Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer

AimsLenvatinib is an oral multi-kinase inhibitor approved for the treatment of adults with progressive, locally advanced or metastatic, differentiated thyroid carcinoma refractory to radioactive iodine.Materials and methodsA literature review was undertaken to inform the development of consensus-based guidance for the routine management of adverse events associated with lenvatinib. PubMed was searched on 24 October 2017; the search terms were ‘lenvatinib’ and ‘thyroid cancer’.ResultsHypertension, diarrhoea, weight loss, skin toxicities and cardiovascular adverse events were considered. For grade 1/2 diarrhoea, initial treatment should be loperamide with a 1-week treatment interruption if diarrhoea persists and dose reduction if diarrhoea recurs on reinitiation of lenvatinib. Blood pressure should be monitored daily in patients with pre-existing hypertension, otherwise from 1 week after the initiation of lenvatinib and weekly for the first 2 months. For patients with systolic blood pressure ≥135 mmHg to <160 mmHg or diastolic blood pressure ≥85 mmHg to <100 mmHg, lenvatinib should be continued but antihypertensive therapy initiated/intensified. For patients who remain hypertensive, a treatment break can be considered with lenvatinib reinitiated at a reduced dose once the patient's blood pressure has stabilised for at least 48 h. Weight loss of 10% of baseline body weight or the onset of anorexia should be managed with a 1-week treatment break; patients should maintain a healthy, active lifestyle. For patients with grade 2 proteinuria, lenvatinib may be continued, but an angiotensin II receptor blocker or angiotensin converting enzyme inhibitor should be commenced. For grade >3 proteinuria, lenvatinib should be interrupted until proteinuria returns to 1+. For chronic proteinuria, lenvatinib should be stopped. Skin toxicities should be managed with moisturisers or emollients and soap substitutes.ConclusionsProphylaxis, regular monitoring and symptomatic management with appropriate short treatment breaks and, for persistent adverse events, dose reductions, are recommended to enable patients to remain on the optimal dose regimen.     

维生素D受体在糖尿病肾病足细胞损伤及蛋白尿缓解中的作用

目的探讨维生素D受体(VDR)在糖尿病肾病(DKD)足细胞中的表达水平及在足细胞损伤及蛋白尿缓解中的作用。方法(1)本研究纳入了65例诊断患有2型糖尿病(伴或不伴蛋白尿)的患者,并纳入了25例年龄和性别相匹配的健康体检者为对照组。根据白蛋白/肌酐(ACR)的尿排泄比例对2型糖尿病患者进行分组,分别为无蛋白尿(ACR<30 mg/g,n=24)、微量白蛋白尿(ACR 30~300 mg/g,n=18)和临床蛋白尿(ACR>300 mg/g,n=23)。另选择25例经肾活检确诊的DKD患者作为DKD组。正常肾脏组织标本均取自泌尿外科同一时期肾脏肿瘤切除患者10例。将各组检测指标进行对比,同时采用实时定量PCR、ELISA法和免疫组化法检测VDR在各组患者的血液、尿液样本和肾脏组织中的表达情况,以及使用Pearson相关分析分析VDR与尿蛋白的相关性。(2)在2型糖尿病肾病小鼠模型中对上述结果进行验证,将遗传背景均为C57BLKs/J的雄性db/db小鼠及同窝出生的db/m小鼠,随机分为正常对照组(A组)、DKD对照组(B组)、DKD二甲基亚砜处理组(C组)、DKD帕立骨化醇(VDR激动剂)处理组(D组),C、D组连续腹腔注射处理8周,对照组不做任何处理。小鼠10周龄时开始连续干预8周,在小鼠22周龄(开始干预后12周)检测各组小鼠体重、血、尿生化指标对比;Western印迹法检测β⁃catenin、VDR的变化;免疫荧光观察足细胞标志蛋白podocin及足细胞损伤蛋白α⁃SMA的表达变化。结果(1)与正常健康对照组相比,无蛋白尿组、微量白蛋白尿组和临床蛋白尿组的糖尿病患者血浆中VDR的mRNA和蛋白水平均较低(均P<0.05);与无蛋白尿组的糖尿病患者相比,微量白蛋白尿组和临床蛋白尿组的糖尿病患者血浆中VDR的mRNA和蛋白水平均较低(均P<0.05)。(2)与正常健康对照组相比,无蛋白尿糖尿病组和DKD组患者血浆中VDR的mRNA和蛋白水平均较低(均P<0.05);与无蛋白尿糖尿病组患者相比,DKD组患者血浆中VDR的mRNA和蛋白水平亦较低(均P<0.05)。(3)免疫组化结果显示,DKD组肾组织中VDR的表达明显少于正常对照组。(4)DKD患者血浆中VDR mRNA相对水平与ACR呈负相关(r=-0.342,P<0.05)。(5)各组尿液上清液中VDR的水平与血浆中的水平呈相反趋势。(6)Western印迹结果显示,B组、C组肾小球足细胞β⁃catenin蛋白表达高于D组(均P<0.05),VDR蛋白的表达低于D组(均P<0.05);免疫荧光结果显示,B组、C组肾小球足细胞podocin的表达低于D组(均P<0.05),α⁃SMA的表达高于D组(均P<0.05)。结论VDR高表达缓解DKD足细胞损伤及蛋白尿。     

Time-varying coefficient of determination to quantify the explanatory power of biomarkers on longitudinal GFR among children with chronic kidney disease

Purpose

Coefficients of determination (R²) for continuous longitudinal data are typically reported as time constant, if they are reported at all. The widely used mixed model with random intercepts and slopes yields the total outcome variance as a time-varying function. We propose a generalized and intuitive approach based on this variance function to estimate the time-varying predictive power (R²) of a variable on outcome levels and changes.

血小板反应蛋白-1在糖尿病大鼠模型肾损害中的作用及机制初步探讨

目的：观察血小板反应蛋白-1（thrombospondin-1,TSP-1）在链脲佐菌素诱导的糖尿病（diabetes mellitus, DM）大鼠模型肾脏中的表达,初步探讨TSP-1在糖尿病肾病大鼠发病机制中的作用及与糖尿病肾损害的关系。方法：成年雄性SD大鼠80只,随机分为正常对照组（ n＝15）和实验组（ n＝65）。采用STZ 70 mg/kg单次腹腔注射建立DM大鼠模型,按照成模标准去除未成模大鼠。检测各组大鼠空腹血糖（ fasting blood glucose,FBG）、尿蛋白及肾功能;分别于2,4,8周处死各组大鼠,通过HE染色观察各组大鼠肾脏的病理改变,免疫荧光观察TSP-1在各组大鼠肾脏的分布;PCR检测肾组织TSP-1和转录生长因子β1（ transforming growth factor,TGF-β1）基因表达水平;采用酶联免疫吸附法（ ELISA）检测肾组织活性TGF-β1水平;Western杂交检测TSP-1的动态变化。分别对尿蛋白、肾功能、肾脏病理损害、活性TGF-β1与TSP-1蛋白表达的相关性进行分析。结果：HE染色可见DM组大鼠肾小球系膜基质增生,肾小球可见分叶现象、K-W结节等典型的糖尿病肾病损伤特点。与正常对照组相比,DM组大鼠的FBG、尿蛋白、肌酐、尿素氮水平均显著增加（ P﹤0．05）,TSP-1在DM组大鼠主要分布于肾小管、肾小球系膜细胞,其蛋白表达在2周时即明显增加,一直持续到第8周。DM 组大鼠肾脏TSP-1的积分光密度（ integrated optical density,IOD）与尿蛋白、肾脏病理损害、肌酐、尿素氮水平、活性TGF-β1浓度均呈正相关。结论：持续高血糖状态可以诱导大鼠肾脏病理损害,引起尿蛋白升高、肾功能异常;高血糖可诱导大鼠肾脏TSP-1蛋白高表达。TSP-1蛋白的高表达可能通过激活TGF-β1信号通路参与DM大鼠蛋白尿的产生及肾损害的发生发展。     

Effects of 1α, 25-dihydroxyvitamin D3 on memory CD4+ T cells of focal proliferative IgA nephropathy

Objective To explore the effects of 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] on memory CD4+ T cells of focal proliferative IgA nephropathy (IgAN）patients. Methods (1) Total of twenty incipient focal proliferative IgAN patients (Lee classification: Ⅲ level) were chosen as IgAN group and 20 healthy volunteers were chosen as healthy control group. The level of serum 1,25(OH)2D3 was measured by radioimmunoassay (RIA). Peripheral blood mononuclear cells (PBMCs) were separated by the method of Ficoll density gradient centrifugation and were stimulated with anti-CD3/anti-CD28 in the absence or presence of various concentrations of 1,25(OH)2D3, Dexamethasone(DEX) and 1,25(OH)2D3 and DEX combined. PBMCs were cultured for 72 hours and the levels of IFN-γ, IL-4, IL-17A, Foxp3 were measured by flow cytometry(FCM), standing for the levels of Th1, Th2, Th17, Treg. (2) IgAN group was divided into two subgroups (proteinuria＜1 g/24 h subgroup, proteinuria≥1 g/24 h subgroup), then the serum levels of 1,25(OH)2D3, IFN-γ, IL-4, IL-17A, Foxp3 were compared. Results Compared with healthy control group, serum 1,25(OH)2D3 level of IgAN group was significantly lower (P＜0.05). Serum 1,25(OH)2D3 level in proteinuria≥1 g/24 h subgroup was significantly lower than proteinuria＜1 g/24 h subgroup and healthy control group (P＜0.05). The level in proteinuria＜1 g/24 h subgroup was lower than healthy control group, but the difference was not statistically significant (P＞0.05). (2) The levels of IFN-γ and IL-17A and the ratios of IFN-γ/IL-4, IL-17A/Foxp3 in IgAN group increased significantly compared with healthy control group (all P＜0.05), and the level of Foxp3 decreased significantly (P＜0.05). The level of IL-4 also increased, but the difference was not statistically significant (P＞0.05). The levels of IFN-γ and IL-17A and the ratio of IL-17A/Foxp3 in proteinuria≥1 g/24 h subgroup increased significantly, and the level of Foxp3 decreased significantly, compared with urinary protein＜1 g/24 h subgroup and healthy control group (P＜0.05). The ratio of IFN-γ/IL-4 in proteinuria≥1 g/24 h subgroup and proteinuria＜1 g/24 h subgroup all increased, compared with healthy control group, and the ratio in proteinuria≥1 g/24 h subgroup increased significantly (P＜0.05). There was no significant difference in the level of IL-4 among all groups. (3) After treatment with 1,25(OH)2D3, the levels of IFN-γ and IL-17A and the ratios of IFN-γ/IL-4 and IL-17A/Foxp3 decreased significantly, and the level of Foxp3 increased significantly (P＜0.05), and these effects were more obvious as the increase of the drug concentration. The level of IL-4 did not change significantly. The combination of 1,25(OH)2D3 and DEX had a synergistic inhibition on the production of IFN-γ, IL-4, IL-17A, and the ratios of IFN-γ/IL-4 and IL-17A/Foxp3, and had a synergistic promotion on the production of Foxp3. Conclusions There is a certain extent of vitamin D deficiency in focal proliferative IgAN patients, which may be associated with the severity of proteinuria. The disorder of immunomodulatory effects of memory CD4+ T cell might exist in the patients of focal proliferative IgAN. 1α,25-dihydroxyvitamin D3 might have beneficial effects on the immunoregulation of memory CD4+T cells of focal proliferative IgAN patients.     

Expression of NLRP3 inflammasome in the BSA-overloaded rats kidney

Objective To observe NLRP3 inflammasome expression and inflammatory cells infiltration in the BSA-overloaded rats kidney, and to investigate the potential mechanism of renal injury induced by proteinuria. Methods After unilateral right nephrectomy, eighteen healthy male Wistar rats were randomly divided into two groups: protein overload nephropathy model group (n=10), treated with intraperitoneal injections of bovine serum albumin (BSA); control group (n=8), treated with intraperitoneal injections of 0.9% saline for 9 weeks. Body weigh were measured every week and 24 h urine were collected in 0, 2, 5, 7, 9 week. The plasma levels of blood total protein (TP), albumin (Alb), serum creatinine (Scr) and blood urea nitrogen (BUN) were determined by automatic analyzers. Renal pathological changes were evaluated by PAS and Masson stains. Immunohistochemical staining was used to detect the expression of NLRP3, caspase-1, IL-1β, and IL-18, as well as the types of inflammatory cells. The NLRP3, caspase-1, IL-1β, and IL-18 protein and mRNA levels were also analyzed by Western blot and real-time PCR in two groups. Results It was found that there was a significant increase of proteinuria and BUN in model group compare to that in control group (all P＜0.05). However, there were no significant changes in body weight, TP, Alb and Scr between the two groups. Morphological study demonstrated that renal tubular epithelial cell injury, proteinaceous casts in tubular lumen, accompanying with the dominant macrophages and lymphocytes infiltration in interstitium in model group. The immunohistochemistry showed that there were more T (CD3+), B cells (CD20+) and macrophages (CD68+) in renal interstitium in model group than that in control group (P＜0.05). Tubulointerstitial injury score was higher than that of the control group (P＜0.05). Immunohistochemistry, Western blot and real-time PCR all showed that the expression of NLRP3, caspase-1, IL-18 and IL-1 β were significantly increased compared to those in control group (P＜0.05). Furthermore, there were significant correlations between proteinuria and IL-1β/IL-18 expression (P＜0.05). Conclusion NLRP3 inflammasome activation is involved in tubulointerstitial inflammation caused by proteinuria.     

H-500尿液分析仪尿蛋白分析评价

目的以经典的双缩脲蛋白定量法及加热乙酸定性法作参照,评价H-500尿液分析仪对尿蛋白分析的准确性并探讨其影响因素。方法临床新鲜尿标本50份,用双缩脲法作尿蛋白定量,并依经典描述的定性"-± "代表的蛋白浓度范围将其分成相对应的正常组、可疑组、低蛋白组、中蛋白组及高蛋白组,同时用加热乙酸法和机测法作蛋白定性分析。结果①加热乙酸法与理论预测值总符合率为94%,机测法与理论预测值的总符合率为82%,除正常组外,其它组两种方法所测值与理论预测值的符合率的差异均有显著性意义(P<0.05)。②机测法标本含量与实测含量差异有显著性意义(P<0.05)。结论本文资料提示机测法虽然一般可用,但有相当病例误差较大,尤其部分标本机测所标示蛋白浓度与实测浓度相差甚远,在评价机测结果时应引起足够重视。     

伴免疫球蛋白G 沉积原发性膜性肾病病人疾病缓解影响因素及与肾小球免疫球蛋白G4 表达强度的关系研究

目的 探讨伴免疫球蛋白(Ig)G沉积原发性膜性肾病(PMN)病人疾病缓解影响因素及与肾小球IgG4表达强度的关系。方法 回顾性纳入山西省运城市中心医院2014年1月至2020年1月收治伴IgG沉积PMN病人共500例,根据有无IgG4表达和表达强度分组,分析临床病理及随访预后资料,采用单因素和多因素Cox回归模型评价伴IgG沉积PMN病人疾病缓解独立影响因素。结果 阳性组24 h尿蛋白量和M型磷脂酶A2受体(PLA2R)表达强度比例显著高于阴性组(P<0.05);弱阳性组、中阳性组及强阳性组血浆白蛋白、IgG1强度比例及IgA强度比例比较差异有统计学意义(P<0.05);阴性组、弱阳性组、中阳性组及强阳性组随访3个月( 30.0%比17.3%比15.9%比9.5%)和6个月(38.4%比30.6%比26.5%比13.0%)累积缓解率比较差异有统计学意义(P<0.05);Cox回归模型单因素和多因素分析结果显示,IgG4阳性高强度、男性、基线高24 h尿蛋白量均是伴IgG沉积PMN病人疾病未缓解独立危险因素［RR=1.33,95%CI:(1.05,1.61);RR=1.80,95%CI:(1.17,3.04);RR=1.51,95%CI:(1.09,2.80)。P<0.05］。结论 伴IgG沉积PMN病人疾病缓解效果与IgG4表达强度、性别及基线24 h尿蛋白量密切相关;而肾小球IgG4表达强度可作为PMN治疗反应性潜在评估指标加以应用。