Clinicopathological features and prognostic analysis of 44 patients with polyomavirus nephropathy after kidney transplantation
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摘要:
目的 探讨肾移植术后多瘤病毒相关性肾病（PyVN）的临床病理学特征及预后。 方法 回顾性分析44例肾移植术后确诊PyVN患者的临床资料，分析患者穿刺原因及病理学诊断时间。按Banff 2018标准进行组织学分级，比较各级患者临床资料及病理特征。分析患者血、尿BK病毒DNA载量及移植肾功能。比较各组患者的预后情况，分析影响预后的危险因素。 结果 患者病理诊断PyVN距肾移植手术时间为16（8，29）个月，血清肌酐升高为穿刺的主要原因。44例患者中，PyVN 1级19例、2级21例、3级4例，各组光学显微镜下病毒包涵体阳性率差异无统计学意义（P=0.148），2级患者炎症细胞浸润、间质纤维化、肾内多瘤病毒载量均多于或高于1级患者，3级患者炎症细胞浸润及肾内多瘤病毒载量多于或高于1级患者，3级患者肾内多瘤病毒载量多于或高于2级患者，差异均有统计学意义（均为P < 0.05/3）。确诊时39例患者具有血、尿BK病毒DNA载量检测记录，其中38例尿BK病毒阳性，30例血BK病毒阳性。患者确诊PyVN时血清肌酐较术后1个月升高，末次随访时血清肌酐较确诊PyVN时升高，差异均有统计学意义（P < 0.001、P=0.049）。不同级别PyVN患者术后1个月血清肌酐差异无统计学意义（P=0.554），确诊时2级患者血清肌酐水平高于1级患者（P=0.007）。肾移植术后1、3、5年移植肾累积存活率分别为95%、69%、62%，不同分级PyVN间移植肾存活率差异有统计学意义，分级越高，存活率越低（P=0.014）。单因素和多因素Cox回归分析提示肾内多瘤病毒载量、确诊时血清肌酐水平为移植肾失功的独立危险因素（均为P < 0.05）。 结论 PyVN多发生在肾移植术后2年内，临床表现以血清肌酐升高、BK病毒血症和BK病毒尿症为主，术后常规监测BK病毒有利于早期诊断并保护移植肾，Banff 2018分级标准可有效预测移植肾预后。 Abstract:Objective To analyze the clinicopathological features and prognosis of polyomavirus nephropathy (PyVN) after kidney transplantation. Methods Clinical data of 44 patients who were diagnosed with PyVN after kidney transplantation were retrospectively analyzed. The causes of puncture and the time of pathological diagnosis were analyzed. Histological grading was carried out according to Banff 2018 classification. Clinical data and pathological characteristics of patients at all grades were statistically compared. BK viral DNA loads in the blood and urine were measured and renal allograft function were assessed. Clinical prognosis of all patients was compared among different groups and the risk factors affecting clinical prognosis were also analyzed. Results The time interval between pathological diagnosis of PyVN and kidney transplantation was 16(8, 29) months, and the increase of serum creatinine level was the main cause for puncture. Among 44 patients, 19 cases were classified as grade ⅠPyVN, 21 cases of grade Ⅱ PyVN and 4 cases of grade Ⅲ PyVN, respectively. Under optical microscope, there was no significant difference in the positive rate of virus inclusion bodies among different groups (P=0.148). Inflammatory cell infiltration, interstitial fibrosis and polyomavirus load in grade Ⅱ PyVN patients were all more or higher than those in grade Ⅰ counterparts. Inflammatory cell infiltration and polyomavirus load in grade Ⅲ patients were more or higher than those in grade Ⅰ counterparts. Polyomavirus load in grade Ⅲ patients was more or higher than that in grade Ⅱ counterparts. The differences were statistically significant (all P < 0.05/3). Upon diagnosis, BK viral DNA load was detected in the blood and urine of 39 patients. Among them, 38 patients were positive for BK virus in the urine and 30 patients were positive for BK virus in the blood. The serum creatinine level upon diagnosis was higher compared with that at postoperative 1 month. The serum creatinine level at the final follow-up was significantly higher than that upon diagnosis. The differences were statistically significant (P < 0.001, P=0.049). There was no significant difference in the serum creatinine level among patients with different grades of PyVN at postoperative 1 month (P=0.554). The serum creatinine level of patients with grade Ⅱ PyVN upon diagnosis was significantly higher than that of those with grade Ⅰ PyVN (P=0.007). The 1-, 3- and 5-year cumulative survival rates of renal allografts were 95%, 69% and 62%, respectively. The survival rates of renal allografts significantly differed among patients with different grades of PyVN. The higher the grade, the lower the survival rate (P=0.014). Univariate and multivariate Cox's regression analyses prompted that intrarenal polyomavirus load and serum creatinine level upon diagnosis were the independent risk factors for renal allograft dysfunction (all P < 0.05). Conclusions PyVN mainly occurs within 2 years after kidney transplantation. Clinical manifestations mainly consist of increased serum creatinine level, BK viremia and BK viruria. Postoperative routine monitoring of BK virus contributes to early diagnosis and protection of renal allografts. Banff 2018 classification may effectively predict the prognosis of renal allografts. -
图 1 PyVN患者移植肾病理学表现
注：A、B图为PyVN 1级（pvl 1、ci 1），C、D图为PyVN 2级（pvl 2、ci 2），E、F图为PyVN 3级（pvl 3、ci 3）。A、C、E图为Masson染色（×400），B、D、F图为SV40-T免疫组织化学染色（×400）。
Figure 1. Pathological findings of transplanted kidney in patients with PyVN
图 2 PyVN患者移植肾存活率
A图为44例PyVN患者移植肾总体存活情况；B图为不同分级PyVN患者移植肾存活情况。
Figure 2. Survival rate of renal allograft in patients with PyVN
表 1 各组患者的临床资料和病理特征比较
Table 1. Comparison of clinical data and pathological features of patients in each group
变量 PyVN 1级（n=19） PyVN 2级（n=21） PyVN 3级（n=4） 统计值 P值 年龄（x±s，岁） 39±13 43±12 39±12 0.524 0.596 性别[n（%）] 0.888 0.776 男 15（79） 14（67） 3/4 女 4（21） 7（33） 1/4 术后1个月血清肌酐[M（P25, P75），μmol/L] 100（64, 140） 126（99, 140） 114（85, 145） 1.180 0.554 确诊时血清肌酐[M（P25, P75），μmol/L] 196（156, 240）a 264（215, 310） 427（181, 618） 8.280 0.016 末次随访血清肌酐[M（P25, P75），μmol/L] 224（165, 324） 370（217, 688） 623（234, 730） 5.625 0.060 移植物失功[n（%）] 2（11） 9（43） 3/4 7.408 0.022 术后至确诊时间[M（P25, P75），月] 17（8, 34） 15（8, 31） 13（4, 18） 0.858 0.651 光镜发现病毒包涵体[n（%）] 14（74） 20（95） 4/4 3.740 0.148 组织学评分[M（P25, P75），分] 肾小管炎（t） 1.00（0.75, 1.25） 1.00（1.00, 1.25） 1.00（1.00, 1.00） 3.863 0.145 间质炎症细胞浸润（i） 1.00（0.75, 2.00）a, b 2.00（2.00, 3.00） 2.00（2.00, 2.00） 9.606 0.008 间质纤维化（ci） 1.00（0.75, 1.00）a 2.00（1.00, 2.00） 1.00（1.00, 1.00） 9.182 0.010 肾内多瘤病毒载量（pvl） 1.00（1.00, 1.00）a, b 2.00（1.00, 2.00）b 3.00（3.00, 3.00） 31.093 < 0.001 肾小管萎缩（ct） 1.00（0.75, 1.00） 1.00（1.00, 1.25） 1.00（1.00, 1.00） 2.393 0.302 IFTA区域内的间质炎症细胞浸润（i-IFTA） 0.50（0, 1.00） 1.00（0.75, 1.00） 1.00（1.00, 1.00） 7.042 0.030 IFTA区域内的肾小管炎（t-IFTA） 1.00（0, 1.00） 1.50（0.75, 2.00） 2.00（1.00, 2.00） 4.249 0.120 注：与PyVN 2级比较，aP < 0.05/3；与PyVN 3级比较，bP < 0.05/3。 
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表 2 确诊时各组患者BK病毒DNA载量
Table 2. BK virus DNA load of patients in each group at diagnosis [M(P25, P75), copies/mL]
指标 PyVN 1级（n=15） PyVN 2级（n=21） PyVN 3级（n=3） 统计值 P值 尿BK病毒DNA载量 9.2×108（1.0×108, 2.1×1010） 5.0×108（9.0×107, 8.2×108） 1.2×109（1.6×108, 1.3×109） 1.543 0.462 血BK病毒DNA载量 1.7×104（1.0×103, 8.1×105） 2.2×104（1.2×103, 6.3×105） 6.4×105（1.8×105, 4.9×106） 3.123 0.210
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表 3 PyVN患者移植肾失功的危险因素分析
Table 3. Risk factor analysis of renal allograft failure in patients with PyVN
变量 单因素Cox回归 多因素Cox回归 HR①（95%CI②） P值 HR（95%CI） P值 性别 2.731（0.746~9.997） 0.129 年龄 0.997（0.956~1.039） 0.891 供者类型 1.124（0.405~3.123） 0.822 术后距确诊时间 0.992（0.966~1.018） 0.533 确诊时血清肌酐水平 7.728（2.637~22.642） < 0.001 12.413（1.939~79.465） 0.008 确诊时血BK病毒DNA载量 1.254（1.005~1.564） 0.045 1.229（0.882~1.713） 0.222 BK病毒血症 0.735（0.196~2.762） 0.649 肾内多瘤病毒载量（pvl） 3.631（1.728~7.631） 0.001 7.827（1.925~31.822） 0.004 间质纤维化（ci） 1.620（0.777~3.378) 0.199 肾小管萎缩（ct） 1.440（0.684~3.034） 0.337 间质炎症细胞浸润（i） 0.938（0.471~1.868） 0.955 肾小管炎（t） 0.798（0.347~1.834） 0.595 IFTA区域内的间质炎症细胞浸润（i-IFTA） 3.263（0.964~11.039） 0.057 2.257（0.317~16.086） 0.416 IFTA区域内的萎缩肾小管炎（t-IFTA） 3.608（0.422~30.879） 0.241 注：①HR为风险比。
②CI为可信区间。
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