Moderate Impairment Of Renal Function Research Articles

Clinical Characteristics and Prognosis of Diabetic Foot Ulcers Patients of Different Renal Function Statuses

To explore the clinical characteristics and the prognosis of diabetic foot ulcers (DFU) inpatients of different renal function statuses. A retrospective analysis of 962 inpatients with DFU was conducted. The patients were divided into three groups according to their renal function statuses, and the clinical characteristics of the three groups were compared to identify differences. In addition, the patients were followed up in outpatient clinics or by telephone and their prognostic status and risk factors for death were analyzed. Analysis of the clinical characteristics showed that, compared with diabetic patients with normal renal function or mild renal function impairment, diabetic patients with moderate and severe renal function impairment had a longer course of disease ( P<0.001). Patients with foot ulcers of Wagner grade 4 predominates the moderate and severe renal function impairment groups ( P<0.05). Patients in the moderate and severe renal function impairment groups had a relatively higher proportion of comorbidities, including hypertension, coronary heart disease, and peripheral arterial disease ( P<0.05). These patients had relatively lower levels of glycosylated hemoglobin and hemoglobin (all P<0.05) and relatively higher levels of neutrophil ratio and procalcitonin (all P<0.05). Of the two groups, patients in the moderate renal function impairment group were older ( P<0.001) and had lower ankle-brachial index ( P<0.001). The severe renal function impairment group had a higher proportion of patients with foot ulcers of Wagner grades 3 and 5 (all P<0.05). For the purpose of conducting prognostic analysis, 748 patients were followed up in outpatient clinics or by telephone for a median length of 41 months. Among them, 239 died. The all-cause mortality was 31.9%, and the mortality in the three groups was 25.8%, 46.2% ( P<0.001), and 59.4% ( P<0.001), respectively. The survival rate of patients in the moderate and severe renal function impairment groups was significantly lower than those in the normal renal function and mild renal function impairment groups ( P<0.001). Univariate Cox regression analysis showed that age, concomitant coronary heart disease and peripheral arterial disease, degree of renal function impairment, and foot ulcers of Wagner grade 4 and 5 were associated with all-cause deaths. Furthermore, multivariate Cox regression analysis showed that moderate and severe renal function impairment was an independent risk factor for all-cause deaths in DFU patients ( P<0.001). As renal function impairment worsens, patients with DFU present clinical characteristics of greater complexity, higher risks of cardiovascular events, and higher mortality. It is essential to prevent kidney damage and foot ulcers, to pay attention to the cardiovascular risks of DFU patients with moderate and severe renal function impairment, and to reduce mortality.

The Urinary Glucose Excretion by Sodium–Glucose Cotransporter 2 Inhibitor in Patients With Different Levels of Renal Function: A Systematic Review and Meta-Analysis

ObjectivePrevious evidence suggested that sodium–glucose cotransporter 2 inhibitor (SGLT2i)-mediated urinary glucose excretion (UGE) appeared to be reduced with a decrease in glomerular filtration rate. Thus, we conducted a systematic review and meta‐analysis to compare SGLT2i-mediated UGE among individuals with different levels of renal function.MethodsWe conducted systematic searches in PubMed, Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrial.gov from inception to May 2021. Clinical studies of SGLT2i with reports of UGE changes in predefined different levels of renal function were included. The results were expressed as pooled effect sizes with 95% confidence interval (CI). A random-effects model was used to calculate the pooled effect sizes.ResultsIn total, eight eligible studies were included. Significant differences were observed in the post-treatment UGE level among subgroups stratified by renal function (P <0.001 for subgroup difference), which were gradually decreased along with the severity of impaired renal function. Consistently, changes in UGE before and after SGLT2i treatment were also decreased along with the severity of impaired renal function [67.52 g/day (95%CI: 55.58 to 79.47 g/day) for individuals with normal renal function, 52.41 g/day (95%CI: 38.83 to 65.99 g/day) for individuals with mild renal function impairment, 35.11 g/day (95%CI: 19.79 to 50.43 g/day) for individuals with moderate renal function impairment, and 13.53 g/day (95%CI: 7.20 to 19.86 g/day) for individuals with severe renal function impairment; P <0.001 for subgroup differences].ConclusionsSGLT2i-mediated UGE was renal function dependent, which was decreased with the extent of renal function impairment.

Echocardiographic Findings in Patients with Mild to Moderate Chronic Kidney Disease without Symptomatic Heart Failure: A Population-Based Study

Background: Renal dysfunction is an established risk factor for cardiovascular disease, but early disease states in both organs are poorly studied. Objective: This cross-sectional population-based study aims to investigate if there is an early association between kidney function and echocardiographic markers of cardiac structure and diastolic function. Methods: The study population consisted of 1,504 individuals with no prior history of congestive heart failure or asymptomatic left ventricular ejection fraction ≤40% and an estimated glomerular filtration rate (eGFR) based on cystatin C >15 mL/min/1.73 m². The participants were categorized according to eGFR ≥90, 75–89, 60–74, 45–59, 30–44, and 15–29 mL/min/1.73 m². We evaluated associations between eGFR categories and echocardiographic findings specific to cardiac structure and diastolic function. Results: Associations between eGFR categories and echocardiographic findings were found for left atrium area/body surface area (p = 0.013) indicating structural changes, and peak early mitral valve velocity (A; p = 0.003), peak late atrial mitral valve velocity/peak systolic myocardial velocity at mitral annulus in the lateral wall (E/Élat; p = 0.002), É mean of lateral and septal wall/Á mean of lateral and septal wall (mean É/Á; p = 0.027) indicating diastolic dysfunction. Associations between E/Élat and mean É/Á and eGFR categories were already present in individuals with eGFR 45–60 mL/min/1.73 m². In sex-specific analysis these associations were only significant among men. Conclusion: A significant association between mild to moderate impairment of renal function and echocardiographic markers of cardiac structure and diastolic function was observed, supporting the hypothesis that interaction between the kidney and heart exists even in the early stages of renal impairment.

Influence of age and renal impairment on the steady state pharmacokinetics of filgotinib, a selective JAK1 inhibitor.

AimsFilgotinib (GS‐6034, formerly GLPG0634) is an oral, selective Janus kinase 1 (JAK1) inhibitor that showed early response and sustained efficacy in patients with rheumatoid arthritis and with Crohn's disease. The aim of the present study was to investigate the impact of age and renal impairment (RI) on the pharmacokinetics (PK) of filgotinib and its main metabolite.MethodsThe effect of age was assessed in two groups of 10 elderly healthy subjects (65–74 and ≥75 years of age) and a control group of 10 younger healthy subjects (40–50 years of age). The impact of RI was investigated in three groups of subjects with mild (n = 6), moderate (n = 6) and severe (n = 3) RI [estimated glomerular filtration rate (eGFR) 60–89, 30–59 and 15–29 ml min–1 1.73 m–2, respectively] and a control group (n = 9) with normal renal function (eGFR ≥90 ml min–1 1.73 m–2). The PK of filgotinib and its metabolite were evaluated following filgotinib 100 mg once‐daily doses for 10 days.ResultsAt steady state, the exposure [area under the concentration–time curve over the dosing interval (AUC0–24 h)] of filgotinib and its metabolite was moderately higher (1.45‐ and 1.33‐fold, respectively) in the elderly subjects (≥75 years) compared with younger subjects. Renal clearance for filgotinib and its metabolite decreased with the degree of RI, leading to a maximum increase in AUC0–24 h of 1.54‐fold for filgotinib and 2.74‐fold for the metabolite in subjects with severe RI. Filgotinib was generally safe and well tolerated.ConclusionsAge and mild to moderate impairment of renal function had limited impact on the PK of filgotinib. In subjects with severe RI, the exposure to the metabolite of filgotinib was elevated, consistent with its renal elimination pathway.

Moderate Renal Impairment and Toxic Metabolites Produced by the Intestinal Microbiome: Dietary Implications

Toxic metabolites produced by the intestinal microbiome from animal proteins, carnitine (mainly from red meat), or phosphatidylcholine (mainly from egg yolk), have important adverse effects on cardiovascular disease. These are renally eliminated and may be termed gut-derived uremic toxins (GDUT). We hypothesized that even moderate renal impairment and intake of nutrient precursors would raise plasma levels of GDUT. A cohort study. Academic medical center. Patients attending stroke prevention clinics at a university medical center were recruited. Nutrient intake was assessed by the 131-item Harvard Food Frequency Questionnaire; estimated glomerular filtration rate (eGFR) was caculated using the Chronic Kidney Disease-Epidemiology (EPI) equations. Plasma levels of trimethylamine n-oxide, p-cresyl sulfate, hippuric acid, p-cresyl glucuronide, pheny acetyl glutamine, and phenyl sulfate were measured by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. Among 316 patients recruited, the mean (standard deviation [SD]) age was 66.74 (10.42) years; 59.7% were men. Mean eGFR was 76.03±20.01; 57 (18%) had eGFR<60mL/min/1.73m2. Plasma levels of all GDUT were significantly higher even with moderate reduction of eGFR. Nutrient intake affected plasma levels of some GDUT; the effects differed by eGFR above and below 60mL/min/1.73m2. Plasma levels were obtained fasting, so we probably underestimated the effect of nutrient intake. Even moderate impairment of renal function was associated with higher plasma levels of GDUT. This has dietary implications for patients at risk of atherosclerosis, particularly in those with impaired renal function (including the elderly): they should limit intake of animal protein, red meat, and egg yolk. It also points the way to novel approaches to vascular prevention, including more intensive dialysis, renal transplantation, and modification of the intestinal microbiome with probiotics or fecal transplantation.

Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes and moderate renal function impairment: A systematic review and meta-analysis

AimsA systematic review and meta-analysis was conducted to evaluate the clinical efficacy and safety of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes (T2D) and moderate renal function impairment. MethodsEmbase, Medline, and Cochrane Central were searched, and randomized controlled trials comparing SGLT2 inhibitors to placebos and other drugs for T2D were collected. ResultsSeven RCTs with a total of 3307 participants were included, and the overall bias was low. In the patients with T2D and moderate renal function impairment (30 ml/min/1.73 m2 ≤ estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2) compared with the placebo, SGLT2 inhibitors improved HbA1c significantly (WMD, −0.23%; 95% CI: −0.38 to −0.08), presented a lower incidence of hypoglycemia (30.1% vs. 34.6%; RR, 0.85; 95% CI: 0.76 to 0.96), led to the reduction of eGFR (WMD, −1.74 ml/min/1.73 m2; 95% CI: −3.45 to −0.03), resulted in an obvious reduction in body weight (WMD, −1.45 kg; 95% CI: −2.01 to −0.89), and presented a similar risk of urinary tract infection and genital infection. ConclusionsSGLT2 inhibitors are safe, but mildly reduce the HbA1c level. The clinical significance of SGLT2 inhibitors in the target population was limited.

Renal function on admission affects both treatment strategy and long-term outcomes of patients with myocardial infarction (from the Polish Registry of Acute Coronary Syndromes).

Impairment of renal function (IRF) is an independent risk factor of myocardial infarction (MI). The aim of study was to determine if the presence of IRF affects the choice of treatment strategy in patients with MI, and if long-term mortality rates are influenced by the use of an invasive strategy in patients with MI according to the grade of IRF. Data from the PL-ACS Registry of 22,431 patients hospitalised for MI during 2007-2008 with an available estimated glomerular filtration rate (eGFR) with 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula were included. Patients were stratified based on eGFR: ≥ 90 (normal); 60-89 (mild IRF); 30-59 (moderate IRF); 15-29 (severe IRF); and < 15 mL/min/1.73 m² (end-stage IRF). After adjustment, each increase in IRF grade reduced the likelihood of percutaneous coronary intervention by 19% (odds ratio [OR] 0.81; 95% confidence interval [CI] 0.78-0.85; p < 0.001). A higher IRF grade was independently associated with mortality (OR 2.01; 95% CI 1.86-2.18; p < 0.001) and major bleeding (OR 1.42; 95% CI 1.22-1.66; p < 0.001) during hospitalisation, and mortality at 12 (hazard ratio [HR] 1.55; 95% CI 1.49-1.62; p < 0.001) and 36 months (HR 1.50; 95% CI 1.45-1.55; p < 0.001). Invasive treatment was independently associated with improved 12-month prognosis in non-ST-segment elevation MI (NSTEMI) patients with mild-to-severe IRF and in ST-elevation MI (STEMI) patients at all IRF grades. Invasive procedures were less frequent with worsening renal dysfunction. Invasive treatment was associ-ated with improved 12-month prognosis in STEMI patients regardless of renal function and in NSTEMI patients with eGFR ≥ 15 mL/min/1.73 m².

Effect of Renal and Hepatic Impairment on the Pharmacokinetics of Cabozantinib.

Cabozantinib is a tyrosine kinase inhibitor approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Two clinical pharmacology studies were conducted to characterize single-dose pharmacokinetics (PK) of cabozantinib in renally or hepatically impaired subjects. Study1enrolled 10subjects, each with mild or moderate impairment of renal function; 12healthy subjects were matched to the moderate group for age, sex, and body mass index (BMI). Study2 enrolled8 males each with mild or moderate hepatic impairment; 10healthy males were matched to the moderate group for age, BMI, and ethnicity. All subjects received one 60 mg cabozantinib oral capsule dose followed by PK sampling over 21days. Plasma concentration and protein binding were determined by liquid chromatography tandem mass spectrometry and equilibrium dialysis, respectively. PK parameters were computed using noncompartmental methods. Geometric least squared mean (LSM) ratios for plasma cabozantinib AUC0-∞ for impaired to normal organ function cohorts were (1)approximately 30% and 6% higher in subjects with mild and moderate renal impairment, respectively, and (2) approximately 81% and 63% higher in subjects with mild and moderate hepatic impairment, respectively. The percentageof unbound drug was slightly higher in both moderately impaired cohorts. No deaths or discontinuations due to adverse events occurred in either study. Cabozantinib should be used with caution in subjects with mild or moderate renal impairment. Subjects with mild or moderate hepatic impairment administered cabozantinib should be monitored closely for potential treatment-emergent drug toxicity that may necessitate a dose hold or reduction.

Approaches to treatment 2: Comparison of American Association of Clinical Endocrinologists (AACE) and American Diabetes Association (ADA) type 2 diabetes treatment guidelines

摘要 总的来说,2015年美国糖尿病协会(American Diabetes Association,ADA)1与美国临床内分泌学家协会(American Association of Clinical Endocrinologists,AACE)2推荐的2型糖尿病治疗指南都对当前控制糖尿病高血糖的方法与概念进行了深刻的分析。 ADA的方法是以选择血糖控制目标为起点,在控制血糖目标之前强调要控制HbA1c,建议通常的HbA1c目标应该设定为7%,虽然也指出了对于一名特定的患者来说更高或者更低水平的HbA1c目标也可能是合适的,这主要依赖于患者的医疗条件(疾病病程、预期寿命、合并疾病,特别是强调了血管并发症),并且还依赖于患者的态度、预期的努力程度以及可用的资源,这些因素都是可改变的,除此之外还有药物不良反应的风险,特别是低血糖。二甲双胍是推荐的首选初始用药,间隔3个月后可以增加到2种药物的联合使用,接着是3种药物的联合使用。另外还对6类治疗药物进行了陈述,其中胰岛素被认为具有“最高”效能;胰高血糖素样肽-1(GLP-1)受体激动剂(RA)、噻唑烷二酮类(TZD)以及磺脲类(SU)具有“高”效能;而二肽基肽酶(DPP)-4抑制剂与钠-葡萄糖共转运体(SGLT)-2抑制剂具有“中等”效能1。提到了将后面这两类药物引入推荐指南是“治疗方法的主要变化”1,但是没有推荐联合使用GLP-1 RAs进行治疗,这主要是因为缺乏临床试验证据。特别是明确提到了膀胱癌与吡格列酮并不相关,以及心脏衰竭在理论上与使用DPP-4抑制剂无关1;但假设根据一项新的来源于临床试验的证据这个结论将被修改3。在特定的治疗方案中,为了使治疗费用最小化需要将DPP-4抑制剂、SGLT2抑制剂、GLP-1 RAs以及胰岛素类似物排除在外;为了避免低血糖需要将SU与胰岛素排除在外;而为了避免体重增加还需将TZDs排除在外1。 如果HbA1c> 9%,推荐启用一种基础胰岛素进行治疗,剂量为10个单位或者0.1-0.2 U/kg体重,根据自我监测的空腹血糖每周调整剂量1到2次1。根据ADA临床实践标准定义的空腹血糖推荐目标为130 mg/dL(7.2 mmol/L),餐后峰值(假定为餐后1小时)血糖目标为180 mg/dL(10.0 mmol/L])4。对于使用基础胰岛素治疗后空腹血糖达标但是总体血糖控制却没有达标的患者来说,推荐的治疗方法有3种:(i)加用一种GLP-1 RA;(ii)在进食最多的餐前加用一针速效胰岛素;或者(iii)改成一种每日注射两次的预混胰岛素,而每餐前注射一次速效胰岛素是最终的选择1。 AACE推荐的(治疗策略)2纳入了所有已被批准的降糖药。4组药物的区别如下:(i)主要降低空腹血糖的药物(例如二甲双胍、TZDs与基础胰岛素);(ii)主要降低餐后血糖的药物(例如α-葡萄糖苷酶抑制剂[AGI]、胰淀素类似物普兰林肽、DPP-4抑制剂、格列奈类以及短效和/或速效胰岛素);(iii)具有两种作用的药物(例如GLP-1 RA、SU、SGLT2抑制剂以及混合性胰岛素制剂;(iv)适度有效的药物如胆汁酸螯合剂考来维仑以及一种多巴胺D2受体激动剂溴隐亭的快速吸收剂型(BCR)。AACE的治疗策略聚焦于安全性以及降糖获益:SU、格列奈类与胰岛素的低血糖问题;胰岛素、SU与TZDs的体重增加效应;以及GLP-1 RA与SGLT2抑制剂的体重减少效应2。中度肾功能受损导致二甲双胍的禁忌使用,而重度肾功能受损可导致艾塞那肽的禁忌使用。其他安全性问题包括使用SGLT2抑制剂治疗后的泌尿生殖道感染与血容量下降,以及使用GLP1 RAs治疗后的恶心、呕吐与腹泻。使用二甲双胍、AGI、考来维仑与BCR治疗后也可能出现胃肠道不良反应。心血管问题,特别是心脏衰竭,是引证过的TZDs不良效应;SU有可能会导致心血管不良效应(并且提到了SGLT2抑制剂可导致低密度脂蛋白胆固醇水平升高,虽然它的真实临床影响还尚未明确);而TZDs与SGLT2抑制剂还有潜在的导致骨量丢失的副作用2。 AACE在推荐治疗策略时有一个重要原则,就是要制定个体化的治疗计划,主要是根据基线HbA1c来确定。与ADA以及欧洲糖尿病研究协会(European Association for the Study of Diabetes,EASD)不同的是,AACE将药物选择按照以下方案进行了分级。如果HbA1c水平 7.5%并且 9.0%,推荐进行二联治疗或者三联治疗,除非患者出现了高血糖症状,对于这些病例来说需要使用胰岛素联用或不联用其他降糖药进行治疗2。 在AACE治疗方法中推荐的胰岛素使用策略是:HbA1c 8%的启始基础胰岛素剂量分别为0.1-0.2与0.2-0.3 U/kg。推荐每3日根据空腹血糖水平进行基础胰岛素剂量的滴定:>180 mg/dL(10.0 mmol/L)增加20%,140-180 mg/dL(7.8-10.0 mmol/L)增加10%,110-139 mg/dL(6.1-7.8 mmol/L)增加1个单位,而低血糖时如果血糖< 70 mg/dL(3.9 mmol/L)或< 40 mg/dL(2.2 mmol/L)则每日剂量分别要减少20%或40%。再次提到了SUs2,建议如果加用胰岛素治疗就要停用SUs或者减量,并且还认为使用基础胰岛素类似物治疗优于中效胰岛素(NPH)。如果加用基础胰岛素治疗后仍然不能达到血糖控制目标,有2种推荐的治疗方法:(i)加用非胰岛素类的治疗药物,建议加用GLP-1 RA或SGLT2抑制剂或DPP-4抑制剂;或者(ii)加用餐时胰岛素,开始时的每日胰岛素总剂量为0.3-0.5 U/kg/天,使用人胰岛素与预混胰岛素治疗是不太理想的治疗方法。如果餐后2小时的血糖水平超过180 mg/dL(10.0 mmol/L)就要对加用的治疗药物剂量进行滴定。 这些推荐的治疗方法都很复杂,并且ADA与AACE的方法具有许多相似性与差异性(表1)。两者都推荐了3个不同的HbA1c目标,通常来说AACE的方法都更为严格;两者都推荐改变生活方式与治疗药物一样重要;两者都强调了启动药物治疗后同时需要每3个月监测一次HbA1c目标,而这也是强化治疗所需。虽然两者都需要使用自我监测血糖(SMBG)水平来调整胰岛素剂量,但是AACE推荐的血糖治疗目标更低,并且AACE还推荐使用SMBG来判断一名特定患者的治疗方案是否最佳,包括空腹或者餐后血糖都要达标。虽然AACE与ADA/EASD都明确表明治疗必须以患者为中心并且要遵循个体化原则,但是ADA/EASD推荐的治疗方案一直都是使用二甲双胍作为初始治疗药物,然而AACE却是根据基线HbA1c水平进行分层治疗,允许一开始就是二联治疗或者三联治疗,更加强调要将那些不适合一开始就使用二甲双胍治疗的亚组患者识别出来(例如晚期肾病患者;在它的2015年更新部分中5,ADA/EASD提到了如果HbA1c超过9%,需要考虑一开始就使用二联治疗)。AACE推荐的治疗药物包括了所有经美国食品与药品管理局(FDA)批准的降糖药物并且将药物选择进行了排名,然而ADA/EASD指南仅仅罗列了主要的6类药物而没有推荐药物的排名顺序。AACE推荐指南明确聚焦于降低空腹与餐后血糖的差异,列出了更多种类的药物,并且对更多不同的潜在药物不良效应作出了评论;AACE与ADA的优化胰岛素使用方法在某种程度上有些差异。 最后,ADA与AACE的治疗方法代表的都是专家共识,因此具有其局限性,因为对于特定的患者来说其特征具有无数种可能性,缺乏来自随机对照试验的证据证实什么才是最佳的治疗方案。对于一名特定的患者来说,我们还缺乏患者水平的meta分析来帮助我们预测何种药物或者是哪一类药物最为安全或是最为有效,特别是在联合用药时。因此我们在治疗高血糖时应该谨慎用药,小心地根据HbA1c与SMBG来明确高血糖情况,逐步调整治疗药物的种类与剂量,并且还要聚焦于潜在的药物不良效应。有些治疗方法可能还具有额外获益(体重、血压以及血脂),因此对于一名特定的患者来说这些药物可能就会显得更加合适或者更加不合适。也许心血管结果数据将可以最终帮助我们提高药物分层选择的特异性6。ADA与AACE推荐的治疗方法都为我们提供了重要的见解。在未来的岁月里随着新型药物以及新研究结果的问世,我们期待会有进一步的变化。

As compared to allopurinol, urate-lowering therapy with febuxostat has superior effects on oxidative stress and pulse wave velocity in patients with severe chronic tophaceous gout

We prospectively evaluated whether an effective 12-month uric acid-lowering therapy (ULT) with the available xanthine oxidase (XO) inhibitors allopurinol and febuxostat in patients with chronic tophaceous gout has an impact on oxidative stress and/or vascular function. Patients with chronic tophaceous gout who did not receive active ULT were included. After clinical evaluation, serum uric acid levels (SUA) and markers of oxidative stress were measured, and carotid-femoral pulse wave velocity (cfPWV) was assessed. Patients were then treated with allopurinol (n = 9) or with febuxostat (n = 8) to target a SUA level ≤ 360 μmol/L. After 1 year treatment, the SUA levels, markers of oxidative stress and the cfPWV were measured again. Baseline characteristics of both groups showed no significant differences except a higher prevalence of moderate impairment of renal function (estimated glomerular filtration rate <60 ml/min) in the febuxostat group. Uric acid lowering with either inhibitors of XO resulted in almost equally effective reduction in SUA levels. The both treatment groups did not differ in their baseline cfPWV (allopurinol group: 14.1 ± 3.4 m/s, febuxostat group: 13.7 ± 2.7 m/s, p = 0.80). However, after 1 year of therapy, we observed a significant cfPWV increase in the allopurinol group (16.8 ± 4.3 m/s, p = 0.001 as compared to baseline), but not in the febuxostat patients (13.3 ± 2.3 m/s, p = 0.55). Both febuxostat and allopurinol effectively lower SUA levels in patients with severe gout. However, we observed that febuxostat also appeared to be beneficial in preventing further arterial stiffening. Since cardiovascular events are an important issue in treating patients with gout, this unexpected finding may have important implications and should be further investigated in randomized controlled trials.

SAT0357 As Compared with Allopurinol Only Febuxostat Preserves Vascular Function in Patients with Chronic Tophaceous Gout

BackgroundGout patients often suffer from metabolic comorbidities, such as arterial hypertension, hyperlipoproteinaemia, or diabetes which, presumably via deteriorating endothelial function, frequently result in increased vascular stiffness. Increased arterial stiffness has...

Clinical feature and efficacy of patients with multiple myeloma and renal impairment treated with bortezomib based chemotherapy

To explore the efficacy and safety of bortezomib (btz) based chemotherapy in multiple myeloma (MM) patients with renal-function impairment (RI). Fifty-six MM patients with impaired renal function treated with bortazomib based regimens in our single center were retrospectively analyzed. The median age was 59 (ranged 30-77) years. 39.3% were κ-restricted MM, while 57.1% were λ-restricted MM. Nine patients were IgD-MM, and 14 were light chain MM. Median creatinine clearance (CrCl) was 25.33 (7.23-59.55) ml/min. The number of patients with mild, moderate and severe RI was 6, 35 and 15, respectively. Overall response rate of MM was 82.4% (≥MR), including 32.4% complete response (CR), 17.6% very good partial response (VGPR) and 26.5% partial response (PR). The rate of renal response was 89.3%, including 62.5% CR, 14.3% PR and 12.5% minor response (MR). A median time of optimal response was 25.5 (ranged 5-240) days. There was no significant difference in the median overall survival and the time to progress in different RI groups. Adverse events observed were similar to those patients with normal renal function previously reported. Most adverse events were manageable, 55.6% patients developed peripheral neuropathy and 10 patients discontinued bortezomib. The incidence of RI is higher in patients with IgD-MM and λ restricted MM. Bortezomib based treatment is a highly effective and safe option in MM patients with impaired renal function. In this analysis, renal function was improved in a substantial proportion of patients. Peripheral neuropathy is the major adverse events which limit its use in MM patients.

GRP-100 Incidence of Errors in Drug Dosage According to Kidney Function-Estimating Equations in Medical Inpatients

BackgroundInpatients frequently require dose adjustments of medicines due to acute changes in renal function. The FDA recommend adjusting medicines according to the estimated glomerular filtration obtained with the Cockcroft-Gault formula....

Spectrum of Clinical Presentations in Human Immunodeficiency Virus (HIV) Infected Patients with Renal Disease.

HIV infection is a multiorgan disease with the kidney not spared. A variety of renal syndromes with varying clinical presentations has been reported amongst HIV infected patients. This study aims to highlight the spectrum of clinical presentations in HIV infected patients with renal disease. HIV infected patients presenting at University of Benin Teaching Hospital (UBTH) Benin City were the study population. A total of 383 patients were studied. Their biodata, clinical presentations and laboratory investigations including serum urea, creatinine and albumin, urine protein and creatinine were assessed. Their glomerular filtration rate (GFR) and protein urine excretion were calculated using six equations of modification of diet in renal disease (MDRD) and protein: creatinine ratio respectively. Patients were stratified according to their renal functions into normal, mild, moderate and severe renal function impairment. The data was analysed using statistical software program SPSS Vs 15.0. 53.3% of 383 patients screened had renal function impairment, 40.2% mild, 37.7% moderate and 22.2% severe impairment. Mean age was 35.6±8.3, 36.0±9.9 and 36.3±8.3 years for mild, moderate and severe renal function impairment (RFI) respectively. Easy fatigability was the commonest symptoms occurring in 47.5%, 30.0%, 37.5% and 22.5% of control, mild RFI, moderate RFI and severe RFI subjects respectively (p = 0.568). Oliguria, facial and body swelling occurred more in patients with RFI especially in patients with severe renal impairment. The difference is statistically significant (p = 0.046, 0.041, and 0.033 respectively). Pallor was the commonest clinical sign occurring in 32.5%, 50.0%, 35.0% and 62.5% of control and patients with mild, moderate, and severe RFI respectively; the difference was not statistically significant (p = 0.459). Ascites, facial puffiness and pedal oedema were commoner in patients with RFI especially those with severe RFI. The differences were statistically significant. (p = 0.048, 0.019, and 0.008 respectively). In conclusion spectrum of clinical presentations in HIV patients with renal impairment are many but few are specific to these patients.

Impact of Mild to Moderate Renal Dysfunction on Left Ventricular Relaxation Function and Prognosis in Ambulatory Patients With Nonischemic Dilated Cardiomyopathy

The relationship between mild-to-moderate renal dysfunction and cardiac diastolic dysfunction and cardiac events in patients with nonischemic dilated cardiomyopathy (NDCM) has not been fully elucidated. The aim of this study was to investigate the relationship between renal and cardiac function, as well as clinical outcome in patients with NDCM.We measured plasma BNP and eGFR, and performed cardiac catheterization in 135 patients with NDCM. LV dP/dt(max)and T(1/2) were determined as indexes of LV contractility and isovolumic relaxation, respectively. During a mean follow-up of 4.8 years, we monitored all patients for the occurrence of cardiac events, which were defined as cardiac death (from worsening HF or sudden death) and unscheduled admission for decompensated HF. Patients were classified into 3 groups on the basis of eGFR (mL min(-1) 1.73 m(-2)): eGFR ≥ 90 (n = 23, group A), 60 ≤ eGFR < 90 (n = 70, group B), and 30 ≤ eGFR < 60 (n = 42, group C). Whereas LV dP/dt(max) did not significantly differ among the 3 groups, T(1/2) was significantly longer in groups B and C than in group A (P < 0.01). Event-free survival in group C was significantly lower than that in groups A and B (P = 0.014, log-rank test). These results suggest that even mild renal dysfunction is associated with LV isovolumic relaxation impairment. In addition, moderate impairment of renal function is independently associated with cardiac events in patients with NDCM.

Effects of Partial Liver Ischemia Followed by Global Liver Reperfusion on the Remote Tissue Expression of Nitric Oxide Synthase: Lungs and Kidneys

Hepatic ischemia followed by reperfusion (IR) results in mild to severe remote organ injury. Oxidative stress and nitric oxide (NO) seem to be involved in the IR injury. Our aim was to investigate the effects of liver I/R on hepatic function and lipid peroxidation, leukocyte infiltration and NO synthase (NOS) immunostaining in the lung and the kidney. We randomized 24 male Wistar rats into 3 groups: 1) control; 2) 60 minutes of partial (70%) liver I and 2 hours of global liver R; and 3) 60 minutes of partial (70%) liver I and 6 hours of global liver R. Groups 2 and 3 showed significant increases in plasma alanine and aspartate aminotransferase levels and in tissue malondialdehyde and myeloperoxidase contents. In the kidney, positive endothelial NOS (eNOS) staining was significantly decreased in group 3 compared with group 1. However, staining for inducible NOS (iNOS) and neuronal NOS (nNOS) did not differ among the groups. In the lung, the staining for eNOS and iNOS did not show significant differences among the groups; no positive nNOS staining was observed in any group. These results suggested that partial liver I followed by global liver R induced liver, kidney, and lung injuries characterized by neutrophil sequestration and increased oxidative stress. In addition, we supposed that the reduced NO formation via eNOS may be implicated in the moderate impairment of renal function, observed by others at 24 hours after liver I/R.

Safety of sildenafil citrate: review of 67 double-blind placebo-controlled trials and the postmarketing safety database

Aim:To review special safety topics associated with sildenafil and to document the tolerability of 50- and 100-mg doses, overall and by age, in men with erectile dysfunction (ED).Methods:Data were collated from 67 double-blind placebo-controlled (DBPC) trials (> 14,000 men) conducted by the manufacturer and from the manufacturer’s postmarketing safety database (39,277 patients). The DBPC data were stratified by dose, starting dose and age (≥ 65 and ≥ 75 years). Special safety topics included cardiovascular risk, priapism, non-arteritic anterior ischaemic optic neuropathy (NAION), impaired renal and hepatic function, drug interactions (i.e. nitrates, cytochrome P3A4 inhibitors, other ED therapies and α-blockers) and incorrect use.Results:Sildenafil was well tolerated at a dose of 50 or 100 mg in men with ED, overall, in those aged ≥ 65 years, and in those aged ≥ 75 years. Analyses of the databases did not reveal any causal link between sildenafil and cardiovascular events, or any new safety risks relating to cardiovascular events, priapism, NAION, hearing loss or drug interactions. In the small number of men with moderate impairment of renal function or hepatic function who were treated with sildenafil in DBPC trials, the safety profile was similar to that in men with no impairment of renal or hepatic function. Overdose with sildenafil was rare in the ED population. No new safety issues, emerging trends or adverse reactions were identified in conjunction with overdose, dependence, abuse or misuse.Conclusion:This collated review confirms generally the good tolerability and established safety profile of sildenafil 50 and 100 mg in men with ED and reveals no new safety issues.

Moderate Renal Function Impairment Does Not Affect Outcomes of Reduced-Intensity Conditioning with Fludarabine and Melphalan for Allogeneic Hematopoietic Stem Cell Transplantation

Nonrelapse mortality (NRM) after reduced-intensity allogeneic transplants is likely to be influenced by abnormalities in renal function. We studied 141 patients diagnosed with acute myelogenous leukemia (AML) (n = 131) or high-risk myelodysplastic syndrome (MDS) (n = 10) who underwent allogeneic transplantation with fludarabine (Flu)/melphalan (Mel)-based regimens and hypothesized that moderate to mild renal function impairment increases NRM in this setting. Flu dose consisted of 25-30 mg/m(2) for 4 days and Mel dose was 100-180 mg/m(2). Donors were HLA-compatible siblings (n = 69) and matched unrelated donors (n = 72). Disease status at transplantation was complete remission (n = 56, 40%) or active disease (n = 85, 60%). The influence of the estimated glomerular filtration rate (GFR) measured before transplantation on outcomes was analyzed. GFR was estimated by both the Cockcroft-Gault (CG) and the modified diet in renal disease (MDRD) equations, using the creatinine value obtained prior to starting chemotherapy. Evaluated outcomes were overall survival (OS), NRM, and treatment-related mortality (TRM) at day 100 and 1-year posttransplantation. Median age was 55 years (range: 21-74 years); 59% of the patients were male. Estimated GFR by CG was > or =90 for 45 (32%), 60-89 for 78 (55%), and <60 for 18 (13%) patients. When estimated by MDRD, GFR was > or =90 for 65 (46%), 60-89 from 66 (47%), and <60 for 10 (7%) patients. The majority of patients by both estimations had a GFR between 60 and 89 (n = 78 by CG and n = 66 by MDRD) with no difference in the evaluated outcomes between this group and the subgroup of patients with a GFR <60 (P > .05). There were no differences in OS and NRM at day 100 and 1-year posttransplantation in the 3 groups by any GFR estimation method. In conclusion, a mild to moderate decrease in GFR was not associated with an increase in NRM.

Effects of partial liver ischemia followed by global liver reperfusion on remote organs: lungs and kidneys

Hepatic ischemia (I) followed by reperfusion (R) results in mild to severe remote organ injury. Oxidative stress and nitric oxide (NO) seems to be involved in I/R injury. The aim was to investigate the effects of liver I/R on liver function and on lipid peroxidation, leukocyte infiltration and NO synthase (NOS) immunostaining in lung and kidney. 24 male Wistar rats were randomized into 3 groups: 1) sham, 2) 60 min of partial (70%) liver I and 2 h of global liver R, and 3) 60 min of partial (70%) liver I and 6 h of global liver R. The groups 2 and 3 presented a significant increase in plasma levels of alanine and aspartate aminotransferase and in tissue levels of malondialdehyde and myeloperoxidase. In the kidney, the positive endothelial NOS (eNOS) staining was significantly decreased in group 3 compared to 1 and the staining for inducible NOS (iNOS) and neuronal NOS (nNOS) did not differ among groups. In the lung, the staining for eNOS and iNOS did not present statistical differences among groups and no positive nNOS staining was observed in any group. These results suggest that partial liver I followed by global liver R induces liver, kidney and lung injuries characterized by neutrophil sequestration and oxidative stress increase. In addition, we can suppose that the reduction in NO formation via eNOS can be implicated in the moderate impairment of renal function, observed by others, 24 hours after liver I/R. Support: FAPESP; FAEPA.

Evaluation of the clinical application of cystatin C, a new marker of the glomerular filtration rate, for the initial dose-setting of arbekacin

Recent studies have shown that serum cystatin C is a better marker for measuring the glomerular filtration rate (GFR) than the conventional method, using serum creatinine concentration. The purpose of this study is to evaluate the clinical application of serum cystatin C as a marker of GFR to determine the initial dosage of arbekacin, an antibiotic primarily excreted via the kidneys. In this study, the predictability of serum arbekacin peak and trough concentrations were assessed using estimated population mean GFR values calculated from either serum creatinine (Cockcroft-Gault equation) or cystatin C (Sjöström equation) concentrations. Ninety-five patients treated with arbekacin for methicillin-resistant Staphylococcus aureus infection were divided into three groups according to their GFR values estimated by the serum cystatin C concentration as follows: normal to mild (GFR > 70 mL/min, n = 40), moderate (30 </= GFR </= 70 mL/min, n = 41) and severe (GFR < 30 mL/min, n = 14) renal impairment. The mean GFR (+/-SD) of 95 patients predicted by serum cystatin C concentration (64.6 +/- 30.6 mL/min) was significantly lower (P < 0.001) than predicted by serum creatinine concentration (77.4 +/- 43.9 mL/min). Prediction (difference of mean prediction error, DeltaME) of the serum arbekacin concentration using the estimated GFR based on the serum cystatin C concentration was significantly less biased at the peak and trough concentrations than those determined using serum creatinine concentration. The accuracy of prediction (difference of the mean absolute error, DeltaMAE) using serum cystatin C concentration was significantly better than with serum creatinine for both serum peak and trough concentrations in patients with moderately decreased GFR. However, there were no significant differences in the DeltaMAE of normal to mild and severe renally impaired patients. These results suggest that serum cystatin C is a useful marker of GFR for determining the initial dosage of arbekacin, especially in patients with moderate impairment of renal function.