Lutz Fritsche

Predictors of Success in Conversion from Calcineurin Inhibitor to Sirolimus in Chronic Allograft Dysfunction

Chronic allograft dysfunction (CAD) is a major cause of graft loss in long‐term kidney transplant recipients. To identify predictors of successful conversion from calcineurin inhibitor (CNI) to sirolimus (SRL) we investigated 59 renal transplant patients with CAD without histological signs of acute rejection. They received 12–15 mg SRL once, then 4–5 mg/day, target trough level 8–12 ng/mL. CNI dose was reduced by 50% simultaneously, and withdrawn at 1–2 months. Concomitant immunosuppression remained unchanged. After 1 year patient survival was 100% and graft survival 92%. In responders (54%) creatinine improved (2.75 ± 0.75 to 2.22 ± 0.64 mg/dL; p < 0.01). In nonresponders (46%) creatinine deteriorated (3.15 ± 1.02 to 4.44 ± 1.60 mg/dL; p < 0.01). Baseline renal function did not differ, however, baseline proteinuria (519 ± 516 vs. 1532 ± 867 mg/day, p < 0.01), histological grade of chronic allograft nephropathy (CAN) (1.2 ± 0.5 vs. 1.9 ± 0.6; p < 0.01), grade of vascular fibrous intimal thickening (1.2 ± 0.7 vs. 1.7 ± 0.7; p = 0.048) and number of acute rejections before conversion (0.73 ± 0.69 vs. 1.27 ± 0.96; p < 0.05) differed significantly between responders and nonresponders. In a multivariate analysis low proteinuria was the only independent variable. Proteinuria below 800 mg/day has a positive predictive value of 90%. Proteinuria at conversion below 800 mg/day is the only independent predictor for positive outcome in conversion from CNI to SRL in CAD.

Do short courses in evidence based medicine improve knowledge and skills? Validation of Berlin questionnaire and before and after study of courses in evidence based medicine

Abstract Objective: To develop and validate an instrument for measuring knowledge and skills in evidence based medicine and to investigate whether short courses in evidence based medicine lead to a meaningful increase in knowledge and skills. Design: Development and validation of an assessment instrument and before and after study. Setting: Various postgraduate short courses in evidence based medicine in Germany. Participants: The instrument was validated with experts in evidence based medicine, postgraduate doctors, and medical students. The effect of courses was assessed by postgraduate doctors from medical and surgical backgrounds. Intervention: Intensive 3 day courses in evidence based medicine delivered through tutor facilitated small groups. Main outcome measure: Increase in knowledge and skills. Results: The questionnaire distinguished reliably between groups with different expertise in evidence based medicine. Experts attained a threefold higher average score than students. Postgraduates who had not attended a course performed better than students but significantly worse than experts. Knowledge and skills in evidence based medicine increased after the course by 57% (mean score before course 6.3 (SD 2.9) v 9.9 (SD 2.8), P<0.001). No difference was found among experts or students in absence of an intervention. Conclusions: The instrument reliably assessed knowledge and skills in evidence based medicine. An intensive 3 day course in evidence based medicine led to a significant increase in knowledge and skills.

Pre-transplant inosine monophosphate dehydrogenase activity is associated with clinical outcome after renal transplantation.

Mycophenolate mofetil (MMF), an inhibitor of inosine monophosphate dehydrogenase (IMPDH) activity, is usually administered as a standard dose of 1 g b.i.d. after renal transplantation. Because MMF dose reductions are associated with inferior outcome, we investigated pre‐transplant IMPDH activity, MMF dose reductions and outcome. IMPDH activity was determined in isolated peripheral mononuclear cells immediately prior to renal transplantation. We observed considerable inter‐individual variability in pre‐transplant IMPDH activity (9.35 ± 4.22 nmol/mg/h). Thirty of 48 patients (62.5%) with standard MMF dose (1 g b.i.d.) had dose reductions within 3 years post‐transplant; these patients also had significantly lower IMPDH activity. The area under the receiver‐operating characteristics curve (AUC‐ROC) for prediction of dose reduction within 6 months post‐transplant was 0.75 (95% CI, 0.61–0.89; p < 0.004). IMPDH activity above the cut‐off value, MMF dose reduction and age of recipient were significant contributors for the occurrence of acute rejection in the multivariate logistic regression. Patients with high IMPDH activity and MMF dose reduction had the highest rejection rate (81.8% vs. 36.4%; p < 0.01). Conclusion: Patients with low IMPDH activity experienced more complications of MMF therapy. High pre‐transplant IMPDH activity and MMF dose reductions were associated with rejection. Determination of IMPDH activity prior to transplantation may help to improve MMF therapy after renal transplantation.

Old-for-Old Kidney Allocation Allows Successful Expansion of the Donor and Recipient Pool

Allocation of kidneys from donors older than 64 years to recipients older than 64 years was started in 1999 to improve use of older donor kidneys. Kidneys are allocated locally without HLA‐matching to keep cold ischemia short.

Age and immune response in organ transplantation.

The immune system undergoes a complex and continuous remodeling as the result of aging. These changes have a major impact on allorecognition and alloresponse. In addition, immunosuppression in the elderly is challenging as a consequence of an increased incidence of associated comorbidities and altered pharmacokinetics. Both advanced donor and recipient age should be considered independent risk factors for poor patient and graft survival rates, albeit acting in a synergistic manner. Consequently, modifications of the immune system because of aging may request an age-adapted allocation and immunosuppression in parallel with close patient monitoring. Interventions to selectively target changes associated with the senescence process seem to be promising therapeutic strategies to improve transplantation outcome. Here, we are going to review the immunologic changes associated with the aging process relevant for transplantation and their impact on immunosuppressive protocols, organ allocation policies, and transplantation outcome.

Quality of life of living kidney donors in Germany: a survey with the Validated Short Form-36 and Giessen Subjective Complaints List-24 questionnaires.

Background. Most studies evaluating the impact of kidney donation on donors’ quality of life (QOL) have limitations such as small cohort size, unmatched references, use of nonstandardized and nonvalidated questionnaires, or low response rates. Methods. We performed a study on donors’ QOL that was designed to avoid these limitations. All available living renal donors in our department in the last 18 years were included in the study. QOL was assessed with two validated, standardized questionnaires (Short Form-36, Giessen Subjective Complaints List [Giessener Beschwerdebogen]-24) and compared with gender- and age-matched references. In addition, specific questions relating to kidney donation were asked. Results. The response rate (89.8%) is one of the highest reported for studies on QOL of living kidney donors. Most donors had an equal or better QOL than the healthy population. Donors’ willingness to donate again (93.4%) or recommend living-donor kidney transplantation (92.4%) was high, irrespective of complications. A small number of donors experienced financial drawbacks or occupational disadvantages. Donors aged 31 to 40 years were found to be at risk of QOL deterioration after organ donation. Donor and recipient complications had a significant impact on donors’ QOL. One third of the donors found that the psychologic care preceding and after kidney donation was insufficient. Conclusions. Our findings support the practice of living-donor kidney transplantation as a good means to meet the persisting organ shortage. Further effort must be put into minimizing donor and recipient complications. The specific demands of younger donors should be further elucidated. In addition to medical follow-up, living kidney donors should also be offered lifelong psychologic counseling.

Testosterone concentrations and sirolimus in male renal transplant patients.

Sirolimus damages the testes in animals; however, human data are sparse. We conducted a case‐control study to obtain further insight into this issue and compared testosterone, follicle‐stimulating hormone (FSH), luteinizing hormone (LH), and prolactin concentrations in matched renal transplant patients who did or did not receive sirolimus. We found that testosterone values were lower (11.2 ± 6.3 nmol/L vs. 15.5 ± 7.7 nmol/L, p < 0.05), in 28 sirolimus‐treated patients, compared to 28 non‐sirolimus‐treated controls. Furthermore, these patients more commonly had testosterone concentrations that were below our reference value for normal men. In contrast, FSH and LH concentrations were higher while prolactin levels were not different. These data are consistent with sirolimus‐related testosterone suppression and suggest a need for further studies.

Estimated one-year glomerular filtration rate is the best predictor of long-term graft function following renal transplant

Background. Long-term success of renal transplantation depends upon the quality of the donor organ, avoidance of peritransplant and early posttransplant damage (rejection), and optimal maintenance of graft function after the first 6–12 months. Glomerular filtration rate (GFR) at 1 year is a standard way to evaluate short-term success, whereas calculated GFR at 5 years gives a better appreciation of long-term outcomes. The objective of this study was to assess the effect of various demographic and transplant-related parameters on renal function via GFR at 1 year and 5 years post transplantation, using univariate and multivariate data analysis. Methods. Data on 1-year GFR were available from 10,397 patients, whereas 2,889 patients provided data on both 1-year and 5-year GFR. All patients were enrolled in the Neoral Multinational Observational Study in Transplantation (Neoral-MOST), an ongoing, prospective, observational study of adult renal transplant recipients. Results. One-year GFR was the most relevant predictor for 5-year GFR. In a multifactorial analysis (ANCOVA) using 1-year GFR as a continuous variable, the effects of several highly relevant parameters from univariate analysis (such as acute rejection and delayed graft function) on 5-year GFR appeared to be fully mediated by their influence on 1-year GFR, whereas immunological risk factors like HLA match or previous transplantation had an ongoing effect on graft function beyond year 1. Conclusions. The findings of this study corroborate and augment data from previous registry surveys, and confirm the importance of observational studies in investigating the role of peritransplant parameters on long-term graft outcome.

Pharmacodynamic monitoring of mycophenolate mofetil.

Abstract The immunosuppressive activity of Mycophenolate Mofetil (MMF) is based on the reversible inhibition of inosine-5′-monophosphate dehydrogenase (IMPDH) by mycophenolic acid. Pharmacodynamic monitoring by measurement of IMPDH activity reflects directly the biological response to MMF. For measurement of IMPDH activity in peripheral mononuclear cells we established a modified non-radioactive procedure, based on the incubation of cell lysates with inosine-5′-monophosphate and the chromatographic quantification of produced xanthosine-5′-monophosphate by isocratic ion-pair reversed phase HPLC. The between-run precision and within-run precision were 7% and 5%, respectively. We determined the time course of IMPDH activity in five patients after 1g MMF and in five healthy subjects without administration of MMF. Additionally, IMPDH activity was determined in a population study of 40 healthy volunteers. In healthy volunteers, we observed a wide range of IMPDH activity (4.7–32.9 nmol/h/mg) with only weak diurnal variation. All patients receiving MMF had a significant reduction of IMPDH activity (65–100%) after administration of the drug. Inhibition persisted for up to 6 hours, and after 11 hours IMPDH activity returned to predose activities. The interindividual variability of IMPDH activity may account for pharmacodynamic differences in MMF-treated patients. Based on pharmacodynamic monitoring better dosing strategies for MMF-treated patients may evolve.

Weight gain in long-term survivors of kidney or liver transplantation—Another paradigm of sarcopenic obesity?

OBJECTIVE Obesity in transplant recipients is a frequent phenomenon but data from body composition analyses in long-term survivors are limited. Body composition and energy metabolism were studied in patients after liver (LTX) and kidney (KTX) transplantation and patients with liver cirrhosis (LCI) or on chronic hemodialysis (HD) and compared to healthy controls. METHODS In 42 patients 50.0 mo (median; range 17.1-100.6) after LTX and 30 patients 93.0 mo (31.2-180.1) after KTX as wells as in LCI (n = 39) or HD (n = 10) patients mid-arm muscle and fat area, body cell mass, and phase angle (bioimpedance analysis), and resting energy expenditure (indirect calorimetry, REE(CALO)) were measured. RESULTS Obesity was more prevalent in LTX (17%) than LCI (3%) and in KTX (27%) than in HD (10%). In LTX and KTX, phase angle was higher than in end-stage disease (LTX 5.6° [4.1-7.2] versus LCI 4.4° [2.9-7.3], P < 0.001; KTX 5.9° [4.4-8.7] versus HD 4.3° [2.9-6.8]) but was lower in all patient groups than in controls (7.1°; 4.6-8.9; P < 0.001). In LCI and HD REE(CALO) was higher than predicted, while in LTX and KTX REE(CALO) was not different from predicted REE. CONCLUSIONS Despite excellent graft function, many long-term LTX or KTX survivors exhibit a phenotype of sarcopenic obesity with increased fat but low muscle mass. This abnormal body composition is observed despite normalization of the hypermetabolism found in chronic disease and cannot be explained by overeating. The role of appropriate nutrition and physiotherapy after transplantation merits further investigation.