Christina Dörje

Early versus late acute antibody-mediated rejection in renal transplant recipients.

Background Over the last decade, the diagnostic precision for acute antibody-mediated rejection (aABMR) in kidney transplant recipients has improved significantly. The phenotypes of early and late aABMR may differ. We assessed the characteristics and outcomes of early versus late aABMR. Methods Between January 1, 2005 and December 31, 2010, aABMR was diagnosed in 67 grafts in 65 kidney recipients, with a median follow-up of 3.6 years (range, 61 days–7.3 years). Recipients were stratified by early aABMR (<3 months after transplantation; n=40) and late aABMR (>3 months after transplantation; n=27). The main outcome was kidney allograft loss. Outcome of aABMR was compared with recipients with acute early (n=276) or late (n=100) non-ABMR during the same period. Results Recipients with late aABMR had significantly reduced graft survival compared with recipients with early aABMR (P<0.001, log-rank test; 40% vs. 75% at 4 years; hazard ratio, 3.72; 95% confidence interval, 1.65–8.42). Graft survival in late aABMR was also inferior to late non-ABMR acute rejections (P=0.008). At transplantation, more patients were presensitized to human leukocyte antigens (22 [55%] vs. 4 [15%] in the early vs. late aABMR group). The late aABMR group was characterized by younger recipient age (37.9±12.9 vs. 50.9±11.6 years; P<0.001), increased occurrence of de novo donor-specific antibodies (52% vs. 13%; P=0.001), and nonadherence/suboptimal immunosuppression (56% vs. 0%; P<0.001). Conclusion Compared with early aABMR, late aABMR had inferior graft survival and was characterized by young age, frequent nonadherence, or suboptimal immunosuppression and de novo donor-specific antibodies.

Belatacept as immunosuppression in patient with recurrence of hemolytic uremic syndrome after renal transplantation.

Address correspondence to: Martin J. Hoogduijn, Ph.D., Department of Internal Medicine, Transplantation laboratory, Erasmus University Medical Center, room Ee559, 3000 CA Rotterdam, The Netherlands. E-mail: m.hoogduijn@erasmusmc.nl Received 26 February 2009. Accepted 12 March 2009. Copyright

Computer-Assisted Cyclosporine Dosing Performs Better Than Traditional Dosing in Renal Transplant Recipients: Results of a Pilot Study

Cyclosporine A (CsA) is widely used after organ transplantation. Its narrow therapeutic window and large pharmacokinetic variability makes therapeutic drug monitoring (TDM) demanding and frequent dose adjustments are needed, especially early after transplantation. The aim of the present pilot study was to compare accuracy of CsA TDM by experienced clinicians against a computer-assisted dosing model. Renal transplant recipients on CsA, prednisolone, and mycophenolate were included 2 weeks after transplantation, randomized (1:1) to either computer dosing (MAP-BE) or control (CONTR) and followed for at least 8 weeks. A maximum a posteriori probability Bayesian estimation method, applying a population pharmacokinetic model and the POSTHOC option in nonlinear mixed effects modeling, was used to individualize CsA doses in the MAP-BE group. Forty patients (31 men, 27.5% living donor) between 28 and 80 years were included. A total of 798 CsA concentration measurements and adherent dosing evaluations/adjustments were performed. During the entire study, blood concentrations were on average 10% ± 5% from the predefined therapeutic target range in the MAP-BE group, as compared with 13% ± 8% in the CONTR group (P = 0.042). However, there was no significant difference between groups regarding the percentage of CsA concentrations truly within the therapeutic windows [MAP-BE: 37% ± 17%, CONTR: 33% ± 15% (P = 0.57)] or in CsA dose [MAP-BE: 3.55 ± 0.8, CONTR: 3.90 ± 0.9 mg/kg/d (P = 0.26)]. Acute rejections were present in 4 and 3 patients, respectively (P = 1.00). The computer-assisted TDM-targeted CsA blood concentrations significantly better than experienced transplant physicians. A possible favorable effect on short- and long-term outcome needs to be verified in further, properly powered, clinical trials.

Inflammation in Early Kidney Allograft Surveillance Biopsies With and Without Associated Tubulointerstitial Chronic Damage as a Predictor of Fibrosis Progression and Development of De Novo Donor Specific Antibodies.

Background Interstitial fibrosis and tubular atrophy (IFTA) associated with interstitial inflammation in nonscarred areas (IFTA+i) is associated with poorer graft outcome than inflammation without IFTA or IFTA without inflammation. Methods We evaluated if histological categories at week 6 could predict the development of interstitial fibrosis and de novo donor specific anti-HLA antibodies (dnDSA) at 1 year. Biopsies were classified according to Banff criteria as normal (i+t⩽1 and ci+ct⩽1), inflammation (i+t≥2 and ci+ct⩽1), IFTA (i+t⩽1 and ci+ct≥2) or IFTA+i (i+t≥2 and ci+ct≥2). Results We analyzed 598 standard immunological risk recipients. The histological diagnosis at 6 weeks was: normal (n = 206), inflammation (n = 29), IFTA (n = 255), and IFTA+i (n = 108). Moderate/severe interstitial fibrosis (ci≥2) at 1 year was observed in 4.2% of patients with prior (6 weeks) normal histology, in 3.4% with inflammation, in 13.8% with IFTA, and in 24.5% with IFTA+i (P = 0.0001). Fifty-three recipients (8.9%) had dnDSA at 1 year. Independent predictors of development of dnDSA at 1 year were: HLA-DR mismatches (odds ratio [OR], 1.95; 95% confidence interval [95% CI], 1.09-3.49), the presence of inflammation (OR, 5.49; 95% CI, 1.67-18.03) or IFTA+i (OR, 4.09; 95% CI, 1.67-10.0) in the 6-week surveillance biopsy. Conclusions Early subclinical inflammation in surveillance biopsies with or without tubulointerstitial chronic lesions is associated with an increased risk of dnDSA development.

Lecithin:Cholesterol Acyltransferase (LCAT) Deficiency: Renal Lesions with Early Graft Recurrence

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency is a rare metabolic disease with lipid deposition in several organs. The authors report a man with hypertension and proteinuria. Renal biopsy revealed glomerular changes, including peculiar thrombus-like deposits, consistent with LCAT deficiency. He was found to be compound heterozygous for two mutations of the LCAT gene. He received a kidney graft from his father. The authors also describe LCAT deficiency-related lesions in the explanted native kidneys and in biopsies at 2 days, 6 weeks, and 1 year after transplantation. The morphology of this disease is characteristic, and the diagnosis should be suspected from the ultrastructural findings.

One-year protocol biopsies from ABO-incompatible renal allografts compared with a matched cohort of ABO-compatible allografts

Early acute antibody‐mediated rejection (ABMR) occurs more frequently in ABO‐incompatible (ABOi) than in ABO‐compatible (ABOc) kidney transplantation. This could lead to increased inflammation/scarring in the ABOi grafts. Protocol biopsy data in ABOi kidney recipients are scarce.

Total inflammation in early protocol kidney graft biopsies does not predict progression of fibrosis at one year post-transplant

There is an uncertainty whether total inflammation in early protocol kidney graft biopsies is associated with fibrosis progression. We investigated whether total inflammation, both in fibrotic and non‐fibrotic areas, at week 6 would predict fibrosis progression at one yr post‐transplant.

Rescue of kidney function in a toddler with anti-GBM nephritis

Anti-glomerular basement membrane (anti-GBM) nephritis is rare in childhood with few published cases. We report a 19-month-old boy with rapidly progressive glomerulonephritis (RPGN) due to anti-GBM nephritis. Treatment was started under 2 weeks after presentation and included plasma exchange, intravenous high-dose methylprednisolone, intravenous cyclophosphamide and mycophenolate as mainstay medication. The treatment was rapidly effective with immediate decrease in anti-GBM titres and plasma creatinine. Three years after presentation, the boy has normal kidney function, blood pressure and no residual disease. The successful outcome was likely due to the rapid recognition of the anti-GBM antibodies as the cause of RPGN and aggressive primary treatment.

Tacrolimus and mycophenolate regimen and subclinical tubulo-interstitial inflammation in low immunological risk renal transplants

The aim was to evaluate the relationship between maintenance immunosuppression, subclinical tubulo‐interstitial inflammation and interstitial fibrosis/tubular atrophy (IF/TA) in surveillance biopsies performed in low immunological risk renal transplants at two transplant centers. The Barcelona cohort consisted of 109 early and 66 late biopsies in patients receiving high tacrolimus (TAC‐C0 target at 1‐year 6–10 ng/ml) and reduced MMF dose (500 mg bid at 1‐year). The Oslo cohort consisted of 262 early and 237 late biopsies performed in patients treated with low TAC‐C0 (target 3–7 ng/ml) and standard MMF dose (750 mg bid). Subclinical inflammation, adjusted for confounders, was associated with low TAC‐C0 in the early (OR: 0.75, 95% CI: 0.61–0.92; P = 0.006) and late biopsies (OR: 0.69, 95% CI: 0.50–0.95; P = 0.023) from Barcelona. In the Oslo cohort, it was associated with low MMF in early biopsies (OR: 0.90, 95% CI: 0.83–0.98; P = 0.0101) and with low TAC‐C0 in late biopsies (OR: 0.77, 95% CI: 0.61–0.97; P = 0.0286). MMF dose was significantly reduced in Oslo between early and late biopsies. IF/TA was not associated with TAC‐C0 or MMF dose in the multivariate analysis. Our data suggest that in TAC‐ and MMF‐based regimens, TAC‐C0 levels are associated with subclinical inflammation in patients receiving reduced MMF dose.

Uric acid and clinical correlates of endothelial function in kidney transplant recipients

Uric acid is associated with increased mortality in kidney transplant recipients (KTRs), but it is uncertain if this involves endothelial dysfunction. We hypothesized, first, that there was an association between uric acid and endothelial function, and second, that there were associations between endothelial function and cardiac and mortality risk scores.