Katsushi Koyama

Significance of histochemical expression of Hanganutziu-Deicher antigens in pig, baboon and human tissues

THERE is increasing interest in the clinical application of xenotransplantation. This interest has been sparked predominantly by the severe shortage of donors. In addition, xenotransplantation might be useful for avoiding the recurrence of viral disease in the transplanted organ. The humoral barrier leading to the immune response is well known for clinical practice of xenotransplantation; that is, xenoreactive natural antibodies to the graft endothelium. Human xenoreactive natural antibodies are directed predominantly against Gala1–3Gal (a-Gal antigen), a saccharide expressed in cells of lower mammals and New World monkeys, but not in cells of Old World monkeys, apes, or humans. Anti–a-Gal antibody plays a major role in hyperacute rejection (HAR) after pig-to-human xenotransplantation. Antibody binding to this sugar, expressed as a modification of endothelial cell membrane glycoproteins and glycolipids, activates complement by the classical pathway. Many investigators believe that pig-to-human xenotransplantation will become a common clinical application and that the pig-to-baboon model represents a good experimental design for study. Hanganutziu–Deicher (HD) antibodies have been known as antibodies detectable in patients with serum sickness. In 1924, the Romanian pathologist Hanganutziu noticed that a serum taken from a patient who received antitetanus horse serum abnormally and strongly agglutinated sheep red blood cells. This agglutination was not sheep-specific, as red blood cells from the horse, guinea-pig, rabbit, calf, and pig expressed similar titers. In 1926, Deicher replicated these results. The antibodies reacting broadly with heterologous antigens were called heterophilic antibodies. HD antibodies are heterophilic antibodies as Forssman antibodies and Paul–Bunnell antibodies. Higashi et al and Merrick et al found that antigens recognized by HD antibodies are gangliosides containing N-glucolylneuramic acid (NeuGc). Gangliosides are sialic acid–containing glycophospholipids present on the surface of all mammalian cells. Sialic acids are a group of nine carbohydrates of two main types: N-acetylneuraminic acid (NeuAc) and N-glucolylneuramic acid. NeuAc is expressed ubiquitously, whereas, NeuGc, the hydroxylated form of NeuAc, is not present in birds or humans. HD antigen is widely distributed in mammalian species with the exception of humans. Some antipig antibodies are directed against epitopes other than the a-Gal antigen. Grafting animals into human patients should be followed by an increase in HD antibodies. Therefore, it is possible that non–a-Gal antibody can cause rejection, even if a-Gal epitopes are successfully removed from donor pig organs. The purpose of this study is to elucidate the significance of HD antigen as non–a-Gal epitopes in clinical xenotransplantation.

Complement fragment C4d deposition in peritubular capillaries in acute humoral rejection after ABO blood group-incompatible human kidney transplantation.

Background. Acute humoral rejection (AHR) is the most important risk factor for early graft loss in ABO-incompatible (ABO-i) kidney transplantation (RTx). The pathogenesis and diagnostic criteria for AHR after ABO-i RTx remain unclear. Complement fragment C4d deposition in peritubular capillaries (PTC), which is a sensitive indicator for activation of the classical complement pathway, was studied to establish the pathologic diagnostic indicator of AHR. Methods. Forty-four graft biopsy specimens from 19 patients with ABO-i living donors were analyzed within 90 days after RTx. Nineteen biopsy specimens with acute rejection after ABO-compatible (ABO-c) living-related RTx were used as controls. Diffuse and bright C4d deposition in PTC was considered significantly positive. Results. All of 8 recipients with AHR showed significantly positive C4d in PTC in the ABO-i group, but 9 of 11 recipients without AHR were negative. In the ABO-c RTx group, 16 of 19 recipients were negative for C4d in PTC. The prevalence of C4d in PTC was significantly higher in ABO-i RTx (P <0.05). Conclusions. C4d deposition is valuable as a specific and sensitive indicator for AHR, even of mild severity, in ABO-i RTx.

Clinicopathological Findings of Bucillamine-Induced Nephrotic Syndrome in Patients with Rheumatoid Arthritis

This paper describes pathological and clinical investigations of glomerular lesions in bucillamine-induced nephropathy by analyzing biopsy materials from 9 patients with rheumatoid arthritis (RA). There was no specific predisposition for nephrotic syndrome induced by bucillamine in clinical profiles related to age, onset, duration of disease, sex, activity and dose of bucillamine. In light-microscopic, electron-microscopic and immunofluorescent findings, the characteristic changes were similar to those of idiopathic membranous glomerulonephritis (MGN). After discontinuance of bucillamine, the nephrotic syndrome improved slowly with or without corticosteroid therapy. Results confirmed that the most common lesion of nephrotic syndrome associated with bucillamine therapy in RA is MGN. We recommend that corticosteroid therapy should be restricted to cases with severe proteinuria.

Kimura's disease associated with minimal change nephrotic syndrome: A case report

Kimuras disease is a rare disorder that involves regional lymph nodes and the major salivary glands, which become infiltrated by eosinophils and lymphocytes. Renal lesions associated with Kimuras disease are rare. We describe the case of a 60-year-old Japanese woman who first noted a nodular mass in a salivary gland. As the nodule grew, nephrotic syndrome and heart failure developed. A biopsy of the nodule revealed Kimuras disease, and surgical excision was performed. After the operation, the heart failure and nephrotic syndrome, which were diagnosed as minimal change disease on renal biopsy, improved rapidly without steroid therapy. Four months later, the nephrotic syndrome recurred without recurrence of Kimuras disease. The patient showed marked improvement during prednisolone therapy (40 mg/d) and was in complete remission 4 weeks after the initiation of steroid therapy. This case shows that surgical excision and prednisolone therapy are useful for nephrotic syndrome associated with Kimuras disease.

A case of rapidly progressive glomerulonephritis associated with bucillamine-treated rheumatoid arthritis

B UCILLAMINE is a new slow-acting antiinflammatory drug developed in Japan l with a chemical structure similar to that of D-penicillamine. The therapeutic effect of bucillamine is believed to be due to the reduction of serum levels of immunoglobulin and rheumatoid factor and the increase in suppressor T cells in patients with rheumatoid arthritis (RA).2 The nephropathies associated with D-penicillamine in patients with RA include membranous glomerulonephritis (MGN), minimal change disease, necrotizing glomerulonephritis, and crescentic glomerulonephritis. The nephropathies of bucillamine may be similar to that of D-penicillamine. This report describes a patient who had rapidly progressive glomerulonephritis (RPGN) following treatment with bucillamine. The renal biopsy specimen had fibrinoid necrosis, . cellular crescents, and adhesions. The variability of bucillamine-associated nephropathy is discussed.

Efficacy of methylcobalamin in subclinical uraemic neuropathy as detected by measuring vibration perception thresholds

Summary: Vibration perception thresholds (VPT) were measured using a new machine, the SMV‐5 (Technolog Company, Tokyo, Japan) in 25 patients receiving maintenance haemodialysis without overt uraemic neuropathy. Patients who had other medical complications such as diabetes mellitus, dialysis amyloidosis or central nervous system dysfunction or peripheral vascular disease were excluded from this study. Forty per cent of the upper extremity VPT and 68% of the lower extremity VPT of the dialysis patients were abnormal, which was defined as greater than 2s.d. above the mean of the normal subjects. the VPT of smokers (n= 7) were significantly higher than those of non‐smokers (n= 18; P<0.01). the VPT of the patients in the treated group (n= 13, including 4 smokers) improved 6 months following the initiation of methylcobalamin therapy (P<0.05). the high incidence of subclinical uraemic neuropathy led us to consider that uraemic neuropathy should be detected at an early stage. the relationship between neurologic disorders and smoking, and the efficacy of methyl cobalamin (analogue vitamin B12) in the treatment oraemic neuropathy (and in the peripheral neuropathy noted in Lebers disease) suggest that cyanide may be the uraemic toxin responsible for the neuropathy. Further studies of chronic cyanide exposure and the metabolism of cyanide in patients with uraemia are necessary.

Exit Site Infection due to Mycobacterium chelonae in an Elderly Patient on Peritoneal Dialysis

Nontuberculous mycobacteria (NTM) are rarely isolated from peritoneal dialysis (PD)-associated catheter infections. However, NTM infection is usually difficult to treat and leads to catheter loss. Prompt diagnosis is essential for appropriate treatment. A 70-year-old Japanese man who had been on PD for 2 years and with a medical history of 2 episodes of exit site infections (ESIs) due to methicillin-resistant Staphylococcus aureus was admitted to the hospital due to suspected ESI recurrence. However, Gram staining of the pus revealed no gram-positive cocci. Instead, weakly stained gram-positive rods were observed after 7 days of incubation, which were also positive for acid-fast staining. Rapidly growing NTM Mycobacterium chelonae was isolated on day 14. Despite administering a combination antibiotic therapy, ESI could not be controlled, and catheter removal surgery was performed on day 21. Although PD was discontinued temporarily, the patient did not require hemodialysis, without any uremic symptoms. The catheter was reinserted on day 48, and PD was reinitiated on day 61. The patient was discharged on day 65. Antibiotic therapy was continued for 3 months after discharge, with no indications of recurrent infections observed. It is important to consider the risk of NTM infections in patients on PD. Acid-fast staining could be a key test for prompt diagnosis and provision of an appropriate treatment.