Acute renal failure mechanisms

Renal Effects. Hemorrhage of the medullary layer of the kidneys was observed in an early report of three fatal cases of acute oral poisoning with endosulfan (Terziev et al. 1974). More recent studies have reported acute renal failure after ingestion of endosulfan as a major contributing cause of death in two individuals in both cases, postmortem examination showed extensive tubular necrosis (Blanco-Coronado et al. 1992 Lo et al. 1995). Neither case discussed the possible mechanism of endosulfan-induced acute renal failure, but in one case, the authors of the report indicate that the renal lesions may relate to sepsis and shock (Blanco-Coronado et al. 1992). Ingested doses were not determined in any of these cases, and it is not totally clear that the effects observed at autopsy were a direct result of endosulfan exposure, although based on results from acute animal studies, it seems likely. 

Parathyroid hormone (PTH) produces CNS effects in normal subjects and neuropsychiatric symptoms are frequently encountered in patients with primary hyperparathyroidism, where EEG changes resemble those described in acute renal failure. Circulating PTH is not removed by hemodialysis. In uremic patients both EEG changes and neuropsychiatric symptoms are improved by either parathyroidectomy or medical suppression of PTH. The mechanism whereby PTH causes disturbances of CNS function is not well understood, but it has been suggested that increased PTH might facilitate the entry of Ca2+ into the cell resulting in cell death. 

Togel, F., Hn, Z., Weiss, K., Isaac, J., Lange, C. and Westenfelder, C. (2005) Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation independent mechanisms. Am J Physiol Renal Physiol. 289, F31-42. 

Lithium intoxication can be precipitated by the use of diuretics, particularly thiazides and metola-zone, and ACE inhibitors. NSAIDs can also precipitate lithium toxicity, mainly due to NSAID inhibition of prostaglandin-dependent renal excretion mechanisms. NSAIDs also impair renal function and cause sodium and water retention, effects which can predispose to interactions. Many case reports describe the antagonistic effects of NSAIDs on diuretics and antihypertensive drugs. The combination of triamterene and indomethacin appears particularly hazardous as it may result in acute renal failure. NSAIDs may also interfere with the beneficial effects of diuretics and ACE inhibitors in heart failure. It is not unusual to see patients whose heart failure has deteriorated in spite of increased doses of frusemide who are also concurrently taking an NSAID. 

Renal failure has a long history of treatment with protein-restricted diets. Dietary plant protein is a possible therapy mechanism for the treatment of chronic and acute renal failure. 

It remains to be clarified why patients with renal hypouricemia frequently develop acute renal failure. The following hypothesis has been proposed. Oxidative stress is essential for the onset of ischemic acute renal failure. In the kidney, uric acid acts as a protective mechanism against oxidative stress. However, in patients with renal hypouricemia, a decrease in uric acid may allow exposure of the kidney to oxidative stress, causing ALPE [152,153]. 

Blantz, R.C. (1975). The mechanism of acute renal failure after uranyl nitrate. J. Clin. Invest. 55 621-35. 

Liu KD. Molecular mechanisms of recovery from acute renal failure. Critical Care Medicine 31 5572-81, 2003. 

Nony PA and Schnellmann RG. Mechanisms of renal cell repair and regeneration after acute renal failure. The Journal of Pharmacology and Experimental Therapeutics 304 905-912, 2003. 

The mechanism of BCNU-induced nephrotoxicity is most hkely based on a direct nephrotoxic effect but differs from that of streptozotocin manifested by proximal tubular dysfunction and acute renal failure that may abate when the drug is discontinued. 

Zager RA. Studies of mechanisms and protective maneuvers in myoglobinuric acute renal failure. Lab Invest 1989 60 619-629. 

Fang HC, Lee Po-Tsang, Lu PJ, Chen CL, Chang TY, Hsu CY, Chung HM, Chou KJ. Mechanisms of star fruit-induced acute renal failure. Food ChemToxicol 2008 46 1744-1752. 

The mechanisms of ibuprofen-induced toxicity have not been clearly defined. Acute renal failure is postulated to result from decreased production of intrarenal prostaglandins via inhibition of the cyclooxygenase pathway. In turn, this will decrease the renal blood flow and glomerular filtration rate. Ibuprofen also interferes with prostaglandin synthesis in the gastrointestinal system that can contribute to its irritating effect on the mucosa of the gastrointestinal tract. 

Celiptinium is useful in the treatment of metastatic breast cancer and is useful in combination therapy because of minimal hematotoxicity. Acute and chronic renal failures have been detected in patients treated with celiptinium. Acute renal failure is dose dependent, while chronic effects appear to be cumulative in nature. The primary manifestation of celiptinium nephrotoxicity is tubular necrosis with celiptinium-induced lipid peroxidation in proximal tubular cells proposed as the mechanism of toxicity. 

S-(l,2-Dichlorovinyl)-L-cysteine (DCVC) is a model nephrotoxicant and cataractogen used to induce acute renal failure and cataracts in experimental animals to study the biochemical, physiological, and molecular mechanisms underlying the disease. 

The terminology associated with kidney diseases has been amended and is clarified here. Previously, renal failure was divided into either acute renal failure (ARF) or chronic renal failure (CRF). These terms indicate the rate at which damage occurs rather than the mechanism by which it occurs. Landmark guidelines developed in the USA by the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) attempt to evaluate, classify, and stratify CKD (see Table 45-6). The term renal has largely been replaced by Iddney when referring to chronic disease since it is better understood by patients and nonspecialists. However, acute renal failure (ARF) remains standard nomenclature along with ESRD. 

Patients at risk for SRMB include those with respiratory failure (need for mechanical ventilation for >48 hours), coagulopathy, hypotension, sepsis, hepatic failure, acute renal failure, multiple trauma, severe burns (>35% of body surface area), head injury, traumatic spinal cord injury, major surgery, or history of GI bleeding. " ""... 

Baliga R, Ueda N, Walker PD, Shah SV. Oxidant mechanisms in toxic acute renal failure. Drug Metab Rev 1999 31 971-997. 

Mechanisms of drug induced acute renal failure 5... 

The mechanisms of the changes in cell viability during renal injury are incompletely understood. Most of the experimental data have been derived from the ischemia-reperfusion model of acute renal failure and have focused on necrotic cell death. Because as many as 50% of patients have ischemia-induced acute renal failure, the observations should be relevant to a large portion of the patients at risk. Also, different stresses initiate common biochemical events, so that understanding the relevant pathways of one stress will most likely be applicable to others. What follows is a detailed analysis of some of the pathways currently thought to execute cell death in a variety of nephrotoxic insults. 

Ischemic, nephrotoxic, and septic rodent models of acute renal injury were developed to study mechanisms of acute renal failure. Decreasing renal blood flow is critical in the pathophysiology of ARF in humans. Ischemic and other animal models are used to reproduce the morphological features of human disease. 

Studies of the pathophysiology of acute renal failure has classically considered both tubular and vascular mechanisms [227,228]. In vitro techniques isolating either the vascular or tubular components have been developed. For example, the use of isolated proximal tubules in suspension or in culture allows the study of tubular mechanisms of injury in the absence of vascular factors [229] [230]. There are both in vitro and in vivo models to study vascular injury in the kidney. In vitro models include the study of vascular smooth muscle cells or endothelial cells in culture. In this section, the in vivo methods to evaluate the renal micro-circulation will be discussed. This is of relevance as many nephrotoxins exert their deleterious effects through pharmacologic actions on the resistance vasculature with parenchymal injury occurring as a consequence of ischemia. In clinical practice nephrotoxins may cause prerenal azotemia as a result of increased renal vascular resistance. Nephrotoxins that cause acute renal failure on a vascular basis include prostaglandin inhibitors e.g. aspirin, non-steroidal anti-... 

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