Chinese Journal of Nephrology

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DNA damage in peripheral blood lymphocytes of patients with autosomal dominant polycystic kidney disease

LI Ming;QIN Song-bing;WANG Li-li;LU Guo-yuan;QIAO Qing;SHEN Lei.

2012, 28(3): 170-173.

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Objective To detect DNA damage of peripheral blood lymphocytes in patients and family members of autosomal dominant polycystic kidney disease (ADPKD), and to study the effect of irradiation on genomic stability of lymphocytes. Methods Before and after 0.5 Gy radiation dose, single-cell gel electrophoresis (SCGE) was employed to analyze DNA damage of lymphocytes in 10 ADPKD patients (group A), 3 members without clinical symptoms of a ADPKD family (group B) and 20 healthy control people (group C). The damage was estimated based on the content of DNA in tail (TDNA%) with comet analysis software (CASP). Results Both before and after irradiation, the TDNA% (8.85%±0.14%, 14.84%±0.77%) and the value-added (6.00%±0.77%) of TDNA% of group A were significantly higher than those of group C (7.50%±0.37%，12.46%±0.26%, 4.96%±0.44%) respectively. There were no significant differences between group B and group C or group A and group B. While 1 person in group B had higher TDNA% as compared to group C both before and after irradiation. Conclusions The lymphocytes of ADPKD patients are more sensitive to ionizing radiation as compared to healthy people. The genomic instability in ADPKD patients or member of ADPKD family may trigger cystic formation in multi-organs when exposing to environmental agents. SCGE may provide a new approach to elucidate the pathogenesis and prognosis of ADPKD.

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Clinical analysis of 43 episodes of cyst infection in autosomal dominant polycystic kidney disease

ZHANG Tong;RONG Shu;MA Yi-yi;SUN Hai-peng;HE Liang-liang;LI Lan-jun;CHEN Zhou;CHEN Ye;YU Sheng-qiang;LI Lin;YE Chao-yang;XU Cheng-gang;ZHAO Xue-zhi;MEI Chang-lin.

2012, 28(3): 174-178.

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Objective To summarize the clinical characteristics and outcome of renal cyst infection in patients with autosomal dominant polycystic kidney disease (ADPKD). Methods Clinical data of 40 ADPKD patients with 43 episodes of renal cyst infection admitted in Shanghai Changzheng Hospital from 1st January 1991 to 31st December 2010 were retrospectively analyzed. Differences of microbiological data and treatments between 1st January 1991 to 31st December 2000 and 1st January 2001 to 31st December 2010 were compared. Results Among 473 identified patients with ADPKD and 662 episodes of hospitalization, 40 patients had 43 episodes of renal cyst infection, including 8 definite and 35 likely cases. Microbiological documentation was available for 34 episodes (79.0%), Escherichia coli accounting for 82.4% of all retrieved bacterial strains. Resistant Escherichia coli to quinolone and certain β-lactamine increased in recent decade. Clinical efficacy of initial antibiotic treatment was noted in 69.8% of episodes. Antibiotic treatment modification was more frequently required for patients receiving initial monotherapy compared with those receiving combination therapy. In the first ten-year group, initial combination therapy and clinical efficacy were noted in 30.0% and 60.0% of episodes respectively, and hospital stay was (20.2±6.7) d. In the second ten-year group, initial combination therapy and clinical efficacy were noted in 61.9% and 78.2% of episodes respectively, and hospital stay was (16.3±3.2) d. Large infected cysts (diameter >5 cm) frequently required drainage. Conclusions In renal cyst infection, the source of the organisms is often a gram negative enteric organism. Empiric therapy is often initiated with two antibiotics. The drainage of large infected cysts remains the main treatment for cyst infection.

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Upgrade of dialysate quality improves the microinflammation in maintenance haemodialysis patients

YUAN Jing;YANG Yi;ZHANG Ping;JIANG Hua;YAO Xiang-feng;WANG Xiao;GU Juan-fen;CHEN Jiang-hua.

2012, 28(3): 179-182.

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Objective To explore the effect of upgrade of dialysate quality on the microinflammation in maintenance haemodialysis （MHD） patients. Methods Fifty-three MHD patients in Kidney Center of the First Affiliated Hospital, Medical College, Zhejiang University in January 2003 were enrolled in the prospectively study. The main end-points were survival at 8 years or weaning from haemodialysis during 8-year period including death, receiving renal transplantation or transferring to peritoneal dialysis. The endotoxin level of dialysate and patients’ serum levels of interleukin-6 (IL-6), tumor necrosis factor α(TNF-α), C reaction protein (CRP), and albumin were recorded during the observation period. Results After the upgrade of water management system, endotoxin level of dialysate obviously decreased [(0.046±0.012) EU/ml vs (0.454±0.002) EU/ml, P<0.01], and serum IL-6 [(3.947±3.624) ng/L vs (13.779±7.106) ng/L, P=0.036], TNF-α [(7.935±3.864) ng/L vs (12.804±8.017) ng/L, P=0.012] as well as CRP [(0.194±0.149) mg/L vs (0.561±0.309) mg/L，P<0.01] decreased significantly, while serum albumin increased [(41.900±6.803) g/L vs (38.140±7.083) g/L, P=0.042]. Hemoglobin level did not change significantly after the system upgrade, however, the dose of erythropoietin decreased [(93.0±12.7) U•kg-1•week-1 vs (131.0±10.1) U•kg-1•week-1, P=0.015]. Conclusions The upgrade of central dialysis fluid delivery and water management system by application of double reverse osmosis, high frequency heat disinfection and endotoxin filter can improve the quality of dialysate. Improvement of dialysate quality can ameliorate the microinflammation state of MHD patients.

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Short-term efficacy of sevelamer hydrochloride on hyperphosphatemia in patients undergoing maintenance hemodialysis

FANG Yi*;DING Xiao-qiang;ZOU Jian-zhou;FANG Yan;QIAN Jia-qi;RONG Shu;MEI Chang-lin;QIU Qiang;CHENG Xiang-mei;ZHENG Zhi-hua;YU Xue-qing.

2012, 28(3): 183-188.

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Objective To evaluate the short-term efficacy and safety of sevelamer hydrochloride in treating maintenance hemodialysis (MHD) patients with hyperphosphemia. Methods A multicenter, open-labeled, self-control study was performed. Phosphate binders were discontinued during a two-week washout period. Patients with more than 1.78 mmol/L serum phosphorus after two-week washout period were eligible for the trial. The dose was adjusted every two weeks as necessary to achieve serum phosphorus control. Sevelamer hydrochloride was administered to 138 MHD patients for 10 weeks and a second two-week washout period followed. Results A total of 111 from 138 patients fulfilled the whole 14-week study. Mean serum phosphorus and calcium-phosphate products starte to decline after two-week sevelamer hydrochloride treatment. By the end of 10-week sevelamer hydrochloride treatment, mean serum level of phosphorus [(1.85±0.50) vs (2.57±0.54) mmol/L, P<0.01], calcium-phosphate product [(4.16±1.72) vs (5.79±1.50) mmol2/L2, P<0.01] and low density lipoprotein [(1.64±0.76) vs (2.31±0.87) mmol/L, P<0.01] were significantly decreased, while the adjusted serum level of calcium and serum intact parathyroid hormone kept steady. Both serum phosphorus and calcium-phosphrus product increased after the second washout period, but the levels were still lower as compared to pre-treatment [(2.26±0.71) vs (2.57±0.54) mmol/L; (5.12±1.63) vs (5.79±1.50) mmol2/L2, P<0.01]. Of the 138 patients involved, 214 episodes in 106 patients and 121 episodes in 89 patients were reported as adverse events and adverse drug reaction respectively. Gastrointestinal symptoms, of which most were mild or moderate, happened to 68.1%(94/138) patients. Conclusions Sevelamer hydrochloride can control serum phosphorus and reduce the levels of calcium-phosphorus product and cholesterol. Slight gastrointestinal symptoms like constipation are common during the treatment.

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Association of type 2 diabetic nephropathy with methylation status of genomic DNA and connective tissue growth factor gene promoter

YI Bin*;CAI Xu;ZHANG Hao;WANG Jian-Wen;LIU Yan;YANG Miao.

2012, 28(3): 189-193.

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Objective To investigate the role of methylation of genomic DNA and connective tissue growth factor (CTGF) gene promoter in the pathogenesis of diabetic nephropathy (DN). Methods According to the WHO 1999 guideline for diabetes mellitus diagnosis and classification standard, 90 patients diagnosed as diabetes mellitus and 30 healthy volunteers were enrolled in this study. All the participants were divided into diabetes mellitus without DN (DM) group (n=48), DN group (n=42) and healthy control group (n=30) accordingly. DNA was extracted from the peripheral blood and high pressure liquid chromatography (HPLC) was used to measure the overall methylation level of genomic DNA. The methylation status of CTGF gene promoter was determined by PCR and sequencing analysis. Serum CTGF protein level was measured by ELISA. Results The overall methylation level of genomic DNA was 5.23%±0.09% for DN group, 4.71% ±0.03% for DM group, and 4.37%±0.01% for healthy control group, with no significant differences among three groups (all P>0.05). The CTGF promoter methylation level in DN group (22.02%±12.90%) was significantly decreased, compared to DM group (49.18%±8.01%, P=0.019) or healthy control group (72.18%±19.30%, P=0.000). Moreover, the serum CTGF protein level in DN group [(193.44±11.90) mg/L] was significantly increased, compared to DM group [(127.65±10.30) mg/L, P=0.031] and healthy control group [(95.84±5.10) mg/L, P=0.001]. Conclusion In DN patients, CTGF gene promoter methylation level is significantly decreased, but CTGF protein level is higher as compared to non-DN patients, which indicates that CTGF gene promoter demethylation may be involved in the pathogenesis of diabetic nephropathy.

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The incidence and risk factors associated with prognosis of acute kidney injury in hospitalized patients

LU Ren-hua;FANG Yan;GAO Jia-yuan;CAI Hong;ZHU Ming-li;ZHANG Min-fang;DAI Hui-li;ZHANG Wei-ming;NI Zhao-hui;QIAN Jia-qi;YAN Yu-cheng.

2012, 28(3): 194-200.

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Objective To investigate the incidence and the prognosis of acute kidney injury (AKI) and to find out the risk factors associated with the outcome for better understanding and preventing AKI among inpatients. Methods All the hospitalized patients were screened by Lab Administration Network of Renji Hospital, Shanghai Jiaotong University School of Medicine from Jan. to Dec. 2009. Study cohort was comprised of all the patients with AKI defined by Acute Kidney Injury Network (AKIN) and with complete clinical data recorded. The incidence, etiology and distribution characteristics, prognosis of AKI in hospitalized patients were retrospectively analyzed. Logistic regression analysis was used to investigate the risk factors of patients and renal outcome. Results A total of 934 patients with AKI were enrolled. The incidence of AKI in hospitalized patients was 2.41% (934/38 734). The ratio of male to female was 1.88:1. Age was (60.82±16.94) years old. Increasing incidence could be seen with age rising. There was 63.4% AKI found in surgical department, 35.4% in internal medicine department and 1.2% in obstetric and gynecologic department. Pre-AKI, acute tubular necrosis (ATN), acute glomerular and renal vascular injury (AGV), acute interstitial nephritis (AIN) and post-AKI were accounted for 51.7%, 37.7%, 3.8%, 3.5% and 3.3% of the causes of AKI, respectively. On day 28, the survival rate was 71.8%, complete renal recovery rate was 65.7%, partial renal recovery rate was 16.9% and renal loss rate was 17.4% among all the patients with AKI. The mortality of AKI with stage Ⅰ, Ⅱ andⅢ among inpatients was 24.8%, 31.2% and 43.7% respectively. Multivariate Logistic regression analysis showed that renal injury drugs [odds ratio (OR)=2.313], hypotension (OR=4.482), oliguria (OR=5.267), the number of failure organs except kidney (OR=1.376) and requiring renal replacement therapy(RRT)(OR=4.221) were independent risk factors for death among AKI patients. The number of failure organs except kidney (OR=1.529) and RRT (OR=2.117) were independent risk factors for kidney loss. Conclusions AKI is one of the most common complications in hospitalized patients. The mortality is high and renal outcome is poor after AKI. The prognosis is closely associated with the severity of AKI. Renal injury drugs, hypotension, oliguria, the number of failure organs except kidney and requiring RRT are independent risk factors for death among AKI patients, while the number of failure organs except kidney and requiring RRT are independent risk factors for renal loss.

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Investigation of sleep quality and its influencing factors in maintenance hemodialysis patients

TANG Chun-yuan*;CHEN Wei-qing;YE Xiao-qing;WANG Rao-ping;ZHENG Zhi-hua.

2012, 28(3): 201-206.

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Objective To investigate the sleep quality of maintenance hemodialysis (MHD) patients and analyze its associated factors. Methods The convenience sample method was used to choose 424 MHD patients from 7 hospitals. A set of questionnaires were used in this investigation, including demographic data form, Pittsburgh sleep quality index (PSQI), restless legs syndrome(RLS), social support rate scale (SSRS), subjective global assessment (SGA), family APGAR index (APGAR) and family burden scale of disease (FBS). Results PSQI score of 395 MHD patients (93.2%) was ≥5. APGAR and social support total points were negatively correlated with sleep quality (r=-0.133, P=0.006; r=-0.105, P=0.031). Family burden total point was positively correlated with sleep quality (r=0.215, P=0.000). Nutrition (F=46.123, P=0.000), restless legs syndrome (F=9.392, P=0.000) and sleep apnea syndrome(F=5.645, P=0.001) were closely associated with sleep index scores. Conclusions Incidence of poor sleep quality in MHD patients of our study is quite high. Sleep quality of MHD patients is correlated with lots of factors, such as family concern, social support.

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Influence of mild hyperuricemia on the function of glomerular endothelial cells and vascular smooth muscle cells in rats

LIAN Xi-yan;HUANG Sheng-hua;ZHAO Jin-tao;LI Jiang;YANG Gui-mei;YUAN Zhi-wei;LIAO Yun-juan.

2012, 28(3): 207-211.

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Objective To discuss whether mild hyperuricemia can lead to kidney damage and the protection of decreased uric acid, through observing that hyperuricemia did damage to glomerulus endothelial function and cell proliferation of vascular smooth muscle in rats. Methods Fifty-four male SD rats were divided into four groups, the control group, model group (Oxonate), allopurinol group and Oxonate＋allopurinol group. Rats were administered on a low sodium diet and their systolic blood pressure (SBP) were measured each 10 days. ELISA was used to detect rat plasma markers of endothelial function damage [nitric oxide (NO), type-1 plasminogen activator inhibitor(PAI-1), endothelin 1(ET-1)] and cell proliferation of vascular smooth muscle[platelet-derived growth factor (PDGF), cycloxygenase 2 (COX2), monocyte chemotactic protein-1(MCP-1)], and the markers of inflammatory reaction[interleukin-18 (IL-18), tumor necrosis factor α(TNF-α)]. PDGF and nitric oxide synthase (NOS) levels of rats were detected by immunohistochemical method. Renal tissue pathology of rats was observed. Results Compared to the control group, the plasmic concentration of COX2, ET-1, IL-18, PAI-1, PDGF, TNF-α, MCP-1 increased, and NO decreased significantly in rats of model group (all P＜0.05), expression of NOS significantly reduced and PDGF increased (all P＜0.05). Under light microscope, vascular wall thickening, intimal proliferation and lumen slight stricture without uric acid crystals in renal tissue were found in model group, which were obviously improved by using allopurinol. Conclusion Mild hyperuricemia can do damage to endothelial function of glomerulus and lead to vascular cell proliferation, which can be improved through decreasing uric acid.

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Effect of pigment epithelium-derived factor on p38MAPK-CREB pathway and fibronectin in high glucose cultured human mesangial cells

GAO Lan;LI Jing;GAO Ling;CHEN Hong-min;HONG Lian.

2012, 28(3): 212-216.

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Objective To investigate the effect of pigment epithelium- derived factor(PEDF) on p38MAPK-CREB pathway and the expression of fibronectin (FN) in human mesangial cells(HMCs) cultured with high glucose. Methods HMCs were treated with different concentrations of glucose and the osmotic control respectively in the presence or absence of PEDF for 24 h: normal glucose(5.6 mmol/L), 24.4 mmol/L mannitol, high glucose(30 mmol/L), high glucose+PEDF(30 mmol/L glucose with 10 nmol/L PEDF, 40 nmol/L PEDF or 100 nmol/L PEDF）. After samples were collected, the expression of phospho-p38MAPK (p-p38) and p-CREB was assessed by Western blotting, while FN mRNA and protein expression was assessed with RT-PCR and ELISA respectively. Results In contrast to normal glucose and mannitol treatments, the expression of p-p38MAPK, p-CREB and FN increased significantly in high glucose group(all P<0.01). However, PEDF abolished the up-regulation of p-p38MAPK, p-CREB and FN induced by high glucose (all P<0.05). Conclusion PEDF may inhibit fibrosis through P38MAPK-CREB pathway in diabetic nephropathy.

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RKIP regulates NF-κB signaling pathway in the pathogenesis of diabetic nephropathy and drug intervention

LI Long;LIU Jia-lin;WANG Xiao-yu;ZHANG Ming-xia;FAN Feng-yi;ZHOU Yi-xia.

2012, 28(3): 217-221.

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Objective To detect the expression of Raf kinase inhibitor protein (RKIP) and NF-κB in renal tissue of diabetic kidney disease (DKD) rats model, and to investigate the effect of rituximab (RTX) on the expression of RKIP in the renal tissue of DKD rats. Methods SD rats were randomly divided into normal group(N), DKD model group(M) and RTX treatment group(D). Blood glucose and 24-hour urine protein of rats were determined in three groups. RKIP protein and NF-κB protein were determined by immunohistochemistry staining. RKIP protein expression was detected by Western blotting. Results Compared with N group, blood glucose, 24-hour urine protein and NF-κB expression in M group increased significantly(all P< 0.01), the expression of RKIP in M group decreased significantly (P<0.05). Compared with M group, the expression of RKIP increased significantly in D group（P<0.05）, and 24-hour urine protein and NF-κB expression decreased in D group(all P<0.05). NF-κB protein expression was negatively correlated with RKIP expression in M group. Conclusions The NF-κB pathway regulated by RKIP plays an important role in the development and pathogenesis of diabetic nephropathy. Rituximab may have a role in treatment of DKD.

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Study of glomerular podocyte injury induced by aristolochic acid

CHENG Hong;CHEN Yi-pu;DONG Hong-rui;WANG Yan-yan;RUI Hong-liang.

2012, 28(3): 222-225.

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Objective To explore whether the glomerular podocytes can be damaged by aristolochic acid. Methods Thirty-two male SD rats were equally divided into the following 2 groups: model group in which the rats received the extract of Aristolochia manshuriensis Kom (AmK) by gavage; control group only received tap water by gavage. 24 h urinary protein excretion was measured at the end of the 1st and 4th week, and SDS-PAGE gel electrophoresis was performed to detect the protein in urine. At the end of the 4th week, all the rats were sacrificed and the glomeruli were isolated by laser capture microdissection technique. The mRNA expression of nephrin, podocin, CDA2P, podocalyxin and podoplanin in isolated glomeruli was determined by RT-PCR, and the average width of glomerular foot process was measured by electron microscopy and image analysis. Results At the end of the 4th week, 24 h urinary protein excretion in the model group was significantly higher than that in the control group (P<0.01) and the urinary albumin content in model group was also obviously increased. The average width of glomerular foot process in the model group was significantly larger than that in control group (P<0.01). The mRNA expressions of nephrin, podocin, CDA2P, podocalyxin and podoplanin in glomeruli were significantly down-regulated in the model group compared with the control group, which decreased by 34%, 62%, 56%, 50%(P<0.01) and 27% (P<0.05), respectively. Conclusions Aristolochic acid can damage the glomerular podocytes, resulting in the down-regulation of nephrin, podocin, CD2AP, podoplanin and podocalyxin mRNA expression, the segmental widening of foot process, and increased urinary protein excretion.

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Role of mTOR signaling in the activation of renal interstitial fibroblasts

CHEN Guo-chun;LIU Hong;WANG Chang;ZHOU Xun;LIU Fu-you.

2012, 28(3): 226-231.

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Objective To evaluate the regulatory role of mTOR signaling in activation of renal interstitial fibroblasts and the potential effect on interstitial fibrosis. Methods 8-week old female C57BL/6 mice (n=30) underwent unilateral ureteral obstruction (UUO) to induce renal interstitial fibrosis. Animals were randomly divided into rapamycin (2 mg·kg-1·d-1) group and UUO group (vehicle-treated) (n=15 each group). Daily intraperitoneal injection of rapamycin or saline was applied to animals from day 1 before operation to the end of experiment. Three mice were sacrificed at day 1, 3, 7, 14 respectively and kidneys were harvested for further analysis. NIH3T3 cells were stimulated by TGF-β for 12 hours with the presence or bsence of rapamycin (100 nmol/L). Results Immunofluorescent co-staining revealed that active fibroblasts highly expressed pS6K and α-SMA in kidney interstitium. Administation of rapamycin significantly inhibited activation of mTOR signaling in fibroblasts and ameliorated interstitial fibrosis of obstructed kidneys. Real-time PCR confirmed that rapamycin decreased the mRNA expression of FSP1, TGF-β, CTGF and Col4A1 in fibrotic kidneys. In vitro experiment revealed that TGF-β induced highly expression of pS6K and αSMA in cultured NIH3T3 cells, which could be markedly inhibited by rapamycin. Conclusions mTOR signaling highly activates in interstitial fibroblasts during kidney fibrosis. Inhibition of mTOR signaling by rapamycin decreases the activation of fibroblasts and ameliorates interstitial fibrosis.

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Efficacy research of immune inhibitors sequential therapy according to the cell cycle for the adriamycin-induced nephropathy rats

WANG Chen-dan;LI Rong-shan;WANG Chen;QIAO Xi;BAI Bo;LI Jing.

2012, 28(3): 232-238.

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Objective To assess the efficacy of different sequential therapy regimens according to the theory of cell cycle on adriamycin-induced nephropathy(AIN) rats. Methods SD rats were randomly divided into five groups: control group (n=8), AIN model group (n=8), MP+CsA+MMF group (n=8), MP+CsA+CTX treated group (n=8) and MP+FK506+Rapa group (n=8). The levels of 24-hour urinary protein, serum total protein(TP), albumin(Alb), cholesterin (Chol), triglyeride (TG), serum urea nitrogen (BUN), serum creatinine (Scr) were measured. The renal pathological changes were observed by light microscope. The expressions of nephrin and podocin were analyzed by immunohistochemistry and real-time PCR. The expression of CTGF was detected by Western blotting. Results (1)Compared with control group, the levels of 24-hour urinary protein in AIN model group were obviously increased at 2nd, 4th, 8th and 12th week(all P<0.01). The level of 24-hour urinary protein were obviously decreased in treatment groups at 8th and 12th week than those in AIN model group(all P<0.05). (2)The levels of TP and Alb were significantly lower in AIN model group than those in control group (all P<0.01), and the levels of TG and Chol were significantly higher in AIN model group than that in control group (all P<0.01). The levels of TP and Alb were significantly higher and the levels of TG and Chol were significantly lower in treatment groups than those in AIN model group(all P<0.05). (3)The results of immunohistochemistry indicated the expressions of nephrin and podocin in treatment group rats were obviously higher than those in AIN model group(all P<0.01). (4)The results of Western blotting indicated the expression of CTGF in treatment group rats was higher than that in AIN model group (P<0.05). The effect of inhibitting fibrous degeneration in MP+FK506+Rapa group was more greater than other treatment groups. Conclusions Sequential combined regimens according to the cell cycle can improve the pathological change in adriamycin-induced nephropathy rats, reduce the urine protein, increase the levels of TP and Alb, decrease the levels of TG and Chol, increase the expression of nephrin and podocin, and ameliorate kidney fibrosis.

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基础研究

临床研究

基础研究