Clin Exp Nephrol DOI 10.1007/s10157-013-0873-x
REVIEW ARTICLE
WCN 2013 Satellite Symposium ‘‘Kidney and Lipids’’
Lipoprotein glomerulopathy in China Yuqing Chen
Received: 27 August 2013 / Accepted: 17 September 2013 Ó Japanese Society of Nephrology 2013
Abstract Lipoprotein glomerulopathy (LPG), a rare renal disease, is mainly reported in Japan and China. Chinese cases of LPG showed similar clinical and pathological features as reports from other countries. Three types of APOE mutation have been detected in those patients: APOE Maebashi (142Arg-144Leu-0) and APOE Kyoto (Arg25-Cys) were initially reported, and APOE Guangzhou (Arg150-Pro) is a novel mutation in Chinese patients with LPG. Asymptomatic carriers of all three mutations exist in families, but serum lipid and apolipoprotein E (apoE) levels are markedly elevated. In most of Chinese patients with LPG, long-term treatment with statins or bezafibrates appears to decrease proteinuria. LPG provides a disease model by which to explore pathogenic roles of apoE in common diseases. Keywords Mutation
Lipoprotein glomerulopathy APOE
Lipoprotein glomerulopathy (LPG) is characterized by intraglomerular lipoprotein thrombi and abnormal lipid metabolism [1, 2]. LPG, a rare renal disease, was first reported in 1989 [3], and since then, more cases have been published, mainly from Japan and China. The first Chinese case was reported in 1997 in the Chinese Journal of Nephrology. The patient was 41-year-old woman who Y. Chen (&) Renal Division, Department of Internal Medicine, Peking University First Hospital, No.8 Xishiku Street, Beijing 100034, China e-mail: [email protected] Y. Chen Institute of Nephrology, Peking University, Beijing, China
presented with nephrotic syndrome and increased serum apolipoprotein E (apoE) levels. Renal pathological examinations revealed typical changes associated with LPG. One report from Najing summarized the clinical and pathological features in Chinese patients. Proteinuria; high levels of triglycerides, apoB, and apoE; and lipoprotein thrombi occupying capillary lumina, were detected in all patients. Immunofluorescence examination showed positive staining for apoA, B, and E, and electron microscopy revealed granules and various sizes of vacuoles in thrombi [4]. Abnormalities of apoE are involved in the pathogenesis of LPG. The binding of lipoproteins to the low-density lipoprotein (LDL) receptors and chylomicron remnant receptors is mediated by apoE; thus, apoE plays an important physiological role in lipid metabolism. Several APOE gene mutations are reported to be associated with LPG and dysbetalipoproteinemia [1, 5–9]. In Chinese patients, three types of APOE mutation have been detected. We reported two types: APOE Maebashi (142Arg-144Leu0) [8] in four unrelated families, and APOE Kyoto (Arg25Cys) [7] in two unrelated families [10]. Asymptomatic carriers of both mutations existed in these families in whom serum lipid and apoE levels were markedly elevated [10]. APOE Guangzhou (Arg150-Pro) is another APOE mutation identified in Chinese patients [11]. It was detected in three generations with a wide variation of clinical features, from asymptomatic to end-stage kidney disease. Other studies also show that APOE mutations are transmitted with incomplete penetrance [7, 8]. These phenomena indicate some other possibilities, participated in renal injury and especially some local mechanisms in glomeruli. Study of APOE prove that glomerular injury is caused by in situ interaction between mutant APOE and glomeruli [12]. One study found that serum apoB levels correlate with urinary protein, and apoB deposition was also
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detected in the enlarged glomeruli [13]. However, not all patients with LPG had a high apoB level. The roles of apoB on renal injury need further investigation. Another interesting study from Nanjing screened APOE mutation in 17 patients with LPG; however, none of the mutations in the coding region was identified, suggested other pathogenic possibilities [13]. In most reported cases of Chinese LPG patients, longterm treatments with statins or bezafibrate appeared to decrease proteinuria. We followed an APOE Kyoto carrier who accepted therapy of prednisone 50 mg per day and simvastatin 200 mg for 3 months, without any signs of remission. Then, prednisone was gradually decreased and leflunomide was added for another 6 months; the patient experienced complete remission [10]. A clinical study from a single center treated 13 biopsy-confirmed LPG patients with staphylococcal protein A immunoadsorption and observed a rapid decline in proteinuria and disappearance of intraglomerular lipoprotein thrombi after treatment. However, proteinuria in LPG patients gradually returned to baseline within 12 months [14]. Local inflammation might be involved in the mechanism of LPG, and immunosuppressive therapy might act on this step, resulting in remission of proteinuria. However, the long-term effects of immunosuppressive therapy in such patients need to be evaluated. In summary, apoE plays a crucial role in lipid metabolism. Although LPG is a rare disease, it provides a model by which to explore pathogenetic roles of apoE in common disease, such as chronic kidney, cardiovascular, and nervous system diseases. Conflict of interest interest exists.
The authors have declared that no conflict of
References 1. Rovin BH, Roncone D, McKinley A, Nadasdy T, et al. APOE Kyoto mutation in European Americans with lipoprotein glomerulopathy. N Engl J Med. 2007;357:2522–4.
123
2. Saito T, Matsunaga A, Oikawa S. Impact of lipoprotein glomerulopathy on the relationship between lipids and renal diseases. Am J Kidney Dis. 2006;47:199–211. 3. Saito T, Sato H, Kudo K, Oikawa S, et al. Lipoprotein glomerulopathy: glomerular lipoprotein thrombi in a patient with hyperlipoproteinemia. Am J Kidney Dis. 1989;13:148–53. 4. Chen HP, Liu ZH, Gong RJ, Tang Z, et al. Lipoprotein glomerulopathy: clinical features and pathological characteristics in Chinese. Chin Med J (Engl). 2004;117:1513–7. 5. Ando M, Sasaki J, Hua H, Matsunaga A, et al. A novel 18-amino acid deletion in apolipoprotein E associated with lipoprotein glomerulopathy. Kidney Int. 1999;56:1317–23. 6. Konishi K, Saruta T, Kuramochi S, Oikawa S, et al. Association of a novel 3-amino acid deletion mutation of apolipoprotein E (Apo E Tokyo) with lipoprotein glomerulopathy. Nephron. 1999;83:214–8. 7. Matsunaga A, Sasaki J, Komatsu T, Kanatsu K, et al. A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy. Kidney Int. 1999;56:421–7. 8. Ogawa T, Maruyama K, Hattori H, Arai H, et al. A new variant of apolipoprotein E (apo E Maebashi) in lipoprotein glomerulopathy. Pediatr Nephrol. 2000;14:149–51. 9. Oikawa S, Matsunaga A, Saito T, Sato H, et al. Apolipoprotein E Sendai (arginine 145 ? proline): a new variant associated with lipoprotein glomerulopathy. J Am Soc Nephrol. 1997;8:820–3. 10. Han J, Pan Y, Chen Y, Li X, et al. Common apolipoprotein E gene mutations contribute to lipoprotein glomerulopathy in China. Nephron Clin Pract. 2010;114:260–7. 11. Luo B, Huang F, Liu Q, Li X, et al. Identification of apolipoprotein E Guangzhou (arginine 150 proline), a new variant associated with lipoprotein glomerulopathy. Am J Nephrol. 2008;28:347–53. 12. Blasiole DA, Oler AT, Attie AD. Regulation of ApoB secretion by the low density lipoprotein receptor requires exit from the endoplasmic reticulum and interaction with ApoE or ApoB. J Biol Chem. 2008;283:11374–81. 13. Zhang B, Liu ZH, Zeng CH, Zheng JM, et al. Clinicopathological and genetic characteristics in Chinese patients with lipoprotein glomerulopathy. J Nephrol. 2008;21:110–7. 14. Xin Z, Zhihong L, Shijun L, Jinfeng Z, et al. Successful treatment of patients with lipoprotein glomerulopathy by protein A immunoadsorption: a pilot study. Nephrol Dial Transplant. 2009;24:864–9.
REVIEW ARTICLE
WCN 2013 Satellite Symposium ‘‘Kidney and Lipids’’
Lipoprotein glomerulopathy in China Yuqing Chen
Received: 27 August 2013 / Accepted: 17 September 2013 Ó Japanese Society of Nephrology 2013
Abstract Lipoprotein glomerulopathy (LPG), a rare renal disease, is mainly reported in Japan and China. Chinese cases of LPG showed similar clinical and pathological features as reports from other countries. Three types of APOE mutation have been detected in those patients: APOE Maebashi (142Arg-144Leu-0) and APOE Kyoto (Arg25-Cys) were initially reported, and APOE Guangzhou (Arg150-Pro) is a novel mutation in Chinese patients with LPG. Asymptomatic carriers of all three mutations exist in families, but serum lipid and apolipoprotein E (apoE) levels are markedly elevated. In most of Chinese patients with LPG, long-term treatment with statins or bezafibrates appears to decrease proteinuria. LPG provides a disease model by which to explore pathogenic roles of apoE in common diseases. Keywords Mutation
Lipoprotein glomerulopathy APOE
Lipoprotein glomerulopathy (LPG) is characterized by intraglomerular lipoprotein thrombi and abnormal lipid metabolism [1, 2]. LPG, a rare renal disease, was first reported in 1989 [3], and since then, more cases have been published, mainly from Japan and China. The first Chinese case was reported in 1997 in the Chinese Journal of Nephrology. The patient was 41-year-old woman who Y. Chen (&) Renal Division, Department of Internal Medicine, Peking University First Hospital, No.8 Xishiku Street, Beijing 100034, China e-mail: [email protected] Y. Chen Institute of Nephrology, Peking University, Beijing, China
presented with nephrotic syndrome and increased serum apolipoprotein E (apoE) levels. Renal pathological examinations revealed typical changes associated with LPG. One report from Najing summarized the clinical and pathological features in Chinese patients. Proteinuria; high levels of triglycerides, apoB, and apoE; and lipoprotein thrombi occupying capillary lumina, were detected in all patients. Immunofluorescence examination showed positive staining for apoA, B, and E, and electron microscopy revealed granules and various sizes of vacuoles in thrombi [4]. Abnormalities of apoE are involved in the pathogenesis of LPG. The binding of lipoproteins to the low-density lipoprotein (LDL) receptors and chylomicron remnant receptors is mediated by apoE; thus, apoE plays an important physiological role in lipid metabolism. Several APOE gene mutations are reported to be associated with LPG and dysbetalipoproteinemia [1, 5–9]. In Chinese patients, three types of APOE mutation have been detected. We reported two types: APOE Maebashi (142Arg-144Leu0) [8] in four unrelated families, and APOE Kyoto (Arg25Cys) [7] in two unrelated families [10]. Asymptomatic carriers of both mutations existed in these families in whom serum lipid and apoE levels were markedly elevated [10]. APOE Guangzhou (Arg150-Pro) is another APOE mutation identified in Chinese patients [11]. It was detected in three generations with a wide variation of clinical features, from asymptomatic to end-stage kidney disease. Other studies also show that APOE mutations are transmitted with incomplete penetrance [7, 8]. These phenomena indicate some other possibilities, participated in renal injury and especially some local mechanisms in glomeruli. Study of APOE prove that glomerular injury is caused by in situ interaction between mutant APOE and glomeruli [12]. One study found that serum apoB levels correlate with urinary protein, and apoB deposition was also
123
Clin Exp Nephrol
detected in the enlarged glomeruli [13]. However, not all patients with LPG had a high apoB level. The roles of apoB on renal injury need further investigation. Another interesting study from Nanjing screened APOE mutation in 17 patients with LPG; however, none of the mutations in the coding region was identified, suggested other pathogenic possibilities [13]. In most reported cases of Chinese LPG patients, longterm treatments with statins or bezafibrate appeared to decrease proteinuria. We followed an APOE Kyoto carrier who accepted therapy of prednisone 50 mg per day and simvastatin 200 mg for 3 months, without any signs of remission. Then, prednisone was gradually decreased and leflunomide was added for another 6 months; the patient experienced complete remission [10]. A clinical study from a single center treated 13 biopsy-confirmed LPG patients with staphylococcal protein A immunoadsorption and observed a rapid decline in proteinuria and disappearance of intraglomerular lipoprotein thrombi after treatment. However, proteinuria in LPG patients gradually returned to baseline within 12 months [14]. Local inflammation might be involved in the mechanism of LPG, and immunosuppressive therapy might act on this step, resulting in remission of proteinuria. However, the long-term effects of immunosuppressive therapy in such patients need to be evaluated. In summary, apoE plays a crucial role in lipid metabolism. Although LPG is a rare disease, it provides a model by which to explore pathogenetic roles of apoE in common disease, such as chronic kidney, cardiovascular, and nervous system diseases. Conflict of interest interest exists.
The authors have declared that no conflict of
References 1. Rovin BH, Roncone D, McKinley A, Nadasdy T, et al. APOE Kyoto mutation in European Americans with lipoprotein glomerulopathy. N Engl J Med. 2007;357:2522–4.
123
2. Saito T, Matsunaga A, Oikawa S. Impact of lipoprotein glomerulopathy on the relationship between lipids and renal diseases. Am J Kidney Dis. 2006;47:199–211. 3. Saito T, Sato H, Kudo K, Oikawa S, et al. Lipoprotein glomerulopathy: glomerular lipoprotein thrombi in a patient with hyperlipoproteinemia. Am J Kidney Dis. 1989;13:148–53. 4. Chen HP, Liu ZH, Gong RJ, Tang Z, et al. Lipoprotein glomerulopathy: clinical features and pathological characteristics in Chinese. Chin Med J (Engl). 2004;117:1513–7. 5. Ando M, Sasaki J, Hua H, Matsunaga A, et al. A novel 18-amino acid deletion in apolipoprotein E associated with lipoprotein glomerulopathy. Kidney Int. 1999;56:1317–23. 6. Konishi K, Saruta T, Kuramochi S, Oikawa S, et al. Association of a novel 3-amino acid deletion mutation of apolipoprotein E (Apo E Tokyo) with lipoprotein glomerulopathy. Nephron. 1999;83:214–8. 7. Matsunaga A, Sasaki J, Komatsu T, Kanatsu K, et al. A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy. Kidney Int. 1999;56:421–7. 8. Ogawa T, Maruyama K, Hattori H, Arai H, et al. A new variant of apolipoprotein E (apo E Maebashi) in lipoprotein glomerulopathy. Pediatr Nephrol. 2000;14:149–51. 9. Oikawa S, Matsunaga A, Saito T, Sato H, et al. Apolipoprotein E Sendai (arginine 145 ? proline): a new variant associated with lipoprotein glomerulopathy. J Am Soc Nephrol. 1997;8:820–3. 10. Han J, Pan Y, Chen Y, Li X, et al. Common apolipoprotein E gene mutations contribute to lipoprotein glomerulopathy in China. Nephron Clin Pract. 2010;114:260–7. 11. Luo B, Huang F, Liu Q, Li X, et al. Identification of apolipoprotein E Guangzhou (arginine 150 proline), a new variant associated with lipoprotein glomerulopathy. Am J Nephrol. 2008;28:347–53. 12. Blasiole DA, Oler AT, Attie AD. Regulation of ApoB secretion by the low density lipoprotein receptor requires exit from the endoplasmic reticulum and interaction with ApoE or ApoB. J Biol Chem. 2008;283:11374–81. 13. Zhang B, Liu ZH, Zeng CH, Zheng JM, et al. Clinicopathological and genetic characteristics in Chinese patients with lipoprotein glomerulopathy. J Nephrol. 2008;21:110–7. 14. Xin Z, Zhihong L, Shijun L, Jinfeng Z, et al. Successful treatment of patients with lipoprotein glomerulopathy by protein A immunoadsorption: a pilot study. Nephrol Dial Transplant. 2009;24:864–9.
