Takashi Wada1,2, Akinori Hara3, Eri Muso4, Shoichi Maruyama5, Sawako Kato5, Kengo Furuichi6, Kenichi Yoshimura7, Tadashi Toyama7, Norihiko Sakai8,3, Hiroyuki Suzuki4, Tatsuo Tsukamoto4, Mariko Miyazaki9, Eiichi Sato10, Masanori Abe11, Yugo Shibagaki12, Ichiei Narita13, Shin Goto13, Yuichi Sakamaki13, Hitoshi Yokoyama6, Noriko Mori14, Satoshi Tanaka14, Yukio Yuzawa15, Midori Hasegawa15, Takeshi Matsubara16, Jun Wada17, Katsuyuki Tanabe17, Kosuke Masutani18, Yasuhiro Abe18, Kazuhiko Tsuruya19, Shouichi Fujimoto20, Shuji Iwatsubo20, Akihiro Tsuda21, Hitoshi Suzuki22, Kenji Kasuno23, Yoshio Terada24, Takeshi Nakata25, Noriaki Iino26, Tadashi Sofue27, Hitomi Miyata28, Toshiaki Nakano29, Takayasu Ohtake30, Shuzo Kobayashi30. 1. Department of Nephrology and Laboratory Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Faculty of Medicine, Kanazawa University, 13-1 Takara-machi, KanazawaKanazawa, 920-8641, Japan. twada@m-kanazawa.jp. 2. Division of Nephrology, Kanazawa University Hospital, Kanazawa, Japan. twada@m-kanazawa.jp. 3. Division of Nephrology, Kanazawa University Hospital, Kanazawa, Japan. 4. Department of Nephrology and Dialysis, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan. 5. Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan. 6. Department of Nephrology, Kanazawa Medical University School of Medicine, Uchinada, Japan. 7. Innovative Clinical Research Center (iCREK), Kanazawa University Hospital, Kanazawa, Japan. 8. Department of Nephrology and Laboratory Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Faculty of Medicine, Kanazawa University, 13-1 Takara-machi, KanazawaKanazawa, 920-8641, Japan. 9. Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. 10. Division of Nephrology, Department of Internal Medicine, Shinmatsudo Central General Hospital, Matsudo, Japan. 11. Divisions of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan. 12. Division of Nephrology and Hypertension, Department of Internal Medicine, St Marianna University School of Medicine, Kanagawa, Japan. 13. Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. 14. Department of Nephrology, Shizuoka General Hospital, Shizuoka, Japan. 15. Department of Nephrology, Fujita Health University School of Medicine, Aichi, Japan. 16. Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 17. Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. 18. Division of Nephrology and Rheumatology, Department of Internal Medicine, Faculty of Medicine, Fukuoka University, Fukuoka, Japan. 19. Department of Nephrology, Nara Medical University, Nara, Japan. 20. Department of Hemovascular Medicine and Artificial Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. 21. Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan. 22. Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan. 23. Division of Nephrology, Department of General Medicine, University of Fukui School of Medical Sciences, Fukui, Japan. 24. Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Kochi, Japan. 25. Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu, Japan. 26. Department of Nephrology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Niigata, Japan. 27. Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan. 28. Department of Nephrology, Kyoto Katsura Hospital, Kyoto, Japan. 29. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 30. Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan.
Abstract
BACKGROUND: Patients with diabetes mellitus and severe proteinuria present with poor renal prognoses, despite improvements in diabetes and kidney disease therapies. In this study, we designed a low-density lipoprotein (LDL)-cholesterol apheresis treatment for patients with diabetic nephropathy (DN)/diabetic kidney disease and severe proteinuria. This was a multicenter prospective LICENSE study to confirm the impact of LDL apheresis on proteinuria that exhibited hyporesponsiveness to treatment. In addition, we sought to determine the efficacy and safety of LDL apheresis by comparing the outcomes to those of historical controls in patients with diabetes, refractory hypercholesterolemia, and severe proteinuria. METHODS: This was a prospective, multicenter study, including 40 patients with diabetes, severe proteinuria, and dyslipidemia. LDL apheresis was performed 6-12 times over a 12-week period. The primary endpoint was the proportion of patients with a decrease in proteinuria excretion of at least 30% in the 6 months after starting therapy. The secondary endpoints included serum creatinine levels and laboratory variables, which were evaluated 4, 6, 12, 18, and 24 months after therapy initiation. RESULTS: LDL apheresis was performed on 40 registered patients with diabetes. The proportion of cases in which proteinuria decreased by 30% or more after 6 months of LDL apheresis was 25%, which was similar to that of historical controls. The overall survival and end-stage kidney disease-free survival rates were significantly higher in the LICENSE group compared to those in historical controls. CONCLUSION: Our results suggest that LDL apheresis may be effective and safe for patients with diabetes, proteinuria, and dyslipidemia. TRIAL REGISTRATION: Trial registration number: jRCTs042180076.
BACKGROUND:Patients with diabetes mellitus and severe proteinuria present with poor renal prognoses, despite improvements in diabetes and kidney disease therapies. In this study, we designed a low-density lipoprotein (LDL)-cholesterol apheresis treatment for patients with diabetic nephropathy (DN)/diabetic kidney disease and severe proteinuria. This was a multicenter prospective LICENSE study to confirm the impact of LDL apheresis on proteinuria that exhibited hyporesponsiveness to treatment. In addition, we sought to determine the efficacy and safety of LDL apheresis by comparing the outcomes to those of historical controls in patients with diabetes, refractory hypercholesterolemia, and severe proteinuria. METHODS: This was a prospective, multicenter study, including 40 patients with diabetes, severe proteinuria, and dyslipidemia. LDL apheresis was performed 6-12 times over a 12-week period. The primary endpoint was the proportion of patients with a decrease in proteinuria excretion of at least 30% in the 6 months after starting therapy. The secondary endpoints included serum creatinine levels and laboratory variables, which were evaluated 4, 6, 12, 18, and 24 months after therapy initiation. RESULTS: LDL apheresis was performed on 40 registered patients with diabetes. The proportion of cases in which proteinuria decreased by 30% or more after 6 months of LDL apheresis was 25%, which was similar to that of historical controls. The overall survival and end-stage kidney disease-free survival rates were significantly higher in the LICENSE group compared to those in historical controls. CONCLUSION: Our results suggest that LDL apheresis may be effective and safe for patients with diabetes, proteinuria, and dyslipidemia. TRIAL REGISTRATION: Trial registration number: jRCTs042180076.
Authors: Vlado Perkovic; Meg J Jardine; Bruce Neal; Severine Bompoint; Hiddo J L Heerspink; David M Charytan; Robert Edwards; Rajiv Agarwal; George Bakris; Scott Bull; Christopher P Cannon; George Capuano; Pei-Ling Chu; Dick de Zeeuw; Tom Greene; Adeera Levin; Carol Pollock; David C Wheeler; Yshai Yavin; Hong Zhang; Bernard Zinman; Gary Meininger; Barry M Brenner; Kenneth W Mahaffey Journal: N Engl J Med Date: 2019-04-14 Impact factor: 91.245