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Background: Angiotensin II receptor blockers (ARBs) provide renoprotective effects in patients with mild-to-moderate chronic kidney disease (CKD). However, there have been few reports regarding whether ARBs show clinical efficacy and safety in patients with advanced CKD. Methods: Seventy-two hypertensive patients with Stages 3 - 4 CKD receiving no ARBs were enrolled in this study and observed up to 48 months. Telmisartan was added to conventional antihypertensive agents (n = 36, mean estimated glomerular filtration ratio [eGFR] 19.7 ml/min/1.73 m 2 ) whilst the remaining control patients were not treated with ARBs (n = 36, mean eGFR 19.2 ml/min/1.73 m 2 ). Urinary protein excretion, kidney function, and the occurrence of end-stage renal disease requiring renal replacement therapy, hyperkalemia, and death were analyzed. Results: Baseline characteristics of each group were similar. During the observation period, the blood pressures of each group decreased at similar rates. In the telmisartan group, 17 patients (47.2%) were introduced to renal replacement therapy, as compared with 31 patients (86.1 %) in the control group (relative risk 0.55, 95% confidence interval 0.19-0.92, p < 0.05). Telmisartan significantly reduced proteinuria levels (from 3.47 ± 3.00 to 2.41 ± 2.46 g/g · creatinine, p < 0.05) and was associated with a reduction of 49.6% in the decline rate of eGFR. The incidence of major adverse events in both groups was similar. Conclusions: The addition of telmisartan to conventional antihypertensive therapy is associated with significant improvement in kidney outcome without increased incidence of adverse effects, even in patients with advanced CKD.

BACKGROUND: Bioincompatible peritoneal dialysis fluids (PDFs) cause pathological changes in the peritoneal membrane, related to membrane dysfunction and progressive peritoneal fibrosis. We investigated the effects of Pro-His-Ser-Arg-Asn (PHSRN) peptide, one of the fibronectin cell-binding domains that activates integrins and reinforces wound healing, on peritoneal remodelling in a rat peritoneal injury model undergoing peritoneal dialysis. METHODS: The peritoneal mesothelial monolayer was removed by a stripping procedure in rats receiving conventional high glucose-containing PDF supplemented with or without PHSRN or control His-Ser-Pro-Asn-Hrg (HSPNR) peptides. Effects of PHSRN on cell motility and signalling molecules were examined in cultured rat peritoneal mesothelial cells (RPMCs) and normal rat kidney fibroblasts (NRKs). RESULTS: The cytokeratin- and HBME-1-positive mesothelial cell monolayer was selectively removed by the procedure. By day 6, HBME-1-positive cells had regenerated to 53.3 +/- 6.5% of the peritoneal surface in the control group. Regeneration of the mesothelial layer was delayed in the PDF group (35.2 +/- 10.2%, P < 0.05), but PHSRN reversed the effects of PDF (51.7 +/- 9.6%, P < 0.05). PDF treatment increased thickening of granulomatous submesothelial tissue and numbers of ED1-, CD31- and alpha-smooth muscle actin-positive cells, but PHSRN ameliorated these effects. HSPNR had no effects on mesothelial regeneration or peritoneal wound healing. PHSRN, but not HSPNR, recovered glucose-induced inhibition of cell motility and phosphorylation of focal adhesion kinase and its downstream p130(Cas) in RPMCs and NRKs. CONCLUSIONS: These results suggest that PHSRN has beneficial effects on peritoneal regeneration by reducing the inhibitory effects of conventional PDF on integrin-mediated wound healing.

Electromagnetic fields may interfere with normal pacemaker function. Despite new device designs and bipolar leads, electromagnetic interference (EMI) remains a concern when pacemaker recipients are exposed to various household appliances. We report the observation of EMI by an induction heating (IH) rice cooker in a patient with sick sinus syndrome who was the recipient of a bipolar dual chamber-pacing system. Stored electrograms revealed episodes of inappropriate ventricular pacing, all coinciding with the opening of an IH rice cooker. Recipients of implantable medical devices must be warned to handle IH rice cookers with caution.

The mechanism of peritoneal fibrosis in patients on continuous ambulatory peritoneal dialysis (CAPD) is poorly elucidated. We investigated the cellular mechanism of high-glucose-induced expression of monocyte chemoattractant protein-1 (MCP-1), which is important in recruiting monocytes into the peritoneum and progression of peritoneal fibrosis, and examined the inhibitory mechanism of glucocorticoids. Rat peritoneal mesothelial cells were cultured in high-glucose-containing medium and then analyzed for phosphorylation levels of p42/44 and p38 mitogen-activated protein (MAP) kinases (MAPK), MAPK or extracellular signal-regulated kinase kinase (MEK)1/2, c-Jun N-terminal kinase (JNK)1/2, and protein kinase C (PKC) by Western blotting. Expression of MCP-1 was examined by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. DNA-binding activity of nuclear factor (NF)-kappaB was measured by electrophoretic mobility shift assay. High glucose increased MCP-1 mRNA and MCP-1 protein expression. Although glucose increased phosphorylation of MEK1/2, p42/44 MAPK, p38 MAPK, JNK1/2, and PKC, and DNA-binding activity of NF-kappaB, its effect on MCP-1 expression was suppressed only by PKC and NF-kappaB inhibitors. Mannitol caused a similar increase in PKC and NF-kappaB activation and MCP-1 synthesis. Prednisolone increased I-kappaB-alpha expression and inhibited glucose/mannitol-induced NF-kappaB DNA binding and MCP-1 expression without affecting PKC phosphorylation. The inhibitory effects of prednisolone on MCP-1 expression were reversed by mifepristone, a glucocorticoid receptor antagonist. Our results indicate that glucose induces MCP-1 mainly through hyperosmolarity by activating PKC and its downstream NF-kappaB, and that such effect was inhibited by prednisolone, suggesting the efficacy of prednisolone in preventing peritoneal fibrosis in patients on CAPD.

AIM Adrenomedullin (AM), a hypotensive and natriuretic peptide, consists of an amidated mature form (mAM) and an intermediate form in human plasma, of which only mAM exerts biological activity. Like atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), plasma levels of mAM are reported to be significantly elevated in hemodialysis (HD) patients, suggesting that mAM may be stimulated partly by increased body fluid volume in a manner similar to the natriuretic peptides. Here, we examined the relationship between mAM levels and ANP or BNP levels and the effect of HD on plasma mAM in HD patients. PATIENTS AND METHODS We measured plasma levels of mAM, total AM (tAM), ANP and BNP before and after HD in patients on long-term HD (n = 22, mean age 56.3 +/- 3.2 years) using radioimmunoassay. RESULTS Baseline mAM (2.7 +/- 0.3 fmol/ml) and tAM (23.6 +/- 2.0 fmol/ml) were significantly higher in HD patients than in healthy subjects (1.1 +/- 0.2 fmol/ml, 9.0 +/- 2.1 fmol/ml, respectively). HD significantly reduced the levels to 1.2 +/- 0.2 fmol/ml and 13.8 +/- 1.4 fmol/ml, respectively, although tAM levels were still elevated compared to healthy subjects. Similar plasma ANP and BNP levels were obtained in HD patients. There were significant correlations between mAM and tAM levels before and after HD and between HD-induced changes in mAM and tAM levels. In the pre-HD state, levels of both mAM and tAM correlated significantly with BNP levels, but the correlation of BNP with mAM was closer than that with tAM. In contrast, no correlations were observed between the 2 forms of AM and ANP. Changes in mAM levels during HD also correlated significantly with BNP but not ANP levels, although the changes in tAM did not correlate with those of the 2 natriuretic peptides. CONCLUSION Our results suggest that the secretion/metabolism of mAM may be regulated in a manner similar to that of BNP in HD patients.

プロスタグランディンE1 (PGE1) は動脈硬化による末梢循環不全に対し有効とされている. 今回我々は閉塞性動脈硬化症 (ASO) を合併した血液透析患者に対し透析中にPGE1投与を行い有効であった症例を経験した.症例は71歳男性. 1995年よりASOによる下肢痛, 間歇性跛行を生じ, 96年と97年にそれぞれ左右の大腿-膝窩バイパス術施行された. 99年4月より末期腎不全のため血液透析を開始した. この際右下肢痛および間歇性跛行を認め, IADSAによりバイパス吻合部近位側の右総腸骨動脈に狭窄が証明された. 6月7日狭窄部に対して動脈内ステント留置を行い症状は軽減, さらにPGE1の透析中投与を行ったところ, 下肢痛は消失, 歩行距離も著明に改善し, なおかつ治療終了後もこの効果は持続した.通常PGE1は投与に長時間を要し, 外来患者への投与は困難であることが多い. リポ化製剤は短時間投与が可能であるが, 投与量は少量とならざるを得ない. しかし今回の投与法を用いれば大量のPGE1を外来透析患者にも投与することが可能となり, 維持透析患者のASOに対する有用な治療法となり得るものと考えられる.

Mizoribine (MZR) has shown to be effective against antineutrophil cytoplasmic antibody (ANCA)-related vasculitis; however, no reports have described the successful treatment of steroid-resistant ANCA-related vasculitis with MZR in patients with renal insufficiency requiring hemodialysis. We herein report the case of a 39-year-old man undergoing hemodialysis in whom MZR successfully lowered the myeloperoxidase (MPO)-ANCA titer accompanied by remission of interstitial pneumonia, together with the pharmacokinetics of MZR. The patient developed severe renal insufficiency and interstitial pneumonia, and was started on hemodialysis. Although prednisolone was administered followed by azathioprine, the MPO-ANCA level and interstitial pneumonia showed insufficient improvement. Azathioprine was replaced by MZR and the administered dose of MZR was determined by measuring serum concentrations of MZR at the start of the dialysis session; this was because we confirmed that MZR could only be removed via dialysis, and that the serum concentration of MZR was maintained until the next dialysis session. The maintenance dose was finally set at MZR 75 mg after each dialysis. Subsequently, the ANCA titer decreased and interstitial pneumonia resolved without any MZR-related side effects. This case demonstrates that MZR is safe and effective, even in patients with steroid-resistant ANCA-related vasculitis undergoing hemodialysis, and can be monitored by measuring serum concentrations of MZR.

Background In the perioperative period, plasma osmotic pressure, systemic blood pressure, and blood volume often change dramatically. Arginine vasopressin is a key factor in the regulation of these parameters. This study was performed to evaluate the direct and the mechanism of the actions of propofol on arginine vasopressin release from magnocellular neurosecretory neurons in the rat supraoptic nucleus. Methods Somatodendritic arginine vasopressin release from supraoptic nucleus slice preparations was measured by radioimmunoassay. Ionic currents were measured using the whole-cell mode of the patch-clamp technique in supraoptic nucleus slice preparations or in single dissociated supraoptic nucleus neurons of the rat. Results Propofol at concentrations greater than 10(-5) M inhibited the arginine vasopressin release stimulated by potassium chloride (50 mM). This inhibition by propofol was not reversed by picrotoxin, a gamma-aminobutyric acid(A)(GABA(A)) receptor antagonist, whereas arginine vasopressin release induced by glutamate (10(-3) M) was also inhibited by propofol at a clinically relevant concentration (10(-6) M). The latter effect was reversed by picrotoxin. Propofol evoked Cl- currents at concentrations ranging 10(-6) to 10(-4) M. Propofol (10(-6) M) enhanced the GABA (10(-6) M)-induced current synergistically. Moreover, propofol (10(-6) M) prolonged the time constant of spontaneous GABA-mediated inhibitory postsynaptic currents. Furthermore, propofol (10(-5) M and 10(-4) M) reversibly inhibited voltage-gated Ca2+ currents, whereas it did not affect currents induced by glutamate (10(-3) M). Conclusions Propofol inhibits somatodendritic arginine vasopressin release from the supraoptic nucleus, and the enhancement of GABAergic inhibitory synaptic inputs and the inhibition of voltage-gated Ca2+ entry are involved in the inhibition of arginine vasopressin release.

症例は71歳男性. 高血圧の治療のためdoxazosin mesilateを内服していた. 平成9年2月18日より3月17日までエシドライ® (1錠中にhydralazine HCl 10mg, hydrochlorothiazide 10mg, reserpine 0.1mg含有) を併用されている. その後エシドライ®は休薬していたが, 血圧上昇のため5月9日から再開となった. 5月16日朝から顔面浮腫, 尿量減少に気付いている. 18日には無尿となり, 急性腎不全の診断で当院緊急入院となった. 利尿剤に反応せず, エコー上は軽度水腎症を認めた. 肺水腫, 著明な代謝性アシドーシスのため, 同日より血液透析を開始した. CTでは大動脈周囲に軟部組織陰影の増大を認め, MRIではT1, T2強調画像ともに低信号の腫瘤を認めた. ガリウムシンチは陰性, 消化管にも異常は認めなかった. 生検は施行していないが, 典型的画像所見と悪性腫瘍が否定できることから, 後腹膜線維症と考えられた. 血液透析9回施行後, 尿量は増加し腎機能が正常化した. 1か月後のCTでは腫瘤陰影は縮小, 1年後には消失した. 抗核抗体, 免疫複合体が陽性であったが, 1年後には抗核抗体は正常化, 免疫複合体も低下している. 薬剤中止後, 急速に腫瘤が縮小したこと, 抗核抗体, 免疫複合体が低下していることから, 薬剤性の自己免疫型の後腹膜線維症ではないかと思われた. 後腹膜線維症は稀な疾患であるが, 薬剤により生じることがあり, 原因薬剤中止によって改善することもあるので注意が必要である.

Plasma arginine vasopressin (AVP) is known to be elevated in patients with uncontrolled insulin-dependent diabetes mellitus who have plasma hyperosmolality with hyperglycaemia. Although osmotic stimuli cause an increase in nitric oxide synthase (NOS) activity as well as synthesis of AVP and oxytocin in the paraventricular (PVN) and supraoptic nuclei (SON), it is not known whether NOS activity in the hypothalamus changes in the diabetic patients who have plasma hyperosmolality with hyperglycaemia caused by insulin deficiency. Expression of the neuronal (n) NOS gene in the PVN and SON in streptozotocin (STZ)-induced diabetic rats was investigated by using in situ hybridization histochemistry and NADPH-diaphorase histochemical staining. Four weeks after intraperitoneal (i. p.) administration of STZ, male Wistar rats developed hyperglycaemia and plasma hyperosmolality. The expression of nNOS gene and NADPH-diaphorase staining in the PVN and SON remarkably increased in STZ-induced diabetic rats compared to control rats. Three weeks after administration of STZ, the diabetic rats were subcutaneously treated with insulin for 1 week, which resulted in significant suppression of the induction of nNOS, AVP and oxytocin gene expression in the PVN and SON. Furthermore, the induction of nNOS gene expression in the PVN and SON was suppressed in STZ-induced diabetic rats treated with phlorizin and diet to normalize hyperglycaemia without insulin treatment. These results suggest that upregulation of nNOS gene expression as well as AVP and oxytocin gene expression in the PVN and SON in STZ-induced diabetic rats may be associated with hyperglycaemia and plamsa hyperosmolality.

肝排泄型ニューキノロン系抗菌剤であるsparfloxacin (SPFX) の腹膜透析患者における体内動態を検討した. 明らかな肝胆道系障害のない腹膜透析患者8名に本剤200mgを朝食後に経口投与し, 血漿中濃度, 透析液中濃度および尿中濃度をHPLC法にて経時的に測定した. 個人差が大きかったが, 最高血漿中濃度 (Cmax) は1.24μg/ml, 最高血漿中濃度到達時間 (Tmax) は5.5時間, 血漿中消失半減期 (T1/2) は34.0時間, 血漿中濃度曲線下面積 (AUC O-∞) は46.4μg・hr/mlであった. 健常成人を対象とした場合に比べ, CmaxおよびTmaxに大差は認めなかったが, T1/2は延長していた. 特に, 心機能の低下した症例や高齢者ではT1/2やAUC O-∞の著明な延長および増大を認めた. 投与後24時間までの透析液中における回収率は投与量の1%程度と少なく, 透析性は極めて低かった. また, 自尿を有する症例での48時間尿中回収率は1%程度であり, 排泄への寄与はほとんど無視できるものと考えられた.以上の結果より, 腹膜透析患者にSPFXの常用量を単回投与した場合, T1/2の延長を認めるものの有効かつ安全域血漿中濃度の得られることが明らかとなった. しかしながら, 本剤には腹膜透析性がほとんど認められないことより, 長期間投与する場合や高齢者および心機能の低下した患者に投与する場合には蓄積性に注意する必要があると考えられた.

Strongyloidiasis, a chronic infection caused by the intestinal parasite Strongyloides stercoralis, is prevalent in the Nansei Islands of Japan. Here, we report our findings on a case of strongyloidiasis complicated with steroid-resistant minimal change nephrotic syndrome in a 69-year-old male resident of Fukuoka Prefecture who had lived in Yakushima, one of the Nansei Islands, until age 15. In October 2006, he developed proteinuria and edema, and was diagnosed with minimal change nephrotic syndrome on the basis of the renal biopsy findings. Following treatment with prednisolone, the level of proteinuria decreased to 0.29 g/day by day 35. However, 5 days later (day 40), the patient developed persistent watery diarrhea and vomiting, leading to dehydration and malnutrition. Pneumonia and bacterial meningitis subsequently developed (day 146); filarial (infectious-type) and rhabditiform (noninfectious-type) S. stercoralis larvae were detected for the first time in the patient’s sputum, gastric juice, feces, and urine. Although treatment with ivermectin was started immediately and the parasitosis responded to the treatment, the patient died of sepsis. Consequently, although strongyloidiasis is a rare infection except in endemic regions, it is essential to consider the possibility of this disease and begin treatment early for patients who have lived in endemic areas and who complain of unexplained diarrhea during steroid-induced or other immunosuppression.

脳腱黄色腫（cerebrotendinous xanthomatosis, CTX）はステロール27位水酸化酵素の障害による脂質代謝異常を呈す，常染色体劣性遺伝の稀な疾患である．今回，我々はCTXの経過中に微小変化型ネフローゼ症候群を合併した症例を経験した．プレドニゾロンの投与のみでは不完全寛解I型までしか改善せず，プレドニゾロンの漸減に伴い再燃したが，LDLアフェレーシスの併用で血清コレスタノール値が低下し完全寛解となった．本例では脂質代謝異常とネフローゼ症候群の発症機序に何らかの関連が疑われた．

Patients on chronic hemodialysis are at high risk for endocarditis due to prosthetic access devices. Right-sided endocarditis without any predisposing factors is rare in dialysis patients. A 76-year-old female, who had chronic renal failure had been treated by hemodialysis and had a permanent pacemaker implanted, was admitted to our hospital with a high fever and lumbago after abscess formation at an autogenous arteriovenous fistula for hemodialysis. Methicillin Resistant Staphylococcus Aureus was identified by blood culture examination. Echocardiography revealed vegetation attached to the tricuspid valve. Chest X-ray and perfusion lung scintigraphy showed pulmonary infarction, perhaps due to vegetation-derived emboli. Computed tomography also showed pyogenic spondylitis in L4 and L5. Repeated vascular punctures even of autogenous grafts expose dialysis patients to bacteremia and imply a higher risk of infectious endocarditis.

Elevated parathyroid hormone (PTH) levels and hyperphosphatemia are thought to be associated with the development of calciphylaxis. We report a patient on hemodialysis who developed proximal calciphylaxis with consistently low PTH levels after parathyroidectomy. A 31-year-old man was admitted to our hospital because of abdominal skin ulcerations. Calciphylaxis spread to the penis, and simultaneous progressive lung calcification was evident on chest X-ray, suggestive of pulmonary calciphylaxis on 99mTc-methylene disphosphonate scintigraphy. The patient died of respiratory failure despite intensive treatment including hyperbaric oxygen therapy. This is the first report of a patient on hemodialysis who developed calciphylaxis involving the penis after parathyroidectomy.

Background: It has been suggested that, like ANP and BNP, high plasma levels of mature adrenomedullin (mAM) indirectly reflect the severity of heart failure or renal failure. However, the relationship between mAM levels and hemodynamics and cardiac function has not been examined in hemodialysis (HD) patients with coronary artery disease (CAD). The best marker, among mAM, ANP and BNP, for left-ventricular function in those patients is also unclear. Patients and Methods: Plasma levels of mAM, total AM (tAM), ANP and BNP were determined before HD in chronic HD patients with CAD (group 1; n = 17) and were compared with those of HD patients without cardiac disease (group 2; n = 22). We examined their relationship to hemodynamics and cardiac function in group 1 using data obtained by cardiac catheterization. Results: Plasma levels of ANP and BNP were significantly higher in group 1 than in group 2, but there was no significant difference in plasma levels of mAM and tAM between the two patient groups. Plasma levels of both mAM and tAM significantly correlated with right atrial pressure (RAP), and only plasma tAM levels correlated with pulmonary artery pressure (PAP) and pulmonary artery wedge pressure (PAWP). However, no correlations were found between levels of the two forms of AM and ejection fraction (EF). In contrast, plasma ANP and BNP levels significantly correlated with both PAP and PAWP, and also with EF, although they did not correlate with RAP. The correlation of PAP and PAWP with ANP and BNP levels was closer than that with tAM levels. The most significant correlation was between BNP levels and EF (r = –0.756, p < 0.0001). Conclusions: Our results suggest that the mAM level may be less useful than natriuretic peptide levels as a marker of cardiac function in HD patients with CAD, and that the BNP level might be the best indicator of left-ventricular function. In addition, cardiac disease such as CAD may have a minor impact on mAM levels compared to renal failure.

The treatment of malnutrition, frequently present in elderly dialysis patients, is important to promote better quality of life and rehabilitation. The aim of this study was to assess the impact of prolonged use of intradialysis parenteral nutrition (IDPN) as a strategy for malnutrition in elderly haemodialysis patients.Twenty-eight elderly patients (non-diabetic, age over 70) on chronic haemodialysis for at least 2 years were evaluated. Ten consenting patients were treated with IDPN containing glucose, essential amino acids, and lipid emulsion during the course of regularly scheduled dialysis treatments for approximately 1 year. Nutritional evaluation using seven parameters (anthropometric measurements such as body mass index, triceps skinfold thickness, mid-arm circumference, mid-arm muscle circumference, and albumin, transferrin, and total lymphocyte count) was performed at various intervals on patients with IDPN and 18 patients without IDPN. The plasma amino-acid profile and dietary protein calorie intake were also determined.In patients receiving IDPN, significant increases in serum albumin and transferrin concentrations and total lymphocyte count in peripheral blood smears paralleled increases in protein-calorie intake beginning after 3 months of treatment and remained favourable throughout the study period. Anthropometric data started to improve significantly after 6 months of treatment. Patients without IDPN had gradual decreases in all parameters during the study period. A significant increase in essential amino acids and a significant decrease in 3-methyl-histidine were observed in patients with IDPN and a further decrease in essential amino acids was observed in patients without IDPN.Prolonged use of IDPN prevents muscle protein catabolism and promotes body protein and fat accumulation. IDPN appears to be effective in malnourished elderly haemodialysis patients.

The authors analyzed data on 59 hemodialyzed patients who did not have significant disorders of calcium and phosphate metabolism and found that more than 60% suffered from disabling pruritus possibly related to chronic uremia. Both biochemical correlates of the prevalence of pruritus and dialysis efficacy calculated by urea kinetics were investigated. Significantly higher values of blood urea nitrogen and plasma beta 2-microglobulin just before the dialysis session were observed in pruritic patients with lower dialysis efficacy estimated by Kt/V urea and normalized protein catabolic rate (nPCR). After 3 months without changing the dialysis prescriptions, 16 patients with a mean Kt/V urea and a normalized protein catabolic rate (nPCR) of 1.28 and 1.22 g/kg/d, respectively, experienced significant reductions in the degree of pruritus estimated by the pruritic score, from 12.6 +/- 5.1 to 6.3 +/- 3.2. Twenty-two patients with a mean Kt/V urea and an nPCR of 1.09 and 1.01, respectively, continued to have severe pruritus (score: 12.3 +/- 4.7 to 12.7 +/- 6.4). In 9 of 22 patients with prolonged severe pruritus, dialysis efficacy was heightened with an increase in dialyzer membrane area of more than 0.3 m2. Seven of nine patients with increased dialysis prescriptions had significant reductions of the mean pruritic score, from 12.6 +/- 4.8 to 6.3 +/- 2.4, which inversely related to the significant increase of Kt/V urea from 1.05 +/- 0.25 to 1.24 +/- 0.33; among patients whose dialysis prescriptions were not changed, only one had a significant reduction in score. The authors concluded that higher dialysis efficacy with good nutritional state reduces the prevalence and degree of pruritus in hemodialyzed patients.