Tolvaptan Use in ADPKD: A New Option for a Progressive Disease

James J. Matera DO, FACOI

Matera JJ. Tolvaptan use in ADPKD: a new option for a progressive disease [published online June 25, 2018]. Consultant360.


Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease affecting 140,000 patients in the United States and can lead to end-stage renal disease (ESRD), requiring dialysis and/or transplantation. In fact, ADPKD is the fourth leading cause of ESRD in adults.1 Each parent who has ADPKD has a 50% chance of passing the gene to each child, who then may develop debilitating progress of the cysts as well as other sequalae prior to ESRD. The genetic defect involves code disruption of polycystin1 (PKD1) and polycystin2 (PKD2). This disruption then leads to renal tubular epithelial cells to proliferate, secrete fluid and express proinflammatory cytokines to promote cysts and renal parenchyma destruction.2

Prior treatment approaches have focused on limiting progression of ADPKD and symptoms, and have been moderately effective in doing such. These treatments have included RAASi, pain control for cyst growth and infections, controlling hypertension, and monitoring for development of stones or other cysts (liver, gallbladder).3

Slowing the progression of ADPKD has been a focus over the last 5 years, and the results of TEMPO 3:4 (Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes) with a primary endpoint of intergroup difference for rate of change of total kidney volume (TKV) normalized as a percentage over 36 months. This endpoint was most prominent in the first year of treatment. Patients enrolled in TEMPO 3:4 were in early stages (i.e., estimated glomerular filtration rate [eGFR] >60 mL/min). Tolvaptan-treated patients had an increase in TKV of 2.8% vs 5.5% in the placebo group.

Secondary endpoints in TEMPO 3:4 focused on disease progression and favored tolvaptan over placebo4:

  • Reduction in renal function (25% reduction in reciprocal creatinine).
  • Reduction in renal or flank pain.
  • Worsening hypertension and albuminuria. 

The REPRISE Trial (Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy in ADPKD) results were announced at Kidney Week in late 2017 (Phase III trial) and showed that tolvaptan decreased the rate of change of eGFR, which was the primary endpoint. These patients were at a later stage of ADPKD than patients in TEMPO 3:4. Patients aged 18 to 55 years had eGFRs 25 to 65 mL/min, and patients aged 56 to 65 years had eGFRs 25 to 44 mL/min. The rate of decline for treated patents in REPRISE was -2.34 mL/min/1.73m2/year vs. -3.61 mL/min/1.73m2/year in the placebo group. The study looked at more than 1300 patients randomized 1:1 to tolvaptan vs placebo for 12 months. Pre-and post-treatment eGFRs were measured, and tolvaptan-treated patients had a smaller decline seen in eGFR.5

Major toxicities involve hepatic dysfunction, and there are clear guidelines for the measurement and management of potential liver function test abnormalities. In REPRISE, tolvaptan-treated patients saw a 10.9% rate of hepatic abnormalities vs 5.3% in the placebo group. The threshold used was 3 times the upper limit of normal and returned to normal after drug cessation. Other less common adverse effects include polyuria, nocturia, thirst, dry mouth (likely due to the mechanism of action of tolvaptan being a selective vasopressin 2 antagonist).5

Tolvaptan approval offers the first disease-modifying agent for slowing progression of ADPKD and potentially impacting the time that ESRD develops. Risk factors for more progressive disease may warrant consideration of drug therapy, including TKV more than what is expected for age, ERSD in family prior to age 58 years, hypertension before age 35 years, male gender, and eGFR decline of more than 5mL/min/1.73m2 in 1 year. It is important to recognize that both TEMPO 3:4 and REPRISE do not determine long-term effectiveness of tolvaptan, but future directions can focus on this.

With the cost impact of ESRD rising annually, risk reduction for development of ESRD can aid in promoting healthier lifestyles, cardiovascular disease modification in chronic kidney disease, and limitation of resources for dialysis and transplantation. The average cost of hemodialysis annually in the United States is $89,000, and ESRD accounts for 7% of the total Centers for Medicare & Medicaid Services budget for 1% of the total beneficiaries.6 Slowing progression of the fourth leading cause of ESRD can help with the triple aim of improving outcomes, reducing costs, and enhancing patient satisfaction.7

James J. Matera DO, FACOI, is the Medical Director of Population Health at CentraState Medical Center in Freehold, New Jersey.


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  2. Grantham JJ, Mulamalla S, Swenson-Fields KI. Why kidneys fail in autosomal dominant polycystic kidney disease. Nat Rev Nephrol. 2011;7:556-566.
  3. Chapman AB. Autosomal dominant polycystic kidney disease: time for a change. J Am Soc Nephrol. 2007;18(5):1399-1407. doi:10.1681/ASN.2007020155.
  4. Torres VE, Chapman AB, Devuyst O, et al; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Eng J Med. 2012;367:2407-2418. doi:10.1056/NEJMoa1205511.
  5. Torres VE, Chapman AB, Devuyst O, et al; REPRISE Trial Investigators. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N Eng J Med. 2017;377:1930-1942. doi:10.1056/NEJMoa1710030.
  6. National Institute of Diabetes and Digestive and Kidney Diseases. US Renal Data System Report, Chapter 9: healthcare expenditures for persons with ESRD. Published November 2017. Accessed June 25, 2018.
  7. Berwick DM, Nolan TW, Whittington J. The triple aim: care, health, and cost. Health Affairs. 2008;27(3):759-769.

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