肾移植受者巨细胞病毒感染及其对移植肾影响的临床研究
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摘要
由于免疫抑制剂的发展，特别是环孢素A(CsA)应用于临床，同种异体肾移植急性排斥反应的发生率和严重程度都已明显降低，肾移植近期效果得到了显著改善。然而，尽管应用了预防急性排斥反应足量的免疫抑制剂，肾移植远期效果却未能得以相应的提高，移植肾的平均半寿期(half-life)仍只有在7-10年，这主要是因为以间质纤维化为特点的慢性移植物肾病(CAN)缓慢而进行性地损害了移植肾，最终导致肾功能衰竭、患者恢复透析。CAN是目前移植肾长期存活的主要障碍和肾移植1年后移植物功能丧失的主要原因。CAN最基本的病理改变为细胞外基质沉积、间质纤维化。许多免疫和非免疫因素都可以导致CAN。在引起CAN的众多病因中，近年来动物实验发现巨细胞病毒(CMV)感染可能是又一个重要的原因。
CMV为人类病毒感染中常见的病原体。60～90％的健康成人曾经感染过CMV。CMV是一种弱致病因子，对免疫力正常的个体不具有明显毒力，但一旦感染，CMV即终生潜伏于宿主体内。当免疫功能下降时，机体又可新感染CMV、或潜伏的病毒再次激活、复制，形成活动性CMV感染。CMV还可与其它病原体构成二重或多重感染，严重时感染者死亡率高。
肾移植后早期由于应用了大剂量免疫抑制剂，患者术后发生活动性CMV感染高达60-80％，为此，CMV感染被认为不仅是肾移植受者术后近期死亡的重要原因，更重要的是它可能与远期慢性移植物失功有关，肾移植后能否有效、及时地防治CMV感染可能是影响移植效果的关键。
在正常情况下，只要血清抗CMV-IgM为阳性，或抗CMV-IgG由阴性转为阳性或双份血清显示抗CMV-IgG滴度升高4倍以上，即可诊为活动性CMV感染。然而，由于肾移植患者术后应用了大剂量的免疫抑制剂，其抗体反应弱而迟钝，在这个特殊的群体中，依靠血清学检查已不能做出正确的诊断。为了克服这一困难，近年来检测CMV-pp65抗原血症以判断体内有无活动性CMV感染正逐渐应用于临床。CMV-pp65为病毒的结构蛋白，它的出现是活动性CMV感染的标志。CMV-pp65抗原血症检测还可提供定量结果，抗原血症的强度可以反映机体内病毒的负荷、CMV感染的严重程度和抗病毒治疗效果等。
慢性移植物肾病(CAN)最基本的病理改变为间质纤维化。TGF-β_1是一个关键的纤
第三军医大学博士学位论文
维发生因子，它通过刺激细胞外基质(胶元、蛋白多糖、纤维连接蛋白等)的合成、提
高整合素(integrin)表达、降低基质降解蛋白酶的活性、调节细胞的生长分化、趋化成
纤维细胞、促进某些间质细胞的增殖等，在组织的纤维化过程中起着重要的作用。TGF-
pl的过度产生，在众多疾病中、特别是肾脏病中引起不可逆的组织纤维化。
目前，临床上肾移植患者术前活动性CMV感染的发生状况及其对术后CMV感
染的影响、特别是 CMV感染与慢性移植物肾病的关系等问题尚未明了。虽然现在国
内外对肾移植受者CMV感染的研究较多，但在临床上从CMV一pp65抗原血症定量分
析的角度，研究肾移植受者术后早期不同cMv一pp65抗原血症水平与远期慢性移植物
肾病(CAN)的关系至今尚未见文献报道。本研究的目的在于:①明确肾移植患者术前
活动性CMV感染的发生状况及其对术后CMV感染的影响;②明确肾移植后早期活
动性cMv感染是否与远期发生的慢性移植物肾病有关联、或者是哪种类型(即不同
cMv一PP65抗原血症水平)的CMV感染才会导致慢性移植物肾病(C AN)的发生。③从
CMv一pp65抗原血症水平上进一步明确肾移植后活动性CMV感染的发生规律。
该研究采用新桥医院1999年8月一2001年3月期间首次进行肾移植手术的217例
患者为对象，术前检测患者血清抗CMV抗体和CMV一pp65抗原血症;术后对
CMV一pp65抗原血症动态观察6个月;根据术后cMv一pp65抗原血症的水平和持续时
间对CMV感染的严重程度进行量化、分组，对部分CMV感染严重的患者给予抗CMV
治疗、或使用血管紧张素H受体拮抗剂抑制肾内TGF一p;的合成和分泌;对各组患者
进行3年以上的前瞻性观察;对移植肾进行穿刺活检，明确不同类型CMV感染对移
植肾内关键的纤维发生因子TGF一p lmRNA和蛋白表达的影响;检测血、尿TGF一pl
浓度，明确血、尿TGF一p，浓度与远期肾功能的关系等。
通过对200多例患者前后共长达四年多的密切观察、对大量的临床移植肾穿刺标
本的直接研究，本实验得出如下结论:
1、’肾移植前不仅患者CMV感染率高，而且有12.4%的患者存在着活动性CMV
感染;
2、’肾移植患者术后6个月内，活动性CMV感染者发生率高达87.1%;
3、肾移植前活动性CMV感染，是导致肾移植后发生高活动性CMV感染和CMV
病的重要原因;
4、在肾移植后最初6个月内，长时间高活动性CMV感染是导致移植肾远期功能
损害、引起慢性移植物肾病的重要原因，而短时间高活动性CMV感染或长时间低活
动性CMV感染均不会导致上述结果;
第三军医大学博士学位论文
5、长时间高活动性CMV感染在导致移植肾远期功能损害的过程中，TGF一p;起
着重要的介导作用;
6、对CMV感染严重的患者，如及时给予抗CMV治疗，或使用血管紧张素H
受体拮抗剂抑制肾内TGF一pl的产生，均能有效地减少肾内TGF一pl的分泌和远期慢
性移植物肾病(CA
Recent improvements in immunosuppression have led to a dramatic increase in short-term renal allograft survival. However, though irnmunosuppressive agents which are sufficient to prevent acute rejection have been used, so-far the long-term result of renal transplant has not improved correspondingly. The rate of graft loss in the late posttransplantation period has remained virtually unchanged. The average half-life of a transplanted kidney is still 7-10 years. It is common that that renal function becomes depleted and dialysis is resumed, one or several years after transplantation. The reasons that have caused this phenomenon are not clear. Pathological investigation has shown that this kind of kidney has obvious scar trend. The allografts demonstrate extracellular matrix deposition, interstitial fibrosis and renal tubule atrophy on pathology. But all of the pathologic alterations are nonspecific. A lot of immunity and non-immune factors may finally cause the changes mentioned above. Depending simply on the
pathologic alterations, it is very difficult to determine the reasons for the pathologic alterations. For this reason, the term "chronic allograft nephropathy (CAN)" which does not refer to etiological factors is used to define all the clinical disorders above-mentioned. CAN is the principal cause of late graft loss after the first year of renal transplantation. However, in recent years animals' experiments show that CMV infection is also an important cause of CAN. It was found that CMV infection accelerates and enhances histologic changes in CAN, especially interstitial fibrosis and collagen synthesis, in a rat model of renal transplantation.
Cytomegalovirus (CMV) is a common virus pathogen which infects human beings. The virus can invade into human bodies through multiple channels, such as respiratory track, digestive system, blood transfusion and organ transplantation, etc.. Epithelial cells, endothelial cells of blood vessels, and leukocytes in peripheral blood are extremely easy to be infected. 60-90% of healthy adults have been infected with CMV. Cytomegalovirus is a very weak poisonous pathogen for a healthy individual whose immunity is normal, but, once infected, the host will carry Cytomegalovirus for the remainder of his life. As the
immune function of an organism drops, especially when cellular immunity is low, the body can become infected by CMV newly, or the virus that was hidden in the body can be reactivated, duplicated again, and form active CMV infection. CMV often forms dual or multiple infections with other pathogens, the condition is critical, and infected individuals have high mortality.
As heavy doses of immunosuppressive agents have been used in early post-transplant, active CMV infection is up to 60- 80%. 15-35% of those infections are CMV disease which shows some symptoms. For this reason, active CMV infection is considered not only the main cause for death of recipients early after kidney transplant, but it might also relate to the dysfunction of transplanted kidneys in the long term after transplantation. In order to get better results from kidney transplantation, prevention and treatment of active CMV infection effectively, and in time, may play an important role.
Under the normal situation, so long as CMV-IgM can be found in serum, CMV-IgG becomes positive from negtive, or the concentration of CMV-IgG grows over four folds, the diagnosis of active CMV infection can be determined. However, as heavy doses of immunosuppressive agents have been used in early post-transplant, this kind of patient has had little ability to produce antibodies. Relying on serology tests can't provide correct diagnosis for active CMV infection in this special group of people. In order to overcome the difficulty existing in diagnosis of active CMV infection, in recent years a new approach in which CMV-pp65 antigen in the leucocyte of periphery blood is detected has been clinically used to determine if active CMV infection exists. The antigen pp65 is a phosphoric acid protein formed by 561 pieces of amino a
CMV为人类病毒感染中常见的病原体。60～90％的健康成人曾经感染过CMV。CMV是一种弱致病因子，对免疫力正常的个体不具有明显毒力，但一旦感染，CMV即终生潜伏于宿主体内。当免疫功能下降时，机体又可新感染CMV、或潜伏的病毒再次激活、复制，形成活动性CMV感染。CMV还可与其它病原体构成二重或多重感染，严重时感染者死亡率高。
肾移植后早期由于应用了大剂量免疫抑制剂，患者术后发生活动性CMV感染高达60-80％，为此，CMV感染被认为不仅是肾移植受者术后近期死亡的重要原因，更重要的是它可能与远期慢性移植物失功有关，肾移植后能否有效、及时地防治CMV感染可能是影响移植效果的关键。
在正常情况下，只要血清抗CMV-IgM为阳性，或抗CMV-IgG由阴性转为阳性或双份血清显示抗CMV-IgG滴度升高4倍以上，即可诊为活动性CMV感染。然而，由于肾移植患者术后应用了大剂量的免疫抑制剂，其抗体反应弱而迟钝，在这个特殊的群体中，依靠血清学检查已不能做出正确的诊断。为了克服这一困难，近年来检测CMV-pp65抗原血症以判断体内有无活动性CMV感染正逐渐应用于临床。CMV-pp65为病毒的结构蛋白，它的出现是活动性CMV感染的标志。CMV-pp65抗原血症检测还可提供定量结果，抗原血症的强度可以反映机体内病毒的负荷、CMV感染的严重程度和抗病毒治疗效果等。
慢性移植物肾病(CAN)最基本的病理改变为间质纤维化。TGF-β_1是一个关键的纤
第三军医大学博士学位论文
维发生因子，它通过刺激细胞外基质(胶元、蛋白多糖、纤维连接蛋白等)的合成、提
高整合素(integrin)表达、降低基质降解蛋白酶的活性、调节细胞的生长分化、趋化成
纤维细胞、促进某些间质细胞的增殖等，在组织的纤维化过程中起着重要的作用。TGF-
pl的过度产生，在众多疾病中、特别是肾脏病中引起不可逆的组织纤维化。
目前，临床上肾移植患者术前活动性CMV感染的发生状况及其对术后CMV感
染的影响、特别是 CMV感染与慢性移植物肾病的关系等问题尚未明了。虽然现在国
内外对肾移植受者CMV感染的研究较多，但在临床上从CMV一pp65抗原血症定量分
析的角度，研究肾移植受者术后早期不同cMv一pp65抗原血症水平与远期慢性移植物
肾病(CAN)的关系至今尚未见文献报道。本研究的目的在于:①明确肾移植患者术前
活动性CMV感染的发生状况及其对术后CMV感染的影响;②明确肾移植后早期活
动性cMv感染是否与远期发生的慢性移植物肾病有关联、或者是哪种类型(即不同
cMv一PP65抗原血症水平)的CMV感染才会导致慢性移植物肾病(C AN)的发生。③从
CMv一pp65抗原血症水平上进一步明确肾移植后活动性CMV感染的发生规律。
该研究采用新桥医院1999年8月一2001年3月期间首次进行肾移植手术的217例
患者为对象，术前检测患者血清抗CMV抗体和CMV一pp65抗原血症;术后对
CMV一pp65抗原血症动态观察6个月;根据术后cMv一pp65抗原血症的水平和持续时
间对CMV感染的严重程度进行量化、分组，对部分CMV感染严重的患者给予抗CMV
治疗、或使用血管紧张素H受体拮抗剂抑制肾内TGF一p;的合成和分泌;对各组患者
进行3年以上的前瞻性观察;对移植肾进行穿刺活检，明确不同类型CMV感染对移
植肾内关键的纤维发生因子TGF一p lmRNA和蛋白表达的影响;检测血、尿TGF一pl
浓度，明确血、尿TGF一p，浓度与远期肾功能的关系等。
通过对200多例患者前后共长达四年多的密切观察、对大量的临床移植肾穿刺标
本的直接研究，本实验得出如下结论:
1、’肾移植前不仅患者CMV感染率高，而且有12.4%的患者存在着活动性CMV
感染;
2、’肾移植患者术后6个月内，活动性CMV感染者发生率高达87.1%;
3、肾移植前活动性CMV感染，是导致肾移植后发生高活动性CMV感染和CMV
病的重要原因;
4、在肾移植后最初6个月内，长时间高活动性CMV感染是导致移植肾远期功能
损害、引起慢性移植物肾病的重要原因，而短时间高活动性CMV感染或长时间低活
动性CMV感染均不会导致上述结果;
第三军医大学博士学位论文
5、长时间高活动性CMV感染在导致移植肾远期功能损害的过程中，TGF一p;起
着重要的介导作用;
6、对CMV感染严重的患者，如及时给予抗CMV治疗，或使用血管紧张素H
受体拮抗剂抑制肾内TGF一pl的产生，均能有效地减少肾内TGF一pl的分泌和远期慢
性移植物肾病(CA
Recent improvements in immunosuppression have led to a dramatic increase in short-term renal allograft survival. However, though irnmunosuppressive agents which are sufficient to prevent acute rejection have been used, so-far the long-term result of renal transplant has not improved correspondingly. The rate of graft loss in the late posttransplantation period has remained virtually unchanged. The average half-life of a transplanted kidney is still 7-10 years. It is common that that renal function becomes depleted and dialysis is resumed, one or several years after transplantation. The reasons that have caused this phenomenon are not clear. Pathological investigation has shown that this kind of kidney has obvious scar trend. The allografts demonstrate extracellular matrix deposition, interstitial fibrosis and renal tubule atrophy on pathology. But all of the pathologic alterations are nonspecific. A lot of immunity and non-immune factors may finally cause the changes mentioned above. Depending simply on the
pathologic alterations, it is very difficult to determine the reasons for the pathologic alterations. For this reason, the term "chronic allograft nephropathy (CAN)" which does not refer to etiological factors is used to define all the clinical disorders above-mentioned. CAN is the principal cause of late graft loss after the first year of renal transplantation. However, in recent years animals' experiments show that CMV infection is also an important cause of CAN. It was found that CMV infection accelerates and enhances histologic changes in CAN, especially interstitial fibrosis and collagen synthesis, in a rat model of renal transplantation.
Cytomegalovirus (CMV) is a common virus pathogen which infects human beings. The virus can invade into human bodies through multiple channels, such as respiratory track, digestive system, blood transfusion and organ transplantation, etc.. Epithelial cells, endothelial cells of blood vessels, and leukocytes in peripheral blood are extremely easy to be infected. 60-90% of healthy adults have been infected with CMV. Cytomegalovirus is a very weak poisonous pathogen for a healthy individual whose immunity is normal, but, once infected, the host will carry Cytomegalovirus for the remainder of his life. As the
immune function of an organism drops, especially when cellular immunity is low, the body can become infected by CMV newly, or the virus that was hidden in the body can be reactivated, duplicated again, and form active CMV infection. CMV often forms dual or multiple infections with other pathogens, the condition is critical, and infected individuals have high mortality.
As heavy doses of immunosuppressive agents have been used in early post-transplant, active CMV infection is up to 60- 80%. 15-35% of those infections are CMV disease which shows some symptoms. For this reason, active CMV infection is considered not only the main cause for death of recipients early after kidney transplant, but it might also relate to the dysfunction of transplanted kidneys in the long term after transplantation. In order to get better results from kidney transplantation, prevention and treatment of active CMV infection effectively, and in time, may play an important role.
Under the normal situation, so long as CMV-IgM can be found in serum, CMV-IgG becomes positive from negtive, or the concentration of CMV-IgG grows over four folds, the diagnosis of active CMV infection can be determined. However, as heavy doses of immunosuppressive agents have been used in early post-transplant, this kind of patient has had little ability to produce antibodies. Relying on serology tests can't provide correct diagnosis for active CMV infection in this special group of people. In order to overcome the difficulty existing in diagnosis of active CMV infection, in recent years a new approach in which CMV-pp65 antigen in the leucocyte of periphery blood is detected has been clinically used to determine if active CMV infection exists. The antigen pp65 is a phosphoric acid protein formed by 561 pieces of amino a
引文
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10. Kaija I, Anu S, Leena K, et al. Cytomegalovirus increases collagen synthesis in chronic rejection in the rat. Nephrol-Dial-Transplant. 2002 May; 17(5): 772-9.
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20. Poirier AS, Milpied N, Cantarovich D, et al. Clinical relevance of direct quantification of pp65 antigenemia using flow cytometry in solid organ and stem cell transplant recipients. J-Clin-Microbiol. 2000, 38(9): 3143-9.
21. Inkinen K, Soots A, Krogerus L, et al. Cytomegalovirus increases collagen synthesis in chronic rejection in the rat. Nephrol-Dial-Transplant. 2002 May; 17(5): 772-9.
22. Pirsch JD. Cytomegalovirus infection and posttransplant lymphoproliferative disease in renal transplant recipients: results of the U. S. multicenter FK506 Kidney Transplant Study Group. Transplantation. 1999 Oct 27; 68(8): 1203-5.
23. Capulong MG, Mendoza M, Chavez J. Cytomegalovirus pneumonia in renal transplant patients. Transplant-Proc. 1998 Nov; 30(7): 3151-3.
24. Rao M, Finny GJ, Abraham P, et al. Cytomegalovirus infection in a seroendemic renal transplant population: a longitudinal study of virological markers. Nephron. 2000 Apr; 84(4): 367-73.
25. Lopez RL, Brennan DC. Current review of cytomegalovirus in renal transplantation. Minerva-Urol-Nefrol. 2001 Sep; 53(3): 145-58.
26. Schleiss MR, McGregor A, Jensen NJ, et al. Molecular characterization of the guinea pig cytomegalovirus UL83 (pp65) protein homolog. Virus-Genes. 1999; 19(3): 205-21.
27. Meyer T, Reischl U, Wolf H, et al. Identification of active cytomegalovirus infection by analysis of immediate-early, early and late transcripts in peripheral blood cells of immunodeficient patients. Mol-Cell-Probes. 1994 Aug; 8(4): 261-71.
28. Siennicka J, Durlik M, Litwinska B, et al. Identification of cytomegalovirus (CMV) infection by different laboratory methods in renal transplant recipients undergoing triple-drug immunosupressive treatment. Acta-Microbiol-Pol. 1999; 48(1): 61-71.
29. Piiparinen H, Hockerstedt K, Gronhagen RC, et al. Comparison of plasma polymerase chain reaction and pp65-antigenemia assay in the quantification of cytomegalovirus in liver and kidney transplant patients. J-Clin-Virol. 2001 Aug; 22(1): 111-6.
30. Mocarski ES, Fields BN, Knipe DM, et al. Cytomegaloviruses and their replication.. Virology, 1996, 143(2): 2447-2449.
31. Varani S, Muratori L, De-Ruvo, N et al. Autoantibody appearance in cytomegalovirus infected liver transplant recipients: correlation with antigenemia. J-Med-Virol. 2002 Jan; 66(1): 56-62.
32. Hoae SK, Lorw CY, Cheng IK, et al. Rapid cytomegalovirus pp65 antigenemia assay by direct erythrocyte lysis and immunofluorescence staining. J-Clin-Microbiol. 1998 Mar; 36(3): 638-40.
33. Yague V, Kanaan A, Cour I, et al. Citomegalovirus: estudio comparativo de tecnicas de diagnostico. Enferm-Infecc-Microbiol-Clin. 1998 Apr; 16(4): 163-8.
34. Anglicheau D, Lautrette A, Scieux C, et al. Lowering immunosuppression is safe and effective to treat altered pattern of CMV infection in renal transplant recipients on valaciclovir prophylaxis. Transplant-Proc. 2002 Nov; 34(7): 2826-7.
35. Egan JJ, Barber L, Lomax J, et al. Detection of human cytomegalovirus antigenemia: a rapid diagnostic technique for predicting cytomegalovirus infection/pneumonitis in lung
and heart transplant recipients [J] Thoraqx, 1995, 50(1): 9-13.
36. Cuhaci B, Kumar MS, Bloom RD, et al. Transforming growth factor-beta levels in human allograft chronic fibrosis correlate with rate of decline in renal function. Transplantation. 1999 Sep 27; 68(6): 785-90.
37. Abdel WN, Weston BS, Roberts T, et al. Connective tissue growth factor and regulation of the mesangial cell cycle: role in cellular hypertrophy. J-Am-Soc-Nephrol. 2002 Oct; 13(10): 2437-45.
38. Huang C, Kim Y, Caramori ML, et al. Cellular basis of diabetic nephropathy: Ⅱ. The transforming growth factor-beta system and diabetic nephropathy lesions in type 1 diabetes. Diabetes. 2002 Dec; 51(12): 3577-81.
39. Okada M, Takemura T, Yanagida H, et al. Response of mesangial cells to low-density lipoprotein and angiotensin Ⅱ in diabetic (OLETF) rats. Kidney-Int. 2002 Jan; 61(1): 113-24.
40. Vazquez MA. Chronic rejection of renal transplants: new clinical insights. Am-J-Med-Sci. 2000 Jul; 320(1): 43-58.
41. Morales JM, Andres A, Rengel M, et al. Influence of cyclosporin, tacrolimus and rapamycin on renal function and arterial hypertension after renal transplantation. Nephrol-Dial-Transplant. 2001; 16 Suppl 1: 121-4.
42. Ishimura T, Fujisawa M, Higuchi A, et al. Transforming growth factor-betal expression in early biopsy specimen predicts long-term graft function following pediatric renal transplantation Clin-Transplant. 2001, 15(3): 185-91.
43. Cuhaci B, Kumar MS, Bloom RD, et al. Transforming growth factor-beta levels in human allograft chronic fibrosis correlate with rate of decline in renal function. Transplantation. 1999 Sep 27; 68(6): 785-90.
44. Paul LC. Chronic allograft nephropathy: An update. Kidney-Int. 1999 Sep; 56(3): 783-93.
45. Catherine M, Bollard IK, Ann L, Eet al. Adoptive immunotherapy for posttransplantation viral infections. Biology of Blood and Marrow Transplantation. 2004, 10: 143-155.
46. Capulong MG, Mendoza M, Chavez J. Cytomegalovirus pneumonia in renal transplant patients. Transplant-Proc. 1998 Nov; 30(7): 3151-3.
47. Rao M, Finny GJ, Abraham P, et al. Cytomegalovirus infection in a seroendemic renal
transplant population: a longitudinal study of virological markers. Nephron. 2000 Apr; 84(4): 367-73.
48. Lopez RL, Brennan DC. Current review of cytomegalovirus in renal transplantation. Minerva-Urol-Nefrol. 2001 Sep; 53(3): 145-58.
49. Schroeder R, Mesko J, Santos A. Cytomegalovirus antigenemia and renal function post-kidney-transplantation. Transplant-Proc. 1999 Nov; 31(7): 3027-8.
50. Wejse C, Birkebaek NH, Nielsen LP, et al. Respiratory tract infections in cytomegalovirus-excreting and nonexcreting infants. Pediatr-Infect-Dis-J. 2001 Mar; 20(3): 256-9.
51. Chome JJ, Allard JP, Floret D, et al. Role of cytomegalovirus infection in the incidence of viral acute respiratory infections in children attending day-care centers. Eur-J-Clin-Microbiol-Infect-Dis. 2001 Mar; 20(3): 167-72.
52. Capulong MG, Mendoza J, Mchavez GH. Cytomegalovirus pneumonia in renal transplant patients. Transplant-Proc. 1998 Nov; 30(7): 3151-3.
53. Holtappels R, Thomas D, Reddehase MJ. Identification of a K(d)-restricted antigenic peptide encoded by murine cytomegalovirus early gene M84. J-Gen-Virol. 2000 Dec; 81 Pt 12: 3037-42.
54. Mazzulli T, Drew LW. Multicenter comparison of the digene hybrid capture CMV DNA assay(version 2.0), the pp65 antigenemia assay, and cell culture for detection of cytomegalovirus viremia. J-Clin-Microbiol. 1999 Apr; 37(4): 958-63.
55. George KS, Boyd M J, Lipson SM, et al. A multisite trial comparing two cytomegalovirus (CMV) pp65 antigenemia test kits, biote st CMV brite and Bartels/Argene CMV antigenemia. J-Clin-Microbiol. 2000 Apr; 38(4): 1430-3.
56. Pellegrin I, Garrigue I, Binquet C, et al. Evaluation of new quantitative assays for diagnosis and monitoring of cytomegalovirus disease in human immunodeficiency virus-positive patients. J-Clin-Microbiol. 1999 Oct; 37(10): 3124-32.
57. Schirm J, Kooistra A, Son WJ, et al. Comparison of the Murex Hybrid Capture CMV DNA (v2.0) assay and the pp65 CMV antigenemia test for the detection and quantitation of CMV in blood samples from immunocompromised patients. J-Clin-Virol. 1999 Dec; 14(3): 153-65.
58. Geddes CC, Woo YM, Jardine AG. The impact of delayed graft function on the
long-term outcome of renal transplantation. J nephrol 2002; 15: 17-21.
59. Wright FH, Banowsky LH. Cytomegalovirus infection and prophylaxis in renal transplantation: financial considerations. Transplant-Proc. 1998, 30(4): 1318-9.
60. Schirm J, Kooistra A, van-Son WJ, et al Comparison. of the Murex Hybrid Capture CMV DNA (v2.0) assay and the pp65 CMV antigenemia test for the detection and quantitation of CMV in blood samples from immunocompromised patients. J-Clin-Virol. 1999 Dec; 14(3): 153-65.
61. Irit A, Suparno C, Donald W M. Incidence and outcome of adenovirus disease in transplant recipients after reduced-intensity conditioning with alemtuzumab. Biology of Blood and Marrow Transplantation. 2004, 10: 186-194.
62. Nordoy I, Muller F, Nordal KP, et al. Immunologic parameters as predictive factors of cytomegalovirus disease in renal allograft recipients. J-Infect-Dis. 1999, 180(1): 195-8.
63. Kunzle N, PetignatC, FrancioliP, et al. Preemptive treatment approach o cytomeglovirus (CMV) infection in solid organ transplant patients: relationship between compliance with the guidelines and prevention of CMV morbidity. Transpl-Infect-Dis. 2000, 2(3): 118-26.
64. Kuypers DR, Evenepoel P, Maes BD, et al. Role of immunosuppressive drugs in the development of tissue-invasive cytomegalovirus infection in renal transplant recipients. Transplant-Proc. 2002 Jun; 34(4): 1164-70.
65. Siu CW, Chan TM. Association between anti-thymocyte globulin administration and cytomegalic virus infection and/or CMV disease in cadaveric renal allograft recipients. Transplant-Proc. 2000 Nov; 32(7): 1932-4.
66. Sijpkens YW, Bruijn JA, Paul LC Chronic allograft nephropathy categorised in chronic interstitial and vascular rejection. Transplant-Proc. 2001 Feb-Mar; 33(1-2): 1153.
67. Besse T, Malaise J, De-Meyer M, et al. Renal allograft outcome from cytomegalovirus seronegative donor into cytomegalovirus seronegative recipient: poor prognosis after seroconversion. Transplant-Proc. 2000 Mar; 32(2): 408-10.
68. De-Maar EF, Verschuuren EAM, Homan-vd-Heide JJ, et al. Effects of changing immunosuppressive regimen on the incidence, duration, and viral load of cytomegalovirus infection in renal transplantation: a single center report. Transpl-Infect-Dis. 2002 Mar; 4(1): 17-24.
69. Krogerus L, Soots A, Loginov R, et al. CMV accelerates tubular apoptosis in a model of chronic renal allograft rejection. Transplant-Proc. 2001 Feb-Mar; 33(1-2): 254.
70. Freese P, Svalander CT, Molne J, et al. Chronic allograft nephropathy--biopsy findings and outcome. Nephrol-Dial-Transplant. 2001 Dec; 16(12): 2401-6.
71. Womer KL, Vella JP Sayegh MH. Chronic allograft dysfunction: mechanisms and new approaches to therapy. Semin-Nephrol. 2000, 20(2): 126-47.
72. Cuhaci B, Kumar MS, Bloom RD, et al. Transforming growth factor-beta levels in human allograft chronic fibrosis correlate with rate of decline in renal function. Transplantation. 1999 Sep 27; 68(6): 785-90.
73. Solez K, Benediktsson H, Cavallo T, et al. Report of The Third Banff Conference on Allograft Pathology(July 20-24, 1995) on classification and lesion scoring in renal allograft pathology. Transplant Proc, 1996; 28(1): 441-444
74. Freese P, Svalander CT, Molne J, et al. Chronic allograft nephropathy--biopsy findings and outcome. Nephrol-Dial-Transplant. 2001, 16(12): 2401-6.
75. Gourishankar S, Philip FH. Late deterioration of organ transplants: a problem in injury and homeostasis. Current Opinion in Immunology. 2002, 14: 576-583.
76. Mandeep RM, Patricia AU, Hector OV, et al. The impact of mode of donor brain death on cardiac allograft vasculopathy: An intravascular ultrasound study. Journal of the American College of Cardiology. 2004, 43: 806-810.
77. Campistol JM, Inigo P, Larios S, et al. Role of transforming growth factor-betal in the progression of chronic allograft nephropathy. Nephrol-Dial-Transplant. 2001; 16 Suppl 1: 114-6.
78. Inigo P, Campistol JM, Lario S, et al. Effects of losartan and amlodipine on intrarenal hemodynamics and TGF-beta(1) plasma levels in a crossover trial in renal transplant recipients. J-Am-Soc-Nephrol. 2001 Apr; 12(4): 822-7.
79. Suthanthiran M. Clinical application of molecular biology: a study of allograft rejection with polymerase chain reaction. Am-J-Med-Sci. 1997 May; 313(5): 264-7.
80. Leask A, Abraham DJ, Finlay DR, et al. Dysregulation of transforming growth factor beta signaling in scleroderma: overexpression of endoglin in cutaneous scleroderma fibroblasts. Arthritis-Rheum. 2002 Jul; 46(7): 1857-65.
81. Yamasaki K, Toriu N, Hanakawa Y, et al. Keratinocyte growth inhibition by high-dose
epidermal growth factor is mediated by transforming growth factor beta autoinduction: a negative feedback mechanism for keratinocyte growth. J-Invest-Dermatol. 2003 Jun; 120(6): 1030-7.
82. Chen F, Ogawa K, Nagarajan RP, et al. Regulation of TG-interacting factor by transforming growth factor-beta.. Biochem-J. 2003 Apr 15; 371(Pt 2): 257-63.
83. Campistol JM, Inigo P, Larios S, et al. Role of transforming growth factor-betal in the progression of chronic allograft nephropathy. Nephrol-Dial-Transplant. 2001; 16 Suppl 1: 114-6.
84. Abdel WN, Weston BS, Roberts T, et al. Connective tissue growth factor and regulation of the mesangial cell cycle: role in cellular hypertrophy. J-Am-Soc-Nephrol. 2002 Oct; 13(10): 2437-45.
85. Nicholson ML, Bicknell GR, Barker G, et al. Intragraft expression of transforming growth factor betal gene in isolated glomeruli from human renal transplants. Br-J-Surg. 1999 Sep; 86(9): 1144-8.
86. Amann K, Koch Ahofstetter J, et al. Glomerulosclerosis and progression: effect of subantihypertensive doses of alpha and beta blockers. Kidney-Int. 2001 Oct; 60(4): 1309-23.
87. Houlihan CA, Akdeniz A, Tsalamandris C, et al. Urinary transforming growth factor-beta excretion in patients with hypertension, type 2 diabetes, and elevated albumin excretion rate: effects of angiotensin receptor blockade and sodium restriction. Diabetes-Care. 2002 Jun; 25(6): 1072-7.
88. Woo YC Jong AH, Young KW, et al. Synergistic effects of mycophenolate mofetil and losartan in a model of chronic cyclosporine nephropathy. Transplantation. 2003 Feb 15; 75(3): 309-15.
89. Ishii H, Tada H, Isogai S. An aldose reductase inhibitor prevents glucose-induced increase in transforming growth factor-beta and protein kinase C activity in cultured mesangial cells. Diabetologia. 1998 Mar; 41(3): 362-4.
90. Ruilope LM, Segura J. Losartan and other angiotensin Ⅱ antagonists for nephropathy in type 2 diabetes mellitus: A review of the clinical trial evidence. Clinical Therapeutics. 2003, 25(12): 3044-3064.
91. Ferder LF, Inserra F, Basso N. Effects of renin-angiotensin system blockade in the aging
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92. Inserra FI,. Kurnek ML. Losartan and enalapril protect against age related kidney lesions in normal rats treated from 12 to 18 months of age. J. Am. Soc. Nephrol. 2001, 12: 679-682.
93. Campistol JM, Inigo P, Jimenez W, et al. Losartan decreases plasma levels of TGF-betal in transplant patients with chronic allograft nephropathy, Kidney-Int. 1999, 56(2): 714-9.
94. Gerstenkorn C, Robertson H, Bel A, et al. CMV infection as a contributory factor for renal allograft injury and loss. Transplant-Proc, 2001, 33(4): 2461-2.
95. Varan S i, Muratori L, De-Ruvo, N et al. Autoantibody appearance in cytomegalovirus-infected liver transplant recipients: correlation with antigenemia. J-Med-Virol. 2002 Jan; 66(1): 56-62.
96. Sijpkens YW, Bruijn JA, Paul LC Chronic allograft nephropathy categorised in chronic interstitial and vascular rejection. Transplant-Proc. 2001 Feb-Mar; 33(1-2): 1153.
97. Guandelin M, Xiuwu H, Juzhong G. Diagnosis and treatment of cytomegalovirus infection after renal transplantation. Transplant-Proc, 2000, 32(7): 1930-1.
98. Kas-Deelen AM, Harmsen MC, De-Maar EF, et al. Acute rejection before cytomegalovirus infection enhances von Willebrand factor and soluble VCAM-1 in blood. Kidneyolnt. 2000 Dec; 58(6): 2533-42.
99. Soderberg-Naucler C, Emery VC. Viral infections and their impact on chronic renal allograft dysfunction. Transplantation. 2001 Jun 15; 71(11 Suppl): SS24-30.
100. Boland GJ, Vlieger A, de-Gast GC, et al. Rapid detection of CMV reactivation after BMT by CMV-IEA expression in granulocytes. Bone-Marrow-Transplant. 1991, 7 Suppl 2: 42.
2. Groetzner J, Kaczmarek I, Landwehr P et al. Renal recovery after conversion to a calcineurin inhibitor-free immunosuppression in late cardiac transplant recipients. European Journal of Cardio-Thoracic Surgery. 2004, 25(3): 333-341.
3. Sezer S, Ozdemir FN, Agca E, et al. Assessment of risk factors for chronic allograft nephropathy in renal transplant patients. Transplantation Proceedings. 2003, 35: 2634-2636.
4. Yamurdur MC, Sevmis S, Emirolu R, et al. Tacrolimus conversion in kidney transplant recipients: analysis of 107 patients. Transplantation Proceedings. 2004, 3: 144-147.
5. Chkhotua AB, Altimari A, Gabusi E, et al. Increased expression of 21CDKI gene in chronic allograft nephropathy correlating with the number of acute rejection episodes. Transplantation Proceedings. 2003, 35: 655-658.
6. Inkinen K, Holma K, Soots A, et al. Expression of TGF-beta and PDGF-AA antigens and corresponding mRNAs in cytomegalovirus-infected rat kidney allografts. Transplant-Proc. 2003 Mar; 35(2): 804-5.
7. Inkinen K, Soots A, Krogerus L, et al. Cytomegalovirus infection enhances connective tissue growth factor mRNA expression in a rat model of chronic renal allograft rejection. Transplant-Proc. 2001 Feb-Mar; 33(1-2): 379.
8. Kloover JS, Soots AP, Krogerus LA, et al. Rat cytomegalovirus infection in kidney allograft recipients is associated with increased expression of intracellular adhesion molecule-1 vascular adhesion molecule-1, and their ligands leukocyte function antigen-1 and very late antigen-4 in the graft. Transplantation. 2000 Jun 27; 69(12): 2641-7.
9. Lautenschlager I, Soots A, Krogerus L, et al. Time-related effects of cytomegalovirus infection on the development of chronic renal allograft rejection in a rat model. Intervirology. 1999; 42(5-6): 279-84.
10. Kaija I, Anu S, Leena K, et al. Cytomegalovirus increases collagen synthesis in chronic rejection in the rat. Nephrol-Dial-Transplant. 2002 May; 17(5): 772-9.
11. Sola R, Diaz JM, GuiradoL N, et al. Significance of cytomegalovirus infection in renal transplantation, Transplantation Proceedings. 2003, 35: 1753-1755.
12. Schroeder R, Mesko J, Santos A. Cytomegalovirus antigenemia and renal function post-kidney-transplantation. Transplant-Proc. 1999 Nov; 31(7): 3027-8.
13. Van-der-Bij W, Speich R. Management of cytomegalovirus infection and disease after solid-organ transplantation. Clin-Infect-Dis. 2001 Jul 1; 33 Suppl 1: S32-7.
14. Karl S. Cytomegalovirus: the role of CMV post-haematopoietic stem cell transplantation. The International Journal of Biochemistry & Cell Biology. 2004, 36,: 695-701.
15. Lee W, Tsang WK, Tong KL, et al. Cytomegalovirus infection and graft rejection in renal transplantation: a single-center experience. Transplant-Proc. 2003 Feb; 35(1): 282-3.
16. Durlik M, Siennicka J, Litwinska B, et al. Clinical manifestations and diagnosis of cytomegalovirus infection in renal allograft recipients. Transplant-Proc. 2001 Feb-Mar; 33(1-2): 1237-9.
17. Guandelin M, Xiuwu H, Juzhong G, et al. Diagnosis and treatment of cytomegalovirus infection after renal transplantation. Transplant-Proc. 2000, 32(7): 1930-1.
18. Basadonna G. The Tricontinental Mycophenylate Mofetil Renal Transplantation study Group. Transplantation, 1996; 61: 11029-1037.
19. Yeung JS, Tong KL, Chart HW, et al. Clinical pattern, risk factors, and outcome of CMV infection in renal transplant recipients: local experience. Transplant-Proc. 1998 Nov; 30(7): 3144-5.
20. Poirier AS, Milpied N, Cantarovich D, et al. Clinical relevance of direct quantification of pp65 antigenemia using flow cytometry in solid organ and stem cell transplant recipients. J-Clin-Microbiol. 2000, 38(9): 3143-9.
21. Inkinen K, Soots A, Krogerus L, et al. Cytomegalovirus increases collagen synthesis in chronic rejection in the rat. Nephrol-Dial-Transplant. 2002 May; 17(5): 772-9.
22. Pirsch JD. Cytomegalovirus infection and posttransplant lymphoproliferative disease in renal transplant recipients: results of the U. S. multicenter FK506 Kidney Transplant Study Group. Transplantation. 1999 Oct 27; 68(8): 1203-5.
23. Capulong MG, Mendoza M, Chavez J. Cytomegalovirus pneumonia in renal transplant patients. Transplant-Proc. 1998 Nov; 30(7): 3151-3.
24. Rao M, Finny GJ, Abraham P, et al. Cytomegalovirus infection in a seroendemic renal transplant population: a longitudinal study of virological markers. Nephron. 2000 Apr; 84(4): 367-73.
25. Lopez RL, Brennan DC. Current review of cytomegalovirus in renal transplantation. Minerva-Urol-Nefrol. 2001 Sep; 53(3): 145-58.
26. Schleiss MR, McGregor A, Jensen NJ, et al. Molecular characterization of the guinea pig cytomegalovirus UL83 (pp65) protein homolog. Virus-Genes. 1999; 19(3): 205-21.
27. Meyer T, Reischl U, Wolf H, et al. Identification of active cytomegalovirus infection by analysis of immediate-early, early and late transcripts in peripheral blood cells of immunodeficient patients. Mol-Cell-Probes. 1994 Aug; 8(4): 261-71.
28. Siennicka J, Durlik M, Litwinska B, et al. Identification of cytomegalovirus (CMV) infection by different laboratory methods in renal transplant recipients undergoing triple-drug immunosupressive treatment. Acta-Microbiol-Pol. 1999; 48(1): 61-71.
29. Piiparinen H, Hockerstedt K, Gronhagen RC, et al. Comparison of plasma polymerase chain reaction and pp65-antigenemia assay in the quantification of cytomegalovirus in liver and kidney transplant patients. J-Clin-Virol. 2001 Aug; 22(1): 111-6.
30. Mocarski ES, Fields BN, Knipe DM, et al. Cytomegaloviruses and their replication.. Virology, 1996, 143(2): 2447-2449.
31. Varani S, Muratori L, De-Ruvo, N et al. Autoantibody appearance in cytomegalovirus infected liver transplant recipients: correlation with antigenemia. J-Med-Virol. 2002 Jan; 66(1): 56-62.
32. Hoae SK, Lorw CY, Cheng IK, et al. Rapid cytomegalovirus pp65 antigenemia assay by direct erythrocyte lysis and immunofluorescence staining. J-Clin-Microbiol. 1998 Mar; 36(3): 638-40.
33. Yague V, Kanaan A, Cour I, et al. Citomegalovirus: estudio comparativo de tecnicas de diagnostico. Enferm-Infecc-Microbiol-Clin. 1998 Apr; 16(4): 163-8.
34. Anglicheau D, Lautrette A, Scieux C, et al. Lowering immunosuppression is safe and effective to treat altered pattern of CMV infection in renal transplant recipients on valaciclovir prophylaxis. Transplant-Proc. 2002 Nov; 34(7): 2826-7.
35. Egan JJ, Barber L, Lomax J, et al. Detection of human cytomegalovirus antigenemia: a rapid diagnostic technique for predicting cytomegalovirus infection/pneumonitis in lung
and heart transplant recipients [J] Thoraqx, 1995, 50(1): 9-13.
36. Cuhaci B, Kumar MS, Bloom RD, et al. Transforming growth factor-beta levels in human allograft chronic fibrosis correlate with rate of decline in renal function. Transplantation. 1999 Sep 27; 68(6): 785-90.
37. Abdel WN, Weston BS, Roberts T, et al. Connective tissue growth factor and regulation of the mesangial cell cycle: role in cellular hypertrophy. J-Am-Soc-Nephrol. 2002 Oct; 13(10): 2437-45.
38. Huang C, Kim Y, Caramori ML, et al. Cellular basis of diabetic nephropathy: Ⅱ. The transforming growth factor-beta system and diabetic nephropathy lesions in type 1 diabetes. Diabetes. 2002 Dec; 51(12): 3577-81.
39. Okada M, Takemura T, Yanagida H, et al. Response of mesangial cells to low-density lipoprotein and angiotensin Ⅱ in diabetic (OLETF) rats. Kidney-Int. 2002 Jan; 61(1): 113-24.
40. Vazquez MA. Chronic rejection of renal transplants: new clinical insights. Am-J-Med-Sci. 2000 Jul; 320(1): 43-58.
41. Morales JM, Andres A, Rengel M, et al. Influence of cyclosporin, tacrolimus and rapamycin on renal function and arterial hypertension after renal transplantation. Nephrol-Dial-Transplant. 2001; 16 Suppl 1: 121-4.
42. Ishimura T, Fujisawa M, Higuchi A, et al. Transforming growth factor-betal expression in early biopsy specimen predicts long-term graft function following pediatric renal transplantation Clin-Transplant. 2001, 15(3): 185-91.
43. Cuhaci B, Kumar MS, Bloom RD, et al. Transforming growth factor-beta levels in human allograft chronic fibrosis correlate with rate of decline in renal function. Transplantation. 1999 Sep 27; 68(6): 785-90.
44. Paul LC. Chronic allograft nephropathy: An update. Kidney-Int. 1999 Sep; 56(3): 783-93.
45. Catherine M, Bollard IK, Ann L, Eet al. Adoptive immunotherapy for posttransplantation viral infections. Biology of Blood and Marrow Transplantation. 2004, 10: 143-155.
46. Capulong MG, Mendoza M, Chavez J. Cytomegalovirus pneumonia in renal transplant patients. Transplant-Proc. 1998 Nov; 30(7): 3151-3.
47. Rao M, Finny GJ, Abraham P, et al. Cytomegalovirus infection in a seroendemic renal
transplant population: a longitudinal study of virological markers. Nephron. 2000 Apr; 84(4): 367-73.
48. Lopez RL, Brennan DC. Current review of cytomegalovirus in renal transplantation. Minerva-Urol-Nefrol. 2001 Sep; 53(3): 145-58.
49. Schroeder R, Mesko J, Santos A. Cytomegalovirus antigenemia and renal function post-kidney-transplantation. Transplant-Proc. 1999 Nov; 31(7): 3027-8.
50. Wejse C, Birkebaek NH, Nielsen LP, et al. Respiratory tract infections in cytomegalovirus-excreting and nonexcreting infants. Pediatr-Infect-Dis-J. 2001 Mar; 20(3): 256-9.
51. Chome JJ, Allard JP, Floret D, et al. Role of cytomegalovirus infection in the incidence of viral acute respiratory infections in children attending day-care centers. Eur-J-Clin-Microbiol-Infect-Dis. 2001 Mar; 20(3): 167-72.
52. Capulong MG, Mendoza J, Mchavez GH. Cytomegalovirus pneumonia in renal transplant patients. Transplant-Proc. 1998 Nov; 30(7): 3151-3.
53. Holtappels R, Thomas D, Reddehase MJ. Identification of a K(d)-restricted antigenic peptide encoded by murine cytomegalovirus early gene M84. J-Gen-Virol. 2000 Dec; 81 Pt 12: 3037-42.
54. Mazzulli T, Drew LW. Multicenter comparison of the digene hybrid capture CMV DNA assay(version 2.0), the pp65 antigenemia assay, and cell culture for detection of cytomegalovirus viremia. J-Clin-Microbiol. 1999 Apr; 37(4): 958-63.
55. George KS, Boyd M J, Lipson SM, et al. A multisite trial comparing two cytomegalovirus (CMV) pp65 antigenemia test kits, biote st CMV brite and Bartels/Argene CMV antigenemia. J-Clin-Microbiol. 2000 Apr; 38(4): 1430-3.
56. Pellegrin I, Garrigue I, Binquet C, et al. Evaluation of new quantitative assays for diagnosis and monitoring of cytomegalovirus disease in human immunodeficiency virus-positive patients. J-Clin-Microbiol. 1999 Oct; 37(10): 3124-32.
57. Schirm J, Kooistra A, Son WJ, et al. Comparison of the Murex Hybrid Capture CMV DNA (v2.0) assay and the pp65 CMV antigenemia test for the detection and quantitation of CMV in blood samples from immunocompromised patients. J-Clin-Virol. 1999 Dec; 14(3): 153-65.
58. Geddes CC, Woo YM, Jardine AG. The impact of delayed graft function on the
long-term outcome of renal transplantation. J nephrol 2002; 15: 17-21.
59. Wright FH, Banowsky LH. Cytomegalovirus infection and prophylaxis in renal transplantation: financial considerations. Transplant-Proc. 1998, 30(4): 1318-9.
60. Schirm J, Kooistra A, van-Son WJ, et al Comparison. of the Murex Hybrid Capture CMV DNA (v2.0) assay and the pp65 CMV antigenemia test for the detection and quantitation of CMV in blood samples from immunocompromised patients. J-Clin-Virol. 1999 Dec; 14(3): 153-65.
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