脂蛋白肾病的诊断与治疗

脂蛋白肾病是以蛋白尿、肾功能损伤和脂蛋白代谢异常为主要表现的一种罕见疾病,主要发病机制是载脂蛋白E基因突变。脂蛋白肾病的发病率尚不清楚。本文总结了脂蛋白肾病的病理生理机制、临床及病理表现、诊断及鉴别诊断,以及当前可能有效的治疗手段。     

Abnormal lipoprotein and apolipoprotein pattern in lipoprotein glomerulopathy

Recently, two cases of renal disease were observed in which there was an abnormal accumulation of lipids, "lipoprotein thrombi," in the glomerular capillary lumen. This disease has been designated as lipoprotein glomerulopathy. Four other cases have been diagnosed independently by renal histology in other clinical laboratories. All six patients showed proteinuria (1.6 to 10 g/d), normal lecithin-cholesterol acyltransferase (LCAT) activity, type III hyperlipoproteinemia-like lipoprotein profiles, and significantly (P less than 0.01) higher levels of plasma apolipoprotein (apo) E (greater than 10 mg/dL) compared with the control patients with hyperlipidemic nephrotic syndrome without lipoprotein thrombi and type IIb hyperlipoproteinemia without renal disease. Lipoprotein glomerulopathy is not familial type III hyperlipoproteinemia (dysbetalipoproteinemia), because apolipoprotein E3 is present. Apo E isoforms were all rare: five cases of E2/3 and one case of E4/4. These results suggest that excessive apo E is associated with apo E isoform and lipoprotein metabolic derangement in such a renal disease. Further studies are needed on the relationship between the apo E hyperlipoproteinemia and the formation of lipoprotein thrombi.     

Familial pheochromocytoma in a daughter (extra-adrenal) and her mother

The nineteenth kindred of familial pheochromocytoma in Japan is reported. A 13-year-old girl had an extra-adrenal pheochromocytoma and her 40-year-old mother had a right adrenal pheochromocytoma. This is the first case of an extra-adrenal pheochromocytoma in familial pheochromocytoma. A statistical analysis was performed on the 46 cases in 19 kindreds reported so far in Japan.     

A case of lipoprotein glomerulopathy in a Greek Caucasian male

International Urology and Nephrology -     

Long-term follow-up of a paediatric case of lipoprotein glomerulopathy

A paediatric case of lipoprotein glomerulopathy, a new kidney disease characterized by glomerular lipoprotein thrombi, is reported. The patient had massive proteinuria from the age of 8 years, when the nephrotic syndrome was first detected. This was resistant to conventional treatment for more than 10 years. During the course of the disease, the hyperlipidaemia characteristic of hyper-pre--lipoproteinaemia and elevation of apoprotein E persisted, and renal function gradually deteriorated. The renal histopathological findings from four biopsies were essentially the same, with storage of -lipoprotein in dilated, balloon-like glomerular capillary lumina. However, the number of glomeruli showing global sclerosis increased and tubulo-interstitial changes progressed in parallel with the gradual clinical deterioration. As in other cases reported in Japan some familial involvement has been noted.     

Successful use of rituximab in fibrillary glomerulopathy

Fibrillary glomerulopathy (FG) can occur either alone or co-existing with other proteinuric glomerular disorders. FG has been associated with poor renal outcomes leading to End Stage Renal Disease (ESRD). Since FG is a relatively rare disorder, limited information is available concerning treatment protocols. We present two patients with FG who were treated with rituximab after they had already progressed to stage 3 chronic kidney disease (CKD) with worsening proteinuria. Rituximab therapy resulted in long-term stabilization of renal function.     

Topics in lipoprotein glomerulopathy: an overview

Here, we introduce four topics in lipoprotein glomerulopathy (LPG). To date, approximately 150 cases of LPG have been reported worldwide. Recently two groups studied hot spots of APOE-Sendai and APOE-Kyoto, the representative variants of LPG, in narrow areas of Japan and China, respectively. They suggest that both variants have descended through a founder effect. APOE-Sendai and APOE-Kyoto cause different transformations of apolipoproteins aggregating lipoproteins and resulting in lipoprotein thrombi within the glomerulus. Moreover, the macrophage impairment in LPG may provide another mechanism for lipoprotein thrombi in which massive lipoproteins accumulate in the glomerulus without foam cells. On the other hand, the administration of fibrate with the intensive control of triglyceride and apolipoprotein E particularly from the early phase will ameliorate LPG and prevent renal dysfunction.     

Charcot-Marie-Tooth disease and nephropathy in a mother and daughter with a review of the literature

We report a mother-and-child combination of Charcot-Marie-Tooth disease and nephropathy. The mother received a cadaveric renal transplant, and the daughter has heavy proteinuria with normal glomerular filtration rate. There have been 7 single case reports of both disease entities and 1 report of 3 patients which includes the only sib pair. The related literature is reviewed.     

脂蛋白肾病患者的临床表现及病理学特征

目的 进一步阐明脂蛋白肾病患者的临床特征及肾活检组织学，免疫组织化学和超微结构特点。方法 回顾性分析7例经肾活检病理及免疫病理证实为脂蛋白肾病患者的临床表现，肾脏损害的实验室检查特征及血脂检测结果，并对肾活检组织学免疫组织化学特点及超微结构改变进行分析。结果 全部患者都有大量蛋白尿及镜下血尿，均存在不同程度的贫血。血清甘油三酯及apoB,apoE水平显著升高，总胆固醇正常或正常增高。B超检查全部患者双肾体积均增大。肾活检组织光镜下肾小球体积明显增大，襻高度扩张，襻内见层状改变的大小不同，多少不等的“栓子”。油红O染色阳性，本组7例患者中4例存在与肾小球病变不相符的小管－间质病为和血管病变。免疫荧光染色证实“栓子”富apoB,apoE，超微结构观察证实“栓子”内含颗粒状的嗜锇脂质空泡。结论 本组脂蛋白肾病患者除存在与文献报告相同的临床特征及组织学，超微结构特点外，尚发现既往文献未曾报道过的一些临床病理特点。     

Lipoprotein glomerulopathy: glomerular lipoprotein thrombi in a patient with hyperlipoproteinemia

An unusual nephropathy presumably induced by abnormal lipid metabolism is described in a 57-year-old woman who presented with proteinuria and edema. Histology at renal biopsy was characterized by marked dilatation of capillary lumina. Sudan staining and electron microscopy demonstrated lipid droplets occupying the capillary lumina. The patient had no particular clinical symptoms of lipidosis, but hyperlipoproteinemia similar to type III was suggested by lipid profiles. The nephropathy is thought to be an inherited disorder because proteinuria was detected in her sisters and similar renal histology and lipid profile were observed in one of her sisters. This is believed to be the first detailed report of glomerular lipoprotein thrombi.     

Clinicopathological and genetic characteristics in Chinese patients with lipoprotein glomerulopathy

OBJECTIVE: In this study, we report on 16 Chinese patients with biopsy-proven lipoprotein glomerulopathy (LPG) investigated for clinical manifestations, pathological characteristics and apolipoprotein E (apoE) genetic analysis. METHODS: A retrospective analysis of the clinical and pathological features was made in 16 patients with LPG. Plasma concentrations and genetic analysis of apoE were completed. Glomerular depositions of apoA, apoB and apoE were detected using monoclonal antibodies on cryostatic sections in all patients. RESULTS: All 16 patients presented with edema; 14 presented with nephrotic syndrome. Anemia, microhematuria, hypertension and abnormal levels of serum creatinine were detected in 12 patients (75%), 11 patients (69%), 8 patients (50%) and 6 patients (37.5%), respectively. All the patients showed hypertriglyceridemia, while only 7 showed slight hypercholesterolemia. The characteristic features of hyperlipidemia in these patients were approximately in accord with those of type IV hyperlipoproteinemia. Concentrations of apoB correlated with urine protein, triglycerides and cholesterol (r=0.558, p=0.038; r=0.6, p=0.023; r=0.65, p=0.012; respectively). No correlation was found between serum level of apoE and clinicopathological features in patients with LPG. The genotype of apoE-epsilon3/epsilon4 is the predominant one in Chinese patients with LPG. No mutated forms of apoE were found, compared with previous reports. CONCLUSION: Unique clinicopathological and genetic features were found in this group of Chinese patients with LPG compared with the general population, including lower serum levels of apoE and cholesterol, as well as anemia and microhematuria. Multiple factors other than apoE were involved in the pathogenesis of LPG.     

Apolipoprotein E mutations: a comparison between lipoprotein glomerulopathy and type III hyperlipoproteinemia

Apolipoprotein E (ApoE) serves as a ligand for the low-density lipoprotein (LDL) receptor and cell surface receptors of the LDL receptor gene family. More than 10 different causative apoE mutations associated with lipoprotein glomerulopathy (LPG) have been reported. ApoE polymorphisms including three common phenotypes (E2, E3, E4), and a variety of rare mutations can affect blood cholesterol and triglyceride levels. The N-terminal domain of apoE is folded into a four-helix bundle of amphipathic α-helices, and contains the receptor-binding domain in which most apoE mutations that cause LPG or dominant mode of type III hyperlipoproteinemia (HL) are located. No single apoE mutation has been reported that causes both LPG and the dominant mode of type III HL.     

Improvement of nephrotic syndrome by intensive lipid-lowering therapy in a patient with lipoprotein glomerulopathy

Lipoprotein glomerulopathy (LPG) is a rare hereditary disease characterized by the accumulation of much thrombi material consisting of lipoproteins at the glomerular capillary lumen. Most patients show nephrotic syndrome; nearly half progress to chronic renal failure. Intensive therapy with lipid-lowering agents reportedly engenders clinical remission with histological resolution. We report the case of a 14-year-old Japanese female patient who had been in a nephrotic condition with hematuria from 4 years old and who had been diagnosed based on pathological and molecular examination at 7 years old. We initially treated the patient with probucol, enalapril (angiotensin-converting enzyme inhibitor: ACEI), and dipyridamole from age 7, but achieved no improvement in her nephrotic status. Subsequently, we replaced probucol with bezafibrate at age 11 and added atorvastatin calcium hydrate and valsartan (angiotensin II receptor blocker: ARB) the following year. The next 3 years’ treatment improved her nephrotic status, decreased serum apolipoprotein E, and markedly decreased intraglomerular lipoprotein thrombi. Early and intensive therapy with antilipidemic drugs combined with ACEI and ARB is inferred to be effective for LPG.     

Role of apolipoprotein E variants in lipoprotein glomerulopathy and other renal lipidoses

Lipoprotein glomerulopathy (LPG) is a new renal lipidosis entity, characterized by peculiar histology and abnormal lipoprotein profiles mimicking type III hyperlipoproteinemia. Recently, it has been clarified that LPG is associated with novel apolipoprotein E (apoE) mutations. In particular, ApoE-Sendai, which substitutes arginine 145 with proline, is observed in most Japanese patients with LPG, although isoelectric focusing polyacrylamide gel electrophoresis has shown that it is consistent with the apoE2 isoform. To confirm the etiological role of these apoE mutations, we established an animal model of LPG. The model was created by the introduction of recombinant adenovirus containing human apoE-Sendai into apoE knockout mice. Both clinical and experimental findings indicate that LPG is caused not only by hyperlipoproteinemia but also by an in situ interaction between apoE variants and glomerular elements. In addition, several studies suggest that the apoE2 mutation is responsible for the development of diabetic nephropathy and IgA nephropathy, as well as renal lipidosis with type III hyperlipoproteinemia. In this review, we present the clinical and histological features of LPG and its pathogenesis, and discuss the role of apoE abnormalities, especially apoE-Sendai and apoE2, in LPG and other renal lipidoses. Received: August 27, 2001 / Accepted: September 11, 2001