Aminoglycoside-associated Fanconi syndrome.

The objective is to describe a case of probable aminoglycoside-induced Fanconi syndrome and make clinicians aware of the existence of this underrecognized and underdiagnosed complication in patients treated with a prolonged course of high-dose aminoglycosides. A 53-year-old man admitted for recurrent infective exacerbations of chronic bronchiectasis already colonized with Pseudomonas aeruginosa was treated intermittently with intravenous gentamicin (320 to 560 mg/d) for a total of 4 months to a total cumulative dose of 9.4 g. The patient developed profound hypophosphatemia, hypocalcemia, hyperphosphaturia, and aminoaciduria. Electrolyte disturbances persisted until gentamicin therapy was stopped, recurred with rechallenge, and did not correct with calcium and phosphate supplementation. This case shows that prolonged exposure to high-dose aminoglycoside therapy can be associated with Fanconi syndrome, which is a manifestation of proximal tubular dysfunction. There are only a few case reports to date of Fanconi syndrome as a probable complication of high-dose aminoglycoside therapy. The Naranjo Adverse Drug Reaction probability scale score indicated that this was a probable adverse reaction associated with administration of high-dose aminoglycosides. The differential diagnosis of electrolyte disturbances as a manifestation of proximal tubule dysfunction and type 2 renal tubular acidosis is vast; however, Fanconi syndrome needs to be considered in patients treated with high doses of aminoglycosides for longer than 6 days, after more common causes of hypophosphatemia are excluded.

D-Serine-induced nephrotoxicity: a HPLC-TOF/MS-based metabonomics approach.

HPLC-MS-based metabonomic analysis was used to investigate urinary metabolic perturbations associated with D-serine-induced nephrotoxicity. D-Serine causes selective necrosis of the proximal straight tubules in the rat kidney accompanied by aminoaciduria, proteinuria and glucosuria. Alderely Park (Wistar-derived) rats were dosed with either D-serine (250 mg/kg ip) or vehicle (deionised water) and urine was collected at 0-12, 12-24, 24-36 and 36-48 h post-dosing. Samples were analysed using a Waters Alliance HT 2795 HPLC system coupled to a Waters Micromass Q-ToF-micro equipped with an electrospray source operating in either positive or negative ion mode. Changes to the urinary profile were detected at all time points compared to control. In negative ion mode, increases were observed in serine (m/z=103.0077), m/z=104.0376 (proposed to be hydroxypyruvate) and glycerate (m/z=105.0215), the latter being metabolites of D-serine. Furthermore, an increase in tryptophan, phenylalanine and lactate and decreases in methylsuccinic acid and sebacic acid were observed. Positive ion analysis revealed a decrease in xanthurenic acid, which has previously been assigned and reported using HPLC-MS following exposure to mercuric chloride and cyclosporine A. A general aminoaciduria, including proline, methionine, leucine, tyrosine and valine was also observed as well as an increase in acetyl carnitine. Investigation of additional metabolites altered as a result of exposure to D-serine is on-going. Thus, HPLC-MS-based metabonomic analysis has provided information concerning the mechanism of D-serine-induced renal injury.

Congenital renal tubular dysfunction associated with maternal sniffing of organic solvents.

Two cases of neonatal renal tubular dysfunction and metabolic acidosis due to maternal sniffing of a product containing toluene are reported. Both mothers had been sniffing regularly throughout their pregnancies. The infants were dysmature and had some dysmorphic features. They had hyperchloraemic acidosis and exhibited amino-aciduria. The metabolic changes were however transient. It is suggested that the sniffing of toluene containing solvents during pregnancy may change membrane permeability in both the proximal as well as distal renal tubules and may also enhance liver enzyme activity in the foetus.

Effect of cadmium pretreatment on nickel toxicity.

Pretreatment with nickel has earlier been shown to protect against cadmium intoxication. The effect of cadmium pretreatment on the nephro- and hepatotoxicity of nickel has been investigated. The administration of cadmium (6 mg/kg, i.m., once) to rats significantly enhanced urinary excretion of ALP, LDH, GOT, amino acids and proteins and increased the activity of serum ALP, GOT, and GPT, while the administration of nickel (6 mg/kg, i.p., 3 days) altered these parameters less significantly. These changes in urine and serum were used as a measure of renal and hepatic damage. The administration of nickel for three days, one week after cadmium treatment, caused significantly more marked enzymuria, aminoaciduria, proteinuria and an increase in the activity of serum enzymes than induced by either of them individually. However, cadmium pretreatment had no influence on urinary excretion or hepatic uptake of nickel, but increased renal uptake of nickel on the fourth day. The results suggest that cadmium enhances the nephro- and hepatotoxicity of nickel.

Dipropylacetate and aminoaciduria.

Dipropylacetate (DPA) is an anticonvulsant, which has been successfully used in the treatment of several types of epilepsy. The mode of action has not yet been definitely elucidated, although evidence of influence on gamma aminobutyric acid (GABA) turnover in brain has been presented. Several recent reports of the occurrence of hyperglycinemia in association with DPA-treatment indicate that this agent also influences other areas of amino acid metabolism. In the present study of 10 patients receiving DPA for epilepsy, high concentrations of glycine in plasma and CSF were observed, whereas the levels of all other amino acids remained virtually unchanged. The effect of DPA on urinary excretion of amino acids seems to be of considerable significance as marked elevation of urine concentrations of alanine, asparagine, cystine, glycine, histidine, isoleucine and leucine, phenylalanine and tyrosine were observed. This secondary hyperglycinemia could be due to suppression of glycine conjugation reactions, whereas DPA or its metabolites might interfere with tubular reabsorption of various amino acids, thereby causing hyperaminoaciduria.

Maleic acid induced aminoaciduria, studied by free flow micropuncture and continuous microperfusion.

The injection of 200 mg/kg BW maleic acid was found to be a suitable dose for exploring the experimental Fanconi syndrome by micropuncture techniques in rats. In clearance experiments, the fractional excretion of glycine, L-alanine, L-aspartate and taurine was measured. After intraperitoneal administration of maleic acid the excretion of these amino acids was increased in the range between the 20-fold and the 230-fold. Free flow micropuncture experiments showed that the reabsorption of these amino acids is reduced drastically along the whole proximal tubule. Continuous microperfusion experiments lead to the result that, in maleic acid pretreated rats, the reabsorption of 14C-glycine from the proximal convolution was strongly inhibited. It was found, furthermore, that after blocking the saturable glycine transport by L-phenylalanine, the remaining reabsorption of glycine (corresponding to passive diffusion) was exactly the same with and without maleic acid. Microinfusion experiments with 8 mumol.1(-1) L-3H-alanine into the early distal tubule showed a fractional recovery of 103 +/- 4.2% (S.D.) in the control and of 101 +/- 6.5% in presence of maleic acid. It is concluded that maleic acid inhibits the saturable reabsorption mechanism of amino acids along the proximal tubule. Passive permeability of the tubular membrane does not seem to be altered by maleic acid.

Cadmium nephropathy.

Cadmium is an inessential trace metal which accumulates in human tissues from contamination of food, water or air. The kidney is the critical organ following long-term, low-level absorption either by inhalation or ingestion; accumulation occurring in tubular epithelium in the form of a cadmium-metallothionein complex, giving rise to tubular dysfunction. In a group of 12 cadmium workers some of whom were followed for up to 16 years, tubular proteinuria, renal glycosuria, aminoaciduria, hypercalciuria and defects of concentration and acidification have been observed. Two men became recurrent renal stone formers and 1 man, who had nephrocalcinosis when first seen, later developed vitamin D-resistant osteomalacia. Renal tubular dysfunction following cadmium exposure may continue symptom-free for long intervals, but in a proportion of cases serious clinical effects may eventually develop.

Menkes kinky hair syndrome: Is it a treatable disorder?

A male infant with Menkes Kinky Hair Syndrome was treated with a 3-week course of cupric acetate infusions, which was terminated when he developed aminoaciduria. The lack of improvement seen in this infant is representative of the reported experience with parenteral copper therapy in this condition, and may be attributable to the presence of a clinically significant abnormality in copper metabolism in utero.

Cadmium-induced proximal tubular dysfunction in a cadmium-polluted area.

Health examinations were performed in 147 people living in a cadmium-polluted area, Kosaka Town, Japan. 33 of 147 residents had some indications of proximal tubular dysfunction, such as renal glucosuria, tubular proteinuria, and aminoaciduria, and 10 of them were diagnosed as having multiple proximal tubular dysfunctions. Detailed examinations revealed that none of the cases had any causal diseases other than chronic cadmium poisoning. Residents' mean cadmium intake and mean urinary cadmium concentration were over 3 times as high as those in control areas. From these findings, renal lesions identified in these residents were concluded as chronic cadmium poisoning induced by environmental cadmium pollution.