Toshihide Naganuma

The Prognostic Role of Brain Natriuretic Peptides in Hemodialysis Patients

Background: Although plasma concentrations of brain natriuretic peptides (BNP) increase in hemodialysis (HD) patients as well as patients with cardiovascular diseases (CD), the clinical significance of BNP in HD patients has yet to be elucidated. In this study, we investigated the pathophysiological significance of BNP in HD patients. Methods: Plasma BNP concentrations were measured in 164 HD patients after HD and 14 healthy volunteers. In 12 patients without CD, BNP was also measured before HD. Multiple regression analysis was performed to determine the important factors causing increased plasma BNP concentrations. Cardiac mortality was monitored for 36 months after baseline analysis, and the prognostic role of BNP was examined by Cox proportional hazards regression analysis. Results: Plasma BNP concentrations of HD patients without CD decreased significantly during HD session (124.5 ± 90.7 vs. 91.4 ± 67.6 pg/ml, mean ± SD, p = 0.004), but were still significantly higher than those of the healthy subjects (9.7 ± 9.2 pg/ml, p = 0.0002). Plasma BNP concentrations of patients with CD were significantly higher than of those without CD (579.6 ± 564.3 vs. 204.0 ± 241.5 pg/ml, p < 0.0001). Plasma BNP concentrations were also significantly higher in diabetes mellitus (DM) patients than in non-DM patients (514.1 ± 585.4 vs. 296.0 ± 347.0 pg/ml, p = 0.0031). Multiple regression analysis showed that left ventricular mass index (LVMI), CD and DM were independent factors for the elevated BNP (R2 = 0.303, p < 0.0001). During a 36-month follow-up period, cardiac death occurred in 13 patients. Kaplan-Meier survival estimates of patients from varying plasma BNP quartiles (<200, 200–450, 450–700 and >700 pg/ml) differed between the four groups (p < 0.0001). The group with the highest BNP level (>700 pg/ml) had the lowest survival. When compared with patients with BNP <200, the hazard ratios for cardiac death of patients with BNP of 200–450, 450–700 and >700 pg/ml were 2.3 [95% confidence interval (CI) 0.14–36.7], 18.7 (1.9–183.4) and 51.9 (6.5–416.3), respectively. The univariate Cox proportional hazards model showed that BNP, left ventricular ejection fraction, LVMI, age, DM, serum albumin and C-reactive protein (CRP) were significantly associated with the risk of cardiac mortality. By stepwise multivariate Cox proportional hazards analysis, only BNP, LVMI and CRP remained powerful independent predictors of cardiac death. The relative risk ratios were 1.002 (95% CI 1.001–1.002) for BNP, 2.192 (1.532–3.135) for CRP and 1.027 (1.013–1.042) for LVMI. Conclusion: High plasma BNP concentrations in HD patients were associated with volume overload, left ventricular hypertrophy, CD and DM. Plasma BNP concentration may be a useful parameter for assessing the risk of cardiac death in HD patients by providing prognostic information independently of other variables previously reported.

Silent Cerebral Infarction in Hemodialysis Patients

Background: Cerebrovascular diseases are very common in hemodialysis (HD) patients. Silent cerebral infarction (SCI) has not been investigated in HD patients although it may be a significant risk factor for cerebrovascular diseases. Hypothesis: Chronic renal failure may be an independent risk factor for SCI and cerebrovascular diseases. Methods: Cranial magnetic resonance imaging (MRI) was performed on 123 HD patients without symptomatic cerebrovascular disease and on 52 control subjects. We investigated the prevalence of SCI and performed cross-sectional study using multiple logistic analysis to assess the relationship between SCI and the risk factors. Results: The prevalence of SCI was significantly higher in HD patients than in the healthy control group (60 patients (48.8%) vs. 5 patients (9.6%), χ2 = 22.4, p < 0.0001). Multiple logistic regression analysis with all subjects showed that independent risk factors of SCI were chronic renal failure, hypertension, smoking and age (R2 = 0.468, p < 0.0001). In only the HD patient group, age and smoking were shown to be independent risk factors of SCI (R2 = 0.378, p < 0.0001) while HD duration and hypertension were not. Conclusions: The findings of the present study indicate that chronic renal failure maintained by hemodialysis increases the prevalence of SCI and that age and smoking habits are also significantly associated with SCI in HD patients.

Cerebral microbleeds in predialysis patients with chronic kidney disease

BACKGROUND Gradient-echo T2*-weighted magnetic resonance imaging (T2*-weighted MRI) is highly sensitive for detecting cerebral microbleeds (CMBs). CMBs have been reported to be a risk factor for future cerebrovascular events and a marker of cerebral small vessel disease in the general population. Chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease. The relationship between CKD and CMBs, which has not been clarified to date, is examined. METHODS In this cross-sectional study, T2*-weighted MRI of brain was performed with a 1.5-T MRI system in 162 CKD patients (CKD stages 1-5, excluding CKD stage 5(D)) and 24 normal subjects. RESULTS CMBs were found in 35 CKD patients (25.6%), but not in control subjects. CMBs were more prevalent in male patients, in those with higher blood pressure, advanced age and poor kidney function. There was a significant association between the prevalence of CMBs and the CKD stage, with higher prevalence of CMBs as the CKD stages advanced (P < 0.01). Estimated glomerular filtration rate was a significant factor associated with the prevalence of CMBs, independent of age, gender and hypertension. There was no significant relationship between CMBs and the presence of diabetes mellitus and dyslipidemia. CONCLUSIONS Decreased renal function is a significant risk factor for CMBs, independent of the presence of hypertension. Poor kidney function could be associated with future cerebrovascular events.

Desensitization Protocol in Highly HLA-Sensitized and ABO-Incompatible High Titer Kidney Transplantation

BACKGROUND A positive crossmatch indicates the presence of donor-specific alloantibodies and is associated with a graft loss rate of >80%; anti-ABO blood group antibodies develop in response to exposure to foreign blood groups, resulting in immediate graft loss. However, a desensitization protocol for highly HLA-sensitized and ABO-incompatible high-titer kidney transplantation has not yet been established. METHODS We treated 6 patients with high (≥1:512) anti-A/B antibody titers and 2 highly HLA-sensitized patients. Our immunosuppression protocol was initiated 1 month before surgery and included mycophenolate mofetil (1 g/d) and/or low-dose steroid (methylprednisolone 8 mg/d). Two doses of the anti-CD20 antibody rituximab (150 mg/m(2)) were administered 2 weeks before and on the day of transplantation. We performed antibody removal with 6-12 sessions of plasmapheresis (plasma exchange or double-filtration plasmapheresis) before transplantation. Splenectomy was also performed on the day of transplantation. Postoperative immunosuppression followed the same regimen as ABO-compatible cases, in which calcineurin inhibitors were initiated 3 days before transplantation, combined with 2 doses of basiliximab. RESULTS Of the 8 patients, 7 subsequently underwent successful living-donor kidney transplantation. Follow-up of our recipients showed that the patient and graft survival rates were 100%. Acute cellular rejection and antibody-mediated rejection episodes occurred in 1 of the 7 recipients. CONCLUSIONS These findings suggest that our immunosuppression regimen consisting of rituximab infusions, splenectomy, plasmapheresis, and pharmacologic immunosuppression may prove to be effective as a desensitization protocol for highly HLA-sensitized and ABO-incompatible high-titer kidney transplantation.

A novel approach to successful ABO-incompatible high-titer renal transplantation.

BACKGROUND Currently the long-term outcome among recipients of ABO-incompatible renal transplantations is excellent in Japan. However, previous reports have documented poor outcomes in patients with high (> 1:256) anti-A/B antibody titers pretreatment. The immunosuppressive protocol for ABO-incompatible high-titer renal transplantation has remained a medical challenge. METHODS We treated 3 patients with high (> 1:512) anti-A/B antibody titers prior to ABO-incompatible renal transplantation. Our immunosuppressive protocol was initiated 1 month prior to surgery and included mycophenolate mofetil (1 g/d) and low-dose steroid (methylprednisolone [8 mg/d]). Two doses of the anti-CD20 antibody rituximab, (150 mg/m2) were administered 2 weeks before and on the day of transplantation. We performed antibody removal with 6 to 8 sessions of plasmapheresis (plasma exchange or double-filtration plasmapheresis) before transplantation. Splenectomy was also performed on the day of transplantation. Postoperative immunosuppression followed the same regimen as ABO-compatible cases, in which calcineurin inhibitors were initiated 3 days before transplantation combined with 2 doses of basiliximab. RESULT With this protocol, the anti-A/B antibody was reduced to below 1:16 in all cases. All 3 patients underwent successful transplantation with a mean current serum creatinine of 1.32 mg/dL (range, 1.22-1.50 mg/dL). There were no episodes of antibody-mediated rejection. No serious complications or side effects were encountered. CONCLUSIONS A preconditioning protocol consisting of rituximab infusions, splenectomy, plasmapheresis, and pharmacologic immunosuppression enabled ABO-incompatible renal transplantation in patients with high (> 1:512) anti-A/B antibody titer.

Excellent Outcomes of ABO-Incompatible Kidney Transplantation: A Single-Center Experience

INTRODUCTION Due to the severe shortage of deceased donors in Japan, ABO-incompatible living donor kidney transplantation has been performed since the late 1980s. Excellent long-term outcomes have been achieved; the rates of graft survival among these patients are currently similar to those of recipients of ABO-compatible grafts. Our single-center experience describing the immunosuppressive protocols, complications, and grafts survivals is documented in this study. PATIENTS AND METHODS Among 123 patients with end-stage renal disease who underwent living donor kidney transplantation between January 1999 and December 2010, 25 cases were ABO-incompatible grafts. All of these patients were followed until August 2011. Analyzing these patients, we focused on their immunosuppressive protocols, complications, and graft survivals. RESULTS Patient and graft survival rates were 100%. One patient experienced antibody-mediated rejection and an intractable acute cellular rejection episode, 1 patient an antibody-mediated rejection, and 6 patients had acute cellular rejection episodes. However, there were no severe complications. CONCLUSION Although ABO-incompatible kidney transplantation is a high-risk procedure, a short-term graft survival rate of 100% may be expected due to recent significant improvements in desensitization and recipient management.

Decreased Kidney Function Is a Significant Factor Associated with Silent Cerebral Infarction and Periventricular Hyperintensities

Background/Aims: Silent cerebral lacunar infarction (SCI) and periventricular hyperintensities (PVH) have been reported to be markers of ischemic cerebral small-vessel disease and risk factors for future cerebrovascular events in the general population. The relationship between CKD and SCI/PVH is examined. Methods: In this cross-sectional study, brain magnetic resonance imaging was performed with a 1.5-T system in 324 predialysis CKD patients and in 60 normal subjects. Results: SCI was found in 103 CKD patients (31.8%), and PVH was found in 174 CKD patients (53.7%). SCI/PVH were more prevalent in patients with higher blood pressure, advanced age and decreased kidney function. There was a significant association between the prevalence of SCI/PVH and the CKD stage, with greater prevalence of SCI/PVH as the CKD stage advanced (p < 0.0001). PVH grade also advanced as the CKD stage advanced. The estimated glomerular filtration rate was a significant factor associated with the presence of SCI/PVH, independent of any other factors. There was a strong association between the prevalence of SCI/PVH (p < 0.0001). Conclusion: In CKD patients, decreased kidney function is a significant factor associated with SCI/PVH, both of which are significantly associated with each other. These results suggest that CKD patients with SCI/PVH are at greater risk of future cerebrovascular events.

The prevalence of metabolic syndrome in Japanese renal transplant recipients.

Background:  The prevalence of metabolic syndrome (MS) after renal transplantation has yet to be elucidated. In the present study, we investigated the prevalence of MS in Japanese renal transplant recipients.

Factors associated with silent cerebral microbleeds in hemodialysis patients.

BACKGROUND The recent development of gradient-echo T2*-weighted magnetic resonance imaging (MRI) has enabled the highly accurate detection of prior cerebral microbleeds (CMBs), which might indicate a higher risk of future intracerebral hemorrhage (ICH) and be a marker of cerebral small-vessel disease in the general population. The present study investigated the clinical factors associated with the presence of CMBs in hemodialysis (HD) patients. METHODS Cranial MRI, including T2*-weighted MRI, was performed on 179 HD patients without symptomatic cerebrovascular disease and 58 healthy control subjects, and we investigated the prevalence of CMBs and clinical factors associated with the presence of CMBs. We also investigated the relationship between CMBs and other cerebral small-vessel diseases. RESULTS The prevalence of CMBs was significantly higher in the HD patients than in the healthy subjects (45 patients (25.1%) vs. none in the healthy controls (0%), p < 0.0001). Multiple logistic regression analysis showed that independent and significant factors associated with the presence of CMBs were age, systolic blood pressure, diastolic blood pressure and pulse pressure. Moreover, the presence of CMBs correlated significantly with the presence of lacunar infarcts, periventricular hyperintensity and deep and subcortical white matter hyperintensity. CONCLUSIONS These findings indicated a high prevalence of CMBs among HD patients, and that older age and high blood pressure were strong factors associated with the presence of CMBs. Moreover, CMBs were closely associated with other cerebral small-vessel diseases.

Conversion of Stable Kidney Transplant Recipients From a Twice-Daily Prograf to a Once-Daily Tacrolimus Formulation: A Short-Term Study on its Effects on Glucose Metabolism

BACKGROUND The adverse effects of tacrolimus are known to play major roles in posttransplantation diabetes mellitus (PTDM). In the present study, we investigated the effects of conversion from a twice-daily (Tac BID) to a once-daily prolonged release of tacrolimus formulation (Tac OD) on glucose metabolism in stable kidney transplant recipients. PATIENTS AND METHODS In this prospective study, 26 patients converted from Tac BID to the same milligram-milligram daily dose of Tac OD were examined for the effects on renal function, drug trough levels, and glucose metabolism over a 4-week period. RESULTS Conversion from Tac BID to Tac OD on a 1:1 mg basis resulted in a significant decrease in tacrolimus trough levels, but no significant changes in renal function. At 4 weeks after conversion, a homeostasis model assessment of β-cell function, and hemoglobin A1c (HbA1c) decreased significantly. CONCLUSIONS This study demonstrated a significant reduction in tacrolimus trough levels after switching from Tac BID to Tac OD, which increased insulin secretion and decreased HbA1c, suggesting that it may decrease the frequency of PTDM among stable renal transplant recipients.