Objectives: Tubulointerstitial diseases is one of the common causes of renal dysfunction. Some rare pathological types are easy to be misdiagnosed and missedly diagnosed because of their low prevalence and relatively insufficient understanding, which affects the treatment and prognosis of patients. This study aims to explore clinical manifestations and pathological characteristics of several rare tubulointerstitial diseases, and therefore to improve their diagnosis and treatment.
Methods: A total of 9 363 patients diagnosed by renal biopsy in the Department of Nephrology, Second Xiangya Hospital, Central South University from November 2011 to September 2021 were selected. Six cases of light chain cast nephropathy (LCCN), 2 cases of light chain proximal tubulopathy (LCPT), 1 case of LCCN with LCPT, 4 cases of genetic tubulointerstitial disease, and 6 cases of non-genetic related tubulointerstitial lesion were screened out, and their clinical manifestations and renal biopsy pathological results were collected, compared, and analyzed.
Results: Patients with LCCN presented with mild to moderate anemia, microscopic hematuria, and mild to moderate proteinuria. Compared with patients with LCPT, proteinuria and anemia were more prominent in patients with LCCN. Five patients with LCCN and 2 patients with LCPT had elevated serum free kappa light chain. Five patients with LCCN presented clinically with acute kidney injury (AKI). Two patients with LCPT and 1 patient with LCCN and LCPT showed CKD combined with AKI, and 1 LCPT patient presented with typical Fanconi syndrome (FS). Five patients with LCCN, 2 patients with LCPT, and 1 patient with LCCN and LCPT were diagnosed with multiple myeloma. Five patients with LCCN had kappa light chain restriction in tubules on immunofluorescence and a "fractured" protein casts with pale periodic acid-Schiff (PAS) staining on light microscopy. Immunohistochemical staining of 2 LCPT patients showed strongly positive kappa light chain staining in the proximal tubular epithelial cells. And monoclonal light chain crystals in crystalline LCPT and abnormal lysosomes and different morphological inclusion bodies in noncrystalline LCPT were observed under the electron microscope. Six patients with LCCN were mainly treated by chemotherapy. Renal function was deteriorated in 1 patient, was stable in 4 patients, and was improved in 1 patient. Two patients with LCPT improved their renal function after chemotherapy. Four patients with genetic tubulointerstitial disease were clinically presented as CKD, mostly mild proteinuria, with or without microscopic hematuria, and also presented with hyperuricemia, urine glucose under normal blood glucose, anemia, polycystic kidneys. Only 1 case had a clear family history, and the diagnosis was mainly based on renal pathological characteristics and genetic testing. Compared with patients with non-genetic related tubulointerstitial lesion, patients with genetic tubulointerstitial disease had an earlier age of onset, higher blood uric acid, lower Hb and estiated glomemlar fitration (eGFR), and less edema and hypertension. Renal pathology of genetic tubulointerstitial disease presented tubular atrophy and interstitial fibrosis, abnormal tubular dilation, glomerular capsuledilation, and glomerular capillary loop shrinkage. Glomerular dysplasia and varying degrees of glomerular sclerosis were observed. Genetic tubulointerstitial disease patients were mainly treated with enteral dialysis, hypouricemic and hypoglycemic treatment. Two genetic tubulointerstitial disease patients had significantly deteriorated renal function, and 2 patients had stable renal function.
Conclusions: Patients with AKI or FS, who present serum immunofixation electrophoresis and/or serum free kappa light chain abnormalities, should be alert to LCCN or LCPT. Renal biopsy is a critical detection for diagnosis of LCCN and LCPT. Chemotherapy and stem cell transplantation could delay progression of renal function in patients with LCCN and LCPT. If the non-atrophic area of the renal interstitium presents glomerular capsule dilatation, glomerular capillary loop shrinkage, and abnormal tubular dilatation under the light microscopy, genetic tubulointerstitial disease might be considered, which should be traced to family history and can be diagnosed by genetic testing.
目的: 肾小管间质性疾病是导致肾功能不全较为常见的原因之一，一些少见病理类型因其患病率低、认识相对不足，易被误诊、漏诊，影响患者的治疗和预后。本研究通过探讨几种少见肾小管间质性疾病的临床、肾脏病理特征，为临床诊治少见肾小管间质性疾病提供参考。方法: 从2011年11月至2021年9月在中南大学湘雅二医院肾内科完善肾活检的9 363例患者中，筛选出轻链管型肾病(light chain cast nephropathy，LCCN)6例、轻链近端肾小管病(light chain proximal tubulopathy，LCPT)2例、LCCN合并LCPT 1例、遗传性肾小管间质性疾病4例、非遗传相关性肾小管间质性病变6例。收集所有患者的临床表现，实验室检查、影像学检查、肾活检病理结果，并进行比较和分析。结果: LCCN患者表现为轻中度贫血、镜下血尿和轻到中度蛋白尿。与LCPT患者相比，LCCN患者24 h尿蛋白定量水平更高，Hb水平更低。5例LCCN患者和2例LCPT患者血清游离轻链以κ升高为主。5例LCCN患者临床表现为急性肾损伤(acute kidney injury，AKI)。2例LCPT患者及1例LCCN合并LCPT患者表现为慢性肾脏病(chronic kidney disease，CKD)合并AKI，其中1例LCPT表现为典型的范科尼综合征(Fanconi syndrome，FS)。5例LCCN、2例LCPT、1例LCCN合并LCPT患者诊断为多发性骨髓瘤。LCCN免疫荧光表现为肾小管管型单克隆轻链阳性，以κ轻链限制为主，光镜下表现为过碘酸希夫(periodic acid-Schiff，PAS)染色淡染的裂纹状蛋白管型。免疫组织化学染色示2例LCPT患者近端肾小管上皮细胞κ轻链染色强阳性。电镜下可见结晶型LCPT单克隆轻链结晶；非结晶型LCPT溶酶体数量增多、体积增大，其内有形态各异的包涵体。6例LCCN患者以化学治疗(以下简称化疗)为主，1例肾功能恶化，4例肾功能稳定，1例肾功能好转。2例LCPT患者行化疗后肾功能均好转。4例遗传性肾小管间质性疾病患者临床均表现为CKD，多为轻度蛋白尿，伴或不伴镜下血尿，还可表现为高尿酸血症、血糖正常的糖尿、贫血、多囊肾，仅1例具有明确家族史，确诊主要依靠特征性肾脏病理表现和基因检测。相较于非遗传相关性肾小管间质性病变，遗传性肾小管间质性疾病患者发病年龄更小、血尿酸更高、Hb水平和估算的肾小球滤过率(estiated glomemlar fitration，eGFR)更低、水肿和高血压程度更轻。遗传性肾小管间质性疾病肾脏病理多表现为肾小管萎缩和间质纤维化、肾小管异常扩张、肾小囊腔扩张、毛细血管袢皱缩于血管极，肾小球可见发育不良及不同程度的硬化；治疗主要以肠道透析、降尿酸或降糖等治疗为主，其中2例患者肾功能明显恶化，2例肾功能稳定。结论: 血清免疫固定电泳异常和/或血清游离轻链阳性患者，若临床表现为AKI或FS，要警惕LCCN或LCPT，肾活检是明确诊断的关键，化疗可延缓肾功能不全的进展。光镜下如果具有非萎缩区肾小囊腔扩张、球袢皱缩、肾小管异常扩张的特点，应警惕遗传性肾小管间质性疾病，应追踪家族史，必要时通过基因检测确诊。.
Keywords: genetic tubulointerstitial disease; light chain cast nephropathy; light chain proximal tubulopathy; non-genetic related tubulointerstitial lesion; renal pathology; tubulointerstitial diseases.