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Saudi Journal of Kidney Diseases and Transplantation
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Year : 1998  |  Volume : 9  |  Issue : 3  |  Page : 231-236
Pathogenesis of Acute Renal Failure: Shock-Kidneys


21 Common Road, North Leigh, Oxford, England, United Kingdom

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   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

How to cite this URL:
Wardle E N. Pathogenesis of Acute Renal Failure: Shock-Kidneys. Saudi J Kidney Dis Transpl [serial online] 1998 [cited 2019 Jul 23];9:231-6. Available from: http://www.sjkdt.org/text.asp?1998/9/3/231/39265

   Introduction Top


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 [1] .


   Endotoxins, ARF and Multi-Organ Failure (MOF) Top


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 [2] . 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 [3] . Endotoxin does sensitize renal tubular tissue to the effects of ischemia, even in the absence of detectable hemodynamic change [4] .

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 [5],[6],[7],[8] . 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 [9] . 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 [10] . In fact hypoxia regulates production of endothelin-I by the inner medullary collection ducts [11] . 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 [12] .

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 [13] . 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 [14] . 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 [15] . We measured levels for plasma lipid­A (an endotoxin) in various states of sepsis with or without ARF as shown in [Table - 3]. [16] . 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 [16] .


   Renal Tubular Cellular Changes in ARF Top


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 [17] . 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 [18] . Furthermore, white cells and leukotrienes re implicated in natural ARF [19] . In models of ischemia, depletion of neutrophils, blockade of neutrophil adhesion to vascular endothelium [20],[21] 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 [22],[23],[24],[25] . [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 [25] . 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 [27] .

There are therapeutic implications to the cell biology of ARF [28] . There is no doubt that a lot of work will be done on the efficacy of endothelin antagonists in the prevention of ATN [29],[30] . 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 [25],[31] . 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 [32] .

 
   References Top

1.Hou SH, Bushinsky DA, Wish JB, Cohen JJ, Harrington JT. Hospital-acquired renal insufficiency: a prospective study. Am J Med 1983;74:243-8.  Back to cited text no. 1  [PUBMED]  
2.Hinshaw LB, Spink WW, Vick JA, Mallet F, Finstad J. Effect of endotoxin on kidney function and renal hemodynamics in the dog. Am J Physiol 1961;201:144-8.  Back to cited text no. 2    
3.Kikeri D, Penell JP, Hwang KH, et al. Endotoxamic acute renal failure in awake rats. J Urol 1989;141:1436-6.  Back to cited text no. 3    
4.Zager RA. Escherichia coli endotoxin injections potentiate experimental ischemic renal injury. Am J Physiol 1986;251:F988-­94.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.Baron P, Traber LD, Traber DI, et al. Gut failure and translocation following burn and sepsis. J Surg Res 1994;57:197-204.  Back to cited text no. 5    
6.Bahrami S, Schlag G, Yao YM, pedl H. Significance of translocation/endotoxin in development of systemic sepsis following trauma and/of hemorrhage. Prog Clin Biol REs 1995;392:197-208.  Back to cited text no. 6    
7.Wardle EN. Acute renal failure and multi­organ failue. Nephron 1994;66:380-5.  Back to cited text no. 7  [PUBMED]  
8.Lemaire LC, van Lanschot JJ, Stoutenbeek CP, van Devnter SJ, Wells CL, Gouma DJ. Bacterial translocation in multiple organ failure: cause or epiphenomenon still unproven. Br J Surg 1997;84:1340-50.  Back to cited text no. 8    
9.Brezis M, Hyeman SN, Dinour D, Epstein FH, Rosen S. Role of nitric oxide in renal medullary oxygenation. J Clin Invest 1991;88:390-5.  Back to cited text no. 9    
10.Brezis M, Rosen S. Hypoxia of the renal medulla-its implications for disease. N Engl J Med 1995;332:647-55.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Miler RL, Kohen DE. Hypoxia regulates endothelin-1 production by the innermedullary collecting duct. J Lab Clin Med 1998;131:45-8.  Back to cited text no. 11    
12.Vetterlein F, Bludau J, petho-Schramm A, Schmidt G. Reconstruction of blood flow distribution in the rat kidney during post ischemic renal failure. Nephron 1994;66:208-14.  Back to cited text no. 12    
13.Masferrer JL, Zweifel BS, Seibert K, Needle-man P. Selective regulation of cellular cyclooxtgenase by dexamethasone and endotoxin in mice. J Clin Invest 1990;86:1375-9.  Back to cited text no. 13    
14.Hack CE, Aarden LA. Thijs LG. Role of cytokines in sepsis. Adv Immunol 1997;66:101-95.  Back to cited text no. 14    
15.Khaber K, El Barhry MA, Khougeer F, Deval E, Al-Gain S, Al-Halees Z. Circulating endotoxin and cytokines after cardiopulmonary bypass. Clin Immunol Immunopathol 1997;85:97-103.  Back to cited text no. 15    
16.Vijaykumar E, Raziuddin S, Wardle EN. Plasma endotoxin in patients with trauma, sepsis and severe haeorrhage. Clin Int Care 1991;2:4-7.  Back to cited text no. 16    
17.Bulkey GB. Reactive oxygen metabolites and reperfusion injury: aberrant triggering of reticuloendothelial function. Lancet 1994;344:934-6.  Back to cited text no. 17    
18.Zager RA, Fuerstenberg SM, Beher PH, Myerson D, Torko-Storb B. An evaluation of antioxidant effects on recovery from post-ischemic acute renal failure. J Am Soc Nephrol 1994;4:1588-97.  Back to cited text no. 18    
19.Klausner JM, Paterson IS, goldman G, et al. Posischemic renal injury is mediated by neutrophils and leukotrienes. Am J Physiol 1989;256:F794-802.  Back to cited text no. 19  [PUBMED]  [FULLTEXT]
20.Kelly KJ, Williams WW Jr, Colvin RB, et al. Intercellular adhesion molecule-1­deficient mice are protected against ischemic renal injury. J Clin Invest 1996;97:1056-63.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]
21.Armstead VE, Minchenko AG, Campbell B, Lefer AM. P-selection is up regulated in vital organs during murine traumatic shock. FASEB J 1997;11:1271-9.  Back to cited text no. 21  [PUBMED]  [FULLTEXT]
22.Iaina A, Schwartz D. Renal tubular cellular and molecular events in acute renal failure. Nephron 1994;68:413-8.  Back to cited text no. 22  [PUBMED]  
23.Fish EM, Molitoris BA. Alterations in epithelial polarity and the pahogenesis of disease states: n Engl J Med 1994;330:1580-8.  Back to cited text no. 23    
24.Thadhani R, Paseual M, Bonventre JV. Acute renal failure. N Engl J Med 1996;334:1448-60.  Back to cited text no. 24    
25.Takeda JA. Pathomorphological study on damage and repair proesses of tubuli after renal ischemia. Japan J Nephrol 1996;38:493-501.  Back to cited text no. 25    
26.Nadasdy T, laszik Z, Blick KE, et al. Human acute tubular necrosis: a lectin and immuno-histochemical study. Hum Pathol 1995;26:230-9.  Back to cited text no. 26  [PUBMED]  
27.Shiizu A, Yamanka N. Apoprosis and cell desquamation in repair process of ischemic tubular necrosis. Virchows Arch B Cell Pathol 1993;64:171-80.  Back to cited text no. 27    
28.Lieberthal W. Biology of acute renal failure: therapeutic implications. Kidney In 1997;52:1102-15.  Back to cited text no. 28    
29.Chan L, chittinandana A, Shapiro JI, Shanley PF, Schrier RW. Effect of an endothelin receptor antagonist on ischemic acute renal failure. Am J Physiol 1994;266:135-8.  Back to cited text no. 29    
30.Gellai M, Jugus M, Fletcher T, Dewolf R, Naimbi P. Reversal of postischemic acute renal failure with a selective endothelin a receptor antagonist in the rat. J clin Invest 1994;93:900-6.  Back to cited text no. 30    
31.Goligorsky MS, Noiri E, Kessler H, Romanov V. therapeutic potential of GD peptides in acute renal injury. Kidney Int 1997;51:1487-92.  Back to cited text no. 31  [PUBMED]  
32.Hammerman MR, Miller SB. Therapeutic use of growth factors in renal failure. J Am Soc Nephrol 1994;5:1-11.  Back to cited text no. 32  [PUBMED]  [FULLTEXT]

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Correspondence Address:
E Nigel Wardle
21 Common road, North Leigh, Oxford, England
United Kingdom
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PMID: 18408295

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