SIS3 Alleviates Cisplatin-Induced Acute Kidney Injury by Regulating the LncRNA Arid2-IR-Transferrin Receptor Pathway.

INTRODUCTION: TGF-ß/Smad3 may be involved in the pathogenesis of acute kidney injury (AKI), but its functional role and mechanism of action in cisplatin-induced AKI are unclear. Here, we established a cisplatin-induced AKI mouse model to demonstrate that Smad3 may have roles in cisplatin nephropathy because of its potential effects on tubular epithelial cell (TEC) death and regeneration. METHODS: Using a cisplatin-induced AKI model, the expression levels of lncRNA Arid2-IR were measured by qRT-PCR and the location detected by FISH. Transfected with overexpression of lncRNA Arid2-IR by lentiviral vector in TECs, and the expression of cleaved caspase 3, Bax, Bcl-2, PCNA, p21, p27, transferrin receptor (TFRC), FTH, and FTL were measured by Western blot. Protein molecules bound to lncRNA Arid2-IR were identified by RIP, RNA pull-down assay, mass spectrometry. RESULTS: LncRNA Arid2-IR was significantly downregulated in vivo and in vitro. SIS3 decreased cell apoptosis and promoted cell regeneration by upregulating lncRNA Arid2-IR expression. LncRNA Arid2-IR regulated the cell cycle by decreasing expression of the cyclin-dependent kinase inhibitors p21 and p27. Finally, lncRNA Arid2-IR interacted with the TFRC, and overexpression of lncRNA Arid2-IR increased TFRC expression and decreased FTH and FTL. CONCLUSION: Smad3 regulated lncRNA Arid2-IR via TFRC, thereby regulating the cell cycle, protecting against cell apoptosis, and promoting cell regeneration.

Sirt3 modulates fatty acid oxidation and attenuates cisplatin-induced AKI in mice.

Fatty acid oxidation (FAO) dysfunction is one of the important mechanisms of renal fibrosis. Sirtuin 3 (Sirt3) has been confirmed to alleviate acute kidney injury (AKI) by improving mitochondrial function and participate in the regulation of FAO in other disease models. However, it is not clear whether Sirt3 is involved in regulating FAO to improve the prognosis of AKI induced by cisplatin. Here, using a murine model of cisplatin-induced AKI, we revealed that there were significantly FAO dysfunction and extensive lipid deposition in the mice with AKI. Metabolomics analysis suggested reprogrammed energy metabolism and decreased ATP production. In addition, fatty acid deposition can increase reactive oxygen species (ROS) production and induce apoptosis. Our data suggested that Sirt3 deletion aggravated FAO dysfunction, resulting in increased apoptosis of kidney tissues and aggravated renal injury. The activation of Sirt3 by honokiol could improve FAO and renal function and reduced fatty acid deposition in wide-type mice, but not Sirt3-defective mice. We concluded that Sirt3 may regulate FAO by deacetylating liver kinase B1 and activating AMP-activated protein kinase. Also, the activation of Sirt3 by honokiol increased ATP production as well as reduced ROS and lipid peroxidation through improving mitochondrial function. Collectively, these results provide new evidence that Sirt3 is protective against AKI. Enhancing Sirt3 to improve FAO may be a potential strategy to prevent kidney injury in the future.

Dysbiosis of gut microbiota in adult idiopathic membranous nephropathy with nephrotic syndrome.

BACKGROUND: Gut bacterial microbiota is altered in patients with chronic kidney disease (CKD) and those on dialysis. However, it is not yet clear what bacterial composition changes occur in patients with idiopathic nephrotic syndrome (INS). We present in this report the changes in gut bacterial microbiota in INS patients with membranous nephropathy. METHODS: A total of 158 individuals were recruited for this study. Of these, 80 patients had stage 3-5 CKD without nephrotic syndrome (CKD group), 48 patients had INS and pathological diagnosis of membranous nephropathy (INS group), and 30 were age- and sex-matched healthy controls (HC group). The gut microbiome composition was analyzed using a 16S ribosomal RNA gene-based sequencing protocol. RESULTS: The results indicate that the nephrotic syndrome patients had a significantly different alpha and beta diversity compared with the CKD group and HC group (P < 0.01). At the phylum level, the INS patients showed increased Fusobacteria and Proteobacteria but reduced Firmicutes when compared with the HC group. At the genus level, Megamonas, Megasphaera, Akkermansia, and the butyrate-producing bacteria Lachnospira, Roseburia, and Fusobacterium were more abundant in the HC group (LDA score > 3) than the CKD and INS group. Fecal organic acid analysis revealed significantly lower quantities of propionate acid and butyric acid in INS than the HC group (P < 0.05). Compared with the HC group, we found that Parabacteroides was increased in CKD and INS patients. In addition, Oscillospira and Ruminococcus were more abundant in CKD patients than in the other two groups (LDA score > 3). At the genus level, ten bacterial taxa were more prevalent in the HC group. Providencia and Myroides were more prevalent in INS patients. CONCLUSION: Our findings highlight that, INS patients had a significantly different alpha and beta diversity and decreased gut microbiota-derived short-chain fatty acids, such as butyrate. However, large-scale prospective studies should be performed to identify the cause and effect factors of these changes in the microbiota in INS patients.

Abnormal circadian rhythm of urinary sodium excretion correlates closely with hypertension and target organ damage in Chinese patients with CKD.

Whether the abnormal circadian rhythm of urinary sodium excretion is associated with hypertension in chronic kidney disease (CKD) is poorly understood. In this study, we assessed the relationship between the circadian rhythm of urinary sodium excretion and hypertension. Urinary samples were collected during both the day (07:00 to 22:00) and night (22:00 to 07:00) to estimate night/day urinary sodium excretion ratios. Blood pressure (BP) and clinical data were also measured. A total of 1,099 Chinese CKD patients were recruited, 308 patients were excluded, and 791 patients were final enrolled in this study. Among them, 291 patients were normotensive and 500 were hypertensive CKD patients. A 1:1 propensity score matching (PSM) analysis was performed with age and estimated glomerular filtration rate (eGFR) matched between 190 normotensive and hypertensive patients. In the full cohort and PSM cohort, multivariate regression analysis showed that the night/day urinary sodium excretion ratio was an independent risk factor for clinical hypertension, whereas 24 h urinary sodium excretion, diurnal and nocturnal urinary sodium excretion were not. When the night/day urinary sodium excretion ratios were further divided into tertiles (tertile 1 < 0.47, tertile 2, 0.47-0.84 and tertile 3 > 0.84), multivariate analysis showed that tertile 3 was independently associated with hypertension in the full and PSM cohorts. In addition, tertile 3 was also independently associated with eGFR ≤ 60 mL/min/1.73 m2 and left ventricular hypertrophy. These data suggested that an abnormal circadian rhythm of urinary sodium excretion was independently associated with hypertension and target-organ damage. Individualized salt intake and therapeutic strategies should be used to normalize the natriuretic dipping profile in CKD patients.

Ambulatory blood pressure is better associated with target organ damage than clinic blood pressure in patients with primary glomerular disease.

BACKGROUND: Blood pressure is an important and modifiable cardiovascular risk factor. Ambulatory blood pressure monitoring (ABPM) provides valuable prognostic information in patients with chronic kidney disease (CKD), yet little is known about the association of various types of BP measurements with target organ damage (TOD) in patients with primary glomerular disease. The goal of this study was to investigate whether ambulatory blood pressure is better associated with TOD than clinic blood pressure in patients with primary glomerular disease. METHODS: 1178 patients with primary glomerular disease were recruited in this cross-sectional study. TOD were assessed by the following 4 parameters: left ventricular mass index (LVMI or LVH, left ventricular hypertrophy), estimated glomerular filtration rate (eGFR< 60 ml/min/1.73m2), albumin-to-creatinine ratio (ACR ≥ 30 mg/g) and carotid intima-media thickness (cIMT) or plaque. Receiver operating characteristic (ROC) curve and multivariate logistic regression analyses were used to evaluate the relationship between ambulatory or clinic systolic blood pressure (SBP) indexes and TOD. RESULTS: Among 1178 patients (mean age, 39 years,54% men), 116, 458, 1031 and 251 patients had LVH, eGFR < 60 ml/min/1.73m2, ACR ≥ 30 mg/g and cIMT≥0.9 mm or plaque respectively. Area under ROC curves for TOD in ambulatory SBP, especially nighttime SBP, was greater than that in clinic SBP (P < 0.05). Multivariate logistic regression analyses showed that 24 h SBP, daytime SBP and nighttime SBP were significantly associated with LVH, eGFR< 60 ml/min/1.73m2 and ACR ≥ 30 mg/g after adjustment for clinic SBP, while the association of clinic SBP was attenuated after further adjustment for nighttime SBP. CONCLUSIONS: Ambulatory blood pressure, especially nighttime blood pressure, is probably superior to clinic blood pressure and has a significant association with TOD in primary glomerular disease patients.

A longitudinal analysis of the relationship between serum uric acid and residual renal function loss in peritoneal dialysis patients.

Background: Hyperuricemia occurs frequently in patients with continuous ambulatory peritoneal dialysis (CAPD). This study aimed to evaluate the impact of serum uric acid (UA) over time on residual renal function (RRF) loss in a cohort of patients with CAPD.Methods: A total of 201 patients who started CAPD therapy between January 1, 2008 and April 30, 2016 were included in this single-center, retrospective cohort study. All patients were followed up until December 31, 2016. The median follow-up time was 23.43 ± 16.60 months. RRF loss was represented as the time to anuria.Results: Eighty-six patients developed anuria within 5 years. Multivariate Cox regression analysis showed that time-averaged serum UA and peritonitis were independent risk factors for RRF loss, while weekly Kt/V urea was a protective factor. Cox proportional hazard regression models showed that both patients with time-averaged uric acid (TA-UA) < 6.77 mg/dL [hazard ratio (HR) = 1.165, 95% confidence interval (CI) 1.054-1.387; p < 0.05] and those with TA-UA≥ 7.64 mg/dL (HR = 1.184, 95% CI 1.045-2.114; p < 0.05) had a higher risk of RRF than those with TA-UA in the range of 6.77-7.64 mg/dL. Penalized spline smoothing also showed a U-shaped relationship between continuous UA and RRF loss.Conclusion: The present study demonstrated that both high and low serum UA over time were associated with RRF loss in patients with CAPD.

Low serum uric acid levels increase the risk of all-cause death and cardiovascular death in hemodialysis patients.

BACKGROUND: Elevated serum uric acid (SUA) is associated with increased cardiovascular (CV) and all-cause mortality risk in the general population, but the impact of UA on mortality in hemodialysis patients is still controversial. The aim of the study was to explore the relationship between SUA and all-cause mortality and CV mortality in hemodialysis patients. METHODS: This retrospective, observational cohort study included 210 HD patients with a mean age of 56.6 ± 16.6 years. All demographic and laboratory data were recorded at baseline. The Kaplan-Meier method and Cox proportional hazard regression model were used to examine the association between SUA and all-cause mortality and CV mortality in HD patients. RESULTS: With 420 µmol/L (20th percentile) and 644 µmol/L (80th percentile) as the boundary points, the patients were divided into three groups. After a median follow-up of 49.8 months, 68 (32.4%) all-cause deaths and 34 (16.2%) CV deaths were recorded. The Kaplan-Meier method showed that with a decrease in SUA, all-cause mortality (log rank χ2 = 15.61, p = .000), and CV mortality (log rank χ2=14.28, p = .000) increased. Each 100 µmol/L increase in SUA was associated with lower all-cause mortality with an hazard ratio (HR) of 0.792 (0.645-0.972) and lower CV mortality with an HR of 0.683 (0.505-0.924) after adjusting for age, sex, and complications. Compared to the lowest quartile, all-cause mortality [HR 0.351(0.132-0.934), p = .036] and CV mortality [HR 0.112 (0.014-0.925), p = .042] were lower in the highest SUA quartile. CONCLUSION: A lower SUA level in HD patients was associated with a higher risk of all-cause mortality and CV mortality. Moreover, higher SUA concentrations may be cardioprotective in HD patients.

Activation of the Nrf2-ARE Pathway Ameliorates Hyperglycemia-Mediated Mitochondrial Dysfunction in Podocytes Partly Through Sirt1.

BACKGROUND/AIMS: Previously we have shown that activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-antioxidant response element (ARE) attenuated hyperglycemia-induced damage in podocytes, but the molecular mechanism remains unknown. METHODS: Tert-butylhydroquinone (t-BHQ) and small interfering RNAs (siRNAs) were used to regulate Nrf2 expression, while nicotinamide and siRNAs were used to regulate sirtuin 1 (Sirt1) activity and expression, respectively. Mitochondrial superoxide, membrane potential and ATP levels were measured to assess changes in mitochondrial function. Nephrin and synaptopodin expression were measured by western blot analysis. Human podocytes and db/db diabetic mice were used in this study. RESULTS: t-BHQ pretreatment of human podocytes exposed to high glucose (HG) alleviated mitochondrial dysfunction, enhanced the expression of Sirt1, nephrin and synaptopodin and lowered BSA permeability compared with podocytes exposed to HG without t-BHQ pretreatment (p< 0.05). Human podocytes exposed to HG had more severe mitochondrial dysfunction, lower expression of Sirt1, synaptopodin and nephrin and higher BSA permeability than podocytes exposed to HG when Nrf2 expression was downregulated by siRNAs (p< 0.05). The protection provided by activation of the Nrf-ARE pathway in podocytes exposed to HG was partially diminished when Sirt1 expression or activity was decreased by siRNAs or inhibitor compared with podocytes exposed to HG and pretreated with t-BHQ (p< 0.05). When nicotinamide and t-BHQ were both administered to db/db mice, we observed higher levels of urinary albumin/creatinine, lower nephrin and synaptopodin expression, more severe mesangial matrix deposition, collagen deposition on pathological slides and mitochondrial structural damage in podocytes compared to db/db mice treated only with t-BHQ. CONCLUSIONS: Our findings suggest that crosstalk between Sirt1 and the Nrf2-ARE anti-oxidative pathway forms a positive feedback loop and that protection provided by t-BHQ activation of the Nrf2-ARE pathway in db/db mice is partly dependent on Sirt1.

Improving precision of glomerular filtration rate estimating model by ensemble learning.

BACKGROUND: Accurate assessment of kidney function is clinically important, but estimates of glomerular filtration rate (GFR) by regression are imprecise. METHODS: We hypothesized that ensemble learning could improve precision. A total of 1419 participants were enrolled, with 1002 in the development dataset and 417 in the external validation dataset. GFR was independently estimated from age, sex and serum creatinine using an artificial neural network (ANN), support vector machine (SVM), regression, and ensemble learning. GFR was measured by 99mTc-DTPA renal dynamic imaging calibrated with dual plasma sample 99mTc-DTPA GFR. RESULTS: Mean measured GFRs were 70.0 ml/min/1.73 m2 in the developmental and 53.4 ml/min/1.73 m2 in the external validation cohorts. In the external validation cohort, precision was better in the ensemble model of the ANN, SVM and regression equation (IQR = 13.5 ml/min/1.73 m2) than in the new regression model (IQR = 14.0 ml/min/1.73 m2, P < 0.001). The precision of ensemble learning was the best of the three models, but the models had similar bias and accuracy. The median difference ranged from 2.3 to 3.7 ml/min/1.73 m2, 30% accuracy ranged from 73.1 to 76.0%, and P was > 0.05 for all comparisons of the new regression equation and the other new models. CONCLUSIONS: An ensemble learning model including three variables, the average ANN, SVM, and regression equation values, was more precise than the new regression model. A more complex ensemble learning strategy may further improve GFR estimates.

Evening versus morning dosing regimen drug therapy for chronic kidney disease patients with hypertension in blood pressure patterns: a systematic review and meta-analysis.

BACKGROUND: Evening dosing regimen drug therapy on blood pressure (BP) control is used widely, but its clinical benefits and preservation or re-establishment of the normal 24-h BP dipping pattern in chronic kidney disease (CKD) patients is not known. AIMS: To investigate the effect of an evening dosing regimen of antihypertensive drugs on BP patterns of CKD patients with hypertension. METHODS: A systematic review was conducted by searching PUBMED, EMBASE, ASN-ONLINE, the Cochrane Library and the reference lists of relevant articles of published papers. All trials designed to evaluate the effects of evening versus morning dosing regimen drug therapy for CKD patients with hypertension were included. Meta-analysis was performed using random or fixed effects models. RESULTS: Five randomised controlled trials and one comparative study, including 3732 patients, met the inclusion criteria. Compared with morning dosing regimen drug therapy, evening administration of antihypertensive medication was associated with a significant reduction of 40% in non-dipper BP patterns (risk ratio (RR), 95% CI, (0.43, 0.84)). We noted a significant decrease in nocturnal systolic blood pressure (SBP) (MD -3.17 mmHg, 95% CI (-5.41, -0.94)), a significant reduction in nocturnal diastolic blood pressure (DBP) (MD -1.37 mmHg, 95% CI (-2.05, -0.69)) and a significant increase in awake SBP (MD 1.15 mmHg, 95% CI (0.10, 2.19)) in patients assigned to the evening dosing regimen drug therapy group. Patients showed no significant differences for all-cause mortality and cardiovascular mortality. CONCLUSION: This review shows that evening dosing regimen drug therapy could reverse non-dipper BP patterns in hypertensive CKD patients.

Poor sleep quality is responsible for the nondipper pattern in hypertensive but not in normotensive chronic kidney disease patients.

AIM: This study was designed to evaluate the relationship between sleep quality and hypertension and to determine if there was an association between nondipper blood pressure (BP) and sleep quality in chronic kidney disease (CKD) patients. METHODS: A total of 775 pre-dialysis CKD patients (314 normal BP patients, 461 hypertension patients) defined as dippers or nondippers by ambulatory BP monitoring were recruited for this study. Demographics and clinical correlates were collected, including body mass index, estimated glomerular filtration rate (eGFR) and other measures. Sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI). RESULTS: A total of 185 (58.9%) patients with normal BP and 341 (74.0%) hypertensive patients had a nondipper BP pattern. The hypertension group had a higher prevalence of the nondipper BP pattern, smoking, alcohol intake and diabetes mellitus (DM) and lower eGFR levels and poorer sleep quality than the normal BP group. Patients with the nondipper BP pattern had lower haemoglobin, worse renal function and poorer sleep quality when compared with hypertensive CKD patients with the dipping BP pattern. PSQI scores were significantly associated with the rate of nocturnal BP decline (P < 0.05) in the hypertension group but not in the normal BP group. Poor sleep quality was an independent factor affecting BP pattern in hypertensive CKD patients using multivariate linear and logistic regression analyses. There was no association between sleep quality and hypertension in CKD patients after multivariate logistic regression analyses. CONCLUSION: Poor sleep quality, which is commonly observed in pre-dialysis CKD patients, is an independent associated factor of the nondipper BP pattern in hypertensive CKD patients. No association was found between poor sleep and nondipper BP in normotensive patients.

Initiation time of renal replacement therapy on patients with acute kidney injury: A systematic review and meta-analysis of 8179 participants.

The early initiation of renal replacement therapy has been recommended for patients with acute renal failure by some studies, but its effects on mortality and renal recovery are unknown. We conducted an updated meta-analysis to provide quantitative evaluations of the association between the early initiation of renal replacement therapy and mortality for patients with acute kidney injury. After applying inclusion/exclusion criteria, 51 studies, including 10 randomized controlled trials, with a total of 8179 patients were analyzed. Analysis of the included trials showed that patients receiving early renal replacement therapy had a 25% reduction in all-cause mortality compared to those receiving late renal replacement therapy (risk ratio [RR] 0.75, 95% CI [0.69, 0.82]). We also noted a 30% increase in renal recovery (RR 1.30, 95% CI [1.07, 1.56]), a reduction in hospitalization of 5.84 days (mean difference [MD], 95% CI [-10.27, -1.41]) and a reduction in the duration of mechanical ventilation of 2.33 days (MD, 95% CI [-3.40, -1.26]) in patients assigned to early renal replacement therapy. The early initiation of renal replacement therapy was associated with a decreased risk of all-cause mortality compared with the late initiation of RRT in patients with acute kidney injury. These findings should be interpreted with caution given the heterogeneity between studies. Further studies are needed to identify the causes of mortality and to assess whether mortality differs by dialysis dose.

C-reactive protein promotes acute kidney injury via Smad3-dependent inhibition of CDK2/cyclin E.

Acute kidney injury (AKI) is exacerbated in C-reactive protein transgenic mice but alleviated in Smad3 knockout mice. Here we used C-reactive protein transgenic/Smad3 wild-type and C-reactive protein transgenic/Smad3 knockout mice to investigate the signaling mechanisms by which C-reactive protein promotes AKI. Serum creatinine was elevated, and the extent of tubular epithelial cell necrosis following ischemia/reperfusion-induced AKI was greater in C-reactive protein transgenics but was blunted when Smad3 was deleted. Exacerbation of AKI in C-reactive protein transgenics was associated with increased TGF-ß/Smad3 signaling and expression of the cyclin kinase inhibitor p27, but decreased phosphorylated CDK2 and expression of cyclin E. Concomitantly, tubular epithelial cell proliferation was arrested at the G1 phase in C-reactive protein transgenics with fewer cells entering the S-phase cell cycle as evidenced by fewer bromodeoxyuridine-positive cells. In contrast, the protection from AKI in C-reactive protein transgenic/Smad3 knockout mice was associated with decreased expression of p27 and promotion of CDK2/cyclin E-dependent G1/S transition of tubular epithelial cells. In vitro studies using tubular epithelial cells showed that C-reactive protein activates Smad3 via both TGF-ß-dependent and ERK/MAPK cross talk mechanisms, Smad3 bound directly to p27, and blockade of Smad3 or the Fc receptor CD32 prevented C-reactive protein-induced p27-dependent G1 cell cycle arrest. In vivo, treatment of C-reactive protein transgenics with a Smad3 inhibitor largely improved AKI outcomes. Thus, C-reactive protein may promote AKI by impairing tubular epithelial cell regeneration via the CD32-Smad3-p27-driven inhibition of the CDK2/cyclin E complex. Targeting Smad3 may offer a new treatment approach for AKI.

Prevalence, determinants, and clinical significance of masked hypertension and white-coat hypertension in patients with chronic kidney disease.

BACKGROUND: Masked hypertension and white-coat hypertension have been studied among the general population and in hypertensive patients. However, little insight is available on masked and white-coat hypertension among patients with chronic kidney disease (CKD). METHODS: We recruited 1322 CKD patients admitted to our hospital division. Patients were divided into four groups: normotension; white-coat hypertension (WCHT); masked hypertension (MHT); sustained hypertension. Multivariable logistic regression analyses were used to evaluate the correlation between WCHT, MHT and renal/cardiovascular parameters. RESULTS: The prevalence of WCHT and MHT was 10.21% and 16.11%, respectively. Patients with WCHT and MHT had more severe target-organ damage (TOD) than patients with normotension, but had less severe TOD than patients with sustained hypertension. MHT correlated with impaired renal function and left-ventricular hypertrophy, whereas WCHT was associated with abnormal carotid intima media thickness. Age, body mass index, clinic and 24-h systolic blood pressure correlated with MHT, whereas clinic, 24-h diastolic blood pressure and night-time systolic blood pressure was associated with WCHT. CONCLUSIONS: Prevalence of WCHT and MHT was 10.21% and 16.11%, respectively. WCHT and MHT show a close relationship with TOD in CKD patients.

Estimating glomerular filtration rate by serum creatinine or/and cystatin C equations: An analysis of multi-centre Chinese subjects.

AIM: Various equations based on serum creatinine or/and cystatin C, required further validation in a Chinese population. We compared the performance of six Chinese equations (Mascr, Peiscr, Macys, Fengcys, Mascr-cys and Fengscr-cys) with the CKD-EPI equations in multi-centre Chinese subjects and evaluated their applicability in clinical practice. METHODS: A total of 1522 adult patients from four different hospitals of China were enrolled in the study. (99m) Tc-DTPA renal dynamic imaging was used as the reference GFR (rGFR), and serum creatinine and cystatin C were measured by standardized assays. An optimal score system was implemented in the study. RESULTS: The average rGFR of recruited subjects was 67.30±28.89 mL/min per 1.73m(2) . All estimated GFR (eGFR) correlated well with rGFR. In accordance with Bland-Altman analysis, the Fengscr-cys equations achieved optimal overall performance (score 14 vs 0-6), with least bias (median difference, -0.57 mL/min per 1.73m(2) ; median absolute difference, 8.83 mL/min per 1.73m(2) ), best precision (17.99 mL/min per 1.73m(2) ), highest accuracy (percentage of eGFR within 15%, 30% and 50% of the rGFR (P15 , P30 and P50 ; 49.7%, 78.7% and 91.8%, respectively); root-mean-square-error (RMSE, 16.28)). The Fengcys equation, a typical cystatin C based equation, was another well-behaved formula with an impressive performance. The Ma equations performed much poorer than the CKD-EPI equations. Consistent results can be observed in the GFR- /age- and sex-specific subgroups, while none equation yielded ideal accuracy in GFR<60 mL/min per 1.73 m(2) subgroup. CONCLUSION: The Fengscr-cys equation appeared to achieve the best performance for GFR estimation in overall Chinese adult patients. However, further research is warranted to improve the accuracy of available equations in GFR less than 60 mL/min per 1.73 m(2) individuals.

Development and validation of new glomerular filtration rate predicting models for Chinese patients with type 2 diabetes.

BACKGROUND: Previous researches has depicted that the performance of the recommended glomerular filtration rate (GFR)-estimating equations in the type 2 diabetic population is inferior to that in the non-diabetic population. We attempted to develop new GFR-predicting models for use in Chinese patients with type 2 diabetes in this study. METHODS: We enrolled 519 type 2 diabetic patients including a development data-set (n = 276), an internal validation data-set (n = 138) and an external validation data-set (n = 105) to establish new GFR-predicting models. 99mTc-DTPA-GFR revised by the dual sample method was referred to as the gold GFR standard. RESULTS: Based on sex, age, serum creatinine and new predictor variables [body mass index (BMI), hemoglobinA1C, and urinary albumin creatinine ratio], eight new regression models and eight artificial neural network (ANN) models were developed. In the external validation group, only ANN3 was superior in both precision and accuracy over the original CKD-EPI equation (precision, 20.5 vs. 24.2 mL/min/1.73 m(2), P < 0.001; 30 % accuracy, 88.6 vs. 80.6 %, P = 0.02). CONCLUSIONS: ANN3 based on sex, age, serum creatinine and BMI is the optimal model for GFR estimation in Chinese patients with type 2 diabetes.

Activation of the Nrf2-ARE pathway attenuates hyperglycemia-mediated injuries in mouse podocytes.

BACKGROUND: Damage to podocytes caused by excessive reactive oxygen species (ROS) contributes to onset and progression of diabetic kidney disease (DKD). Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a redox-sensing transcription factor that can induce the expression of antioxidant enzymes. We explored whether activation of Nrf2 pathway attenuated hyperglycemia-induced injuries in mouse podocytes. METHODS: Tert-Butylhydroquinone (tBHQ) and small interfering RNAs (siRNAs) were used to regulate Nrf2 expression. Apoptosis and intracellular superoxide anion production were measured by flow cytometry. The activity of the Nrf2 antioxidant pathway was measured by an antioxidant response element (ARE)-driven luciferase reporter gene assay, and Nrf2 expression was assessed by real-time PCR and western blot analyses. RESULTS: Podocytes incubated with high-glucose (HG) medium had higher intracellular superoxide anion and hydrogen peroxide production, higher apoptosis rate, higher bovine serum albumin (BSA) permeability and lower synaptopodin expression compared with podocytes exposed normal glucose (NG) (p<0.05). tBHQ increased the activity of the Nrf2 antioxidant pathway and enhanced nuclear Nrf2 expression, reduced intracellular superoxide anion and hydrogen peroxide production, apoptosis rate and BSA permeability, and restored synaptopodin expression in podocytes exposed to HG (p

Association between sleep quality and cardiovascular damage in pre-dialysis patients with chronic kidney disease.

BACKGROUND: Poor sleep quality, a novel risk factor of cardiovascular diseases (CVD), is highly prevalent in patients with chronic kidney disease (CKD). The association between poor sleep quality and cardiovascular damage in patients with CKD is unclear. This study is aimed to assess the prevalence and related risk factors of sleep disturbance and determine the relationship between sleep quality and cardiovascular damage in Chinese patients with pre-dialysis CKD. METHODS: A total of 427 pre-dialysis CKD patients (mean age = 39 ± 15 years, 260 male/167 female) were recruited in this study. The demographics and clinical correlates were collected. The sleep quality was measured by the Pittsburgh Sleep Quality Index (PSQI), whereas the cardiovascular damage indicators (the Early/late diastolic peak flow velocity (E/A) ratio and left ventricular mass index (LVMI)) were determined by an echocardiographic examination. RESULTS: Of the CKD patients, 77.8% were poor sleepers as defined by a PSQI score > 5. Median estimated glomerular filtration rate (eGFR) was 69.4(15.8-110.9) ml/min/1.73 m(2). Logistic regression analysis revealed that left ventricular hypertrophy (LVH) was independently associated with the PSQI score (OR = 1.092, 95% CI = 1.011-1.179, p = 0.025), after adjustment for age, sex and clinical systolic blood pressure, diastolic blood pressure, Phosphate, Intact parathyroid hormone (iPTH), Hemoglobin and eGFR. The linear regression analysis showed that the E/A ratios were independently associated with the PSQI score (ß = -0.115, P = 0.028) after adjustment for a series of potential confounding factors. CONCLUSIONS: Poor sleep quality, which is commonly found in pre-dialysis CKD patients, is an independent factor associated with cardiovascular damage in CKD patients. Our finding implies that the association between poor sleep and CVD might be mediated by cardiac remodeling.

Identification of proteins related to SIS3 by iTRAQ and PRM-based comparative proteomic analysis in cisplatin-induced acute kidney injury.

Background: Cisplatin is a commonly used nephrotoxic drug and can cause acute kidney injury (AKI). In the present study, isobaric tags for relative and absolute quantification (iTRAQ) and parallel reaction monitoring (PRM)-based comparative proteomics were used to analyze differentially expressed proteins (DEPs) to determine the key molecular mechanism in mice with cisplatin-induced AKI in the presence or absence of SIS3, a specific p-smad3 inhibitor, intervention. Methods: The cisplatin-induced AKI mouse model was established and treated with SIS3. We used iTRAQ to search for DEPs, PRM to verify key DEPs and combined Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for bioinformatics analysis. We then assessed lipid deposition, malondialdehyde (MDA) and reactive oxygen species (ROS) and detected the expression of SREBF1, SCD1, CPT1A, PPARα and NDRG1 in vitro. Results: Proteomic analysis showed that the identified DEPs were mainly enriched in energy metabolism pathways, especially in lipid metabolism. When SIS3 was applied to inhibit the phosphorylation of Smad3, the expression of NDRG1 and fatty acid oxidation key proteins CPT1A and PPARα increased, the expression of lipid synthesis related proteins SREBF1 and SCD1 decreased and the production of lipid droplets, MDA and ROS decreased. Conclusion: SIS3 alleviates oxidative stress, reduces lipid accumulation and promotes fatty acid oxidation through NDRG1 in cisplatin-induced AKI. Our study provides a new candidate protein for elucidating the molecular mechanisms of fatty acid metabolism disorders in cisplatin-induced acute kidney injury.

A comparison of the performances of an artificial neural network and a regression model for GFR estimation.

BACKGROUND: Accurate estimation of glomerular filtration rate (GFR) is important in clinical practice. Current models derived from regression are limited by the imprecision of GFR estimates. We hypothesized that an artificial neural network (ANN) might improve the precision of GFR estimates. STUDY DESIGN: A study of diagnostic test accuracy. SETTING & PARTICIPANTS: 1,230 patients with chronic kidney disease were enrolled, including the development cohort (n=581), internal validation cohort (n=278), and external validation cohort (n=371). INDEX TESTS: Estimated GFR (eGFR) using a new ANN model and a new regression model using age, sex, and standardized serum creatinine level derived in the development and internal validation cohort, and the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) 2009 creatinine equation. REFERENCE TEST: Measured GFR (mGFR). OTHER MEASUREMENTS: GFR was measured using a diethylenetriaminepentaacetic acid renal dynamic imaging method. Serum creatinine was measured with an enzymatic method traceable to isotope-dilution mass spectrometry. RESULTS: In the external validation cohort, mean mGFR was 49±27 (SD) mL/min/1.73 m2 and biases (median difference between mGFR and eGFR) for the CKD-EPI, new regression, and new ANN models were 0.4, 1.5, and -0.5 mL/min/1.73 m2, respectively (P<0.001 and P=0.02 compared to CKD-EPI and P<0.001 comparing the new regression and ANN models). Precisions (IQRs for the difference) were 22.6, 14.9, and 15.6 mL/min/1.73 m2, respectively (P<0.001 for both compared to CKD-EPI and P<0.001 comparing the new ANN and new regression models). Accuracies (proportions of eGFRs not deviating >30% from mGFR) were 50.9%, 77.4%, and 78.7%, respectively (P<0.001 for both compared to CKD-EPI and P=0.5 comparing the new ANN and new regression models). LIMITATIONS: Different methods for measuring GFR were a source of systematic bias in comparisons of new models to CKD-EPI, and both the derivation and validation cohorts consisted of a group of patients who were referred to the same institution. CONCLUSIONS: An ANN model using 3 variables did not perform better than a new regression model. Whether ANN can improve GFR estimation using more variables requires further investigation.