- Email: [email protected]
Lipoprotein glomerulopathy may provide a key to unlock the puzzles of renal lipidosis
commentary
differentiation pathways of myofibroblasts in fibrotic kidney disease.13 In conclusion, while the potential benefits of RAAS blockade in kidney transplant recipients remain to be fully elucidated, it is to be hoped that the work of Issa et al.10 and the clinical trial from which it was derived9 will serve as a stimulus for additional datarich, randomized controlled trials of non-immunosuppressive medical therapies to alter the course of progressive IF/TA and other processes that currently limit long-term transplant success. DISCLOSURE
Matthew D. Griffin and Hatem Amer have received grant funding from Abbott Laboratories for research projects not directly related to the content of this Commentary. ACKNOWLEDGMENTS
M.D.G. is funded by grants from Science Foundation Ireland (SFI SRC 09/SRC/B1794) and the Health Research Board of Ireland (HRA/HSR/2010/63).
10.
11.
Issa N, Ortiz F, Reule SA et al. The renin– aldosterone axis in kidney transplant recipients and its association with allograft function and structure. Kidney Int 2014; 85: 404–415. Beckerhoff R, Uhlschmid E, Vetter W et al. Plasma renin and aldosterone after renal transplantation. Kidney Int 1974; 5: 39–46.
12.
13.
Wolf G. Renal injury due to renin-angiotensinaldosterone system activation of the transforming growth factor-beta pathway. Kidney Int 2006; 70: 1914–1919. LeBleu VS, Taduri G, O’Connell J et al. Origin and function of myofibroblasts in kidney fibrosis. Nat Med 2013; 19: 1047–1053.
see clinical investigation on page 416
Lipoprotein glomerulopathy may provide a key to unlock the puzzles of renal lipidosis Takao Saito1 and Akira Matsunaga2 Lipoprotein glomerulopathy is an inherited renal disease characterized by unique lipoprotein thrombi in the glomerulus and is associated with the APOE mutation. Hu and colleagues investigated the genetic and clinical features of a large group of patients with lipoprotein glomerulopathy who carried APOE Kyoto, a major APOE variant. Their findings suggest its descent through a founder effect. Fibrate therapy in this group showed favorable results in the patient and renal survival rates. Kidney International (2014) 85, 243–245. doi:10.1038/ki.2013.404
REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
Nankivell BJ, Borrows RJ, Fung CL et al. The natural history of chronic allograft nephropathy. N Engl J Med 2003; 349: 2326–2333. Stegall MD, Park WD, Larson TS et al. The histology of solitary renal allografts at 1 and 5 years after transplantation. Am J Transplant 2011; 11: 698–707. Amer H, Lieske JC, Rule AD et al. Urine high and low molecular weight proteins one-year post-kidney transplant: relationship to histology and graft survival. Am J Transplant 2013; 13: 676–684. Park WD, Griffin MD, Cornell LD et al. Fibrosis with inflammation at one year predicts transplant functional decline. J Am Soc Nephrol 2010; 21: 1987–1997. Morath C, Schmied B, Mehrabi A et al. Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers after renal transplantation. Clin Transplant 2009; 23(Suppl 21): 33–36. Hiremath S, Fergusson D, Doucette S et al. Renin angiotensin system blockade in kidney transplantation: a systematic review of the evidence. Am J Transplant 2007; 7: 2350–2360. Opelz G, Dohler B. Treatment of kidney transplant recipients with ACEi/ARB and risk of respiratory tract cancer: a collaborative transplant study report. Am J Transplant 2011; 11: 2483–2489. Heinze G, Mitterbauer C, Regele H et al. Angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor antagonist therapy is associated with prolonged patient and graft survival after renal transplantation. J Am Soc Nephrol 2006; 17: 889–899. Ibrahim HN, Jackson S, Connaire J et al. Angiotensin II blockade in kidney transplant recipients. J Am Soc Nephrol 2013; 24: 320–327.
Kidney International (2014) 85, 232–247
Lipoprotein glomerulopathy (LPG) is a new glomerular disease that we first documented in 1989.1 Thereafter, cases of LPG were found mainly in east Asia, including Japan and China, but were also seen in Europe and the United States.2 At the time of discovery, extremely dilated glomerular capillaries that were filled with huge lipoprotein-rich materials called lipoprotein thrombi were noted. In addition to histological findings, several clinical manifestations, including proteinuria and dyslipidemia, are characteristic of this disorder. Proteinuria is sometimes mild but progresses to nephrotic syndrome in most cases.2 Dyslipidemia is generally classified into type III hyperlipoproteinemia and is 1 General Medical Research Center, Fukuoka University School of Medicine, Fukuoka, Japan and 2Department of Laboratory Medicine, Fukuoka University School of Medicine, Fukuoka, Japan Correspondence: Takao Saito, General Medical Research Center, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. E-mail: [email protected]
associated with increased serum apolipoprotein E (apoE) levels. However, no systemic manifestations related to lipidosis, such as corneal opacity, xanthoma striatum palmare, and other xanthomas, are observed. Moreover, the familial occurrence of LPG has been frequently recognized. On the basis of these features, we believe that LPG may be an inherited disease in which abnormal lipoproteins composed of apoE mutants accumulate within the glomerulus. This hypothesis was supported by the discoveries of apoE Sendai (Arg145Cys) in 19973 and apoE Kyoto (Arg25Cys) in 1998.4 The polymorphism of the APOE mutation in LPG has become clear, as 15 novel APOE variants have been identified to date. However, the histological findings and clinical manifestations seem to be common among patients with different APOE variants. The geographical distributions of patients with LPG are shown in Figure 1. One of the major variants, APOE Sendai, was found in only patients who lived in east Japan, particularly in a 243
commentary
Italy (1)
China (65) USA (4)
France (1)
Taiwan (1) Hong Kong (1)
APOE Sendai (25) APOE Kyoto (49) APOE Tokyo/Maebashi (7) APOE Guangzhou (4) Other APOE mutants (15) No APOE gene mutation (17)
Japan (44)
Figure 1 | Map of lipoprotein glomerulopathy. Cases are limited to those assayed by DNA sequencing.
narrow area lying across Yamagata and Miyagi prefectures. From this point of view, Toyota et al.5 investigated the haplotype of APOE Sendai in 13 Japanese patients with LPG from nine unrelated families and suggested that the APOE Sendai mutation is common in Japanese patients through a founder effect. In contrast, Hu et al.6 (this issue) elucidated the genetic and clinical features of 35 patients with LPG and the APOE Kyoto mutation and 28 asymptomatic carriers from 31 families in a narrow area of the Sichuan Basin, China. This indepth study, which targeted the largest group of patients with LPG to date, suggests that APOE Kyoto also descended from a single founder. Accordingly, it is of interest that the incidence of APOE Sendai and APOE Kyoto, the major LPG mutants, may increase through a founder effect. However, unlike APOE Sendai, APOE Kyoto was detected not only in Asians living in Japan, China, Taiwan, and the United States but also in Caucasians in Europe and the United States.2 This finding suggests that APOE Kyoto spread from a single hot spot in China to the world. To determine the difference in propagation between APOE Sendai and APOE Kyoto, it is necessary to consider the structural change in apoE variants and the positions of the mutations. The substitution of proline for arginine-145 in apoE 244
Sendai breaks the a-helical structure of apoE in the low-density lipoprotein receptor-binding domain and transforms the apoE molecules that extend to the lipoprotein thrombi.3 The substitution of cysteine for arginine-25 in apoE Kyoto also seems to break the interhelical salt bridge and lead to a change in the tertiary structure, reducing receptor activity.4 As we discuss later, however, there are many asymptomatic carriers of the APOE Kyoto or APOE Sendai mutation, and the penetrance of each variant is similarly low.5,6 Therefore, the difference in geographical distribution cannot be explained with the use of mutation characteristics alone. From ancient times, the international exchange of Chinese people has been higher than that of Japanese people, who are surrounded by the sea. Therefore, even if APOE Kyoto was founded in an isolated narrow area of the Sichuan Basin, it might have spread worldwide—in a manner similar to the expansion of tea culture worldwide from China. Several other variants have recently been reported, not only in Asia but also in Europe and the United States. It may be possible that other hot spots of patients with LPG descended from a single founder and will be detected across the world. Until now, most LPG studies were limited to case reports and review articles, because LPG cases were so rare. However, the study by Hu et al.6
(this issue) targeting a large group of homogeneous patients with LPG exposes the various aspects of LPG. Hu et al.6 and Toyota et al.5 suggest that other genetic or epigenetic factors are involved in the pathogenesis of LPG because of the low penetrance based on many asymptomatic carriers of APOE variants. Kanamaru et al.7 reported that an Fcg receptor (FcRg) deficiency associated with graft-versus-host disease caused murine LPG independently of the apoE abnormality. Our experiments also clarified that the formation of lipoprotein thrombi in this murine LPG model was induced by the impairment of macrophages activating low-density lipoprotein and scavenger receptors due to the FcRg deficiency.8,9 These experiments may be clinically confirmed by the therapeutic effect of immunoadsorption on LPG using protein A columns.10 Because protein A has strong affinity to the Fc portion of IgG and acts as FcRg, protein A may be able to improve LPG by absorbing the accumulated lipoproteins in LPG, although its ability to bind to lipoproteins remains unknown. These experimental and clinical results indicate that the macrophage impairment related to FcRg dysfunction is among the pivotal factors for the development of LPG. In renal lipidosis, following the mechanism of atherosclerosis proposed by Brown and Goldstein,11 mesangial cells or macrophages infiltrating the mesangial areas are suspected to uptake lipoproteins and contribute to the development of glomerulosclerosis. In contrast, the various findings in LPG as described above may provide different mechanisms of renal lipidosis in which the excess accumulation of lipoproteins may directly induce glomerular damage without inducing a foamy change in macrophages. Another important strategy proposed by Hu et al.6 consists of confirming the therapeutic effect of fibrates using long-term follow-up. The efficacy of lipid-lowering therapy containing fibrates has been reported by several authors from Japan, both clinically and histologically. However, all of them were case studies. Hu et al.6 reviewed the literature in detail and compared the Kidney International (2014) 85, 232–247
commentary
3-year patient and renal survival rates between their own fenofibrate and control groups. This is the first clinically controlled study on lipid-lowering therapy for LPG. The significantly higher survival rates in the fenofibrate group of this study confirm the effect of fibrates. LPG, which is thought to be an inherited kidney disease, occasionally appears without hyperlipidemia. However, high levels of serum triglyceride (TG), TG-rich lipoprotein, and apoE are risk factors for the progression of LPG. Hu et al.6 state that dyslipidemia was marked in patients with LPG compared with asymptomatic carriers, although the high cholesterol levels might result in part from nephrotic syndrome in most patients with LPG. Moreover, the use of fenofibrate treatment with intensive control of TG and apoE from the early phase achieved complete remission and stabilized renal function. This finding suggests that LPG can be ameliorated by the elimination of TG-rich lipoproteins composed of abnormal apoE. In the late stage of chronic kidney disease (CKD), levels of atherogenic TG-rich lipoproteins, including very-low-density lipoprotein and remnants, are increased. Regardless of the etiology, the abnormal lipid profile of LPG is similar to that of CKD. Accordingly, the treatment for LPG may provide information about preventing CKD aggravation, although the side effects of lipid-lowering agents such as fibrates should be considered. The investigation by Hu et al.6 may play a key role in unlocking the puzzles of renal lipidosis, the incidence of which has increased in LPG studies. We hope that the information reported here facilitates further advances in this field.
4.
5.
6.
7.
145-proline): a new variant associated with lipoprotein glomerulopathy. J Am Soc Nephrol 1997; 8: 820–823. Matsunaga A, Sasaki J, Komatsu T et al. A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy. Kidney Int 1999; 56: 421–427. Toyota K, Hashimoto T, Ogino D et al. A founder haplotype of APOE-Sendai mutation associated with lipoprotein glomerulopathy. J Hum Genet 2013; 58: 254–258. Hu Z, Huang S, Wu Y et al. Hereditary features, treatment, and prognosis of the lipoprotein glomerulopathy in patients with the APOE Kyoto mutation. Kidney Int 2014; 85: 416–424. Kanamaru Y, Nakao A, Shirato I et al. Chronic graft-versus-host autoimmune disease in Fc receptor gamma chain-deficient mice results in lipoprotein glomerulopathy. J Am Soc Nephrol 2002; 13: 1527–1533.
8.
9.
10.
11.
Ito K, Nakashima H, Watanabe M et al. Macrophage impairment produced by Fc receptor gamma deficiency plays a principal role in the development of lipoprotein glomerulopathy in concert with apoE abnormalities. Nephrol Dial Transplant 2013; 27: 3899–3907. Miyahara Y, Nishimura S, Watanabe M et al. Scavenger receptor expressions in the kidneys of mice with lipoprotein glomerulopathy. Clin Exp Nephrol 2012; 16: 115–121. Xin Z, Zhihong L, Shijun L et al. Successful treatment of patients with lipoprotein glomerulopathy by protein A immunoadsorption: a pilot study. Nephrol Dial Transplant 2009; 24: 864–869. Brown MS, Goldstein JL. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem 1983; 52: 223–261.
see clinical investigation on page 425
Can we prevent donor-specific antibodies from developing after ABO-incompatible kidney transplantation? Lionel Rostaing1,2,3 and Nassim Kamar1,2,3 The burden of chronic kidney disease is increasing worldwide and its costs are skyrocketing, particularly for those with end-stage kidney disease (ESKD). Thus, kidney transplantation needs to be available to as many as ESKD patients as possible. In countries where a donor swap or a donor-chain program is not feasible, ABO-incompatible (ABO-i) and/or HLA incompatible (HLAi) programs have been developed. In the setting of ABOi kidney transplantation, pretransplant desensitization is mandatory; this is based on the removal of isoagglutinins by plasmapheresis or immunoadsorption, and often using splenectomy (SPx) or, more recently, rituximab (RTx) infusion instead. Because RTx and SPx interfere with B-cell function, one wonders whether these desensitization protocols alter the occurrence of post-transplant donor-specific alloantibodies. Kidney International (2014) 85, 245–247. doi:10.1038/ki.2013.425
DISCLOSURE
The authors declared no competing interests. REFERENCES 1.
2.
3.
Saito T, Sato H, Kudo K et al. Lipoprotein glomerulopathy: glomerular lipoprotein thrombi in a patient with hyperlipoproteinemia. Am J Kidney Dis 1989; 13: 148–153. 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. Oikawa S, Matsunaga A, Saito T et al. Apolipoprotein E Sendai (arginine
Kidney International (2014) 85, 232–247
1 Department of Nephrology, Dialysis and Organ Transplantation, Centre Hospitalier Universitaire Rangueil, TSA 50032, Toulouse, France; 2Inserm U563 IFR-BMT, Centre Hospitalier Universitaire Purpan, Toulouse, France and 3Universite´ Paul Sabatier, Faculte´ de Me´decine de Rangueil, Toulouse, France Correspondence: Lionel Rostaing, Department of Nephrology, Dialysis and Organ Transplantation, Centre Hospitalier Universitaire Rangueil, TSA 50032, 31059 Toulouse, Cedex 9, France. E-mail: [email protected]
The burden of chronic kidney disease is increasing worldwide and its costs are skyrocketing, particularly for those with end-stage kidney disease. Thus, kidney transplantation needs to be available to as many end-stage kidney disease patients as possible. However, the number of deceased donors is plateauing, hence the development of living-unrelated-donor and living-related-donor 245
differentiation pathways of myofibroblasts in fibrotic kidney disease.13 In conclusion, while the potential benefits of RAAS blockade in kidney transplant recipients remain to be fully elucidated, it is to be hoped that the work of Issa et al.10 and the clinical trial from which it was derived9 will serve as a stimulus for additional datarich, randomized controlled trials of non-immunosuppressive medical therapies to alter the course of progressive IF/TA and other processes that currently limit long-term transplant success. DISCLOSURE
Matthew D. Griffin and Hatem Amer have received grant funding from Abbott Laboratories for research projects not directly related to the content of this Commentary. ACKNOWLEDGMENTS
M.D.G. is funded by grants from Science Foundation Ireland (SFI SRC 09/SRC/B1794) and the Health Research Board of Ireland (HRA/HSR/2010/63).
10.
11.
Issa N, Ortiz F, Reule SA et al. The renin– aldosterone axis in kidney transplant recipients and its association with allograft function and structure. Kidney Int 2014; 85: 404–415. Beckerhoff R, Uhlschmid E, Vetter W et al. Plasma renin and aldosterone after renal transplantation. Kidney Int 1974; 5: 39–46.
12.
13.
Wolf G. Renal injury due to renin-angiotensinaldosterone system activation of the transforming growth factor-beta pathway. Kidney Int 2006; 70: 1914–1919. LeBleu VS, Taduri G, O’Connell J et al. Origin and function of myofibroblasts in kidney fibrosis. Nat Med 2013; 19: 1047–1053.
see clinical investigation on page 416
Lipoprotein glomerulopathy may provide a key to unlock the puzzles of renal lipidosis Takao Saito1 and Akira Matsunaga2 Lipoprotein glomerulopathy is an inherited renal disease characterized by unique lipoprotein thrombi in the glomerulus and is associated with the APOE mutation. Hu and colleagues investigated the genetic and clinical features of a large group of patients with lipoprotein glomerulopathy who carried APOE Kyoto, a major APOE variant. Their findings suggest its descent through a founder effect. Fibrate therapy in this group showed favorable results in the patient and renal survival rates. Kidney International (2014) 85, 243–245. doi:10.1038/ki.2013.404
REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
Nankivell BJ, Borrows RJ, Fung CL et al. The natural history of chronic allograft nephropathy. N Engl J Med 2003; 349: 2326–2333. Stegall MD, Park WD, Larson TS et al. The histology of solitary renal allografts at 1 and 5 years after transplantation. Am J Transplant 2011; 11: 698–707. Amer H, Lieske JC, Rule AD et al. Urine high and low molecular weight proteins one-year post-kidney transplant: relationship to histology and graft survival. Am J Transplant 2013; 13: 676–684. Park WD, Griffin MD, Cornell LD et al. Fibrosis with inflammation at one year predicts transplant functional decline. J Am Soc Nephrol 2010; 21: 1987–1997. Morath C, Schmied B, Mehrabi A et al. Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers after renal transplantation. Clin Transplant 2009; 23(Suppl 21): 33–36. Hiremath S, Fergusson D, Doucette S et al. Renin angiotensin system blockade in kidney transplantation: a systematic review of the evidence. Am J Transplant 2007; 7: 2350–2360. Opelz G, Dohler B. Treatment of kidney transplant recipients with ACEi/ARB and risk of respiratory tract cancer: a collaborative transplant study report. Am J Transplant 2011; 11: 2483–2489. Heinze G, Mitterbauer C, Regele H et al. Angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor antagonist therapy is associated with prolonged patient and graft survival after renal transplantation. J Am Soc Nephrol 2006; 17: 889–899. Ibrahim HN, Jackson S, Connaire J et al. Angiotensin II blockade in kidney transplant recipients. J Am Soc Nephrol 2013; 24: 320–327.
Kidney International (2014) 85, 232–247
Lipoprotein glomerulopathy (LPG) is a new glomerular disease that we first documented in 1989.1 Thereafter, cases of LPG were found mainly in east Asia, including Japan and China, but were also seen in Europe and the United States.2 At the time of discovery, extremely dilated glomerular capillaries that were filled with huge lipoprotein-rich materials called lipoprotein thrombi were noted. In addition to histological findings, several clinical manifestations, including proteinuria and dyslipidemia, are characteristic of this disorder. Proteinuria is sometimes mild but progresses to nephrotic syndrome in most cases.2 Dyslipidemia is generally classified into type III hyperlipoproteinemia and is 1 General Medical Research Center, Fukuoka University School of Medicine, Fukuoka, Japan and 2Department of Laboratory Medicine, Fukuoka University School of Medicine, Fukuoka, Japan Correspondence: Takao Saito, General Medical Research Center, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. E-mail: [email protected]
associated with increased serum apolipoprotein E (apoE) levels. However, no systemic manifestations related to lipidosis, such as corneal opacity, xanthoma striatum palmare, and other xanthomas, are observed. Moreover, the familial occurrence of LPG has been frequently recognized. On the basis of these features, we believe that LPG may be an inherited disease in which abnormal lipoproteins composed of apoE mutants accumulate within the glomerulus. This hypothesis was supported by the discoveries of apoE Sendai (Arg145Cys) in 19973 and apoE Kyoto (Arg25Cys) in 1998.4 The polymorphism of the APOE mutation in LPG has become clear, as 15 novel APOE variants have been identified to date. However, the histological findings and clinical manifestations seem to be common among patients with different APOE variants. The geographical distributions of patients with LPG are shown in Figure 1. One of the major variants, APOE Sendai, was found in only patients who lived in east Japan, particularly in a 243
commentary
Italy (1)
China (65) USA (4)
France (1)
Taiwan (1) Hong Kong (1)
APOE Sendai (25) APOE Kyoto (49) APOE Tokyo/Maebashi (7) APOE Guangzhou (4) Other APOE mutants (15) No APOE gene mutation (17)
Japan (44)
Figure 1 | Map of lipoprotein glomerulopathy. Cases are limited to those assayed by DNA sequencing.
narrow area lying across Yamagata and Miyagi prefectures. From this point of view, Toyota et al.5 investigated the haplotype of APOE Sendai in 13 Japanese patients with LPG from nine unrelated families and suggested that the APOE Sendai mutation is common in Japanese patients through a founder effect. In contrast, Hu et al.6 (this issue) elucidated the genetic and clinical features of 35 patients with LPG and the APOE Kyoto mutation and 28 asymptomatic carriers from 31 families in a narrow area of the Sichuan Basin, China. This indepth study, which targeted the largest group of patients with LPG to date, suggests that APOE Kyoto also descended from a single founder. Accordingly, it is of interest that the incidence of APOE Sendai and APOE Kyoto, the major LPG mutants, may increase through a founder effect. However, unlike APOE Sendai, APOE Kyoto was detected not only in Asians living in Japan, China, Taiwan, and the United States but also in Caucasians in Europe and the United States.2 This finding suggests that APOE Kyoto spread from a single hot spot in China to the world. To determine the difference in propagation between APOE Sendai and APOE Kyoto, it is necessary to consider the structural change in apoE variants and the positions of the mutations. The substitution of proline for arginine-145 in apoE 244
Sendai breaks the a-helical structure of apoE in the low-density lipoprotein receptor-binding domain and transforms the apoE molecules that extend to the lipoprotein thrombi.3 The substitution of cysteine for arginine-25 in apoE Kyoto also seems to break the interhelical salt bridge and lead to a change in the tertiary structure, reducing receptor activity.4 As we discuss later, however, there are many asymptomatic carriers of the APOE Kyoto or APOE Sendai mutation, and the penetrance of each variant is similarly low.5,6 Therefore, the difference in geographical distribution cannot be explained with the use of mutation characteristics alone. From ancient times, the international exchange of Chinese people has been higher than that of Japanese people, who are surrounded by the sea. Therefore, even if APOE Kyoto was founded in an isolated narrow area of the Sichuan Basin, it might have spread worldwide—in a manner similar to the expansion of tea culture worldwide from China. Several other variants have recently been reported, not only in Asia but also in Europe and the United States. It may be possible that other hot spots of patients with LPG descended from a single founder and will be detected across the world. Until now, most LPG studies were limited to case reports and review articles, because LPG cases were so rare. However, the study by Hu et al.6
(this issue) targeting a large group of homogeneous patients with LPG exposes the various aspects of LPG. Hu et al.6 and Toyota et al.5 suggest that other genetic or epigenetic factors are involved in the pathogenesis of LPG because of the low penetrance based on many asymptomatic carriers of APOE variants. Kanamaru et al.7 reported that an Fcg receptor (FcRg) deficiency associated with graft-versus-host disease caused murine LPG independently of the apoE abnormality. Our experiments also clarified that the formation of lipoprotein thrombi in this murine LPG model was induced by the impairment of macrophages activating low-density lipoprotein and scavenger receptors due to the FcRg deficiency.8,9 These experiments may be clinically confirmed by the therapeutic effect of immunoadsorption on LPG using protein A columns.10 Because protein A has strong affinity to the Fc portion of IgG and acts as FcRg, protein A may be able to improve LPG by absorbing the accumulated lipoproteins in LPG, although its ability to bind to lipoproteins remains unknown. These experimental and clinical results indicate that the macrophage impairment related to FcRg dysfunction is among the pivotal factors for the development of LPG. In renal lipidosis, following the mechanism of atherosclerosis proposed by Brown and Goldstein,11 mesangial cells or macrophages infiltrating the mesangial areas are suspected to uptake lipoproteins and contribute to the development of glomerulosclerosis. In contrast, the various findings in LPG as described above may provide different mechanisms of renal lipidosis in which the excess accumulation of lipoproteins may directly induce glomerular damage without inducing a foamy change in macrophages. Another important strategy proposed by Hu et al.6 consists of confirming the therapeutic effect of fibrates using long-term follow-up. The efficacy of lipid-lowering therapy containing fibrates has been reported by several authors from Japan, both clinically and histologically. However, all of them were case studies. Hu et al.6 reviewed the literature in detail and compared the Kidney International (2014) 85, 232–247
commentary
3-year patient and renal survival rates between their own fenofibrate and control groups. This is the first clinically controlled study on lipid-lowering therapy for LPG. The significantly higher survival rates in the fenofibrate group of this study confirm the effect of fibrates. LPG, which is thought to be an inherited kidney disease, occasionally appears without hyperlipidemia. However, high levels of serum triglyceride (TG), TG-rich lipoprotein, and apoE are risk factors for the progression of LPG. Hu et al.6 state that dyslipidemia was marked in patients with LPG compared with asymptomatic carriers, although the high cholesterol levels might result in part from nephrotic syndrome in most patients with LPG. Moreover, the use of fenofibrate treatment with intensive control of TG and apoE from the early phase achieved complete remission and stabilized renal function. This finding suggests that LPG can be ameliorated by the elimination of TG-rich lipoproteins composed of abnormal apoE. In the late stage of chronic kidney disease (CKD), levels of atherogenic TG-rich lipoproteins, including very-low-density lipoprotein and remnants, are increased. Regardless of the etiology, the abnormal lipid profile of LPG is similar to that of CKD. Accordingly, the treatment for LPG may provide information about preventing CKD aggravation, although the side effects of lipid-lowering agents such as fibrates should be considered. The investigation by Hu et al.6 may play a key role in unlocking the puzzles of renal lipidosis, the incidence of which has increased in LPG studies. We hope that the information reported here facilitates further advances in this field.
4.
5.
6.
7.
145-proline): a new variant associated with lipoprotein glomerulopathy. J Am Soc Nephrol 1997; 8: 820–823. Matsunaga A, Sasaki J, Komatsu T et al. A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy. Kidney Int 1999; 56: 421–427. Toyota K, Hashimoto T, Ogino D et al. A founder haplotype of APOE-Sendai mutation associated with lipoprotein glomerulopathy. J Hum Genet 2013; 58: 254–258. Hu Z, Huang S, Wu Y et al. Hereditary features, treatment, and prognosis of the lipoprotein glomerulopathy in patients with the APOE Kyoto mutation. Kidney Int 2014; 85: 416–424. Kanamaru Y, Nakao A, Shirato I et al. Chronic graft-versus-host autoimmune disease in Fc receptor gamma chain-deficient mice results in lipoprotein glomerulopathy. J Am Soc Nephrol 2002; 13: 1527–1533.
8.
9.
10.
11.
Ito K, Nakashima H, Watanabe M et al. Macrophage impairment produced by Fc receptor gamma deficiency plays a principal role in the development of lipoprotein glomerulopathy in concert with apoE abnormalities. Nephrol Dial Transplant 2013; 27: 3899–3907. Miyahara Y, Nishimura S, Watanabe M et al. Scavenger receptor expressions in the kidneys of mice with lipoprotein glomerulopathy. Clin Exp Nephrol 2012; 16: 115–121. Xin Z, Zhihong L, Shijun L et al. Successful treatment of patients with lipoprotein glomerulopathy by protein A immunoadsorption: a pilot study. Nephrol Dial Transplant 2009; 24: 864–869. Brown MS, Goldstein JL. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem 1983; 52: 223–261.
see clinical investigation on page 425
Can we prevent donor-specific antibodies from developing after ABO-incompatible kidney transplantation? Lionel Rostaing1,2,3 and Nassim Kamar1,2,3 The burden of chronic kidney disease is increasing worldwide and its costs are skyrocketing, particularly for those with end-stage kidney disease (ESKD). Thus, kidney transplantation needs to be available to as many as ESKD patients as possible. In countries where a donor swap or a donor-chain program is not feasible, ABO-incompatible (ABO-i) and/or HLA incompatible (HLAi) programs have been developed. In the setting of ABOi kidney transplantation, pretransplant desensitization is mandatory; this is based on the removal of isoagglutinins by plasmapheresis or immunoadsorption, and often using splenectomy (SPx) or, more recently, rituximab (RTx) infusion instead. Because RTx and SPx interfere with B-cell function, one wonders whether these desensitization protocols alter the occurrence of post-transplant donor-specific alloantibodies. Kidney International (2014) 85, 245–247. doi:10.1038/ki.2013.425
DISCLOSURE
The authors declared no competing interests. REFERENCES 1.
2.
3.
Saito T, Sato H, Kudo K et al. Lipoprotein glomerulopathy: glomerular lipoprotein thrombi in a patient with hyperlipoproteinemia. Am J Kidney Dis 1989; 13: 148–153. 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. Oikawa S, Matsunaga A, Saito T et al. Apolipoprotein E Sendai (arginine
Kidney International (2014) 85, 232–247
1 Department of Nephrology, Dialysis and Organ Transplantation, Centre Hospitalier Universitaire Rangueil, TSA 50032, Toulouse, France; 2Inserm U563 IFR-BMT, Centre Hospitalier Universitaire Purpan, Toulouse, France and 3Universite´ Paul Sabatier, Faculte´ de Me´decine de Rangueil, Toulouse, France Correspondence: Lionel Rostaing, Department of Nephrology, Dialysis and Organ Transplantation, Centre Hospitalier Universitaire Rangueil, TSA 50032, 31059 Toulouse, Cedex 9, France. E-mail: [email protected]
The burden of chronic kidney disease is increasing worldwide and its costs are skyrocketing, particularly for those with end-stage kidney disease. Thus, kidney transplantation needs to be available to as many end-stage kidney disease patients as possible. However, the number of deceased donors is plateauing, hence the development of living-unrelated-donor and living-related-donor 245