Nodular B-cell aggregates associated with treatment refractory renal transplant rejection resolved by rituximab.

Acute rejection episodes leading to treatment refractory early graft loss are increasingly rare events in living related renal transplantation today. Pathophysiologic pathways often remain unsolved. We report on tubulointerstitial and vascular rejection developing within 2 weeks after transplantation in a 12-year-old boy treated with cyclosporine, mycophenolate, steroids and double blinded basiliximab. Despite steroid pulses, switch to tacrolimus and ATG serum creatinine peaked at 347 micromol/L with imminent graft loss and ongoing C4d negative cellular vascular rejection. Permanent gain of function was only achieved after a single dose of rituximab. Retrospectively CD20+ nodular B-cell aggregates could be demonstrated in all three biopsies obtained prior to rituximab and resolved concomitantly with functional improvement. Our case for the first time demonstrates resolution of nodular CD20+ infiltrates and decline of OX40, NF-kappaB and CTL transcription shortly after rituximab indicating a B-cell facilitated C4d negative pathway. Single dose rituximab may effectively reverse even long-lasting refractory rejection.

Alterations of cyclosporin A metabolism induced by mycophenolate mofetil.

Unexpectedly lower CsA 2-h levels were found in patients who received additional immunosuppression by MMF in our center. The aim of this study is to prove whether there are differences in CsA metabolization when MMF is added to treatment. In 33 children who received an immunosuppression of prednisolone and CsA as well as in 15 children who were treated with additional MMF, C2 and C0 were taken. In 11 children, full AUC of CsA were obtained. C2 levels differed significantly (p < 0.05) between patients treated with (617 +/- 230 ng/mL) and without MMF (750 +/- 271 ng/mL) but with similar CsA dosages. C2 correlated better with the AUC than CsA levels at other time points with r = 0.95. The equation AUC = 139 + 6.17 x C2 was calculated to match best in a C2-limited sampling strategy. This formula proved to be safer than equations that had been published before. According to our findings, we suspect that MMF alters the CsA metabolism. When MMF is used in pediatric transplant recipients, either target values of CsA have to be changed or patients may require higher doses of CsA.

Interleukin-2 receptor antibody-induced alterations of ciclosporin dose requirements in paediatric transplant recipients.

In a retrospective analysis of paediatric renal-transplant recipients receiving basiliximab, we noted significantly increased blood concentrations of cyclosporin, early cyclosporin toxicity, and a lower dose requirement within the first 10 days compared with controls. As the CD25 saturation fades at days 28-50, cyclosporin concentrations decline and 20% higher doses are required to maintain adequate trough concentrations. We suggest that an interleukin-2 receptor-mediated alteration of the cytochrome P450 system causes this systemic drug interaction and propose that the initial ciclosporin dose should be limited to 400 mg/m2 if used in combination with basiliximab.

Increased nuclear factor-kappaB and angiotensinogen gene expression in posttransplant recurrent focal segmental glomerulosclerosis.

In an attempt to identify potential markers of steroid-resistance in focal segmental glomerulosclerosis (FSGS) we evaluated intra-graft gene expression of IkappaBalpha, nuclear factor-kappaB (NF-kappaB), and angiotensinogen in 60 biopsies from 27 pediatric renal transplant recipients. Intra-graft NF-kappaB expression was significantly elevated in recurrent FSGS (R-FSGS) (218.3 + 55.6 ag/fg versus NON-FSGS 121.1 + 19.9, P=0.04) but not in acute rejection. NF-kappaB:IkappaBalpha ratios were higher in cadaveric donor versus living related donor recipients (15.7 + 2.8 vs. 8.8 + 1.3, respectively, P=0.015), and in African-American versus Caucasian recipients (15.6 + 2.9 vs. 9.1 + 1.3, respectively, P=0.03). Intra-graft angiotensinogen gene expression was significantly elevated in R-FSGS (30.5 + 8.8 ag/fg R-FSGS vs. 16.0 + 4.7 NON-FSGS, P=0.009). We conclude that increased NF-kappaB and angiotensinogen gene expression are associated with R-FSGS. Increased NF-kappaB:IkappaBalpha ratios are associated with cadaveric donor recipients and African-American race.

Dosing of MMF in combination with tacrolimus for steroid-resistant vascular rejection in pediatric renal allografts.

Steroid-resistant vascular rejection was treated in seven adolescent renal allograft recipients using the combination of mycophenolate mofetil (MMF) and tacrolimus (FK506). Since there are no published pediatric dose recommendations for MMF using this combination, trough concentrations and pharmacokinetic profiles were used for therapeutic drug monitoring. In order to keep the mycophenolic acid (MPA) concentrations between 2-5 micrograms/ml, mean MMF doses were reduced from 600 to 250 mg/m2 b.i.d. Apparent clearance of MPA decreased from 5 to 1 ml/min per kg within 2 weeks. Pharmacokinetic monitoring revealed substantial variability among patients of both MMF and FK506. The MPA dose ranged from 178 to 1008 mg/m2 per day to achieve an area under the curve (AUC) of 59.9 micrograms x h/ml +/- 10.5 SD (range 49-65 micrograms). FK506 dose ranged from 1.3 to 8.8 mg/m2 per day to achieve an AUC of 116 ng x h/ml +/- 27 SD (range 83-145). We recommend adjusting MMF doses using therapeutic drug monitoring.

Increased CD40 ligand gene expression during human renal and murine islet allograft rejection.

BACKGROUND: The interaction between CD40 and its ligand CD40L is essential for the development and maintenance of vigorous immunity. We have sought to determine: (i) whether a heightened level of CD40L transcripts is evident during acute allograft rejection and (ii) the kinetics of CD40L gene expression during allograft rejection. METHODS: By using quantitative reverse transcriptase-assisted polymerase chain reaction techniques, we found that heightened CD40L gene expression is a correlate of acute human renal allograft rejection (P<0.01). RESULTS: In a murine model of MHC-mismatched islet allografts, our results showed that CD40L transcripts were rarely detected at day 2 after transplantation, but were remarkably heightened at day 5 after transplantation. The transcript levels then steadily increased and peaked at the time of rejection. CONCLUSION: These data suggest that therapy aimed at blocking the CD40 to CD40L interaction should be applied during the immediate posttransplant period.