Combination Therapy with Tolvaptan and Everolimus in Two Adult Sisters with PKD1/TSC2 Contiguous Gene Syndrome

PKD1/TSC2 contiguous gene syndrome (CGS) is a rare disorder caused by a large chromosomal deletion involving both the PKD1 and TSC2 genes on chromosome 16p13.3, resulting in clinical manifestations of both autosomal dominant polycystic kidney disease (ADPKD) and tuberous sclerosis complex (TSC). While tolvaptan, a vasopressin V2 receptor antagonist, has been proven to slow kidney volume growth and renal function decline in ADPKD, and everolimus, an mTOR inhibitor, is effective in reducing renal angiomyolipoma (AML) size in TSC, no previous reports have described their combined use in PKD1/TSC2 CGS. We herein report two adult sisters with genetically confirmed PKD1/TSC2 CGS who received concomitant tolvaptan and everolimus therapy and achieved stabilization of renal function without major adverse events.

From our hereditary kidney disease registry, six cases of PKD1/TSC2 CGS were identified using multiplex ligation-dependent probe amplification (MLPA). Among these, two adult sisters with renal and pulmonary manifestations were treated with everolimus for AML and lymphangioleiomyomatosis (LAM), followed by add-on tolvaptan therapy for progressive renal cyst enlargement and eGFR decline. Clinical parameters including total kidney volume (TKV), estimated glomerular filtration rate (eGFR), and adverse events were retrospectively analyzed during combination therapy.

The elder sister was diagnosed with PKD1/TSC2 CGS at age 45 after identification of bilateral renal cysts, AML, hepatic cysts, and LAM. Everolimus 5 mg/day was initiated for AML; however, her eGFR declined to 25.2 mL/min/1.73 m² with a TKV of 1,295 mL and an annual eGFR change of –5.52 mL/min/1.73 m²/year. Tolvaptan was introduced at 15 mg/day for safety reasons due to impaired renal function and limited water intake. After 15 months of combination therapy, the annual eGFR slope improved to +1.09 mL/min/1.73 m²/year, and the annual TKV growth rate decreased from 9.4% to 1.25% per year.

The younger sister was diagnosed with TSC at age 24 and later developed AML and LAM. Everolimus 5 mg/day was started at age 39 but was reduced to 2.5 mg/day following everolimus-induced interstitial pneumonia. Despite mTOR inhibition, her renal cysts enlarged and TKV increased to 3,196 mL, with an annual eGFR decline of –4.36 mL/min/1.73 m²/year. Tolvaptan was initiated at 15 mg/day at age 45 and titrated up to 60 mg/day over two years. At 48 months, her eGFR was 30.7 mL/min/1.73 m², with an improved annual decline of –2.59 mL/min/1.73 m²/year. Neither patient experienced hepatotoxicity, hyponatremia, or worsening pulmonary function. Both continued combination therapy for over one year without discontinuation.

This is the first report to demonstrate the safety and potential efficacy of combined tolvaptan and everolimus therapy in patients with PKD1/TSC2 CGS. Dual-targeted inhibition of vasopressin-mediated cAMP signaling and mTOR hyperactivation may provide additive renoprotective effects, leading to stabilization of renal function and suppression of kidney volume growth. Given the rarity of PKD1/TSC2 CGS and the absence of established treatment strategies, our findings suggest that combination therapy with tolvaptan and everolimus could represent a promising therapeutic option for managing both ADPKD and TSC manifestations in these patients. Further accumulation of cases and long-term observation are warranted to validate these results and optimize treatment protocols.