Search

OCT (22-oxa-calcitriol), a vitamin D analog, has been reported to show strong inhibitory effects on mesangial cell proliferation in vitro. In the present study, we report a study of the effect of OCT on anti-thy-1 glomerulonephritis. Both OCT and 1,25(OH)(2)D(3) significantly inhibited mesangial cell proliferation, the degree of glomerulosclerosis, and albuminuria at day 8 compared to the disease control group. The OCT-treated group showed normal calcium levels but the 1,25(OH)(2)D(3)-treated group showed higher levels. The disease control group showed a marked increase of type I and type IV collagens, and alpha-smooth muscle actin (alpha-SMA) compared to the normal group. The treatment of OCT or 1,25(OH)(2)D(3) significantly reduced the expression of these proteins. The mRNA of the glomeruli of anti-thy-1 model expressed significantly higher levels of type I and type IV collagens, and alpha-SMA at day 8 compared to normal rats. Treatment with OCT or 1,25(OH)(2)D(3) inhibited the mRNA expressions of type I and type IV collagens, as well as that of alpha-SMA. These data demonstrate that OCT inhibits mesangial cell proliferation and extracellular matrix expansion with a low calcemic activity. Disease control rats showed significantly increased levels of transforming growth factor-beta1 protein in the glomeruli, but treatment with OCT or 1,25(OH)(2)D(3) markedly reduced this expression. The levels of mRNA in glomeruli were also consistent with these protein levels. Therefore, the suppressive effect of OCT may be mediated by inhibition of transforming growth factor-beta1. The present results suggest that OCT has potential for use in therapeutic strategy for the treatment of glomerulonephritis without inducing hypercalcemia.

慢性関節リウマチ (RA) に対してmethotrexate (MTX) 低用量パルス療法を施行し, 早期に汎血球減少症となった維持透析患者の2症例を経験した. 症例1:46歳, 女性, 血液透析歴16年. RAの治療にMTX 5.0mg/週で2回投与した後, 突然大量の性器出血をきたし, 緊急入院となった. 入院時の白血球数200/μl, Hb 3.8g/dl, 血小板数3.5万/μlと汎血球減少症をきたしていた. MTXによる骨髄抑制と考え, granulocyte colony stimulating factor (G-CSF) 製剤, 赤血球, 血小板輸血, 抗生剤の投与を行った. 第12病日に白血球数3,600/μlと正常化した. 症例2:49歳, 女性. 血液透析歴9か月. RAの治療目的にて入院した. Prednisolone, NSAIDs投与にても関節痛が改善しないため, MTX低用量パルス療法を施行した. MTXを2.5mg/週で2回投与した後に白血球数300/μl, Hb 5.8g/dl, 血小板数1.3万/μlと汎血球減少症をきたした. MTXによる骨髄抑制と考え, G-CSF製剤, 赤血球, 血小板輸血, 抗生剤, leucovorinの投与を行い, 第19病日に白血球数6,700/μlと正常化した. MTXは腎不全症例では排泄遅延のため, 副作用が強くでる可能性がある. MTXの50-60%がアルブミンと結合するため, 通常の血液透析ではMTXの除去は不十分で血中濃度が高値となりやすい. また, 本症例のごとくMTX少量投与で短期間のうちにアレルギー反応と思われる副作用が発現しているため, 透析患者においても副作用の出現のリスクが高く, MTXは少量投与であっても使用しないほうが望ましいと思われる.

症例は36歳の男性. IgA腎症から慢性腎不全となり, 1994年5月13日に血液透析導入となった. 患者の希望でCAPDに変更したが, そのコンディショニング中に陰嚢腫大と陰茎浮腫がみられた. 当初はカテーテル挿入部からの漏液によるものと考え, 2週間の経過観察後に再び, コンディショニングを行った. その結果, 陰嚢腫大はみられたが陰茎浮腫は認めなかった. peritoneoscrotogram (腹腔シンチグラム) を施行し, 腹腔内から右陰嚢部への連続したRI集積像を認め, 交通性の陰嚢水腫と診断した. 交通性の陰嚢水腫は外科的に根治術を行った.術後, peritoneoscrotogramを施行したが, 右陰嚢部へのRI集積はみられず, 1.5%ブドウ糖加灌流液2,000mlを貯留させても陰嚢腫大はみられなかった. その後, CAPDを施行しているが, 特に問題は認めていない. CAPDの合併症で陰嚢腫大の報告例は少ないが, 腹膜鞘状突起の開存は成人男性剖検例の15-37%に認められる. このことはCAPDでみられる陰嚢腫大が解剖学的に稀な合併症でないと推察される. また, CAPD施行時に陰嚢腫大がみられた場合, peritoneoscrotogramは安全で比較的容易に施行でき, 診断や治療方法の検討, 手術部位の同定に有用な検査であった.

BACKGROUND 22-Oxacalcitriol (OCT), an analogue of vitamin D, has been shown to inhibit cell proliferation in cultured mesangial cells. OCT also prevented albuminuria and glomerular injury in an acute model of anti-Thy1 glomerulonephritis. However, potential side effects, including calcaemic actions and tubular dysfunction, of chronic OCT treatment remain unclear. In the present study, we evaluated the effect of OCT in a chronic model of progressive glomerulosclerosis in subtotally nephrectomized (SNX) rats. METHODS At one week after subtotal nephrectomy, SNX rats were divided into 3 groups having equivalent serum creatinine levels and body weight. OCT (0.08 or 0.4 micro g/kg body weight) was administered intravenously three times per week for 8 weeks to SNX rats. We evaluated effects of OCT on renal function during treatment and on morphologic parameters in glomeruli at 8 weeks. We additionally measured calcium and phosphate levels in serum and urine, and tubular dysfunction markers, including beta(2)-microgloblin (beta(2)m) and N-acetyl-beta-D-glycosaminidase (NAG) levels in urine. RESULTS OCT treatment significantly suppressed urinary albumin excretion, prevented increases in serum creatinine and serum urea nitrogen, and inhibited glomerular cell number, glomerulosclerosis ratio and glomerular volume in SNX rats at 8 weeks. At that time, OCT-treated groups did not show hypercalcaemia, hypercalciuria or hyperphosphaturia. Furthermore, OCT treatment did not affect beta(2)m or NAG levels in urine, and did not induce histological changes in tubular or interstitial regions. CONCLUSIONS These findings suggest that OCT may provide a clinically useful agent for preventing the progression of glomerulosclerosis without adversely affecting calcium and phosphorus metabolism or causing subsequent tubular dysfunction.

A microemulsion formulation of cyclosporin (Neoral) has been developed to overcome the problems of poor and variable absorption of cyclosporin. Neoral is a potent immunosuppressive agent that is highly bound in the plasma. It has been proposed that low-density lipoprotein (LDL) delivers cyclosporin (CsA) to T-lymphocytes via the LDL receptor pathway, where it produces its therapeutic effects. Herein, we report a case of minimal change nephrotic syndrome with type 2 diabetes mellitus treated by Neoral and fluvastatin. A 65-year-old male with a 10-year history of type 2 diabetes mellitus suddenly developed nephrotic syndrome. The potential causative drugs, such as NSAIDs and antibiotics, had not been administered. The laboratory findings were as follows: proteinuria 23 g/day, serum albumin 1.9 g/dl, total cholesterol 629 mg/dl, LDL-Cho 1,930 mg/dl. Renal biopsy was normal on light microscopy, and immunofluorescence demonstrated no staining. Due to the risk of deterioration of diabetes by administering prednisolone, he was given Neoral at 2.0 mg/kg/day. He was also given fluvastatin (40 mg/day) for hyperlipidemia after the renal biopsy. At four weeks after the start of Neoral and fluvastatin, his nephrosis continued, but his LDL-Cho and total cholesterol decreased. At six weeks after treatment, proteinuria gradually reduced. At eight weeks after treatment, the proteinuria had disappeared. Nephrotic syndrome is often associated with abnormal lipid metabolism, and many patients with nephrotic syndrome show high levels of LDL-Cho. It has been reported recently that LDL apheresis is effective against nephrotic syndrome. However, in the present case, it can be speculated that the improvement of hyperlipidemia by fluvastatin probably augmented the effect of Neoral, presumably through the increased cellular uptake of Neoral. This suggests that fluvastatin may be considered as the treatment of choice for the disturbed lipoprotein profile in patients with nephrotic syndrome.