Assessment of tubular reabsorption of phosphate as a surrogate marker for phosphate regulation in chronic kidney disease.

BACKGROUND/AIMS: Fibroblast growth factor 23 (FGF23) and soluble α-Klotho are emerging potential biomarkers of phosphorus and vitamin D metabolism which change in concentration in early chronic kidney disease (CKD) in order to maintain normal phosphorus levels. Tubular reabsorption of phosphate (TRP) has been commonly used to assess renal tubular phosphate transport. The aim of this study was to evaluate the usefulness of TRP as a surrogate marker of parameters of CKD-mineral bone disease (CKD-MBD) in CKD. METHODS: A cross-sectional study was performed in 93 stable patients with predialysis CKD stage 1-5. In all patients, TRP, estimated glomerular filtration rate (eGFR), calcium, phosphate, intact parathyroid hormone (iPTH), 25-hydroxyvitamin D, serum FGF23 and urine soluble α-Klotho levels were measured. RESULTS: As renal function declined, TRP significantly decreased (P < 0.001; r = 0.763) and both iPTH and serum FGF23 increased (P < 0.001; r = -0.598, P < 0.001; r = -0.453, respectively). The prevalence of hyperphosphatemia, secondary hyperparathyroidism, FGF23 excess and abnormal TRP increased progressively with declining eGFR. Although TRP level changed later than FGF23, abnormal levels of both TRP and FGF23 were observed earlier than changes in iPTH and serum phosphate. Decreased TRP was found to be independently associated with decreased eGFR and increased iPTH but was not associated with urine soluble α-Klotho or serum FGF23 level in multiple linear regression analysis. CONCLUSION: TRP is a simple, useful and cost-saving surrogate marker of the assessment of altered mineral metabolism in CKD patients and can be used as an alternative to serum FGF23, especially for mild to moderate renal insufficiency.

Use of bortezomib as anti-humoral therapy in kidney transplantation.

This study aimed to investigate the effect of bortezomib in the desensitization and treatment of acute antibody mediated rejection (AAMR) in kidney transplantation. Nine patients who received bortezomib therapy for desensitization (DSZ group, n = 3) or treatment of AAMR (AAMR group, n = 6) were included in this study. In the DSZ group, 2 patients required DSZ owing to positive cross match and 1 owing to ABO mismatch with high baseline anti-ABO antibody titer (1:1,024). Bortezomib was used at 1, 3, 8, and 11 days from the start of the treatment. In the AAMR group, 3 patients showed full recovery of allograft function after bortezomib use and decrease in donor specific anti-HLA antibody (HLA-DSA). However, 3 patients did not respond to bortezomib and experienced allograft failure. In the DSZ group, negative conversion of T-CDC (complement-dependent cytotoxicity) was achieved, and HLA-DSA was decreased to lower than a weak level (median fluorescence intensity [MFI] < 5,000) in 2 patients. In the case of ABO mismatch kidney transplantation, the anti-A/B antibody titer decreased to below the target (≤ 1:16) after bortezomib therapy. Therefore, bortezomib could be an alternative therapeutic option for desensitization and treatment of AAMR that is unresponsive to conventional therapies.

Clinical significance of preexisting microcalcification in the iliac artery in renal transplant recipients.

BACKGROUND: The clinical significance of preexisting microcalcification in the iliac artery is undetermined in renal transplant recipients. METHODS: We obtained iliac artery segments from 90 transplant recipients at the time of renal transplantation and performed von Kossa staining for microcalcification. The clinical significance of intimal microcalcification was evaluated with allograft survival rate, rate of graft function decline, and composite of any cardiovascular event or patient death. Expression of fetuin-A and C-reactive protein, key regulators of calcification, was also investigated in the iliac artery. RESULTS: Intimal microcalcification was positive in 48 (53.3%) patients, and its intensity was correlated positively with intimal C-reactive protein intensity (P = 0.019). Allograft survival in patients positive for intimal microcalcification was lower than patients who were negative (P = 0.017). The patients with positivity for both intimal microcalcification and fetuin-A showed lower allograft survival rate than patients with intimal microcalcification positivity alone (P = 0.012). The rate of renal graft function decline was significantly steeper in patients positive for intimal microcalcification than in patients who were negative (P = 0.036). In multivariate analysis, positivity for both intimal microcalcification and fetuin-A was an independent predictor for renal graft function decline (ß = -10.21; P = 0.011). The intimal microcalcification was not associated with composite-event free survival. CONCLUSION: Preexisting intimal microcalcification in the iliac artery predicts a lower allograft survival rate and rapid decline of allograft function. Positivity of fetuin-A with intimal microcalcification further reduces allograft survival rate and an independent predictor for renal graft function decline.

Fenofibrate improves renal lipotoxicity through activation of AMPK-PGC-1α in db/db mice.

Peroxisome proliferator-activated receptor (PPAR)-α, a lipid-sensing transcriptional factor, serves an important role in lipotoxicity. We evaluated whether fenofibrate has a renoprotective effect by ameliorating lipotoxicity in the kidney. Eight-week-old male C57BLKS/J db/m control and db/db mice, divided into four groups, received fenofibrate for 12 weeks. In db/db mice, fenofibrate ameliorated albuminuria, mesangial area expansion and inflammatory cell infiltration. Fenofibrate inhibited accumulation of intra-renal free fatty acids and triglycerides related to increases in PPARα expression, phosphorylation of AMP-activated protein kinase (AMPK), and activation of Peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)-estrogen-related receptor (ERR)-1α-phosphorylated acetyl-CoA carboxylase (pACC), and suppression of sterol regulatory element-binding protein (SREBP)-1 and carbohydrate regulatory element-binding protein (ChREBP)-1, key downstream effectors of lipid metabolism. Fenofibrate decreased the activity of phosphatidylinositol-3 kinase (PI3K)-Akt phosphorylation and FoxO3a phosphorylation in kidneys, increasing the B cell leukaemia/lymphoma 2 (BCL-2)/BCL-2-associated X protein (BAX) ratio and superoxide dismutase (SOD) 1 levels. Consequently, fenofibrate recovered from renal apoptosis and oxidative stress, as reflected by 24 hr urinary 8-isoprostane. In cultured mesangial cells, fenofibrate prevented high glucose-induced apoptosis and oxidative stress through phosphorylation of AMPK, activation of PGC-1α-ERR-1α, and suppression of SREBP-1 and ChREBP-1. Our results suggest that fenofibrate improves lipotoxicity via activation of AMPK-PGC-1α-ERR-1α-FoxO3a signaling, showing its potential as a therapeutic modality for diabetic nephropathy.

Vascular endothelial growth factor-receptor 1 inhibition aggravates diabetic nephropathy through eNOS signaling pathway in db/db mice.

The manipulation of vascular endothelial growth factor (VEGF)-receptors (VEGFRs) in diabetic nephropathy is as controversial as issue as ever. It is known to be VEGF-A and VEGFR2 that regulate most of the cellular actions of VEGF in experimental diabetic nephropathy. On the other hand, such factors as VEGF-A, -B and placenta growth factor bind to VEGFR1 with high affinity. Such notion instigated us to investigate on whether selective VEGFR1 inhibition with GNQWFI hexamer aggravates the progression of diabetic nephropathy in db/db mice. While diabetes suppressed VEGFR1, it did increase VEGFR2 expressions in the glomerulus. Db/db mice with VEGFR1 inhibition showed more prominent features with respect to, albuminuria, mesangial matrix expansion, inflammatory cell infiltration and greater numbers of apoptotic cells in the glomerulus, and oxidative stress than that of control db/db mice. All these changes were related to the suppression of diabetes-induced increases in PI3K activity and Akt phosphorylation as well as the aggravation of endothelial dysfunction associated with the inactivation of FoxO3a and eNOS-NOx. In cultured human glomerular endothelial cells (HGECs), high-glucose media with VEGFR1 inhibition induced more apoptotic cells and oxidative stress than did high-glucose media alone, which were associated with the suppression of PI3K-Akt phosphorylation, independently of the activation of AMP-activated protein kinase, and inactivation of FoxO3a and eNOS-NOx pathway. In addition, transfection with VEGFR1 siRNA in HGECs also suppressed PI3K-Akt-eNOS signaling. In conclusion, the specific blockade of VEGFR1 with GNQWFI caused severe renal injury related to profound suppression of the PI3K-Akt, FoxO3a and eNOS-NOx pathway, giving rise to the oxidative stress-induced apoptosis of glomerular cells in type 2 diabetic nephropathy.

A case of left ventricular pseudoaneurysm in the left atrioventricular groove after mitral valve replacement.

Left ventricle-coronary sinus fistula and left ventricular pseudoaneurysm are unusual and frightening complications after mitral valve replacement. A 27-year-old female patient underwent mitral valve replacement 5 years previously and trans-thoracic echocardiography showed an outpouching lesion at the atrioventricular groove. It was difficult to differentiate whether the lesion was a left ventricle-coronary sinus fistula or a left ventricular pseudoaneurysm by two-dimensional echocardiography. Cardiac computed tomography confirmed a left ventricular pseudoaneurysm compressing the coronary sinus.