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近年,高血圧を伴う慢性腎炎において,アンギオテンシン変換酵素阻害薬(ACE-I)およびアンギオテンシン受容体拮抗薬(ARB)は,抗蛋白尿効果と腎保護作用を有すると考えられるようになってきた.本研究の目的は, IgA腎症に対するACE-IとARBの効果に影響する組織学的因子を検討することである.対象は, 1993年1月から2000年5月まで当科でIgA腎症と診断された327例のうち,生検直後より2.5年以上にわたってACE-IもしくはARB投与した26症例である.経過中にステロイド加療を受けていない症例を選別した.腎生検時と比較して尿蛋白の減少が50%以上の群を反応群(n=12), 50%未満の群を非反応群(n=14)に分けて検討した.平均観察期間は61.1±28.6 vs 65.6±24.0ヵ月,生検時の臨床所見では年齢は42.8±12.6 vs 40.4±11.3歳,男女比5:7 vs 6:8,血清クレアチニン値(S-Cr)は1.35±0.33 vs 1.25±0.23mg/dl, 24hrクレアチニンクリアランス(Ccr)は67.5±17.1 vs 70.6±20.5ml/min,尿中赤血球数は35.7±58.4 vs 39.6±53.6/HPFと両群間に有意差はなかった.両群間で生検時の尿蛋白量に有意差は認められなかったが, 1.41±0.76→0.41±0.41(p=0.0006) vs 1.50±0.90→1.53±1.28(NS)g/dayと反応群では有意に蛋白尿が減少した.最終観察時では, S-Crは1.51±0.51 vs 1.64±0.68mg/dlと有意差は認めず,血圧は両群とも低下傾向を示したが有意ではなかった.病理所見では,糸球体硬化率,半月体形成率,癒着糸球体率,メサンギウムの増殖性変化,間質炎症細胞浸潤,間質線維化において有意差は認められなかった.しかし,「grade 0:なし, grade 1:軽度,grade 2:中等度, grade 3:高度」とgradingした動脈硬化の評価では,細動脈(0.92±0.52 vs 1.91±1.08, p=0.043)および小葉間動脈硬化(1.08±0.79 vs 1.78±0.97, p=0.033)は反応群において有意に軽い傾向を示し,細動脈の硝子様硬化部の面積率は有意に非反応群で高く(7.17±9.99 vs 21.0±17.5, p=0.01),内腔の面積率は有意に反応群で高かった(17.8±8.45 vs 13.6±6.73, p=0.02).これらの結果から,腎生検所見で動脈硬化が軽度なIgA腎症の症例に対して, ACE-IあるいはARBの抗蛋白尿効果がより期待できると考えられた., Recent studies have shown that inhibitors of the renin-angiotensin system (I-RAS) such as angiotensin converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARE) are effective for IgA nephropathy (IgAN). However, the precise mechanism of the effects remains unknown. The present study was conducted to elucidate the pathological factors affecting the therapeutic benefits of I-RAS in IgAN. Twenty-six IgAN patients were studied retrospectively. The patients were divided into two groups according to the grade of reduction of urinary protein excretion: the responder group (n=12) and the non-responder group (n=14). The modality of treatment was determined by the clinical and histological findings of each patient. No significant difference before treatment was observed between the responder and non-responder groups. In the evaluation of the outcome after treatment, the amounts of urinary protein excretion one year after treatment and at the final observation significantly decreased in the responder group but remained unchanged in the non-responder group. However, the levels of serum-creatinine, urinary red blood cell sediment, and mean blood pressure were not significantly different between both groups. Histologically, the rate of glomerular obsolescence, interstitial inflammatory cell infiltration and interstitial fibrosis tended to be higher in the non-responder group than in the responder group, and the rate of crescent formation tended to be higher in the responder group than in the non-responder group, but did not reach statistical significance. The grades of mesangial cell proliferation and mesangial matrix increase were not significantly different between both groups. The grade of arterio- and arteriolo-sclerosis was significantly higher in the non-responder group than in the responder group (0.92±0.52 vs 1.91±1.08, p=0.043, 1.08±0.79 vs 1.78±0.97, p=0.033). These findings suggest that arterio- and arteriolo-sclerosis could be a predictor for the effectiveness of I-RAS in IgAN patients.

血糖コントロールが不良の糖尿病患者においては,骨密度の低下が認められることが報告されている. Osteoprotegerin (OPG)は骨芽細胞の分化や骨吸収を修飾する因子として注目されているため,糖尿病を合併する透析患者の腎性骨症の病態に関与している可能性がある.本研究の目的は,インスリン非依存性の糖尿病を合併する血液透析愚者において,骨代謝マーカーとしての血清OPG濃度測定の意義に関して検討することである.対象は62例の維持透析患者(糖尿病合併は32例)で,平均年齢は57.1±1.3歳である.血清OPG濃度は市販のELISAキットで測定し,第2中手骨の骨密度はCXD(computed X-ray densitometry)法で計測した.骨代謝マーカーとして,副甲状腺ホルモン(iPTH),オステオカルシン(iOC)および骨型アルカリフォスファターゼ(BAP)も同時に測定した.透析患者の血清OPG濃度(240.9±13.1pg/ml)は,健常者(66.6±6.2pg/ml)に比して有意に増加していた. iPTH濃度により3群に分けた場合,各群間における血清OPG濃度には有意な差異を認めなかった.全症例における検討では,血清OPG濃度は骨代謝マーカーおよび骨密度との間に有意な相関はなかった.しかし,糖尿病合併例では,血清OPG濃度はiPTH濃度との間に正の相関(r=0.587, p, In diabetic patients with poor glycemic control, a reduction in bone mineral density (BMD) has been reported. Since osteoprotegerin (OPG) has an inhibitory effect on osteoclast differentiation and bone resorption, OPG might be involved in the pathogenesis of renal osteodystrophy (ROD) in diabetic patients receiving hemodialysis (HD). The aim of the present study was to examine the role of OPG in the bone metabolism of HD patients with noninsulin-dependent diabetes mellitus (NIDDM). Serum OPG levels were measured in 62 patients (32 diabetic and 30 non-diabetic) with a mean age of 57.1 ± 1.3 years using a sandwich enzyme immunoassay. Computed X-ray densitometry was used to measure BMD. Bone biochemical markers, such as intact parathyroid hormone (iPTH), osteocalcin and bone alkaline phosphatase, were determined simultaneously. Serum OPG levels were significantly increased in HD patients, compared with age-matched healthy volunteers (240.9 ± 13.1 vs 66.6 ± 6.2 pg/ml). No significant difference in serum OPG levels was observed in subgroups classified according to their serum iPTH levels. In addition, no significant correlation was observed between serum OPG levels and serum levels of bone metabolic markers or BMD in all HD patients. However, serum OPG levels were positively correlated with serum iPTH levels (r=0.587, p

腹膜硬化症は腹膜透析の重大な合併症であり,誘因の一つとして長期にわたる腹膜への高糖暴露が報告されているが,その発症機序に関しては不明な点が多い.腹膜中皮細胞は透析液による暴露を最も受ける細胞である.今回我々は,培養腹膜中皮細胞に高糖刺激を行い, mitogen-activated protein kinase (MAPK)の動態を評価した.ラット腹膜中皮細胞は 0.5% FCS含有DMEM培地で24時間培養した後, 4%グルコースと4%マニトール刺激を行った.細胞増殖能はWST-1法を用いて測定し,上清中のfibronectin (FN)およびMAPKの変化はWestern blottingで半定量化した. FN mRNAの変化はRT-PCRで判定した. 4%グルコースと4%マニトール刺激は,いずれも経時的にFN mRNAとFN蛋白を増加させた.また, 4%グルコースと4%マニトール刺激は,いずれもMAPKのうちextracellular signal-regulated kinase (ERK)とp38MAPKを活性化し, MAPK阻害剤で4%グルコースによるFN mRNA増加は抑制された.最後に, 4%グルコース刺激によるFNの増加は, transforming growth factor (TGF)-β中和抗体の添加で抑制されず,培養上清中へのTGF-βの分泌増加を伴わなかった.これらの結果より,高糖刺激によるFNの増加には, TGF-βを介さないMAPKの活性化が関与していると考えられた.同濃度のマニトール刺激でも,グルコースと同様に MAPKの活性化やFNの増加が見られたことから,高糖刺激は浸透圧刺激として作用したものと思われた.したがって,高糖刺激によりMAPKが活性化された結果として,腹膜中皮細胞によるFNの産生が亢進し,腹膜線維化を惹起していることが示唆された., Peritoneal fibrosis is a serious complication in long-term continuous ambulatory peritoneal dialysis (CAPD) patients, but the underlying mechanism is not well understood. Since high glucose activates the p38 mitogen-activated protein kinase (MAPK) pathway in various kinds of cells, and because mesothelial cells always exposed to high glucose dialysate, we investigated the involvement of MAPK in rat peritoneal mesothelial cells (PMCs) under high glucose conditions. Rat PMCs were grown in Dulbecco's modified Eagle's medium with 0.5% FBS in 24 hours and then exposed to 4% glucose or 4% mannitol. Cell viability was assessed by using WST-1 assay. Fibronectin (FN) accumulation in the supernatant was determined by Western blot. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were performed to determine mRNA and protein expression, respectively. High glucose and mannitol caused time-dependently increase in FN accumulation and FN mRNA in rat PMCs. High glucose also activated the extracellulaer signal-regulated kinase (ERK) and p38 MAPK. These increase in FN accumulation were not inhibited with anti-transforming growth factor (TGF)-β neutralizing antibody. Moreover, high glucose does not promote TGF-β accumulation in the culture media. Therefore, MAPK pathway may play an important role in high glucose-induced FN accumulation via TGF-β-independent mechanism. It is considered that high glucose acts as osmotic stimulation in the regulation of FN production in these cells. Taken together, these findings suggest that the activation of MAPK signaling pathways in rat PMCs by high glucose may contribute to the pathogenesis of peritoneal fibrosis in CAPD therapy.

IgA腎症患者の糸球体濾過値(GFR)のマーカーとして,シスタチンCとクレアチニンの血清濃度(Scyst vs. Screat)を比較した.対象は,臨床的および病理学的にIgA腎症と診断された179例である.平均年齢は34.2±11.5歳で,男女比は男性:女性=67:112であった.標準GFR測定法として,イヌリン・クリアランス(Cin)を施行し,Cin値により対象を4群(I群:Cin, Serum cystatin C (Scyst) has been proposed as a novel indicator of glomerular filtration rate (GFR). The present study was performed to evaluate practical use of a commercially available kit to measure Scyst as a new marker of GFR in patients with IgA nephropathy. A total of 179 patients aged 34.2 ± 11.5 years (male/female: 67/112) were enrolled in this study. We simultaneously measured the Scyst levels and other GFR markers such as inulin clearance (Cin) and serum levels of β_2 and α_1-microglobulin. A highly significant correlation was found between Scyst and serum creatinine (Screat) (r=0.892, p

本研究の目的は,IgA腎症患者における腎組織におけるL-セレクチン発現および可溶性L-セレクチンの血清濃度と腎間質病変との関連性を検討することである.対象は,腎生検の結果と臨床所見からIgA腎症と診断された37例(男性18例,女性19例)で,平均年齢は38.4±2.2歳である.可溶性L-セレクチンの血清濃度は,市販のELISAキットを用いて測定した.腎生検組織におけるL-セレクチンの発現は,凍結切片を用いてLSAB法で免疫染色して確認した.IgA腎症患者における可溶性L-セレクチンの血清濃度(1.2±0.2μg/ml)は,年齢および性別を一致させた健常者のそれ(0.8±0.1μg/ml)に比し有意に高値を示した.腎生検組織におけるL-セレクチンは,間質における浸潤細胞に多量に発現していた.血清L-セレクチン濃度は,間質における細胞浸潤の程度と正の相関を示したが,腎機能や蛋白尿量との間には有意な相関性は認められなかった.これらの結果から,IgA腎症患者において,L-セレクチンは間質への細胞浸潤に関与していると推測された.また,可溶性L-セレクチンの血清濃度の測定は,腎間質病変の存在を予想するための指標になると考えられた., The purpose of the present study was to assess the correlations among expression of L-selectin in renal tissues, serum levels of soluble L-selectin, and renal injuries in patients with IgA nephropathy (IgAN). The serum levels of soluble L-selectin from 37 IgAN patients and 30 healthy controls were measured by the human soluble L-selectin immunoassay. To examine the localization of L-selectin, we immunohistochemically stained three serial sections from all biopsy specimens of 37 IgAN patients. The expression of L-selectin in renal tissues was detected by L-strepto-avidin biotin method. We observed marked expression of L-selectin in the cells infiltrated into interstitium, but not in those without interstitial cell infiltration. The serum levels of soluble L-selectin in IgAN patient (1.2 ± 0.2 μg/ml) was significantly higher than those in healthy controls (0.8 ± 0.1 μg/ml). There was a significant positive correlations between grade of interstitial cell infiltration and serum levels of L-selectin (r=0.44, p

IgA腎症患者に対するアンジオテンシン受容体拮抗薬(ARB)の蛋白尿減少効果を,男性7例,女性10例の計17症例で検討した.このうち,15例はlosartanで,2例はcandesartanで加療した.加療後,30%以上の蛋白尿減少を認めた群をresponder(R)群,それ以外をnon-responder(NR)群としたところ,R群は9例,NR群は8例であった.両群間にステロイドやACE阻害薬の併用など,臨床上の有意差は認めなかった.また,病理組織学的にも両群間に有意差を認めなかった.一方,R群ではARBの治療前後において,平均血圧(MAP)を有意に低下させたが,NR群では降圧効果を認めなかった.また,ARBによる降圧効果と蛋白尿減少効果は相関することも明らかになった.以上より,ARBはlgA腎症患者に対し,血圧に依存して蛋白尿を減少させると考えられる., The aim of the present study was to examine the antiproteinuric effects of two angiotensin II receptor blockers (ARB), losartan and candesartan, in patients with IgA nephropathy. Seventeen patients (7 men and 10 women; mean age, 43.2 ± 12.9 years) were enrolled in this study. Fifteen patients was given 12.5～100 mg/day of losartan, and two patients ware given 2～8 mg/day of candesartan. Nine patients responded to the treatment (R group) and 8 patients did not (NR group). The clinical parameters, including the percentage of patients who also received steroid or angiotensin-converting enzyme inhibitor combination therapy, were not significantly different between the groups. The administration of an ARB significantly reduced the proteinuria from a basal value of 1.0 ± 0.4 g/day to 0.4 ± 0.4 g/day (p

本研究の目的は,IgA腎症を合併した妊娠の予後に影響する腎性因子を検討することである.対象は,妊娠前に腎生検でIgA腎症と診断された10例の女性で,平均年齢は30.5(21～36)歳である.臨床経過から次の2群に分けて検討した.I群(5例)は,妊娠後も血清クレアチニン(Cr)値の有意な上昇を認めなかったグループで,II群(5例)は妊娠後に腎機能が悪化したグループである.血圧,尿蛋白量,血清Cr値,および腎生検所見を比較検討した.I群に比しII群では妊娠中毒症などの母体の合併症が多かった.妊娠前における血清Cr値は,両群で有意差を認めなかったが,妊娠後にはII群で有意な尿蛋白量の増加を認め,拡張期血圧の高値を伴っていた.また,I群に比しII群では半月俸形成率が高く,尿細管間質障害の程度が強かった.これらの結果から,IgA腎症を合併した妊婦は,拡張期血圧のコントロールと腎生検所見に基づいた注意深い経過観察が重要であると考えられた., The present study was designed to determine the renal prognostic factors influencing the clinical outcome of pregnant women with IgA nephropathy (IgAN). The clinical courses of 10 women, ranging in age from 26 to 36 years (average age of 30.5 years) with biopsy-proven IgAN were studied. The patients were divided into two groups on the basis of their renal function outcome: group I consisted of five patients with no changes in renal function during pregnancy, and group II consisted of five patients who experienced a deterioration in renal function as a result of their pregnancy. The patients in group II had a greater incidence of maternal complications than those in group I. The serum creatinine levels before pregnancy were not significantly different in the two groups. However, patients in group II experienced an increase in proteinuria after pregnancy. The increase in proteinuria was associated with an elevated diastolic blood pressure. Histological features, such as crescent formation and tubulo-interstitial injury, were poor prognostic factors of renal function outcome in pregnant women with IgAN. Careful observation of diastolic blood pressure and a knowledge of the underlying histological pattern in IgAN patients may have predictive value in identifying high risk pregnancies.

当教室で腎生検によりIgA腎症と組織診断が得られ,臨床データ解析が可能であった31症例を対象とした.対照として,22例の健常者から採血した.IgA腎症は,軽症群と進行群に分けて検討した.比較症例として,IgA沈着を認めない巣状糸球体硬化症(FGS)を無作為に選択した.すべての症例はインフォームドコンセントを得たのち検討した.IgA腎症における疾患活動性を判定するために,血清vascular endothelial growth factor (VEGF)濃度の測定が有用であるか検討するのが,本研究の目的である.血清VEGF濃度は,VEGF_とVEGF_を認識する2種類の抗体を用いたsandwich ELISAで測定した.疾患活動性として,一日尿蛋白量,血尿の程度,クレアチニン・クリアランス(Ccr)および糸球体における半月体形成率を用いた.進行群のIgA腎症における血清VEGF濃度(70.6±7.8pg/ml)は,健常者(22.6±3.8pg/ml),軽症群のIgA腎症(374±3.8pg/ml)およびFGS症例(34.1±4.9pg/ml)に比し,有意に高値を示した(p, To investigate if serum levels of vascular endothelial growth factor (VEGF) reflect disease activity of IgA nephropathy, the serum VEGF levels were measured in 31 patients with IgA nephropathy and 13 patients with focal glomerulosclerosis (FGS) without glomerular IgA deposition as controls using a sandwich ELISA method. The serum VEGF levels of patients with advanced stage IgA nephropathy (70.59 ± 7.84 pg/ml) were significantly higher than those in mild stage IgA nephropathy (37.36 ± 3.8 pg/ml), FGS (34.14 ± 4.87 pg/ml) and the healthy controls (22.6 ± 3.8 pg/ml). The results demonstrated that advanced stage IgA nephropathy patients with heavy proteinuria and the presence of glomerular crescents had high serum VEGF levels. This suggested that measurement of serum VEGF levels is potentially useful in evaluating the degree of renal injury in patients with IgA nephropathy.