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 LD450 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.

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.

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.

Ontogenetic aspects of thallium-induced nephrotoxicity in rats.

The effect of Tl2SO4 (Tl, 20 mg kg-1 body wt.) on renal function was investigated in 10- and 20-day-old rats. Nephrotoxic effects were evaluated by the determination of glomerular filtration rate, urinary volume, electrolyte and protein excretion, as well as by morphological investigations. In contrast to adult rats there were no morphological destructions in 10- and 20-day-old rats. Changes in renal function seemed to be less expressed in 10- and 20-day-old than in adult rats. The smaller nephrotoxicity in 10-day-old rats may be caused by lower Tl concentration in renal tissue, whereas in 20-day-old rats decreased nephrotoxicity cannot be explained in this way. The activity of Na+/K(+)-ATPase in rat renal tissues was found to be involved in the mechanisms of Tl enrichment in renal tissue, being an indirect determinant of Tl nephrotoxicity.

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.

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.

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).

Effects of calcitriol on expression of triiodothyronine-stimulated renal tubular transport of p-aminohippurate in rats of different ages.

Following treatment of rats of various age groups with calcitriol (2 micrograms/kg b.w., 3 days, once daily) renal tubular transport of p-aminohippurate (PAH) is reduced in kidney cortical slices prepared from 5-, 15-, 33-, and 55-day-old rats. The decrease in renal excretion of PAH following such treatment has a longer degree and is demonstrable in 15- and 33-day-old rats only. Repeated treatment with calcitriol provokes a decrease in body weight, statistically significant in 5- and 55-day-old rats. In 33- and 55-day-old rats repeated treatment with calcitriol (2 micrograms/kg b.w., 3 days, once daily) causes an increase of kidney weight. Repeated treatment with calcitriol is connected with an increase in plasma level and in renal excretion of calcium, statistically significant in most age groups. In rats of various age groups, renal tubular transport of PAH can be stimulated by repeated administration of triiodothyronine (T3; 100 micrograms/kg b.w., 3 days, once daily). This increase in PAH transport, measured in kidney cortical slices, cannot be observed in rats simultaneously treated with calcitriol and T3. Obviously, the expression of higher transport rates for PAH can be prevented by renal effects of calcitriol. Simultaneous treatment with T3 and calcitriol causes an increase in kidney weight and a decrease in body weight in rats of various age groups.

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).

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)

Influence of sympathetic nervous system on dexamethasone-stimulated renal tubular transport of p-aminohippurate in young rats.

After simultaneous administration of dexamethasone together with 6-hydroxydopamine or adrenergic neuronal blocking agents (alpha-methyldopa, reserpine, guanethidine) the dexamethasone-stimulated increase in renal excretion of p-aminohippurate (PAH) is distinctly diminished. The same is true for dopamine. This depressive effect could be proved by measurement of transport rates of PAH in renal cortical slices in vitro. The increase in kidney weight and in the protein content of kidney tissue in dexamethasone-treated rats is lower in rats simultaneously treated with adrenergic neuronal blocking agents of 6-hydroxydopamine. Adrenoceptor agonists and antagonists (pholedrine, orciprenaline, phentolamine, propranolol) are without influence on the dexamethasone-stimulated increase in PAH transport.

[The renal effects of dopamine therapy in premature infants in the first week of life]. / Untersuchungen zu renalen Auswirkungen der Dopamintherapie bei Frühgeborenen in der ersten Lebenswoche.

It is known that Dopamine therapy induces loss of water and sodium on the first or second days of life. On the other hand, no studies have been published on renal function under long-term therapy. In our study we could prove an altered excretion of water and sodium as well as fractional sodium excretion in preterm infants who received dopamine for at least the first week of life. Conclusions for clinical practice are drawn.

Liver function after bilateral nephrectomy.

Consequences of bilateral nephrectomy (NX) for liver functions and for hepatic excretion of various endogenous substances were characterized in rats 24 h after NX. Plasma concentrations of urea, creatinine, fibrinogen, and glutathione increased significantly after NX, whereas the concentrations of total protein, albumin, and lipids decreased. The hepatic excretion of urea, creatinine, phospholipids, cholesterol, and aldosterone significantly increased in uremia, and excretions of protein and glutathione diminished. Active biliary transport can be diminished after NX by the effects of uremic toxins on the liver cells or by the competition phenomena between endogenous substances, which are normally excreted in urine, at the hepatocellular level. Reduced glutathione content and increased lipid peroxidation in hepatocytes have been found. Changes in lipid and protein metabolism after NX can be proved.

[The occurrence of aluminum-containing lysosomes in the kidney of experimentally treated rats]. / Zum Vorkommen von aluminiumhaltigen Lysosomen in der Niere experimentell vorbehandelter Ratten.

Aluminium was detected by electron spectroscopic imaging and electron energy loss spectra in the lysosomes of all cell types of the nephron in rats treated with aluminium chloride after 5/6 nephrectomy. The lysosomes of kidney cells of untreated rats did not demonstrate any detectable amounts of aluminium. Electron energy loss spectra showed the regular occurrence of iron (and also other elements) in the lysosomes of both groups of rats.

Stimulation of renal tubular transport of p-aminohippurate in rats of different ages by treatment with adrenocortical steroids.

Treatment with prednisolone or dexamethasone is followed by an increase in renal excretion of p-aminohippurate (PAH) and in accumulation of PAH in renal cortical slices, particularly in 5- and 10-day-old rats with immature kidney function. Treatment with triamcinolone is effective both in immature and in 55-day-old rats. There is no stimulation of PAH transport after treatment with mineralocorticoids (desoxycorticosterone, aldosterone).

Synergistic effect of triiodothyronine and dexamethasone on renal tubular transport of p-aminohippurate in rats of different ages.

Postnatal maturation of the renal tubular transport of p-aminohippurate (PAH) was verified in rats both in diuresis experiand on renal cortical slices in vitro. Following treatment with various doses of triiodothyronine (T3) or dexamethasone (3 days, once a day), the increase in renal tubular transport of PAH was more distinct in young rats with immature kidney function. The synergistic effects of simultaneous treatment with both hormones indicate differences between T3 and dexamethasone in the modulation of cellular function.