The ability to take up substances from the surrounding environment not only provides cells with vital nutrients, but also enables the selective transport of substances from one compartment to another. Megalin and cubilin are two structurally different endocytic receptors that interact to serve such functions. Evidence has accumulated in recent years to indicate that these receptors have important functions in both normal physiology and pathology.

Megalin and cubilin: multifunctional endocytic receptors

Daily injections of any one of several foreign serum proteins produced in rabbits functional and morphological alterations similar to those seen in acute, subacute, and chronic human glomerulonephritis. The critical factor determining whether a rabbit would develop renal disease and the type of disease developed was the amount of antibody the rabbit formed. Those responding with much antibody were likely to develop an acute, self-limited glomerulonephritis and to be subsequently immune to further renal damage. Those responding with antibody barely sufficient to neutralize the antigen injected developed subacute and chronic glomerulonephritis. In the circulation of the rabbits with chronic glomerulonephritis, there was a daily recurring antigen-antibody reaction in the region of near antigen excess to near antibody excess which presumably led to the disease. Antigen apparently in the form of antigen-antibody complexes was deposited along the renal capillary basement membranes coincident with the development of subacute and chronic glomerulonephritis. Once developed, the morphologic stigmata of chronic glomerulonephritis persisted even after injections of antigen were stopped. However, in milder instances the renal function recovered in part after stopping antigen. This experimental model has several implications: first, the renal injury is precipitated by antigens with no known affinity for, or immunologic relationship to, kidney; second, antigen antibody complexes localize in the kidney, apparently on the basis of non-immunologic factors, and may be an etiologic agent of renal injury; third, severe hypersensitivity disorders can be related specifically to relatively poor as well as to good antibody responses; and finally, the pathogenesis suggested here offers an alternative to that of nephrotoxic serum nephritis for the experimental approach to the study of human glomerulonephritis.

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Experimental glomerulonephritis. The pathogenesis of a laboratory model resembling the spectrum of human glomerulonephritis.

Data from 227 men in 10 sets of controlled dietary experiments in 5 institutions gave the least-squares solution: [see text] with S.E. of slope --±0.44, where X is the serum cholesterol level of an individual, X is the average for all men on the same diet, and Δ is the response to a given dietary change. Equations, a chart and a table are provided for the prediction of the serum cholesterol response when change is made from one diet to another when cholesterol and fatty acid compositions of the diets are known. Comparison of predicted with observed average values in recently published data on samples of free-living people changing diets on prescription designed to lower serum cholesterol gave, predicted versus observed Δ: −30.0 vs. −28.5 and −27.2 vs. -30.1 mg./l00 ml. in men and women in caloric balance. In a sample of men who were also losing weight on a low-fat, low-cholesterol diet a change of −33.5 was predicted versus −39.8 observed.

Serum cholesterol response to changes in the diet: III. Differences among individuals.

Adjuvants--a balance between toxicity and adjuvanticity.

This book on vitamin A deficiency not only addresses ocular manifestations but also the broader context of child health and survival. The introduction examines the historical and modern perspectives of vitamin deficiency what vitamin A is and the relationship of xerophthalmia (severe vitamin A deficiency) to vitamin A status. The second section of the book discusses consequences of vitamin A deficiency. Chapter 2 looks at mortality associated with moderate to severe deficiency and the fact that vitamin A supplementation reduces preschool-age mortality and measles mortality. Chapter 3 covers infectious morbidity particularly diarrhea measles respiratory disease urinary tract infection otitis and other infections (e.g. HIV). Chapter 4 examines ocular manifestations (xerophthalmia keratomalacia night blindness and conjunctiva). The effect of vitamin A on anemia and iron metabolism and the extent of vitamin A deficiency-associated anemia are discussed in chapter 5. Chapter 6 examines vitamin As role in growth in animals and children. The third section of the book is dedicated to mechanisms of vitamin A. Chapter 7 looks at contributory and precipitating events (i.e. systemic infections and protein energy malnutrition). Chapter 8 addresses the biochemistry of vitamin A and carotenoids. Chapter 9 examines the relationship between immunocompetence and vitamin A status particularly lymphoid organs and hematopoiesis cell-mediated immunity humoral immunity effect of vitamin A administration on immune response and identification of and requirements for immunoregulatory retinoids. The fourth section chapter 10 is dedicated to treatment of vitamin A deficiency and xerophthalmia. The last section covers assessment and prevention. Chapters 11 and 12 discuss assessment of vitamin A status and epidemiology of deficiency respectively. The last three chapters examine prevention interventions: dietary interventions supplementation and fortification of dietary items with vitamin A.

Vitamin A Deficiency: Health, Survival, and Vision

Summary1) A severe nephrotic syndrome was noted in 20 rats given Freund's adjuvants and a supernate of rat kidney suspension by intraperitoneal injection. When kidney tissue was replaced by liver, only 3 of 21 animals developed a much milder renal disease. Lung or muscle suspensions failed to induce proteinuria in 10 rats. 2) In large doses (0.5 ml) Freund's adjuvants alone produced a mild nephrotic disease in 3 of 10 rats. Even though the smaller amounts of the adjuvants usually used (0.25 ml) never produced proteinuria, slight histological alterations of the glomerular structure were frequently noted. 3) In contradistinction to other tissue suspensions addition of rat kidney supernate enhanced the effect of adjuvants markedly and regularly. 4) The small amounts of rat kidney proteins used, support the interpretation that an isoand autosensitization mechanism is at play.

Production of nephrotic syndrome in rats by Freund's adjuvants and rat kidney suspensions.

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Studies on the Causal Role of Hypoalbuminemia in Experimental Nephrotic Hyperlipemia

1. Chronic renal disease was produced in 235 4 to 5 week-old rats of the Long-Evans strain by the intravenous injection of nephrotoxic sera obtained from rabbits.\n 2. Massive proteinuria, largely without hematuria, was noted without delay. Severe edema and ascites was observed in 35% of the animals within the first 2 to 3 weeks. Thirty-two per cent died within the first two weeks. A spontaneous cure of the disease occurred in 30% and chronic renal disease that lasted in some instances as long as 13 months, was observed in the remaining animals.\n 3. From 125 sick rats, 74% remained normotensive. A fluctuating and moderately severe hypertension was noted in the remaining 26%.\n 4. The blood chemistry revealed marked hypoproteinemia and hyperlipemia in the earliest phase. This subsided slowly as the disease progressed but did not reach normal values as long as the disease persisted. With a few exceptions the creatinine concentration remained normal during all phases of the disease. Marked azotemia was frequently obtained in severe disease at onset. It subsided regularly within the first two months and slight degrees of azotemia in late stages of the disease were noted in approximately 50% of the rats.\n 5. A histologic analysis was obtained in 119 sick, 12 recovered and 31 control rats. By correlating the chronologic order of clinical evidence with the pathologic picture, the following conclusions were drawn: (a) The nephrotoxin produces primarily a degenerative lesion with changes in glomeruli and tubules; (b) There may be recovery from the degenerative phase or it may be followed at variable intervals by a variable degree of fibrous proliferation in the glomerular tufts and capsules.

Nephrotic syndrome in rats.

The nephrotic syndrome produced in rats by administration of the aminonucleoside of Puromycin® appears after a latent period which can be shortened or lengthened by increasing or reducing the daily dose. Young rats which survive the initial course lose their proteinuria, but some relapse after 3 to 4 months. Upon re-administration of the nucleoside a chronic disease can be induced which causes death in 3 to 8 months from renal failure. Older rats given a single intravenous injection develop a chronic disease with a natural history the details of which are still not known.\n It is unlikely that the pathogenesis is based on an antigen-antibody reaction, since ACTH, cortisone and inhibition of antibody formation by x-radiation fail to prevent the disease.\n The nucleoside fails to produce a similar disease in dogs, rabbits, guinea pigs, and mice. Both 3-amino-3-deoxy-D-ribose, and and 6-dimethyl aminopurine, which in combination form the nucleoside, are inactive in producing renal disease individually. It is possible that dogs, rabbits, guinea pigs and mice are able to break down this compound while rats cannot.

Aminonucleoside nephrosis in rats.

THE USE of cytotoxic agents in the treatment of renal diseases was first reported in 1949 by Chasis1,2using nitrogen mustard (mechlorethamine) in adults with chronic glomerulonephritis. Shortly thereafter, Kelley and Panos3confirmed improvement in children with nephrosis, and Taylor4in adults with chronic glomerulonephritis, using the same approach. These reports were followed by others,5-9but as the therapeutic value of steroids became more widely accepted, cytotoxic drugs were displaced as therapeutic agents. Interest was renewed in 1963 by Coldbeck,10Kellum and Haserick,11and Goodman and Wolff.12There has been further encouragement in the use of these agents in the treatment of other nonneoplastic diseases12-15as well as in renal diseases.15-22 This report will review 3½ years' experience in 25 children with cytotoxic drugs in addition to corticosteroids in the treatment of chronic renal diseases. Patients and Methods The agents used

Cytotoxic Drugs in Steroid-Resistant Renal Disease Alkylating and Antimetabolic Agents in the Treatment of Nephrotic Syndrome, Lupus Nephritis, Chronic Glomerulonephritis, and Purpura Nephritis in Children

Walter Heymann

Papers

Production of nephrotic syndrome in rats by Freund's adjuvants and rat kidney suspensions.

Studies on the Causal Role of Hypoalbuminemia in Experimental Nephrotic Hyperlipemia

Nephrotic syndrome in rats.

Aminonucleoside nephrosis in rats.

Cytotoxic Drugs in Steroid-Resistant Renal Disease Alkylating and Antimetabolic Agents in the Treatment of Nephrotic Syndrome, Lupus Nephritis, Chronic Glomerulonephritis, and Purpura Nephritis in Children