Identification of Highly Responsive Kidney Transplant Recipients Using Pretransplant Soluble CD30
Caner Süsal,
Steffen Pelzl,
Bernd Döhler and
Gerhard Opelz the Collaborative Transplant Study
Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Heidelberg, Germany.
Correspondence to Dr. Caner Süsal, Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D–69120 Heidelberg, Germany. Phone: 49-6221-565545; Fax: 49-6221-564200; E-mail: caner_suesal{at}med.uni-heidelberg.de
ABSTRACT. The identification of high immunologic respondersis desirable for the selection of appropriate immunosuppressiveregimens. With the collaboration of 29 transplant centers in15 countries, we investigated whether the pretransplant serumcontent of soluble CD30 (sCD30), a marker for the activationstate of Th2-type cytokine producing T cells, is a useful predictorof kidney graft outcome. Pretransplant sera of 3899 cadaverkidney recipients were tested for serum sCD30 concentrationusing a commercially available enzyme-linked immunosorbent assaykit. Subsequent kidney graft survival was analyzed. The 5-yrgraft survival rate in 901 recipients with a high pretransplantserum sCD30 (100 U/ml) was 64 ± 2%, significantly lowerthan the 75 ± 1% rate in 2998 recipients with low sCD30(<100 U/ml) (P < 0.0001). High sCD30 was associated primarilywith graft loss and not with patient death. The sCD30 effecton graft survival was evident in first transplants as well asin retransplants, in presensitized patients with lymphocytotoxicantibodies as well as in nonsensitized patients, and in patientswho received HLA well-matched kidneys as well as in patientswho received poorly matched grafts. Recipients with a high pretransplantsCD30 needed significantly more rejection treatment after thefirst posttransplant year and continued to lose grafts at ahigher rate during the 5-yr follow-up period, indicating thatpretransplant sCD30 predicts not only the risk of acute rejectionbut also of chronic allograft nephropathy.
Pretransplant determination of a recipient’s risk of graftrejection is an important prerequisite for the application ofrecipient-tailored immunosuppression. Administration of potentimmunosuppressive regimens has been shown to improve graft outcomein preimmunized recipients (1,2). In low risk recipients, onewould like to avoid high-dose immunosuppression to reduce drugside effects, such as toxicity, infection, and development ofcancer. Until now, panel reactive antibodies (PRA) are the onlyestablished indicator of increased immunologic responsivenessbefore transplantation. Highly reactive PRA predict an increasedrisk of early acute rejection (3,4). Tests that predict an increasedrisk of chronic allograft nephropathy are currently not available.
The CD30 molecule, a member of the tumor necrosis factor/nervegrowth factor receptor superfamily, was originally identifiedas a cell surface antigen on Hodgkin and Reed Sternberg cells(5). CD30 is preferentially expressed on human CD4+ and CD8+T cells that secrete Th2-type cytokines, whereas no or low CD30expression is found on Th1-type cytokine-secreting T cells (6).A soluble form of CD30 (sCD30) is released into the bloodstreamafter activation of CD30+ T cells (7). In diseases in whichTh2-type immune responses predominate, such as lupus erythematosusor atopic dermatitis, elevated serum sCD30 was found to be associatedwith increased disease activity (8,9). Elevated serum sCD30in early stages of HIV-1 infection predicted a more rapid progressionto AIDS (10). In multiple sclerosis, a disease in which Th1-typeimmune responses predominate, increased sCD30 serum levels werecorrelated with disease remission (11).
On the basis of preliminary evidence showing that kidney transplantrecipients with a high pretransplant serum sCD30 content hadan impaired graft outcome (12), we conducted the present largemulticenter study involving nearly 3900 transplants and performeda comprehensive analysis of sCD30 against the background ofother established risk factors for graft loss.
Pretransplant sera of 3899 cadaver kidney recipients were providedby 29 centers in 15 countries (see Appendix). Consecutivitywas not a criterion, as the centers were asked to send seraon all transplanted patients on whom a sufficient volume ofthe last serum obtained before transplantation was available.The sera were shipped frozen to the study center in Heidelbergand tested for serum sCD30 content using a commercially availableenzyme-linked immunosorbent assay (ELISA) kit (Bender MedSystems,Vienna, Austria). In addition, 50 adult healthy controls whohad a similar age and gender distribution as adult kidney recipientswere tested (mean age, 44 ± 2; male:female, 60:40%).For the transplant analysis, an sCD30 cut-off level of 100 U/mlwas chosen on the basis of receiver operating characteristicsand multivariate Cox regression analysis for the cut-off levelsof 50, 75, 100, 125, and 150 U/ml. An intra-assay variance of<10% and an inter-assay variance of <20% was indicatedby the manufacturer. No significant differences were observedin sCD30 values in sera of 10 chronic dialysis patients collectedat four different time points (first value, 74 ± 21 U/ml;3 mo, 85 ± 25 U/ml; 6 mo, 84 ± 24 U/ml; 9 mo,84 ± 22 U/ml). Moreover, sera of five dialysis patientsobtained before, during (2.5 h after begin), and immediatelyafter dialysis during two subsequent dialysis cycles did notshow significant changes in the sCD30 values. sCD30 values ofdialyzed and nondialyzed end-stage renal disease patients didnot differ significantly (adults, 73 ± 1 [n = 3631] versus77 ± 7 [n = 40], P = 0.2792; young patients, 189 ±8 [n = 210] versus 212 ± 34 [n = 6], P = 0.4285). Torule out an effect of variations in sera handling at differentcenters, the effect of repeated serum thawing or storage conditionswas tested using the sera of six different patients with differentsCD30 values. Five thawing cycles and storage at 4°C for1 to 3 d did not affect serum sCD30 values (72 ± 16 versus73 ± 17, and 72 ± 16 versus 72 ± 15, respectively).
The results were entered into the Collaborative Transplant Studydatabase (13) and connected with previously registered informationon the transplants in a blinded manner. Ninety-three percentof the patients studied received cyclosporine-based immunosuppression.The demographic characteristics of the recipients are summarizedin Table 1. HLA typings and panel reactive lymphocytotoxic antibodydeterminations were performed at the tissue typing laboratoriesof participating centers. Patients with 5% antibody reactivityagainst a randomly chosen lymphocyte test panel were categorizedas sensitized. Information on recipient or donor HLA-A+B+DRtyping was missing in 85 cases, on PRA in 240 cases, and onrecipient age in 12 cases. Information on graft function andpatient survival was documented at 3 and 6 mo and at 1, 2, 3,4, and 5 yr. Actuarial survival rates were computed accordingto the Kaplan-Meier method (14) and are expressed as % ±SEM. Log-rank test, Mann-Whitney U test, Spearman rank-correlation,Fisher’s exact test, 2, receiver operating characteristics,and multivariate Cox regression were used for statistical analyses.
When the recipients were separated into two groups accordingto their pretransplant serum sCD30 content, 2998 recipientswith a low sCD30 of <100 U/ml had a 5-yr graft survival rateof 75 ± 1% compared with a 64 ± 2% rate in 901recipients with a high sCD30 of 100 U/ml (P < 0.0001) (Figure 1).An analysis of death-censored functional graft survivalshowed that sCD30 was associated primarily with graft failure(low sCD30, 83 ± 1% versus high sCD30, 73 ± 2%;P < 0.0001). The influence of pretransplant sCD30 on patientsurvival was only marginal (low sCD30, 88 ± 1% versushigh sCD30, 85 ± 1%; P = 0.0389) (Figure 2).
Figure 1. Association of soluble CD30 (sCD30) content in pretransplant serum with cadaver kidney graft survival. Recipients with low serum sCD30 had a significantly better graft survival rate than recipients with high sCD30 (P < 0.0001). Numbers of patients studied are indicated.
Figure 2. Association of sCD30 content in pretransplant serum with (A) functional kidney graft survival. In this analysis, death with a functioning graft was not counted as graft failure (censored). (B) Patient survival. Functional graft survival was significantly influenced by pretransplant sCD30 (high versus low, P < 0.0001). Only a marginal effect of sCD30 was observed on patient survival (high versus low, P = 0.0389).
A total of 546 regraft recipients had a higher serum sCD30 contentthan 3353 first graft recipients (mean ± SEM, 93 ±3 U/ml versus 77 ± 1 U/ml; P < 0.0001), and 695 presensitized(PRA 5%) patients had a higher serum sCD30 content than 2964nonsensitized (<5% PRA) patients (mean ± SEM, 84 ±2 U/ml versus 77 ± 1 U/ml; P < 0.0001). As shown inTable 2, the sCD30 effect on graft survival was present in regraftrecipients (low versus high sCD30, P = 0.0077) as well as infirst graft recipients (P < 0.0001), in presensitized patients(P = 0.0003) as well as in nonsensitized patients (P < 0.0001),and in patients who received a well-matched kidney with 0 to1 HLA-A+B+DR mismatches (P = 0.0006) as well as in patientswho received a poorly matched kidney with four to six mismatches(P < 0.0001). The association of serum sCD30 content withserum PRA appeared to be marginal (first grafts, r = 0.085;retransplants, r = -0.017; <20 yr old, r = -0.165; 20 yrold, r = 0.111), whereas, as shown in Figure 3, the effectsof the two parameters on graft outcome were additive.
Figure 3. Combined effect of serum sCD30 content and lymphocytotoxic panel reactivity (PRA) on kidney graft survival. sCD30-positive and PRA-positive recipients (sCD30+/PRA+) had a significantly impaired graft outcome, compared with sCD30-negative and PRA-negative (sCD30-/PRA-), sCD30-negative and PRA-positive (sCD30-/PRA+), or sCD30-positive and PRA-negative recipients (sCD30+/PRA-) (P < 0.0001, P = 0.0003, and P = 0.0048, respectively).
A total of 3671 adult (20 yr old) kidney graft recipients hada significantly higher serum sCD30 content before transplantationthan 50 age- and gender-matched adult healthy controls (73 ±1 U/ml versus 22 ± 1 U/ml; P < 0.0001). An exceptionallyhigh serum sCD30 content was observed in 216 recipients youngerthan 20 yr (190 ± 8 U/ml [P < 0.0001] compared withadult recipients). Among these young recipients, 75% had a highsCD30 of >100 compared with only 20% of adult recipients(P < 0.0001). Due to the relatively small number of pediatricpatients in the series, the graft survival difference betweenrecipients with low or high sCD30 did not reach statisticalsignificance in patients younger than 20 yr (P = 0.0906); however,the numerical difference between the graft survival rates, andthus the clinical impact, was similar in young and adult recipients(Table 2).
Semilogarithmic data conversion showed that, after the firstposttransplant year, patients with a high pretransplant serumsCD30 continued to lose grafts at an increased constant rateduring the 5-yr follow-up period. The death-censored half-lifetimes for patients with high or low sCD30 were 20.5 yr and 29.4yr, respectively (Figure 4). That the increased long-term failurerate in patients with high pretransplant sCD30 was in all likelihoodattributable to more rejections was further supported by ananalysis of the need for rejection treatment. When patientswith functioning grafts at the end of the second posttransplantyear were examined, those with a high pretransplant serum sCD30had been treated for rejection during the preceding year significantlymore often than patients with a low sCD30 (low, 5% versus high,10%; P = 0.0003) (Figure 5A). Similarly, patients with functioninggrafts at the end of the third year showed a trend toward morerejection treatments during the preceding year if they had ahigh pretransplant sCD30 (low, 3% versus high, 5%; P = 0.0538)(Figure 5B). Among patients who did not receive rejection treatmentduring the first year, recipients with a high sCD30 were treatedsignificantly more often for rejection during the second yearand had a lower 5-yr graft survival rate than recipients witha low sCD30 (rejection treatments: high, 8% versus low, 4% [P= 0.0012]; 5-yr graft outcome: high, 83 ± 2% versus low,88 ± 1% [P = 0.0398]). A similar tendency was observedin patients who received rejection treatment during the firstyear but did not lose their grafts; however, the differencebetween patients with a high or low sCD30 did not reach statisticalsignificance (rejection treatments during the second year: high,12% versus low, 9% [P = 0.3463]; 5-yr graft outcome: high, 76± 4% versus low, 82 ± 2% [P = 0.1120]).
Figure 4. Graft half-life for period after the first posttransplant year on the basis of 5-year follow-up. Death-censored analysis. The shorter half-life time in recipients with high sCD30 suggests a continuous effect of sCD30 on long-term graft outcome.
Figure 5. Incidence of rejection treatment during the preceding year in patients with functioning grafts at the end of the second (A) or third (B) posttransplant year. Y, with rejection treatment; N, no rejection treatment. Recipients with a high pretransplant serum sCD30 were treated for rejection more often than patients with a low sCD30 (second year, P = 0.0003; third year, P = 0.0538).
Among 1283 patients who were treated with prophylactic antilymphocyteantibodies (ATG, ALG, or OKT3), recipients with a high pretransplantsCD30 had a 5-yr graft survival of 60 ± 3%, significantlyworse than the 74 ± 2% rate in recipients with a lowsCD30 (P < 0.0001), indicating that antilymphocyte antibodiesdid not improve graft outcome in patients with a high sCD30.Although the number of mycophenolate mofetil–treated patientswith a sufficient follow-up was small, the sCD30 effect appearedless pronounced in these patients than in patients who receivedazathioprine (3-yr graft outcome, mycophenolate mofetil: low,81 ± 3% [n = 160] versus high, 80 ± 5% [n = 74],P = 0.702; azathioprine: low, 82 ± 1% [n = 2007] versushigh, 72 ± 2% [n = 588], P < 0.0001). Due to the smallnumber of patients available for analysis with a high sCD30(n = 16), the influence of tacrolimus on the sCD30 effect couldnot be analyzed.
To ascertain the validity of our observations and in the lightof the observation that young patients tended to have highersCD30 values, a multivariate Cox regression analysis was performed.Recipient and donor age and gender, year of transplantation,transplant number, number of HLA-A+B+DR mismatches, originaldisease, type of immunosuppression, panel-reactive lymphocytotoxicantibodies, number of transfusions, geographic origin, and coldischemia time in hours were considered as co-variables. Comparedwith patients with a low sCD30, patients with an increased sCD30showed a significantly increased risk ratio for graft loss (relativerisk, 1.53; 95% confidence interval [CI], 1.31 to 1.79; P <0.0001). For comparison, the risk ratio for graft loss was 1.27(95% CI, 1.07 to 1.51) in presensitized patients (PRA of 5%)as compared with nonsensitized patients (PRA <5%) (P = 0.0069),1.01 (95% CI, 1.01 to 1.02) for each 1 yr change in donor age(<0.0001), and 1.35 in retransplant recipients as comparedwith recipients of first grafts (95% CI, 1.17 to 1.56; P = 0.0001).
In current clinical practice, PRA is the only established immunologicparameter that provides clinically useful information concerningthe responder status of a cadaver kidney recipient. For recipientswithout PRA, a categorization into high or low immunologic riskis not possible. In this large series of nearly 3900 kidneytransplants performed at 29 centers, we were able to demonstratethat pretransplant determination of the Th2-type activationmarker sCD30 is a powerful indicator for estimating the riskof graft rejection not only in presensitized but also in nonsensitizedrecipients. Patients possessing both PRA and high sCD30 in theirpretransplant serum had a particularly poor graft outcome. Fromthe data shown in Table 2, it is evident that, from a clinicalviewpoint, sCD30 is at least as relevant as PRA. Serum sCD30determinations are easy to perform and, although there are differencesin the sensitivity of different commercially available ELISAkits, the results obtained with the same kit are highly reproduciblewith a between-run variation coefficient of 4 to 15% (15). Unfortunately,we did not have histopathologic information on posttransplanthumoral rejections to investigate whether patients with a highsCD30 are more prone to antibody-mediated or cellular-type rejection.The half-life time estimates depicted in Figure 4 as well asthe higher rates of rejection treatment shown in Figure 5 suggestthat sCD30 is not only an indicator of early acute rejectionbut also of chronic allograft nephropathy.
Whereas the Th1-type cytokines interleukin-2 (IL-2) and interferon-(INF-) are capable of activating macrophages as well as CD4+and CD8+ T cells, the Th2-type cytokines IL-4 and IL-10 arecapable of inhibiting Th1-type immune responses (8). It wastherefore hypothesized that a Th2-type immune response may begraft protective by blocking the graft damaging Th1-type anti-donorresponse (16). Our data show evidence to the contrary, namelypoor graft survival in patients with high levels of sCD30, aproduct of Th2-type cytokine producing lymphocytes.
Presensitized patients are preferentially transplanted withHLA well-matched kidneys and receive stronger posttransplantimmunosuppression, including prophylactic treatment with antilymphocyteantibodies (1,2,4). Whether recipients with high sCD30 wouldprofit from receiving especially potent immunosuppression couldnot be answered conclusively. However, our data show that evenamong patients who were treated with prophylactic antilymphocyteantibodies (ATG or OKT3), those with a high pretransplant sCD30fared significantly worse than those with a low sCD30. Thus,to improve graft outcome in patients with a high sCD30, otherstrategies seem to be necessary, possibly immunosuppressiveregimens that specifically inhibit CD30+ T cells. Treatmentwith mycophenolate mofetil instead of azathioprine appears promising;however, the number of patients with sufficient follow-up wastoo small for a conclusive statement.
Although patients with end-stage renal disease show severe alterationsof the immune system, including defective antigen presentationand constantly present Th1-type cytokine-mediated chronic inflammation(17), it remains unknown why dialysis patients generally haveincreased sCD30 in their serum. The majority of chronic dialysispatients are incapable of generating an intact immune responseagainst specific stimuli. Interestingly, the small fractionof patients who are capable of producing high amounts of theTh2-type cytokine IL-10 compensate this immune defect (17),suggesting that IL-10 promotes the generation of specific immuneresponses by inhibiting the unspecific proinflammatory Th1 response.In line with these findings, Gerli et al. (18) observed in rheumatoidarthritis patients with increased serum sCD30 that synovialCD30+ T cells secreted high amounts of IL-4 and IL-10. In contrastto patients with low serum sCD30, these patients responded wellto so-called second-line anti-rheumatic therapy, suggestingthat increased serum sCD30 reflects the presence of IL-10–producingCD30+ T cells that are able to downmodulate the inflammationcaused by Th1-type immune responses (19). It is therefore reasonableto speculate that, among patients with end-stage renal disease,only those with high sCD30 may be capable of producing IL-10,which inhibits the unspecific chronic inflammatory Th1-typeimmune response and thereby allows generation of an effectivealloimmune response against the graft. This contention is supportedby our previous finding that patients with a high pretransplantIL-10–dominated Th2-type immune response had a poor kidneygraft outcome (20).
In line with recent observations (12,15), we found strikinglyhigher serum sCD30 levels in young kidney graft recipients thanin adult recipients in the present study, which might serveas a possible explanation for the generally observed increasedrate of acute graft rejection in young patients. The increasedserum sCD30 levels in presensitized patients and regraft recipientsindicate that elevated sCD30 is associated with increased alloreactivity.In line with these findings is the work of Martinez et al. (21),who identified CD30+ T cells as the major -interferon and IL-5cytokine-producing human T lymphocyte subset generated in responseto stimulation with alloantigens. Despite the close relationshipof sCD30 with Th2-type immune responses, it is conceivable thatCD30+ T cell activation represents a novel graft rejection pathwayin which both Th1- and Th2-type cytokines are involved. Morestudies are needed to clarify the role, origin, and characteristicsof sCD30 and CD30+ T cells in alloimmune responses. An intriguingunresolved question is whether elevated sCD30 results from agenetic tendency toward high CD30+ T cell activation or whethersCD30 production is triggered by immunologic events that thepatient experienced in the past.
In conclusion, this study demonstrates that the pretransplantserum sCD30 content is a clinically useful parameter for theidentification of high responders in kidney transplantation.Pretransplant sCD30 testing may contribute further to the selectionof appropriate immunosuppressive regimens in high-risk recipientsfor the prevention of acute graft rejection and chronic allograftnephropathy.
Sera for this multicenter study were provided by transplantationcenters in the following cities: Barcelona, Spain (Dr. JaumeMartorell, n = 49); Berlin, Germany (Dr. Constanze Schönemann,n = 336); Budapest, Hungary (Dr. Agnes Padanyi, n = 111); Cardiff,United Kingdom (Dr. Timothy J. Rees, n = 173); Dallas, Texas(Dr. Peter Stastny, n = 3); Essen, Germany (Dr. Uwe Vögeler,n = 94); Freiburg, Germany (Dr. Helmut Lang, n = 8); Geneva,Switzerland (Dr. Michel Jeannet, n = 86); Glasgow, United Kingdom(Dr. Alex M. Farrell, n = 343); Heidelberg, Germany (Dr. ManfredWiesel, n = 589); Helsinki, Finland (Dr. Saija Koskimies, n= 486); Lexington, Kentucky (Dr. John S. Thompson, n = 82);Lausanne, Switzerland (Dr. Vincent Aubert, n = 57); Leicester,United Kingdom (Dr. Terry Horsburgh, n = 95); Liege, Belgium(Dr. Claire Bouillenne, n = 68); Ljubljana, Slovenia (Dr. MatejaBohinjec, n = 47); Mannheim, Germany (Dr. Peter Schnülle,n = 46); Marburg, Germany (Dr. Harald Lange, n = 54); Munich,Germany (Dr. Siegfried Scholz, n = 13); New York, New York (Dr.Marilena Fotino, n = 35); Phoenix, Arizona (Dr. Theona M. Vyvial,n = 93); Prague, Czech Republic (Dr. Eva Ivaskova, n = 128);Quebec, Canada (Dr. Reynald Roy, n = 353); Reims, France (Dr.Jacques H. Cohen, n = 172); Rijeka, Croatia (Dr. Ksenija Vujaklija-Stipanovic,n = 45); Rio de Janeiro, Brazil (Dr. Maria E. Goncalves De Freitas,n = 77); Strasbourg, France (Dr. Marie-Marthe Tongio, n = 78);Sydney, Australia (Dr. Trevor Doran, n = 129); Zagreb, Croatia(Dr. Adrija Kastelan, n = 49).
Acknowledgments
We wish to thank Martina Stolp, Nicole Schach, and ChristineMatheis for excellent technical assistance, Andrea Ruhenstrothand Gunter Laux for assistance with the computer analysis, andstaff members at the participating laboratories and clinicalunits for supplying us with sera and clinical follow-up data.This study was supported in part by a grant of ForschungsschwerpunktTransplantation Heidelberg.
Vela C, Cristol JP, Chong G, Okamba A, Lorho R, Mion C, Mourad G: Antilymphocyte globulins versus OKT3 as prophylactic treatment in highly sensitized renal transplant recipients. Transpl Int 7 [Suppl 1]: S259–S262, 1994
Opelz G: Efficacy of rejection prophylaxis with OKT3 in renal transplantation. Collaborative Transplant Study. Transplantation 60: 1220–1224, 1995[Medline]
Shenton BK: The detection and relevance of pretransplant antibodies. Transpl Immunol 2: 135–137, 1994[CrossRef][Medline]
Opelz G, Wujciak T: Cadaveric kidneys should be allocated according to the HLA match. Transplant Proc 27: 93–99, 1995[Medline]
Durkop H, Latza U, Hummel M, Eitelbach F, Seed B, Stein H: Molecular cloning and expression of a new member of the nerve growth factor receptor family that is characteristic for Hodgkin’s disease. Cell 68: 421–427, 1992[CrossRef][Medline]
Del Prete G, De Carli M, Almerigogna F, Daniel CK, D’Elios MM, Zancuoghi G, Vinante F, Pizzolo G, Romagnani S: Preferential expression of CD30 by human CD4+ T cells producing Th2-type cytokines. FASEB J 9: 81–86, 1995[Abstract]
Romagnani S, Del Prete G, Maggi E, Chilosi M, Caligaris-Cappio F, Pizzolo G: CD30 and type 2 T helper (Th2) responses. J Leukoc Biol 57: 726–730, 1995[Abstract]
Del Prete G: The concept of type-1 and type-2 helper T cells and their cytokines in humans. Int Rev Immunol 16: 427–455, 1998[Medline]
Frezzolini A, Paradisi M, Ruffelli M, Cadoni S, De Pita O: Soluble CD30 in pediatric patients with atopic dermatitis. Allergy 52: 106–109, 1997[Medline]
Pizzolo G, Vinante F, Morosato L, Nadali G, Chilosi M, Gandini G, Sinicco A, Raiteri R, Semenzato G, Stein H, Perona G: High serum level of the soluble form of CD30 molecule in the early phase of HIV-1 infection as an independent predictor of progression to AIDS. AIDS 8: 741–745, 1994[Medline]
McMillan SA, McDonnell GV, Douglas JP, Droogan AG, Hawkins SA: Elevated serum and CSF levels of soluble CD30 during clinical remission in multiple sclerosis. Neurology 51: 1156–1160, 1998[Abstract/Free Full Text]
Pelzl S, Opelz G, Wiesel M, Schnülle P, Schönemann C, Döhler B, Süsal C: Soluble CD30 as a predictor of kidney graft outcome. Transplantation 73: 3–6, 2002[CrossRef][Medline]
Collaborative Transplant Study, University of Heidelberg, Germany, Web site. Available at: www.ctstransplant.org. Accessed April 23, 2002
Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457–481, 1958[CrossRef]
Barbano G, Cappa F, Prigione I, Pistoia V, Cohen A, Chiesa S, Gusmano R, Perfumo F: Plasma levels of soluble CD30 are increased in children with chronic renal failure and with primary growth deficiency and decrease during treatment with recombination human growth hormone. Nephrol Dial Transplant 6: 1807–1813, 2001
Strom TB, Roy-Chaudhury P, Manfro R, Zheng XX, Nickerson PW, Wood K, Bushell A: The Th1/Th2 paradigm and the allograft response. Curr Opin Immunol 8: 688–693, 1996[CrossRef][Medline]
Girndt M, Sester M, Sester U, Kaul H, Kohler H: Molecular aspects of T- and B-cell function in uremia. Kidney Int 59 [Suppl 78]: S206–S211, 2001
Gerli R, Pitzalis C, Bistoni O, Falini B, Costantini V, Russano A, Lunardi C: CD30+ T cells in rheumatoid synovitis: Mechanisms of recruitment and functional role. J Immunol 164: 4399–4407, 2000[Abstract/Free Full Text]
Gerli R, Bistoni O, Lunardi C, Giacomelli R, Tomassini C, Biagini P, Pitzalis C: Soluble CD30 in early rheumatoid arthritis as a predictor of good response to second-line therapy. Rheumatology 38: 1282–1284, 1999[Abstract/Free Full Text]
Weimer R, Zipperle S, Daniel V, Carl S, Staehler G, Opelz G: Pretransplant CD4 helper function and interleukin 10 response predict risk of acute kidney graft rejection. Transplantation 62: 1606–1614, 1996[CrossRef][Medline]
Martinez OM, Villanueva J, Abtahi S, Beatty PR, Esquivel CO, Krams SM: CD30 expression identifies a functional alloreactive human T-lymphocyte subset. Transplantation 65: 1240–1247, 1998[CrossRef][Medline]
Received for publication December 14, 2001.
Accepted for publication February 1, 2002.
This article has been cited by other articles:
C. Sommerer, T. Giese, S. Meuer, and M. Zeier Pharmacodynamic monitoring of calcineurin inhibitor therapy: Is there a clinical benefit?
Nephrol. Dial. Transplant.,
October 15, 2008;
(2008)
gfn556v2.
[Full Text][PDF]
W. Altermann, G. Schlaf, A. Rothhoff, and B. Seliger 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.,
October 1, 2007;
22(10):
2795 - 2799.
[Abstract][Full Text][PDF]
K. M. A. Rouschop, J. J. T. H. Roelofs, A. T. Rowshani, J. C. Leemans, T. van der Poll, I. J. M. ten Berge, J. J. Weening, and S. Florquin Pre-transplant plasma and cellular levels of CD44 correlate with acute renal allograft rejection
Nephrol. Dial. Transplant.,
October 1, 2005;
20(10):
2248 - 2254.
[Abstract][Full Text][PDF]
C. Ponticelli Renal transplantation 2004: where do we stand today?
Nephrol. Dial. Transplant.,
December 1, 2004;
19(12):
2937 - 2947.
[Abstract][Full Text][PDF]
Top
Abstract
Introduction
100 U/ml) was 64 ± 2%, significantly lower than the 75 ± 1% rate in 2998 recipients with low sCD30 (<100 U/ml) (P < 0.0001). High sCD30 was associated primarily with graft loss and not with patient death. The sCD30 effect on graft survival was evident in first transplants as well as in retransplants, in presensitized patients with lymphocytotoxic antibodies as well as in nonsensitized patients, and in patients who received HLA well-matched kidneys as well as in patients who received poorly matched grafts. Recipients with a high pretransplant sCD30 needed significantly more rejection treatment after the first posttransplant year and continued to lose grafts at a higher rate during the 5-yr follow-up period, indicating that pretransplant sCD30 predicts not only the risk of acute rejection but also of chronic allograft nephropathy. 
2, receiver operating characteristics, and multivariate Cox regression were used for statistical analyses. 
(INF-
