Evolution of experimental mild and severe chronic renal failure in the rat. Mathematical models.

Two degrees of renal insufficiency were obtained in female Wistar rats, one mild (M) and the other severe (S) by surgical resection of 2/3 or 3/4 of one kidney, followed by contralateral nephrectomy. The serum creatinine concentration (Cr) s was evaluated as an index of renal function and followed in the two mentioned groups under a normal protein diet and in "S" also under a low protein diet. The evolution was assessed by two functions of time: 1/(Cr) s and log e (Cr) s. Several differences between M and S were detected. In M a smaller initial and maximal increase in (Cr) s than in S followed by a plateau was observed; in S a decrease in (Cr) s posterior to the initial increase was detected attributed to hyperfiltration followed by a sustained increment. The lowering of protein content in the diet caused a decrement in (Cr) s. In both groups a better adjustment with the logarithmic than with the inverse function was obtained, although poorer in S rats owing to a larger variability. In order to look for a mathematical link between inulin clearance (Cl In) and (Cr) s, the relationship between Cl In vs. 1/(Cr) s, and log e Cl In vs. log e (Cr) s was studied in normal and in rats in renal insufficiency. By regression analysis we found a good adjustment with both functions from 0.58 to 1.60 mg % (Cr) s.

Evolution of experimental mild and severe chronic renal failure in the rat. Mathematical models.

Two degrees of renal insufficiency were obtained in female Wistar rats, one mild (M) and the other severe (S) by surgical resection of 2/3 or 3/4 of one kidney, followed by contralateral nephrectomy. The serum creatinine concentration (Cr) s was evaluated as an index of renal function and followed in the two mentioned groups under a normal protein diet and in [quot ]S[quot ] also under a low protein diet. The evolution was assessed by two functions of time: 1/(Cr) s and log e (Cr) s. Several differences between M and S were detected. In M a smaller initial and maximal increase in (Cr) s than in S followed by a plateau was observed; in S a decrease in (Cr) s posterior to the initial increase was detected attributed to hyperfiltration followed by a sustained increment. The lowering of protein content in the diet caused a decrement in (Cr) s. In both groups a better adjustment with the logarithmic than with the inverse function was obtained, although poorer in S rats owing to a larger variability. In order to look for a mathematical link between inulin clearance (Cl In) and (Cr) s, the relationship between Cl In vs. 1/(Cr) s, and log e Cl In vs. log e (Cr) s was studied in normal and in rats in renal insufficiency. By regression analysis we found a good adjustment with both functions from 0.58 to 1.60 mg

(Cr) s.

Possible mechanism of unconjugated bilirubin toxicity on renal tissue.

1. The effects of unconjugated bilirubin on rat renal tissue metabolism and organic anion transport were investigated using cortical slices. 2. Unconjugated bilirubin in the medium decreased slice-to-medium ratio of p-aminohippurate, altered intracellular Na+ and K+, and decreased ATP content without modifications of (Na+-K+) ATPase. 3. The effects were similar to those of ethacrynic acid and cyanide but less marked. 4. The presence of probenecid blocked the effect of pigment on intracellular electrolytes. 5. The results suggest that pigment is taken up by renal tissue using the organic anion transport system, and within the cell inhibits ATP production.

Inhibitory effect of unconjugated bilirubin on p-aminohippurate transport in rat kidney cortex slices.

The effects of unconjugated bilirubin on the accumulation of p-aminohippurate, kinetics of p-aminohippurate uptake, the efflux of pre-accumulated p-aminohippurate and water and electrolyte distribution were investigated in the rat kidney cortical slice. (2) The addition of unconjugated bilirubin to the incubation medium decreased the 60 min slice-to-medium concentration ratio of p-aminohippurate. (3) The decrease in p-aminohippurate accumulation by unconjugated bilirubin was found to be more pronounced by increasing the concentration of pigment in the medium. (4) The rate of uptake of p-aminohippurate as a function of p-aminohippurate concentration differed in aerobiosis and anaerobiosis, and unconjugated bilirubin decreased only the uptake of p-aminohippurate in aerobic conditions. (5) The efflux of pre-accumulated p-aminohippurate decreased when unconjugated bilirubin concentration in the medium was low (10-20 microM) but the efflux increased when the concentration of pigment was much higher (100 microM). (6) The addition of unconjugated bilirubin to the medium (40-100 microM) increased intracellular sodium and total tissue water content, and decreased intracellular potassium and oxygen consumption of tissue. However the slices incubated with low concentration of pigment (20 microM) did not exhibit significative changes in cellular functional parameters. (7) These findings suggest that unconjugated bilirubin impairs p-aminohippurate transport by a complex mechanism that might involve binding of pigment to sites necessary for anion transport, although effects related to pigment toxicity or to its oxidative decomposition are not excluded.

Peritubular interaction of unconjugated bilirubin in isolated perfused rat kidney.

1. The interaction of unconjugated bilirubin with peritubular cell membranes of the rat kidney was studied by means of an isolated rat-kidney preparation applying the multiple-indicator-dilution technique. 2. Inulin was used as an extracellular marker and p-aminohippuric acid as a model of organic anion that interacts with the peritubular membrane. 3. A single renal artery injection of a mixture containing inulin and unconjugated bilirubin was followed by the appearance of the two compounds in the venous effluent. The unconjugated bilirubin curve was always under the curve of inulin and its mean transit time was always less than that of inulin. 4. The cumulative venous recovery of inulin was higher than that of unconjugated bilirubin. 5. When unconjugated bilirubin uptake was plotted against the injected dose of pigment the relationship suggested a saturation phenomenon. 6. The recovery of p-aminohippuric acid was significantly increased when unconjugated bilirubin was added. 7. The results provide evidence for the interaction of unconjugated bilirubin with the peritubular cell membranes of rat kidney.