limit alcohol to ≤1 drink/day for women, ≤2 drinks/day for men 1, 2
• Avoid excessive caffeine intake, particularly during pregnancy 1
• Refrain from cannabis products (risk of acute kidney injury from contamination), recreational drugs, and anabolic steroids 1

Therapies NOT Recommended

Do not use mTOR inhibitors, metformin (in non-diabetics), or statins specifically for slowing ADPKD progression, as they lack efficacy and cause significant adverse effects. 1

• mTOR inhibitors showed no eGFR benefit and caused angioedema, oral ulceration, infections, and diarrhea in clinical trials 1, 5
• Sodium-glucose cotransporter-2 inhibitors and GLP-1 receptor agonists should not be used for slowing eGFR decline until further research establishes efficacy and safety 1
• Ketogenic interventions lack long-term safety and efficacy data 1
• Somatostatin analogues should not be prescribed solely for slowing eGFR decline, but may be considered for severe symptoms from massively enlarged kidneys when no better options exist 1

Pain Management

Pain management should follow a stepwise approach: start with non-pharmacological interventions, progress to medications, then consider procedural interventions, reserving nephrectomy only for intractable severe pain in advanced disease. 2

• First-line: Non-pharmacological and non-invasive interventions 2
• Second-line: Pharmacological treatment if non-pharmacological measures fail 2
• Third-line: For pain from dominant cysts, perform cyst aspiration or aspiration sclerotherapy 2
• Fourth-line: For chronic refractory visceral pain, consider celiac plexus block or percutaneous renal denervation 2
• Last resort: Nephrectomy reserved for intractable severe pain, typically in advanced kidney disease 2
• All refractory pain requires multidisciplinary management with shared decision-making 2

Infection Management

Never treat asymptomatic bacteriuria in ADPKD patients. 2

• For uncomplicated symptomatic UTIs: Use first-line agents (nitrofurantoin, trimethoprim-sulfamethoxazole, fosfomycin) 2
• Obtain urine culture before starting antibiotics 2
• Treat acute cystitis with the shortest reasonable duration (generally ≤7 days) 2
• For suspected cyst infections: Use lipid-soluble antibiotics (trimethoprim-sulfamethoxazole or fluoroquinolones) for better cyst penetration 1
• Caution with fluoroquinolones: Associated with increased risk of tendinopathies, aortic aneurysms, and dissections 1
• Investigate recurrent UTIs for underlying predisposing factors 2

Kidney Stone Management

• Treat nephrolithiasis in ADPKD identically to the general population 2
• Obstructive kidney stones require management at specialized centers 2
• Discuss the possibility, causes, and natural history of gross hematuria with patients at diagnosis 2

Chronic Kidney Disease Management

Manage CKD complications in ADPKD similarly to other kidney diseases, with awareness of disease-specific features. 1

• ADPKD patients maintain higher hemoglobin levels than other CKD patients due to regional hypoxia driving erythropoietin production 1
• Erythrocytosis (hematocrit >51% or hemoglobin >17 g/dL) may occur, more frequently post-transplant 1
• Therapeutic phlebotomy indicated when ACE inhibitor or ARB is contraindicated or ineffective at maximal tolerated dose 1
• For diabetes management: Use metformin when eGFR ≥30 mL/min/1.73 m², or GLP-1 receptor agonist when eGFR <30 mL/min/1.73 m² 1
• Initiate lipid-lowering therapy for primary cardiovascular disease prevention per KDIGO lipid guidelines 1

Kidney Replacement Therapy

Preemptive living-donor kidney transplantation is the preferred treatment for kidney failure in ADPKD. 1

• Subtract estimated total kidney and liver weights (derived from volumes) from body weight for accurate BMI assessment during pre-transplant workup 1
• Perform kidney imaging within 1 year before anticipated transplantation to exclude solid or complex cystic lesions 1
• Use standard immunosuppressive protocols as for other transplant recipients 1
• Native nephrectomy indications: Severe symptoms from massive kidney enlargement, recurrent/severe infection or bleeding, complicated nephrolithiasis, intractable pain, suspected renal cell carcinoma, insufficient space for graft, or severe ventral hernia 1
• Perform nephrectomy at time of or after transplantation, never before (risk of transfusion need, preventing preemptive transplant, increased complications) 1
• Use hand-operated laparoscopic nephrectomy rather than open nephrectomy 1
• Post-transplant complications more common in ADPKD: new-onset diabetes, erythrocytosis, worsening valvular regurgitation, aortic root dilatation, subarachnoid hemorrhage, thromboembolic events, skin cancers, cyst infections, and diverticulitis 1

Polycystic Liver Disease Management

Most ADPKD patients develop liver cysts with age, but only a minority develop symptomatic polycystic liver disease requiring intervention. 1

• Liver cysts typically do not impair synthetic or secretory liver function 1
• Symptoms arise from mass effect: pressure on diaphragm/abdominal wall, compression of organs and vascular structures 1
• Treatment options based on severity:
  • Aspiration sclerotherapy: For one or few large dominant symptomatic cysts (72-100% symptomatic improvement, <1% mortality) 1
  • Transarterial embolization: For diffuse symptomatic cysts with at least one functioning liver segment (72-93% symptomatic improvement, 100% post-embolization syndrome) 1
  • Laparoscopic cyst fenestration: For large symptomatic cysts located anteriorly and caudally (34% symptomatic recurrence, 29% complications) 1
• Refer for liver transplantation in massive PLD without contraindications or alternative options 1
• Refer for combined kidney-liver transplantation when liver transplant indicated and eGFR <30 mL/min/1.73 m² 1

Pregnancy Management

Pregnant women with ADPKD require multidisciplinary care at expert centers with specific blood pressure targets and medication adjustments. 1, 2

• Target BP during pregnancy: ≤130/85 mmHg 2
• Stop ACE inhibitors, ARBs, tolvaptan, and all teratogenic drugs before pregnancy and do not restart until breastfeeding is complete 1, 2
• Administer low-dose aspirin from week 12 to week 36 for preeclampsia prevention 2
• Offer preconception counseling to both men and women regarding reproductive options to prevent ADPKD transmission 1
• For women with liver cysts: Educate about contraceptive choices, as estrogen (and possibly progesterone) may accelerate polycystic liver disease progression 1
• Contraceptive recommendations based on liver disease severity:
  • Mild PLD: Combined low-estrogen/progestin contraceptives acceptable 1
  • Moderate PLD: Progestin-only intrauterine devices likely safe (low systemic exposure) 1
  • Severe PLD: Non-hormonal methods (barrier-based, copper IUD) safest 1

Screening for Complications

Screen for intracranial aneurysms in patients with family history of aneurysms or subarachnoid hemorrhage. 2

• Intracranial aneurysms occur in 9-14% of ADPKD patients with rupture rate of 0.57 per 1000 patient-years 4
• Consider echocardiography in patients with severe/uncontrolled hypertension, cardiac murmur, or family history of thoracic aortic aneurysm 2
• Screen for and periodically assess psychosocial issues related to physical, social, family, and hereditary stressors 1

Disease Monitoring and Prognosis

Total kidney volume assessment using Mayo Imaging Classification (MIC) is essential for predicting disease progression and guiding treatment decisions. 2, 4

• MIC stratifies patients from 1A to 1E based on height-adjusted total kidney volume and age 2, 4
• MIC 1A-1B: Slower kidney growth (1-5% per year) 4
• MIC 1C-1E: Rapid kidney growth (6-10% per year) with earlier progression to kidney failure 4
• Mean age at kidney replacement therapy: 58.4 years (MIC 1C), 52.5 years (MIC 1D), 43.4 years (MIC 1E) 4
• Approximately 50% of ADPKD patients require kidney replacement therapy by age 62 4