Efficacy and Safety of Sevelamer Carbonate in Chinese Nondialysis Chronic Kidney Disease Patients with Hyperphosphatemia: A Randomized, Double-Blind, Parallel-Group Study.

Introduction: Previous studies suggested that sevelamer carbonate is well tolerated with a favorable efficacy and safety profile in both dialysis and nondialysis patients in Europe; however, the efficacy remains controversial, and few studies have examined sevelamer carbonate therapy in other ethnic nondialysis CKD patients. This study assessed the efficacy and safety of sevelamer carbonate in Chinese nondialysis CKD patients with hyperphosphatemia. Methods: The multicenter, randomized, double-blind, parallel-group, placebo-controlled, and phase 3 clinical trial enrolled 202 Chinese nondialysis CKD patients with serum phosphorus ≥1.78 mmol/L. Patients were randomly assigned 1:1 to receive sevelamer carbonate (2.4-12 g per day) or placebo for 8 weeks. The primary outcome was the change in serum phosphorous between baseline and week 8. Results: Totally 482 Chinese patients were screened and 202 were randomized (sevelamer carbonate, n = 101; placebo, n = 101). The mean serum phosphorous decreased significantly in patients treated with sevelamer carbonate compared with placebo (-0.22 ± 0.47 vs. 0.05 ± 0.44 mmol/L, p < 0.0001). Significantly (p < 0.0001), decreases of serum total cholesterol, low-density lipoprotein cholesterol, and calcium-phosphorus (Ca × P) product levels from baseline to week 8 were shown in sevelamer carbonate group compared with placebo group. Serum intact parathyroid hormone was not significantly changed in the sevelamer carbonate group (p = 0.83). Patients in the sevelamer carbonate group experienced similar adverse events as the placebo group. Conclusion: Sevelamer carbonate is an effective and well-tolerated phosphate binder in advanced nondialysis CKD Chinese patients with hyperphosphatemia.

Prevalence and risk factors for vascular calcification in Chinese patients receiving dialysis: baseline results from a prospective cohort study.

OBJECTIVE: With limited data available on calcification prevalence in chronic kidney disease (CKD) patients on dialysis, the China Dialysis Calcification Study (CDCS) determined the prevalence of vascular/valvular calcification (VC) and association of risk factors in Chinese patients with prevalent hemodialysis (HD) or peritoneal dialysis (PD). METHODS: CKD patients undergoing HD/PD for ≥6 months were enrolled. Prevalence data for calcification and medical history were documented at baseline. Coronary artery calcification (CAC) was assessed by electron beam or multi-slice computed tomography (EBCT/MSCT), abdominal aortic calcification (AAC) by lateral lumbar radiography, and cardiac valvular calcification (ValvC) by echocardiography. Serum phosphorus, calcium, intact parathyroid hormone (iPTH), and 25-hydroxyvitamin D and FGF-23 were evaluated. A logistic regression model was used to evaluate the association between risk factors and VC. RESULTS: Of 1,497 patients, 1,493 (78.3% HD, 21.7% PD) had ≥1 baseline calcification image (final analysis cohort, FAC) and 1,423 (78.8% HD, 21.2% PD) had baseline calcification data complete (BCDC). Prevalence of VC was 77.4% in FAC (80.8% HD, 65.1% PD, p < .001) and 77.5% in BCDC (80.7% HD, 65.8% PD). The proportion of BCDC patients with single-site calcification were 20% for CAC, 4.3% for AAC, and 4.3% for cardiac valvular calcification (ValvC), respectively. Double site calcifications were 23.4% for CAC and AAC, 6.5% for CAC and ValvC, and 1.1% for AAC and ValvC, respectively. In total, 17.9% patients had calcification at all three sites. CONCLUSIONS: High prevalence of total VC in Chinese CKD patients will supplement current knowledge, which is mostly limited, contributing in creating awareness and optimizing VC management.

[Protective Effect of Hydrogen Sulfide in the Secondary Renal Disease and Renal Transplantation].

The prevalence of kidney disease was increasing,which has become an important threaten to the health of the population.Hydrogen sulfide is the third gas signaling molecules after CO and NO.It has toxic effect at high concentration,but plays an important role in relaxing blood vessel ,antioxidation anti -inflammation and anti-apoptosis at physiological concentration.Kidney disease,especially seconda-ry kidney disease such as obstructive nephropathy,renal transplantation,diabetic nephropathy and hyper-tensive kidney lesion are closely related to vascular leision,oxidative stress and inflammation.Then what's the relationship between hydrogen sulfide and kidney disease?This article will review the relationship between hydrogen sulfide and kidney disease.

Inhibition of Uncoupling Protein 2 Attenuates Cardiac Hypertrophy Induced by Transverse Aortic Constriction in Mice.

BACKGROUND: Uncoupling protein 2 (UCP2) is critical in regulating energy metabolism. Due to the significant change in energy metabolism of myocardium upon pressure overload, we hypothesize that UCP2 could contribute to the etiology of cardiac hypertrophy. METHODS: Adult male C57BL/6J mice were subjected to pressure overload by using transverse aortic constriction (TAC), and then received genipin (a UCP2 selective inhibitor; 25 mg/kg/d, ip) or vehicle for three weeks prior to histologic assessment of myocardial hypertrophy. ATP concentration, ROS level, and myocardial apoptosis were also examined. A parallel set of experiments was also conducted in UCP2-/- mice. RESULTS: TAC induced left ventricular hypertrophy, as reflected by increased ventricular weight/thickness and increased size of myocardial cell (vs. sham controls). ATP concentration was decreased; ROS level was increased. Apoptosis and fibrosis markers were increased. TAC increased mitochondrial UCP2 expression in the myocardium at both mRNA and protein levels. Genipin treatment attenuated cardiac hypertrophy and the histologic/biochemical changes described above. Hypertrophy and associated changes induced by TAC in UCP2-/- mice were much less pronounced than in WT mice. CONCLUSIONS: Blocking UCP2 expression attenuates cardiac hypertrophy induced by pressure overload.

Exposure to atrazine during gestation and lactation periods: toxicity effects on dopaminergic neurons in offspring by downregulation of Nurr1 and VMAT2.

High atrazine (2-chloro-4-ethytlamino-6-isopropylamine-1,3,5-triazine; ATR) contents in the environment threaten the health conditions of organisms. We examined the effects of ATR exposure on Sprague-Dawley rats during gestation and on the dopaminergic neurons of offspring during lactation. Pregnant dams were orally treated with 0 mg/kg/day to 50 mg/kg/day of ATR from gestational day 5 to postnatal day 22. Afterward, neither offspring nor dams received ATR. Dopamine (DA) content was examined in striatum samples by HPLC-FL; the mRNA expressions of tyrosine hydroxylase (TH), orphan nuclear hormone (Nurr1), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) in the ventral midbrain samples were examined by fluorescence PCR when the offspring reached one year of age. After the pregnant rats were exposed to ATR, the DA concentrations and mRNA levels of Nurr1 were decreased in their offspring. Decreased Nurr1 levels were also accompanied by changes in the mRNA levels of VMAT2, which controls the transport and reuptake of DA.

Role of microRNA-214-targeting phosphatase and tensin homolog in advanced glycation end product-induced apoptosis delay in monocytes.

Advanced glycation end products (AGEs) delay spontaneous apoptosis of monocytes and contribute to the development of inflammatory responses. However, the mechanism by which AGEs affect monocyte apoptosis is unclear. We studied the role of microRNA-214 (miR-214) and its target gene in AGE-induced monocytic apoptosis delay. Using microRNA (miRNA) microarray and stem-loop, quantitative RT-PCR assay, we studied genome-wide miRNA expression in THP-1 cells treated with or without AGEs. Significant upregulation of miR-214 was consistently observed in THP-1 and human monocytes treated with various AGEs, and AGE-induced monocytic miR-214 upregulation was likely through activation of receptor for AGEs. A striking increase in miR-214 was also detected in monocytes from patients with chronic renal failure. Luciferase reporter assay showed that miR-214 specifically binds to the phosphatase and tensin homolog (PTEN) mRNA 3'-untranslated region, implicating PTEN as a target gene of miR-214. PTEN expression is inversely correlated with miR-214 level in monocytes. Compared with normal monocytes, AGE-treated monocytes and monocytes from chronic renal failure patients exhibited lower PTEN levels and delayed apoptosis. Overexpression of pre-miR-214 led to impaired PTEN expression and delayed apoptosis of THP-1 cells, whereas knockdown of miR-214 level largely abolished AGE-induced cell survival. Our findings define a new role for miR-214-targeting PTEN in AGE-induced monocyte survival.

Effect of taurine-conjugated ursodeoxycholic acid on endoplasmic reticulum stress and apoptosis induced by advanced glycation end products in cultured mouse podocytes.

BACKGROUND: Activations of death receptors and mitochondrial damage are well-described common apoptotic pathways. Recently, a novel pathway via endoplasmic reticulum (ER) stress has been reported. METHODS: We assessed the role of tauroursodeoxycholic acid (TUDCA) in inhibition of ER stress and its protective effect on advanced glycation end products (AGEs)-induced apoptosis in murine podocytes. Podocytes were incubated with increasing doses of AGEs for variable time periods. Apoptosis was quantitatively determined by flow cytometry detecting propidium iodide expression and annexin V binding simultaneously. Level of glucose-regulated protein 78 (ER stress marker) expression was determined by Western blot. Intracellular calcium concentration ([Ca(2+)](i)) was recorded by a laser confocal microscope and the Ca(2+) indicator Fluo-3 labeling. RESULTS: AGEs induced podocyte apoptosis and increased the expression of glucose-regulated protein 78 in a dose- and time-dependent manner as compared with bovine serum albumin. These changes were accompanied by a rapid rise in [Ca(2+)](i) of podocytes. TUDCA was capable of abolishing AGEs-induced expression of glucose-regulated protein 78 and subsequently inhibited apoptosis in a dose-dependent manner. CONCLUSION: We propose that ER stress plays an important role in AGEs-induced apoptosis and that TUDCA prevents apoptosis by blocking an ER stress-mediated apoptotic pathway. This novel mechanism of TUDCA action suggests new intervention methods for AGEs-induced apoptosis of mouse podocytes in diabetic nephropathy.

Cytotoxic activity and probable apoptotic effect of Sph2, a sphigomyelinase hemolysin from Leptospira interrogans strain Lai.

Our previous work confirmed that Sph2/LA1029 was a sphigomyelinase-like hemolyisn of Leptospira interrogans serogroup Icterohaemorrhagiae serovar Lai. Characteristics of both hemolytic and cytotoxic activities of Sph2 were reported in this paper. Sph2 was a heat-labile neutral hemolysin and had similar hemolytic behavior as the typical sphingomyelinase C of Staphylococcus aureus upon sheep erythrocytes. The cytotoxic activity of Sph2 was shown in mammalian cells such as BALB/C mouse lymphocytes and macrophages, as well as human L-02 liver cells. Transmission electron microscopic observation showed that the Sph2 treated BALB/C mouse lymphocytes were swollen and ruptured with membrane breakage. They also demonstrated condensed chromatin as a high-density area. Cytoskeleton changes were observed via fluorescence confocal microscope in Sph2 treated BALB/C mouse lymphocytes and macrophages, where both cytokine IL-1beta and IL-6 were induced. In addition, typical apoptotic morphological features were observed in Sph2 treated L-02 cells via transmission electron microscope and the percentage of apoptotic cells did increase after the Sph2 treatment detected by flow cytometry. Therefore, Sph2 was likely an apoptosis-inducing factor of human L-02 liver cells.

[Expression of connective tissue growth factor in renal interstitial fibrosis after ureteral obstruction and effects of rapamycin thereupon: experiment with rats].

OBJECTIVE: Is a common feature of progressive renal diseases regardless of the initiating insult To clarify the role of connective tissue growth factor (CTGF) in after (UUO) in renal interstitial fibrosis and effects of rapamycin (RAP) thereupon. METHODS: Eighteen Sprague-Dawley rats were randomly divided into 3 equal groups: unilateral ureteral obstruction (UUO) model group, undergoing ligation of the left ureter; RAP treatment group, undergoing ligation of the left ureter and intraperitoneal injection of RAP 0.04 mg.kg(-1).d(-1); and sham operation group. The right kidneys were taken out 7 and 14 days after the operation respectively to undergo renal pathological examination by Masson staining. Semi-quantitative RT-PCR was used to detect the mRNA expression of CTGF. Western blotting was performed to examine the protein expression of CTGF and fibronectin (FN). RESULTS: In comparison with the sham operation group, renal interstitial fibrosis was significant more expression in the 2 UUO groups, especially the UUO model group (P < 0.01). Seven and 14 days after the operation the levels of CTGF mRNA expression of the UUO model and RAP treatment groups (both P < 0.01), and the level of CTGF mRNA expression of the RAP treatment group was significantly lower than that of the UUO model group (P < 0.01), however, there was no significant difference in the level of CTGF mRNA expression between the 2 UUO groups 14 days after the operation. Seven and 14 days after the operation the levels of CTGF protein expression of the UUO model and RAP treatment groups were both significantly higher than that of the sham operation group (both P < 0.01), and the levels of CTGF protein expression of the RAP treatment group were significantly lower than that of the UUO model group (P < 0.05 and P < 0.01). The levels of FN expression 7 and 14 days after the operation of the 2 UUO groups were both significantly higher than that of the sham operation group (both P < 0.01). and the level of FN expression 7 days after of the RAP treatment group was significantly lower than that of the UUO model group (P < 0.01), however, there was no significant difference in the level of FN expression between the 2 UUO groups 14 days after the operation. CONCLUSION: The expression of CTGF mRNA and that of CTGF protein increase after UUO. Rapamycin play a protective role in the kidney by downregulating the CTGF expression and alleviating the renal interstitial fibrosis following UUO.

[Efficiency of total parathyroidectomy and autotransplantation in 31 patients with uremic hyperparathyroidism].

OBJECTIVE: To analyse the efficacy of total parathyroidectomy with autotransplantation (total PTX + AT) in treating uremic secondary hyperparathyroidism and to discuss the relevant medical treatment used. METHODS: The clinical data of 31 patients with uremic SHPT admitted into our hospital from 1996-2005 were analysed with respect to total PTX + AT. RESULTS: The period of hemodialysis were for the patients was on the average 9.2 years. There were 22 male and 9 female with an average age of 42.4 (31 - 67) years. The clinical manifestations consisted of osteoarticular pain in 83.9%, fractures in 35.5%, soft tissue and vascular calcification in 45.2% and pruritus in 80.6%. Laboratory examination yielded the following results: haematocrit 0.25 +/- 0.04, serum Ca (2.61 +/- 0.35) mmol/L, serum P (2.14 +/- 0.31) mmol/L, plasma total alkaline phosphatase (AKP) (885 +/- 335) U/L and parathyroid hormone (iPTH) (1811 +/- 879) ng/L (700 - 2500 ng/L). Cervical ultrasonography and/or emission computed tomography showed 2 - 4 hyperplastic glands. All of the patients showed no response to medical treatment including vitamin D. Total PTX + AT was performed on the 31 cases. Clinical symptoms and signs markedly improved after operation in 1 to 2 weeks. However, fracture and ectopic calcification showed no improvement. Plasma iPTH decreased rapidly (< 200 ng/L) postoperatively in 1 to 2 days. Serum Ca and P returned to normal. AKP was corrected in 1 to 3 months. CONCLUSION: Total parathyroidectomy with autotransplantation is an effective treatment for severe uremic secondary hyperparathyroidism patients.