amphotericin-b and Acidosis--Renal-Tubular

Drug interactions in the gastrointestinal tract, liver and kidneys result from alterations in pH, ionic complexation, and interference with membrane transport proteins and enzymatic processes involved in intestinal absorption, enteric and hepatic metabolism, renal filtration and excretion. Azole antifungals can be involved in drug interactions at all the sites, by one or more of the above mechanisms. Consequently, azoles interact with a vast array of compounds. Drug-drug interactions associated with amphotericin B formulations are predictable and result from the renal toxicity and electrolyte disturbances associated with these compounds. The echinocandins are unknown cytochrome P450 substrates and to date are relatively devoid of significant drug-drug interactions. This article reviews drug interactions involving antifungal agents that affect other agents and implications for patient care are highlighted.

Topics: Acidosis, Renal Tubular; Amphotericin B; Antifungal Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biotransformation; Caspofungin; Clinical Trials as Topic; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; Drug Therapy, Combination; Echinocandins; Enzyme Inhibitors; Fluconazole; Humans; Itraconazole; Lipopeptides; Liver; Mycoses; Patient Care; Peptides, Cyclic

Amphotericin B (AmB) has been in clinical use for more than 30 yr but has remained the most effective drug for treatment of serious fungal infections. Its use has increased in recent years, as the result of increases in aggressive intensive care support and increased numbers of immunocompromised patients. Nephrotoxic manifestations are common, and this is the major factor limiting the clinical use of the drug. A number of recent studies have contributed to a better understanding of the mechanism by which AmB exerts its nephrotoxic effect. AmB alters cell membrane permeability and probably as a consequence alters tubular and vascular smooth muscle cell function, leading to various tubular transport defects and vasoconstriction. Decreased RBF appears to play a major role in AmB-induced reduction GFR, and recurrent ischemia may be the basis of permanent structural nephrotoxic effects. Salt loading is the only measure proven by controlled prospective study to ameliorate AmB nephrotoxicity in humans. Liposomal AmB and the formulation of an emulsion of AmB in lipid may provide a protective effect based on altering the affinity of AmB for mammalian cell membranes, while preserving high efficacy against fungal cells. However, further studies are needed to evaluate the efficacy and safety of these new AmB formulations.

Topics: Acidosis, Renal Tubular; Amphotericin B; Cell Membrane Permeability; Humans; Hypokalemia; Kidney; Kidney Diseases; Vasoconstriction

A number of potential defects may impair acidification either directly or indirectly in the CCT, the OMCT, the IMCD, or in all segments. These defects are summarized in Table 1. Findings from studies in animal models of DRTA have enhanced out understanding of the pathophysiological basis of these disorders. Nevertheless, considerable effort needs to be directed in the future toward defining the cellular basis of these defects, especially in the inherited forms of classical hypokalemic DRTA, for which an adequate experimental model does not yet exist.

Topics: Acid-Base Equilibrium; Acidosis, Renal Tubular; Aldosterone; Amiloride; Amphotericin B; Animals; Humans; Kidney Concentrating Ability; Kidney Tubules; Lithium; Toluene; Turtles

Topics: Acetazolamide; Acidosis, Renal Tubular; Amphotericin B; Animals; Cadmium; Heparin; Humans; Indomethacin; Lithium; Metals; Spironolactone; Tetracycline

Topics: Acidosis, Renal Tubular; Aldosterone; Amiloride; Amphotericin B; Animals; Carbon Dioxide; Disease Models, Animal; Hydrogen; Hydrogen-Ion Concentration; Kidney Tubules, Distal; Lithium; Partial Pressure; Ureteral Obstruction

Topics: Acidosis, Renal Tubular; Amiloride; Amphibians; Amphotericin B; Animals; Biological Transport, Active; Carbonates; Disease Models, Animal; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Kidney Tubules; Kidney Tubules, Distal; Lithium; Membrane Potentials; Rats; Turtles

A 39-year-old male with multiple myeloma was admitted for treatment with melphalan and autologous stem cell reinfusion. He presented with hypokalemia and hyperchloremic non-anion-gap metabolic acidosis with a high urinary pH. He also had hypomagnesemia, hypophosphatemia, hypouricemia, proteinuria and glucosuria. The patient subsequently developed polyuria with a low urine osmolality, hypernatremia and, finally, acute renal failure.. Physical examination, blood and urine analyses, kidney biopsy and tonicity balance.. Fanconi syndrome with proximal (type II) renal tubular acidosis caused by myeloma kidney. Renal tubular acidosis was complicated by probable nephrogenic diabetes insipidus and acute renal failure.. Potassium supplementation, sodium bicarbonate therapy, intravenous fluid therapy and dialysis.

Topics: Acidosis, Renal Tubular; Acute Kidney Injury; Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Diabetes Insipidus, Nephrogenic; Fanconi Syndrome; Hematologic Diseases; Humans; Male; Multiple Myeloma; Myelodysplastic Syndromes

Recent classifications of the several pathophysiologic types of distal renal tubular acidosis (secretory, voltage dependent, and gradient) have been based on the response of acidification parameters to a series of provocative maneuvers in vivo and in vitro. A reduction in the difference in urine and blood CO2 tension during bicarbonate loading (U-B pCO2 gradient), a widely applied parameter, has been employed as an index of reduced distal nephron proton secretion. This study was designed to test the validity of the U-B pCO2 gradient in a variety of experimental models of distal renal tubular acidosis by measuring and comparing disequilibrium pH (a direct technique to detect H+ secretion in situ) with the pCO2 in the papillary collecting duct of the rat in vivo during bicarbonate loading. Chronic amiloride, lithium chloride, and amphotericin-B administration, and the post-obstructed kidney models were employed. Amiloride resulted in an acidification defect which did not respond to sulfate infusion (urine pH = 6.15 +/- 0.08), and was associated with an obliteration of the acid disequilibrium pH (-0.26 +/- 0.05- -0.08 +/- 0.03) and reduction in papillary pCO2 (116.9 +/- 3.2 - 66.9 +/- 2.5 mmHg). The defect induced by lithium administration responded to Na2SO4 (urine pH = 5.21 +/- 0.06) but was similar to amiloride with respect to the observed reduction in disequilibrium pH (-0.04 +/- 0.02) and pCO2 (90.3 +/- 3.0 mmHg). The post-obstructed kidney model was characterized by an abnormally alkaline urine pH unresponsive to sulfate (6.59 +/- 0.06) and a reduction in disequilibrium pH (+0.02 +/- 0.06) and pCO2 (77.6 +/- 3.6 mmHg). Amphotericin-B resulted in a gradient defect as characterized by excretion of an acid urine after infusion of sodium sulfate (5.13 +/- 0.06). Unlike other models, however, amphotericin-B was associated with a significant acid disequilibrium pH (-0.11 +/- 0.05) and an appropriately elevated urine pCO2 (119.8 +/- 6.4 mmHg) which did not differ from the respective values in control rats. Thus, these findings support the use of the U-B pCO2 as a reliable means of demonstrating impaired distal nephron proton secretion in secretory and voltage-dependent forms of distal renal tubular acidosis (RTA) and supports the view that proton secretion is not impaired in gradient forms of distal RTA.

Topics: Absorption; Acid-Base Equilibrium; Acidosis, Renal Tubular; Amphotericin B; Animals; Bicarbonates; Carbon Dioxide; Disease Models, Animal; Hydrogen-Ion Concentration; Male; Nephrons; Rats; Rats, Inbred Strains

Topics: Acidosis, Renal Tubular; Amphotericin B; Animals; Carbon Dioxide; Male; Rats

It has been proposed that distal renal tubular acidosis is a gradient-limited disorder an that the low urine Pco2 observed in this condition is caused by back diffusion of carbonic acid. This study was designed to examine this hypothesis using the amphotericin B model of gradient-limited distal renal tubular acidosis in rats. After induction of acute metabolic acidosis the minimum urine pH in 12 of 24 amphotericin B-treated rats exceeded 5.63 (mean 5.76 +/- 0.04), whereas it was 5.41 +/-0.04 in control rats. These animals with impaired urine acidification were presumed to have a gradient lesion and were studied in bicarbonate-loading experiments. The urine minus blood Pco2 gradient in these rats was 24.9 +/- 1.5 mm. Hg, a value similar to that of the control rats (26.7 +/- 2.1 mm. Hg). The presence of a normal urine minus blood Pco2 value in this experimentally induced gradient-limited type of acidification lesion indicates that a permeability defect for hydrogen ions was not associated with a similar defect for carbonic acid and that the urine minus blood Pco2 gradient is a valid index of distal nephron hydrogen ion secretion in amphotericin B-like gradient-type lesions.

Topics: Acidosis, Renal Tubular; Amphotericin B; Animals; Carbon Dioxide; Furosemide; Kidney; Kidney Concentrating Ability; Male; Osmolar Concentration; Rats

Topics: Acid-Base Equilibrium; Acidosis, Renal Tubular; Amphotericin B; Blastomycosis; Carbon Dioxide; Glomerular Filtration Rate; Histoplasmosis; Humans; Hydrogen-Ion Concentration; Hypokalemia; Kidney Diseases; Kidney Tubules; Mycoses; Partial Pressure; Potassium; Uric Acid

Topics: Acid-Base Equilibrium; Acidosis, Renal Tubular; Amphotericin B; Blastomycosis; Carbon Dioxide; Glomerular Filtration Rate; Histoplasmosis; Humans; Hydrogen-Ion Concentration; Hypokalemia; Kidney Diseases; Kidney Tubules; Mycoses; Partial Pressure; Potassium; Uric Acid

Topics: Acidosis, Renal Tubular; Ammonium Chloride; Amphotericin B; Animals; Bicarbonates; Bile Acids and Salts; Body Weight; Carbon Dioxide; Creatinine; Disease Models, Animal; Hydrogen-Ion Concentration; Injections, Intraperitoneal; Kidney Concentrating Ability; Kidney Diseases; Kidney Function Tests; Male; Polyuria; Potassium; Quaternary Ammonium Compounds; Rats; Sodium

Topics: Acid-Base Equilibrium; Acidosis, Renal Tubular; Alkalies; Ammonia; Amphotericin B; Bicarbonates; Blood Urea Nitrogen

An experimental defect in urinary acidification was induced in the isolated turtle bladder by amphotericin B and the nature of the defect was examined. Net hydrogen ion secretion was little affected by amphotericin when passive electrochemical forces across the epithelium were held at a minimum in the short-circuited state under isohydric conditions. Hydrogen ion secretion against a gradient, however, was markedly reduced by amphotericin and abolished at gradients of more than 2 pH units.The results suggest that impaired acidification is caused by increased passive permeability of the luminal membrane and increased back diffusion of hydrogen ion rather than by failure of active transport. This interpretation is supported by evidence that amphotericin causes a large increase in the permeability to potassium and smaller increases in the sodium and chloride permeabilities. This mechanism of impaired acidification in vitro may have bearing on the renal tubular defect observed in patients treated with amphotericin B.

Topics: Acidosis, Renal Tubular; Acids; Amphotericin B; Animals; Chlorides; Electrophysiology; Epithelium; Hydrogen; Hydrogen-Ion Concentration; In Vitro Techniques; Kidney Tubules; Permeability; Sodium; Turtles; Urinary Bladder

Topics: Acidosis, Renal Tubular; Amphotericin B; Electrolytes; Histoplasmosis; Humans; Kidney; Kidney Concentrating Ability; Male; Middle Aged

Topics: Acidosis, Renal Tubular; Amphotericin B; Humans; Kidney Tubules

Topics: Acidosis, Renal Tubular; Alkalies; Ammonium Chloride; Amphotericin B; Blood Urea Nitrogen; Calcium, Dietary; Glomerular Filtration Rate; Humans; Hydrogen-Ion Concentration; Kidney Function Tests; Mycoses; Potassium

Topics: Acidosis, Renal Tubular; Amphotericin B; Humans; Phenotype