Shigehisa Koide

Urinary neutrophil gelatinase-associated lipocalin as a predictor of cardiovascular events in patients with chronic kidney disease

Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular (CV) events. Recently, elevated neutrophil gelatinase-associated lipocalin (NGAL) levels have been reported in patients with heart failure, coronary heart disease, or stroke. Our aim was to assess urinary NGAL as a predictor of CV events in patients with CKD. This was a prospective observational cohort study of 404 patients with predialysis CKD. CV events were defined as CV death, acute coronary syndrome, hospitalization for worsening heart failure, stroke and dissection of aorta. During a mean follow-up period of 33 months, 77 CV events (19.1 %) occurred. After adjustment for gender, age, diabetes, previous cardiovascular disease, urinary albumin/creatinine ratio (UACR), estimated glomerular filtration rate, hemoglobin, and high-sensitivity C-reactive protein, patients with the other quartiles of urinary NGAL had significantly higher risk of CV events compared with patients with the lowest quartile (hazard ratio (HR) 2.81, 95 % confidence interval (CI) 1.01–7.81, P = 0.047 for Q2, HR 3.31, 95 % CI 1.22–9.00, P = 0.019 for Q3, and HR 3.27, 95 % CI 1.15–9.29, P = 0.026 for Q4). Regarding the combination of urinary NGAL with UACR, we also stratified patients into four groups according to whether the level of each marker was above or below the median (61.8 μg per gram creatinine (gCr) for NGAL and 351.1 mg/gCr for UACR). Four-year CV event-free survival rates were 89.2, 79.6, 71.8, and 51.5 % in order for the four respective groups (P < 0.0001). Elevated urinary NGAL was able to predict future CV events in CKD patients, and had incremental predictive value with elevated UACR.

Plasma Neutrophil Gelatinase-Associated Lipocalin as a Predictor of Cardiovascular Events in Patients with Chronic Kidney Disease.

Background. Our aim was to assess plasma neutrophil gelatinase-associated lipocalin (NGAL) as a predictor of cardiovascular (CV) events in patients with chronic kidney disease (CKD) and no history of CV events. Methods. This was a prospective observational cohort study of 252 patients with predialysis CKD. CV events were defined as CV death, acute coronary syndrome, and hospitalization for worsening heart failure, stroke, and aortic dissection. Results. During a median follow-up period of 63 months, 36 CV events occurred. On Cox stepwise multivariate analysis, plasma NGAL and B-type natriuretic peptide (BNP) were significant predictors of CV events. Kaplan-Meier incidence rates of CV event-free survival at 5 years were 96.6%, 92.9%, 85.9%, and 61.3%, respectively, among quartiles of plasma NGAL (P < 0.0001). The C-index for the receiver-operating characteristic curves for CV events was greater when plasma NGAL was added to an established risk model (0.801, 95% CI 0.717–0.885), compared to the model without plasma NGAL (0.746, 95% CI 0.653–0.840, P = 0.021). Conclusion. Elevated plasma NGAL could predict future CV events in CKD patients with no history of CV events and add incremental value to the established risk model.

Efficacy of Granulocytapheresis and Leukocytapheresis for the Treatment of Microscopic Polyangiitis

Abstract:  We evaluated the efficacy of granulocytaperesis and leukocytapheresis for the treatment of rapidly progressive glomerulonephritis (RPGN) and lung hemorrhage caused by microscopic polyangiitis. Three patients with RPGN were treated by granulocytapheresis (GCAP) and five patients with RPGN were treated by leukocytapheresis (LCAP). The prednisolone dose was 0.4 ± 0.2 g/kg/day (mean ± SD; range 0.2–0.8 g/kg/day). Pre‐treatment serum creatinine was 3.2 ± 1.4 mg/dL (1.4–5.1 mg/dL). The patients were followed for a mean period of 15 ± 6 months (6–23 months). Renal function improved in five of the eight RPGN patients. Three lung hemorrhage episodes in two different patients were treated with GCAP and one lung hemorrhage episode was treated with LCAP combined with various doses of corticosteroids. All four lung hemorrhage episodes were ameliorated. We concluded that combined therapy of GCAP or LCAP and corticosteroids is effective for the treatment of RPGN and lung hemorrhage due to microscopic polyangiitis.

Suppression of parathyroid hormone secretion in CAPD patients by intraperitoneal administration of Maxacalcitol.

BackgroundMaxacalcitol (22-oxacalcitriol; OCT) is a novel vitamin D analogue. In previous clinical studies, OCT was administered three times a week to hemodialysis patients with refractory secondary hyperparathyroidism (2HPT), in whom it acted by inhibiting parathyroid hormone secretion, as well as causing mildly elevated serum calcium. However, intravenous injection of OCT, which requires frequent visits to the outpatient clinic, degrades the quality of life of patients with continuous ambulatory peritoneal dialysis (CAPD) who otherwise visit the clinic only once or twice per month. In the present study, we investigated whether transperitoneal absorption of OCT inhibited intact parathyroid hormone (i-PTH) in CAPD patients when the OCT was added to the peritoneal dialysis fluid.MethodsPeritoneal dialysis fluid containing 20 µg of OCT was injected into the peritoneal cavity of five CAPD patients. The serum and peritoneal fluid levels of OCT, i-PTH, calcium, and phosphate were measured before and after treatment.ResultsThe mean concentration of OCT in peritoneal dialysis fluid rapidly decreased, from 25268.0 pg/ml at 0 h to 1694.0 pg/ml at 2 h and 44.9 pg/ml at 4 h. In contrast, the mean serum OCT level increased from the pretreatment level, which was below the detection limit of the assay, to 656.0 pg/ml at 0.5 h and a peak of 759.0 pg/ml at 1 h, and thereafter gradually decreased, to 713.8 pg/ml at 2 h and 555.8 pg/ml at 4 h. Mean i-PTH significantly decreased, to 83.9% of the baseline level, at 1 h (P < 0.05) and thereafter stayed at around 90%. No consistent trends in calcium and phosphate levels were observed in the five patients.ConclusionsBy injecting OCT into the peritoneal cavity, i-PTH levels could be significantly decreased. These findings indicate the therapeutic efficacy of intraperitoneal administration of OCT for CAPD patients.

Acute renal failure after exercise in a patient with renal hypouricemia

Abstract A 22-year-old man had recurrent exercise-induced acute renal failure (ARF). He was found to have isolated renal hypouricemia: serum uric acid level was 0.7–1.0 mg/dl and fractional excretion of uric acid (FEUA) was 37%–43%. He showed no suppression of FEUA following the the administration of pyrazinamide, and no increase of FEUA after benzbromarone, suggesting a subtotal defect. We investigated renal function, FEUA, and serum nitric oxide after a treadmill exercise test in our patient and two control subjects. On the day after the exercise test, plain and enhanced abdominal computed tomography (CT) scans were performed in our patient. During the arterial phase, early equilibration phase, equilibration phase, and 2, 6, and 24 h after the injection of contrast medium, renal CT scans were performed at the same slice level. Although ARF was not induced by this level of exercise, the CT scans showed patchy contrast enhancement 2, 6, and 24 h after contrast medium administration. This finding suggests that patchy renal vasoconstriction may occur in patients with renal hypouricemia after strenuous exercise, even in the setting of normal creatinine clearance.

The Level of IgA Antibodies to Endothelial Cells Correlates with Histological Evidence of Disease Activity in Patients with Lupus Nephritis

Anti-endothelial cell antibodies (AECA) are frequently detected in patients with systemic lupus erythematosus (SLE), but their pathological role remains unclear. We recently developed a solubilized cell surface protein capture enzyme-linked immunosorbent assay (CSP-ELISA) to detect antibodies against membrane proteins involved in autoimmune reactions. In this study, sera from 51 patients with biopsy-proven lupus nephritis (LN), 25 with SLE without renal involvement (non-LN SLE), 42 disease control (DC) subjects, and 80 healthy control (HC) subjects were tested for IgG- and IgA-AECA for human umbilical vein endothelial cells (HUVEC) and human glomerular EC (HGEC) by using CSP-ELISA. IgG- and IgA-AECA titers were significantly higher in LN and non-LN SLE patients than in the DC or HC (P < 0.001) groups. IgG- and IgA-AECA titers for HUVEC corresponded well with those for HGEC. The IgA-AECA level correlated with the SLE disease activity index and with histological evidence of active lesions (cellular proliferations, hyaline thrombi and wire loops, leukocytic infiltration, and fibrinoid necrosis) in LN patients (P < 0.001). The sensitivity of IgA-AECA as a diagnostic test for histological evidence of active lesions in LN patients was 0.92, with a specificity of 0.70. The significant correlation of IgA-AECA with glomerular hypercellularity indicates that IgA-AECA are associated with endothelial damage in LN.

Combination Therapy with Renin-Angiotensin System Blockers and Vitamin D Receptor Activators for Predialysis Patients Is Associated with the Incidence of Cardiovascular Events after Dialysis Initiation: A Multicenter Nonrandomized Prospective Cohort Study

Background: Several human studies reported that the combined use of renin-angiotensin system blockers (RASBs) and vitamin D receptor activators (VDRAs) resulted in decreased urinary protein excretion. However, it is unknown whether this combination therapy influences the incidence of cardiovascular (CV) events in dialysis patients. Methods: The study was a multicenter nonrandomized prospective cohort analysis including 1,518 patients. Patients were classified into 4 groups based on medications prescribed before dialysis initiation: those who did not receive RASBs or oral VDRAs (N group), those receiving only RASBs, those receiving only VDRAs, and those receiving a combination of RASBs and VDRAs (RD group). CV events after dialysis initiation were compared using the log-rank test. Factors contributing to the incidence of CV events were examined using multivariate Cox proportional hazard regression analysis. Results: Significant differences were observed in the incidence of CV events and all-cause mortality between the 4 groups (p = 0.021 and p = 0.001, respectively). Cox proportional hazard analysis revealed that the incidence of CV events was significantly lower in the RD group than in the N group (hazard ratio [HR] = 0.65, 95% confidence interval [CI]: 0.50-0.86, p = 0.002). Multivariate analysis revealed that the incidence of CV events was significantly lower in the RD group than in the N group (HR = 0.66, 95% CI: 0.47-0.93, p = 0.016). Conclusion: Combination therapy with RASBs and VDRAs in patients before dialysis initiation was associated with a reduction in CV events during maintenance dialysis.

Relationship between history of coronary heart disease at dialysis initiation and onset of events associated with heart disease: a propensity-matched analysis of a prospective cohort study

BackgroundChronic kidney disease (CKD) is an independent risk factor for cardiovascular disease (CVD) events, and a number of reports have shown a relationship between CKD and CVD in pre-dialysis or maintenance dialysis patients. However, few studies have reported serial observations during dialysis initiation and maintenance. Therefore, we examined whether the incidence of heart disease events differed between CKD patients with and without a history of coronary heart disease (CHD) at dialysis initiation.MethodsThe subjects were patients in the 17 centers participating in the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis (AICOPP) from October 2011 to September 2013. We excluded nine patients whose outcomes were unknown, as determined by a survey conducted at the end of March 2015. Thus, we enrolled 1,515 subjects into the study. We classified patients into 2 groups according to the history of CHD (i.e., a CHD group and a non-CHD group). Propensity scores (PS) represented the probability of being assigned to a group with or without a history of CHD. Onset of heart disease events and associated mortality and all-cause mortality were compared in PS-matched patients by using the log-rank test for Kaplan-Meier curves. Factors contributing to heart disease events were examined using stepwise multivariate Cox proportional hazards analysis.ResultsThere were 254 patients in each group after PS-matching. During observation, heart disease events occurred in 85 patients (33.5%) in the CHD group and 48 (18.9%) patients in the non-CHD group. The incidence was significantly higher in the CHD group (p < 0.0001). The CHD group was associated with higher incidence of heart disease events (vs. the non-CHD group, hazard ratio = 1.750, 95% confidence interval = 1.160–2.639). In addition, comorbidities such as diabetes mellitus, low body mass index, and low serum high-density lipoprotein cholesterol were associated with higher incidence of events.ConclusionHistory of CHD at dialysis initiation was associated with a higher incidence of heart disease events and mortality and all-cause mortality.Trial registrationUMIN 000007096. Registered 18 January 2012.

A retrospective study on the outcomes of MPO-ANCA-associated vasculitis in dialysis-dependent patients

Objectives. This study investigated the clinical course of myeloperoxidase-antineutrophil cytoplasm autoantibody (MPO-ANCA)-associated vasculitis after starting dialysis. Methods. A retrospective review was conducted of the clinical charts of dialysis-dependent patients with MPO-ANCA-associated vasculitis who attended one of 8 associated clinics over the past 21 years. Results. Eighty-nine patients were included in the study; 88 had microscopic polyangiitis (MPA) and 1 had granulomatosis with polyangiitis. Of the 88 patients with MPA, 18 had renal-limited vasculitis. Twenty-one relapses occurred among 13 patients (frequency, 0.05 relapses/person-year; 95% confidence interval, 0.03–0.08). Mean time from start of dialysis to relapse was 65 ± 59 months. Cox multivariate analysis showed that pulmonary involvement was a predictor of relapse (hazard ratio [HR], 21.4) and mortality (HR, 4.60), and that patient age (HR, 1.10) and cyclophosphamide use (HR, 0.20) were significant predictors of mortality. Postdialysis 1- and 5-year survival rates were 83.0% and 65.6%, respectively; infection was the most frequent cause of death. Conclusion. Pulmonary involvement was a predictor of relapse and mortality. Although relapse can occur long after the start of dialysis, incidence was low among dialysis-dependent patients. Prolonged maintenance immunosuppressive therapy might be limited to patients with pulmonary involvement in dialysis-dependent ANCA-associated vasculitis.

Association between resting heart rate just before starting the first dialysis session and mortality: A Multicenter Prospective Cohort Study

Some observational studies of the general population showed that resting heart rate was associated with mortality. However, the relationship was unclear in dialysis patients.