肾移植免疫抑制剂研究进展

肾移植是终末期肾病的有效替代治疗方法,新型免疫抑制剂的应用极大提高了肾移植受者的存活率。新型免疫抑制剂的广泛应用促进了免疫抑制方案的改善和优化,术后急性排斥反应发生率不断降低和移植物短期存活率不断提高验证了免疫抑制剂发展的巨大成功。然而,其伴随的不良反应也逐渐显现。如何正确、高效、合理地应用免疫抑制剂是临床医师面临的新挑战。现从以T淋巴细胞为靶点的免疫抑制剂、以B淋巴细胞为靶点的免疫抑制剂、以补体为靶点的免疫抑制剂、以细胞因子为靶点的免疫抑制剂、以混合多克隆抗体为靶点的免疫抑制剂以及以多种细胞为靶点的免疫抑制剂的种类及机制等做一综述,从而为免疫抑制剂的选择应用提供理论基础。     

Influence of the new immunosuppressive combinations on arterial hypertension after renal transplantation

Arterial hypertension is highly prevalent after renal transplantation and may contribute to the risk of cardiovascular disease. Also, arterial hypertension has been reported to be an independent risk factor for graft failure. Immunosuppressive drugs such as corticosteroids, cyclosporine and tacrolimus may be important contributing factors to post-transplant hypertension. Recent data from multicenter trials and from conversion studies (cyclosporine to tacrolimus) suggest that renal transplant patients under tacrolimus-based therapy showed less arterial hypertension compared with cyclosporine treated patients. New immunosuppressive drugs, including mycophenolate mofetil and rapamycin, are not nephrotoxic and they do not have any hypertensive effect. New immunosuppressive combinations including mycophenolate mofetil in a triple therapy regimen (associated with corticosteroids and cyclosporine) can reduce blood pressure so that corticosteroids can be stopped or cyclosporine reduced or even eliminated. Non-nephrotoxic regimens using rapamycin (sirolimus) as basic immunosuppression, associated with azathioprine or mycophenolate mofetil, could reduce the incidence of post-transplant arterial hypertension. Also, in renal transplant patients initially immunosuppressed with rapamycin, cyclosporine and corticosteroids, after the elimination of CSA, a lower blood pressure is achieved. In summary, new protocols with mycophenolate mofetil and/or rapamycin may permit several combinations that offer important alternatives to classical immunosuppressive regimens to reduce the incidence and clinical impact of arterial hypertension after renal transplantation.     

Effects of immunosuppressive agents on magnesium metabolism early after allogeneic hematopoietic stem cell transplantation

BACKGROUND: The calcineurin inhibitors, cyclosporine A (CSA) and tacrolimus, cause hypomagnesemia by suppressing reabsorption of magnesium (Mg) from renal tubules. To assess whether the effect on Mg metabolism after allogeneic hematopoietic stem cell transplantation (HSCT) differs among calcineurin inhibitors, we prospectively evaluated the Mg metabolism in recipients of allogeneic HSCT who received CSA or tacrolimus METHODS: Patients who underwent allogeneic HSCT were enrolled. CSA and tacrolimus were given by continuous infusion starting from day -1. Serum Mg and the total amount of urinary Mg excretion were measured once before starting of CSA or tacrolimus, and once weekly after HSCT for 4 weeks. Mg was supplemented with magnesium l-aspartate by continuous infusion to maintain the serum Mg level >1.4 mEq/L. RESULTS: Thirty-six patients were evaluated (12 in the CSA group, 24 in the tacrolimus group). The serum Mg level began to decrease in both groups at the first week after HSCT, and the mean serum Mg levels were significantly lower in the tacrolimus group than in the CSA group from the first to the third week. The total amount of urinary Mg excretion and Mg supplementation began to increase in both groups at the second week after HSCT, and the amounts in the tacrolimus group were significantly higher than those in the CSA group. CONCLUSIONS: Although both calcineurin inhibitors increased urinary Mg excretion and caused hypomagnesemia shortly after HSCT, the effect was more significant with tacrolimus than with CSA. This observation may explain the higher incidence of renal impairment and encephalopathy in patients receiving tacrolimus.     

肾移植术后早期主动减少免疫抑制剂用量的前瞻性研究

目的探讨对肾移植术后受者早期主动减少免疫抑制剂用量的临床必要性和安全性。方法随机选择63例尸体肾移植受者为观察组,58例尸体肾移植受者为对照组,两组受者均采用环孢素(CsA)+麦考酚吗乙酯(MMF)+泼尼松三联免疫抑制方案。于术后第6周对观察组63例受者予以主动减少免疫抑制剂用量(将CsA血药谷浓度维持在200～250 ng/ml,MMF按受者体质量主动减药),术后4～6个月开始按个体状况将MMF用量调至减药前水平。对照组按常规免疫抑制方案治疗。观察两组受者术后6周至1年的血清肌酐(Scr)、血尿素氮(BUN)、CsA血药谷浓度、肺部感染发生率、急性排斥反应(AR)发生率。结果随访1年期间,观察组受者Scr、BUN基本稳定在同一水平,且与对照组比较差异无统计学意义(均为P>0.05)。观察组与对照组的AR发生率分别为8%与9%,比较差异无统计学意义(P>0.05)。两组的肺部感染率分别为8%(5/63)和14%(8/58),比较差异有统计学意义(P<0.05),对照组有2例发展为严重的肺部感染。结论肾移植术后早期主动减少免疫抑制剂用量能有效降低此阶段肺部感染发生率,且AR发生率并没有增加。     

Gonadal function and immunosuppressive therapy after renal transplantation

End-stage renal disease is associated with disorders in hypothalamic-pituitary-gonadal function. Immunosuppressive therapies may influence the restoration of normal levels of gonadal hormones after renal transplantation. The aim of the present study was to evaluate the hormonal status of successful renal transplant recipients who were treated with different immunosuppressive agents.

Methods

Testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) were measured in 59 male renal transplant recipients with stable graft function with serum creatinine <2.5 mg/dL. Patients were treated with three different immunosuppressive regimens: group I, calcineurin inhibitors (CI; n = 15), group II, sirolimus without calcineurin inhibitors (SRL; n = 15), group III, sirolimus in combination with calcineurin inhibitors (SRL * CI; n = 29).

Results

Testosterone was significantly lower in group II versus group I (3.12 ± 1.23 versus 4.39 ± 1.53 ng/mL; P < .0197). Group III had higher testosterone values than group II, but lower than group I. FSH and LH were also higher in the SRL group, but the differences were not statistically significant, perhaps because of the small number of patients. No relationship was found between testosterone blood levels and age, posttransplant follow-up, renal function, time on dialysis, body mass index, steroid use, or posttransplant diabetes.

Conclusion

Sirolimus seems to impair the improvement of gonadal function after renal transplantation. Further prospective studies are needed to confirm these data before patients are advised of this potential side effect.     

肾移植术后肺部感染患者免疫抑制剂的应用

目的:探讨肾移植术后肺部感染患者救治过程中免疫抑制剂的应用方案.方法:报告22例肺部感染的肾移植患者的临床资料.重症肺部感染13例,肺部感染早期或症状较轻的9例.前者立即停用所有免疫抑制剂,给予甲基泼尼松龙;后者减少或调整免疫移植剂用药方案等.13例检出病原菌,其中混合感染10例.结果:18例治愈,移植肾功能正常;死亡2例,放弃治疗2例.结论:对肾移植术后肺部感染及时停用或调整免疫抑制剂用量和组合方案,保护移植.肾的功能和及早确定病原菌等,均有利于提高其治愈率,减少死亡率.     

肾移植后膀胱恶性肿瘤的临床特征(附2例报告并文献复习)

目的：探讨肾移植后膀胱恶性肿瘤的临床特征。方法：报道经治的2例肾移植后膀胱癌患者的临床资料;并查阅中文数据库收集的国内50例肾移植后并发膀胱恶性肿瘤患者的临床与病理表现。结果：50例中,单一组织器官肿瘤34例,其中移行上皮癌33例,鳞状上皮细胞癌1例;多器官多组织起源肿瘤16例(32％)．同时性发生占81．25％(13／16)。膀胱肿瘤患者1年生存率为46．3％,5年生存率21．3％。结论：肾移植后膀胱恶性肿瘤的临床特征不同于非肾移植,多器官多组织起源肿瘤增多,近远期生存率低。     

Effects of immunosuppressive agents on Th17 cells involved in transplantation

The lymphocyte‐derived helper T (Th) cells are critical regulators of the adaptive immune response and are associated with inflammatory disease. The most recently recognized Th‐cell lineage, Th17, plays an important role in host defense against extracellular pathogens by secreting the proinflammatory cytokine, interleukin 17, and recruiting reactive oxygen species (ROS)‐producing monocytes to the site of infection. However, accumulating evidence has implicated Th17‐cell dysregulation as an underlying cause for some immune‐related pathogenic conditions, including allograft rejection. Recent studies of human transplant patients have indicated that Th17 cells exhibit resistance to current immunosuppressive therapies that would otherwise prevent allograft rejection. In this review, we will discuss the most current research findings related to Th17‐cell function in various kinds of allografts.     

Lymphocele after renal transplantation: the influence of the immunosuppressive therapy

Lymphocele is a complication of renal transplantation, representing a lymphatic collection around the grafted kidney. The use of the immunosuppressive agent sirolimus (SRL) has been associated with a significant increase in lymphocele formation. This complication has been related to the antiproliferative activity of SRL, which delays surgical wound repair and closure of injured lymphatic vessels. The aim of this study was to relate the incidence of lymphocele with immunosuppression among 158 renal transplant patients operated with routine closure of all the visible lymphatic vessels around the iliac vessels and at the renal hilum. The incidence of lymphocele was not significantly different among the various immunosuppressive regimens.     

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.     

New immunosuppressive therapies and surgical complications after renal transplantation

Background

To analyze the association between the principal immunosuppressive drugs (mycophenolate mofetil, calcineurin inhibitors and mammalian target of rapamycin [mTOR] inhibitors) used in the routine management of kidney transplant patients and the development of postoperative surgical complications.

Materials and Methods

We analyzed 415 kidney transplants, studying the influence of various immunosuppressive regimens on the main postoperative surgical complications.

Results

The mean follow-up for the entire group was 72.8 months (± 54.2 SD). Patients treated with myeophonolate mofetil (MMF) and cyclosporine (n = 121) experienced a higher frequency of wound eventration odds ratio [OR], 5.2; 95% confidence interval [CI], 1.2-23.5; P = .03) compared with azathioprine and cyclosporine (n = 71). Compared with transplant recipients treated with tacrolimus and MMF (n = 181), transplant recipients treated with cyclosporine and MMF (n = 121) had a significantly greater frequency of wound eventration (OR, 3.7; 95% CI, 1.5-9.5; P = .005), urologic (OR, 2; 95% CI; 1.02-3.9; P = .04), wound (OR; 2.2; 95% CI; 1.07-4.6; P = .03), late (OR, 1.7; 95% CI; 1.01-3.03; P = .04), and Clavien grade 3 surgical complications (OR; 1.9; 95% CI, 1.1-3.37; P = .01). Patients treated with mTOR inhibitors (n = 26) had higher rates of lymphocele (OR, 3.6; 95% CI, (1.1-11.4; P = .002) compared with those who received tacrolimus (n = 197).

Conclusions

New immunosuppressive drugs have improved short-term functional results; however, in some cases they seem to increase surgical complications rates.     

Studies on the multiple-drug induction immunosuppressive therapies with cyclosporine after renal transplantation

Our induction immunosuppressive therapies were carried out on patients split into three groups. The first group of 25 recipients were treated with regimen I [cyclosporin (CsA); 12 mg/kg/day and prednisolone (Pred)]. The second group of 16 recipients were treated with regimen II [CsA; 6 mg/kg/day, Pred and mizoribine (MIZ) or azathioprine (AZA)]. The third group of 14 recipients were treated with regimen III [CsA; 10 mg/kg/day, Pred and MIZ or AZA]. There was no significant difference among the three groups in renal function three months after renal transplantation. The frequency and grade of rejection were significantly higher in Group II than in the other groups. One of group I had CsA nephrotoxicity and none of group III had liver dysfunction three months after renal transplantation. Group I had a higher incidence of posttransplant hypertension. Hypertension of group I was very severe. We concluded that the triple-drug therapy on group III was the best induction immunosuppressive therapy after renal transplantation of the above three.     

Growth after renal transplantation: Correlation with immunosuppressive therapy

The growth data for children transplanted between 1973 and 1987 were analysed according to their immunosuppressive regimen. All patients treated before 1985 received conventional treatment (prednisone, azathioprine); 37% of the prepubertal children with a follow-up of longer than 2 years showed catch-up growth, and 30% of the pubertal children exhibited a normal adolescent growth spurt. Reduced renal function and corticosteroid treatment are the two main causes of growth delay. The children transplanted between January 1985 and September 1987 were given either triple therapy [cyclosporine (CsA), prednisone, azathioprine] or conventional treatment after randomisation. Growth data were significantly better with CsA. The mean height gain for prepubertal children was +0.24 SD/year on triple therapy and +0.14 SD/year on conventional therapy during the 1st year after transplantation; and 0.4 SD/year and 0 SD/year during the 2nd year (P<0.05). The mean height gain for pubertal children was 5.6 cm/year on triple therapy and 3.6 cm/year on conventional therapy (P<0.005). The patients on triple therapy also received a significantly lower cumulative dose of prednisone. Some selected patients on triple therapy were taken off prednisone 12 months after transplantation. All patients showed catch-up growth (+0.83 SD/year in prepubertal children, 7.2 cm/year in pubertal children). In conclusion, protocols including CsA and the lowest cumulative dose of steroid (with alternate-day or even steroid withdrawal) allow the best restoration of growth.     

Posttransplant diabetes mellitus after kidney transplantation with different immunosuppressive agents

Posttransplant diabetes mellitus (PTDM) is a disturbing side effect of immunosuppression. The aim of this study was to evaluate the effect of different immunosuppressive agents on the development of PTDM in renal transplant recipients (KTx). The incidence of PTDM was evaluated in 538 consecutive KTx. Baseline immunosuppression was azathioprine (AZA), cyclosporine (CSA), or tacrolimus (TAC), or sirolimus in combination with calcineurin inhibitors (SIR). All patients received steroids for both induction and maintenance therapy during the first 6 months posttransplantation. Mean follow-up after KTx was 73 +/- 53.5 months (range 6 months to 16 years). PTDM was defined as two consecutive blood glucose determinations above 126 mg/dL. Thirty-six of 538 (6.7%) recipients experienced PTDM, 31 of whom required insulin treatment and five oral antidiabetic medications. PTDM occurred at 25.3 +/- 38 months posttransplantation in 4.8% of KTx treated with AZA, 4.8% of CSA, 6.5% of KTx treated with TAC and 12.5% of KTx treated with SIR. The time of onset of PTDM was significantly shorter (P =.003) among TAC (2.1 +/- 1.7 months posttransplantation) versus CSA (27.8 +/- 34 months). PTDM disappeared in 6 of 36 patients. We conclude that with current levels of immunosuppression, there is no difference in the incidence of PTDM between TAC- and CSA-treated KTx.     

New immunosuppressive agents for pediatric transplantation

Pediatric transplantation has always been challenging for transplant surgeons. Although the higher immunoreactivity and the faster metabolism showed by this unique population when compared with adults requires a heavy immunosuppressive regimen, the possibility of disrupting the delicate balance of correct psychophysical development calls for a regimen of more selective and less toxic immunosuppressive drugs. In the past decade several new drugs have been investigated and some of them appear to be very promising, although pleiotropic toxicities have not yet been eliminated. An appropriate pharmacokinetic approach and the evaluation of synergistic multi-drug combinations by rigorous mathematical models would lead to highly selective immunosuppressive regimens which may result in virtually no toxicity.     

Future immunosuppressive agents in solid-organ transplantation

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of mycophenolate sodium, everolimus, and FTY720. STUDY SELECTION AND DATA EXTRACTION: Clinical trials and abstracts evaluating mycophenolate sodium, everolimus, and FTY720 in solid-organ transplantation were considered for evaluation. English-language studies and published abstracts were selected for inclusion. DATA SYNTHESIS: Mycophenolate sodium has recently been approved by the Food and Drug Adminstration for marketing in the United States; everolimus and FTY720 are immunosuppressive agents that may soon be available in the United States. These agents have proven efficacy in reducing the incidence of acute rejection in solid-organ transplantation. Clinical trials have shown that these newer agents are relatively well tolerated. The most common adverse events associated with these agents were gastrointestinal and hematologic effects (mycophenolate sodium); hyperlipidemia, increased serum creatinine, and hematologic effects (everolimus): and gastrointestinal effects, headache, and bradycardia (FTY720). CONCLUSION: Mycophenolate sodium has been approved in some European countries and the United States. Everolimus has been approved in some European countries and a new drug application has been submitted to the Food and Drug Administration. FTY720 is currently in phase III clinical trials and submission to the Food and Drug Administration for approval is a few years away. The approval of these agents will furnish the transplant practitioner with even more options for immunosuppression.