Akinobu Ochi

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.

Trace Elements in the Hair of Hemodialysis Patients

Trace element disturbance is often observed in hemodialysis patients. While trace element concentrations have been reported in blood samples from hemodialysis patients, they have not been well investigated in scalp hair. In the present study, 22 trace elemental concentrations were measured by inductively coupled plasma-atomic emission spectrometry in the scalp hair of 80 male hemodialysis patients and compared with those of 100 healthy male subjects. In hemodialysis patients, the concentrations of beryllium, arsenic, magnesium, chromium, manganese, iron, selenium, molybdenum, iodine, vanadium, and cobalt were significantly higher than those in healthy subjects, while lead, mercury, copper, germanium, and bromine were significantly lower than those in the former group. No significant differences were observed for lithium, aluminum, cadmium, zinc, boron, or nickel. There were significant positive correlations between the duration of hemodialysis and the magnesium and manganese concentrations. There was a significant negative correlation between cadmium concentration and the duration of hemodialysis. There were significant positive correlations between dialysis efficacy (Kt/V) and magnesium, manganese, zinc, and selenium concentrations. In conclusion, trace element concentrations of the scalp hair are different between hemodialysis patients and healthy subjects. Essential trace elements, such as magnesium, manganese, zinc, and selenium, may be affected by the duration of hemodialysis and Kt/V.

Direct Inhibitory Effects of Pioglitazone on Hepatic Fetuin-A Expression

Fetuin-A, a circulating glycoprotein synthesized in the liver, is involved in insulin resistance and type 2 diabetes. However, regulation of fetuin-A synthesis has remained obscure. We previously reported that pioglitazone treatment significantly reduced serum fetuin-A levels in patients with type 2 diabetes. To clarify whether pioglitazone can directory inhibit hepatic fetuin-A synthesis, we investigated the effects of pioglitazone on fetuin-A expression both in vitro and in vivo. Pioglitazone treatment suppressed mRNA and protein expression of fetuin-A in Fao hepatoma cells. Interestingly, rosiglitazone but not metformin, also inhibited fetuin-A expression. In addition, GW 9662, an inhibitor of peroxisome proliferator-activated receptor (PPAR) γ, reversed pioglitazone-induced suppression of fetuin-A, suggesting that thiazolidinedione derivatives may have common characteristics with regard to fetuin-A suppression, possibly through PPARγactivation. Finally, oral administration of pioglitazone to mice for 8 weeks resulted in suppression of hepatic fetuin-A mRNA. These findings suggest that pioglitazone may partially ameliorate insulin resistance through its direct inhibitory effects on fetuin-A expression in the liver.

Elemental Concentrations in Scalp Hair, Nutritional Status and Health-Related Quality of Life in Hemodialysis Patients

Elemental concentrations in hair from hemodialysis (HD) patients have not been well investigated. We examined the relationships between the elemental concentrations in scalp hair and health‐related quality of life (HRQOL) and nutritional status in HD patients. Twenty six elemental concentrations were measured in scalp hair samples from 60 male HD patients using inductively‐coupled plasma mass spectrometry. To evaluate HRQOL, the Short Form 36 item health survey (SF36) was used. As indices of nutritional status, body mass index, serum parameters, and geriatric nutritional risk index (GNRI) were used. Phosphorus correlated positively with serum creatinine, blood urea nitrogen (BUN), GNRI and the physical domains of the SF36. Zinc correlated positively with serum creatinine, BUN and the physical domains of the SF36. Mercury and arsenic correlated positively with BUN. Cadmium correlated negatively with serum albumin, BUN and GNRI. Copper correlated positively with the physical domains of the SF36. Iodine correlated negatively with the physical domains of the SF36. Selenium correlated negatively with the mental domains of the SF36. In conclusion, phosphorus and zinc concentrations in scalp hair can be additional biomarkers of HRQOL and/or nutritional status in HD patients. Cadmium accumulation correlated with malnutrition. Iodine and selenium accumulation may adversely affect HRQOL. Further investigation is necessary to determine precisely how these elements affect these measures.

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.

Indoxyl sulfate suppresses hepatic fetuin-A expression via the aryl hydrocarbon receptor in HepG2 cells

BACKGROUND Fetuin-A is a liver-derived circulating protein that has potent calcification-inhibitory activity. Uraemic patients exhibit decreased serum fetuin-A levels, increased vascular calcification and elevated cardiovascular mortality. Because the mechanisms for fetuin-A deficiency are unknown, we hypothesized that some uraemic toxins suppressed hepatic fetuin-A production, which resulted in accelerated vascular calcification and poor outcome. Among these potential candidates, indoxyl sulfate (IS) has highly toxic properties. METHODS We examined the direct effects of IS on hepatic fetuin-A expression using the human hepatoma HepG2 cell line. RESULTS IS, but not p-cresyl sulfate, suppressed the mRNA and protein expression of fetuin-A in a dose- and time-dependent manner. As reported previously, IS stimulated p38 MAPK phosphorylation and reactive oxygen species (ROS) production, although the knockdown of p38 and inhibition of ROS generation had no effect on IS-induced fetuin-A suppression. Then, because IS is a potent endogenous ligand of the aryl hydrocarbon receptor (AhR), we assessed whether IS suppresses fetuin-A production via AhR. The knockdown of AhR prevented IS-induced fetuin-A suppression. However, some attention should be paid to no effect of IS on fetuin-A expression in mouse and human primary cultured hepatocytes. CONCLUSIONS These findings suggest that IS could suppress hepatic fetuin-A expression by activating AhR, suggesting a relationship between uraemia and fetuin-A deficiency.

MIF-2/D-DT enhances proximal tubular cell regeneration through SLPI- and ATF4-dependent mechanisms

Macrophage migration inhibitory factor (MIF) is a cytokine with pleiotropic actions that is produced by several organs and cell types. Depending on the target cell and the inflammatory context, MIF can engage its two component receptor complex CD74 and CD44 and the chemokine receptors CXCR2/4. MIF is constitutively expressed in renal proximal tubular cells, stored in intracellular preformed pools, and released at a low rate. Recently, a second MIF-like protein (i.e., MIF-2/D-DT) has been characterized in mammals. Our study was aimed at examining the role of MIF-2/D-DT, which mediates tissue protection in the heart, in tubular cell regeneration from ischemia-reperfusion injury. We found that Mif-/-, Mif-2-/-, and Cd74-/- mice had significantly worse tubular injury compared with wild-type (WT) control mice and that treatment with MIF-2/D-DT significantly improved recovery of injured epithelial cells. RNAseq analysis of kidney tissue from the ischemia-reperfusion injury model revealed that MIF-2/D-DT treatment stimulates secretory leukocyte proteinase inhibitor (SLPI) and cyclin D1 expression. MIF-2/D-DT additionally activates of eukaryotic initiation factor (eIF) 2α and activating transcription factor (ATF) 4, two transcription factors involved in the integrated stress response (ISR), which is a cellular stress response activated by hypoxia, nutrient deprivation, and oxygen radicals. MIF-2/D-DT also inhibited apoptosis and induced autophagy in hypoxia-treated mouse proximal tubular (MPT) cells. These results indicate that MIF-2/D-DT is an important factor in tubular cell regeneration and may be of therapeutic utility as a regenerative agent in the clinical setting of ischemic acute kidney injury.

Quantitative Analysis of Abdominal Aortic Calcification in CKD Patients Without Dialysis Therapy by Use of the Agatston Score

Background/Aim: The aim of the present study was to quantitatively examine factors associated with aortic calcification in non-dialysis CKD patients. Methods: We quantitatively investigated aortic calcification from the renal artery to the bifurcation in 149 non-dialysis CKD patients (58±16 years; 96 males and 53 females, 48 diabetics; eGFR 40.3±29.3 ml/min), and measured Agatston scores using multi-slice computed tomography. Result: Of 149 patients, aortic calcification was present in 117. In patients with aortic calcification, age (p<0.001), C-reactive protein (p<0.001), and intact-PTH (p < 0.001) were significantly higher, estimated glomerular filtration rate (eGFR) was significantly lower (p<0.001), and diabetes was observed more often (p<0.05). In regards to the degree of aortic calcification, the Agatston scores correlated significantly and positively with age (ρ=0.438, p<0.001) and serum phosphate (ρ=0.208, p=0.024), and correlated significantly but negatively with e-GFR (ρ=-0.353, p<0.001). In multiple regression analysis, eGFR was associated significantly and independently with the log [Agatston score] (β=-0.346, p<0.01), after adjustment for several confounders including serum phosphate and the presence of diabetes. Conclusions: Hyperphospatemia, chronic inflammation, diabetes, and decreased GFR are associated significantly with the presence of aortic calcification in non-dialysis CKD patients. Decreased eGFR was associated significantly and independently with the quantitative degree of aortic calcification.

The protective role of macrophage migration inhibitory factor in acute kidney injury after cardiac surgery

Clinical data after cardiac surgery and experimental mouse models of acute kidney injury suggest a renoprotective role of macrophage migration inhibitory factor (MIF). MIF muffles kidney injury Patients undergoing open-heart surgery are susceptible to complications, including acute kidney injury (AKI). Stoppe et al. observed that patients who had high serum concentrations of macrophage migration inhibitory factor (MIF) after cardiac surgery had lower risk of AKI. Renal ischemia-reperfusion injury induced more inflammation and kidney cell death in mice lacking Mif than in wild-type mice. Treating isolated kidney cells with MIF protected against hypoxia-induced cell death. Mice treated with MIF or a soluble form of CD74 (MIF receptor) showed reduced kidney injury after ischemia-reperfusion. This study suggests that MIF may protect the kidney from ischemia-reperfusion injury. Acute kidney injury (AKI) represents the most frequent complication after cardiac surgery. Macrophage migration inhibitory factor (MIF) is a stress-regulating cytokine that was shown to protect the heart from myocardial ischemia-reperfusion injury, but its role in the pathogenesis of AKI remains unknown. In an observational study, serum and urinary MIF was quantified in 60 patients scheduled for elective conventional cardiac surgery with the use of cardiopulmonary bypass. Cardiac surgery triggered an increase in MIF serum concentrations, and patients with high circulating MIF (>median) 12 hours after surgery had a significantly reduced risk of developing AKI (relative risk reduction, 72.7%; 95% confidence interval, 12 to 91.5%; P = 0.03). Experimental AKI was induced in wild-type and Mif−/− mice by 30 min of ischemia followed by 6 or 24 hours of reperfusion, or by rhabdomyolysis. Mif-deficient mice exhibited increased tubular cell injury, increased regulated cell death (necroptosis and ferroptosis), and enhanced oxidative stress. Therapeutic administration of recombinant MIF after ischemia-reperfusion in mice ameliorated AKI. In vitro treatment of tubular epithelial cells with recombinant MIF reduced cell death and oxidative stress as measured by glutathione and thiobarbituric acid reactive substances in the setting of hypoxia. Our data provide evidence of a renoprotective role of MIF in experimental ischemia-reperfusion injury by protecting renal tubular epithelial cells, consistent with our observation that high MIF in cardiac surgery patients is associated with a reduced incidence of AKI.

Serum β2-microglobulin correlates positively with left ventricular hypertrophy in long-term hemodialysis patients.

Background/Aims: β2-Microglobulin (β2-MG) is a major protein component of dialysis-related amyloidosis. In long-term hemodialysis (HD) patients, β2-MG amyloid deposits not only in osteoarticular tissues, but also in systemic tissues, including the heart. The purpose of this study was to investigate the relationship between serum β2-MG concentrations and echocardiographic parameters in long-term HD patients in a cross-sectional study. Methods: Measurement of serum β2-MG concentrations and echocardiography were performed in 251 patients who had undergone HD therapy for more than 10 years. Results: The left ventricular mass index (LVMI) of the higher serum β2-MG (≥30 mg/l) group was significantly higher than that of the lower serum β2-MG (<30 mg/l) group (151.5 ± 45.7 vs. 137.0 ± 44.5 g/m2, p = 0.020). In simple regression analyses, serum β2-MG concentrations correlated significantly and positively with interventricular septum thickness (IVST) (r = 0.215, p < 0.001), posterior left ventricular wall thickness (PWT) (r = 0.249, p < 0.001), left ventricular wall thickness (LVWT) (r = 0.252, p < 0.001), relative wall thickness (RWT) (r = 0.153, p = 0.015) and LVMI (r = 0.171, p = 0.007). Multiple regression analyses revealed that serum β2-MG concentrations correlated significantly and positively with IVST, PWT, LVWT and RWT. Conclusion: Serum β2-MG concentrations correlated significantly and positively with the echocardiographic parameters of left ventricular hypertrophy (LVH) in long-term HD patients. Thus, deposition of β2-MG amyloid in the heart may be associated with LVH progression.