Nephrotoxicity kidney injury

Serum creatinine and BUN, the most common indicators of renal function used in both clinical and preclinical safety laboratory panels, are relatively insensitive markers of injury, particularly for the renal tubules. Urinary measurements of alanine aminopeptidase and A-acetyl-beta-D-glucosaminidase and kidney injury molecule-1 (KIM-1) can provide much more sensitivity when nephrotoxicity is a potential safety concern [28,29], These are also suitable for safety monitoring in early-phase human trials if preclinical studies validate such use to monitor product nephrotoxicity. 

The array of industrial chemicals, negligence during use, and the long-term health consequences need to be understood by workers. The rational understanding of the mechanism of nephrotoxicity in animals and man provides the basis for safe use. Reports of Kluwe et al. and Porter and Bennett indicate the type of adverse health effects vis-a-vis nephrotoxicity caused by aminoglycosides, halogenated hydrocarbons and aromatic amines produce chronic kidney injury in humans and species of mammals. 

Hemodynamically mediated nephrotoxicity intrinsic acute kidney injury... 

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 kidney injury and have focused on necrotic cell death. Because as many as 50% of patients have ischemia-induced acute kidney injury, 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 apphcable 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. 

ATP depletion, cation shifts and oxygen-derived free radical injury Site of renal ischemia-reperfusion injury A link between proximal and distal tubular injury and recovery Tubuloglomerular feedback and autoregulation Endothelin in ischemia-reperfusion injury Treatment of ischemic acute kidney injury Nephrotoxic injury Cyclosporine... 

A major difficulty in interpreting in vivo studies of nephrotoxic acute kidney injury in whole animals is the amount and localization of nephrotoxin uptake by the kidney. It may be difficult to ascertain whether a given... 

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

Tune BM., Fravert D, Hsu C-Y. Thienamycin nephrotoxicity. Mitochondrial injury and oxidative effects of imipenem in the rabbit kidney. Biochem Pharmacol 1989 38(21) 3779-3783. 

Treatment of sulfadiazine nephrotoxicity consists in stopping sulfadiazine or decreasing its dosage. The acute kidney injury, however, may resolve despite continuation of the treatment [41]. Hydration and especially alkalinization are the basis for the treatment. Urinary tract obstruction may require placement of ureteral stents [13] or nephrostomy [33]. This complication is essentially reversible and dialysis is rarely needed [27]. 

Antoniskis et al reported four cases of reversible acute kidney injury in patient with AIDS who received both intravenous pentamidine (for PCP) and amphotericin B (for systemic mycoses). Of note, nephrotoxicity did not develop in three AIDS patients treated with both TMP-SMZ and amphotericin B or in two patients who concomitantly received inhaled pentamidine and amphotericin B [160]. Reports of renal damage in patients receiving parenteral pentamidine for the treatment of non-HIV diseases continue. Reversible acute kidney injury and nephrotic syndrome were documented in a young child given pentamidine mesylate and an antimonial salt for the treatment of visceral leishmaniasis [161]. In Africa (Kenya) patients with visceral leishmaniasis have developed renal toxicity during prolonged treatment (1 to 10 months) with pentamidine [162]. 

In summary, parenteral pentamidine administration for the treatment of PCP can be associated with the development of usually mild, reversible acute kidney injury. Compounding risk factors, of which volume depletion is the most important, are found in the majority of cases of pentamidine nephrotoxicity. There is no convincing evidence that the aerosol route of pentamidine administration for PCP prophylaxis results in nephrotoxicity. Hypocalcemia and hypomagnesemia with renal magnesium wasting, and particularly, hyperkalemia are seen with pentamidine therapy. 

Acute kidney injury can be severe with foscarnet. Some degree of kidney injury has been reported to occur in as many as two-thirds of patients treated with foscarnet and has been a dose-limiting toxicity in 10-20% of cases [51-56]. Despite dose reduction or discontinuation of foscarnet, azotemia typically progresses for at least a few days before resolving. It may be possible to continue foscarnet at reduced doses in some patients with mild azotemia. Foscarnet-induced AKI is usually reversible, although temporary dialysis may be required [57]. Recovery may be slow, particularly in patients with preexisting kidney insufficiency. Elevated serum creatinine concentrations may persist for several months after discontinuation of foscarnet. Foscarnet nephrotoxicity may be also associated with mild proteinuria. Volume expansion with isotonic saline was effective in reducing the incidence of foscarnet nephrotoxicity to 13%, compared to 66% in non-hydrated historical controls, and allowed patients with prior kidney insufficiency to receive foscarnet without further reduction of kidney function [54, 58]. Intermittent, rather than continuous, infusion of foscarnet may also reduce the incidence of nephrotoxicity [52]. 

Other protease inhibitors have also been rarely associated with kidney injury. A single case of interstitial nephritis and reversible AKI in a patient treated with atazanavir has also been reported [153] Acute kidney injury attributed to ritonavir has been reported in several patients [154-157], the majority of whom were receiving concomitant nephrotoxic medications, while others had preexisting kidney disease or were volume depleted. In several patients, AKI recurred upon ritonavir rechallenge. Kidney biopsies were not performed, so histopathologic correlates and etiology of kidney injury were not precisely defined. 

There are four potential clinical presentations for acute CSA nephrotoxicity asymptomatic increases in serum creatinine (SCr) without overt renal dysfunction, acute kidney injury, delayed graft function after renal transplantation and recurrent or de novo hemolytic uremic syndrome (Table 2). 

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