Anti-kidney Antibodies Research Articles

Prevalence of autoantibodies that bind to kidney tissues in cats and association risk with antibodies to feline viral rhinotracheitis, calicivirus, and panleukopenia

BackgroundThe feline viral rhinotracheitis, calicivirus, and panleukopenia (FVRCP) vaccine, prepared from viruses grown in the Crandell-Rees feline kidney cell line, can induce antibodies to cross-react with feline kidney tissues.ObjectivesThis study surveyed the prevalence of autoantibodies to feline kidney tissues and their association with the frequency of FVRCP vaccination.MethodsSerum samples and kidneys were collected from 156 live and 26 cadaveric cats. Antibodies that bind to kidney tissues and antibodies to the FVRCP antigen were determined by enzyme-linked immunosorbent assay (ELISA), and kidney-bound antibody patterns were investigated by examining immunofluorescence. Proteins recognized by antibodies were identified by Western blot analysis.ResultsThe prevalences of autoantibodies that bind to kidney tissues in cats were 41% and 13% by ELISA and immunofluorescence, respectively. Kidney-bound antibodies were observed at interstitial cells, apical border, and cytoplasm of proximal and distal tubules; the antibodies were bound to proteins with molecular weights of 40, 47, 38, and 20 kDa. There was no direct link between vaccination and anti-kidney antibodies, but positive antibodies to kidney tissues were significantly associated with the anti-FVRCP antibody. The odds ratio or association in finding the autoantibody in cats with the antibody to FVRCP was 2.8 times higher than that in cats without the antibody to FVRCP.ConclusionsThese preliminary results demonstrate an association between anti-FVRCP and anti-cat kidney tissues. However, an increase in the risk of inducing kidney-bound antibodies by repeat vaccinations could not be shown directly. It will be interesting to expand the sample size and follow-up on whether these autoantibodies can lead to kidney function impairment.

Safe Nanocomposite-Mediated Efficient Delivery of MicroRNA Plasmids for Autosomal Dominant Polycystic Kidney Disease (ADPKD) Therapy.

There is currently no cure for gene mutation-caused autosomal dominant polycystic kidney disease (ADPKD). Over half of patients with ADPKD eventually develop kidney failure, requiring dialysis or kidney transplantation. Current treatment modalities for ADPKD focus on reducing morbidity and mortality from renal and extrarenal complications of the disease. MicroRNA has been shown to be useful in treating ADPKD. This study combines anti-miRNA plasmids and iron oxide/alginate nanoparticles for conjugation with antikidney antibodies. These nanocomposites can specifically target renal tubular cells, providing a potential treatment for ADPKD. Magnetic resonance imaging and in vivo imaging system results show effective targeting of renal cells. Anti-miRNA plasmids released from the nanocomposites inhibit cell proliferation and cyst formation in the PKD cellular and animal models. The results suggest the novel combination of the anti-miRNA plasmids and nanomaterials provides potential clinical implications for ADPKD treatment.

Non-sendromic interlobular pausity appearing in adolesant age: case report

Interlobular pausity (ILP) is a disease characterized lower cholestatic chanels as well as hepatocellular giant cell transformation or/and fibrosis. A 14 year-old boy was referred us for itching, jaundice and weight loss for 3 months. On examination, both sclera were icteric. Laboratory analysis revealed alanin aminotransferase 178 IU, aspartat amino transferase 89 IU, total/direct bilirubine:5.5/3.9 mg/dl, anti Hepatitis A Virus IgA and IgG negative, HBs Ag negative, anti HBs pozitive, anti HCV negative, AntiHIV negative, antinuclear antibody negative, anti double strand DNA negative, anti smooth muscle antibody negative, anti mitechondrial antibody negative and anti liver kidney antibody negative. Copper in 24 hour urine and seruloplasmine were normal. Liver biopsy showed lower interlobular cholestatic chanels and hepatocellular giant cell transformation. Phsycians should not delay for liver biopsy to diagnosis of interlobular pausity in adolescents with cholestatic signs if there is no primary disease for cholestasis.

English

Introduction Glomerulonephritis is seen as a serious immunologic disease of the glomeruli. However, permanent renal damage has never been produced experimentally by immunisation without the concomitant use of Freund’s adjuvant or other tubulotoxic chemicals. Also contradictory is that renal failure is strongly associated with the degree of tubulointerstitial damage, both in experimental and human glomerulonephritis, whereas weak or no association at all has been found with the degree of glomerular damage. There is solid clinical and experimental evidence that the exposure to tubulotoxic chemicals alone is able to produce glomerulonephritis and renal failure, and there is increasing evidence that such exposure is a major cause of renal failure in other kidney diseases. The aim of this review was to discuss the role of tubulotoxic chemicals in renal failure. Conclusion As several studies have observed improvement of renal function after cessation of hydrocarbon exposure, it is reasonable to expect that avoiding other types of toxic exposure may be beneficial as well. It should therefore be mandatory to ask all the patients with renal failure about possible exposure to tubulotoxic chemicals, preferably by experienced occupational hygienists, and to support attempts to avoid such exposure. Introduction Glomerulonephritis (GN) is an innocent disease as long as renal function is normal. To prevent or to treat serious GN it is therefore necessary to know what causes renal failure. For many years, the interest has been focused on various immunological reactions, either between foreign antigens that arrive into the glomeruli after having reacted with circulating antibodies and complement; or between autologous anti-kidney antibodies and various kidney cells or membranes. In addition severe proteinuria has been considered noxious for the tubular cells. However, there are a host of contradictory observations. This review discusses the crucial role of tubulotoxic chemicals in renal failure. Discussion The author has referenced some of his own studies in this review. These referenced studies have been conducted in accordance with the Declaration of Helsinki (1964) and the protocols of these studies have been approved by the relevant ethics committees related to the institution in which they were performed. All human subjects, in these referenced studies, gave informed consent to participate in the studies. The role of the immunological processes If the immunological reactions in the glomeruli are the cause of renal failure, directly or indirectly, there should exist an association between the number of glomerular immune complexes (ICs) or the degree of glomerular damage, and renal function, but it is not so. Greater amount of glomerular ICs are often seen in sheep, steers, guinea pigs, horses, mice and rabbits with normal renal function and normal urine1. Patients with malignancies, alcoholic liver disease and essential hypertension may have such deposits as well, although their renal function and their urine are normal1. A single injection of a foreign antigen into experimental animals results in the production of circulating and glomerular ICs, but unless the animals are injected with Freund’s adjuvant (FA) as well, or unless the foreign antigen is injected repeatedly, no renal damage is seen apart from mild and transient proteinuria1,2. In accordance, most cases of human GN following an acute infection may heal without permanent damage of the kidneys, but renal failure may be seen in patients with chronic infections, or if the patients are exposed to tubulotoxic chemicals. Experimental GN can also be produced in rats by autologous antibrush border or anti-podocyte antibodies, either by immunisation with rat kidney cells (active Heymann nephritis), or by injecting rabbit antirat brush border antibodies into rats (passive Heymann nephritis). These models are used as an argument for the idea that serious GN is caused by immunologic mechanisms. However, without FA autologous anti-kidney antibodies do not produce more than mild and transient proteinuria. In passive Heymann nephritis injected heterologous rabbit antibodies bind to the glomerulus immediately, but no harm is produced until a few days later, when the autologous anti-rabbit Ig antibodies lead to complex formation in situ1,2. However, this model cannot be used as an argument for an immunologic mechanism, as the presence of heterologous antibodies is most unlikely in human GN. * Corresponding author Email: ravnskov@tele2.se Magle Stora Kyrkogata 9, S 22350 Lund, Sweden

Immunohistochemical localization of extracellular matrix in various types of fibrinoid of the normal human term placenta

Kidney allografts were transplanted through cervical blood vessels to dogs, normal or with induced glomerulonephritis (those producing antirenal antibodies). Fifteen minutes after the introduction of the allogenic kidney into the recipient's circulation, a sharp decline in the anti-kidney antibody titer was observed in the blood in flowing out of the transplanted kidney. It was accompanied by a lowering in the platelet count, and by a decrease in the content of fibrinogen and complement. Considerable amount of FDP appeared. A high degree of correlation was found between the immunological alterations and hemocoagulative indices. Examined by means of light microscopy, allograft tissue samples, withdrawn three hours after the transplantation, demonstrated the typical hyperacute rejection phenomen: fibrin deposition in the capillaries of the glomeruli, and fibrinoid impregnation of the walls of large and medium size interstice arteries. Immunoglobulins eluted from the transplants precipitated kidney antigen specifically, and if fluorescent-dye-labeled, caused luminescence in the capillar loops of glomeruli and the walls of larger vessels. These findings suggest an explanation for acute kidney allotransplant damages occuring soon after the operation in patients with glomerulonephritis even in the absence of preexistent lymphocytotoxic antibodies.

Urinary Proteins of Tubular Origin: Basic Immunochemical and Clinical Aspects

A variety of tubular marker proteins, as compared to healthy controls, are excreted at an increased rate in the urine of patients with renal damage. Beside cytoplasmic glutathione-S-transferase and lysosomal beta-N-acetyl-glucosaminidase (beta-NAG) the majority of kidney-related urine proteins derives from membrane surface components of the most vulnerable proximal tubule epithelia, among them ala-(leu-gly)-aminopeptidase, gamma-glutamyl transpeptidase (GGT), the tubular portion of angiotensinase A, the major brush border glycoprotein 'SGP-240' and adenosine-deaminase-binding protein. Urinary tissue proteins, e.g. brush border (BB) microvilli, are immunologically identical with those antigens prepared from cell membranes of the human kidney itself. BB antigens are shed into the urine of patients with glomerulonephritis, interstitial nephritis, systemic diseases, e.g. systemic lupus erythematosus (SLE), diabetes mellitus and multiple myeloma, arterial hypertension, infectious diseases (malaria, AIDS) and after operations, renal grafting and administration of X-ray contrast media, aminoglycosides or certain cytostatics (cis-platinum). Tissue proteinuria of tubular proteins is determined by enzyme-kinetic or quantitative immunological assays applying either poly- or monoclonal antikidney antibodies. Clinical, ultrastructural and histochemical studies support the idea that both 'soluble' and high-molecular-weight membrane particles (vacuolar blebs, greater than 10(6) dalton) as well as microfilamental components of the epithelial cytoskeleton contribute to tubular 'histuria' which appears as a sensitive parameter in monitoring tubular damage under clinical conditions at a very early phase.

Anti-kidney antibody teratogenesis: evidence for a direct action on the rat conceptus by a mechanism involving the yolk sac

IgG from anti-rat kidney antiserum (anti-K) was added to 48-h cultures of 9.5-day whole rat conceptuses. At concentrations of 25 μg/ml and above, dysmorphogenesis of embryos (optic vesicle defects) was observed. Significant embryonic growth retardation was apparent at 75 μg/ml and above. Other abnormalities (neural tube defects, deficits in axial rotation, reduced somite numbers) were seen at 100 and 150 μg/ml. In separate experiments, anti-K inhibited pinocytosis of 125I-polyvinylpyrrolidone by isolated yolk sacs. All of these effects of anti-K are similar to those produced by anti-visceral yolk sac antiserum suggesting a similar mechanism of teratogenic action, namely interference with yolk-sac-mediated embryotrophic nutrition.

Mechanism of inducing autologous antibody formation in nephrotoxic serum nephritis.

The role of the heterologous antibody fixed in the kidney was evaluated by means of transplantation of a nephritic kidney to a normal recipient in the rat. An intravenous injection of 0.5 ml of nephrotoxic serum could not induce distinct changes in the heterologous phase, but it could cause mild or moderate changes in the autologous phase. Titration of rat antibody to rabbit IgG according to passive hemagglutination test showed that rabbit IgG fixed in the transplant could induce autologous antibody formation with a similar intensity to nephrotoxic serum given intravenously, indicating that fixed antigen played the most important role in autologous antibody formation and other factors, such as the kidney-fixing rabbit IgG remained in circulation or fixed in other tissues and the gamma-globulin other than anti-kidney antibody, might be less important. It was unclear which antibody, fixed or dissociated from the transplant, played the more important role in stimulating antibody formation.

Plasma proteins and anti-kidney antibodies in renal carcinoma.

Occurrence of the nephrotic syndrome in association with renal carcinoma has been reported earlier. There is a risk of masking of carcinoma due to symptoms of nephrotic syndrome/glomerulonephritis. In this study the serum protein profile in patients with renal carcinoma was found to be similar to that of patients with glomerulonephritis. However, increased levels of complement factors C3 and C4 were found, indicating low or none complement consumption. Patients with metastasis had higher blood ESR, orosomucoid, CRP, C3 and C4 but lower Hb and albumin than patients without evidence of metastasis. Immunofluorescence examination of kidneys and sera indicated the occurrence of antibodies against glomerular structures, IgG antibodies were demonstrated in most patients, IgA and IgM in some.

Specificities of antibodies eluted from human cadaveric renal allografts. Multiple mechanisms of renal allograft injury.

The purpose of the present experiments was to evaluate the role of circulating antibodies in the rejection of human renal allografts and to study the apparent target(s) for antibody binding. Eluates obtained from surgical biopsy and nephrectomy specimens of rejecting, cadaveric human renal allografts were tested for antibodies directed to structural antigens of normal kidney and for cytotoxic antibody activity against mononuclear cell populations. By indirect immunofluorescence 23 of 35 eluates contained immunoglobulin that bound to normal kidney. Staining was in smooth muscle only in 10 patients, in smooth muscle and other structures such as tubular basement membranes, proximal cells, or brush border in 9 patients, and in structures other than smooth muscle in 4 patients. All 16 eluates tested contained antibodies cytotoxic for cells derived from a panel of normal volunteers. Six were cytotoxic to T cells and 10 to B cell and monocyte-enriched preparations. Absorption of eluates with pooled buffy coat cells, platelet concentrates and packed, cultured B cells removed antibodies reactive with vascular wall smooth muscle and endothelium, but not antibodies to tubular basement membranes, proximal or distal tubular cells, brush border, or other structures of kidney sections. Two of five eluates containing antikidney antibodies were found to bind to rat kidneys in vivo. These results suggest that circulating antibodies participate in cadaveric renal allograft destruction and demonstrate that they can be recovered directly from the allograft. Moreover, the data indicate that there are different antibody populations involved: some clearly directed to allo-specific differences and others that are apparently kidney-specific.

Hemocoagulation disorders in kidney allotransplants, caused by preformed antirenal antibodies

Kidney allografts were transplanted through cervical blood vessels to dogs, normal or with induced glomerulonephritis (those producing antirenal antibodies). Fifteen minutes after the introduction of the allogenic kidney into the recipient's circulation, a sharp decline in the anti-kidney antibody titer was observed in the blood in flowing out of the transplanted kidney. It was accompanied by a lowering in the platelet count, and by a decrease in the content of fibrinogen and complement. Considerable amount of FDP appeared. A high degree of correlation was found between the immunological alterations and hemocoagulative indices. Examined by means of light microscopy, allograft tissue samples, withdrawn three hours after the transplantation, demonstrated the typical hyperacute rejection phenomen: fibrin deposition in the capillaries of the glomeruli, and fibrinoid impregnation of the walls of large and medium size interstice arteries. Immunoglobulins eluted from the transplants precipitated kidney antigen specifically, and if fluorescent-dye-labeled, caused luminescence in the capillar loops of glomeruli and the walls of larger vessels. These findings suggest an explanation for acute kidney allotransplant damages occuring soon after the operation in patients with glomerulonephritis even in the absence of preexistent lymphocytotoxic antibodies.

Development of a Lesion Resembling Diabetic Nephropathy in a Renal Homograft

One month following a cadaver renal transplant for obstructive uropathy, a 27-year-old man developed diabetes mellitus. Two years later, marked proteinuria and decreased renal function were detected. Eight months later, a second decline in function occurred. Light microscopy of graft biopsy specimens obtained after each decline in renal function showed increased mesangial cells and matrix, thickening of Bowman capsule, and tubular atrophy with basement membrane thickening. Vascular changes, interstitial infiltrate, and fibrosis were not prominent. Electron microscopic studies of the second biopsy specimen confirmed the light microscopic changes; subepithelial dense deposits were also detected. Immunofluorescent studies of both biopsy specimens demonstrated linear staining of glomerular and tubular basement membranes and Bowman capsule for IgG and albumin. Antikidney antibodies were not detected in the patient's serum. These observations suggest development of the diffuse form of diabetic nephropathy in a renal homograft following steroid-induced diabetes mellitus.

Anti-kidney cytotoxic antibodies in human renal allografts.

Periodic comparisons were made of sera from two groups of patients, ten who rejected their renal transplants within a year after transplantation and ten who successfully maintained their transplanted kidneys for five years or more. What appeared to be anti-kidney cytotoxic antibodies were found in much higher levels in the sera of those patients with the short-lived transplants, the difference in titer levels between the two groups being significant at the .0001 levels. This antibody showed no correlation with either the presence or the absence of lymphocytotoxic antibodies, nor did it appear to have any relationship to the HL-A antigens or the previous renal disease of the recipient patient. While it was cytotoxic to tissue cultures of cells obtained from random human kidneys, human kidney tumor cells (Wilms), and human embryonic kidneys, this antibody did not react with non-renal human tissues (lung, spleen, deltoid muscle, foreskin). It did not react with nonhuman (simian) kidney tissue culture cells. The findings suggest the appearance of an organ-specific, cytotoxic anti-kidney antibody in patients undergoing renal homograft rejection.

Antiheart antibody production of cardiovascular malformations in the mouse: a preliminary study.

AbstractCardiovascular malformations were produced in 17% of A/J and C57BL/6 mice using isogeneic antiheart antibody (RAMHS) and in 22% of C57BL/6 mice using allogeneic RAMHS by injecting on four consecutive days of gestation (days 8–11 or 12–15). The antiheart antibody was raised in rabbits and adsorbed against mouse kidney and liver to yield an antiserum with high antiheart activity and low activity against other organs, demonstrably kidney. Cardiovascular maldevelopment occurred in 9% of mice injected with antikidney antibody (RAMKS), 7% receiving normal rabbit serum, and 1% receiving normal saline. A highly significant (P < .001) difference between all of the RAMHS and the normal saline groups demonstrated that antiheart antibody is teratogenic to the developing heart; and a significant difference (P < .05) between allogenic RAMHS and RAMKS antibody in the frequency of induction of cardiovascular anomalies suggests that there is organ‐specific activity to antiheart antibody. The type of cardiovascular anomalies caused in the mice studied were the same (VSD in C57BL and ASD in A/J) as those that occur spontaneously or are produced by other teratogens such as dextroamphetamine. Antiheart antibody thus did not appear to produce a specific type of maldevelopment but rather made manifest the malformation to which there appears to be a hereditary predisposition (genetic‐environmental interaction).

MECHANISM FOR PROLONGED SURVIVAL OF PIG RENAL ALLOGRAFTS

SUMMARY Ten of 12 pigs did not reject renal allografts when treated with antilymphocyte globulin (ALG) daily for 10 days. Animals with functioning allografts were sensitized to alloantigens, as evidenced by the development of antikidney antibody and by accelerated rejection of skin allografts. Analyses of the immune status of these animals suggested that neither tolerance nor enhancement was responsible for graft survival. Possible mechanisms were discussed, with emphasis upon the uniqueness of the cellular immune response of this species and its low threshold for suppression.

Immunologic aspects of renal disease.

Almost a century and a half ago, Richard Bright suggested that in flammation of the kidney in nephritis was a morbid action directly in­ volving the organ, or a consequence of a morbid action elsewhere, resulting in a deposit in the kidney. After a number of years of intensive investigation in experimental animals and man, we now know that the morbid action is an immunological one, and that the kidney may be damaged by the direct assault of antikidney (glomerular basement membrane) antibodies, or by passive deposition of circulating antigen-antibody complexes in the glo­ merular capillaries. Although there are a number of experimental animal models for the production of acute and chronic glomerulonephritis, the immune injury seems always to be a result of either of th ese two patho­ genetic mechanisms [reviewed in (1)]. As detailed immunopathological studies are made of human glomerulonephritis, clear-cut examples of these mechanisms are being obtained, although a number of cases do not fit a clear-cut pattern of either antikidney antibody disease or complex deposit disease. Most naturally occurring nephritis in man now appears to be of the complex type, but little is known of the qualitative and quantitative aspects of the antigens and antibodies involved in such soluble complex formation. Furthermore, in the less frequently occurring cases due to antiglomerular basement membrane antibody, there are few clues as to why such an auto­ immune process can begin. Both pathogenetic mechanisms can result in either an acute massive inflammatory reaction, or an indolent, slowly pro­ gressing one (2). Regardless of the limitations in our understanding of the unusual anti­ body responses in nephritis, considerable insight has been gained into the proximate causes of inflammation and tissue damage which occur once antibody or antigen-antibody complexes become concentrated in the wall of

CANDIDIASIS: STUDIES PERTAINING TO ITS ASSOCIATION WITH ENDOCRINOPATHIES AND PERNICIOUS ANEMIA

Forty-four patients with chronic or recurrent candidiasis of the dermis, mucous membranes, or both, have been studied in relation to associated diseases. Thirty-one patients (Group I) had at least one associated disease. Thirteen (Group II) had only candidiasis. Neonates with oral moniliasis, children with chronic debilitation, and children receiving antibiotics were eliminated from the study. Idiopathic hypoparathyroidism was the most common associated disease of the patients in Group I (26 of 31 patients). Addison's disease also was common (14 of 31 patients). Hypothyroidism, alopecia, cirrhosis, pernicious anemia, and primary gonadal failure also occurred. Evidence for subclinical disease of the thyroid, adrenal cortex, and gastric mucosa, as reflected by tissue specific antibodies, was common in patients with candidiasis. Anti-kidney antibodies also were found in 18 patients, but their significance is unclear. No etiological relationship between the candidiasis and the associated diseases could be demonstrated.

Immunchemische untersuchungen am nephrotoxischen antigen der glomerulären basalmembran

Zusammenfassung Glomerular basement membranes of normal rats, before and after treatment with collagenase and hyaluronidase, were injected into rabbits. Using the 131I-labelled γ-globulin of each antiserum the amount of kidney-fixing antibody (KFAb) could be determined quantitatively. The hydroxyproline and glucosamine content of glomerular basement membranes was determined after exposure to enzymes. With decollagenized membranes as antigen, the amount of KFAb produced was somewhat diminished. However, immunization with basement membranes, which had been treated with hyaluronidase, resulted in a drastically reduced formation of KFAb. The nature of the apparent effect of hyaluronidase on the antigenic structure of basement membranes is not yet known, especially since there is no concomitant reduction of the glucosamine content. Glomerular basement membranes contain collagen and may function as a weak antigen which fixes anti-kidney antibody as well as cross-reacting KFAb. It is suggested, that the true nephrotoxic antigen (NTA) is not collagen but a glycoprotein participating in the production of KFAb of high affinity for renal antigenic sites.

Highly Specific Lung Localizing Antibodies

Summary Rabbit antibodies against rat lung or kidney were labeled with 125I and injected into rats. The distribution of the antibodies on cellular fractions obtained by differential centrifugation was different for the lungs and kidneys. In lung, the antibody was found in the microsome fraction. In contrast, the antibodies localized in kidneys were associated mostly with a fraction sedimentable at 700 RCF. Both anti-lung and anti-kidney antibodies behaved very similarly in this respect. Antibodies associated with cellular fractions of lungs and kidneys were eluted and the localizing properties of the eluates were determined. The microsome fraction of lung gave the eluate which showed the highest as well as the most preferential localization in lungs. On the other hand, the low speed sediment fraction of kidney gave the eluate which showed the highest as well as the most preferential localization in kidneys. Exhaustive absorption of in vivo purified anti-lung antibodies with sediments of kidney and liver revealed that 20% of the antibodies were lung specific localizing antibodies. A smaller proportion of kidney specific localizing antibody was isolated from an anti-kidney antibody preparation.

Nephritogenic Properties of Cross-Reacting Kidney-Fixing Antibodies to Heart, Spleen and Muscle

Summary Cross-reacting kidney-fixing antibodies may cause an immediate (heterologous) nephrotoxic serum nephritis if: a) a sufficient amount of antibody is injected, and b) if the kidney has enough cross-reacting antigenic determinants to allow fixation of a nephritogenic amount of antibody. If these two conditions are met, cross-reacting kidney-fixing antibodies are effective in inducing immediate nephritis. A cross-reacting kidney-fixing antiserum which reacts with only a small number of glomerular antigenic determinants cannot alone cause immediate nephritis. However, if such antisera are injected simultaneously with subnephritogenic amounts of anti-kidney antibody, their combined effect may be immediately nephritogenic. All cross-reacting kidney-fixing antibodies are so anatomically situated in the glomerulus that they can participate in delayed or autologous nephrotoxic serum nephritis. The cross-reacting kidney-fixing antibodies have shorter half-disappearance times from the kidney than true anti-kidney antibodies.