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Biomedical subjects

E Kemp

Publications and source records attributed to E Kemp.

At least 91 records · Page 5Linked to original sources
PubMed1987

Cataractogenic effect of cyclosporin A: a new adverse effect observed in the rat.

In a study designed to test the long-term nephrotoxic effects of cyclosporin A (CyA), 11 of 13 rats given CyA, 25 mg/kg per day for 8 months, developed cataract. None of the 15 rats given CyA 12.5 mg/kg per day, nor of the controls given vehicle only (n = 10), developed this lesion. In a subsequent study, 15 rats were given CyA 25 mg/kg per day, 15 were given 12.5 mg/kg per day, and 10 controls were given the vehicle only. After 16 weeks, three rats of the group on CyA 25 mg/kg per day had developed cataract. The SPF Sprague-Dawley rats were maintained on a controlled breeding diet (Ewos R3). Perforating eye lesions or infections were not observed, but one rat without opacity of the lens had antibodies against sialodacryoadenitis virus. Thus, in the rat, high-dose CyA has significant cataractogenic effects when administered for 15%-25% of the rat life-span.

Animals↗
PubMed1986

Platelet aggregation is not essential for xenograft rejection.

Five rabbit kidneys were perfused at 80 mm Hg with heparinized human blood, five with platelet poor human blood, and five with human blood added prostacyclin. Time until blood flow decreased to 2 ml/min was significantly delayed by removal of platelets or addition of prostacyclin. Histological examination did not reveal any difference between the groups. It is concluded that platelets play an enhancing role, but they are not essential for xenograft rejection.

Animals↗
PubMed1986

Nephrotoxicity of cyclosporin A. A lithium clearance and micropuncture study in rats.

Renal function was studied in rats treated with cyclosporin A (CyA). Peroral CyA 25 mg kg-1 day-1 depressed glomerular filtration rate (GFR) from 1284 +/- 429 to 500 +/- 228 microliters min-1 g-1 kidney weight (KW) (P less than 0.01). Absolute rate of proximal tubular reabsorption (APR) decreased from 1075 +/- 437 to 468 +/- 203 microliters min g KW-1 (P less than 0.01). Proximal tubular fractional reabsorption (PFR) was 67.7 and 68.5% measured with the TT/OT and fractional lithium-clearance methods, respectively. Amiloride had no effect on lithium-clearance in CyA treated rats. Acute isotonic volume expansion increased GFR and APR towards normal, while PFR remained increased. Increased sodium clearance did not normalize renal function. CyA intravenously (12.5 mg kg-1) depressed GFR and APR acutely, while PFR increased. Proximal intratubular pressures were low normal (mean 11.6 mmHg). Proximal transit times were prolonged (mean 25.2 s, P less than 0.01). Renal morphology was normal. The data are evidence against a primary tubular damage of CyA, and makes it less likely that the major lesion is located to the glomerular membrane. The results suggest that CyA nephrotoxicity mainly is due to a haemodynamic effect.

Amiloride↗
PubMed1986

Antagonist capacities of nifedipine, captopril, phenoxybenzamine, prostacyclin and indomethacin on cyclosporin A induced impairment of rat renal function.

Experimental evidence indicates that cyclosporin A (CyA) nephrotoxicity is due to renal arteriolar constriction, reducing renal blood flow, glomerular filtration rate (GFR), and delivery of tubular fluid from the end of the proximal tubule to the loop of Henle. The proximal tubular fractional reabsorption (PFR) is increased. Therefore, the impact on renal function of vasodilating agents was studied in rats given CyA. Conscious catheterized rats and clearance techniques were used. In acute experiments a preexisting CyA-nephrotoxicity was resistant to infusion of phenoxybenzamine, prostacyclin, captopril, nifedipine and indomethacin. Concomitant treatment with captopril and CyA did not improve renal function, while concomitant treatment with CyA and nifedipine improved GFR to 1.13 +/- 0.34 ml min-1 g-1 kidney weight (gKW) (n = 19, P less than 0.05), as compared to CyA and placebo treated controls (n = 12, 0.83 +/- 0.32 ml min-1 g-1 KW). Nifedipine also reduced FPR (88.6 +/- 5.1% vs. 83.2 +/- 5.6%. P less than 0.01), and increased lithium clearance from 99 +/- 54 to 184 +/- 64 microliters min-1 g-1 KW (P less than 0.001). The results are further evidence that CyA nephrotoxicity includes renal vasoconstriction, and indicates that calcium entry blockade is nephroprotective in the case of CyA toxicity.

Animals↗
PubMed1986

On the role of platelets and leucocyte in renal xenoperfusion.

Five rabbit kidneys were perfused with heparinized human blood, five with platelet-rich, leucocyte-poor blood, five with platelet-poor, leucocyte-rich blood, and five with platelet-poor, leucocyte-poor, heparinized human blood. The kidneys were perfused at a constant pressure of 80 mm Hg and the time until the flow decreased to 2 ml/min was determined. Removal of platelets from the blood significantly delayed rejection. The effect of removing leucocytes was insignificant. Morphologically all groups revealed platelet aggregates, endothelial damage and ischemic changes of distal tubular epithelium.

Animals↗
PubMed1986

Cyclosporine A: effectiveness and toxicity in a rat model.

In an effort ot elucidate the effectiveness of Cyclosporine A (CyA) relative to the toxicity, Lewis to Sprague-Dawley first and second set skin transplantation and evaluation of the renal function with clearance methods was performed. CyA 12.5 mg/kg/day delayed first set rejection from 12.3 to 15.4 days (p less than 0.001), and second set from 10.5 to 12.1 days (p less than 0.05); 25 mg/kg/day prolonged the survival times to 18.3 (p less than 0.01) and 19.5 (p less than 0.002) days, respectively. The majority of the skin grafts were still not rejected at the end of the 3 weeks CyA 25 mg/kg/day treatment in contrast to the results during 12.5 mg/kg; the second set skin graft survival was significantly better (p less than 0.01) during the higher dosage. It is concluded, that CyA is not fully immunosuppressive at the 12.5 mg/kg/day dosage. In the doses 12.5 and 25 mg/kg GFR (inulin clearance [Cin]) was reduced to 80 and 48%, respectively, of the control value; the lithium clearance (CLi) was reduced to 69 and 27%. Proximal fractional reabsorption, as calculated from 1-CLi/Cin, was increased from a control value of 82% to 86 and 92% (p less than 0.02) in the 12.5 and 25 mg/kg/day group, respectively, suggesting that CyA nephrotoxicity is due to a decrease in the glomerular ultrafiltration pressure rather than being secondary to proximal tubular damage. In conclusion, in this model there does not seem to exist a therapeutic window between nephrotoxicity and the immunological effectiveness of CyA.

Animals↗
PubMed1986

Ketoconazole and cyclosporine A: combined effects on rat renal function and on serum and tissue cyclosporine A concentration.

The effects of ketoconazole (Kcnz) on cyclosporine A (CyA) serum levels and CyA-nephrotoxicity were studied. To rats later anesthetized with pentobarbital sodium, CyA 12.5 and Kcnz 20 mg/kg/day (n = 20), or CyA 12.5 mg/kg and Kcnz-vehicle (n = 21), was dosed. To rats anesthetized with etomidate (n = 14), CyA 12.5 mg/kg and Kcnz-carrier was dosed. S-CyA was monitored during 14 days, and then the rats were investigated with clearance (C) methods (inulin [(in), lithium (Li)], sodium, and potassium), and liver (L) and kidney (K) CyA was measured. Kcnz increased S-CyA, L-CyA and K-CyA (+50 -80%). There were significant (p less than 0.05) correlations between S- and L- or K-CyA. Kcnz increased CyA nephrotoxicity: Mean Cin was 1.012 ml/min/gKW (kidney weight) after CyA treatment (a subnormal value), but decreased to 0.556 ml/min/gKW in the group also given Kcnz (p less than 0.001). CLi decreased from 0.135 to 0.048 ml/min/gKW (p less than 0.001), and absolute proximal tubular reabsorption decreased from 0.877 to 0.508 ml/min/gKW (p less than 0.001), while the fractional reabsorption in the proximal tubule (FPR), expressed as a percentage of GFR, increased from 86.9 to 91.6% (p less than 0.005). Thus, after Kcnz treatment to rats given CyA 12.5 mg/kg/day, their renal function was indistinguishable from that in rats given CyA 25 mg/kg/day.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1986

Glomerulotubular function in cyclosporine A treated rats.

A total of 178 rats treated with Cyclosporine A (CyA, dose range 0-50 mg/kg/day) during 14 days were investigated with clearance methods (inulin, lithium, sodium and potassium), serum CyA and plasma renin concentration (PRC). Inulin clearance (Cin) decreased to a mean of 68% of the control value in the 12.5 mg/kg/day group, 44% in the 25 mg/kd/day group and 47% in the 50 mg/kg/day group, respectively. Lithium clearance (CLi) was reduced in all CyA treated groups, while the absolute proximal tubular reabsorption as calculated from Cin-CLi was decreased during increased fractional proximal reabsorption (1-CLi/Cin). As proximal intratubular hydrostatic pressure has been shown to be low in the normal range (excluding tubular obstruction) these findings are considered due to a decrease in ultrafiltration pressure. Furthermore we found the reabsorption of sodium distal to the proximal tubule to be decreased, both absolute (PNa X (CLi-CNa)) and fractional to the delivery from the end of the proximal tubule (1-CNa/CLi). Also the distal potassium reabsorption was decreased PK X (CLi-CK). These findings were not primary, but rather secondary, to the altered proximal function, since it has been shown that i.v. CyA immediately produces increased fractional proximal reabsorption. PRC was increased from a mean of 2.5 to 4.9 and 5.3 X 10(-4) Goldblatt units (GU)/ml (12.5 and 25 mg/kg group, respectively), to be explained by the decreased sodium delivery to the macula densa region and/or by a direct CyA effect. In conclusion CyA reduces the net ultrafiltration pressure, and due to an insufficient decrease in absolute proximal tubular reabsorption, fractional proximal reabsorption increases.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Xeno- and auto-perfusion of rabbit kidney. Machine perfusion with blood at 37 degrees C.

Five rabbit kidneys were perfused with human blood and another five with their own blood in a re-circulating oxygenated system at 37 degrees C. The flow decreased to 2 ml/min. within 30 min. in all xenoperfusions, while none of the autoperfused had decreased to this level by 60 min. Endothelial damage, exudation, and IgG deposits along the basement membrane of the glomerular capillaries were the discriminative features of the xenoperfusion. In these experiments, we were unable to demonstrate any major role of platelets in the process leading to decreased blood flow.

Animals↗
PubMed1985

Glomerulotubular function in cyclosporine-treated rats. A lithium clearance, occlusion time/transit time and micropuncture study.

Sprague-Dawley rats treated with cyclosporine (Cys) and appropriate controls were investigated with inulin, lithium and sodium clearances. It was found that Cys depressed glomerular filtration rate (GFR) and absolute proximal tubular reabsorption, while fractional proximal reabsorption was increased. As a normal proximal tubular reabsorptive capacity was found after volume expansion, and the intratubular pressure was normal, tubulotoxicity or obstruction of the tubular system by Cys was excluded. Increased fractional proximal reabsorption was also found with the occlusion time/transit time method. Intravenous Cys resulted in instantaneous renal functional changes qualitatively identical to those of prolonged Cys treatment. It was concluded that Cys nephrotoxicity is due to decreased ultrafiltration pressure, most probably due to a reversible spasm in the afferent glomerular arteriole.

Animals↗
PubMed1983

The survival of pig to rabbit renal xenografts during inhibition of thromboxane synthesis.

Five rabbits treated with the thromboxane synthetase inhibitor Dazoxiben and five control rabbits received pig renal xenografts. Plasma albumin, complement factor C3, TXB2, 6-keto-PGF1 alpha, and serum TXB2 and 6-keto-PGF1 alpha were determined before and 1/2 hour after transplantation. The xenograft survival was significantly decreased in the Dazoxiben treated animals compared to the placebo treated animals determined as time to total cyanosis of the graft, total urine production, and time to stop of urine production. Lack of TXB2 production during blood coagulation confirmed inhibition of platelet thromboxane synthesis. The other determined variables showed no significant differences between the treated and the placebo animals.

6-Ketoprostaglandin F1 alpha↗