Masatomo Yashiro

Significantly high regional morbidity of MPO-ANCA–related angitis and/or nephritis with respiratory tract involvement after the 1995 great earthquake in Kobe (Japan)

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.

Evaluation of Markers to Estimate Volume Status in Hemodialysis Patients: Atrial Natriuretic Peptide, Inferior Vena Cava Diameter, Blood Volume Changes and Filtration Coefficients of Microvasculature

Abstract:  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 (▵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 ▵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 κ value, and the sensitivity and specificity of each marker to distinguish overhydrated patients were analyzed by a receiver‐operating characteristic (ROC) curve. IVCe, ANP, ▵BV/TUF and Lpst, significantly correlated with each other. The correlation coefficients of Lpst with IVCe, ANP and ▵BV/TUF were higher than the others. The κ 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 ▵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.

Intraglomerular deposition of intact cross-linked fibrin in IgA nephropathy and Henoch-Schönlein purpura nephritis.

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%; p < 0.05). 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; p < 0.01). 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; p < 0.05). 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.

Relationship between Filtration Coefficients of Microvasculature and Levels of Atrial Natriuretic Peptide or Echocardiographic Measurements

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.

Simulation of post-dialysis urea rebound using regional flow model

BackgroundA 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.MethodsEight 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.ResultsThe 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.ConclusionsBy 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.

Evaluation of estimated creatinine clearance before steady state in acute kidney injury by creatinine kinetics

BackgroundA 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.MethodsWe 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.ResultsMost 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.ConclusionseCrCl-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.

The Na+-excreting efficacy of indapamide in combination with furosemide in massive edema.

BackgroundMassive 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.MethodsThe 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.ResultsUrinary 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 (P < 0.01); urine volume was also increased, from 1070 ± 230 ml to 1359 ± 296 ml after 1 week of the combination therapy (P < 0.05). 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.ConclusionsThis combination therapy appears to be effective in patients with massive edema, as it increased diuresis, and achieved potent Na+ excretion.

How Does Higher Ultrafiltration within the Conventional Clinical Range Impact the Volume Status of Hemodialysis Patients

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) (<3%, 3–5%, ≥5%). ANP, the ratio of extracellular water to total body water and excess fluid mass (ExF/PDW) by bioimpedance spectroscopy, inferior vena cava diameter by ultrasound were measured at the end of HD. The ratio of post-HD blood volume to pre-HD (BVpost/BVpre) and standardized filtration coefficients (Lpst) of the microvasculature in the vicinity of PDW were calculated. 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.

Estimation of Filtration Coefficients and Circulating Plasma Volume by Continuously Monitoring Hematocrit during Hemodialysis

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.

Inhibitory effects of the herbal medicine Saiboku-to on the proliferation of cultured murine mesangial cells

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.