Vinita Sehgal

Cyclosporine-associated end-stage nephropathy after cardiac transplantation : Incidence and progression

BACKGROUND The salutary immunosuppressive effects of cyclosporine in extending cardiac allograft survival may be curtailed by its nephrotoxic effects. We reviewed our first 9 years of experience with cyclosporine after cardiac transplantation, to evaluate the incidence and progression of cyclosporine-associated end-stage renal failure necessitating chronic hemodialysis. METHODS Retrospective computer-based file review and personal interview when possible. RESULTS The population at risk was comprised of all adult cardiac recipients surviving at least 3 years (n=293). Of these, 19 (6.5%) developed end-stage renal failure requiring chronic hemodialysis. There were 17 men and 2 women (mean age of 45 +/- 11 years). The mean creatinine clearance for the study group decreased by 38% (P<0.001 vs. before transplant) by 6 months after transplantation and by 48% by 3 years postoperatively (P<0.001 vs. before transplant). The mean serum creatinine rose by 80% (P< 0.001 vs. before transplant) by 6 months after transplantation and by 125% by 3 years postoperatively (P<0.001 vs. before transplant). Time elapsed from transplantation to hemodialysis ranged from 3.7 to 9.5 years (mean 6.4 +/- 2). Actuarial 1- year survival after onset of hemodialysis was 75%. CONCLUSIONS Although cyclosporine remains the central immunosuppressive agent for cardiac allograft recipients, its use leads to a greater than one-third decrease in creatinine clearance by 6 months after transplantation and progression to end-stage renal failure, requiring hemodialysis in 6.5% of cardiac transplant recipients. Moreover, these patients are at increased risk of death compared with other cardiac allograft recipients. This data warrants the search of alternative or adjunctive agents that would allow decreased dosing or reduced nephrotoxicity of cyclosporine, while maintaining equivalent survival.

Immune Reconstitution Following Rabbit Antithymocyte Globulin

Depletional induction therapies are routinely used to prevent acute rejection and improve transplant outcome. The effects of depleting agents on T‐cell subsets and subsequent T‐cell reconstitution are incompletely defined. We used flow cytometry to examine the effects of rabbit antithymocyte globulin (rATG) on the peripheral T‐cell repertoire of pediatric and adult renal transplant recipients. We found that while rATG effectively depleted CD45RA+CD27+ naïve and CD45RO+CD27+ central memory CD4+ T cells, it had little effect on CD45RO+CD27− CD4+ effector memory or CD45RA+CD31−, CD45RO+CD27+ and CD45RO+CD27− CD8+ T cell subsets. When we performed a kinetic analysis of CD31+ recent thymic emigrants and CD45RA+/RO+ T cells, we found evidence for both thymopoiesis and homeostatic proliferation contributing to immune reconstitution. We additionally examined the impact of rATG on peripheral CD4+Foxp3+ T cells. We found that in adults, administration of rATG‐induced peripheral expansion and new thymic emigration of T cells with a Treg phenotype, while CD4+Foxp3+ T cells of thymic origin predominated in children, providing the first evidence that rATG induces Treg in vivo. Collectively our data indicate that rATG alters the balance of regulatory to memory effector T cells posttransplant, providing an explanation for how it positively impacts transplant outcome.

Addition of Plasmapheresis Decreases the Incidence of Acute Antibody-Mediated Rejection in Sensitized Patients with Strong Donor-Specific Antibodies

BACKGROUND AND OBJECTIVES The objective of this study was to investigate the effects of desensitization protocols using intravenous Ig with or without plasmapheresis in patients with donor-specific anti-HLA antibodies on prevention of antibody-mediated rejection and downregulation of donor-specific antibodies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Thirty-five complement-dependent cytotoxicity T cell cross-match-negative but complement-dependent cytotoxicity B cell and/or flow cytometry cross-match-positive kidney transplant recipients were treated with high-dosage intravenous Ig plus Thymoglobulin induction treatment. Donor-specific antibody strength was stratified as strong, medium, or weak by Luminex flow beads. Group 1 patients had weak/moderate and group 2 strong donor-specific antibodies RESULTS Whereas no group 1 patients had acute rejection, 66% of group 2 had acute rejection (44% antibody-mediated rejection, 22% cellular rejection). The protocol was then changed to the addition of peritransplantation plasmapheresis to patients with strong donor-specific antibodies (group 3). This change resulted in a dramatic decrease in the acute rejection rate to 7%. During a median 18 mo of follow-up, patient survival was 100, 100, and 93% and graft survival was 100, 78, and 86% in groups 1, 2, and 3, respectively. During follow-up, 17 (52%) patients lost donor-specific antibodies completely, and 10 (30%) lost some of donor-specific antibodies and/or decreased the strength of existing donor-specific antibodies. CONCLUSIONS These results indicated that in patients with strong donor-specific antibodies, the addition of plasmapheresis to high-dosage intravenous Ig decreases the incidence of acute rejection. The majority of the patients, whether they received intravenous Ig alone or with plasmapheresis, lost their donor-specific antibodies during follow-up.

Intravenous immunoglobulin and thymoglobulin facilitate kidney transplantation in complement-dependent cytotoxicity B-cell and flow cytometry T- or B-cell crossmatch-positive patients.

Background. The aim of this study was to investigate the effect of Thymoglobulin and intravenous immunoglobulin (IVIG) therapy on the clinical outcome of a putatively high-risk group of kidney transplant recipients who have positive B-cell complement-dependent cytotoxicity (CDC) along with positive T- or B-cell flow cytometry (FC) crossmatch results. Methods. We prospectively studied the effects of IVIG and Thymoglobulin induction treatment in B-cell CDC, and T- or B-cell FC crossmatch-positive kidney transplant recipients (seven women and one man; mean age, 43±12 years). Results. Mean peak panel-reactive antibody (PRA) was 47±32. Three patients had donor-specific antibody by flow PRA (two anti-DR4 and one anti-A2). Each recipient received induction treatment with IVIG 100 mg/kg for 3 days and Thymoglobulin 1.5 mg/kg for 5 days after transplantation. No acute cellular rejections occurred during a median follow-up of 15 months (range, 12–17 months). Only one acute humoral rejection occurred 8 days after transplantation, which responded to plasmapheresis, IVIG, and rituximab. One allograft was lost because of polyoma nephritis. Patient survival was 100% and allograft survival was 88%. Conclusion. Our results indicate that IVIG and Thymoglobulin induction treatment may facilitate kidney transplantation in B-cell CDC and T- or B-cell FC crossmatch-positive patients.

Transplant Glomerulopathy May Occur in the Absence of Donor-Specific Antibody and C4d Staining

BACKGROUND AND OBJECTIVES Transplant glomerulopathy (TGP) has been proposed to be a component of chronic antibody-mediated rejection (AMR). We have studied 36 patients with TGP and 51 patients with chronic allograft nephropathy (CAN) but without TGP for C4d staining and donor-specific anti-HLA antibodies (DSA) to investigate the alloantibody-mediated mechanisms. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Allograft biopsies were stained with C4d staining and DSAs were studied by Luminex Flow Beads. Allograft biopsies were done at a mean of 5.3 +/- 5.0 and 5.6 +/- 4.6 yr after transplantation in patients with CAN and TGP, respectively. RESULTS The mean creatinine level at the time of the biopsy was 2.7 +/- 1.2 mg/dl in each group. Proteinuria of >1.0 g/d was more common in patients with TGP (61 versus 25%; P = 0.002). Whereas three patients with TGP had a history of acute AMR, none of the patients with CAN had. Mean chronicity score of the biopsies were 1.7 +/- 0.7 in patients with CAN and 1.9 +/- 0.8 in patients with TGP. Biopsies from only two (4%) patients with CAN and four (11%) patients with TGP had diffuse C4d positivity. DSA were found in 36% of TGP and 33% of CAN patients. CONCLUSIONS These results suggest that a substantial number of patients with TGP did not have positive C4d staining or DSA, indicating that a non-alloantibody-mediated process may be involved in the development of TGP in some patients.

Antibodies Reactive to Non-HLA Antigens in Transplant Glomerulopathy

Although T and B cell alloimmunity contribute to transplant injury, autoimmunity directed at kidney-expressed, non-HLA antigens may also participate. Because the specificity, prevalence, and importance of antibodies to non-HLA antigens in late allograft injury are poorly characterized, we used a protein microarray to compare antibody repertoires in pre- and post-transplant sera from several cohorts of patients with and without transplant glomerulopathy. Transplantation routinely induced changes in antibody repertoires, but we did not identify any de novo non-HLA antibodies common to patients with transplant glomerulopathy. The screening studies identified three reactivities present before transplantation that persisted after transplant and strongly associated with transplant glomerulopathy. ELISA confirmed that reactivity against peroxisomal-trans-2-enoyl-coA-reductase strongly associated with the development of transplant glomerulopathy in independent validation sets. In addition to providing insight into effects of transplantation on non-HLA antibody repertoires, these results suggest that pretransplant serum antibodies to peroxisomal-trans-2-enoyl-coA-reductase may predict prognosis in kidney transplantation.

Decreased Incidence of Cytomegalovirus Infection in Thymoglobulin-Treated Transplant Patients with 6 Months of Valganciclovir Prophylaxis

Cytomegalovirus (CMV) infection is still the most common opportunistic infection following solid organ transplantation despite the introduction of newer anti-viral medications for prophylaxis, such as ganciclovir, valacyclovir, and valganciclovir (1). We recently reported that the overall incidence of CMV disease at 1 year post transplant was 14% (4% tissue-invasive, 10% non-invasive) in 129 kidney or pancreas transplant recipients with 3 months of ganciclovir or valganciclovir prophylaxis (2). However, of the 18 patients who developed CMV disease, 83% (n = 15) had received thymoglobulin induction treatment, and 25% of all thymoglobulin-treated patients developed CMV disease. Four of 15 (27%) patients had tissue-invasive CMV disease (two CMV colitis, one CMV gastritis, and one CMV nephritis).

Factors associated with failure to list HIV-positive kidney transplant candidates.

With improved survival in the antiretroviral era, data from ongoing studies suggest that HIV patients can be safely transplanted. The disproportionate burden of HIV‐related end‐stage renal disease in minority populations may impose additional obstacles to successful completion of the transplant evaluation. We retrospectively reviewed 309 potentially eligible HIV patients evaluated for kidney transplant at our institution since 2000. Only 20% of HIV patients have been listed, compared to 73% of HIV‐negative patients evaluated over the same period (p < 0.00001). Failure to provide documentation of CD4 and viral load (36% of candidates) was the most common reason for failure to progress beyond initial evaluation. Other factors independently associated with failure to complete the evaluation included CD4 < 200 at initial evaluation (OR 15.17; 95% CI 1.94–118.83), black race (OR 2.33; 95% CI 1.07–5.06), and history of drug use (OR 2.56; 95% CI 1.22–5.37). More efficient medical record sharing and an awareness of factors associated with failure to list HIV‐positive transplant candidates may enable transplant centers to more effectively advocate for these patients.

Intravenous immunoglobulin and thymoglobulin induction treatment in immunologically high-risk kidney transplant recipients.

Kidney transplant recipients with complement-dependent cytotoxicity (CDC) B-cell or flow-cytometry (FC) T/B crossmatch positivity are at higher risk for the development of acute and chronic rejection, and decreased graft survival due to anti-HLA donor-specific antibodies (DSA) (1, 2). Intravenous im

Safety of using hepatitis B virus core antibody or surface antigen‐positive donors in kidney or pancreas transplantation

Abstract:  Hepatitis B virus core antibody (HBcAb) or surface antigen (HBsAg)‐positive organ donors have the potential to transmit infection to transplant recipients. We investigated the safety of using HBcAb(+) or HBsAg(+) donors in kidney or pancreas transplant recipients with 1 yr lamivudine prophylaxis. While HBsAb(−) recipients of HBcAb(+) donors received prophylaxis, HBsAb(+) recipients did not. HBsAg(+) organs were only used in patients who were both HBcAb and HBsAb(+). Forty‐six patients received HBcAb(+) and four received HBsAg(+) organs (47 kidney, two pancreas, and one kidney/pancreas). All but one recipient were HBsAg(−), 25 were HBsAb(+), and 19 HBcAb(+). During a median 36 months of follow‐up (range 6–66 months), with 43 of a total 50 patients having at least 1 yr follow‐up and were off lamivudine, and none of the patients developed hepatitis B viremia or seroconversion to HBsAg or HBsAb(+). These results suggest that HBcAb(+) or HBsAg(+) organs can be used safely in selected recipients with lamivudine prophylaxis without requiring hepatitis B immunglobulin.