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Elevated serum immunoglobulins after steroid withdrawal in renal allograft recipients
Elevated Serum Immunoglobulins After Steroid Withdrawal in Renal Allograft Recipients E. Nowacka-Cieciura, M. Durlik, T. Cieciura, K. Kukula, D. Lewandowska, T. Bac˛zkowska, D. Deb˛orska, M. Lao, J. Szmidt, and W. Rowin´ski
G
LUCOCORTICOSTEROIDS (GS) still play an important role in the immunosuppressive treatment of allograft recipients. They are known to suppress mainly cellular immune response.1 The effect of corticotherapy on serum immunoglobulins is still a matter of controversy. Some authors have reported decreases in serum IgG,2 others have observed no effect.3 The aim of the study was to observe the effect of prednisone (Pred) withdrawal on serum immunoglobulin concentration in renal transplant recipients treated with cyclosporine A (CsA) and mycophenolate mofetil (MMF). PATIENTS AND METHODS In this prospective study 23 adult renal allograft recipients were randomly assigned to one of the two groups: (1) No-S, treated with Pred till the end of the month 3, when Pred was withdrawn, and (2) S, treated with the standard dose of Pred; from the third posttransplant month the maintenance dose of Pred did not exceed 10 mg per day. All patients concomitantly received CsA and MMF. Serum levels of the immunoglobulin classes IgG, IgA, and IgM were determined at months 1, 6, 12, and 24 after transplantation by rate nephelometry (Array Protein System, Beckman). Creatinine and albumin levels were determined using an automated multichannel biochemical analyser. The incidence of infectious complications was recorded. Statistical analyses were carried out using the SSTAT4 statistical package. P less than 0.05 was considered statistically significant.
RESULTS
From among 23 patients (12 men, 11 women, aged 19 to 52 years) 12 were assigned to the GS withdrawal group (No-S), and 11 to the standard Pred treatment group (S). There were no statistically significant differences between No-S (n ⫽ 12) and S (n ⫽ 11) treatment groups with respect to sex, age, body mass index, duration, and type of dialysis, and primary renal disease. The full characteristic of the patients was published earlier.4 There was no difference in basal serum immunoglobulin concentrations between the groups. Mean serum IgG concentration was higher in patients after GS withdrawal compared to patients continuing corticoid therapy. The difference was significant at 12 (P ⬍ .02) and 24 months (P ⬍ .04) after transplantation (Fig 1). There was no difference in IgA and IgM serum levels during the whole observation period (Table 1). No difference with respect to serum albumin and creatinine concentrations or proteinuria between the groups was From the Transplantation Institute, Medical University of Warsaw, Warsaw, Poland. Address reprint requests to Ewa Nowacka-Cieciura, Transplantation Institute, Medical University of Warsaw, Nowogrodzka str 59, 02-006 Warsaw, Poland.
Fig 1. Serum IgG concentration in renal allograft recipients not treated (No-S) and treated (S) with glucocorticosteroids (mean ⫾ SD). 0041-1345/0⫺2000/$–see front matter PII S0041-1345(01)02847-0 564
© 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 564–566 (2002)
SERUM IMMUNOGLOBULINS AFTER STEROID WITHDRAWAL
565
Table 1. Serum IgA, IgG, Albumins, Creatinine Concentrations and Proteinuria in Renal Allograft Recipients Not Treated and Treated With Glucocorticosteroids
IgA (mg/dL) IgM (mg/dL) Albumin (mg/dL) Proteinuria (g/24 h) Creatinine (mg/dL)
No-S S No-S S No-S S No-S S No-S S
1 month
6 months
12 months
24 months
178.0 ⫾ 76.84 222.5 ⫾ 111.62 164.8 ⫾ 67.43 185.1 ⫾ 175.65 3.5 ⫾ 0.42 3.5 ⫾ 0.51 — — 1.32 ⫾ 0.39 1.24 ⫾ 0.27
209.9 ⫾ 105.29 183.8 ⫾ 84.43 154.1 ⫾ 63.95 194.7 ⫾ 66.22 4.3 ⫾ 0.70 4.2 ⫾ 0.46 0.27 ⫾ 0.13 0.51 ⫾ 0.49 1.33 ⫾ 0.27 1.32 ⫾ 0.32
196.1 ⫾ 105.29 160.4 ⫾ 61.67 162.4 ⫾ 59.62 180.7 ⫾ 73.21 4.2 ⫾ 0.13 4.1 ⫾ 0.26 0.20 ⫾ 0.11 0.51 ⫾ 0.75 1.32 ⫾ 0.18 1.38 ⫾ 0.51
204.9 ⫾ 105.64 184.5 ⫾ 135.91 161.6 ⫾ 53.68 190.5 ⫾ 84.40 4.2 ⫾ 0.51 4.2 ⫾ 0.45 0.25 ⫾ 0.18 0.43 ⫾ 0.62 1.38 ⫾ 0.27 1.54 ⫾ 0.54
No-S, not treated with glucocorticosteroids; S, treated.
found (Table 1). Mean MMF dose was comparable in the groups (in No-S group 32.5 ⫾ 5.75 mg/kg per 24 hours vs 32.7 ⫾ 6.49 in S group at month 12 and 26.9 ⫾ 4.38 mg/kg per 24 hours vs 29.7 ⫾ 5.93 at month 24, respectively). Median 2-year cumulative GS dose was higher in S group than in No-S group (9070.0 mg; range: 9070.0 to 14318.0 mg vs 2607.5 mg; range: 1840.0 to 9410.0 mg; P ⬍ .0005). No difference in the frequency of infections was observed between the groups; there were 17 episodes documented in the No-S group and 16 episodes in the S group.
DISCUSSION
During 2 years of prospective follow-up we found that the IgG serum concentration was higher in renal allograft recipients after GS withdrawal compared to patients continuing corticoid therapy. There were no significant differences in IgA and IgM levels, however, the IgA concentration tended to be lower in patients undergoing GS therapy. The results of our findings are consistent with those of others, suggesting that GS cause a decrease of serum IgG2,5,6 and IgA levels, but essentially have no effect on serum IgM.2 Inhaled7 and systemic6 GS also decrease serum IgE levels. Some authors reported no significant changes in serum immunoglobulins under corticoid therapy.3,8 It may depend on the short duration of GS treatment,3,8 use of inhaled GS8 or evaluation of patients with active immunodependent disease.3 There are several studies on immunoglobulins in external secretions. Topical corticosteroids decrease secretory IgA, IgG and IgM concentrations in nasal secretions,9 dexamethasone decreases IgA and IgG levels in vaginal and salivary secretions.4 The amount of IgA in tears is a potential parameter for measurement of long-term stress in birds.10 Glucocorticosteroids reduce circulating IgG by inhibiting antibody formation rather than increasing IgG catabolism.11 They may act directly on B lymphocytes or indirectly by regulating the synthesis of cytokines. In vitro GS inhibit not only Th1 but also Th2 type cytokine production.12 In animal studies, dexamethasone suppressed B lymphocyte
activity, measured by immunoglobulin production and antigen-specific antibody responses.13 In rats, dexamethasone has a dual effect on IgA, decreasing secretory IgA at mucosal surfaces and increasing serum IgA levels. It may be a consequence of redistribution of IgA from mucosal associated lymphoid tissues to central sites, such as spleen or lymph nodes.5 Treatment with MMF could potentially affect serum immunoglobulin levels as suggested by the reduced incidence and titre of IgG anti-ATGAM antibody formation14 and suppression of the humoral response to influenza vaccination15 were observed under MMF therapy in renal transplant recipients. In our study the dose of MMF was comparable between the groups. Other factors, potentially modifying immunoglobulin concentration, like proteinuria, were also comparable. The effects of corticoid therapy on serum immunoglobulin levels depend on the route of administration, dosage of corticosteroids, and duration of the treatment. In our study, a prolonged 2 years) administration of standard maintenance oral GS dose decreased IgG levels compared to patients after Pred withdrawal. The changes were discrete and immunoglobulin levels stayed within normal limits so we were not able to observe the difference in the frequency of infections between the groups. We conclude that long-term corticoid therapy decreases serum IgG levels. Steroid withdrawal may prevent this effect in renal transplant recipients.
REFERENCES 1. Hrick DE, Almawi WY, Strom TB: Transplantation 57:979, 1994 2. Settipane GA, Pudupakkam RK, McGowan JH: J Allergy Clin Immunol 62:162, 1978 3. Wandinger KP, Wessel K, Trillenberg P, et al: Acta Neurol Scand 97:359, 1998 4. Nowacka-Cieciura E, Soluch L, Cieciura T, et al: Transplant Proc 32:1339, 2000 5. Wira CR, Sandoe CP, Steel MG: J Immunol 144:142, 1990 6. Pacheco A, Cuevas M, Carbelo B, et al: Eur Respir J 12:502, 1998
566 7. Ohrui T, Funayama T, Sekizawa K, et al: Clin Exp Allergy 29:357, 1999 8. Van Schoor J, Toogood JH, Pauwels RA: J Allergy Clin Immunol 97:113, 1996 9. Biewenga J, Stoop AE, van der Heijden HAMD, et al: J Allergy Clin Immunol 96:334, 1995 10. Florence BD, Svendsen L, Stodulski G, et al: In Vivo 9:19, 1995 11. McMillan R, Longmire R, Yelenosky R: J Immunol 116: 1592, 1976
NOWACKA-CIECIURA, DURLIK, CIECIURA ET AL 12. Snijdewint FGM, Kapsenberg ML, et al: Immunopharmacology 29:93, 1995 13. Carlsten H, Verdrengh M, Taube M: Inflamm Res 45:26, 1996 14. Kimball JA, Pescovitz MD, Book BK, et al: Transplantation 60:1379, 1995 15. Smith KGC, Isbel NM, Catton MG, et al: Nephrol Dial Transplant 13:160, 1998
G
LUCOCORTICOSTEROIDS (GS) still play an important role in the immunosuppressive treatment of allograft recipients. They are known to suppress mainly cellular immune response.1 The effect of corticotherapy on serum immunoglobulins is still a matter of controversy. Some authors have reported decreases in serum IgG,2 others have observed no effect.3 The aim of the study was to observe the effect of prednisone (Pred) withdrawal on serum immunoglobulin concentration in renal transplant recipients treated with cyclosporine A (CsA) and mycophenolate mofetil (MMF). PATIENTS AND METHODS In this prospective study 23 adult renal allograft recipients were randomly assigned to one of the two groups: (1) No-S, treated with Pred till the end of the month 3, when Pred was withdrawn, and (2) S, treated with the standard dose of Pred; from the third posttransplant month the maintenance dose of Pred did not exceed 10 mg per day. All patients concomitantly received CsA and MMF. Serum levels of the immunoglobulin classes IgG, IgA, and IgM were determined at months 1, 6, 12, and 24 after transplantation by rate nephelometry (Array Protein System, Beckman). Creatinine and albumin levels were determined using an automated multichannel biochemical analyser. The incidence of infectious complications was recorded. Statistical analyses were carried out using the SSTAT4 statistical package. P less than 0.05 was considered statistically significant.
RESULTS
From among 23 patients (12 men, 11 women, aged 19 to 52 years) 12 were assigned to the GS withdrawal group (No-S), and 11 to the standard Pred treatment group (S). There were no statistically significant differences between No-S (n ⫽ 12) and S (n ⫽ 11) treatment groups with respect to sex, age, body mass index, duration, and type of dialysis, and primary renal disease. The full characteristic of the patients was published earlier.4 There was no difference in basal serum immunoglobulin concentrations between the groups. Mean serum IgG concentration was higher in patients after GS withdrawal compared to patients continuing corticoid therapy. The difference was significant at 12 (P ⬍ .02) and 24 months (P ⬍ .04) after transplantation (Fig 1). There was no difference in IgA and IgM serum levels during the whole observation period (Table 1). No difference with respect to serum albumin and creatinine concentrations or proteinuria between the groups was From the Transplantation Institute, Medical University of Warsaw, Warsaw, Poland. Address reprint requests to Ewa Nowacka-Cieciura, Transplantation Institute, Medical University of Warsaw, Nowogrodzka str 59, 02-006 Warsaw, Poland.
Fig 1. Serum IgG concentration in renal allograft recipients not treated (No-S) and treated (S) with glucocorticosteroids (mean ⫾ SD). 0041-1345/0⫺2000/$–see front matter PII S0041-1345(01)02847-0 564
© 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 564–566 (2002)
SERUM IMMUNOGLOBULINS AFTER STEROID WITHDRAWAL
565
Table 1. Serum IgA, IgG, Albumins, Creatinine Concentrations and Proteinuria in Renal Allograft Recipients Not Treated and Treated With Glucocorticosteroids
IgA (mg/dL) IgM (mg/dL) Albumin (mg/dL) Proteinuria (g/24 h) Creatinine (mg/dL)
No-S S No-S S No-S S No-S S No-S S
1 month
6 months
12 months
24 months
178.0 ⫾ 76.84 222.5 ⫾ 111.62 164.8 ⫾ 67.43 185.1 ⫾ 175.65 3.5 ⫾ 0.42 3.5 ⫾ 0.51 — — 1.32 ⫾ 0.39 1.24 ⫾ 0.27
209.9 ⫾ 105.29 183.8 ⫾ 84.43 154.1 ⫾ 63.95 194.7 ⫾ 66.22 4.3 ⫾ 0.70 4.2 ⫾ 0.46 0.27 ⫾ 0.13 0.51 ⫾ 0.49 1.33 ⫾ 0.27 1.32 ⫾ 0.32
196.1 ⫾ 105.29 160.4 ⫾ 61.67 162.4 ⫾ 59.62 180.7 ⫾ 73.21 4.2 ⫾ 0.13 4.1 ⫾ 0.26 0.20 ⫾ 0.11 0.51 ⫾ 0.75 1.32 ⫾ 0.18 1.38 ⫾ 0.51
204.9 ⫾ 105.64 184.5 ⫾ 135.91 161.6 ⫾ 53.68 190.5 ⫾ 84.40 4.2 ⫾ 0.51 4.2 ⫾ 0.45 0.25 ⫾ 0.18 0.43 ⫾ 0.62 1.38 ⫾ 0.27 1.54 ⫾ 0.54
No-S, not treated with glucocorticosteroids; S, treated.
found (Table 1). Mean MMF dose was comparable in the groups (in No-S group 32.5 ⫾ 5.75 mg/kg per 24 hours vs 32.7 ⫾ 6.49 in S group at month 12 and 26.9 ⫾ 4.38 mg/kg per 24 hours vs 29.7 ⫾ 5.93 at month 24, respectively). Median 2-year cumulative GS dose was higher in S group than in No-S group (9070.0 mg; range: 9070.0 to 14318.0 mg vs 2607.5 mg; range: 1840.0 to 9410.0 mg; P ⬍ .0005). No difference in the frequency of infections was observed between the groups; there were 17 episodes documented in the No-S group and 16 episodes in the S group.
DISCUSSION
During 2 years of prospective follow-up we found that the IgG serum concentration was higher in renal allograft recipients after GS withdrawal compared to patients continuing corticoid therapy. There were no significant differences in IgA and IgM levels, however, the IgA concentration tended to be lower in patients undergoing GS therapy. The results of our findings are consistent with those of others, suggesting that GS cause a decrease of serum IgG2,5,6 and IgA levels, but essentially have no effect on serum IgM.2 Inhaled7 and systemic6 GS also decrease serum IgE levels. Some authors reported no significant changes in serum immunoglobulins under corticoid therapy.3,8 It may depend on the short duration of GS treatment,3,8 use of inhaled GS8 or evaluation of patients with active immunodependent disease.3 There are several studies on immunoglobulins in external secretions. Topical corticosteroids decrease secretory IgA, IgG and IgM concentrations in nasal secretions,9 dexamethasone decreases IgA and IgG levels in vaginal and salivary secretions.4 The amount of IgA in tears is a potential parameter for measurement of long-term stress in birds.10 Glucocorticosteroids reduce circulating IgG by inhibiting antibody formation rather than increasing IgG catabolism.11 They may act directly on B lymphocytes or indirectly by regulating the synthesis of cytokines. In vitro GS inhibit not only Th1 but also Th2 type cytokine production.12 In animal studies, dexamethasone suppressed B lymphocyte
activity, measured by immunoglobulin production and antigen-specific antibody responses.13 In rats, dexamethasone has a dual effect on IgA, decreasing secretory IgA at mucosal surfaces and increasing serum IgA levels. It may be a consequence of redistribution of IgA from mucosal associated lymphoid tissues to central sites, such as spleen or lymph nodes.5 Treatment with MMF could potentially affect serum immunoglobulin levels as suggested by the reduced incidence and titre of IgG anti-ATGAM antibody formation14 and suppression of the humoral response to influenza vaccination15 were observed under MMF therapy in renal transplant recipients. In our study the dose of MMF was comparable between the groups. Other factors, potentially modifying immunoglobulin concentration, like proteinuria, were also comparable. The effects of corticoid therapy on serum immunoglobulin levels depend on the route of administration, dosage of corticosteroids, and duration of the treatment. In our study, a prolonged 2 years) administration of standard maintenance oral GS dose decreased IgG levels compared to patients after Pred withdrawal. The changes were discrete and immunoglobulin levels stayed within normal limits so we were not able to observe the difference in the frequency of infections between the groups. We conclude that long-term corticoid therapy decreases serum IgG levels. Steroid withdrawal may prevent this effect in renal transplant recipients.
REFERENCES 1. Hrick DE, Almawi WY, Strom TB: Transplantation 57:979, 1994 2. Settipane GA, Pudupakkam RK, McGowan JH: J Allergy Clin Immunol 62:162, 1978 3. Wandinger KP, Wessel K, Trillenberg P, et al: Acta Neurol Scand 97:359, 1998 4. Nowacka-Cieciura E, Soluch L, Cieciura T, et al: Transplant Proc 32:1339, 2000 5. Wira CR, Sandoe CP, Steel MG: J Immunol 144:142, 1990 6. Pacheco A, Cuevas M, Carbelo B, et al: Eur Respir J 12:502, 1998
566 7. Ohrui T, Funayama T, Sekizawa K, et al: Clin Exp Allergy 29:357, 1999 8. Van Schoor J, Toogood JH, Pauwels RA: J Allergy Clin Immunol 97:113, 1996 9. Biewenga J, Stoop AE, van der Heijden HAMD, et al: J Allergy Clin Immunol 96:334, 1995 10. Florence BD, Svendsen L, Stodulski G, et al: In Vivo 9:19, 1995 11. McMillan R, Longmire R, Yelenosky R: J Immunol 116: 1592, 1976
NOWACKA-CIECIURA, DURLIK, CIECIURA ET AL 12. Snijdewint FGM, Kapsenberg ML, et al: Immunopharmacology 29:93, 1995 13. Carlsten H, Verdrengh M, Taube M: Inflamm Res 45:26, 1996 14. Kimball JA, Pescovitz MD, Book BK, et al: Transplantation 60:1379, 1995 15. Smith KGC, Isbel NM, Catton MG, et al: Nephrol Dial Transplant 13:160, 1998