Hiroaki Io

Serum Cystatin C Is a More Sensitive Marker of Glomerular Function than Serum Creatinine

We determined the relationship between the levels of serum cystatin C or creatinine (s-Cr) and the grade of creatinine clearance (CCr) in patients with various glomerular diseases. Serum samples from 96 patients with glomerular diseases were obtained from our hospital. The levels of serum cystatin C were measured using the Dade Behring Cystatin C assay with the automated Dade Behring Nephelometer II (BNII). CCr levels were classified into six groups according to the Guidelines of the Japanese Society of Nephrology as follows: grade 1 (normal renal function); grade 2 (slight decrease of renal function); grade 3 (moderate decrease of renal function); grade 4 (severe decrease of renal function); grade 5 (renal failure), and grade 6 (uremia). The mean levels of serum cystatin C in grade 3 patients were significantly higher than those in grade 1. The mean levels of serum cystatin C in grades 4, 5 and 6 patients were also significantly higher than those in grade 1. However, the mean levels of serum Cr in grade 3 patients were not significantly higher than those in grade 1. The levels of s-Cr in grades 4, 5 or 6 patients were significantly higher than those in grade 1. In this study, an increase of serum cystatin C levels occurred earlier than that of s-Cr in various glomerular diseases. It appears that the levels of serum cystatin C may provide early prognostic marker of patients with various glomerular diseases rather than the levels of s-Cr.

Risk factors associated with increased left ventricular mass index in chronic kidney disease patients evaluated using echocardiography

BACKGROUND It is still not clear which factors are associated with left ventricular mass index (LVMI) in chronic kidney disease (CKD) patients, based on the patients physical and biochemical parameters at the time of echocardiography. The objective of the present study was to identify factors associated with LVMI in CKD patients (predialysis patients), using echocardiography. METHODS Physical, biochemical and LVMI data evaluated by echocardiography were retrospectively analyzed in 930 CKD patients in Juntendo University Hospital, Tokyo, Japan. RESULTS Levels of systolic blood pressure (SBP) and hemoglobin (Hb) were independent risk factors for increased LVMI in multivariate regression analysis. SBP was significantly correlated with LVMI (r=0.314, p<0.0001). The level of Hb was inversely correlated with LVMI (r=-0.372, p<0.0001). LVMI increased with decreasing renal function. SBP was significantly higher in patients with left ventricular hypertrophy (LVH) in CKD stages 2 and 5, and Hb was significantly lower in patients with LVH in stages 4 and 5 than in the group without LVH. CONCLUSIONS It is important to treat hypertension and anemia to prevent LVH in CKD patients. These findings have some therapeutic implications for treatment strategies for predialysis patients.

Quantitative evaluation and assessment of peritoneal morphologic changes in peritoneal dialysis patients

BACKGROUND Morphologic changes of the peritoneum such as peritoneal fibrosis and vasculopathy develop during peritoneal dialysis (PD). In 2002, Williams et al. reported microscopic characteristics of peritoneal changes in PD patients. These studies pointed out the importance of establishing a global standard for qualitative and quantitative histological evaluations. The objectives of the present study are (i) to verify the methods for assessing peritoneal thickness and classifying vasculopathy in peritoneal specimens using the assessment of Williams et al. and (ii) to propose a simple assessment that reflects clinical features such as PD duration and peritoneal function. METHODS Parietal peritoneal samples were obtained from 35 patients that included 27 patients with PD and 8 uraemic patients without PD. In all samples, the maximum and average thicknesses of the submesothelial compact (SMC) zone were measured to assess peritoneal interstitial fibrosis using KS400 imaging analysis. Vasculopathy was also assessed by calculation of patency rates of the vascular lumens using the diameter and area, and by measurement of dimensions of vascular wall hyalinization in each vessel specimen. RESULTS The median values of maximum and average thicknesses of the SMC zone exceeded 200 μm in uraemic patients without PD treatment. There was a significant relationship between the maximum and average thicknesses of the SMC zone (P < 0.0001). Four to 30 vessels were examined in each participant. Various grades of vasculopathy were observed in each specimen. According to the predominant vasculopathy found in each vessel, the prevalence of serious vasculopathy increased with increasing PD duration. Vascular patency calculated from wall thickness was significantly related to that calculated by the area and to the thickness of hyalinization. Average vascular patency assessed from 5 to 10 vessels in each patient having diameters ranging from 10 to 40 μm was related to PD duration and to peritoneal function (D4/P). CONCLUSIONS A random-points measurement of average SMC thickness provides a descriptive evaluation of the severity of peritoneal fibrosis that minimizes artefacts during processing and avoids human error. In addition, the average patency in post-capillary venules appears to accurately reflect clinical features such as PD duration and peritoneal permeability.

Effect of AST-120 on Endothelial Dysfunction in Adenine-Induced Uremic Rats

Aim. Chronic kidney disease (CKD) represents endothelial dysfunction. Monocyte adhesion is recognized as the initial step of arteriosclerosis. Indoxyl sulfate (IS) is considered to be a risk factor for arteriosclerosis in CKD. Oral adsorbent AST-120 retards deterioration of renal function, reducing accumulation of IS. In the present study, we determined the monocyte adhesion in the adenine-induced uremic rats in vivo and effects of AST-120 on the adhesion molecules. Methods. Twenty-four rats were divided into control, control+AST-120, adenine, and adenine+AST-120 groups. The number of monocytes adherent to the endothelium of thoracic aorta by imaging the entire endothelial surface and the mRNA expressions of adhesion and atherosclerosis-related molecules were examined on day 49. The mRNA expressions of ICAM-1 and VCAM-1 in human umbilical vein endothelial cells were also examined. Results. Adenine increased the number of adherent monocytes, and AST-120 suppressed the increase. The monocyte adhesion was related to serum creatinine and IS in sera. Overexpression of VCAM-1 and TGF-β1 mRNA in the arterial walls was observed in uremic rats. IS induced increase of the ICAM-1 and VCAM-1 mRNA expressions in vitro. Conclusion. It appears that uremic condition introduces the monocyte adhesion to arterial wall and AST-120 might inhibit increasing of the monocyte adherence with CKD progression.

Differentiation of bone marrow-derived cells into regenerated mesothelial cells in peritoneal remodeling using a peritoneal fibrosis mouse model

Marked thickening of the peritoneum and vasculopathy in the submesothelial compact zone have been reported in long-term peritoneal dialysis patients. Bone marrow (BM)-derived cell lines are considered to be useful tools for therapy of various diseases. To clarify the role of BM-derived cells in the peritoneal fibrosis (PF) model, we analyzed several lineages of cells in the peritoneum. BM cells from green fluorescent protein (GFP) transgenic mice were transplanted into naïve C57Bl/6 mice. Chlorhexidine gluconate (CG) was injected intraperitoneally to induce PF. Immunohistochemical analysis was performed with parietal peritoneum using anti-Sca-1 or -c-Kit and -GFP antibodies. Isolated BM cells were also transplanted into the CG-stimulated peritoneum. BM-derived cells from GFP transgenic mice appeared in the submesothelium from days 14 to 42. Both GFP- and stem cell marker-positive cells were observed in the submesothelium and on the surface. Isolated c-Kit-positive cells, transplanted into the peritoneal cavity, differentiated into mesothelial cells. In this study, we investigated whether or not BM-derived cells play a role in the repair of PF and immature cells have the potential of inducing repair of the peritoneum. The findings of this study suggest a new concept for therapy of PF.

Predictive factors associated with left ventricular hypertrophy at baseline and in the follow-up period in non-diabetic hemodialysis patients.

Hemodialysis (HD) patients frequently have an elevated left ventricular mass index (LVMI). Currently, left ventricular (LV) hypertrophy and dysfunction are considered to be the strongest predictors of cardiovascular mortality in dialysis patients. The objectives of the present study are to investigate the factors associated with elevated LVMI and to discuss therapeutic implications for the treatment strategy for pre‐dialysis and HD patients. The correlation among biochemical values, physical specimens, and LVMI using echocardiography was prospectively analyzed in 30 non‐diabetic HD patients in the Juntendo University Hospital. Measurement of these parameters was performed at 0, 12, and 24 months after initiation of HD. Systolic blood pressure (SP), human atrial natriuretic peptide (hANP), and hemoglobin (Hb) levels were significantly correlated with LVMI. SBP, residual glomerular filtration rate (rGFR), and serum albumin levels were identified as independent risk factors for LVMI in multivariate regression analysis at initiation of HD. SBP, hANP, and Hb levels were identified as independent risk factors for LVMI in multivariate regression analysis after 24 months. SBP, rGFR, and serum albumin levels were predictive factors for LVMI at initiation of HD. SBP, hANP, and Hb levels were also predictive factors for LVMI after initiation of HD.

Predictive Factors Associated with the Period of Time before Initiation of Hemodialysis in CKD Stages 4 and 5

Background: A majority of patients with chronic kidney disease (CKD) have cardiovascular disease at the initiation of dialysis therapy, suggesting that periodic echocardiographic examinations are important in such patients. The purpose of the present study was to evaluate the correlation between echocardiographic parameters and period of time before initiation of hemodialysis (iHD) in patients with CKD. Methods: 140 patients with CKD stages 4 and 5 were enrolled. They were divided into diabetes and nondiabetes groups. Cardiac predictive parameters for the period of time before iHD were investigated in the patients using univariate and multivariate regression analyses. Results: In the nondiabetes group, systolic blood pressure (SBP) and left atrial volume index (LAVi) were identified as independent risk factors for the period of time before iHD by multivariate regression analysis. Serum albumin level was identified as an independent risk factor in the diabetes group. SBP, LAVi and serum albumin level were identified as independent risk factors in the combined diabetes and nondiabetes groups. Conclusion: LAVi measurements during echocardiography, together with SBP and serum albumin levels, may be useful predictive factors for the period of time before iHD in patients with CKD stages 4 and 5.

CARDIAC FUNCTION AND STRUCTURE IN LONGITUDINAL ANALYSIS OF ECHOCARDIOGRAPHY IN PERITONEAL DIALYSIS PATIENTS

♦ Background: Echocardiography is widely used for the evaluation of cardiac structures and function. The prognostic value of assessment of left cardiac atrium (LA) size in peritoneal dialysis (PD) patients is still unclear. The objective of the present study is to investigate prospectively a longitudinal monitoring of echocardiography parameters after start of PD. We also investigated a correlation study among plasma atrial natriuretic peptide (ANP) level, LA size, and cardiac function undergoing aggressive treatment. ♦ Methods: Correlation among plasma ANP, LA size, and cardiac function was prospectively analyzed by Doppler echocardiography in 32 PD patients in Juntendo University Hospital, Tokyo. Measurement of these parameters was performed at 0, 6, 12, 18, and 24 months after start of PD. All patients were treated with an angiotensin type 1 receptor blocker to control blood pressure to less than 140/90 mmHg. Other antihypertensive drugs such as diuretics and/or calcium channel blockers were added if blood pressure rose to over 140/90 mmHg. Hemoglobin and hematocrit levels were targeted at 10.0 g/dL and 30.0% respectively with recombinant human erythropoietin treatment. A diuretic was added or patients decreased their water intake if ANP was more than 43.0 pg/mL or LA diameter (LAD) more than 39 mm, and for other basic markers of volume status. Cardiac function was measured before and after drainage of PD fluid to evaluate the influence of cardiac function. ♦ Results: LAD at start of dialysis (36 ± 4.6 mm) decreased significantly to 33 ± 3.3 mm (p < 0.05), 33 ± 3.2 mm (p < 0.05), and 33 ± 3.6 mm (p < 0.05) after 6, 12, and 24 months, respectively. Ejection fraction after 6 months was significantly increased compared with that at start of dialysis (p < 0.05). Left ventricular mass index (LVMI) after 6, 12, and 24 months was significantly decreased compared with that at start of dialysis (p < 0.05). ANP was 56 ± 39 pg/mL at start of dialysis and decreased significantly to 33 ± 19 pg/mL after 24 months (p < 0.05). ANP was significantly correlated with LAD (r = 0.412, p < 0.01), transmitral A wave flow velocity (r = 0.429, p < 0.01), and LVMI (r = 0.426, p < 0.01). Instillation of the dialysis fluid did not affect any parameters except inferior vena cava dimension. ♦ Conclusion: This study demonstrates a reduction in LA size and LVMI in PD patients followed over 24 months. Left ventricular structure, contraction, and compliance were well preserved in PD patients undergoing aggressive treatment based on measurements of plasma ANP and LAD.

Improvement of peritoneal calcification after parathyroidectomy in a peritoneal dialysis patient.

Peritoneal calcification is one of the complications of peritoneal dialysis (PD). It can become serious, leading to severe abdominal pain and even death. Possible mediators of peritoneal calcification in PD patients are assumed to include acetate buffer, overdosage of vitamin D, repeated peritonitis, hypertonic dialysate, calciphylaxis and secondary hyperparathyroidism (SHPT). However, the mechanism and treatment of peritoneal calcification are controversial. Few reports have appeared on improvement of peritoneal calcification after parathyroidectomy (PTX) for SHPT of long duration. We report herein the case of a 48-year-old man on dialysis for 17 years including PD for 14 years. In 1989, he was admitted to hospital because of end-stage renal disease (ESRD), and started treatment with PD. Abdominal computed tomography (CT) first showed peritoneal calcification in August 2002. Peritoneal calcification did not improve despite conventional treatment including discontinuation of PD, control of calcium phosphate product to less than 55 mg2/dl2, removal of the peritoneal catheter and empirical prednisolone (PSL) usage. The intact parathyroid hormone (i-PTH) level was increased over 1,000 pg/ml and extra-osseous calcification occurred. Total PTX was performed in November 2004. Postoperatively, the i-PTH level decreased immediately and calcium phosphate product was maintained in the reference range. Abdominal CT after PTX showed improvement of peritoneal calcification in September 2005. It appeared that PTX could be used to treat patients with persistent peritoneal calcification not responding to conventional treatment. It was postulated that SHPT might play a crucial role in accelerating peritoneal calcification in PD patients.

Predictive factors associated with change rates of LV hypertrophy and renal dysfunction in CKD patients

BACKGROUND This longitudinal study is the first report on the factors associated with change rates of the estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMI) using echocardiography in chronic kidney disease (CKD) patients. METHODS Measurements of biochemical and physical values, and LVMI evaluated by echocardiography were performed twice (baseline and follow-up period) in pre-dialysis CKD patients. Blood and urine samples were collected at the time of the echocardiographic study. RESULTS The change rates of hemoglobin (Hb) and transferrin saturation (TSAT: (serum iron/total iron binding capacity)) were identified as independent risk factors for changes in eGFR by multivariate regression analysis. In the LVMI improvement group, the change rate of systolic blood pressure (sBP) was identified as an independent factor for change in LVMI. In the LVMI worsening group, the change rates of sBP, proteinuria and Hb were identified as independent risk factors for changes in LVMI. CONCLUSIONS It appears that treatment of renal and iron deficiency anemia might prevent progression of renal dysfunction. To prevent LV hypertrophy in CKD patients, renal anemia, hypertension and proteinuria should be treated.