Shanyan Lin

Meta-analysis of the clinical value of Astragalus membranaceus in diabetic nephropathy.

AIM OF STUDY Nowadays diabetic nephropathy (DN) has become a serious problem. Astragalus membranaceus is a traditional herb used for thousands of years in China and East Asia for kidney disease. In modern medicine, Astragalus shows significant renal protective effect in DN. We aimed to systematically review the randomized and semi-randomized control trials to ascertain its role in the treatment of DN. MATERIALS AND METHODS PUBMED, MEDLINE, Chinese journal full-test database (CJFD), Chinese biological and medical database were searched by computer and manual searching. Two assessors independently reviewed each trial. 25 studies comprising 21 RCTs and 4 CCTs were involved including 1804 patients (945 in treatment group and 859 in control group). RESULTS AND CONCLUSIONS Astragalus injection had more therapeutic effect in DN patients including renal protective effect (BUN, SCr, CCr and urine protein) and systemic state improvement (serum albumin level) compared with the control group. ETHNOPHARMACOLOGICAL RELEVANCE This study investigates the effect of Astragalus in DN patients. It suggests that although of unknown bioactive ingredients and mechanism of renal protection, the role of Astragalus in the treatment of DN can be disclosed and of profound significance.

The ratio of CRP to prealbumin levels predict mortality in patients with hospital-acquired acute kidney injury

BackgroundAnimal and human studies suggest that inflammation and malnutrition are common in acute kidney injury (AKI) patients. However, only a few studies reported CRP, a marker of inflammation, albumin, prealbumin and cholesterol, markers of nutritional status were associated with the prognosis of AKI patients. No study examined whether the combination of inflammatory and nutritional markers could predict the mortality of AKI patients.Methods155 patients with hospital-acquired AKI were recruited to this prospective cohort study according to RIFLE (Risk, Injury, Failure, Lost or End Stage Kidney) criteria. C-reactive protein (CRP), and the nutritional markers (albumin, prealbumin and cholesterol) measured at nephrology consultation were analyzed in relation to all cause mortality of these patients. In addition, CRP and prealbumin were also measured in healthy controls (n = 45), maintenance hemodialysis (n = 70) and peritoneal dialysis patients (n = 50) and then compared with AKI patients.ResultsCompared with healthy controls and end-stage renal disease patients on maintenance hemodialysis or peritoneal dialysis, patients with AKI had significantly higher levels of CRP/prealbumin (p < 0.001). Higher level of serum CRP and lower levels of albumin, prealbumin and cholesterol were found to be significant in the patients with AKI who died within 28 days than those who survived >28 days. Similarly, the combined factors including the ratio of CRP to albumin (CRP/albumin), CRP/prealbumin and CRP/cholesterol were also significantly higher in the former group (p < 0.001 for all). Multivariate analysis (Cox regression) revealed that CRP/prealbumin was independently associated with mortality after adjustment for age, gender, sepsis and sequential organ failure assessment (SOFA, p = 0.027) while the others (CRP, albumin, prealbumin, cholesterol, CRP/albumin and CRP/cholesterol) became non-significantly associated. The hazard ratio was 1.00 (reference), 1.85, 2.25 and 3.89 for CRP/prealbumin increasing according to quartiles (p = 0.01 for the trend).ConclusionsInflammation and malnutrition were common in patients with AKI. Higher level of the ratio of CRP to prealbumin was associated with mortality of AKI patients independent of the severity of illness and it may be a valuable addition to SOFA score to independent of the severity of illness and it may be a valuable addition to SOFA score to predict the prognosis of AKI patients.

Aldosterone promotes fibronectin synthesis in rat mesangial cells via ERK1/2-stimulated Na-H+ exchanger isoform 1.

Background: Aldosterone plays an important role in fibrosis. Recent studies showed that Na+-H+ exchanger isoform 1 (NHE1) is involved in mineralocorticoid-induced organ fibrosis. In this study, we examined the role of NHE1 in aldosterone-induced fibronectin accumulation in rat mesangial cells and the signaling pathway involved. Methods: We detected the expression of mineralocorticoid receptor and 11β-hydroxysteroid dehydrogenase 2 in rat glomeruli by immunochemistry and Western blot. Then the eukaryotic vectors of shRNA with insert targeting on NHE1 were successfully constructed and transfected into rat mesangial cells. The mRNA was quantified by real-time PCR. We measured the protein abundance of NHE1, ERK1/2 and phosphor-ERK1/2 by Western blot and the level of fibronectin by ELISA. Results: First we demonstrated the local action of aldosterone on rat glomeruli in vivo. Then, after exposure to aldosterone, the NHE1 protein abundance was found increased in rat mesangial cells. Aldosterone treatment markedly increased the fibronectin level, which can be reduced by PD98059, spironolactone and shRNA-NHE1. PD98059 substantially reduced the aldosterone-induced NHE1 expression, while the knocking down of NHE1 did not alter aldosterone-stimulated phospho-ERK1/2 stimulation. Conclusion: The present study suggests that NHE1 may play an important role in aldosterone-mediated fibronectin accumulation in rat mesangial cells via the ERK1/2 pathway.

Effect of Short-Term Low-Protein Diet Supplemented with Keto Acids on Hyperphosphatemia in Maintenance Hemodialysis Patients

Aim: To evaluate the effects of short-term restriction of dietary protein intake (DPI) supplemented with keto acids on hyperphosphatemia in maintenance hemodialysis (MHD) patients. Methods: Forty MHD patients with uncontrolled hyperphosphatemia were randomized to either low DPI with keto acid-supplemented (sLP) or normal DPI (NP) group for 8 weeks. After 8 weeks, the sLP group was shifted to NP for another 8 weeks. Low-protein diet (LPD) was individualized with total caloric intake 30–35 kcal/kg/day, protein intake of 0.8 g/kg/day and phosphate intake of 500 mg/day. Keto acids were supplied in a dosage of 12 pills per day. Calcium phosphorous metabolism index and nutritional index (serum albumin, total protein, somatometric measurements, 3-day diaries and Mini-Nutritional Assessment score) were recorded. C-reactive protein, CO2 combining power and Kt/V were measured to evaluate the inflammation, metabolic acidosis and dialysis adequacy, respectively. Results: Serum phosphorus level and calcium-phosphate product were significantly decreased at the end of the first 8 weeks in the sLP group compared to the basal value and the NP group (p < 0.001). No difference was observed in C-reactive protein, Kt/V and nutritional index, while CO2 combining power was significantly higher at week 8 in the sLP group (p < 0.001). Conclusion: Short-term restriction of DPI supplemented with keto acids could decrease hyperphosphatemia and calcium-phosphate product, while keeping stable nutritional status among MHD patients.

Twelve weeks of pioglitazone therapy significantly attenuates dysmetabolism and reduces inflammation in continuous ambulatory peritoneal dialysis patients--a randomized crossover trial.

♦ Background: The aim of the present study was to investigate the effect of oral pioglitazone (PIO) on lipid metabolism, insulin resistance, inflammation, and adipokine metabolism in continuous ambulatory peritoneal dialysis (CAPD) patients. ♦ Methods: In this randomized crossover trial, 36 CAPD patients with serum triglyceride levels above 1.8 mmol/L were randomly assigned to receive either oral PIO 15 mg once daily or no PIO for 12 weeks. Then, after a 4-week washout, the patients were switched to the alternative regimen. The primary endpoint was change in serum triglycerides during the PIO regimen compared with no PIO. Secondary endpoints included changes in other lipid levels, homeostatic model assessment of insulin resistance (HOMA-IR), adipocytokines, and C-reactive protein (CRP). ♦ Results: All 36 CAPD patients (age: 64 ± 11 years; 33% men; 27.8% with diabetes mellitus) completed the study. Comparing patients after PIO and no PIO therapy, we found no significant differences in mean serum triglycerides (3.83 ± 1.49 mmol/L vs 3.51 ± 1.98 mmol/L, p = 0.2). However, mean high-density lipoprotein (0.94 ± 0.22 mmol/L vs 1.00 ± 0.21 mmol/L, p = 0.004) and median total adiponectin [10.34 μg/mL (range: 2.59 - 34.48 μg/mL) vs 30.44 μg/mL (3.47 - 93.41 μg/mL), p < 0.001] increased significantly. Median HOMA-IR [7.51 (1.39 - 45.23) vs 5.38 (0.97 - 14.95), p = 0.006], mean fasting blood glucose (7.31 ± 2.57 mmol/L vs 6.60 ± 2.45 mmol/L, p = 0.01), median CRP [8.78 mg/L (0.18 - 53 mg/L) vs 3.50 mg/L (0.17 - 26.30 mg/L), p = 0.005], and mean resistin (32.70 ± 17.17 ng/mL vs 28.79 ± 11.83 ng/mL, p = 0.02) all declined. The PIO was well tolerated, with only one adverse event: lower-extremity edema in a patient with low residual renal function. ♦ Conclusions: Blood triglycerides were not altered after 12 weeks of PIO 15 mg once daily in CAPD patients, but parameters of dysmetabolism were markedly improved, including insulin resistance, inflammation, and adipokine balance, suggesting that PIO could be of value for this high-risk patient group. Larger, more definitive studies are needed to confirm these findings.

Double filtration plasmapheresis benefits myasthenia gravis patients through an immunomodulatory action.

Double filtration plasmapheresis (DFPP) is used to treat myasthenia gravis (MG). However, the definite mechanism is unclear. This study investigated whether DFPP improves MG through an immunomodulatory action. Thirty-five MG patients were randomly divided into two treatment groups: Group A (DFPP combined with oral methylprednisolone) and Group B (oral methylprednisolone alone). Their antibody levels, clinical scores, cytokine levels, and CD4(+)CD25(high)Foxp3(+) (regulatory T cell [Treg]) levels were then determined. Anti-titin antibody levels were significantly lower in Group A compared with Group B after treatment. The clinical remission rate in Group A was significantly higher than in Group B. The changes in cytokine levels (interleukin [IL]-2, IL-4, IL-10, and interferon-γ) in sera and the peripheral blood mononuclear cell culture supernatants did not significantly differ before and after the treatments in both groups (p<0.05). The soluble intercellular adhesion molecule-1 (sICAM-1) levels were lower in Group A than in Group B (p<0.05). MG patients exhibited a lower percentage of Treg cells than normal patients. DFPP combined with methylprednisolone treatment increased the Treg cell percentage more than treatment with methylprednisolone alone (p<0.05). DFPP treatment more effectively lowers sICAM-1 and increases Treg cell expression, consequently benefiting MG patients.

Efficacy of Cytokine Removal by Plasmadiafiltration Using a Selective Plasma Separator: In Vitro Sepsis Model

More effective removal of pro‐ and anti‐inflammatory cytokines may play an important role in the treatment of sepsis. Plasmadiafiltration (PDF) with a larger selective plasma separator was performed to study the cytokine and plasma protein permeability profiles of the membrane in an in vitro sepsis model. The in vitro sepsis model was constructed by exposure of human whole blood to bacterial lipopolysaccharide. EVACURE 2A, a selective plasma separator, was placed in the blood circuit of PDF. Sieving coefficients of cytokines and plasma protein were tested in post‐dilution PDF mode at the following operating parameters: blood flow rate 150 mL/min; dialysate flow rate 33.33 mL/min; replacing fluid flow rate 6.67 mL/min; ultrafiltration rate 5 mL/min. An enzyme linked immunoadsorbent assay was used to measure the concentrations of tumor necrosis factor‐α (TNF‐α), high‐mobility group box 1 protein (HMGB1), interleukin‐1β (IL‐1β), interleukin‐1 receptor antagonist (IL‐1ra), interleukin‐2 (IL‐2), interleukin‐2 receptor (IL‐2r), interleukin‐6 (IL‐6), interleukin‐8 (IL‐8), interleukin‐10 (IL‐10) in plasma and ultrafiltrate. Sieving coefficients of different solutes ranged from 0.1 to 1.0 at first, decreased 10%–60% after 1 h of PDF, and then remained stable. Total clearance rates of cytokines ranged from 15 to 80 mL/min. The concentrations of cytokines decreased 20–80% after 1 hour of PDF. The sieving coefficient of albumin was 0.1 at first and then decreased to 0.05 after 1 hour of therapy. Plasmadiafiltration with Evacure 2A plasma separator can effectively remove almost all of the inflammatory mediators with low albumin loss.

Angiopoietin-1 inhibits mouse glomerular endothelial cell senescence via Tie2 receptor-modulated ERK1/2 signaling.

Background: The vasculature plays a key role in the progression of renal damage in aging, with reduction in glomerular and peritubular capillary density and decreased endothelial proliferative response. In this study, we examined the role of angiopoietin-1 (Ang1) in H2O2-induced senescence in mouse glomerular endothelial cells (MGECs) and the signaling pathway involved. Methods: MGECs were subjected to H2O2-induced senescence, which was evaluated by senescence-associated β-galactosidase (SA-β-Gal) staining, cell cycle analysis and expression of p16. Endothelial cell function was assessed by nitric oxide, von Willebrand factor secretion and capillary-like structure formation. Signal transduction was examined by Western blot with or without a specific inhibitor. Results: Ang1 significantly inhibited H2O2-induced senescence in MGECs, attenuated SA-β-Gal activity, resumed growth, and downregulated p16INK4a levels. Moreover, Ang1 regulated the secretion and capillary-like structure formation of endothelial cells with aging. However, these changes were markedly blocked by treatment with Ang2, sTie2-Fc and PD98059. Ang1 treatment markedly increased elevated Tie2 and ERK1/2 phosphorylation levels which were reduced by Ang2 and sTie2-Fc. PD98059 substantially reduced senescence while not altering Ang1-stimulated phosphor-Tie2 stimulation. Conclusion: The present studies suggest that Ang1 inhibits H2O2-induced senescence in MGECs via the Ang1–Tie2–ERK1/2 signaling pathway.

The Role of Na+-H+ Exchanger Isoform 1 in Aldosterone-Induced Glomerulosclerosis in Vivo

Aldosterone is reported to promote fibrosis of multiple organs. Recent studies showed that Na+-H+ exchanger isoform 1 (NHE1) was involved in mineralocorticoid-induced tissue fibrosis. The present study examined the role of NHE1 in aldosterone-induced glomerulosclerosis in rats. SD male rats were subjected to 5/6 nephrectomy and divided into four groups: rats subjected to sham operation were used as control (SHAM group), 5/6 nephrectomy (SNX group), SNX treated with aldosterone via osmotic mini-pump (ALDO group), and SNX treated with aldosterone plus NHE1 inhibitor 5-(N, N-Dimethyl) amiloride hydrochloride (DMA) (ALDO+DMA group). The rats were sacrificed at the 12th week. We found that aldosterone treatment significantly increased kidney weight/body weight ratio and systolic blood pressure compared with SNX rats. Aldosterone also increased proteinuria and serum creatinine level. The NHE1 antagonist DMA significantly reversed the effect of aldosterone on proteinuria, but had no effect on the aldosterone associated hypertension and the elevation of serum creatinine. The remnant kidney of 5/6 nephrectomized rats exhibited increased glomerulosclerosis score, tubulointerstitial fibrosis, and tubular proteinaceous cast, which were significantly enhanced by aldosterone treatment. DMA treatment significantly reduced aldosterone-associated glomerulosclerosis, but failed to improve aldosterone-induced tubulointerstitial fibrosis and tubular proteinaceous cast. The aldosterone-induced increase in renal TGFβ1 and PCNA was significantly prevented by treatment with DMA. Our data showed that NHE1 inhibitor reduced aldosterone-induced glomerulosclerosis but not hypertension in 5/6 nephrectomized rats. The present study suggested that NHE1 contributed to aldosterone-induced-glomerulosclerosis and could be a potential therapeutic target for chronic kidney disease.

Low-protein diet supplemented with ketoacids ameliorates proteinuria in 3/4 nephrectomised rats by directly inhibiting the intrarenal renin-angiotensin system.

Low-protein diet plus ketoacids (LPD+KA) has been reported to decrease proteinuria in patients with chronic kidney diseases (CKD). However, the mechanisms have not been clarified. As over-activation of intrarenal renin-angiotensin system (RAS) has been shown to play a key role in the progression of CKD, the current study was performed to investigate the direct effects of LPD+KA on intrarenal RAS, independently of renal haemodynamics. In this study, 3/4 subtotal renal ablated rats were fed 18 % normal-protein diet (Nx-NPD), 6 % low-protein diet (Nx-LPD) or 5 % low-protein diet plus 1 % ketoacids (Nx-LPD+KA) for 12 weeks. Sham-operated rats fed NPD served as controls. The level of proteinuria and expression of renin, angiotensin II (AngII) and its type 1 receptors (AT1R) in the renal cortex were markedly higher in Nx-NPD group than in the sham group. LPD+KA significantly decreased the proteinuria and inhibited intrarenal RAS activation. To exclude renal haemodynamic impact on intrarenal RAS, the serum samples derived from the different groups were added to the culture medium of mesangial cells. It showed that the serum from Nx-NPD directly induced higher expression of AngII, AT1R, fibronectin and transforming growth factor-β1 in the mesangial cells than in the control group. Nx-LPD+KA serum significantly inhibited these abnormalities. Then, proteomics and biochemical detection suggested that the mechanisms underlying these beneficial effects of LPD+KA might be amelioration of the nutritional metabolic disorders and oxidative stress. In conclusion, LPD+KA could directly inhibit the intrarenal RAS activation, independently of renal haemodynamics, thus attenuating the proteinuria in CKD rats.