Childhood ADPKD: Answers and more questions

Abstract

Over the past 15 years, it has become clear that autosomal-dominant polycystic kidney disease (ADPKD) (previously known as “adult polycystic kidney disease”) is an important clinical entity in the pediatric population. Indeed, 60% of children younger than 5 years of age, and 75 to 80% of children 5 to 18 years of age with a PKD-1 mutation have renal cysts detectable by ultrasound1.Gabow P. Kimberling W. Strain J. Manco-Johnson A. Utility of ultrasonography in the diagnosis of autosomal dominant polycystic kidney disease in children.J Am Soc Nephrol. 1997; 8: 105-110PubMed Google Scholar. Renal cysts in children with ADPKD have been associated with a wide clinical spectra, ranging from totally asymptomatic patients to those who present as newborns with massive renal enlargement, hypertension, oliguria, and pulmonary hypoplasia2.McDonald R.A. Watkins S.L. Avner E.D. Polycystic kidney disease.Pediatric Nephrology. Lippincott, Williams and Wilkins, Baltimore1999: 459-474Google Scholar. These latter patients may be clinically indistinguishable from those with autosomal-recessive PKD. The clinical spectrum of childhood ADPKD has largely been defined through study of the enormous clinical database of ADPKD patients at the University of Colorado Health Sciences Center3.Fick G. Duley I. Johnson A. et al.The spectrum of autosomal dominant polycystic kidney disease in children.J Am Soc Nephrol. 1994; 4: 1654-1660PubMed Google Scholar, 4.Dunbar Ivy D. Shaffer E. Johnson A. et al.Cardiovascular abnormalities in children with autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 1995; 5: 2032-2036PubMed Google Scholar, 5.Fick-Brosnahan G. Johnson A. Strain J. Gabow P. Renal asymmetry in children with autosomal dominant polycystic kidney disease.Am J Kidney Dis. 1990; 34: 639-645Abstract Full Text Full Text PDF Scopus (38) Google Scholar. This clinical database, established over 30 years ago by the late Joseph Holmes, M.D., now consists of 420 ADPKD families from which 745 affected adults and 185 affected children have been studied by the Denver Polycystic Kidney Disease Research Group. In this issue of Kidney International, Fick-Brosnahan et al have taken a critical step in bridging the descriptive phenomenology of the past to investigational strategies of the future by providing detailed longitudinal data on the rate of progression of ADPKD in childhood and delineating factors associated with disease progression6.Fick-Brosnahan G.M. Vu Tran Z. Johnson A.M. et al.Progression of autosomal-dominant polycystic kidney disease in children.Kidney Int. 2001; 59: 1654-1662Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar. Such data are critical to identify possible clinical outcome measures for interventional studies as well as high-risk groups for targeted therapeutic intervention. In their study, longitudinal mean renal volume curves were constructed from ultrasonographic renal measurements of 182 affected and 127 unaffected children. Results demonstrated that children with ADPKD had faster renal growth than unaffected children, and that severe renal enlargement at a young age and/or hypertension were risk factors for accelerated renal growth6.Fick-Brosnahan G.M. Vu Tran Z. Johnson A.M. et al.Progression of autosomal-dominant polycystic kidney disease in children.Kidney Int. 2001; 59: 1654-1662Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar. As these authors note, using the rate of renal enlargement as a marker for disease progression is clinically relevant because much of the morbidity of ADPKD [pain, hematuria, stones, hypertension, proteinuria, progression to end-stage renal disease (ESRD)] is associated with large kidneys. However, it is important to note that mean glomerular filtration rates (GFRs; calculated by the Schwartz formula) were similar in affected versus unaffected children in all age groups and did not correlate with mean renal volume. Unfortunately, only 108 of the 182 ultrasound-positive children and 67 of the 127 unaffected children reported for more than one visit. Therefore, the presented curves of “mean renal volume” are mathematical derivations of population data and cannot be used by clinicians to plot their own patients' progressive changes in renal volume. Despite these limitations, this study emphasizes an important message for clinicians treating children with ADPKD. Hypertension should be identified and aggressively treated, particularly in children under 12 years of age with more than ten renal cysts. This is consistent with data emerging from clinical studies of the adult ADPKD population7.DAVIS I.D. DELL K.M. SWEENEY W.E. AVNER E.D. Can progression of autosomal dominant or autosomal recessive polycystic kidney disease be prevented?.Semin Nephrol. 1945; (in press)Google Scholar. Like most valuable clinical studies, this current study by Fick-Brosnahan et al generates more questions than it answers. Are changes in cyst size, cyst number, and renal size more accurately determined by radiocontrast-enhanced computed tomography (CT)8.Sise C. Kusaka M. Wetzel L. et al.Volumetric determination of progression in autosomal dominant polycystic kidney disease by computed tomography.Kidney Int. 2000; 58: 2492-2501Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar or fast electron-beam CT scanning9.King B. Reed J. Bergstralh E. et al.Quantification and longitudinal trends of kidney, renal cyst, and renal parenchymal volumes in autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2000; 11: 1505-1511PubMed Google Scholar? Since progression of renal disease in patients with ADPKD has been associated with progressive interstitial fibrosis (which would be expected to limit renal growth), is renal growth less likely to correlate with disease progression at later disease stages? What is the correlation of renal growth with nonrenal manifestations of pediatric ADPKD such as cardiovascular abnormalities? Are there other clinical or laboratory parameters that can be used to monitor disease progression or response to therapy? Now that disease-specific therapies are on the horizon for children (and adults) with ADPKD7.DAVIS I.D. DELL K.M. SWEENEY W.E. AVNER E.D. Can progression of autosomal dominant or autosomal recessive polycystic kidney disease be prevented?.Semin Nephrol. 1945; (in press)Google Scholar, the answers to these and other questions will be critical in the design of future interventional studies.