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- Acute renal failure: aminoglycoside-induced acute renal failure generally appears after 7 days of exposure and its urinary pattern is usually a non-oligoanuric one. High urinary enzyme levels usually is one of the earliest sign of nephrotoxicity. Alanin-aminopeptidase, N-acetil-beta-D-glucosaminidase and gammaglutamiltransferase are the discharged enzymes2. Urinalysis usually shows proteinuria and hyaline and granular casts1, 4, 5). When acute renal failure develops in the course of aminoglycoside therapy, antibiotic withdrawal and replacement with non-aminoglycoside agent is prudent. Recovery of renal function generally occurs if renal failure is recognized early and the offending agent is discontinued4. Prolonged therapy have led to irreversible damage and dialysis dependence1. Neomicin is the most nephrotoxic aminoglycoside while streptomycin is the least one4.
- Fanconi syndrome and tubular electrolyte wasting: aminoglycoside-induced renal tubular toxicity include from an isolated tubular wasting of amino acids, glucose, potassium, calcium, magnesium or/and phosphorus to a complete Fanconi syndrome. These wasting syndromes can occur in the absence of renal failure and they even appear before the instalation of acute tubular necrosis2, 6, 7).
- Diabetes insipidus: aminoglycoside can induced water diuresis due to an inability to concentrate urine because of a reduction of the epythelial sensitivity to antidiuretic hormone through an adenilciclyse inhibition2, 8).
- Hypercloremic metabolic acidosis: due to a reduction in the renal capability to proton excretion and amonium generation2.
- Insuficiencia renal aguda: suele aparecer a la semana de la exposición al fármaco y se presenta habitualmente con un patrón no-oligoanúrico. La elevación de enzimuria: alanina aminopeptidasa, Nacetil-beta-D glucosaminidasa y gamaglutamiltransferasa, es uno de los marcadores más tempranos de daño renal2. Los análisis urinarios suelen mostrar proteinuria, cilindros hialinos y granulosos1, 4, 5. La suspensión del antibiótico y su sustitución por uno no nefrotóxico constituye la principal medida en función de mejorar la función renal. Pese a la habitual reversibilidad de esta toxicidad el uso prolongado de estas drogas puede generar una insuficiencia renal crónica con requerimiento dialítico. La neomicina es la forma más nefrotóxica y la estreptomicina la menos4.
- Síndrome de Fanconi: consiste en la pérdida urinaria de origen tubular proximal de sustancias como glucosa, aminoácidos, potasio, calcio, magnesio y fósforo en forma aislada o conjunta. Este cuadro puede verse en ausencia de insuficiencia renal e incluso suele precederla2, 6, 7.
- Diabetes Insípida: consiste en la inducción de diuresis acuosa debido a una resistencia de los túbulos colectores a la hormona antidiurética a raíz de una inhibición de la adenilato ciclasa 2, 8.
- Acidosis Metabólica Hiperclorémica: secundaria a una reducción de la excreción de protones y de la amonigénesis2.
Rev Electron Biomed / Electron J Biomed 2004;2:2-4.
Editorial: AMINOGLYCOSIDES AND NEPHROPATHY
Despite nephrotoxicity complicates 10 to 20 percent of therapeutic courses based on aminoglycosides these drugs maintain a leading role in bactericidal therapy of severe Gram negative infections1.
Aminoglycosides are cationic molecules that undergo renal excretion by glomerular filtration, although a small percentage of the filtered drug is reabsorbed proximally2. It has been suggested that the aminoglycosides bind to specific receptors and undergo endocytosis via the same mechanism used by amino acids and small peptides in the cells lining the S1 and S2 portions of the proximal convoluted tubules3. These vesicles fuse with lysosome membranes where many enzymes are inhibited into these organelles. As a consequence cellular membranes, that are normally degradeted inside these vesicles, accumulate as myeloid bodies. The progression of this phenomenon leads to lysosomal membrane disruption, allowing many enzymes to reach the cytoplasm2, 3.
Described factors that increase severity of aminoglycoside-induced renal injury are: advanced age, prolonged exposure and increased frequency to this drug, more toxic aminoglycoside, concomitant exposure to other nephrotoxic drugs, volume contraction, acidosis, magnesium, calcium and potassium deplection, preexisting hepatic disease or nephropathy (specially if dose is not adjusted to level of renal function)3, 4. On the other hand factors postulated as renal protective are: potassium supplements, urinary alcalinitation, high calcium diets, and use of polymers of aspartic acid, calcium antagonist, carbenicilin and ticarcilin2.
The following are the four aminoglycoside-induced renal syndromes that may appear as isolated or combined entities:
In conclusion aminoglycosides are usuful antibiotics but they have to be used cautiously because of their nephrotoxicity. Four are the aminoglycoside-induced renal syndromes: acute renal failure, partial or complete Fanconi syndrome, diabetes insipidus and tubular acidosis. Recovery of renal function generally occurs if renal failure is recognized early and the offending agent is discontinued.
Editorial: AMINOGLYCOSIDES AND NEPHROPATHY
Despite nephrotoxicity complicates 10 to 20 percent of therapeutic courses based on aminoglycosides these drugs maintain a leading role in bactericidal therapy of severe Gram negative infections1.
Aminoglycosides are cationic molecules that undergo renal excretion by glomerular filtration, although a small percentage of the filtered drug is reabsorbed proximally2. It has been suggested that the aminoglycosides bind to specific receptors and undergo endocytosis via the same mechanism used by amino acids and small peptides in the cells lining the S1 and S2 portions of the proximal convoluted tubules3. These vesicles fuse with lysosome membranes where many enzymes are inhibited into these organelles. As a consequence cellular membranes, that are normally degradeted inside these vesicles, accumulate as myeloid bodies. The progression of this phenomenon leads to lysosomal membrane disruption, allowing many enzymes to reach the cytoplasm2, 3.
Described factors that increase severity of aminoglycoside-induced renal injury are: advanced age, prolonged exposure and increased frequency to this drug, more toxic aminoglycoside, concomitant exposure to other nephrotoxic drugs, volume contraction, acidosis, magnesium, calcium and potassium deplection, preexisting hepatic disease or nephropathy (specially if dose is not adjusted to level of renal function)3, 4. On the other hand factors postulated as renal protective are: potassium supplements, urinary alcalinitation, high calcium diets, and use of polymers of aspartic acid, calcium antagonist, carbenicilin and ticarcilin2.
The following are the four aminoglycoside-induced renal syndromes that may appear as isolated or combined entities:
In conclusion aminoglycosides are usuful antibiotics but they have to be used cautiously because of their nephrotoxicity. Four are the aminoglycoside-induced renal syndromes: acute renal failure, partial or complete Fanconi syndrome, diabetes insipidus and tubular acidosis. Recovery of renal function generally occurs if renal failure is recognized early and the offending agent is discontinued.
Editorial: AMINOGLUCÓSIDOS Y NEFROTOXICIDAD
Los aminoglucósidos son moléculas catiónicas eliminadas por filtración glomerular , aunque un pequeño porcentaje filtrado es reabsorvido a nivel de los túmulos proximales2. Se ha sugerido que los aminoglucósidos se unen a receptores específicos y luego son incorporados a las células tubulares por endocitosis a través del mismo mecanismo que reabsorven aminoácidos y pequeños péptidos en las células que tapizan el S1 y S2 de los túbulos contorneados proximales3. Estas vesículas se fusionan con lisosomas donde muchas enzimas son inhibidas dentro de estas organelas. Como consecuencia las membranas celulares, que normalmente son degradadas dentro de estas vesículas, se acumulan conformando los llamados cuerpos mieloides. La progresión de este fenómeno lleva a la disrupción de los lisosomas permitiendo la salida de sus enzimas al citoplasma2, 3.
Los factores descriptos como facilitadores del daño renal por aminoglucósidos son: edad avanzada, exposición prolongada o en alta frecuencia a estas drogas, uso se las fórmas más nefrotóxicas, exposición concomitante a otros nefrotóxicos, contracción de volumen, acidosis, depleción de magnesio, potasio y/o calcio, hepatopatía o nefropatía preexistente (sobre todo si la dosis no es ajustada al grado de insuficiencia renal)3, 4. En cuanto a los factores descriptos como protectores hallamos: suplementos de potasio, alcalinización urinaria, dietas ricas en calcio, polímeros de ácido aspártico, antagonistas cálcicos, carbenicilina y ticarcilina2.
Cuatro son los síndromes renales que los aminoglucósidos pueden generar, ya sea como entidades aisladas, o combinadas:
Conclusión: los aminoglucósidos son antibióticos útiles pero deben ser usados con precaución a raíz de su potencial nefrotoxicidad. Cuatro son las entidades renales que pueden generar: insuficiencia renal aguda, síndrome de Fanconi parcial o completo, diabetes insípida y acidosis tubular. La injuria renal suele ser reversible y mejora con la temprana suspensión de la droga.
References / Referencias
1) Swan S, Bennett W. Nephrotoxic acute renal failure. In Lazarus JM, Brenner BM (Eds).Acute renal failure. New York. Curchill Livingstone. 1993: 361-362
2) Ahijado FJ, Garcia S. Insuficiencia renal aguda por nefrotóxicos. In Liaño F, Pascual J. (Eds). Insuficiencia renal aguda. Barcelona. Masson.2000: 143-146.
3) Gilbert D. Aminoglycosides. In Mandell D, Bennett S (Eds). Principles and practice of infectious diseases. Philadelphia. Churchill Livingstone.2000: 318-321
4) Chambers H. The aminoglycosides. In Goodman Gilman A, Limbird LE, Hardman JG (Eds). The pharmacological basis of therapeutic. New York. Medical Publishing Division. 2002: 1229-1230
5) Lacy C, Armstrong L, Goldman M, Lance L. Drug information handbook Hudson. Lexi-Comp; 2003: 1115-1116.
6) Tannen R. Potassium disorders. In Kokko J, Tannen R (eds). Fluids and electrolytes. Philadelphia. W.B Saunders Company. 1996: 153
7) Pollak M, Yu A. Clinical disturbances of calcium, magnesium, and phosphate metabolism. In Brenner B, Rector (eds). The kidney. Saunders. 2004:1053-1061
8) El Mouedden M, Laurent G, Mingeot-Leclercq MP, Taper H, Cumps J, Tulkens. Apoptosis in renal proximal tubules of rats treated with low dosis of aminoglycosides. Antimicrobial Agents and Chemotherapy. 2000; 44: 665-675.