Search

BACKGROUND Dialysis unit blood pressure (BP) pattern showed superiority in prognostic evaluation and interdialytic BP burden assessment. However previous studies mainly focused on the recurrent BP pattern within a session (intradialytic BP change or intradialytic BP slope), the clinical value of the weekly pattern of dialysis unit BP is unknown. METHODS We performed a prospective cohort study in adult end stage renal disease (ESRD) patients on thrice weekly hemodialysis (HD). The slope and the change of the postdialysis systolic BP (SBP) in the course of a week (post-SBP slope and post-SBP change) were used to characterize the weekly pattern of dialysis unit BP. Outcomes included all-cause mortality, cardiovascular mortality, and first cardiovascular event. We also measured the home BP in our cohort. RESULTS One hundred and twenty-nine subjects were followed over a median of 31 months. Higher post-SBP slope (≥0.185) was independently associated with increased risk of all-cause mortality, cardiovascular mortality, and first cardiovascular event. Results were similar for increased post-SBP change. HD patients with a higher post-SBP slope or an increased post-SBP change also had significant increased interdialytic BP burden measured by home SBP on both dialysis days and non-dialysis days. CONCLUSIONS Post-SBP slope and post-SBP change might be promising dialysis unit BP markers for prognostic evaluation and interdialytic BP burden assessment.

Background: Cardiovascular disease (CVD) is the leading cause of death in haemodialysis (HD) patients. Vascular calcification (VC) is dramatically accelerated and is strongly associated with CVD events and mortality in HD patients. VC coexists with osteoporosis in many studies. Fibroblast growth factor 21 (FGF21) as an adipocytokines is a new hypoglycemic strategy and is inversely related to bone mineral density.Methods: To evaluate the contribution of FGF21 to VC in HD patients, we preliminary sreened 802 HD patients of two large HD centers in China. At last 388 HD patients were entered this cross-sectional study. We detected circulating FGF21 levels and measured the whole thoracic aorta calcification scores (TACS) and calcification scores of the three segments of thoracic aorta (TA), including ascending thoracic aorta (ATACS), aortic arch (AoACS), and descending thoracic aorta (DTACS) of our 388 HD patients. In addition, we pre-incubated human aortic endothelial cells (HAECs) with FGF21 in the presence or absence of parathyroid hormone (PTH) in vitro.Results: The median serum FGF21 level in HD patients was 11-fold higher than that in healthy controls. Ln(FGF21) was positively correlated with Ln(TACS+1), Ln(ATACS+1), Ln(AoACS+1) and Ln(DTACS+1) respectively in HD patients. Serum FGF21 was independently associated with TACS and ATACS, AoACS, and DTACS. FGF21 combined with age, calcium and intact parathyroid hormone demonstrated a high area under the curve (AUC=0.84) with optimal sensitivity (84%) and specificity (71%) for the prediction of VC in HD patients. Our vitro results showed that FGF21 enhanced the calcification effect of PTH on HAECs by increasing calcium deposition and endothelial-to-mesenchymal transition (EndMT).Conclusions: Circulating FGF21 was notably higher and was a potential predictor and promoter of VC in HD patients.Trial registration Chinese Clinical Trial Registry, identifier: ChiCTR1900028249. Registered 16 December 2019-Retrospectively registered,http://www.medresman.org.cn/uc/project/projectedit.aspx?proj=5981

Muscle wasting is associated with increased mortality and morbidity in chronic kidney disease (CKD) patients, especially in the haemodialysis (HD) population. Nevertheless, little is known regarding diaphragm dysfunction in HD patients. We conducted a cross-sectional study at the Institute of Nephrology, Southeast University, involving 103 HD patients and 103 healthy volunteers as normal control. Ultrasonography was used to evaluate diaphragmatic function, including diaphragm thickness and excursion during quiet and deep breathing. HD patients showed lower end-inspiration thickness of the diaphragm at total lung capacity (0.386 ± 0.144 cm vs. 0.439 ± 0.134 cm, p

AIM Lipoprotein(a) [Lp(a)] is considered a risk factor for cardiovascular disease. However, the role of Lp(a) in chronic kidney disease (CKD) patients is not well understood. The aim of this study was to evaluate the association between Lp(a) levels and the presence of coronary artery disease (CAD) and the severity of coronary artery stenosis (CAS) in patients with stage 3-5 CKD. PATIENTS AND METHODS We retrospectively studied patients who were diagnosed with stage 3-5 CKD and underwent coronary artery angiography in Zhongda Hospital. The Gensini scoring system was used to assess the severity of coronary stenosis. RESULTS A total of 1003 patients were enrolled in this cross-sectional study, and 776 of these patients were diagnosed with CAD. The Lp(a) levels were significantly higher in the CAD group than the non-CAD group [271.50 (168.00-459.25) vs. 195.00 (131.00-347.00) mg/l, P

Introduction Osteoporosis is one of the important bone abnormalities in chronic kidney disease-mineral and bone disorder (CKD-MBD) and still lacks a sensitive biomarker to diagnose. Fibroblast growth factor 21 (FGF21) can stimulate bone loss in patients with diabetes and increase in CKD patients. In this study, we investigated whether FGF21 could serve as a biomarker to predict osteoporosis in a haemodialysis cohort. Methods We recorded demographic information, biochemical data, and serum FGF21 and FGF23 levels and measured the CT attenuation values of 339 haemodialysis patients from two large medical centres. We assessed the correlation of CT attenuation values with serum FGF21 and FGF23 levels and tested whether they were independent factors for osteoporosis. ROC curves were constructed to compare the prognostic value of FGF21 and FGF23 for osteoporosis. Results Based on the CT attenuation value, serum FGF21 levels were higher in our osteoporosis group (median 640.86 pg/ml vs. 245.46 pg/ml, P ˂ 0.01). Meanwhile, FGF21 (r = -0.136, P r = -0.151, P β = -0.067, P Conclusions FGF21 has a positive relationship with the incidence of osteoporosis in patients on haemodialysis. FGF21 combined with age is a good predictive biomarker for osteoporosis in patients on haemodialysis, especially those with less residual renal function.

Blood pressure (BP) management posed great challenge in hemodialysis (HD) population. We conducted a dose-response meta-analysis to investigate the quantitative features and the potential threshold effect of the associations between peridialysis BP levels and all-cause mortality risk in HD population. We searched all of the prospective cohort studies (published before 18 March 2017) on the associations between peridialysis BP levels and all-cause mortality risk. A total of 229,688 prevalent HD patients from 8 studies were included. Significant non-linear associations were noted between peridialytic BP levels and all-cause mortality risk. Significant increased risk of death was found in four peridialysis BP ranges, that is, low levels of predialysis SBP (135 mmHg, 140 mmHg as the reference), two extremes of predialysis DBP (55 and95 mmHg, 90 mmHg as the reference), high levels of postdialysis SBP (180 mmHg, 130 mmHg as the reference), and low levels of postdialysis DBP (75 mmHg, 80 mmHg as the reference). Threshold effect was determined in the associations between peridialysis BP and all-cause mortality risk, and potential BP thresholds were identified (149 mmHg for predialysis SBP, 79 mmHg for predialysis DBP, 147 mmHg for postdialysis SBP and 76 mmHg for postdialysis DBP). In conclusion, the proposed peridialysis BP ranges and the threshold values could help clinicians identify high risk HD patients. The interpretation of the peridialysis BP mortality associations should be based on the features of HD population (especially the cardiovascular conditions, volume status and the dialysis vintage).

Background: Muscle wasting is associated with increased mortality and morbidity in chronic kidney disease (CKD) patients, especially in the haemodialysis (HD) population. Little is known regarding diaphragmatic dysfunction under CKD conditions. Methods: We conducted a cross-sectional study at the Institute of Nephrology, Southeast University, involving 103 HD patients and 103 healthy volunteers as normal control. Ultrasonography was used to evaluate diaphragmatic function, including diaphragm thickness and excursion. We further examined the prevalence of diaphragmatic dysfunction and its influence factor and relationship with debilitating symptoms (dyspnoea, hiccups, and fatigue) in HD patients. Results: HD patients showed lower end-inspiration thickness of the diaphragm at total lung capacity and thickening fraction compared to controls. The velocity and excursion of the diaphragm were significantly lower in the HD patients during deep breathing. Changes in diaphragm displacement from quiet breathing to deep breathing (△m) were lower in HD patients than in controls. After multivariate adjustment, hemoglobin level may have effects on diaphragmatic functions such as diaphragm excursion at total lung capacity (DMTLC) and △m. Diaphragm thickness during deep breathing was positively correlated with weight and was greater in males than in females. We also found that the incidence of dyspnoea and snoring and the fatigue scores, all of which were related to diaphragmatic dysfunction, were significantly higher in HD patients than in controls (all p < 0.01). In addition, diaphragmatic dysfunction was confirmed in a CKD mouse model. Conclusions: Improving diaphragm function through targeted therapies may positively impact clinical outcomes in HD patients. Trial Registration Information: Chinese Clinical Trials Registry, 2018ZDKYSB167. Retrospectively registered on May 18, 2018. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (81700618), the Natural Science Foundation of Jiangsu Province (BK20181487), the China Young Nephrologist Research Project, and a Southeast University High Level Thesis Project to Bin Wang. It was supported by additional grants from the National Natural Science Foundation of China (81720108007, 81470922, 31671194, 81720108007, and 81670696), the National Key Research Programme (2018YFC130046, 2018YFC1314000) and the Clinic Research Center of Jiangsu Province (BL2014080) to Bi-cheng Liu. Declaration of Interests: None of the authors has any conflict of interest to declare. Ethics Approval Statement: The study protocol was approved by the Ethics Committee of Zhongda Hospital affiliated to Southeast University. The details of the study were explained to each patient; if he or she agreed to participate, a written informed consent was signed.

Age is an independent risk factor for acute kidney injury (AKI). The causes and outcomes of AKI in children, middle-aged, and older patients are different. The objective of this country-based study was to identify the characteristics and mortality factors for AKI in different age groups in China.Using data from 374,286 adult patients (≥18 years) admitted to 44 study hospitals, we investigated the characteristics and mortality risk factors for AKI in four different age groups: 18-39 years of age, 40-59 years of age, 60-79 years of age, and ≥80 years of age. The identification criteria for AKI included the 2012 KDIGO AKI definition and an expanded criterion.The country-based survey included 7604 AKI patients (7604/374,286, 2.03%). The proportions of AKI in the four age groups were 11.52%, 30.79%, 41.03%, and 16.66%, respectively. In any age group, the patients with AKI stage 1 were the majority (43.4%, 42.4%, 46.4%, and 52.2%, respectively), and the most common classification of AKI was pre-renal AKI (44.3%, 51.3%, 52.3%, and 56.4%, respectively). The higher AKI peak stage occurred for the in-hospital mortality factors for AKI in all age groups; except for the AKI stage 2 patients in the 18-39 age group.The characteristics and mortality factors for AKI vary by age in China. Elderly patients were the primary population with AKI, and the most common type of AKI was pre-renal AKI. Special caution should be taken to the old population in hospitalized patients to prevent the pre-renal AKI.

Experimental studies found that cinacalcet (CINA) markedly attenuated vascular calcification in uremic rats, but its underlying mechanisms are still largely unknown. Recent evidence have demonstrated that endothelial cells (ECs) participate in ectopic calcification in part by mediating endothelial-to-mesenchymal transition (EndMT). In this study, we investigated whether CINA ameliorated aortic calcification in uremic rats via suppression of EndMT. Uremia was induced in rats by feeding rats a 0.75% adenine diet for 4 weeks. After adenine withdrawal, the rats were maintained on a 1.03% phosphorus diet for next 8 weeks. At initiation of the adenine diet, rats were orally administered CINA (10mg/kg one day) for 12 weeks. The aortic expression of EndMT- and chondrocyte- markers was examined. The effect of elevated PTH on EndMT was also studied in aortic ECs. In uremic rats, CINA treatment significantly decreased the serum PTH concentrations, but did not affect the elevated levels of serum calcium (Ca), phosphorus (P) and Ca×P product. Besides, CINA significantly attenuated aortic calcification, and inhibited the expression of chondrocyte markers (SOX9 and COL2A1) and chondrocyte proteoglycan in uremic aortas. Moreover, CINA treatment largely abolished the up-regulation of mesenchymal markers (FSP1 and α-SMA) and down-regulation of the endothelial marker (CD31), which accompanied aortic calcification in uremic aorta samples. In vitro, PTH increased the expression of EndMT-markers in a concentration- and time-dependent manner. These findings suggest that strategies aiming at reducing serum PTH might prevent uremic aortic calcification by abrogating EndMT.

The objective of this study was to determine whether the baseline estimated glomerular filtration rate (eGFR) level was independently associated with in-hospital mortality in generalized patients with hospital-acquired acute kidney injury (HA-AKI) in China. All of the patients admitted to a tertiary medical center of Nanjing, China, between January 1, 2013, and December 31, 2013, were involved. Through the use of an electronic database and the Acute Kidney Injury Network (AKIN) classification, the patients with HA-AKI were indentified. We included the hospitalized adult patients with HA-AKI. Epidemiological information and in-hospital outcomes were collected and were analyzed according to different baseline eGFR strata of the included individual patients. Of the 42,664 admissions during the study period, 1327 patients were identified as AKI. The incidence of HA-AKI was 3.1 %. HA-AKI patients with a compromised baseline eGFR tended to be older and had a higher prevalence of various comorbid conditions. With the gradual deterioration of the baseline eGFR, the odds ratio of in-hospital mortality increased incrementally and a graded independent association between the baseline eGFR and in-hospital mortality was observed when the baseline eGFR dropped below 60 ml/min per 1.73 m2. Baseline eGFR was a potential risk factor for in-hospital mortality in HA-AKI. Serum Creatinine (SCr)-based definition of AKI needs to incorporate baseline eGFR to optimize or refine risk stratification.

Cardiac fibrosis is a common feature in patients with chronic kidney disease (CKD). Increasing evidence has shown that elevated parathyroid hormone (PTH) is causally involved in cardiac fibrosis [1–4]. Cinacalcet (CINA), a calcimimetic agent, reduces PTH levels without increasing circulating levels of calcium and phosphorus [5,6]. Recent studies have shown that CINA treatment markedly attenuated myocardial fibrosis and vascular remodeling [6,7]. However, the underlying mechanisms of this action are still unknown. Endothelial-to-mesenchymal transition (EndMT) plays an important role in the development of cardiac fibrosis [8,9]. The purpose of this study was to investigate whether CINA ameliorated cardiac fibrosis in rats with uremia was mediated by suppression of EndMT. Study protocols were approved by the Ethical Committee of Southeast University. The rat model of uremia and secondary hyperparathyroidism was established as previously described [10]. Briefly, 8-week-old male Wistar rats were randomly divided into three groups: the control group (CTL, n = 6), the uremia group (U, n = 8) and the CINA-treated uremia group (U + CINA, n = 8). Uremia was induced by feeding rats a 0.75% adenine diet for 4 weeks. After adenine withdrawal, all animals were maintained on a 1.03% phosphorus diet for next 8 weeks. At initiation of the adenine diet, rats in the U + CINA group were orally treated with CINA (Santa Cruz Biotechnology, USA) once daily (10 mg/kg) until the end of experiment. The effect of elevated PTH on EndMT was also studied in primary aortic endothelial cells (ECs). It was demonstrated that the area of cardiac fibrosis in the U group was significantly increased compared to controls, and it was significantly attenuated by the administration of CINA (Fig. 1A–B). And CINA also inhibited the expression of the extracellular matrix elements type I collagen and fibronectin in uremic hearts (Fig. 1C–E). Furthermore, there was significant up-regulation of mesenchymal markers FSP1 and α-SMA, and down-regulation of the endothelial marker CD31, while CINA markedly abrogated expression of EndMT-associated markers in uremic hearts (Fig. 2). Compared with the U group, serum PTH concentrations were significantly lower in uremic rats treated with CINA (440.64 ± 43.25 vs 326.54 ± 47.86, p < 0.05). To further confirm the causal effect of elevated PTH on induction of EndMT, an in vitro experiment with primary aortic ECs was performed. The results showed that PTH incubation increased expression of FSP1 and α-SMA and decreased expression of CD31 at mRNA and protein levels in a concentration and time dependent manner (p < 0.05). Fig. 1 Effect of CINA on fibrotic lesions in uremic hearts. (A) Cardiac fibrosis was assessed by Masson’s trichrome staining. Images with different magnifications are shown. (B) Quantitative determination of cardiac fibrosis in the different groups. ... Fig. 2 Effect of CINA on the expression of EndMT-related markers in uremic hearts. (A) Representative micrographs showing immunohistochemical staining for cardiac expression of CD31 and FSP1 (original magnification is ×200). (B) Representative micrographs ... In conclusion, our data demonstrated that elevation of PTH induces EndMT and contributes to cardiac fibrosis in uremic rats, which could be prevented by CINA treatment. These results suggest that strategies aiming at lowering PTH levels might exert cardiac protective effects through an anti-EndMT mechanism.

Aims Podocyte injury plays an important role in the pathogenesis of kidney disease. Urinary exosomes are microvesicles released by tubular epithelial cells and podocytes containing information of their originated cells. This study investigated for the first time whether podocyte related mRNA in urinary exosome could serve as novel biomarkers for kidney disease. Methods Urine samples were collected from 32 patients of kidney disease who underwent kidney biopsy and 7 controls. CD2AP, NPHS2 and synaptopodin were detected by real-time RT-PCR on RNA isolated from urinary exosome. Results The pellet microvesicles were positively stained with exosome and podocyte marker, AQP2, CD9 and nephrin. CD2AP mRNA was lower (p = 0.008) in kidney disease patients compared with controls and decreased with the increasing severity of proteinuria (p = 0.06). CD2AP correlated with serum creatinine (r = − 0.373, p = 0.035), BUN (r = − 0.445, p = 0.009) and eGFR (r = 0.351, p = 0.046). Neither NPHS2 nor synaptopodin correlated with parameters of renal function. CD2AP mRNA correlated negatively with 24 hour urine protein (r = − 0.403, p = 0.022), severity of tubulointerstitial fibrosis (r = − 0.394, p = 0.026) and glomerulosclerosis (r = − 0.389, p = 0.031) and could discriminate kidney disease from controls with AUC of 0.821 (p = 0.008). Conclusions Urinary exosome mRNA of CD2AP might be a non-invasive tool for detecting both renal function and fibrosis of kidney disease.

Nerve growth factor (NGF), a member of the neurotrophin family, is essential for the development and maintenance of sensory neurons and for the formation of central pain circuitry. The current study was designed to evaluate the expression of NGF in the brain of rats with spared nerve injury (SNI), using immunohistochemical technique. The results showed that the level of NGF in the Red nucleus (RN) of SNI rats was apparently higher than that of sham-operated rats. To further study the effect of NGF in the development of neuropathic pain, different doses of anti-NGF antibody (20, 2.0 and 0.2 microg/ml) were microinjected into the RN contralateral to the nerve injury side of SNI rats. The data suggested that the higher doses of anti-NGF antibody (20 and 2.0 microg/ml) significantly attenuated the mechanical allodynia of neuropathic rats, while the 0.2 microg/ml antibody showed no analgesic effect. These results suggest that the NGF of RN is involved in the development of neuropathic allodynia in SNI rats.

Background Adverse outcome of chronic kidney disease, such as end stage renal disease, is a significant burden on personal health and healthcare costs. Urinary tubular injury markers, such as NGAL, KIM-1 and NAG, could provide useful prognostic value for the early identification of high-risk patients. However, discrepancies between recent large prospective studies have resulted in controversy regarding the potential clinical value of these markers. Therefore, we conducted the first meta-analysis to provide a more persuasive argument to this debate. Methods In the current meta-analysis, based on ten prospective studies involving 29366 participants, we evaluated the role of urinary tubular injury markers (NGAL, KIM-1 and NAG) in predicting clinical outcomes including CKD stage 3, end stage renal disease and mortality. The prognostic values of these biomarkers were estimated using relative risks and 95% confidence interval in adjusted models. All risk estimates were normalized to those of 1 standard deviation increase in log-scale concentrations to minimize heterogeneity. Fixed-effects models were adopted to combine risk estimates. The quality of the research and between-study heterogeneity were evaluated. The level of research evidence was identified according to the GRADE profiler. Results uNGAL was identified as an independent risk predictor of ESRD (pooled adjusted relative risk: 1.40[1.21 to 1.61], p

Elevated serum parathyroid hormone (PTH) is an important complicated phenomenon in patients with chronic kidney disease (CKD). Emerging evidence indicates the involvement of PTH in organ fibrosis, and suppression of PTH by cinacalcet (CINA) ameliorates the progression of fibrotic disorders. However, the underlying mechanisms are largely unknown. The endothelial-to-mesenchymal transition (EndMT) has been shown to be an important mechanism involved in renal fibrosis. The present study aimed to investigate whether CINA treatment attenuated renal EndMT in rats with adenine-induced chronic renal failure (CRF). Compared with the control group, serum PTH was significantly higher in the CRF group and was suppressed after CINA treatment. Serum calcium, phosphorus, and calcium × phosphorus product levels were similar in the CRF group and CINA-treated CRF group. Renal collagen accumulation was significantly increased in the CRF group, which was markedly ameliorated by CINA treatment. Expression of the endothelial marker CD31 was significantly downregulated in rats with CRF, whereas expression of the mesenchymal markers fibroblast specific-protein 1 and α-smooth muscle actin was markedly upregulated. These changes were inhibited by CINA treatment. The protein levels of these EndMT-related markers were strongly correlated with serum PTH concentrations. Furthermore, the in vitro study showed that PTH could significantly increase the expression of fibroblast specific-protein 1 and α-smooth muscle actin and decrease CD31 in mRNA and protein levels in a concentration- and time-dependent manner. In conclusion, our study suggests that reducing serum PTH by CINA treatment could attenuate renal fibrosis via suppression of EndMT in the adenine-induced CRF rat model.

Tubulointerstitial fibrosis is a common pathway that leads to kidney failure, and persistent tubulointerstitial inflammation is a key event in the development of tubulointerstitial fibrosis. The new immunosuppressive drug FTY720 modifies lymphocyte migration into injured tissues by sequestering lymphocytes within secondary lymphoid organs. However, its therapeutic effect on tubulointerstitial inflammation and fibrosis had not been well understood. This study was designed to explore the effect of FTY720 on tubulointerstitial inflammation and fibrosis in subtotally nephrectomized (SNX) rats. In total, 24 male Sprague-Dawley rats were used. Seven days after 5/6 nephrectomy, rats were randomized to FTY720 (1 mg/kg/d) and placebo-treated groups. Sham-operated rats served as controls. FTY720 significantly attenuated the rise in proteinuria, serum creatinine, urea nitrogen and N-acetyl-β-D-glucosaminidase activity in SNX rats, and reduced the count of peripheral white blood cells and lymphocytes in SNX rats. Morphological analysis revealed that there was severe tubulointerstitial inflammation and fibrosis in SNX group and much more tubulointerstitial infiltrating inflammatory cells with high expression of CD3, CD4, CD8, CD20, CD68, CD163 and CCR-7 in SNX group, as compared with the controls, but the lesions were attenuated significantly by treatment with FTY720. Furthermore, the expressions of proinflammatory molecules (IL-6, TNF-α and MCP-1), profibrotic molecule (TGF-β1) and production of extracellular matrix proteins such as fibronectin and types I and III collagens were upregulated in SNX rats. FTY720 administration significantly reduced these abnormalities. In summary, FTY720 exerts therapeutic effects on tubulointerstitial fibrosis in SNX rats by inhibiting the tubulointerstitial inflammatory response.

Recent studies have shown that chronic endothelial dysfunction can impair multiple aspects of renal physiology and, in turn, contribute to renal fibrosis. Sphingosine 1-phosphate (S1P) has been highlighted as an endothelial barrier-stabilizing mediator. The aim of our study was to investigate the effect of FTY720, an S1P analog, on the progression of renal fibrosis by inhibiting renal microvasculature endothelial dysfunction in a rat model of chronic kidney disease. Thirty male Sprague–Dawley rats were used in this study. Seven days after surgery, we placed the animals into three groups: sham surgery; 5/6 nephrectomized (Nx) rats; and 5/6Nx + FTY720 (1 mg/kg/day). All of the animals were sacrificed 12 weeks after surgery. We obtained and analyzed blood and kidney tissue samples from all of the groups. Glomerular capillary density and peritubular capillary (PTC) density were determined by CD31 immunostaining. The expression of transforming growth factor beta 1 (TGF-β1), collagen IV, fibronectin, endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) were analyzed by immunohistochemistry, reverse transcription-polymerase chain reaction and western blotting. The 5/6Nx group exhibited increased blood urea nitrogen and serum creatinine, visible renal histological changes, pro-fibrotic molecule (TGF-β1) and production of extracellular matrix proteins such as collagen IV and fibronectin and decreased glomerular and PTC density, compared to the sham controls (P < 0.01). We observed that treatment with FTY720 reduced these abnormalities. Furthermore, the level of NO, the expression levels of eNOS and VEGF were downregulated in the kidney tissue in 5/6Nx rats, FTY720 treatment significantly attenuated this decrease. FTY720 prevents the progression of renal fibrosis by inhibiting renal microvasculature endothelial dysfunction in a rat model of chronic kidney disease.

The present study aimed to investigate the effects of Cordyceps sinensis on renal fibrosis and its possible mechanisms. Sprague-Dawley rats were randomly divided into three groups: sham operation (SHAM) group, 5/6 subtotal nephrectomy (SNx) untreated group, and 5/6 subtotal nephrectomy treated with C. sinensis (2.0 g/kg d) (CS) group. Rats were studied 12 weeks after the surgery, and the CS group presented with significantly lower proteinuria, and better renal function compared with the SNx group (p0.05). Pathological study showed that the glomerulosclerosis tubulointerstitial injury score was significantly reduced in the CS group compared with the SNx group. Furthermore, the mRNA expression of TGF-β1, Smad2 and Smad3 and the protein expression of TGF-β1, TβRI, TβRII and p-Smad2/3 were attenuated by the C. sinensis treatment. In constrast, the mRNA and protein expression of Smad7 was upregulated. Furthermore, the expression of α-SMA and FSP1 was also significantly attenuated, accompanied by the increasing expression of E-cadherin, suggesting the inhibition of the epithelial-mesenchymal transition (EMT).C. sinensis exerted its antifibrotic effect on the SNx rats through the inhibition of the TGF-β1/Smad pathway.

Tubulointerstitial macrophage infiltration is a hallmark of chronic kidney disease involved in the progression of renal fibrosis. Pirfenidone is a newly identified antifibrotic drug, the potential mechanism of which remains unclear. The aim of this study was to investigate the effects of pirfenidone on M1/M2 macrophage infiltration in nephrectomized rats. Nephrectomized rats were treated with pirfenidone by gavage for 12 wk. Twenty-four hour urinary protein, N-acetyl-β-d-glycosaminidase (NAG) activity, systolic blood pressure, and C-reactive protein were determined. Paraffin-embedded sections were stained for CD68, CCR7, and CD163 macrophages. Monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α), as well as M1 and M2 macrophages secretory markers, were evaluated by real-time RT-PCR and Western blotting analysis. Pirfenidone significantly improved the elevated proteinuria and NAG activity from week 2 onward after surgery. Pirfenidone attenuated interstitial fibrosis and decreased expression of fibrotic markers including transforming growth factor-β1, connective tissue growth factor, α-smooth muscle actin, fibronectin, and fibroblast-specific protein-1. Pirfenidone significantly decreased the infiltrating macrophages. The number of M1 and M2 macrophages was significantly lower after pirfenidone treatment. MCP-1 and MIP-1α were increased in nephrectomized rats at mRNA and protein levels. Pirfenidone treatment significantly inhibited their expression. The TNF-α, IL-6, and nitric oxide synthases-2 expressed by M1 macrophages were increased in nephrectomized rats, and pirfenidone significantly attenuated their expression. Pirfenidone treatment also significantly decreased arginase-1, dectin-1, CD206, and CD86 expressed by M2 macrophages. Thus pirfenidone inhibits M1 and M2 macrophage infiltration in 5/6 nephrectomized rats, which suggests its efficacy in the early and late periods of renal fibrosis.