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Background We designed a prospective and randomized trial of mizoribine (MZR) therapy combined with prednisolone (PSL) for idiopathic membranous nephropathy (IMN) with steroid-resistant nephrotic syndrome (SRNS). Methods Patients with IMN were divided into 2 groups, and MZR combined with PSL was administered for 2 years. PSL was initially prescribed at 40 mg/day and tapered. MZR was given once-a-day at 150 mg and 3-times-a-day at 50 mg each to groups 1 and 2. Serum MZR concentrations from 0 to 4 h after administration were examined within one month of treatment. The concentration curve and peak serum level (C max) of MZR were estimated by the population pharmacokinetic (PPK) parameters of MZR. Results At 2 years, 10 of 19 patients (52.6 %) in group 1 and 7 of 18 patients (38.9 %) in group 2 achieved complete remission (CR). The time-to-remission curve using the Kaplan–Meier technique revealed an increase in the cumulative CR rate in group 1, but no significant difference between the groups. Meanwhile, there was a significant difference in C max between groups 1 and 2 (mean ± SD: 1.20 ± 0.52 vs. 0.76 ± 0.39 μg/mL, p = 0.04), and C max levels in CR cases were significantly higher than those in non-CR cases. Receiver operating characteristic analysis showed that C max more than 1.1 µg/mL was necessary for CR in once-a-day administration. Conclusion Administration of MZR once a day is useful when combined with PSL for treatment of IMN with SRNS. In addition, it is important to assay the serum concentration of MZR and to determine C max, and more than 1.1 µg/mL of C max is necessary for CR.

Elevated urine Mg excretion and its correlation with histological damage in tubulo-interstitial nephropathy (TIN) were reported. Here we investigated the clinical significance of the fractional excretion of Mg (FEMg) for the prediction of TIN.We enrolled and assessed 94 adult patients with various renal diseases diagnosed principally by renal biopsy.Our stratified analysis based on the value of the conventional TIN parameter N-acetylglucosaminidase (NAG) excretion showed that the high-NAG index group (more than median value of NAG-to-Cr ratio, n = 47) demonstrated significantly high FEMg values (p = 0.017). A univariate analysis revealed a significant correlation between the FEMg and the NAG index (R = 0.60) but not for other parameters. A multivariate regression analysis confirmed the significance of the FEMg as an effective predictor of the NAG index. The FEMg showed a significant correlation with the estimated glomerular filtration rate (eGFR) in the patients with eGFR ≤ 30 mL/min. The correlation of FEMg with the NAG index was not observed in the primary glomerulonephritis patients but was apparent in the patients with hypertensive nephrosclerosis or interstitial nephritis.Our findings may indicate that the combination of the FEMg and the NAG index can provide a specific, sensitive assessment for TIN in patients without renal insufficiency.

Water intoxication is a life-threatening disorder accompanied by brain function impairment due to severe dilutional hyponatremia. We treated a 22-year-old man without psychotic illness who had been put in a detention facility. He drank 6 liters of water over a 3-hour period at the facility as a game's penalty, and he showed progressive psychiatric and neurological signs including restlessness, peculiar behavior and convulsions. On his admission, 15 h after the discontinuation of the water drinking, he was in a coma, showing intermittent convulsions and remarkable hyponatremia (120 mmol/l). Because his laboratory tests showed hypertonic urine and normal sodium excretion, the diagnosis of secondary development of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was strongly suggested and later confirmed by the suppression of the renin-aldosterone system and the inappropriately elevated secretion of ADH. Saline infusion and an initial administration of furosemide in addition to dexamethasone as treatments for the patient's brain edema successfully improved his laboratory data and clinical signs by the 3rd hospital day, and he was returned to the facility without physical or psychiatric abnormalities on the 6th day. The secondary SIADH might have been due to the prolonged emesis, recurrent convulsions and rapid elevation of intracranial pressure.

The purpose of this study was to assess the factors affecting the efficacy of combination therapy with losartan and thiazide, with a focus on the significance of salt excretion, via a multicenter observational study. Adult patients with essential hypertension showing therapy resistance to angiotensin receptor blocker (ARB) as a monotherapy or in combination with Ca channel blockers (CCB) were enrolled, and their previously administered ARBs were replaced with the combination tablet containing losartan (50 mg per day) and hydrochlorothiazide (12.5 mg per day). Blood pressure and biochemical parameters were monitored for a year. The baseline blood pressure (153.4±14.8/86.4±11.3 mm Hg) was significantly lowered at the 3rd month (137.3±17.4/78.2±11.1 mm Hg, n=93) and was maintained at this lower level until the 12th month (135.3±14.0/76.4±11.1 mm Hg, n=74). The baseline value of estimated salt excretion (eSE), calculated using Tanaka’s formula, differed significantly between the high and low treatment response groups, which were defined by the average change in mean blood pressure (MBP-C, −11.3 mm Hg; eSE=10.8±2.9 g per day in high responders vs. 9.2±2.3 g per day in low responders, P=0.004). Univariate and multivariate analyses showed a significant correlation between eSE and MBP-C (R=−0.288, P=0.007) and indicated the clinical effectiveness of eSE as a possible predictor for MBP-C (P=0.021). In addition, the urine Na-to-Cr ratio (NCR) demonstrated significant correlations with eSE (R=0.848, P

Background Adrenomedullin (AM) possesses vasodilative and cell-protective properties. Glycine combines with the C-terminal of AM to form mature, physiologically active AM (mAM). AM is reportedly induced by high glucose condition in vascular endothelial or smooth muscle cells; however, little is known on how AM is activated by amidation. To investigate the behavior of AM in patients undergoing peritoneal dialysis (PD), the concentrations of AM, mAM and CA125 were measured. The mAM to AM ratio (mAM/AM ratio) was also evaluated as a marker of amidation activity. Methods Twenty patients were recruited for this study. The effluent at the time of the peritoneal equilibration test was collected and AM, mAM and CA125 concentrations were measured. The expression of AM in peritoneal mesothelial cells (PMCs) collected from effluent was also examined with an indirect immunofluorescent method. Results Mean values of AM and mAM in effluent were 18.1 ± 1.6 and 4.1 ± 0.3 fmol/mL, respectively. In plasma, they were 42.6 ± 3.3 and 5.6 ± 0.6 fmol/mL, respectively. AM concentrations in effluent did not correlate with plasma AM level but correlated well with the dialysate-to-plasma ratio of creatinine (D/P ratio of creatinine). Moreover, in 7 of 20 cases, concentrations of the mAM and mAM/AM ratio in effluent were higher than in plasma. In effluent, AM concentration but not the mAM/AM ratio correlated with CA125 concentration. Immunocytological study revealed diffuse, cytoplasmic expression of AM in PMCs which were collected from effluent during PD. Conclusion AM is expressed by PMCs and actively amidated in the abdominal cavity of patients undergoing PD.

BACKGROUND Bacterial peritonitis in patients undergoing peritoneal dialysis (PD) is a major cause of therapy interruption due to peritoneal insufficiency. Here we studied the effect of a selective mineralocorticoid receptor (MR) blocker, eplerenone, on the prevention of peritoneal damage. METHODS Male Sprague-Dawley rats were treated with a daily infusion of human use PD solution (100 mL/kg i.p., PD group, n = 5), or with PD solution and intermittent intraperitoneal injections of lipopolysaccharide (LPS group, n = 5) or with LPS and eplerenone (100 mg/ kg/d, po, Ep group, n = 5) for 4 weeks. Peritoneal samples were subjected to assessment following the peritoneal equilibration test (PET). RESULTS Histological observations revealed that LPS treatment resulted in significant peritoneal thickening associated with increased ED-1-positive cell infiltration and the number of transforming growth factor (TGF)-β1-positive cells, and that eplerenone reduced these changes. LPS administration also evoked significant upregulation of monocyte chemotactic protein-1 and TGF-β1, which were inhibited by eplerenone. PET revealed that ultrafiltration and transperitoneal osmotic diffusion were significantly impaired by LPS and restored by eplerenone. Increased value of the mass transfer area coefficients for creatinine values was also recovered by Ep (0.10 ± 0.01 in the PD, 0.14 ± 0.02 in the LPS and 0.08 ± 0.0 in the Ep groups). Immunostaining for von Willebrand factor showed a significant increase by LPS and its restoration by Ep. CONCLUSIONS Ep effectively diminished LPS-induced peritoneal insufficiency. A selective blockade of MR might prevent peritoneal insufficiency associated with bacterial peritonitis.

Most dialysis clinics in Japan have mainly adopted the central dialysis fluid delivery system (CDDS) to provide constant treatment to many patients. Chemical disinfection is the major maintenance method of the CDDS. Our clinic introduced an automated hot water disinfection system that used the heat conduction effect to disinfect a reverse osmosis (RO) device and dialysis fluid supply equipment. Endotoxin level and the amount of viable bacteria often showed abnormal values before introduction of this system. After its introduction, weekly disinfection resulted in endotoxin levels and the amount of viable bacteria lower than measurement sensitivity. In hot water disinfection, water heated to 90°C in the RO tank flows into the dialysis fluid supply equipment. The maximum temperature inside the tank of the supply equipment is 86.3°C. (We confirmed that the temperature was maintained at 80°C or more for 10 minutes or more during the monitoring.) Dialysate purification was maintained even after introduction of the automated hot water disinfection system and the dialysate could be supplied stably by the CDDS. Therefore, this disinfection system might be very useful in terms of both cost and safety, and can be used for dialysis treatment of multiple patients.

In Japan, self-monitoring of blood glucose (SMBG) devices are widely used both at home and in hospitals, but many analytical errors and safety concerns have been reported about the SMBG devices used in hospitals. Analytical performances of StatStrip (Nova Biomedical Corporation, MA, USA), a new point-of-care testing device and Glutest (Sanwa Chemical, Aichi, Japan), a routinely used SMBG device were compared in glucose measurement of pre- and postdialysis blood samples and we evaluated which factors in blood modified by hemodialysis affect accuracy of these devices. Subjects in this study were 44 hemodialysis patients. Blood samples were obtained from patients just before and just after the hemodialysis. Blood glucose concentrations of samples were measured by StatStrip and Glutest. Hematocrit and plasma concentrations of electrolytes, metabolites, etc. of the samples were measured in the central laboratory. StatStrip showed no difference between pre- and postdialysis blood samples and showed very little bias from reference method. On the other hand, Glutest showed difference between pre- and postdialysis samples. Although there is no problem in the data of predialysis blood samples by Glutest, however, these of the postdialysis blood samples by Glutest were >10% less than reference method. Factors in blood modified by hemodialysis such as hematocrit, uric acid, albumin, potassium, and calcium affected glucose readings by Glutest. Glucose readings by Glutest of samples from hemodialysis patients were affected by hematocrit and several factors, which were modified by hemodialysis. StatStrip is considered as a better device in dialysis hospitals.

OBJECTIVE The objective of this study was to evaluate the utility of brachial artery blood flow measurement in assessing the need for arteriovenous fistula (AVF) repair. METHODS In 236 hemodialysis patients, the relationships between the brachial artery blood flow measurement results and subsequent AVF repair and prognosis were investigated. RESULTS Mean brachial artery blood flow was significantly lower in patients requiring percutaneous transluminal angioplasty (PTA; treatment group, n = 161) than in patients followed without any treatment (no treatment group, n = 64; 250.3 mL/min versus 656.7 mL/min, p

The continuous increase in the number of people requiring dialysis is a major clinical and socioeconomical issue in Japan and other countries. This study was designed to encourage chronic kidney disease (CKD) patients to consult a physician, enhance cooperation between nephrologists and general practices, and prevent the progression of kidney disease. Subjects comprise CKD patients aged between 40 and 74 years consulting a general physician, and patients in CKD stage 3 with proteinuria and diabetes or hypertension. This trial is a stratified open cluster-randomized study with two intervention groups: group A (weak intervention) and group B (strong intervention). We have recruited 49 local medical associations (clusters) in 15 different prefectures, which were classified into four regions (strata) based on the level of increase rate of dialysis patients. The patients in group A clusters were instructed initially to undergo treatment in accordance with the current CKD treatment guide, whereas patients in group B clusters were not only instructed in the same fashion but also received support from an information technology (IT)-based system designed to help achieve the goals of CKD treatment, consultation support centers, and consultations by dietitians visiting the local general practice offices. We assessed the rates of continued consultation, collaboration between general practitioners and nephrologists, and progression of CKD (as expressed by CKD stage). Through this study, filling the evidence-practice gap by facilitating effective communication and supporting general physicians and nephrologists, we will establish a CKD care system and decrease the number of advanced-stage CKD patients.

長期型バスキュラーカテーテル（VC）の恒久的なバスキュラーアクセス（VA）に規定しない使用方法を検討した．対象症例は，全身状態不良な腎不全患者47例（男26例，女21例）で，急性腎不全（ARF）21症例，慢性腎不全（CRF）26症例（導入例16例，慢性透析患者10例）であった．平均年齢は66±14歳，平均血清アルブミン値（Alb）は2.37±0.54 g/dL，CRPは5.14±5.36 mg/dLであった．長期型VCの使用本数は48本で，留置部位は右内頸静脈44例，左内頸静脈3例，左鎖骨下静脈1例で，平均留置期間は49.5±56日であった．長期型VCの転帰は，内シャント（AVF）作製による抜去16例，死亡16例（悪性腫瘍関連死9例，敗血症7例），感染徴候による抜去5例，透析離脱4例，閉塞・脱血不良2例，継続2例などであった．AVF造設，死亡，透析離脱を除いた長期型VCの開存率は，挿入後30日で約80％，90日でも約60％あった．全身状態不良なARFおよびCRF症例に長期型VCを使用することで，平均7週間の安定した血液透析療法が施行できた．長期型VCは恒久的なVAとしての適応以外に，早期のAVF作製困難なCRF症例におけるbridging VAおよび短期間での透析離脱が難しいARF症例などのVAとしても有用と考えられた．

Citrullination preferentially proceeds in glomerular Bowman's capsule and increases in obstructive nephropathy. Background Peptidylarginine deiminases (PADs) are a group of posttranslational modification enzymes that citrullinate (deiminate) protein arginine residues, yielding citrulline residues. Citrullination of arginine residues abolishes their positive charge, markedly altering their structure. We undertook this study to investigate the actions of PADs in the kidney. Methods In male rats, we ligated the unilateral ureter, then analyzed the obstructed and contralateral kidneys 1 week later. Controls were rats simultaneously given sham operations. In another experiment, we ligated unilateral ureters of eight rats, four of which received a ureter-bladder anastomosis 1 week later. These rats were subjected to histologic examinations 5 weeks after unilateral ureteral obstruction (UUO). Results Reverse transcription-polymerase chain reaction (RT-PCR) revealed that, of PADs (type I, II, III, and IV), only PAD type II was expressed in kidneys. Western blot study showed that PAD type II expression and citrullinated protein content increased greatly in kidneys that underwent unilateral ureteral ligation compared to that in contralateral or sham-operated kidneys. Immunohistochemical analyses revealed that PAD type II was preferentially expressed by parietal epithelial cells and that only in Bowman's capsule were proteins citrullinated. Additionally, these PAD type II and citrullinated proteins in obstructed nephropathy were significantly attenuated by the release of the obstruction. Proteome analysis revealed that one of citrullinated proteins in the kidney should be actin. Conclusion This result indicates that PAD type II and citrullinated proteins are suitable markers of Bowman's capsule. Not only are these markers preferentially expressed in Bowman's capsules but their expression is also increased in damaged kidneys by UUO, features that promise the further clarification of kidney diseases.

We investigated the pathophysiological significance of the mature form of adrenomedullin (AM) in hemodialysis (HD) patients. Thirty-nine HD patients were enrolled and divided into two groups: those undergoing ultrafiltration (UF) during an HD session, group I; and those not undergoing UF, group II. We measured mature AM, atrial natriuretic peptide (ANP), endothelin-1, nitric oxide, cyclic guanosine 3',5'-monophosphate, and catecholamine levels at 1-hour intervals during HD sessions. On-line optical measurement of hematocrit was used to estimate change in blood volume during HD. In group II, blood volume did not change significantly during HD, nor did plasma mature AM concentrations estimated at the beginning and end of the HD treatment (3.0 +/- 0.3 and 2.8 +/- 0.2 fmol/mL, respectively). However, blood volume decreased significantly in group I patients (-7.3% +/- 0.6%), as did plasma mature AM concentrations (from 4.4 +/- 0.3 to 3.1 +/- 0.3 fmol/mL; P0.01). In contrast to mature AM, plasma ANP concentrations declined in both groups (from 193 +/- 32 to 87 +/- 14 pg/mL in group I and 67 +/- 12 to 46 +/- 8 pg/mL in group II). We conclude that mature AM is a useful marker to evaluate circulating blood volume in HD patients. Circulating blood volume may regulate the conversion of AM from the inactive to the mature form.

Mizoribine has been shown to possess an immunosuppressive action that inhibits the proliferation of lymphocytes selectively by interfering with inosine monophosphate dehydrogenase. Recent studies have demonstrated that mizoribine improves renal tubulointerstitial fibrosis in the rat model of unilateral ureteral obstruction (UUO) by inhibiting the infiltration of macrophages. We, therefore, examined the dose dependency of the suppressive effect of mizoribine on the infiltration of interstitial macrophages and T lymphocytes and the interstitial volume in UUO-treated kidneys. Furthermore, we investigated the expression of osteopontin (OPN), known to be a chemoattractant protein for macrophages, in the renal cortex. In rats with UUO, the interstitial volume was markedly expanded, and macrophage and T lymphocyte infiltration in the interstitium and the expression of OPN in the cortical tubules were greatly increased. Treatment with mizoribine ameliorated the increase in interstitial volume induced by UUO. Interstitial infiltration of macrophages and T lymphocytes was dose dependently suppressed by mizoribine, and the decreased macrophage infiltration was correlated with inhibition of tubular OPN expression. These results suggest that mizoribine has a beneficial effect on several steps contributing to the progression of tubulointerstitial fibrosis caused by obstruction of the ureter.

Adrenomedullin (AM) is a potent vasodilating peptide secreted from the vasculature of various organs. It is biologically active when its C-terminus is amidated. Recently, an RIA method was developed for measurement of the active form of AM, or mature AM. We here employed this method to investigate the significance of amidation of AM in controlling cardiovascular function. Thirty-six patients under hemodialysis were recruited and divided into hypertensive (n = 25; 157/86 mmHg) and normotensive (n= 11; 116/66 mmHg) groups. Mature AM, immature AM and blood pressure were monitored during hemodialysis in all patients. There was a significant reduction in blood pressure during hemodialysis in both groups, although after hemodialysis blood pressure was still higher in hypertensives than in normotensives (139 +/-14.8/76 +/- 2.5 mmHg vs. 110 +/- 5.1/66.7 +/- 3.1 mmHg). Mature AM before hemodialysis were lower in hypertensives than normotensives and it decreased in both groups. Although mature AM decreased more in normotensives than in hypertensives (-27 +/- 8% vs. -17 +/- 5%), at the end point, its level was still higher in normotensives. The ratio of mature AM/immature AM decreased only in normotensives (-11.4 8.7%), whereas it remained stable in hypertensives (0.2 +/- 5.6%). Both groups showed similar changes in ANP, endothelin, catecholamines, cGMP, and NOx. The low level in mature AM level in hypertensives may have contributed to the higher blood pressure in this group. The attenuation of AM amidation in normotensives indicates that an unspecified amidative enzyme of AM was regulated in order to normalize blood pressure.

Background. Patients with impaired renal function have been known to have elevated concentrations of serum pepsinogens, which are raised by Helicobacter pylori infection of the stomach. The present study was performed to examine the effect of H. pylori infection on serum pepsinogen concentrations in dialysis patients. Methods. Forty nine patients on dialysis and 48 subjects with no known kidney disease were examined for upper gastroduodenal endoscopy, H. pylori infection and serum concentrations of pepsinogen I and II. The status of H. pylori infection was evaluated from results of a urease test, histology and culture of biopsy specimens of the gastric mucosa. Serum pepsinogen levels were measured by radioimmunoassay. Results. Serum concentrations of pepsinogen I and II were elevated in the dialysis patients in comparison with those in the controls (277.4±24.2 vs 52.6±4.0 pg/ml, P

カリウム(K)は細胞膜電位の維持に関与するため筋肉の収縮・弛緩に関係し, Kの異常では神経,筋症状と心電図異常が問題となるが,重篤な心電図異常を呈する高K血症や低K血症では緊急の対処が必要である.一方,ナトリウム(Na)は血清浸透圧を規定する主要な電解質で, Naの異常では浸透圧の変化に対応して中枢神経細胞の容量調節機序が変化しており,特に低Na血症の急速な補正は橋中心性髄鞘壊死を引き起こすので注意が必要である.

⋄ Background In patients on continuous ambulatory peritoneal dialysis (CAPD), dialysate calcium concentration has a strong influence on correction of serum calcium, phosphorus, and parathyroid hormone (PTH); however, the optimal concentration of Ca in PD solution is still uncertain. The aim of the survey reported here was to evaluate the prevalence of patients treated with standard- [SCD (approximately 3.25 – 4.0 mEq/L)] or low-calcium [LCD (approximately 1.8 – 2.5 mEq/L)] dialysate and differences in the clinical effects for correction of abnormalities in divalent ions and PTH. ⋄ Materials and Methods We used a questionnaire to survey 333 peritoneal dialysis facilities nationwide in Japan. Then, we analyzed serum Ca, P, and PTH levels and the prescription rates for CaCO3 as a P binder and for vitamin D (VitD) analogs. ⋄ Results The 2384 CAPD patients enrolled in this analysis had a mean age of 60.5 ± 14.2 years and a mean duration of CAPD of 44.1 ± 39.2 months. The prevalences of SCD, LCD, and combination of SCD and LCD were, respectively, 49%, 50%, and 1% at initiation, and 40%, 38%, and 22% at the time of the survey. In 735 and 876 patients respectively, LCD and SCD had been prescribed from initiation to the time of the survey. In these two groups, we observed no difference in initiation and current serum levels of Ca and P. But prescription rates for CaCO3 and VitD analogs were higher in the LCD group than in the SCD group, and PTH levels were higher in the LCD group than in the SCD group. ⋄ Conclusions A beneficial effect of LCD was revealed in the increased doses of CaCO3 and VitD analogs seen in that group without the occurrence of hypercalcemia; however, PTH levels in that group were not maintained within an acceptable range. The survey suggests that more serious attention should be paid to the Ca concentration in peritoneal dialysate so as to lessen mineral and PTH disorders in CAPD.

The purpose of this study was to examine the effects of bacterial suporantigens, which can derange the immune response and contribute to the renal lesions of immunoglobulin A (lgA) nephropathy. Twenty-five micrograms of a bacterial superantigen, staphylococcal enterotoxin B (SEB), was injected into IgA nephropathy-prone ddY mice intrathymically when they reached 6 weeks of age. Evaluation included measurement of albumin excretion in urine, immunoglobulin concentration, and lymphokine production in vitro, as well as analysis of T-cell receptor expression in splenic T-cell subsets and examination of renal histology by light and fluorescence microscopy. At 40 weeks of age, the serum level of IgA in these mice was substantially increased and the number of Vβ8+ CD4+splenic T-cells was significantly decreased compared with measurements in untreated controls. Both control and SEB-treated mice excreted less than 30 μg/mL of urinary albumin. In mice given SEB, the amount of interleukin 2 (IL-2) and tumor necrosis factor-α (T helper 1 [Th1]-type cytokines) produced by the in vitro-stimulated lymphocytes significantly decreased. whereas that of interleukin 4 (IL-4) and interleukin 6 (IL-6) (Th2-type cytokines) markedly increased compared with measurements in control mice. At 40 weeks of age, mice given SEB showed marked glomerular hypercellularity and enhanced glomerular C3 deposition by renal histology, compared with control mice. These results suggest that bacterial superantigen SEB may modify glomerular lesions through activating Th2 cells, while inducing deletion of Th1 cells in this experimental model.

The efficacy and safety of combination therapy with amoxicillin, lansoprazole, and plaunotol for the eradication of Helicobacter pylori in patients on dialysis were evaluated. The study subjects comprised 15 dialysis patients in whom H pylori had been found in the gastric mucosa. The patients were given 500 mg amoxicillin once a day for 3 weeks, 30 mg lansoprazole once a day for 8 weeks, and 80 mg plaunotol three times a day for 24 weeks. Endoscopy was performed on entry and at 4 and 24 weeks after cessation of amoxicillin. The concentrations of serum gastrin and gastric juice ammonia also were measured. Fourteen patients completed the treatment protocol, one having dropped out because of nausea and diarrhea. H pylori was eradicated in 11 of the 14 patients 4 weeks after the end of amoxicillin therapy (eradication rate, 78.6%). All but one patient was free of H pylori 24 weeks after the amoxicillin was discontinued. Patients who became negative for H pylori had significantly decreased serum gastrin and gastric juice ammonia concentrations. Our findings indicate that a combination of amoxicillin, lansoprazole, and plaunotol can be used to eradicate H pylori in patients on dialysis.

高homocysteine血症は古くから動脈硬化の危険因子として注目されているが, 透析患者や保存期慢性腎不全患者においても高homocysteine血症の存在が指摘されている. そこで, CAPD患者16名, HD患者14名, および健常者15名を対象にmethionine負荷試験を施行し, 透析患者における高homocysteine血症の成因について検討した. 絶食12時間後にmethionine 0.05g/kgを経口投与し, 血漿総homocysteine濃度はfluoro-HPLC法で, その他の含硫アミノ酸濃度はninhydrin法で測定した. CAPD患者の血漿総homocysteine濃度は上昇, 血漿methionine濃度は低下, 血漿cystine濃度は上昇しており, HD患者にも同様の傾向が認められた. methionine負荷試験において, 透析患者ではmethionineが血中に停滞し, homocysteine, cystathionine, およびcystineが持続的に上昇することが観察され, 透析患者における共通した特有の含硫アミノ酸代謝異常の存在が示された. さらに, 血漿methionine濃度の低下と血漿cystine濃度の上昇を総合すると, 透析患者はhomocysteineからmethionineへの再メチル化反応が障害されていると推察され, 高homocysteine血症の成因になっている可能性が考えられた.

We assessed the expression profile of Mg2+-transporting molecules in obese diabetic rats as a cause of hypermagnesiuric hypomagnesemia, which is involved in the development of insulin resistance, hypertension, and coronary diseases. Kidneys were obtained from male Otsuka Long-Evans Tokushima fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) obese diabetic rats at the ages of 16, 24, and 34 wk. Expression profiles were studied by real-time PCR and immunohistochemistry together with measurements of urine Mg2+excretion. Urine Mg2+excretion was increased in 24-wk-old OLETF rats and hypomagnesemia was apparent in 34-wk-old OLETF rats but not in LETO rats (urine Mg2+excretion: 0.16 ± 0.01 μg·min−1·g body wt−1in 24-wk-old LETO rats and 0.28 ± 0.01 μg·min−1·g body wt−1in 24-wk-old OLETF rats). Gene expression of transient receptor potential (TRP)M6 was downregulated (85.5 ± 5.6% in 34-wk-old LETO rats and 63.0 ± 3.5% in 34-wk-old OLETF rats) concomitant with Na+-Cl−cotransporter downregulation, whereas the expression of claudin-16 in tight junctions of the thick ascending limb of Henle was not different. The results of the semiquantitative analysis of immunohistochemistry were consistent with these findings (TRPM6: 0.49 ± 0.04% in 16-wk-old LETO rats, 0.10 ± 0.01% in 16-wk-old OLETF rats, 0.52 ± 0.03% in 24-wk-old LETO rats, 0.10 ± 0.01% in 24-wk-old OLETF rats, 0.48 ± 0.02% in 34-wk-old LETO rats, and 0.12 ± 0.02% in 34-wk-old OLETF rats). Gene expression of fibrosis-related proinflammatory cytokines as well as histological changes showed that the hypermagnesiuria-related molecular changes and tubulointerstitial nephropathy developed independently. TRPM6, located principally in distal convoluted tubules, appears to be a susceptible molecule that causes hypermagnesiuric hypomagnesemia as a tubulointerstitial nephropathy-independent altered tubular function in diabetic nephropathy.

Background/Aims: This multicenter, prospective, observational study assessed the renoprotective effects of losartan/thiazide combination therapy in terms of lowering the estimated glomerular filtration rate (eGFR). Methods: Adult patients with angiotensin receptor blocker (ARB)-resistant essential hypertension (n = 104) were enrolled and switched to combination therapy with losartan (50 mg/day) and hydrochlorothiazide (12.5 mg/day). Results: eGFR values declined significantly during the first 3 months, and changes in eGFR were assessed according to tertiles of the eGFR decrease ratio at 3 months. Only the high eGFR decrease (1st tertile) group showed significantly greater decreases in baseline eGFR and albumin-to-creatinine ratio (ACR) during the first 3 months. Additionally, the assessment according to tertiles of the baseline eGFR showed a signifcant decrease in eGFR and ACR during the first 3 months in the high baseline eGFR (1st tertile) group, but not in the moderate (2nd tertile) and low baseline eGFR (3rd tertile) groups. Conclusion: The present results revealed that losartan/thiazide combination therapy attenuated glomerular overload, indicating that this therapy may provide glomerular protection in patients with an elevated GFR without causing prolonged damage to renal function.

Collagenofibrotic glomerulonephropathy is a recently recognized disease entity. Although an autosomal recessive inheritance pattern has been suggested for this condition, there are few reports of familial cases. Only four pairs of child siblings, with histological confirmation of the glomerular lesions, have been reported. The current report describes a family including two sisters with histological evidence of collagenofibrotic glomerulonephropathy. Serum concentrations of the procollagen III peptide were elevated in the affected sisters, whereas their parents and other siblings demonstrated neither proteinuria nor increased blood levels of the procollagen III peptide. Our findings support an autosomal recessive pattern of inheritance for this type of glomerulonephropathy. They also suggest that the serum concentration of the procollagen III peptide is a useful marker for collagenofibrotic glomerulonephropathy.

透析患者の含硫アミノ酸代謝を検討する目的で, CAPD患者36名 (48.0±12.3歳), HD患者14名 (54.9±16.4歳), および健常者20名 (40.7±14.5歳) を対象とし, methionine (Met), cystine, homocysteine (Hcy), ビタミンB6, B12, および葉酸の空腹時血中濃度を測定した. 血漿総Hcy濃度はdithioerythritol還元処理と蛍光誘導体化を組み合わせたHPLC法で測定した. 血漿総Hcy濃度 (μmol/l) は, CAPD患者が38.2±37.2, HD患者が27.3±10.2, 健常者が19.0±14.9で, CAPDとHD患者は有意に上昇していた. 健常者では血漿総Hcy濃度と血中葉酸濃度に有意な負の相関を認めたことから, HcyからMetへの再メチル化反応が血漿総Hcy濃度を規定すると考えられた. しかし, CAPDとHD患者ではこの相関関係が認められず, 透析患者では血漿総Hcy濃度は他の要因からも規定されていると思われた. さらに, CAPD患者の中から12名を抽出して血漿総Hcy濃度と動脈硬化スコアとの関連を検討したところ, 両者には有意な相関関係が認められた. 従って, 透析患者においても高Hcy血症は動脈硬化の危険因子になっていると考えられた.

SUMMARY Although prostaglandins have been shown to inhibit the evolution of the nephritis in NZB/W mice, the mechanisms of this effect are unknown. To characterize such inhibition, we injected the prostacyclin (PGI2) analogue, beraprost, into NZB/W mice, using 0·5mg, 1·0mg or 5·0mg beraprost/kg body weight of test animals three times in 1 week when the mice were 2 months old. Evaluation included measurement of urine albumin excretion, serological parameters and splenic T cell subset, as well as examination of renal histology by light and fluorescence microscopy. Mice given beraprost showed a marked decrease in urine albumin excretion and in glomerular hypercellularity compared with untreated controls. Maximal beneficial effects occurred when the dose was 5·0mg/kg of beraprost. These effects correlated with a reduction of immune complex deposition in glomeruli. In addition, beraprost reduced serum levels of immunoglobulins and anti-double-stranded DNA antibodies, and decreased the number of helper (L3T4+) T cells in splenocytes. These results indicate that beraprost attenuates the nephritis of NZB/W mice, and that the source of this effect is the reduced production of autoantibodies and deposition of immune complexes in glomeruli.

Helicobacter pyloriは上部消化管粘膜病変の病因に重要な役割を果たしていると考えられている. Helicobacter pyloriが検出された維持血液透析患者の難治性胃潰瘍におけるHelicobacter pyloriの除菌を試み, その結果潰瘍が治癒した症例を経験したので報告する.症例は45歳, 男性で1990年9月より維持血液透析 (HD) を開始し, 1992年8月に胃潰瘍を合併した. 潰瘍はomeprazoleやranitidineの投与によりH2 Stageまで改善したが, 再びH1 stageに増悪した. このとき施行した胃粘膜生検組織の培養によりHelicobacter pyloriが検出された. Helicobacter pyloriの除菌を目的にamoxicillin (750mg, 毎透析終了時内服) を投与したところHelicobacter pyloriは消失し, 潰瘍も治癒した. 18か月後の内視鏡検査でも潰瘍の再発はなくHelicobacter pyloriも検出されていない.

We report on a case of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with lupus erythematosus in the central nervous system (CNS). A 73-year-old woman with essential hypertension suddenly demonstrated consciousness disturbance. Upon her admission, laboratory data showed significant hyponatremia (114 mEq/L) and a lack of body fluid loss. Diminished free water excretion (urine osmolality 684 mOsm/kg) and normal urine Na excretion (FENa 1.70 %) were consistent with the diagnosis of SIADH, which was confirmed by an inappropriately high concentration of plasma antidiuretic hormone (ADH) (15.3 pg/mL at 256 mOsm/kg of plasma osmolality). The hyponatremia was corrected by a combination of oral water intake restriction and saline infusion with furosemide administration until the 20th hospital day. Simultaneously, the presence of exudative pleural effusion in both chest cavities, suggesting the existence of pleuritis, and high titer of anti-nuclear antibody (ANA, 5120×) and anti-double-strand DNA antibody (6500 IU/mL), indicated the subclinical development of systemic lupus erythematosus (SLE), although the diagnostic criteria were not satisfied at that time. On the 34th hospital day, the sudden onset of unknown consciousness disturbance confirmed the diagnosis of SLE as CNS lupus. In previous case reports on SLE and/or SIADH, a few cases in which SLE and SIADH developed concomitantly regularly showed high immunological activities, as in our case. Some common pathophysiological bases might be involved in the concomitant appearance of those disorders.

Background/Aims: Pioglitazone (PGZ), one of the thiazolidinediones, has been known to show renoprotective effects. In this study, we focused on the effect of PGZ on glomerular hyperfiltration (GHF), resultant glomerular injury and altered macula densa signaling as a cause of sustained GHF through modified tubuloglomerular feedback in rats with diabetic nephropathy. Methods: Kidneys from 24-week-old male OLETF rats and LET rats, nondiabetic controls, were used for the experiment. PGZ was administered (10 mg/kg/day, p.o.) for 2 weeks from 22 to 24 weeks of age in some of the OLETF rats (OLETF+PGZ). Results: Parameters relating GHF, kidney weight, creatinine clearance, urine albumin/creatinine ratio and glomerular surface were all increased in OLETF rats and partially restored in OLETF+PGZ rats. Expressions of desmin and TGF-β were also increased in OLETF rats and restored in OLETF+PGZ rats. The changes in TGF-β expression were confirmed to be independent of podocyte number. Finally, the immunoreactivity of neuronal nitric oxide synthase (nNOS) and cyclooxygenase 2 (COX-2) in the macula densa was assessed for the evaluation of macula densa signaling. Altered intensities of nNOS and COX-2 in OLETF rats were restored in OLETF+PGZ rats, which agreed with the gene expression analysis (nNOS: 100.2 ± 2.9% in LET, 64.2 ± 2.7% in OLETF, 87.4 ± 12.1% in OLETF+PGZ; COX-2: 100.8 ± 7.4% in LET, 249.2 ± 19.4% in OLETF, 179.9 ± 13.5% in OLETF+PGZ; n = 5) and the semiquantitative analysis of nNOS/COX-2-positive cells. Conclusion: PGZ effectively attenuated the GHF and hyperfiltration-associated glomerular injury in diabetic nephropathy. The restoration of altered macula densa signaling might be involved in the renoprotective effect of PGZ.

Background and aims Subcutaneous aseptic abscess is one phenotype of neutrophilic dermatitis. We were interested to see if a case of steroid refractory Crohn's disease (CD) complicated by subcutaneous aseptic neutrophilic abscesses responds to intensive granulocyte/monocyte adsorptive apheresis (GMA). Methods The patient was a 21-year-old male with worsening severe CD while on oral prednisolone (30 mg/day). His symptoms included fever, bloody diarrhoea and multiple painful subcutaneous nodules throughout his body. Skin biopsy showed chronic panniculitis with neutrophilic infiltrates. Further, colonoscopy showed oedematous sigmoid colon, while colonic biopsy showed non-caseous granuloma. Because biologics were feared to increase the risk of bacteraemia as the result of germ culture on his pus was not known at the time, we decided to treat this case with GMA. Five GMA sessions with the Adacolumn over 5 consecutive days (daily GMA) were initiated. Results On admission, his CD activity index (CDAI) was 355, C-reactive protein (CRP) 11.2 mg/dL. After 5 GMA sessions, CDAI decreased to 170, and CRP fell to 5.0 mg/dL, with no fever. GMA was restarted at 2 sessions/week (total 10 sessions). The patient's CDAI fell to Conclusions In this CD case complicated by subcutaneous aseptic neutrophilic abscesses, GMA appeared to be effective. Our impression is that when biopsy reveals neutrophil infiltrate is a major feature of the lesions, GMA should be considered. As GMA appears to have no safety concerns, a frequent GMA protocol, like daily followed by 2 to 3 times/week should be preferred over the routine weekly GMA.

The aim of this study is to examine the transcriptional regulation of matrix metalloproteinase transin in glomerular mesangial cells responding to inflammatory cytokines and heparin. Northern blot analysis revealed that IL-1 beta preferentially induced transin mRNA. The stimulatory effect was not specific to transin, and upregulation of procollagen alpha 1(IV), laminin B2 and tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNAs was also observed. After IL-1 stimulation, expression of the transin transcript increased progressively for up to 48 hours, differing from the limited induction of procollagen alpha 1(IV) or TIMP-1. When mesangial cells were stimulated by IL-1 beta in the presence of heparin, transin expression was markedly suppressed in a dose-dependent manner. The inhibitory effect of heparin was specific to transin, and induction of procollagen alpha 1(IV), laminin B2 or TIMP-1 by IL-1 beta was not affected. These findings revealed the selective counter regulation by IL-1 beta and heparin of the transin expression in mesangial cells.

Ly-49 can be expressed in interspecies hybridoma cells resulting from the fusion of Ly-49 negative lymphoid cells from normal mice and Ly-49 negative T cells from the rat thymoma W/ Fu(C58NT)D (C58). Several hundred hybridoma clones of this type were studied. Hybridoma clones derived from the fusion between activated C57BL/6 mouse spleen cells and C58 expressed Ly-49 on their surface although Ly-49 was undetectable on both parental cells. No Ly-49 antigen was expressed on hybrids when BW5147, a T lymphoma derived from AKR mouse, replaced C58 as parental cell. Thymocytes from C57BL/6 mice also produced Ly-49 positive interspecies hybridomas with C58. Subsequent manipulation of these thymocytes with a mixture of anti-CD4 and anti-CD8 antibodies plus complement to obtain double negative cells (CD4-/CD8-) prior to the fusion abolished the expression of Ly-49 on hybridomas. On the other hand, if the thymocytes were treated with either anti-CD4 or anti-CD8 antibody plus complement, the resultant thymocytes which were a mixture of cells with a single positive (CD4+/CD8- or CD4-/CD8+) and a double negative phenotype (CD4-/CD8-) retained the ability to produce Ly-49 positive hybridomas. Interspecies hybridomas between either CD4+/CD8- or CD4-/CD8+ functional T cell clones and C58 expressed Ly-49 on their surface, though these parental T cells lacked Ly-49 on their surfaces. Northern hybridization analysis using Ly-49 cDNA revealed that C58 cells do not express Ly-49 mRNA, indicating that a trans-acting factor(s) from C58 plays an important role in the induction of cell surface Ly-49 expression on interspecies hybridomas. Our data indicate the complex nature of the regulatory mechanisms for expression of the Ly-49 molecule.

This report describes a case of light chain deposition disease (LCDD) with unusual findings of fibrillar structures in the deposits and marked calcification in several organs. A forty-year-old man was initially diagnosed with LCDD in 1987, and died of sepsis three and one-half-years later. Histological examination of autopsy specimens demonstrated eosinophilic amorphous materials, which differed from amyloid, in vessel walls or around parenchymal cells in almost every organ examined. Ultrastructurally, in addition to granular deposits, fibrillar structures were also seen in the deposits. Marked calcification was present in the myocardium, skeletal muscles, adrenal glands and arteries.

症例は69歳の男性で慢性腎不全のため1986年, CAPDに導入した. 腹膜透析液はBaxter社製ダイアニールを1日4回の交換としていたが, 血清Mg濃度が高値となったためMg濃度が低いダイアニールPD2に変更した. 特記すべき合併症もなく良好に経過したが, 1988年6月に初めて大動脈弁無冠尖の石灰化を指摘された. 定期的心エコー検査で経過観察していたが, 弁石灰化は急速に進行し, 1991年7月の心エコーでは左冠尖・無冠尖の石灰化が著しく, 弁口面積は0.68cm2と狭小化し重症大動脈弁狭窄症 (AS) と診断された. 待機手術を予定していたが突然死した. 剖検で大動脈弁の3尖全体にわたる石灰化を認め, aortic calclfic stenosis (ACS) と診断された. 経過中PTH値, Ca×P積, 血清脂質濃度, 血清Mg値と石灰化の進行時期は一致しなかった. しかし腹膜透析液を乳酸濃度の高いPD2に変更後, 血漿重炭酸濃度は23-27mEq/lと高値が持続した. アルカローシスが組織への石灰沈着を促進するという報告があり, 大動脈弁石灰化が急速に進行した原因となっている可能性が示唆された.

糸球体疾患に起因する急性腎不全の原因として,急速進行性糸球体腎炎症候群がある.この症候群には種々の疾患が含まれるが,半月体形成性腎炎の頻度が高い.半月体形成性腎炎の診断は,最終的には腎生検が必要だが,抗GBM抗体,抗白血球細胞質抗体(ANCA)などの血清診断を用いることで早期診断が可能になってきた.