Ten postcardiac surgical patients with acute renal failure (ARF) were infused with inulin and dextran 40. Plasma and urine were then submitted to gel-permeation chromatography to ascertain the apparent fractional clearance profile for the dextrans. Compared to normal volunteer controls, the fractional clearance profile was substantially elevated for dextran molecules in the Einstein-Stokes radius (r) range 20-40 A. For the smaller molecules (r = 20-28 A), fractional dextran clearance in ARF was frequently in excess of unity. A simple mass conservation model which assumes that the "true" fractional dextran clearance profile for the glomerulus (in Bowman's space) in ARF is the same as that for normal controls, when applied to the experimental observations, revealed that in ARF, on the average, 50% of filtered inulin is lost by tubular backleakage. Furthermore, the model permitted an estimate of the permeability properties of the damaged tubular wall. This indicated tubular permeability not unlike that of the normal glomerulus to dextran molecules with r less than 30 A, but relative impermeability to larger dextran molecules.

A tubular injury characterized by intraluminal obstruction and transtubular backleak of glomerular filtrate occurs in experimental acute renal failure (ARF) in animals. To determine whether these alterations also occur in human ARF, we studied 44 patients developing nonoliguric ARF following cardiac surgery. The delay in appearance of i.v. administered inulin in urine (Tu) was used as a measure of tubular fluid flow rate. Tu was not longer in 13 ARF patients than it was in control subjects (7.2 vs 9.0 min), suggesting that at least a subpopulation of tubules was widely patent. The fractional urinary dextran clearance profile (thetaD; radii, 20 to 40 A) was then determined in 20 patients with sustained ARF in whom inulin clearance averaged 11 +/- 1 ml/min/1.73 m2. A mass conservation model, which assumes that thetaD in Bowman's space in ARF is the same as that measured in controls, when applied to the experimental observations revealed that, on the average, 42% of filtered inulin was lost by transtubular backleak. A similar fractional inulin backleak (38%) persisted in 11 additional patients in whom ARF had begun to recover and in whom inulin clearance averaged 26 +/- 3 ml/min/1.73 m2. These findings suggest that in hemodynamically-mediated and nonoliguric ARF, (1) tubular obstruction is not homogeneous, and (2) backleak of glomerular filtrate contributes to but does not fully account for depression of inulin clearance.

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The relationships between pHi (intracellular pH) and phosphate compounds were evaluated by nuclear magnetic resonance (NMR) in normo-, hypo-, and hypercapnia, obtained by changing fractional inspired concentration of CO2 in dogs anesthetized with 0.75% isoflurane and 66% N2O. Phosphocreatine (PCr) fell by 2.02 mM and Pi (inorganic phosphate) rose by 1.92 mM due to pHi shift from 7.10 to 6.83 during hypercapnia. The stoichiometric coefficient was 1.05 (r2 = 0.78) on log PCr/Cr against pHi, showing minimum change of ADP/ATP and equilibrium of creatine kinase in the pH range of 6.7 to 7.25. [ADP] varied from 21.6 +/- 4.1 microM in control (pHi = 7.10) to 26.8 +/- 6.3 microM in hypercapnia (pHi = 6.83) and 24.0 +/- 6.8 microM in hypocapnia (pHi = 7.17). ATP/ADP X Pi decreased from 66.4 +/- 17.1 mM-1 during normocapnia to 25.8 +/- 6.3 mM-1 in hypercapnia. The ADP values are near the in vitro Km; thus ADP is the main controller. The velocity of oxidative metabolism (V) in relation to its maximum (Vmax) as calculated by a steady-state Michaelis-Menten formulation is approximately 50% in normocapnia. In acidosis (pH 6.7) and alkalosis (pH 7.25), V/Vmax is 10% higher than the normocapnic brain. This increase of V/Vmax is required to maintain cellular homeostasis of energy metabolism in the face of either inhibition at extremes of pH or higher ATPase activity.

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