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Objectives: Our aim was to clarify the impact of the nature of the capillary wall, defined by the contribution of large (LP), small (SP), and ultrasmall (UP) pores, on plasma refilling in a hemodialysis session. Methods: This study included data from 78 patients. The relative blood volume change (ΔBV%) was monitored using a Crit-Line monitor. A bioimpedance device was used to measure extracellular and intracellular fluid volumes, and the excess fluid mass (MExF) was calculated. We simulated blood volume change (sΔBV%) based on a three-pore model. Hydraulic permeability of the capillary wall (LpS) and fractional contribution of LP to LpS (αLP) were determined by fitting sΔBV to ΔBV. The total refilling volume (TVref) was calculated from the total ultrafiltration volume and total blood volume change. Values were standardized to a body surface area of 1.73 m2 and are denoted by the subscript BSA. Results: LpS and αLP were 3.09 (2.32, 4.68) mL/mmHg/min and 0.069 (0.023, 0.109), respectively. The standardized regression coefficient (β) of the ultrafiltration rate (UFRBSA) and initial excess fluid mass (MExF,BSA,0) by multiple linear regression analysis of TVref,BSA without (Model 1) and with (Model 2) αLP were as follows: UFRBSA, 0.714/ExF,BSA,0, 0.247/BSA, 0.799/ExF,BSA,0, 0.066/0.237; and αLP, −0.327/Conclusions: The impact of volume overload (MExF,BSA,0) on plasma refilling became insignificant with the addition of αLP in the model, suggesting that the nature of the capillary wall described by inter-endothelial gaps (LP) may have a greater impact on plasma refilling than volume overload.

Our aim is to clarify the association of the bioelectrical impedance-derived 50-kHz phase angle (φ50 ) with electrical parameters regarding the Cole-Cole model and clinical parameters. A total of 440 sets of bioelectrical impedance data from pre- and post-hemodialysis from 157 patients were used. Resistance at infinite frequency (Rinf ), resistance at 0 frequency (R0 ), capacitance of the cell membrane (Cm), and a parameter for the distribution of the time constant (α) were examined as electrical parameters. Normally hydrated lean tissue mass as a percentage of the dry weight (PNHLT ), excess fluid mass as a percentage of the dry weight (PExF ), body mass index (BMI), age, and sex (Nsex , 0 for male, 1 for female) were examined as clinical parameters. φ50 increased with the decrease in Rinf /R0 and α and also with the increase in Cm (multiple regression coefficients [β]: pre/post, -0.886/-0.936, -0.175/-0.212, and 0.167/0.141), which determined the ratio of intra- to extracellular fluid volume (ICV/ECV), tissue homogeneity, and total cell mass. φ50 increased with an increase in PNHLT and BMI and decrease in PExF , Nsex , and age (β: pre/post, 0.654/0.581, 0.466/0.412, -0.483/-0.473, -0.216/-0.154, and -0.145/-0.127). The concordance correlation coefficient between φ50 for pre- and post-hemodialysis (ρ = 0.772) may be improved (ρ = 0.950) by adding a multiplication of 0.2 and PExF to φ50 for correction. φ50 may be used to estimate body composition through the association with ICV/ECV, tissue homogeneity, and total cell mass. The correction for excess fluid is essential in order to use φ50 as a marker of body composition related to nutrition.

Background MLT-550N is a device to measure the body fluid volume based on bioimpedance spectroscopy. When extracellular water (ECW) or total body water (TBW) is measured with MLT-550N before and after hemodialysis, the change in ECW (ΔECW) or TBW (ΔTBW) is markedly larger than the change in body weight (ΔW). Good agreements between ΔECW and ΔTBW calculated by Moissl equations with ΔW were reported. The aim of this study was to develop novel equations to calculate the body fluid volume by modifying Moissl equations. Methods A total of 466 measurements of 351 hemodialysis patients were used to develop the novel equations. The equations were based on the agreement between ΔECW and ΔW as a guide. The volume of intracellular water was postulated to be constant during hemodialysis. For evaluation of the equations, 5485 measurements of 627 patients were used. Agreements between values of two groups were assessed with Lin’s concordance correlation coefficients. The normal edema ratio (ER = ECW/TBW) corrected with the fat ratio (fcER) according to the parameters of normally hydrated lean and adipose tissues was used as the reference for normal hydration. The fluid status at dry weight was considered to be close to normal. The absolute values of the deviated ratio of actual ER (aER) from fcER (dER = (aER−fcER)/fcER) were compared. In this study, 1 L of body water corresponded to 1.02 kg of body fluid according to a previous report. Results The concordance correlations between ΔW and 1.02∙ΔECW or 1.02∙ΔTBW with the novel equations were higher than with the MLT method or Moissl equations (0.896, 0.596 vs. 0.411, 0.375 or 0.813, 0.411, respectively). The median value of dER with the novel equations was the lowest (0.062) compared with those of the MLT method and Moissl equations (0.164 and 0.144) (p

We have reported a significant correlation between hydraulic permeability of microvasculature adjusted with ultrafiltration rate (AdjLpst) and excess fluid divided by dry weight (ExF/DW) in a cross-sectional study of hemodialysis patients. We aimed to study longitudinally whether a similar relationship between them exists in each patient. Twelve hemodialysis (HD) patients in whom AdjLpst and ExF/DW had been measured more than four times (total of 85 measurements) were enrolled. AdjLpst was calculated by monitoring blood volume during HD. ExF was calculated from the fluid volume measured via bioimpedance spectroscopy. The borders of overhydration were 1.66 mL/mm Hg per min for AdjLpst and a positive value for ExF/DW. There was a significant correlation between AdjLpst and ExF/DW (r = 0.517). When the 85 measurements were classified into four quadrants according to ExF/DW and AdjLpst, the evaluations of fluid status agreed in 66 measurements. In six patients, significant positive correlations were found. In nine patients, equal to or more than 80.0% of evaluations by AdjLpst and those by ExF/DW agreed. In only one patient was there neither significant correlation nor agreement. AdjLpst of two patients suffering from chronic heart failure and microscopic polyangiitis was reduced compared with that of others loaded with the same extent of excess fluid. We concluded that there was a significant correlation between AdjLpst and ExF/DW and high agreement between evaluation by AdjLpst and evaluation by ExF/DW in the majority of patients. However, the relationship between them was patient-specific to some extent.

Purpose Bioimpedance spectroscopy (BIS) is widely used to assess fluid status in hemodialysis (HD) patients. Our purpose is to evaluate filtration coefficients (Lpst) as an alternative test to assess fluid status by utilizing BIS as a reference test. Methods 106 HD patients (determined group) were divided into two groups with (EX group: 53) or without excess fluid mass (ExF). ExF calculated from extracellular water and intracellular water measured by BIS. Multiple linear regression equation of Lpst was made using ExF (ExF/DW) and ultrafiltration rate (UFR/DW) to adjust Lpst (AdjLpst). The cut-off values of the tests for detection of EX were determined by receiver-operator characteristic curve analysis. Lpst, AdjLpst, serum atrial natriuretic peptide concentration (ANP), ultrasonically measured inferior vena cava diameter (IVCe/BSA), and blood volume change (ΔBV/TUF/DW) were examined. The detection abilities of these tests were evaluated in the distinct 61 patients (evaluated group). Results Patients of the EX group numbered 29 in the evaluated group. The correlation between AdjLpst and ExF/DW was the highest. The sensitivity of AdjLpst and specificity of Lpst were the highest. The specificity of AdjLpst was equivalent to that of Lpst. Unadjusted and adjusted odds ratios of AdjLpst were the higher (20.80, 95% CI, 5.61-77.10, 16.06, 95% CI 4.00-64.59, respectively) than those of the other tests. Conclusions AdjLpst can detect patients of the EX group more accurately than other tests. Because AdjLpst is related to plasma refilling, it may indicate removable fluid overload. AdjLpst in conjunction with BIS may contribute to more adequate fluid management.

Rapid amelioration of hypercholesterolemia in nephrotic syndrome (NS) using low density lipoprotein-apheresis (LDL-A) sometimes leads to NS remission, along with improvement of impaired biodefense system; however, the mechanism of how LDL-A affects NS is still unknown. We studied IFN-γ production under IL-12 stimulation for 24 h in whole blood from 30 NS patients, 31 non-NS patients, 35 healthy volunteers and another four persistent NS patients due to refractory focal segmental glomerulonephritis and minimal change type nephrotic syndrome. We compared IFN-γ production in whole blood and peripheral blood mononuclear cells (PBMC) from persistent NS patients before and after each of 14 LDL-A procedures. Finally, we studied the effect that persistent NS patients' serum before and after LDL-A had on IFN-γ production in healthy volunteers' PBMC. Whole blood IFN-γ production was significantly lower in NS patients compared with healthy volunteers or non-NS patients. In persistent NS, after LDL-A, IFN-γ production returned to normal levels. IFN-γ production in PBMC varied greatly among these patients and did not show consistent changes after LDL-A. Healthy volunteers PBMC incubated with persistent NS patients' serum obtained after LDLA showed higher IFN-γ production than before LDL-A. IFN-γ production in peripheral blood is impaired if a patient is in a nephrotic state. LDL-A might restore suppressed PBMC function in persistent NS patients, thereby ameliorating the nephrotic state, possibly through removing interfering serum factors.

シャントなどのバスキュラーアクセスが確立していない患者に対して血液浄化療法が必要になった場合，ダブルルーメンカテーテルを中心静脈に留置して治療を開始することが一般的であるが，この方法は血流感染症・血栓形成など重篤な合併症のリスクを伴う．われわれは各種血液浄化法が必要となった症例に対し，バスキュラーアクセスが確立されるか血液浄化療法を離脱するかいずれの状況まで血液浄化のたびに超音波ガイド下で大腿静脈に透析針を挿入することで，ダブルルーメンカテーテルを使用することなく血液浄化を施行した．2008年6月から2011年8月まで当院で超音波ガイド下大腿静脈反復穿刺法にて血液浄化法を施行した16例を対象とした．基礎疾患は慢性腎不全が9例（糖尿病性腎症5例，腎硬化症2例，慢性糸球体腎炎1例，原因不明1例），膠原病が3例，ネフローゼ症候群が2例（微小変化群1例，原因不明1例），急性腎不全とM蛋白血症に伴う多発ニューロパチーが各1例であった．ステロイド・免疫抑制剤を投与中の患者は16例中6例であった．血液浄化法の内訳は血液透析が11例，二重濾過血漿交換・単純血漿交換併用が1例，二重濾過血漿交換単独が2例，ECUMが1例とLDL吸着が各1例であった．16ゲージの透析用長針を用い，穿刺に際して穿刺針に生じる音響陰影に着目し，積極的に超音波プローブを走査することで針先位置を特定した．大腿静脈は脱血側とし，返血側は四肢の皮静脈に通常の方法で穿刺した．16例に対し総計156回（1～48回，平均9.8回），本法による血液浄化を施行したが，新たな血流感染症や血腫形成は認めなかった．大腿動脈には分枝が多く解剖学的知識や触診に基づいた大腿静脈反復穿刺法では一定の確率で動脈性出血を起こしうるが，本法により安全・確実な血液浄化療法が施行可能であった．ダブルルーメンカテーテルの留置を避けたい場合に本法は一時的バスキュラーアクセスとして有用と思われた．

動脈を表在化した血液透析患者の返血用皮静脈が荒廃して穿刺困難になると，グラフトへ変更することが一般的であるが，その後グラフト感染による敗血症が疑われるような場合は，ダブルルーメンカテーテルの留置は感染治療において不利と考えられる．グラフト感染による敗血症を契機にバスキュラーアクセス不全に陥った2症例に対し，リアルタイムエコーガイド下に上腕の皮下深い位置にあるbrachial vein（上腕静脈）を反復穿刺して返血路とすることで，感染が沈静化するまでダブルルーメンカテーテル留置を避けることが可能であった．穿刺は当科の医師3名のいずれかが行い，リニアプローブ付きポータブル超音波装置（iLook25，ソノサイト社）を用いた．その際，(1) 術者はあらかじめ当科で自作したシミュレータで訓練を行った上で，(2) 穿刺前に上腕静脈の走行と上腕動脈・神経との位置関係をエコーにより十分観察し，(3) 穿刺時に血管短軸横断像を描出し，血管穿刺針とエコービームを直交させ，針の輝度を向上させることで皮下における正確な針先位置を同定し，(4) 血管内に針先が到達後もプローブと穿刺針を交互に僅かに進める操作を繰り返し，血管壁損傷を避けつつ，透析針外筒先端が血管内に十分入るように留置した．その結果，2症例合わせて計51回上腕静脈穿刺を行い，透析針外筒留置成功率100％，動脈誤穿刺0％，神経損傷0％であり，重篤な合併症を認めなかった．結論：返血用皮静脈が荒廃した上腕動脈表在化患者等でも上腕静脈は温存されていることが多く，新たなバスキュラーアクセス確立までの間の一時的アクセスとして，エコーガイド下で反復穿刺し返血路として使用することが可能である．特に，すでに感染症を合併している場合にはダブルルーメンカテーテルを留置するよりも感染治療上有利と考える．

We report on three patients with postrenal acute kidney injury (AKI) showing a remarkably low level of cystatin C (CysC) compared with that of creatinine (Cr). The levels of Cr and CysC (Cr/CysC) were respectively as follows: 12.16 mg/dl/1.26 mg/l, 17.92 mg/dl/0.95 mg/l and 18.94 mg/dl/0.55 mg/l. The causes of urinary tract obstruction were benign prostatic hypertrophy, urinary bladder carcinoma and urethral stenosis due to radiation therapy for bladder carcinoma. Renal function was promptly recovered after relief of the obstruction. It is considered that the discrepancy strongly indicated AKI because of urinary tract obstruction and encouraged relief of the obstruction in order to recover renal function. Although the precise mechanism for the discrepancy was not determined, the maintenance of glomerular filtration and proximal tubular reabsorption of CysC long after the cessation of Cr excretion because of urinary tract obstruction seemed to be involved. This finding may be beneficial for the diagnosis and reversal of postrenal AKI and provides new insight into the process of postrenal AKI.

We have reported a significant correlation between hydraulic permeability of microvasculature adjusted with ultrafiltration rate (AdjLpst) and excess fluid divided by dry weight (ExF/DW) in a cross-sectional study of hemodialysis patients. We aimed to study longitudinally whether a similar relationship between them exists in each patient. Twelve hemodialysis (HD) patients in whom AdjLpst and ExF/DW had been measured more than four times (total of 85 measurements) were enrolled. AdjLpst was calculated by monitoring blood volume during HD. ExF was calculated from the fluid volume measured via bioimpedance spectroscopy. The borders of overhydration were 1.66 mL/mm Hg per min for AdjLpst and a positive value for ExF/DW. There was a significant correlation between AdjLpst and ExF/DW (r = 0.517). When the 85 measurements were classified into four quadrants according to ExF/DW and AdjLpst, the evaluations of fluid status agreed in 66 measurements. In six patients, significant positive correlations were found. In nine patients, equal to or more than 80.0% of evaluations by AdjLpst and those by ExF/DW agreed. In only one patient was there neither significant correlation nor agreement. AdjLpst of two patients suffering from chronic heart failure and microscopic polyangiitis was reduced compared with that of others loaded with the same extent of excess fluid. We concluded that there was a significant correlation between AdjLpst and ExF/DW and high agreement between evaluation by AdjLpst and evaluation by ExF/DW in the majority of patients. However, the relationship between them was patient-specific to some extent.

Purpose Phosphorus removal is a major issue to assess for physicians engaging in hemodialysis. A pseudo-one-compartment model was reported as a novel model for phosphorus kinetics. We aimed to evaluate the adequacy of this model from the standpoint of the total mass of removed phosphorus during prolonged treatment. Methods Dialysate was collected during 6-h hemodialysis and hemodiafiltration treatment in 5 patients. Later-phase (from 4 to 6 h) dialysate was collected separately. Mobilization clearance (Km and dialyzer clearance (K) were calculated by simple arithmetic operations utilizing stable serum phosphorus concentrations in this later phase. Volume of the accessible compartment (V0) was estimated by a fitting method. Amounts of removed phosphorus were calculated with these parameters and compared with measured values. The best sampling time points during treatment were also assessed, when the parameters were determined by serial serum phosphorus concentrations alone. Results Pearson's correlation coefficient (R) between calculated and measured values of removed phosphorus was 0.991 and the concordance correlation coefficient (ρ) was 0.987. When Km, K and V0 were determined by serial serum concentrations alone, including those at 0, 1, 4, and 6 h, the calculated mass of removed phosphorus had high R (0.974–0.975) or ρ (0.966–0.972) with the measured values. Conclusions We confirmed that a pseudo-one-compartment model is useful for the estimation of removed phosphorus mass during prolonged blood purification by collecting dialysate. When the parameters are determined by a fitting method using serial serum concentrations alone, sampling at 0, 1, 4, and 6 h seems to be adequate.

Background/Aims: Assessing the volume status of hemodialysis (HD) patients and determining their adequate dry weight (DW) present great challenges for physicians involved in HD. In this study the relationship between standardized filtration coefficients of microvasculature (Lpst) and the plasma atrial natriuretic peptide (ANP) levels or echocardiographic measurements (UCGm) were clarified. The aim of this study was to evaluate the possibility of utilizing Lpst as one of the tools for assessing volume status of patients undergoing HD. Methods: 52 patients on maintenance HD were examined. Lpst was calculated by utilizing continuous measurements of blood volume during HD by means of monitoring changes of hematocrit with CRIT-LINETM. Plasma ANP levels were measured shortly after HD. Plasma ANP levels were elevated beyond the normal limit in 32 patients (Hi group) and were within the normal range in the remaining 20 patients (Lo group). UCGm were performed within 1 month prior to the study. Inferior vena cava diameters in quiet expiration (IVCe) were dilated in 21 patients (Hivc group) and were within the normal range in the remaining 31 patients (Livc group). Lpst was compared with plasma ANP level and UCGm. Results: Lpst in Lo group were significantly lower than those in the Hi group (0.83 ± 0.19 vs. 2.64 ± 2.73 ml/mm Hg/min; p < 0.001). Lpst correlated significantly with plasma ANP levels (r = 0.613; p < 0.001). Lpst in the Livc group were significantly lower than those in the Hivc group (1.33± 1.61 vs. 2.85 ± 2.88 ml/mm Hg/min; p < 0.001). Lpst also correlated with IVCe (r = 0.630; p < 0.001). The receiver operating characteristic (ROC) curves for high plasma ANP level and for dilated IVCe were significant for Lpst. Area under the ROC curve for elevated ANP was 0.909 (95% confidence interval (CI) 0.834–0.985) and for dilated IVCe was 0.833 (95% CI 0.724–0.941). Conclusion: We conclude that there exists a significant association between Lpst and plasma ANP levels at the end of a dialysis session. There is a possibility that high plasma ANP levels cause elevation of Lpst. Besides ANP, Lpst significantly correlated with IVCe. These results suggested that Lpst can be utilized as one of the tools for assessing volume status of patients undergoing HD.

Background. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been demonstrated to suppress glomerular injuries in various renal diseases. However, it is not fully clear whether HMG-CoA reductase inhibitors directly regulate matrix protein accumulation in mesangial cells. Methods. We investigated the effect of simvastatin (SIM), an HMG-CoA reductase inhibitor, on DNA synthesis in cultured murine mesangial cells stimulated by fetal calf serum (FCS). We then determined whether SIM affected the expression of regulatory factors of cell growth and matrix protein accumulation, using Northern analysis. Results. SIM dose-dependently inhibited FCS-induced DNA synthesis after 24 h of incubation. SIM treatment for 24 h suppressed the mRNA expression of platelet-derived growth factor (PDGF)-B chain, PDGF receptor β-subunit and c-myc, while the expression of transforming growth factor β (TGF-β) was not affected. Concerning matrix protein synthesis, the mRNA expression of type IV collagen was suppressed, whereas that of type III collagen was markedly upregulated. As for matrix turnover proteins, SIM had a markedly suppressive effect on the mRNA expression of plasminogen activator inhibitor-1 (PAI-1), with a constant expression of tissue-type plasminogen activator (tPA). Conclusions. These results indicate that SIM may sup-press mesangial cell proliferation in part through the downregulation of PDGF, PDGF-receptor, and c-myc mRNA expressions. In addition, the suppression of the synthesis of collagen IV and PAI-1 appears to be a direct inhibitory effect of SIM on glomerular matrix accumulation.

Within a 3-year period after the Great Earthquake of Kobe (Japan) resulted in more than 6,000 deaths and complete destruction of the central area of Kobe City, 14 patients (group 1 [G1]) with myeloperoxidase (MPO)-antineutrophil cytoplasmic autoantibody (ANCA)-related angitis and/or nephritis presented to Nishi-Kobe Medical Center in western Kobe City. On the other hand, only 15 patients with this disease were encountered between 1990 and 1997 at Kyoto University Hospital in Kyoto City, which is located 80 km from Kobe City and was only minimally affected by the earthquake. These 15 patients and 1 patient who presented to Nishi-Kobe Medical Center before the Great Earthquake were classified as group 2 (G2). Although the average MPO-ANCA titer in G1 was almost the same as that in G2, G1 showed a significantly greater average value for white blood cells than G2 (11,321 +/- 4,369 versus 8,116 +/- 2, 389/microL; P < 0.05). Concerning renal function, a significant elevation in creatinine (Cr) levels at diagnosis (7.4 +/- 3.8 versus 2.1 +/- 1.4 mg/dL; P < 0.01) and rapidly declining rates of reciprocal Cr levels were noted in G1 (0.325 +/- 0.304 versus 0.087 +/- 0.069 dL/mg. wk; P < 0.01). The number of patients who required emergency hemodialysis was significantly greater in G1 than G2 (nine versus three patients; P < 0.02); however, the incidence of renal death and mortality were not significantly different between the groups. The number of patients who reported upper respiratory tract inflammation as an initial symptom was also significantly greater in G1 than G2 (eight versus two patients; P < 0.01). Moreover, patients in G1 experienced a significantly greater rate of severe pulmonary involvement during the hospital course than G2 (pulmonary hemorrhage, five versus no patients; interstitial pneumonitis, four versus two patients, respectively; P < 0.01). The relatively uniform and distinctive clinical features of the disease after the Great Earthquake, in conjunction with a high morbidity, suggest a relationship between disease development and this urban type of earthquake. Severely provoking air pollution caused by massive destruction and reconstruction of the city may have caused high frequencies of upper respiratory tract inflammation as an initial symptom and severe pulmonary involvement.

To investigate how the interruption of the renin-angiotensin system (RAS) and reduction of blood pressure (BP) affect the lesions of chronic focal and segmental glomerulosclerosis (FGS), we studied the effects of high and low doses of angiotensin-converting enzyme inhibitors (temocapril – TEM) a newly developed ACE inhibitor with biliary tract excretion, on the hypertensive model of FGS. A high dose of TEM significantly lowered BP and suppressed both intense proteinuria and glomerular extracapillary lesions including macrophage infiltration. On the other hand, although a low dose of TEM did not significantly lower BP throughout the experimental period, it prevented renal lesions almost in the same manner as high-dose TEM with suppression of c-myc gene expression in glomeruli. These findings suggest that in PAN-induced chronic FGS, the systemic BP elevation could not be the major factor for the progression of renal damage which TEM could prevent without significant lowering of BP.

Direct inhibitory effects of simvastatin on matrix accumulation in cultured murine mesangial cells Background 3-Hydroxy-3-methylglutarylcoenzymeA(HMG-CoA) reductase inhibitors have been demonstrated to suppress glomerular injuries in various renal diseases. These agents inhibit in vitro proliferation of several cell types, including mesangial cells. This effect indicates the ability to ameliorate mesangioproliferative lesions, independent of the improvement of hypercholesterolemia. On the other hand, it is not clear whether HMG-CoA reductase inhibitors directly regulate extracellular matrix (ECM) accumulation from mesangial cells. Methods In this study, to examine the in vitro effects of simvastatin, an HMG-CoA reductase inhibitor, on mRNA expressions of matrix proteins, growth factors, and matrix turnover proteins, we incubated cultured murine mesangial cells stimulated by fetal calf serum (FCS) with or without simvastatin for 24 hours, and Northern analysis was performed. Results Simvastatin showed a slightly suppressive effect on mRNA expression of type IV collagen and fibronectin and a slightly up-regulative effect on that of type I collagen, whereas mRNA expression of type III collagen was markedly up-regulated. mRNA expression of platelet-derived growth factor (PDGF)-B chain and PDGF receptor β-subunit was suppressed, whereas that of transforming growth factor-β (TGF-β) was not affected by simvastatin. Concerning matrix turnover proteins, simvastatin markedly reduced mRNA expression of plasminogen activator inhibitor-1 (PAI-1) without affecting the expression of tissue-type plasminogen activator (tPA). Conclusion These results suggest type-specific modulation of matrix protein production independent of TGF-β and the suppressive effects of autocrine PDGF by administration of HMG-CoA reductase inhibitors in mesangial cells. Moreover, the beneficial effects of these agents on matrix protein accumulation may be through promoting ECM degradation derived from PAI-1 suppression.

Up-regulation of glomerular extracellular matrix and transforming growth factor-βbgr; expression in RF/J mice. Background RF/J mice were first reported as a murine model of spontaneous glomerulosclerosis by Gude and Lupton in 1960, but the precise histologic characteristics and immunopathological background of this mouse have not been investigated further. Methods Measurements of serum levels of immunoglobulins, anti-single strand DNA (anti-ss-DNA) antibody, complement (C 3 ), and circulating immune complex (IC) were performed. Analyses of glomerular histological and immunopathological lesions in association with the detection of mRNA expression of collagen IV, TGF-βbgr;, matrix protein turnover related enzymes, matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-2 (TIMP-2) and platelet-derived growth factor (PDGF) were also performed in young (10-week-old) and elderly (60-week-old) RF/J mice with age-matched BALB/C mice as the controls. Results High levels of serum IgA and IgG from as early as 20 weeks of age were noted in the RF/J mice. Serum anti-ss-DNA antibody of aged RF/J mice increased up to 23% of that of aged MRL- lpr/lpr mice, and serum C 3 concentration significantly decreased with age, reaching lower levels than that of BALB/c mice. IgA-IC levels were significantly high compared to BALB/C mice both in the early and late stages of life, whereas IgG-IC levels were high only in mice younger than 20 weeks. Semiquantitative and quantitative analyzes of renal histopathological findings revealed significantly marked and age-related mesangial matrix expansion in RF/J mice, with increasing frequency of global glomerular sclerosis and tubulointerstitial damage. On the other hand, although precise measurements of glomerular cell numbers also showed an apparent augmentation in both young and old RF/J mice compared to BALB/C mice, glomerular cellularity decreased with age in RF/J mice. Immunohistochemical study revealed massive immunoglobulin deposition from a young age in association with significantly higher accumulation of matrix proteins, such as types I and IV collagen and laminin from the early stage of life. In addition, in these glomeruli, transforming growth factor-βbgr;1 (TGF-βbgr;1) was highly expressed both in young and old mice. The mRNA expression of MMP-2 was up-regulated only in the early stage of life. Although PDGF mRNA of RF/J mice was significantly up-regulated in the early stage of life, the differences between the mice disappeared in the late stage of life. Conclusions These findings suggest that in RF/J mice, an immunopathological background inducing high serum immunoglobulin and IC levels from the early stage of life is closely related to mesangioproliferative glomerular lesions mediated by PDGF, and that development of massive extracellular matrix accumulation in glomeruli was induced by up-regulated expression of TGF-βbgr; with inappropriate regulation of protein turnover-related enzyme production.

SUMMARY: Patients with certain types of glomerulonephritis often present with upper respiratory tract infection (URTI). In this in vitro study, we have examined several Japanese herbal medicines, Shosaiko-to (TJ-9), Saiboku-to (TJ-96), Sairei-to (TJ-114) and Ryokankyomi-singenin-to (TJ-119), which are occasionally used for collagen diseases, chronic inflammatory diseases or renal diseases. In these drugs, TJ-96 is used to treat bronchial asthma or URTI, which has anti-inflammatory effects. In this study, we demonstrate that TJ-9, TJ-96 or TJ-114 inhibits the proliferation of murine mesangial cells induced by platelet derived growth factor (PDGF) or tumour necrosis factor (TNF)-α. Quiescent mesangial cells were stimulated with 10 ng/mL of PDGF or 100 U/mL of TNF-α together with various concentrations of the medicines for 20 h. After incubation with 50μ/mL of TJ-9, TJ-96 or TJ-114, 3H-thymidine incorporation induced by PDGF was reduced to 26, 19 and 29% of the control; and 66, 56 and 75% on TNF-α stimulation, respectively. TJ-96 had a more intense inhibitory effect than TJ-9 or TJ-114. TJ-119 had no significant inhibitory effect at the same dose. Northern blot analysis for PDGF-B transcript after addition of TJ-96 revealed a 24% reduction in PDGF-B mRNA levels stimulated by recombinant PDGF-BB, suggesting inhibitory mechanisms of autocrine production of PDGF. No cytotoxic effect against mesangial cells in culture was observed up to a concentration of 100 μg/mL of TJ-9, TJ-96 or TJ-114 by lactic dehydrogenase release assay. By another cell viability assay, after medium with 50 μg/mL of TJ-96 was replaced with only PDGF-BB-containing medium, 3H-thymidine incorporation was found to exceed the control, suggesting rebound proliferation. the present findings suggest that administration of TJ-96 is beneficial for patients with mesangioproliferative glomerulonephritis accompanied by URTI, serving to regulate the effect on mesangial cell proliferation.

Mesangiolytic glomerulopathy in severe congestive heart failure. To study the glomerular morphological abnormalities in congestive heart failure (CHF), we analyzed 27 autopsy cases without other causes of renal disease. Their mean age was 59 years, and they showed mild prerenal azotemia. They had generally been treated with digitalis and diuretics, and a few of them with captopril or nifedipine. The abnormal glomerular findings of enlargement, hyperemia, and mesangial thickening were observed at high frequencies (61%, 64%, and 57%, respectively). They characteristically showed mesangiolysis (ML) by the findings of microaneurysms (81%) and mesangial degeneration (70%) such as loose reticular matrix and poor matrix area. In addition, glomerular infiltration of mononuclear leukocytes including macrophages was noted in 70% of the cases. Glomerular enlargement was not correlated with the grade of hyperemia, but it was correlated with the grade of ML index of % glomeruli with microaneurysms (F = 7.22, p < 0.004). There was an inverse relationship between the grades of mesangial thickening and of the ML index (P < 0.005). The number of glomerular leukocytes was positively correlated with mean glomerular size (P < 0.002) and with the ML index (P < 0.03). Notably, the glomerular macrophage-positive cases showed a prominently higher mean ML index than the negative cases (P < 0.005). There was an inverse correlation between the mean glomerular size and the partial oxygen pressure in arterial blood (PaO2; P < 0.01), and a positive correlation between the mean glomerular size and hematocrit (Hct) levels (P < 0.02). The cases positive for mesangiolytic mesangial degeneration showed significantly lower PaO2 values than the cases negative for this lesion (P < 0.04). In the analysis of the various causes of CHF, the patients with congenital cardiac anomalies showed mean levels of the lowest PaO2 (P < 0.02) and the highest Hct (P < 0.03) and histologically the largest mean glomerular size (P < 0.04). There was no difference in the ML index and the glomerular leukocyte number among the subgroups classified by the causes. These results indicate that ML associated with glomerular enlargement is the major glomerular abnormality characteristic in patients with severe CHF and suggest that glomerular infiltration of leukocytes, especially of macrophages, should play an important role in the progression of both ML and glomerulomegaly. The contributions of persistent hypoxia and up-regulated angiotensin II as the causative factors of these glomerular abnormalities in congestive heart failure are discussed.

Plasma refilling from the extravascular compartment during hemodialysis (HD) is a major compensatory mechanism to maintain the blood pressure. Plasma refilling rates are proportional to the filtration coefficients of the microvasculature (Lpst) and colloid-osmotic pressure gradients minus hydrostatic pressure gradients. A decreasing tendency of Lpst according to the volume reduction with ultrafiltration (UF) was reported. The aim of this study is to investigate the relation of Lpst with other markers of the fluid status and to clarify that Lpst can be utilized as a marker of the fluid status of HD patients.

Rapid amelioration of hypercholesterolemia in nephrotic syndrome (NS) using low density lipoprotein-apheresis (LDL-A) sometimes leads to NS remission, along with improvement of impaired biodefense system; however, the mechanism of how LDL-A affects NS is still unknown. We studied IFN-γ production under IL-12 stimulation for 24 h in whole blood from 30 NS patients, 31 non-NS patients, 35 healthy volunteers and another four persistent NS patients due to refractory focal segmental glomerulonephritis and minimal change type nephrotic syndrome. We compared IFN-γ production in whole blood and peripheral blood mononuclear cells (PBMC) from persistent NS patients before and after each of 14 LDL-A procedures. Finally, we studied the effect that persistent NS patients' serum before and after LDL-A had on IFN-γ production in healthy volunteers' PBMC. Whole blood IFN-γ production was significantly lower in NS patients compared with healthy volunteers or non-NS patients. In persistent NS, after LDL-A, IFN-γ production returned to normal levels. IFN-γ production in PBMC varied greatly among these patients and did not show consistent changes after LDL-A. Healthy volunteers PBMC incubated with persistent NS patients' serum obtained after LDLA showed higher IFN-γ production than before LDL-A. IFN-γ production in peripheral blood is impaired if a patient is in a nephrotic state. LDL-A might restore suppressed PBMC function in persistent NS patients, thereby ameliorating the nephrotic state, possibly through removing interfering serum factors.

Cholesterol kinetics in the time course after LDL apheresis using a dextran sulfate cellulose column was analyzed by adapting a two-compartment cholesterol kinetic model. Fifteen sets of serial serum cholesterol concentrations after LDL apheresis from 4 patients with drug-resistant nephrotic hypercholesterolemia due to focal glomerulosclerosis (FGS) were analyzed and cholesterol kinetic parameters were estimated with the nonlinear least-squares method. The fractional cholesterol catabolic rates (Kc; 0.171 +/- 0.073/day, mean +/- SD) were markedly decreased as reported in familial hypercholesterolemia (homo: 0.101/day, hetero: 0.280/day). Cholesterol generation rates (G; 68.0 +/- 28.7 mg/dl/day, mean +/- SD) considerably overlapped the normal range (39.2-77.5 mg/dl/day). This result was compatible with an earlier report that Kc was reduced earlier than G in nephrotic hypercholesterolemia. The time average serum cholesterol concentrations (TAC) in the rebound phase after LDL apheresis can be simulated using these kinetic parameters by the Runge-Kutta-Gill method. According to our previous report, TAC must be reduced to under a near-normal level in order to obtain a beneficial effect on nephrotic syndrome due to FGS. In 10 sets out of the 15, once-weekly treatment of LDL apheresis was sufficient to achieve this aim, but in the remaining 5 cases, more frequent LDL apheresis up to twice a week was necessary in the early phase of treatment. In conclusion, the two-compartment cholesterol kinetic model is useful in clarifying the abnormal cholesterol kinetics in nephrotic syndrome and may be helpful in establishing a more rational strategy of LDL apheresis for nephrotic hypercholesterolemia.

A simple method to calculate estimated creatinine clearance using two serum creatinine concentration (Cr) values in acute kidney injury (AKI) was developed (eCrCl-AKI). We aimed to evaluate its accuracy and to clarify its contribution to the classification of AKI. We validated the errors in eCrCl-AKI in a simulation study after various reductions in creatinine clearance (CrCl) at various levels of chronic kidney disease (CKD). We compared the eCrCl-AKI-based classification of RIFLE criteria with the Cr-based classification or that proposed by Waikar and Bonventre. The regression equations of eCrCl-AKI on time were determined and Cr values were reconstructed by creatinine kinetics substituting CrCl with eCrCl-AKI in actual patients. Most errors in eCrCl-AKI were relatively small (from −13.6 to +7.9%) with the exception of two Cr values that straddled the changing trend of Cr. The classification according to RIFLE criteria based on Cr was unstable and did not enable adequate classification, especially in milder reductions of CrCl with advanced CKD. The classification based on eCrCl-AKI was stable and enabled adequate classification. There were good agreements between measured Cr and reconstructed Cr with eCrCl-AKI. The regression equations of eCrCl-AKI revealed changes of renal function that were unexpected only from fluctuations of Cr. eCrCl-AKI can provide relatively accurate estimates for fluctuating CrCl. eCrCl-AKI enables more stable and earlier classification of AKI than Cr, at least in the simulation study. The more widespread use of eCrCl-AKI in actual clinical settings of AKI is necessary to evaluate this formula.

巣状糸球体硬化症 (FGS) による7例のネフローゼ症候群 (男性3例, 女性4例, 年齢16-56歳, 平均30.3歳) に対してLDL吸着療法を施行しその効果を検討した. LDL吸着はdextransulfate cellulose column (Liposorba LA-15) を使用し1回の血漿処理量は4,000mlとした. LDL吸着前のネフローゼ持続期間は1.5か月から26か月, 吸着療法の施行回数は2から13回であった. 7例中4例が不完全寛解I型となり, 2例はネフローゼ状態のままで, 1例では末期的腎不全に進行し透析導入となった. 寛解した4例では, LDL吸着療法前のネフローゼ持続期間が1.5-4 (平均2.4) か月だったのに対し, 無効例では3-26 (平均13) か月とより長期であった. 治療前の血清総コレステロール (TC) 値, 1回の吸着療法でのTCの平均低下率には, 寛解例, 無効例で差を認めなかったが, 吸着療法施行中のTCのtime average concentration (TAC) は寛解例では173-269 (平均234.5) mg/dl, 無効例では280-302 (平均292.7) mg/dlと, 前者でより低い値に維持されており, またより高頻度で吸着療法が施行されていた. 腎組織のapoprotein B (apo B) の蛍光抗体所見では, 改善した3例中2例で治療後にapo Bのメサンギウムへの分布低下が見られたが, 一方TC維持レベルが高値であり腎不全へと移行した例では治療後にむしろ増強傾向にあった. 薬剤療法が無効のFGSによるネフローゼ症候群では90%が腎不全に至るとの報告があるが, 今回の検討では薬剤が無効であった5例中2例が不完全寛解I型以上の改善を示し, 1例が腎不全に陥ったのみで, LDL吸着療法の有効性が示唆された.

Because of the limitations of creatinine (Cr) as a marker for the glomerular filtration rate (GFR), cystatin C (CysC) has been proposed as an alternative substance. The aim here was to clarify the characteristics of CysC compared with Cr. CysC and Cr were measured in 199 patients with chronic kidney disease. Regression analysis between CysC and Cr and comparisons of the effect of gender, inflammation, prescription of prednisolone, smoking and diabetes mellitus (DM) on these markers were performed. Sensitivity and specificity of CysC and Cr to discriminate estimated GFR of less than 50 ml/min/1.73 m2 were computed and evaluated by the receiver-operating characteristic curve (ROC). The correlation coefficient between natural logarithmic Cr [ln(Cr)] and ln(CysC) was higher than that between these variables per se (0.941 vs. 0.906). When Cr was lower than 1.10 mg/dl, CysC rose more sharply than Cr. CysC divided by Cr (CysC/Cr) was higher in females (1.35 ± 0.33 vs. 1.16 ± 0.30; p

Aims: The higher ultrafiltration (UF) induces poor outcomes. The impact of higher UF on the volume status was investigated. Methods: 60 hemodialysis (HD) patients were divided into three groups according to the ratio of total UF to post-dialysis body weight (TUF/PDW) (Results: Only Lpst and BVpost/BVpre showed significant differences among the three groups. A stepwise multiple linear regression model revealed that BVpost/BVpre was correlated with TUF/PDW, ExF/PDW and Lpst (R = 0.778, p < 0.001), independently. Conclusion: Higher UF causes decreases in BVpost/BVpre and Lpst. BVpost/BVpre was determined by TUF/PDW, ExF/PDW and Lpst.

術後の肝不全症例に対して血漿吸着療法を行ってきたが, その治療効果を高めるため, 非被覆性チャコール (N350) とstyrenedivinylbenzene (BR 350) を使用した血漿吸着療法を血漿交換療法に併用する方法を考え, 灌流実験ならびに臨床応用してその結果を検討した.灌流実験では, 以前に行った血漿交換時に得られた高ビリルビン血漿を用いて, 3時間吸着カラムを灌流した. 総ビリルビンは, BR350およびN350の単独使用では40%以上の残存率を, BR350とN350の直列併用では21%にまで減少していた. アミノ酸についてはBR350単独では, 総・分枝鎖・芳香族アミノ酸は87%, 93%, 70%の残存率を示したが, N350ならびにBR350とN350の直列併用では, 各々50%, 40%, 7%であり良好な吸着能が認められた. 臨床症例においては, 総ビリルビンは57±6%に, 芳香族アミノ酸は84±7%に減少した. 症例の長期的な予後は決して良好とはいえないものの, 臨床症状の改善やデータの改善がみられた.この血漿吸着療法は, 肝不全症例, 特に肝性昏睡や高ビリルビン血症を有する症例に対して, 従来の血漿交換療法とほぼ同等のビリルビン低下効果と臨床症状の改善を認め, 高価でかつ入手困難な新鮮凍結血漿 (FFP) の使用量を1/4に低下させ得たことより評価し得る治療法と考えられる.

Relationships among five markers of volume status - cardio-thoracic ratio (CTR), atrial natriuretic peptide (ANP), inferior vena cava diameter at quiet expiration (IVCe), blood volume change (Delta BV/TUF) during ultrafiltration and filtration coefficients of microvasculature (Lpst) - were investigated. Fifty stable hemodialysis patients were enrolled. The CTR was measured before hemodialysis (HD), and ultrasonic measurement of IVCe and sample collection for ANP were performed shortly after HD. Lpst and Delta BV/TUF were calculated using a CRIT-LINE monitor. Overhydrated patients determined by each marker (OVERctr, OVERivc, OVERanp, OVERlp and OVERbv) were compared. The agreement of volume status determined by each marker was assessed by kappa value, and the sensitivity and specificity of each marker to distinguish overhydrated patients were analyzed by a receiver-operating characteristic (ROC) curve. IVCe, ANP, Delta BV/TUF and Lpst, significantly correlated with each other. The correlation coefficients of Lpst with IVCe, ANP and Delta BV/TUF were higher than the others. The kappa value between ANP and Lpst was the highest. OVERanp was the highest, then OVERlp, OVERivc and OVERbv, in this order. The OVERlp and OVERivc patients were completely included in OVERanp. All patients, except one OVERbv patient, were included in OVERlp. The relatively high distinguishing ability of Lpst was demonstrated by ROC analysis. These results suggest that the determination of overhydration solely by ANP was an overestimation and by Delta BV/TUF was an underestimation. The relatively high correlation coefficients of Lpst with other markers, as well as its distinguishing ability, suggest that Lpst fluctuates in close relation to other markers.

Massive systemic edema is often observed in patients with severe nephrotic syndrome, including diabetic nephropathy. Although furosemide, a loop diuretic, is often administered to these patients, some patients do not respond to this treatment, still showing massive edema.The efficacy of indapamide which has a thiazide-like effect on distal convoluted tubules in combination with furosemide, was evaluated in eight patients with massive edema, in regard to both Na+ excretion and diuresis. Indapamide 2 mg was administered once a day, in the morning, to patients in whom it was considered that furosemide treatment of 40-120 mg a day for 1 week was ineffective.Urinary Na+ excretion was markedly increased, from 83.7 +/- 82.2 mEq/day to 140.7 +/- 33.8 mEq/day after 1 week of the combination therapy compared with furosemide alone (P0.01); urine volume was also increased, from 1070 +/- 230 ml to 1359 +/- 296 ml after 1 week of the combination therapy (P0.05). In this context, body weight was significantly decreased, from 57.2 +/- 12.3 kg to 53.4 +/- 12.8 kg, after the combination therapy (P = 0.01). Indapamide in combination with furosemide was well tolerated, and no significant changes in serum levels of creatinine and potassium were observed.This combination therapy appears to be effective in patients with massive edema, as it increased diuresis, and achieved potent Na+ excretion.

A regional flow model (RFM) can establish the missing link between hemodynamics and solute removal. We tried to simulate post-dialysis urea rebound using a RFM for the purpose of evaluating the validity of this model. Eight patients on maintenance hemodialysis with negligible renal function were investigated. The parameters of the RFM were estimated so as to fit the calculated values of urea nitrogen to the measured values during a dialysis session. The estimated parameters were total urea distribution volume (TUV), systemic blood flow (Qsys), flow fraction (fQH) and volume fraction (fVH) of the high-flow system. Thirteen types of parameter sets were used for the estimation. The urea rebound at 60 min after a dialysis session (Creb) and the rebound ratio (RR) were calculated using these estimated parameters. The accuracy of the calculated Creb and RR was assessed. The accuracy of Creb and RR determined using estimated TUV, by taking Qsys as systemic blood flow calculated from ultrasonic echo cardiogram (Qucg), fQH as 0.8, and fVH as 0.2, was insufficient (method 1a). The accuracy of these values was significantly increased by taking fQH as 0.85 (method 1b). The estimation of Qsys with TUV did not improve the accuracy of Creb and RR (methods 2a and 2b). The estimation of fQH, fVH, and TUV (method 8) increased the accuracy of Creb and RR significantly compared with method 1a, but not compared with method 1b. Even with method 1b or method 8, the percentage RR was less than 90% in two patients. By taking fQH as 0.85, an acceptably accurate simulation of urea rebound can be accomplished with the necessity to estimate only TUV. The simulation was not significantly improved by the estimation of Qsys, fQH, and fVH. The RFM is useful in practice, although it has some limitations.

Background/Aims: Filtration coefficients (Lp) and plasma volume were estimated in order to investigate whether suppressed Lp associates with intradialytic hypotension and/or diabetic nephropathy. Methods: Twenty-one patients were evaluated. Nine patients were diabetic (DM) and 12 were nondiabetic (non-DM). Three of DM and 4 of non-DM were prone to dialysis-induced hypotension (hypo(+)) and others (hypo(–)) were not. Changes in hematocrit (Ht) were measured for 60 min after the start of ultrafiltration. Lp and plasma volume at the start of ultrafiltration (Vp0) were estimated to fit calculating values of Ht based on Schneditz’s open two compartment model to actual value. Results: There was no significant difference in the mean values of Lp/Vp0 either between hypo(+) and hypo(–) (0.87 ± 0.37 vs. 1.24 ± 0.48 ml/mm Hg·min·liter; n.s.) or between DM and non-DM (1.04 ± 0.32 vs. 1.17 ± 0.56 ml/mm Hg·min· liter; n.s.). However, the comparisons of Lp/Vp0 among the four groups (hypo(+)/DM, hypo(–)/DM, hypo(+)/non-DM and hypo(–)/non-DM) showed significant differences between hypo(+)/non-DM and hypo(–)/non-DM (1.08 ± 0.40, 1.02 ± 0.32, 0.71 ± 0.29*, 1.40 ± 0.53* ml/mm Hg·min·liter; *p < 0.05). Differences in the percentage of Vp0 to body weight (Vp0/BW) among four groups and correlation between Lp/Vp0 and Vp0/BW were not significant. Conclusion: These data indicated that reduction of Lp/Vp0 was not simply caused by decreased circulating plasma volume (Vp0/BW) and that the suppressed filtration coefficients may have substantial association with dialysis-induced hypotension in non-DM. The estimation of Lp using in-line measurement of Ht was a useful method for analyzing intradialytic hypotension.

Background/Aim: RF/J mice are a model of spontaneous immune complex mediated glomerulonephritis showing massive extracellular matrix accumulation and progressive glomerulosclerosis. The aim of this study was to investigate whether there is an altered cultured mesangial cell (MC) phenotype in RF/J mice associated with these glomerular changes. Methods: The nature of cultured MCs from RF/J mice in the proliferative response to platelet-derived growth factor (PDGF) BB was compared with that of normal mice (BALB/c) by 3H-thymidine incorporation. The binding of PDGF-BB was examined with Scatchard analysis, and the messenger RNAs (mRNAs) of PDGF β-receptor, collagen I, collagen IV, and fibronectin were detected using Northern blot analysis in the MCs of each mouse. Results: The 3H-thymidine incorporation of MCs from RF/J mice showed significantly lower responses to PDGF-BB stimulations with concentrations ranging from 0.5 to 10.0 ng/ml in comparison with those of BALB/c mice which exhibited a proportional dose- dependent increase of the incorporation (p < 0.05 for 0.5 ng/ml PDGF-BB, p < 0.01 for 1.0–10.0 ng/ml). According to the Scatchard analysis, MCs from BALB/c mice showed aKD of 105 pM of PDGF-BB binding to its receptors, and the density of receptors was 5.82 fmol/105 cells. However, no binding PDGF-BB site on the surface of MCs from RF/J mice was noted. Northern blot analysis of MCs from RF/J mice indicated negative expression of detectable PDGF-β receptor mRNA. As for matrix protein messages, MCs from RF/J mice did not express mRNA of type I collagen, but did express a higher amount of type IV collagen and fibronectin in comparison with MCs from normal BALB/c mice. Conclusions: An altered phenotype in MCs of RF/J mice was demonstrated, possibly contributing to the characteristic pathological glomerular changes. However, the precise association remains to be clarified.

To investigate the significance of intraglomerular coagulation and fibrinolysis in IgA nephropathy (IgA-N) and Henoch-Schönlein purpura nephritis (HSPN), the distribution of intact cross-linked fibrin (XFb) modulated by plasmin activity was examined in 25 patients with IgA-N and in 12 with HSPN. In addition to the conventional method detecting fibrin-related antigen (FRA) with an antibody against fibrinogen, the enhanced intensity of immunoreactivity of cross-linked FRA (KL-FRA) using the monoclonal antibody DD3B6/22 after plasmin exposure was evaluated to assess intraglomerular deposition of intact XFb. Also, intraglomerular invasion of macrophages was detected using the monoclonal antibody KP1 against CD68. Sixteen of a total of 37 specimens (43%) showed increased intensity of XL-FRA staining after plasmin treatment which is considered to reflect the distribution of intact XFb. Increases in the intensity of XL-FRA staining were observed mainly in mesangium and partially along glomerular capillary loops and also in a few cases in the crescents. The incidence (67%) of increases in XL-FRA staining after plasmin exposure in HSPN specimens was significantly higher than that in IgA-N specimens (32%; p0.05). In the group positive for XL-FRA after plasmin exposure, the numbers of macrophages per glomerulus were significantly higher (n = 15; mean +/- SD = 1.6 +/- 0.9) than in the negative group (n = 6; 0.5 +/- 0.6; p0.01). In HSPN, the number of macrophages per glomerulus (n = 8; 1.9 +/- 1.0) was higher than that in IgA-N (n = 13; 0.9 +/- 0.9; p0.05). Based on these results, we conclude that XFb is often produced and distributed in intact form in the glomeruli both in IgA-N and HSPN, associated with a relatively low intraglomerular plasmin activity, and that intraglomerular coagulation may progress in accordance with macrophage infiltration, especially in HSPN.

Enhanced production of glomerular extracellular matrix in a new mouse strain of high serum IgA ddY mice. To investigate the relationship between high serum levels of IgA and glomerular lesions, selective mating was performed in high serum IgA ddY mice, a murine modelof spontaneously developing mesangioproliferative glomerulonephritis mimicking human IgA nephropathy. The selection and mating of high IgA ddY mice were accomplished when the mice were three to fourmonths old. In the 12th generation of high IgA ddY (HIGA) mice, significantly higher levels of serum IgA from 10 age weeks to 60 weeks (P < 0.0002 to 0.0001) were observed in comparison with BALB/c mice. Relatively high proteinuria was observed at 40 weeks of age, although hematuria was consistently negative. Microscopic observations of renal tissue disclosed a marked glomerular mesangial matrix increase and a reduction of cell proliferation with age by both semiquantitative and morphometric analyses with moderate tubulointerstitial damage. These mesangial matrices were stained markedly by antisera for collagen type IV and by fibronectin, but not by collagen type I. Localization of TGF-β protein was also detected in the mesangium of the HIGA mice. The positive mesangial IgA deposition was maintained consistently by this mating procedure and became more marked with age. Size analysis of IgA from ten pooled HIGA mice aged 50 to 60 weeks revealed dominant polymeric IgA insera and dimeric IgA in glomerular eluates. Clonal analysis of serum IgA disclosed heterogeneous spectrotypes in a wide pH range (4.5 to 6.5), in contrast to very limited spectrotypes in the acidic pH range (4.5 to 5.2) of IgA in the glomerular eluates from these mice. The analyses of retroviral gp70 antigen involvement in the HIGA mice disclosed a significant increase of serum levels of gp70 anti-gp70 immune complexes with age, with no relationship to the severity of glomerular gp70 deposition. Northern blot analysis of renal tissue revealed markedly high mRNA expression of collagen type I, IV, fibronectin and TGF-β even in 10-week-old HIGA mice in comparison with BALB/c mice. The expression became more significant in 60-week-old animals. The genetic background required to induce the expansion of IgA-producing B-cell clones is suggested to be closely related to the increased gene expressionof TGF-β, which induces enhanced glomerular extracellular matrix (especially fibronectin) accumulation in HIGA mice, being possibly mediated by the mesangial deposition of dimeric and highly acidic IgA. This newly established strain may provide a model for investigating the relationship between progressive glomerular sclerotic lesions and the induction of pathogenic IgA in human IgA nephropathy.

Low-density lipoprotein apheresis (LDL-A) was performed for nine episodes of steroid-resistant nephrotic syndrome in eight patients. The clinical and immunohistological findings were analysed retrospectively. Six of the patients had focal glomerular sclerosis (FGS), one had minimal-change nephrotic syndrome (MCNS), and one had membranous nephropathy (MN) with FGS. The LDL-A treatment, carried out 2-13 times (mean 7.33 +/- 4.05) for one nephrotic episode, at average intervals of 3-16 days (mean: 8.5 +/- 5.1 days) and combined with steroid pulse therapy and the administration of an antihyperlipidaemic agent in some cases, led to rapid amelioration of hyperlipidaemia. In six nephrotic episodes (5 patients) more than 50% reduction of proteinuria occurred (less than 3.5 g/day) (response-group). A significant elevation of serum albumin (more than 3.0 g/dl) was obtained in five of these episodes. The other three patients were resistant (resistant-group). The number of and intervals between LDL-A treatments in the response group (5 +/- 2.8 times and 5.8 +/- 4.1 days) were significantly less than those in the resistant-group (12.0 +/- 0.8 times and 13.2 +/- 1.8 days) (P < 0.05). After LDL-A, significant reductions were observed in the serum total cholesterol (T-CHO), phospholipid (PL), triglyceride (TG), free-CHO (F-CHO), and beta-lipoprotein (beta-lipo) (P < 0.05). HDL-cholesterol (HDL-C) increased somewhat after LDL-A. Further, Ccr was elevated in all nephrotic episodes, except in one patient who manifested renal failure after 6 months.(ABSTRACT TRUNCATED AT 250 WORDS)