Bilateral Renal Ischemia-Reperfusion Model for Acute Kidney Injury in Mice.

Acute kidney injury (AKI) is defined as a rapid decline in renal function, in which persistent kidney dysfunction gradually progresses to chronic kidney disease (CKD) due to the irreversible loss of nephrons and their maladaptive repair. In recent years, the incidence of AKI has been increasing concerning diverse etiologies, including volume depletion, sepsis, nephrotoxicity, muscle injury, and major trauma, in which ischemia-reperfusion injury (IRI) accounts for most episodes. Development of the IRI model in mice is induced by surgical clamping of the renal pedicles, which provides powerful and controllable tools for preclinical models of AKI. Importantly, the IRI model is deployed at different stages of the AKI development, especially in the processes of AKI to CKD. Despite the IRI model being widely practiced in many laboratories, a series of variables still influence the results of this model. Here, we describe the procedure of IRI model development to provide a repeatable and reliable method for researchers to explore the underlying pathogenesis in the development of AKI and the progression of AKI to CKD.

IFN-ß Pretreatment Alleviates Allogeneic Renal Tubular Epithelial Cell-Induced NK Cell Responses via the IRF7/HLA-E/NKG2A Axis.

Immune checkpoint molecules are promising targets for suppressing the immune response but have received little attention in immune tolerance induction in organ transplantation. In this study, we found that IFN-ß could induce the expression of HLA-E as well as PD-L1 on human renal tubular epithelial cell line HK-2 and renal tissue of the C57BL/6 mouse. The JAK/STAT2 pathway was necessary for this process. Upregulation of both HLA-E and PD-L1 was fully abrogated by the JAK1/2 inhibitor ruxolitinib. Signaling pathway molecules, including STAT1, STAT2, mTOR, Tyk2, and p38 MAPK, were involved in HLA-E and PD-L1 upregulation. IRF7 is the key transcription factor responsible for the activation of HLA-E and PD-L1 promoters. Through screening an epigenetic regulation library, we found a natural compound, bisdemethoxycurcumin, enhanced IFN-ß-induced HLA-E and PD-L1 expression in vitro and in vivo. In PBMC-derived CD56+ NK cells, we found that NKG2A but not PD1 was constitutively expressed, indicating HLA-E/NKG2A as a more potent target to induce tolerance to innate immune cells. Pretreating HK-2 cells by IFN-ß significantly attenuated the degranulation of their coincubated NK cells and protected cells from NK-mediated lysis. In conclusion, IFN-ß pretreatment could activate HLA-E and PD-L1 transcription through the JAK/STAT/IRF7 pathway and then could protect renal tubular epithelial cells from allogeneic immune attack mediated by NK cells.

The risk factors and predictive model for cardiac valve calcification in patients on maintenance peritoneal dialysis: a single-center retrospective study.

BACKGROUND: Cardiovascular calcification includes cardiac valve calcification (CVC) and vascular calcification. We aimed to analyze risk factors for CVC, and construct a predictive model in maintenance peritoneal dialysis (MPD) patients. METHODS: We retrospectively analyzed MPD patients who began peritoneal dialysis between January 2014 and September 2021. Patients were randomly assigned to the derivation cohort and validation cohort in a 7:3 ratio. The patients in the derivation cohort were divided into the CVC group and non-CVC group. Logistic regression was used to analyze risk factors, then the rms package in R language was used to construct a nomogram model to predict CVC. RESULTS: 1,035 MPD patients were included, with the age of 50.0 ± 14.2 years and 632 males (61.1%). Their median follow-up time was 25 (12, 46) months. The new-onset CVC occurred in 128 patients (12.4%). In the derivation cohort, multivariate logistic regression indicated old age, female, high systolic blood pressure (SBP), high calcium-phosphorus product (Ca × P), high Charlson comorbidity index (CCI) and long dialysis time were independent risk factors for CVC (p < 0.05). We constructed a nomogram model for predicting CVC in the derivation cohort, with a C index of 0.845 (95% CI 0.803-0.886). This model was validated with a C index of 0.845 (95%CI 0.781-0.909) in the validation cohort. CONCLUSION: We constructed a nomogram model for CVC in MPD patients, using independent risk factors including age, sex, SBP, Ca × P, CCI and dialysis time. This model achieved high efficiency in CVC prediction.

A circular RNA, circPTPN14, increases MYC transcription by interacting with FUBP1 and exacerbates renal fibrosis.

Fibrosis is a relentlessly progressive and irreversible cause of organ damage, as in chronic kidney disease (CKD), but its underlying mechanisms remain elusive. We found that a circular RNA, circPTPN14, is highly expressed in human kidneys with biopsy-proved chronic interstitial fibrosis, mouse kidneys subjected to ischemia/reperfusion (IR) or unilateral ureteral obstruction (UUO), and TGFß1-stimulated renal tubule epithelial cells (TECs). The intrarenal injection of circPTPN14 shRNA alleviated the progression of fibrosis in kidneys subjected to IR or UUO. Knockdown of circPTPN14 in TECs inhibited TGFß1-induced expression of profibrotic genes, whereas overexpressing circPTPN14 increased the profibrotic effect of TGFß1. The profibrotic action of circPTPN14 was ascribed to an increase in MYC transcription. The binding of circPTPN14 to the KH3 and KH4 domains of far upstream element (FUSE) binding protein 1 (FUBP1) enhanced the interaction between FUBP1 and FUSE domain, which was required for the initiation of MYC transcription. In human kidneys (n = 30) with biopsy-proved chronic interstitial fibrosis, the expression of circPTPN14 positively correlated with MYC expression. Taken together these studies show a novel mechanism in the pathogenesis of renal fibrosis, mediated by circPTPN14, which can be a target in the diagnosis and treatment of CKD.

Impaired Amino Acid Metabolism and Its Correlation with Diabetic Kidney Disease Progression in Type 2 Diabetes Mellitus.

BACKGROUND: Metabolomics is useful in elucidating the progression of diabetes; however, the follow-up changes in metabolomics among health, diabetes mellitus, and diabetic kidney disease (DKD) have not been reported. This study was aimed to reveal metabolomic signatures in diabetes development and progression. METHODS: In this cross-sectional study, we compared healthy (n = 30), type 2 diabetes mellitus (T2DM) (n = 30), and DKD (n = 30) subjects with the goal of identifying gradual altering metabolites. Then, a prospective study was performed in T2DM patients to evaluate these altered metabolites in the onset of DKD. Logistic regression was conducted to predict rapid eGFR decline in T2DM subjects using altered metabolites. The prospective association of metabolites with the risk of developing DKD was examined using logistic regression and restricted cubic spline regression models. RESULTS: In this cross-sectional study, impaired amino acid metabolism was the main metabolic signature in the onset and development of diabetes, which was characterized by increased N-acetylaspartic acid, L-valine, isoleucine, asparagine, betaine, and L-methionine levels in both the T2DM and DKD groups. These candidate metabolites could distinguish the DKD group from the T2DM group. In the follow-up study, higher baseline levels of L-valine and isoleucine were significantly associated with an increased risk of rapid eGFR decline in T2DM patients. Of these, L-valine and isoleucine were independent risk factors for the development of DKD. Notably, nonlinear associations were also observed for higher baseline levels of L-valine and isoleucine, with an increased risk of DKD among patients with T2DM. CONCLUSION: Amino acid metabolism was disturbed in diabetes, and N-acetylaspartic acid, L-valine, isoleucine, asparagine, betaine, and L-methionine could be biomarkers for the onset and progression of diabetes. Furthermore, high levels of L-valine and isoleucine may be risk factors for DKD development.

Mitophagy induced by UMI-77 preserves mitochondrial fitness in renal tubular epithelial cells and alleviates renal fibrosis.

Renal fibrosis is the final common outcome of chronic kidney disease (CKD), which remains a huge challenge due to a lack of targeted treatment. Growing evidence suggests that during the process of CKD, the integrity and function of mitochondria in renal tubular epithelial cells (TECs) are generally impaired and strongly connected with the progression of renal fibrosis. Mitophagy, a selective form of autophagy, could remove aberrant mitochondria to maintain mitochondrial homeostasis. Deficiency of mitophagy has been reported to aggravate renal fibrosis. However, whether induction of mitophagy could alleviate renal fibrosis has not been stated. In this study, we explored the effect of mitophagy activation by UMI-77, a compound recently verified to induce mitophagy, on murine CKD model of unilateral ureteral obstruction (UUO) in vivo and TECs in vitro. In UUO mice, we found the changes of mitochondrial damage, ROS production, transforming growth factor (TGF)-ß1/Smad pathway activation, as well as epithelial-mesenchymal transition phenotype and renal fibrosis, and these changes were ameliorated by mitophagy enhancement using UMI-77. Moreover, TEC apoptosis, nuclear factor (NF)-κB signaling activation, and interstitial inflammation after UUO were significantly mitigated by augmented mitophagy. Then, we found UMI-77 could effectively and safely induce mitophagy in TECs in vitro, and reduced TGF-ß1/Smad signaling and downstream profibrotic responses in TGF-ß1-treated TECs. These changes were restored by a mitophagy inhibitor. In conclusion, we demonstrated that mitophagy activation protected against renal fibrosis through improving mitochondrial fitness, downregulating TGF-ß1/Smad signaling and alleviating TEC injuries and inflammatory infiltration in kidneys.

Mannose-binding lectin activates the nuclear factor-κB and renal inflammation in the progression of diabetic nephropathy.

Increased serum mannose-binding lectin (MBL) level has been proven to correlate with the development of diabetic nephropathy (DN). Here, we aim to find the role and mechanism of MBL involved in the progression of DN. Patients with DN were recruited and divided into two groups according to different rs1800450 genotypes of the MBL2 gene, and inflammatory profiles in monocytes/macrophages were compared between the two groups. MBL was given to treat macrophages, HK2, and HMC, and a co-culture transwell system was then employed. Renal inflammation and fibrosis parameters were measured after knocking down or overexpressing MBL genes in mice. Proinflammatory profile, manifesting as enhanced IL-1ß production and M1 polarization, was found in monocytes/macrophages from DN with a rs1800450 GG genotype of MBL2 gene who had higher MBL level, compared with those with a rs1800450 GA genotype. In mechanism, MBL directly induced inflammatory responses in macrophages, which promoted inflammatory and fibrotic markers in HK2 and HMCs during co-culture. Further experiments showed that MBL can promote macrophages transforming to the M1 subset mainly by activating the nuclear factor-κB pathway. After downregulation of MBL, the blood glucose, triglyceride, urine protein, injuries of glomerulus and tubules, and the degree of renal inflammation and fibrosis were ameliorated in db/db mice treated with AAV-MBL1/2-shRNA. Overexpression of MBL promoted macrophage infiltration in the kidney. In conclusion, MBL is a crucial mediator in the progression of DN via activating the nuclear factor-κB pathway in macrophages. This will serve as a genetic base for some patients with DN who have poor outcomes and provide a direction for the screening.

ADAMs family in kidney physiology and pathology.

A disintegrin and metalloproteinases (ADAMs) family are proteolytic transmembrane proteases that modulate diverse cell functions and coordinate intercellular communication. ADAMs are responsible for regulating cell proliferation, differentiation, migration, and organ morphogenesis in kidney development. Abnormally activated ADAMs drive inflammation and fibrosis in response to kidney diseases such as acute kidney injury, diabetic kidney disease, polycystic kidney disease, and chronic allograft nephropathy. ADAM10 and ADAM17, known as the most characterized members of ADAMs, are extensively investigated in kidney diseases. Notably, ADAM proteases have the potential to be targets for developing novel treatment approaches in kidney diseases.

DNA demethylase Tet2 suppresses cisplatin-induced acute kidney injury.

Demethylase Tet2 plays a vital role in the immune response. Acute kidney injury (AKI) initiation and maintenance phases are marked by inflammatory responses and leukocyte recruitment in endothelial and tubular cell injury processes. However, the role of Tet2 in AKI is poorly defined. Our study determined the degree of renal tissue damage associated with Tet2 gene expression levels in a cisplatin-induced AKI mice model. Tet2-knockout (KO) mice with cisplatin treatment experienced severe tubular necrosis and dilatation, inflammation, and AKI markers' expression levels than the wild-type mice. In addition, the administration of Tet2 plasmid protected Tet2-KO mice from cisplatin-induced nephrotoxicity, but not Tet2-catalytic-dead mutant. Tet2 KO was associated with a change in metabolic pathways like retinol, arachidonic acid, linolenic acid metabolism, and PPAR signaling pathway in the cisplatin-induced mice model. Tet2 expression is also downregulated in other AKI mice models and clinical samples. Thus, our results indicate that Tet2 has a renal protective effect during AKI by regulating metabolic and inflammatory responses through the PPAR signaling pathway.

MicroRNA-874-3p/ADAM (A Disintegrin and Metalloprotease) 19 Mediates Macrophage Activation and Renal Fibrosis After Acute Kidney Injury.

[Figure: see text].

The Right-Skewed Distribution of Fine-Root Size in Three Temperate Forests in Northeastern China.

Trees can build fine-root systems with high variation in root size (e.g., fine-root diameter) and root number (e.g., branching pattern) to optimize belowground resource acquisition in forest ecosystems. Compared with leaves, which are visible above ground, information about the distribution and inequality of fine-root size and about key associations between fine-root size and number is still limited. We collected 27,573 first-order fine-roots growing out of 3,848 second-order fine-roots, covering 51 tree species in three temperate forests (Changbai Mountain, CBS; Xianrendong, XRD; and Maoershan, MES) in Northeastern China. We investigated the distribution and inequality of fine-root length, diameter and area (fine-root size), and their trade-off with fine-root branching intensity and ratio (fine-root number). Our results showed a strong right-skewed distribution in first-order fine-root size across various tree species. Unimodal frequency distributions were observed in all three of the sampled forests for first-order fine-root length and area and in CBS and XRD for first-order fine-root diameter, whereas a marked bimodal frequency distribution of first-order fine-root diameter appeared in MES. Moreover, XRD had the highest and MES had the lowest inequality values (Gini coefficients) in first-order fine-root diameter. First-order fine-root size showed a consistently linear decline with increasing root number. Our findings suggest a common right-skewed distribution with unimodality or bimodality of fine-root size and a generalized trade-off between fine-root size and number across the temperate tree species. Our results will greatly improve our thorough understanding of the belowground resource acquisition strategies of temperate trees and forests.

Mannose-binding lectin activation is associated with the progression of diabetic nephropathy in type 2 diabetes mellitus patients.

BACKGROUND: We aimed to investigate whether mannose-binding lectin (MBL) activation contributed to the progression of diabetic nephropathy (DN), and its role in predicting the renal prognosis of DN. METHODS: Seventy-seven patients who received renal biopsy in the First Affiliated Hospital, College of Medicine, Zhejiang University between August 2013 and September 2016 were enrolled in the study. These patients were followed up until the endpoint of end-stage renal disease (ESRD) or the last follow-up time of August 31, 2018. They were divided into ESRD group (33 patients) and non-ESRD group (44 patients). Their baseline characteristics and MBL levels (serum and urine) were compared between groups. The correlation between single nucleotide polymorphisms (SNPs) of the MBL2 gene and renal outcomes was also analyzed. RESULTS: The median (interquartile ranges) of serum and urine MBL levels were significantly higher in ESRD group than those in non-ESRD group [2,783.75 (1,244.28, 3,837.07) vs. 1,141.60 (652.67, 3,188.44) ng/mL, P=0.016; 1.02 (0.43, 2.05) vs. 0.27 (0.04, 0.58) ng/mg, P<0.01, respectively]. Both univariate and multivariate Cox analysis showed that serum MBL >1,108.75 ng/mL (stratified by maximum Youden index) was an independent predictor for ESRD [hazard ratio (HR) =4.164, 95% confidence interval (CI): 1.601-10.833, P=0.003; HR =4.644, 95% CI: 1.320-16.337, P=0.017; respectively]. For the patients with rs1800450 SNPs of MBL2 gene, patients with homozygous genotype (GG) had higher serum MBL level (median 2,963.52 ng/mL) compared with those with heterozygous genotype (GA) (median 665.38 ng/mL) (P<0.001). MBL2 rs1800450 GA genotype was an independent protective factor for ESRD with a HR of 0.485 (95% CI: 0.237-0.991; P=0.047). CONCLUSIONS: Activation of MBL contributed to the progression of DN. The rs1800450 SNP of the MBL2 gene may be of value in predicting the progression to ESRD in DN patients.

Preconditioning is an effective strategy for improving the efficiency of mesenchymal stem cells in kidney transplantation.

The inevitable side effects caused by lifelong immunosuppressive agents in kidney transplantation patients spurred the exploration of novel immunosuppressive strategies with definite curative effects and minimal adverse effects. Mesenchymal stem cells (MSCs) have become a promising candidate due to their role in modulating the immune system. Encouraging results obtained from experimental models have promoted the translation of this strategy into clinical settings. However, the demonstration of only marginal or transient benefits by several recent clinical controlled studies has made physicians hesitant to adopt the routine utilization of this procedure in clinical settings. Impaired MSC function after infusion in vivo was thought to be the main reason for their limited effects. For this reason, some preconditioning methods were developed. In this review, we aim to outline the current understanding of the preconditioning methods being explored as a strategy to improve the therapeutic effects of MSCs in kidney transplantation and promote its clinical translation.

Regenerative abilities of mesenchymal stem cells via acting as an ideal vehicle for subcellular component delivery in acute kidney injury.

Cell-to-cell communication and information exchange is one of the most important events in multiple physiological processes, including multicellular organism development, cellular function regulation, external stress response, homeostasis maintenance and tissue regeneration. New findings support the concept that subcellular component delivery may account for the beneficial effects of mesenchymal stem cell (MSC)-based therapy-mediated protection against acute kidney injury (AKI). Through the secretion of extracellular vesicles (EVs), formation of tunnelling nanotubes (TNTs) and development of cellular fusions, a broad range of subcellular components, including proteins, nucleic acids (mRNA and miRNA) or even organelles can be transferred from MSCs into injured renal cells, significantly promoting cell survival, favouring tissue repair and accelerating renal recovery. In this review, we outline an extensive and detailed description of the regenerative consequences of subcellular component delivery from MSCs into injured renal cells during AKI, by which the potential mechanism underlying MSC-based therapies against AKI can be elucidated.

Upregulation of BCAM and its sense lncRNA BAN are associated with gastric cancer metastasis and poor prognosis.

Patients with metastatic gastric cancer (GC) have a poor prognosis; however, the molecular mechanism of GC metastasis remains unclear. Here, we employed bioinformatics to systematically screen the metastasis-associated genes and found that the levels of basal cell adhesion molecule (BCAM) were significantly increased in GC tissues from patients with metastasis, as compared to those without metastasis. The upregulation of BCAM was also significantly associated with a shorter survival time. Depletion of BCAM inhibited GC cell migration and invasion. Knockout (KO) of BCAM by the CRISPR/Cas9 system reduced the invasion and metastasis of GC cells. To explore the mechanism of BCAM upregulation, we identified a previously uncharacterized BCAM sense lncRNA that spanned from exon 6 to intron 6 of BCAM, and named it as BCAM-associated long noncoding RNA (BAN). Knockdown of BAN inhibited BCAM expression at both mRNA and protein levels. Knockdown of BAN suppressed GC cell migration and invasion, which was effectively rescued by ectopic expression of BCAM. Further clinical data showed that BAN upregulation was associated with GC metastasis and poor prognosis. Importantly, BAN expression was also significantly associated with that of BCAM in GC tissues. Taken together, these results indicate that increased expression of BCAM and its sense lncRNA BAN promote GC cell invasion and metastasis, and are associated with poor prognosis of GC patients.

Current understanding of the administration of mesenchymal stem cells in acute kidney injury to chronic kidney disease transition: a review with a focus on preclinical models.

Incomplete recovery from acute kidney injury (AKI) can result in long-term functional deficits and has been recognized as a major contributor to chronic kidney disease (CKD), which is termed the AKI-CKD transition. Currently, an effective intervention for this disorder is still lacking. Principally, therapeutic strategies targeting the AKI-CKD transition can be divided into those reducing the severity of AKI or promoting the regenerative process towards beneficially adaptive repair pathways. Considering the fact that mesenchymal stem cells (MSCs) have the potential to address both aspects, therapeutic regimens based on MSCs have a promising future. In light of this information, we focus on the currently available evidence associated with MSC therapy involved in the treatment of the AKI-CKD transition and the underlying mechanisms. All of these discussions will contribute to the establishment of a reliable therapeutic strategy for patients with this problem, who can be easily ignored by physicians, and will lead to a better clinical outcome for them.

High serum uric acid level is a mortality risk factor in peritoneal dialysis patients: a retrospective cohort study.

BACKGROUND: The results remain controversial with regards to the impact of serum uric acid on clinical outcomes from peritoneal dialysis population. The aim of our study was to investigate the influence of serum uric acid levels on mortality in peritoneal dialysis patients. METHODS: Data on 9405 peritoneal dialysis patients from the Zhejiang Renal Data system were retrospectively analyzed. All demographic and laboratory data were recorded at baseline. The study cohort was divided into quintiles according to baseline uric acid level (mg/dL): Q1 (< 6.06), Q2 (6.06-6.67), Q3 (6.68-7.27) (reference), Q4 (7.28-8.03), and Q5 (≥8.04). Hazards ratio (HR) of all-cause and cardiovascular mortality was calculated. RESULTS: Mean serum uric acid was 7.07 ± 1.25 mg/dL. During a median follow-up of 29.4 (range, 3.0 to 115.4) months, 1226 (13.0%) patients died, of which 515 (5.5%) died of cardiovascular events. The Kaplan-Meier survival curves showed that patients in the middle uric acid quintile (Q3: 6.68-7.27) exhibited the highest patient and cardiovascular survival rates (log-rank test P < 0.05). Multivariate Cox regression analysis showed that, using Q3 as the reference, in the fully adjusted model, a higher uric acid level (Q4: 7.28-8.03, and Q5: ≥8.04) was significantly associated with higher all-cause mortality (Model 3; Q4: HR, 1.335, 95% CI, 1.073 to 1.662, P = 0.009; Q5: HR, 1.482, 95% CI, 1.187 to 1.849, P = 0.001), but not with cardiovascular mortality. The adverse effect of higher uric acid level (≥7.28 mg/dL) on all-cause mortality was more prominent in groups such as male, hypoalbuminemia, normal weight, non-diabetes mellitus at baseline rather than in their counterparts respectively. CONCLUSIONS: A higher uric acid level was an independent risk factor for all-cause mortality in peritoneal dialysis patients.

Dialysate cell-free mitochondrial DNA fragments as a marker of intraperitoneal inflammation and peritoneal solute transport rate in peritoneal dialysis.

BACKGROUND: Mitochondrial DNA (mtDNA) released into extracellular subsequent to cell injury and death can promote inflammation in patients and animal models. However, the effects of peritoneal dialysate cell-free mtDNA on intraperitoneal inflammation and peritoneal solute transport rate (PSTR) in peritoneal dialysis (PD) patients remain unclear. METHODS: We select the incident patients who began PD therapy between January 1, 2009, and December 30, 2010. Peritoneal dialysate was collected at the time of peritoneal equilibration test. The cell-free mtDNA, IL-6, IL-17A, TNF-α and IFN-γ were measured. All patients were followed till December 2017. The results were compared with PSTR and patient survival. RESULTS: One hundred and eighty-nine patients were included in the study. The average age was 47.1 ± 13.5 years, 55.6% of the patients were males. The average PSTR was 0.66 ± 0.12, the median dialysate mtDNA levels were 4325 copies/ul. The median concentrations of IL-6, IL-17A, TNF-α and IFN-γ were 25.9, 10.8, 25.8 and 17.9 pg/ml, respectively. We found that dialysate mtDNA was significantly correlated with PSTR (r = 0.461, P < 0.001), IL-6 (r = 0.568, P < 0.001), TNF-α (r = 0.454, P < 0.001) and IFN-γ (r = 0.203, P = 0.005). After adjustment for multiple covariates, dialysate mtDNA levels were independently correlated with IL-6 and PSTR. Dialysate mtDNA levels were not associated with patient survival. CONCLUSIONS: We found that dialysate mtDNA levels correlated with the degree of intraperitoneal inflammatory status in PD patients. Peritoneal effluent mtDNA was an independent determinant of PSTR but did not affect patient survival.

A Fast Decline of Residual Renal Function in the First Year is a Predictor for Early Withdrawal from Peritoneal Dialysis in Non-Diabetic Patients.

BACKGROUND/AIMS: Little is known about the relationship between residual renal function (RRF) decline in early period and survival in non-diabetic peritoneal dialysis (PD) patients. METHODS: A total of 567 non-diabetic patients who began PD from January 1, 2005 to June 30, 2013 was investigated. The rate of RRF decline was determined by the "slope of the trend equation" of serial RRFs. A composite end-point of all-cause mortality and conversion to hemodialysis (HD) was used, survival status was censored on June 30, 2016. RESULTS: The median of "the slope of RRF decline equation" was 0.308 (0.001-2.111) ml/min/1.73 m2/ month. In the median follow-up period of 43 months (range 12 to 120 months), 65 (11.5%) patients died, 90 (15.9%) patients converted to HD and 171 (30.2%) patients received kidney transplantation. Multivariate linear regression showed male, high baseline RRF, high baseline peritoneal Kt/V urea, low serum albumin and low uric acid were independently associated with the rate of RRF decline in the first year of PD. Multivariate Cox models revealed that RRF decline in the first year remained a predictor for composite end-point (HR, 2.74, 95% CI, 1.53 to 4.90, P=0.001). The patients were divided into high RRF decline group (> 0.308ml/ min/1.73m2/month) and low RRF decline group (≤0.308 ml/min/1.73m2/month). In the first three years of PD, the rate of end-point events was higher in high RRF decline group (23.2%) than that in low RRF decline group (11.0%) (P< 0.001). There were 189 patients in low RRF decline group and 171 patients in high RRF decline group maintaining PD for more than 3 years, in a median follow-up of 54 months (range 37 to 120 months), the survival rate was 30.9% in high RRF decline group and 46.4% in low RRF decline group (P=0.883). In high RRF decline group, there were 92 patients reaching composited end-point and 112 patients maintaining PD; multivariate Cox model showed high peritoneal Kt/V urea after 1 year of PD and high albumin level were protective factors (HR, 0.29, 95% CI, 0.13 to 0.61, P= 0.001; HR, 0.94, 95% CI, 0.90-0.99, P=0.022, respectively), while fast RRF decline remained risk factor for composite end-point (HR, 3.28, 95% CI,1.48-7.31, P=0.004). CONCLUSION: A faster RRF decline in the first year was a predictor for all-cause mortality and conversion to HD in non-diabetic PD patients, mainly in the first three year. For patients with faster RRF decline, increasing PD dose was effective to improve survival.

Critical role of top-down processes and the push-pull mechanism in semantic single negative priming.

The present study investigated the roles of bottom-up mask-triggered inhibition and top-down inhibition in semantic categorization using the single negative priming (NP) paradigm. The masking (bottom-up) and ignore instructions (top-down, i.e., instructing participants to ignore the primes) were manipulated in Experiments 1-3 and Experiment 4, respectively. No priming was observed when only the masking was manipulated (Experiments 2 and 3), but NP was observed when a possible top-down ignore strategy (Experiment 1) or an ignore instruction (Experiment 4) was added. The results indicate that bottom-up mask-triggered inhibition cannot elicit semantic single NP by itself. However, top-down inhibition from an ignore instruction or ignore strategy is critical for triggering reliable semantic single NP. The findings suggest that semantic single NP originates from a push-pull mechanism by facilitating responses to unrelated trials and inhibiting responses to related trials. The experimental evidence also suggests that unconscious processes can be modulated by top-down control.