Mitsuru Ichii

Relationship Between Serum Sclerostin, Bone Metabolism Markers, and Bone Mineral Density in Maintenance Hemodialysis Patients

BACKGROUND Sclerostin, which is secreted exclusively by osteocytes, is a negative regulator of bone formation. The role of sclerostin in chronic kidney disease-mineral and bone disorder is not well known. In the present study, we examined the relationship between serum sclerostin levels, bone turnover markers, and bone mineral density (BMD) of the radius in maintenance hemodialysis patients. METHODS This was a cross-sectional study that analyzed sclerostin, bone alkaline phosphatase (a bone formation marker), and tartrate-resistant acid phosphatase 5b (a bone resorption marker) in stored serum samples from 181 hemodialysis patients (age, 68 ± 11 y; 105 males and 76 females; hemodialysis duration, 6.9 ± 5.9 y). The BMD in the distal one-third of the radius and in the ultradistal radius, which are enriched with cortical and cancellous bone, respectively, was examined by dual-energy x-ray absorptiometry. RESULTS Serum sclerostin was 125 ± 53 pmol/L (mean ± SD). Serum sclerostin correlated significantly and negatively with serum bone alkaline phosphatase and tartrate-resistant acid phosphatase 5b (r = -0.265, P < .001; r = -0.218, P < .01, respectively). The BMD in the distal one-third of the radius and in the ultradistal radius both correlated significantly and positively with serum sclerostin levels (r = 0.454, P < .0001; r = 0.329, P < .0001, respectively). In multiple regression analysis, serum sclerostin was associated significantly and independently with BMD of both parts of the radius (β = 0.200, P < .001; β = 0.218, P < .05), after adjustment for age, hemodialysis duration, and bone metabolism markers. CONCLUSION Serum sclerostin was associated significantly, independently, and positively with BMD of both cortical and cancellous bone. Sclerostin is considered to be one of the factors associated with chronic kidney disease-mineral and bone disorder in hemodialysis patients.

Poor Glycemic Control Is a Major Factor in the Overestimation of Glomerular Filtration Rate in Diabetic Patients

OBJECTIVE Serum creatinine levels are lower in diabetic patients compared with their nondiabetic counterparts. Therefore, estimated glomerular filtration rate (eGFR) is higher in the former than in the latter group. Factors associated with overestimation of renal function in diabetic patients were examined, and new formulae reflecting precise eGFR were created. RESEARCH DESIGN AND METHODS Eighty subjects (age 56.5 ± 15.4 years; 35 males [43.8%]; 40 patients with diabetes and 40 nondiabetic subjects) were enrolled. GFR was evaluated by inulin clearance (Cin). eGFR values were calculated based on serum creatinine and/or serum cystatin C levels. The factors related to the dissociation between eGFR and Cin in diabetic patients and the agreement among each of three eGFR and Cin were compared. RESULTS Although Cin was not significantly different between the diabetic and nondiabetic subjects (P = 0.2866), each of three eGFR measures from the diabetic patients was significantly higher than that of the nondiabetic subjects (P < 0.01). There were significant and positive correlations between the ratio of each eGFR/Cin, hemoglobin A1c, and glycated albumin. The intraclass correlation coefficients in diabetic patients were weaker than those in the nondiabetic subjects, and the intercepts of the regression lines between each eGFR measure and Cin in the diabetic patients were significantly higher than those of the nondiabetic subjects. New formulae for the calculation of eGFR corrected by the glycemic control indices were better than the original eGFR, particularly in diabetic patients. CONCLUSIONS eGFR overestimates Cin as glycemic controls worsen. eGFR corrected by hemoglobin A1c is considered to be clinically useful and feasible.

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.

Relationship between serum TSH levels and intrarenal hemodynamic parameters in euthyroid subjects.

OBJECTIVE Low thyroid function may be associated with a reduced glomerular filtration rate (GFR) calculated on the basis of creatinine metabolism. Thyroid hormone directly affects serum creatinine in muscle and low thyroid function might exert a similar direct effect in the kidney. The goal of the study was to evaluate this possibility by assessment of the inulin-based GFR and to examine the mechanism underlying the reduction of GFR. PATIENTS AND METHODS Renal and glomerular hemodynamics were assessed by simultaneous measurements of plasma clearance of para-aminohippurate (CPAH) and inulin (Cin) in 26 patients with serum creatinine <1.00 mg/dl and without thyroid disease. All subjects were normotensive with or without antihypertensive treatment and were kept in a sodium-replete state. Renal and glomerular hemodynamics were calculated using Gomezs formulae. RESULTS Serum TSH, including within the normal range (0.69-4.30 μIU/ml), was positively correlated with vascular resistance at the afferent arteriole (Ra) (r=0.609, P=0.0010), but not at the efferent arteriole (Re). Serum TSH was significantly and negatively correlated with renal plasma flow (RPF), renal blood flow (RBF), and GFR (r=-0.456, P=0.0192; r=-0.438, P=0.0252; r=-0.505, P=0.0086 respectively). In multiple regression analysis, serum TSH was significantly positively associated with Ra after adjustment for age and mean blood pressure. CONCLUSIONS These findings suggest that low thyroid function, even within the normal range, is associated with reduced RPF, RBF, and GFR, which might be caused by a preferential increase in Ra.

Impaired Response of FGF-23 to Oral Phosphate in Patients with Type 2 Diabetes: A Possible Mechanism of Atherosclerosis

BACKGROUND Fibroblast growth factor (FGF)-23, secreted from osteocytes/osteoblasts, plays major roles in phosphate (Pi)-mediated stimulation of PTH secretion and consequently in regulation of serum Pi. Osteocyte/osteoblast dysfunction develops in patients with type 2 diabetes mellitus (DM). OBJECTIVE Our objective was to examine whether increases in serum FGF-23 and PTH after oral Pi stimulation are impaired in type 2 DM. DESIGN AND METHODS The subjects were 10 DM and 10 non-DM patients without chronic kidney disease stage 3-5. Serum FGF-23, intact PTH (iPTH), and Pi were measured serially after oral Pi administration at a daily dose of 2.0 g. RESULTS Pi administration caused significant increases of FGF-23 by 2 h and iPTH by 4 h in non-DM patients. These increases were attenuated in DM patients. After 2 d of Pi stimulation, serum FGF-23 and iPTH remained elevated in non-DM patients but not in DM. In all subjects, initial changes of serum FGF-23 (0-2 h) and iPTH (0-4 h) were positively correlated (r = 0.528) and showed significant negative correlations with later changes in serum Pi (2-4 h) (r = -0.457 and r = -0.673, respectively). Serum Pi (2-4 h) significantly increased in DM patients, consistent with the lack of change in serum FGF-23 and iPTH, whereas serum Pi did not change significantly in non-DM patients. CONCLUSION These results show that increases of serum FGF-23 and PTH in response to Pi stimulation are impaired in type 2 DM and that serum Pi is significantly increased thereafter. This may be a mechanism underlying advanced atherosclerosis in type 2 DM.

Greater potency of darbepoetin‐α than erythropoietin in suppression of serum hepcidin‐25 and utilization of iron for erythropoiesis in hemodialysis patients

The potency of darbepoetin‐α (DPO‐α) to improve anemia in hemodialysis (HD) patients is greater than that of recombinant human erythropoietin (rHuEPO).

Decreases in parathyroid gland volume after cinacalcet treatment in hemodialysis patients with secondary hyperparathyroidism.

Background/Aim: Cinacalcet, an allosteric modulator of the calcium-sensing receptor, effectively reduces serum parathyroid hormone (PTH). It was examined whether a regression of parathyroid glands in hemodialysis patients with secondary hyperparathyroidism was induced by cinacalcet treatment. Methods: Ultrasonography of the parathyroid glands was performed to examine the changes in the parathyroid gland volumes after cinacalcet treatment in 58 patients. Results: After cinacalcet treatment, serum calcium, phosphate, alkaline phosphatase, and intact PTH significantly decreased (p < 0.0001). The total volumes of the parathyroid glands were significantly decreased 6 months after cinacalcet treatment (942 ± 747 vs. 708 ± 550 mm3, p < 0.0005). There was a significant positive correlation between the parathyroid gland volumes at the start of cinacalcet treatment and the volume reduction in parathyroid glands (r = 0.716, p < 0.0001). Of the 58 patients, the total parathyroid gland volume was decreased in 42 patients and increased in 16 although the doses of cinacalcet, phosphate binders or vitamin D were not significantly different. In both groups, the intact PTH serum levels were significantly decreased after cinacalcet treatment. Conclusion: Cinacalcet treatment in patients with secondary hyperparathyroidism significantly reduced the total parathyroid gland volume in a short 6-month period. This study suggests that cinacalcet treatment may postpone parathyroidectomy and/or reduce cases.

Relationship between serum uric acid levels and intrarenal hemodynamic parameters.

Background/Aims: Hyperuricemia has been reported to affect renal hemodynamics in rat models. We evaluate the relationship between serum uric acid and intrarenal hemodynamic parameters in humans, utilizing the plasma clearance of para-aminohippurate (CPAH ) and inulin (Cin). Methods: Renal and glomerular hemodynamics were assessed by simultaneous measurement of CPAH and Cin in 58 subjects. Of these, 19 subjects were planned to provide a kidney for transplantation; 26 had diabetes without proteinuria; and 13 had mild proteinuria. Renal and glomerular hemodynamics were calculated using Gomez`s formulae. Results: Cin was more than 60 ml/min/1.73m2 in all subjects. Serum uric acid levels correlated significantly with vascular resistance at the afferent arteriole (Ra) (r = 0.354, p = 0.006) but not with that of the efferent arteriole (Re). Serum uric acid levels (β = 0.581, p = <0.001) were significantly and independently associated with Ra after adjustment for several confounders (R2 = 0.518, p = <0.001). Conclusions: These findings suggest, for the first time in humans, that higher serum uric acid levels are associated significantly with Ra in subjects with Cin > 60 ml/min/1.73m2. The increase in Ra in subjects with higher uric acid levels may be related to dysfunction of glomerular perfusion.

Poor glycemic control and decreased renal function are associated with increased intrarenal RAS activity in Type 2 diabetes mellitus.

AIMS The renin-angiotensin system (RAS) plays an important role in the pathogenesis of diabetic nephropathy. The aim of the present study was to investigate intrarenal RAS activity in patients with type 2 diabetes (T2DM). METHODS We measured urinary angiotensinogen, a reliable biomarker of intrarenal RAS activity, in 14 controls without T2DM, 25 T2DM patients without nephropathy, 11 chronic kidney disease (CKD) patients without T2DM and 46 CKD patients with T2DM. Associations between urinary angiotensinogen and clinical parameters were examined. RESULTS Compared with the controls, urinary [angiotensinogen:creatinine] were significantly higher in T2DM patients without nephropathy (4.70 ± 2.22 vs. 8.31 ± 5.27 μg/g, p=0.037). Age, hemoglobin A1c (HbA1c) and fasting plasma glucose correlated significantly and positively with the log{urinary [angiotensinogen:creatinine]} (r=0.632, p=0.007; r=0.405, p=0.027; r=0.583, p=0.003, respectively) in T2DM patients without nephropathy. In contrast, the urinary [angiotensinogen:creatinine] were not significantly different between CKD patients with and without T2DM (22.7 ± 27.8 vs. 33.5 ± 40.8 μg/g, p=0.740); although they were significantly higher when compared with non-CKD patients. In the CKD patients with T2DM systolic blood pressure, serum creatinine, estimated glomerular filtration rate and urinary [albumin:creatinine] correlated significantly with the log{urinary [angiotensinogen:creatinine]} (r=0.412, p=0.004; r=0.308, p=0.037; r=-0.382, p=0.001; r=0.648, p<0.001, p<0.001, respectively). CONCLUSIONS Our findings indicate that poor glycemic control is significantly associated with intrarenal RAS activity in T2DM patients without nephropathy, and that decreased renal function is significantly associated with intrarenal RAS activity in CKD patients with T2DM.

Comparison of the Estimated Glomerular Filtration Rate (eGFR) in Diabetic Patients, Non-Diabetic Patients and Living Kidney Donors.

Background/Aims: We have reported that the eGFR overestimates renal function when glycemic control is poor. It has been reported that eGFR calculated by serum creatinine underestimates GFR in living kidney donors. We compared the utility of the eGFR in diabetic patients, non-diabetic patients and living kidney donors. Forty diabetic patients, 40 non-diabetic patients, and 40 living kidney donors were enrolled. Methods: GFR was measured by inulin clearance (C_in). eGFR was calculated based on serum creatinine (eGFR_cr) or serum cystatin C (eGFR_cys). We compared the agreements between each of the eGFR and C_in in each group. Results: There were significant and positive correlations between each eGFR and C_in in diabetic patients and non-diabetic patients. However, the intraclass correlation coefficients (ICC) between each eGFR and C_in in diabetic patients (ICC: eGFR_cr 0.699, eGFR_cys 0.604) were weaker than those in non-diabetic patients (ICC: eGFR_cr 0.865, eGFR_cys 0.803). The correlation coefficients between each eGFR and C_in (eGFR_cr; r = 0.422, p = 0.0067 and eGFR_cys; r = 0.358, p = 0.0522) in living kidney donors were significantly weaker than those in non-diabetic patients. The ICCs between each eGFR and C_in (ICC: eGFR_cr 0.340, eGFR_cys 0.345) in living kidney donors were significantly weaker than those in non-diabetic patients. Conclusions: Based on C_in, eGFR was accurate in non-diabetic patients. However, eGFR was inaccurate in living kidney donors and relatively inaccurate in diabetic patients.