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The glomerular filtration of circulating proteins takes place at the level of the slit membrane where a porous structure, which limits or halts the passage of protein molecules of medium size, has been singled out. The small proteins, and among them many proteic hormones, are filtered, reabsorbed, and, to a great extent, catabolized by the tubular epithelia by means of at least partly selective mechanisms. Besides producing proteinuria, glomerular hyperpermeability, which does not modify the metabolism of microproteins, exposes to tubular catabolism a non-measurable quota of medium-sized nolecules whose survival in circulation is thus abbreviated. Reduced glomerular permeability does not influence the metabolism of medium-sized molecules, but reduces the catabolism of microproteins which are retained in the blood, a fact which is biologically very important. The clinical consequences of this retention have not yet been investigated.

Low molecular weight (LMW) proteinurias vary widely in their microprotein composition. In general, there is little correlation between a given microprotein composition and a defined clinical disease (with the exception of the predominant beta-2-microglobulin in Wilson's disease). Free immunoglobulin light chains are a practically invariable component of, and may be the only detectable LMW protein in, 'tubular' proteinuria. The origins and significance of some frequently occurring urinary LMW proteins are discussed.

We have analyzed the protein content of proximal tubular fluid (PTF) by ultramicro disc electrophoresis and measured total protein excretion rates both in control conditions and during angiotensin infusion to the rat. Under control conditions PTF albumin concentration was 1.49 +/- 1.12 (SD) mg/100 ml and did not increase with distance from the glomerulus. Immediate postcapsular samples (Munich-Wistar strain) yielded nearly identical values so that both probably represent filtered albumin concentration. During infusion of angiotensin (0.15 mug/mix x 100 g of body wt), PTF albumin concentration increased on the average 26-fold in re-collections from control tubules. Total protein excretion increased from a control of 7.91 to 24.37 mg/24 hr x 100 g of body wt. Glomerular filtration rate (FGR), single nephron GFR (SNGFR), proximal transit time and tubular fluid to plasma (tf/p) inulin values did not change significantly. Net afferent filtration pressure decreased from 24.7 to 15.6 mm Hg and renal plasma flow fell from 2.16 to 1.31 mo/min x g of kidney wt. Data describe a protein reabsorptive system normally operating near capacity. Angiotensin-induced proteinuria derives from an increase in filtered protein (mostly albumin) resulting from permeability changes in the glomerular membrane.

Urinary proteins from human leukemic patients have been found to alter quantitatively macromolecular synthesis in primary mouse bone marrow cultures. Urinary protein-stimulated incorporation of [3H]uridine into RNA was found after 1 day of culture. Increased levels of adenine phosphoribosyltransferase and lysozyme were demonstrable at 3 and 5 days, respectively, with urinary protein-supplemented cultures. The incorporation of 3H-labeled deoxynucleosides into DNA was higher in the presence of urinary proteins after 2 days of culture. The rate of incorporation of [3H]deoxyuridine into DNA was strongly inhibited by 10(-5) M Methotrexate and 10(-6) M 5-fluorodeoxyuridine, however, the effect of urinary proteins on incorporation of [3H]uridine into RNA and lysozyme accumulation were not inhibited. Urinary proteins also stimulated the formation of "colonies" (groups of at least 30 cells) in media containing methylcellulose. This latter phenomenon was also not inhibited by 10(-5) M Methotrexate or 10(-6) M 5-fluorodeoxyuridine. The results of these studies are consistent with the postulate that in the presence of human urinary proteins, mouse bone marrow cells in culture proceed to a phenotype characteristic of circulating peripheral white cells.

A test of placental function was assessed by measurement of plasma oestradiol levels in 32 patients after intravenous injection of 50 mg dehydroepiandrosterone sulphate (DHAS). Every pregnant patient showed a rise in plasma oestradiol after DHAS; two puerperal patients showed no rise. It was not possible to distinguish the variable response in normal pregnancy from that in patients with severe hypertension and proteinuria or with retarded intrauterine fetal growth. The test was of no value in one hypertensive patient as a predictor of fetal death eight days later or, in another, to confirm fetal death of two days duration. Our results do not suggest that this test is a useful addition to currently available tests of placental endocrine function.

Dextrans and other macromolecular inert polymers such as polyvinyl pyrrolidone fulfil all the criteria of an ideal test material for measuring glomerular permeability. Following a single intravenous injection of radioactively labelled polydisperse material serial plasma and urine samples can be analysed by gel filtration chromatography and the polymer fractionated into its constituent molecular sizes. Polymer of molecular size 24 A is capable of passing through the glomerulus as readily as water while material larger than 60 A is affectively excluded from the glomerular filtrate and one can determine the clearance of 20--30 intermediate molecular sized fractions. The accumulated data can be analysed by a number of different theoretical mathematical models; furthermore the technique can be employed in the study of proteinuria induced by vasoactive amines such as renin or angiotensin.

Diacetylbenzidine was used to induce a nephrotic syndrome in female rats. Enzymes involved in glycoprotein metabolism were evaluated during an early stage of induced renal disease before extensive histologic changes occurred. The results show that lysosomal acid hydrolases are not activated or released to any measurable degree during the early stages of the disease. Minimal differences in the composition of glomerular basement membrane of nephrotic rats were found despite heavy proteinuria. Glomerular specific activities of certain glycoprotein:glycosyl transferases were depressed in nephrotic animals. A new viewpoint to explain the pathology of glomerular proteinuria is presented based on the phenomenon of sublethal autolysis affecting cell surface structure and function, of which activity levels of glycoprotein:glycosyl transferases are an example. Increased activities of glycosyl transferases and Na-D ATPase were noted in the cortex from nephrotic animals. These studies involving cortex indicate that the pathologic process is not confined to the glomerulus and may contribute information concerning Na+ transport in the nephrotic rat.

The SDS polyacrylamide gelelectrophoresis (SDS-PAA) as used in this study has proven to be an excellent tool to differentiate urinary proteins qualitatively and quantitatively, since the proteins are differentiated exclusively according to their molecular radius. Selectivity was estimated by the ratio transferrin:IgG. Some of the proteins were identified by specific antisera. For clinical use SDS-PAA may distinguish: chronic glomerulonephritis from chronic pyelonephritis; the different diabetic nephropathies; some cases of minimal change nephritis from proliferative and degenerative glomerular diseases; the uncomplicated posttransplantation course from (interstitial) rejection crises and from glomerular diseases (recurrent GN, glomerular rejection disease), and the persisting small glomerular proteinuria after acute glomerulonephritis from proteinurias becoming physiological.

Experiments were done to investigate whether molecular discrimination occurred in the renal handling of two species of serum albumin. Human albumin, 40 mg, was infused into rats; it was removed from serum (t1/2 equal to 15.8 hr) more rapidly than previously reported measurements of removal of endogenous rat albumin (t1/2 equal to 46 hr). Human albumin was cleared by the rat kidney at a constant rate of 0.0026 mul/min--a value virtually identical to that of rat albumin (0.0020 mul/min). In rats with proteinuria following the single iv injection of puromycin aminonucleoside, human albumin was removed from serum with a half-life of 17.6 hr. During the development of the nephrotic syndrome, the renal clearances of human and rat albumin increased proportionately. Despite the difference in the serum concentration and rates of removal of the two species of albumin, renal handling of the two species was similar. Thus the kidney did not appear to discriminate in its handling of these two proteins.