Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “AMINOHIPPURIC ACID”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 469 records · Page 26Linked to original sources
PubMed1989

In vivo indicator dilution kinetics of PAH transport in dog kidney.

In vivo multiple indicator-dilution (MID) data were analyzed using a computer-assisted mathematical model of transepithelial cell transport to determine p-aminohippuric acid (PAH) transport kinetics across the proximal tubular antiluminal (ALM) and luminal (LM) membranes. A bolus of 125I-labeled albumin (plasma reference), [14C]creatinine (interstitial reference), and tracer [3H]PAH was injected into the left renal artery of anesthetized mongrel dogs (n = 21), and immediate serial sampling of the left renal venous and left and right urine outputs was performed (control). MID runs were then repeated in the same dog following intravenous infusion of unlabeled PAH. For all plasma PAH concentrations ([PAH]P), the steady-state unidirectional flux coefficients were calculated at the ALM and LM. The computer-derived unidirectional flux coefficients were in keeping with active ALM transport and passive, carrier-mediated LM transport. The Km calculated for ALM uptake (interstitium to cell) was 0.51 mM. PAH transport was completely inhibited by probenecid. As [PAH]P increased, the renal vein mean transit time ratio t[3H]PAH/t[14C]creatinine was greater than 1.0, indicating backflux from cells into the interstitium, then declined toward unity, as ALM and LM transport became saturated. This study, which used PAH as a model substrate demonstrated the feasibility of utilizing computer-assisted mathematical models to quantitate the kinetics of transepithelial transport from in vivo experimentation.

Animals↗
PubMed1981

Postnatal adjustment in renal function.

Renal function was studied serially in 17 healthy term infants during the hours immediately following birth. Of 14 infants delivered vaginally eight received placental blood transfusion and six did not. The remaining three infants were delivered by cesarean section and received placental blood transfusion. Results indicate that the general pattern of change in urine output (V), clearance of inulin (CIN), and p-aminohippuric acid (CPAH), was similar in all infants despite a wide range in each of the functions measured. The pattern showed an initial increase in V, CIN, and CPAH followed by a decline to low values in all infants by 3 hours of age. Urine osmolality and output generally changed in opposite directions. During the first hour the values for V ranged from 0.02 to 0.47 ml/min; for CIN, from 0.5 to 9.1 ml/min; for CPAH, from 1.4 to 21.8 ml/min; and for osmolality, from 98 to 457 mOsm/kg. By 4 hours of age the values for V ranged from 0.01 to 0.15 ml/min; for CIN, from 0.8 to 3.7 ml/min; for CPAH, from 0.8 to 7.5 ml/min; and for osmolality, from 240 to 520 mOsm/kg. The initial values of V, CIN, and CPAH, as well as the changes, were greatest in those infants who received a placental transfusion; however, there were no statistical differences among the means of the various groups. By 4 hours of age, the range of values observed in the initial measurement was much less pronounced. This probably reflects the achievement of stability of renal circulation following adaptation to a variety of stresses during the intrapartum period.

Adaptation, Physiological↗
PubMed1972

A micropuncture study of postobstructive diuresis in the rat.

In order to investigate the syndrome of postobstructive diuresis, clearance and micropuncture studies were carried out in rats after relief of 24 hr of bilateral (BUL) or unilateral (UUL) ureteral ligation. In rats with BUL, a striking diuresis and natriuresis occurred when the obstruction to one kidney (the experimental kidney) was relieved. The results were not influenced by administration of vasopressin or d-aldosterone. Whole kidney clearances of inulin and p-aminohippuric acid (PAH) in the experimental kidney were reduced to 10% and 20% of normal, respectively. Superficial nephron inulin and PAH clearances were also reduced, but only to 40% and 45%, respectively. These findings suggest a heterogeneity of nephron function in which deep nephrons were functioning poorly or not at all. To investigate the site of impaired tubular reabsorption in the surface nephrons, absolute and fractional water reabsorption was measured. Absolute reabsorption was found to be decreased all along the nephron. Fractional reabsorption in proximal tubules was normal, as indicated by an average endproximal tubular fluid per plasma inulin (TF/P(In)) of 2.16 vs. 2.30 in controls. TF/P(In) was markedly decreased in distal tubules (2.91 vs. 8.02) and final urine (5.56 vs. 263). These observations indicate that the major sites of impaired sodium reabsorption leading to the diuresis were beyond the proximal tubule.Rats with 24 hr of UUL did not demonstrate a comparable natriuresis or diuresis either spontaneously when the obstruction was relieved or after i.v. infusion of urea. A major difference between the BUL and UUL rats was that prerelease intrarenal hydrostatic pressure was markedly elevated (30.1 mm Hg) in the former but was below normal free-flow values (9.2 mm Hg) in the latter. Thus, elevation of intrarenal pressure during the period of obstruction may be causally related to the natriuresis and diuresis which occurs after the obstruction is relieved.

Aminohippuric Acids↗
PubMed1969

Effects of potassium deficiency on renal function in the dog.

Serial determinations of the renal clearance for inulin and para-aminohippuric acid (PAH), maximum renal tubular reabsorptive rate for glucose, maximum urinary concentrating ability, total exchangeable potassium, extracellular volume, and plasma sodium and potassium concentrations were done in seven dogs before and after dietary potassium depletion. The same measurements were also made in two of the dogs during potassium repletion. Inulin and PAH clearances and transport maxima for glucose decreased progressively during depletion. These changes correlated well with both the duration of depletion and the extent of depletion as measured by total exchangeable potassium. Decreases in inulin and PAH clearance closely paralleled each other, suggesting that there might be a renal hemodynamic basis for both effects. The decreases in transport maxima for glucose were greater than those for inulin or PAH clearance, indicating the presence of a defect in the cellular transport mechanism for glucose. In the dogs that were repleted, renal function gradually returned to the predepletion state. No significant changes were found in extracellular volume or plasma sodium concentration during depletion. Renal concentrating ability decreased only moderately during depletion, with the decrease correlating better with plasma potassium concentration than with total exchangeable potassium. This finding contrasts with the marked decrease in concentrating ability and the severe polydipsia and polyuria found in animals depleted of potassium with the aid of corticosteroids. The results of the present study emphasize the importance of considering species differences and the method of producing depletion in interpreting studies of the effects of hypokalemia on renal function.

Aminohippuric Acids↗
PubMed1985

Structure/activity studies of the nephrotoxic and mutagenic action of cysteine conjugates of chloro- and fluoroalkenes.

The cysteine conjugates of the nephrotoxins hexachlorobutadiene (HCBD), tetrafluoroethylene (TFE) and hexafluoropropene (HFP), together with those of trichloroethylene and perchloroethylene, have been chemically synthesized and a relationship determined between their structures and their nephrotoxicity and mutagenicity in vitro. All of the conjugates had a marked effect on the uptake of both the organic anion p-aminohippuric acid (PAH) and the cation tetraethylammonium bromide (TEA) into rat kidney slices, suggesting activation of the conjugates in the slices to a toxic species which interferes with ion transport. This observation is consistent with the known nephrotoxicity of HCBD, TFE and HFP in vivo. Each of the conjugates was found to be metabolised by rat kidney slices and by semi-purified rat kidney beta-lyase to pyruvate, ammonia and an unidentified reactive metabolite. When semi-purified beta-lyase was used stoichiometric amounts of pyruvate and ammonia were produced. Although all of the conjugates were activated by beta-lyase and had a similar effect on ion transport their mutagenicity differed markedly. The conjugates of HCBD, trichloroethylene and perchloroethylene were mutagenic in the Ames bacterial mutation assay when activated by rat kidney S9. Metabolic cofactors were not required suggesting that activation was due to the enzyme beta-lyase. In the same assay the conjugates of TFE and HFP were not mutagenic either in the presence or absence of rat kidney S9 and cofactors. With a limited number of cysteine conjugates a clear distinction has been identified between the conjugates of chloroalkenes which were were similarly nephrotoxic but were not mutagenic. The mutagenicity of the cysteine conjugate of HCBD is consistent with the known renal carcinogenicity of this chemical.

Alkenes↗
PubMed1988

Effects of cadmium-metallothionein on renal organic ion transport and lipid peroxidation in rats.

The effects of cadmium-metallothionein (Cd-MT) on organic ion uptake in renal cortical slices and lipid peroxidation in the kidney were studied in rats. For in vitro studies, slices were prepared from kidneys of control animals and incubated in buffer containing either cadmium chloride (CdCl2) or Cd-MT in equimolar Cd concentrations ranging from 5 x 10(-6) to 2 x 10(-4) M. Uptake into the slices of the organic anion p-aminohippuric acid (PAH) was found to be inhibited by both forms of Cd in a dose-dependent manner. Although this inhibition was slightly greater in the presence of Cd-MT, accumulation of Cd into the slices was approximately 12 times greater with CdCl2 than Cd-MT. Tetraethylammonium (TEA) uptake was less sensitive to the inhibitory effects of both CdCl2 and Cd-MT, although a dose-dependent inhibition did occur with higher Cd concentrations. To study the in vivo effects of Cd-MT on transport function and lipid peroxidation in the kidney, rats were injected with Cd-MT (0.3 mg Cd per kilogram body weight [bw]) and sacrificed at specific time intervals. Similar to the in vitro studies, PAH uptake into the renal cortical slices was markedly inhibited within 12 hours after Cd-MT injection whereas inhibition of TEA uptake was less and not observed until 48 hours after injection. Only a small increase (1.4-fold) in lipid peroxidation, as measured by generation of malondialdehyde (MDA), in the kidney was detected at four hours postinjection, and no further increase was observed at later time periods. The results suggest that Cd-MT affects the transport of organic anions and cations during its renal uptake but that lipid peroxidation may play only a minor role in Cd-MT-induced renal toxicity.

Animals↗
PubMed1991

Reversible compensatory hypertrophy in transplanted brown Norway rat kidneys.

Recently we described methods for optimizing the function of transplanted rat kidneys. In unilaterally nephrectomized recipients, one week after surgery, the left transplanted kidney was identical to the right native kidney with respect to wet weight and the clearances of inulin and para-aminohippuric acid (PAH). The goals of the present experiments were first, to extend the post-surgery period to three weeks (sufficient to allow hypertrophic changes), and second, to study function of transplanted hypertrophied kidneys. Genetically identical Brown Norway rats were used as donor and recipients. Three weeks after transplanting a normal kidney into a unilaterally-nephrectomized recipient, the transplanted kidney had a normal plasma flow and was identical to the contralateral native kidney with respect to wet weight and the clearances of inulin and PAH. Three weeks after transplanting a normal kidney into a bilaterally-nephrectomized recipient, the wet weight, inulin and PAH clearances, and plasma flow of the transplanted kidney were all higher than control, and not significantly different from those observed in unilaterally-nephrectomized control rats. Thus, transplanted and native kidneys exhibited the same degree of compensatory hypertrophy. Hypertrophied donor kidneys (that is, the donor rat had been unilaterally-nephrectomized three weeks previously) remained hypertrophied in bilaterally-nephrectomized recipients, but in unilaterally-nephrectomized recipients, they regressed towards normal (that is, the values of wet weight, inulin and PAH clearances and plasma flow were significantly less than those in rats with only one kidney) while the contralateral native kidney remained normal (values of wet weight and inulin and PAH clearances were not different from control).(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1985

Renal effects of the high ceiling diuretic torasemide in rats and dogs.

The mode of action of torasemide was investigated by clearance experiments in dogs and rats. In the dog, torasemide (1 mg/kg i.v.) had no significant effect on glomerular filtration rate (GFR) but increased p-aminohippuric acid (PAH) clearance by 16% (p less than 0.01). In the rat both GFR and PAH clearance were significantly decreased, on an average 8-17%, by torasemide infused in the dose range of 1 to 20 mg/kg i.v. After i.v. injection the onset of diuresis was observed within 5 to 10 min and peak effect within 20 to 40 min in the rat and within 40 to 60 min in the dog. Fractional water and sodium excretions of nearly 25% were obtained in the rat with a dose of 8 mg/kg i.v. At equipotent doses, torasemide and furosemide induced similar diuretic and natriuretic effects in function of time in the rat. In the dog the effects lasted much longer with torasemide than with furosemide. This difference can be related to the longer half-life (about 8 h) of torasemide in the dog. In both species significant differences could be noted between torasemide and furosemide with respect to the time course of their effects on the urinary excretion of potassium. From the first experimental hour on, torasemide proved to be significantly less kaliuretic than furosemide as shown by increased Na/K ratios, during the third experimental hour they reached 20.5 vs 9.9 in the dog and 11 vs 7.5 in the rat with torasemide and furosemide, respectively. In hydropenic dogs, free water reabsorption was significantly reduced with torasemide and osmolar clearance significantly increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1996

Effects of feeding and short-term fasting on water and electrolyte turnover in female mink (Mustela vison).

Daily (24 h) rates of water and electrolyte turnover were measured in a conventional balance study in ten adult female pastel mink (Mustela vison) given free access to a standard mink feed for a 1-week conditioning period, followed by a 4 d experimental period and a 2 d fasting period. Drinking water was available throughout. In addition, the completeness of urine collection and the fraction of urine collected with the faeces were determined using a new experimental technique based on 24 h recoveries of specific urinary markers such as tritiated p-aminohippuric acid ([3H]PAH) or 14C-labelled inulin ([14C]IN) continuously delivered by small Alzet osmotic pumps implanted intraperitoneally. During feeding the mean individual percentage recovery in urine of [3H]PAH released from the osmotic pumps ranged from 68 to 88% (median 78%). The mean percentage of urinary [3H]PAH recovered from faecal collections was 6% (range 3-12%). In response to fasting the mean individual percentage recovery of [3H]PAH in urine ranged from 62 to 78% (median 68%). For urinary [14C]IN the mean percentage recoveries in fed and fasted animals were 79 and 63% respectively. Furthermore, during fasting, withdrawal of the supplies of dietary water caused a slight but insignificant (P = 0.17) increase in the daily intake of drinking water and, hence, the animals maintained their normal water balance by a dramatic reduction in urine excretion (P < 0.001). At the same time urinary solute excretion declined significantly (P < 0.001), due in part to the cessation of dietary electrolyte intake and in part to reduced formation of urea, whereas urinary osmolality decreased only moderately. The mean 24 h balances of Na, K, Ca, Mg, Cl and P were close to zero and only minor differences between the feeding and fasting periods were observed. When corrected for the measured inaccuracies in urine collection the balance data obtained in the present study represent useful reference standards for normally fed and fasted non-growing mink and, to some extent, useful guidelines for future studies in experimental animals.

Animals↗
PubMed2005

A compartmental capillary, convolution integration model to investigate nutrient transport and metabolism in vivo from paired indicator/nutrient dilution curves.

Thirty-three paired indicator/nutrient dilution curves across the mammary glands of four cows were obtained after rapid injection of para-aminohippuric acid (PAH) plus glucose into the external iliac artery. For the measurement of extracellular volume and kinetics of nutrient uptake from indicator dilution curves, several models of solute dispersion and disappearance have been proposed. The Crone-Renkin models of exchange in a single capillary assume negligible washout of solutes from the extracellular space and do not describe entire dilution curves. The Goresky models include a distribution of capillary transit times to generate whole system outflow profiles but require two indicators to parametize extracellular behavior. A compartmental capillary, convolution integration model is proposed that uses one indicator to account for the extracellular behavior of the nutrient after a paired indicator/nutrient injection. With the use of an iterative approach to least squares, unique solutions for nonexchanging vessel transit time t(mu) and its variance sigma were obtained from all 33 PAH curves. The average of heterogeneous vascular transit times was approximated as 2sigma = 8.5 s. The remainder of indicator dispersion was considered to be due to washout from a well-mixed compartment representing extracellular space that had an estimated volume of 5.5 liters or 24% of mammary gland weight. More than 99% of the variation in the time course of venous PAH concentration after rapid injection into the arterial supply of the mammary glands was explained in an unbiased manner by partitioning the organ into a heterogeneous nonexchanging vessel subsystem and a well-mixed compartmental capillary subsystem.

Animals↗
PubMed2001

Pathophysiology of cyclosporine-induced nephrotoxicity in humans: a role for nitric oxide?

BACKGROUND: The causes for the nephrotoxicity of cyclosporine A (CsA) have not been fully elucidated. Intrarenal vasoconstriction induced by several different mediators, both in humans and experimental animals, have been proposed. METHODS: We studied prostaglandin metabolites, endothelin and nitric oxide in kidney transplant patients receiving their first CsA dose. Prostaglandin metabolites in the urine and endothelin and nitric oxide (NO2/NO3 in urine and plasma were measured in 14 patients before and 3 and 6 h after oral ingestion of CsA (10 mg/kg b.w.). Clearances for inulin and p-aminohippuric acid (PAH) were measured before and in two separate 3-hour periods after CsA. Blood pressure, heart rate, and CsA blood levels were also determined. RESULTS: Clearances of inulin and PAH decreased progressively after CsA dosage while renal vascular resistance increased. Nitric oxide plasma levels decreased in nearly all patients from 21.0 +/- 2.8 to 19.1 +/- 2.6 (p = 0.003) and then rose slightly to 19.5 +/- 2.5 micromol/l (p = 0.1) 3 and 6 h after CsA ingestion, respectively. Urinary excretion of NO2/NO3 decreased nonsignificantly from 269 +/- 38.8 to 259 +/- 27.7 and 254 +/- 41.6 micromol/min (p = 0.5 and 0.5). At the same time, urinary prostaglandin E2 and 6-keto-prostaglandin F(1 alpha) excretion rate declined significantly [from 1,187 +/- 254 to 1,186 +/- 351 and 730 +/- 148 pg/min (p = 0.27 and 0.02) and from 697 +/- 115 to 645 +/- 134 and 508 +/- 58.2 pg/min (p = 0.34 and 0.05)]. Urinary thromboxane B2 and plasma and urinary endothelin first increased and then decreased nonsignificantly. Mean arterial pressure rose from 107 +/- 2.5 to 110 +/- 2.6 and 114 +/- 3.4 mm Hg (p = 0.1 and 0.05). CONCLUSION: The pathophysiology of CsA-induced acute renal vasoconstriction involves several different mechanisms including a decrease of the vasodilating prostaglandins E2 and 6-keto-prostaglandin F(1 alpha) and possibly nitric oxide.

6-Ketoprostaglandin F1 alpha↗
PubMed1995

Differential effects of recombinant human growth hormone on glomerular filtration rate and renal plasma flow in chronic renal failure.

In normal subjects recombinant human growth hormone (rhGH) increases glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) through the action of insulin-like growth factor-I (IGF-I). We have measured clearance of inulin and para-aminohippuric acid in 18 children with chronic renal failure (CRF) during their 1st year of rhGH treatment to look at the immediate (first 3 h), short-term (1 week) and long-term (1 year) effects of treatment. On day 1 mean (range) age was 9.1 (4.9-13.9) years, GFR 19 (9-58) and ERPF 77 (34-271) ml/min per 1.73 m2. During treatment height velocity increased from 4.5 (1.7-6.5) to 9.5 (4.8-12.7) cm/year (P < 0.0001). Two children required dialysis after 0.75 years and 1 child was electively transplanted after 0.5 years. There were no other serious adverse events. GFR and ERPF were unchanged in the 3 h following rhGH. GFR remained constant on day 8, 22 (6-56) and after 1 year, 20 (9-59) ml/min per 1.73 m2. ERPF increased to 96 (33-276) ml/min per 1.73 m2 on day 8 (P = 0.005), and remained elevated, but not significantly so, at 99 (24-428) ml/min per 1.73 m2 at 1 year. Fasting IGF-I increased from 147 (46-315) ng/ml to 291 (61-673) by day 8 (P < 0.003), and to 341 (101-786) ng/ml at 1 year. There was no correlation between the change in IGF-I and renal function. Blood pressure, albumin excretion and dietary protein intake were unchanged by treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1983

Role of angiotensin II-induced renal functional changes in mesangial deposition of exogenous ferritin in rats.

The relationship between acute angiotensin II (AII)-induced functional changes of the kidney and mesangial localization of macromolecules was investigated in rats utilizing native horse spleen ferritin as an exogenous tracer. One group of rats received a 30-minute infusion of a pressor dose of AII. Ten minutes before sacrifice they were injected with a single intravenous dose of ferritin. In the other group the injection of ferritin was followed by an 80-minute infusion of AII. Serial measurements of systolic blood pressure (BP), inulin clearance (CIN), p-aminohippuric acid (PAH) clearance (CPAH), filtration fraction (FF), and excretion of albumin (UAlb V) and ferritin (UFe V) were obtained. Although AII-treated rats showed significant increases of BP, FF, UAlb V and UFe V over controls, they were not different from controls with respect to plasma ferritin concentrations, renal delivery of ferritin, CPAH, and CIN. Semiquantitative evaluation of renal tissue by immunofluorescence and electron microscopy revealed that at 10 minutes no differences in the early and mild deposition of ferritin in the mesangium were appreciable. In contrast, at 80 minutes, AII-treated rats had markedly enhanced mesangial localization of ferritin when compared with controls. In the animals infused with AII for 80 minutes, the amount of glomerular ferritin deposition correlated strongly with UAlb V and UFe V. Combining the results of both, AII and controls at 80 minutes, these correlations were still present, in addition to weaker yet significant correlations of glomerular ferritin with BP and absolute changes of FF during the treatment period. The results show that, over a time interval of 80 minutes, AII augments the mesangial accumulation of ferritin in the presence of normal tracer delivery to the kidney. The enhanced mesangial localization of ferritin is observed under circumstances where overall increases in glomerular capillary permeability to albumin and ferritin are present. Although the precise mechanisms underlying these effects are not identified, AII-induced changes of glomerular microcirculatory forces and permeability properties of the glomerular capillary appear to be involved.

Albuminuria↗
PubMed2001

Oxidative stress and renal dysfunction in salt-sensitive hypertension.

Hypertension is a risk factor for the development of end-stage renal disease. The mechanisms underlying hypertensive nephropathy are poorly understood. There is evidence, however, that in hypertension there is an accumulation of partially reduced oxygen and its derivatives, known collectively as reactive oxygen species, which may contribute to progressive renal dysfunction. In the present study, we assess the contribution of oxidative stress in the development of salt-dependent hypertensive nephrosclerosis. Going beyond previous end point studies, which inferred renal function either indirectly or only qualitatively, we have determined oxidative stress concurrently with direct and quantitative measurements of renal function (via inulin and p-aminohippuric acid clearances). Moreover, in this time-dependent study, the measurements have been taken under low- as well as high-salt diets. As was expected from previous studies, in the Dahl salt-sensitive rat, a high-salt diet (8% NaCl) resulted in the development of hypertension, in a decreased glomerular filtration rate, and in a decreased renal plasma flow as compared with the normotensive control, the Dahl salt-resistant rat. In addition, however, we found clear evidence for the accumulation of reactive oxygen species in renal tissue homogenates of Dahl salt-sensitive rats on the high-salt diet. Our time-dependent protocol also indicated that renal oxidative stress follows, in time, the development of hypertension. We also found that after 2 weeks of increased salt loading, Dahl salt-sensitive rats excreted less cyclic guanosine monophosphate and NO(x) than Dahl salt-resistant rats on the same diet. It is known that urinary cyclic guanosine monophosphate and NO(x) represent the activity and stable derivatives of renal NO., respectively, and that they closely correlate with renal vascular resistance. Therefore, our results suggest that, in the Dahl salt-sensitive rat, increased oxidative stress is associated with salt-dependent hypertensive nephrosclerosis and that decreased NO. bioavailability may represent a common factor responsible for the vascular and glomerular dysfunction.

Animals↗
PubMed1985

Effect of gentamicin on isolated glomeruli and proximal tubules of the rabbit.

Alterations in both glomerular filtration rate and tubular transport occur in clinical gentamicin nephrotoxicity. We have studied the function of isolated tubules and glomeruli from rabbits treated with gentamicin. Gentamicin was administered subcutaneously to sexually immature (1400 to 1800 gm) or sexually mature (3800 to 4600 gm) New Zealand White rabbits in a dose of 15 mg/kg twice a day. Immature rabbits were treated for 28 to 31 days and developed only minimal renal insufficiency. About one-half of the mature rabbits developed azotemia. The mature rabbits that did not become azotemic were sacrificed after 28 to 30 days, and those that became azotemic were killed when their serum creatinine reached 2.5 mg/dl or higher (10 to 24 days). Animals were anesthetized and kidneys were removed for histologic examination and isolation of tubules and glomeruli. The ratio of p-aminohippuric acid (PAH) concentration in isolated tubule cells to that in medium after incubation in 3H-PAH (1 microM) at 37 degrees C for 30 minutes (T/M PAH) was used as an indicator of transport capacity of tubules. T/M PAH ratios averaged 196 +/- 18 and 111 +/- 21 for control immature and mature rabbits, respectively, and 135 +/- 22, 80 +/- 16, and 9 +/- 2 for gentamicin-treated immature and mature nonazotemic and mature azotemic rabbits, respectively. Glomeruli were isolated and filtration induced in vitro by a transcapillary oncotic gradient. Ultrafiltration coefficient, Kf, of glomeruli of immature and mature control rabbits averaged 3.78 +/- 0.29 and 5.84 +/- 0.51 nl/minute X mm Hg. Kf from gentamicin-treated immature rabbits averaged 2.82 +/- 0.20 and from mature azotemic rabbits 3.14 +/- 0.44 nl/minute X mm Hg. Kf of both mature and immature rabbits were decreased compared with controls (p less than 0.01). When all animals were considered, relative glomerular filtration rate, estimated from 1/serum creatinine, was positively correlated with the T/M PAH and Kf. When only experimental animals were studied, 1/serum creatinine and T/M PAH were also correlated. Decreased glomerular filtration rate and dysfunction of proximal tubules were also correlated with abnormal tubule histology. We suggest that injury to glomeruli and tubules may represent independent manifestations of gentamicin toxicity. Dysfunction may be present even when there are only mild histologic changes and glomerular filtration rate is near normal. Kf does not appear to limit glomerular filtration rate after treatment with gentamicin; rather, some direct or indirect effect of tubular injury may determine the decrement in glomerular filtration rate.

Aging↗
PubMed2000

Atractyloside nephrotoxicity: in vitro studies with suspensions of rat renal fragments and precision-cut cortical slices.

The consumption of plants containing atractyloside, a diterpenoid glycoside, causes selective proximal tubule injury leading to renal failure and death in humans. The underlying mechanisms responsible for its toxicity are still not well understood. The present study was therefore carried out to determine the mechanism and the exact sequence of events that lead to molecular toxic injury. A comparative study using renal cortical slices, suspension of freshly isolated renal proximal tubular fragments and glomeruli of male Wistar rat was made. These in vitro systems were exposed to 100-1000 mM atractyloside for 2-3 h at 37 degrees C. Atractyloside caused a significant alteration in various toxicity parameters in a concentration- and time-dependent manner in renal cortical slices and proximal tubular fragments, but not in glomeruli. The earliest change following exposure to atractyloside (1000 microM) was a significant reduction of intracellular adenosine 5'-triphosphate (ATP) content occurring within 1 h in the tubules and 2 h in slices. The significant depletion of reduced glutathione (GSH) inhibitor of p-aminohippuric (acid) (PAH) uptake and gluconeogenesis occurred simultaneously following loss of cellular energy. These events were only limited to the renal cortical slices and proximal tubular fragments. Increased severity of cellular injury resulted in cytotoxicity with the significant increase in the leakage of alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) in proximal tubular fragments (occurring at 2 h) and renal cortical slices (occurring at 3 h). There were, however, no alterations in oxidized glutathione (GSSG) levels or in the ratio of GSH/GSSG. Only limited lipid peroxidation in proximal tubular fragments and glomeruli was observed at atractyloside concentrations of 500 microM and above. In all cases of toxicity, the glomeruli were unaffected. Pretreatment of slices or fragments with probenecid (1.0 mM) failed to completely abolish atractyloside toxicity. These data demonstrate dose- and time-dependent toxicity of atractyloside and clearly confirmed the proximal tubular fragments as the target tissue. Atractyloside exhibits a toxicity profile that indicates early alteration in mitochondrial function and consequently loss of cellular energy, followed by reduced metabolic function and transport processes and ultimately cell death. This appears to be the most likely mechanism by which atractyloside exerted its acute cytotoxicity. Renal cortical slices, which maintain proximal tubule and glomeruli in their anatomic relationship, responded similarly to atractyloside toxicity as the proximal tubular fragments, and might be suggested as the most suitable in vitro model system for studying the mechanisms of atractyloside toxicity as they are more likely to mirror changes seen in the whole organ.

Adenosine Triphosphate↗
PubMed2006

Application of the isolated perfused rat kidney model to assess gender effects on drug excretion.

PURPOSE: To study the effect of gender on the renal disposition of two organic anions, p-aminohippuric acid (PAH) and furosemide (FSM) in the isolated perfused rat kidney (IPK). METHODS: IPK experiments (3-4 per treatment group) were conducted using kidneys from male and female Sprague Dawley rats. PAH was administered as a continuous infusion (with loading dose, targeted steady-state concentration 10 ug/mL). FSM was added as a bolus dose (2.65 mg, targeted concentration 33 ug/mL). Urine was collected in 10-min. intervals and perfusate was sampled at the midpoint of each collection period. Control (drug naïve) perfusions were performed for both genders. PAH and FSM were measured by HPLC. Kidney viability (GFR [estimated using inulin clearance], sodium reabsorption, glucose reabsorption) was monitored continuously during each perfusion experiment (2-h duration). RESULTS: Good kidney function was maintained across all study groups, and lower GFR estimates in female kidneys were due to differences in kidney weight. For PAH, kidney weight corrected renal clearance (0.88 +/- 0.37 mL/min/g vs. 0.59 +/- 0.19 mL/min/g) and excretion ratio (3.8 +/- 1.7 vs. 2.2 +/- 0.72) were significantly higher in male kidneys. For FSM, renal clearance was significantly lower in female (0.10 +/- 0.05 mL/min/g) compared to male kidneys (0.15 +/- 0.07 mL/min/g). Mass balance analysis showed that FSM cumulative urinary excretion was significantly higher and kidney accumulation was significantly lower in experiments with male kidneys. CONCLUSIONS: The study demonstrates that the IPK is a useful model to assess gender effects on renal drug disposition. The renal excretion of organic anions is reduced in female rats, possibly due to gender differences in expression and/or activity of membrane transporters (both basolateral and luminal) in the kidney.

Animals↗
PubMed2003

Effect of chronic accumulation of aluminum on renal function, cortical renal oxidative stress and cortical renal organic anion transport in rats.

The aim of the present work was to study the nephrotoxicity of aluminum lactate administered for 3 months (0.57 mg/100 g bodyweight aluminum, i.p., three times per week) to male Wistar rats. Renal function was studied after 6 weeks of treatment (urine was obtained from rats in metabolic cages) and at the end of the treatment using clearance techniques. Another group of rats was used as kidneys donors at the end of treatment. The renal cortex was separated and homogenized to determine glutathione (GSH) level, glutathione S-transferase (GST) activity and lipid peroxidation (LPO) level. Renal cortex slices were also used to study the p-aminohippuric acid (PAH) accumulation during steady-state conditions and the kinetics of uptake process. Clearance results, at the end of the treatment, indicated that renal functions in treated-rats were not different from those measured in control rats, although the renal concentration parameters differ when they were measured in treated rats after 24 h of food and water deprivation. Balances of water and sodium were also modified at both 1.5 and 3 months of treatment. The activity of alkaline phosphatase (AP) relative to inulin excreted in urine was significantly impaired: controls 2.2+/-0.6 IUI/mg, Al-treated 5.1+/-0.5 IU/mg, P<0.05. These data indicated that proximal tubular cells were loosing apical brush border membranes. Data obtained in cortex homogenates indicated that both GSH and GST activity were significantly decreased, and a significant increase of LPO was noted simultaneously in Al-treated rats. Renal accumulation of PAH, estimated as slice-to-medium ratio, decreased significantly in the Al-treated rats: control rats 3.06+/-0.02 ( n=12), Al-treated rats 2.26+/-0.04 ( n=12), P<0.0001. The maximal rate of uptake was also diminished in treated rats, while the apparent affinity remained unchanged. All these results indicate that aluminum accumulation in renal tissue affects cellular metabolism, promotes oxidative stress and induces alterations in renal tubular PAH transport, together with an impairment in sodium and water balance only detected under conditions of water deprivation, without other evident changes in glomerular filtration rate or other global functions measured by clearance techniques at least at this time of chronic toxicity.

Aluminum↗