Comparative Analysis of Determinants and Outcome of Early and Late Acute Antibody Mediated Rejection (ABMR).

Introduction: Antibody-mediated rejection (ABMR) is one of the major determinants of graft survival. Although diagnostic precision and treatment options have improved, response to therapy and graft survival has not improved very significantly. The phenotypes of early and late acute ABMR differ in many ways. In this study, we assessed the clinical characteristics, response to therapy, DSA positivity, and outcomes of early and late ABMR. Methods: During the study period, 69 patients with acute ABMR diagnosed on renal graft histopathology were included with a median follow-up of 10 months after rejection. Recipients were stratified into early acute ABMR (<3 months of transplant; n = 29) and late acute ABMR (>3 months of transplant; n = 40). Graft survival, patient survival, response to therapy, and doubling of serum creatinine were assessed and compared between the two groups. Results: Baseline characteristics and immunosuppression protocols were comparable between the early and late ABMR groups. Late acute ABMR had an increased risk of doubling of serum creatinine than the early ABMR group (P = 0.002). Graft and patient survival were not statistically different between the two groups. Response to therapy was inferior in the late acute ABMR group (P = 0.00). Pretransplant DSA was present in 27.6% in the early ABMR group. Late acute ABMR was frequently associated with nonadherence or suboptimal immunosuppression and low DSA positivity (15%). Infections such as CMV, bacterial, and fungal infections were similar in the earlier and late ABMR groups. Conclusion: Late acute ABMR group had a poor response to anti-rejection therapy and also an increased risk of doubling of serum creatinine compared to the early acute ABMR group. There was also a tendency toward increased graft loss in late acute ABMR patients. Late acute ABMR patients are more frequently associated with nonadherence/suboptimal immunosuppression. There was also a low incidence of anti-HLA DSA positivity in late ABMR.

Vitamin D Receptor Activity, Vitamin D Status, and Development of De-novo Donor-specific Antibody after Renal Transplantation.

INTRODUCTION: Vitamin D has immunomodulatory properties and could have a role in allograft outcome. METHODS: Fifty-two chronic kidney disease patients going for transplantation were studied for vitamin-D receptor (VDR) activity, 25(OH)D, estimated glomerular filtration rate (e-GFR), and de-novo donor-specific antibody (d-DSA). RESULTS: Vitamin D deficiency was seen in 25% of recipients before transplant (26.09 ± 12.19 ng/ml), in 48.1% at 6 months posttransplant (23.36 ± 15.11 ng/ml). VDR activity before the transplant was 15.41 ± 31.41 ng/ml, which was similar to control group (13.24 ± 9.78 ng/ml), and after transplantation showed an increase at 3 months to 21.91 ± 38.80 ng/ml and at 6 months to 26.03 ± 53.90 ng/ml. d-DSA developed in 27.3% and 6.7% patients of vitamin D-deficient patients (levels <31 ng/ml) and non-deficient (levels ≥20 ng/ml) patients respectively (P < 0.042). Low VDR activity at 3 months posttransplant was associated with significantly higher d-DSA positivity (33.3%) as compared to the group with normal VDR activity where d-DSA developed only in 5.9% of patients (P < 0.009). Patients with vitamin D levels <20 ng/ml and the group with low VDR activity at 3 months had significantly less e-GFR at 1 year after transplant. CONCLUSION: d-DSA was associated with vitamin D deficiency and low VDR activity with decreased graft GFR at 12 months posttransplant.

Vitamin D, 1,25-Dihydroxyvitamin D, FGF23, and Graft Function after Renal Transplantation.

Vitamin-D has immuno-modulatory properties besides its role in mineral and bone disorder (MBD) and could have a role in allograft outcome. Fifty-two chronic kidney disease patients on dialysis going for transplantation were prospectively studied before and after renal transplantation. FGF23, 25(OH) vitamin D, 1,25-Dihydroxyvitamin D, PTH, serum Ca, serum PO4, and e-GFR status were evaluated. Vitamin D deficiency was seen in 25.0% of recipients before transplant (26.09 ± 12.19 ng/mL) and in 48.1% at 6 months post-transplant (23.36 ± 15.11 ng/mL). 1,25-(OH)2D levels before transplant were 102.37 ± 108.44 pmol/L, which were less than control (143.30 ± 108.0 pmol/L) and decreased further to 46.20 ± 42.11 pmol/mL at 3 months and started increasing to 78.37 ± 60.12 pmol/mL at 6 months post-transplantation without vitamin D supplementation. The prevalence of hypophosphatemia after transplantation was 32.0%, hyperkalemia was 12.0%, elevated intact PTH levels at 3 and 6 months after transplant were seen in 66.7% and 30.8% patients, respectively. FGF-23 levels were high in 72.5% of patients before transplant (495.94 ± 690.68 pg/mL) and decreased to normal levels at 3 months post-transplant (31.63 ± 14.17 pg/m) (control 32.07 ± 9.78 pg/mL). Serum intact PTH levels were 379.54 ± 281.27 pg/mL before transplant and came down to 103.96 ± 68.34 at 3 months and 69.87 ± 116.03 at 6 months post-transplantation. There was trend of higher e-GFR at 1 year post-transplant in patients without vitamin D deficiency (levels ≥30 ng/mL). The dysregulated mineral metabolism continues in post-transplant despite improvement in renal function and normalization of FGF-23.

Efficacy and safety of sofosbuvir-based antiviral therapy to treat hepatitis C virus infection after kidney transplantation.

BACKGROUND: The objectives of this pilot study were to assess the efficacy and safety of an interferon-free sofosbuvir and ribavirin combination regimen to treat chronic hepatitis C virus (HCV) infection in kidney transplant recipients and to study the impact of sofosbuvir on calcineurin inhibitor (CNI) drug levels. METHODS: A total of 10 kidney transplant recipients with chronic HCV infection were included in the study. All received sofosbuvir and ribavirin combination therapy. The virological response to therapy and the adverse effects of the drugs were studied. The area under the curve (AUC) and pharmacokinetic data of levels of CNI were compared while the patients were receiving sofosbuvir and ribavirin drugs and when they were no longer on these drugs. RESULTS: In all, 9 of 10 patients (90%) achieved rapid virological response (RVR) with undetectable HCV RNA at 4 weeks and the remaining patient achieved undetectable HCV RNA at 8 weeks. A sustained virological response was seen at 3, 6 and 12 months and was maintained in all 10 patients (100%). The important aspect of the study is the effect of treatment with the sofosbuvir-ribavirin combination regimen on the CNI AUC levels, which resulted in a reduction in the CNI AUC. While used as part of triple-drug immunosuppression, no change in the dose of CNI (tacrolimus and cyclosporine) was required based on measurement of C0 levels. CONCLUSIONS: The sofosbuvir and ribavirin combination therapy is effective and safe to treat HCV infection in the post-renal transplant setting. There is a need for close CNI level monitoring while these patients are on sofosbuvir therapy. With therapy and viral clearance, there could be reduction in CNI levels due to increased clearance of CNI drugs, which is shown by the AUC measurements. This could be important for patients at high risk for rejection.

Luminex Solid-Phase Crossmatch for De Novo Donor-Specific Antibodies in Living-Donor Related Transplants.

OBJECTIVES: There are no reports of de novo donor-specific antibody monitoring by a low-cost solid-phase crossmatch assay using donor lysate after renal transplant. MATERIALS AND METHODS: We prospectively evaluated 121 complement-dependant cytotoxicity crossmatch-negative living-donor kidney transplant recipients for development of de novo donor-specific antibodies (class I and II HLA) by solid-phase crossmatch Luminex assay after transplant. RESULTS: Of 121 recipients in our study group, 26 (21.5%) developed de novo donor-specific antibody within 3 months after transplant. Fifteen (58%) of these 26 recipients developed class II de novo donor-specific antibody, 8 patients (30%) developed class I, and 3 (12%) developed both class I and class II. Of the remaining 95 patients (79%) who did not develop de novo donor-specific antibody, 6 (33.3%) had antibody-mediated rejection with glomerulitis (2 with C4d-positive disease). Donor-specific antibody was detected by Luminex solid-phase crossmatch in 18 patients (5 with class I, 11 with class II, and 2 with both class I and II), all with no evidence of clinical rejection. Development of de novo donor-specific antibody detected by solid-phase crossmatch was associated with more acute rejection (31% in de novo donor-specific antibody-positive group versus 19% in the negative group). The positive group had more antibody-mediated rejection (75% of acute rejections), whereas only 33.3% of acute rejections in the negative group were antibody-mediated rejection. Of 12 patients with antibody-mediated rejection, 9 were C4d negative (75%) and were diagnosed by donor-specific antibody positivity detected by solid-phase cros?match testing and histologic findings. The use of donor lysate in solid-phase crossmatch assays is more economical than the single-antigen bead Luminex assay (per test cost of US $45.20 vs $403.20).