A natriuretic factor in the serum of patients with chronic uremia.

Sera from chronically uremic and normal individuals were subjected to gel filtration with Sephadex G-25 and the same fraction of both was infused into rats with a decreased nephron population to determine the effects on sodium excretion. Sodium excretion rate and fractional sodium excretion increased slightly with the normal fractions; but the increase in both functional parameters produced by the uremic fractions was substantially and significantly greater. The natriuresis could not be explained by associated changes in glomerular filtration rate (GFR), para-aminohippurate (PAH) clearance, filtration fraction, hematocrit, or blood pressure. The possibility thus exists that the inhibitor affected some component part of the transepithelial sodium transport system. The elution characteristics of the fraction plus certain of its physicochemical properties suggest that the inhibitor of sodium reabsorption by the rat nephron may be identical with the inhibitor of PAH uptake by kidney slices and the inhibitor of transepithelial sodium transport by the frog skin and toad bladder previously found in the serum of chronically uremic patients.

Renal response to chronic intravenous salt loading in the rat.

The natriuresis of acute Ringer's loading is associated with a rise in the rate of delivery of fluid beyond the proximal tubule due both to a rise in glomerular filtration and a fall in absolute reabsorption, the latter being causally mediated, at least in part, by the accompanying fall in postglomerular vascular [protein]. To determine whether these factors also contribute to the renal response to chronic Ringer's loading, nine rats given continuous infusions, 30% body weight/day over 5-14 days, were studied using free-flow micro-puncture techniques. Results were compared with data from 10 chronic control rats given less than 1.5% body wt/day. Late proximal tubule fluid-to-plasma [inulin] ratios, (TF/P)(IN), single nephron glomerular filtration rate (SNGFR), absolute proximal reabsorption, and postglomerular vascular [protein] in chronic control rats and chronically loaded rats averaged 2.2+/-SE 0.1 (n = 35) and 1.5+/-0 (35), P<0.001; 37+/-2 (35) and 47+/-4 nl/min (35), P<0.05; 19+/-1 (35) and 16+/-2 nl/min (35), P>0.2; and 9.5+/-0.3 (8) and 8.6+/-0.3 g/100 ml (8), P>0.05, respectively. Thus the fall in (TF/P)(IN) and the rise in distal delivery during chronic Ringer's loading were due almost entirely to the rise in SNGFR, and not to any large fall in absolute reabsorption. Hence chronic and acute Ringer's loading increase delivery of proximal tubule fluid by different mechanisms, with chronic sodium homeostasis being governed overwhelmingly by adjustments in GFR. When, however, an acute Ringer's load was infused into chronically loaded rats, we observed significant and parallel reductions in absolute proximal reabsorption and postglomerular vascular [protein]. These findings suggest that the difference between the effects of chronic vs. acute Ringer's loading on absolute proximal reabsorption may have been due, at least in part, to the corresponding difference in the effects these two loading procedures have on postglomerular vascular [protein].

Effects of acute volume expansion and altered hemodynamics on renal tubular function in chronic caval dogs.

It is well established that dogs with chronic partial constriction of the thoracic inferior vena cava develop sodium retention, ascites, and respond poorly to acute saline loading. A group of such chronic caval dogs, and a group of normal controls were studied during hydropenia, and again after acute saline loading by clearance and recollection micropuncture techniques. After volume expansion, the caval dogs excreted 52 muEq/min per kidney of sodium compared with 370 muEq/min per kidney for the normal controls. During hydropenia and after the saline infusions, single nephron filtration rates, fractional reabsorption of sodium within the proximal tubule, and proximal delivery of filtrate to the distal nephron were comparable in both groups of dogs. Micropuncture of distal tubular segments confirmed that the loop of Henle was the major site for salt and water retention in the expanded caval dogs. Alteration of intrarenal hemodynamics by vasodilating one kidney and elevating systemic arterial blood pressure induced a normal natriuretic response in the saline-loaded caval dogs. Proximal tubular function remained unchanged and the loop of Henle appeared to be the major site responsive to these hemodynamic maneuvers. These same experiments in saline-loaded control dogs had no effect on function of the proximal or distal nephron and did not increase urinary excretion of sodium or water. These experiments provide evidence that the loop of Henle is the major site for sodium retention in volume-expanded chronic caval dogs excreting minimal amounts of sodium.

Tubular reabsorption of sodium during acute and chronic volume expansion in man.

Renal hemodynamics and tubular fractional sodium reabsorption (FSR) were evaluated by clearance techniques during acute and chronic extracellular volume expansion in man. (1 - V/GFR) x 100 was used as an index of proximal and (C(H2O)/V) x 100 as an estimate of distal fractional reabsorption. After acute loading with isotonic saline 37 ml/kg body wt, proximal FSR decreased by 4.8% and distal FSR decreased by 4.4%. After comparable chronic expansion by mineralocorticoids ("escape"), proximal FSR also decreased by 3.9%, but distal reabsorption was not altered.In separate studies, subjects were progressively infused with saline to 57 (E(1)) and to 80 (E(2)) ml/kg body wt, and appeared to divide into "excreters" (maximum U(Na)V > 1000 muEq/min) and "nonexcreters" (maximum U(Na)V < 550 muEq/min). In the excreters, GFR rose, proximal FSR decreased by 7.1% after E(1) and only 0.9% further after E(2). Distal FSR fell by 14.8% after E(1) and by an additional 4.9% after E(2). In the nonexcreters, GFR was stable and proximal FSR did not fall significantly after E(1) or E(2). Distal FSR decreased 4.5% after E(1) and 1.3% further after E(2). It is concluded that both acute and chronic extracellular expansion decrease proximal FSR in man, but only acute loading depresses distal FSR. Ability of some men to excrete sodium rapidly after acute infusion is related to larger increases in GFR and greater decreases in both proximal and distal FSR than occur in men in whom natriuresis is more limited.

Simple HPLC-UV method for determination of iohexol, iothalamate, p-aminohippuric acid and n-acetyl-p-aminohippuric acid in human plasma and urine with ERPF, GFR and ERPF/GFR ratio determination using colorimetric analysis.

A simple high-performance liquid chromatographic (HPLC) method was developed for the simultaneous determination of iohexol, iothalamate, p-aminohippuric acid (PAH) and n-acetyl-p-aminohippuric acid (n-acetyl-PAH) in human plasma and urine. A C(18) column at a flow rate of 1 ml/min with an aqueous mobile phase of trifluoroacetic acid (0.1% TFA in deionized water (pH 2.2), v/v) and methanol gradient was used for component separation. The plasma and urine assay demonstrated linearity from 10 to 50 microg/ml for iohexol and iothalamate, 5 to 40 microg/ml for PAH and 2.5 to 40 microg/ml for n-acetyl-PAH. The HPLC plasma and urine results obtained for PAH were used to calculate the subject kidney effective renal plasma flow (ERPF) and the iohexol results were used to calculate the subject kidney glomerular filtration rate (GFR). The HPLC results for PAH were then compared to an alternative colorimetric method for analyzing PAH to determine if subject metabolism (acetylation) of PAH affected the ERPF results obtained using the colorimetric method, the subsequent ERPF/GFR ratio and clinical impression of subject patient kidney function. The method was utilized in several different clinical studies evaluating the effect of kidney function from medications (phase IV evaluations) marketed for patients with cardiovascular disease.