Tumour necrosis factor soluble receptors I and II and interleukin-1 receptor antagonist in acute pyelonephritis in relation to bacterial virulence-associated traits and renal function

Urinary tract infections activate both mucosal and systemicinflammatory responses reflected by elevation of cytokine concentrationsin serum and urine. We determined urine and serum concentrationsof tumour necrosis factor soluble receptors I and II (sTNFRI and sTNFR II) and interleukin-1 receptor antagonist (IL-1ra)in 41 women with acute pyelonephritis caused by Escherichiacoli, 2 weeks after the infection, during a subsequent episodeof cystitis or asymptomatic bacteriuria and also later whenthe same patients were free from bacteriuria. Concentrationsof sTNFR I, sTNFR II and IL-1ra were related to the expressionof five virulence markers of E. coli, glomerular filtrationrate (GFR) and to the concentration of C-reactive protein (CRP)in serum. Patients with acute pyelonephritis had elevated serumconcentrations of sTNFR I and sTNFR II compared to healthy women(P<0.001 for both comparisons). The concentrations of sTNFRI and sTNFR II in urine were significantly higher in patientswith acute pyelonephritis compared to controls (P<0.001 inboth cases). The concentration of sTNFR II in urine was higherin patients infected by E. coli producing haemolysin (P=0.05)and in patients infected by E. coli expressing hydrophobic properties(P=0.05) compared to patients infected by strains without thesevirulence traits. Patients who had high concentrations of sTNFRII in serum during acute pyelonephritis had lower GFR at follow-up(r=–0.48, P=0.05). Patients who responded with a markedincrease in CRP had higher sTNFR I and sTNFR II in urine (r=0.58,P<0.01 and r=0.48, P<0.01, respectively). The concentrationsof sTNFR I and sTNFR II in serum and urine decreased duringfollow-up and were lower 2 weeks after the infection when allpatients were free from bacteriuria. IL-1ra in serum was elevatedduring pyelonephritis (P<0.001) while that in urine was significantlylower compared to controls (P<0.001). It is concluded thatthe     

A profile of multiple circulating tumor necrosis factor receptors associated with early progressive kidney decline in Type 1 Diabetes is similar to profiles in autoimmune disorders

1. Download : Download high-res image (406KB)
2. Download : Download full-size image

     

Circulating Angiopoietin‐2 levels predict mortality in kidney transplant recipients: a 4‐year prospective case–cohort study

Angiopoietin 2 (Angpt2) impairs endothelial function by preventing angiopoietin 1 from binding to their common endothelial‐specific receptor Tie2. Here, we examined whether circulating Angpt2 predicts outcome in kidney transplant recipients. For this case–cohort study, we selected 130 kidney transplant recipients who had died or returned to dialysis within the first 2 years of follow‐up of our cohort study, as well as 130 age‐ and gender‐matched kidney transplant recipients without an event (controls) from a total of 993 kidney transplant recipients. The total of 260 selected patients were followed in median 4 years. Serum Angpt2 at baseline was measured using an in‐house immunoluminometric assay. Median Angpt2 concentrations were significantly higher in patients who died [median (interquartile range – IQR) 3.6 (2.8–5.9) ng/ml] as compared to patients who did not die during the study period [2.8 (2.1–4.1) ng/ml; P < 0.001]. Ln (natural log) Angpt2 levels correlated positively with C‐reactive protein levels (r = 0.315, P < 0.001) and the Charlson Comorbidity Index (r = 0.188, P = 0.002) and were inversely associated with eGFR (r = ?0.301, P < 0.001) hemoglobin (r = ?0.269, P < 0.001), and serum albumin concentrations (r = ‐0.382, P < 0.001). On multivariate analyses, baseline Angpt2 levels independently predicted all‐cause mortality (multivariable‐adjusted hazard ratio associated with one natural log unit higher Angpt2 level: 1.70 (95% confidence interval: 1.10–2.61)). In our analysis, circulating Angpt2 was an independent predictor of all‐cause mortality in stable, prevalent kidney transplant recipients.     

Altered kidney function induced by SARS-CoV-2 infection and acute kidney damage markers predict survival outcomes of COVID-19 patients: a prospective pilot study

BackgroundLiterature with regard to coronavirus disease 2019 (COVID-19) associated morbidities and the risk factors for death are still emerging. In this study, we investigated the presence of kidney damage markers and their predictive value for survival among hospitalized subjects with COVID-19.MethodsForty-seven participants was included and grouped as: ‘COVID-19 patients before treatment’, ‘COVID-19 patients after treatment’, ‘COVID-19 patients under treatment in intensive care unit (ICU)’, and ‘controls’. Kidney function tests and several kidney injury biomarkers were compared between the groups. Cumulative rates of death from COVID-19 were determined using the Kaplan–Meier method. The associations between covariates including kidney injury markers and death from COVID-19 were examined, as well.ResultsSerum creatinine and cystatin C levels, urine Kidney Injury Molecule-1 (KIM-1)/creatinine ratio, and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), CKD-EPI cystatin C, and CKD-EPI creatinine–cystatin C levels demonstrated significant difference among the groups. The most significant difference was noted between the groups ‘COVID-19 patients before treatment’ and ‘COVID-19 patients under treatment in ICU’. Advancing age, proteinuria, elevated serum cystatin C, and urine KIM-1/creatinine ratio were all significant univariate correlates of death (p < 0.05, for all). However, only elevated urine KIM-1/creatinine ratio retained significance in an age, sex, and comorbidities adjusted multivariable Cox regression (OR 6.11; 95% CI: 1.22–30.53; p = 0.02), whereas serum cystatin C showing only a statistically non-significant trend (OR 1.42; 95% CI: 0.00–2.52; p = 0.09).ConclusionsOur findings clearly demonstrated the acute kidney injury related to COVID-19. Moreover, urine KIM-1/creatinine ratio was associated with COVID-19 specific death.     

Combined interleukin 1 and tumour necrosis factor α blockade in rat crescentic anti-glomerular basement membrane glomerulonephritis

SUMMARY: Studies in experimental models have established that blockade of either interleukin 1 (IL‐1) or tumour necrosis factor α (TNF‐α) is effective in suppressing crescentic glomerulonephritis. However, it is not known whether simultaneous blockade of both cytokines will provide additional disease suppression compared with that produced by single cytokine blockade. We have addressed this question in a study of accelerated crescentic anti‐glomerular basement membrane (GBM) glomerulonephritis in the rat. Groups of six animals were treated with an IL‐1 receptor antagonist (IL‐1ra), TNF‐α‐binding protein (TNFbp), IL‐1ra + TNFbp (combined) or saline (control) from the time of anti‐GBM serum injection until being killed, 10 days later. Saline‐treated animals developed crescentic glomerulonephritis with tubulointerstitial damage, heavy proteinuria and renal impairment. Compared with saline, treatment with either IL‐1ra or TNFbp alone resulted in significant suppression of crescent formation (3.0% and 3.3%, respectively, vs. 21.0%; both P < 0.001 vs. control), tubulointerstitial leucocytic infiltration (262 ± 31 and 282 ± 32 cells/mm² vs. 481 ± 71 cells/mm²; both P < 0.001 vs. control) and proteinuria (167 ± 44 and 164 ± 23 mg/24 h vs. 279 ± 36 mg/24 h; both P < 0.001 vs. control) and prevented the loss of renal function. Combined IL‐1ra and TNFbp treatment resulted in a virtually identical degree of disease suppression as individual cytokine blockade in terms of crescent formation (2.7%), interstitial leucocytic infiltration (274 ± 45 cells/mm²), proteinuria (190 ± 18 mg/24 h) and renal function preservation. In conclusion, this study has demonstrated that blockade of either IL‐1 or TNF‐α alone substantial suppresses experimental crescentic glomerulonephritis to a similar extent to that achieved by simultaneous blockade of both cytokines. These findings provide a rationale for the use of cytokine monotherapy, rather than multiple cytokine blockade, in the treatment of human crescentic glomerulonephritis.     

A prospective cohort study of acute kidney injury and kidney outcomes,cardiovascular events,and death

1. Download : Download high-res image (369KB)
2. Download : Download full-size image

     

Association between polymorphism of tumour necrosis factor alpha-308 gene promoter and asthma: a meta-analysis

BACKGROUND: Asthma is a complex polygenic disease in which gene-environment interactions are important. The gene encoding tumour necrosis factor alpha (TNFalpha) is one of several candidate loci for asthma pathogenesis and is highly polymorphic. A number of studies have investigated the polymorphism of TNFalpha-308 gene promoter (substitution G-->A, designated as TNF1 and TNF2) in relation to asthma susceptibility in different populations. However, the results of individual studies have been inconsistent. METHODS: To address the inconsistent findings in studies of the association of the polymorphism of TNFalpha-308 gene promoter with susceptibility to asthma, a systematic review was undertaken of the published data and a meta-analysis was performed. The MEDLINE database was searched for case-control studies published in English language journals from 1966 to October 2005. Data were extracted using standardised forms and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: Fifteen eligible studies, comprising 2409 patients with asthma and 3266 controls, were included in the meta-analysis. Using the random effects model, the pooled result showed that the TNF2 allele is associated with overall susceptibility to asthma (OR 1.37, 95% CI 1.02 to 1.84, p=0.04). The ORs for asthma susceptibility in TNF2 homozygote individuals were significantly increased at 2.01 (95% CI 1.26 to 3.20, p=0.009) and 1.51 (95% CI 1.02 to 2.22, p=0.041) compared with TNF1 homozygotes and TNF2/1 heterozygotes, respectively. In addition, the pooled OR for asthma risk in TNF2/1 heterozygotes was also significantly higher than that in TNF1/1 homozygotes (OR 1.47, 95% CI 1.01 to 2.13, p=0.045). CONCLUSIONS: The TNF2 allele confers a significant risk for developing asthma. A large scale case-control study is needed to clarify the functional effect of the polymorphism of the TNFalpha gene in the pathogenesis of asthma.     

Association between peri‐operative angiotensin‐converting enzyme inhibitors and angiotensin‐2 receptor blockers and acute kidney injury in major elective non‐cardiac surgery: a multicentre,prospective cohort study

The peri‐operative use of angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers is thought to be associated with an increased risk of postoperative acute kidney injury. To reduce this risk, these agents are commonly withheld during the peri‐operative period. This study aimed to investigate if withholding angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers peri‐operatively reduces the risk of acute kidney injury following major non‐cardiac surgery. Patients undergoing elective major surgery on the gastrointestinal tract and/or the liver were eligible for inclusion in this prospective study. The primary outcome was the development of acute kidney injury within seven days of operation. Adjusted multi‐level models were used to account for centre‐level effects and propensity score matching was used to reduce the effects of selection bias between treatment groups. A total of 949 patients were included from 160 centres across the UK and Republic of Ireland. From this population, 573 (60.4%) patients had their angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers withheld during the peri‐operative period. One hundred and seventy‐five (18.4%) patients developed acute kidney injury; there was no difference in the incidence of acute kidney injury between patients who had their angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers continued or withheld (107 (18.7%) vs. 68 (18.1%), respectively; p = 0.914). Following propensity matching, withholding angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers did not demonstrate a protective effect against the development of postoperative acute kidney injury (OR (95%CI) 0.89 (0.58–1.34); p = 0.567).     

Concomitant treatment of MBT-2 bladder tumour by tumour necrosis factor alpha and interferon alpha in conjunction with delayed type hypersensitivity immunotherapy

Summary In our previous study [9], we reported the anti-tumour effect of TNF on mouse bladder tumour (MBT-2) both in vivo and in vitro. Inoculation of a single dose of TNF alone caused significant but transient tumour growth inhibition. Subsequent repeated doses of TNF did not sustain or augment the antitumour effect. The current experiments were undertaken to assess the anti-tumour activity of (i)-concomitant treatment of TNF-A and IFN-A against MBT-2 bladder tumour and (ii)-concomitant TNF+IFN-A treatment in conjunction with T-DTH (delayed-type hypersensitivity) immunotherapy. Systemic administration of multiple doses of TNF+IFN-A in vivo caused initial partial tumour regression followed by tumour growth inhibition up to 14 days following treatment. This combined treatment showed an enhanced anti-tumour effect compared to TNF-A treatment alone. Immunotherapy of MBT-2 tumour-bearing mice with T-DTH immune effector cells alone did not cause significant tumour growth inhibition. In contrast, concomitant administration of both T-DTH effector cells and TNF+IFN-A in MBT-2 tumour-bearing mice resulted in significant tumour growth inhibition for up to 16 days. The immune effector cells conferring immunotherapy were isolated from the spleens of tumour-immunized, DTH-primed animals and were characterized as Lyt 1⁺2^- helper/DTH T cells (CD4⁺ phenotype). These cells mediate both DTH response to MBT-2 tumour antigens as well as anti-MBT-2 tumour protection. In vitro treatment of the immune cells with TNF-A resulted predominantly in the proliferation of Lyt 1⁺ T cells versus Lyt 2⁺ cells. The anti-tumour effect of TNF+IFN-A can be augmented by immunotherapy possibly via the immune capacity of tumour sensitized T-DTH effector cells.     

Beta2‐adrenergic receptor in kidney biology: A current prospective

Beta2‐adrenergic receptor (β₂‐AR) is a G‐protein‐coupled adrenergic receptor family member, whose clinical significance has been extensively investigated in lung, cardiovascular and muscular diseases, but its role in kidney biology remains understudied. In this review, we discuss some of the recent studies, where the effect of agonist/antagonist‐mediated activation/inhibition of β₂‐AR on disease pathogenesis process was studied, and highlighted the role of β₂‐AR in kidney biology. The expression of β₂‐AR has been noted in many kidney subunits including proximal tubules, glomeruli and podocytes. In vivo studies have shown that in cultured proximal tubules β₂‐AR is involved in Na‐ATPase activity and transcellular Na‐transport through protein kinase‐C activation; whereas in cultured podocytes, it was associated with depolarization of the membrane. The animal studies further revealed that β₂‐AR activation by short‐acting β₂ agonists attenuated monocyte activation, pro‐inflammatory and pro‐fibrotic responses through β‐arrestin2 dependent NF‐kB inactivation in diabetic kidney disease; in contrast, activation by long‐acting β₂ agonists restored mitochondrial and renal function in the acute kidney injury mice models through PGC‐1α dependent mitochondrial biogenesis. In conclusion, the activation of β₂‐AR may present a rapidly developing therapeutic target for renal diseases.     

Musosal tumour necrosis factor α in diverticular disease of the colon is overexpressed with disease severity

Aim Inflammation occurs in diverticular disease (DD), but there is little information on inflammatory cytokines such as tumour necrosis factor α (TNF‐α). The aim of this study was to assess TNF‐α expression in DD and to see whether it is related to the severity of the disease. Method Twenty‐four patients with symptomatic DD were divided into those with acute uncomplicated diverticulitis (AUD) (12 patients) and those with symptomatic uncomplicated diverticular disease (SUDD) (12 patients). Twelve further patients with asymptomatic diverticulosis (AD), six with segmental colitis associated with diverticulosis (SCAD), with ulcerative colitis (UC) and six healthy individuals (HC) were enrolled as controls. TNF‐α expression in the colonic mucosa was assessed by the amount of mRNA codifying for the synthesis of TNF‐α. Results TNF‐α expression was significantly higher in AUD than in HC (P = 0.0007), in AD (P = 0.0001) and in SUDD (P = 0.0179). It was significantly higher also in SUDD than in HC (P = 0.0007) and in AD (P = 0.0001). TNF‐α expression in AUD did not differ significantly from that in UC (P = 0.0678) and SCAD (P = 0.0610). It was significantly higher in UC, SCAD and AUD than in SUDD (P = 0.0007, P = 0.0001, P = 0.0179). Conclusion TNF‐α expression in DD seems to be related to the severity of the disease. In particular, it appears to be overexpressed in DD with inflammation (AUD and SUDD) compared with DD without (AD).     

Prognostic value of the donor-derived cell-free DNA assay in acute renal rejection therapy: A prospective cohort study

Donor-derived cell-free DNA (dd-cfDNA) is a promising biomarker for monitoring allograft status. However, whether dd-cfDNA can reflect real-time anti-rejection treatment effects remains unclear. We prospectively recruited 28 patients with acute renal rejection, including 5 with ABMR, 12 with type IA or type IB rejection, and 11 with type IIA or IIB rejection. dd-cfDNA levels in peripheral blood were measured using human single nucleotide polymorphism (SNP) locus capture hybridization. The percentage of dd-cfDNA (dd-cfDNA%) declined significantly from 2.566 ± 0.549% to 0.773 ± 0.116% (P < .001) after anti-rejection therapy. The dd-cfDNA% decreased steadily over the course of 3 days with daily methylprednisolone injections, but no significant difference in the dd-cfDNA% was observed between the end of anti-rejection therapy and 2 weeks later. Changes in the dd-cfDNA% (∆dd-cfDNA%) demonstrated a positive correlation with estimated glomerular filtration rates at 1 month (ρ = 2.570, P = .022), 3 months (ρ = 3.210, P = .027), and 6 months (ρ = 2.860, P = .019) after therapy. Thus, the dd-cfDNA assay shows prognostic capabilities in therapy outcome and allograft recovery; however, its ability is inhibited by methylprednisolone regardless of the types of rejection. Additionally, a reassessment of frequency intervals for testing is required.     

The liver recipient with acute renal dysfunction: A single institution evaluation of the simultaneous liver‐kidney transplant candidate

The Organ Procurement Transplant Network (OPTN) listing criteria for simultaneous liver‐kidney transplant (SLK) are not well defined. Concerns remain about rising numbers of SLKs, which divert quality kidneys from candidates awaiting kidney transplants (KT). We performed a retrospective review of liver transplants (LTs) at our center from 2004 to 2014; 127 recipients (liver transplant alone; 102 LTA, 25 SLK) were identified with short‐term preoperative kidney dysfunction (creatinine >4 mg/dL or preoperative hemodialysis [HD] for <6 weeks). Both cohorts had comparable baseline demographic characteristics with the exception of higher model for end‐stage liver disease (MELD) score in the LTA group (41.4 vs 32.9, P < .0001) and higher incidence of pre‐LT diabetes in the SLK cohort (52% vs 26.5%, P = .0176). Duration of pre‐LT HD was higher in SLK recipients, but the difference was not statistically significant (P = .39). Renal nonrecovery (RNR) rate in LTA cohort was low (<5%). No significant difference was noted in 1‐year mortality, liver graft rejection/failure, or length of stay (LOS) between the cohorts. Thus, it appears that liver recipients with short‐term (<6 weeks) HD or AKI without HD have comparable outcomes between LTA and SLK. With provisions for a KT safety net, as proposed by OPTN, LTA may be the most adequate option for these patients.     

肿瘤坏死因子α、肾损伤分子1在急性缺血再灌注损伤大鼠肾脏及血清中的表达变化

目的观察肾脏急性缺血再灌注损伤(ischermic reperfusion,I/R)后大鼠肾脏及血清中肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)、肾损伤分子1(kidney injury molecule-1,Kim-1)的表达变化。方法选取雄性SD大鼠96只,体质量250~300 g,随机分为假手术组(Sham组,n=48),缺血再灌注组(I/R组,n=48),通过夹闭双肾动脉建立大鼠肾脏缺血再灌注模型,各组于术后2h、6 h、12 h、24 h、48 h、72 h每时点随机选取8只大鼠,分别取血及肾皮质标本。全自动生化分析仪检测血清肌酐、尿素氮,酶联免疫吸附试验(enzyme linked immunosorbent assay,ELISA)检测血清TNF-α、Kirm-1水平,免疫组织化学检测肾组织TNF-α、Kim-1表达。结果与Sham组血清肌酐、尿素氮水平[(50.8±6.8)μmol/L、(4.7±0.5)mmol/L]比较,I/R组均于I/R损伤后6 h开始升高[血清肌酐I/R 6 h时为(79.6±8.8)μmol/L、尿素氮I/R 6 h时为(9.3±1.6)mmol/L,均P0.05]。ELISA检测结果显示,与Sham组血清TNF-α(843.0±60.5)、Kim-1(453.7±56.4)水平比较,I/R组均于I/R 2 h开始升高[I/R 2 h时血清TNF-α为(944.2±68.3)、Kim-1为(1081.3±126.2),均P0.05],48 h达高峰,但TNF-α于72 h明显下降(3 094.4±230.5),血清Kim-1水平48~72 h保持高值。免疫组织化学检测显示I/R损伤后TNF-α、Kim-1主要表达于肾小管,且均在12 h表达最多。结论血清TNF-α与Kim-1能较早提示急性肾脏损伤,但Kim-1优于TNF-α。