Shengqiang Yu

Urinary Interleukin 18 for Detection of Acute Kidney Injury: A Meta-analysis

BACKGROUND Interleukin 18 (IL-18) has been proposed as a biomarker for the early detection of acute kidney injury (AKI), but a broad range of its predictive accuracy has been reported. STUDY DESIGN Meta-analysis of diagnostic test studies. SETTING & POPULATION Various clinical settings of AKI, including after cardiac surgery, after contrast infusion, in the emergency department, or in the intensive care unit. SELECTION CRITERIA FOR STUDIES Prospective studies that investigated the diagnostic accuracy of IL-18 level to predict AKI. INDEX TESTS Increasing or increased urinary IL-18 excretion. REFERENCE TESTS The primary outcome was AKI development, mainly based on serum creatinine level (definition varied across studies). The other outcome was in-hospital mortality. RESULTS We analyzed data from 23 studies and 7 countries involving 4,512 patients. Of these studies, 18 could be included in the meta-analysis. Across all settings, the diagnostic odds ratio (DOR) for urinary IL-18 level to predict AKI was 4.22 (95% CI, 2.90-6.14), with sensitivity and specificity of 0.58 and 0.75, respectively. The area under the receiver operating characteristic curve (AUROC) of urinary IL-18 level to predict AKI was 0.70 (95% CI, 0.66-0.74). Subgroup analysis showed the DOR/AUROC of urinary IL-18 was 5.32 (95% CI, 2.92-9.70)/0.72 (95% CI, 0.68-0.76) in cardiac surgery patients and 3.65 (95% CI, 1.88-7.10)/0.66 (95% CI, 0.62-0.70) in intensive care unit or coronary care unit patients. After stratification for age, IL-18 level had better diagnostic accuracy in children and adolescents versus adults: 8.12 (95% CI, 3.79-17.41)/0.78 (95% CI, 0.75-0.82) versus 3.31 (95% CI, 2.28-4.80)/0.66 (95% CI, 0.62-0.70). There was no significant difference in predictive performance of urinary IL-18 level among various times. LIMITATIONS Various clinical settings; different definition of AKI and serum creatinine level as the reference standard test for the diagnosis of AKI. CONCLUSIONS Urinary IL-18 is a useful biomarker of AKI with moderate predictive value across all clinical settings.

Celecoxib inhibits growth of human autosomal dominant polycystic kidney cyst-lining epithelial cells through the VEGF/Raf/MAPK/ERK signaling pathway

Autosomal dominant polycystic kidney disease (ADPKD) is a progressive chronic kidney disease. To date there are no effective medicines to halt development and growth of cysts. In the present study, we explored novel effects of celecoxib (CXB), a COX-2 specific inhibitor, on primary cultures of human ADPKD cyst-lining epithelial cells. Primary cultures of ADPKD cyst-lining epithelial cells were obtained from five patients. Effects of CXB were measured by various assays to detect BrdU incorporation, apoptosis and proliferation in vitro. Additionally, effects of CXB on kidney weight, the cyst index, the fibrosis index, blood urea nitrogen (BUN), serum creatinine (SCr), serum 6-keto-PGF-1α, serum thromboxane-2 (TXB2) and renal PCNA expression were assessed in Han:SPRD rat, a well-characterized rodent model of PKD. CXB inhibited proliferation of ADPKD cyst-lining epithelial cells, blocked the release of VEGF from the cells and induced extensive apoptosis in a time- and dose-dependent manner. Moreover, CXB up-regulated the cell cycle negative regulator p21CIP/WAF1 and the cell cycle positive regulator Cyclin A, blocked ERK1/2 phosphorylation, induced apoptotic factors (Bax and caspase-3) and reduced Bcl-2. Furthermore, CXB inhibited the expression of VEGFR-2 and Raf-1 in ADPKD cyst-lining epithelial cells. CXB markedly reduced the cyst index, the fibrosis index, leukocyte infiltration, BUN, SCr, serum 6-keto-PGF-1α, TXB2 and renal PCNA expression in Han:SPRD rat. We demonstrated for the first time that CXB could suppress renal cyst-lining growth both in vitro and in vivo in Han:SPRD rat. CXB can inhibit proliferation, suppress cell cycle progression, and induce apoptosis in ADPKD cyst-lining epithelial cells through the inhibition of the VEGF/VEGFR-2/Raf-1/MAPK/ERK signaling pathway.

Clinical characteristics and disease predictors of a large Chinese cohort of patients with autosomal dominant polycystic kidney disease

Objective Autosomal dominant polycystic kidney disease (ADPKD) is a relentlessly progressing form of chronic kidney disease for which there is no cure. The aim of this study was to characterize Chinese patients with ADPKD and to identify the factors which predict cyst growth and renal functional deterioration. Methods To analyze disease predicting factors we performed a prospective longitudinal observational study in a cohort of 541 Chinese patients with ADPKD and an eGFR ≥30 ml/min/1.73 m2. Patients were followed clinically and radiologically with sequential abdominal magnetic resonance imaging (MRI). Clinical characteristics and laboratory data were related to changes in estimated glomerular filtration rate (eGFR) and total kidney volume (TKV). A linear regression model was developed to analyze the factors which determine eGFR and TKV changes. Results The age range of this unselected cohort ranged from 4 to 77 years. Median follow-up time was 14.3±10.6 months. Although inter-individual differences in eGFR and TKV were large, there was a consistent link between these two parameters. Baseline log10-transformed TKV and urinary protein/creatinine ratio were identified as the major predictors for a faster eGFR decline and were associated with a higher TKV growth rate. Interestingly, a lower thrombocyte count correlated significantly with lower eGFR (r = 0.222) and higher TKV (r = 0.134). Conclusions This large cohort of Chinese patients with ADPKD provides unique epidemiological data for comparison with other cohorts of different ethnicity. In Chinese patients we identified a lower thrombocyte count as a significant predictor of disease progression. These results are important for the design of future clinical trials to retard polycystic kidney disease progression.

Fibroblast Growth Factor 23 Predicts All-Cause Mortality in a Dose-Response Fashion in Pre-Dialysis Patients with Chronic Kidney Disease

Background: Quantitative dose-response associations between fibroblast growth factor 23 (FGF23) and risks of mortality, cardiovascular disease (CVD), and renal events in chronic kidney disease (CKD) are not known. This study aimed to summarize and quantify the predictive effects of FGF23 among the pre-dialysis CKD stages 1-5 population. Methods: Data sources included PubMed, EMBASE, and Web of Science. Prospective cohort studies assessing the associations between FGF23 and all-cause mortality, CVD, and renal events in CKD patients were selected. Summary risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using the random-effects model. The composite higher or the highest level in FGF23 categories of each study was considered the high level. The reference level was regarded as the low level in the overall analysis. The restricted cubic spline model was used to estimate dose-response associations. Results: Fifteen prospective cohort studies centered around 15,355 subjects were analyzed. A high FGF23 level was associated with increased risks of all-cause mortality (RR 1.46, 95% CI 1.38-1.55, p < 0.001), CVD (RR 1.37, 95% CI 1.15-1.63, p < 0.001), and renal events (RR 1.31, 95% CI 1.07-1.59, p = 0.008), respectively. There was a positive, nonlinear, dose-response relationship between FGF23 and all-cause mortality. The reference level in dose-response analysis was defined as 51 RU/mL of c-terminal FGF23. We then calculated RRs for increments of 20 RU/mL, which was associated with increased risks of mortality (RR 1.04, 95% CI 1.00-1.07, p = 0.038), CVD (RR 1.02, p < 0.001), and renal events (RR 1.01, p < 0.001), respectively. Conclusions: There may be positive dose-response predictive effects of FGF23 on all-cause mortality, CVD, and renal events in patients with CKD.

Acute kidney injury burden in different clinical units: Data from nationwide survey in China

Background The inpatient morbidity and mortality of acute kidney injury (AKI) vary considerably in different clinical units, yet studies to compare the difference remain limited. Methods We compared the clinical characteristics of AKI in Intensive Care Unit (ICU), medical and surgical departments by using the data derived from the 2013 nationwide cross-sectional survey of AKI in China to capture variations among different clinical departments in recognition, management, and outcomes of AKI. Suspected AKI patients were identified based on changes in serum creatinine during hospitalization, and confirmed by reviewing medical records. Results The detection rate of AKI was the highest in ICU (22.46%), followed by the rates in medical (1.96%) and surgical departments (0.96%). However, the absolute number of cases was the largest in medical departments, which contributed to 50% of the cases. In medical departments, 78% of AKI cases were extensively distributed in cardiac, nephrology, oncology, gastroenterology, pneumology and neurology departments. In contrast, 87% of AKI cases in surgical departments were mainly from urology, general surgery and cardiothoracic departments. The in-time recognition rates were extremely low in all departments except nephrology. Only 10.5~15.0% AKI patients from non-nephrology departments received renal referral. Among all the death cases, 50% and 39% came from ICU and medical departments while only 11% from surgical departments. Older age, higher AKI stage and renal replacement therapy indication were identified as risk factors for high mortality in all departments. Delayed recognition and no renal referral were significantly associated with increased mortality in medical and ICU patients. Conclusions These findings suggest that ICU and medical departments are major affected departments in China with a large number of AKI cases and subsequent high mortality. The reality is more alarming considering the low awareness of AKI and the paucity of effective interventions in the high-risk patients in these departments.

The mutation-free embryo for in vitro fertilization selected by MALBAC-PGD resulted in a healthy live birth from a family carrying PKD 1 mutation

BackgroundAutosomal dominant polycystic kidney disease (ADPKD, autosomal dominant PKD or adult-onset PKD) is the most prevalent and potentially lethal kidney disease that is hereditary and lacks effective treatment. Preimplantation genetic diagnosis (PGD) of embryos in assistant reproductive technology (ART) helps to select mutation-free embryos for blocking ADPKD inheritance from the parents to their offspring. However, there are multiple pseudogenes in the PKD1 coding region, which make blocking ADPKD inheritance by PGD complicated and difficult. Therefore, this technique has not been recommended and used routinely to ADPKD family plan.Methods and ResultsHere, we report a new strategy of performing PGD in screening (target-) mutation-free embryos. We firstly used a long-range PCR amplification and next generation sequencing to identify the potential PKD1 mutant(s). After pathogenic variants were detected, multiple annealing and looping-based amplification cycles (MALBAC), a recently developed whole genome amplification method, was used to screen embryo cells. We successfully distinguished the mutated allele among pseudogenes and obtained mutation-free embryos for implantation. The first embryo transfer attempt resulted in a healthy live birth free of ADPKD condition and chromosomal anomalies which was confirmed by aminocentesis at week 18 of gestation, and by performing live birth genetic screening.ConclusionsThe first MALBAC-PGD attempt in ADPKD patient resulted in a healthy live birth free of ADPKD and chromosomal anomalies. MALBAC-PGD also enables selecting embryos without aneuploidy together and target gene mutation, thereby increasing implantation and live birth rates.

Comparison of efficacy and safety between benidipine and hydrochlorothiazide in fosinopril-treated hypertensive patients with chronic kidney disease: protocol for a randomised controlled trial

Introduction Co-administration of a diuretic or calcium channel blocker with an ACE inhibitor are both preferred combinations in patients with hypertensive chronic kidney disease (CKD). According to the available evidence, it is still unknown which combination plays a more active role in renal protection. We hypothesised that a combination of fosinopril and benidipine may delay the progression of CKD more effectively than a combination of fosinopril and hydrochlorothiazide (HCTZ). Methods and analysis This study will be a multicentred, prospective, double-blind, randomised parallel controlled trial for hypertensive CKD patients in China. Patients will be randomised to one of two treatment groups: a combination of benidipine 4–8 mg/day and fosinopril 20 mg/day; or a combination of HCTZ 12.5–25 mg/day and fosinopril 20 mg/day. Patients will be followed up for 24 months after a months fosinopril run-in. There will be dose-titration after 1 and 2 months. The primary endpoint is changes in estimated glomerular filtration rate (eGFR) from baseline to month 24. Secondary endpoints include changes in home blood pressure (BP), ambulatory BP, proteinuria, urinary albumin/creatinine ratio, and composite renal events in 24 months. Inclusion criteria are: age 18–80 years, non-dialysis CKD patients with eGFR >30 mL/min/1.73 m2, home BP >130 mm Hg systolic or BP >80 mm Hg diastolic at the screening and randomisation, and 24 hour proteinuria <3.5 g. Principal exclusions are hypertensive crisis, transplantation, cancer, severe diabetes complications, hyperkalaemia and severe allergy. The required sample size was 511 patients for detecting a difference in the change of eGFR (one sided α=0.025, power 1-β=0.90). Ethics and dissemination BEAHIT (Benidipine and Hydrochlorothiazide in Fosinopril Treated Chronic Kidney Disease Patients with Hypertension) was approved by Changzheng Hospital Ethics Committee (CZ-20160504-16). The outcomes will be published in a peer-reviewed journal. Trial registration number NCT02646397.

Antihypertensive treatments in adult autosomal dominant polycystic kidney disease: network meta-analysis of the randomized controlled trials.

Background Blood pressure (BP) control is one of the most important treatments of Autosomal dominant polycystic kidney disease (ADPKD). The comparative efficacy of antihypertensive treatments in ADPKD patients is inconclusive. Methods Network meta-analysis was used to evaluate randomized controlled trials (RCT) which investigated antihypertensive treatments in ADPKD. PubMed, Embase, Ovid, and Cochrane Collaboration were searched. The primary outcome was estimated glomerular filtration rate (eGFR). Secondary outcomes were serum creatinine (Scr), urinary albumin excretion (UAE), systolic BP (SBP), diastolic BP (DBP), mean artery pressure (MAP) and left ventricular mass index (LVMI). Results We included 10 RCTs with 1386 patients and six interventions: angiotensin-converting enzyme inhibitors (ACEI), Angiotensin II receptor blocker (ARB), combination of ACEI and ARB, calcium channel blockers (CCB), β-blockers and dilazep. There was no difference of eGFR in all the treatments in both network and direct comparisons. No significant differences of Scr, SBP, DBP, MAP, and LVMI were found in network comparisons. However, ACEI significantly reduced SBP, DBP, MAP and LVMI when compared to CCB. Significantly increased UAE was observed in CCB compared with ACEI or ARB. Bayesian probability analysis found ARB ranked first in the surrogate measures of eGFR, UAE and SBP. Conclusions There is little evidence to detect differences of antihypertensive treatments on kidney disease progression in ADPKD patients. More RCTs will be needed in the future. Use of ARB may be an optimal choice in clinical practice.