Improvement in Solute Delivery

For many years hypoproteinemic states have been assumed to be associated with reductions in effective intravascular volume. This event has been postulated to play a seminal role in the intense renal sodium retention associated with nephrotic syndrome and cirrhosis through activation of a number of volume sensitive neurohumoral mechanisms stimulating sodium reabsorption. Additionally changes in vascular volume could induce direct increases in peritubular physical forces favoring sodium uptake in the renal proximal tubule. Intravenous infusions of albumin could therefore increase vascular volume, increase filtered sodium load, blunt neurohumoral mechanisms stimulating sodium reabsorption, and directly decrease the fraction of filtered sodium reabsorbed in the proximal tubule. In the presence of a diuretic, the resultant increase in distal delivery would be more effectively excreted. Data from a number of investigators, however, now suggest that most patients with hypopro-teinemia from nephrotic syndrome and many patients with cirrhosis are not intravascularly volume depleted. Defects in the intrarenal regulation of sodium reabsorption are now felt to account for much of the sodium retention occurring in those disorders. A 1979 review of data obtained from 217 nephrotic patients in 10 published series found that plasma volume was reduced in one-third, normal in one-half, and increased in the remainder of untreated nephrotics with hypoproteinemia [2], A more recent study of 88 patients with nephrotic syndrome has found normal or increased vascular volume in all of those individuals [4], Plasma volume in animals with experimental nephrotic syndrome is also reported to be normal or increased. There have been some suggestions that patients with minimal change disease, especially children, may be more likely to present with a decreased effective intravascular volume, although this is not uniformly accepted. The finding that intravascular volume is not decreased in most patients with nephrotic syndrome is also supported by findings that hormones sensitive to changes in effective circulating volume such as renin and aldosterone are decreased in the majority of nephrotics [2,4, 5, 9]. It also seems unlikely that albumin has any direct effects on the renal mechanisms for sodium retention in nephrotic syndrome. Albumin infusion given without diuretics induce little or no increase in sodium excretion in the majority of nephrotics [9]. Furthermore, albumin had no effect on proximal sodium reabsorption as determined from maximal free water clearance studies. Normal proximal tubule function is also found in the majority of animal models of nephrotic syndrome examined by micropuncture techniques. Thus, most evidence does not support a specific role for albumin in the correction of the an-tinatriuretic defect associated with nephrotic syndrome. Such a conclusion is consistent with other observations that natriuresis occurs prior to an increase in plasma protein concentration during the recovery phase of minimal change disease [5],

Similar evaluations in the hypoproteinemia associated with cirrhosis suggest that a decreased intravascular volume does not uniformly account for reduced renal sodium excretion in that condition as well [ 12]. Measurements of plasma volume suggest that this parameter is not reduced in the majority of cirrhotics. However, the increase in vascular capacitance associated with severe liver disease complicates determination of plasma volume in this condition. Plasma norepinephrine levels and plasma renin levels are frequently elevated in cirrhotics and have been interpreted as evidence for intravascular volume depletion in these patients. However a recent longitudinal evaluation of patients with alcoholic liver disease has shown no change in blood volume, plasma norepinephrine, plasma renin levels, atrial natriuretic factor, or several other parameters during episodes of ascites formation and spontaneous recovery in individual patients [12]. Thus the role of these factors as markers for volume depletion as well as the role of volume depletion in the pathogenesis of sodium retention in liver disease remains unclear. Finally, while vascular volume expansion with saline or albumin increases sodium excretion in many cirrhotics, it does not do so in all. Epstein using head-out water immersion to increase central vascular volume in cirrhotics has suggested that increased sodium reabsorption in the distal nephron may account for decreased sodium excretion in some cirrhotics [4].

Albumin infusion could function as a nonspecific volume expander in hy-poproteinemic conditions. However, any increase in plasma volume is transient. In nephrotic syndrome 10% of the initial increase in plasma volume and none of the initial increase in plasma albumin concentration or oncotic pressure remain 24 hr after albumin infusion [10], Exudation of albumin from the vascular space may occur even more rapidly in cirrhosis as a result of the elevated portal pressure. Thus, multiple doses of albumin must be administered for any sustained effect on vascular volume.

FIGURE 1. Effect of 30 mg of furosemide administered intravenously alone (point "F" top) or premixed with 6 g of albumin (point "AF", bottom) on urine flow rate in four hypoalbuminemic patients with serum albumin concentrations of less than 2.2 g/dl. Patients were resistant to furosemide administered alone but had significant increases in urine flow rate following administration of the albumin-furosemide complex. From Inoue (1987, Fig. 7, p. 201) with permission.

Time, hr

FIGURE 1. Effect of 30 mg of furosemide administered intravenously alone (point "F" top) or premixed with 6 g of albumin (point "AF", bottom) on urine flow rate in four hypoalbuminemic patients with serum albumin concentrations of less than 2.2 g/dl. Patients were resistant to furosemide administered alone but had significant increases in urine flow rate following administration of the albumin-furosemide complex. From Inoue (1987, Fig. 7, p. 201) with permission.

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