Marked Proteinuria Research Articles

Urinary procoagulant excretion and its relation to kidney function.

A powerful procoagulant is normally excreted in large amounts in the urine of man, rats and rabbits. The secretion is not altered in a variety of diseases including hemorrhagic diathesis and thromboembolism. In parenchymatous kidney diseases, however, there is a marked reduction of procoagulant excretion. The procoagulant excretion is negatively correlated with BUN, blood creatinine and degree of proteinuria. With marked proteinuria in human or experimental renal disease, the procoagulant content per ml urine and the 24 h excretion drop to very low or zero values. In man, complete recovery of procoagulant excretion is obtained after homotransplantation of a well functioning kidney.

The experimental induction of glomerulonephritis like that in man by infection with group A streptococci.

106 rabbits received one or more courses of inoculations, spaced 1-4 months apart, with Group A streptococci, usually of strains isolated from patients with acute glomerulonephritis. 8 days to a few weeks after onset of a given infection with streptococci known to have been nephritogenic for man, marked proteinuria, often with hematuria and occasionally with azotemia, was detected in 22 of the animals. 15 of these were sacrificed a few days to a few weeks thereafter, and 10 showed renal changes like those of acute or recurrent acute glomerulonephritis in man. Such changes occurred in three other rabbits whose urine was not examined that died or were sacrificed 1-3 wk after onset of infection with streptococci of a serotype known to include a strain nephritogenic for man. The remaining seven animals in which marked proteinuria had occurred died or were sacrificed many months later, in some cases after additional infections. Two of these had become azotemic and two convulsed and died after giving birth; in these animals, there were renal changes like those that occur in man in chronic latent glomerulonephritis, toxemia of pregnancy super-imposed on chronic latent glomerulonephritis, or chronic active glomerulonephritis. Anatomical changes in the kidneys in the experimentally induced and in naturally occurring glomerulonephritis, from acute to chronic stages, are compared and illustrated. The pathogenesis of poststreptococcal glomerulonephritis is discussed.

Nephrotoxic Effects of Penicillamine in Cystinuria

In three female patients with cystinuria, marked proteinuria developed after two to 36 months of therapy with penicillamine (D-penicillamine). The proteinuria disappeared after cessation of treatment. We conclude that penicillamine as well as DL-penicillamine can cause serious nephrotoxicity and that all patients treated with this drug must be followed up indefinitely for evidence of this complication. The mechanism of the observed nephrotoxicity is under current investigation.

Effect of renin, ischemia, and plasma protein loading on the isolated perfused kidney.

Normal renal function has been maintained in an isolated artificial heart-lung, whole-blood perfused rabbit kidney for periods of 2–4 hr. The isolated kidney responds to changes in perfusion pressure, changes in plasma protein concentration, and exposure to a 10-min period of ischemia, in a manner similar to that described for the kidney of the normal intact animal. Elevation of the plasma protein concentration produces a fall in the rate of urine flow, sodium excretion, and creatinine clearance, and a marked proteinuria. The administration of renin produces a marked diuresis, natriuresis, and proteinuria. This effect is also produced by the exposure of the isolated kidney to a 10-min period of ischemia, suggesting that this response may be mediated by a renin mechanism. The responses of the kidney to these two procedures differ only in that ischemia produces an increase in renal blood flow and renin produces a slight reduction in renal blood flow and a more pronounced proteinuria.

NEPHROTIC SYNDROME WITH HIG HEMOGLOBIN VALUES (A CASE REPORT).

A nephrotic syndrome is reported in a 22 year old man. High hemoglobin values and erythrocyte counts were dominant features. Despite very low serum proteins there was no edema. For more than a year the condition was fairly stationary with mild symptoms. During steroid therapy a dramatic change occurred. During the first 11 days the marked proteinuria disappeared and the hemoglobin concentration fell from 21.5 to 18.4 g/l00 ml. Concomitantly, there was a rapid rise in the serum proteins and a fall in the serum cholesterol level. It is suggested that this patient had a normal red cell volume and a markedly reduced plasma volume which was restored during the steroid therapy. This might explain the rapid reduction in the hemoglobin concentration. This view is in accordance with previous investigations which have shown that the nephrotic syndrome may be accompagnied by a very low plasma volume.

Mechanisms of edema in experimental nephrosis.

In a study of nephrosis induced experimentally by antiserum or by the aminonucleoside of puromycin, it was demonstrated that edema in the former type was transitory, was not associated with endogenous hyperaldosteronism, and could be induced in adrenalectomized animals. The onset of sodium retention, leading to the edema, preceded marked proteinuria. It was associated with a profound reduction in inulin clearance, inability to excrete a sodium load, and an increase in plasma volume. The disappearance of edema was associated with recovery of ability to excrete a sodium load and with a return of inulin clearance almost to normal. It is concluded that the edema was primarily due to temporary renal impairment of Na excretion. In aminonucleoside nephrosis, edema was normally dependent on increased aldosterone production. High Na intake, however, led to edema in the absence of aldosterone, probably because of the presence of a relatively mild degree of impairment of Na excretion, which alone was insufficient to result in edema when Na intake was at a normal level.

OBSTRUCTION OF THE INFERIOR VENA CAVA IN CHILDHOOD

FORTY-THREE cases of obstruction of the inferior vena cava in childhood have been found in a search of the English literature, more than one-half of them collected by Pleasants in 1911 (Table I). Of the total cases, 13 survived the disease; 9 of these were congenital in origin. Only three had demonstration of the obstruction by venography; of these, two were congenital and did not reveal any deep collateral circulation. The most common factors in the etiology were infection, congenital obliteration of the inferior vena cava with anomalous drainage, and thrombus or invasion of the vessel by a malignant tumor (Table II). Sequelae varied with the particular etiology of the obstruction, the acuteness of onset, the location, and the rapidity of its progression (Table III). CLINICAL MANIFESTATIONS The most common symptoms of this condition are found to be inconstant pain generally referred to the lumbar area, edema of the legs when the iliac veins are also obstructed, and the presence of superficial collateral circulation. Ascites, jaundice hemorrhoids and splenomegaly are uncommon and dilated superficial veins do not appear unless other deep veins are also obstructed. Marked albuminuria or oliguria which was not present previously may suggest the progression of the process to involve the renal vein. Almost complete anuria may supervene before adequate collateral circulatory adjustment takes place. When the lower third of the inferior vena cava is obstructed, collateral circulation is usually evident in the groin, abdomen and flank. Albuminuria is rare, edema of the abdominal wall is unusual, and edema of the legs is usually absent unless there is concomitant obstruction of the iliac vein.

ACUTE GLOMERULONEPHRITIS WITH THE NEPHROTIC SYNDROME

Five cases in children of acute glomerulonephritis associated with mild and transient nephrotic syndrome are described. At the beginning of the illness each patient developed more marked edema than usually seen, marked proteinuria, hypoproteinemia, hypoalbuminemia and hyperlipemia and thus presented the characteristic features of the nephrotic syndrome. A diagnosis of acute glomerulonephritis was established by (a) the short duration of the disease, (b) the presence in four of the five patients of elevated titers of antistreptolysin "O" and the presence of beta hemolytic streptococci in throat cultures, and (c) followup examination, which showed that all had recovered completely without exacerbations. Mild nephrotic syndrome may complicate approximately 4 to 5% of cases of acute glomerurlonephritis in children.

Prolonged intermittent steroid therapy for nephrosis in children and adults.

Aqueous ACTH, to induce diuresis, was given for at least 12 but preferably for 21 days, unless marked side-effects necessitated earlier cessation of therapy, to patients with nephrosis and clinical and laboratory findings consisting of massive edema, marked proteinuria (3+ to 4+), hypoproteinemia, hyperlipemia, and, in most instances, a lowering of the serum complement activity. Prolonged intermittent therapy with cortisone, given orally, was begun five days after the onset of diuresis but only when diuresis led to complete freedom from edema. After one year, therapy was gradually terminated by prolonging the intervals between maintenance courses rather than by decreasing the daily dosage. Prolonged intermittent steroid therapy not only resulted in an improved prognosis but also permitted the patients to live a more gainful and happy life. The growth and development of these children has remained within normal limits during and after prolonged intermittent maintenance therapy. Continuous steroid therapy, in contrast, has resulted in marked developmental disturbances.

Thrombocytopenia and renal lesions associated with acetazoleamide (diamox) therapy.

Recently both thrombocytopenia and renal lesions similar to those produced by sulfonamides have been reported in association with the use of acetazoleamide (Diamox),1,2a carbonic anhydrase inhibitor of sulfonamide origin used as a diuretic. Both types of reaction occurred in the following case. Report of Case A 61-year-old white man was admitted to the Veterans Administration Hospital, Philadelphia, on March 5, 1956, with a history of recurrent peripheral edema of nine months' duration. One month before admission the edema became persistent and progressive. There were no cardiac or pulmonary complaints, and review of symptoms by systems was essentially negative. Except for edema of the legs, scrotum, and presacral region, the physical examination was within normal limits. The blood pressure was 130/70. Study of the urine disclosed a specific gravity fixed at 1.010. There was marked proteinuria, and the urinary sediment contained occasional casts, red blood cells, and white blood

The Treatment of the Nephrotic Syndrome with Steroids in Children and Adults

The may be defined as a combination of clinical and laboratory findings including massive edema, marked proteinuria, hypoproteinemia, and hyperlipemia. This syndrome may be associated with such diseases as diabetes mellitus (Kimmelstiel-Wilson syndrome), renal amyloidosis, renal vein thrombosis, syphilis, and heavy-metal poisoning. However, in common usage nephrosis or the nephrotic syndrome refers to the so called pure or lipid nephrosis and to the nephrotic stage of glomerulonephritis. It is possible that the latter two forms are caused by the same basic mechanisms. Pathogenesis and Pathologic Physiology We believe that nephrosis is a distinct disease with an immunologic basis and is characterized by a complement-binding antigen-antibody reaction. This antigen-antibody reaction acts to produce functional and, when persistent, morphologic tissue damage. It is probable that not only the glomerular capillary but many of the other capillaries in the body are similarly altered, leading to a generalized increase in glomerular and

STUDIES ON ALDOSTERONE: II. HYPERTENSION AS A CUMULATIVE EFFECT OF ALDOSTERONE ADMINISTRATION

Aldosterone has been injected subcutaneously into young rats in doses of 0.5 μg. per 48 hours and later 1.0 μg. per 24 hours. After 6–12 weeks a rise in blood pressure was noted which in about 5 or 6 months reached a maximum averaging 75 mm. above control values. This effect was noted in intact animals on a normal diet and was the same for either dose employed. The drinking of 1% saline instead of water had no significant effect on the result. In adrenalectomized rats a similar rise was noted and may have occurred sooner, but this observation requires confirmation. Aldosterone can account for at least part of the syndrome resulting from regeneration of cortical tissue in an enucleated adrenal. Desoxycorticosterone was tested in intact rats at dose levels of 25 μg. per 48 hours or 100 μg. daily and produced a smaller rise in blood pressure than that observed with aldosterone. None of the adrenalectomized rats showed protein in the urine, but one in five of the intact animals developed moderate to marked proteinuria after 1 to 5 months of hypertension. It is suggested that these observations may represent the experimental counterpart of human essential hypertension.

STUDIES ON ALDOSTERONE: II. HYPERTENSION AS A CUMULATIVE EFFECT OF ALDOSTERONE ADMINISTRATION

Aldosterone has been injected subcutaneously into young rats in doses of 0.5 μg. per 48 hours and later 1.0 μg. per 24 hours. After 6–12 weeks a rise in blood pressure was noted which in about 5 or 6 months reached a maximum averaging 75 mm. above control values. This effect was noted in intact animals on a normal diet and was the same for either dose employed. The drinking of 1% saline instead of water had no significant effect on the result. In adrenalectomized rats a similar rise was noted and may have occurred sooner, but this observation requires confirmation. Aldosterone can account for at least part of the syndrome resulting from regeneration of cortical tissue in an enucleated adrenal. Desoxycorticosterone was tested in intact rats at dose levels of 25 μg. per 48 hours or 100 μg. daily and produced a smaller rise in blood pressure than that observed with aldosterone. None of the adrenalectomized rats showed protein in the urine, but one in five of the intact animals developed moderate to marked proteinuria after 1 to 5 months of hypertension. It is suggested that these observations may represent the experimental counterpart of human essential hypertension.

Glomerular lesions and the nephrotic syndrome in rabbits given saccharated iron oxide intravenously; with special reference to the part played by intracapillary precipitates in the pathogenesis of the lesions.

Intravascular precipitates, comprised at least in part of iron, formed regularly in rabbits given one or more injections of a saccharated iron oxide preparation intravenously, and these lodged in numerous capillaries throughout the body, particularly those of the lungs and kidneys. Large numbers of the brownish precipitates remained in the capillaries of the renal glomeruli during the first few days following injection of the iron, but most of them disappeared after 5 to 7 days, with only moderate amounts of brown pigment remaining in the endothelial cells of the renal glomeruli. Signs of acute injury of the glomerular tufts-namely) pyknosis of some of the endothelial cells, margination of leukocytes within the glomerular capillaries, and slight proliferation of the epithelial cells-also developed some 5 to 7 days following injection of the iron, along with marked proteinuria, which proved transitory if no further injections were given. When the iron preparation was given repeatedly over prolonged intervals, however, the proteinuria persisted and became extreme, and hypoproteinemia developed, often with hypercholesterolemia and transitory edema as well. Histological studies of the kidneys of rabbits manifesting the nephrotic syndrome, as just described, disclosed that virtually all the renal glomeruli were greatly altered, mainly owing to proliferation of the epithelial cells, together with some fibrosis and atrophy. Some of the rabbits having marked proteinuria and other functional changes eventually developed azotemia following repeated injections of the iron, and several of them lost weight and died; the renal glomeruli of these animals showed changes like those just described, but the alterations were more extensive. Considered together, the findings provide evidence that the intravascular precipitates first occluded the glomerular capillaries for a period of several days following injection of the iron and then largely disappeared from them just prior to the development of morphologic signs of glomerular injury and proteinuria. Hence the possibility was considered that the intracapillary precipitates might have produced acute injury to the walls of the glomerular capllaries through the agency of anoxia. But it is plain that the findings of the present study do not disclose the essential nature of the anatomical change responsible for the proteinuria, or the means whereby this was produced. The findings as a whole were briefly considered in relation to the pathogenesis of the nephrotic syndrome as it occurs naturally in human beings.

ANAPHYLACTOID PURPURA (SCHÖNLEIN-HENOCH SYNDROME)

A long-term follow-up study of 26 children with anaphylactoid purpura (Schönlein-Henoch Syndrome) is presented. The average length of follow-up was 4½ years. Of these 26 children, 10 were found to have an apparent latent nephritis characterized by hematuria and cylinduria, but without marked proteinuria. Nine of the ten children were over the age of 6 years at the time of onset of purpura; 6 had proteinuria or hematuria during the acute phase of the disease. It is suggested that this renal sequela of anaphylactoid purpura may constitute one of the origins of chronic renal disease "of unknown etoiology" which occurs in adult patients.

Studies on Experimental Proteinuria I

Experimental proteinuria was induced in-10 rats receiving equal amounts of a renal antiserum prepared according to Smadel and Farr. The course of the disease was followed for 43 days, after which time the animals were killed. The following results were obtained:1. Seven of the animals developed a severe proteinuria which reached its maximum during the first 3 days after the injection and then slowly decreased but did not reach the normal level by the end of the experiment. One animal reached the normal level of proteinuria in a week, the other two animals did not develop any marked proteinuria at all. The proteinuria showed parallelism to water output in forced oliguria and polyuria. Oliguria occurred 6 times in all in three of the animals. At the end of the experiment all of the animals showed an intact diuresis regulating power.2. The electrophoresis at the end of the observation time indicated rather small changes in serum proteins: a small decrease of albumin in most cases and a distinct increase of a...

Surgical correction of coarctation of the aorta in pregnancy

THIS is a report of a congenital cardiovascular complication in an otherwise normal pregnancy. The patient, a 20-year-old white gravida ii, para i, entered our prenatal clinic on Aug. 8, 1951, with an intrauterine pregnancy of approximately two and one-half months ' gestation. Her past obstetrical history included a 5% pound stillborn male infant on Oct. 20, 1950, the result of marked hypertension, proteinuria, and complete placental abruption.

Water and electrolyte balance during recovery from severe congestive failure on a 50 milligram sodium diet

The clinical and metabolic effects of a diet furnishing 50 mg. of sodium, 1.32 Gm. of chloride, 4.33 Gm. of potassium and adequate water, protein, and total calories were determined in seven patients with severe congestive failure. The major lesion was rheumatic mitral stenosis in four patients and hypertensive and/or arteriosclerotic heart disease in the other three patients. Prior to the institution of the special diet, the congestive failure had proved refractory to a standard regimen consisting of bed rest, low-sodium diet, digitalization, and frequent mercurial diuretics, carried out for a nine to forty-nine-day control period of hospitalization in four patients and for several weeks under medical supervision at home in two patients. Progressive decompensation developed in the remaining patient despite digitalization at home. The cardiac failure was manifested by marked passive congestion and edema of both circuits in four patients, and by marked pulmonary congestion but little or no peripheral edema in three patients. The extracellular volume decreased by an average of 8.28 L. in the four patients with marked peripheral edema and by 1.44 L. in the three with little or no clinically detectable edema. Chloride and water were lost from the extracellular space in isotonic proportions in the two patients with initially normal plasma levels, whereas relatively less chloride was lost in the five patients with initial hypochloremia, permitting a rise in plasma level. Plasma sodium concentrations were initially elevated in four patients and normal in three and maintained a plateau during recovery from congestive failure, indicating parallelism in losses of extracellular sodium and water, even in the presence of hypernatremia. Plasma potassium concentrations were initially normal in all patients and were also maintained at a plateau through proportionate reduction of total extracellular potassium and water. In six patients there was a net cellular gain of 3.7 to 33.9 Gm. of nitrogen available for protein synthesis, and in one patient there was a loss of 21.6 Gm., attributable to a marked proteinuria. During recovery from congestive failure on the special diet, the intracellular compartment lost from 230 to 2,890 ml. of water (average 1,325 ml.), but it gained from 115 to 385 meq. of sodium (average 234 meq.) in six of the seven patients and gained significant amounts of potassium in all patients. The cellular uptake of potassium for purposes other than protein synthesis ranged from 62 to 454 meq. (average 259.9) in the four patients with marked peripheral edema and from 97 to 338 meq. (average 222.2) in the three patients with marked pulmonary congestion but little or no peripheral edema. The positive intracellular balances of potassium and sodium observed during recovery probably represented replenishment of a deficit incurred during the development of congestive failure. The findings in this study are in accord with the hypothesis that the development of congestive failure is accompanied by an alteration of cellular metabolism, manifested by liberation of ionized base from osmotically inactive constituents of the protoplasm, followed by shifts of potassium and sodium out of the cells and water in the opposite direction to maintain osmotic equilibrium with the extracellular compartment. Recovery from congestive failure is accompanied by cellular release of water and uptake of potassium and sodium, with coincident osmotic inactivation of cell base.

THE DIET AND HORMONALLY INDUCED NEPHROSCLEROSIS

Kidney lesions resembling those of chronic nephritis and nephrosclerosis developed in rats treated with L.A.P. (lyophilized anterior pituitary) and fed 'Purina', but did not develop in similar rats similarly treated and fed Purina mixed with cornstarch in a 1: 1 ratio. When synthetic diets, differing only in their relative carbohydrate and protein content, were fed, only those L.A.P.-treated rats that consumed a regimen containing 30% casein and 54% cornstarch developed nephrosclerosis. No such lesions were seen in treated rats kept on a 15% casein and 69% cornstarch diet. This difference in response is due to the protein and not to the cornstarch content of these diets; the entire amount of cornstarch was substituted by wheat starch or 15% of it was replaced by an equicaloric amount of fat, without influencing the development of kidney lesions.Various protein preparations differed in their ability to cause kidney damage. Casein, egg albumen, and wheat gluten were more damaging than lactalbumin, gelatin, or zein.The severity of nephrosclerosis caused by L.A.P. roughly paralleled the kidney hypertrophy, adrenal enlargement, and increased appetite for water, but not necessarily the food intake or the growth rate. The appearance of these renal lesions was not associated with any gross change in urine pH, but was preceded by a marked albuminuria. By the fifth day, large amounts of albumin were present in the urine of the majority of treated rats consuming the 30% casein diet. Albumin rarely appeared in the urine of treated rats consuming the 15% casein diet.These findings were discussed in relation to the literature concerning the dietary production of chronic nephritis. The procedure described in this paper greatly accelerates the development of kidney lesions, apparently identical with those shown previously to ensue on the feeding of high protein diets.

ACUTE EXPERIMENTAL GLOMERULAR NEPHRITIS IN RABBITS: A CORRELATION OF MORPHOLOGICAL AND FUNCTIONAL CHANGES

It has been shown in this paper that structural and functional changes in acute glomerular nephritis in rabbits produced by nephrotoxins by the method of Masugi are the same as those found in human glomerular nephritis. The morbid anatomy is characterized by glomerular cell proliferation, and in some cases by deposition of fibrin and crescent formation of the glomeruli and by fatty changes of the tubules. The functional changes are: oliguria, proteinuria, hematuria, cylindruria, edema, rise in blood urea, and according to Masugi (1933, 1934) and Smadel (1936, 1937), rise in blood pressure, lipuria, and fall in urea clearance and plasma proteins. As we are unaware of any discrepancies between the experimentally induced disease and human nephritis, the conclusion follows that the two so closely resemble each other that they appear to be identical. As to the pathogenesis, it has been shown that the disease begins with a period of latency. This is characterizied anatomically by hyperemia of the glomeruli; and functionally, in at least a number of cases, by an increased diuresis. It follows, therefore, that the theory of Volhard, according to which glomerular nephritis is caused by arteriolar spasms, can no longer be maintained. It has further been demonstrated that proliferation of glomerular cells is the typical lesion, and that deposition of fibrin and crescent formation occur only in certain cases, and in these only in a widely varying number of glomeruli. As crescents are found as early as the proliferation itself, it follows that they should not be regarded as pathognomonic of the subacute phase, but that they represent a complication which probably aggravates the disease. As to correlation of morphological and functional changes, it has been demonstrated that oliguria, marked proteinuria and diminished excretion of cyanol appear at the time when the glomerular changes are at their peak. Evidence has been presented that the oliguria and the decrease in cyanol excretion in acute glomerular nephritis are chiefly the result of the glomerular damage. It has further been demonstrated that the excretion of azofuchsin was unchanged, except for a diminution in the rabbit which at autopsy showed a marked fatty change of the tubules. We regard these observations as evidence, that, in acute glomerular nephritis in rabbits, glomeruli and tubules may function independently of each other.