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Am J Physiol Renal Physiol 293: F41-F42, 2007. First published May 16, 2007; doi:10.1152/ajprenal.00224.2007
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EDITORIAL FOCUS

Subclinical kidney injury incites endotoxin hyperresponsiveness

Subhashini Bolisetty and Anupam Agarwal

Department of Medicine, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama

GENTAMICIN, AN AMINOGLYCOSIDE discovered in 1963 from micromonospora, is one of the most commonly used antibiotics against Gram-negative infections. Aminoglycosides achieve bacterial killing by binding to bacterial ribosomes, causing blockade of protein synthesis through failure of initiation and misreading of messenger RNA. The effectiveness of these antibiotics is emphasized by the following factors: 1) efficient bactericidal nature (fast and concentration-dependent killing), 2) postantibiotic effect (continued suppression of bacterial growth when concentrations fall below MIC), 3) low development rate of resistance to the antibiotic, and 4) synergism when combined with beta-lactam antibiotics (8). Due to the aforementioned factors, gentamicin is considered a breakthrough in the treatment of Gram-negative sepsis and remains one of the most frequently used aminoglycosides in clinical practice. However, the dose-dependent effects of gentamicin on the kidney resulting in acute renal failure (~15–20% of all cases) have restricted its use (2, 9).

Several mechanisms have been suggested to account for gentamicin-induced acute renal failure (2, 9). These include generation of reactive oxygen and nitrogen species (17, 21), release of inflammatory components from dying bacteria, and inhibition of protein synthesis (3). Gentamicin accumulates in the kidneys of both experimental animals (6, 12) and humans (1, 5, 11) and is taken up selectively by proximal tubular cells of the nephron (11) by high-affinity binding to megalin (13). This feature has helped establish the use of gentamicin as a model for segment-specific injury to the proximal tubule. Besides nephrotoxicity, gentamicin is also known to cause ototoxicity, which results from transient high peak concentrations in the serum and inner ear (18).

In the course of treatment for Gram-negative sepsis with gentamicin or other antimicrobial agents, lipopolysaccharide (LPS) and components of the bacterial cell wall are released and these can induce inflammatory cascades. This phenomenon known as the Jarisch-Herxheimer reaction was first described in syphilitic patients treated with mercury. Studies have shown increased levels of LPS following antibiotic treatment of infections in clinical (10) and experimental settings (7, 14, 19). LPS, in the presence of infection, trauma, ischemia, or nephrotoxins, induces synthesis of cytokines/chemokines such as TNF-{alpha}, interleukin-10 (IL-10), and monocyte chemotactic protein-1 (MCP-1) (4, 20). The presence of Gram-negative sepsis also predisposes to increased susceptibility to acute renal failure from ischemia or nephrotoxins (22, 27).

In a paper in the present issue of the American Journal of Physiology-Renal Physiology, Zager's laboratory (23) has explored the risk of gentamicin treatment on the potentiation of endotoxin-driven inflammatory responses. Previous studies from his laboratory had explored this link under settings of urinary tract obstruction, renal ischemia-reperfusion, and cisplatin nephrotoxicity, where it was observed that overt kidney injury resulted in hyperresponsiveness to LPS (24–26). In this most recent work, the author sought to examine whether selective proximal tubule injury alone could heighten this response and whether this state of hyperresponsiveness could be expressed in the absence of obvious tubular injury and renal failure. Gentamicin was chosen due to its inherent nature of selective uptake by the proximal tubular cells, and a low subclinical dose of the agent that did not inflict structural or functional renal damage was utilized. LPS was administered at 0, 24, or 72 h after gentamicin treatment, and cytokine profiles were measured in the kidney, liver, spleen, and serum. Even a single subclinical dose of gentamicin followed by LPS administration was capable of dramatically altering the cytokine profiles for TNF-{alpha} and MCP-1 in the kidney. This response was not restricted to the kidney alone, where gentamicin is preferentially concentrated, but was also observed in extrarenal organs such as the liver. This hyperresponsiveness was observed when mice were pretreated with gentamicin 1 or 3 days before LPS administration or when both the agents were simultaneously administered. The findings also highlight that gentamicin, known to inhibit protein synthesis, perhaps preferentially upregulates transcription of inflammatory genes, thereby producing the expected outcome. Interestingly, levels of the anti-inflammatory cytokine IL-10 were also upregulated in the kidney. It is possible that this may represent an adaptive mechanism to balance the otherwise increased proinflammatory response.

The priming effect of LPS is not restricted to subclinical gentamicin-induced proximal tubular injury but also extends to other nephrotoxins. A recent study by Ramesh and colleagues (15) has reported similar findings following a nonnephrotoxic dose of cisplatin (15). Low-dose cisplatin (10 mg/kg) had no effect on renal function but sensitized the kidney to subsequent LPS exposure, resulting in increased intrarenal production of TNF-{alpha}, worse renal function, and increased mortality in mice. Using TLR-4-deficient and TNF-{alpha}-deficient mice, these authors showed that the priming effect of LPS following cisplatin was dependent mainly on TLR-4 signaling and partially dependent on TNF-{alpha}.

The findings of Zager (23) are germane to our clinical practice, where the dose of gentamicin is usually decreased in patients with kidney disease and reduced renal function. The results showing that even low doses of gentamicin can prime not only the kidney but also extrarenal organs to endotoxin-mediated hyperresponsiveness provide an important and relevant concept that will impact the use of gentamicin in the treatment of Gram-negative sepsis. It would be of great interest to evaluate whether the newly described nonnephrotoxic gentamicin congeners (that retain bactericidal properties with no significant nephrotoxicity) (16) exhibit similar effects in terms of endotoxin hyperresponsiveness.


   FOOTNOTES
 

Address for reprint requests and other correspondence: A. Agarwal, Div. of Nephrology, ZRB 614, Univ. of Alabama at Birmingham, Birmingham, AL 35294 (e-mail: agarwal{at}uab.edu)


   REFERENCES
TOP
 REFERENCES
 

  1. Alfthan O, Renkonen OV, Sivonen A. Concentration of gentamicin in serum, urine and urogenital tissue in man. Acta Pathol Microbiol Scand [B] Microbiol Immunol Suppl 241: 292–244, 1973.
  2. Bennett WM. Mechanisms of aminoglycoside nephrotoxicity. Clin Exp Pharmacol Physiol 16: 1–6, 1989.[Web of Science][Medline]
  3. Bennett WM, Mela-Riker LM, Houghton DC, Gilbert DN, Buss WC. Microsomal protein synthesis inhibition: an early manifestation of gentamicin nephrotoxicity. Am J Physiol Renal Fluid Electrolyte Physiol 255: F265–F269, 1988.[Abstract/Free Full Text]
  4. Damas P, Ledoux D, Nys M, Vrindts Y, De Groote D, Franchimont P, Lamy M. Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg 215: 356–362, 1992.[Web of Science][Medline]
  5. Edwards CQ, Smith CR, Baughman KL, Rogers JF, Lietman PS. Concentrations of gentamicin and amikacin in human kidneys. Antimicrob Agents Chemother 9: 925–927, 1976.[Abstract/Free Full Text]
  6. Fabre J, Rudhardt M, Blanchard P, Regamey C. Persistence of sisomicin and gentamicin in renal cortex and medulla compared with other organs and serum of rats. Kidney Int 10: 444–449, 1976.[Web of Science][Medline]
  7. Friedland IR, Jafari H, Ehrett S, Rinderknecht S, Paris M, Coulthard M, Saxen H, Olsen K, McCracken GH Jr. Comparison of endotoxin release by different antimicrobial agents and the effect on inflammation in experimental Escherichia coli meningitis. J Infect Dis 168: 657–662, 1993.[Web of Science][Medline]
  8. Hansen M, Christrup LL, Jarlov JO, Kampmann JP, Bonde J. Gentamicin dosing in critically ill patients. Acta Anaesthesiol Scand 45: 734–740, 2001.[CrossRef][Web of Science][Medline]
  9. Humes HD. Aminoglycoside nephrotoxicity. Kidney Int 33: 900–911, 1988.[Web of Science][Medline]
  10. Hurley JC, Louis WJ, Tosolini FA, Carlin JB. Antibiotic-induced release of endotoxin in chronically bacteriuric patients. Antimicrob Agents Chemother 35: 2388–2394, 1991.[Abstract/Free Full Text]
  11. Kuhar MJ, Mak LL, Lietman PS. Autoradiographic localization of [3H]gentamicin in the proximal renal tubules of mice. Antimicrob Agents Chemother 15: 131–133, 1979.[Abstract/Free Full Text]
  12. Luft FC, Kleit SA. Renal parenchymal accumulation of aminoglycoside antibiotics in rats. J Infect Dis 130: 656–659, 1974.[Web of Science][Medline]
  13. Moestrup SK, Cui S, Vorum H, Bregengard C, Bjorn SE, Norris K, Gliemann J, Christensen EI. Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs. J Clin Invest 96: 1404–1413, 1995.[Web of Science][Medline]
  14. Mohler J, Fantin B, Mainardi JL, Carbon C. Influence of antimicrobial therapy on kinetics of tumor necrosis factor levels in experimental endocarditis caused by Klebsiella pneumoniae. Antimicrob Agents Chemother 38: 1017–1022, 1994.[Abstract/Free Full Text]
  15. Ramesh G, Zhang B, Uematsu S, Akira S, Reeves WB. Endotoxin and cisplatin synergistically induce renal dysfunction and cytokine production in mice. Am J Physiol Renal Physiol. First published May 9, 2007; doi:10.1152/ajprenal.00158.2007. In press.
  16. Sandoval RM, Reilly JP, Running W, Campos SB, Santos JR, Phillips CL, Molitoris BA. A non-nephrotoxic gentamicin congener that retains antimicrobial efficacy. J Am Soc Nephrol 17: 2697–2705, 2006.[Abstract/Free Full Text]
  17. Sayed-Ahmed MM, Nagi MN. Thymoquinone supplementation prevents the development of gentamicin-induced acute renal toxicity in rats. Clin Exp Pharmacol Physiol 34: 399–405, 2007.[CrossRef][Web of Science][Medline]
  18. Selimoglu E. Aminoglycoside-induced ototoxicity. Curr Pharm Des 13: 119–126, 2007.[CrossRef][Web of Science][Medline]
  19. Shenep JL, Barton RP, Mogan KA. Role of antibiotic class in the rate of liberation of endotoxin during therapy for experimental gram-negative bacterial sepsis. J Infect Dis 151: 1012–1018, 1985.[Web of Science][Medline]
  20. van Deuren M, van der Ven-Jongekrijg J, Bartelink AK, van Dalen R, Sauerwein RW, van der Meer JW. Correlation between proinflammatory cytokines and antiinflammatory mediators and the severity of disease in meningococcal infections. J Infect Dis 172: 433–439, 1995.[Web of Science][Medline]
  21. Walker PD, Barri Y, Shah SV. Oxidant mechanisms in gentamicin nephrotoxicity. Ren Fail 21: 433–442, 1999.[Web of Science][Medline]
  22. Zager RA. Gentamicin nephrotoxicity in the setting of acute renal hypoperfusion. Am J Physiol Renal Fluid Electrolyte Physiol 254: F574–F581, 1988.[Abstract/Free Full Text]
  23. Zager RA. "Subclinical" gentamicin nephrotoxicity: a potential risk factor for exaggerated endotoxin-driven TNF-{alpha} production. Am J Physiol Renal Physiol. First published April 18, 2007; doi:10.1152.ajprenal.00144.2007.
  24. Zager RA, Johnson AC, Hanson SY, Lund S. Acute nephrotoxic and obstructive injury primes the kidney to endotoxin-driven cytokine/chemokine production. Kidney Int 69: 1181–1188, 2006.[CrossRef][Web of Science][Medline]
  25. Zager RA, Johnson AC, Hanson SY, Lund S. Ischemic proximal tubular injury primes mice to endotoxin-induced TNF-{alpha} generation and systemic release. Am J Physiol Renal Physiol 289: F289–F297, 2005.[Abstract/Free Full Text]
  26. Zager RA, Johnson AC, Lund S, Hanson S. Acute renal failure: determinants and characteristics of the injury-induced hyperinflammatory response. Am J Physiol Renal Physiol 291: F546–F556, 2006.[Abstract/Free Full Text]
  27. Zager RA, Prior RB. Gentamicin and gram-negative bacteremia. A synergism for the development of experimental nephrotoxic acute renal failure. J Clin Invest 78: 196–204, 1986.[Web of Science][Medline]




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