Antibiotics and Nephrotoxicity - Term Paper Example

The main cause of these symptoms appears to be the accumulation of drugs in renal cells, resulting from an endocytic receptor complex (which has the function of transporting proteins in cells) formed from megalin and tubulin (Quiros et al, 2011). Gentamicin in particular accumulates in the endosomal compartment and the endoplasmic reticulum, causing stress and unleashing a protein response throughout the cells. The destabilization that this causes destabilizes the intracellular membranes and the drug is then free to pass into the cytosol, where it can activate the apoptosis pathway (Quiros et al, 2011).

There are several other mechanisms by which antibiotics, particularly aminoglycosides, can cause nephrotoxicity. For example, high concentrations of the drug can cause cell death by causing oxidative stress in the cells (Naughton, 2008), again activating the apoptosis pathway and occasionally causing irreversible damage to renal cells. Additionally, fewer nephrotoxic effects do occur that compound the effects outlined above. For example, gentamicin has been shown to reduce renal blood flow, making it more difficult for kidneys to perform their filtration duties and thus furthering the problems caused by accumulation (Quiros et al, 2011). Additionally, there is evidence that gentamicin could cause inflammation, which would prevent pain in the patient and can affect urinary output (Naughton, 2008) – these signs may be useful when assessing a patient for potential kidney damage after a course of antibiotics.

Denamur et al (2011) completed some interesting research on the function of oxidative stress in kidney damage resulting from aminoglycoside antibiotics. This study found that gentamicin in particular accumulates in lysosomes during long courses of antibiotic therapy and that this induces apoptosis – particularly in the proximal tubular cells. Additionally, the LLC-PK1 cells in the kidney can release acridine orange from lysosomes, a pre-emptive sign of the impending apoptotic pathway. The reason for this lysosome-based damage is purported to stem from the activity of reactive oxygen species (ROS). ROS are produced in reaction to taking gentamicin (Naughton, 2008), which then causes the acridine orange release in some cells. Denamur et al (2011) also suggested that there are several ways to prevent this nephrotoxic effect from ROS, including the use of ROS antioxidant, catalase, or N-acetylcysteine.

Another way in which antibiotics can cause nephrotoxicity is through acute allergic interstitial nephritis. Ricketson, Kimel, Spence & Weird (2009) focused on a specific case of an individual showing signs of kidney damage (malaise, myalgia, fever, nausea, vomiting, polyuria, and polydipsia) after a long course of pantoprazole. Acute interstitial nephritis here is an immunological response to taking several types of drugs – mainly penicillins, cephalosporins, sulfonamides, and NSAIDS (Ra & Tobe, 2004). Geevasinga, Coleman, Webster & Roger (2004) found evidence that acute interstitial nephritis may be a result of the inhibition of proton pumps in renal cells and causing a reduction in the glomerular filtration rate. Additionally, damage may be caused simply by the fact that allergic responses can cause severe inflammation that results in damage typical of the release of histamine (Naughton, 2008).

It has been suggested that almost 70% of acute interstitial nephritis is caused by drugs, meaning that it is important to fully understand the mechanisms underlying the cause (Perazella & Markowitz, 2010). It is suggested that the cause of symptoms in patients comes from interstitial inflammation, tubulitis, edema, and interstitial fibrosis. Perazella & Markowitz provide some evidence that the presence of ROS in these cases can exacerbate the symptoms and cause mild acute interstitial nephritis to blossom into fibrosis.
Tanaka & Nangaku (2011) examined injury to the interstitium in more detail.

It is assumed that this type of damage is one of the leading precursors to end-stage renal failure. Again, the main causes of histological changes are inflammatory-related, including edema, leukocyte infiltration, tubular dilation, and atrophy. It is purported that the B-lactam antibiotics are mainly responsible for nephrotoxicity by activating an allergic response in susceptible patients. Other antibiotics can cause damage, particularly in patients with underlying tubular interstitial injury, by triggering the release of inflammatory cytokines and growth factors. Tanaka & Nangaku (2011) also found evidence that there may be an epithelial-mesenchymal transition of the tubular epithelium and eventual apoptosis, although the underlying mechanism of these results is not fully understood.

There are several ways in which the mechanisms of nephrotoxicity from antibiotics can be useful in a clinical context. Damage to or necrosis of the tubular cells of the kidney would usually present as in any other form of kidney damage, with symptoms including vomiting, nausea, myalgia, and polyuria (Lisowska-Myjak, 2010). These symptoms come from the fact that the kidney is not able to filter toxins through as effectively with damaged tubular cells and there may, therefore, be a build-up of both the original antibiotic and other toxic substances (Lisowska-Myjak, 2010). Tubular cell damage may also present as changes in serum creatinine levels and urine output and these can be measured as a way of diagnosing nephrotoxicity (Lerma, 2013). Read More