血清学阴性的乙型肝炎病毒相关性肾炎的临床病理分析及治疗

目的  探讨血清学阴性的乙型肝炎病毒相关性肾炎（HBV-GN）的临床病理特征及治疗方案，评估他克莫司联合激素治疗的安全性及有效性。方法  选取2009年1月-2012年9月该院其经肾活检诊断为HBV-GN的患者，根据血清学特点选出HBV血清学阴性组患者20例，分析其临床及病理特点；将确诊为肾病综合征的17例患者分为两组，拉米夫定联合激素组（B组）和他克莫司联合激素组（A组），比较两种治疗方案的疗效，并定期监测HBV血清学指标及肝、肾功能等评价治疗的安全性。结果  ①20例血清学阴性HBV-GN患者，男女比为1.86∶1.00，17例（85%）表现为肾病综合征，3例（15%）表现为肾炎综合征；血清HBsAg、HBeAg、HBsAb、HBeAb、HBcAb阴性，HBV-DNA阴性。②HBV-GN病理特点。a.光镜100%表现为不典型膜性肾病（MN）；免疫组织化学法检查肾组织HBsAg、HBcAg和HBsAg+HBcAg阳性率分别为90%（18/20）、40%（8/20）和30%（6/20）。免疫荧光多种免疫复合物多部位、高强度沉积。b.电镜下电子致密物多部位沉积。③A组总有效率为100.0%，高于B组（12.5%）（P <0.05）；A组血清白蛋白（ALB）水平高于B组（P <0.05），而A组24 h尿蛋白定量（UPRO）低于对照组（P <0.05）。④两组治疗过程中无明显不良反应。结论  ①血清学阴性HBV-GN以男性多见，病理类型表现为不典型膜性肾病。血清学阴性HBV-GN患者拉米夫定+激素治疗无效；FK506+激素治疗所有患者均有效，并且不引起HBV活动及肝肾功能异常。②建议对乙肝病毒血清学阴性的肾病综合征或慢性肾炎综合征患者，尤其病理表现为非典型膜性肾病的患者，肾活检时应常规行肾组织病理乙肝抗原检测，以免漏诊HBV-GN。③他克莫司联合激素是治疗血清学阴性HBV-GN的安全、有效方法之一。

Clinical pathological analysis and treatment of hepatitis B virus associated-glomerulonephritis with negative serological markers

Objective To study clinicopathological features and therapeutic regimen of hepatitis B virus associated glomerulonephritis (HBV-GN) with negative serological markers, and assess the efficacy and safety of Tacrolimus combined hormone therapy. Methods A retrospective study was carried out in the HBV-GN patients diagnosed by renal biopsy in our hospital from January 2009 to September 2012. Twenty patients of HBV-GN with serologically negative markers were selected according to HBV serological test, their clinical and pathological features were analyzed. Seventeen patients with nephrotic syndrome (MN) were divided into group A (n = 9) and group B (n = 8). The group B was treated by Lamivudine combined with Prednisone and the group A was treated with Tacrolimus combined with Prednisone. The levels of 24-h urinary protein, serum albumin (ALB), liver and kidney functions, HBV serological indexes and adverse reactions were observed before and after treatment. The therapeutic effect was compared between both groups. Results In the 20 HBV-GN patients with negative serological markers, male to female ratio was 1.86 : 1.00. There were 17 cases of nephritic syndrome (85%) and 3 cases of chronic nephritis syndrome (15%). Their serum HBsAg, HBeAg, HBsAb, HBeAb, HBcAb and HBV-DNA were negative. HBV-GN pathological features: light microscope showed untypical membranous nephropathy (100%) in all the cases; positive detection rates of HBsAg, HBcAg and HBsAg+HBcAg in renal tissues were 90%, 40% and 30% respectively, the immunofluorescence showed various immune-complexes deposited in many spots with high intensity; and the electron microscopy showed electron dense depositions were located in many spots. The total effective rate was 100% in the group B, which was significantly higher than 12.5% in the group A (P < 0.05). The level of ALB in the group B was significantly higher than that in the group A (P < 0.05), while the level of 24-h urinary protein in the group B were significantly lower than that in the group A (P < 0.05). There was no obvious adverse reaction in either group. Conclusions The main characteristics of serologically-negative HBV-GN were male in sex and MN, especially untypical MN in pathology. To avoid missed diagnosis of HBV-GN, for patients with negative serological markers of hepatitis B virus, especially those with the pathology of untypical membranous nephropathy, hepatitis B antigens should be regularly detected in renal biopsy. Tacrolimus combined with Prednisone is one of the effective and safe methods to treat serologically-negative HBV-GN.