肾脏移植后转换咪唑立宾治疗骨髓抑制

在肾脏移植手术后的随诊当中，经常会接触到因服用免疫抑制剂而发生白细胞减少的患者，对这些患者在免疫抑制剂的使用和调整上很棘手。咪唑立宾(MZR，商品名：布累迪宁)是日本旭化成株式会社开发研制的免疫抑制剂。在日本已临床使用多年。鉴于其对骨髓无明显的抑制作用，我们在临床对因免疫抑制剂应用而发生的白细胞减少的患者，将原用的免疫抑制剂转换成MZR，在临床上取得了较好的效果。现报告如下。     

不同剂量咪唑立宾在临床肾移植中的应用研究

目的 探讨不同剂量咪唑立宾(MZR)在临床肾移植中的应用效果及其安全性.方法 将206例首次接受肾移植的受者按手术时间排序,以奇偶数将受者列入吗替麦考酚酯(MMF)组,MZRⅠ组和MZRⅡ组.MMF组受者术后采用MMF+环孢素A(CsA)+泼尼松(Pred)的免疫抑制方案,MZRⅠ组和MZRⅡ组采用MZR+CsA+Pred的免疫抑制方案;MMF组MMF的用量为1.0g/d,MZRⅠ组和MZRⅡ组MZR的用量分别为100和200mg/d,3组间CsA和Pred的用法相同.排除失随访受者,MMF组、MZRⅠ组和MZRⅡ组分别有100、60和30例受者获得完整随访,研究终点为肾移植术后5年.比较各组受者人、肾存活率和排斥反应发生率,以及与药物相关不良反应的发生情况等.结果 MZR Ⅰ组、MZRⅡ组和MMF组受者术后总体存活率分别为88.3%(53/60)、90%(27/30)和88%(88/100),移植肾总体存活率分别为85%(51/60)、86.7%(26/30)和86%(86/100),急性排斥反应发生率分别为10%(6/60)、6.7%(2/30)和9%(9/100),3组间人、肾存活率以及急性排斥反应发生率的差异均无统计学意义(P>0.05);严重肺部感染发生率分别为3.3%(2/60)、10%(3/30)和15%(15/100),MZRⅠ组显著低于MMF组(P<0.05),而MZRⅡ组与其他两组的差异均无统计学意义(P>0.05).MZR Ⅰ组和MZRⅡ组发生严重感染者均经治疗后痊愈,而MMF组死亡11例,死亡率为73.3%(11/15).MZRⅠ组和MZRⅡ组腹泻发生率均显著低于MMF 组(P<0.05),而高尿酸血症发生率均显著高于MMF组(P<0.05).结论 咪唑立宾对预防肾移植后排斥反应是安全、有效的,受者耐受性好,对于免疫功能低下易发生感染的高危人群,以及使用MMF致顽同性腹泻者,可将含咪唑立宾的免疫抑制方案作为首选.

Abstract：

Objective To observe the efficacy and safety of different doses of mizoribine to prevent rejection after renal transplantation. Methods Sorted by time of operation and odevity, 206 primary kidney transplant recipients were divided into 3 groups, including MMF group, MZR Ⅰ group and MZR Ⅱ group. All recipients in 3 groups were administrated CsA and Pred, combined with mycophenolate mofitile (MMF) in MMF group and mizoribine (MMF) in MZR Ⅰ and Ⅱ groups.The dosage of MMF was 1. 0 g/day, while dosage of MZR in MZR Ⅰ and Ⅱ groups was 100 and 200 mg/day, respectively. There was no difference in usage of cyclosporine (CsA) and prednisone (Pred) among 3 groups. 100, 60 and 30 recipients were followed up in MMF, MZR Ⅰ and MZR Ⅱ groups respectively in 5 years. During the follow-up period of 5 years, the incidence of acute rejection, patient/graft survival and adverse effects associated with drugs in three groups were observed. Results The patient/graft survival was 88. 3 % (53/60), 85 % (51/60) in MZR Ⅰ group, 90 % (27/30),86.7 % (26/30) in MZR Ⅱ group, and 88% (88/100), 86% (86/100) in MMF group, respectively (P>0. 05). There was no significant difference in incidence of acute rejection among MZR Ⅰ (10 %, 6/60), MZR Ⅱ (6. 7 %, 2/30) and MMF groups (9 %, 9/100). The incidence of severe pulmonary infection in MZR Ⅰ group was 3. 3 % (2/60), and 10 % (3/30) in MZR Ⅱ , and the former was lower than MMF group (15 %, 15/100) significantly. There was significant difference in mortality of severe pulmonary infection between MZR Ⅰ group (0, 0/2) and MMT group (73. 3 %, 11/15). The rate of ACR in MZR Ⅱ group (10 %, 3/30) was lower significantly than MMF group (30 %, 30/100) and MZR Ⅰ group (31.7 %, 19/60). There was significant difference in the incidence of hyperuricacidemia between two MZR groups (30 %, 56. 7 %) and MMF group (10 %)(P<0. 05), while the incidence of diarrhea and myelosuppression was lower significantly in MZR Ⅰ group than in MMF group. Conclusion MZR can prevent acute rejection after kidney transplantation effectively and safely. Immunosuppressive therapy including mizoribine is the best choice especially for high risk group because of susceptibility to infection and those who suffer from tenacious diarrhea owing to the side effect.     

咪唑立宾在肾脏病中的应用

咪唑立宾（mizoribine，MZR）是一种免疫抑制剂，为日本学者1971年从土壤中分离的子囊菌M-2166株培养滤液中分离出来的一种咪唑类核苷，分子式为C9H13N3O6。为白色或微带黄色的结晶粉末，无臭，在水或二甲亚砜中易溶，本品1g溶于100ml水中，pH值为3．5～4．5。在甲醇、乙醇或氯仿中几乎不溶。熔点约为198℃。     

咪唑立宾导致肾移植术后严重骨髓抑制二例报告

肾移植术后应用咪唑立宾引起严重骨髓抑制者比较少见，我院收治2例。现报告如下。     

咪唑立宾治疗儿童紫癜性肾炎的临床观察

目的探讨咪唑立宾(mizoribine,MZR)治疗儿童紫癜性肾炎的安全性及疗效。方法纳入33例紫癜性肾炎(Ⅱb级)患儿,按其治疗方案不同分为2组:治疗组18例给予口服咪唑立宾片治疗(剂量2.5～3 mg·kg~(-1)·d~(-1)),治疗3个月后逐渐减量。对照组15例给予口服泼尼松片(1 mg·kg~(-1)·d~(-1))联合吗替麦考酚酯片(剂量20～30 mg·kg~(-1)·d~(-1)),治疗3个月后逐渐减量。两组疗程均为9～12个月,观察两组血常规、尿常规、24 h尿蛋白定量、血清白蛋白、肝肾功能及药物不良反应。结果治疗后,治疗组与对照组临床总有数率相当。两组治疗后24 h尿蛋白定量均低于治疗前,血清白蛋白水平均高于治疗前,差异有统计学意义(P0.05),血丙氨酸转氨酶、血肌酐及血尿酸变化差异无统计学意义(P0.05)。治疗组仅有2例在治疗初期出现轻微皮疹的不良反应。对照组不良反应有上呼吸道感染3例,白细胞下降3例,腹泻1例,恶心、呕吐1例。结论 MZR治疗临床表现为中度蛋白尿的紫癜性肾炎患儿,具有一定临床疗效,其疗效与泼尼松联合吗替麦考酚酯片相当,但其治疗更为简单经济、不良反应少,为儿童紫癜性肾炎的治疗提供了一种新的方案。     

一例同种异体部分颜面移植围手术期免疫抑制治疗方案

目的探讨同种异体颜面复合组织移植术在围手术期的免疫抑制方案和其他用药治疗措施，以期为同种异体颜面移植术探索一条行之有效的药物治疗方案。方法对一例同种异体颜面移植患者围手术期的药物治疗进行系统观察。免疫抑制治疗采用FK506、霉酚酸酯（MMF）、激素（Pred）、赛尼哌四联免疫抑制方案；并应用各种抗感染药物预防细菌、病毒和真菌感染，同时应用奥美拉唑、肝泰乐等药物保护胃肠和肝肾功能。通过观察移植物术后的色泽、肿胀情况、及血液中T细胞分化抗原（CD）系列和病理学等指标，观察免疫排斥情况；通过观察患者的症状、体征，及肝肾功能、血常规等各种化验指标，监测免疫抑制剂的不良反应和各种并发症，并及时调整用药方案和剂量，以免对患者造成永久性伤害。结果移植的复合组织瓣在围手术期血运良好，皮肤色泽正常，术后1周后开始消肿，半个月后恢复正常。于1个月内多次分析血液中辅助T淋巴细胞（Th，CD3＋、CD4＋）和抑制T淋巴细胞（Ts，CD3＋、CD8＋），未发现异常。病理切片未显示急性排异反应的指征。在围手术期，除在冲击治疗过程中有一过性的血糖升高外，未发现各种药物的不良反应和身体机能的损伤。结论本例异体颜面移植患者应用四联免疫抑制方案和其他辅助用药，有效地控制了急性排异反应，在各种辅助用药的支持下，平安地渡过了危险期。     

1例心肝肾联合移植术后患者行连续性肾脏替代治疗的护理

对1例行心肝肾联合移植术患者于术后第7天应用连续性肾脏替代治疗（CRRT）,肾功能好转。提出对心肝肾联合移植术后患者行CRRT治疗,需做好病室环境准备,积极预防压疮,保持血管通路通畅、体外循环血路严格无菌,严密观察治疗期间病情变化,随时调整血泵速度,做好置换液的管理及血流动力学的监护和机器报警处理等。可提高治疗效果。     

1例心肝肾联合移植术后患者行连续性肾脏替代治疗的护理

对1例行心肝肾联合移植术患者于术后第7天应用连续性肾脏替代治疗(CRRT),肾功能好转。提出对心肝肾联合移植术后患者行CRRT治疗,需做好病室环境准备,积极预防压疮,保持血管通路通畅、体外循环血路严格无菌,严密观察治疗期间病情变化,随时调整血泵速度,做好置换液的管理及血流动力学的监护和机器报警处理等,可提高治疗效果。     

肾脏替代治疗在外科危重病救治中的应用

近来研究证明,肾脏替代治疗（renal replacemment therapy,RRT）不仅可用于急性肾功能衰竭的治疗,而且在缓解和控制全身过度炎症反应、调节免疫功能紊乱和稳定免疫平衡状态以及严重凝血功能异常等方面均具有独特疗效。RRT是多种血液净化方法或模式的总称,例如持续血液滤过、血液透析、持续血液透析滤过、间断血液透析、缓慢低效血液透析（SLED）等,在外科危重患者的救治过程中,也常常需要RRT,然而不同疾病以及不同疾病状态所需要的治疗模式以及参数各异。     

Hypertension in kidney transplant recipients

Arterial hypertension is frequently observed in renal transplant recipients. Its pathogenesis is multifactorial in most cases. Calcineurin inhibitors (CNI) can increase peripheral vascular resistance by inducing arteriolar vasoconstriction and can cause extracellular fluid expansion by reducing the glomerular filtration rate (GFR), activating the renin–angiotensin system (RAS), and by inactivating the atrial natriuretic peptide. Glucocorticoids can impair urinary water and salt excretion. Poor graft function can lead to increased extracellular volume and inappropriate production of renin. Native kidneys, older age of the donor and transplant renal artery stenosis (TRAS) may also contribute to the development of hypertension. Arterial hypertension not only can increases the risk for cardiovascular events but can also deteriorate renal allograft function. A number of studies have shown that the higher the levels of blood pressure are, the higher is the risk of graft failure. On the other hand, a good control of blood pressure may prevent many cardiovascular and renal complications. Appropriate lifestyle modification is the first step for treating hypertension. Calcium channel blockers (CCB) and renin–angiotensin system (RAS) inhibitors are the most frequently used antihypertensive agents, but in many cases, a combination of these and other drugs is required to obtain good control of hypertension.     

Revival of effective and safe high-dose mizoribine for the kidney transplantation

We investigated whether high-dose Mizoribine (MIZ: a water-soluble anti-metabolite), 4-6 mg/kg/d was as effective and safe as mycophenolate mofetil (MMF) for patients after kidney transplantation. Between January 2001 and December 2005, 36 recipients at a stable phase more than one month passed after transplantation underwent conversion from MMF to MIZ, two from Azathioprine to MIZ, and two cases on MIZ from the beginning. There were 24-male and 16-female patients whose average age was 43.3 yr old and average weight was 54.0 kg. The types of transplantations were living donor renal transplantation 25, cadaveric renal transplantation 11, and simultaneous pancreas-kidney transplantation four examples. Of these, 33 patients were on Tacrolimus-based triple regimen and seven patients on Cyclosporine A base. The drugs used together with MIZ were basically the same as those before conversion. The reasons for conversion to MIZ were infection in 18 cases (45.0%), bone marrow suppression in nine cases (22.5%) and diarrhea in eight cases (20.0%), and post-transplant lymphoproliferative disorder in one case (2.5%). We initiated 4-6 mg/kg/d of MIZ divided twice a day depending on the serum creatinine (sCr) value of each patient. There was no big difference in the sCr value before and after MIZ administration in each individual patient, 1.79 +/- 1.37 and 1.65 +/- 1.30 mg/dL, respectively. A 12 h pharmaco-kinetic study of MIZ revealed that a peak value reached 2.87 microg/mL on average at three h (C3) followed by a slow decrease afterward. Acute rejection occurred in two cases and adverse effects were seen in five cases. The results of analysis of 349 points divided into three groups by renal function were as follows; poor renal function Group A revealed a trough level of 2.21 +/- 0.99 microg/mL and dosage 2.20 +/- 1.06 mg/kg, good renal function Group B had a trough level of 1.06 +/- 0.82 microg/mL and dosage 4.40 +/- 1.72 mg/kg, and excellent function Group C had a trough level of 0.92 +/- 0.55 microg/mL and dosage of 4.36 +/- 1.08 mg/kg. High-dose MIZ 4-6 mg/kg/d is an anti-metabolite having an equivalent immunosuppressive effect, fewer serious adverse events and good cost-effectiveness as MMF even for patients with prolonged hemodialysis period and declined digestive function in Japan.     

Outcomes of kidney allograft in recipients with kidney disease of unknown etiology

The etiology of renal disease is important because the primary renal pathology may affect the outcomes of kidney allograft with respect to recurrence, rejection, and survival. However, for a significant number of patients who undergo kidney transplantation, the disease etiology is unknown. Here, allograft outcomes for patients with kidney disease of unknown etiology (UEK) at three affiliated Korean hospitals were identified. The incidence of biopsy‐proven acute rejection (BPAR) for UEK was 22.9%, which was similar to the rates for diabetic nephropathy (DN, 24.4%) and IgA nephropathy (IgAN, 20.0%; p = 0.345). The cumulative incidence of post‐transplant glomerulonephritis (PTGN) among patients with UEK was significantly lower than that among patients with IgAN (p < 0.001). Overall graft survival of the UEK group was superior to that of the DN group (hazards ratio 0.39, 95% confidence interval 0.17–0.92, p = 0.030). Preemptive transplantation for UEK significantly reduced the incidence of BPAR (preemptive vs. non‐preemptive 9.6% vs. 30.3%, p = 0.001), but graft survival and recurrence were not affected by preemptive transplantation. The outcomes of kidney transplantation for patients with UEK were not inferior to those for patients with IgAN or DN. Preemptive kidney transplantation may be encouraged for UEK patients.     

Conversion to belatacept maintenance immunosuppression in HIV-positive kidney transplant recipients

There are only scattered case reports documenting belatacept use in HIV + kidney transplant recipients. We performed a retrospective review to describe short-term outcomes following conversion to belatacept in a cohort of HIV + patients. Patients were included if they were converted to belatacept between May 2015 and May 2019, had an HIV- donor, and received ≥4 doses of belatacept. All patients were treated with non-depleting induction and triple maintenance immunosuppression. Allograft and HIV-related outcomes were collected from the date of belatacept infusion until May 2020. Ten HIV + kidney transplant recipients were identified, who were converted to belatacept a median of 364 days post-transplant. At last follow-up (median 3.3 years), 8 patients remained on belatacept therapy, and all patients were alive with functioning allografts. Mean estimated glomerular filtration rates (eGFR) improved from 31.6 mL/min at baseline to 42.8 mL/min at 1 year (P = .03). Two patients developed acute rejection, with one necessitating conversion back to tacrolimus. All patients maintained undetectable HIV-1 viral loads at last follow-up. One patient each developed pneumocystis pneumonia and Kaposi sarcoma following conversion, which were responsive to standard medical therapy. In our cohort of stable HIV + kidney transplant recipients, conversion to belatacept was associated with excellent early patient and allograft survival and improved eGFR at 1 year.     

Quality of life in kidney recipients: comparison of tacrolimus and cyclosporine-microemulsion

Treatment of end-stage renal disease (ESRD) is evaluated by survival, quality of life (QOL) and cost-effectiveness. Little is known about the influence of immunosuppressive agents on global and disease-specific QOL in kidney recipients. In winter 1997/98 (t0) as well as in winter 1998/99 (t1), all kidney recipients of our University were asked to participate in a QOL study. The psychodiagnostic approach combined a global QOL-measure (SF-36 Health Survey) and a disease-specific questionnaire (ESRD-SCL, Nephron 1999). Inclusion criteria for the final analysis were (a) participation in both surveys and (b) eligibility after the matching procedure: patients with tacrolimus-based immunosuppressive regimen were matched to patients with cyclosporin-microemulsion (CsA-ME)-based immunosuppressive-regimen as to age, gender and duration of graft function. Group data were compared by performing a two-variate ('immunosuppression', 'time') analysis of variance. Both groups consisted of 63 patients. Analysis of QOL revealed statistically significant advantages for the tacrolimus treated patients concerning global (SF-36 'Physical Component Summary') as well as disease-specific QOL (ESRD-SCLTM 'Global Severity Index'; both p < 0.05). In detail, these results were due to statistically significant better QOL in tacrolimus treated patients as to the SF-36 subscales 'Physical Functioning' and 'General Health' (p < 0.05) and the ESRD-SCL subscales 'Limited Physical Capacity' (p < 0.05), 'Cardial and Renal Dysfunction' (p < 0.01) and 'Increased Growth of Gum and Hair' (p < 0.001). The factor 'time' did not contribute statistically significant to explanation of variance. In terms of QOL in kidney recipients, tacrolimus is superior to CsA-ME. Tacrolimus improves disease-specific QOL and also shows slight advantages concerning global QOL compared with CsA-ME. To record differentiated aspects of QOL in kidney recipients, the diagnostic approach should include a global QOL measure completed by a sensitive disease-specific instrument.     

Serum neutrophil gelatinase-associated lipocalin correlates with kidney function in renal allograft recipients

Abstract:  The value of neutrophil gelatinase-associated lipocalin (NGAL) as a novel marker for early detection of acute renal failure has been highlighted recently. The aim of this study was to assess whether serum NGAL correlates with kidney function in kidney allograft recipients. Serum NGAL, creatinine, and estimated glomerular filtration rate (GFR) were evaluated in 100 kidney allograft recipients on triple therapy: calcineurin inhibitor, mycophenolate mofetil or azathioprine, prednisone and healthy volunteers. Kidney transplant recipients had significantly higher NGAL than the control group. Serum NGAL in univariate analysis was strongly correlated with serum creatinine ( r  = 0.78). Estimated GFR ( r  = −0.69), on the other hand, was moderately correlated with white blood cell count ( r  = 0.43) and only weakly with other parameters. In multiple regression analysis, the best predictor of serum NGAL was eGFR (beta −0.69), with other predictors being white blood cell count (beta 0.25) and high sensitivity C-reactive protein (hsCRP) (beta 0.23) explaining 82% of NGAL concentration. Even a successful kidney transplantation is associated with kidney injury as reflected by elevated serum NGAL and lowered eGFR. Therefore, NGAL needs to be investigated as a potential early marker for impaired kidney function/kidney injury, especially in patients with other risk factor for kidney damage, i.e., hypertension or diabetes.     

Breast cancer arisingde novo in recipients of kidney allograft

Immunosuppressive therapy is not only an etiologic factor ofde novo malignant disease but it also accelerates progression of the already developed malignant disease in immunosuppressed recipients. Two cases ofde novo breast cancer arising in kidney transplant recipients are reported herein. A 25 year-old woman, transplanted one haploidentical kidney transplant 4 years and 9 months ago, developed a left breast tumor. Within one month the tumor had rapidly enlarged from 3.5 cm to 8 cm in diameter by the time she underwent a radical mastectomy. Nine axillary lymph nodes were positive for metastasis. Although her graft function had been poor due to chronic rejection, she was treated with standard immunosuppressive therapy, but not adjuvant therapy. Since local recurrent disease appeared two months postoperatively, the immunosuppressive therapy was ceased and⁶⁰Co therapy started. Recurrent disease progressed rapidly, however, and she died 7 months after her operation. A 27 year-old woman, having allograft from an identical sibling, noted a right breast tumor, 8 years and 7 months later. Again the tumor had grown rapidly from 1.8 cm to 3 cm in diameter within one month. She underwent a standard radical mastectomy. One axillary lymph nodes was positive for metastasis. She has been treated with standard immunosuppressive therapy and adjuvant endocrinochemotherapy. Presently, she is alive with a well functioning graft and no disease.     

Prophylactic treatment of antibody-mediated rejection with high-dose mizoribine and pharmacokinetic study.

Although mizoribine (MZ), which inhibits inosine monophosphate dehydrogenase in the same way as mycophenolate mofetil, recently proved more effective when higher doses were administered than previously approved, neither the optimal dosage nor blood concentration has yet been clarified. We aimed at investigating the effect of high-doses of MZ on prevention of anti-donor antibody (Ab) production and acute Ab-mediated rejection (AMR) on the basis of the pharmacokinetic profile in a pig kidney transplantation model. Group 1 (n = 5) received cyclosporin microemulsion (6 mg/kg) and prednisolone (0.1 mg/kg). Groups 2, 3 and 4 (each n = 5) were treated, respectively, with 30, 10 and 3 mg/kg of MZ in addition to cyclosporin and prednisolone. The incidences of AMR in groups 1, 2, 3 and 4 were 5/5, 1/5, 3/5 and 5/5, respectively. Anti-donor IgG/IgM Ab levels (relative to pretransplantation levels) on day 14 in groups 1, 2, 3 and 4 were 10.3/9.3, 1.8/1.0, 2.3/1.8 and 6.5/3.5, respectively. While only 2 (28.6%) of seven pigs with Cmax > 3 microg/ml during the first 2 weeks had AMR, 7 (87.5%) of eight pigs with Cmax < 3 microg/ml elicited anti-donor Abs and experienced AMR (P = 0.0406). Effective Cmax seemed to be over 3 microg/ml at minimum. Higher doses of MZ efficiently prevented AMR. However, therapeutic drug monitoring is essential before clinical application.     

Potential value of high-dose mizoribine as rescue therapy for ongoing acute humoral rejection

Mizoribine (MZ) inhibits the proliferation of lymphocytes selectively via inhibition of inosine monophosphate dehydrogenase, like mycophenolate mofetil (MMF). The clinical dosage of MZ (2-5 mg/kg) is much lower than that of MMF (20-60 mg/kg). The purpose of this study was to examine whether high-dose MZ would be effective for treatment of acute humoral rejection. Renal transplantation was performed in a different pig strain combination. Group 1 (n = 2) received no treatment. Group 2 (n = 4) received cyclosporine microemulsion (6 mg/kg) and prednisolone (0.1 mg/kg) as baseline immunosuppression. Groups 3 (n = 4), 4 (n = 4) and 5 (n = 4) were additionally treated with MZ for rescue therapy, 30, 10 and 3 mg/kg, respectively, immediately after rejection was observed. All pigs developed acute vascular rejection between days 4 and 8. Complete reversal of acute rejection including reduction of elevated serum creatinine, suppression of anti-donor antibody production and pathological finding, was obtained in 3/4 (group 3), 1/4 (group 4) and 0/4 (group 5). Rescue with high-dose MZ (30 mg/kg) reversed ongoing acute humoral rejection. Such a high dose of MZ was tolerable for pigs. However, leukocytopenia was observed when MZ trough level was maintained over 10 mug/ml. Treatment with high-dose MZ would be applicable to a clinical trial, if blood level is carefully monitored.