Renal Function and Patient-Reported Outcomes in Stable Kidney Transplant Patients Following Conversion From Twice-Daily Immediate-Release Tacrolimus to Once-Daily Prolonged-Release Tacrolimus: A 12-Month Observational Study in Routine Clinical Practice in Germany (ADAGIO).

INTRODUCTION: This 12-month, noninterventional study on routine clinical practice in Germany evaluated renal function in stable kidney transplant recipients converted from immediate-release tacrolimus (IR-T) to prolonged-release tacrolimus (PR-T). METHODS: Renal function was assessed in 183 patients by estimated glomerular filtration rate using the modification of diet in renal disease-4 formula. Self-reported gastrointestinal health-related quality of life, adherence, satisfaction with PR-T, suspected rejection episodes, and safety were also assessed at conversion and at 3, 6, and 12 months. RESULTS: Conversion from IR-T to PR-T resulted in stable kidney function over 12 months, with a difference in estimated glomerular filtration rate between the first and final visits of 0.1 mL/min/1.73 m2 (95% confidence interval, -1.6, 1.8). Eight patients experienced an acute rejection episode (4.4%). At each assessment, gastrointestinal health-related quality of life was low and adherence was high. Most patients reported that they were very satisfied (69.8%) or satisfied (28.1%) with PR-T at the final visit. Among patients reporting a preference, 78.4% preferred PR-T, 2.2% preferred IR-T, and 19.4% reported no preference. The safety profile of PR-T was consistent with that previously described. CONCLUSION: Conversion of stable kidney transplant recipients from IR-T to PR-T provided stable kidney and graft function over 12 months (Verband Forschender Arzneimittelhersteller--registered study: NIS ADV-02).

Association of circulating interleukin (IL)-12- and IL-10-producing dendritic cells with time posttransplant, dose of immunosuppression, and plasma cytokines in renal-transplant recipients.

BACKGROUND: Interleukin (IL)-12-producing dendritic cells (IL-12+DC) polarize T helper (Th) differentiation toward Th1, whereas IL-10+DC induce Th differentiation toward Th2. We investigated DC and plasma cytokine patterns early and late after transplantation. METHODS: Twenty-five hospitalized renal-transplant recipients without acute rejection or infection early (<40 days) posttransplant, 32 symptom-free outpatients with long-term functioning transplants (2,762+/-2,423 days posttransplant), and 17 healthy controls were studied. The intracellular production of IL-12 and IL-10 in CD11c+ CD83+ CD40+ DC was measured in freshly obtained whole blood using four-color fluorescence flow cytometry. In addition, plasma cytokine levels were investigated. RESULTS: Early and late posttransplant patients had significantly lower proportions of IL-12+DC (early: P=0.001; late: P=0.034) and lower ratios of IL-12+/IL-10+DC (early: P=0.0001; late: P<0.0001) than healthy controls. IL-10+DC (P=0.0004) and IL-12+DC (P=0.002) increased with time posttransplant in association with dose reductions of cyclosporine (IL-10+DC: P=0.003; IL-12+DC: P=0.005), methylprednisolone (IL-10+DC: P<0.0001; IL-12+DC: P=0.001) and mycophenolate mofetil (IL-10+DC: P<0.0001; IL-12+DC: P=0.004). Both IL-10+DC and IL-12+DC were associated with low plasma IL-10 (IL-10+DC: P=0.010; IL-12+DC: P=0.011) and high plasma IL-6 (IL-10+DC: P=0.001; IL-12+DC: P=0.009). IL-10+DC were also associated with high plasma levels of IL-3 (P=0.003), interferon (IFN)-gamma (P=0.014), and IL-2 (P=0.058). CONCLUSION: IL-10+DC and IL-12+DC in peripheral blood are associated with time after transplantation and dosage of immunosuppression. IL-10+DC dominate late posttransplant in the presence of Th1 plasma cytokines (high IFN-gamma and IL-2), high IL-3, and low IL-10. These findings could be a reflection of immunoregulatory processes favoring long-term allograft acceptance.

Strong inflammatory cytokine response in male and strong anti-inflammatory response in female kidney transplant recipients with urinary tract infection.

Urinary tract infection (UTI) is the most common post-transplant infection in renal transplant recipients. The relationship of plasma and urine cytokines with UTI after kidney transplantation has not yet been delineated and literature reports on cytokine and UTI are rare. In a retrospective study, we compared post-transplant plasma and urine cytokine levels of 132 outpatient renal transplant recipients with or without UTI. Soluble interleukin-1 receptor antagonist (sIL-1RA), IL-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-8, IL-10, transforming growth factor-beta2 (TGF-beta2), interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) levels were determined using commercially available enzyme-linked immunosorbent assay (ELISA) kits. We found gender-related urine cytokine patterns. Anti-inflammatory sIL-1RA was significantly higher in females than in males and this gender-related difference was more pronounced in bacteriuric (P < 0.0001) than in nonbacteriuric (P = 0.001) patients. Urine proinflammatory cytokines IL-6 (P = 0.001) and IL-8 (P = 0.007) were significantly higher in male patients with bacteriuria than in males without bacteriuria and sIL-2R (P = 0.001) and sIL-6R (P = 0.03) were significantly higher in males with leukocyturia than in males without leukocyturia. Bacteriuria in males was associated with higher doses of immunosuppressive drugs (P = 0.02). Male renal transplant recipients with UTI have a strong inflammatory cytokine response with activation of IL-6, IL-8, sIL-2R and sIL-6R producing cells, whereas female patients with UTI block the inflammatory response to UTI by production of sIL-1RA.

High urine sIL-6R as a predictor of late graft failure in renal transplant recipients.

BACKGROUND: Chronic allograft nephropathy is an important cause of late renal transplant failure. Although numerous studies on cytokines have been carried out, the pathogenetic role of cytokines in chronic renal allograft nephropathy remains unclear. METHODS: In a retrospective study, the authors compared posttransplant plasma and urine cytokine levels (interleukin [IL]-1alpha, IL-1beta, soluble [s] IL-1 receptor [R] antagonist [A], IL-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-10, tumor necrosis factor-alpha, transforming growth factor-beta2, and interferon-gamma) in 34 matched pairs of patients with or without late graft failure and in 50 matched pairs with either normal or increased serum creatinine levels and continued stable graft function. RESULTS: Twelve and 6 months before late graft failure, urine levels of sIL-6R were significantly increased (P=0.003 and P=0.01, respectively). Serum creatinine levels were not associated with increased urine sIL-6R. CONCLUSION: High urine sIL-6R appears to be predictive of late graft failure in renal transplant recipients.

Assessment of renal graft function by perioperative monitoring of cortical microcirculation in kidney transplantation.

BACKGROUND: We evaluated the significance of perioperative cortical microperfusion for graft function and long-term prognosis after renal allotransplantation. Thermodiffusion technology was clinically applied for the first time, after previous validation for perfusion monitoring of the renal cortex in pigs. METHODS: A thermodiffusion probe was inserted into the renal cortex in 30 transplant recipients after graft reperfusion. Real-time measurements were recorded until the end of the operation. In 14 patients perfusion was measured daily until postoperative day 7. Microcirculation was correlated to serum creatinine level, scintigraphic findings, and long-term outcome. RESULTS: In primary graft function, intraoperative perfusion was 85+/-7 mL/100 g per min compared with significantly lower values in cases with subsequent graft dysfunction. The best discrimination was defined for a level of 70 mL/100 g per min with a positive predictive value of 88% for detection of good graft function and 86% for nonfunction. Intraoperative perfusion was significantly different in patients with normal grafts, delayed function, and graft loss. Postoperatively, lower perfusion was found in acute tubular necrosis; a significant correlation could be noted between microcirculation and perfusion index measured by nuclear scanning (r=0.78, P<0.01). Living-related grafts were characterized by higher intraoperative perfusion and superior graft quality. CONCLUSION: Thermodiffusion could be clinically applicable for the perioperative monitoring of renal graft perfusion. Intraoperative reduction of cortical microcirculation has a high predictive value with respect to detection of delayed renal function. Postoperatively, impaired renal microperfusion is associated with acute tubular necrosis. Living-related donor grafts show less microcirculatory alteration than cadaveric kidneys.