Porth's Essentials of Pathophysiology, 4e

641

Acute Kidney Injury and Chronic Kidney Disease

C h a p t e r 2 6

(NSAIDs) can also reduce renal blood flow by inhibiting the synthesis of prostaglandins, which normally have a vasodilatory effect on renal blood vessels. Prerenal injury is manifested by a sharp decrease in urine output and a disproportionate elevation of blood urea nitrogen (BUN) in relation to serum creatinine lev- els. The kidney normally responds to a decrease in the GFR with a decrease in urine output. Thus, an early sign of prerenal injury is a sharp decrease in urine output. A low fractional excretion of sodium (<1%) suggests that oliguria is due to decreased renal perfusion and that the nephrons are responding appropriately by decreasing the excretion of filtered sodium in an attempt to pre- serve vascular volume. Blood urea nitrogen levels also depend on the GFR. A low GFR allows more time for small particles such as urea to be reabsorbed into the blood. Creatinine, which is larger and nondiffusible, remains in the tubular fluid, and the total amount of creatinine that is filtered, although small, is excreted in the urine. Consequently, there also is a disproportionate elevation in the ratio of BUN to serum creatinine, from a normal value of 10:1 to a ratio greater than 20:1. 1 Postrenal Injury Postrenal injury results from obstruction of urine out- flow from the kidneys. The obstruction can occur in the ureter (i.e., calculi and strictures), bladder (i.e., tumors or neurogenic bladder), or urethra (i.e., prostatic hyper- plasia). Prostatic hyperplasia is the most common under- lying problem. Because both ureters must be occluded to produce renal injury, obstruction of bladder outflow rarely causes AKI unless one of the kidneys already is damaged or a person has only one kidney. The treat- ment of acute postrenal injury consists of treating the underlying cause of obstruction so that urine flow can be reestablished before permanent nephron damage occurs. Intrarenal Injury Intrarenal injury results from conditions that dam- age structures within the kidney. The major causes of intrarenal injury are ischemia associated with prerenal injury, injury to the tubular structures of the nephron, and intratubular obstruction. Acute glomerulonephritis and acute pyelonephritis also are intrarenal causes of AKI. However, injury to the tubular structures of the nephron (acute tubular necrosis) is the most common cause and often is ischemic or toxic in origin. AcuteTubular Necrosis. Acute tubular necrosis (ATN) is characterized by the destruction of tubular epithelial cells with acute suppression of renal function (Fig. 26-2). It can be caused by a number of conditions, including acute tubular damage due to ischemia, sepsis, nephro- toxic effects of drugs, tubular obstruction, and toxins from a massive infection. 3–5,10 Tubular epithelial cells are particularly sensitive to ischemia and toxins. The tubu- lar injury that occurs in ATN frequently is reversible. The process depends on recovery of the injured cells, removal of the necrotic cells and intratubular casts, and

Decreased glomerular filtration rate

Afferent arteriolar constriction

Ischemic/toxic insult

Tubular injury

Back-leak

Obstruction

regeneration of tubular cells to restore the normal conti- nuity of the tubular epithelium. 5,10 Acute tubular necrosis occurs most frequently in per- sons who have major surgery, severe hypovolemia, or overwhelming sepsis, trauma, or burns. 3 Sepsis produces ischemia by provoking a combination of systemic vaso- dilation and intrarenal hypoperfusion. In addition, sep- sis results in the generation of toxins that sensitize renal tubular cells to the damaging effects of ischemia. ATN complicating trauma and burns frequently is multifac- torial in origin, resulting from the combined effects of hypovolemia, myoglobinuria, and other toxins released from damaged tissue. In contrast to prerenal injury, the GFR does not improve with the restoration of renal blood flow in AKI caused by ischemic ATN. Many drugs are nephrotoxic, causing tubular injury by inducing varying combinations of renal vasoconstric- tion, direct tubular damage, or intratubular obstruction. The kidney is particularly vulnerable to nephrotoxic injury because of its rich blood supply and ability to con- centrate toxins to high levels in the medullary portion of the kidney. In addition, the kidney is an important site for metabolic processes that transform relatively harm- less agents into toxic metabolites. Pharmacologic agents that are directly toxic to the renal tubule include anti- microbials such as aminoglycosides (e.g., gentamicin), cancer chemotherapeutic agents such as cisplatin and decreased glomerular capillary filtration pressure.Tubular injury and increased intraluminal pressure cause fluid to move from the tubular lumen into the interstitium (back-leak). (Modified from Jennette JC.The kidney. In: Rubin R, Strayer DS, eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine. 6th ed. Philadelphia, PA: Wolters Kluwer Health | Lippincott Williams &Wilkins; 2012:792.) FIGURE 26-2. Pathogenesis of acute tubular necrosis (ATN). Sloughing and necrosis of tubular epithelial cells lead to obstruction and increased intraluminal pressure, which reduce glomerular filtration. Afferent arteriolar vasoconstriction caused in part by tubuloglomerular feedback mechanisms results in