Serotonin (5-HT1_A-Receptor) Agonist-Induced Collecting Duct Vacuolation and Renal Papillary Necrosis in the Rat

Abstract

General anxiety in humans is treated with azaspirodecanedions, which act through a reduction of serotonin transmission. Ipsapirone also represents a serotonin (5-HT,,) receptor agonist and was under development as an anxiolytic drug. Histopathologic evaluation of animal experiments revealed cellular swelling andor vacuolation of renal papillary and medullary collecting duct (MCD) epithelium in rats but not in dogs or mice. The changes ensued already after 1 wk of dosing and were first localized in the inner MCDs. Longer treatment periods showed that these changes proceeded from proximal to distal, approaching the papillary collecting ducts. The changes were most likely the result of altered hemodynamics in the papillary tip. Swelling resulted in partial or total papillary necrosis in some cases. Furthermore, rats treated with ipsapirone showed a sharp and transient rise in urinary endothelin excretion. Concomitantly, urinary PGE, levels were elevated. In contrast, no elevated levels of endothelin were detected in urine samples of patients from a volunteer study, leading to the conclusion that the human kidney is not susceptible to the ipsapirone-induced alterations seen in the collecting ducts of rats.

Urinary Tract

“…Its incidence appears to have diminished following better control of the use of analgesics, notably phenacetin. 386 Although histological features of papillary necrosis vary with drug, dose, period of dosing and other variables, the fully developed lesion is characterized by necrosis of the tip of the renal papilla that may become completely lost (Figure 10.9). 372,373 It is characterized histologically in patients by the presence of papillary necrosis and interstitial inflammation along with capillary sclerosis which is regarded as the cause of the papillary necrosis as well as a pathognomic histological feature.…”

Successful Drug Development Despite Adverse Preclinical Findings Part 2: Examples

“…Of greatest concern are analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclo-oxygenases and therefore inhibit the formation of vasodilatory prostaglandins by papillary interstitial cells 75 . Renal papillary necrosis was reported also for tyrosine kinase inhibitors and serotonin (5-HT1A) receptor agonists 76 . Recently, renal papillary antigen (RPA-1) was proposed as biomarker to detect early renal papillary lesions in rats 77 .…”