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.

Stimulation of renal sodium excretion in mature rats.

In adult rats a saline load is followed by an increase in renal excretion of sodium and by a low rate of ion exchange (hydrogen ions and potassium for sodium), caused by inhibited aldosterone secretion. Under analogous conditions a saline load provoked sodium retention and a distinct increase in renal excretion of hydrogen ions and potassium in young rats, which can be explained by a non-regulated, very intensive ion exchange. The repeated administration of NaCl solution alone and in combination with cyclopenthiazide produced an accelerated maturation of kidney function in 10- and 33-day-old rats measurable by an increase in sodium excretion and reduced ion exchange. In adult rats as well as immediately after birth (5-day-old rats) this effect cannot be provoked by the various pretreatments acting in mature rats.

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.

Age differences in cisplatinum nephrotoxicity.

Male and female Wistar rats (5-105-day-old) were administered 3 different doses of cisplatinum (CP) (0.15, 0.3 or 0.6 mg/100 g body wt, intraperitoneally) After 3 days the renal excretory functions were investigated. There were no sex differences in nephrotoxicity. In rats of all age groups a dose dependent decrease in body weight appeared. In 5- and 33-105-day-old rats the 2 lower doses did not or only mildly influence renal function. 0.6 mg CP/100 g body wt in these age groups lead to a significant reduction in urine volume. The excretion of osmotically active substances and p-aminohippurate were reduced. There is a statistically significant proteinuria. In 10- and 15-day-old rats the 2 lower doses were without any pathologic consequences, but 0.6 mg CP/100 g body wt was followed by a significant increase in the protein excretion of 15-day-old rats. Consequently, regarding the parameters measured 10-15-day-old rats seemed to be less susceptible to CP-nephrotoxicity.

Failure of physostigmine in intoxications with tricyclic antidepressants in rats.

In experiments on rats there is a moderate antagonistic effect of physostigmine against intoxications with the tricyclic antidepressants (TAD) clomipramine, desipramine and imipramine, respectively. During the first hours after TAD intoxication the survival rate is higher in physostigmine treated rats. Especially after relatively low doses of TAD the lethality seems to be reduced by physostigmine treatment. However, at the end of the observation period (96 h) the lethality after TAD is equal with and without physostigmine treatment. The effectivity of physostigmine does not depend on the mode of administration: repeated administration and intravenous infusion are not more effective than a single injection of physostigmine. The influence of TAD on heart rate and respiratory rate was not abolished by physostigmine salicylate. Intoxications with high doses of physostigmine were antagonized by atropine; on the other hand there are no signs for an antagonistic effect of desipramine against physostigmine intoxication, that means their anticipated anticholinergic properties could not be proved.

Functional and morphological aspects of thallium-induced nephrotoxicity in rats.

Until now the effect of thallium (Tl) on renal function has not been investigated systematically. Therefore, the dose (5, 10, 15, 20 mg Tl2SO4/kg body wt., intraperitoneally) and time-dependence of renal damage was investigated in diuresis experiments on conscious rats. Morphology was evaluated after perfusion fixation in situ. Morphologic changes were localized in the thick ascending limb of the loop of Henle, mostly expressed at the 2nd day after Tl administration, which were completely normalized again at the 10th day. Other parameters such as Tl concentration, changes in water content and the activity of Na+/K(+)-ATPase as well as the diuretic effect of furosemide confirmed the Tl effect to be localized in the renal medulla. One single Tl administration is followed by a decrease in glomerular filtration rate (GFR) and urine volume and an increase of proteinuria. Electrolyte excretion was only slightly changed. All changes were reversible within the 10-day investigation period.

[Electron microscopic evidence of aluminum in lysosomes of kidney cells by electron energy loss spectroscopy]. / Elektronenmikroskopischer Nachweis von Aluminium in Lysosomen von Nierenzellen über Energieverlustspektroskopie.

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).

Postnatal development of sex differences in renal tubular transport of p-aminohippurate (PAH) in rats.

Compared with female rats a distinctly higher rate of accumulation of p-aminohippurate (PAH) in renal cortical slices from mature male rats can be proved; there are no sex differences in young rats with immature kidney function. Postnatal development of sex differences in kidney weight shows the same pattern. The lack of sex differences in the renal excretion of PAH in all age groups could be caused by a higher fraction of glomerularly filtered PAH in female rats. In mature male rats the high rate of tubular transport of PAH can be diminished by castration or by blockade of testosterone receptor sites (treatment with cyproterone). Stimulation of PAH transport by repeated treatment with testosterone is more expressed in male than in female rats. Furthermore, estrogens seem not to be responsible for sex differences in renal tubular transport of PAH (no influence of ovarectomy, low effects of treatment with estradiol in male rats).

Renal excretion and renal tubular transport of p-aminohippurate (PAH) in methimazole treated, hypothyroid rats of different ages.

Thyroid hormone deficiency following treatment with methimazole for 7 days does not reduce PAH secretion in renal tubular cells as expected from data in thyroid hormone treated rats. This treatment with methimazole causes an increase in renal excretion of PAH in rats of various age groups, statistically significant in 5-, 10- and 20-day-old rats. In 20-day-old, methimazole treated rats the increase in renal excretion of PAH is obviously caused by a higher transport rate in renal tubular cells, proved also in 33-day-old rats. An increased filtered fraction of PAH in 5- and 10-day-old rats could be the reason for the rise in renal excretion of PAH after repeated treatment with methimazole. The mechanism of renal effects of methimazole treatment remains unclear.

Glutathione status, lipid peroxidation and kidney function in streptozotocin diabetic rats.

In adult female rats diabetic nephropathy was induced by i.v. administration of streptozotocin (6 mg/100 g b.w.). The animals survive for 3 weeks when very low daily doses of insulin (0.3 IU/animal) are administered. High blood urea concentrations and distinct proteinuria indicate the impairment of kidney function in streptozotocin diabetic rats. Streptozotocin induces mild polyuria and increased renal excretion of potassium; there is also an increase in renal excretion of administered p-aminohippurate. Three weeks after administration of streptozotocin the formation of lipid peroxides is increased in the kidney. At this time glutathione content (GSH, GSSG) is unchanged in liver and kidney of streptozotocin diabetic rats. Impairment of kidney function in streptozotocin diabetic rats can be prevented by daily supplementation with sufficient doses of insulin (about 3 IU/animal).

Influence of vitamin E treatment on glutathione system after renal ischemia in immature and adult rats.

Survival rates were not significantly different 5 days after 20-min unilateral ischemia followed by contralateral nephrectomy: 58% in 20-day-old vs. 77% in 55-day-old rats. This experimental approach was used to characterize age dependent differences in the susceptibility of the glutathione system to ischemia and protective effects of treatment with vitamin E (10 mg/100 g b.wt. once daily s.c.) on the outcome after renal ischemia. The degree of postischemic changes (GSH, gamma-GT, TBARS) was the highest on days 1 and 2 after ischemia; at this time, survival rates were similar in young and adult rats. In adult animals, both glutathione content and the activity of gamma-GT were significantly reduced after ischemia whereas in immature rats only the glutathione content was distinctly diminished. At the 5th day after ischemia the parameters were almost normalized in the two age groups. Repeated administration of vitamin E improved the survival rate in adult rats up to 100%; in young animals, lethality was not influenced by vitamin E treatment. This reflects the beneficial effects of vitamin E on the glutathione system in adults whereas the vitamin was without effect on the immature rats' glutathione system.

Kidney function in rats after 5/6 nephrectomy (5/6 NX); effort of treatment with vitamin E.

In adult female rats various kidney functions were measured 3 weeks after 5/6 nephrectomy (5/6 NX). The distinct rises in blood urea nitrogen and in renal excretion of proteins indicate the impairment of the kidney. In 5/6 NX rats, the renal excretion of creatinine, glucosaminoglycan, and of p-aminohippurate was diminished. The concentrations of hydroxypyroline and of free hydrogen ions were distinctly increased in urine samples from 5/6 NX rats. The concentration of lipid peroxides was enhanced in kidney tissue whereas 3 weeks after 5/6 NX the concentration of GSH and GSSG in the remnant kidney tissue was unchanged. Long-term administration of vitamin E increased its concentration in plasma, kidney, and liver. Nevertheless, daily treatment with vitamin E (1 or 10 mg/100 g b.w. s.c. for 5 weeks) did not reduce the degree of impairment of kidney function following 5/6 NX.

Age dependent different consequences of bilateral nephrectomy (NX) in rats.

Adult rats survived the removal of both kidneys (NX) for about 48 hours; survival time was distinctly lower in 10- and 20-day-old rats (about 24 hrs). Some of the measured parameters indicate age dependent differences in uremic impairment. In the prefinal period after NX blood urea nitrogen concentrations were distinctly higher in adult than in young rats. After nephrectomy diminution of the concentrations of GSH and GSSG in liver tissue is more distinct in adult than in young rats. Similarly, 24 hrs after NX the content of lipid peroxides in liver tissue was higher in adult than in 10- and 20-day-old rats. Furthermore, the prolongation of bleeding time in uremic rats was more distinct in adult than in young rats. The following parameters indicate uremic impairment clearly, but age dependent differences do not exist: Increase of potassium concentration in plasma, enhanced activities of liver specific enzymes in plasma, reduced concentration of various amino acids in plasma and distinct increase in plasma concentration of taurine.

Evaluation of methods indicating higher susceptibility of immature rats to renal ischemia.

After 45-min bilateral warm renal ischemia lethality amounted to 45% and 82% in 55- and 20-day-old rats, respectively (n = 176). Lethality rates were not significantly different after 20-min unilateral ischemia followed by contralateral nephrectomy after 24 hours (34 vs. 48% in young vs. adult rats; n = 168). The latter experimental approach was used to characterize age dependent differences in the susceptibility to ischemia. The degree of postischemic renal damage was the highest at the 1st and 2nd days after ischemia; at this time, lethality rates were similar in young and adult rats. However, urea concentration in serum was significantly more enhanced in young animals whereas that of creatinine was increased to the same extent in both age groups. The increase in protein excretion into urine was similar in young and adult rats, too. Furthermore, urine flow rates and GFR were significantly diminished after ischemia, independent of age. However, excretion of Na+ and K+ was distinctly more depressed in immature individuals. Finally, the glutathione content in kidney tissue of both age groups was reduced and lipid peroxidation was significantly higher after ligation of the renal arteries. The relative changes were similar in both age groups although the glutathione content was significantly lower in 20-day-old control rats. 4-5 days after ischemia, most parameters returned to baseline values. In 55-day-old rats, 45-min ischemia has more severe consequences on renal function compared to 20-min ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

[Inhibition of the renal excretion of PAH by probenecid homologs]. / Hemmung der renalen PAH-Ausscheidung durch Probenecid-Homologe.

The authors studied the effects of probenecid and five of its homologues on the renal excretion of p-amino-hippuric acid (PAH). All the compounds under study inhibited the excretion of PAH. Probenecid and its homologues were injected 15 min before the administration of PAH. With all the substances tested, the inhibition of the excretion of PAH was most marked during the first 30 min of the diuresis experiment. The extent of efficiency increases within the homologous series up to the diethyl compound; after that, the inhibitory effect decreases with the increase in chain length. In the dosage range under study, the probenecid homologues show linear dose-response relationships. With due regard to toxicity and efficiency, the authors conclude from the results obtained that the diethyl compound is the most potent substance; probenecid itself is less efficient, being twice as toxic.

Renal handling of nourseothricin.

Nourseothricin 1 is preferentially excreted via kidney and signs of nephrotoxicity can be observed after its administration. Renal handling of 1 was characterized in experiments on renal cortical slices under various experimental conditions. Following administration in vivo or in vitro the renal tubular transport system for organic anions (p-aminohippurate, PAH) is not influenced by 1. There is a high degree of accumulation of 1 in renal cortical slices. In contrast to PAH accumulation there is no influence of nitrogen atmosphere, simultaneous administration of PAH, probenecid or trishydroxyaminomethane on 1 accumulation. Age dependent differences in 1 accumulation does not exist. Our data show a distinct uptake of 1 in kidney tissue. Accumulation of 1 in renal cortical slices is caused by binding; an active tubular transport of 1 in renal cortical slices could be excluded.

Testing of dioxolan-methyl-metaacrylate (DMA) for hepatotoxicity and nephrotoxicity.

Dioxolan-methyl-metaacrylate (DMA) is applied as an adhesive for optical glasses and as a tooth filling material using the polymerisation properties. In rat LD50 was estimated at about 500 mg/100 g b.m. following i.p. or i.m. administration without distinct sex differences. DMA is less toxic following oral administration. Hypnotic or myorelaxing effects could be observed in a dose-dependent manner. DMA antagonized pentetrazole-induced convulsions. Prolongation of hexobarbital sleeping time without influence on awakening concentration of hexobarbital inhibition of biotransformation reactions, proved in vivo and in in vitro experiments measuring ethylmorphine-N-demethylation, ethoxycoumarin-O-deethylation and cytochrome P-450 content. There are no influences of DMA on urine concentrating ability. Oliguric effects of DMA might be caused by central depressive effects of DMA. There are no distinct effects of DMA on p-aminohippurate transport. Signs of a selective hepatotoxic or nephrotoxic effectiveness of DMA can be excluded because the respective functions were altered only following administration of extremely high doses of DMA (50% of LD50 values).

[Renal actions of bendamustin (Cytostasan) in rats]. / Renale Wirkungen von Bendamustin (Cytostasan) bei Ratten.

In adult rats influences of single doses of bendamustin (0.5, 1 or 5 mg/100 g b.wt. i.p.) on kidney function were measured (time of experimentation 8 d following administration). Bendamustin administration is followed by an increase of kidney weight caused by a higher water content of kidney tissue. An increase of plasma concentrations of creatinine and of urea following bendamustin (1 or 5 mg/100 g b.wt. i.p.) indicates a reduced excretion capacity of kidney. Bendamustin administration is not connected with a distinct proteinuria. The highest administered does (5 mg bendamustin/100 g b.wt. i.p.) caused an oliguric effect connected with a distinctly reduced renal excretion of osmotically active substances. There is a distinct diminution of renal excretion of sodium following bendamustin administration and a decrease of renal excretion of PAH can be stated. It is most likely that bendamustin can reduce the glomerular function: Following administration of 1 mg bendamustin/100 g b. wt. i.p. CIn is reduced whereas a statistically significant increase of tubular transport capacity for organic anions can be measured (TmPAH).

Hemodynamic parameters and renal blood flow following stimulation of renal tubular transport processes by treatment with thyroid hormones.

In adult rats, renal excretion of p-aminohippurate (PAH) can be stimulated by repeated administration of thyroid hormones. Data on renal cortical slices show clearly that a stimulation of active, carrier-mediated tubular transport processes is the most important cause. In vivo experiments also show an influence of treatment with thyroid hormones on various hemodynamic parameters. The diminution of vascular resistance in cortical and medullary regions of the kidney might contribute to the increased PAH excretion in thyroid hormone-treated rats.