CONSENSUS STATEMENT EVIDENCE-BASED GUIDELINE International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people Charlotte Gimpel 1*, Carsten Bergmann2,3, Detlef Bockenhauer 4, Luc Breysem5, Melissa A. Cadnapaphornchai6, Metin Cetiner7, Jan Dudley8, Francesco Emma9, Martin Konrad10, Tess Harris11,12, Peter C. Harris13, Jens König10, Max C. Liebau 14, Matko Marlais4, Djalila Mekahli15,16, Alison M. Metcalfe17, Jun Oh18, Ronald D. Perrone19, Manish D. Sinha20, Andrea Titieni10, Roser Torra21, Stefanie Weber22, Paul J. D. Winyard4 and Franz Schaefer23 Abstract | These recommendations were systematically developed on behalf of the Network for Early Onset Cystic Kidney Disease (NEOCYST) by an international group of experts in autosomal dominant polycystic kidney disease (ADPKD) from paediatric and adult nephrology , human genetics, paediatric radiology and ethics specialties together with patient representatives. They have been endorsed by the International Pediatric Nephrology Association (IPNA) and the European Society of Paediatric Nephrology (ESPN). For asymptomatic minors at risk of ADPKD, ongoing surveillance (repeated screening for treatable disease manifestations without diagnostic testing) or immediate diagnostic screening are equally valid clinical approaches. Ultrasonography is the current radiological method of choice for screening. Sonographic detection of one or more cysts in an at- risk child is highly suggestive of ADPKD, but a negative scan cannot rule out ADPKD in childhood. Genetic testing is recommended for infants with very-early-onset symptomatic disease and for children with a negative family history and progressive disease. Children with a positive family history and either confirmed or unknown disease status should be monitored for hypertension (preferably by ambulatory blood pressure monitoring) and albuminuria. Currently, vasopressin antagonists should not be offered routinely but off-label use can be considered in selected children. No consensus was reached on the use of statins, but mTOR inhibitors and somatostatin analogues are not recommended. Children with ADPKD should be strongly encouraged to achieve the low dietary salt intake that is recommended for all children. Autosomal dominant polycystic kidney disease ADPKD in childhood is thought to be higher than that (ADPKD) is the most common genetic disease in adults, of other severe paediatric kidney diseases such as auto- with an estimated prevalence of 1 in 500–2,500 (REFS1–4). somal recessive polycystic kidney disease (~1 in 20,000), Cyst development starts early in life, and macroscopic nephrotic syndrome (~1 in 50,000)8 or haemolytic cysts can become detectable in childhood. Substantial uraemic syndrome (~1 in 100,000 children)9. disease burden with massively enlarged kidneys or The past 25 years have seen remarkable progress in decreased glomerular filtration rate (GFR) usually does knowledge of ADPKD. Advances have been made in 5 *e- mail: charlotte.gimpel@ not occur until adulthood ; however, approximately 3% unravelling the genetic origins of the disease, in non- uniklinik- freiburg.de of children who carry ADPKD- causing mutations have invasive monitoring and in predicting disease pro- https://doi.org/10.1038/ either very- early-onset or unusually rapid progressive gression; multiple large- scale clinical trials have been s41581-019-0155-2 disease5–7. Thus, the absolute incidence of symptomatic conducted; and the first pharmacological treatment for NATURE REVIEWS | NEPHROLOGY VOLUME 15 | NOVEMBER 2019 | 713 CONSENSUS STATEMENT slowing disease progression — the vasopressin antago- The objective of this Consensus Statement is to pro- nist tolvaptan — has been licensed in the USA, Europe vide clinical guidance on counselling, diagnosing and and Japan10. However, most ADPKD studies have been monitoring children with ADPKD in light of the current performed in adults, and their results are not always evidence and a multi- stakeholder discussion of ethical easily transferable to children. issues surrounding early diagnosis and monitoring. Children with ADPKD constitute a mixed cohort of healthy individuals who may not require treatment for Methods decades (referred to here as asymptomatic patients) and The consensus process was initiated by the Network individuals who have disease manifestations, such as for Early Onset Cystic Kidney Disease (NEOCYST), hypertension, and will benefit from treatment started as which is a consortium of clinical, genetic and transla- early as possible. Few children suffer from symptomatic tional researchers devoted to the study of early- onset disease manifestations such as pain, enuresis, haematuria cystic kidney diseases11. In addition to paediatric or urinary tract or cyst infections. Both symptomatic nephrologists from the consortium, external experts and asymptomatic children are likely to be confronted in paediatric ADPKD, adult ADPKD, cystic kidney with the effects of ADPKD in older relatives and to have disease genetics, paediatric radiology and patient rep- questions or anxieties about their own future health. resentatives were invited to participate (Supplementary In addition, many children with an affected parent are information). C.G., M.C., R.D.P., R.T., J.K., M.D.S., J.K., unaware of their own disease status (referred to here as A.M.M., A.T. and D.M. prepared systematic literature at- risk children), either because diagnostic testing has reviews in advance of the consensus conference held on not been performed or because a negative ultrasonog- 1 December 2017 in Leuven, Belgium. Tabulated raphy scan does not exclude ADPKD in childhood. results of the literature reviews are included in the An important dilemma in the medical care of children Supplementary information. with ADPKD is the balance between not medicalizing Initial recommendations were developed during the currently healthy individuals and not missing treat- conference by discussion in thematic workgroups and able disease manifestations in those affected at an early plenary sessions. Evidence and recommendations were age. Medical professionals from different backgrounds, graded according to the method used in the current nurses, affected parents and at- risk children naturally American Academy of Pediatrics (AAP) guidelines12,13 have different views on where this balance lies. (Fig. 1). The grading of recommendations into strong, moderate and weak recommendations takes into account not only the quality of the evidence but also the balance Author addresses of potential benefits and harms assessed by the con- 1Division of Pediatric Nephrology, Department of General Pediatrics, Adolescent sensus group12. The preliminary results of the consen- Medicine and Neonatology, Center for Pediatrics, Medical Center–University of Freiburg, sus meeting were presented on 2 December 2017 at an Faculty of Medicine, Freiburg, Germany. international symposium on ‘Management of Polycystic 2 Department of Medicine IV, Medical Center–University of Freiburg, Faculty of Medicine, Kidney Diseases from Childhood to Adulthood’ in University of Freiburg, Freiburg, Germany. Leuven, Belgium, where 104 participants voted live and 3Center for Human Genetics, Bioscientia, Ingelheim, Germany. 4University College London, Great Ormond Street Hospital, Institute of Child Health, anonymously on the major drafted recommendations. A London, UK. first written draft was compiled by C.G. and reviewed by 5Department of Pediatric Radiology, University Hospital of Leuven, Leuven, Belgium. all members of the consensus group. Consequently, two 6Rocky Mountain Pediatric Kidney Center, Rocky Mountain Hospital for Children at rounds of anonymous voting were performed using the Presbyterian St Luke’s Medical Center, Denver, CO, USA. Delphi method until each recommendation reached at 7Department of Pediatrics II, University Hospital Essen, Essen, Germany. least 70% support. The results of the symposium votes 8Renal Department, Bristol Royal Hospital for Children, Bristol, UK. and the Delphi votes are presented in the Supplementary 9Division of Nephrology and Dialysis, Ospedale Pediatrico Bambino Gesù-IRCCS, Rome, information. Italy. The final draft of the Consensus Statement was 10Department of General Pediatrics, University Children’s Hospital, Münster, Germany. endorsed by the council of the International Pediatric 11PKD International, Geneva, Switzerland. 12PKD Charity, London, UK. Nephrology Association (IPNA) and the European 13Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA. Society of Paediatric Nephrology (ESPN) after thor- 14Department of Pediatrics and Center for Molecular Medicine Cologne, University of ough review by members of the ESPN Workgroup for Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. inherited kidney diseases. The manuscript was also 15Department of Pediatric Nephrology, University Hospital of Leuven, Leuven, Belgium. reviewed by ADPKD experts from the European Rare 16PKD Research Group, Laboratory of Pediatrics, Department of Development and Kidney Disease Reference Network (ERKNet), whose Regeneration, GPURE, KU Leuven, Leuven, Belgium. helpful comments were incorporated. Suggestions 17Faculty of Health and Wellbeing, Sheffield Hallam University, Sheffield, UK. for further research are listed in the Supplementary 18 Department of Pediatrics, University Medical Center Hamburg–Eppendorf, Hamburg, information. Germany. 19 Division of