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PubMed1986

Acute changes in renal function induced by bisoprolol, a new cardioselective beta-blocking agent.

The acute effects of bisoprolol 10 mg i.v., a new beta1-selective adrenoceptor antagonist, on heart rate, mean blood pressure (mBP), glomerular filtration rate (GFR), para-aminohippuric acid clearance (CPAH), sodium clearance, urine volume and plasma renin activity (PRA), were studied in 6 patients with essential hypertension. Heart rate decreased by 23%, mBP remained unchanged, and GFR decreased by 14% and CPAH by 23%. PRA was depressed on average by 25%. Urine volume and sodium clearance also declined by 9 and 13%, respectively, but the changes were not statistically significant. The fall in heart rate was significantly correlated with that in GFR and CPAH. Changes in GFR were correlated significantly with those in CPAH. The acute changes in renal function induced by bisoprolol are considered to be due to a reduction in cardiac output and increased systemic vascular resistance.

Adrenergic beta-Antagonists↗
PubMed1991

Prediction of the renal clearance of cimetidine using endogenous N-1-methylnicotinamide.

We investigated the influence of the type rather than the degree of renal insufficiency on the renal clearance of drugs. Different models of site specific experimental renal failure (ERF) have been developed in the rat; proximal tubular necrosis, induced by cisplatin; papillary necrosis, induced by 2-bromoethylamine, and glomerulonephritis, induced by sodium aurothiomalate or by antiglomerular basement membrane antibody. Several parameters of kidney function were assessed: the clearance of inulin, PAH, and endogenous N-1-methylnicotinamide (NMN). Plasma BUN and creatinine concentrations, and the presence of proteinuria and glucosuria were also measured. Our results showed a nonparallel decrease in glomerular filtration rate (GFR) and tubular secretion as measured by the secretory clearance of endogenous NMN or by the secretory clearance of p-aminohippuric acid (PAH), that is incompatible with the "intact nephron hypothesis." As a result, the renal clearance of cimetidine, a drug eliminated mainly by renal secretion, correlated better with the renal clearance of endogenous NMN than with the GFR. We conclude that (i) our models of ERF demonstrated the existence of glomerulo-tubular imbalance that is contrary to expectations based on the intact nephron hypothesis; (ii) the type of the renal disease has a direct influence on the renal clearance of cimetidine; (iii) the clearance of endogenous NMN may be a valuable noninvasive test for assessing renal tubular secretion which could be useful in predicting the clearance of drugs eliminated predominantly by tubular secretion.

Acute Kidney Injury↗
PubMed1992

Acetaminophen nephrotoxicity in male Wistar rats.

Acute acetaminophen (APAP) nephrotoxicity was studied in male Wistar rats 1 h after different APAP single doses (200, 500 and 1000 mg/kg body wt, i.p.). Significant impairments in glomerular filtration rate (GFR) and clearance of p-aminohippuric acid (ClPAH) were observed in a dose-dependent way, although tubular parameters measured, water and electrolyte fractional excretion, remained at control values, while the urine to plasma osmolality ratios (Uosm/Posm) were diminished in APAP-1000 rats (control = 2.93 +/- 0.20, APAP-1000 = 1.40 +/- 0.04). The time course of renal function was also studied in APAP-1000 mg/kg-treated animals; parallel impairments were observed in GFR, ClPAH and tubular functions. Maximal alteration was observed at 16 h and restorement began at 24 h post-injection. Glucose renal handling, either at low or at high tubular glucose loads, remained at control values. Thus, our data suggest that the early stage of acetaminophen nephrotoxicity might be due to renal hemodynamic changes which might induce an alteration in tubular function principally in distal structures of medullary tissue, as shown by the Uosm/Posm results. These effects occurred coupled with a diminution in hepatic glutathione (GSH) levels at every APAP dose and in renal GSH levels in APAP-1000 mg/kg-treated rats. Moreover, renal damage was observed both in the presence or absence of hepatic damage.

Acetaminophen↗
PubMed1993

An experimental model for unilateral ischaemic acute renal failure in dog.

We determined the recovery of unilateral ischaemic acute renal failure in both ischaemic and non-ischaemic canine kidneys. Split renal clearance studies were repeated for seven weeks after 90 minutes of left renal artery clamping. Clearance of inulin and para-aminohippuric acid in the ischaemic kidneys dropped significantly for 3 weeks. Significant increase of the fractional excretion of sodium in those kidneys was observed at only 1 week after ischaemia. In the contralateral non-ischaemic kidneys, these indices did not change significantly throughout the experiments. This animal model of acute renal failure would be helpful in testing possible preventive measures and therapy for human acute renal failure.

Acute Kidney Injury↗
PubMed1990

Influence of hydration on ultrafilterable platinum kinetics and kidney function in patients treated with cis-diamminedichloroplatinum(II).

It has been reported that hypertonic saline provides protection against the renal toxicity of cisplatin (CDDP). We therefore evaluated its influence on the plasma and urinary pharmacokinetics of ultrafilterable platinum and kidney function as estimated by creatinine, inulin and PAH clearance. We undertook a randomized trial including two groups of ten patients receiving 100 mg/m2 CDDP in isotonic (group 1) or hypertonic saline (group 2) by a 20-min infusion. The hydration consisted of dextrose in group 1 and isotonic saline in group 2. Maximal concentration (Cmax), protein binding and cumulative urinary excretion were significantly higher in the dextrose group. Urinary flow decreased in this group but not in the other one. Inulin clearance was higher in the dextrose group than in the saline group and P-aminohippuric acid (PAH) clearance was not significantly different in these groups of patients. Hyponatremia was observed in the dextrose group. These results suggest that hypertonic saline infusion and saline hydration may enhance the diffusion of CDDP into tissues, lowering Cmax and renal excretion of platinum. The reduction of protein binding may indicate a diminution of aquation of CDDP in plasma. Our results suggest that the infusion of CDDP in hypertonic saline with salt hydration could exert a protective effect on the kidney. Moreover, there is a lessening of the risk of cellular hyperhydration. However, the better influence of dextrose hydration on glomerular filtration leads us to recommend a combination of the two methods of hydration for better tolerance and efficacy.

Chlorides↗
PubMed2002

Synthesis of a palladium(II)-dithiocarbamate complex: biological assay and nephrotoxicity in rats.

A new palladium(II)-dithiocarbamate complex, [Pd(ESDT)Cl](n), was synthesised and its chemical characteristics are discussed. This complex was examined for its cytotoxic properties in human tumour cell lines; for comparison, the cytotoxicity of cisplatin was evaluated under the same experimental conditions. In particular, Pd(II)-complex cytotoxicity on ovarian carcinoma C13 cells, resistant to cisplatin, showed that there seemed to be no cross-resistance between [Pd(ESDT)Cl](n) and cisplatin. The effects on the kidney were also studied. Biochemical investigation on urinary parameters showed that the effects after a single injection are similar to those of cisplatin, with an increase of urinary proteins and enzyme excretion in urine, and a significant decrease of glutamine synthetase activity in the renal tissue. In addition, the Pd(II)-complex caused a significant decrease of p-aminohippuric acid uptake in renal cortical slices relative to cisplatin. On the other hand, histopathological findings showed that the effects of the Pd(II)-complex are more severe and diffuse than the damage caused by cisplatin. Biochemical and histopathological findings show that the Pd(II)-complex affects the pars recta and pars convoluta, in contrast to cisplatin, which only affects the pars recta.

Animals↗
PubMed1998

Haemodynamic and renal effects of felodipine in young and elderly subjects.

OBJECTIVE: To study the influence of age on renal and haemodynamic effects of the calcium antagonist felodipine. METHODS: Eight young (mean age 27 years) and eight elderly (mean age 75 years) healthy normotensive subjects were given felodipine intravenously for 120 min aiming at close to therapeutic plasma level concentration. Renal blood flow (RBF) and renal vascular resistance (RVR) was estimated from para-aminohippuric acid (PAH) clearance 51CrEDTA clearance was used to measure glomerular filtration rate (GFR) and used in the calculations of fractional excretion (FE) of electrolytes. Impedance cardiography was performed to assess stroke volume and for the calculation of cardiac output and ejection fraction. RESULTS: At the end of felodipine infusion, the concentration of felodipine was on average 10.0 nmol x l(-1) in young and 12.0 nmol x l(-1) in elderly subjects (NS). During felodipine infusion blood pressure (BP) decreased from 138/76 to 120/68 in elderly subjects. The BP in young subjects was 126/74 at basal and 125/70 after infusion of felodipine. The systemic and renal vascular resistance decreased to a similar extent in young and elderly subjects after felodipine infusion. Felodipine caused a decrease in systemic vascular resistance from 25.6 to 23.3 in elderly and from 23.8 to 21.8 in the young subjects. Mean values for RVR at baseline and during infusion of felodipine were significantly higher in the elderly (10.1-15.1) than in the young subjects (5.4-6.7). Felodipine reduced RVR by 10% in the young and by 12% in the elderly at the end of infusion. The young subjects had 31% higher GFR than the elderly subjects at the start of infusion. Felodipine infusion did not affect GFR. There were no effects on stroke volume and ejection fraction. An initial natriuretic effect was found after infusion of felodipine in the young subjects. The fractional excretion of all electrolytes tended to increase after both felodipine and placebo, more in the elderly than in the young subjects. CONCLUSION: The effects of felodipine on central and renal haemodynamics previously observed in young and middle-aged subjects also seem to exist in the elderly. Volume expansion seems to increase the excretion of electrolytes more in elderly than in young people, and therefore the effect of felodipine on natriuresis is more evident in young subjects.

Adult↗
PubMed2004

Follow-up of kidney biopsies in normoalbuminuric patients with type 1 diabetes.

To study the development of diabetic glomerulopathy, we performed two kidney biopsies after 10.5 and 17 years of type 1 diabetes in 19 normoalbuminuric, normotensive adolescents (10 males). The biopsies were examined with light and electron microscopy. The glomerular filtration rate and effective renal plasma flow, determined with inulin and para-aminohippuric acid clearances, respectively, and ambulatory blood pressure were studied. Between the biopsies, significant increases occurred in glomerular volume, foot process width, mesangial matrix, and mesangial volume fraction/glomerulus. The metabolic control affected the basement membrane thickness, mesangial matrix, and mesangial volume fraction/glomerulus. The mesangial matrix and mesangial volume fraction/glomerulus were higher in female patients on the first biopsy, but on the second biopsy, the levels in males increased to those in females. The night-time systolic and mean arterial blood pressures from the first biopsy seemed to predict the mesangial matrix and mesangial volume fraction/glomerulus, foot process width, and slit pore length on the second biopsy. Despite normoalbuminuria and normal blood pressure, patients with type 1 diabetes have morphological changes of diabetic glomerulopathy that progress. The night-time blood pressure can be used to predict morphological changes of diabetic nephropathy in adolescents who are normoalbuminuric and normotensive.

Adolescent↗
PubMed2006

Indomethacin decreases furosemide-induced natriuresis and diuresis on the neonatal kidney.

Indomethacin is used to pharmacologically occlude patent ductus arteriosus in preterm infants. It induces renal untoward effects and furosemide is administered simultaneously to counteract them. The effect of furosemide is blunted by indomethacin. We analyzed comparatively the interactions of furosemide and indomethacin at the organic anion transport system in adult and newborn individuals. Adult and 5-day-old Wistar rats were allocated into three groups: (1) indomethacin (10 mg/kg, ip); (2) furosemide (2 mg/kg, ip); and (3) indomethacin/furosemide, at the same doses. Urinary flow, glomerular filtration rate (GFR), sodium and potassium fractional excretions, and free-water and osmolal clearances were estimated. Para-aminohippuric acid (PAH) uptake was measured in renal cortical slices to study the organic anion's secretory pathway. In adult and newborn rats, furosemide-induced increments in urinary fluxes and excretions of sodium and potassium were blunted by indomethacin administered simultaneously. PAH uptake was decreased to a further extent by indomethacin than by furosemide, suggesting that inhibition of the diuretic effect might be related to competition in the secretion of furosemide. Inhibitory interaction between indomethacin and furosemide was achieved at approximately 10-fold lower concentrations in the newborn than in the adult rats, suggesting that tubular secretion in the neonate is more sensitive to the action of these drugs than in the adult individual.

Animals↗
PubMed1996

Incidence of microalbuminuria in children with pyelonephritic scarring.

There is experimental evidence that loss of renal parenchyma results in hyperfiltration in the remnant glomeruli followed by development of glomerulosclerosis. Microalbuminuria, i.e., a urinary albumin excretion rate of 20-200 micrograms/min, is considered to be an early predictor of diabetic glomerulosclerosis. Hypothetically, increased urinary albumin excretion in patients with pyelonephritic scarring may also indicate glomerulosclerosis, with risk for future deterioration of renal function. This study was performed to determine the incidence of increased albumin excretion in children with mild to moderate pyelonephritic scarring, and to relate the information to glomerular filtration rate (GFR; clearance of inulin) and effective renal plasma flow (clearance of para-aminohippuric acid), as well as to the degree of scarring. The functional investigations were performed under water diuresis. Fifty-seven children, aged 1.7-17.9 years, with pyelonephritic renal scarring were included in the study. Nine young healthy adults were used as controls. The GFR was significantly lower in the children with pyelonephritic scarring than in the controls (median 93 ml/min per 1.73 m2, range 48-133 vs. 111 ml/min per 1.73 m2, range 89-121, P < 0.05), and the urine albumin excretion was significantly higher (median 20 micrograms/min per 100 ml GFR, range 0.8-170 vs. 9.2 micrograms/min per 100 ml GFR, range 3.3-21, P < 0.05). An inverse correlation was found between urine albumin excretion and GFR. Increased urine albumin excretion was found in 70% of the children with a GFR below 90 ml/min per 1.73 m2 compared with 41% of the children with a GFR above this level. Increased urine albumin excretion (> 20 micrograms/min per 100 ml GFR) was found in 51% of the children with pyelonephritic scarring, while only 14% had increased age-adjusted serum creatinine concentrations. The high incidence of microalbuminuria in children with pyelonephritic scarring indicates long-term follow-up until the ultimate outcome has been better defined.

Adolescent↗
PubMed1998

Nitric oxide metabolism following unilateral renal ischemia/reperfusion injury in rats.

Renal ischemia/reperfusion (I/R) injury results in decreased glomerular filtration and renal blood flow (RBF) and increased urine output, characterized by natriuresis and impaired concentrating ability. We studied unilateral I/R in rats to assess renal handling of nitric oxide (NO). Prior to I/ R, we measured urine flow rate (V), inulin clearance (C[IN]), para-aminohippuric acid clearance (C[PAH]), NO clearance (C[NOx] determined from metabolites NO2 and NO3), tubular transport of NOx (T[NOx], filtered load +/- urinary excretion), urine sodium and potassium excretion (U[Na]V, U[K]V), fractional excretion of sodium (FENa), and fractional excretion of NOx (FENOx) in each kidney. The left renal artery was then ligated for 30 min, followed by 30 min of reperfusion, and all measurements were repeated. C(IN) and C(PAH) were decreased in I/R kidneys compared with the contralateral kidney or pre-ischemia controls. V, FENa, and U(K)V were all significantly increased in I/R kidneys. Plasma NOx concentration was lower after injury in all animals (23.3 +/- 2.8 post injury vs. 30.4 +/- 7.7 microM pre injury, P < 0.05). C(NOx) was significantly higher in I/R kidneys (0.14 +/- 0.05 ml/min per g kidney weight) than in pre-injury kidneys (0.03 +/- 0.02 right, 0.04 +/- 0.30 left) or the contralateral controls (0.04 +/- 0.02) (P < 0.05 for all three controls). T(NOx) showed net tubular reabsorption of NOx in all kidneys (11 +/- 6 in post-ischemic left kidneys vs. 25 +/- 20 in left pre-ischemia, 33 +/- 13 in right pre-ischemia, and 21 +/- 4 right post-ischemia, nM/min per g kidney weight, P = NS). FENOx was higher in injured kidneys (28% +/- 18) than in pre-injury (3% +/- 0.6, 5% +/- 3) or contralateral controls (6% +/- 3) (P < 0.05 for all three controls). Renal NOx excretion and clearance are increased despite decreased plasma levels of NO metabolites after I/R injury. This increased excretion is not dependent on RBF or glomerular filtration, but may be related to impaired tubular reabsorption of NOx combined with increased intra-renal NO production.

Animals↗
PubMed1999

Influence of serum albumin on renal function in nephrotic syndrome.

Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), determined by the clearances of inulin and para-aminohippuric acid, were evaluated in 119 children with different types of nephrotic syndrome and in different stages: the nephrotic stage (serum albumin < 25 g/l), recovery stage (25-35 g/l), and remission (> 35 g/l). GFR in the nephrotic stage was significantly lower than in remission and in controls, and was lowest at onset of the disease (84 +/- 6, 111 +/- 4, and 119 +/- 2 ml/min per 1.73 m2). ERPF was higher in the nephrotic stage than in recovery, especially in children with histological lesions. Thus the filtration fraction (FF) was greatly decreased in the nephrotic stage. In patients investigated both in the nephrotic and the remission phase, GFR and FF increased significantly. There was a direct correlation between the serum albumin concentration and FF and an inverse correlation between mean arterial pressure (MAP) and GFR and FF in all patients, a direct correlation between the serum albumin concentration and GFR in minimal change nephrotic syndrome patients, and an inverse correlation between ERPF and serum albumin in children with histological lesions. In conclusion, GFR and FF were decreased and ERPF increased in the nephrotic stage, normalizing in remission. The low GFR in the nephrotic stage was thus not dependent on hypoperfusion. We suggest that the low GFR is dependent on a very low ultrafiltration coefficient. The direct correlation between GFR and serum albumin and the indirect correlation between GFR and MAP suggest compensatory mechanisms that increase the ultrafiltration pressure to counteract the severely reduced ultrafiltration coefficient.

Adolescent↗
PubMed2001

Long-term follow-up of renal function in recipients and donors following pediatric kidney transplantation.

Of 125 children undergoing kidney transplantation (tx), 87 received their grafts from living donors. Renal function of recipients (R) and donors (D) was assessed by glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) determined by clearances of inulin and para-aminohippuric acid. Rs were investigated yearly and Ds on alternate years. Within 5 months of tx, absolute GFR and ERPF (ml/min) were significantly lower in R than in D, and the differences in absolute GFR and ERPF between D and R were directly related to the difference in body surface area (BSA) between the two subjects. R and D pairs were repeatedly followed for 4, 6, and 8 years and the absolute GFR of R did not change during follow-up, while relative GFR decreased. Relative GFR decreased most in R, with the greatest difference in BSA between D and R at tx. In the donors, however, both absolute and relative GFR increased significantly up to 8 years. In conclusion, renal function of the two kidneys from the donor, i.e., the grafted kidney in the R and the single native kidney of the D, differed. The native kidney showed a capacity to increase its absolute and relative function with time. The grafted kidney, however, did not show an increase in absolute GFR, resulting in decrease in relative GFR, and the greater difference in BSA between D and R at tx, the greater fall in relative GFR of the R.

Body Surface Area↗
PubMed1997

Morphological and biochemical characterization of primary culture of rabbit proximal kidney tubule cells grown on collagen-IV coated Millicell-CM.

The aim of this study was to better characterize rabbit proximal kidney tubule cells cultured on collagen IV-coated porous inserts, as compared to the same cells seeded in standard plastic wells. Total protein contents in confluent monolayers on permeable membranes were about twofold higher than those measured in confluent cultures in plastic wells. Microscopy examinations suggested that such a difference was probably due to a higher cell density and to an impressive development of the apical brush-border membrane. Moreover, measurement of unidirectional transport of p-aminohippuric acid and tetraethylammonium bromide confirmed the high polarization level of cultures on porous inserts. Results of methyl(alpha-D-[U-14C]glyco)pyranoside uptake suggested that cell phenotype was probably influenced by culture conditions. Analysis of different markers as a function of time in culture showed decreases of alkaline phosphatase (AP), gamma-glutamyltranspeptidase (GGT), and Na(+)-K(+)-ATPase activities as well as increases in LDH, ATP, and glutathione levels, similar to those formerly reported for cells cultured in standard plastic plates. However, comparative data from 6-d-old monolayers have shown that AP, GGT, Na(+)-K(+)-ATPase, glutathione reductase (GRED), and selenium-dependent glutathione peroxidase (Se-GPX) activities were 2.8-, 2.6-, 1.6-, 1.2-, and 2.1-fold, respectively, better preserved on precoated permeable membranes. On the other hand, this paper reports for the first time in the literature that GRED and SE-GPX, two phase II detoxification enzymes, were well maintained in cultures of rabbit proximal kidney tubule cells. Our results show that culturing rabbit proximal kidney tubule cells on collagen IV-coated porous membranes was accompanied by an improvement of both morphological and biochemical properties of the cells.

Adenosine Triphosphate↗
PubMed1989

Cytochrome P-450-dependent formation of alkylating metabolites of the 2-chloroethylnitrosoureas MeCCNU and CCNU.

Rat liver microsomes catalyzed the biotransformation of the clinically important nitrosourea anticancer agents 1-(2-chloroethyl)-3-(trans-4-methyl-cyclohexyl)-1-nitrosourea (MeCCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) to alkylating metabolites that bound covalently to microsomal protein and to DNA. The enzyme-mediated microsomal alkylation required NADPH and oxygen and was inhibited by carbon monoxide, indicating the participation of a cytochrome P-450-dependent monooxygenase. Additional studies with inhibitors such as piperonyl butoxide and with the inducers 3-methylcholanthrene and phenobarbital were consistent with this view. In contrast to these observations on the formation of alkylating metabolites, carbamylation reactions were not affected significantly by microsomal metabolism. Reduced glutathione, cysteine or N-acetylcysteine decreased the microsomal alkylation by MeCCNU and produced a corresponding increase in the formation of polar metabolites that was resolved by HPLC as three distinct N-acetylcysteine-MeCCNU adducts. The addition of semicarbazide to the reaction decreased microsomal alkylation by 30%, indicating that the formation of the alkylating species may proceed via an aldehyde intermediate. Renal microsomes were not found to catalyze the alkylation reaction. Moreover, MeCCNU inhibited the renal slice accumulation of p-aminohippuric acid only in the presence of liver microsomes and NADPH, suggesting that a liver metabolite may be responsible for the renal toxicity of the parent nitrosourea.

Acetylcysteine↗