Renal Papillary Necrosis—40 Years On

Abstract

Analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) are well recognized as a major class of therapeutic agent that causes renal papillary necrosis (RPN). Over the last decade a broad spectrum of other therapeutic agents and many chemicals have also been rcportcd that have the potential to cause this lesion in animals and man. There is consensus that RPN is the primary lesion that can progress to cortical degeneration; and it is only at this stage that the lesion is easily diagnoscd. In the absence of sensitive and selective noninvasive biomarkers of RPN there is still no clear indication of which compound, under what circumstances, has the greatest potential to cause this lesion in man. Attempts to mimic RPN in rodents using analgesics and NSAIDs have not provided robust models of the lesion. Thus, much of the research has concentrated on those compounds that cause an acute or subacute RPN as the basis by which to study the pathogenesis of the lesion. Based on the mechanistic understanding gleaned from these model compounds it has been possible to transpose an understanding of the underlying processes to the analgesics and NSAIDs. The mechanism of RPN is still controversial. There are data that support microvascular changes and local ischemic injury as the underlying cause. Alternatively, several model papillotoxins, some analgesics, and NSAIDs target selectively for the medullary interstitial cells, which is the earliest reported aberration, after which there are a series of degenerative processes affecting other renal cell types. Many papillotoxins have the potential to undergo prostaglandin hydroperoxidase-mediated metabolic activation, specifically in the renal medullary interstitial cells. These reactive intermediates, in the presence of large quantities of polyunsaturated lipid droplets, result in localized and selective injury of the medullary interstitial cells. These highly differentiated cells do not repair, and it is generally accepted that continuing insult to these cells will result in their progressive erosion. The loss of these cells is thought to be central to the degenerative cascade that affects the cortex. There is still a need to understand better the primary mechanism and the secondary consequences of RPN so that the risk of chemical agents in use and novel molecules can be fully assessed.

Cells adapted to high NaCl have many DNA breaks and impaired DNA repair both in cell culture and in vivo

“…Is activation of proliferation dangerous for the cells? Excessive ingestion of nonsteroidal analgesic drugs (NSAIDs) damages inner medullas (33). Early passage rat inner medullary cells exposed to a high level of NaCl and urea, similar to that in vivo, grow slowly.…”

Renal Papillary Necrosis

“…It is more common in women than men. This probably re ects a physiologi c difference, because female rats are more susceptible to the disease (1,4,5).…”

“…However, in the presence of volume depletion (for example, due to diuretics or congestive heart failure), underlying renal disease, or long-term analgesic abuse, RPN may occur (10,11). The incidence and/or severity of RPN has been shown to increase when analgesics are taken in combination, or when a patient is dehydrated (1).…”

“…Renal papillary necrosis can be dif cult to diagnose with radiology if the necrosed papilla remains in place, but the use of computerized tomography and ultrasound has increased diagnostic sensitivity (1). Magnetic resonance microscopy has been used experimentally but it is technically dif cult (1,13).…”

“…One possible mechanism is a direct toxic effect on cells in the medulla. The initial target in analgesic nephropathy may be the medullary interstitial cell, as previously mentioned (1,14,19). Toxic effects to the interstitial cells could come about from reactive intermediates, acetylation of critical cellular proteins, or inhibition of cellular functions (8,20).…”