When acute kidney injury develops because of diminished perfusion of the kidney, it is termed prerenal kidney injury because the etiology occurs before the kidney itself.10 As seen in Box 28-1, this can be due to an absolute or relative decrease in circulating volume, or abnormalities of renal hemodynamics. Actual or relative depletion of volume are the most common etiologies.²⁷ Fever, vomiting, diarrhea, burns, hemorrhage, and overuse of diuretic therapy produce fluid volume deficits that can lead to prerenal kidney injury. Decreased renal perfusion also results if large volumes of fluid collect in extravascular spaces as in edema (interstitial space) or ascites (peritoneal space). Any number of conditions reduces the ability of the heart to generate a cardiac output sufficient to meet the needs of body organ systems. Even though the kidney receives 20% to 25% of the cardiac output,⁷ that volume may be inadequate when the cardiac output is markedly decreased by cardiogenic shock, heart failure, or lethal ventricular dysrhythmias.

Although most patients who develop prerenal kidney injury have an episode of decreased blood pressure that results in decreased perfusion to the kidney, in some cases perfusion drops without the blood pressure falling below normal.⁹ These “normotensive” cases of prerenal kidney injury arise in susceptible individuals with very modest reductions in blood pressure who have preexisting impairments in renal autoregulation. Use of nonsteroidal antiinflammatory drugs (NSAIDs), angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin II (AII) receptor blockers is known to interfere with renal vascular autoregulation and can precipitate prerenal kidney injury in certain populations of patients. This includes those who are older than 60 years of age with atherosclerotic cardiovascular disease or have preexisting renal insufficiency (elevated serum creatinine level), heart failure, advanced liver disease, or nephrotic syndrome.^2,9 These drugs cause either vasoconstriction of afferent arterioles (NSAIDs) or vasodilation of efferent arterioles (ACE inhibitors and AII blockers); either of these actions results in a decrease in glomerular perfusion pressure.^2,9 Thrombus, embolus, dissection, or stenosis of the renal arteries will also result in prerenal kidney injury,^2,9 and the risk increases significantly if ACE inhibitors or AII blockers are being used.^2,9

Prerenal oliguria is the kidney’s normal physiologic response to a decrease in perfusion,^7,9 and at least for a time the renal tissue is unharmed. Neurohumoral mechanisms of local autoregulation are activated as the kidneys attempt to autoregulate perfusion and maintain GFR, and systemic mechanisms such as the renin-angiotensin-aldosterone system (RAAS) act to increase the total circulating volume.^2,7 The sensed decrease in renal blood flow results in a decrease in GFR and urine output. Because of the kidney’s ability to tolerate significant reduction in perfusion (as long as it is not greater than 20% to 25% of normal), and as long as the hypoperfusion etiology is identified and corrected, prerenal oliguria will not affect the parenchyma of the kidney.^2,7 Efforts to restore adequate perfusion should be fully effective in restoring normal renal function within 1 to 2 days.⁹ In the case of normotensive patients who have impaired perfusion, by far the smallest subset of prerenal kidney injury cases, interventions must be targeted to the specific etiology.⁹ Regardless of the etiology, persistent prerenal kidney injury will result in hypoxic renal cells. If hypoxia continues and ischemia lasts more than a few hours, prerenal kidney injury will progress to acute tubular necrosis (intrinsic kidney injury).^7,8

Obstruction of the normal outflow of urine from the kidneys can result in postrenal kidney injury.2,7,8 Box 28-1 lists the most common etiologies of this type of AKI. If only one kidney is affected, the activity of the remaining kidney will increase to maintain fluid and electrolyte balance.^2,7 Obstruction of the renal pelvis or ureters of both kidneys, of the bladder outlet, or of the urethra will result in discernible postrenal kidney disease. This type of AKI is the least common and the most amenable to intervention. Normalization of renal function depends on the length of time the obstruction persists.⁷ Should obstruction persist, the increasing retrograde pressure of urine will result in acute tubular necrosis (intrinsic AKI), and if the obstruction continues over several days or weeks, irreversible damage to the kidney will result.^7,8

AKI intrinsic to the kidney itself is further classified by the specific anatomic area involved: vascular, interstitial, glomerular, or tubular2 (see Box 28-1). Some references incorporate the vascular and tubular classifications together because damage to one ultimately leads to damage of the other.⁷ All of these etiologies are capable of producing the potentially reversible rapid decline in renal function that is AKI. When the small vessels within the kidney are inflamed, obstructed, or damaged by an acute hypertensive episode, the injury may be sufficient to impair nephron functioning. Acute glomerulonephritis is due to an abnormal immune reaction, whereby immune complexes are deposited in the basement membrane of the glomerulus, thereby damaging the glomeruli.⁷ Normal renal function is disrupted to some degree during this acute inflammatory process, usually lasting about 2 weeks. Acute glomerulonephritis is discussed in detail in Chapter 27. Inflammation of interstitial tissues may be sufficient to result in intrinsic kidney injury. This is usually due to an infection of the kidney (pyelonephritis), an allergic reaction to medications, or an autoimmune disease.^2,5 Long-standing pyelonephritis causes damage to the renal medulla and progressive loss of functional renal tissue.⁷

By far the most common cause of intrinsic kidney injury is acute tubular necrosis (ATN), which itself has many potential etiologies.^2,7 Acute tubular necrosis is the result of tubular cell injury, primarily attributable to ischemia or exposure to nephrotoxic substances. Acute tubular necrosis accounts for nearly half of all cases of AKI in hospitalized patients. Sepsis is the most common cause of ischemic ATN and may develop in about 50% of critically ill patients. It causes vasodilation leading to hypoperfusion within the kidney.¹⁰ In the elderly, about 30% of ischemic cases are due to sepsis and another third are due to surgical interventions.² Prolonged prerenal kidney injury, perioperative and postoperative hypotension, hemorrhage, gastrointestinal drainage, and preoperative cardiac complications also contribute to many case of ATN.²

The list of medications and chemicals toxic to the kidney is expansive,^2,7 each one inducing a specific toxic reaction in the tubular cells and causing the death of many of them.⁷ Of all of these nephrotoxins, contrast medium is the most common offending agent.^2,7 Contrast-induced AKI (also known as contrast-induced nephropathy) is a major cause of AKI in hospitalized elderly patients, and can develop within 12 to 24 hours of contrast administration.¹⁰ Risk factors for developing contrast-induced AKI are underlying kidney insufficiency, age greater than 70, volume depletion, repeated exposures to contrast media in a short time, and coexisting heart failure or diabetes mellitus.¹⁰ Prevention is aimed at avoidance of unnecessary contrast administration to high-risk patients, avoidance of multiple procedures over a 24- to 48-hour period, and adequate administration of hypotonic and isotonic intravenous (IV) fluids before and after contrast administration.^2,10 ATN caused by contrast media results in prolonged hospitalization, increased health care costs, and an increased risk of death.³⁷ Other nephrotoxic agents include commonly used medications such as aminoglycosides, NSAIDs, amphotericin B, cisplatin, and tetracycline.^2,7,10

In ATN, there are two pathophysiologic processes that result in the rapid decrease in glomerular filtration rate: a vascular process and a tubular process.¹¹ The two processes are interrelated, and the severity of one contributes to the severity of the other. Renal blood flow is decreased by 30% to 50% in ATN, and blood is shunted from the medulla to the cortex, further compromising the medullary cells.^11,12 Local vasoconstrictors such as prostaglandins and leukotrienes are released, and the effects of sympathetic nervous system (SNS) stimulation contribute further to the vasoconstriction.¹² Hypoxia or direct tubular damage, attributable to toxins, initiates an inflammatory response, activating the cascade of inflammatory mediators. When perfusion is restored, more inflammatory cells are enlisted and reperfusion injury perpetuates damage in some areas. Cells in part of the proximal tubule and outer cortex begin the repair process when perfusion is returned, but endothelial cells and those in the ascending limb continue to be injured, become necrosed, and commit apoptosis, resulting in a further decline in GFR.^11,12

The pathogenesis of the tubular process is a reflection of the ischemia¹¹ and the inflammatory process (Figure 28-1). Damaged tubular epithelial cells, both viable and nonviable, are shed from the basement membrane and accumulate in the tubular filtrate, where they obstruct filtrate flow.^7,11 These cells combine with inflammatory cells and debris to form casts that contribute further to the urinary obstruction.¹¹ Obstructed urinary flow produces an increased pressure within the nephron that is communicated backwards to the glomerulus, further reducing the GFR. The increasing pressure generated by the tubular obstruction forces filtrate through the partially denuded tubular basement membrane into the interstitial space and even into the bloodstream, a process known as tubular backleak.¹⁰ Half of the already limited quantity of glomerular filtrate may be lost to the interstitium by this process.

Recovery following ATN is highly dependent on the extent of injury and slower than in the other two types of AKI.7,12 If sufficient destruction of the basement membrane occurs, there may be no recovery and the patient develops end-stage renal disease, the final stage of chronic kidney disease. But the tubules can repair themselves within 10 to 20 days when the basement membrane is intact and new epithelial cells are produced on that surface.⁷ As with the other types of renal failure, the clinical presentation of ATN is primarily a reflection of the loss of the normal functions performed by the kidney.