W. Ernst

Post‐Transplant sCD30 and Neopterin as Predictors of Chronic Allograft Nephropathy: Impact of Different Immunosuppressive Regimens

Immunological monitoring for chronic allograft nephropathy (CAN) is of great potential interest. We assessed serum soluble CD30 (sCD30) together with in vitro Th2‐type responses (IL‐4, IL‐10, CD4 helper activity) and neopterin in a prospective study of 84 renal transplant recipients with 2‐year follow‐up. Patients were randomized to CsA/Aza, CsA/MMF and Tacr/Aza, respectively, to analyze the effect of immunosuppression on posttransplant sCD30 and neopterin. ATG induction and acute rejections did not alter sCD30 levels whereas CMV disease was associated with transient upregulation of sCD30 (p = 0.003 at 4 months) and sustained upregulation of neopterin (corrected for graft function (Neo/CR) p = 0.005 at 2 years). Tacr versus CsA treatment proved to be an independent variable associated with downregulation of 1‐year sCD30, which was positively related to Neo/CR (p = 0.007 and 0.01, respectively; logistic regression). Importantly, increased 1‐year sCD30 and Neo/CR were associated with decreased glomerular filtration rate at 2 years (p = 0.02 and p < 0.0005, respectively) and evidence of CAN (p < 0.0005). High 1‐year sCD30 could not be attributed to enhanced Th2‐type responses and was not associated with HLA antibody formation. Our data suggest that elevated sCD30 and neopterin predict graft deterioration by CAN. Tacr effectively downregulates these responses and might be of advantage in patients with elevated sCD30 or neopterin.

ATG induction therapy: long‐term effects on Th1 but not on Th2 responses

Antithymocyte globulin (ATG) induction therapy is associated with an increased long‐term risk of infection‐ and cancer‐related death. To analyze long‐term effects of ATG induction on lymphocyte function, we prospectively assessed CD4 helper function, B‐cell/monocyte and cytokine responses in 84 renal transplant recipients (ATG, n = 44) up to 1 year post‐transplant. A PWM‐driven allogeneic coculture system was used to assess helper function of CD4+ T cells and T‐cell‐dependent B‐cell responses. SAC I was used for T‐cell‐independent stimulation of B‐cell cultures. In vitro cytokine secretion and serum soluble CD30 (sCD30) were determined by enzyme‐linked immunosorbent assay (ELISA). ATG induced a persistent decrease of peripheral blood lymphocyte counts compared with non‐ATG treatment because of a predominant decrease of CD4+ T cells (4 months, 1 year; P < 0.0005) which was associated with a decreased CD28 expression (1 year, P = 0.02) and CD4 cell interleukin 2 (IL‐2) response (4 months, P < 0.0005). However, Th2 responses (CD4 help, CD4 cell IL‐4 and IL‐10 responses, sCD30), which proved to be predictive of graft outcome, were not affected, and neither was the secretion of the lymphoma growth factors IL‐6 and IL‐10 by B cells and monocytes. Our data show that ATG induction therapy in immunological high‐risk patients induces a profound long‐term decrease in cell counts and Th1 but not Th2 responses of CD4+ T cells which may explain long‐term effects on infection and post‐transplant lymphoproliferative disease (PTLD) incidence because of inadequate T‐cell control.

Impact of maintenance immunosuppressive regimens – balance between graft protective suppression of immune functions and a near physiological immune response

The Symphony study showed superior 1‐year kidney graft outcome in patients on immunosuppression with tacrolimus/mycophenolate mofetil (Tacr/MMF). To analyze whether differences in clinical outcome between maintenance regimens may be explained by their impact on clinically relevant immune parameters, we assessed CD4 helper activity, immunoglobulin‐secreting cell (ISC) formation, neopterin, sCD30, and intracellular cytokine production in a prospective study in 77 renal transplant recipients treated with cyclosporine A/azathioprine (CsA/Aza), CsA/MMF, Tacr/Aza or Tacr/MMF at 2 years post‐transplant. Tacr‐ compared with CsA‐based immunosuppression was independently associated with increased IL‐2 (P < 0.0001, CD4 cells; P = 0.014, CD8 cells) and CD4 cell IL‐4 responses (P = 0.046; stepwise logistic regression) resulting in physiological responses in Tacr/Aza patients as compared with 25 healthy controls. MMF versus Aza treatment was proven to be an independent variable associated with suppression of CD4 cell IL‐10 responses (P = 0.008), B‐cell IL‐6R expression (P < 0.0001) and ISC formation [P = 0.020, staphylococcus cowan strain I (SAC I); P = 0.021, pokeweed mitogen (PWM)]. Our data suggest that Tacr/MMF had the most effective impact on graft protective Th2 responses (enhanced CD4 cell IL‐4 by Tacr, decreased CD4 cell IL‐10 responses by MMF) and suppression of B‐cell functions (MMF), whereas Tacr/Aza was associated with physiological IL‐2 and IL‐4 and stronger humoral responses which may reduce the risk of infectious disease complications.

One hundred six live kidney donors in a single German transplantation center: renal, physical, and psychological follow-up.

OBJECTIVE The objective of this study was to analyze the psychological and physical status as well as renal outcomes of 106 live kidney donors between 1993 and 2003. METHODS We performed general and nephrological examinations, including measurements of creatinine clearance (ClCr), proteinuria, and 24-hour blood pressure monitoring. We evaluated the psychological and general health situation using the standardized SF-36 questionnaire. RESULTS We evaluated 69/106 (65%) live kidney donors at 5.3 ± 0.4 years after donation. The reason for the 37 drop-outs were unknown current address (n = 21), refusal of study participation (n = 14), and death due to accident and suicide (n = 2). In the 69 donors renal function was well preserved: serum creatinine 1.3 ± 0.0 mg/dL; ClCr 81 ± 2 mL/min; postdonation to predonation ClCr ratio 0.73 ± 0.02; and proteinuria 104 ± 11 mg/d. None of the donors experienced renal failure, although 36/69 (52%) patients have developed de novo hypertension. Compared with normotensive donors, the hypertensive subgroup was significantly older at the time of donation (50.7 ± 1.4 vs 46.4 ± 1.6 years; P = .010) and had a longer interval since donation (6.4 ± 0.2 vs 3.9 ± 0.1 years; P = .001). SF-36 questionnaire results in live kidney donors showed higher scores regarding physical (54.3 ± 0.8 vs 49.3 ± 0.1; P = .048) and psychological health (53.8 ± 0.6 vs 50.7 ± 0.1; P = .043) compared with the average German population. CONCLUSION Our cohort of live kidney donors showed good renal outcomes and superior SF-36 scores in both physical and psychological health compared with the German population. The risk of de novo hypertension increased with age and time after donation. Blood pressure screening should be regularly performed especially in the long term after donation.

IMPACT OF MAINTENANCE IMMUNOSUPPRESSIVE REGIMENS ON THE IMMUNE RESPONSE OF RENAL TRANSPLANT RECIPIENTS - BALANCE BETWEEN GRAFT PROTECTIVE SUPPRESSION OF IMMUNE FUNCTIONS AND A NEAR PHYSIOLOGICAL IMMUNE RESPONSE: 1007

R. Weimer1, S. Deisz2, F.C. Renner1, H. Dietrich2, V. Daniel3, S. Kamali-Ernst4, W. Ernst5, W. Padberg6, G. Opelz3 1Nephrology, University Clinic Giessen, Giessen/GERMANY, 2Department Of Internal Medicine, University of Giessen, Giessen/ GERMANY, 3Institute Of Immunology, University of Heidelberg, Heidelberg/GERMANY, 4, Dialysis Center, Wetzlar/GERMANY, 5, Dialysis Center, Langenselbold/GERMANY, 6Abdominal Surgery, University Clinic Giessen, Giessen/GERMANY