重度病理分级IgA肾病的免疫抑制治疗研究

  本文关键词：重度病理分级IgA肾病的免疫抑制治疗研究，，由笔耕文化传播整理发布。

        研究背景IgA肾病(Immunoglobulin A nephropathy, IgAN)是世界范围内最常见的原发性肾小球疾病。其临床表现谱广泛,异质性强,疾病进展具有免疫相关性。预后评估直接影响治疗决策的制定,一些临床指标如初始肾功能、病理分级以及随访蛋白尿、血压水平已用于预后风险评估。进展性IgAN患者的临床及病理表现更严重,更易进展至终末期肾病,预后不佳,因此有必要积极免疫抑制治疗,或可阻断甚至逆转肾功能进展过程。有研究指出,积极初始免疫抑制治疗的缓解情况与肾脏预后密切相关,但上述结论基于病理较轻的IgAN患者群体,目前尚缺乏针对重度病理分级IgAN患者的治疗及预后研究,因而治疗方案的选择亦缺乏足够证据,最新KDIGO (Kidney Disease Improving Global Outcomes, KDIGO)治疗指南肾小球肾炎部分几乎所有推荐项目均基于较低级别证据。免疫抑制治疗决策制定的主要考量在于权衡控制疾病进展的需要以及治疗可能带来的不良反应。目前针对重度病理分级IgAN免疫抑制治疗加用时机、疗效及不良反应(尤其是重症肺炎感染)的研究甚少。研究目的1.评估重度病理分级IgAN患者的尿蛋白、血压、初始肾功能、初始缓解复发情况与疗效及预后的关系；2.分析重度病理分级IgAN患者免疫抑制治疗相关的常见重要不良反应,进一步研究北京协和医院院IgAN患者免疫抑制治疗中出现重症不良反应肺孢子菌肺炎(PCP)的临床特点、治疗以及预后情况；3.评价北京协和医院(PUMCH)重度病理分级IgAN患者的治疗方案,以及激素联合环磷酰胺(CTX)的使用情况与疗效；研究方法选取2006年3月至2010年3月接受肾活检且于北京协和医院门诊随访,临床和病理资料保存完整,病理分级Lee氏Ⅳ级以上的IgAN患者,除外肝硬化、人类免疫缺陷病毒(HIV)感染等系统性疾病继发IgA沉积肾病以及狼疮肾炎等免疫病。对符合上述条件且规律随访至少1年的患者共99例进行分析。收集临床、病理及随访资料,回顾性分析患者起病临床表现、随访指标、治疗及预后情况。研究结果1.全组99名患者起病年龄32(13-70)岁,起病平均动脉压(MAP)105.12±18.77mmHg,估测肾小球滤过率(eGFR[CKD-EPI公式])67.65±27.85ml/min/1.73m2,24小时尿蛋白定量(24hUP)2.43(0.25-25.00) g/d,随访时长41(12-84)个月,随访过程总时间平均尿蛋白定量(TA-UP)1.29±1.20g/d,总时间平均动脉压(TA-MAP)93.22±12.44mmHg, eGFR变化率0.1143±1.3600ml/min/1.73m2/月。随访过程总TA-UP (P<0.001)和总TA-MAP水平(P=0.002)与血肌酐(SCr)变化速率密切相关。且TA-UP<1g/d组肾功能下降速率较总TA-UP≥1g/d组更慢。2.与初始不缓解组相比,初始缓解组随访期间肾功能下降速率更慢,总TA-UP水平更低(P=0.008),主要治疗方案单用激素的比例更高(P=0.031)。初始缓解后2年内出现复发的患者(n=8),与未出现复发的患者(n=9)相比,肾功能下降速率更快,随访终点缓解率也更低(P=0.009)。3.与非感染风险组(n=86)相比,感染风险组(n=13) eGFR下降率(P=0.047)及SCr上升率(P=0.011)较高,联合治疗激素日均剂量(P=0.001)较大,免疫抑制剂使用数目(P=0.011)较多,且终点事件数目(P=0.035)较多。11名(25.0%)月经异常患者中3名表现为绝经,5名表现为停经数月。4.北京协和医院IgAN免疫抑制治疗中临床诊断PCP的10名患者中,7名(70%)患者诊断IgAN后4个月之内出现PCP。9名患者(90%)PCP起病时eGFR<60ml/min/1.73m2。2007年后发病的患者自PCP出现至针对性用药的时间间隔为9.50±3.89天。8名患者经治疗获得临床缓解,平均住院时间为32.8±23.1天。5.北京协和医院重度病理分级IgAN患者,绝大多数患者接受联合免疫抑制治疗78名(78.8%),其中激素联合CTX比例最高(88.5%)。全组患者初始6个月、第一年、第二年、超过2年的随访终点缓解率分别为55.2%、59.3%、67.2%、50.0%。严重不良反应6(6.1%)例,终点事件6(6.1%)例。研究结论1.重度病理分级IgAN患者的随访中总TA-UP和总TA-MAP水平与肾功能下降速度密切相关；初始缓解的患者肾功能下降速率慢,预后更好,初始缓解后2年内出现复发与肾功能恶化和预后不良相关。2.感染风险的发生或与疾病进展及不良预后相关；联合免疫抑制治疗中激素日均剂量、免疫抑制剂使用数目影响感染风险的发生；3. IgAN患者接受强化免疫抑制治疗开始后,前6个月PCP的发生风险高；慢性肾功能不全很可能是发生重症感染PCP的危险因素,早期疑诊及时针对性用药对改善IgAN免疫抑制治疗合并PCP感染的预后或有重要意义。4.北京协和医院对重度病理分级IgAN患者积极采用免疫抑制治疗,联合免疫抑制治疗比例高,其中激素联合CTX方案最为常用,治疗缓解率高,严重不良反应发生率低,治疗方案的选择较好地平衡了肾病进展的控制与不良反应的规避。

    BackgroundIgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. It has a wide spectrum of clinical presentations and the prevalence rate varies across different geographical regions. Immunological factors could be partially responsible for disease progression. Key to therapeutic decision making is assessment of the individual’s prognosis. Clinical parameters (such as renal function, pathology stage, proteinuria and hypertension) are used to predict prognosis and risk of progression. More severe clinical and pathological manifestations in progressive IgAN patients are associated with a worse renal prognosis and higher incidence of end-stage renal disease. In this case, active immunosuppressive therapy should be considered in order to block or even reverse the progression of this disease. Furthermore, close relationship between clinical remission initially achieved after immunosuppressive therapy and the long-term renal outcome of IgAN has been reported, however it is more likely to be seen in early pathology stages and has not been clarified in individuals with severe pathology stages. Moreover, treatment options for progressive IgAN is still largely based on opinion or weak evidence. Consequently, the recent Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for Glomerulonephritis have assigned low levels of evidence for almost all recommendations and suggestions related to the disease. The immunosuppressive therapy for IgAN is still a controversial issue because of scepticism regarding expected results and concerns about possible side effects. Currently, only a few studies have evaluated the indication, efficacy and side effects (especially for infection like severe pneumonia) of immunosuppressive therapy for progressive IgAN.Objectives1. Investigating the relationship between proteinuria, blood pressure, initial renal function and prognosis, and further explore relationship between clinical remission achieved after initial therapy, recurrence after initial remission and prognosis;2. Analyzing common and important side effects associated with immunosuppressive therapy in IgAN patients with severe pathology stages, and taking a further research on the clinical features, treatment and prognosis of PneumoCystis (jirovecii) Pneumonia (PCP) infection in IgAN patients under immunosuppressive therapy in Peking Union Medical College Hospital (PUCMH).3. Evaluating the treatment options for IgAN patients with severe pathology stages in PUMCH, and further evaluating the administration and efficacy of corticosteroids plus cyclophosphamide (CTX).Methods We enrolled99patients who were diagnosed as IgAN with Class IV or higher pathology stages according to the Lee classification by renal biopsy result in PUMCH, and regularly followed up for at least1year between March2006and March2010, with intact clinical and pathological data. Patients with cirrhosis, HIV infection, or other secondary forms of IgAN or rheumatological disease such as lupus nephritis are ruled out for final analysis. Baseline features, follow-up records, treatment and prognosis were reviewed and analyzed retrospectively.Results1. There are99patients enrolled with the onset age of32(13-70), Mean arterial pressure (MAP) of onset105.12±18.77mmHg, estimated glomerular filtration rate (eGFR [CKD-EPI formula])67.65±27.85ml/min/1.73m2,24h urinary protein (24hUP)2.43(0.25-25.00)g/d. The mean follow-up time was41(12-84) months with total time-average proteinuria (TA-UP)1.29±1.20g/d, total time-average mean arterial blood pressure (TA-MAP)93.22±12.44mmHg, eGFR decline rate0.1143±1.3600ml/min/1.73m2/month. Total TA-UP (P<0.001) and total TA-MAP (P=0.002) levels were discovered to be strongly correlated with serum creatinine (SCr) change rate. The renal function decline rate was lower in TA-UP<1g/d group compared with TA-UP≥1g/d group.2. Comparing to the initial non-remission group, the initial remission group had lower renal function deterioration rate during follow-up, lower total TA-UP (P=0.008), and higher proportion of corticosteroids monotherapy (P=0.031). Comparing to patients who had non-recurrence (non-recurrence group) within2years after initial remission (n=9), the recurrence group (n=8) had higher deterioration rate of renal function and lower remission rate (P=0.009) at the end of the follow-up duration.3. Infection risk group (n=13) had higher renal function deterioration rate, higher average daily steriod dose in combination therapy (P=0.001), more immunosuppressants use (P=0.011), more endpoint events (P=0.035). Of11patients (25.0%) with menstrual abnormalities,3presented as permanent menopause,5presented as short-term menopause.4. Of10patients clinically diagnosed as PCP in PUMCH,7(70%) developed PCP within4months of the diagnosis of IgAN.9patients (90%) had chronic renal dysfunction impairment (eGFR<60ml/min/1.73m2, mean eGFR34.7±13.8ml/min/1.73m) at onset of PCP, The mean duration of symptoms before specific medication for PCP was9.50±3.89days after2007.8patients had achieved clinical remission and average duration of hospitalization was32.8±23.1days.5. For the patients with severe pathology stage IgAN in PUMCH, most patients (78.8%) received combinated immunosuppressive therapy.88.5%of them received corticosteroids plus cyclophosphamide. The remission rate at initial6months,1,2, and>2year were55.2%,59.3%,67.2%,50.0%, respectively.6(6.1%) patients developed serious side effects.6(6.1%) reached end-point events.Conclusions1. In IgAN patients with severe pathology stages, the total TA-UP and total TA-MAP levels had strong correlation with deterioration rate of renal function; Patients with initial remission have a slower decline of renal function and a better prognosis. Recurrence within2years after initial remission is associated with renal functional deterioration and poor prognosis.2. The infection risk is probably related to the progression of the disease and poor prognosis, The daily steriod dose and the number of immunosuppressive agents affect the risk of infection in combined immunosuppressive therapy.3. High risk of PCP develops in the first half year after intensive immunosuppressive therapy. Chronically impaired renal function in IgAN might be a risk factor for PCP infection, Significant deterioration of renal function during potent immunosuppressive therapy requires special attention on the side effect of PCP infection. Early suspection and proper treatment of PCP in IgAN patients under immunosuppressive therapy are important to improve prognoses.4. PUMCH positively supplies immunosuppressive therapy to severe pathology stage IgAN patients, and combined immunosuppressive therapy occupies a high proportion. Combined corticosteroids and cyclophosphamide therapy, as the most common option, has a high remission rate, a low incidence of serious side effects. Renal disease progression and side effects risk are well balanced in the treatment strategy.

重度病理分级IgA肾病的免疫抑制治疗研究

缩略词4-5中文摘要5-7Abstract7-9前言10-12研究对象及方法12-15研究结果15-32讨论32-38结论38-39参考文献39-44综述44-59    参考文献54-59致谢59-60

  本文关键词：重度病理分级IgA肾病的免疫抑制治疗研究，由笔耕文化传播整理发布。