Mechanisms of Injury in Renal Disease and Toxicity

Robin Goldstein, Robin S. Goldstein

• Publisher: CRC Press
• Year: 2020
• ISBN:
  9781000159745
• Edition: 1
• Topic: Medicina
• Subtopic: Toxicología

Dr. Goldstein has authored more than 50 publications and co-edited two books. Her latest contribution to the field of nephrology, Mechanisms of Injury in Renal Disease and Toxicity, promotes an understanding of the pathophysiologic mechanisms mediating renal dysfunction in disease. It provides an important perspective in understanding mechanisms of chemically induced renal injury.
Over the past decade, understanding of the pathophysiologic and molecular basis of renal disease has grown tremendously. New and evolving concepts on the pathophysiology of glomerulonephritis, chronic glomerular injury, diabetic nephropathy, and acute renal failure are changing the clinical management of these disease states.

MECHANISMS OF ACUTE AND CHRONIC RENAL FAILURE

Chapter 1

Pathophysiologic Mechanisms of Acute Renal Failure

Mark S. Paller

INTRODUCTION

Acute renal failure is one of the most common problems in nephrology. It occurs in a wide variety of clinical settings because acute renal failure can result from hypotension and shock, septicemia, rhabdomyolysis, and nephrotoxic drugs, such as aminoglycoside antibiotics, amphotericin B, radiographic contrast agents, acetaminophen, and cisplatin. Common to all forms of acute renal failure is cellular injury involving primarily the renal tubular epithelial cells in the S2 and S3 segments of the proximal tubule, but also involving epithelial cells in the thick ascending limb of the loop of Henle, as well as possibly involving glomerular epithelial and endothelial cells and renal vascular cells.^{1, 2, 3} Depending on whether one is studying ischemic or toxic injury and experimental or human disease, the specific sites and distribution of injury may vary somewhat. Nevertheless, there are some commonalities among all forms of acute renal failure in terms of nephronal patterns of injury as well as cellular mechanisms of injury. In any particular instance of acute renal failure, the factors to be discussed below will participate in varying degrees.

MORPHOLOGIC FINDINGS IN RENAL INJURY

Since the studies of Bywaters and Beall⁴ of victims of the London air-raids who suffered crush injury and developed acute renal failure, there has been a recognition that tubular cells undergo degenerative changes and that tubules develop obstruction with casts composed of necrotic cells and cellular debris when acute renal failure occurs.⁴ The detailed microdissection studies of Oliver et al.⁵ confirmed these findings and further suggested that in ischemic acute renal failure in man there were patchy areas of cellular necrosis involving the proximal tubule with the straight segment being most vulnerable.⁵ Additionally, casts were found throughout the distal convoluted tubule and collecting duct. In acute renal failure due to nephrotoxins, necrosis occurred in the S2 and S3 segments of the proximal tubule and was more extensive than after renal ischemia. As in ischemic acute renal failure, casts occluded the lumens of the entire distal nephron.

To study ischemic acute renal failure in an experimental model, the renal artery of the rat can be occluded for 15 to 60 min. Venkatachalam et al.³ observed that after 25 min of renal artery occlusion, S1 and S2 segment cells underwent reversible changes, whereas S3 segment cells underwent progressive cell injury and death.³ Within 5 min of blood reflow, brush border microvilli in all three segments of the proximal tubule underwent coalescence and interiorization. A small number of microvilli were fragmented and shed into the lumen of the proximal tubule. By 30 min of reflow, microvillous changes began to reverse so that by 4 h of reflow the S1 and S2 segment cells appeared normal. In contrast, the damaged S3 cells developed progressive necrosis and were exfoliated into the lumen. The surviving tubular epithelial cells underwent mitosis to repopulate the tubule 24 to 48 h following the ischemic insult.³ When kidneys were subjected to 1 h of ischemia, Reimer et al.¹ observed more extensive cellular necrosis and more debris in the urinary space. Brush border microvilli were also found to develop extensive blebs that were capable of obstructing the lumen of the proximal tubule.

An objection to using animal models to study acute renal failure is that differences in the extent of histologic injury have been found when comparing animals with man. The extent of blood flow limitation is also different. In experimental animals renal blood flow is totally abolished or severely depressed for up to 1 h, whereas patients who develop acute renal failure more often have less profound hypoperfusion of the kidneys, but of longer duration. Some studies of renal biopsy material from patients with acute renal failure have found minimal differences compared with normal kidneys.⁶ In other studies, tubular necrosis is usually more focal and tubular obstruction is less common in patients than in experimental animals with acute renal failure.⁷ On the other hand, in human biopsy material microvilli changes in the proximal tubule are frequent. Other changes such as flattening of tubular cells and mitosis are also common, suggesting that regeneration is occurring following a prior episode of necrosis even if necrotic cells are no longer present. In addition, Racusen et al.⁸ have recently demonstrated extensive shedding of viable tubular epithelial cells into the urine of patients with ischemic acute renal failure.⁸ This latter finding suggests that epithelial cells may be lost from the tubule even without developing necrosis. This would help to explain the paucity of necrotic cells in renal biopsies from some patients with acute renal failure, yet account for the extensive changes in renal function, which will be discussed below.

CELLULAR EVENTS IN ACUTE RENAL FAILURE

Acute renal failure has been described as consisting of three sequential phases, the initiation or injury phase, the maintenance phase, and the recovery phase. Although there is considerable overlap among these stages, and although the time course for these stages is not precisely defined, this classification is conceptually useful. The initiation phase lasts for only several hours and is characterized by marked changes in renal hemodynamics and in renal function. Hemodynamic changes may be due, ...