Nephrotic syndrome associated with N-hydroxyureas, inhibitors of 5-lipoxygenase

Abstract

The N-hydroxyurea derivatives 70C ((E)-N-{3-[3-(4-fluorophenoxy)phenyl]-1-(R,S)-methylprop-2-enyl}-N-hydroxyurea) and its (R) 225C and (S) 404C enantiomers, which were being developed as 5-lipoxygenase inhibitors for the treatment of certain allergic and inflammatory conditions, were found to cause severe glomerulonephropathy in the rat. The lesion appeared to be of greater severity in female rats compared with male rats. In addition, 70C and 225C treated animals appeared more severely affected than 404C treated animals. Detailed examination of the lesion in animals dosed with 225C showed that there was a clear relationship between the onset of the lesion and the dose given, i.e. the higher the dose the sooner the lesion developed. The earliest changes detected in the kidney by transmission electron microscopy were noted in the glomeruli, in which the visceral cells appeared enlarged and showed varying degrees of foot process loss. In the more advanced lesion, the degree of foot process loss became more obvious and changes in the kidney tubules were seen by light microscopy. The morphological changes were mirrored by a dose-related increase in water consumption, an increased kidney to body weight ratio and gastrointestinal oedema, suggesting impaired renal function. Shortly after the onset of foot process loss, decreases in the total plasma protein and albumin and increases in the plasma cholesterol, triglycerides, urea and creatinine were recorded. These changes, particularly the foot-process loss, together with increased proteinuria, hypoalbuminaemia, hypercholesterolaemia and lipaemia, are all characteristic of “minimal change nephrotic syndrome”. Because of the serious nature of the kidney lesion caused by these N-hydroxyureas in the rat, it was considered that it precluded their development as therapeutic agents for use in man.