Tolvaptan for Autosomal Dominant Polycystic Kidney Disease in Children: Why, Who, and When?

Although autosomal dominant polycystic kidney disease (ADPKD) typically does not cause kidney function decline until adulthood, cyst initiation can occur early in kidney development and cysts continue to grow and multiply throughout the lifetime.¹ With more widespread use of pediatric imaging and greater attention to hypertension screening, an increasing proportion of patients are diagnosed with ADPKD in childhood. Although many of these children will remain asymptomatic, pediatric clinical manifestations can include hypertension, glomerular hyperfiltration, enuresis resulting from urinary concentrating defect, urinary tract infection, and cyst hemorrhage or infection.^1,2 In addition, a small subset of patients present either prenatally or in infancy as very-early-onset ADPKD and may have a more severe and rapidly progressive course.³ Given this greater awareness of early disease burden, pediatric nephrologists have naturally asked the question of whether early initiation of disease-modifying therapy could prolong kidney survival.

The landscape of adult ADPKD care has changed in recent years following the approval of tolvaptan to slow kidney function decline.⁴ In adults with rapidly progressive ADPKD, defined by the Mayo imaging classification⁵ on the basis of age and height-adjusted total kidney volume (htTKV), extrapolations from the TEMPO 3:4 trial⁶ estimate that tolvaptan could delay kidney failure by about 7 years in patients with normal baseline eGFR⁴ (Figure 1). Could kidney failure be delayed even further by starting tolvaptan during childhood?

Figure 1.

Estimations of the benefit of tolvaptan in delaying kidney failure. Extrapolations from the TEMPO 3:4 (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes) trial allow estimations of the potential benefit of tolvaptan treatment in delaying the need of KRT depending on the eGFR at baseline. 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 TEMPO 3:4 trial. Adapted from ref. 4, with permission.

In this issue of CJASN, Mekahli et al.⁷ take an important first step toward answering this question. They report results from the 1-year double-blind portion of a phase 3b, randomized, placebo-controlled trial of tolvaptan in 91 children aged 4–17 years (EudraCT no.: 2016-000187-42; ClinicalTrials.gov identifier: NCT02964273), with primary end points focused on pharmacodynamic activity and secondary end points focused on kidney volume, eGFR, safety/tolerability, and quality of life. This trial will continue for an additional 2 years in an open-label extension.

Mekahli et al.⁷ report that children in the tolvaptan arm had a greater reduction in urine osmolality and specific gravity after 1 week than those in the placebo arm, confirming pharmacodynamic activity of tolvaptan. In children aged 12–17 years who completed MRI at baseline and 12 months, htTKV increased by 2.6% with tolvaptan and 5.8% with placebo, a difference that was not statistically significant. In the entire study population, change in eGFR from week 1 to month 12 was 1.9 ml/min per 1.73 m² with tolvaptan and −1.8 ml/min per 1.73 m² with placebo, a difference that was also not statistically significant and whose clinical significance is difficult to assess in the context of normal baseline eGFR.

As expected, children in the tolvaptan arm reported a significantly higher incidence of aquaretic side effects such as thirst, polydipsia, and polyuria (65%) compared with children in the placebo arm (16%). In the subset of patients in whom it was recorded, mean 24-hour urine volumes were substantially higher in the tolvaptan arm (approximately 7 L) than the placebo arm (approximately 2.5 L). Despite this, only one participant in the tolvaptan arm discontinued treatment due to urinary frequency, and overall drug/study discontinuation rates and measures of quality of life and fatigue were similar between tolvaptan and placebo arms. Reassuringly, none of the participants had clinically significant changes in serum sodium. Four participants in the tolvaptan arm had clinically significant increases in serum creatinine, but this resolved in all cases. Notably, none of the tolvaptan-treated participants experienced liver toxicity, an important adverse event that had been reported in 4%–6% of patients in adult trials and necessitated a risk evaluation and mitigation strategy of regular liver function testing for adults who are prescribed tolvaptan.⁴ There were no significant differences between tolvaptan and placebo arms in linear growth or pubertal progression; however, a 1-year trial is likely too brief to fully assess these effects.

Overall, this study provides important initial data to confirm the pharmacologic activity of tolvaptan in children with ADPKD, as well as its dosing feasibility and tolerability. Although this study has neither sufficient power nor duration to allow assessment of efficacy on the basis of htTKV and eGFR, these initial results support additional evaluation of the long-term effects of tolvaptan on ADPKD progression in children. The ongoing 2-year open-label extension phase of this trial should provide additional data regarding safety, tolerability, and efficacy.

In the future, if larger studies of tolvaptan eventually show it to be safe and effective to slow ADPKD progression in children, two key questions will need to be answered before its use could be considered in clinical practice: Which children would benefit from tolvaptan therapy, and when should therapy be initiated?

Given its side effect profile, tolvaptan use in adults is currently recommended only for patients at high risk of rapid ADPKD progression, namely those who fall into Mayo class 1C, 1D, or 1E. The existence of a risk stratification system such as the Mayo classification is the result of many years of work through rigorous long-term observational studies such as the Consortium for Radiologic Imaging Studies of PKD (CRISP),⁸ which established the link between htTKV and eGFR decline. Unfortunately, we do not yet have similar predictive models in children to identify key risk factors for rapid ADPKD progression. Although htTKV increases over time in children with ADPKD,⁹ the link between htTKV in childhood and long-term kidney survival has not yet been established. The importance of other progression risk factors in children will also need to be clarified, such as mutation type (PKD1 versus PKD2, truncating versus nontruncating), age at presentation, htTKV, and presence of symptoms such as hypertension, hyperfiltration, or proteinuria.³ Larger, long-term imaging studies and observational cohorts will be needed to establish predictors of rapid ADPKD progression in children and eventually inform patient selection for tolvaptan therapy.

The other key consideration will be tolvaptan's safety for long-term use across the pediatric age spectrum. Although we hypothesize that earlier initiation of tolvaptan could confer benefits for long-term kidney survival in ADPKD, treatment of children must account for unique safety concerns during growth and development. Children are especially vulnerable to the risks of profound aquaresis, as evidenced by clinical complications seen in children with nephrogenic diabetes insipidus including hypernatremia, impaired growth, and urologic complications.¹⁰ These risks may be magnified in very young children, so it is likely that criteria for prescribing tolvaptan will need to be increasingly stringent at younger ages. Additional real-world considerations for tolvaptan in children and adolescents will include potential effects on school and sports participation and social functioning. The timing of treatment initiation will therefore require careful balancing of patient-specific risks of ADPKD progression and medication side effects.

In conclusion, as ADPKD is increasingly recognized as a pediatric-onset disorder, more and more patients, families, and providers will be interested in the option of initiating treatment during childhood to prolong kidney survival. Whether tolvaptan will become the first approved disease-modifying agent for children with ADPKD remains to be seen. Important prerequisites for clinical use of tolvaptan in children will include development of robust predictive models to identify children most likely to benefit from disease-modifying therapy and careful assessment of risks of side effects.

Disclosures

E.A. Hartung reports having advisory or leadership roles for Polycystic Kidney Disease Foundation—Scientific Advisory Committee and PKD in Children Council/ARPKD Task Force, serving as a member of the American Society of Pediatric Nephrology, and serving as a Nephrology Subboard Member of the American Board of Pediatrics.

Funding

Institute of Diabetes and Digestive and Kidney Diseases grants P50DK114786, R03DK127132, and U01DK066174. PKD Foundation grant 826362.

Author Contributions

E.A. Hartung conceptualized the study, wrote the original draft, and reviewed and edited the manuscript.