Toxic factors in human urine that injure urothelium

Abstract

Loss of the lower urinary permeability barrier and passive potassium cycling into tissue are an initiating event in interstitial cystitis. We tested whether a low molecular weight cytotoxic fraction from normal urine causes sensitivity to intravesical potassium in rats and whether the sulfated anionic polysaccharide pentosan polysulfate can neutralize this fraction's cytotoxic activity. A low molecular weight (> 100 < 3500) toxic urinary fraction was prepared from normal human urine by dialysis and the lyophilized, salt free product (toxic factor) further investigated. Anaesthetized adult male Sprague-Dawley rats received intravesical sodium or potassium, and urodynamic parameters, including number of voids and non-voiding contractions, were recorded. Then protamine sulfate, rehydrated toxic factor, or toxic factor plus pentosan polysulfate was infused, followed by potassium, and urodynamic measurements repeated. The toxic factor was evaluated in a commercial cytotoxicity protocol using cultured rat urothelial cells. Rat bladder non-voiding contractions increased markedly over baseline when potassium was infused after toxic factor (1.681 +/- 0.1131 non-voiding contractions/min; P = 0.0004) but not after toxic factor premixed with pentosan polysulfate. Toxic factor had a significant (P < 0.001) cytotoxic effect in cultured rat bladder epithelial cells; toxic factor plus pentosan polysulfate was significantly less cytotoxic than toxic factor alone (P < 0.007). Normal urine contains a cationic cytotoxic factor that increases urothelial permeability by injuring the mucosa, allowing potassium to penetrate the urothelium and depolarize the underlying nerves and muscles. Pentosan polysulfate neutralizes the toxic factor, attenuates urothelial damage, and suppresses potassium-mediated bladder hyperactivity.