Yosuke Ogura

Effect of Orally Administered Shao-Yao-Gan-Cao-Tang (Shakuyaku-kanzo-to) on Muscle Cramps in Maintenance Hemodialysis Patients: A Preliminary Study

Muscle cramps are one of the most common complications of hemodialysis (HD), and often are a source of great pain in spite of various clinical measures. The traditional herbal medicine, shao-yao-gan-cao-tang (Japanese name: Shakuyaku-kanzo-to), consists of equal amounts of paeony and licorice roots, and has been used in Japan and China for muscle pain or skeletal muscle tremors. To determine whether this medicine is able to prevent frequent and unendurable muscle cramps in patients undergoing HD, Shakuyaku-kanzo-to at 6 g per day was prospectively administered for 4 weeks to five patients on HD who were suffering from frequent muscle cramps. The frequency and severity of cramping before and after the treatment treatment were carefully observed and compared. Skeletal muscle cramps completely disappeared in two of the treated patients after the start of oral administration of Shakuyaku-kanzo-to. Moreover, the frequency of cramping was significantly decreased in two of the remaining three patients after persistent administration. The severity of muscle cramps was also decreased by this treatment in the responsive patients. No serious side effects were detected during the treatment period. The inhibitory effect of Shakuyaku-kanzo-to on muscle contraction was also experimentally examined by using phrenic nerve-diaphragm preparations from male Wistar rats. Differences between the twitch responses were determined when the diaphragms and the nerves were stimulated in the presence and absence of the extract of Shakuyaku-kanzo-to. The results demonstrated that extracts of paeony and licorice roots inhibit contraction of skeletal muscles in rats. Taken together, we suggest that administration of Shakuyaku-kanzo-to is a safe, effective treatment for preventing muscle cramps in patients undergoing HD.

Experimental IgA Nephropathy Induced by a Low-Dose Environmental Mycotoxin, Nivalenol

Based on the hypothesis that IgA nephropathy (IgAN) is triggered by some exogenous antigen(s) which induces dysregulation of the mucosal immune system, we developed an experimental model of orally induced IgAN by an environmental mycotoxin, nivalenol (NIV), which often contaminates agricultural products in Southeast Asia and Japan. In the present study, low doses of oral NIV reproducibly induced significant IgA deposits in the glomerular mesangium and elevated serum IgA levels in mice irrespective of the strain; the degree of immunopathological changes analogous to human IgAN was associated with the dose and duration of NIV treatment. Furthermore, a competitive enzyme-linked immunosorbent assay with an NIV analogue-protein conjugate disclosed that the IgA antibody in the sera from the NIV model mice had a higher affinity to the mycotoxin. Conclusively, these findings suggest that NIV induces some pathological changes in mice which resemble those in human IgAN, and that this mycotoxin is associated with pathogenesis in some types of glomerulonephritis.

Proteoglycans in haemodialysis-related amyloidosis

Changes in extracellular matrices of articular tissue, intervertebral discs and systemic organs in patients with haemodialysis-related amyloidosis were investigated by immunohistochemical and biochemical examination of proteoglycans. Increased staining for chondroitin sulfate (CS) was detected in the amyloid deposits of all patients, ranging from early to advanced stages. Degenerative tissue changes around early-stage amyloid deposits in the intervertebral discs also showed positive staining for CS. Heparan sulfate (HS) was detected in amyloid deposits, especially in the synovial membrane. Biochemical analysis of connective tissues containing amyloid supported the immunohistochemical studies; CS was the major glycosaminoglycan species in these tissues, accounting for 55–81% of the total glycosaminoglycans. Although previous studies have stressed the importance of HS in amyloidogenesis, the present study showed that CS, which increased significantly in articular tissues associated with mechanical stress, also has a close relationship with amyloidogenesis.

Increased matrix metalloproteinases as possible cause of osseoarticular tissue destruction in long-term haemodialysis and β2-microglobulin amyloidosis

Immunolocalization of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in periarticular tissues of β2-microglobulin amyloidosis patients was investigated. MMP-1 (interstitial collagenase) the most strongly expressed of the MMPs, was localized in the synovial lining cells, mesenchymal cells in granulation tissue and nodular amyloid deposits, and chondrocytes within areas of cartilage erosion. Expression of MMP-1 was correlated with the degree of macrophage infiltration and synovial cell hyperplasia, but it was not correlated with the degree of amyloid deposition or haemodialysis period. Expression of MMP-1 appeared more intense than that of TIMP-1 and TIMP-2 in highly inflammatory cases. MMP-2 was mildly expressed in the interstitial fibroblasts and MMP-3 was faintly stained in the extracellular matrix of the synovial membrane. MMP-9 (gelatinase B) was found to be strongly positive in the osteoclasts which increased in the progressing osteolytic lesion from the destructive arthropathy. These results suggest involvement of MMPs in inflammation with an imbalance between expression of MMPs and TIMPs being closely related to pathogenesis of the destructive arthropathy.

Clinical Trial of 26,26,26,27,27,27-Hexafluoro-1,25-Dihydroxyvitamin D3 in Uremic Patients on Hemodialysis: Preliminary Report

A clinical trial was done by the Group, Japan to evaluate the efficacy of 26,27-F6-1,25(OH)2D3 on the calcium and bone metabolism of 43 uremic patients on hemodialysis, 24 men and 19 women with a mean age of 50.9 +/- 2.1 years. The initial dose administered orally was 0.05 micrograms/day for 2 weeks. Then the dose was increased every 2 weeks by 0.05 micrograms each time until the dose of 0.3 micrograms/day was reached or until serum calcium increased. 26,27-F6(OH)2D3 increased serum calcium levels significantly at a mean dose of 0.08 +/- 0.03 micrograms/day and at 0.05 micrograms/day of dose comparison in hemodialyzed patients. It decreased the serum level of PTH significantly at a mean dose of 0.14 +/- 0.06 micrograms/day and at 0.3 micrograms/day by dose comparison. The serum level of bone Gla protein increased significantly at a mean dose of 0.18 +/- 0.07 micrograms/day and at 0.25 micrograms/day by dose comparison in the same patients. These results suggest that 26,27-F6-1,25(OH)2D3 has a higher potency in calcium mobilization than 1,25(OH)2D3 in uremic patients on hemodialysis.

Hyperammonemia in a Patient with Short Bowel Syndrome and Chronic Renal Failure

A patient with short bowel syndrome (SBS) and renal failure developed a disturbance of consciousness with hyperammonemia. Abnormally low concentrations of ornithine, citrulline, and arginine were observed on the plasma aminogram. These results suggested that the activities of amino acid synthetase localized in the small intestinal flora were lost. The small intestine is required for arginine synthesis; thus, infusion limited to the essential amino acids to SBS patients will cause a deficiency of the urea cycle intermediates, ornithine, citrulline, and arginine and may lead to hyperammonemia. In addition, the renal insufficiency may have caused decreased excretion of ammonia. In this patient, supplemental arginine improved the symptoms.

Plasma Levels of Vitamin D Metabolites in Renal Diseases1

Plasma levels of 25-OH-D, 1,25-(OH)2-D and 24,25-(OH)2-D in acute renal failure, chronic glomerulonephritis and chronic renal failure were determined by competitive protein binding assay and evaluated for the correlation with the degree of renal impairment and the influence of dialysis, renal transplantation and the administration of vitamin D and 1-alpha-OH-D3. In this study it is revealed that 25-OH-D deficiency could be normalized by the administration of vitamin D2. Plasma levels of 1,25-(OH)2-D are decreased in proportion to the degree of renal impairment and it is clearly depressed in patients, with a Ccr of 30 ml/min or less. Although biosynthesis of 24,25-(OH)2-D is not remarkably depressed, it is necessary to resolve various questions including the methods of measurement in this respect. It is also disclosed in the present study that 1-alpha-OH-D3 is faster in action than vitamin D2 when used to correct 1,25-(OH)2-D3 deficiency.

A Case of Nephrotic Syndrome Developing during Postoperative Gamma Interferon Therapy for Renal Cell Carcinoma

A 70-year-old man developed minimal-change nephrotic syndrome and acute interstitial nephritis while undergoing gamma interferon therapy following right nephrectomy for renal cell carcinoma. It appears that gamma interferon as well as renal cell carcinoma may have played a role as etiologic factors in this nephropathy. We report this extremely rare case of renal cell carcinoma complicated by minimal-change nephrotic syndrome and acute interstitial nephritis, and present a review of the literature.

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.

HLA class II display by circulating T lymphocytes in nonsteroidal anti-inflammatory nephritis induced by drugs.

Yosuke Ogura, MD, Kidney Center, Toranomon Hospital, 2-2-2 Toranomon, Minatoku, Tokyo 105 (Japan) CD lib, and moreover, stained by 12 or 13 antibodies. Therefore, the renal interstitium was infiltrated by cytotoxic T cells expressing HLA class II antigen. Consequently, prednisolone treatment was started with 30 mg per day. After 2 weeks of prednisolone therapy, blood urea nitrogen and creatinine levels returned to normal, being 19 and Dear Sir, Nonsteroidal anti-inflammatory drugs (NSAIDS) have been reported increasingly as causes of renal dysfunction [1-3]. In spite of the abundant clinical data available to characterize the natural history of nephritis with or without nephrotic syndrome, there has been limited information concerning im-munopathogenic mechanisms [4]. Renal biopsies performed by several groups have demonstrated a predominance of cytotoxic T cells in the interstitium [5, 6], while some biopsies taken early in the acute phase have shown significant infiltration by helper T cells [7]. Even when the predominant lymphocyte subset expressed in the interstitium has varied among groups, it has been speculated that cellmediated immune mechanisms may be involved in the patho-genesis of NSAID-induced interstitial nephritis. We had a 56-year-old male manifesting an acute renal failure without the nephrotic syndrome. He had taken diclofenac sodium 200-300 mg daily in the past 4 weeks because of persistent shoulder pain. On admission, blood urea nitrogen was 36 mg/dl, and serum creatinine was 2.6 mg/dl. A first renal biopsy was performed in the 4th week of hospitalization (fig. 1) to determine the indication of steroid treatment for the persistent renal dysfunction. It revealed interstitial nephritis, and the lymphocyte subpopulations within the interstitial inflammatory infiltrates confirmed that, in good accordance with previous reports [5, 6], 90% of them were T cells with a CD4+/CD8+ ratio of 1:4. These CD 8+ cells were also positive to