Xiuqing Dong

Prevalence and risk factors associated with chronic kidney disease in an adult population from southern China.

BACKGROUND Population-based studies evaluating the prevalence of kidney damage in different communities have been limited in developing countries. We conducted a population-based screening study in the southern Chinese city of Guangzhou that aimed to identify the prevalence and associated risk factors of chronic kidney disease (CKD) in southern Chinese populations. METHODS We interviewed 6311 residents (>20 years) from six districts of Guangzhou from July 2006 to June 2007 and tested for haematuria, albuminuria and reduced renal function. Associations between age, gender, smoking, diabetes mellitus, hypertension, hyperuricaemia and kidney damage were examined. RESULTS There were 6311 subjects enrolled in this study. After adjustment for age and gender, the prevalence of albuminuria, haematuria and reduced estimated glomerular filtration rate (eGFR) was 6.6% [95% confidence interval (CI): 5.5-7.6%], 3.8% (95% CI: 3.4%, 4.3%) and 3.2% (95% CI: 2.4%, 3.3%), respectively. Approximately 12.1% (95% CI: 11.3%, 12.9%) of the sample population had at least one indicator of kidney damage. Age, diabetes mellitus, hypertension, central obesity, hyperlipidaemia and use of nephrotoxic medications were independently associated with albuminuria; hyperuricaemia, age, gender, hypertension and use of nephrotoxic medications were independently associated with reduced eGFR, and female gender was independently associated with haematuria. CONCLUSIONS In the general adult population from southern China, 12.1% has either proteinuria, haematuria and/or reduced eGFR, indicating the presence of kidney damage, with an awareness of only 9.6%. The high prevalence and low awareness of CKD in this population suggest an urgent need for CKD prevention programmes in China.

Prevalence and risk factors of chronic kidney disease: a population study in the Tibetan population

BACKGROUND The prevalence of chronic kidney disease (CKD) at high altitude is not known. We conducted a population-based survey in Tibet to identify the prevalence and associated risk factors of CKD in subjects living at altitudes of > 3500 m. METHODS One thousand two hundred and eighty-nine Tibetans (≥ 18 years) from four districts of Lhasa city (altitude 3658 m) and eight villages of Dangxiong County (altitude 4200 m) were interviewed and tested for haematuria, albuminuria and estimated glomerular filtration rate (eGFR). RESULTS The adjusted prevalence of hypertension, albuminuria, haematuria and reduced eGFR were 38.8% (95% CI: 36.2-41.5%), 16.2% (95% CI: 14.1-18.2%), 3.9% (95% CI: 2.8-4.9%) and 2.1% (95% CI: 1.3-2.9%), respectively. Both the presence of hypertension and the presence of albuminuria were strongly and independently associated with hyperuricaemia and elevated haematocrit. CONCLUSIONS This is the first population-based epidemiological study of CKD in the Tibetan population. We found a higher prevalence of CKD and associated high prevalence of albuminuria, hypertension, hyperuricaemia and high haematocrit in the Tibetan population. The present study indicates the urgent need to develop comprehensive strategies targeted at reducing the CKD burden in this area and may lead to a better understanding of CKD in high-altitude populations.

HSP72 Inhibits Smad3 Activation and Nuclear Translocation in Renal Epithelial-to-Mesenchymal Transition

Although heat shock protein 72 (HSP72) ameliorates renal tubulointerstitial fibrosis by inhibiting epithelial-to-mesenchymal transition (EMT), the underlying mechanism is unknown. Because Smad proteins transduce TGF-beta signaling from the cytosol to the nucleus and HSP72 assists in protein folding and facilitates nuclear translocation, we investigated whether HSP72 inhibits TGF-beta-induced EMT by modulating Smad expression, activation, and nuclear translocation. To evaluate the roles of distinct HSP72 structural domains in these processes, we constructed vectors that expressed wild-type HSP72 or mutants lacking either the peptide-binding domain (HSP72-DeltaPBD), which is responsible for substrate binding and refolding, or the nuclear localization signal (HSP72-DeltaNLS). Overexpression of wild-type HSP72 or HSP72-DeltaNLS inhibited TGF-beta1-induced EMT, but HSP72-DeltaPBD did not, suggesting a critical role for the PBD in this inhibition. HSP72 overexpression inhibited TGF-beta1-induced phosphorylation and nuclear translocation of Smad3 and p-Smad3, but not Smad2; these inhibitory effects required the PBD but not the NLS. Coimmunoprecipitation assays suggested a physical interaction between Smad3 and the PBD. siRNA knockdown of endogenous HSP72 enhanced both TGF-beta1-induced Smad3 phosphorylation and EMT and confirmed the interaction of HSP72 with both Smad3 and p-Smad3. In vivo, induction of HSP72 by geranylgeranylacetone suppressed Smad3 phosphorylation in renal tubular cells after unilateral ureteral obstruction. In conclusion, HSP72 inhibits EMT in renal epithelial cells primarily by exerting domain-specific effects on Smad3 activation and nuclear translocation.

High Prevalence and Associated Risk Factors for Impaired Renal Function and Urinary Abnormalities in a Rural Adult Population from Southern China

Background The prevalence of chronic kidney disease (CKD) has increased and will continue to rise worldwide. However, data regarding the prevalence of CKD in a rural area of China are limited. We therefore investigated the prevalence and associated risk factors of impaired renal function and urinary abnormalities in an adult rural population in southern China. Methods Between December 2006 and January 2007, residents older than 20 years from four villages in Zhuhai city were randomly selected using a stratified, multistage sampling technique. All participants were interviewed and tested for hematuria, albuminuria and estimated glomerular filtration rate (eGFR). The associations between age, gender, diabetes mellitus, hypertension, hyperuricemia, education level and indicators of renal damage were examined. Results Overall, 1,214 subjects were enrolled in this study. After adjustment for age and gender, the prevalence of albuminuria was 7.1% (95% CI: 4.5, 8.1), reduced eGFR was 2.6% (95% CI: 1.7%, 3.3%), and hematuria was 4.6% (95% CI: 3.3%, 6.0%). Approximately 13.6% (95% CI: 12.0%, 15.1%) of the patients had at least one indicator of renal damage, but only 8.3% were previously aware. Age, diabetes, hyperlipidemia, hypertension, hyperuricemia, use of nephrotoxic medications, coronary heart disease and history of CKD were independently associated with impaired renal function and urinary abnormalities. Additionally, age, diabetes, and hypertension were independently associated with albuminuria. Age, hypertension, hyperuricemia, central obesity, and coronary heart disease were independently associated with reduced renal function. Conclusions The high prevalence and low awareness of impaired renal function and urinary abnormalities in this population illustrates the urgent need to implement a CKD prevention program in the rural areas of southern China.

Characterization of infiltrating macrophages in high glucose-induced peritoneal fibrosis in rats

Alternatively activated macrophages (M2 macrophages) are involved in tissue remodeling and fibrosis, but their effects on peritoneal fibrosis (PF) induced by high glucose peritoneal dialysate have yet to be fully established. In this study, PF was induced in male Sprague-Dawley rats by intraperitoneal injection with Lactate-G4.25% dialysate (20 ml/rat/day) for 4 weeks. Control rats were given an intraperitoneal injection with saline. Establishment of the PF model was verified by Massons trichrome and H&E staining. M1 macrophages (co-localization of CD68 and CCr7) and M2 macrophages (co-localization of CD68 and CD206) was assayed by immunofluorescence and immunohistochemistry. The levels of dialysate cytokines driving macrophage differentiation (including IFN-γ, IL-2 and IL-4) were detected by ELISA. The expression of transforming growth factor (TGF)-β, p-Smad3, p-Smad2/3 and Smad7 in M2 macrophages (co-localization of CD68, CD206 and TGF-β, or p-Smad3, or p-Smad2/3, or Smad7) was measured by immunofluorescence. We found that PF rats had significantly thicker peritoneal membranes compared to control rats, indicating the successful establishment of our PF model. Compared to controls, PF rats had more peritoneal macrophages (CD68+ cells), more peritoneal M1 macrophages and a greater percentage of peritoneal M2 macrophages. PF rats also had significantly greater levels of dialysate cytokine IL-4, which promotes differentiation to M2 macrophages, higher expression levels of TGF-β in peritoneal M2 macrophages, upregulation of phosphorylated Smad3 and Smad2/3, and downregulation of Smad7 in peritoneal M2 macrophages. Our results indicate that M2 macrophages may play an important role in PF induced by high glucose, and that the cytokine environment in the abdominal cavities of PF rats promotes differentiation to M2 macrophages. The function of M2 macrophages in PF may be related to the TGF-β/Smad signaling pathways.

Upregulation of Rat Renal Cortical Organic Anion Transporter (OAT1 and OAT3) Expression in Response to Ischemia/Reperfusion Injury

Background/Aims: Renal organic anion transporters (OAT1 and OAT3) localized in the basolateral membrane mediate the uptake of organic anions from the blood into proximal tubules. This study aimed to examine the effects of renal ischemia/reperfusion injury (IRI) on the expression of cortical renal OAT1 and OAT3 and the functional impact. Methods: Male rats underwent a right nephrectomy and clamping of the left renal pedicle for 50 min or sham operation, followed by reperfusion for 1, 2, 4 and 6 days. The expression of OAT1 and OAT3 was detected by RT-PCR, immunohistochemistry and Western blot analysis. Na+-K+-ATPase activity was also estimated. Results: The renal clearance of para-aminohippurate was significantly decreased on day 1 in IRI rats compared with sham-operated rats and returned to normal when the tubular injury recovered. There were significant increases in the mRNA and protein levels of OAT1 and OAT3 in renal cortex homogenates and basolateral membranes on day 1 after IRI, while on days 2 and 4 after IRI, the renal expression of OAT1 and OAT3 decreased gradually but was still significantly higher than that of the sham-operated rats. The Na+-K+-ATPase activity in renal cortex homogenates decreased significantly on day 1 after IRI but gradually increased on days 2, 4 and 6. Conclusions: Renal para-aminohippurate clearance was depressed in response to IRI; however, the expressions of renal cortex OAT1 and OAT3 were significantly elevated in the early stage of IRI which may have substantial impact on renal excretion of some drugs and toxic compounds.

Ectopic expression of Ligand-of-Numb protein X promoted TGF-β induced epithelial to mesenchymal transition of proximal tubular epithelial cells

Ligand-of-Numb protein X (LNX) was initially characterized as a RING finger type E3 ubiquitin ligase that targeted the intrinsic cell fate determinant Numb for ubiquitination dependent degradation. However, the physiological function of LNX remains largely unknown. In the present study, we demonstrate that ectopic expression of LNX in human proximal tubular epithelial cells (HK-2 cells) significantly enhanced TGF-beta1 induced epithelial to mesenchymal transition (EMT). The EMT-promoting effect of LNX manifested as strong inhibition of E-cadherin expression, enhanced expression of vimentin, fibronectin or PAI-1, and increased cell migration. This function of LNX was shown to be independent of its ligase activity because ectopic expression of a mutant form of LNX (C48ALNX) that lacks E3 ligase activity had the similar effect as the wild-type LNX. Overexpression of E-cadherin could inhibit LNX augmented EMT. This study suggests a potential role for LNX in promoting EMT in human proximal tubular epithelial cells.

Glucose-Based Peritoneal Dialysis Fluids Downregulate Toll-Like Receptors and Trigger Hyporesponsiveness to Pathogen-Associated Molecular Patterns in Human Peritoneal Mesothelial Cells

ABSTRACT The objective of this study was to investigate the effects of glucose-based peritoneal dialysis (PD) fluids and icodextrin-based PD fluids on the expression of Toll-like receptor 2 (TLR2)/TLR4 and subsequent ligand-induced mitogen-activated protein kinase (MAPK) and NF-κB signaling and tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) mRNA expression in human peritoneal mesothelial cells (HPMCs). A human peritoneal mesothelial cell line (HMrSV5) was stimulated with glucose-based and icodextrin-based peritoneal dialysis fluids. Cell viability was assessed using MTT [3-(4,5-dimethylthiazolyl)-2,5-diphenyl-2H-tetrazolium bromide]. TLR2/TLR4 expression was determined by real-time PCR, Western blotting, and an immunofluorescence assay. In addition, cells were pretreated with different PD solutions and then incubated with Pam3CSK4 or lipopolysaccharide (LPS), and the degrees of MAPK and NF-κB activation were reflected by detecting the phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, and p65, using a Western blot method. TNF-α and IL-1β mRNA expression was measured by real-time PCR. Glucose-based peritoneal dialysis fluids suppressed the expression of TLR2 and TLR4 proteins in HPMCs. Challenge of cells with either Pam3CSK4 or LPS resulted in impaired TNF-α and IL-1β production. Moreover, reduced TLR2 and TLR4 levels in glucose-based peritoneal dialysis solution-treated mesothelial cells were accompanied by reduced p42/44 (ERK1/2), JNK, p38 MAPK, and NF-κB p65 phosphorylation upon TLR ligand engagement. No significant changes in MAPK and NF-κB signaling and TNF-α and IL-1β mRNA expression were observed in icodextrin-based PD solution-treated mesothelial cells. Glucose-based PD solution, but not icodextrin-based PD solution, downregulates expression of TLR2/TLR4 by human peritoneal mesothelial cells and triggers hyporesponsiveness to pathogen-associated molecular patterns.

Proteomic Profiling Identifies Haptoglobin as a Potential Serum Biomarker for Steroid-Resistant Nephrotic Syndrome

Background: Long-term outcomes for patients with adult idiopathic nephrotic syndrome correlate closely with steroid responsiveness. The aim of this prospective study was to evaluate the difference in serum proteomes between steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS) patients and identify potential biomarkers for the prediction of SRNS. Methods: We performed a gel-based proteomic study of serum obtained from SRNS and SSNS patients and healthy controls at the time of presentation (n = 6 for each group). Proteins from the serum samples were separated using 2-D electrophoresis, digested in-gel and subjected to MALDI-TOF-MS/MS analysis. Further validation was performed utilizing Western blot and ELISA. The sensitivities and specificities of the candidate proteins for predicting SRNS were determined using receiver operating characteristic curves. Results: Thirteen differentially expressed proteins were identified as haptoglobin (Hp) with different isoelectric points and molecular weights. Western blot and ELISA analysis of samples from 146 subjects (healthy controls = 52, SSNS = 54, SRNS = 40) showed a markedly increased level of Hp in the serum, but not urine, of SRNS compared to SSNS patients. The optimal serum cutoff level of Hp was set at ≥1,279 µg/ml using the receiver operating characteristic curve. The sensitivity and specificity for predicting SRNS were 85.0 and 96.3%, respectively. Conclusions: This study provides a novel overview of the difference in serum proteomes of SSNS and SRNS patients. Serum Hp may be a useful predictive biomarker for steroid therapy efficacy in the treatment of idiopathic nephrotic syndrome.

Prevalence and Risk Factors of CKD in Chinese Patients with Periodontal Disease

Background Periodontal disease is common among adults and is associated with an increasing risk of chronic kidney disease (CKD). We aimed to investigate the prevalence and risk factors of CKD in patients with periodontal disease in China. Methods In the current cross-sectional study, patients with periodontal disease were included from Guangdong Provincial Stomatological Hospital between March 2011 and August 2011. CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, the presence of albuminuria, or hematuria. All patients with periodontal disease underwent a periodontal examination, including periodontal probing pocket depth, gingival recession, and clinical attachment level by Florida Probe. They completed a questionnaire and had blood and urine samples taken. The adjusted prevalence of indicators of kidney damage was calculated and risk factors associated with CKD were analyzed. Results A total of 1392 patients with periodontal disease were invited to participate this study and 1268 completed the survey and examination. After adjusting for age and sex, the prevalence of reduced eGFR, albuminuria, and hematuria was 2.7% (95% CI 1.7–3.7), 6.7% (95% CI 5.5–8.1) and 10.9% (95% CI 9.2–12.5), respectively. The adjusted prevalence of CKD was 18.2% (95% CI 16.2–20.3). Age, male, diabetes, hypertension, history of CKD, hyperuricemia, and interleukin-6 levels (≥7.54 ng/L) were independent risk factors for reduced eGFR. Female, diabetes, hypertension, history of CKD, hyperuricemia, high level of cholesterol, and high sensitivity C-reactive protein (hsCRP) (≥1.03 mg/L) and TNF-α levels (≥1.12 ng/L) were independently associated with an increased risk of albuminuria. Female, lower education (<high school), and history of CKD were independent risk factors for hematuria. Conclusions 18.2% of Chinese patients with periodontal disease have proteinuria, hematuria, or reduced eGFR, indicating the presence of kidney damage. Whether prevention or treatment of periodontal disease can reduce the high prevalence of CKD, however, remains to be further investigated.