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Letters to the Editor December (P = 0.001 vs. September). Hb levels were stable during this period. Blood urea nitrogen levels did not decrease, which suggested a stable dietary intake. The difference in HbA1c between May and September (ΔHbA1c) marginally correlated with HbA1c levels in May (r = 0.547, P = 0.06), but did not correlate with the SH dose in May (r = 0.275, P = 0.38). The glucose-lowering effect (a decrease in HbA1c levels) of sevelamer has been reported in a randomized trial including 20 diabetic patients with chronic kidney disease stage 2–4 (2), but is not widely recognized. In this study, an in vitro analysis certified binding of advanced glycation end products (AGE) by sevelamer and serum levels of AGE of the subjects were reduced by sevelamer (2). It has been shown that an AGE-restricted diet improves insulin resistance (3). In addition, bile acid sequestrants including colesevelam hydrochloride, which structurally resembles SH,similarly affect blood glucose levels in type 2 DM (4). It seems plausible to attribute the glucose-lowering effect of sevelamer to its characteristic of binding AGE and bile acid. The cholesterollowering effect of sevelamer arises from its bile acidbinding capacity. Although we did not evaluate the change in lipid profile during this study period, the change in HbA1c may correlate with that in lipid profile. In addition to small sample size, there are some limitations in our study. As recently recommended by the Japanese Society for Dialysis Therapy, glycated albumin is more reliable than HbA1c for monitoring glycemic control in HD patients. However, we conventionally evaluated HbA1c as a glycemic marker. In addition, we did not evaluate HD efficacy reflected by Kt/V urea, but HD prescription was not changed in all patients during this study period.We substituted BUN for normalized protein catabolic rate for evaluating oral intake. In conclusion, the glucose-lowering effect of sevelamer should be recognized as one of its pleiotropic effects.
1
Ryota Ikee1,2 and Nobuo Hashimoto2 Department of Nephrology and Dialysis, H. N. Medic Kitahiroshima, and 2Department of Nephrology and Dialysis, H. N. Medic, Kitahiroshima, Hokkaido, Japan Email: [email protected] REFERENCES
1. Ikee R, Tsunoda M, Sasaki N, Sato N, Hashimoto N. Emerging effects of sevelamer in chronic kidney disease. Kidney Blood Press Res 2013;37:24–32. © 2015 The Authors Therapeutic Apheresis and Dialysis © 2015 International Society for Apheresis
413
2. Vlassara H, Uribarri J, Cai W et al. Effects of sevelamer on HbA1c, inflammation, and advanced glycation end products in diabetic kidney disease. Clin J Am Soc Nephrol 2012;7:934–42. 3. Uribarri J, Cai W, Ramdas M et al. Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. Diabetes Care 2011;34:1610–16. 4. Handelsman Y. Role of bile acid sequestrants in the treatment of type 2 diabetes. Diabetes Care 2011;34(Suppl 2):S244–50.
Serum Cytokine Profiling of Leukocytapheresis in Pediatric Ulcerative Colitis Dear Editor, Our patient was a 10-year-old girl who presented with a one week history of approximately 10 hematochezia episodes per day, fever, and abdominal pain. Her condition was diagnosed as pancolitis-type ulcerative colitis (UC) by colonoscopy. She was treated with intravenous prednisolone and mesalazine. However, this was regarded as a steroidresistant case. Leukocytapheresis (LCAP) therapy was chosen after informed parental consent. LCAP was performed over 11 sessions (three sessions per week for 4 consecutive weeks) without complications. The Cellsorba EX (Asahi Kasei Kuraray Medical, Tokyo, Japan) was used as previously described (1). Total body weight was 40 kg. The EX column was used at a blood flow rate of 30 mL/ min. The volume of blood processed was 45 mL/kg. Serum samples were collected on the first, fifth, and 11th sessions before and after (0, 2, 6, 24, and 48 h) LCAP treatment. The levels of 17 cytokines (interleukin [IL]-1β/2/4/5/6/7/8/10/12/13/17, granulocytecolony stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF], interferon-γ [IFN-γ], monocyte chemoattractant protein-1 [MCP-1], macrophage inflammatory protein-1β [MIP-1β], and tumor necrosis factor-α [TNF-α]) were measured using a Bio-Plex suspension array (Bio-Rad Laboratories, Tokyo, Japan). After LCAP therapy, the patient’s abdominal pain resolved and the frequency of hematochezia decreased. Cytokine profiling before and after the first session of LCAP revealed that several cytokines (IL-6, 8, 10, 12, G-CSF, IFN-γ, MCP-1, and MIP-1β) were elevated immediately after LCAP and returned to the previous values after approximately 24 h (Fig. 1a). The levels of IL-6, IL-8, and TNF-α before
Ther Apher Dial, Vol. 19, No. 4, 2015
414
Letters to the Editor
pg/mL
A
50
LCAP 1 before
25
LCAP 1 after
LCAP 1 2 h
LCAP 1 6 h
LCAP 1 24 h
0 LCAP 1 48 h
B
3.5
IL-6
3 2.5 2 1.5 1 0.5
pg/mL
0 LCAP 1 before
LCAP 1 24 h
LCAP 5 24 h
LCAP 11 24 h
200 0.7 150
0.6 0.5
100
0.4 0.3 0.2
50
pg/mL
pg/mL
0 LCAP 1 before
LCAP 1 24 h
IL-8
LCAP 5 24 h
LCAP 11 24 h
0.1 0 LCAP 1 before
LCAP 1 24 h
LCAP 5 24 h
LCAP 11 24 h
TNF-α
FIG. 1. (a) Cytokine profiling before and after (0, 2, 6, 24, and 48 h) the first leukocytapheresis ( LCAP) session. (b) The levels of interleukin (IL)-6, IL-8, and tumor necrosis factor-α (TNF-α) before the first LCAP and 24 h after the first, fifth, and 11th LCAP sessions.
Ther Apher Dial, Vol. 19, No. 4, 2015
© 2015 The Authors Therapeutic Apheresis and Dialysis © 2015 International Society for Apheresis
Letters to the Editor the first LCAP and 24 h after the first, fifth, and 11th sessions of LCAP are shown in Figure 1b. All levels of serum cytokines were low throughout; IL-6 levels decreased gradually. The Japanese study group for pediatric ulcerative colitis demonstrated that LCAP was effective (2). Fluctuations in cytokine levels during LCAP remain poorly understood. Several cytokines were elevated immediately after LCAP. Cytokines may also have been adsorbed to the Cellsorba EX column matrix. The level of IL-6 of first LCAP 48 h was higher than that of first LCAP before. The effect of LCAP might be transient, and therefore a clinical effect might appear whenever LCAP is done. The mechanism that decreased circulating IL-6 is considered not only to be the effect of LCAP since steroid therapy was used simultaneously. However, the gradual decrease in IL-6 can be interpreted as a decreased inflammatory reaction. This result is a positive clinical benefit for the patient based on the leukapheresis treatments. Figure 1b shows the two aberrant spikes in concentration for IL-8 at fifth LCAP and TNF-α at first
© 2015 The Authors Therapeutic Apheresis and Dialysis © 2015 International Society for Apheresis
415
LCAP; however, all levels of serum cytokines including TNF-α were low throughout. The efficacy of antiTNF-α drug infliximab (IFX) might have been limited since serum levels of TNF-α were low in our case. Yasuyo Kashiwagi, Soken Go, Naoko Kinjo, Shigeo Nishimata, and Hisashi Kawashima Department of Pediatrics, Tokyo Medical University, Tokyo, Japan Email: [email protected]
REFERENCES 1. Matsumoto T, Andoh A, Okawa K et al. Multivariate analysis for factors predicting rapid response of leukocytapheresis in patients with steroid-resistant ulcerative colitis: a multicenter prospective open-label study. Ther Apher Dial 2008;12:484–90. 2. Tomomasa T, Tajiri H, Kagimoto S et al. Japanese Study Group for Pediatric Ulcerative Colitis. Leukocytapheresis in pediatric patients with ulcerative colitis. J Pediatr Gastroenterol Nutr 2011;53:34–9.
Ther Apher Dial, Vol. 19, No. 4, 2015
Letters to the Editor December (P = 0.001 vs. September). Hb levels were stable during this period. Blood urea nitrogen levels did not decrease, which suggested a stable dietary intake. The difference in HbA1c between May and September (ΔHbA1c) marginally correlated with HbA1c levels in May (r = 0.547, P = 0.06), but did not correlate with the SH dose in May (r = 0.275, P = 0.38). The glucose-lowering effect (a decrease in HbA1c levels) of sevelamer has been reported in a randomized trial including 20 diabetic patients with chronic kidney disease stage 2–4 (2), but is not widely recognized. In this study, an in vitro analysis certified binding of advanced glycation end products (AGE) by sevelamer and serum levels of AGE of the subjects were reduced by sevelamer (2). It has been shown that an AGE-restricted diet improves insulin resistance (3). In addition, bile acid sequestrants including colesevelam hydrochloride, which structurally resembles SH,similarly affect blood glucose levels in type 2 DM (4). It seems plausible to attribute the glucose-lowering effect of sevelamer to its characteristic of binding AGE and bile acid. The cholesterollowering effect of sevelamer arises from its bile acidbinding capacity. Although we did not evaluate the change in lipid profile during this study period, the change in HbA1c may correlate with that in lipid profile. In addition to small sample size, there are some limitations in our study. As recently recommended by the Japanese Society for Dialysis Therapy, glycated albumin is more reliable than HbA1c for monitoring glycemic control in HD patients. However, we conventionally evaluated HbA1c as a glycemic marker. In addition, we did not evaluate HD efficacy reflected by Kt/V urea, but HD prescription was not changed in all patients during this study period.We substituted BUN for normalized protein catabolic rate for evaluating oral intake. In conclusion, the glucose-lowering effect of sevelamer should be recognized as one of its pleiotropic effects.
1
Ryota Ikee1,2 and Nobuo Hashimoto2 Department of Nephrology and Dialysis, H. N. Medic Kitahiroshima, and 2Department of Nephrology and Dialysis, H. N. Medic, Kitahiroshima, Hokkaido, Japan Email: [email protected] REFERENCES
1. Ikee R, Tsunoda M, Sasaki N, Sato N, Hashimoto N. Emerging effects of sevelamer in chronic kidney disease. Kidney Blood Press Res 2013;37:24–32. © 2015 The Authors Therapeutic Apheresis and Dialysis © 2015 International Society for Apheresis
413
2. Vlassara H, Uribarri J, Cai W et al. Effects of sevelamer on HbA1c, inflammation, and advanced glycation end products in diabetic kidney disease. Clin J Am Soc Nephrol 2012;7:934–42. 3. Uribarri J, Cai W, Ramdas M et al. Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. Diabetes Care 2011;34:1610–16. 4. Handelsman Y. Role of bile acid sequestrants in the treatment of type 2 diabetes. Diabetes Care 2011;34(Suppl 2):S244–50.
Serum Cytokine Profiling of Leukocytapheresis in Pediatric Ulcerative Colitis Dear Editor, Our patient was a 10-year-old girl who presented with a one week history of approximately 10 hematochezia episodes per day, fever, and abdominal pain. Her condition was diagnosed as pancolitis-type ulcerative colitis (UC) by colonoscopy. She was treated with intravenous prednisolone and mesalazine. However, this was regarded as a steroidresistant case. Leukocytapheresis (LCAP) therapy was chosen after informed parental consent. LCAP was performed over 11 sessions (three sessions per week for 4 consecutive weeks) without complications. The Cellsorba EX (Asahi Kasei Kuraray Medical, Tokyo, Japan) was used as previously described (1). Total body weight was 40 kg. The EX column was used at a blood flow rate of 30 mL/ min. The volume of blood processed was 45 mL/kg. Serum samples were collected on the first, fifth, and 11th sessions before and after (0, 2, 6, 24, and 48 h) LCAP treatment. The levels of 17 cytokines (interleukin [IL]-1β/2/4/5/6/7/8/10/12/13/17, granulocytecolony stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF], interferon-γ [IFN-γ], monocyte chemoattractant protein-1 [MCP-1], macrophage inflammatory protein-1β [MIP-1β], and tumor necrosis factor-α [TNF-α]) were measured using a Bio-Plex suspension array (Bio-Rad Laboratories, Tokyo, Japan). After LCAP therapy, the patient’s abdominal pain resolved and the frequency of hematochezia decreased. Cytokine profiling before and after the first session of LCAP revealed that several cytokines (IL-6, 8, 10, 12, G-CSF, IFN-γ, MCP-1, and MIP-1β) were elevated immediately after LCAP and returned to the previous values after approximately 24 h (Fig. 1a). The levels of IL-6, IL-8, and TNF-α before
Ther Apher Dial, Vol. 19, No. 4, 2015
414
Letters to the Editor
pg/mL
A
50
LCAP 1 before
25
LCAP 1 after
LCAP 1 2 h
LCAP 1 6 h
LCAP 1 24 h
0 LCAP 1 48 h
B
3.5
IL-6
3 2.5 2 1.5 1 0.5
pg/mL
0 LCAP 1 before
LCAP 1 24 h
LCAP 5 24 h
LCAP 11 24 h
200 0.7 150
0.6 0.5
100
0.4 0.3 0.2
50
pg/mL
pg/mL
0 LCAP 1 before
LCAP 1 24 h
IL-8
LCAP 5 24 h
LCAP 11 24 h
0.1 0 LCAP 1 before
LCAP 1 24 h
LCAP 5 24 h
LCAP 11 24 h
TNF-α
FIG. 1. (a) Cytokine profiling before and after (0, 2, 6, 24, and 48 h) the first leukocytapheresis ( LCAP) session. (b) The levels of interleukin (IL)-6, IL-8, and tumor necrosis factor-α (TNF-α) before the first LCAP and 24 h after the first, fifth, and 11th LCAP sessions.
Ther Apher Dial, Vol. 19, No. 4, 2015
© 2015 The Authors Therapeutic Apheresis and Dialysis © 2015 International Society for Apheresis
Letters to the Editor the first LCAP and 24 h after the first, fifth, and 11th sessions of LCAP are shown in Figure 1b. All levels of serum cytokines were low throughout; IL-6 levels decreased gradually. The Japanese study group for pediatric ulcerative colitis demonstrated that LCAP was effective (2). Fluctuations in cytokine levels during LCAP remain poorly understood. Several cytokines were elevated immediately after LCAP. Cytokines may also have been adsorbed to the Cellsorba EX column matrix. The level of IL-6 of first LCAP 48 h was higher than that of first LCAP before. The effect of LCAP might be transient, and therefore a clinical effect might appear whenever LCAP is done. The mechanism that decreased circulating IL-6 is considered not only to be the effect of LCAP since steroid therapy was used simultaneously. However, the gradual decrease in IL-6 can be interpreted as a decreased inflammatory reaction. This result is a positive clinical benefit for the patient based on the leukapheresis treatments. Figure 1b shows the two aberrant spikes in concentration for IL-8 at fifth LCAP and TNF-α at first
© 2015 The Authors Therapeutic Apheresis and Dialysis © 2015 International Society for Apheresis
415
LCAP; however, all levels of serum cytokines including TNF-α were low throughout. The efficacy of antiTNF-α drug infliximab (IFX) might have been limited since serum levels of TNF-α were low in our case. Yasuyo Kashiwagi, Soken Go, Naoko Kinjo, Shigeo Nishimata, and Hisashi Kawashima Department of Pediatrics, Tokyo Medical University, Tokyo, Japan Email: [email protected]
REFERENCES 1. Matsumoto T, Andoh A, Okawa K et al. Multivariate analysis for factors predicting rapid response of leukocytapheresis in patients with steroid-resistant ulcerative colitis: a multicenter prospective open-label study. Ther Apher Dial 2008;12:484–90. 2. Tomomasa T, Tajiri H, Kagimoto S et al. Japanese Study Group for Pediatric Ulcerative Colitis. Leukocytapheresis in pediatric patients with ulcerative colitis. J Pediatr Gastroenterol Nutr 2011;53:34–9.
Ther Apher Dial, Vol. 19, No. 4, 2015
