eMedicine Specialties > Nephrology > Acute Kidney Failure

Acute Tubular Necrosis

Author: Edgar V Lerma, MD, Clinical Associate Professor of Medicine, Section of Nephrology, Department of Medicine, University of Illinois at Chicago College of Medicine; Consulting Staff, Associates in Nephrology, SC
Coauthor(s): Brent Kelly, MD, Resident Physician, Department of Internal Medicine, University of Texas Medical Branch School of Medicine; Mahendra Agraharkar, MD, MBBS, FACP, FASN, Clinical Associate Professor of Medicine, Baylor College of Medicine, President & CEO, Space City Associates of Nephrology
Contributor Information and Disclosures

Updated: Aug 28, 2009

Introduction

Background

The causes of acute renal failure (ARF) are conventionally and conveniently divided into 3 categories: prerenal, renal, and postrenal. Prerenal ARF involves an essentially normal kidney that is responding to hypoperfusion by decreasing the glomerular filtration rate (GFR). Renal, or intrinsic, ARF refers to a condition in which the pathology lies within the kidney itself. Postrenal failure is caused by an obstruction of the urinary tract. Acute tubular necrosis (ATN) is the most common cause of ARF in the renal category.

Renal biopsy findings are shown below.

ARF is commonly defined as an abrupt decline in renal function, manifested by acute elevation in plasma BUN (blood urea nitrogen) and serum creatinine, occurring in hours to days to weeks, and usually reversible. However, a consistent lack of consensus regarding the actual degree of elevation in serum creatinine that defines the syndrome has posed a major limitation to epidemiologic studies.

In 2002, the Acute Dialysis Quality Initiative (ADQI) was created with the primary goal of developing consensus- and evidence-based guidelines for the treatment and prevention of ARF. The first order of business was to create a uniform, accepted definition of ARF; hence the RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure or Loss of kidney function, and End-stage renal disease [ESRD]) criteria were born.

Table: RIFLE Classification System for Acute Kidney Injury (AKI)¹

Open table in new window

Note: Patients can be classified by GFR criteria and/or UO criteria. The criteria that support the most severe classification should be used. The superimposition of acute on chronic failure is indicated with the designation RIFLE-F_C; failure is present in such cases even if the increase in SCreat is less than 3-fold, provided that the new SCreat is greater than 4.0 mg/dL (350 μmol/L) and results from an acute increase of at least 0.5 mg/dL (44 μmol/L).

When the failure classification is achieved by UO criteria, the designation of RIFLE-F_O is used to denote oliguria. The initial stage, risk, has high sensitivity; more patients will be classified in this mild category, including some who do not actually have renal failure. Progression through the increasingly severe stages of RIFLE is marked by decreasing sensitivity and increasing specificity.

Classification of AKI

In September 2004, the Acute Kidney Injury Network (AKIN) was formed. The group consists of well-renowned nephrologists and intensivists (including members of ADQI and representatives from the American Society of Nephrology, the International Society of Nephrology, the National Kidney Foundation, the European Society of Intensive Care Medicine, and the Society of Critical Care Medicine), each representing a major clinical nephrology or critical care society. Among its proposals, AKIN has advised that the term acute kidney injury (AKI) be used to represent the full spectrum of renal injury, from mild to severe, with the latter having increased likelihood for unfavorable outcomes (eg, loss of function and ESRD).²

Definition and diagnostic criteria for acute kidney injury

A report by the AKIN proposed the following criteria for acute kidney injury:

An abrupt (within 48 hours) reduction in kidney function currently defined as an absolute increase in serum creatinine of more than or equal to 0.3 mg/dL (≥ 26.4 μmol/L), a percentage increase in serum creatinine of more than or equal to 50% (1.5-fold from baseline), or a reduction in urine output (documented oliguria of less than 0.5 mL/kg per hour for more than six hours).^2,3

Knowing the above limitations of currently used kidney function markers, it is accepted that they may be unable to detect any acute injury or process; in fact, their levels may rise coincident with a late period in the injury process. This has led to research to find more accurate kidney function biomarkers (serum and/or urine).⁴

Most likely a handful of kidney function biomarkers exist, rather than a single one. It is hoped that such biomarkers, once identified, will permit early diagnoses, as well as aid in rendering appropriate treatment strategies long before permanent damage has set in.

Several previously identified molecules—including N-acetyl-β-glucosaminidase, β₂ -microglobulin, α₁ -microglobulin, and retinol binding protein—have led to the discovery of potential biomarkers, such as kidney injury molecule 1 (KIM-1), human neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), cystatin C, clusterin, fatty acid binding protein, and osteopontin.

Although the discovery of new biomarkers could revolutionize our understanding of AKI, prospective clinical trials will be needed to compare them to each other over a period of many months and to investigate such factors as their natural tendencies to occur in certain disease states or in periods of high stress and their occurrence in specific demographics.

NGAL

The exact physiologic role played in the kidney by NGAL (also called lipocalin - 2 or siderocalin), a 25-kD protein, remains a mystery. One possibility, however, is that it is involved in renal morphogenesis, eg, induction of repair and reepithelialization. It has been shown to be elevated in the plasma and urine of animal models of ischemic and nephrotoxic acute kidney injury, and hence is considered by some to be a novel urinary biomarker for ischemic injury.⁵

The expression of the NGAL mRNA (messenger ribonucleic acid) and protein in the kidney has been shown to be significantly increased in the kidney tubules of patients with ischemic, septic, or post-transplantation AKI,⁶ as well as within 2-6 hours post–cardiopulmonary bypass surgery,⁷ at frequent intervals for 24 hours post–cardiopulmonary bypass surgery in children,⁸ and even following contrast administration.⁹

Urinary NGAL expression has been suggested as an early marker of AKI in children, although the results in adults have been less convincing.¹⁰

IL-18

A candidate biomarker for renal parenchymal injury, the cytokine interleukin-18 (IL-18), is formed in the proximal tubules and detected in the urine.¹¹ It has been shown in animal models to exacerbate tubular necrosis; neutralizing antibodies formed against IL-18 were found to reduce renal injury in mice.

Parikh et al¹² determined that patients with ATN had significantly higher levels of IL-18 in their urine than did control subjects or persons with other forms of kidney disease. On the other hand, patients with delayed graft function during the immediate post-transplantation period had higher urinary levels of IL-18 than did patients who had immediate graft function.

After evaluating the potential use of such biomarkers in patients with AKI (post-cardiopulmonary bypass), there has been some suggestion that urinary levels of NGAL and IL-18 may be sequential markers; NGAL levels peak within the first 2-4 hours following AKI, while IL-18 peaks at the 12th hour.

KIM-1

Another molecule that is upregulated in post–ischemic injury in the proximal tubule is KIM-1. Urinary KIM-1 has been suggested as another biomarker for the diagnosis of ischemic ATN.¹³

It has been suggested that high urinary KIM-1 may be an independent predictor (versus creatinine clearance, proteinuria, or donor age) for graft loss in post–renal transplantation patients.¹⁴

Cystatin C

Cystatin C is a 13-kD cysteine protease inhibitor that has gained popularity as an alternative to serum creatinine in the measurement of renal function of GFR. In contrast to the 3 previously discussed biomarkers, however, serum cystatin C levels are usually noted when the tissue injury has led to significant changes in the kidneys’ filtration function or capability. This is the same drawback that is encountered with serum creatinine.

Sodium/hydrogen exchanger isoform 3 (NHE3)

NHE3 is the most abundant apical membrane sodium transporter in the proximal tubules. Believed to be shed into the urine after tubular injury, it is analogous to serum troponins after cardiac muscle injury.

In one study, it was shown that urinary NHE3 proved to be a better gauge than did the time-honored fractional excretion of sodium (FENa) in distinguishing prerenal versus intrinsic kidney failure. A clinical assay is yet waiting to be developed and tested (the current NHE3 assay being particularly cumbersome, requiring ultracentrifugation and Western blot analysis.¹⁵ )

Conclusion

Further research (phase 4 clinical trials) will be needed for the development and clinical validation of new biomarkers for the eventual definition of kidney injury. Such trials will require large cohorts of subjects; some trials are already underway in government- and industry- sponsored studies.

As these new biomarkers evolve, so will our understanding of AKI. The work of Parikh et al has shown that some of these biomarkers might enable the distinction between prerenal azotemia, ATN, and other glomerular disorders.¹²

Ultimately, the goal of biomarker research is the early diagnosis of AKI (within hours, rather than within days or weeks). In that way, appropriate preventative and preemptive strategies, as well as treatment regimens, can be rendered at a phase whereby permanent loss of function can be avoided, making AKI truly reversible.

Pathophysiology

Acute tubular necrosis

ATN usually occurs after an acute ischemic or toxic event, and it has a well-defined sequence of events. The initiation phase is characterized by an acute decrease in GFR to very low levels, with a sudden increase in serum creatinine and blood urea nitrogen (BUN) concentrations. The maintenance phase is characterized by a sustained severe reduction in GFR, and this phase continues for a variable length of time, most commonly 1-2 weeks. Because the filtration rate is so low during the maintenance phase, the creatinine and BUN continue to rise. The recovery phase, in which tubular function is restored, is characterized by an increase in urine volume (if oliguria was present during the maintenance phase) and by a gradual decrease in BUN and serum creatinine to their preinjury levels.

Ischemic acute tubular necrosis

Ischemic ATN is often described as a continuum of prerenal azotemia. Indeed, the causes of the 2 conditions are the same (see Causes). Ischemic ATN results when hypoperfusion overwhelms the kidney's autoregulatory defenses. Under these conditions, hypoperfusion initiates cell injury that often, but not always, leads to cell death. Injury of tubular cells is most prominent in the straight portion of the proximal tubules and in the thick ascending limb of the loop of Henle, especially as it dips into the relatively hypoxic medulla. The reduction in GFR that occurs from ischemic injury is a result not only of reduced filtration due to hypoperfusion but also of casts and debris obstructing the tubule lumen, causing back leak of filtrate through the damaged epithelium (ie, ineffective filtration).

In addition, ischemia leads to decreased production of vasodilators (ie, nitric oxide, prostacyclin [PGI2]) by the tubular epithelial cells, leading to further vasoconstriction and hypoperfusion.

On a cellular level, ischemia causes depletion of adenosine triphosphate (ATP), an increase in cytosolic calcium, free radical formation, metabolism of membrane phospholipids, and abnormalities in cell volume regulation. The decrease or depletion of ATP leads to many problems with cellular function, not the least of which is active membrane transport. With ineffective membrane transport, cell volume and electrolyte regulation are disrupted, leading to cell swelling and intracellular accumulation of sodium and calcium. Typically, phospholipid metabolism is altered, and membrane lipids undergo peroxidation. In addition, free radical formation is increased, producing toxic effects. Damage inflicted by free radicals apparently is most severe during reperfusion.

The earliest changes in the proximal tubular cells are apical blebs and loss of the brush border membrane followed by a loss of polarity and integrity of the tight junctions. This loss of epithelial cell barrier can result in the above-mentioned back leak of filtrate. Another change is relocation of Na⁺/K⁺ -ATPase pumps and integrins to the apical membrane. Cell death occurs by both necrosis and apoptosis. Sloughing of live and dead cells occurs, leading to cast formation and obstruction of the tubular lumen. See the images below.

The recovery phase of ATN is characterized by regeneration of tubular epithelial cells.¹⁶ During recovery, an abnormal diuresis sometimes occurs, causing salt and water loss and volume depletion. The mechanism of the diuresis is not completely understood, but it may in part be due to the delayed recovery of tubular cell function in the setting of increased glomerular filtration. In addition, continued use of diuretics (often administered during initiation and maintenance phases) may also add to the problem.

Nephrotoxic acute tubular necrosis

Most of the pathophysiologic features of ischemic ATN are shared by the nephrotoxic forms. Thus, the cellular events described above apply to nephrotoxic ATN as well. Nephrotoxic ATN has induction, maintenance, and recovery phases, and recovery can be associated with an abnormal diuresis as is described above in ischemic ATN.

Nephrotoxic injury to tubular cells occurs by multiple mechanisms. These include direct drug toxicity, intrarenal vasoconstriction, and intratubular obstruction.

Frequency

United States

The syndrome of ARF is observed in about 5% of all hospital admissions. In the ICU, it occurs in up to 30% of patients admitted. Prerenal causes are responsible for approximately half of all cases. The frequency of each type of intrinsic renal disease varies depending on the population studied, but ATN (other than prerenal azotemia) is the most common cause of ARF in hospitalized patients.

Mortality/Morbidity

As with other causes of ARF, complications associated with ATN are often life threatening. The in-hospital survival rate of patients with ATN is approximately 50%, with about 30% of patients surviving for 1 year. Factors that are associated with an increased mortality rate include poor nutritional status, male sex, the presence of oliguria, the need for mechanical ventilation, acute myocardial infarction, stroke, or seizures.

• Disturbances in fluid and electrolyte balance
  • Hyperkalemia can be associated with life-threatening cardiac arrhythmias (see Complications).
  • Salt and water retention often leads to hypertension, edema, and congestive heart failure (CHF).
  • Hyponatremia causes concern because of its effects on the central nervous system.
  • Other electrolyte disturbances include hyperphosphatemia, hypocalcemia, and hypermagnesemia.
  • Metabolic acidosis
• Uremia results from the accumulation of nitrogenous waste. It is a potentially life-threatening complication associated with ARF.
  • Neurologic impairment and pericarditis can occur.
  • Platelet dysfunction is common and can lead to life-threatening hemorrhage.
• Infections
  • For ARF, the mortality rate is 20-50% in patients with underlying medical illnesses, but the mortality rate is as high as 60-70% with patients in a surgical setting. If multiorgan failure is present, especially severe hypotension or acute respiratory distress syndrome, the mortality rate ranges from 50-80%.
  • With dialysis intervention, the frequency of uremia, hyperkalemia, and volume overload as causes of death have decreased. The most common causes of death now are sepsis, cardiovascular and pulmonary dysfunction, and withdrawal of life support.

Clinical

History

The patient's history is very important in the diagnosis of ATN. It frequently reveals recent hypotension, sepsis, muscle necrosis, or volume depletion, as well as exposure to nephrotoxic agents. ATN is more likely to occur in patients with a history of recent surgery, sepsis, or hypovolemia. The history is also important in establishing risk factors for the development of ATN.

Physical

Physical examination findings may be unremarkable because ARF is often found incidentally during routine laboratory studies (ie, elevated BUN and creatinine levels). However, if symptoms are present, they may include a pericardial friction rub, asterixis, and/or excoriation marks related to uremic pruritus. Hypertension or edema may be noted. Otherwise, the physical examination findings are more likely to reflect the underlying disease process.

Causes

ATN is generally caused by an acute event, either ischemic or toxic.

Ischemic acute tubular necrosis

Ischemic ATN may be considered part of the spectrum of prerenal azotemia, and, indeed, ischemic ATN and prerenal azotemia have the same causes and risk factors. Specifically, these include the following:

• Hypovolemic states - Hemorrhage, volume depletion from GI or renal losses, burns, fluid sequestration
• Low cardiac output states - CHF and other diseases of myocardium, valvulopathy, arrhythmia, pericardial diseases, tamponade
• Systemic vasodilation - Sepsis, anaphylaxis
• Disseminated intravascular coagulation
• Renal vasoconstriction - Cyclosporine, amphotericin B, norepinephrine, epinephrine, hypercalcemia
• Impaired renal autoregulatory responses - Cyclooxygenase (COX) inhibitors, ACE inhibitors, angiotensin receptor blockers
  • Angiotensin II and prostaglandins play central roles in the maintenance of GFR in the face of volume depletion. ACE inhibitors and angiotensin receptor blockers have gained popularity not only as antihypertensive agents but also as renoprotective agents that either slow or halt the progression of diabetic and nondiabetic kidney disease. They have also been shown in several studies to have a role in CHF as well as ventricular remodeling. The use of these agents is limited by the tendency to cause prerenal failure, especially in patients who are considered to be at high risk; risk factors include advanced age, underlying renovascular disease, concomitant use of diuretics or vasoconstrictors, such as nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, and calcineurin inhibitors, and elevated baseline serum creatinine.
  • Serum creatinine and electrolytes, especially potassium, should be measured before and at least 1 week after starting or changing the dose of the medication. An increase in serum creatinine of greater than 0.5 mg/dL if the initial serum creatinine is less than 2.0 mg/dL, or an increase in serum creatinine of greater than 1.0 mg/dL if the baseline serum creatinine is greater than 2.0 mg/dL, has been suggested as a threshold for discontinuation of therapy. An increase in serum creatinine of up to 30% is acceptable, but a continued rise of over 30% should prompt immediate discontinuation of the medication. Alternatively, discontinuation of ACE inhibitor or angiotensin receptor blocker therapy is not necessary if smaller increases in serum creatinine occur. If and when prerenal ARF does develop, one should commence looking for underlying heart disease, volume depletion, hypotension, concomitant use of vasoconstrictors, or renovascular disease.

Nephrotoxic acute tubular necrosis

The kidney is a particularly good target for toxins. Not only does it have a rich blood supply, receiving 25% of cardiac output, but it also helps in the excretion of these toxins by glomerular filtration and tubular secretion.

• Exogenous nephrotoxins
  • Aminoglycosides
    • ATN occurs in 10-30% of patients receiving aminoglycosides, even when blood levels are in apparently therapeutic ranges. Risk factors for the development of aminoglycoside-induced ATN include preexisting liver disease, preexisting renal disease, concomitant use of other nephrotoxins (eg, amphotericin B, radiocontrast media, cisplatin), advanced age, shock, female sex, and a higher aminoglycoside level 1 hour after dose. A high trough level has not been shown to be an independent risk factor. Patients usually present with nonoliguric renal failure, with onset of nephrotoxicity (manifested by an elevation in serum creatinine), that occurs after 7-10 days of therapy. Characteristically, an elevated FENa is usually accompanied by wasting of potassium, calcium, and magnesium.
    • Aminoglycosides preferentially affect the proximal tubular cells. These agents are freely filtered and quickly taken up by the proximal tubular epithelial cells, where they are incorporated into lysosomes after first interacting with phospholipids on the brush border membranes. They exert their main toxic effect within the tubular cell by altering phospholipid metabolism. In addition to their direct effect on cells, aminoglycosides cause renal vasoconstriction.
    • The 2 critical factors in the development of ARF secondary to aminoglycoside nephrotoxicity are namely dosing and duration of therapy.
    • Aminoglycoside uptake by the tubules is a saturable phenomenon, so uptake is limited after a single dose. Not surprisingly, a single daily large dose is preferable to 3 doses per day. One dose per day presumably causes less accumulation in the tubular cells once the saturation point is reached. In fact, clinical nephrotoxicity develops much more commonly with 3 doses per day than with 1 dose per day; in one study, 24% of patients receiving 3 daily doses developed clinical nephrotoxicity, compared to only 5% of patients receiving 1 daily dose. However, other studies comparing a single daily dose to multiple daily doses have failed to find a difference in the incidence of nephrotoxicity.
    • Therapeutic efficacy is not diminished by single daily dosing.
  • Amphotericin B
    • Amphotericin B tends to bind to sterols in cell membranes, thereby creating pores that compromise membrane integrity and increase membrane permeability. It binds not only to ergosterol in fungal cell walls but also to cholesterol in human cell membranes; this is what accounts for its nephrotoxicity. Multiple segments of the renal tubule are involved, namely, the proximal tubule, the medullary ascending limb of the loop of Henle, and the collecting duct. Characteristic electrolyte abnormalities include wasting of potassium and magnesium. The back-leak of hydrogen ions in the collecting duct leads to distal renal tubular acidosis (dRTA).
    • Several risk factors for the development of amphotericin B nephrotoxicity include male sex, maximum daily dose (nephrotoxicity is more likely to occur if > 3 g is administered) and duration of therapy, hospitalization in the critical care unit at the initiation of therapy, and concomitant use of cyclosporine.
    • Prevention is key in amphotericin B nephrotoxicity. By saline loading, maintenance of a high urine flow rate has been shown to be helpful. Likewise, various lipid formulations of amphotericin B have been developed, namely, amphotericin B colloid dispersion (ABCD), amphotericin B complex (ABLC), and liposomal amphotericin B; these lipid formulations are believed to be less nephrotoxic intrinsically. Whereas amphotericin B is suspended in bile salt deoxycholate, which has a detergent effect on cell membranes, such lipid formulations do not contain deoxycholate. The lipid formulations also bind more avidly to fungal cell wall ergosterol as opposed to the cholesterol in human cell membranes. Liposomal amphotericin B is preferred in patients with renal insufficiency or evidence of renal tubular dysfunction.
  • Radiographic contrast media
    • ARF occurring secondary to exposure to contrast media used in radiologic or angiographic procedures is referred to as contrast-induced nephropathy (CIN) or radiocontrast nephropathy (RCN). This type of nephropathy commonly occurs in patients with several risk factors, such as elevated baseline serum creatinine, preexisting renal insufficiency, underlying diabetic nephropathy, CHF, or high or repetitive doses of contrast media. Other risk factors include volume depletion and concomitant use of diuretics, ACE inhibitors, or angiotensin receptor blockers.
    • Although the pathogenesis of CIN remains incompletely understood, it is most likely the result of renal vasoconstriction and direct renal tubular epithelial cell toxicity.
    • Whereas FENa below 1% usually indicates prerenal failure, although CIN is a common cause of exogenous nephrotoxic ATN, FENa tends to be less than 1%, characteristically. (This is an exception to the rule. See myoglobinuric renal failure, below.)
    • Patients usually present with nonoliguric renal failure, with an acute elevation in serum creatinine that is noted 24-48 hours after the contrast-requiring procedure; it may peak 3-5 days after the onset of renal failure and then may return to baseline within 7-10 days. More importantly, the temporal relationship between the time of administration of contrast media and the onset of elevation in serum creatinine is particularly suggestive of the diagnosis. One must differentiate CIN from atheroembolic renal disease, which occurs in the same scenario, but atheroembolic renal disease is characterized by embolic lesions (mottling of the skin over the lower extremities), peripheral eosinophilia, and serum hypocomplementemia, all of which are notably absent in CIN.
    • Most patients with CIN will have subsequent renal recovery; however, those patients with preexisting renal insufficiency may show a further decline in renal function.
    • Prevention is important in the management of CIN. Some investigators recommend the avoidance of contrast-requiring procedures, if at all possible. Magnetic resonance imaging (MRI) studies usually necessitate the use of gadolinium as a contrast agent, which, in several studies, has been shown to be less nephrotoxic than conventional contrast media.
    • Other risk factors should be corrected, including saline infusion to correct volume depletion and discontinuation of potential nephrotoxic agents, such as NSAIDs and COX-2 inhibitors. In those patients with underlying volume depletion, withholding ACE inhibitors and/or angiotensin receptor blockers may even be necessary. Using the lowest possible amount of contrast media in the procedure is also recommended.
    • To date, several interventions have been suggested to decrease the risk of CIN, such as furosemide, mannitol, dopamine, and fenoldopam, but none of these agents have been shown to be significantly effective. The use of N -acetylcysteine (NAC) as a prophylactic agent has gained popularity; based on the theory that contrast media cause direct renal tubular epithelial cell toxicity as a result of exposure to reactive oxygen species (ROS), NAC is believed to have antioxidant properties that potentially counteract the effects of ROS.
    • Based on what is known now, making a strong, evidence-based recommendation for the use of NAC in the prevention of CIN is not possible. Recognizing that NAC is inexpensive and is not associated with significant complications, in the absence of other effective pharmacologic therapy, its use in clinical practice is not entirely inappropriate. Additional large randomized controlled trials of NAC are needed to better define its proper role in preventing CIN.
    • Several studies have looked at the possibility of using theophylline as a prophylactic agent. Based on the idea that contrast media causes local release of adenosine, a known vasoconstrictor, and considered by some to have a potential role in the pathogenesis of CIN, theophylline is a known adenosine antagonist. Although theophylline appears to be promising, just as with NAC, further randomized trials are required to show any proven benefit of theophylline in the prevention of CIN.
    • The prevention of contrast nephrotoxicity has received attention. In susceptible patients, the use of nonionic, low-osmolar contrast media reduces the likelihood of clinical nephrotoxicity. Isotonic saline, given at 1 mL/kg of body weight/h for 24 hours, starting on the morning of the contrast-requiring procedure, has been shown to be superior to half normal saline infusions. A single center, randomized, controlled trial demonstrated that isotonic sodium bicarbonate (3 mL/kg of body weight/h given 1 h prior to the contrast-requiring procedure and then continued at 1 mL/kg of body weight/h for 6 h postprocedure) may offer even greater protection than isotonic sodium chloride. The postulated mechanism is being attributed to the inhibition of oxidant injury by the administered alkali.
    • Studies have also suggested that pretreatment with oral NAC (600 mg or 1200 mg bid on the day prior and on the day of the contrast-requiring procedure) acts as an antioxidant, scavenging ROS, thereby reducing the nephrotoxicity of contrast media.
    • Similarly, theophylline, an adenosine antagonist, with a similar mechanism of action as NAC, is viewed as another potential agent to prevent CIN; the main difference being the lower risk profile associated with the latter.
    • Aside from the recommended prophylactic medications discussed above, other guidelines recommend withholding NSAIDs, COX inhibitors, diuretics, ACE inhibitors, and angiotensin receptor antagonists at least 24 hours before and after the procedure. Metformin should be withheld at least 48 hours before the procedure and until CIN has been ruled out.
  • Cyclosporine and tacrolimus (calcineurin inhibitors): These drugs cause ARF by inducing afferent arteriolar vasoconstriction. Usually, renal insufficiency is easily reversed by a reduction of the dosage. On the other hand, persistent injury can lead to interstitial fibrosis.
    • Clinically, patients may present with hypertension. They may also be hyperkalemic and have tubular injury induced urinary wasting of phosphate and magnesium.
    • Tacrolimus has been shown to cause thrombotic microangiopathy as a result of endothelial injury.
  • Others: Cisplatin, ifosfamide, foscarnet, and pentamidine are other causes of drug-induced tubular toxicity.
    • Cisplatin usually affects the proximal and distal tubules. Characteristically, it is associated with urinary wasting of magnesium. Cisplatin causes the release of toxic hydroxyl radicals when chloride ions in the cis position are replaced by water. The key is prevention by volume loading with saline. Some investigators advocate the use of amifostine, a thiol donor that serves as an antioxidant. Others prefer using carboplatin, a less nephrotoxic alternative.
    • Ifosfamide usually causes a Fanconi syndrome (proximal tubule dysfunction) presentation with significant hypokalemia. It is a known analog of cyclophosphamide. While the latter is not nephrotoxic, ifosfamide, by virtue of its metabolite chloroacetaldehyde, is, with preferential involvement of the proximal tubule.
    • Foscarnet is used to treat resistant cytomegalovirus (CMV) infections. It causes acute interstitial nephritis and intratubular crystal obstruction. It is notable for inhibiting proximal tubular reabsorption of phosphate (leading to hypophosphatemia) by virtue of it being a phosphate analog. Hypocalcemia is also noted, secondary to chelation of calcium.
    • Pentamidine is used to treat Pneumocystis carinii infection in individuals who are immunocompromised. Risk factors for nephrotoxicity include volume depletion and concomitant use of other nephrotoxic antibiotic agents, such as aminoglycosides, which is common practice in the immunosuppressed. It is noted for hypomagnesemia and hyperkalemia.
  • Sulfa drugs, acyclovir, and indinavir cause ARF by tubular obstruction due to crystal formation in the tubular urine. Acyclovir may lead to the formation of intratubular crystals, which appear as birefringent needle shaped crystals when viewed on microscopy. Occasionally, such crystals can also elicit an acute interstitial nephritis.
• Endogenous nephrotoxins
  • Myoglobinuria
    • Rhabdomyolysis refers to the breakdown of skeletal muscle fibers, which leads to the release of potentially nephrotoxic intracellular contents into the circulation. Rhabdomyolysis is the most common cause of heme-pigment associated ARF. Three mechanisms cause the development of ARF in this setting, as follows: renal vasoconstriction, heme-mediated proximal tubular epithelial cell toxicity, and intratubular cast formation. Heme-proteins are believed to be involved in the generation of ROS, which are known to cause tubular injury through peroxidation of membrane lipids and intracellular enzymes.
    • Rhabdomyolysis can be caused by traumatic or nontraumatic injuries. Most cases of rhabdomyolysis are nontraumatic (eg, alcohol abuse, drug-induced muscle toxicity [statins alone or in combination with fibrates]).
    • Clinically, patients present with severe muscle pains and generalized soreness. Physical examination may disclose tender "dough" muscles, with significant edema of the involved extremities. In severe cases, compartmental compression syndromes, particularly characterized by neurovascular compromise, may occur.
    • Whereas FENa under 1% usually indicates prerenal failure, although rhabdomyolysis is a common cause of endogenous nephrotoxic ATN, FENa tends to be less than 1%, characteristically. (This is another exception to the rule. See CIN, above)
    • An important finding on urinalysis is that of a positive dipstick test for blood, with typical absence of RBCs on microscopy. Furthermore, hyperkalemia, hyperphosphatemia, and hyperuricemia are characteristic. Calcium tends to deposit in the injured muscle, thereby leading to hypocalcemia. Such deposited calcium is eventually released back into the circulation during the recovery phase, thereby accounting for transient hypercalcemia. For this reason, calcium administration is generally not recommended during the acute phase of rhabdomyolysis, unless the patient is symptomatic.
    • Preventive strategies include aggressive volume resuscitation with normal saline at 1000-1500 mL/h with a goal urine output of 300 mL/h. Caution should be exercised to avoid producing a compartment syndrome, especially in those patients who remain oligoanuric despite infusions of large volumes of fluid. In the presence of sufficient urine output, urine alkalinization to achieve a urine pH of greater than 6.5 is recommended to increase the solubility of the heme-proteins within the tubules. This has also been shown to reduce the generation of ROS. Mannitol has not been shown to be more efficacious as compared to volume expansion with normal saline alone.
  • Hemoglobinuria: ARF is a rare complication of hemolysis and hemoglobinuria. Most often, it is associated with transfusion reactions. In contrast to myoglobin, hemoglobin has no apparent direct tubular toxicity, and the ARF in this setting is probably related to hypotension and decreased renal perfusion.
  • Crystals: Acute crystal-induced nephropathy is encountered in conditions where the crystals are generated endogenously due to high cellular turnover (ie, uric acid, calcium phosphate), as observed in certain malignancies or the treatment of malignancies. However, this condition is also associated with ingestion of certain toxic substances, such as ethylene glycol, or nontoxic substances, such as vitamin C.
  • Multiple myeloma: Multiple myeloma causes renal failure by several mechanisms, such as prerenal azotemia due to volume contraction, cast nephropathy due to increased light chain proteins precipitated into the tubular lumen, hypercalcemia, uric acid nephropathy, and drug-induced interstitial nephritis.

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