- Email: [email protected]
Association Between Serum Soluble CD30 and Serum Creatinine Before and After Renal Transplantation
Association Between Serum Soluble CD30 and Serum Creatinine Before and After Renal Transplantation M. López-Hoyos, D. San Segundo, M.J. Benito, G. Fernández-Fresnedo, J.C. Ruiz, E. Rodrigo, C. Gómez-Alamillo, A. Benito, and M. Arias ABSTRACT Objective. There is increasing evidence that circulating levels of soluble CD30 (sCD30) may represent a biomarker for outcome in kidney transplantation. The aim of this study was to measure the pre- and posttransplantation serum levels of sCD30 in cadaveric kidney transplant recipients and correlate them with serum creatinine. Patients and Methods. Serum sCD30 was measured by a commercial enzyme-linked immunosorbent assay (ELISA) from prospective samples of 38 kidney allograft recipients serially transplanted at our center. Samples were collected at day 0 pretransplantation and at months 6, 12, 18, and 24 posttransplantation. We also studied sera from 29 patients with chronic kidney disease (CKD) at different stages of the K/DOQI guidelines, as a control group. Results. Serum levels of sCD30 decreased significantly in samples posttransplantation compared with pretransplantation. The significant decrease after transplantation may be related to the improvement in renal function since we observed a significant correlation between serum levels of sCD30 and creatinine (sCr) at all times of the study. In addition, the patients with chronic renal failure showed a significant association between serum sCD30 and sCr (r ⫽ .454; P ⫽ .013). Conclusions. Our results did not suggest that the measurement of sCD30 may be used as a valuable biomarker in renal transplantation. Increased levels may be related to a decrease in its renal elimination.
T
HE CD30 MOLECULE, a member of the tumor necrosis factor (TNF) receptor superfamily, is a 120 kDa cell-surface glycoprotein that is expressed on the cell surface of activated CD4⫹ Th2 and CD8⫹ T cells, as well as in several lymphoma cells. It has been suggested that CD30 has immunoregulatory activities, especially in alloimmune responses. After activation, CD30 is released from the cell surface and can therefore be measured in the circulation in its soluble form (sCD30).1 Abnormal circulating levels of sCD30 have been found in a number of inflammatory and autoimmune disorders. A number of reports have shown that pretransplantation serum levels of sCD30 may represent a biomarker for outcome in kidney transplantation, independent of alloantibody sensitization.2– 4 It has been suggested that both HLA antibodies and high sCD30 may serve as indicators of poor graft outcome.5,6 However, serum levels of sCD30 show important inter- and intraindividual variations, as well as timedependent changes.7
The aim of this study was to measure the pre- and posttransplantation serum levels of sCD30 in cadaveric kidney transplant recipients serially recruited at our center and correlate them with serum creatinine (sCr).
From the Servicios de Inmunologı´a (M.L.-H., D.S.S., M.J.B.) and Nefrologı´a (G.F.-F., J.C.R., E.R., C.G.-A., A.B., M.A.), Hospital Universitario Marqués de Valdecilla-IFIMAV, Santander, Spain, and Fundación Marqués de Valdecilla-IFIMAV3, Santander, Spain (A.B.). This work was partially supported by grants from the Fondo de Investigaciones Sanitarias (PI050047, PI070683, REDINREN 06/16 from ISCIII), from the Fundación Marqués de ValdecillaIFIMAV (API07/12), and from the Fundación Mutua-Madrileña. D.S.S. is a recipient of a Lopez-Albo grant (Fundación Marqués de Valdecilla-IFIMAV). Address reprint requests to Marcos López-Hoyos, Servicio Inmunologı´a, Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain. E-mail: [email protected]
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.08.087
Transplantation Proceedings, 40, 2903–2905 (2008)
2903
2904
LÓPEZ-HOYOS, SAN SEGUNDO, BENITO ET AL
PATIENTS AND METHODS
DISCUSSION
Serum sCD30 was measured from prospective samples of 38 kidney allograft recipients serially transplanted at our center. Samples were collected at day 0 pretransplantation and at months 6, 12, 18, and 24 posttransplantation. We also studied sera from 29 patients with chronic kidney disease (CKD) due to nephroangiosclerosis (to exclude a possible immunological activation due to the original renal disease or clinical situation) who were followed in our nephrology outpatient clinic, as a control group. These patients were divided according to the various stages of CKD defined in the K/DOQI of the National Kidney Foundation guidelines.8 sCD30 was measured using a commercial enzyme-linked immunosorbent assay (ELISA) kit (Bender Medsystems, Vienna, Austria) following the manufacturer’s instructions. Results are expressed as mean values ⫾ SD and correlated with clinical data and renal function. Statistical analysis was performed with SPSS software (SPSS Inc, Chicago, Ill, United States) and included the Spearman correlation coefficient and the MannWhitney U test. P ⬍ .05 was considered significant.
Many reports have supported a role for sCD30 in the immune response associated with renal allograft rejection. The presence of increased pretransplantation concentrations of sCD30 has been associated with the development of acute rejection2– 4 and, more recently, with humoral rejection and graft loss.5,6 Even though sCD30 may be a feasible noninvasive biomarker to predict allograft rejection, there is no clear evidence for its clinical use. In addition, very few studies have measured serial changes in circulating sCD30 concentrations after transplantation.2,3 They usually have shown a decrease of sCD30 in stable transplant recipients, in agreement with our results. Since our patients had conserved renal function and showed a significant although weak correlation between sCr and sCD30 at all times of sample collection, this suggested that sCD30 may be, in part, modified by renal filtration.9 Nothing is known about the route of elimination of sCD30, but our data on CKD patients due to nephroangiosclerosis further supported the renal elimination concept. In these CKD patients the correlation was stronger than in transplant recipients because their primary disease or clinical situation was not due to immunological activation. However, immune alteration that occurs in renal transplant patients may also have a bias effect on sCD30 levels and reduce the strength of association between sCD30 levels and renal function. On the other hand, novel data have shown high inter- and intraindividual variations in sCD30 levels, as well as heterogeneity over time.7 In conclusion, our results did not suggest that the measurement of sCD30 may be a valuable biomarker in renal transplantation. Increased levels may be related to a decrease in its renal elimination. However, our follow-up period was not long enough and our cohort was too small to discard its role as a long-term prognostic marker, as recently suggested.
RESULTS
Serum levels of sCD30 decreased significantly in samples posttransplantation (6 months: 12.5 ⫾ 10.1 ng/mL; 12 months: 10.2 ⫾ 5.3 ng/mL; 18 months: 5.9 ⫾ 4.1 ng/mL; 24 months: 8.1 ⫾ 3.1 ng/mL) compared with pretransplantation (19.4 ⫾ 6.9 ng/mL; P ⬍ .001). Importantly, all patients had stable renal function during the study with 100% graft survival at 1 year posttransplantation. Twelve of the 38 patients included in the study suffered from acute rejection within the first 6 months posttransplantation and recovered after standard therapy. When divided according to the development of acute rejection, there was no difference in serum sCD30 levels between patients suffering from acute rejection (6 months: 14.7 ⫾ 15.6 ng/mL; 12 months: 9.2 ⫾ 5.5 ng/mL; 18 months: 6.7 ⫾ 3.5 ng/mL; 24 months: 6.7 ⫾ 2.5 ng/mL) and those free of acute rejection (6 months: 11.5 ⫾ 6.5 ng/mL; 12 months: 10.7 ⫾ 5.3 ng/mL; 18 months: 5.5 ⫾ 4.3 ng/mL; 24 months: 8.8 ⫾ 3.3 ng/mL). The significant decrease after transplantation may be related to the improvement in renal function. Thus, we observed a significant correlation between serum levels of sCD30 and sCr at all times of the study: pretransplantation (r ⫽ .127; P ⫽ .039), and at months 6 (r ⫽ .169; P ⫽ .064), 12 (r ⫽ .202; P ⫽ .005), and 18 (r ⫽ .197; P ⫽ .026) posttransplantation. We also measured serum sCD30 in patients with chronic renal failure due to nephroangiosclerosis who were followed in our clinic to analyze whether the serum concentration of this molecule was influenced by renal function. Results demonstrated a significant association between serum sCD30 and sCr (r ⫽ .454; P ⫽ .013). In agreement with this, patients within higher K/DOQI CKD stages showed higher serum levels of sCD30: CKD stage 2 (n ⫽ 2; 11.7 ⫾ 11.6), CKD stage 3 (n ⫽ 16; 14.6 ⫾ 10.1), CKD stage 4 (n ⫽ 6; 15.2 ⫾ 8.3), and CKD stage 5 (n ⫽ 5; 23.6 ⫾ 12.7).
REFERENCES 1. Chan KW, Hopke CD, Krams SM, et al: CD30 expression identifies the predominant proliferating T lymphocyte population in human alloimmune responses. J Immunol 169:1784, 2002 2. Pelzl S, Opelz G, Weisel M, et al: Soluble CD30 as a predictor of kidney graft outcome. Transplantation 73:3, 2002 3. Sengul S, Keven K, Gormez U, et al: Identification of patients at risk of acute rejection by pretransplantation and posttransplantation monitoring of soluble CD30 levels in kidney transplantation. Transplantation 81:1216, 2006 4. Vaidya S, Partlow D, Barnes T, et al: Soluble CD30 concentrations in ESRD patients with and without panel reactive HLA antibodies. Clin Transplant 20:461, 2006 5. Langan LL, Park LP, Hughes TL, et al: Post-transplant HLA class II antibodies and high soluble CD30 levels are independently associated with poor kidney graft survival. Am J Transplant 7:847, 2007 6. Weimer R, Süsal C, Yildiz S, et al: Post-transplant sCD30 and neopterin as predictors of chronic allograft nephropathy: impact of
SERUM sCD30 AND Cr IN RENAL TRANSPLANTATION different immunosuppressive regimens. Am J Transplant 6:1865, 2006 7. Altermann W, Schlaf G, Rothhoff A, et al: High variation of individual soluble serum CD30 levels of pre-transplantation patients: sCD30 a feasible marker for prediction of kidney allograft rejection? Nephrol Dial Transplant 22:2795, 2007
2905 8. National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis 39 (suppl 1):1, 2002 9. Alcalde G, Merino J, Sanz S, et al: Circulating adhesion molecules during kidney allograft rejection. Transplantation 59: 1695, 1995
T
HE CD30 MOLECULE, a member of the tumor necrosis factor (TNF) receptor superfamily, is a 120 kDa cell-surface glycoprotein that is expressed on the cell surface of activated CD4⫹ Th2 and CD8⫹ T cells, as well as in several lymphoma cells. It has been suggested that CD30 has immunoregulatory activities, especially in alloimmune responses. After activation, CD30 is released from the cell surface and can therefore be measured in the circulation in its soluble form (sCD30).1 Abnormal circulating levels of sCD30 have been found in a number of inflammatory and autoimmune disorders. A number of reports have shown that pretransplantation serum levels of sCD30 may represent a biomarker for outcome in kidney transplantation, independent of alloantibody sensitization.2– 4 It has been suggested that both HLA antibodies and high sCD30 may serve as indicators of poor graft outcome.5,6 However, serum levels of sCD30 show important inter- and intraindividual variations, as well as timedependent changes.7
The aim of this study was to measure the pre- and posttransplantation serum levels of sCD30 in cadaveric kidney transplant recipients serially recruited at our center and correlate them with serum creatinine (sCr).
From the Servicios de Inmunologı´a (M.L.-H., D.S.S., M.J.B.) and Nefrologı´a (G.F.-F., J.C.R., E.R., C.G.-A., A.B., M.A.), Hospital Universitario Marqués de Valdecilla-IFIMAV, Santander, Spain, and Fundación Marqués de Valdecilla-IFIMAV3, Santander, Spain (A.B.). This work was partially supported by grants from the Fondo de Investigaciones Sanitarias (PI050047, PI070683, REDINREN 06/16 from ISCIII), from the Fundación Marqués de ValdecillaIFIMAV (API07/12), and from the Fundación Mutua-Madrileña. D.S.S. is a recipient of a Lopez-Albo grant (Fundación Marqués de Valdecilla-IFIMAV). Address reprint requests to Marcos López-Hoyos, Servicio Inmunologı´a, Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain. E-mail: [email protected]
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.08.087
Transplantation Proceedings, 40, 2903–2905 (2008)
2903
2904
LÓPEZ-HOYOS, SAN SEGUNDO, BENITO ET AL
PATIENTS AND METHODS
DISCUSSION
Serum sCD30 was measured from prospective samples of 38 kidney allograft recipients serially transplanted at our center. Samples were collected at day 0 pretransplantation and at months 6, 12, 18, and 24 posttransplantation. We also studied sera from 29 patients with chronic kidney disease (CKD) due to nephroangiosclerosis (to exclude a possible immunological activation due to the original renal disease or clinical situation) who were followed in our nephrology outpatient clinic, as a control group. These patients were divided according to the various stages of CKD defined in the K/DOQI of the National Kidney Foundation guidelines.8 sCD30 was measured using a commercial enzyme-linked immunosorbent assay (ELISA) kit (Bender Medsystems, Vienna, Austria) following the manufacturer’s instructions. Results are expressed as mean values ⫾ SD and correlated with clinical data and renal function. Statistical analysis was performed with SPSS software (SPSS Inc, Chicago, Ill, United States) and included the Spearman correlation coefficient and the MannWhitney U test. P ⬍ .05 was considered significant.
Many reports have supported a role for sCD30 in the immune response associated with renal allograft rejection. The presence of increased pretransplantation concentrations of sCD30 has been associated with the development of acute rejection2– 4 and, more recently, with humoral rejection and graft loss.5,6 Even though sCD30 may be a feasible noninvasive biomarker to predict allograft rejection, there is no clear evidence for its clinical use. In addition, very few studies have measured serial changes in circulating sCD30 concentrations after transplantation.2,3 They usually have shown a decrease of sCD30 in stable transplant recipients, in agreement with our results. Since our patients had conserved renal function and showed a significant although weak correlation between sCr and sCD30 at all times of sample collection, this suggested that sCD30 may be, in part, modified by renal filtration.9 Nothing is known about the route of elimination of sCD30, but our data on CKD patients due to nephroangiosclerosis further supported the renal elimination concept. In these CKD patients the correlation was stronger than in transplant recipients because their primary disease or clinical situation was not due to immunological activation. However, immune alteration that occurs in renal transplant patients may also have a bias effect on sCD30 levels and reduce the strength of association between sCD30 levels and renal function. On the other hand, novel data have shown high inter- and intraindividual variations in sCD30 levels, as well as heterogeneity over time.7 In conclusion, our results did not suggest that the measurement of sCD30 may be a valuable biomarker in renal transplantation. Increased levels may be related to a decrease in its renal elimination. However, our follow-up period was not long enough and our cohort was too small to discard its role as a long-term prognostic marker, as recently suggested.
RESULTS
Serum levels of sCD30 decreased significantly in samples posttransplantation (6 months: 12.5 ⫾ 10.1 ng/mL; 12 months: 10.2 ⫾ 5.3 ng/mL; 18 months: 5.9 ⫾ 4.1 ng/mL; 24 months: 8.1 ⫾ 3.1 ng/mL) compared with pretransplantation (19.4 ⫾ 6.9 ng/mL; P ⬍ .001). Importantly, all patients had stable renal function during the study with 100% graft survival at 1 year posttransplantation. Twelve of the 38 patients included in the study suffered from acute rejection within the first 6 months posttransplantation and recovered after standard therapy. When divided according to the development of acute rejection, there was no difference in serum sCD30 levels between patients suffering from acute rejection (6 months: 14.7 ⫾ 15.6 ng/mL; 12 months: 9.2 ⫾ 5.5 ng/mL; 18 months: 6.7 ⫾ 3.5 ng/mL; 24 months: 6.7 ⫾ 2.5 ng/mL) and those free of acute rejection (6 months: 11.5 ⫾ 6.5 ng/mL; 12 months: 10.7 ⫾ 5.3 ng/mL; 18 months: 5.5 ⫾ 4.3 ng/mL; 24 months: 8.8 ⫾ 3.3 ng/mL). The significant decrease after transplantation may be related to the improvement in renal function. Thus, we observed a significant correlation between serum levels of sCD30 and sCr at all times of the study: pretransplantation (r ⫽ .127; P ⫽ .039), and at months 6 (r ⫽ .169; P ⫽ .064), 12 (r ⫽ .202; P ⫽ .005), and 18 (r ⫽ .197; P ⫽ .026) posttransplantation. We also measured serum sCD30 in patients with chronic renal failure due to nephroangiosclerosis who were followed in our clinic to analyze whether the serum concentration of this molecule was influenced by renal function. Results demonstrated a significant association between serum sCD30 and sCr (r ⫽ .454; P ⫽ .013). In agreement with this, patients within higher K/DOQI CKD stages showed higher serum levels of sCD30: CKD stage 2 (n ⫽ 2; 11.7 ⫾ 11.6), CKD stage 3 (n ⫽ 16; 14.6 ⫾ 10.1), CKD stage 4 (n ⫽ 6; 15.2 ⫾ 8.3), and CKD stage 5 (n ⫽ 5; 23.6 ⫾ 12.7).
REFERENCES 1. Chan KW, Hopke CD, Krams SM, et al: CD30 expression identifies the predominant proliferating T lymphocyte population in human alloimmune responses. J Immunol 169:1784, 2002 2. Pelzl S, Opelz G, Weisel M, et al: Soluble CD30 as a predictor of kidney graft outcome. Transplantation 73:3, 2002 3. Sengul S, Keven K, Gormez U, et al: Identification of patients at risk of acute rejection by pretransplantation and posttransplantation monitoring of soluble CD30 levels in kidney transplantation. Transplantation 81:1216, 2006 4. Vaidya S, Partlow D, Barnes T, et al: Soluble CD30 concentrations in ESRD patients with and without panel reactive HLA antibodies. Clin Transplant 20:461, 2006 5. Langan LL, Park LP, Hughes TL, et al: Post-transplant HLA class II antibodies and high soluble CD30 levels are independently associated with poor kidney graft survival. Am J Transplant 7:847, 2007 6. Weimer R, Süsal C, Yildiz S, et al: Post-transplant sCD30 and neopterin as predictors of chronic allograft nephropathy: impact of
SERUM sCD30 AND Cr IN RENAL TRANSPLANTATION different immunosuppressive regimens. Am J Transplant 6:1865, 2006 7. Altermann W, Schlaf G, Rothhoff A, et al: High variation of individual soluble serum CD30 levels of pre-transplantation patients: sCD30 a feasible marker for prediction of kidney allograft rejection? Nephrol Dial Transplant 22:2795, 2007
2905 8. National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis 39 (suppl 1):1, 2002 9. Alcalde G, Merino J, Sanz S, et al: Circulating adhesion molecules during kidney allograft rejection. Transplantation 59: 1695, 1995