Antibiotics and Acute Renal Failure

Caitriona M. Matthews, DVM; Melinda S. Camus, DVM; Bruce E. LeRoy, DVM, DACVP, PhD

Department of Medicine, College of Veterinary Medicine, University of Georgia (Matthews) and the Department of Pathology (Camus, LeRoy), College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388

Introduction

The primary antibiotics linked to acute renal failure in humans and animals include: aminoglycosides, beta lactams (cephalosporins, penicillins, penems), rifampin, vancomycin, sulfonamides, fluoroquinolones, and tetracylines. Aminoglycosides and beta lactams predominate the literature regarding nephrotoxicosis. Research indicates that aminoglycosides cause renal failure primarily through proximal tubular necrosis and beta lactams initiate both acute tubulointerstitial nephritis and proximal tubular necrosis. (Tune, 1990) Since the proximal tubules are responsible for reabsorbing glucose, sodium, chloride, amino acids and calcium from glomerular ultrafiltrate, inadequate uptake can cause severe electrolyte disturbances and abnormal kidney function. The focus of this report is to describe the pathophysiology of acute renal failure, to characterize the clinicopathologic findings associated with acute renal failure, to review case reports of antibiotic induced nephrotoxicity, to discuss when to avoid potentially nephrotoxic antibiotics, and to suggest alternative treatment options that will reduce the possibility of acute renal failure.

Renal Physiology Review

Renal function consists of three primary goals: filtration, absorption, and secretion. The glomerulus is responsible for blood filtration and the principal function of the proximal tubules is absorption. Sixty percent of all reabsorption of the filtered solute occurs in the proximal tubules, which are located near peritubular capillaries. Movement of solute into the bloodstream occurs through either active or passive transport mechanisms.

Paracellular transport is a passive transport mechanism. Solutes are directed toward the zona occludens (connecting permeable structure between two proximal tubule cells) and then enter the lateral intercellular space which communicates with the interstitial fluid. From the interstitial fluid, solutes are reabsorbed into the bloodstream via the peritubular capillaries.

Transcellular transport involves carrier mediated transport of solutes from the brush border into the interstitial space and then to the peritubular capillary. Transcelluar transport is primarily driven by the active transport of sodium via the Na/K ATPase pump. Normally, the pump moves sodium ions out of the tubular cell and potassium ions into the cell. An electrochemical gradient is created when potassium moves out of the cell through potassium channels which encourages the movement of sodium into the cell. Solutes including glucose, amino acids, phosphate, sulfate, and organic ions are coupled with sodium and co-transported from the tubular lumen to the interstitial space, also through this mechanism.

Pathophysiology of Acute Renal Failure

Disruption of the active and passive reabsorption function of the proximal tubules in acute renal failure creates significant electrolyte abnormalities which are potentially fatal.  A primary cause of intrinsic renal failure involves nephrotoxicity due to exogenous toxins, such as antimicrobials. Aminoglycoside and beta lactam administration can result in renal dysfunction through four mechanisms including: reduced renal blood flow/renal artery vasoconstriction, intratubular obstruction, filtrate back leak, and decreased glomerular permeability. (Ettinger, 2005)

Reduction of renal blood flow and vasoconstriction develops during toxic insults to the kidney through catecholamine release, upregulation of the renin-angiotensin system, and release of vasoactive agents. Intratubular obstruction occurs due to antibiotic precipitate formation or desquamation of the tubular epithelial cells caused by antibiotic-induced damage. Damaged proximal tubular epithelium allows back leak of ultrafiltrate, which further contributes to the developing uremia. Finally, acute renal failure can cause damage to the podocytes associated with the glomerulus resulting in decreased glomerular permeability. (Ettinger, 2005)

Clinicopathologic Findings of Acute Renal Failure

1. Hyperkalemia
Hyperkalemia is present in early acute renal failure due to impaired excretory function. The ratio of potassium inside the cell to outside the cell decreases, causing a decrease in the transmembrane potassium gradient, and thus partial depolarization of the cells. Cardiovascular and systemic effects occur including bradycardia, resulting in potential cardiac arrest, in addition to weakness and flaccid muscle paralysis.

2. Sodium alterations
Alterations in sodium depend on the amount of urine production. With polyuric renal failure, patients are typically hyponatremic, as they are not adequately resorbing sodium at the tubular level. Patients with oliguric/anuric acute renal failure present with hypernatremia due to decreased glomerular filtration rate. Hypernatremia can also develop after treatment with intravenous fluids containing sodium.

3. Hyperphosphatemia
Hyperphosphatemia is a normal finding in acute renal failure due to decreased glomerular filtration rate.

4. Acid-base disturbances: Metabolic acidosis and high anion gap
Acute renal failure results in excess uremic acids as the products of protein metabolism are unable to be adequately excreted. Bicarbonate ions buffer by converting to salts of the excess organic acids. The decrease in bicarbonate along with the increase in unmeasured ions (uremic acids) results in metabolic acidosis. The anion gap is elevated due to the presence of uremic acids.  (Duncan and Prasse, 2003)

5. Inadequate urine production
Oliguria, defined as <0.5-1.0ml/kg/day of urine, is a common finding with drug induced renal toxicity. Approximately 1/3 of dogs with acute renal failure, however develop anuria and 1/3 are non-oliguric.   Of those patients that develop oliguria or anuria, glomerular filtration rate is decreased through four mechanisms: reduced renal blood flow/renal artery vasoconstriction, intratubular obstruction, filtrate back leak and decreased glomerular permeability. As the kidneys fail, vasoconstriction occurs in an attempt to redirect the renal blood flow from the medulla to the cortex to facilitate an appropriate glomerular filtration rate. Intratubular obstruction occurs as antibiotic precipitates accumulate in the tubular epithelial cells and cause tubular necrosis and sloughing. Filtrate back leak is a result of ultrafiltrate moving back through damaged tubular epithelium, thus decreasing urine output. Finally, decreased glomerular permeability is caused by disruption to the normal glomerular podocyte architecture. (Ettinger, 2005)

6. Azotemia
Progressive azotemia indicates acute renal failure. Azotemia refers to an increase in serum creatinine and/or blood urea nitrogen. Serum creatinine levels increase first in a patient with acute renal failure, due to decreased GFR. Since creatinine is typically completely excreted via the urinary tract as ultrafiltrate, with no tubular resorption and minimal tubular secretion, it is a more specific indicator of renal disease. Urea is primarily reabsorbed in the proximal tubules. A patient with acute renal failure has a significant decrease in functional nephrons and, therefore, GFR, which results in accumulation of urea in the blood.

7. Hematuria
Damage to proximal tubule cells allows escape of blood cells into the ultrafiltrate.

8. Enzymuria
Measuring tubular epithelial enzymes in urine can be good indicator of early renal disease. The enzymes most commonly measured are GGT (gamma-glutamyl transpeptidase) and NAG (N-acetyl-beta-D-glucosaminidase). Increased levels of either of these enzymes indicate renal tubular cellular leakage, which corresponds to tubular injury.

9. Cylinduria
Granular casts are the primary type of cast in acute renal failure patients which result from acute tubular epithelial cell shedding secondary to necrosis. (Gonzalez, 1998)

10. Isosthenuria
Proximal tubule necrosis and tubulointerstitial nephritis prevent the renal tubules from diluting or concentrating the urine. The specific gravity of the ultrafiltrate, therefore remains similar to the specific gravity of plasma.

Aminoglycoside Toxicity

Aminoglycoside antibiotics are the most common cause of drug-induced nephrotoxicity in both humans and animals. Aminoglycosides include drugs such as gentamycin, neomycin, streptomycin, tobramycin, paromomycin and amikacin. Aminoglycosides collect in the proximal renal tubular cells where they damage mitochondria, ribosomes, and other intracellular components. The exact mechanism of how acute renal failure develops is not completely understood. However, aminoglycosides appear to cause acute proximal tubular necrosis due to drug accumulation and interaction with the tubular epithelium.  (Porter, 1981)  Indications of aminoglycoside nephrotoxicity include elevated serum blood urea nitrogen and creatinine levels, polyuria, proteinuria, cylinduria, hypomagnesemia, hypocalcemia, and increased fractional sodium excretion. Several conditions that predispose an animal to aminoglycoside nephrotoxicity include advanced age, concurrent exposure to other nephrotoxins, aciduria, acidosis, dehydration and hypovolemia, severe sepsis or endotoxemia, and compromised renal function.

Gentamicin is one of the most commonly utilized aminoglycosides. Nephrotoxicity has been reported in humans, dogs and rats.  However this occurs primarily in patients with pre-existing renal dysfunction (Hirsch, 1974) or with concurrent administration of other nephrotoxic drugs or vascular disease (Dovas, S. et al 2008). In one case report, a four year old cat, developed acute renal failure after gentamycin was used to lavage an open wound infected with Pseudomonas spp. (Mealey, Boothe 1994)

Paromomycin is a common aminoglycoside used in the treatment of Cryptosporidium in cats. There have been reports of four cats with infectious enteritis developing renal failure after treatment with paromomycin. (Gookin, 1999)  The cats were treated with fluid therapy and returned to normal or near-normal renal function. Three of the cats, however, developed cataracts and deafness after restoration of adequate excretory function. Current research suggests that nitazoxanide, a synthetic antiprotozoal agent that is approved to treat Cryptosporidium in horses and humans, may be an effective alternative to paromomycin therapy in companion animals. (Lappin, 2006)

The most common cause of acute renal failure is proximal tubular necrosis as with aminoglycoside toxicity. Clinical findings include isosthenuria, glucosuria, proteinuria, cylinduria, and hematuria. Metabolic acidosis is another common finding with acute renal failure through several mechanisms. With oliguric/anuric renal failure, hydrogen ions, which are normally excreted in the urine, are retained. With poorly functioning tubules, bicarbonate is not reabsorbed. There is also accumulation of uremic acids, resulting in an increased anion gap.

Prevention

Renal toxicosis due to aminoglycosides has decreased in recent years, because of awareness of the potential for nephrotoxicity. To continue to prevent aminoglycoside-induced renal failure, several factors should be considered.  Aminoglycosides are dose and duration dependent, therefore prevention of renal damage depends on administering therapeutic levels for the shortest duration possible. Regular monitoring of serum chemistry values, kidney function, and peak and trough measurements of drug concentrations is crucial.  Urinary enzymes, such as GGT (gamma-glutamyl transferase) and NAG (N-acetyl-beta-D-glucosaminidase) can also be monitored to indicate early renal damage during treatment with aminoglycosides.

Age should be a consideration when using aminoglycosides. Older patients may have compromised immune systems and one report suggests that these patients may be more susceptible to aminoglycoside toxicity than those patients with fully functional immune systems. Immune status, renal function, hydration status, and acid base balance should all be evaluated prior to administration of aminoglycosides. Consider an alternative antibiotic when abnormalities are detected. Also, do not use aminoglycosides in conjunction with other potentially nephrotoxic agents, such as cephalosporins, or drugs causing hypovolemia or hypotension, such as loop diuretics (furosemide) or alpha-adrenergic antagonists (acepromazine or chlorpromazine). (Mazzaferro, 2008)

Current research is being performed on a naturally occurring serum protease called kallikrein that may be beneficial in the treatment or prevention of aminoglycoside toxicity. A recent study conducted on rats concluded that administration of tissue kallikrein in conjunction with gentamicin reduced renal injury. (Bledsoe, 2006) Kallikrein, a peptidase of the serum protease family, reduced renal dysfunction by inhibiting pro-inflammatory mediator recruitment and oxidative stress, thus decreasing apoptosis and fibrotic lesions. Reports have shown that reduced levels of kallikrein exist in urine of rats treated with gentamicin, indicating that kallikrein potentially has a role in nephrotoxicity.

Beta Lactam Toxicity

Beta lactam antibiotics include penicillins, cephalosporins, and penems, in increasing order of nephrotoxicity.   
Beta lactam antibiotics cause acute renal failure primarily through acute tubulointerstitial nephritis (ATN). There is evidence in the human literature suggesting that penicillin causes ATN through an immune reaction. The proposed mechanism states that the drug behaves as a hapten to elicit an immune response in the kidney. (Rossert, 2001) Once the process is initiated, proliferative lymphocytes and macrophages invade the tubular interstitium. The inflammation causes tubular damage and secondary fibrosis. Common pathologic findings include azotemia, proteinuria, hematuria, pyuria and occasionally eosinophilia.

Penicillins administered at the therapeutic dose very rarely cause nephrotoxicity. There are human case reports, however of overdosage causing three different types of renal dysfunction including tubular interstitial nephritis, glomerulonephritis and oliguric acute renal failure. Jones, et al. reported two separate cases of penicillin overdose in children causing reversible renal failure. (Jones, 1993) Ingestion of approximately twenty four times the therapeutic dose caused hematuria and oliguric renal failure that was reversed with supportive care. Renal biopsy revealed parenchymal edema, inflammation and tubular injury. However, no tubular necrosis or glomerular abnormalities were observed.

Cephalosporins are relatively non-toxic to the renal parenchyma compared to aminoglycosides. First generation cephalosporins, including Cephalexin and Cefazolin, have reportedly caused nephrotoxicity in animals. However, this is reported primarily in patients who are geriatric or have pre-existing renal dysfunction (Plumb, 2005). A human case report described a Cephalexin overdose in a child causing hematuria and crystalluria. (Clark, 1992) Second generation cephalosporins are infrequently used in veterinary medicine. Third generation cephalosporins (especially Cephalothin) have rarely been associated with nephrotoxicity.

Penems are the most nephrotoxic of the beta lactam antibiotics. A common penem used in veterinary medicine is Imipenem. This beta lactam is a broad spectrum antibiotic that is used for serious infections when a less potent antibiotic is ineffective. Imipenem is a bactericidal agent with activity against gram-positive cocci (some ineffectiveness against Enterococci), gram-positive bacilli (some activity against Listeria), gram-negative aerobes (Haemophilus, Enterobacteriaceae, Pseudomonas) and anaerobes. Nephrotoxocity of imipenem can develop due to two mechanisms which cause proximal tubule necrosis: direct transport into tubules and acylation of target proteins causing mitochondrial respiration toxicity. Acylation causes denaturation of proteins which changes the enzyme activity and interferes with respiration in cell mitochondria. The basilar location of the mitochondria in the renal tubules facilitates damage and eventually progresses to tubular necrosis and acute renal failure. (Tune, 1997)

Prevention

Beta lactams used at the appropriate doses in patients with normal renal function have an extremely low probability of causing acute renal failure. Ensure that administration of beta lactams is not in combination with other nephrotoxic agents and that patients do not have predisposition to renal failure.

Research is being conducted to develop beta lactams, specifically penems, which have little to no tubular cell uptake, but still maintain appropriate levels in circulation to retain their efficacy. By preventing accumulation in the proximal renal tubules, the penems would be unable to cause renal damage. Combination therapy is another possibility. Currently imipenem is administered in conjunction with Cilastatin, a chemical compound that prevents hydrolysis of Imipenem, which decreases its tubular secretion and, therefore, its nephrotoxcity. (Tune, 1990)

Treatment of Acute Renal Failure

Acute renal failure has four distinct phases including inititation, extension, maintenance and recovery. Initiation involves the period of renal injury. Therapy during the initiation phase is most likely to result in a complete return to normal or near-normal renal function.

The primary concern with treating acute oliguric/anuric renal failure is increasing the urine outflow. Treatment should therefore initiate with polyionic intravenous fluid administration. Monitor the animal closely by checking central venous pressure to ensure overhydration does not occur. (Merck, 2005) Once the animal’s fluid requirements have been replenished, urine outflow should be 1-2 ml/kg/day. If the animal remains oliguric, treatment with diuretics may be necessary. Diuretic administration should not be used, however in conjunction with aminoglycoside therapy due to increased risk of renal failure and death. (Ettinger, 2000; Gonzalez, 1998)

There are several diuretic options. Furosemide is the most common diuretic used in the treatment of renal failure. Furosemide is a loop diuretic that acts on the ascending loop of Henle to prevent absorption of sodium and chloride, which causes increased ultrafiltrate to form and thus increases urinary output.  Additional consequences of furosemide diuresis include excretion of potassium and temporary increase in glomerular filtration rate.

If furosemide fails to restore appropriate urine output, mannitol is another diuretic that has been used with moderate success in patients with acute renal failure. Mannitol may be a preferable treatment to furosemide, because it directly affects the proximal tubule since it diureses the complete nephron. Mannitol is contraindicated, however in patients that are in danger of being over hydrated due to vascular overload.

Renal vasodilators (e.g. dopamine) are also helpful in reversing the vasoconstriction caused by the stimulation of the renin-angiotensin system. Dopamine can act in conjunction with furosemide to vasodilate renal arteries to increase renal blood flow and thus urine output.

Restoration of normokalemia is crucial in the survival of renal failure patients due to the adverse cardiovascular effects associated with hyperkalemia. To immediately counteract life threatening cardiac arrhythmias, calcium gluconate can be slowly administered while constantly monitoring cardiac function to restore the threshold potential. The effects of calcium gluconate are short lived, therefore long term management of hyperkalemia should ensue once cardiac toxicity has been resolved. Possible treatments include replacing fluids with those devoid of potassium and administering sodium bicarbonate, which will also reverse metabolic acidosis. (Ettinger, 2005)

Replacing the animal’s nutritional needs is vital to recovery from acute renal failure. A feeding tube may need to be placed for any animal experiencing azotemia. Finally, if the aforementioned treatments do not improve urine production and electrolyte imbalances, peritoneal dialysis or hemodialysis may be necessary. If neither of these treatments restores appropriate renal function, euthanasia may be the only option.

Conclusion

In conclusion, research has shown that antibiotics, especially aminoglycosides and beta lactams can cause acute renal failure. Most studies have indicated that nephrotoxicity occurs primarily in patients with predisposing factors such as age, pre-existing renal insufficiency, immunosuppression, or concurrent treatment with other nephrotoxic drugs. The risk-to-benefit ratio must always be considered when prescribing potentially nephrotoxic drugs. If culture and sensitivities indicate that an aminoglycoside or beta lactam is necessary, choose the least nephrotoxic treatment and stringently monitor blood work and renal function.

Continued research is necessary to discover alternative treatments to nephrotoxic agents and to develop innovative combination therapies such as gentamycin and kallikrein for all potentially nephrotoxic agents.

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