A Practical Guide for Treatment of Rapidly Progressive ADPKD with Tolvaptan

Abstract

In the past, the treatment of autosomal dominant polycystic kidney disease (ADPKD) has been limited to the management of its symptoms and complications. Recently, the US Food and Drug Administration (FDA) approved tolvaptan as the first drug treatment to slow kidney function decline in adults at risk of rapidly progressing ADPKD. Full prescribing information approved by the FDA provides helpful guidelines but does not address practical questions that are being raised by nephrologists, internists, and general practitioners taking care of patients with ADPKD, and by the patients themselves. In this review, we provide practical guidance and discuss steps that require consideration before and after prescribing tolvaptan to patients with ADPKD to ensure that this treatment is implemented safely and effectively. These steps include confirmation of diagnosis; identification of rapidly progressive disease; implementation of basic renal protective measures; counseling of patients on potential benefits and harms; exclusions to use; education of patients on aquaresis and its expected consequences; initiation, titration, and optimization of tolvaptan treatment; prevention of aquaresis-related complications; evaluation and management of liver enzyme elevations; and monitoring of treatment efficacy. Our recommendations are made on the basis of published evidence and our collective experiences during the randomized, clinical trials and open-label extension studies of tolvaptan in ADPKD.

Keywords: ADPKD; Tolvaptan; V2 Receptor Antagonist; hepatotoxicity; polycystic kidney disease; vasopressin.

Figure 1.

A stepwise approach should be followed to evaluate patients with ADPKD for treatment eligibility and management of potential side effects.

Figure 2.

These cases illustrate the importance of an accurate diagnosis of the renal cystic disease, particularly when the renal cystic burden is not congruent with the renal function. Five cases (A–E) could have qualified as ADPKD per ultrasound/MRI imaging criteria but renal phenotype and function were inconsistent in four of them. Genetic testing revealed the presence of mutations in genes other than PKD1 or PKD2. (A) A 41 year old (y.o) man with seven and ten cysts in the right and left kidney, respectively. His htTKV was 274 ml/m. His eGFR was 48 ml/min per 1.73 m². He had a strong family history of renal cystic disease reaching ESRD (early fifth decade). Genetic studies revealed a mutation in the MUC1 gene. (B) A 29 y.o woman with bilateral renal cysts (more than ten cysts in each kidney) with htTKV of 186 ml/m. Her eGFR was 70 ml/min per 1.73 m². Her 66 y.o mother had 13 cysts on her CT scan. She was found to have a mutation in the HNF1B gene. (C) A 40 y.o woman with more than ten cysts in each kidney and htTKV of 210 ml/m and eGFR 92 ml/min per 1.73 m². She was found to have a mutation in DNAJB11. (D) A 48 y.o woman with negative family history of renal disease was found to have bilateral renal cysts incidentally on her MRI scan. Her htTKV was 179 ml/m. Her eGFR was 67 ml/min per 1.73 m². She had gout at age 44 years. She was found to have a mutation in the UMOD gene. (E) A 50 y.o woman with numerous small bilateral small cysts on ultrasound and family history of renal cystic disease and intracranial aneurysm. Her eGFR was 39 ml/min per 1.73 m². She was enrolled in Halt Progression of Polycystic Kidney Disease study B and was later found to have a mutation in DNAJB11.

Figure 3.

The Mayo imaging classification provides a simple tool for the identification of patients with rapidly progressive ADPKD. This imaging classification predicts the change in eGFR over time in patients with typical, bilateral, and diffuse distribution of cysts. (A) The A–E classification is on the basis of htTKV and age at the time of imaging, assuming kidney growth rates of <1.5%, 1.5%–3%, 3%–3.5%, 4.5%–6%, or >6% per year and a theoretical initial htTKV of 150 ml/m; the dots correspond to the patients in (B). (B) MRI studies corresponding to three 41-year-old patients in classes A (bottom), C (middle), and E (top). (C) eGFR slopes in cohort of 376 patients stratified by imaging class (−0.23, −1.33, −2.63, −3.48, and −4.78 ml/min per 1.73 m² per year for classes A–E, respectively). Average eGFR at baseline (75 ml/min per 1.73 m²) and average age at baseline (44 years) for all patients were used for the model; values for normal slope were obtained from a population of healthy kidney donors; eGFR slopes were significantly different among the classes, and all but class A were significantly different from the control population of healthy kidney donors. The table shows the estimated eGFR slopes for each class by sex. Reprinted from reference , with permission.

Figure 4.

The algorithm depicted in the Figure summarizes a practical approach to identify the patients more likely to benefit from treatment with tolvaptan and optimize their overall management. After confirming ADPKD diagnosis, the patients are classified into typical and atypical ADPKD on the basis of their kidney imaging features. This is followed by measurement of htTKV, which allows the stratification of the typical patients into slowly (Mayo class 1A or 1B) or rapidly progressing (Mayo class 1C, 1D, and 1E). Treatment with tolvaptan to slow down the disease progression should be considered for 18- to 55-year-old patients at risk for rapid progression (Mayo class 1C, 1D, or 1E) with eGFR>25 ml/min per 1.73 m². The reduced benefit of treatment in the patients with advanced CKD should be pondered in the decision. The Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD trial did not show benefit from tolvaptan in patients older than 55 years probably because many of them had slowly progressive disease. General measures that may improve the outcome of ADPKD should be implemented in all patients. BMI, body mass index.

Figure 5.

Extrapolations from the results of the TEMPO 3:4 and REPRISE trials allow estimations of the potential benefit of tolvaptan treatment in delaying the need of renal replacement therapy depending on the eGFR at the initiation of treatment. The effect of tolvaptan is predicted to be sustained and cumulative on the basis of tolvaptan trial extension and single-center experiences. (A) According to baseline GFR at time of treatment initiation, tolvaptan might delay reaching stage 5 CKD by 7.3, 4.4, 2.9, or 1.5 years if baseline eGFR was 90, 60, 45, or 30 ml/min, respectively. These extrapolations are made using the average decline in eGFR between placebo (−3.7 ml/min per year) and tolvaptan (−2.72 ml/min per year) groups in the TEMPO3:4 trial. (B) According to baseline GFR at time of treatment initiation, tolvaptan might delay reaching stage 5 CKD by 6.8, 4.5, or 2.3 years if baseline eGFR was 60, 45, or 30 ml/min, respectively. These extrapolations are made using the average decline in eGFR between placebo (−3.61 ml/min per year) and tolvaptan (−2.34 ml/min per year) groups in the REPRISE trial. Although this prediction model is simplistic as it assumes that all patients progress at the same slope to ESRD, it allows for visualizing of the benefit gained by patients if treated with tolvaptan early in their disease state. Predictions in (A) may underestimate the long-term benefit because the treatment effect observed in the TEMPO 3:4 trial in patients with earlier disease was less than that observed in the REPRISE trial in patients with more advanced disease. REPRISE, Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD; TEMPO 3:4, Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes.

Figure 6.

The algorithm depicted in the Figure summarizes the recommended steps for the initiation, titration and optimization of tolvaptan treatment and the schedule of laboratory tests to monitor its safety. LFT, liver function tests; Na⁺, sodium; Q1Mo, every 1 month; Q3Mo, every 3 months.

Figure 7.

The algorithm depicted in the figure summarizes the recommendations for evaluation and management of potential drug-induced liver injury. LFT, liver function tests.