[Nephrotoxicity of Sandimmune and Consupren in an experiment]. / Nefrotoxicita Sandimmunu a Consuprenu v experimentu.

Cyclosporin A is a basic immunosuppresive drug after organ transplantation. Morphological and functional features of Cyclosporin A nephrotoxicity caused by Sandimmune (Sandoz) and Consupren (of the Czech origin) were investigated in male Wistar rats. Rats were subjected to a right side nephrectomy followed by 45-minute- ischemia of remaining left kidney. Sandimmune was administered to one group of animals, Consupren to another group, both in the amount of 10 mg/kg/day. The second part of the experiment was performed in animals with right side nephrectomy only (without ischemia of the left side kidney) followed by the same administration of drugs. Changes were checked the 3rd and 21st day after nephrectomy. Ischemic arterial insudation lasted in the 3rd day set of animals with nephrectomy and left kidney ischemia treated by Consupren and was lacking after Sandimmune. Microvascularization of tubular epithelial cells was observed in significant frequency in the 21st day set of animals with unilateral nephrectomy without ischemia after Consupren and not after Sandimmune. The finding correlated with significantly higher blood level of Consupren and higher creatinine concentrations in serum than those of Sandimmune in rats with unilateral nephrectomy only.

[An experimental model of the effect of uremia on cyclosporin A availability]. / Experimentální modelování vlivu urémie na dostupnost cyklosporinu A.

BACKGROUND: The aim of the study was to determine whether or not uraemia has an effect on cyclosporine A intestinal resorption. METHODS AND RESULTS: Model experiments were conducted in rats to monitor the effect of acute uraemia (bilateral nephrectomy) on the kinetics of cyclosporine A. Using intragastric tube, Cyclosporine A was administered to one group of rats in the form of Consupren (Galena, Czech Republic) and to another group in the form of Sandimmune (Sandoz, Switzerland), at a dose of 10 mg/kg/24 h either case. Blood levels of cyclosporine A were determined using RIA and specific and non-specific antibodies (cyclosporine and its metabolites). Cyclosporine A kinetics in nephrectomized rats was compared with that in control rats and in rats undergoing sham nephrectomy. The blood levels of cyclosporine A were significantly lower, and the area under the curve (AUC) of blood cyclosporine A in nephrectomized rats significantly smaller than in control rats. No significant differences in the evaluated parameters after Consupren or Sandimmune were observed. CONCLUSIONS: Our findings support the hypothesis that uraemia decreases cyclosporine A availability. The results suggest that the changes in cyclosporine A kinetics in nephrectomized rats following Consupren and Sandimmune administration are of the same character.

[Renal excretion of amino acids in patients on a regular dialysis program]. / Renální vylucování aminokyselin u nemocných v pravidelném dialyzacním programu.

In 10 patients with chronic renal failure and a polyfructosan S clearance (CPFS): 1.91-12.70 ml/min (mean 5.68 ml/min) with a preserved residual diuresis (more than 1000 ml/24 hours) renal excretion of 22 amino acids by residual nephrons was investigated before and 12 hours after haemodialysis. It was revealed that 12 hours after haemodialysis a significant drop of the filtered amount of all investigated amino acids occurred. Renal clearance of Ser, Pro, Glu, Gly, Ala, Tyr, Met, Leu and Cit after haemodialysis declined significantly (p < 0.05-0.001). Haemodialysis was not associated with significant changes of fractionated excretions (FE) of amino acids with the exception of Gly (p < 0.01) and Trp (p < 0.05) where an increase of FE was recorded. Hitherto assembled results are consistent with the idea that a reduction of the tubular resorption of amino acids in the residual nephrons in subjects with chronic renal failure cannot be explained by a change of their filtered amount (as "overflow" aminoaciduria) nor as the consequence of retention of some dialyzable substances which could inhibit tubular transport of amino acids. The reduced tubular transport of some of the investigated amino acids (Cys, Lys, Cit, Met, Asn+Gln, Orn, Ile) was significantly related with the drop of tubular sodium transport.

[Comparison of the effects of 2 preparations of cyclosporin A-- Consupren and Sandimmune--from the aspect of functional and morphologic changes in rats with renal ischemia]. / Srovnání úcinku dvou preparátu cyclosporinu A--Consuprenu a Sandimmunu--z hlediska funkcních a morfologických zmen u krys s ischemizovanou ledvinou.

BACKGROUND: Cyclosporine A is in transplantology an irreplaceable immunosuppressive agent. Its only manufacturer preparation Sandimmune--was the Swiss firm Sandoz. In 1990 the Czech firm Galena introduced cyclosporine A with the name Consupren on the market. The objective of the present investigation was to assess whether the nephrotoxic effect of the two preparations is comparable, or whether it differs. METHODS AND RESULTS: In a group of 65 rats after unilateral nephrectomy and 45-minute ischaemia of the remaining kidney the nephrotoxic action of cyclosporine preparations Sandimmune (Sandoz) and Consupren (Galena, CZ) administered in doses of 10 mg/kg body weight/24 hours throughout the experiment was investigated. The functional and morphological examination was made 3 or 21 days following nephrectomy. After three days the serum levels of creatinine, urea, sodium, osmolality and their urinary excretion as well as the intensity of proteinuria and morphological findings using light and electron microscopy did not differ in the two groups. The same was found during follow-up after 21 days; the small difference in the serum creatinine level only (Sandimmune 96.0 +/- 9.7 mumol/l, Consupren 111.4 +/- 11.2 mumol/l; p < 0.005) may be associated with the significantly higher cyclosporin levels following Consupren administration. CONCLUSIONS: The findings of the investigation support the idea that even after ischaemic kidney damage the nephrotoxicity of Consupren is not higher than that of Sandimmune.

[Preclinical models of the effect of acute renal ischemia on creatinine plasma levels]. / Predklinické modelování vlivu akutní ischemie ledvin na plazmatickou hladinu kreatininu.

The effect of temporary and complete renal artery clamping on the plasma concentrations of creatinine (Pcr) and morphologic alterations was studied in the remaining kidney of unilaterally nephrectomized rats. It was demonstrated that 20-minute ischaemia did not entail a significant increase in Pcr although histologic changes were already detectable in the kidney. Thirty-minute ischaemia was associated with appreciable histologic changes in the kidney even though the rise in Pcr was mild and transient. Forty-five and sixty-minute ischaemia was found to be associated with severe histologic changes and a distinct increase in Pcr. Seen from the perspective of transplantation requiring evaluation of the functional status of cadaverous donors, the experimental findings show that normal levels of Pcr do not exclude the possible presence of morphologic changes, and that even major histologic change may manifest themselves in an insignificant increase in Pcr.

[Comparison of functional and morphologic changes after administration of Consupren and Sandimmune in rats with a 5/6 nephrectomy]. / Srovnání funckcních a morfologických zmen po podávání Consuprenu a Sandimmunu u krys s 5/6 nefrektomií.

Rats with 5/6 nephrectomy were used to compare the nephrotoxic effects of Consupren (cyclosporine A by Galena, Czech Republic) and Sandimmun (Sandoz, Switzerland). Twenty-one days after the administration of the same dosage, 10 mg/kg 24 hr, the blood levels of cyclosporine A were statistically significantly higher (P < 0.025) in rats given Consupren than in rats receiving Sandimmun. The serum concentrations of creatinine, urea, electrolytes, and osmolality did not differ after Consupren and Sandimmun. No significant difference between the two drugs was found in urinary excretion or proteinuria. The increase in the weight of residual renal parenchyma at 21 days after 5/6 nephrectomy did not differ significantly between rats administered Consupren or Sandimmun. Histology revealed gross hypergranularities in the juxtaglomerular apparatus equally present in both studied groups. Results show no significant differences in any of the evaluated parameters of the functional capacity of residual renal parenchyma or in the nephrotoxic effect as demonstrated in the histologic picture.

[The critical value of residual kidney function in patients with chronic kidney failure from the viewpoint of the concentration of urea and potassium in the plasma]. / Kriticheskaia velichina ostatochnoi funktsii pochek u bol'nykh s khronicheskoi pochechnoi nedostatochnost'iu s tochki zreniia kontsentratsii mocheviny i kaliia v plazme.

Residual kidney function was examined in 10 patients with chronic renal insufficiency under balance conditions and in 30 outpatients on the basis of urea clearance (Curea) and potassium clearance (CK). Protein intake was 35-40 g/day (0.5 g/kg/day) and potassium intake was 30-40 mmol/day. Under these conditions the critical values of residual kidney function were as follows: 1) plasma urea concentration (Purea) did not exceed 30 mmol/l if Curea did not drop below 3.8 ml/min; 2) plasma potassium concentration (PK) did not exceed 5 mmol/l if CK did not decrease below 4.1 ml/min. Clinical examination of Curea and CK provides additional information to the examination of creatinine clearance (Ccr) or its plasma concentration (Pcr). Our results suggest that the critical value of residual kidney function cannot be defined only on the basis of examination of Ccr or Pcr. Examination of Curea and CK can help in the interpretation of very high Purea and hyperkalemia in patients with chronic renal insufficiency.

Renal amino acid excretion and aging.

The urinary excretion and serum concentration of amino acids were studied in 62 healthy individuals aged 15 to 70 years. In elderly subjects (61-70 years), it was found that renal amino acid clearance per 100 ml GFR (fractional excretion, FE) rose significantly in the following amino acids: CYS, VAL, MET, ILE and LEU. Since the serum concentrations of these amino acids showed no significant changes, but the GFR was reduced, it can be concluded that the raised FE of these amino acids was due to a decrease in their effective tubular reabsorption. A significant correlation was found between FENa and FE of most amino acids including those mentioned above. The findings support the assumption that changes in tubular Na+ transport probably participate in the changes of tubular amino acid transport in elderly individuals.

[Preclinical modeling of the possible effect of acute uremia on drug resorption in the gastrointestinal tract]. / Preklinické modelování mozného vlivu akutní urémie na resorpci léku v gastrointestinálním traktu.

The authors investigated in experiments on rats the course of serum concentrations of sulfisoxazole (S) and acetylsulfisoxazole (AS) in normal rats and in rats after bilateral nephrectomy after intra gastric administration of S. Serum concentrations of S and AS during the first three hours following administration did not differ significantly or were very close. During the subsequent hours the serum concentrations of S and AS in uraemic animals were significantly higher than in controls. The value of the absorption constant in the uraemic animals was on average higher and the absorption half-life lower than in controls. The assembled results suggest that in acute uraemia in rats the intestinal reabsorption of S and its metabolism in the liver are not reduced. The findings support the idea that the model used could be useful in preclinical research of drugs used in the treatment of acute uraemia.

[The critical level of renal function in patients with chronic renal failure from the aspect of maintaining normal levels of potassium in the blood]. / Kritická hodnota cinnosti ledvin u nemocných s chronickým ledvinovým selháním z hlediska udrzování normální plazmatické koncentrace draslíku.

In 29 subjects with chronic renal failure (Pkr = 826 +/- 69 mumol/, Ckr 0.128 +/- +0.039 ml/s) treated by conservative therapy the urinary excretion and residual renal potassium clearance (CK) was investigated. In 17% of these patients the plasma potassium level (PK) was higher than 5 mmol/l. The PK levels were not significantly related to the value of the residual diuresis, to the daily urinary potassium excretion nor the value of residual creatinine clearance. A significant relationship was found between values PK and CK. The critical CK value where PK rises above 5 mmol/l (under conditions of reduced protein intake 0.5 g/kd/day and a potassium intake not exceeding 40 mmol/l/24 hours) suggests the participation of extrarenal factors (excessive K intake or it's increased shift from cells to extracellular fluid).

Residual kidney function and plasma urea concentration in patients with chronic renal failure.

The relationships between the plasma levels of urea (P(urea)), renal clearance of urea (C(urea)) and creatinine (Ccr) at an intake of 0.5 g protein/kg body weight/day were followed in 10 patients with chronic renal failure (CRF) under balance conditions. Under these conditions, P(urea) attained a value of 30 mmol/l when C(urea) had decreased below 3.8 ml/min. By contrast, no correlation could be demonstrated between P(urea) and Ccr under these conditions. The same relationships were followed in another group of 30 outpatients with CRF. Even in patients not followed under balance conditions, C(urea) determination makes it possible to establish whether the high increase in P(urea) is due to the decrease in residual renal function below the critical level or whether extrarenal factors are involved. Likewise, no significant correlation between P(urea) and Ccr could be demonstrated under these conditions. The findings suggest that C(urea) measurement in CRF patients helps to assess residual renal function in terms of P(urea) regulation and provides information that cannot be obtained by Ccr measurement.

[Urinary excretion of catecholamines by the transplanted kidney]. / Mocové vylucování katecholaminu transplantovanou ledvinou.

In 88 patients after kidney transplantation (Tx) and in 30 healthy volunteers the urinary adrenaline, noradrenaline and dopamine excretion in 24 hours was examined. The results were calculated per values of glomerular filtration rate (Ccr). In patients after Tx an increased adrenaline excretion was found and its relative predominance over noradrenaline in urine, as it is the case in renal insufficiency. The absolute reduction of noradrenaline excretion was, when calculated per Ccr values, proportional to the number of functional nephrons. The absolute dopamine excretion was proportional to Ccr values and when calculated per glomerular filtration rate it was significantly higher than in controls. The elevated values of fractional sodium excretion in group Tx suggest that in the residual functional nephrons the increased sodium supply may act as a stimulus for dopamine formation in the kidney.

The plasma concentration and renal elimination of phenols in patients with chronic renal insufficiency.

The plasma concentration and renal elimination of phenols was studied in 32 individuals with various renal insufficiency (CRI) and in 30 healthy subjects. In patients with chronic renal insufficiency the increase in P phenols values correlated directly with Per and P urea. Daily urinary excretion of phenols in patients with CRI is only mildly decreased compared with that in healthy controls. Renal clearance (C phenols), 8.52 (+/- 2.69) ml/min on an average, decreases significantly in patients with CRI. While fraction excretion of phenols (FE phenols) was 9.53 (+/- 4.14) % on an average in healthy persons, patients with CRI displayed a significant increase. A significant linear correlation in the values of FE phenols and FEH2O and those of FE phenols and FE urea was documented. Our findings support the assumption that phenols are excreted by the kidney by a mechanism similar to that of urea excretion. Filtration of phenols in the glomeruli is followed, in healthy volunteers, by their significant reabsorption which is a flow-dependent process. In the residual nephrons of patients with CRI, the tubular reabsorption of phenols is decreased, a mechanism largely compensating the effect of decreased filtration of phenols on their total urinary excretion.