Association between anemia-related biomarkers and the adequacy of peritoneal dialysis in Chinese patients with chronic kidney disease.

Objectives: The study aimed to examine the association of three anemia-related biomarkers with the adequacy of peritoneal dialysis (PD) in patients with chronic kidney disease (CKD). Methods: This study included 127 PD patients. The total Kt/V urea (Kt/V) was calculated according to the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines. All patients were classified into two groups based on Kt/V, viz., adequate (Kt/V ≥1.7) and inadequate (Kt/V <1.7) groups. Effect sizes are expressed as odds ratios (ORs) and 95% confidence interval (CI). Results: After adjusting for age, gender, hypertension, diabetes, and PD duration, 20 g/L increment in hemoglobin (Hgb) was observed to significantly reduce the risk of inadequate PD by 19% (OR; 95% CI; P: 0.81; 0.70 to 0.95; 0.009), 5 g/L increment in the mean corpuscular hemoglobin concentration (MCHC) by 7% (0.93; 0.88 to 0.98; 0.009), and 5% increment in transferrin saturation (TS) by 23% (0.77; 0.64 to 0.94; 0.012). The gender-specific nomogram model was constructed by incorporating three significant anemia-related biomarkers and convenient influencing factors, and the prediction accuracy was good (concordance index (C-index): 0.686 for men and 0.825 for women). Conclusion: Our findings indicate that the deterioration of three anemia-related biomarkers (Hgb, MCHC, and TS) can precipitate the development of inadequate PD in Chinese patients with CKD.

Is serum hemoglobin level an independent prognostic factor for IgA nephropathy?: a systematic review and meta-analysis of observational cohort studies.

BACKGROUND: Decreased serum hemoglobin (Hb) level is associated with Immunoglobulin A nephropathy (IgAN) progression. However, whether serum Hb level is an independent prognostic factor of IgAN remains controversial. Herein, we aimed to investigate the prognostic value of serum Hb level in IgAN. METHODS: The Cochrane Library, Embase, PubMed and Open Grey databases were systematically searched and reviewed. Kidney disease progression of IgAN was defined as a doubling of serum creatinine (SCr), a 30% reduction in estimated glomerular filtration rate (eGFR), end-stage renal disease (ESRD), or death. We evaluated the hazard ratio (HR) between serum Hb level and the incidence of kidney disease progression in IgAN before and after adjusting for relevant covariates. RESULTS: We included nine studies with 10006 patients in the meta-analysis. As a continuous variable, we found that serum Hb was an independent prognostic factor of IgAN [unadjusted HR = 0.89, 95% confidence interval (CI) = 0.84-0.95, I2 = 98%; adjusted HR = 0.85, 95% CI = 0.79-0.91, I2 = 0%]. The sensitivity analysis confirmed the stability of these results. Consistently, as a dichotomous variable defined as the below/above cutoff for anemia, we observed a positive correlation between serum Hb and kidney disease progression in IgAN (unadjusted HR = 2.12, 95% CI = 1.44-3.12, I2 = 79%; adjusted HR = 1.65, 95% CI = 1.20-2.27, I2 = 0%). CONCLUSION: Serum Hb level was independently correlated with the incidence of kidney disease progression in IgAN.

Is hyperuricemia an independent prognostic factor for IgA nephropathy: a systematic review and meta-analysis of observational cohort studies.

BACKGROUND: Hyperuricemia has been reported to be correlated with IgA nephropathy (IgAN). However, whether hyperuricemia or elevated serum uric acid (SUA) is an independent prognostic factor of IgAN remains unknown. Therefore, this systematic review and meta-analysis evaluated the prognostic value of hyperuricemia and elevated SUA in IgAN. METHODS: Databases including PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and Open Gray were reviewed systematically. The kidney failure events of IgAN were defined as a doubling of serum creatinine, halving of eGFR, end-stage renal disease (ESRD), or death. The risk ratio (RR) between hyperuricemia and IgAN-caused kidney failure was evaluated before and after adjustment for relevant covariates. The RR between elevated SUA and IgAN-caused kidney failure was evaluated after adjustment for relevant covariates. RESULTS: A total of 11 548 patients from 14 studies were included in this meta-analysis. Hyperuricemia was found to be an independent prognostic factor of IgAN (unadjusted RR = 2.79, 95% CI = 1.93-4.03, p for heterogeneity <0.00001, I2 = 91%; adjusted RR = 2.12, 95% CI = 1.64-2.73, p for heterogeneity = 0.86, I2 = 0%). Subgroup and sensitivity analyses confirmed the stability of these results. Similarly, elevated SUA was positively correlated with kidney failure events of IgAN (adjusted RR = 1.25, 95% CI = 1.19-1.31, p for heterogeneity = 0.6, I2 = 0%). CONCLUSION: Our meta-analysis showed that hyperuricemia and elevated SUA were both independently associated with an increased incidence of kidney failure events in IgAN patients.

Effect of Tang-Shen-Ning decoction on podocyte epithelial-esenchymal transformation via inhibiting Wnt/ß-catenin pathway in diabetic mice.

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). Podocyte epithelial-esenchymal transformation (EMT) induced by the activated Wnt/ß-catenin pathway plays a key role in DN. Tang-Shen-Ning (TSN), a Chinese herbal formula, has been shown to decrease proteinuria and protect the renal function in DN. However, the effect of TSN on the Wnt/ß-catenin pathway and podocyte EMT is unclear. METHODS: TSN was orally administrated in KK-Ay mice for 4 weeks, at a daily dose of 20 g/kg body weight in our in vivo study. Rat serum containing TSN was added in podocyte cultured in high glucose for 24 h. The levels of 24 h urine protein, serum creatinine and blood urea nitrogen were detected by ELISA. Nephrin, Synaptopodin, P-cadherin, desmin, FSP-1, and collagen I protein and mRNA expressions were detected by western blot, immunohistochemistry, immunofluorescence, and RT-PCR. Snail, ß-catenin, and TCF/LEF were detected by Western blot, RT-PCR and luciferase. RESULTS: TSN significantly decreased 24-h urine protein, serum creatinine, and blood urea nitrogen in DN mice. Further, TSN also significantly increased the expression of nephrin, synaptopodin, and P-cadherin, while the expression of desmin, fibroblast-specific protein 1 (FSP-1), and collagen I of podocytes was significantly decreased. Moreover, TSN significantly inhibited the activation of the Wnt/ß-catenin pathway in podocytes cultured under high glucose (HG). Notably, the effect of TSN on podocyte EMT was reversed by activation of the Wnt/ß-catenin pathway. CONCLUSIONS: TSN could protect podocytes from injury in DN, partly via inhibiting the activation of the Wnt/ß-catenin pathway and ameliorating podocyte EMT.

Effects of BSF on Podocyte Apoptosis via Regulating the ROS-Mediated PI3K/AKT Pathway in DN.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). The ROS-mediated PI3K/AKT pathway plays a key role in podocyte apoptosis and DN progression. Our previous study demonstrated that Baoshenfang (BSF) can decrease proteinuria and attenuate podocyte injury. However, the effects of BSF on podocyte apoptosis induced by the ROS-mediated PI3K/AKT pathway remain unclear. Herein, in vivo and in vitro studies have been performed. In our in vivo study, BSF significantly decreased 24-h urinary protein, serum creatinine, and blood urea nitrogen levels in DN mice. Meanwhile, BSF significantly inhibited oxidative stress and podocyte apoptosis in our in vivo and in vitro studies. Moreover, BSF significantly decreased the inhibition of the PI3K/AKT pathway induced by HG in DN. More importantly, the effects of BSF on podocyte apoptosis were reversed by PI3K siRNA transfection. In conclusion, BSF can decrease proteinuria and podocyte apoptosis in DN, in part through regulating the ROS-mediated PI3K/AKT pathway.

Effect of Baoshenfang Formula on Podocyte Injury via Inhibiting the NOX-4/ROS/p38 Pathway in Diabetic Nephropathy.

Diabetic nephropathy (DN) is a serious kidney-related complication of type 1 and type 2 diabetes. The Chinese herbal formula Baoshenfang (BSF) shows therapeutic potential in attenuating oxidative stress and apoptosis in podocytes in DN. This study evaluated the effects of BSF on podocyte injury in vivo and in vitro and explored the possible involvement of the nicotinamide adenine dinucleotide phosphate-oxidase-4/reactive oxygen species- (NOX-4/ROS-) activated p38 pathway. In the identified compounds by mass spectrometry, some active constituents of BSF were reported to show antioxidative activity. In addition, we found that BSF significantly decreased 24-hour urinary protein, serum creatinine, and blood urea nitrogen in DN patients. BSF treatment increased the nephrin expression, alleviated oxidative cellular damage, and inhibited Bcl-2 family-associated podocyte apoptosis in high-glucose cultured podocytes and/or in diabetic rats. More importantly, BSF also decreased phospho-p38, while high glucose-mediated apoptosis was blocked by p38 mitogen-activated protein kinase inhibitor in cultured podocytes, indicating that the antiapoptotic effect of BSF is p38 pathway-dependent. High glucose-induced upexpression of NOX-4 was normalized by BSF, and NOX-4 siRNAs inhibited the phosphorylation of p38, suggesting that the activated p38 pathway is at least partially mediated by NOX-4. In conclusion, BSF can decrease proteinuria and protect podocytes from injury in DN, in part through inhibiting the NOX-4/ROS/p38 pathway.

Exosomes from high glucose-treated glomerular endothelial cells activate mesangial cells to promote renal fibrosis.

The interaction between glomerular endothelial cells (GECs) and glomerular mesangial cells (GMCs) is an essential aspect of diabetic nephropathy (DN). Therefore, understanding how GECs communicate with GMCs in the diabetic environment is crucial for the development of new targets for the prevention and treatment of DN. Exosomes, nanometer-sized extracellular membrane vesicles secreted by various cell types, play important roles in cell-to-cell communication via the transfer of mRNA, microRNA and protein. In this study, we demonstrate that high glucose (HG)-treated GECs secrete a higher number of exosomes highly enriched in TGF-ß1 mRNA compared with normal glucose (NG)-treated GECs. Exosomes released by HG-treated GECs can promote α-smooth muscle actin (α-SMA) expression, proliferation and extracellular matrix protein overproduction in GMCs through the TGF-ß1/Smad3 signaling pathway. Thus, we provide new insights into the pathogenesis of DN that involves intercellular transfer of TGF-ß1 mRNA in the GEC-to-GMC direction via exosomes.

Tongxinluo ameliorates renal structure and function by regulating miR-21-induced epithelial-to-mesenchymal transition in diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most important diabetic microangiopathies. The epithelial-to-mesenchymal transition (EMT) plays an important role in DN. The physiological role of microRNA-21 (miR-21) was closely linked to EMT. However, it remained elusive whether tongxinluo (TXL) ameliorated renal structure and function by regulating miR-21-induced EMT in DN. This study aimed to determine the effect of TXL on miR-21-induced renal tubular EMT and to explore the relationship between miR-21 and TGF-ß1/smads signals. Real-time RT-PCR, cell transfection, in situ hybridization (ISH), and laser confocal microscopy were used, respectively. Here, we revealed that TXL dose dependently lowered miR-21 expression in tissue, serum, and cells. Overexpression of miR-21 can enhance α-smooth muscle actin (SMA) expression and decrease E-cadherin expression by upregulating smad3/p-smad3 expression and downregulating smad7 expression. Interestingly, TXL also increased E-cadherin expression and decreased α-SMA expression by regulating miR-21 expression. More importantly, TXL decreased collagen IV, fibronectin, glomerular basement membrane, glomerular area, and the albumin/creatinine ratio, whereas it increased the creatinine clearance ratio. The results demonstrated that TXL ameliorated renal structure and function by regulating miR-21-induced EMT, which was one of the mechanisms to protect against DN, and that miR-21 may be one of the therapeutic targets for TXL in DN.