Hiroshi Kanbayashi

Experimental Immunoglobulin A Nephropathy Induced by Gram-Negative Bacteria

A study was conducted to determine whether intraperitoneal and oral administration of formalin-fixed gram-negative bacteria induced immunohistologically and ultrastructurally evident glomerular deposition of IgA and C3 in C3H/HeN mice. Separate treatments with strains of Pseudomonas aeruginosa, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, and two kinds of lipopolysaccharide (LPS) were used. Two mice in each treatment group were sacrificed at 10, 20 and 30 weeks of age to examine sequential glomerular changes. In addition to the intraperitoneal administration (IP) groups receiving whole formalin-fixed bacterial cells, cell precipitate and supernatant fractions of each bacterial strain after sonication were injected intraperitoneally once a week, and the mice were sacrificed at 30 weeks of age. Sequential quantitation or IgG, IgA or IgM in serum and the isotypes specific for each of the bacterial strains or LPS administered was performed by ELISA. The incidence of immunofluorescence positivity for glomerular IgA and C3 was 37-71 and 37-66.7%, respectively, in the IP groups that had received bacterial cells of each strain, which was significantly higher than that in the IP groups given LPS or in the controls. These results suggest that cell wall components common among gram-negative bacteria, other than LPS, play a major role in the glomerular deposition of IgA and C3. This is the first use of gram-negative bacteria to establish an active model of IgA nephropathy.

Induction of Anti-Carbonic-Anhydrase-II Antibody Causes Renal Tubular Acidosis in a Mouse Model of Sjögren’s Syndrome

Background/Aim: We recently reported that renal tubular acidosis (RTA) in Sjögren’s syndrome (SjS) is associated with high titers of an autoantibody against carbonic anhydrase (CA) II, an important enzyme in renal acid-base regulation. The purpose of this study was to determine whether a CA-II antibody could cause RTA in a mouse model of SjS. Methods: PL/J mice were immunized with human CA II to induce CA II antibody formation, whereas controls were injected with phosphate-buffered saline and adjuvant. After 6 weeks, anti-CA-II antibody titers were measured, then ammonium chloride was administered orally for 1 week to detect any acidification defect. Results: CA-II-immunized mice showed higher anti-CA-II antibody titers than control mice. Pathologically, lymphocytic and plasma cell infiltration was seen in the salivary glands and kidneys of CA-II-immunized mice, but not in controls. On acid loading, blood pH and urine pH decreased in both groups of mice, but the slope of urine pH versus blood pH was less steep in the CA-II-immunized mice, suggesting that these mice had an impaired ability to reduce their urine pH in the face of metabolic acidosis. Conclusion: CA-II-immunized mice had a urinary acidification defect, which may be similar to that seen in patients with SjS.

Etiology of IgA nephropathy syndrome

Since Bergers original paper on mesangial IgA‐IgG deposition with hematuria, there have been a number of clinical and pathological studies regarding IgA immune complexes, the mechanisms of glomerular IgA deposition leading to glomerular injury and animal models of IgA nephropathy. During the last quarter of this century, glomerular changes such as IgA nephropathy have also been observed in cases associated with other diseases, such as systemic lupus erythematosus, Schoenlein‐Henoch purpura, liver cirrhosis and chronic inflammatory diseases of the lung. This evidence supports the idea of an IgA nephropathy syndrome. On the other hand, IgA is thought to be an important humoral factor at the mucosal immune system and appears to have an antibody function against various etiologic candidates of extrinsic or intrinsic substances at the mucosal and systemic immune system. Glomerular IgA deposition in IgA nephropathy syndrome is thought to result from elevated levels of circulating immune complexes or aggregated IgA due to an overproduction of polymeric IgA as antibodies in the serum and due to the clearance impairment of IgA immune complexes in the hepatic and splenic phagocytic system. The glomerular IgA subclass is not one‐sided, but should be evaluated in comparison with the age of patients at renal biopsy; this indicates the approximate age of onset. Cirrhotic IgA glomerulonephritis is not related to Hepatitis B or C virus infection, but to the pathophysiologic condition of liver cirrhosis. Various etiologic candidates such as viral, microbial, dietary antigens or auto‐antigens have been listed and experimental models of IgA nephropathy syndrome have provided some clues in understanding the etiology of primary IgA nephropathy. However much still remains to be clarified and some specific epitopes common among these etiologic candidates will have to be identified.

Renal Lesion of Type la Glycogen Storage Disease: The Glomerular Size and Renal Localization of Apolipoprotein

In order to investigate the glomerular size and renal localization of apolipoprotein in type Ia glycogen storage disease, a renal biopsy was performed in two proteinuric patients. Histopathological examination of the biopsy specimens revealed focal sclerotic glomerular sclerosis in both patients. The mean glomerular area was 21.6 +/- 11.6 x 10(3) microns 2, indicating enlargement of the glomeruli. Immunohistochemical staining of the specimens for apolipoprotein showed localization of apolipoprotein AI on the inner side of the glomerular capillary wall, and in proximal tubular epithelial cells. In one patient with a history of several episodes of hypoglycemia, treatment with corn starch improved the carbohydrate and lipid metabolic profile and reduced the daily urinary protein excretion from 2.23 to 0.5 g. These results suggest that focal sclerotic glomerular lesions associated with type Ia glycogen storage disease may be related to disorders of carbohydrate and lipid metabolism.