Kenichiro Iio

Cardiac troponin T predicts occult coronary artery stenosis in patients with chronic kidney disease at the start of renal replacement therapy

BACKGROUND The high prevalence of asymptomatic coronary artery stenosis (CAS) in chronic kidney disease (CKD) has emerged as an important predictor of outcome. However, diagnostic tools that can identify asymptomatic CAS have not yet been established. We investigated whether asymptomatic patients at the initiation of renal replacement therapy (RRT) could be screened using cardiac troponin T (cTnT) and atherosclerotic surrogate markers such as ankle-brachial blood pressure index (ABPI) and intima-media thickness (IMT). METHODS AND RESULTS Among 142 patients who were about to start RRT, 60 who were asymptomatic underwent coronary evaluation by multi-slice computed tomography (MSCT) and/or coronary angiography (CAG). CAG diagnosed 35 patients (43.8%) as CAS positive and 27 of them had multi-vessel disease. Factors associated with CAS were smoking, elevated cTnT, low ABPI and high IMT. Moreover, the severity of CAS was associated with smoking, cTnT and ABPI. Stepwise logistic regression analyses revealed that cTnT was a powerful predictor of asymptomatic multi-vessel CAS. Receiver operating characteristic analysis documented the usefulness of cTnT as a screening tool with a cut-off point 0.05 ng/ml. The optimal screening tool for multi-vessel CAS was cTnT (sensitivity, 92.6%; 95% CI, 82.7-99.9; specificity, 63.6%; 95% CI, 47.2-80.0). CONCLUSION We concluded that cTnT should be measured as part of a strategy for detecting asymptomatic CAS, especially multi-vessel disease in patients with CKD at the start of RRT.

Plasma B-type natriuretic peptide level predicts kidney prognosis in patients with predialysis chronic kidney disease

BACKGROUND As a cardiorenal syndrome, there is a dynamic interplay between the heart and the kidney. We conducted a prospective study to evaluate the prognostic impact of plasma B-type natriuretic peptide (BNP) level, a cardiac biomarker, on the long-term kidney prognosis in chronic kidney disease (CKD) patients. METHODS We prospectively enrolled 508 patients with CKD Stages 3, 4 and 5 not on dialysis, from a single nephrology department between 2004 and 2010. The exclusion criteria were over 90 years of age, malignancy, active infection, low cardiac ejection fraction and rapid progressive glomerulonephritis. Relationships between BNP and kidney end point [defined as doubling of baseline serum creatinine and end-stage kidney disease (ESKD) requiring kidney replacement therapy] were measured using Cox models for case-mix and laboratory variables. RESULTS The final analysis covered 485 participants with no loss to follow-up. The median follow-up period was 3.2 years. Two hundred and twenty-eight of the 485 patients reached ESKD requiring dialysis, and baseline serum creatinine levels doubled in another 31. The kidney end point was significantly poorer among patients with plasma BNP levels above, compared with below a cut-off value of 86.1 pg/mL indicated from receiver operating characteristic analysis. Multivariable Cox regression analysis identified the common logarithm BNP as a predictor of kidney end point (adjusted hazard ratio 1.78, 95% CI: 1.28-2.46, P < 0.01). CONCLUSIONS Elevation of BNP level is associated with an increased risk for accelerated progression of CKD ultimately to ESKD. Monitoring the BNP level could be helpful in the management of combined heart and kidney disease.

Microarray analysis of tonsils in immunoglobulin A nephropathy patients.

BACKGROUND Recently, combination of tonsillectomy and steroid pulse therapy was reported to be effective as the treatment of the immunoglobulin A nephropathy (IgAN). However, the gene expression difference between the tonsils in patients with IgAN and those in control patients is not established. METHODS We performed tonsillectomy combined with steroid pulse as a treatment to IgAN, analyzed the gene expression in the tonsils (N=23) using microarray, compared with those with patients suffering from chronic tonsillitis (N=22). From some candidate genes related with IgAN, we confirmed the apolipoprotein B messenger RNA-editing enzyme catalytic polypeptides 2 (APOBEC2) gene expression in the tonsil and we also analyzed its expression levels and clinical features. RESULTS Up-regulated genes seem to be categorized into two groups. One group belongs to the muscle related genes which might be caused by structural differences. The other group includes the immune system-related genes, such as APOBEC2, CALB2, DUSP27, and CXCL11. APOBEC2 was positively stained in the epithelium and the peripheral region of the germinal center in both tonsils. APOBEC2 expression level was negatively related with serum igg level, but did not correlate with clinical course after tonsillectomy. CONCLUSION We confirmed gene expression differences related with immune system and muscle structure. The APOBEC2 was confirmed to be elevated in the tonsils with IgAN patients, and the gene expression level was negatively related with serum igg level in overall patients. These results might be helpful to reveal the mechanism of IgAN.

Periodontal Disease Bacteria Specific to Tonsil in IgA Nephropathy Patients Predicts the Remission by the Treatment

Background Immunoglobulin (Ig)A nephropathy (IgAN) is the most common form of primary glomerulonephritis in the world. Some bacteria were reported to be the candidate of the antigen or the pathogenesis of IgAN, but systematic analysis of bacterial flora in tonsil with IgAN has not been reported. Moreover, these bacteria specific to IgAN might be candidate for the indicator which can predict the remission of IgAN treated by the combination of tonsillectomy and steroid pulse. Methods and Findings We made a comprehensive analysis of tonsil flora in 68 IgAN patients and 28 control patients using Denaturing gradient gel electrophoresis methods. We also analyzed the relationship between several bacteria specific to the IgAN and the prognosis of the IgAN. Treponema sp. were identified in 24% IgAN patients, while in 7% control patients (P = 0.062). Haemophilus segnis were detected in 53% IgAN patients, while in 25% control patients (P = 0.012). Campylobacter rectus were identified in 49% IgAN patients, while in 14% control patients (P = 0.002). Multiple Cox proportional-hazards model revealed that Treponema sp. or Campylobactor rectus are significant for the remission of proteinuria (Hazard ratio 2.35, p = 0.019). There was significant difference in remission rates between IgAN patients with Treponema sp. and those without the bacterium (p = 0.046), and in remission rates between IgAN patients with Campylobacter rectus and those without the bacterium (p = 0.037) by Kaplan-Meier analysis. Those bacteria are well known to be related with the periodontal disease. Periodontal bacteria has known to cause immune reaction and many diseases, and also might cause IgA nephropathy. Conclusion This insight into IgAN might be useful for diagnosis of the IgAN patients and the decision of treatment of IgAN.

Urinary type IV collagen in nondiabetic kidney disease.

Background: Type IV collagen is one of the major components of basement membrane. In diabetic nephropathy, it is already known that urinary excretion of type IV collagen increases with the disease progression. However, in nondiabetic kidney disease, urinary type IV collagen (u-IVc) levels have not been extensively investigated. The aim of this study was to evaluate u-IVc levels in various nephropathies except diabetic nephropathy. Methods: u-IVc levels were measured cross-sectionally from 527 biopsy-proven nondiabetic renal disease patients at tertiary care hospitals by one-step sandwich enzyme immunoassay. Results: On simple regression analyses, u-IVc levels had positive correlation with age, blood pressure, urinary protein (u-Prot), urinary β2 microglobulin, urinary N-acetyl-β-D-glucosaminidase, HbA1c, and selectivity index (SI), while u-IVc had negative correlation with eGFR and serum albumin. Multiple regression analyses revealed that u-IVc was positively correlated with u-Prot, HbA1c and SI. Among biopsy-proven nondiabetic nephropathies, elevation of u-IVc was distinctively observed in membranous nephropathy and anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. Conclusion: u-IVc levels were elevated with the increase in u-Prot, HbA1c and SI. In addition, among nondiabetic kidney disease, elevation of u-IVc was observed in patients with membranous nephropathy and ANCA, which might reflect the thickening of basement membrane or severe kidney damage.

Early plasma exchange for progressive liver failure in recipients of adult-to-adult living-related liver transplants.

Background/Aims: Little information is available concerning the effectiveness of plasma exchange for progressive liver failure in liver transplant recipients. The aims of the present study were to evaluate the effectiveness of plasma exchange and discuss its indication. Methods: Forty-six ABO-compatible recipients of living-related liver transplants operated on in Osaka University hospital were retrospectively studied. Results: Total bilirubin was identified as the most accurate predictor of the short-term prognosis of 46 recipients (optimal cut-off point: 13.3 mg/dl). Eleven patients received 14 plasma exchange sessions. Elevation of total bilirubin was significantly suppressed after plasma exchange in the patients with total bilirubin below the median (24 mg/dl), whereas total bilirubin significantly increased even after plasma exchange in those with total bilirubin above the median. Conclusion: Plasma exchange improved liver function in recipients with progressive liver failure and appears to be indicated in patients with total bilirubin levels ranging between 13 and 24 mg/dl.

Assessment of coronary stenosis by a 16-slice MDCT scanner in asymptomatic diabetic patients starting dialysis therapy.

Background: The accuracy for the detection of coronary stenosis by multidetector row computed tomography (MDCT) has been getting more recognition. However, the usefulness of MDCT in patients with chronic kidney disease (CKD) has not been confirmed. Methods: Weanalyzed 19 consecutive patients with asymptomatic diabetic CKD who underwent both MDCT and coronary angiography (CAG) at the initiation of dialysis. The definition of stenosis in this study was lesions with ≧50% stenosis by CAG. Results: CAG revealed stenosis in 35 of 76 branches in 19 patients. Vessel diameter could not be evaluated by MDCT in 11 (14%) major vessels because of motion artifacts, pericardial effusion, pleural effusion, and severe calcification. Almost all of such lesions were located in the right coronary (4/11; 36%) or left circumflex (5/11; 45%) artery. The sensitivity, specificity, positive and negative predictive values of MDCT for a diagnosis of stenosis in the 65 evaluable major vessels were 86, 81, 78, and 88%, respectively. The severity of vessel calcification was increased in a stepwise manner with increments in the proportion of major vessels with ≧50% stenosis (p = 0.004 for trend). Conclusion: MDCT seemed to be an effective non-invasive method of screening patients with diabetic CKD for CAD.

Successful Treatment of Tacrolimus (FK506)-Related Leukoencephalopathy with Cerebral Hemorrhage in a Patient Who Underwent Nonmyeloablative Stem Cell Transplantation

A 46-year-old woman with Hodgkin’s disease who underwent nonmyeloablative allogeneic stem cell transplantation developed cortical blindness, seizures, and left hemiparesis on day 100 while receiving tacrolimus (FK506) and prednisone for the treatment of graft-versus-host disease (GVHD). Magnetic resonance imaging revealed multiple changes, mainly in the bilateral occipital lobes, suggesting FK506-related leukoencephalopathy. These abnormalities improved after discontinuation of FK506. However, 3 days after the episode, cerebral hemorrhage in the left occipital lobe with perforation to the left subdural space occurred.Although FK506-induced leukoencephalopathy with cerebral hemorrhage is considered the more severe form of such leukoencephalopathy, the patient’s neurological symptoms almost completely resolved and radiographic findings improved after discontinuation of FK506, tapering of methylprednisolone, and initiation of mycophenolate mofetil. FK506-related leukoencephalopathy is a rare complication after allogeneic stem cell transplantation. Although the symptoms usually subside after discontinuation of FK506, therapeutic intervention in many cases may result in severe complications, including GVHD and vascular disease.We consider it important to use immunosuppressive agents without vascular endothelial toxicity for preventing the development of fatal GVHD after discontinuation of FK506.

CD16+CD56+ cells are a potential culprit for hematuria in IgA nephropathy

BackgroundHematuria is the first manifestation of urinary abnormality in immunoglobulin A nephropathy (IgAN). Hematuria has recently been reported as a risk factor for deterioration of renal function; however, its cause remains unknown.MethodsWe analyzed the surface marker of peripheral blood mononuclear cells before and immediately after tonsillectomy in IgAN patients and controls (chronic tonsillitis or tonsillar hypertrophy) by flow cytometry and investigated the association with hematuria. To prove our hypothesis that NK cells induce hematuria, we administered IL-12, activator of NK cells, to HIGA mice. In addition, we transferred cultured NK cells to nude rats and transferred the CD16+CD56+ cells, including NK cells, that are derived from the peripheral blood of IgAN patients immediately after tonsillectomy to nude rats to assess the hematuria level and renal histology of the recipients. We also performed cytotoxicity assays against glomerular endothelial cells by NK cells.ResultsWe found that IgAN patients who showed rapid deterioration of hematuria after tonsillectomy also displayed a significant increase in CD16+CD56+ cells in the peripheral blood immediately after tonsillectomy. Exogenous administration of IL-12 to HIGA mice induced hematuria. Adoptive transfer of either cells of an NK cell line, or of CD16+CD56+ cells derived from IgAN patients, into nude rats induced hematuria in the recipients. In vitro analysis showed that NK cells exert cytotoxic activity toward human glomerular endothelial cells in a dose-dependent manner.ConclusionsCD16+CD56+ cells seem to be responsible for hematuria in IgAN.

Specialist care and improved long-term survival of dialysis patients

BACKGROUND The quality of dialysis care provided by specialists is expected to be superior to that by nonspecialists. However, little is known about the actual effect of specialist care on long-term prognosis in dialysis patients. We sought to determine whether specialist care can actually be associated with better survival rates in a nationwide Japanese dialysis cohort. METHODS The Japanese Society for Dialysis Therapy (JSDT) has annually reported clinical and demographic variables of dialysis patients for each prefecture in Japan since 1983. We analysed the data for the 47 prefectures from 1983 to 2006 to evaluate the relationship between the proportion of specialists and the cumulative survival rates for 5-year periods. RESULTS Trend analyses revealed that a higher quintile of specialists was associated with a better cumulative survival rate at 5-, 10-, 15- and 20-year periods. Univariate analyses for the 47 prefectures showed a higher proportion of specialists to be correlated with a better cumulative survival at 10-, 15- and 20-year periods. Multivariate analyses revealed that the proportion of specialists persisted as an independent contributor for better survival at 10-, 15- and 20-year periods even after adjustment for age, sex, diabetes mellitus and socioeconomical status, while the survival rate at 5 years was at a nonsignificant level. CONCLUSIONS While our study should be confirmed using data for individuals, this was not possible due to privacy issues. Therefore, based on our current findings, we conclude that for patients on maintenance dialysis, specialist care can be associated with better survival rates, particularly with longer follow-up.