Helmut Bräunlich

Comparative nephrotoxicity of some antitumour-active platinum and ruthenium complexes in rats

The nephrotoxicity of three platinum (CPL, KP734, KP735) and three ruthenium coordination complexes (KP418, KP692, KP1019) was tested in rats in comparison to cisplatin (CP). Renal functional changes (excretion of water, protein, p‐aminohippurate (PAH) and osmolytes) were not observed after the administration of 10% of the LD50 of the compounds given twice a week for up to 5 weeks. After a relatively high single dose of the substances (50% of the LD50), signs of nephrotoxicity on the day of maximal renal damage decreased in the following order: CP, KP418, CPL, KP734, KP735, KP692 and KP1019. In comparison to CP, proteinuria was significantly lower after the administration of any of the compounds, especially KP692 and KP1019. Neither renal lipid peroxidation (TBARS) nor glutathion status (GSH, GSSG) was affected. In summary, KP735 in the group of platinum complexes and KP1019 in the ruthenium group had the lowest nephrotoxicity. Other investigators have shown that all complexes induced anti‐neoplastic activity under analogous experimental conditions.

Protective Effects of Methimazole against Cisplatin-induced Nephrotoxicity in Rats

In adult rats 6 mg kg−1 body wt. cisplatin given i.p. was nephrotoxic. Four days of i.p. treatment with 40 mg kg−1 body wt. methimazole, which started 1 day before CP, prevented increases in blood urea nitrogen and in the renal excretion of proteins. Furthermore, methimazole treatment reduced the oliguric effect of cisplatin and the depression of renal sodium excretion. However, it had no effect on the increased formation of lipid peroxides in cisplatin‐damaged kidneys, although repeated treatment with methimazole enhanced the renal glutathione content. Methimazole acts as a radical scavenger, maintaining the glutathione pool in the kidney. © 1997 by John Wiley & Sons, Ltd.

Hormonal control of postnatal development of renal tubular transport of weak organic acids

We have postulated that the maturation of the renal transport mechanism for weak organic acids is controlled by thyroid and adrenal hormones. Administration of T3 and T4 (20 μg/100 g body wt. for 3 days) to immature rats enhanced by ∼50% the accumulation of p-aminohippurate (PAH) in renal cortical slices of 5- to 30-day-old rats. The effect of T3 was lower, while T4 had no effect, in 50- and 105-day-old animals. Enhancement of PAH transport became apparent 24 h and disappeared by 9 days after the end of hormone treatment. Administration of a booster dose of T3 (1 μg/100 g body wt.) on day 9 brought the level of PAH accumulation to values similar to those observed 24 h after the end of the initial 3 days of T3 administration. Dexamethasone administration (80 mg/100 g body wt. for 3 days) affected PAH uptake only in cortical slices obtained from 5-day-old rats. Changes in PAH accumulation did not correlate with changes in kidney weight or protein synthesis, indicating that they were mediated by the hormones rather than being consquent to growth.

Renal handling of drugs and amino acids after impairment of kidney or liver function—Influences of maturity and protective treatment

Renal tubular cells are involved both in secretion and in reabsorption processes within the kidney. Normally, most xenobiotics are secreted into the urine at the basolateral membrane of the tubular cell, whereas amino acids are reabsorbed quantitatively at the luminal side. Under different pathological or experimental circumstances, these transport steps may be changed, e.g., they may be reduced by renal impairment (reduction of kidney mass, renal ischemia, administration of nephrotoxins) or they may be enhanced after stimulation of transport carriers. Furthermore, a distinct interrelationship exists between excretory functions of the kidney and the liver. That means liver injury can influence renal transport systems also (hepato-renal syndrome). In this review, the following aspects were included: based upon general information concerning different transport pathways for xenobiotics and amino acids within kidney cells and upon a brief characterization of methods for testing impairment of kidney function, the maturation of renal transport and its stimulation are described. Similarities and differences between the postnatal development of kidney function and the increase of renal transport capacity after suitable stimulatory treatment by, for example, various hormones or xenobiotics are reviewed. Especially, renal transport in acute renal failure is described for individuals of different ages. Depending upon the maturity of kidney function, age differences in susceptibility to kidney injury occur: if energy-requiring processes are involved in the transport of the respective substance, then adults, in general, are more susceptible to renal failure than young individuals, because in immature organisms, anaerobic energy production predominates within the kidney. On the other hand, adult animals can better compensate for the loss of renal tissue (partial nephrectomy). With respect to stimulation of renal transport capacity after repeated pretreatment with suitable substances, age differences also exist: most stimulatory schedules are more effective in young, developing individuals than in mature animals. Therefore, the consequences of the stimulation of renal transport can be different in animals of different ages and are discussed in detail. Furthermore, the extent of stimulation is different for the transporters located at the basolateral and at the luminal membranes: obviously the tubular secretion at the contraluminal membrane can be stimulated more effectively than reabsorption processes at the luminal side.

Methods in testing interrelationships between excretion of drugs via urine and bile

The liver and kidney are largely responsible for inactivating and eliminating drugs and other chemicals. As the excretory capabilities of the two organs overlap, a damage of one system might be compensated by the other. Because of the specificity of both renal and hepatic elimination mechanisms such an alternative excretion route is not possible generally. Several interferences are possible to characterize the relation between hepatic and renal excretion of drugs and xenobiotics. Firstly, the simultaneous assay of excreted drug amounts in urine and bile can give some information concerning the main transport routes of this drug. Thereafter the total interruption of liver or kidney function elucidates the general possibility of alternative excretion routes. But it is important for clinical practice to distinguish between different localizations of organ damages. Today some experimental possibilities exist to exclude partial functions of both kidney and liver separately. Thus it can be clarified why a compound might be excreted via liver or kidney. Moreover it can be characterized whether or not a compensation for the loss of one main excretion organ is possible or not. Such investigations are of some practical importance. Dosing guidelines for drug therapy must be completed for cases of renal or hepatic failure. Moreover the developmental pattern of both elimination routes has consequences for drug use in paediatrics as well as geriatrics. Beside this point of view such investigations are necessary for the prediction of changes in the toxicity of drugs after renal or hepatic insufficiency.

Age dependent differences in the functional and morphological impairment of kidney following cisplatin administration

In adult rats the clearance of inulin, urinary p-aminohippurate (PAH) excretion, TmPAH, as well as PAH accumulation in renal cortical slices were decreased 48-72 h following 0.6 mg cisplatin/100 g body mass (b.m.). Morphological investigations showed changes preferentially in proximal tubules. Reduced inulin clearance is discussed to be rather the consequence of inulin back leak in destroyed tubules than of a real decrease in glomerular function. The ultrastructure of glomeruli, distal tubules, and collecting ducts was not affected by cisplatin (CP) in 10- and 55-day-old rats. In 10-day-old rats, inulin clearance and urinary PAH excretion remained unaffected by CP, whereas TmPAH and PAH accumulation in vitro were significantly decreased following CP. Most significant ultrastructural changes occurring in mitochondria are discussed to cause decreased PAH accumulation following CP. The high portion of PAH filtered in young rats masked this impairment of active PAH secretion. Lower nephrotoxicity in young rats seems to be caused by low state of a differentiation of cell structure and transport function.

Nephrotoxic effects of diethylene glycol (DEG) in rats

Diethylene glycol (DEG) is a widely used substance with various risks of intoxication. In adult rats influences of DEG on functional parameters are characterized, indicating early signs of nephrotoxicity. A dose dependent proteinuria, an oliguric effect, an increased excretion of free hydrogen ions and a compensated impairment of renal tubular transport processes can be stated (0.25, 0.5 and 0.75 ml DEG/100 g b.m. i.p.). Following a single dose of 0.5 ml DEG/100 g b.m. i.p. the maximally expressed nephrotoxic effect is measurable 4 to 8 days after administration.

Kinetics of p-aminohippurate transport in renal cortical slices from neonatal and adult rats

Abstract PAH accumulation in renal cortical slices of rats is age-related different. Kinetic parameters were quantified using the Lineweaver-Burk analysis. The Michaelis constant for PAH uptake is 0.50 mM in all age groups, i.e., the affinity of PAH for the transport sites is the same. The maximum PAH concentrations (steady-state) in renal cortical slices from 5-, 20-, 33-, and 55-day-old rats are 0.91, 1.72, 2.57, and 1.72mM, respectively. This finding suggests that the number of transport sites is increasing during the postnatal development of the kidney.

P-aminohippurate (PAH) transport and Na-K-ATPase activity in rat renal cortical slices during postnatal maturation and drug-induced stimulation

PAH transport and Na-K-ATPase activity markedly increase during the first month of postnatal life. Pretreatment of rats with PAH or cyclopenthiazide induces a stimulation of in vitro PAH accumulation in renal cortical slices, whereas Na-K-ATPase activity is unchanged in comparison to saline-pretreated controls. 5 mM ouabain in the incubation medium reduces PAH accumulation. Developmental pattern and stimulation effects are pronounced as in controls. The ouabain-insensitive component of net PAH accumulation progressively increases with age and is significantly enhanced following drug pretreatment, whereas the ouabain-sensitive component of net PAH accumulation shows relatively slight modifications. Consequently, Na-K-ATPase seems not to be linked with postnatal maturation or drug-induced stimulation in tubular PAH transport.

Elektronenmikroskopischer Nachweis von Aluminium in Lysosomen von Nierenzellen über Energieverlustspektroskopie

Summary Aluminium effects have increasing attention in long term dialysis of kidney patients and in a number of cerebral diseases. At present, however, there are still many open points concerning its localization and actions in the cell. If using electron spectroscopic imaging (ESI), aluminium could be directly demonstrated in the lysosomes of the kidney cells of uraemic rats experimentally loaded with aluminium. These findings were corroborated by means of electron energy loss spectroscopy (EELS).