Desensitization with intravenous immune globulin (IVIG) and rituximab improves transplantation rates. It is unclear if desensitization increases the risk of polyomavirus BK (BKV) viremia. Here, BKV viremia in HLA-sensitized patients after desensitization with IVIG and rituximab was analyzed.Baseline characteristics and outcomes were compared in the desensitized group (N=187) and the non-desensitized group (N=284). Surveillance for BKV viremia was done at 1, 2, 3, 6, 9, and 12 months posttransplant. Univariable and multivariable analyses were performed.BKV viremia was observed in 20% of the desensitized and 10% of the non-desensitized (P<0.001) groups by 2 years posttransplant. The desensitized group had more lymphocyte depleting induction and more rejection. They also had a greater degree of viremia with more patients having a peak viral load greater than 10,000 copies per milliliter (P<0.001). However, there was no significant difference in BKV-associated nephropathy or graft loss in the two groups. There was an association of BKV viremia with desensitization and lymphocyte induction. Only desensitization remained a significant predictor in the multivariable model with an adjusted HR of 2.13 (95% CI 1.21-3.77, P=0.009).Desensitization with IVIG and rituximab is associated with a higher incidence of BKV viremia with high viral copies and was the major predictor of BKV viremia in the multivariable model. More frequent surveillance for BKV viremia and an early, aggressive treatment strategy are essential for preventing high BKV viral loads in this patient population.
Purpose of review Human leukocyte antigen (HLA) sensitization is a major barrier to kidney transplantation induced by exposure to alloantigens through pregnancy, blood product exposure and previous transplantations. Desensitization strategies are undertaken to improve the chances of finding compatible organ offers. Standard approaches to desensitization include the use of plasmapheresis/low dose intravenous immunoglobulin (IVIG) or high dose IVIG plus anti-CD20. However, current methods to reduce HLA antibodies are not always successful, especially in those with calculated panel reactive antibody 99–100%. Recent findings Newer desensitization strategies such as imlifidase [immunoglobulin G (IgG) endopeptidase] rapidly inactivates IgG molecules and creates an “antibody-free zone”, representing an important advancement in desensitization. However, pathogenic antibodies rebound, increasing allograft injury that is not addressed by imlifidase. Here, use of anti-IL-6R (tocilizumab) or anti-interleukin-6 (clazakizumab) could offer long-term control of B-memory and plasma cell DSA responses to limit graft injury. Agents aimed at long-lived plasma cells (anti-CD38 and anti-BCMAxCD3) could reduce or eliminate HLA-producing plasma cells from marrow niches. Other agents such as complement inhibitors and novel agents inhibiting the Fc neonatal receptor (FcRn) mediated IgG recycling will likely find important roles in desensitization. Summary Use of these agents alone or in combination will likely improve the efficacy and durability of desensitization therapies, improving access to kidney transplantation for immunologically disadvantaged patients.
Preliminary data from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia patients indicate that a cytokine storm may increase morbidity and mortality. Tocilizumab (anti-IL-6R) is approved by the Food and Drug Administration for treatment of cytokine storm associated with chimeric antigen receptor T-cell therapy. Here we examined compassionate use of tocilizumab in patients with SARS-CoV-2 pneumonia.
Purpose. The safety and efficacy of reduced-dose cyclosporine in renal transplantation were studied. Methods. Patients receiving their first renal transplant received daclizumab 1 mg/kg every 14 days for a total of five doses, mycophenolate mofetil 1 g twice daily, corticosteroids per the institution’s routine protocol, and half of the institution’s usual cyclosporine dosage. Trough cyclosporine concentrations targeted were half the customary goals, or 150–200 ng/mL for the first six months and 125–175 ng/mL for months 7–12. A retrospective control group included 15 matched patients who had received full-dose cyclosporine, mycophenolate mofetil, and corticosteroids without daclizumab induction therapy. Results. Thirty patients were studied (15 in each group). At baseline, the control group had a significantly lower panel reactive antibody level (0.13%) than the treatment group (5.2%) (p = 0.01). Mean cyclosporine concentrations at 1, 6, and 12 months were significantly lower in the treatment group (p < 0.0001). No patient in either group had an acute rejection episode. All control patients had cyclosporine-associated adverse effects, compared with seven treatment-group patients (p = 0.0022). The treatment group had 19 infections, versus 29 in the control group (p = 0.39). Three study-group patients and eight control patients required a fine-needle aspiration or biopsy (p = 0.13). Conclusion. Among kidney transplant patients at low risk of acute rejection, those treated with daclizumab and low-dose cyclosporine had an identical rate of acute rejection (none) and fewer cyclosporine-associated adverse effects compared with patients in a retrospective control group who received full-dose cyclosporine without daclizumab.
Introduction TG has a poor prognosis and treatments have not been established. Pathological correlates of TG progression are not well defined and may help identify those at risk for progression. Methods We included all patients diagnosed with TG who also had a subsequent indication biopsy. The biopsies were reviewed by the pathologist and assigned microvascular injury scores (g+ptc), and chronic tubulointerstitial injury scores (ci+ct). Chronic glomerulopathy scores (cg) were also assigned. Change in the (g+ptc), (ci+ct), and cg scores were measured. A serum creatinine (Cr) increase of < 20% was considered stable. Changes in pathological scoring were compared in patients with and without a stable creatinine. Treatment with rituximab and changes in donor specific Ab (DSA) were also evaluated. Results Thirteen patients were evaluated. Average follow-up was 731 days from the index biopsy. The mean Δ(g+ptc) was -1.5, Δ(ci+ct) 1.7, and Δcg 0.8. There was a similar decrease in the g+ptc score in those with a stable Cr vs. unstable Cr (-1.6 vs. -1.5). Those was a stable Cr had less chronic change [Δ(ci+ct) 1.2 vs. 2.0) and less chronic glomerular changes (Δcg 0.4 vs. 1). Patients treated with rituximab had a better Δ(g+ptc) and Δ(ci+ct) scores but no differences in cg [Δ(g+ptc) -2.5 vs. -0.7, Δ(ci+ct) 0.83 vs. 2.4, Δcg 0.86 vs. 0.86). Rituximab treated patients also had an improvement in the DSA relative intensity score, a measure that takes into account the number and strength of DSAs. Finally, those with a stable Cr who also received rituximab did the best in regards to changes in ci+ct scores while those who did not receive rituximab tended toward worse scores (table 1) Conclusion Changes in (g+ptc) scores in patients with TG did not seem to correlate with clinical stability, but changes in (ci+ct) scores did. Rituximab seemed to improve microvascular inflammation while slowing down progression of chronic tubulointerstitial injury. It is possible that the effect of rituximab on DSA plays a role in slowing down the development of chronic tubulointerstitial changes.Table: No Caption available.
Background: Belatacept treated pts are at high risk for viral infections and their complications, especially PTLD by EBV and PML by JCV. Here we report the incidence of EBV, CMV, BKV and JCV viremia and explore possible risk factors in renal transplant pts treated with Belatacept. Methods: Twenty-eight pts treated with Belatacept + MMF + steroids for a median of 10M were monitored for viremia by PCR. Fourteen pts were de novo and 14 converted from tacrolimus at a median of 8M post-Tx. All were EBV sero (+), 6 CMV sero (-). BKV and JCV serology unknown. Eighteen received Thymoglobulin® and 10 basilixmab induction. All received anti-viral prophylaxis for 6M. We considered viremia as a viral load of >5 copies/PCR for EBV & CMV, and >500 copies/ml plasma for BKV & JCV. Results:Table: No Caption available.Overall, 14/28 pts (50%) developed at least one episode of viremia. De novo pts had a significantly higher rate of viremia than conversion pts (11/14 [78.6%] vs. 3/14 [21.4%], p<0.003). Among pts with viremia, the 1st viremia episode occurred at median 3M post-Tx in both de novo and conversion pts despite a median conversion time of 8M (2-143M) post-Tx. Most pts with viremia received Thymoglobulin® (11/14 [78.6%]). Although the EBV viremia rate was high, low EBV copies (peak 31±13 copies) and short viremia duration (2.3±1.3M) were observed. Two pts were CMV sero (-), both in the de novo group, and had severe CMV viremia (10300±6700 copies, 8.3±1.3M), while 4 CMV sero (+) in the de novo and 3 in conversion groups showed mild viremia (163±241 copies, 0.7±0.3M). All 3 BKV and all 2 JCV viremia were severe (BKV: 135000±49500 copies/ml, 7.7±2.5M; JCV: 3001625±2998375 copies/ml, 6.7±2.5M). No pts developed PTLD, PML or BKV-associated nephropathy. Conclusions: Viremia for Belatacept-treated pts was frequent early post-Tx, especially in de novo pts with Thymoglobulin® induction. However, viremia was mild in viral sero (+) pts. Close monitoring of EBV, CMV, BKV and JCV are recommended in at risk pts to prevent serious complications of undetected viremia. DISCLOSURES:Jordan, S.: Grant/Research Support, Genentech Roche, CSL-Behring grant support.
Abstract: Despite better understanding of the impact of development of the human leukocyte antigen (HLA) antibody and numerous advancements in immunosuppressive therapy, the ability to successfully transplant highly sensitized patients remains a significant challenge. As the percentage of the waiting list becomes increasingly populated with highly sensitized patients, there is a growing demand for effective strategies to manage these patients. Over the past 20 years, desensitization therapies have been modified and developed, and are mainly utilized at transplant centers that have developed expertise. In addition, recognition that the highly sensitized patient population is disadvantaged on the transplant waiting list has led to recent changes in national kidney allocation policy. Furthermore, creative strategies, such as enrollment of sensitized patients into paired kidney exchange programs, have been developed to find compatible matches for these patients. The goal of this article is to address some of the specific challenges related to transplanting the highly sensitized patient at a high-volume transplant center with experience in desensitization and to review established and emerging solutions to help this patient population. Keywords: human leukocyte antigen, antibodies, desensitization, high-dose intravenous immunoglobulin, rituximab
