造血干细胞移植后输尿管狭窄1例

Abstract

Ureteral stenosis is a comparatively rare complication following hematopoietic stem cell transplantation (HSCT). The etiology is still unclear and most believe that this may be due to the reactivation of BK virus in a state of immunodeficiency. In the later stages of ureteral stenosis with scarring, invasive interventions must be taken to relieve the hydronephrosis. Common treatments, such as D-J stent placement and permanent nephrostomy may not only entail the risk of infection, but also seriously affect the quality of life. Few cases of surgical intervention have been reported. In this article, a 25-year-old female was admitted to Peking University First Hospital suffering from recurrent flank pain. Seven years before, she developed hemorrhagic cystitis and bilateral urethritis 40 days after allogeneic HSCT. After continuous bladder irrigation and antiviral therapy, the left-sided hydronephrosis gradually alleviated while the right-sided one did not improve. D-J stents were used for urine drainage for 7 years before percuta-neous nephrostomy. Preoperative antegrade pyelography revealed significant hydronephrosis in the right kidney with long stricture of proximal-middle ureter. After comprehensive decision, she underwent ileal ureter replacement. The operation was successful. The segmental lesion was dissected and the scar tissue was removed. A 25 cm intestinal tube was isolated to connect the pelvis and bladder. An anti-reflux nipple was created at the distal end of ileal ureter to prevent the potential infection. The blood loss was minimal. After surgery, the drainage tube was removed in 2 weeks, the nephrostomy tube and the D-J stent was removed in 3 months. Follow-up mainly included clinical assessment, serologic testing, renal ultrasonography, blood gas analysis and radiological examination. During the follow-up of 6 years, she was symptom-free and no postoperative complications occurred. The serum creatinine level was stable. No hydronephrosis was observed under ultrasonography. Obvious peristaltic waves and ureteral jets of the ileal ureter was confirmed on cine magnetic resonance urography. To sum up, ureteral stenosis after HSCT is relatively rare. Obstruction caused by scarring is usually irreversible and surgical intervention should be designed according to the location and length of the lesion. Ileal ureter replacement can be a safe, feasible and effective method to solve this kind of complex stricture.

造血干细胞移植(hematopoietic stem cell transplantation，HSCT)是多种血液系统疾病的治疗方法，随着移植技术的进步和免疫抑制药物的发展，患者的生存期也有所延长。输尿管狭窄是HSCT的罕见并发症，临床常采用留置输尿管支架管、肾造瘘等方法治疗，影响患者生活质量。目前国内外鲜有外科手术治疗HSCT后输尿管狭窄的报道。北京大学第一医院2015年收治HSCT后输尿管狭窄1例，行回肠代输尿管术，术后长期随访，疗效满意，现报告如下。

1. 病例资料

患者为26岁女性，主因“腰痛7年”入院。7年前患者因急性B细胞淋巴细胞白血病于外院行异基因造血干细胞移植术，术前接受白消安、环磷酰胺、抗胸腺细胞球蛋白预处理，术后予环孢A+短程甲氨蝶呤预防治疗，术后10 d因皮肤急性移植物抗宿主病予激素治疗。患者术后40 d发生出血性膀胱炎(Ⅱ级)、双侧输尿管炎，并发巨细胞病毒感染，继发双肾积水，经膀胱冲洗及抗炎治疗后左肾积水缓解，右肾积水同前。遂行右侧双猪尾管置入术，症状反复，间断换管。3个月前因支架管置入失败行右肾造瘘术。辅助检查：血肌酐91 μmol/L，估算肾小球滤过率(estimated glomerular filtration rate，eGFR)75.257 mL/min。肾造瘘管造影示右肾盂肾盏扩张，右输尿管上段狭窄，造影剂未能通过，狭窄段以下输尿管未显影(图 1)。

图 1.

术前顺行造影

Preoperative antegrade pyelography

There is significant hydronephrosis in the right kidney with long stricture of proximal-middle ureter.

手术资料：患者平卧位，患侧稍抬高，取下腹正中绕脐切口25~30 cm，逐层切开进入腹腔。打开结肠旁沟，将结肠及盲肠翻至内侧，探查病变输尿管段，见右侧输尿管中上段周围明显粘连，管壁增厚，管腔狭窄，右髂血管水平病变最为严重。切除部分右输尿管及周围瘢痕组织，送病理检查。充分游离膀胱，使用带刻度的支架管测量输尿管断端至膀胱距离。距回盲部15 cm处取长约25 cm有独立血供的回肠袢，切开处理系膜，缝线标记游离肠袢远端，稀碘伏水冲洗肠腔。将切断的回肠断端以双直线切割缝合器法侧侧吻合恢复肠管连续性，浆肌层间断缝合加固。右侧输尿管9点方向纵行剖开呈勺状，置入F7双猪尾管并从肠袢远端牵出，输尿管切口与肠袢近端行端端吻合；肠袢远端使用3-0可吸收线套叠缝合，构建抗反流乳头，切开膀胱右侧顶壁，将肠壁与膀胱壁全层间断缝合(图 2A)。患者术中出血少量。

图 2.

回肠代输尿管手术模式图及术后动态磁共振尿路造影检查

Surgical technique of ileal ureter replacement and postoperative cine magnetic resonance urography

A, surgical technique of right-sided ileal ureter replacement; B, postoperative cine MRU showed no hydronephrosis and excellent peristalsis of the ileal ureter.

术后病理回报：(1)右输尿管组织：局部管腔极小，肌层局部组织结构不规则，可见增生的平滑肌组织长入周围脂肪，黏膜固有层及肌层可见炎细胞浸润，伴血管增生，并可见厚壁血管。(2)腹膜后瘢痕组织：送检为瘢痕、脂肪组织及平滑肌组织，局部可见黏液变性。免疫组织化学染色：SMA(+)，CD34(血管)(+)。

术后处理：术后观察患者体温、引流量、排气情况及腹部体征变化情况。肠道恢复通气后逐渐由流质饮食过渡至普通饮食。术后2周拔除尿管，3个月拔除双猪尾管及肾造瘘管。随访时间6年，患者症状缓解，血肌酐保持稳定。规律监测泌尿系彩色多普勒超声和计算机断层尿路造影(computed tomography urography，CTU)，提示仅有轻度肾积水；动态磁共振尿路造影(magnetic resonance urography，MRU)示肠代输尿管通畅、蠕动好，吻合口无狭窄，未见尿液反流(图 2B)。随访期间未发生泌尿系感染、代谢性酸中毒、贫血、代输尿管结石等并发症。

2. 讨论

HSCT已逐渐成为多种血液系统疾病的治疗方法，但其并发症不容忽视。HSCT后肾积水发生较常见，多继发于出血性膀胱炎、输尿管炎，多数可通过保守治疗好转；输尿管狭窄则较为罕见，国内外报道极少，继发肾积水可引起腰痛、乏力等症状，严重者危及肾功能^[1]。HSCT后输尿管狭窄的原因尚不明确，多数学者认为与免疫抑制后BK病毒感染有关。BK病毒广泛潜伏于尿路上皮细胞，移植后免疫抑制状态下病毒激活、大量复制，可以介导引起HSCT后早发型出血性膀胱炎^[2]；免疫重建后，免疫细胞靶向攻击感染的尿路上皮细胞，可以引起HSCT后迟发型出血性膀胱炎、输尿管炎，此时可以通过免疫组织化学检测尿路上皮细胞中的病毒包涵体^[3-4]；炎症长期刺激继发纤维化，造成输尿管瘢痕狭窄，此时常难以通过免疫组织化学检测找到病毒复制的证据^[5]。

HSCT后输尿管狭窄目前尚无明确的治疗方案。本例患者HSCT后40 d出现迟发型出血性膀胱炎、输尿管炎，长期留置输尿管支架管缓解肾积水症状，病变输尿管出现瘢痕狭窄，输尿管梗阻难以逆转。常规治疗如留置输尿管支架管、肾造瘘术会严重影响生活质量，给患者生理、心理、经济带来较重负担^[6]；且长期导管刺激会引起腰痛、耻骨上区疼痛、尿路刺激征、血尿，肾积水引流不畅还可继发泌尿系感染，甚至肾积水加重，危及肾功能^[7]。有报道采用输尿管球囊扩张、内切开等方式处理HSCT后输尿管狭窄^[8]，但该患者尿路造影提示输尿管中上段狭窄，缺损长度较大，腔内治疗仍有一定困难。肾盂成型术、自体补片修复术对于此类长段复杂狭窄亦难以修复。患者输尿管周围炎症渗出较重，与周围组织广泛粘连，自体肾移植术取肾、修肾难度较大，且可供膀胱吻合的输尿管长度较短。回肠具有管状结构、蠕动功能、血运丰富、取材方便的特点，使得回肠代输尿管术可以不受输尿管缺损长度的限制，适用于复杂输尿管狭窄。经综合考虑，本例患者选择回肠代输尿管术。

针对本例患者，我们结合既往回肠代输尿管术治疗经验提出HSCT后输尿管狭窄的几项技术要点^[9]：(1)输尿管炎症急性期组织水肿、质地糟脆，部分患者合并凝血功能异常，出血风险高^[10]，此时优先采取输尿管支架管、肾造瘘术等方式缓解肾积水，保护肾功能^[8]，炎症消退后如果肾积水仍无法缓解，则应及时采取手术治疗修复尿路结构。(2)术前肾造瘘有利于保护患肾功能，术前血肌酐应低于1.7~2.0 mg/dL^[11-12]，减少术后高氯血症、代谢性酸中毒的风险；同时使输尿管充分休息，术中充分显露输尿管狭窄段，增加手术成功率^[13-14]。(3)HSCT后输尿管狭窄患者输尿管周围瘢痕较重，应注意识别病变输尿管，避免过度游离，尽量保留健康输尿管周围脂肪组织，保留血供。(4)将输尿管断端纵行裁开，与肠管端端吻合，以保证近端吻合口宽大，不易狭窄。(5)既往文献表明，替代肠管大于15 cm时，肠管的顺向蠕动作用具有抗反流作用，不必设置抗反流机制^[15]；但考虑本例患者为特殊免疫人群，我们在代输尿管远端设置抗反流乳头，进一步防止膀胱输尿管反流的发生，减少感染风险。(6)我们使用细线，对近端吻合口采取外翻吻合，远端采取外翻乳头吻合，保证吻合口黏膜面相对，吻合严密不漏水，避免吻合口瘘及吻合口狭窄。

回肠代输尿管术后应进行严密的随访。本例患者术后症状缓解，肾功能长期保持稳定(图 3)。泌尿系彩超是评估肾积水的常用方法，但上尿路修复手术后肾盂扩张并不能完全反映尿路梗阻情况^[16]。动态MRU是一种无创、无放射性的辅助检查，我们将其应用于回肠代输尿管术后随访，观察术后重建结构的解剖形态和排尿功能，评估代输尿管蠕动情况、喷尿过程及尿液反流情况^[17-18]。本例患者动态MRU示患侧肾盂、代输尿管未见扩张，各吻合口未见狭窄，肠管蠕动好，未见反流。

图 3.

回肠代输尿管术后患者肌酐变化散点图

Scatter diagram of serum creatinine level after surgery

综上所述，对于HSCT后输尿管复杂狭窄，回肠代输尿管术是一种安全、有效的治疗方法，可以恢复上尿路连续性及排尿功能，保护肾功能，同时避免永久留置输尿管支架管或肾造瘘，改善患者生活质量。