Renal papillary injury

Axelsen, R.A. (1978) Experimental renal papillary necrosis in the rat the selective vulnerability of medullary structures to injury. Virchows Arch. A. Pathol. Anal, 381,79-84... 

Small numbers of lipid droplets (representing neutral lipid, lipoprotein or phospholipid) are considered normal in dogs, cats, mice and humans (Gross et al. 1991 Streather et al. 1993 Finco 1997). Increased excretion of lipid droplets (which may cause increased urine turbidity) may indicate glomerular injury (de Mendoza et al. 1976 Gherardi and Calandra 1982). Increased urinary phospholipid excretion (confirmed by thin layer chromatography) may indicate early papillary injury/renal papillary necrosis in rodents (Thanh etal. 2001). 

The timing of the urine collections is a critical factor in detecting renal injury. Tubular necrosis is an event more likely to occur early in a study, and therefore urine samples are best taken during this early period, whereas renal papillary necrosis is more likely to occur in a later part of a study (Heywood 1981). In some acute cardiac toxic events, the cardiac biomarkers increase within a few hours of injury, so sampling needs to be timed within this window because later samples may not show elevations of these biomarkers. 

Long-term administration of NSAIDs can result in renal papillary necrosis and other renal injury. Diclofenac should be used with caution in patients at greatest risk, including the elderly, those with impaired renal function, heart failure, liver dysfunction, and those taking diuretics and ACE inhibitors. 

Renal papillary necrosis and other renal injury with long-term use. Most of the unwanted renal side effects of the class of NSAIDs are related to the inhibi-ton of prostanoid synthesis. The COX-2 enzyme has been implicated as a mediator of renal blood flow, renin release and sodium excretion. As a result, COX-2 inhibitors may lead to an alteration of renal homeostasis resulting in decreases in glomerular filtration rate, renal blood flow, sodium and water retention, and hyperkalemia [1]. 

The papilla is the smallest anatomical portion of the kidney. Papillary tissue consists primarily of terminal portions of the collecting duct system and the vasa recta. Papillary blood flow is low relative to cortex and medulla less than 1% of total renal blood flow reaches the papilla. However, tubular fluid is maximally concentrated and the volume of luminal fluid is maximally reduced within the papilla. Potential toxicants trapped in tubular lumens may attain extremely high concentrations within the papilla during the process of urinary concentration. High intraluminal concentrations of potential toxicants may result in diffusion of these chemicals into papillary tubular epithelial and/or interstitial cells, leading to cellular injury. 

In the Wistar rat model, the daily administration of 10 mg per kg body weight of AA induced, after 35 days, renal failure wifh interstitial fibrosis (Figure 2) as well as a papillary urothehal cardnoma of the pelvis in some animals [63,64]. Nephrotoxidty of different components of AA was also studied in three strains of inbred male mice. The C3H/He mice intraperitoneaUy injected with 2.5 mg/Kg of AA, five days a week, for 2 weeks, developed on day 14 foci of proximal tubule injury surrounded by mononuclear cell infiltration. Two weeks later, signs of proximal tubule cell prohf-eration were observed whereas the inflammatory ceUs infiltration became more severe and interstitial fibrosis occurred [65]. In this mice model, AAI exhibited a higher nephrotoxidty than AAII [65], which was also confirmed in in vitro studies on proximal tubular LLC-PKl ceUs line [66]. 

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