本文關(guān)鍵詞：重度病理分級(jí)IgA腎病的免疫抑制治療研究，，由筆耕文化傳播整理發(fā)布。

        研究背景IgA腎病(Immunoglobulin A nephropathy, IgAN)是世界范圍內(nèi)最常見(jiàn)的原發(fā)性腎小球疾病。其臨床表現(xiàn)譜廣泛,異質(zhì)性強(qiáng),疾病進(jìn)展具有免疫相關(guān)性。預(yù)后評(píng)估直接影響治療決策的制定,一些臨床指標(biāo)如初始腎功能、病理分級(jí)以及隨訪(fǎng)蛋白尿、血壓水平已用于預(yù)后風(fēng)險(xiǎn)評(píng)估。進(jìn)展性IgAN患者的臨床及病理表現(xiàn)更嚴(yán)重,更易進(jìn)展至終末期腎病,預(yù)后不佳,因此有必要積極免疫抑制治療,或可阻斷甚至逆轉(zhuǎn)腎功能進(jìn)展過(guò)程。有研究指出,積極初始免疫抑制治療的緩解情況與腎臟預(yù)后密切相關(guān),但上述結(jié)論基于病理較輕的IgAN患者群體,目前尚缺乏針對(duì)重度病理分級(jí)IgAN患者的治療及預(yù)后研究,因而治療方案的選擇亦缺乏足夠證據(jù),最新KDIGO (Kidney Disease Improving Global Outcomes, KDIGO)治療指南腎小球腎炎部分幾乎所有推薦項(xiàng)目均基于較低級(jí)別證據(jù)。免疫抑制治療決策制定的主要考量在于權(quán)衡控制疾病進(jìn)展的需要以及治療可能帶來(lái)的不良反應(yīng)。目前針對(duì)重度病理分級(jí)IgAN免疫抑制治療加用時(shí)機(jī)、療效及不良反應(yīng)(尤其是重癥肺炎感染)的研究甚少。研究目的1.評(píng)估重度病理分級(jí)IgAN患者的尿蛋白、血壓、初始腎功能、初始緩解復(fù)發(fā)情況與療效及預(yù)后的關(guān)系；2.分析重度病理分級(jí)IgAN患者免疫抑制治療相關(guān)的常見(jiàn)重要不良反應(yīng),進(jìn)一步研究北京協(xié)和醫(yī)院院IgAN患者免疫抑制治療中出現(xiàn)重癥不良反應(yīng)肺孢子菌肺炎(PCP)的臨床特點(diǎn)、治療以及預(yù)后情況；3.評(píng)價(jià)北京協(xié)和醫(yī)院(PUMCH)重度病理分級(jí)IgAN患者的治療方案,以及激素聯(lián)合環(huán)磷酰胺(CTX)的使用情況與療效；研究方法選取2006年3月至2010年3月接受腎活檢且于北京協(xié)和醫(yī)院門(mén)診隨訪(fǎng),臨床和病理資料保存完整,病理分級(jí)Lee氏Ⅳ級(jí)以上的IgAN患者,除外肝硬化、人類(lèi)免疫缺陷病毒(HIV)感染等系統(tǒng)性疾病繼發(fā)IgA沉積腎病以及狼瘡腎炎等免疫病。對(duì)符合上述條件且規(guī)律隨訪(fǎng)至少1年的患者共99例進(jìn)行分析。收集臨床、病理及隨訪(fǎng)資料,回顧性分析患者起病臨床表現(xiàn)、隨訪(fǎng)指標(biāo)、治療及預(yù)后情況。研究結(jié)果1.全組99名患者起病年齡32(13-70)歲,起病平均動(dòng)脈壓(MAP)105.12±18.77mmHg,估測(cè)腎小球?yàn)V過(guò)率(eGFR[CKD-EPI公式])67.65±27.85ml/min/1.73m2,24小時(shí)尿蛋白定量(24hUP)2.43(0.25-25.00) g/d,隨訪(fǎng)時(shí)長(zhǎng)41(12-84)個(gè)月,隨訪(fǎng)過(guò)程總時(shí)間平均尿蛋白定量(TA-UP)1.29±1.20g/d,總時(shí)間平均動(dòng)脈壓(TA-MAP)93.22±12.44mmHg, eGFR變化率0.1143±1.3600ml/min/1.73m2/月。隨訪(fǎng)過(guò)程總TA-UP (P<0.001)和總TA-MAP水平(P=0.002)與血肌酐(SCr)變化速率密切相關(guān)。且TA-UP<1g/d組腎功能下降速率較總TA-UP≥1g/d組更慢。2.與初始不緩解組相比,初始緩解組隨訪(fǎng)期間腎功能下降速率更慢,總TA-UP水平更低(P=0.008),主要治療方案單用激素的比例更高(P=0.031)。初始緩解后2年內(nèi)出現(xiàn)復(fù)發(fā)的患者(n=8),與未出現(xiàn)復(fù)發(fā)的患者(n=9)相比,腎功能下降速率更快,隨訪(fǎng)終點(diǎn)緩解率也更低(P=0.009)。3.與非感染風(fēng)險(xiǎn)組(n=86)相比,感染風(fēng)險(xiǎn)組(n=13) eGFR下降率(P=0.047)及SCr上升率(P=0.011)較高,聯(lián)合治療激素日均劑量(P=0.001)較大,免疫抑制劑使用數(shù)目(P=0.011)較多,且終點(diǎn)事件數(shù)目(P=0.035)較多。11名(25.0%)月經(jīng)異常患者中3名表現(xiàn)為絕經(jīng),5名表現(xiàn)為停經(jīng)數(shù)月。4.北京協(xié)和醫(yī)院IgAN免疫抑制治療中臨床診斷PCP的10名患者中,7名(70%)患者診斷IgAN后4個(gè)月之內(nèi)出現(xiàn)PCP。9名患者(90%)PCP起病時(shí)eGFR<60ml/min/1.73m2。2007年后發(fā)病的患者自PCP出現(xiàn)至針對(duì)性用藥的時(shí)間間隔為9.50±3.89天。8名患者經(jīng)治療獲得臨床緩解,平均住院時(shí)間為32.8±23.1天。5.北京協(xié)和醫(yī)院重度病理分級(jí)IgAN患者,絕大多數(shù)患者接受聯(lián)合免疫抑制治療78名(78.8%),其中激素聯(lián)合CTX比例最高(88.5%)。全組患者初始6個(gè)月、第一年、第二年、超過(guò)2年的隨訪(fǎng)終點(diǎn)緩解率分別為55.2%、59.3%、67.2%、50.0%。嚴(yán)重不良反應(yīng)6(6.1%)例,終點(diǎn)事件6(6.1%)例。研究結(jié)論1.重度病理分級(jí)IgAN患者的隨訪(fǎng)中總TA-UP和總TA-MAP水平與腎功能下降速度密切相關(guān)；初始緩解的患者腎功能下降速率慢,預(yù)后更好,初始緩解后2年內(nèi)出現(xiàn)復(fù)發(fā)與腎功能惡化和預(yù)后不良相關(guān)。2.感染風(fēng)險(xiǎn)的發(fā)生或與疾病進(jìn)展及不良預(yù)后相關(guān)；聯(lián)合免疫抑制治療中激素日均劑量、免疫抑制劑使用數(shù)目影響感染風(fēng)險(xiǎn)的發(fā)生；3. IgAN患者接受強(qiáng)化免疫抑制治療開(kāi)始后,前6個(gè)月PCP的發(fā)生風(fēng)險(xiǎn)高；慢性腎功能不全很可能是發(fā)生重癥感染PCP的危險(xiǎn)因素,早期疑診及時(shí)針對(duì)性用藥對(duì)改善IgAN免疫抑制治療合并PCP感染的預(yù)后或有重要意義。4.北京協(xié)和醫(yī)院對(duì)重度病理分級(jí)IgAN患者積極采用免疫抑制治療,聯(lián)合免疫抑制治療比例高,其中激素聯(lián)合CTX方案最為常用,治療緩解率高,嚴(yán)重不良反應(yīng)發(fā)生率低,治療方案的選擇較好地平衡了腎病進(jìn)展的控制與不良反應(yīng)的規(guī)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.

重度病理分級(jí)IgA腎病的免疫抑制治療研究

縮略詞4-5中文摘要5-7Abstract7-9前言10-12研究對(duì)象及方法12-15研究結(jié)果15-32討論32-38結(jié)論38-39參考文獻(xiàn)39-44綜述44-59    參考文獻(xiàn)54-59致謝59-60

  本文關(guān)鍵詞：重度病理分級(jí)IgA腎病的免疫抑制治療研究，由筆耕文化傳播整理發(fā)布。