Tomoki Asai

Diagnostic usefulness of bone mineral density and biochemical markers of bone turnover in predicting fracture in CKD stage 5D patients—a single-center cohort study

BACKGROUND In chronic kidney disease stage 5D, diagnostic usefulness of bone mineral density (BMD) in predicting fracture has not been established because of variable results in previous studies. The reason for this may be the heterogeneity of underlying pathogenesis of the fracture. METHODS BMD was measured annually and serum biochemistry monthly for 485 hemodialyzed patients from April 2003 to March 2008, and all fractures were recorded. RESULTS Forty-six new episodes of any type of fracture and 29 cases of prevalent spine fracture were recorded. Serum bone-specific alkaline phosphatase (b-AP) was a very useful surrogate marker for any type of incident fracture risk [area under curve (AUC) = 0.766, P < 0.0001]. A significantly greater risk of any type of incident fracture was associated with parathyroid hormone (PTH) levels either <150 pg/mL [hazard ratio (HR) = 3.47, P < 0.01] or >300 pg/mL (HR = 5.88, P < 0.0001) compared with 150-300 pg/mL. Receiver-operating characteristic analysis demonstrated a significant predictive power for incident of any type of fracture by BMD at the total hip (AUC = 0.760, P < 0.0001) and other hip regions in females in the lower PTH group (PTH < 204 pg/mL). BMDs at every site but whole body or lumbar spine had significant power to discriminate prevalent spine fracture regardless of gender or PTH. CONCLUSIONS Hemodialyzed patients with low or high PTH or increased b-AP had a high fracture risk. BMD by Dual Energy X-ray Absorptiometry (DEXA), especially at the total hip region, was useful to predict any type of incident of fracture for females with low PTH or to discriminate prevalent spine fracture for every patient.

Aquaporin‐2 trafficking is regulated by PDZ‐domain containing protein SPA‐1

Targeted positioning of water channel aquaporin‐2 (AQP2) strictly regulates body water homeostasis. Trafficking of AQP2 to the apical membrane is critical to the reabsorption of water in renal collecting ducts. Controlled apical positioning of AQP2 suggests the existence of proteins that interact with AQP2. A biochemical search for AQP2‐interacting proteins led to the identification of PDZ‐domain containing protein, signal‐induced proliferation‐associated gene‐1 (SPA‐1) which is a GTPase‐activating protein (GAP) for Rap1. The distribution of SPA‐1 coincided with that of AQP2 in renal collecting ducts. The site of colocalization was concomitantly relocated by hydration status. AQP2 trafficking to the apical membrane was inhibited by the SPA‐1 mutant lacking Rap1GAP activity and by the constitutively active mutant of Rap1. AQP2 trafficking was impaired in SPA‐1‐deficient mice. Our results show that SPA‐1 directly binds to AQP2 and regulates at least in part AQP2 trafficking.

Renal expression of metallothionein in rats treated with cadmium

AbstractBackground. The intrarenal localization of metallothionein (MT) expression has not been studied in detail. Therefore, we investigated the effects of acute exposure to cadmium on the renal expression of MT. Methods. MT mRNA expression was estimated quantitatively at 2, 6, 24, and 72 h after the injection of cadmium (1 mg/kg) to the intraperitoneum of male Sprague-Dawley rats. The site of cadmium-induced MT mRNA expression was determined, by the reverse transcription polymerase chain reaction (RT-PCR), using microdissected tubules. Immunoblotting and immunohistochemistry were also performed, to determine the localization of MT protein. Results. The mRNAs of MT-I and MT-II were significantly upregulated at 2 h and peaked at 24 and 6 h, respectively. RT-PCR revealed the expression of cadmium-induced MT mRNA mainly in the proximal tubules. Immunoblotting detected a clear 14-kDa band corresponding to MT protein, and immunohistochemistry showed abundant MT protein in the renal cortices of cadmium-treated rats. Conclusions. Our findings suggest that the proximal tubules are responsible for the cadmium-induced renal expression of MT mRNA and protein.

Type II Diabetes Mellitus Is a Risk Factor for Heart Failure in Pre‐Dialysis Patients

Chronic kidney disease (CKD) increases the risk of developing cardiovascular diseases such as heart failure (HF) and ischemic heart disease (IHD). The characteristics of patients with CKD complicated with HF at the time of starting hemodialysis have not yet been evaluated. We enrolled 347 patients in this study and compared gender, age, body mass index, laboratory data, causative disease, complications, and echocardiographic findings between groups with (n = 105) and without (n = 242) HF. Type II diabetic nephropathy and estimated glomerular filtration rate (eGFR; mL/min/1.73 m2) were the independent factors for HF (OR: 3.004, 95% CI: 1.754 to 5.146 and OR: 1.215, 95% CI: 1.101 to 1.330, [per 1 mL/min/1.73 m2 increase], respectively). The higher GFR appeared to be not a risk factor for HF, probably because the HF group included patients who required periodic dialysis to prevent fatal HF, even if their renal function was not extremely deteriorated. The prevalence of hypertension, IHD and values of body mass index, triglycerides, and LDL‐cholesterol did not differ between these two groups. Echocardiographic data showed that left ventricular mass index was an independent risk factor for HF (OR: 1.006, 95% CI: 1.001 to 1.012, per 1 g/m2 increase) and more than half of the patients appeared to have left ventricular diastolic dysfunction. Our findings suggest that not only CKD, but also type II DM, is a potent risk for left ventricular dysfunction, which causes HF and IHD in pre‐dialysis patients with CKD.

Collagen type Iα1 gene polymorphism may be associated with the rate of bone mineral density decrease in female hemodialyzed patients

AbstractBackground. Polymorphism of the collagen type Iα1 gene (COLIA1) has been shown to be involved in bone density in the general population. However, the significance of this polymorphism has not been examined in patients with chronic renal failure. Methods. We first determined the COLIA1 Bal I restriction fragment length polymorphism (RFLP) at the Sp 1 binding site, and, next, we measured biochemical bone markers and the bone mineral density (BMD) of the lumbar spine (L2–L4) and radius (distal one-third) in 181 hemodialyzed patients. Results. Distributions of the Bal I RFLP were: SS, 62%; Ss, 32%; and ss, 6%. The Z scores for the BMD and for the serum levels of Ca, P, alkaline phosphatase, intact-parathyroid hormone (PTH), osteocalcin, and tartrate-resistant acid phosphatase were not significantly different among the three genotype groups. The slope of the regression line in the age-BMD relationship, a measure of the rate of BMD decrease, was similar among the three genotypes in men, but was significantly (P < 0.05) larger in the ss group than in the SS and Ss groups in women. Conclusions. The COLIA1 polymorphism may be associated with the bone loss seen in female patients on hemodialysis.