What is the management of Autosomal Dominant (AD) Polycystic Kidney Disease (PKD)?

From the Guidelines

The management of Autosomal Dominant Polycystic Kidney Disease (ADPKD) should prioritize the use of tolvaptan, a vasopressin V2 receptor antagonist, as the cornerstone of treatment, along with lifestyle modifications and blood pressure control, to slow disease progression and improve quality of life. According to the most recent and highest quality study, the KDIGO 2025 clinical practice guideline for the evaluation, management, and treatment of ADPKD 1, tolvaptan has been shown to reduce the decline in eGFR and total kidney volume growth, with a net difference in eGFR decline of 1.3 ml/min per 1.73 m2 per year and in total kidney volume growth of 2.7%. Key aspects of management include:

• Initiating tolvaptan with a daily dose of 45 mg upon waking, and of 15 mg 8 hours later, with potential titration to 90/30mg based on tolerability 1
• Maintaining adequate hydration (2-3 liters daily) and following a low-sodium diet (less than 2,300mg daily) to reduce polyuria and support kidney function 1
• Controlling blood pressure with ACE inhibitors or ARBs (like lisinopril 10-40mg daily or losartan 25-100mg daily) as first-line agents, targeting levels below 130/80 mmHg, or even lower if tolerated, as recommended by the KDIGO 2025 guideline 1
• Encouraging moderate-intensity physical activity, for a cumulative duration of at least 150 minutes per week, and strength training at least 2 sessions per week, while considering individual cardiovascular and physical tolerance 1
• Promoting a healthy lifestyle, including physical activity and maintenance of normal weight, as recommended by the international consensus statement on the diagnosis and management of ADPKD in children and young people 1. Regular monitoring, including kidney function tests, blood pressure checks, and imaging (ultrasound or MRI) every 1-3 years, is essential to assess disease progression and adjust treatment as needed. Genetic counseling is also important for family planning. These interventions aim to preserve kidney function, reduce cyst growth, and manage the increased vasopressin activity and abnormal cell proliferation that characterize the disease.

From the FDA Drug Label

WARNING: (B) NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

Because of the risk of hepatotoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS [see Contraindications ( 4)] .

What are tolvaptan tablets? Tolvaptan tablets are a prescription medicine used to help increase low sodium levels in the blood, in adults with conditions such as heart failure, and certain hormone imbalances Tolvaptan tablets help raise salt levels in your blood by removing extra body water as urine.

Who should not take tolvaptan tablets? Do not take tolvaptan tablets if: • you are allergic to tolvaptan or any of the ingredients in tolvaptan tablets • the sodium level in your blood must be increased right away. • you cannot replace fluids by drinking or you cannot feel if you are thirsty. • you are dizzy, faint, or your kidneys are not working normally because you have lost too much body fluid. • you take certain medicines These medicines could cause you to have too much tolvaptan in your blood:

CONTRAINDICATIONS • Use in patients with autosomal dominant polycystic kidney disease (ADPKD) outside of FDA-approved REMS ( 4) • Patients who are unable to respond appropriately to thirst ( 4) • Hypovolemic hyponatremia ( 4) • Concomitant use of strong CYP3A inhibitors ( 4) • Anuria ( 4) • Hypersensitivity ( 4)

The management of Autosomal Dominant (AD) Polycystic Kidney Disease (PKD) is not directly addressed by the provided drug labels for tolvaptan, as they explicitly state that tolvaptan is not for use in patients with ADPKD outside of the FDA-approved REMS 2, 2, 2.

• Key points:
  • Tolvaptan is not indicated for ADPKD.
  • The use of tolvaptan in ADPKD is contraindicated outside of the FDA-approved REMS.
  • There is no information provided on the management of ADPKD.

Therefore, the provided drug labels do not answer the question regarding the management of ADPKD.

From the Research

Management of Autosomal Dominant (AD) Polycystic Kidney Disease (PKD)

The management of AD PKD involves several approaches, including:

• Blood pressure control: Intensive control of systolic blood pressure to 95-110 mmHg has been associated with a slower rate of kidney volume growth 3
• Use of disease-modifying drugs: Tolvaptan, a vasopressin V2 receptor antagonist, has been introduced to inhibit cyclic adenosine monophosphate, attenuate cyst growth, and delay renal failure 4
• Targeting aberrant signaling pathways: Peptides may be used as targeting ligands to direct therapies to diseased renal tissue or as therapeutic agents themselves 5
• Management of water balance: Tolvaptan may have adverse effects on water and sodium balance, and its use requires careful monitoring 4

Pharmacological Interventions

Several pharmacological interventions have been investigated for the prevention of ADPKD progression, including:

• Angiotensin-converting enzyme inhibitors (ACEi): ACEi have been shown to reduce diastolic blood pressure, but their effects on kidney volumes, GFR, and SCr are uncertain 6
• Angiotensin receptor blockers (ARBs): ARBs have been compared to ACEi, but their effects on GFR and SCr are uncertain 6
• Vasopressin receptor 2 (V2R) antagonists: V2R antagonists have been shown to increase thirst and dry mouth, but their effects on kidney function and volumes are limited 6
• Mammalian target of rapamycin (mTOR) inhibitors: mTOR inhibitors have uncertain effects on kidney function and volume, but may cause angioedema, oral ulceration, infections, and diarrhea 6
• Somatostatin analogues: Somatostatin analogues may improve SCr and total kidney volume, but may cause diarrhea 6

Considerations for Treatment

The treatment of ADPKD should take into account the potential risks and benefits of each intervention, including:

• The use of ACE inhibitors may worsen renal function in patients with compromised renal function and massive cystic involvement 7
• The use of Tolvaptan may require careful monitoring of water and sodium balance 4
• The potential for adverse effects, such as angioedema, oral ulceration, infections, and diarrhea, should be considered when using mTOR inhibitors 6