摘要
目的：分析早期移植肾功能异常的危险因素和病因，总结早期移植肾功能异常的诊断和鉴别诊断方法以及预防和治疗措施。
方法：回顾性分析我院1999年12月至2002年12月间155例同种异体肾移植。10例术后早期死亡，6例因早期移植肾无功能而行移植肾切除，139例术后早期（3月内）肾功能恢复正常。根据受者肾移植术后早期肾功能恢复情况，将139例受者分为两组：1、早期移植肾功能异常组(DGF/SGF，79例)；2、早期移植肾功能正常组(IGF， 60例)。分组定义：IGF为肾移植术后肾功能迅速恢复正常，术后7天内Scr降至140umol/L以下；SGF为术后肾功能缓慢恢复正常，术后7天内Scr不能降至140umol/L以下，不需要透析治疗（SGF，51例）；如术后7天内无尿或少尿，需要透析过渡治疗的为DGF（DGF， 28例）。应用非条件LOGISTIC回归分析各种相关因素与早期移植肾功能异常、ATN、AR的关系。相关因素包括受者性别、年龄、原发病种类、供肾热/冷缺血时间、取肾时间、修肾时间、血管吻合时间、手术时间、术中是否发生低血压（移植肾血流开放前低于基础血压）、术前Scr、供/受者血型相同与否、PRA、HLA配型、再次移植等因素。总结DGF/SGF病因诊断、鉴别诊断和治疗方法。
结果：多因素回归分析提示早期移植肾功能异常的独立危险因素有：男性受者（OR=4.325, 95%CI=1.548~11.587）、术中发生低血压(OR=8.124，95%CI=2.014~32.764)、HLA错配(OR=2.602，95%CI=1.421~ 4.768)、手术时血管吻合时间（OR=1.092，95%CI=1.032~1.155）等; 移植术中血流开放前低血压（OR=13.692, 95%CI=3.120~60.085）是ATN的主要危险因素; 受者PRA阳性（OR=6.762, 95%CI=2.551~17.920）、HLA错配（OR=2.750, 95%CI=1.493~5.065）是AR的独立危险因素。
DGF组ATN发生率为71.4%，ATN是DGF的主要病因。DGF、SGF时AR发生率显著升高，与IGF比较差异显著（分别为60.7%, 47.1%、13.3%, p<0.01）。通过CsA血浓度C0和C2监测比较，C2监测组AR发生率比C0监测组低（分别为11.4%、30.3%，p<0.05），4例CsA-NT均出现在C0组。另外DGF/SGF组发生出血性并发症（10例）、输尿管并发症（4例，包括输尿管梗阻2例、尿瘘2例）、感染（3例，包括肺部感染2例，尿路感染1例），它们也是引起早期移植肾功能异常的病因。
CDFI检查AR组肾动脉各段RI值显著高于ATN组（分别为0.85±0.11， 0.76
±0.07, p = 0.009），而ATN组比非ATN/AR高（分别为0.76±0.07，0.64±0.07, P< 0.001）。根据RI≥0.80诊断AR，其敏感度、特异度和准确度分别为77.5%、90.2%、 84.0%。于术后7~14天仍需要透析或不明原因肌酐上升者常规行移植肾穿刺活检33例，其中ATN合并AR8例，单纯AR25例（其中轻微AR5例）。
所有DGF患者均经过血液透析（HD）以渡过少尿期，透析次数1~18（平均6.00±4.48）次，其中3例患者因术后初期循环不稳定，予以CRRT治疗后平稳渡过不稳定期。DGF/SGF组26例经过CsA→FK506切换治疗，肾功能均顺利恢复。临床诊断AR者根据患者病情予以相应的抗排斥治疗后AR得到有效治疗。本组有8例于术后早期再次手术，其中4例因血肿行血肿清除术，有4例因尿瘘或输尿管梗阻行尿瘘修补、移植肾输尿管膀胱再植或移植肾输尿管-自体输尿管吻合术。
DGF/SGF组CR发生率比IGF组高（分别为21.5%、8.3%，p<0.05），AR组与非AR组比较，CR发生率显著增高（分别为30.6%、7.8%，p<0.05），而DGF/SGF组未发生AR者与IGF组未发生AR者比较，CR发生率差异不显著（分别为13.2%、3.8% p>0.05）。DGF/SGF组、IGF组1年存活率分别为94.9%、95.0%，两组无显著差异（p>0.05）。死亡原因：肺部感染6例，肠结核1例。
结论：
1、 早期移植肾功能异常的危险因素有：供受者HLA错配，术前患者预致敏（PRA阳性），供肾冷缺血、热缺血、温缺血时间延长，受/供者体重比例大，术中低血压等。
2、 病因：ATN、AR、CsA-NT、输尿管并发症、出血性并发症、感染等。
3、 诊断：根据CDFI可初步诊断和鉴别早期移植肾功能异常病因。早期移植肾功能异常时常规移植肾穿刺活检可发现更多排斥反应证据，定期活检是监测移植肾病理状态、指导临床治疗的积极措施。
4、 预防：术前严格HLA配型，致敏受者尽可能鉴定出抗体特异性，按CREG或氨基酸残基配型方案有助于避开抗体。选择体重匹配的供受者，提高取肾、修肾及植肾手术技巧，尽量供肾缩短热、冷、温缺血时间，控制术中血压等至关重要。
5、 治疗：术后发生少尿、无尿的患者，应尽快恢复血液透析，CRRT有利于渡过术后不稳定期。早期移植肾功能异常时，宜选择强效、肾毒性小的免疫抑制剂组合方案，CsA浓度C2监测有利于预测排斥反应，减少肾毒性。DGF/SGF时CsA→FK506切换可有效预防AR发生。针对不同的病因采取相应的治疗措施，积极处理并发症。
6、 对人/肾长期存活的影响： 早期AR是影响CR发生的危险因素。早期移植肾功能状态对人1年存活率无影响，一年内死亡的主要病因为肺部感染。
Objective：To analyze the risk factors of early graft dysfunction after renal transplantation; To present and evaluate the methods of diagnosis, prevention and treatment of it.
Methods：One hundred and fifty-five cases of allograft renal transplantation performed between December 1999 and December 2002 in our center were analyzed retrospectively. The graft function of the major recipients (139 cases) had recovered to normal in three months after transplantation, but 10 recipients had lost their lives and 6 recipients had the invalid grafts removed in two months posttransplantation. According to their early allograft function, above-mentioned 139 cases were divided into two groups: early graft dysfunction (DGF/SGF n=79) and immediate graft function (IGF, n=60). At the 7th day post-operation, early allograft function was assessed clinically by urine output and serum creatinine (Scr). Patients who had a urine output >2000ml/24h and serum creatinine <140umol/L at the 7th day posttransplantation were classified as IGF. Patients who had a serum creatinine >140umol/L at the 7th day posttransplantation were classified as delayed graft function (DGF, n=28) if they needed dialysis or as slow graft function (SGF, n=51) if they did not. Using the unconditional logistic regression model, we studied the following related factors for DGF/SGF, ATN and AR: recipient gender, recipient age, primary disease, warm ischemia time, cold ischemia time, kidney harvesting time, kidney fitting time, anastomosis time, operation time, hypotension before allograft reperfusion during operation, Scr of recipients pretansplantation, donor/recipient ABO blood type, PRA, HLA-matching, retransplantation etc. The etiological diagnosis, differential diagnosis and treatment of DGF/SGF were analyzed.
Results：Multivariate analysis revealed the following independent risk factors for DGF/SGF: male recipient（OR=4.325, 95%CI=1.548~11.587），hypotension before allograft reperfusion during operation(OR=8.124，95%CI=2.014~32.764)、HLA mismatching (OR=2.602，95%CI=1.421~4.768), anastomosis time（OR=1.092，95%CI=1.032~1.155）. A multivariate analysis of risk factors for ATN showed hypotension before allograft reperfusion during operation（OR=13.692, 95%CI=3.120~60.085）to be the most significant
risk factor. Recipient panel reactive antibodies of more than 10%（OR=6.762, 95%CI=2.551~17.920）, HLA mismatching（OR=2.750, 95%CI=1.493~5.065）were independent risk factors for AR.
The incidence of ATN was 71.4% in DGF group and it was the main cause of the DGF. The incidence of AR in DGF or SGF groups was significantly higher than that of IGF group (60.7%, 47.1% and 13.3%, respectively; p<0.01)。Using C2 (2-hr post-dose CsA levels) monitoring, the overall incidence of AR was lower compared with the C0 (trough CsA blood levels) group (11.4% vs. 30.3%，p<0.05). There were 4 cases of CsA-NT in C0 group, while none in C2 group. Besides ATN and AR, hemorrhagic complications (10 cases), CsA-NT (4 cases), infection (comprised 2 cases of pulmonary infection and 1 case of urinary tract infection), ureteric complications(comprised 2 cases of obstruction and 2 cases of ureteric necrosis presenting as urinary leakage) were observed in DGF/SGF patients and were also the causes of the DGF/SGF.
The mean renal artery resistent index（RI）of allografts was significantly higher in the AR group compared with the ATN group (0.85±0.11 vs 0.76±0.07, P = 0.009). The RI was significantly higher in the ATN group compared with the non-ATN/AR group (0.76±0.07 vs 0.64±0.07, P< 0.001). Using RI≥0.80 to diagnose AR , the sensitivity, specificity and accuracy were77.5%, 90.2% and 84.0% respectively. We routinely carried out protocol biopsies in patients requiring dialysis 7 to 14 days posttransplant or unknown causes for Scr levels rising in 33 cases of recipients and revealed 8 cases of ATN/AR and 25 cases of AR (5 cases of slight AR).
All recipients suffered from DGF were required 1 to 18 (6±4.48) post-operative haemodialysis (HD) treatments. 3 cases of DGF received CR
引文
1． Joseph JT; Jindal RM. Influence of dialysis on post-transplant events. Clin Transplant 2002 Feb; 16(1): 18-23
2． Gonwa TA; Mai ML; Smith LB et al. Immunosuppression for delayed or slow graft function in primary cadaveric renal transplantation: use of low dose tacrolimus therapy with post-operative administration of anti-CD25 monoclonal antibody. Clin Transplant 2002 Apr; 16(2): 144-9
3． Fernandez-Juarez G; Marcen R; Pascual J. Prolonged delayed graft function decreases graft survival in transplant patients taking cyclosporine. Transplant Proc 2002 Feb; 34(1): 338-9
4． Geddes CC; Woo YM; Jardine AG. The impact of delayed graft function on the long-term outcome of renal transplantation. J Nephrol 2002 Jan-Feb; 15(1):17-21
5． 齐隽，杨继平，闵志廉等. 肾移植术后早期肾功能状态对移植肾长期存活的影响. 肾脏病与透析肾移植杂志，2002，11（5）：419~423
6． Ibrahim S; Jacobs F; Zukin Y et al. Immunohistochemical manifestations of unilateral kidney ischemia. Clin Transplant 1996 Dec; 10(6 Pt 2): 646-52
7． Ojo AO, Wolfe RA, Held PJ, et al. Delayed graft function: risk factors and implications for renal allograft survival. Transplantation (United States), Apr 15 1997, 63(7) p968-74
8． Dragun D; Hoff U; Park JK et al. Ischemia-reperfusion injury in renal transplantation is independent of the immunologic background. Kidney Int 2000 Nov; 58(5): 2166-77
9． Daemen MA; de Vries B; Buurman WA. Apoptosis and inflammation in renal reperfusion injury. Transplantation 2002 Jun 15; 73(11): 1693-700
10． 于立新，白喜文，徐健等. 肾移植术后肾功能延迟恢复的原因和处理. 第一军医大学学报，1998，18（4）：301~304
11． Tilney NL, Guttmann RD. Effects of initial ischemia/reperfusion injury on the transplanted kidney. Transplantation (United States), Oct 15 1997, 64(7) p945-7
12． Senel FM; Karakayali H; Moray G et al. Delayed graft function: predictive factors and impact on outcome in living-related kidney transplantations. Ren Fail 1998 Jul;20(4):589-95
Hetzel GR; Klein B; Brause M et al. Risk factors for delayed graft function after renal transplantation and their significance for long-term clinical outcome. Transpl Int 2002
13． Jan; 15(1): 10-6
14． McLaren AJ; Jassem W; Gray DW et al. Delayed graft function: risk factors and the relative effects of early function and acute rejection on long-term survival in cadaveric renal transplantation. Clin Transplant 1999 Jun; 13(3): 266-72
15． van Es A,, Hermans J, van Bockel JH, et al.Effect of warm ischemia time and HLA (A and B) matching on renal cadaveric graft survival and rejection episodes. Transplantation (United States), Sep 1983, 36(3) p255-8
16． Polyak MM; Arrington BO; Stubenbord WT et al. Prostaglandin E1 influences pulsatile preservation characteristics and early graft function in expanded criteria donor kidneys. J Surg Res 1999 Jul; 85(1):17-25
17． Hollenbeck M; Dinter K; Torsello G et al. Prostaglandin E1 reduces the risk of delayed graft function after cadaveric renal transplantation. Nephrol Dial Transplant 1999; 14 Suppl 4:32-3
18． 王平贤, 张艮甫, 黄赤兵等. 前列腺素E1在肾移植中的应用. 中华器官移植杂志2002, 23(1):48~50
19． Oehlschlager S; Albrecht S; Hakenberg OW et al. Measurement of free radicals and NO by chemiluminescence to identify the reperfusion injury in renal transplantation. Luminescence 2002 Mar-Apr; 17(2):130-2
20． Kahan BD, Welsh M, Knight R, et al. Pharmacokinetic strategies for cyclosporin therapy in organ transplantation. J Autoimmun (England), Apr 1992, 5 Suppl A p333-41
21． Neumayer HH, Kunzendorf U, Schreiber M. Protective effects of calcium antagonists in human renal transplantation. Kidney Int Suppl (United States), May 1992, 36 pS87-93
22． Riemsdijk IC, Mulder PG, de Fijter JW, et al. Addition of isradipine (Lomir) results in a better renal function after kidney transplantation: a double-blind, randomized, placebo-controlled, multi-center study. Transplantation (United States), Jul 15 2000, 70(1) p122-6
23． Bleyer AJ; Burkart JM; Russell GB et al. Dialysis modality and delayed graft function after cadaveric renal transplantation. J Am Soc Nephrol 1999 Jan; 10(1): 154-9
24． Takemoto S, Terasaki PI, Cecka JM et al. Survival of nationally shared, HLA-matched kidney transplants from cadaveric donors. N Engl J Med, 1992, 327:834
Ichikawa Y; Hashimoto M; Hanafusa T et al. Delayed graft function does not
25． influence long-term outcome in cadaver kidney transplants without mismatch for HLA-DRB1. Transpl Int 1995;8(6): 421-5
26． Thompson JS, Thacker LR. CREG matching for first cadaveric kidney transplants (TNX) performed by SEGO centers between 1987 and 1995. Clin Transplant, 1996, 10(6pt2): 586
27． Martin S, Commolly J, Jos V. Importangce of HLA matching in highly sensitized renal transplant recipients with high transplant survival rates. Transplant Proc, 1993, 25(1): 265
28． 潘健涛，吴培根，朱兰英等. 血浆置换预防和治疗肾移植术后加速性排斥反应及超急性排斥反应的观察. 中华器官移植杂志，2001，22（2）：100~102
29． Schweitzer EJ, Wilson JS, Fernandez-Vina M, et al. A high panel-reactive antibody rescue protocol for cross-match-positive live donor kidney transplants. Transplantation (United States), Nov 27 2000, 70(10) p1531-6
30． Higgins RM, Bevan DJ, Carey BS, et al. Prevention of hyperacute rejection by removal of antibodies to HLA immediately before renal transplantation. Lancet (England), Nov 2 1996, 348(9036) p1208-11
31． 李民，赵明，李留洋等. 致敏受者肾移植术后疗效观察. 中华器官移植杂志，2002，23（5）：276~278
32． Bohmova R; Viklicky O. Renal ischemia--reperfusion injury: an inescapable event affecting kidney transplantation outcome. Folia Microbiol (Praha) 2001; 46(4):267-76
33． Herrero-Fresneda I; Torras J; Lloberas N et al. Cold ischemia in the absence of alloreactivity induces chronic transplant nephropathy through a process mediated by the platelet-activating factor. Transplantation 2000 Dec 15; 70(11):1624-31
34． Grinyo JM. Role of ischemia-reperfusion injury in the development of chronic renal allograft damage. Transplant Proc (United States), Nov-Dec 2001, 33(7-8) p3741-2
35． Azuma H; Nadeau K; Takada Met al. Cellular and molecular predictors of chronic renal dysfunction after initial ischemia/reperfusion injury of a single kidney. Transplantation 1997 Jul 27; 64(2):190-7
36． Qureshi F; Rabb H; Kasiske BL. Silent acute rejection during prolonged delayed graft function reduces kidney allograft survival. Transplantation 2002 Nov 27;74(10):1400-4
Humar A, Ramcharan T, Kandaswamy R, Gillingham K, Payne WD, Matas AJ. Risk factors for slow graft function after kidney transplants: a multivariate analysis. Clin
37． Transplant 2002: 16: 425-429.
38． Shoskes DA, Parfrey NA, Halloran PF. Increased major histocompatibility complex antigen expression in unilateral ischemic acute tubular necrosis in the mouse. Transplantation (United States), Jan 1990, 49(1) p201-7
39． Hoffmann SC, Kampen RL, Amur S, et al. Molecular and immunohistochemical characterization of the onset and resolution of human renal allograft ischemia-reperfusion injury. Transplantation (United States), Oct 15 2002, 74(7) p916-23
40． 李黔生，靳风烁，葛成国等. 肾缺血再灌注损伤时血小板衍化因子的表达及意义. 中华泌尿外科杂志，2003，24（3）：216
41． Satoh S; Suzuki A; Asari Y et al. Glomerular endothelium exhibits enhanced expression of costimulatory adhesion molecules, CD80 and CD86, by warm ischemia/reperfusion injury in rats. Lab Invest 2002 Sep;82(9):1209-17
42． 于立新. 肾移植术后的处理. 见：夏穗生 主编. 临床移植医学. 杭州：浙江科学技术出版社. 1999:265~267
43． Kashi SH, Lodge JP, Giles GR, et al. Ureteric complications of renal transplantation. Br J Urol (England), Aug 1992, 70(2) p139-43
44． 齐隽,何长民,闵志廉,等.肾移植后输尿管外科并发症.肾脏病透析肾移植杂志,1995,4:230 233.2
45． 孙君泓，吴孟超. 免疫抑制剂现状. 中华器官移植杂志，1991，12（2）：94
46． 殷立平，胡伟新. 移植肾功能延迟恢复. 肾脏病与透析肾移植杂志，2001，10（6）：579~583
47． 刘文渊, 董磊, 孟晓丽等.尸肾移植后肾功能延迟恢复不同病因的超声诊断. 中国超声医学杂志1999；15（7）：523~5
48． 李馨，高云华. 床旁超声监测移植肾早期急性排异和急性肾小管坏死的临床研究. 中国超声医学杂志. 1998, 14(12): 52~56
49． Silvester W. Outcome studies of continuous renal replacement therapy in the intensive care unit. Kidney Int Suppl (United States), May 1998, 66 pS138-41
50． Knotek M, Prkacin I, Skegro D, et al. Continuous renal replacement therapy. Lijec Vjesn (Croatia), Sep-Oct 2001, 123(9-10) p255-8
51． Cuhaci B.Continuous renal replacement therapy versus intermittent hemodialysis in acute renal failure. Kidney Int (United States), Apr 2002, 61(4) p1548-9;
Hong JC; Kahan BD. A calcineurin antagonist-free induction strategy for
52． immunosuppression in cadaveric kidney transplant recipients at risk for delayed graft function. Transplantation 2001 May 15; 71(9):1320-8
53． Chang GJ; Mahanty HD; Vincenti F et al. A calcineurin inhibitor-sparing regimen with sirolimus, mycophenolate mofetil, and anti-CD25 mAb provides effective immunosuppression in kidney transplant recipients with delayed or impaired graft function. Clin Transplant 2000 Dec; 14(6):550-4
54． 王跃闽,谢桐. ATG和ATHG在肾移植术后急性肾功能衰竭中的应用. 中华泌尿外科杂志,1995,16(3):138
55． Woo YM; Jardine AG; Clark AF et al. Early graft function and patient survival following cadaveric renal transplantation. Kidney Int 1999 Feb;55(2):692-9
56． Massy ZA, Guijarro C, Wiederkehr MR, et al. Chonic renal allograft rejection: immunologic and nonimmunologic risk factors. Kindey Int 1996; 49:518.
57． Helderman JH.Renal transplant rejection. In: Jacobson F, Striker G, Klahr S, eds. The principles and practices of nephrology, 2nd ed. St Louis: Mosby-Year Book, 1995: 811-821
58． Ashraf S, Parrot NR, Dyer P et al. Clinical response and temporal patterns of acute cellular rejection: relationship to chronic transplant nephropathy. Transpl Int 1998, 1998,11(Suppl 1): 85-89
59． Moreso F; Seron D; Gil-Vernet S et al. Donor age and delayed graft function as predictors of renal allograft survival in rejection-free patients. Nephrol Dial Transplant 1999 Apr; 14(4): 930-5
60． Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med (United States), Jun 11 1998, 338(24) p1741-51
61． 肖序仁，敖建华，李炎唐等. 肾移植176例死亡原因分析. 中华泌尿外科杂志，2003，24（3）：183~187