| Abstract|| |
Causes of acute renal failure (ARF) are summarized. The article focuses on "shock kidneys" as they occur following traumatic or septic shock. There may be low-grade intermittent but persisting endotoxemia in the former together with other factors like rhabdomyolysis, and marked endotoxemia at least for a few hours in the latter. Endotoxin is a prime cause of release of noxious cytokines like tumor necrosis factor-alpha (TNFa). At present, many studies support the evidence for its role in multi-organ failure (MOF). One can account for endotoxemia along with bacterial translocation through the gastrointestinal mucosa if there is transient mesenteric ischemia during shock. Hence, monocytemacrophages can be stimulated to release their cytokines that predispose to MOF. The cell biology of renal tubular changes in ARF is then briefly discussed in order to mention new therapeutic approaches.
Keywords: Acute renal failure, Shock, Pathogenesis.
|How to cite this article:|
Wardle E N. Pathogenesis of Acute Renal Failure: Shock-Kidneys. Saudi J Kidney Dis Transpl 1998;9:231-6
| Introduction|| |
Pre-renal failure is caused generally by loss of blood or other body fluids, whereas post-renal failure results from acute of chronic urinary tract obstruction, and is often detected by ultrasonography. These conditions are reversible provided that they are recognized early in the course of disease.
Intrinsic acute renal failure (ARF), in which there is increasing retention of the break-down products of protein metabolism (urea and creatinine) and diminished urinary flow has many causes as listed in [Table - 1] but usually we think of events causing acute tubular necrosis (ATN).
In a country like India, many cases of ARF are consequent to diarrhea, malaria or hemolysis due to G6PD deficiency. Infectious diseases are also relevant in Saudi Arabia, besides the western afflictions like road traffic accidents and septic shock.
This article will focus on "shock kidneys" i.e. ATN resulting from ischemia due to hypotension that is an accompaniment of major trauma or septicemia with Grampositive or Gram-negative organisms.
It has to be pointed out that 50% of postoperative ATN occurs without documented hypotension  .
| Endotoxins, ARF and Multi-Organ Failure (MOF)|| |
Experimental ARF in animals has often utilized bilateral clamping of the renal arteries. This certainly causes extensive tubular necrosis and release of endothelins. However, in renal situations, the blood supply to the kidneys is severely reduced but not completely interrupted. Intravenous injection of endotoxin, the lipopolysaccharide component of cell walls of the Gram-negative organisms, causes a 40% reduction of renal blood flow and a greater than 50% reduction of glomerular filtration rate (GFR) within 3 hours  . Oliguria ensues, the fractional excretion of sodium is increased and free water clearance becomes zero. There is patchy tubular necrosis. This is not a truly toxic effect on the tubules but the result of renal ischemia. As viewed by electron microscopy, by 3 hours the endothelial cells of the renal vessels are swollen and leukocytes are sequestered in the glomeruli and the peritubular capillary  . Endotoxin does sensitize renal tubular tissue to the effects of ischemia, even in the absence of detectable hemodynamic change  .
Where does endotoxin come from in the natural situation? Obviously it originates from Gram-negative bacteria in the circulation if they are destroyed by complement, as is common. The bacteria may arise from foci of sepsis in the peritoneum, gallbladder, urinary tract, and pancreatic ducts, or enter the portal circulation via the gastrointestinal mucosa as "bacterial translocation" that we know now to occur when there is septic, traumatic or hemorrhagic shock ,,, . Glycoproteins on the surface of the gut epithelium stop the passage of endotoxins through the mucosa. However, when their synthesis is curtailed, as is the case during mesenteric ischemia for a time as short as 30-40 minutes, then endotoxin can be absorbed, especially if there is small bowel contamination in sick or elderly patients. The effects of endotoxin on the kidneys are listed in [Table - 2].
Arteriolar vasoconstriction causes marked renal cortical ischemia but in the early stages there is shunting of blood through AV shunts and the renal medullary flow can increase  . This is fortunate because the pO 2 is normally low in the medulla and the high-energy requirement of the ascending loops of Henle render them very susceptible to damage, and this may result in polyuric acute renal failure, which occurs commonly in patients with sepsis. Hypoxia of the renal medulla is important, as is the loss of the protective nitric oxide that helps maintaining medullary blood flow  . In fact hypoxia regulates production of endothelin-I by the inner medullary collection ducts  . The medulla produces the highest concentrations of the endothelin-I. So there will be constriction of the descending vasa rectae, which are the only sources of medullary blood flow  .
It is also important to note that when endotoxins act on the vasculature, there should be compensatory production of prostaglandin E2. This is a cytoprotective agent. Yet work in mice shows that this does not happen in the kidneys  . It is such a pity that this work has not been extended to other species. Both rabbit and man are very susceptible to organ damage by endotoxemia, mice and pigs moderately so, but dogs, rats and baboons are quite resistant.
There has been so much discussion in the last 5 years on the relevance of cytokines to MOF  . From our viewpoint, the general principle is that trauma that creates complement activation and dead tissue or sepsis, which creates complement activation and activation of monocyte-macro-phages, leads to a massive release of cytokines such as tumor necrosis factor alpha (TNFa). Injection of TAFa is known to mediate multiple organ damage with disseminated intravascular coagulation (DIC), which more naturally can be produced by an injection of endotoxin. Patients with trauma and/or sepsis release endotoxin intermittently into their circulation. Hence after a while, one might see the development of ARF, or fullblown MOF.
There needs to be more clinical investigations along these lines. The first problem is that endotoxemia can be intermittent. The second problem is that some plasma assays are not sensitive enough. However, levels of 2 pg/ml have recently been assayed adequately after cardiopulmonary bypass  . We measured levels for plasma lipidA (an endotoxin) in various states of sepsis with or without ARF as shown in [Table - 3].  . The values were clearly elevated in septic situations and after trauma.
[Table - 4] shows some indirect evidence for endotoxemia in patients brought to the intensive care unit because of septicemia or major trauma. There is a rise of IgG and IgM antibody titers to Lipid-A after 5-7 days. Compare these antibody levels with those of chronic renal failure (CRF) patients on dialysis, who are naturally exposed to low levels of endotoxin via the haemodialysis membranes  .
| Renal Tubular Cellular Changes in ARF|| |
Whatever is the stimulus to renal vascoconstriction, the tubules usually suffer from ischemia-reperfusion injury. The restoration of blood flow in capillaries that have been Ischemic results in release of oxygen radicals, like superoxide, anions and hydroxyl radicals from the parenchymal cells, which help inflicting damage  . Allopurinol and antioxidants like sodium benzoate or dimethylurea do protect against such changes in experimental nephritides and vasculitides. However, there is observed protection after clamping of renal arteries. This may be attributed to differences in the experimental models, and the latter represents too severe induction of injury  . Furthermore, white cells and leukotrienes re implicated in natural ARF  . In models of ischemia, depletion of neutrophils, blockade of neutrophil adhesion to vascular endothelium , and inhibition of the complement system all reduce tissue injury.
There have been several recent reviews on the biological response of renal tubular cells to injury ,,, . [Table - 5], summarizes these responses.
A recent study illustrated how the renal tubular cells start to proliferate in order to effect repair at 4-6 days after ischemia induced by clamping of the renal arteries  . Proliferating cells can be quantitated by their proliferating cell nuclear antigen (PCNA).
In this study, there was an immediate peak of apoptotic cells at 24 hours after injury, and then a later peak at 10-14 days, as the structure of the tubules was re-established.
Another path used lectin and immunohistochemical study of ATN 926), mainly a seen in transplant biopsies, the percentage of PCNA positive nuclei as of the order 48% of tubular cells. Regenerating tubules with thin epithelium were observed mainly in the distal tubules. Casts were often seen at this level. The study is really of interest for the technology involved. During recovery from the ARF, the hyperplastic epithelial cells are removed by cell desquamation as much as by apoptosis  .
There are therapeutic implications to the cell biology of ARF  . There is no doubt that a lot of work will be done on the efficacy of endothelin antagonists in the prevention of ATN , . Since timing of administration is important, one looks forward to date from studies on hepatorenal failure.
RGD peptides that bind to P1-integrins, even of injured tubular cells, can have a therapeutic action in ischemic injury, presumably because they help preserve the integrity of renal tubular cells and certainly there is reduced tubular obstruction following their administration , . Well-chosen growth factors could accelerate recovery from acute tubular necrosis. Either growth hormone or insulin growth factor (IGF-I) is anabolic and aid tubular recovery. Epidermal growth factor and hepatocyte growth factor promote tubular growth in embryo and aid tubular re-growth after injury  .
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E Nigel Wardle
21 Common road, North Leigh, Oxford, England
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5]