Clinical approach to lupus nephritis: Recent advances

Kidney involvement is common in systemic lupus erythematosus (SLE). Its clinical presentations are highly variable, ranging from mild asymptomatic proteinuria and/or hematuria to rapidly progressive uremia. Histological evidence of lupus nephritis is present in most patients with SLE, even when they do not yet have clinical manifestations. Current classification ISN/RPS 2003 (International Society of Nephrology/Renal Pathology Society) of lupus nephritis was promoted by a widely perceived need to re-examine existing classification, provide clearer distinctions between the histological classes, and improve diagnostic reproducibility and interobserver agreement. Lupus nephritis is a serious disease whose prognosis can usually be improved dramatically by treatment, but treatment is potentially toxic, prolonged, and complex. Current treatment regimens combine corticosteroids with cyclophosphamide, azathioprine or ciclosporin; mycophenolate mofetil has received much recent attention as a potentially immune suppressive agent and less aggressive immunosuppressive regimens can be prescribed. SLE patients should be regular followed to detect early kidney involvement.     

肾移植患者MRP2C3972T基因多态性对吗替麦考酚酯药动学参数、不良反应及急性排斥反应的影响

目的：研究MRP2 C3972T基因突变对肾移植术后患者服用吗替麦考酚酯药动学参数.不良反应及急性排斥反应的影响.方法：采用聚合酶链反应（PCR）和限制性内切片段长度多态性（RFLP）方法检测肾移植患者MRP2 C3972T基因型,比较不同基因型患者之间吗替麦考酚酯的药动学参数.不良反应及急性排斥反应发生率的差异.结果：肾移植术后第7天.第14天.第30天各基因型患者在C0、C0/D、AUC0-12、AUC0-12/D等值上没有显著性差异,但突变型患者（C/C＋T/T）在术后第7天、第14天、第30天的C0/D、AUC0-12/D均低于野生型（C/C）患者.三组间不良反应及急性排斥反应发生率没有显著差异.结论：MRP2C3972T突变可以在一定程度上降低血浆中麦考酚酸的浓度.     

吗替麦考酚酯胶囊含量和有关物质的测定

目的采用反相高效液相色谱法建立吗替麦考酚酯胶囊的有关物质测定法。方法色谱柱symmetry C18150＊4.6mm,流动相为：乙腈-水-三乙胺磷酸缓冲液（取三乙胺10mL,加水990mL,混匀,磷酸调节pH值至5.4±0.1）（40∶40∶20）;流速：1.0mL·min-1,检测波长为249nm;柱温45℃。结果制剂中辅料对主药测定无干扰,吗替麦考酚酯在60.2μg~602.4μg.mL-1浓度范围内,峰面积与浓度线性关系良好,相关系数r=0.99995;平均回收率为99.9%,变异系数为1.4%。溶液在冷藏5℃条件下,4h内稳定,24h降解产物明显增加,因此供试品溶液宜现配现用;麦考酚酸在4.6μg~46.05μg.mL-1范围内R=0.99995;平均回收率为98.5%;精密度测定变异系数为：0.46%。结论本法简便,准确,专属性强,可用于吗替麦考酚酯胶囊的有关物质检查和含量测定。     

Mycophenolate mofetil is effective in reducing lupus glomerulonephritis proteinuria

Mycophenolate mofetil (MMF) significantly reduces proteinuria in experimental model of human membranous nephropathy (Heymann nephritis). Twenty consecutive SLE patients with persistent isolated severe proteinuria and/or proteinuric flare were studied for 18 months of MMF therapy. All of them presented stable renal function and 12 had biopsy proven membranous glomerulonephritis (WHO class V). The starting daily dose for MMF was 1.5 g to a maximum of 3 g. Patients were divided into: partial response, ≥50% decrease of baseline proteinuria; complete response, normal proteinuria levels (less than 0.3 g/24 h); flare, increase of at least 50% of the mean baseline proteinuria. All 20 SLE patients (100%) presented a 50% reduction of baseline proteinuria which was achieved in 8.2±3.3 months of MMF therapy, at a mean daily dose of 2.3±0.5 g. A significant decrease in 24-h protein excretion was observed compared to entry (3.47±1.26 vs. 1.33±0.67 g, P<0.0001) as well as a correspondent increase of serum albumin (3.2±0.4 vs. 3.7±0.4 mg/dl, P=0.02) and reduction of prednisone dose (33.7±20.0 to 18.6±14.1 mg/day, P=0.01). Complete response was observed in 11 SLE patients (55%) in 12.2±3.0 months of therapy with a significant decrease in proteinuria (P<0.0001), prednisone dose (P<0.0001) and an increase of serum albumin (P=0.003). Interestingly, initial proteinuria or serum albumin levels did not identify patients with complete response and those with partial response at the end of the study (P=0.543 and 0.657, respectively). Our pilot prospective study suggests that MMF appears to be effective in reducing severe persistent proteinuria in lupus glomerulonephritis, even in patients unresponsive to other immunosuppressive treatments.Dr. Bonfá’s work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico, grant 304756/2003-2.     

吗替麦考酚酯软胶囊的药动学及生物等效性研究

目的:研究吗替麦考酚酯软胶囊与吗替麦考酚酯胶囊在健康人体内的相对生物利用度及药动学,评价2种制剂的生物等效性。方法:采用双周期随机交叉设计,20名男性健康志愿者单剂量口服试验软胶囊或参比胶囊4粒(每粒0.25g),以高效液相色谱法测定血浆中霉酚酸(MPA)浓度。运用DAS2.0软件处理血药浓度数据和计算药动学参数,对2种制剂做出生物等效性评价。结果:受试者口服1.0g吗替麦考酚酯软胶囊试验药或参比胶囊,其AUC0→t分别为(69.95±14.13)、(66.95±19.05)μg·h·mL-1,AUC0→∞分别为(85.18±20.51)、(77.39±23.78)μg·h·mL-1,Cmax分别为(31.26±13.09)、(31.90±14.45)μg·mL-1,tmax分别为(0.875±0.358)、(0.775±0.291)h,t1/2分别为(20.342±12.546)、(18.837±11.579)h。20名健康志愿者单剂量口服吗替麦考酚酯软胶囊试验药的相对生物利用度为(109.6±26.9)%。结论:试验软胶囊与参比胶囊具有生物等效性。     

Mycophenolate Mofetil Reduces Tissue Damage and Inflammation in an Experimental Model of Colitis in Rats

Background: Lymphocytes are widely believed to be responsible for persistent intestinal inflammation in inflammatory bowel diseases. Mycophenolate mofetil (MMF) is a potent immunosuppressant that inhibits lymphocyte proliferation and has been shown to be effective in preventing allograft rejection after organ transplantation. The purpose of this study was to assess the modulating effects of MMF on intestinal inflammation in an experimental model of colitis in rats. Methods: Colitis was induced by rectal instillation of trinitrobenzenesulfonic acid (TNBS) in ethanol in male Sprague-Dawley rats. One group of rats (n=10) was treated with MMF i.p. (25 mg/kg b.w.) daily for 1 week starting 24 h after induction of colitis. A second group of rats (n=10) was treated with MMF at the same dose 2 days, 1 day and 1 h prior to induction of colitis. Control animals (n=10) received vehicle only. After being killed, colonic tissue was macroscopically evaluated for necrosis and microscopically for ulcerations. Sections were stained and examined for the presence of granulocytes. Results: Administration of MMF after induction of TNBS colitis reduced macroscopic injury by 62% compared to control animals (P=0.01). Microscopic ulcerations were reduced by 64% compared to controls (P=0.009). In addition, posttreatment significantly reduced the number of granulocytes. MMF pretreatment did not significantly prevent macroscopic or microscopic tissue damage, or change the number of granulocytes. Conclusion: Systemic administration of MMF significantly ameliorates tissue damage in a model of experimental colitis in rats suggesting that this compound may play an important role as an immunosuppressant in the therapy of inflammatory bowel diseases.     

Mycophenolic acid trough level monitoring in solid organ transplant recipients treated with mycophenolate mofetil: association with clinical outcome

ABSTRACT

Background: Mycophenolate mofetil (MMF) is widely and successfully used in immunosuppressive regimens for the prophylaxis of organ rejection following transplantation. Conventionally, it is administered at a fixed dose without serial measurements of plasma concentrations of mycophenolic acid (MPA), the active metabolite. Recently, there has been an increased interest in therapeutic drug monitoring (TDM) of MMF therapy to optimize the benefit/risk index of the drug. Predose trough samples of MPA are considered most convenient and economic, thereby allowing an increased use of TDM in the transplant setting. However, the added value of TDM for MMF therapy is still under debate.

Objective: This paper reviews (based on a systematic PubMed and EMBASE search, 1995–June 2006) the current evidence of the usefulness and clinical relevance of MPA trough level monitoring during MMF therapy in solid organ transplantation.

Findings and conclusions: Based on data available in the public domain, the contribution of MPA trough level monitoring during MMF therapy in solid organ transplant recipients remains unproven. Available studies have limitations and report conflicting results. There is a lack of prospective randomized trials, particularly in pediatric renal transplant recipients and in cardiac and liver transplantation. While there is a suggestion that there may be a relationship between efficacy and MPA trough levels, the majority of studies showed no correlation between MPA plasma concentrations and adverse effects. Based on current evidence, the adherence to presently recommended target ranges for MPA troughs in solid organ transplantation cannot assure an improved clinical outcome with MMF therapy. Whether MPA trough level monitoring leads to improved efficacy and less toxicity is currently subject to a large randomized trial; final results are eagerly awaited.     

HPLC法测定狼疮肾病患者口服吗替麦考酚酯后的血药浓度

目的:建立测定狼疮肾病患者口服吗替麦考酚酯后血药浓度的方法。方法:狼疮肾病患者血样处理后采用高效液相色谱法测定吗替麦考酚酯体内代谢物霉酚酸。色谱柱为SGE Protecol C18,流动相为甲醇-乙腈-0.01%磷酸(23∶37∶40,V/V/V),检测波长为216nm,流速为1.0ml/min,进样量为20μl,柱温为30℃。结果:霉酚酸血药浓度在0.125～10mg/L范围内线性关系良好(r=0.9999);方法回收率为98.67%～104.31%;萃取回收率为83.43%～97.54%,内标(尼美舒利)萃取回收率为79.35%;日内、日间RSD分别为2.6%～7.7%、2.3%～8.5%。结论:本法简单、准确,可用于狼疮肾病患者服用吗替麦考酚酯后霉酚酸的血药浓度检测。     

来氟米特与霉酚酸酯治疗乙肝病毒相关性肾炎的疗效比较

目的比较来氟米特(LEF)与霉酚酸酯(MMF)治疗乙型肝炎病毒相关性肾炎(HBV-GN)的临床疗效。方法 20例血清HBV标记物阳性、病理诊断为乙型肝炎病毒相关性肾炎的患者,随机分为两组,每组10例,第一组采用LEF联合激素治疗,第二组采用MMF联合激素治疗,LEF或MMF正规使用6个月以上。两组中有HBV-DNA复制的均给予干扰素-α或恩替卡韦治疗。观察治疗前及治疗6个月以后的血尿常规、24h尿蛋白定量、肝肾功能、白蛋白及血脂等指标变化,以及用药期间所有不良反应。结果①两组接受治疗后,尿蛋白明显减少(P<0.01),血白蛋白明显上升(P<0.01)。②治疗6个月后LEF组总有效率为80.0%,MMF组总有效率为80.0%,两组之间无统计学差异;其中完全缓解率分别为40.0%和50.0%,部分缓解率分别为40.0%和30.0%,均无统计学差异(P>0.05)。③两组患者均耐受良好,无明显副作用。结论 LEF和MMF联合激素治疗均能有效缓解乙型肝炎病毒相关性肾炎,不良反应轻微。     

New immunosuppressive agents in transplantation

Immunosuppressive agents have enabled the development of allogenic transplantation during the last 40 years, allowing considerable improvement in graft survival. However, several issues remain such as the nephrotoxicity of calcineurin inhibitors, the cornerstone of immunosuppressive regimens and/or the higher risk of opportunistic infections and cancers. Most immunosuppressive agents target T cell activation and may not be efficient enough to prevent allo-immunization in the long term. Finally, antibody mediated rejection due to donor specific antibodies strongly affects allograft survival.Many drugs have been tested in the last decades, but very few have come to clinical use. The most recent one is CTLA4-Ig (belatacept), a costimulation blockade molecule that targets the second signal of T cell activation and is associated with a better long term kidney function than calcineurin inhibitors, despite an increased risk of acute cellular rejection.The research of new maintenance long-term immunosuppressive agents focuses on costimulation blockade. Agents inhibiting CD40-CD40 ligand interaction may enable a good control of both T cells and B cells responses. Anti-CD28 antibodies may promote regulatory T cells. Agents targeting this costimulation pathways are currently evaluated in clinical trials.Immunosuppressive agents for ABMR treatment are scarce since anti-CD20 agent rituximab and proteasome inhibitor bortezomib have failed to demonstrate an interest in ABMR. New drugs focusing on antibodies removal (imlifidase), B cell and plasmablasts (anti-IL-6/IL-6R, anti-CD38…) and complement inhibition are in the pipeline, with the challenge of their evaluation in such a heterogeneous pathology.