Causes and prognostic value of pre-transplant elevated kynurenine level in kidney allograft recipients.

BACKGROUND: The activation of the tryptophane catabolizing enzyme Indoleamine 2,3-dioxygenase leads to the formation of kynurenine and other metabolites that counter-regulate immune activation resulting in restoration of immune homeostasis. But in chronic immune activation, as in hemodialysed patients, the immunosuppressive feedback mechanisms continue as indicated by elevated kynurenine concentrations. However, its relevance is still a matter of debate. MATERIAL/METHODS: This retrospective analysis presents the pre-transplant kynurenine levels (quantified photometrically) of 307 kidney graft recipients in connection with some pre- and post-transplant variables and the type of immunosuppression (cyclosporine-based triple drug therapy without/with ATG-Fresenius-induction). Statistical analyses performed were analysis of variance, Scheffé's test for pairwise comparisons, Cox regression, Spearman's rank correlation, and extended segmentation analysis. RESULTS: The pre-transplant kynurenine level was significantly elevated as compared to healthy adults (14.1±5.9 vs. 2.7±0.6 nmol/ml, p<0.0001), significantly higher in PRA positive than in PRA negative patients (16.1 vs. 12.9 nmol/ml, p<0.001) and, supporting this observation, also higher (p<0.0001) in a cohort with predominant (89.7%) pre-sensitized patients (16.4±6.4 nmol/ml) having the longest time on the waiting list (median 39 months) as compared to cohorts with fewer (16.8-22%) pre-sensitized patients (12.7±4.4 resp. 13.4±5.8 nmol/ml) having shorter times on the waiting list (16-24 months). Patients with immediately functioning grafts showed a lower pre-transplant kynurenine level than patients with non-immediately functioning grafts (13.5±6.0 vs. 14.9±5.7 nmol/ml, p=0.053). No associations were found with basic diseases, rejections, or graft survival. CONCLUSIONS: The pre-transplant elevated serum kynurenine levels were highly associated with the patient's pre-sensitization status and their longer time on hemodialysis treatments, but did not allow prognostic assessments.

High graft protection and low incidences of infections, malignancies and other adverse effects with intra-operative high dose ATG-induction: a single centre cohort study of 760 cases.

BACKGROUND: In 1990 we introduced the intra-operative single high-dose induction (HDI) with ATG-Fresenius as a novel renal sparing concept. The aim of this analysis was to compare both the long-term patient and graft survival and the incidences of adverse effects in recipients treated with standard triple-drug therapy (TDT) alone or with an additional HDI with ATG-F. MATERIAL AND METHODS: A total of 760 renal transplant recipients receiving either TDT, consisting of steroids, azathioprine and cyclosporine (n=238) or TDT + 9mg/kg ATG-F intra-operatively (n=522) were included in this retrospective analysis. RESULTS: Compared to the TDT cohort the graft and patient survival over the entire ten year period was significantly prolonged in the TDT+HDI cohort. In contrast, main adverse effects (TDT+HDI vs. TDT) such as malignancies (4.4 vs. 2.1%), PTLD (0.4 vs. 0.4%), CMV diseases (18.6 vs. 15.5%), Herpes zoster infections (2.9 vs. 1.3%), bacterial pneumonias (3.1 vs. 1.3%) and post-operative thrombocytopenia <50×10³/µl (0.5 vs. 1.3%) did not significantly differ between the two immunosuppressive regimens. Only CMV-IgM seroconversions occurred significantly more in the HDI cohort (39.3 vs. 23.5%). The absolute numbers of CD3, CD4 and CD8 cell counts were significantly reduced in TDT+ATG-F HDI cohort only over a time period of about five days. CONCLUSIONS: This world-wide largest single-centre cohort analysis clearly shows the superiority of the HDI with ATG-F compared to TDT alone in improving long-term graft survival without increasing the risk for infections, malignancies or other adverse effects.

Factors impacting short and long-term kidney graft survival: modification by single intra-operative -high-dose induction with ATG-Fresenius.

BACKGROUND: A majority of recipients benefited from the intra-operative single high-dose induction (HDI) with ATG-Fresenius (ATG-F) still leaving a group of recipients who did not profit from this kind of induction. Therefore the aim of this retrospective analysis was 1st to identify the risk factors impacting short and long-term graft survival, and 2nd to assess the efficacy of this type of induction in kidney graft recipients with or without these risk factors. MATERIAL/METHODS: A total of 606 recipients receiving two different immunosuppressive treatment regimens (1st: Triple drug therapy [TDT, n=196] consisting mainly of steroids, azathioprine and cyclosporine; 2nd: TDT + 9 mg/kg ATG-F intra-operatively [HDI, n=410]) were included in this analysis and grouped according to their kidney graft survival time (short GST: ≤1 yr, n=100 and long GST: >5 yrs, n=506). RESULTS: The main risk factors associated with a shortened graft survival were pre-transplant sensitization, re-transplantation, rejections (in particular vascular or mixed ones) and the necessity of a long-term anti-rejection therapy. Adding ATG-F single high dose induction to TDT was more efficient in prolonging kidney graft survival than TDT alone not only in recipients without any risk factors (p<0.005) but also in recipients with at least one risk factor (p<0.021). Only in 4.6% of recipients having two or more risk factors this effect could not be demonstrated. CONCLUSIONS: The intra-operative single high-dose induction with ATG-F significantly improves the kidney graft survival in recipients with or without risk factors and can therefore be recommended.

Improved long-term survival after intra-operative single high-dose ATG-Fresenius induction in renal transplantation: a single centre experience.

BACKGROUND: In organ grafts donor-specific sensitization is initiated immediately after revascularization. Therefore, in 1990 we introduced the intra-operative single high-dose ATG-Fresenius (ATG-F) induction in addition to standard triple drug therapy (TDT) consisting of steroids, azathioprine and cyclosporin. A total of 778 first renal transplantations from deceased donors, performed between 1987 and 1998, were included in this evaluation. MATERIAL/METHODS: This retrospective analysis of clinic records and electronic databases presents data of all recipients of first kidney grafts who received two different ATG-F inductions (1(st) group: 9 mg/kg body weight as single high-dose intra-operatively, n=484; 2(nd) group: 3 mg/kg body weight on 7 or 8 consecutive days as multiple-dose starting also intra-operatively, n=78) and standard TDT alone (3(rd) group: TDT alone, n=216). RESULTS: The 10-year patient survival rates were 72.6+/-2.6% (TDT + ATG-F single high-dose), 79.5+/-5.1% (TDT + ATG-F multiple-dose) and 67.2+/-3.7%% (TDT alone; Kaplan-Meier estimates with standard errors; ATG-F vs TDT alone, p=0.001). The 10-year graft survival rates with censoring of patients that died with a functioning graft were 73.8+/-2.4%, 57.7+/-5.8% and 58.4+/-3.6% (Kaplan-Meier estimates with standard errors; 1(st) vs 2(nd )and 3(rd) group, respectively, p<0.001) and the 10-year graft survival rates with patient death counted as graft failure were 58.3+/-2.7%, 55.7+/-5.8% and 48.2+/-3.5% (Kaplan-Meier estimates with standard errors; ATG-F single high-dose vs TDT, p=0.023). In pre-sensitized recipients there were also significant differences in favour of ATG-F, more notably in the single high-dose ATG-F induction. A total of 69% of the patients in the two cohorts receiving ATG-F did not experience any transplant rejections compared to 56% in patients undergoing TDT alone (p=0.018). The incidence of infectious complications was comparable across all groups. CONCLUSIONS: According to evidence obtained from the routine documentation of 778 renal transplantations, ATG-F induction therapy administered as a part of immunosuppressive therapy significantly improves patient survival and reduces the risk of graft failure and transplant rejections.

Are heart valves from donors over 65 years of age morphologically suitable for transplantation?

Since there is no upper age limit for general organ donation, unlike heart valve donation, and since a quarter of all organ donors are 65 years and older, we examined whether the heart valves from these donors are suitable as allografts. In the period 1999-2004 the aortic valve and pulmonary valve of 100 organ donors above 65 years of age were examined to establish whether they would have been suitable as valve grafts. To compare the valve grafts above and below the age limit of 65 years, we used data on the aortic and pulmonary valves of 380 organ donors below the age limit in the same time period. Examination of the 200 heart valves showed that - just like valves from donors below the age limit - 100 of them would have met the medical quality standards for transplantation, which discriminate among optimal, suitable and unsuitable tissue morphology. The morphological suitability of the aortic valves decreases rapidly during the 4th decade of life and near to the age limit only 6% of them are accepted as grafts. The rate of potentially acceptable aortic valve grafts from organ donors aged over 65 years of 15% is also small. By contrast, the pulmonary valves are not affected by age-related tissue changes that might reduce their transplantability. The predominant majority (85%) of potential pulmonary valve grafts from organ donors over 65 years of age fulfilled the acceptance criteria, half of them (48%) even showing good tissue quality. In light of these results the age limit was raised to 70 years in 2005.

How large is the organ donor potential in Germany? Results of an analysis of data collected on deceased with primary and secondary brain damage in intensive care unit from 2002 to 2005.

The number of potential organ donors depends on various factors, among which the number of deceased with primary or secondary brain damage is the most decisive. In the north-east donor region of Germany with 7.69 million inhabitants, 2019 cases of deceased with primary or secondary brain damage were reported by 136 intensive care units during 2002-2005. In a study, 64% of these deceased were identified as potential donors. This represents 40.7 potential donors per million inhabitants. It can be concluded that in the other donor regions of Germany a comparable number of potential donors exists, yet not all possible donors are being detected and referred. The conversion rate (percentage of potential donors who become effective donors) in the years 2002-2005 was 47%. The main reason for the conversion rate being so low was the large number of relatives who declined an organ donation (73%). More than 90% of the relatives in the north-east region did not know the deceased's will in the acute situation. From our point of view the high refusal rate can be decreased mainly by two measures: improvement of the family approach and integrating the topic of organ donation into schools' curricula.