Roles of Hemodynamic and Tubular Factors in Gentamicin-Mediated Nephropathy

Hishida, Akira; Nakajima, Toshiaki; Yamada, Masahito; Kato, Akihiko; Honda, Nishio

doi:10.3109/08860229409044852

Cited by 20 publications

(12 citation statements)

References 17 publications

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“…While the determinants of cell damage still remain undefined, more knowledge concerning the mechanisms causing the impairment of the renal function is available. Activation of the renin-angiotensin system and the ensuing local vasoconstric-tion appear to be primarily responsible for the decrease in glomerular filtration (45). This explains very well the aggravating effect of nonsteroidal anti-inflammatory drugs on aminoglycoside nephrotoxicity, since these drugs inhibit the production of the vasodilatatory prostaglandin PGE 2 (4).…”

Section: Renal Failurementioning

confidence: 97%

“…At this stage, a large number of structural, metabolic, and functional alterations are observed in tubular cells (Table 1), and several of these alterations have been claimed to be responsible for cell death or dysfunction. Many of the changes observed at the level of the apical membrane (25,45,46,113,116) could, however, be merely mediated by a direct effect of the drug on this structure during its initial stages of uptake in proximal tubular cells. Conversely, other effects, such as inhibition of protein synthesis and modulation of gene expression, mitochondrial alterations, or inhibition of enzymes located on the cytosolic side of the pericellular membrane, must involve uptake and intracellular distribution of the drug to the corresponding targets.…”

Section: Effects Of High Dose In Animalsmentioning

confidence: 99%

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Aminoglycosides: Nephrotoxicity

Mingeot‐Leclercq

Tulkens

1999

Antimicrob Agents Chemother

691

428

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Aminoglycosides have long been one of the commonest causes of drug-induced nephrotoxicity (137). Although a clear recognition of the patient-and treatment-related risk factors (91), combined with the once-a-day schedule and effective monitoring procedures (98), have definitely improved the situation over what prevailed in the early 1980s (115), we are still short of having brought the safety of aminoglycosides to that of the main other wide-spectrum antibiotics. Chemical research aimed at obtaining intrinsically less toxic compounds has met with only modest success, and few of the other approaches proposed to reduce the toxicities of the available agents have reached practical clinical applications. Yet, because aminoglycosides are very effective antibiotics well suited to the treatment of severe infections (35), it seems important to maintain and even develop efforts to improve their therapeutic indices. The present minireview tries to present in a prospective way the status of both the basic and the clinical research on aminoglycoside nephrotoxicity in order to clarify the main issues and to pinpoint strategies that may eventually lead to their safer use. Ototoxicity, which is the second main adverse effect of aminoglycosides and which, in contrast to nephrotoxicity, is irreversible, will not be considered here since it has already been reviewed in this journal (52) and elsewhere (10). A companion minireview (83) examines and discusses the recent research dealing with the activities of aminoglycosides and bacterial resistance.on July 5, 2020 by guest http://aac.asm.org/ Downloaded from a Low doses refer to either clinical dosages for humans or of dosages less than 20 mg/kg per day for animals. b References are given as a source for illustration of the typical effect that is described or refer to review papers; see text for more comprehensive citations. c These alterations have often been used for the early detection of aminoglycoside insult; however, their measurement is of limited practical value in diseased patients. d These cells show markedly enlarged lysosomes, with a decreased buoyant density and prominent myeloid bodies. e Electron microscopy shows widespread alteration of the cell ultrastructure and subcellular organelles, including mitochondria, endoplasmic reticulum, and nuclei. f Myeloid bodies are abundant in lumen and urine. 1004MINIREVIEWS ANTIMICROB. AGENTS CHEMOTHER.on July 5, 2020 by guest http://aac.asm.org/ Downloaded from

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Section: Renal Failurementioning

confidence: 97%

Section: Effects Of High Dose In Animalsmentioning

confidence: 99%

Aminoglycosides: Nephrotoxicity

Mingeot‐Leclercq

Tulkens

1999

Antimicrob Agents Chemother

691

428

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“…Gentamicin induces a reduction in renal blood flow (RBF), 116,117 which is the consequence of an increased resistance of the renal vascular bed rather than that of a lower perfusion pressure. 118 A lower RBF causes GFR to fall 119 (see Figure 3), and sensitizes tubule cells to cell death by reduction of oxygen and ATP availability (as explained above).…”

Section: Vascular Effectsmentioning

confidence: 99%

New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view

Quirós

Vicente

et al. 2011

Kidney International

580

421

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Nephrotoxicity is one of the most important side effects and therapeutical limitations of aminoglycoside antibiotics, especially gentamicin. Despite rigorous patient monitoring, nephrotoxicity appears in 10-25% of therapeutic courses. Traditionally, aminoglycoside nephrotoxicity has been considered to result mainly from tubular damage. Both lethal and sub-lethal alterations in tubular cells handicap reabsorption and, in severe cases, may lead to a significant tubular obstruction. However, a reduced glomerular filtration is necessary to explain the symptoms of the disease. Reduced filtration is not solely the result of tubular obstruction and tubular malfunction, resulting in tubuloglomerular feedback activation; renal vasoconstriction and mesangial contraction are also crucial to fully explain aminoglycoside nephrotoxicity. This review critically presents an integrative view on the interactions of tubular, glomerular, and vascular effects of gentamicin, in the context of the most recent information available. Moreover, it discusses therapeutic perspectives for prevention of aminoglycoside nephrotoxicity derived from the pathophysiological knowledge.

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“…In addition, the newly established polyuric state (urine output 3.6ml/kg/h) was not taken into account when her fluid allowance was set. It has been demonstrated that dehydration serves as a contributor to the known nephrotoxicity of agents such as liposomal amphotericin and amikacin and even more so in the case of pentamidine [6,7].…”

Section: Questionmentioning

confidence: 99%