Combination treatment of PKD utilizing dual inhibition of EGF-receptor activity and ligand bioavailability

Kidney Int. 2003 Oct;64(4):1310-9. doi: 10.1046/j.1523-1755.2003.00232.x.


Background: We have previously demonstrated an essential role for increased epidermal growth factor receptor (EGFR) activity in mediating renal cyst formation and biliary ductal ectasia (BDE) in murine models of autosomal-recessive polycystic kidney disease (ARPKD) such as the BPK mouse. The current study was designed to determine (1). if treatment with a second-generation inhibitor of EGFR tyrosine kinase activity, EKB-569, was effective in treatment of ARPKD; (2). if tyrosine kinase inhibitor therapy used in combination with pharmacologic reduction of the availability of transforming growth factor-alpha (TGF-alpha), using WTACE2, could provide improved therapeutic efficacy and/or decrease potential toxicity; and (3). if effectiveness of treatment could be monitored noninvasively in murine ARPKD models by use of serial ultrasonography.

Methods: BPK litters were treated with EKB-569 by intraperitoneal injection from postnatal day 7 to postnatal day 21. EKB-569's effectiveness alone or in combination with WTACE2 was measured by reduction in kidney weight/body weight ratios, morphometric renal cystic index, and evaluation of renal function. Renal ultrasound was performed on normal and cystic animals, under different therapeutic regimens, utilizing a 15 mHz linear array transducer, and ultrasound data were compared with histology and renal functional data.

Results: Treatment of BPK mice with EKB-569 alone resulted in a marked reduction of kidney weight/body weight ratios, dramatically reduced collecting tubule cystic index, as well as BDE, and improved renal function. The combined treatment with EKB-569 and WTACE2 permitted a 67% reduction in EKB-569 dosage necessary to achieve results equivalent to those produced with EKB-569 alone. Untreated cystic animals died of renal failure, on average, at postnatal day 24 with a collecting tubule cystic index of 4.8, significant BDE, and maximal urine osmolarity of 361 mOsm. Cystic animals treated with EKB-569 and WTACE2 to postnatal day 21 were alive and well with normal renal function, a reduced collecting tubule cystic index of 1.7 (P < 0.02), improvement in BDE, and a threefold increase in maximum urinary concentrating ability (P < 0.01). Renal ultrasound could reliably detect cystic kidneys as early as postnatal day 7 and the natural history as well as effects of therapeutic intervention were clearly delineated by ultrasound evaluation.

Conclusion: This study demonstrates that in murine ARPKD (1). EKB-569 is as effective as first-generation EGFR tyrosine kinase inhibitors in reducing cyst formation and preserving renal function; (2). combination therapy with EKB-569 and WTACE2 provides maximum efficacy in improving renal and biliary abnormalities, at lower doses, thereby minimizing potential toxicity; and (3). renal ultrasound provides a simple, reliable, noninvasive method of following natural history and effect of treatment regimens.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aminoquinolines
  • Aniline Compounds
  • Animals
  • Biological Availability
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • ErbB Receptors / antagonists & inhibitors*
  • Hydroxamic Acids / administration & dosage
  • Hydroxamic Acids / adverse effects
  • Hydroxamic Acids / therapeutic use*
  • Hydroxamic Acids / toxicity
  • Kidney / diagnostic imaging
  • Kidney / drug effects
  • Kidney / pathology
  • Ligands
  • Mice
  • Mice, Inbred BALB C
  • Organic Chemicals / administration & dosage
  • Organic Chemicals / adverse effects
  • Organic Chemicals / therapeutic use*
  • Organic Chemicals / toxicity
  • Polycystic Kidney, Autosomal Recessive / diagnostic imaging
  • Polycystic Kidney, Autosomal Recessive / drug therapy*
  • Polycystic Kidney, Autosomal Recessive / pathology
  • Sulfonamides / administration & dosage
  • Sulfonamides / adverse effects
  • Sulfonamides / therapeutic use*
  • Sulfonamides / toxicity
  • Ultrasonography


  • Aminoquinolines
  • Aniline Compounds
  • Hydroxamic Acids
  • Ligands
  • Organic Chemicals
  • Sulfonamides
  • WTACE2 compound
  • ErbB Receptors
  • EKB 569