Although the kidneys receive approximately 20% of the total cardiac output, they are still at very high risk for ischemic injury. This dichotomy is explained by the fact that most renal blood flow (80%-90%) is directed toward the renal cortex, where it passes through the glomerulus and is filtered.2 The most metabolically active portion of the kidney, however, is not the cortex but the medulla, which is responsible for creating the osmotic gradient that serves to reabsorb water and concentrate urine. In order to maintain this osmotic gradient, blood flow to the medulla is kept low. In fact, the oxygen tension in the medulla is only approximately 10 mm Hg.2 This lack of luxury perfusion to a metabolically active portion of the kidney predisposes it to ischemic injury. Furthermore, the kidney concentrates toxins that the body is exposed to, thereby amplifying the exposure of renal cells to toxic substances.
The etiology of AKI is traditionally divided into prerenal, intrinsic renal, and postrenal. Prerenal azotemia occurs as a complication of decreased renal perfusion with preservation of the cellular architecture of the renal parenchyma. Direct injury to the kidneys results in renal azotemia, or intrinsic renal injury. Postrenal azotemia occurs as a result of obstruction of the urinary outflow tract. The overwhelming majority of AKI in critically ill patients is caused by sepsis, whose mechanism does not quite fit within any of the traditional categories of AKI. It was traditionally thought that sepsis-induced AKI was caused by renal hypoperfusion due to systemic hypotension and renal vasoconstriction, along with reperfusion injury to the kidneys. However, this theory has recently come into question. It is now thought that while ischemia may play a role, there are many other pathophysiologic mechanisms at work. Recent human and animal studies have shown that renal blood flow is preserved in sepsis. Current concepts of AKI in sepsis indicate that systemic inflammation, microvascular dysregulation, and mitochondrial alteration, leading to cell death may be more important than global renal hypoperfusion.3 This theory claims that sepsis induces an “inflammatory danger signal” that is initially adaptive and later becomes maladaptive, leading ultimately to, metabolic reprioritization of renal cells which favors cell adaptive processes (like maintenance of cell membrane potential and cell cycle arrest) at the expense of actual filtration of blood.3
Renal hypoperfusion is the hallmark of prerenal AKI. Renal hypoperfusion (resulting from prolonged hypotension, hemorrhage, abdominal compartment syndrome, low cardiac output states, or cirrhosis) is a common cause of prerenal AKI in the ICU. Medications that interfere with normal renal autoregulation (nonsteroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, cyclosporine, and tacrolimus) can precipitate AKI in patients with marginal renal perfusion. Prerenal azotemia presents with decreased glomerular filtration rate (GFR) and little evidence of cellular damage in most cases. Therefore, the condition is usually completely reversible. Prolonged prerenal azotemia, however, can lead to evidence of cellular damage, usually in the form of acute tubular necrosis.
Intrarenal AKI has many causes and is best understood when classified by the location of the lesion: glomerulus, tubule, vasculature, or interstitium. Most intrarenal AKI in the ICU setting is due to acute tubular necrosis from prolonged hypotension, nephrotoxic medications, recent exposure to radiographic contrast agents; or interstitial nephritis from nephrotoxic medications, such as antibiotics. Glomerular and vascular causes of intrarenal AKI are more commonly causes of renal failure outside of the ICU.
Urinary indices can be helpful in distinguishing prerenal and renal azotemia in non-ICU settings. A fractional excretion of sodium (FENa) less than 1% is commonly used in the non-ICU setting to identify patients with prerenal AKI. However, in the ICU, where many patients receive diuretics, the FENa becomes unreliable and should not be routinely used as a diagnostic test. An elevated blood urea nitrogen (BUN)/creatinine ratio is also not necessarily indicative of prerenal AKI in ICU patients due to the lengthy list of comorbidities that may elevate the BUN/creatinine ratio in a euvolemic ICU patient (gastrointestinal hemorrhage, total parenteral nutrition, steroids, catabolic stress). Analysis of urinary sediment can be used to distinguish prerenal and intrarenal AKI, but these tests have limited use in an ICU setting. Generally, the microscopic examination of urine in patients with prerenal or postrenal AKI is normal. Red blood cell casts, protein, white blood cells or leukocyte casts, or hematuria suggest intrarenal causes of AKI.
Postrenal AKI occurs when there is bilateral or unilateral obstruction in urinary flow. This leads to an increase in intratubular pressure, eventually leading to a decrease in glomerular filtration pressure. Postrenal AKI is a very rare cause of AKI in the ICU, since most patients in the ICU have a urinary catheter. Obstruction of the urinary tract can be extrarenal or renal. Extrarenal causes include prostatic hypertrophy, and abdominal/retroperitoneal masses compressing the ureters. Intrarenal obstruction can be caused by deposition of stones, crystals, clots, or tumors.