The Causal Role of Plasma Albumin Deficiency in Experimental Nephrotic Hyperlipemia and Hypercholesteremia 1

Abstract

Previous studies ( 1-8) from this laboratory have indicated that the hypercholesteremia and hyperlipemia occurring in the experimental nephrotic syndrome induced in rats by injection of anti-rat kidney seruim are due primarily to some intravascular "trapping" phenomenion whereby the animal appears unable to remove either endogenously-produced or dietary-derived cholesterol and lipid from the plasma with its customary efficiency. However, since renal changes seemingly initiate the total nephrotic syndrome, it seems probable that this "trapping" of cholesterol and lipid which occurs in the plasma in this syndrome is related in some manner to such renal changes. In the present study, an attempt was made to determine the nature of this relationship. The observations herein reported suggest (a) that the hypercholesteremia and the hyperlipemia observed in the experimental nephrotic syndrome are initiated and maintained by the external renal loss of some plasma constituent, and (b) that this substance specifically is albumin.I. The Relationship of Nlephrotic HVperlipenetia and Hypercholesteremlia to Renal Dawnage and External Renal Excretion MethodsDrastic alteration in renal function was accomplished in several series of experimental and control male rats (Long-Evans strain) by 1) nephrectomy, 2) bilateral ligation of renal pedicles, 3) bilateral ureteral ligation, and 4) ureter-vena caval anastomosis. 1) Conttrol rats. Pooled rabbit anti-rat kidney serum (AKS) was prepared as described by Heymann and Lund (9). The hypercholesteremic effect of the AKS 1 Aided by Grants from the American Heart Association, the San Francisco and Monterey County Heart Associations and from the National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, Public Health Service, A-46 (C4) and Grant H-119 from the National Heart Institute, National Institutes of Health, Public Health Service.was established by injection of 1.0 ml. of it intravenously into 25 intact rats (group 1) and into 16 sham-operated (splenectomy) rats (group 2) that were bled 24 hours later for determination of plasma total cholesterol (10) and lipids (11). At the same time, 15 other normal control rats (group 3) that had been injected with 1.0 ml. of ntormiial rabbit serum were bled in order to establish normal plasma lipid levels.2) Nephrectomiiy. The second series of 45 rats was subjected to bilateral nephrectomy. Twenty-nine of these rats (group 4) were given intravenously 1.0 ml. of potent AKS immediately after the nephrectomy. The remaining 16 nephrectomized rats (group 5) served as controls, receiving 1.0 ml. of normal rabbit serum.Blood samples taken 24 hours later were analyzed for total cholesterol and those of group 4 also for total lipids. In addition, five other rats (group 6) that had been fed a protein-electrolyte-free diet (12), enabling them readily to survive for at least five days after nephrectomy, also were given 1.0 ml. of AKS immediately after nephrectomy.3) Bilateral ligationi of the renlal pedicles. A third series of r...

In Vivo Studies of the Role of Albumin in Endogenous and Heparin-Activated Lipemia-Clearing in Nephrotic Rats 1

“…An additional factor would appear to be the short intravascular existence of any given albumin molecule. Thus, in certain of the treated chronic nephrotic rats, the renal loss of infused albumin occurred so rapidly (3,26) as to preclude any rise of plasma albumin, and in this instance no lipemia-clearing was induced by the injected albumin or by the concurrently administered heparin.…”

“…It is likely that the clearance of excess cholesterol from the nephrotic rat's plasma, following administration of albumin and/or heparin, is secondary to the effects of these substances on the hydrolysis of triglycerides (10), since in turn, the accumulation of excess cholesterol in nephrotic plasma is probably secondary to the hypertriglyceridemia induced by the albumin deficiency (3). Thus, in the normal rat (21), progressive hypercholesteremia occurs when a sustained rise of plasma triglycerides is induced by the latter's continuous intravenous infusion.…”

“…Therefore a second study (3) was done in which bovine serum albumin was infused into rats during both the induction and chronic phases of experimental nephrosis. This was found to be far more effective than heparin in respectively preventing and correcting the hyperlipemia otherwise occurring in such rats.…”

“…This suggested that the accumulation of lipids in the plasma of the nephrotic rat is due not only to a quantitative deficiency of plasma albumin (3) but also to the excessive renal loss of some other essential plasma constituent of the lipid-clearing mechanism which might be escaping pan passu, either separately or combined with the escaping albumin. If this substance were heparin, or its plasma equivalent, the combined administration of heparin and albumin would be expected to be 'Aided by Grants from the National Institute of Arthritis and Metabolic Diseases of the National Institutes of Health, (A-46, C-4), the American Heart Association and the San Francisco Heart Association.…”

Hyperproteinemic Proteinuria Induced by Plasma Infusion

“…A relation was observed between the serum cholesterol level and the degree of hyperproteinemia. Many explanations for hyperlipemia in proteinuric states have been proposed and include the role of hypoalbuminemia [23], increased lipid and low density p-lipoprotein synthesis [19], and mobilization of hepatic cholesterol into the intravascular compartment [27]. The patients were not hypoalbuminemic; no attempt was made to study lipid or lipoprotein metabolism.…”