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Suppression of the renin-angiotensin system is known to slow progression of chronic kidney disease (CKD). However, few trials have been performed with Japanese patients. This study investigated whether the angiotensin receptor blocker (ARB) valsartan would delay the progression of kidney disease more effectively than conventional treatment in Japanese hypertensive patients with advanced, predialysis CKD. In a multicenter, randomized, open-label trial, 303 patients with hypertension and CKD with serum creatinine levels 2.0 mg dl(-1) were assigned to receive either conventional therapy plus valsartan (valsartan add-on group) or conventional therapy without ARB (control group). The primary outcome was a change in serum creatinine levels. Changes in urinary protein levels and time to onset of renal events were analyzed as secondary end points. There were no between-group differences in blood pressure during the study. Changes in serum creatinine and urinary protein levels did not differ between the groups. However, the rate of renal events, including doubling of serum creatinine levels or end-stage renal disease, was significantly lower in the valsartan add-on group than in the control group. The addition of valsartan decreased the risk by 42.6% after adjustment for baseline variables. The addition of valsartan to conventional therapy significantly slowed the rate of renal function decline and delayed the need for renal replacement therapy in Japanese hypertensive patients with advanced CKD.

Background: Chronic renal failure has increased among aged population in Japan. Protein-restricted diets have been successfully used to treat chronic renal failure. However, concerns over sarcopenia and other nutritional disorders have made doctors in Japan reluctant to recommend low-protein diets.Study Design: A cross-sectional study was carried out based on dietary records, urine and blood samples and DEXA measurements to evaluate body composition.Setting & Participants: The study was carried out at Keio University Hospital and National Institute of Health and Nutrition, Tokyo, over the 3-day period in June, 2009. Subjects were 10 CKD patients (1 male, 9 female); ten members of the patients’ families (3 male, 7 female) and 11 dieticians (all female) were used as control subjects.Factor: The CKD patients maintained a daily protein intake of less than 0.5 g/kg body weight (VLPD) for periods averaging 7 years. Members of the control group all had a daily protein intake of over 1g/kg body weight.Outcomes: Indicators of nutritional disorders, metabolic abnormalities or changes in body composition were sought.Measurements: Intake of various nutrients was calculated from dietary records. Blood plasma and urine content was analyzed. Body composition was measured using DEXA.Results: The CKD subjects were found not to suffer from sarcopenia, osteoporosis, hyperkalemia, hyperphosphatemia, hyperuremia or high levels of uric acid, although slight anemia was observed. Vitamin and mineral intakes were lower than controls, but no recognizable symptoms from nutrient deficiency occurred. Urinary excretion of amino acids was different from controls.Limitations: Results are limited by the relatively small number of test subjects, variation in time on the VLPD, and gender imbalance.Conclusion: Results suggest that VLPD did not show any abnormality in body composition when energy requirement was fulfilled. Different amino acid metabolism would lead to cautious prescription of amino acid supplement.

BackgroundThe factors that predict baseline peritoneal permeability remain largely unknown. We noticed that patients that adhered to a strict low protein diet (LPD) during the predialysis period seldom showed high peritoneal permeability on the peritoneal equilibration test (PET) at the introduction of peritoneal dialysis (PD). Therefore, we investigated whether a strict LPD during the predialysis period affects peritoneal permeability.MethodWe retrospectively analyzed 37 patients that started PD in a single Japanese center. Patients were divided into group A and group B by the median amount of daily protein intake (PI) during the predialysis period using urine collected over 24 hours.ResultsThere were no differences between groups A and B in age, gender, proportion of diabetic nephropathy, blood pressure, body mass index, or body surface area. There were also no differences between the groups in laboratory findings, including hematocrit, serum albumin, and serum creatinine. The PETs showed a significantly lower dialysate-to-plasma ratio of creatinine at 4 hours (Cr D/P) for group A than for group B ( p = 0.02). Furthermore, a significant positive correlation between Cr D/P and PI was observed ( r = 0.53, p < 0.01).ConclusionIt is suggested that a strict LPD during the predialysis period may suppress peritoneal permeability at induction of PD.

The BUF/Mna strain of rat is a model of focal and segmental glomerulosclerosis (FSGS) in which a quantitative trait locus (QTL) for proteinuria, Pur1, has been identified. The aim of the present study was to identify candidates for the Pur1 gene. To narrow the Pur1 QTL, we performed fine QTL mapping and single nucleotide polymorphism (SNP) genotyping. To identify candidate genes, sequencing and gene-expression analyses of all genes contained in the narrowed locus were conducted. The narrowed Pur1 region contained 25 genes. Among these genes, only the Arp3 gene was mutated in the BUF/Mna strain; it contained a missense mutation that caused an (L)111(F) substitution. This leucine is conserved across species. Gene-expression analysis failed to identify any other candidate genes for Pur1. Arp3-mediated actin assembly abnormalities were visible in immunohistochemical and electron microscopic examinations of podocytes in old BUF/Mna rats. Taken together, these data suggest that Arp3 is a candidate for the Pur1 gene. This observation is consistent with our growing recognition that abnormal signaling-induced assembly of actin in podocytes leads to the development of FSGS.

Collagenofibrotic glomerulopathy is considered as a form of glomerulopathy in which organized collagen type III progressively deposits. We report a case of this disease with widespread expression of collagen type V. A 65-year-old woman was admitted to our hospital for further evaluation of nephrotic-range proteinuria. The patient had had anemia and hypertension for 9 years, and proteinuria for 3 years. A renal biopsy specimen showed a remarkable mesangial expansion with Congo red-negative and periodic acid-Schiff-positive deposits. At the ultrastructural level, two forms of bundling fibers were found in the mesangium and subendothelial side of the glomerular basement membranes (GBM). The GBM itself appeared normal. Immunohistochemical investigation showed that the glomerular lesions were strongly reactive with both anti-collagen type-III and -V antibodies. Immunoelectron microscopy demonstrated collagen type V in both forms of bundling fibers. Despite therapy, her renal function declined. The clinical course and renal pathology of this case were in accordance with collagenofibrotic glomerulopathy except for the widespread expression of collagen type V. Collagen type V is a fibrillar collagen capable of forming banding fibrils. This report poses the question whether collagen type V accumulates only in this particular case or whether it is a normal component in collagenofibrotic glomerulopathy.

Summary Background Present angiotensin-converting-enzyme inhibitor treatment fails to prevent progression of non-diabetic renal disease. We aimed to assess the efficacy and safety of combined treatment of angiotensin-converting-enzyme inhibitor and angiotensin-II receptor blocker, and monotherapy of each drug at its maximumdose, in patients with non-diabetic renal disease. Methods 336 patients with non-diabetic renal disease were enrolled from one renal outpatient department in Japan. After screening and an 18-week run-in period, 263 patients were randomly assigned angiotensin-II receptor blocker (losartan, 100 mg daily), angiotensin-converting-enzyme inhibitor (trandolapril, 3 mg daily), or a combination of both drugs at equivalent doses. Survival analysis was done to compare the effects of each regimen on the combined primary endpoint of time to doubling of serum creatinine concentration or end-stage renal disease. Analysis was by intention to treat. Findings Seven patients discontinued or were otherwise lost to follow-up. Ten (11%) of 85 patients on combination treatment reached the combined primary endpoint compared with 20 (23%) of 85 on trandolapril alone (hazard ratio 0·38, 95% CI 0·18–0·63, p=0·018) and 20 (23%) of 86 on losartan alone (0·40, 0·17–0·69, p=0·016). Covariates affecting renal survival were combination treatment (hazard ratio 0·38, 95% CI 0·18–0·63, p=0·011), age (1·30, 1·03–2·29, p=0·009), baseline renal function (1·80, 1·02–2·99, p=0·021), change in daily urinary protein excretion rate (0·58, 0·24–0·88, p=0·022), use of diuretics (0·80, 0·30–0·94, p=0·043), and antiproteinuric response to trandolapril (0·81, 0·21–0·91, p=0·039). Frequency of side-effects with combination treatment was the same as with trandolapril alone. Interpretation Combination treatment safely retards progression of non-diabetic renal disease compared with monotherapy. However, since some patients reached the combined primary endpoint on combined treatment, further strategies for complete management of progressive nondiabetic renal disease need to be researched.

目的: バイフィル®-S (B-S) とバイフィル®専用炭酸水素ナトリウム補充液 (補充液) を使用したacetate free biofiltration (AFBF) 施行時における血液流量 (QB), および膜面積に応じた補充液の至適投与量について検討した. 対象・方法: 安定期透析患者6名を対象に1.3m2のPS-1.3UWと1.6m2のPS-1.6UWの膜面積の違う2種類を使用し, 週1回のみQBをそれぞれ100, 150, 175, 200mL/minと変化させた治療を行い, 血清ナトリウム濃度およびHCO3-のクリアランスを経時的に測定した. ヘマトクリット (Ht) 値はクリットライン®により経時的に測定し, その他の治療条件は一定とした. 結果: 血中HCO3-濃度を終了時に25.0mEq/L以上30.0mEq/L未満にコントロールする至適補充液流量は, QBの12.5-13.5%で設定可能であった. また, 同量の補充液の置換に伴う血清Na濃度の変動は認められず, 治療中の除水に由来したHt値の経時的な上昇を認めた. 結論: バイフィル®-Sとバイフィル®専用炭酸水素ナトリウム補充液を使用したAFBF施行時において至適補充液流量は, 血液流量の12.5-13.5%であると考えられた.

Pulmonary involvement in cryoglobulinemia usually is mild. We present a rare case of severe lung involvement in mixed cryoglobulinemia. A 73-year-old woman with cryoglobulinemic glomerulonephritis was admitted. Dyspnea appeared suddenly two days later. She received the diagnosis of acute lung injury according to the concept proposed by the American-European Consensus Conference. Management required corticosteroid pulse therapy and plasma exchange. This case is the first description of successful early and long-term management of severe lung involvement observed in cryoglobulinemia. Although she has been free of chest symptoms for seven months, further follow-up may be necessary to assess the potential danger of relapse.

The basic or h1 calponin gene, which encodes an actin-binding protein involved in the regulation of smooth-muscle shortening velocity, is known to be a smooth-muscle differentiation-specific gene. It was found that basic calponin was expressed by cultured mesangial cells and localized along the actin filaments. Among the growth factors involved in the mesangial cell pathophysiology, including platelet-derived growth factor-BB (PDGF-BB), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta1 (TGF-beta1), TNF-alpha potently downregulates basic calponin expression in both the mRNA and protein levels, whereas TGF-beta1 upregulates the calponin expression. PDGF-BB also reduced its mRNA expression. The half-life of basic calponin mRNA was determined to be similar between TNF-alpha-treated and -untreated mesangial cells, whereas cell transfection assays that used a luciferase reporter gene construct containing the functional basic calponin promoter showed that TNF-alpha and PDGF-BB reduced the transcriptional activity. Because stimulation with TNF-alpha and PDGF-BB was associated with mesangial cell proliferation, basic calponin may play a role in the suppression of mesangial cell proliferation. Treatment with anti-glomerular basement membrane antibody in calponin knockout mice induced more severe nephritis than in wild type mice, as judged from an increase in the urinary protein excretion, glomerular cellularity, and number of proliferating cell nuclear antigen-positive cells in glomerulus. These results suggest that basic calponin expression may serve as one of the intrinsic regulators of glomerular nephritis. Elucidation of the molecular mechanisms for regulation of the basic calponin expression in mesangial cells may improve the understanding of the molecular basis and pathogenesis of the glomerular response to injury.

The function of intrinsic glomerular cells in active glomerular inflammation may be similar to that of monocytes/macrophages. Mesangial cells have phagocytic properties and release numerous mediators. In this study we examined whether human mesangial cells (hMCs) express a monocyte/macrophage phenotype in active glomerular inflammation. We report that the proto-oncogene c-fms, the macrophage colony-stimulating factor (M-CSF) receptor, which is a characteristic gene of monocytes/macrophages, is expressed in hMCs. Normal unmanipulated hMCs express weak c-fms mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR), and its expression increases after stimulation with platelet-derived growth factor-BB (PDGF-BB) and epidermal growth factor (EGF). The expression of c-fms was also demonstrated by flow cytometry with a specific polyclonal antibody. By immunohistochemistry, c-fms was prominently detected in acute glomerulonephritis, IgA nephritis, and lupus nephritis. These results indicate that hMCs express c-fms in active glomerular inflammation and are consistent with mesangial cells acquiring some macrophage-like characteristics in diseased states.

A common form of methicillin-resistant Staphylococcus aureus (MRSA) associated glomerulonephritis is either an endocapillary proliferative glomerulonephritis or a crescentic glomerulonephritis. This report describes the development of reversible nephrotic syndrome following MRSA infection in a patient with amyloid A amyloidosis. The patient had been diagnosed as having rheumatoid arthritis for 50 years. Suppurative arthritis due to MRSA became complicated 2 years prior to admission to our hospital. In the meantime, a nonnephrotic-range proteinuria developed. Two weeks before admission, nephrotic syndrome developed. The serum creatinine level remained unchanged throughout the course, but common features characteristic of MRSA-associated glomerulonephritis were observed in this patient, such as elevated serum IgG and IgA levels. A renal biopsy specimen showed glomerular amyloid A amyloidosis of a nodular type, infiltrated mononuclear cells in the mesangium, deposition of IgG, IgA, and C3, and swelling of glomerular endothelial cells. There were no crescentic glomeruli. Following surgical eradication of the MRSA focus in the right knee joint, nephrotic syndrome disappeared. Hence, it was highly possible that MRSA infection induced a reversible nephrotic syndrome by causing reversible injuries to glomerular endothelial cells. The description of this case serves to illustrate the range of MRSA infections that may cause various forms of glomerulonephritides.

血液透析患者にビタミンK2 (VK2) を3か月間投与し, 投与前後の骨代謝マーカーを比較検討した. 対象は安定期透析患者21例, 全例女性, 平均年齢56.4±9.6歳, 平均透析期間12.7±5.9年, 原疾患は慢性糸球体腎炎18例, その他3例であった. 21例をVK2投与群15例, 非投与群6例に分類し, 投与前, 投与1か月後, 3か月後のγ-カルボキシル化オステオカルシン (Gla-OC), 非カルボキシル化オステオカルシン (Glu-OC), intact-PTH (i-PTH), 骨型アルカリホスファターゼ (骨型ALP) を測定した. 結果は, 1) i-PTHとGla-OC, Glu-OCはいずれも有意な (p

A 48-year-old man with chronic renal failure underwent placement of a continuous ambulatory peritoneal dialysis (CAPD) eatheter using a microlaparoscopical surgical technique. He had previously undergone appendectomy due to appendicitis with panperitonitis and left nephrectomy due to hydronephrosis of unknown origin. Under general anethesia, the patient was placed in a supine position. The 2mm Minisitegold was inserted through a 2mm introducer placed in the left paraumbilical area. Multiple adhesions between the bowel or emontum and the peritoneal surface of the anterior abdominal wall were detected. Adhesiolysis was perfomed with a Microscissors, then a 10mm port was placed in another site. A CAPD catheter was inserted through this second port, and the distal end of the catheter was guided into the pelvic cavity under direct visualization. To prevent leakage, the peritoneum around the catheter was closed by Endoclose and 1-0 Vycryl. This technique proved to be safe, effective and non-invasive.

安定期血液透析患者53名 (男性20名, 女性33名, 平均年齢53歳, 平均透析期間9.3年) を対象にPTHで二群に分け, CXD法により橈骨骨塩量, ΣGS/Dを, DXA法により橈骨, 腰椎正面, 頭部骨塩量を12か月間隔で2年間経時的に測定した. さらに研究開始時のCXD法で測定した橈骨骨塩量とDXAで測定した各種骨塩量との相関を算出し, これからCXD法による橈骨骨塩量のもつ透析患者骨塩量評価上の意義を検討した.CXD法による橈骨骨塩量は男女とも12か月以降有意に低下し, 低下は主としてPTH高値群に認められた. DXA法による橈骨骨塩量やΣGS/Dは, 女性ではCXD法による橈骨骨塩量と同様の変化を示したが, 男性ではPTHにかかわらず両群いずれも有意な骨量低下を検出できなかった. また, 骨塩量の年間減少率は男女いずれもCXD法による橈骨骨塩量がDXA法による橈骨骨塩量に比較して有意に高値であった. CXD法による橈骨骨塩量にはDXA法で測定した骨塩量のうち, 橈骨, 上肢, 全身骨塩量などの皮質骨塩量と高い相関が認められた. 腰椎正面骨塩量との相関は男性に比して女性で高く, 女性ではPTHにかかわらず高い相関を認めた. 今回測定した各種骨塩量と年齢との相関は認めなかったが, CXD, DXA法による橈骨骨塩量は透析期間と負の相関を示した. 以上の成績から, CXD法による橈骨骨塩量は他の骨塩量測定法に比し皮質骨塩量のみならず海綿骨塩量の変化をも鋭敏に反映し, 透析患者の骨塩量評価において皮質骨, 海綿骨両者の変化を総合的に評価する有用な検査法と考えられた.

Although most studies suggest that the hypercellularity in mesangial proliferative nephritis is due to increased cell proliferation, we hypothesized that it may also be due to increased expression of survival factors that may block their removal (apoptosis). We therefore studied the expression of apoptosis preventing/delaying the bcl-2 gene product in the glomerulus with various human glomerulonephritides. Immunohistochemistry for Bcl-2, proliferating cell associated protein (Ki-67) and α-smooth muscle actin (α-SMA) was performed on 55 biopsied kidney tissues: 6 cases of orthostatic proteinuria as a control (OP); 6 cases of diffuse proliferative lupus nephritis (WHO type IV, LN-MPGN); 24 cases of IgA nephropathy (IgA); 9 cases of minimal change nephrosis and 10 cases of idiopathic membranous nephropathy. The number of Ki-67-positive cells and the expression of α-SMA in the glomerulus were significantly higher in LN-MPGN and IgA. There was a significant positive correlation between glomerular Bcl-2 expression and glomerular cell proliferation evaluated by the number of Ki-67-positive cells (r = 0.605, p < 0.01) or glomerular α-SMA expression (r = 0.674, p < 0.01). Glomerular expression of Bcl-2 in IgA or LN-MPGN was significantly higher than that in OP (p < 0.01 and p < 0.05 vs. OP, respectively). The Bcl-2-positive cells were present in mesangial locations and demonstrated a perinuclear pattern. These results suggest that maintenance of glomerular hypercellularity in human glomerular diseases is partly due to the prevention of mesangial cell death via Bcl-2 expression.

Silver sulfadiazine (SSD) cream is a potent agent for the treatment of burns. In a patient with end-stage renal disease, we observed a marked elevation in serum silver concentration in the course of 2 weeks of SSD cream therapy (200 g/d). Serum concentration of silver reached a maximum of 291 ng/mL in association with a rapid deterioration of mental status. SSD therapy was discontinued, and hemodialysis, hemofiltration, or plasma exchange was continually performed. Four months later, the patient died. At autopsy, profoundly elevated levels of silver were found in brain tissues of this patient (617.3, 823.7 ng/g wet tissue weight in the cerebrum and cerebellum, respectively). To determine the most efficient therapy to remove silver from serum, we compared hemodialysis (HD), hemofiltration (HF), and plasma exchange (PE). Both plasma exchange and hemofiltration were effective in decreasing serum silver, and their effects were additive. By contrast, HD was ineffective in reducing serum silver. This case illustrates that, on SSD cream therapy, burn patients with disturbed renal function are at risk of accumulating silver in serum and tissue to the level that may cause neuralgic decompensation. Removal of serum silver can best be effected by PE, particularly when combined with HF. In contrast, HD per se does not appear efficacious. None of these blood purification modalities improves deterioration of neurological status potentially attributable to silver deposition in brain tissues.

rHuEPO enhances the production of plasminogen activator inhibitor-1 in cultured endothelial cells. The direct effects of recombinant human erythropoietin(rHuEPO) on coagulation and fibrinolysis factors were evaluated in a cultured endothelial cell (EC) system. Confluent quiescent ECs were incubated with or without 5.0 U/ml rHuEPO for 1, 6, and 18 hours, and supernatant concentrations of plasminogen activator inhibitor-1 (PAI-1):antigen (Ag), tissue plasminogen activator and thrombomodulin, and supernatant activities of tissue factor pathway inhibitor and von Willebrand factor were measured. The results showed that only PAI-1 levels were increased by the presence of rHuEPO. In order to assess the effect of rHuEPO on PAI-1 production by EC more precisely, confluent ECs were incubated with various doses of rHuEPO (0, 1.0, 2.5, 5.0, 10.0 U/ml) for 1, 6, 12, and 18 hours, and PAI-1:Ag concentrations in the supernatants of media were measured. PAI-1:Ag in the supernatants were increased by the presence of rHuEPO at all incubation times (P < 0.01) and the increase in PAI-1:Ag was dependent on rHuEPO concentration. The increases in PAI-1:Ag by 5.0 U/ml rHuEPO were comparable to those by 0.1 U/ml tumor necrosis factor-α, 1.0 μg/ml lipopolysaccharide, and 0.5 U/ml thrombin. The increase in PAI-1:Ag by rHuEPO was suppressed by pre-incubation with 10 μg/ml cycloheximide (P < 0.01) or 0.2 μg/ml actinomycin D (P < 0.01). These results indicate that rHuEPO directly stimulates PAI-1 production in cultured EC via de novo protein and RNA syntheses.

Among many substances accumulated or generated by renal failure, much attention has focused on the pathogenetic effects of advanced glycation end-product (AGE)-bound proteins such as AGE-modified beta 2-microglobulin, and bioactive substances such as inflammatory cytokines. In order to remove these substances efficiently, dialysis membranes in the year 2000 should have a higher molecular cut-off point and a sharper cut-off curve, with less formation of concentration polarization, or a greater adsorbing capacity for target substances with less ensuing protein gel layer. Adequate supplementations for depleted substances by more efficient dialysis will be necessary as at present with carnitine and vitamins. Further, from now until the year 2000, membranes in which biocompatibility nearly corresponds to that of capillary endothelium, and safe and economical purification systems of dialysate should be realized.

Endothelin-1 and endothelin B type receptor are induced in mesangial proliferative nephritis in the rat. We studied whether endothelin-1 (ET-1) and its receptor subtypes (ETaR, endothelin A type receptor; and ETbR, B type receptor) were up-regulated in the glomerulus of a rat model of mesangial proliferative glomerulonephritis induced by anti-thymocyte serum (anti-Thy-1 GN). A marked increase in preproET-1 mRNA could be demonstrated in glomerular RNA 3 and six days after disease induction (4.1- and 4.9-fold vs. day 0, respectively), corresponding to the time of mesangial cell proliferation, to the time of macrophage infiltration into glomeruli, and also to the time of increase in glomerular PDGF B-chain mRNA expression. The localization of ET-1 protein in the mesangial area and along the inner aspect of the glomerular capillary wall was also demonstrated by immunohistochemistry from day 3 and maximal at day 6. The major source of the cells expressing ET-1 in glomeruli appeared to be mesangial cells, glomerular endothelial cells and monocyte/macrophages. Furthermore, both gene and protein expression of ET-1 were associated with increased urinary excretion of ET-1. There was no increase in the plasma ET-1 immunoreactivity. Glomerular expression of ETbR mRNA increased in anti-Thy-1 GN (1.5-fold vs. day 0 at day 3 after disease induction, 3.6-fold at day 6 and 2.7-fold at day 10), but there was minimal change in ETaR mRNA expression. These results suggest that preproET-1 mRNA, which is induced in anti-Thy-1 GN, is linked primarily with ETbR mRNA expression. Up-regulated expressions of both preproET-1 mRNA and ET-1 protein, and increased urinary ET-1 excretion in the proliferative phase of anti-Thy-1 GN were dramatically suppressed by complement depletion with cobra venom factor treatment, and these ruled out the possibility that the change of ET-1 might be from the direct effect by anti-Thy-1 antibody itself. In conclusion, there is an induction of glomerular ET-1 and ETbR gene transcription and ET-1 protein synthesis in rat mesangial proliferative glomerulonephritis. PreproET-1 mRNA expression was closely associated with PDGF B-chain mRNA expression and the up-regulation of ET-1 expression may stimulate PDGF-dependent mesangial cell proliferation in anti-Thy-1 nephritis. ET-1 production in glomeruli may allow an amplification of mesangial cell proliferation and subsequent matrix expansion in this model.

妊娠中毒症は概念がまだ確定していない.そのため,臨床面においても研究面においても多少の混乱が見られる.したがってそのコントロールあるいは治療にも確定的なものがない.しかし一方では高血圧が本症の発症機序の重要な鍵を握っていることはほぼ間違いなく,したがって高血圧のコントロールがきわめて重要である.腎の特徴的な病理学的変化も,この高血圧を中心とした血行動態の負荷が大きな役割を果たしていると考えられる.

The ultrastructure of anionic sites in the lamina rara externa (LRE) of rat glomerular basement membrane (GBM) was studied in three dimensions by a quick-freezing and deep-etching method using polyethyleneimine (PEI) as a cationic tracer. Results were compared with those obtained with conventional ultrathin sections examined by transmission electron microscopy. Examination with the quick-freezing and deep-etching method was done without (group 1) or with (group 2) contrasting/fixation with a phosphotungstic acid and glutaraldehyde mixture and post-fixation with osmium tetroxide, which were necessary for visualization of PEI particles by conventional ultrathin sections. Using the quick-freezing and deep-etching method without following contrasting/fixation and post-fixation (group 1), many PEI particles were observed to decorate around fibrils, which radiated perpendicularly from the lamina densa to connect with the podocyte cell membrane. The arrangement of PEI particles was not as regular as that previously reported using conventional ultrathin sections. In contrast, the tissue that was studied with quick-freezing and deep-etching followed by contrasting/fixation and post-fixation (group 2) showed a shrunken appearance. The arrangement of PEI particles was regular (about 20 particles/1000 nm of LRE) as that previously observed using conventional ultrathin sections. However, the number of PEI particles on the LRE was markedly decreased and interruption of decorated fibrils was prominent, as compared with group 1. Ultrastructural examination using conventional ultrathin sections with contrasting/fixation and post-fixation (group 3) demonstrated PEI particles on the LRE in reasonable amounts (18–21 particles/1000 nm of LRE) with fairly regular interspacing (45–65 nm) as reported previously. This is the first report to identify the three-dimensional ultrastructure of anionic sites of GBM, and provides new information on the location and distribution of anionic sites in the glomerular capillary wall. In addition, these studies suggest that several chemical procedures used in conventional transmission electron microscopy to visualize PEI tracers, may produce structural changes and disarrangement of PEI particles that can be avoided with the quick-freezing and deep-etching method.

A patient with acquired hemophilia complicated with chronic renal failure and lung tuberculosis was successfully treated by consecutive plasma exchange (PE). A 71-year-old man with serious bleeding tendency showed low coagulation factor levels and a high titer of factor VIII (FVIII) inhibitor, and he was diagnosed with acquired hemophilia. Because of the complication of active lung tuberculosis, instead of immunosuppressive therapy, he undertook a series of PE with fresh frozen plasma replacement for 3 months. After the start of PE, his bleeding symptoms and activated partial thromboplastin time (APTT) improved gradually according to the decrease in FVIII inhibitor levels. These results suggest that PE is an effective therapeutic tool for refractory acquired hemophilia.

A case of hemophagocytic syndrome (HPS) refractory to corticosteroid therapy was successfully treated by plasma exchange. The patient was a 56-year-old woman who had undergone regular hemodialysis for 10 years for complicated myelodysplastic syndrome (MDS) and then had had lung tuberculosis. After the onset of tuberculosis, she suffered from HPS and was treated by antituberculosis agents and high dose corticosteroid administration without any effect on the HPS. After adding a series of plasma exchanges, the HPS improved gradually, and her MDS began to respond to corticosteroid therapy. Plasma hypercytokinemia due to HPS was corrected by plasma exchange, and the correction of a high level of plasma inflammatory cytokine was considered to be one of the contributing factors for the improvement of HPS. These results suggest that therapeutic plasma exchange should be considered as a therapeutic tool for HPS refractory to conventional therapy.

Background: Although it is well-known that the restriction of protein intake in chronic renal failure (CRF) is effective in slowing the progressive loss of renal function, recent randomized controll

The remarkable effect of plasma exchange (PE) was observed on thrombocytopenia in a patient with antiphospholipid syndrome (APS) associated with systemic lupus erythematosus. Three times PE led to recovery from severe thrombocytopenia refractory to treatment with corticosteroid, anticoagulant, and antiplatelet drugs accompanied by a decrease in the serum cardiolipin beta2 glycoprotein I antibody level. This result suggests that PE is a valuable therapeutic tool for refractory thrombocytopenia in APS.

To study the effect of once-daily administration of a nitrendipine tablet 10 mg on 24-hour ambulatory blood pressure in inpatients with renal parenchymal hypertension.Sixteen patients participated in the present study, and one patient was withdrawn because the baseline office blood pressure was less than 140/90 mmHg. In the baseline period, ambulatory blood pressure was monitored every 30 minutes for 30 hours. After the baseline measurement, nitrendipine 10 mg was orally administered once daily every morning for 7 days. The 30-hour ambulatory blood pressure monitoring was repeated after Day 6.Fifteen patients (aged 64.9 +/- 15.0 years) completed the study protocol. Baseline office blood pressure was 157.9 +/- 17.5/84.7 +/- 12.5 mmHg (mean +/- SD). Nitrendipine 10 mg tablets significantly reduced both systolic blood pressure (SBP) and diastolic blood pressure (DBP) at least for 11 hours after administration compared with those at baseline. The rate of "Decrease" (reduction in blood pressureor = 20/10 mmHg and/or achieved blood pressure140/90 mmHg at trough point) was 60.0% (9/15). Eleven patients were considered as effective cases at peak point (maximal reduction in blood pressureor = 20/10 mmHg). The rate of "Decrease" in effective cases at peak point was 72.7% (8/11).These results suggest that a once-daily administration of nitrendipine 10 mg tablets is effective for the 24-hour control of blood pressure in patients with renal parenchymal hypertension.

A 12-month, multicenter (57 clinical institutions), randomized, open-labeled trial was undertaken to compare the efficacy of the angiotensin II receptor antagonist losartan and the calcium channel blocker amlodipine in patients with proteinuric chronic kidney disease (CKD) and hypertension. A total of 117 patients (79, chronic glomerulonephritis; 14, diabetic nephropathy; 24, other CKD) were randomly allocated into two treatment groups. Losartan and amlodipine exerted the same efficacy for blood pressure (BP) control; however, losartan significantly reduced the 24-h urinary protein excretion at months 3, 6, and 12, with the reduction of 20.7%, 35.2%, 35.8%, whereas amlodipine did not change the amount of proteinuria over the 12-month study period. When patients were stratified into groups according to the level of BP control at 3 months, the reduction in urinary protein excretion by losartan was evident in the group for which a BP of140/90 mmHg was achieved, as well as in the group for which the goal BP (130/85 mmHg) for treatment of CKD was not achieved. When patients were stratified according to baseline urinary protein excretion, those withor = 2 g/day showed a reduction in proteinuria by losartan of 23.3%, 39.4%, and 47.9% at months 3, 6, and 12, and those with2 g/day showed a reduction of 18.5% and 31.2% at months 3 and 6, respectively. No fatal adverse events were experienced in either drug group. We conclude that losartan reduced proteinuria in patients with CKD and hypertension. This positive effect may contribute to the renal protective benefit of losartan, and is beyond the magnitude of BP control.

Staphylococcal scalded skin syndrome (SSSS), a generalized exfoliative dermatitis complicating infections by exfoliative toxin-producing strains of Staphylococcus aureus, is rarely observed in adults, especially in those with chronic renal failure. In contrast to the mortality in infants, the mortality in adults is usually high. A case of generalized SSSS in a peritoneal dialysis patient is reported. A-62-year old Japanese man in whom peritoneal dialysis had been carried out was admitted to our hospital with acute peritonitis. It was intractable peritonitis in terms of resistance to various antibiotics; however, improvement of the peritonitis was shown after the injection of vancomycin. Nine days after the completion of this medication, erythema appeared in the eyes and mouth, and around the nostrils, with an exothermic reaction at 39.0 degrees C. Radial cracks formed in the face within a few days, and the erythema rapidly expanded to the neck, axilla, the whole body. The blood pressure was also lowered, and this led to a state of shock. Culture of skin biopsy specimens yielded identical strains of S. aureus. A presumptive diagnosis of SSSS was made. The patient was treated with antibiotics that were effective against the organisms and with both fluid supplementation and dopamine, resulting in subsidence of the signs and symptoms. The exothermic reaction and skin symptoms were improved promptly, with improvement in the general condition, including the state of shock. This appears to be the first reported case of SSSS caused by S. aureusin an adult patient with peritoneal dialysis who was treated successfully. It is very important that SSSS be differentiated from toxic epidermal necrosis, as the treatment is different.

Background. Percutaneous ethanol injection therapy (PEIT) effectively suppresses PTH secretion, but the change in the serum calcium and phosphorus product (Ca × P) after PEIT has not been fully evaluated. Methods. Twenty-seven haemodialysis patients with severe secondary hyperparathyroidism (2HPT) were divided into two groups according to their intact PTH (i-PTH) concentrations 6 months after PEIT: (i) effective (E) group, i-PTH concentration < 360 pg/ml; and (ii) non-effective (N) group i-PTH ≥360 pg/ml. The changes in serum calcium and phosphorus concentrations and the Ca × P were recorded for the following 2 years under post-PEIT medical treatment with oral calcitriol or intravenous 22-oxacalcitriol (OCT). Result. In the E group, the i-PTH concentrations decreased to < 300 pg/ml 1 year after PEIT (801 ± 302 to 280 ± 134 pg/ml), then increased to 435 ± 201 pg/ml at 2 years. Serum calcium concentration did not show any significant change except for a transient reduction at 1 month after PEIT. The Ca x P decreased for 1 year (from 66.3±15.3 to 56.2±10.3 mg 2 /dl 2 ; P

There are few reports of the effect of a low-protein diet on very late-stage chronic renal failure (CRF), eg, serum creatinine level greater than 10 mg/dL (884 micromol/L). In this retrospective study, we examined the effects of a very low-protein diet in patients with very late-stage CRF.A very low-protein diet (0.25 to 0.54 g/kg body weight/d [0.39 +/- 0.01g/kg body weight/d]) without supplementation of essential amino acids or keto analogues was administered to 76 patients with very late-stage CRF who had serum creatinine levels greater than 10 mg/dL (884 micromol/L). Twenty-one patients with the same serum creatinine level and protein intake of 0.55 to 1.2 g/kg body weight/d (0.68 +/- 0.03 g/kg body weight/d) were observed in lieu of controls.Blood urea nitrogen was significantly suppressed to 43.1 +/- 1.9 g/dL (15.4 +/- 0.7 mmol/L) in the low-protein group compared with 111.2 +/- 7.0 mg/dL (39.7 +/- 2.5 mmol/L; P0.001) in the control group. The rate of decline in glomerular filtration rate (creatinine clearance) was 36-fold slower with the low-protein diet (-7.1 +/- 1.0 versus -0.2 +/- 0.4 mL/mon, respectively; P0.001). Nutritional state in the low-protein group exceeded that of the control group. Consequently, the renal survival rate improved significantly (P0.0001). All patients in the control group were initiated on dialysis treatment within 6 months from a serum creatinine level of 10 mg/dL (884 micromol/L). Conversely, 58% of the low-protein group are still on predialysis treatment.A severe low-protein diet is effective not only in preventing deterioration in renal function, but also in maintaining nutritional state despite no supplementation of essential amino acids or keto analogues, even as serum creatinine level is more than 10 mg/dL (884 micromol/L).

Insufficiency of renal function and high blood pressure influence each other and eventually result in life-threatening endstage renal disease. It has been proposed that proteinuria per se is a determinant of the progression of chronic kidney disease (CKD). The therapeutic strategy for patients with proteinuric CKD and hypertension should therefore be targeted with a view not merely toward blood pressure reduction but also toward renoprotection.We examined the effect of the angiotensin (AT)1 receptor antagonist losartan and the calcium channel blocker amlodipine, throughout a period of 12 months, on reduction of blood pressure and renoprotection. This was done by assessing amounts of urinary protein excretion, serum creatinine (SCr), and creatinine clearance (CCr) in patients with hypertension (systolic blood pressure [SBP]or = 140 mmHg or diastolic blood pressure [DBP]or = 90 mmHg) and CKD (male, body weight [BW]or = 60 kg: 1.5or = SCr3.0 mg/dl; female or male BW60 kg: 1.3or = SCr3.0 mg/dl), manifesting proteinuria of 0.5 g or more/day. Losartan was administered once daily at doses of 25 to 100 mg/day, and amlodipine was given once daily at 2.5 to 5 mg/day. No antihypertensive combination therapy was allowed during the first 3-month period.A 3-month interim analysis revealed that, despite there being no difference in blood pressure between the two groups, there was a significant reduction in 24-h urinary protein excretion in the losartan group ( n = 43), but there was no change in the amlodipine group ( n = 43). Analysis of stratified subgroups with proteinuria of 2 g or more/day and less than 2 g/day showed that losartan lowered proteinuria by approximately 24% in both subgroups, while amlodipine lowered proteinuria by 10%, but only in the subgroup of less than 2 g/day (NS). SCr and CCr did not change throughout the period of 3 months in either group. No severe or fatal adverse event was experienced in either group during the study period.Losartan appeared to be efficacious for renoprotection in patients with proteinuric CKD and hypertension, with the mechanism being independent of its antihypertensive action.

Bcl-2 may account in part for the maintenance of hypercellularity in human glomerular diseases through preventing cell death and by counteracting bax which may be expressed to regulate excessive proliferation. This process is associated with the effect of PDGF B-chain expression. Bax expression may be important in the cell loss leading to glomerulosclerosis and TGF-beta1 participates in this process by increasing bax expression. Thus, the balance of bcl-2/bax expression may be critical in the course of human glomerular diseases.

Inhibition of 3-hydro-3-methylglutaryl coenzyme A reductase inhibits the production of mevalonate and has been shown to suppress proliferation in many cell types. Therefore, 3-hydro-3-methylglutaryl coenzyme A reductase inhibitors may have a beneficial effect in glomerular disease, because glomerular cell proliferation is a central feature in the active glomerular injury. This study examines the effect of simvastatin on glomerular pathology in a rat mesangial proliferative glomerulonephritis (GN) induced by anti-thymocyte antibody (anti-Thy 1.1 GN). There was no difference in the degree of the antibody and complement-mediated initial injuries between simvastatin-treated and control GN rats. The most pronounced feature of simvastatin-treated GN was the suppression of the early glomerular cell proliferation. The proliferative activity was maximal at day 4 after disease induction (26.5+/-7.0 of proliferating cell nuclear antigen-positive cells/glomerulus); however, approximately 70% of proliferation was suppressed by simvastatin treatment. At day 4 after disease induction, simvastatin administration also decreased alpha-smooth muscle actin expression in the glomerulus, which is a marker for mesangial cell activation. Inhibition of monocyte/macrophage recruitment into glomeruli by simvastatin was also a prominent feature. There was a 30% decrease in the number of glomerular ED-1+ cells by simvastatin treatment at day 2 after disease induction. Furthermore, simvastatin remarkably suppressed subsequent mesangial matrix expansion and type IV collagen accumulation in glomeruli. We also found that the platelet-derived growth factor expression was reduced in simvastatin-treated nephritic rats, which might simply reflect the reduction in mesangial cell proliferation and mesangial cellularity. There was no significant difference in plasma cholesterol or triglyceride levels between simvastatin- and vehicle-treated nephritic rats at day 2 and day 4, which corresponded to the times when simvastatin treatment resulted in a reduction in mesangial cell proliferation. In conclusion, this is the first report to find that mesangial cell proliferation and matrix expansion have been blocked by simvastatin in vivo. The protective effect of simvastatin in the matrix expansion in anti-Thy1.1 GN was partly by inhibition of mesangial cell proliferation and monocyte/ macrophage recruitment into glomeruli, which were independent of a change in circulating lipids.

Dialytic performance and biocompatibility of a newly developed cellulose triacetate (CTA) membrane with a microgradient porous structure, produced without using polyvinylpyrrolidone (PVP) and liquid paraffin, were compared with those of a conventional polysulfone (PS) membrane dialyzer. In vitro and clinical results demonstrated no significant difference in the dialytic performance and biocompatibility of the two dialyzers, but the CTA dialyzer lost less albumin during dialysis than the PS. These results suggest that a CTA membrane dialyzer with a porous microgradient structure attained comparable performance and biocompatibility to PS, and the risk of albumin loss was suppressed by the new CTA membrane.

Urinary immunoreactive epidermal growth factor (EGF) levels decrease, and renal immunoreactive EGF levels increase in rats with ischaemic acute renal failure (ARF). We investigated the immunohistochemical localization of EGF and EGF receptor in rabbits with ischaemic ARF to clarify the significance of renal EGF. Male New Zealand White rabbits underwent right nephrectomy prior to a 60 min renal artery clamp. At 3, 6, 24, 48, 72 and 96 h after ischaemia, serum urea nitrogen and serum creatinine were determined. Guinea pig anti-rabbit EGF antibody and monoclonal anti-EGF receptor antibody were used for the primary incubation. EGF was immunolocalized to the ascending limb of Henle and the distal convoluted tubule in the normal right kidneys. However, in the post ischaemic left kidneys at 6, 24, 48 and 72 h, immunoreactivity of EGF was associated with proximal tubules. In the normal kidneys, antibody to EGF receptor reacted with distal tubules and collecting ducts. In the ischaemic kidneys, EGF receptor was localized in the basolateral membrane in the proximal tubules. The expression of EGF and EGF receptor in renal tubules may play an important role in repair following ischaemic renal damage.

There are few reports about therapeutic effects of low protein diet on the progression of chronic renal failure due to autosomal dominant polycystic kidney disease (ADPKD), although the disease is common.The annual incidence rate for end-stage renal disease caused by ADPKD is around 6 per million.In this retrospective study in one center, ten chronic renal failure patients due to ADPKD with creatinine clearnce of 17.0±3.3 mL/min /1.73 m2 and serum creatinine (Cr) level of 4.4±0.7 mg/dL were studied for 40 months after the introduction of severe low protein diet (SLPD) (0.48±0.03 g/kgBW/day) without supplementation of essential amino acids or keto-analogues. Dietary protein intake was estimated by urea appearance rate from 24hr urine sample according to Mitch-Maroni's formula. The results clearly showed that ▵1/Cr/month(×10−3) was significantly suppressed from 5.8±0.9 to 2.0±0.6 following the introduction of SLPD (p