Laparoscopic sleeve gastrectomy improves renal transplant candidacy and posttransplant outcomes in morbidly obese patients.

Morbid obesity is a barrier to kidney transplantation due to inferior outcomes, including higher rates of new-onset diabetes after transplantation (NODAT), delayed graft function (DGF), and graft failure. Laparoscopic sleeve gastrectomy (LSG) increases transplant eligibility by reducing BMI in kidney transplant candidates, but the effect of surgical weight loss on posttransplantation outcomes is unknown. Reviewing single-center medical records, we identified all patients who underwent LSG before kidney transplantation from 2011-2016 (n = 20). Post-LSG kidney recipients were compared with similar-BMI recipients who did not undergo LSG, using 2:1 direct matching for patient factors. McNemar's test and signed-rank test were used to compare groups. Among post-LSG patients, mean BMI ± standard deviation (SD) was 41.5 ± 4.4 kg/m2 at initial encounter, which decreased to 32.3 ± 2.9 kg/m2 prior to transplantation (P < .01). No complications, readmissions, or mortality occurred following LSG. After transplantation, one patient (5%) experienced DGF, and no patients experienced NODAT. Allograft and patient survival at 1-year posttransplantation was 100%. Compared with non-LSG patients, post-LSG recipients had lower rates of DGF (5% vs 20%) and renal dysfunction-related readmissions (10% vs 27.5%) (P < .05 each). Perioperative complications, allograft survival, and patient survival were similar between groups. These data suggest that morbidly obese patients with end-stage renal disease who undergo LSG to improve transplant candidacy, achieve excellent posttransplantation outcomes.

Eculizumab and Belatacept for De Novo Atypical Hemolytic Uremic Syndrome Associated With CFHR3-CFHR1 Deletion in a Kidney Transplant Recipient: A Case Report.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is associated with significant morbidity and mortality and occurs due to genetic or acquired abnormalities that result in the dysregulation of the alternative complement pathway. CASE REPORT: We report a case of post-living kidney transplantation de novo aHUS in a setting of heterozygous deletion in the complement factor H-related protein (CFHR)3-CFHR1 gene. The aHUS episode was possibly triggered by antibody-mediated rejection or tacrolimus. The patient responded well to eculizumab and substituting belatacept for tacrolimus. Her serum creatinine level was stable at 1.5 mg/dL after 2.5 years of follow-up. CONCLUSION: This case highlights the success of using a strategy that combines eculizumab and belatacept, as an alternative to calcineurin inhibitors, in treating aHUS in a patient with heterozygous deletion in the CFHR3-CFHR1 gene.

A Steady-State Head-to-Head Pharmacokinetic Comparison of All FK-506 (Tacrolimus) Formulations (ASTCOFF): An Open-Label, Prospective, Randomized, Two-Arm, Three-Period Crossover Study.

This two-sequence, three-period crossover study is the first pharmacokinetic (PK) study to compare all three innovator formulations of tacrolimus (twice-daily immediate-release tacrolimus capsules [IR-Tac]; once-daily extended-release tacrolimus capsules [ER-Tac]; novel once-daily tacrolimus tablets [LCPT]). Stable renal transplant patients were dosed with each drug for 7 days, and blood samples were obtained over 24 h. Thirty subjects were included in the PK analysis set. A conversion factor of 1:1:0.80 for IR-Tac:ER-Tac:LCPT was used; no dose adjustments were permitted during the study. The median (interquartile range) total daily dose was 6.0 (4.0-8.0) mg for IR-Tac and ER-Tac and 4.8 (3.3-6.3) for LCPT. Significantly higher exposure on a per milligram basis, lower intraday fluctuation and prolonged time (Tmax ) to peak concentration (Cmax ) were found for LCPT versus IR-Tac or ER-Tac. ER-Tac showed no differences versus IR-Tac in exposure, Cmax , Tmax or fluctuation. The observed exposure of IR-Tac was used to normalize exposure for LCPT and ER-Tac, resulting in the following recommended total daily dose conversion rates: IR-Tac:ER-Tac, +8%; IR-Tac:LCPT, -30%; ER-Tac:LCPT, -36%. After exposure normalization, Cmax was ~17% lower for LCPT than for IR-Tac or ER-Tac; Cmin was ~6% lower for LCPT compared with IR-Tac and 3% higher compared with ER-Tac.

Plasma-Derived C1 Esterase Inhibitor for Acute Antibody-Mediated Rejection Following Kidney Transplantation: Results of a Randomized Double-Blind Placebo-Controlled Pilot Study.

Antibody-mediated rejection (AMR) is typically treated with plasmapheresis (PP) and intravenous immunoglobulin (standard of care; SOC); however, there is an unmet need for more effective therapy. We report a phase 2b, multicenter double-blind randomized placebo-controlled pilot study to evaluate the use of human plasma-derived C1 esterase inhibitor (C1 INH) as add-on therapy to SOC for AMR. Eighteen patients received 20 000 units of C1 INH or placebo (C1 INH n = 9, placebo n = 9) in divided doses every other day for 2 weeks. No discontinuations, graft losses, deaths, or study drug-related serious adverse events occurred. While the study's primary end point, a difference between groups in day 20 pathology or graft survival, was not achieved, the C1 INH group demonstrated a trend toward sustained improvement in renal function. Six-month biopsies performed in 14 subjects (C1 INH = 7, placebo = 7) showed no transplant glomerulopathy (TG) (PTC+cg≥1b) in the C1 INH group, whereas 3 of 7 placebo subjects had TG. Endogenous C1 INH measured before and after PP demonstrated decreased functional C1 INH serum concentration by 43.3% (p < 0.05) for both cohorts (C1 INH and placebo) associated with PP, although exogenous C1 INH-treated patients achieved supraphysiological levels throughout. This new finding suggests that C1 INH replacement may be useful in the treatment of AMR.

Complete Remission of Post-transplantation Recurrence of Focal Segmental Glomerulosclerosis With the Use of Adrenocorticotrophic Hormone Gel: Case Report.

BACKGROUND: Post-transplantation recurrence of primary focal and segmental glomerulosclerosis (FSGS) is estimated to occur in 30%-50% of cases and doubles the risk of allograft failure. Treatment of recurrent FSGS is challenging because specific pathogenic targets are unknown and available therapeutic options have limited efficacy. CASE REPORT: We report a case of recurrent FSGS with nephrotic-range proteinuria (urine protein creatinine ratio [UPCR], >50) and debilitating edema that was resistant to rituximab and plasmapheresis. The patient had a remarkable response to adrenocorticotropic hormone (ACTH) gel and achieved complete remission (UPCR, 0.5; serum albumin, 4.1 g/dL; serum creatinine, 1.0 mg/dL) which was maintained over 10 months on this treatment. CONCLUSIONS: We conclude that ACTH gel is a potential therapeutic option for post-transplantation recurrence of FSGS and warrants further evaluation.

Case Report: Hemolytic Anemia Following Deceased Donor Renal Transplantation Associated With Tranexamic Acid Administration for Disseminated Intravascular Coagulation.

BACKGROUND: Long-term outcomes of kidney transplantation with organs from donors with disseminated intravascular coagulation (DIC) are comparable with those from other deceased donors. The use of tranexamic acid to impair fibrinolysis in the treatment of DIC is becoming increasingly frequent, particularly in the trauma setting. However, the effects of tranexamic acid on a transplanted kidney allograft are unknown. RESULTS: We report 2 cases of kidney transplantation following administration of tranexamic acid to the donor prior to organ donation. Microthrombi were present in the renal allografts. Both recipients experienced clinically significant hemolytic anemia, which typically occurs at a very low frequency. CONCLUSIONS: These cases illustrate a potential concern for the use of tranexamic acid in deceased kidney donors with DIC.

Case Report: Successful Living Donor Kidney Transplantation in a Highly Human Leukocyte Antigen-Sensitized Recipient With a Positive Cytotoxic Crossmatch Using Bortezomib-Based Desensitization Without Intravenous Immunoglobulin.

BACKGROUND: Highly sensitized patients, who produce antibodies against multiple anti-human leukocyte antigens, have significantly reduced chances for renal transplantation. Traditionally, desensitization protocols to reduce the levels of antibodies have relied on the use of intravenous immunoglobulin and plasmapheresis. RESULTS: Here we report the case of a patient with a calculated panel-reactive antibody level of 100% who was desensitized using multiple courses of bortezomib, a proteasome inhibitor, in an intravenous immunoglobulin-free regimen. The patient underwent a successful transplantation with an allograft from a living donor and has continued to do well post-transplantation. CONCLUSIONS: The expression of anti-human leukocyte antigen antibodies decreases the likelihood of transplantation for patients by restricting the available donor pool. New protocols that reduce antibody expression in these patients and allow for renal transplantation are needed. Bortezomib, as used in the patient reported here, represents a promising new medication for successful desensitization and transplantation.

New-Onset Diabetes After Transplantation: Results From a Double-Blind Early Corticosteroid Withdrawal Trial.

New-onset diabetes after transplantation (NODAT) is an important complication following kidney transplantation. Data from the 5-year early steroid withdrawal double-blind randomized trial were analyzed to determine if steroid avoidance reduced the NODAT risk. Incidence, timing and risk factors for NODAT were evaluated using eight definitions. By American Diabetes Association definition, 36.3% of patients on chronic corticosteroids (CCS) and 35.9% on early corticosteroid withdrawal (CSWD) were diagnosed with NODAT by 5 years. The definition combining fasting blood glucose ≥126 mg/dL on two occasions or treatment identified slightly more cases of NODAT: CCS (39.3%) and CSWD (39.4%). Through 5 years posttransplant, the proportion of NODAT patients requiring treatment were similar (CSWD 22.5% vs. CCS 21.5%); however, insulin therapy was lower with CSWD (3.7% vs. 11.6%; p = 0.049). By multivariate analysis, only age, but not corticosteroid use, was a significant risk factor for NODAT for more than one definition. Numerical, but not statistically significant trends toward lower NODAT rates with CSWD were observed through 5 years for insulin use, HbA1c ≥6.0% and ≥6.5% on two occasions. This prospective, randomized trial of CSWD indicates that CSWD has a limited impact in reducing NODAT when compared to low-dose prednisone (5 mg/day from month 6 to 5 years).

Should HLA mismatch acceptability for sensitized transplant candidates be determined at the high-resolution rather than the antigen level?

Defining HLA mismatch acceptability of organ transplant donors for sensitized recipients has traditionally been based on serologically defined HLA antigens. Now, however, it is well accepted that HLA antibodies specifically recognize a wide range of epitopes present on HLA antigens and that molecularly defined high resolution alleles corresponding to the same low resolution antigen can possess different epitope repertoires. Hence, determination of HLA compatibility at the allele level represents a more accurate approach to identify suitable donors for sensitized patients. This approach would offer opportunities for increased transplant rates and improved long term graft survivals.

Equipoise: ethical, scientific, and clinical trial design considerations for compatible pair participation in kidney exchange programs.

Compatible living donor/recipient pair participation (CPP) in kidney exchange (KE) transplantation may substantially increase transplant volumes and significantly mitigate the O blood group donor shortage in KE. Initial ethical analysis did not support CPP for two primary reasons: (1) KE would be "unbalanced," and (2) the possibility of undue influence experienced by the compatible pair living donor. Recent developments with CPP (modeling studies and small clinical experiences), have demonstrated substantial potential for increasing KE volumes. This encouraged us to reconsider initial ethical concerns, with a focus on the potential for a design of a prospective CPP clinical trial. This ethical reconsideration led us to conclude that the concept of unbalanced kidney exchanges (manifested primarily by differential benefit between compatible and incompatible pairs) is no longer as clear cut as originally conceived. In addition, application of two concepts substantially diminishes ethical concerns including: (1) "quasi-compatible" pairs, and (2) a priori definition of mitigating factors. We conclude that genuine uncertainty exists regarding whether kidney exchange is best performed with or without compatible pair participation and that a clinical trial is therefore warranted.

Addressing morbid obesity as a barrier to renal transplantation with laparoscopic sleeve gastrectomy.

Morbid obesity is a barrier to renal transplantation and is inadequately addressed by medical therapy. We present results of a prospective evaluation of laparoscopic sleeve gastrectomy (LSG) for patients failing to achieve significant weight loss with medical therapy. Over a 25-month period, 52 obese renal transplant candidates meeting NIH guidelines for metabolic surgery underwent LSG. Mean age was 50.0 ± 10.0 years with an average preoperative BMI of 43.0 ± 5.4 kg/m(2) (range 35.8-67.7 kg/m(2)). Follow-up after LSG was 220 ± 152 days (range 26-733 days) with last BMI of 36.3 ± 5.3 kg/m(2) (range 29.2-49.8 kg/m(2)) with 29 (55.8%) patients achieving goal BMI of <35 kg/m(2) at 92 ± 92 days (range 13-420 days). The mean percentage of excess weight loss (%EWL) was 32.1 ± 17.6% (range 6.7-93.8%). A segmented regression model was used to compare medical therapy versus LSG. This revealed a statistically significant increase in the BMI reduction rate (0.3 kg/m(2)/month versus 1.1 kg/m(2)/month, p < 0.0001). Patients also experienced a 40.9% decrease in anti-hypertensive medications (p < 0.001) and a 49.7% decrease in total daily insulin dose (p < 0.001). LSG is a safe and effective means for addressing obesity in kidney transplant candidates in the context of a multidisciplinary approach.

Clinical implications of basic science discoveries: janus resurrected--two faces of B cell and plasma cell biology.

B cells play a complex role in the immune response. In addition to giving rise to plasma cells (PCs) and promoting T cell responses via antigen presentation, they perform immunoregulatory functions. This knowledge has created concerns regarding nonspecific B cell depletional therapy because of the potential to paradoxically augment immune responses. Recent studies now indicate that PCs have immune functions beyond immunoglobulin synthesis. Evidence for a new role for PCs as potent regulatory cells (via IL-10 and IL-35 production) is discussed including the implications for PC-targeted therapies currently being developed for clinical transplantation.

Prospective iterative trial of proteasome inhibitor-based desensitization.

A prospective iterative trial of proteasome inhibitor (PI)-based therapy for reducing HLA antibody (Ab) levels was conducted in five phases differing in bortezomib dosing density and plasmapheresis timing. Phases included 1 or 2 bortezomib cycles (1.3 mg/m(2) × 6-8 doses), one rituximab dose and plasmapheresis. HLA Abs were measured by solid phase and flow cytometry (FCM) assays. Immunodominant Ab (iAb) was defined as highest HLA Ab level. Forty-four patients received 52 desensitization courses (7 patients enrolled in multiple phases): Phase 1 (n = 20), Phase 2 (n = 12), Phase 3 (n = 10), Phase 4 (n = 5), Phase 5 (n = 5). iAb reductions were observed in 38 of 44 (86%) patients and persisted up to 10 months. In Phase 1, a 51.5% iAb reduction was observed at 28 days with bortezomib alone. iAb reductions increased with higher bortezomib dosing densities and included class I, II, and public antigens (HLA DRß3, HLA DRß4 and HLA DRß5). FCM median channel shifts decreased in 11/11 (100%) patients by a mean of 103 ± 54 mean channel shifts (log scale). Nineteen out of 44 patients (43.2%) were transplanted with low acute rejection rates (18.8%) and de novo DSA formation (12.5%). In conclusion, PI-based desensitization consistently and durably reduces HLA Ab levels providing an alternative to intravenous immune globulin-based desensitization.

The role of donor-specific HLA alloantibodies in liver transplantation.

The impact of donor-specific HLA alloantibodies (DSA) on short- and long-term liver transplant outcome is not clearly defined. While it is clear that not all levels of allosensitization produce overt clinical injury, and that liver allografts possess some degree of alloantibody resistance, alloantibody-mediated adverse consequences are increasingly being recognized. To better define the current state of this topic, we assembled experts to provide insights, explore controversies and develop recommendations for future research on the consequences of DSA in liver transplantation. This article summarizes the proceedings of this inaugural meeting. Several insights emerged. Acute antibody-mediated rejection (AMR), although rarely diagnosed, is increasingly understood to overlap with T cell-mediated rejection. Isolated liver allograft recipients are at increased risk of early allograft immunologic injury when preformed DSA are high titer and persist posttransplantation. Persons who undergo simultaneous liver-kidney transplantation are at risk of renal AMR when Class II DSA persist posttransplantation. Other under-appreciated DSA associations include ductopenia and fibrosis, plasma cell hepatitis, biliary strictures and accelerated fibrosis associated with recurrent liver disease. Standardized DSA testing and diagnostic criteria for both acute and chronic AMR are needed to distil existing associations into etiological processes in order to develop responsive therapeutic strategies.

Randomized controlled pilot study of B cell-targeted induction therapy in HLA sensitized kidney transplant recipients.

Optimal induction regimens for patients at high risk for antibody and/or cell-mediated rejection have not been established. This pilot, prospective, randomized study evaluated addition of B cell/plasma cell-targeting agents to T cell-based induction with rabbit antithymocyte globulin (rATG) in high immunologic risk renal transplant recipients. Patients were randomized to induction with rATG, rATG + rituximab, rATG + bortezomib or rATG + rituximab + bortezomib. Inclusion criteria were: (1) current cytotoxic panel reactive antibody (PRA) ≥20% or peak cytotoxic PRA ≥50% or (2) T or B cell positive flow crossmatch with donor-specific antibody (DSA) or (3) historical positive serologic or cytotoxic crossmatch or DSA to donor or (4) prior allograft loss with more than one acute rejection. Median overall follow-up was 496 days: 1-year and overall acute rejection were 25% and 27.5%, and 25% of patients developed de novo DSA within 1 year. One-year and overall patient survival were 97.5% and 92.5%, and 1-year and overall death-censored allograft survival were 97.5% and 95%. Renal allograft function posttransplant was similar among all arms. Eight of nine cases of peripheral neuropathy were mild, whereas one case was moderate and required a narcotic prescription. In conclusion, addition of rituximab and/or bortezomib to rATG induction has an acceptable safety/toxicity profile in a high immunologic risk renal transplant population.

Efficacy of sotrastaurin plus tacrolimus after de novo kidney transplantation: randomized, phase II trial results.

Sotrastaurin, a novel immunosuppressant, blocks early T cell activation through protein kinase C inhibition. Efficacy and safety of sotrastaurin with tacrolimus were assessed in a dose-ranging non-inferiority study in renal transplant recipients. A total of 298 patients were randomized 1:1:1:1 to receive sotrastaurin 100 (n = 77; discontinued in December 2011) or 200 mg (n = 73) b.i.d. plus standard tacrolimus (sTAC; 5-12 ng/mL), sotrastaurin 300 mg (n = 75) b.i.d. plus reduced tacrolimus (rTAC; 2-5 ng/mL) or enteric-coated mycophenolic acid (MPA) plus sTAC (n = 73); all patients received basiliximab and corticosteroids. Composite efficacy failure (treated biopsy-proven acute rejection ≥ grade IA, graft loss, death or loss to follow up) rates at Month 12 were 18.8%, 12.4%, 10.9% and 14.0% for the sotrastaurin 100, 200 and 300 mg, and MPA groups, respectively. The median estimated glomerular filtration rates were 55.7, 53.3, 64.9 and 59.2 mL/min, respectively. Mean heart rates were faster with higher sotrastaurin doses and discontinuations due to adverse events and gastrointestinal adverse events were more common. Fewer patients in the sotrastaurin groups experienced leukopenia than in the MPA group (1.3-5.5% vs. 16.5%). Sotrastaurin 200 and 300 mg had comparable efficacy to MPA in prevention of rejection with no significant difference in renal function between the groups.

Effect of corticosteroid withdrawal on tacrolimus and mycophenolate mofetil exposure in a randomized multicenter study.

As corticosteroid-sparing protocols are increasingly utilized in kidney transplant recipients, it is crucial to understand potential drug interactions between tacrolimus (TAC) and the effect of corticosteroid withdrawal as well as to characterize dose adjustments of mycophenolate mofetil (MMF) in this setting. This prospective, multicenter, randomized, double-blind study included 397 patients who were randomized on posttransplant day 8 to receive either placebo (CSWD) or corticosteroid continuance (CCS). TAC trough levels at week two posttransplant were significantly greater in the CSWD group whereas TAC doses were comparable to the CCS group. This interaction was not observed in the African American subgroup. Higher serum creatinine and potassium levels were also observed in the CSWD group. MMF dose was significantly reduced in the CSWD group by the investigators because of decreased WBC counts, mostly outside of study protocol criteria, despite similar incidence of neutropenia and reported cytomegalovirus infection. Understanding TAC and MMF exposure in the context of corticosteroid-sparing protocols should allow for improved dosing of immunosuppressants and better management of posttransplant patients.