Recommendations

1. We suggest that all patients be referred to a nephrologist for initial assessment to determine what treatment should be initiated, in particular to initiate tolvaptan as soon as possible in patients determined to be appropriate candidates who would benefit from this therapy.
2. We recommend treatment with tolvaptan for patients who fulfill the enrollment criteria of the TEMPO 3:4 study: 18 to 50 years of age, Cockcroft-Gault GFR >60 mL/min, and TKV >750 mL. In the absence of Cockcroft-Gault GFR, CKD-EPI >45 mL/min may be used, and in the absence of TKV, US KL >16.5 cm may be used.
3. We suggest treatment with tolvaptan for patients who, according to the Mayo Classification, are classified as 1D or 1E with eGFR in CKD stage 3 or higher. Treatment with tolvaptan should be considered for patients who are classified as 1C and are younger than 50 years or have other risk factors for rapid progression. We do not recommend tolvaptan for patients classified as 1A or 1B.
4. We suggest that treatment with tolvaptan be stopped when the patient develops ESRD. In the predialysis setting, there are no data to guide when treatment with tolvaptan should be stopped.

ADPKD-Specific Treatment Options

A recent meta-analysis of 4 randomized, controlled trials of the mTOR inhibitor sirolimus in adults with ADPKD showed a positive impact on TKV but not on eGFR.⁵⁵ Similar results have been reported with the mTOR inhibitor everolimus.⁵⁶ Thus, sirolimus and everolimus are effective in reducing the increase in TKV in patients with ADPKD but have not been shown to slow or improve loss of renal function.

Treatment with the somatostatin analogue octreotide in its standard or long-acting formulation inhibits or slows renal enlargement in patients with ADPKD but has not been shown to improve loss of renal function.^57-59 The efficacy of pravastatin in the treatment of ADPKD has been demonstrated in pediatric patients.⁶⁰ At the end of 3 years of treatment with pravastatin, a significant decrease in percent change in htTKV was observed when adjusted for age, sex, and hypertension status, compared with placebo (23 ± 3% vs 31 ± 3%, respectively, P = .02). Further studies are required to assess efficacy in adults.

Tolvaptan, a selective vasopressin V2-receptor antagonist approved by Health Canada in 2015, is indicated to slow the progression of kidney enlargement in patients with ADPKD.^9,61 Tolvaptan received approval based on the results of the phase 3, double-blind TEMPO 3:4 trial.⁶² In this 3-year trial, 1445 ADPKD patients aged 18 to 50 years with a TKV ≥50 mL and a creatinine clearance of ≥60 mL/min, as estimated by the Cockroft-Gault formula, were randomized to either tolvaptan (highest of 3 doses based on tolerability) or placebo. The annual rate of change in TKV (primary endpoint) was 2.8% with tolvaptan, compared with 5.5% with placebo (P < .0001). The rate of growth was reduced by 2.7 percentage points per year with tolvaptan, and the ratio of the geometric means of growth rate was 0.97 (P < .001). Loss in kidney function, determined as the reciprocal of the serum creatinine level, from the end of dose escalation to month 36, was significantly reduced with tolvaptan (slope of −2.61 [mg/mL]⁻¹ per year) compared with placebo (slope of −3.81 [mg/mL]⁻¹ per year).⁶² The overall treatment effect was an increase of 1.20 (mg/mL)⁻¹ per year (P < .001). Analysis of the annual estimated GFR slope (which gave results similar to those of the slopes of the reciprocal of the serum creatinine level) showed an estimated GFR slope of −2.72 mL per minute per 1.73 m² per year in the tolvaptan group versus −3.70 in the placebo group (treatment effect, an increase of 0.98 mL per minute per 1.73 m² per year; 95% confidence interval, 0.60 to 1.36; P < .001).⁶³ Figure 3 shows the effect of tolvaptan on TKV growth and eGFR stratified by CKD stage.⁶³ Tolvaptan also significantly reduced the occurrence of clinically significant kidney pain—defined as pain necessitating medical leave, pharmacological treatment (opioid or last-resort analgesic agents), or invasive intervention—compared with placebo (hazard ratio [HR] 0.64; P = .007).⁶²

A post hoc analysis of TEMPO 3:4 clinical data was carried out using Mayo Classification to exclude 10% of the original patient population who had a lesser risk for progression (classes 1A-B and 2), resulting in a patient population enriched in categories 1C-E.⁶⁴ A comparison of the enriched population to the original cohort showed that the effect of tolvaptan on TKV and eGFR slopes increased in classes 1C to E: TKV was significantly lower with tolvaptan versus placebo (5.8% vs 2.9%; P < .001; 2.8% in TEMPO 3:4) and reduced the decline in the eGFR slope (−3.93 mL/min/1.73 m² per year to −2.82 mL/min/1.73 m² per year; P < .001; −2.78 mL/min/1.73 m² per year in TEMPO 3:4), and significantly reduced the risk of clinical progression (HR 0.84; P = .0032).

Cost-effectiveness of Tolvaptan

There have been no published manuscripts addressing the cost-effectiveness of tolvaptan. The Canadian Agency for Drugs and Technologies in Health (CADTH) recently recommended that tolvaptan not be listed on provincial formularies to slow the progression of kidney enlargement in patients with ADPKD.⁶⁵ The manufacturer submitted a costutility analysis comparing tolvaptan with the standard of care that suggested a base-case incremental cost utility ratio (ICUR) of $244 402 per quality-adjusted life year (QALY).⁶⁶ From their conclusions, it appears that the model is sensitive to varying assumptions around rate of disease progression and lower drug efficacy, which inflate the ICUR considerably. Although we are unable to comment directly on how sensitive the model is to pricing of the drug, it is logical that the model would be exquisitely sensitive to this parameter. If we assume a liberal willingness-to-pay threshold of $100 000 per QALY to fund new health interventions, further negotiation on pricing may influence decisions to list this medication on provincial formularies moving forward. Therefore, at the time of writing this article, tolvaptan is only available through private insurance, and our recommendations are predicated on patients having private health care insurance that will cover the cost of the drug.

Figure 3. Effect of tolvaptan on eGFR (left panel) and TKV (right panel) by CKD stage in the TEMPO 3:4 trial.

Source. Republished from Torres et al⁶³ with permission of the American Society of Nephrology; permission conveyed through Copyright Clearance Center, Inc.

Note. eGFR = estimated glomerular filtration rate; TKV = total kidney volume; CKD = chronic kidney disease.