Sonia Mehrotra

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

ABSTRACT 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.

Fibroblast growth factor-23, vitamin D and mineral metabolism in renal transplant recipients

In CKD patients various disturbances in vitamin D metabolism in addition to their classical effects on mineral bone disorder (MBD), also can have important effects on innate or adaptive immunity through various signaling pathways. Vitamin D deficiency could be a factor for triggering rejection, chronic allograft nephropathy and infections in post-transplant period. Patients with CKD are known to be both 25-hydroxyvitamin D (25OHD3) and 1,25-dihydroxyvitamin D (1,25[OH]2D3) deficient. Several observational studies have shown that treatment of ESRD patients with vitamin D analogues is associated with improved survival. 1,25(OH)2-D3 has long been recognized to have an immune regulatory function besides its role in calcium homeostasis. There is evidence in literature that indicates that 1,25(OH)2-D3 could have an important role in the regulation of immune function. This could have important clinical implications. Transplant physicians and surgeons should understand that vitamin D has a variety of immunological actions which can have important effect on patient and graft survival after transplantation.

Effect of Vitamin D Deficiency on Antibody-Mediated Rejection (ABMR): A Comparative Analysis of Live-Related ABO-Incompatible and ABO-Compatible Renal Transplantation

To compare the outcomes of Living-Donor ABO-incompatible renal transplantation (ABO-i) with matched recipients of ABO-compatible (ABOc) transplantation in relation to vitamin D status. Material and Methods We retrospectively analysed the results of 33 ABOi live-donor kidney transplants (LDKTs) performed between January 2013 and June 2016 at our centre. We compared patient and graft survival, acute rejection episodes, vitamin D status and graft function of the ABO i group with an equal number of matched Live-related ABO-c KTs done during the same time-period. Results The patient-survival in both the groups was 97%, however death-censored graft survival was 94% in the ABOi recipients versus 100% in ABOc group over a mean follow-up of 14 to 15 months respectively. Graft function was overall better in the ABOc recipients, with statistical significance seen at 6 and 12 months post-transplant. We also observed a significantly higher incidence of Acute Antibody-mediated rejections (ABMR) in the ABOi cohort, with 11 episodes of ABMR versus just 2 in the ABOc recipients (p=0.005). Vitamin D deficiency was associated with higher levels of anti ABO antibody and increased development of ABMR due to ABO antibodies (p=0.01). Conclusion ABO incompatible transplantation is an option with excellent patient and graft survival; results almost comparable to the ABO compatible grafts. However, in our study ABOi transplants were associated with higher risk of Acute ABMR. These episodes were amenable to treatment and thus the overall graft survival had similar outcomes. Vitamin D deficiency was associated with increased ABMR in ABOi renal transplants.

Dental and periodontal disease in hemodialysis patients is associated with inflammation; a study from North India

Introduction: Poor oral health and periodontitis is an important problem in chronic kidney disease (CKD) patients on hemodialysis (HD) awaiting kidney transplantation. This could contribute to increased morbidity and mortality as a result of infections and consequences of inflammation. Objectives: To study the oral health status and assess its impact in inducing inflammation in CKD patients on HD. Patients and Methods: Fifty CKD patients on HD (group I) were compared with 50 healthy controls (group-II) in a prospective cohort study. Oral health assessment was done with the WHO oral health assessment form with a mouth mirror and a community periodontal index (CPI) probe by a trained dentist. The demographic clinical data of oral health and periodontitis was collected in dialysis patients and healthy controls. CRP levels were assayed as markers of inflammation. Results: Data shows that patients on dialysis have evidence of increased inflammation as indicated by raised CRP values. Our study shows the poor oral and mouth hygiene and periodontitis and inflammation was much more in dialysis patients as compared to control group (P<0.05). Amongst dialysis patients with higher inflammation (CRP values), there was poorer oral health and more periodontitis (P<0.05). This indicates that higher inflammation could result from poor dental hygiene and periodontitis. Conclusion: Poor oral and mouth hygiene was associated with inflammation as indicated by high CRP values in CKD patients on dialysis with poor dental hygiene. Periodontitis was significantly associated with development of inflammation.

The importance of donor-specific anti-HLA antibodies (DSA) identification in renal transplant patients with C4d-negative biopsies

Two index cases of living-related donor renal allografts patients developed C4d-negative rejection. Both cases had negative cytotoxic crossmatch and negative flow crossmatch before transplantation. The serum creatinine levels were tabulated. Both cases experienced augmented anti-T cell therapy (intravenous methyl prednisolone) at the time of rejection, which failed to improve renal function. Meantime, our HLA lab identified circulating anti-class I and/or II HLA antibodies towards donor mismatched antigens by Luminex multiplex bead array. Additional therapy included high-dose IVIg and plasma exchange. The renal function improved significantly. Furthermore, the donor-specific antibody strength decreased after combined plasmapheresis and IVIG therapy. These cases highlight the importance of donor-specific antibody detection by sensitive solid phase assays in the context of C4d-negative ABMR.

Pre transplant PRA (penal reactive antibody) and DSA (donor specific antibody) screening status and outcome after renal transplantation

Background: Forty six renal transplant recipients were evaluated by pre-transplant PRA screening (Class I and Class II) by luminex assay (Lifecodes Life-screen Deluxe (LMX) by Gen-Probe). PRA screening results and DSA positivity were correlated with development of rejection episodes. Single Antigen (SA) solid phase antibody assay (One-lambda) was also correlated with rejection episodes. Method: All the 46 kidney transplant recipients were complement dependant cytotoxicity (CDC) crossmatch negative at room, warm, and cold temperatures pretransplant. PRA and Donor Specific Antibody (DSA) (Lifecode) assays were done by luminex. SA antibody assay was done by One-lambda kit by luminex system. Results: All the 46 kidney transplant recipients had PRA screening done on luminex platform. They were divided in to two groups: Group (Gr)-I (PRA negative) n = 30, 65% of patients studied. Group (Gr)-II (PRA Positive) n = 16, 35% of patients. In PRA negative group, only 3 of 30 patients (10%) were DSA positive; one against class I and two recipients had antibody against class-II HLA antigens. Of the PRA negative group, 16 patients received kidney transplantation. Induction with Basiliximab (BSA) was given in 9 and by anti-thymocyte globulin (ATG) in 7 recipients. Two of 16 (12.5%) PRA negative patients developed acute rejection (AR) episodes. Of PRA positive group (16 recipients) only one was DSA positive (6.2%) of PRA positive group, only 6 were transplanted (4 were given induction with BSA, two recipients got ATG induction. Two recipients out of 6 (33%) from PRA positive group who were transplanted had acute rejection (one had evidence of acute cellular rejection and another had glomerulitis on allograft histology) despite being CDC cross match negative. PRA positivity was associated with increased acute rejection episodes. On SA antibody assay, three recipients showed antibody against donor class-II antigens by single bead Luminex assay. All these three patients with single antigen DSA positivity developed acute rejection. All these three recipients showed no donor specific antibody pre transplant and CDC cross match against donor was also negative at the time of kidney transplantation. Conclusion: There was no correlation between DSA positivity and PRA screen positivity. PRA screen negative group had lesser no of acute rejection episodes. PRA positive patients had higher acute rejection episodes despite no evidence of DSA. Single Antigen (SA) antibody positivity was associated with increased episodes of acute rejection (AR).