Chinese Journal of Nephrology

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Mutation analysis of ATP6V0A4 and ATP6V1B1 gene in autosomal recessive distal renal tubular acidosis children

GAO Yan-xia;DOU Yi-he;SUI Ai-hua;LANG Ｙan-hua;SHAO Le-ping.

2012, 28(1): 1-4.

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Objective To analyze and identify the mutations of ATP6V0A4 and ATP6V1B1 gene in autosomal recessive distal renal tubular acidosis (rdRTA) children, and study the association of genotype and phenotype. Methods Genome DNA was amplified by PCR. Mutations of ATP6V0A4 and ATP6V1B1 gene in 3 children from 3 families were examined by direct sequencing. One hundred unrelated healthy subjects were selected to evaluate all mutations found in this study. Results A novel homozygous nonsense mutation was identified in ATP6V0A4 gene in one child, and a novel heterozygous nonsense variant and a frame-shift alteration were found in another child. No mutation of both genes was found in the third child. Conclusions Study of mutant genes of rdRTA in Chinese patients is helpful to understand the association in genotype and phenotype and increase the level of cognition and treatment to this disease.

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Hyperplasia of parathyroid cells induced by high phosphate via local cyclooxygenase 2 pathway in uremic patients

LI Hai-ming;ZHANG Qian;LU Yan-wen;NI Li;WANG Shao-qing;ZHANG Li-yin;GU Yong;HAO Chuan-ming;CHEN Jing.

2012, 28(1): 5-9.

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Objective To explore whether the stimulation effect of high phosphate on hyperplasia of human parathyroid cells and hyperparathyroidism through local cyclooxygenase 2 (COX2) up-regulation pathway. Methods Parathyroid glands were collected from 19 uremic patients undergoing parathyroidectomy. Expressions of COX1, COX2 and proliferative cell nuclear antigen (PCNA) of the glands were detected by immunohistochemistry. Primary parathyroid cells were cultured and treated with high or normal phosphate for 48 hours. Then expressions of COX2 and PCNA were detected by Western blotting and real-time PCR. Results Among 62 glands from above 19 patients, 43 glands were nodular hyperplasia and 19 diffuse hyperplasia. Both high expressions of COX2 and PCNA were found in these blands. Expression of COX2 was found in both oxyphil and chief cells and was more in the diffuse hyperplasia glands than that in the nodular hyperplasia(P<0.05). 80.60% and 85.20% of COX2 positive cells in diffuse hyperplasia glands and nodular hyperplasia also expressed PCNA. High phosphate could stimulate iPTH secretion in vitro(P<0.05). Expressions of COX2 and PCNA were higher in high phosphate group.(P<0.05). Conclusion High phosphate may stimulate the hyperplasia of parathyroid cells by up-regulating the local COX2 expression.

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The awareness rate, treatment rate and control rate of mineral and bone disorder in patients with moderate or advanced stage chronic kidney disease

YAN Jia-yi;ZHANG Min-fang;NI Zhao-hui;JIANG Rong;ZHANG Hai-fen;YAN Yu-cheng;ZHANG Wei-ming;HUANG Jia-ying;FANG Wei;MOU Shan;WANG Qin;QIAN Jia-qi.

2012, 28(1): 10-15.

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Objective To investigate the awareness rate, treatment rate and control rate of mineral and bone disorder in patients with moderate or advanced stage chronic kidney disease (CKD). Methods The awareness rate, treatment rate and control rate of mineral and bone disorder were evaluated based on a questionnaire and related laboratory examinations in 503 CKD stage 3 to 5 patients. Results The awareness rate of mineral and bone disorder in patients with moderate or advanced stage CKD was highest in hemodialysis patients, moderate in peritoneal dialysis patients and lowest in non-dialyzed patients (all P<0.01). The total scores of the questionnaire were lowest in non-dialyzed patients [6(5,8)] and were significantly higher in peritoneal dialysis [11(9,12)] and hemodialysis patients [13(11,15)] (P<0.01). The extent of awareness was negatively correlated with age (r=-0.11, P<0.05), and positively correlated with educational background (r=0.226, P<0.01), duration of CKD (r=0.597, P<0.01) and duration of dialysis (r=0.366, P<0.01). The source of knowledge was mainly from publicity and education made by medical staff, which accounted for 94.0%, 79.5% and 69.4% respectively in non-dialyzed, peritoneal dialysis and hemodialysis patients. The treatment rate was significantly higher in peritoneal dialysis (88.6%) and hemodialysis patients (96.9%) than that in non-dialyzed patients (58.2%) (all P<0.01). According to K/DOQI guideline, the control rate of serum calcium, phosphorus, calcium and phosphorus product and parathyroid hormone (PTH) were much better in non-dialyzed patients as compared to dialyzed ones. The percentage of number of lab indicators meeting the standard was significantly higher in non-dialyzed patients as compared to dialyzed ones (P<0.01). According to KDIGO guideline, the control rate of serum phosphorus was significantly lower in hemodialysis patients (23.6%) than that in peritoneal dialysis (36.9%) and non-dialyzed patients (46.7%) (P<0.01). Conclusions In non-dialyzed patients with moderate or advanced stage CKD, the awareness rate and treatment rate of mineral and bone disorder are relatively low, and the control rate is relatively high. Whereas in dialyzed patients, the awareness rate and treatment rate are relatively high, and the control rate is relatively low.

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Influence of nocturnal prolonged hemodialysis on nutrition status in uremic patients

SUN Li-jun;MEI Chang-lin;RONG Shu;MA Yi-yi;HE Liang-liang;HU Xiao-hong;XU Cheng-gang;ZHANG Yi-xiang;YE Chao-yang;ZHAO Xue-zhi.

2012, 28(1): 16-20.

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Objective To observe the influence of nocturnal prolonged hemodialysis (INHD) on patients' nutrition status. Methods Thirty-two maintenance hemodialysis patients received INHD(3 times per week and 7.5 hours each session) and thirty-five maintenance hemodialysis patients received conventional hemodialysis(3 times per week and 4 hours each session) as control were observed for 6 months. The nutrition status of these patients on various aspects which concluded physical measurements, laboratory tests, and dietary record at baseline(0 month) and exit(6 months) were recorded. Results (1)There were no differences in age,sex,body weight,and primary diseases between two groups. (2)The body weight, triceps skinfold thickness(TSF), and hand grip strength increased at exit point, but no statistical difference compared with the control group. Mid-upper arm circumference(MAC) increased signicantly from (27.1±4.2) to (30.5±6.1) cm (P<0.05). Compared with the control group (26.9±3.4) cm, there was a significant difference (P<0.05). (3)Serum phosphate decreased significantly from (0.5±0.5) to (0.1±0.6) ?滋mol/L (P=0.001) in INHD group. (4)The nutrition status were improved in INHD group evaluated by subjective global assessment (SGA)(P=0.03). (5) Dietary intake was recorded by a 3-day food record. Dietary intake of energy, protein, lipid, calcium, potassium, and phosphate increased in INHD group. None of the differences achieved statistical significance between two groups. Conclusion As compared with conventional hemodialysis, INHD can increase the dietary intake, decrease serum phosphate level, and improve patients nutrition status.

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Oral activated charcoal decreases serum phosphate level and calcium phosphorus products in dialysis patients with refractory hyperphosphataemia

CHENG Xu-yang;GAN Hong-bing;LV Ji-cheng;WANG Fang;ZUO Li.

2012, 28(1): 21-24.

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Objective To study the effect of medically activated charcoal on serum phosphorus level and calcium-phosphorus products in dialysis patients with poorly controlled hyperphosphatemia. Methods A single-center, prospective, self-controlled study was performed. Medically activated charcoal was administered 4.5-7.2 g per day with meals for three months to hemodialysis or peritoneal dialysis patients with hyperphosphatemia after taking calcium-based phosphate binders. The levels of blood phosphorus, calcium, calcium-phosphorus products, intact parathyroid hormone (iPTH), albumin and hemoglobin were detected before and after the treatment. The results were analyzed using paired t-test. Results After 3 months of treatment, the patients’ serum phosphorus level was significantly reduced from (2.16±0.34) mmol/L (pre-treatment) to (1.85±0.30) mmol/L (post-treatment) (P<0.01). Similarly, the serum calcium-phosphorus products were lowered from pre-treatment level of (63.93±8.83) mg2/dl2 to post-treatment of (54.12±8.37) mg2/dl2 (P<0.01). Serum albumin level was slightly reduced from (41.7±2.9) g/L to (40.1±2.2) g/L (P=0.001). In contrast, there were no significant changes in serum calcium and iPTH levels when compared pre- to post-treatment values (P=0.734 and P=0.665, repectively). Conclusion In combination with calcium-based phosphate binder therapy, oral medically activated charcoal can effectively reduce the levels of blood phosphorus and calcium-phosphorus products in dialysis patients with refractory hyperphosphatemia.

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Clearance of protein-bound uremic toxins associated with cardiovascular disease in high-flux hemodialysis

DU Qiu-na;GAO Jia-yuan;ZHU Ming-li;LU Ren-hua;DAI Hui-li;ZHANG Wei-ming;JIANG Rong;WANG Yong-mei;QIAN Jia-qi;NI Zhao-hui;YAN Yu-cheng.

2012, 28(1): 25-30.

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Objective To investigate protein-bound uremic toxins clearance in high-flux hemodialysis patients. Methods Twenty-three high-flux hemodialysis patients from Renji Hospital, Shanghai Jiaotong University School of Medicine were enrolled. Concentrations of p-cresyl sulfate(PCS), indoxylsulfate(IS) and homocysteine(Hcy) were tested by HPLC-MS-MS. Reduction ratios (RRs) and the amount of these toxins in drained dialysate were determined. The relationship of clearance of PCS, IS and Hcy with BUN or Scr was analyzed. Results Plasma levels of the protein-bound toxins were decreased in high-flux hemodialysis. The RRs of total PCS, IS and Hcy were (32.43±11.41)%, (37.38±10.99)% and (57.16±10.43)%，respectively, which were significantly lower than those of BUN or Scr (all P<0.05). Moreover, no correlation was found between the RRs of the total protein-bound compounds and BUN or Scr. The RRs of free PCS, IS and Hcy were (55.54±20.75)%, (55.33±19.49)% and (74.63±11.45)%，respectively. Although RRs of free protein-bound toxins were slightly higher than that of their total, RRs of free PCS and free IS were still inferior to those of BUN or Scr (all P<0.05). Elimination of protein-bound toxins assessed by their mass in dialysate was (60.58±39.41) mg,(34.87±23.64)mg for total and free PCS; (72.47±45.18) mg, (33.82±24.28) mg for total and free IS; (5.27±3.31) mg, (3.73±1.68) mg for total and free Hcy, respectively. The total and free protein-bound uremic toxins mass in dialysate were positively correlated with the pre-treatment plasma concentrations (all P<0.05). Conclusions Protein-bound toxins PCS,IS and Hcy can be partly removed by high-flux hemodialysis, and the elimination of these compounds into dialysate can be predicted by the levels of pre-treatment plasma concentrations. Additionally, the behavior of the protein-bound toxins under study during hemodialysis may be different from water-soluble substances like BUN and Cr. Alternative efficient therapy forms should be explored.

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Pulmonary hypertension in patients on long-term maintenance hemodialysis

YE Wen-ling;MA Jie;SHI Tao;SUN Wei;ZHANG Shu-yang;FANG Li-gang;LI Xue-mei.

2012, 28(1): 31-35.

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Objective To prospectively investigate the characteristics and correlative influential factors of pulmonary hypertension (PHT) in patients on long-term maintenance hemodialysis(MHD). Methods Pulmonary artery systolic pressure (PASP) was assessed by echocardiography according to the guideline from the American Society of Echocardiography in 2010 and PASP more than 35 mm Hg was diagnosed as PHT. Echocardiography and pulse wall velocity (baPWV) was performed in the next day after hemodialysis. Arteriovenous fistula (AVF) flow was evaluated by the ultrasound dilution method. Hemodialysis-related informations and laboratorial parameters were detected in the same period. Results One hundred and eleven MHD patients [male 45, female 66, mean age (57.32±12.49) years old] in our hemodialysis center were included in the study. All of the patients received MHD treatment for more than 6 months with AVF as the vascular access. The patients with any possible diseases causing PHT were excluded. The mean MHD period was (70.51±44.98) months. Twenty-eight patients (25.32%) were diagnosed as PHT with mean PASP (45.68±10.83) mm Hg. Left ventricular diastolic dysfunction was severer in patients with PHT than that in patients without PHT. The prevalence of moderate to severe diastolic dysfunction was statistically higher in PHT group compared to non-PHT group (53.60% vs 6.02%, P<0.01). Ejection fraction (EF), fractional shortening of left ventricular diameter in PHT group were also significantly lower than those in non-PHT patients(62.06%±14.90% vs 69.72%±8.60%, 36.46%±10.04% vs 40.20%±7.86%, P<0.01). The patients with EF less than 50% were 21.43% and 3.61% in PHT and non-PHT group respectively. However, there were no significant differences in age, sex, MHD periods, body mass index(BMI), interval dialysis weight growth, blood pressure before dialysis, hemoglobin, albumin, pre-albumin, serum calcium and phosphorus, iPTH, nPCR, Kt/V, baPWV and AVF flow between the two groups. Conclusions PHT is a common complication of patients on long-term MHD. There is close relationship between PHT and left ventricular insufficiency. PHT is not significantly relevant to mineral metabolic disturbance, AVF flow, hemoglobin, dialysis adequacy and nutrition status.

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Clinical status at first hospitalization and analysis of risk factors in 1242 patients with diabetic kidney diseases

HUANG You-qun;LIU Fang;GOU Rong;WU Min;ZANG Li;FU Ping.

2012, 28(1): 36-40.

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Objective To investigate the clinical status of 1242 patients with diabetic kidney diseases (DKD) during their first hospitalization, and to analyze the risk factors of prognosis, so as to provide reference for clinical practice. Methods Retrospective case-control study was performed. Clinical data of 1242 patients diagnosed as DKD in first hospitalizaton from January 2003 to December 2008 were reviewed, and patients were followed up to realize the prognosis. Multiple regression analysis was carried out to screen the risk factors. Results Most of the patients were Mogensen stage Ⅳ or Ⅴ in their first hospitalization, accounting for 77.2%. 24.8% of cases was complicated with cardiocerebrovascular diseases. Scr of 36.6% patients was higher than 176.8 μmol/L. One way ANOVA indicated that diabetes course, hemoglobin, serum albumin, Scr and Charlson index were significantly different among Mogensen stage Ⅲ,Ⅳ,Ⅴ patients. Logistic regression showed that age, albumin, Scr, cardiocerebrovascular diseases and Chalson index were risk factors for death in DKD patients (OR=1.057, 0.908, 1.002, 2.006, 1.371)，but sex, diabetes course and hemoglobin were not risk factors, which was in accord with the result from 416 non-dialysis patients. Multiple linear regression analysis revealed serum albumin level was positively correlated with survival in non-dialysis DKD patients (P=0.003). The mean survival time was only 1.2145 year in 162 non-dialysis dead patients. Conclusions DKD patients in our hospital refer quite late, usually with poor conditions and complications. Most of DKD patients are Mogensen stage Ⅳ or Ⅴ in the first hospitalization. Age, serum albumin, Scr, cardiocerebrovascular diseases and Charlson index are risk factors of death, while gender, diabetes course and hemoglobin are not significantly correlated with death. In addition, serum albumin is positively correlated with survival time. Early diagnosis and management of risk factors are crucial for improving the prognosis of DKD patients.

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Oxidative stress-dependent Ras-ERK activation involves in aldosterone-induced mesangial cell proliferation

ZHAO Fei;HUANG Song-ming;DING Gui-xia;BAO Hua-ying;CHEN Ying;HAN Yuan;ZHANG Wei-zhen;ZHANG Ai-hua.

2012, 28(1): 41-46.

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Objective To investigate the role of oxidative stress-dependent Ras-extracellular signal-regulated kinase (ERK1/2) signaling in aldosterone (ALDO)-induced mesangial cell proliferation. Methods The incorporation of 3H-thymidine (3H-TdR) and cell count were used as the measure of mesangial cell (MC) proliferation. Western blotting was used to detect the activation of Ki-RasA, c-Raf, MEK1/2, ERK1/2 and PI3K. Results Aldosterone significantly induced human mesangial cell proliferation, and anti-oxidant N-Acetylcysteine (NAC), catalase, and super oxide dismutase (SOD) significantly inhibited ALDO-induced mesangial cell proliferation(P<0.01, respectively). Stimulation by ALDO for 3 h, Ki-RasA, c-Raf, MEK1/2, and ERK1/2 activity increased by 4.05-, 3.62-, 4.52-, and 3.40-fold compared with control group(P<0.01, respectively）. NAC almost completely blocked ALDO-induced Ki-RasA, c-Raf, MEK1/2, and ERK1/2 activation(P<0.01, respectively). Ki-RasA siRNA dose-dependently inhibited Ki-RasA expression, ALDO-induced Ki-RasA activation, and mesangial cell proliferation(P<0.01, respectively）. c-Raf inhibitor GW5074 and MEK1/2 inhibitor PD98059 also reduced ALDO-induced mesangial cell proliferation by 65% respectvely (P<0.01). Ki-RasA siRNA had no effect on ALDO-induced PI3K phosphorylation. Combining LY294002 and PD98059 completely blocked ALDO-induced mesangial cell proliferation(P<0.01). Conclusions ALDO-induced Ki-RasA-c-Raf-MEK-ERK signaling activation is dependent on reactive oxygen species (ROS) production, which mediates ALDO-induced mesangial cell proliferation. Inhibition of both ERK1/2 and PI3K signaling simultaneously completely blocks ALDO-induced mesangial cell proliferation.

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Effect of irbesartan on osteopontin expression and fibrosis in diabetic rat kidney

SHEN Jie;HU Yuan-yuan;ZHU Yan;TANG Jie-long;LIU Shuai.

2012, 28(1): 47-51.

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Objective To explore the effect of different doses of irbesartan on osteopontin expression and fibrosis in diabetic rat kidney. Methods Sixty-three 8-week old male Wistar rat were randomly divided into control group (Ctrl group, n=7), diabetes group(DM group, n=14), 30 mg•kg-1•d-1 hydralazine administrated group(DM+Hyd group, n=12), 25 mg•kg-1•d-1 irbesartan administrated group (DM+Irb25 group, n=10), 50 mg•kg-1•d-1 irbesartan administrated group(DM+Irb50 group, n=9) and 200 mg•kg-1•d-1 irbesartan administrated group (DM+Irb200 group, n=11). Four weeks after modeling, rats were administered with the corresponding dose of irbesartan. After 12 weeks, urinary albumin excretion rate (UAER), endogenous creatinine clearance rate (Ccr) were measured; morphology and collagen deposition in rat kidney were observed by PAS and Masson staining respectively; AngⅡ content in kidney was measured by ELISA; renal tissue TGF-β1 and OPN mRNA expression were detected by real-time PCR. Results UAER and Ccr in the intervention groups of irbesartan were significantly decreased compared with DM group (P<0.05). UAER and Ccr in DM+Irb200 group were significantly lower than those in DM+Irb25 group and DM + Irb50 group (P<0.05). Glomerular hypertrophy, mesangial matrix expansion, tubular lesions and deposition of collagen fiber were siginficant in diabetic rats compared with Ctrl, and prevented after administration with different doses of irbesartan. AngⅡ protein level and TGF-β1, OPN mRNA expression in renal tissue of diabetic rats were significantly higher than those in Ctrl group. AngⅡ, TGF-β1, and OPN mRNA expression was significantly reduced after administration with different doses of irbesartan, and with the increase of irbesartan, the above indicators were decreased P<0.05). Renal local AngⅡ level was positively correlated with OPN mRNA expression (r=0.74, P<0.01). Conclusion Irbesartan reduces renal TGF-β1, OPN mRNA expression by decreasing kidney local AngⅡ in dose-dependent manner, and eventually reduces tubulointerstitial fibrosis, which plays a role in kidney protection.

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Up-regulation of intermedin protects kidney from ischemia/reperfusion injury

ZHU Guo-zhen;LI Rong-shan;QIAO Xi;HUANG Xiao-guang;ZHANG Xiao-qin;WANG Chen;SHAO Shan;BAI Bo.

2012, 28(1): 52-57.

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Objective To investigate the effect of intermedin (IMD) on renal ischemia/reperfusion(I/R) injury after the up-regulation of IMD. Methods A total of 24 healthy Wistar male rats were randomly divided into four groups, sham-operated group, I/R group, IMD gene transfection +I/R group and empty plamid +I/R group. All the animals were killed at the end of 24 h of reperfusion. Histological changes and renal function were estimated. The expression and site of IMD were determined by Immunohistochemistry method, semi-quantitative RT-PCR and Western blotting. The protein expressions of endothelin 1 (ET-1), tumor necrosis factor α (TNF-α) were detected by Western blotting. Results Compared with sham-operated group, tubulointerstitial pathological injury was significant aggravated in I/R group (7.6±2.3) and empty plamid +I/R group(7.0±1.8), and such injury was improved in IMD+I/R group (1.5±0.8) (P<0.05). Compared with I/R group and empty plamid +I/R group, the renal dysfunction of IMD +I/R group was obviously lessened [BUN：(7.73±1.03) mmol/L vs (10.13±2.14) mmol/L， (9.77±1.92) mmol/L; Scr: (58.50±3.27) μmol/L vs (80.33±7.15) μmol/L, (75.67±7.58) μmol/L, all P<0.05]. IMD expression was weak in the plasma of tubulointerstitial cells in sham-operated group, and was up-regulated in I/R group. Compared with I/R group, immunohistochemical IMD expression increased obviously (262.03±67.89 vs 175.57±48.06, P＜0.01). The mRNA expression of IMD in IMD+I/R group was up-regulated significantly by 60.7% , 66.1% and the protein expression of IMD in IMD+I/R group increased significantly by 51.4%, 55.9% as compared to I/R and empty plasmid +I/R group. Meanwhile, the protein expressions of ET-1 and TNF-α in IMD+I/R group were obviously lower compared with those in I/R group (ET-1: 0.08±0.02 vs 0.17±0.02; TNF-α: 0.21±0.04 vs 0.35±0.02, all P<0.05). Conclusion IMD gene transfected into kidneys of rats prior to I/R surgery can attenuate the over-expressions of both ET-1 and TNF-α in I/R injured rat kidneys as well as the damages to the structure and function of the kidneys.

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Effect of intermedin on renal interstitial fibrosis of unilateral ureteral obstruction rats

CUI Lu-ping*;ZHOU Yun;ZHOU Qin.

2012, 28(1): 58-62.

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Objective To observe the effect of intermedin on renal interstitial fibrosis of unilateral ureteral obstruction rats. Methods Forty male Wistar rats were randomly divided into two groups: the sham-operation group (n=10) underwent the left ureteral dissection, the other 30 rats were made as unilateral ureteral obstruction models and divided into the model group (UUO), the losartan group, the IMD group (each group n=10). At the day 14, 21 after operation, randomly 5 rats from each group were blooded by abdominal arotic and obstructive kidneys were taken out. The renal histopathological changes were observed by HE and Masson staining.The BUN, Scr, and hydroxyproline (Pro) of the obstructive kideys were measured by colorimetry. The expression of TGF-β1 and intermedin was observed by immunohistochemisty staining. Results Compared with the sham-operated group, the levels of BUN, Scr, Pro, TGF-β1 and IMD in the model group increased (P<0.05). Compared with the UUO group, the levels of Scr, BUN, Pro, TGF-β1 and IMD in the losartan group were lower (P<0.05). However, IMD in the IMD group was significantly up-regulated(P< 0.05), the others were down-regulated (P<0.05). Conclusion IMD can improve the renal interstitial fibrosis, and the mechanism maybe antagonizes the TGF-β1.

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临床研究

基础研究

临床研究

基础研究