Patricia West-Thielke

Living donor kidney transplantation across positive crossmatch: The University of Illinois at Chicago Experience

Background. To increase living donation for kidney transplantation, we investigated desensitization of recipients with positive crossmatch against a potential living donor. Methods. Between June 2001 and March 2007, 57 consecutive sensitized candidates for kidney transplantation, with crossmatch positive potential living donors, were treated with various desensitization protocols. All patients received plasmapheresis every other day with intravenous immune globulin 100 mg/kg starting 1 week before the scheduled transplant. Postoperatively, the recipients continued to receive every other day plasmapheresis with intravenous immune globulin for the initial week. Immunosuppression therapy consisted of induction with thymoglobulin and a combination of tacrolimus, mycophenolate, and corticosteroids. Results. Six patients failed to convert with pretransplant immunomodulation and were not transplanted; 51 underwent live donor kidney transplant. Mean follow-up was 23 months and 36 patients have more than 1-year follow-up. One-year patient and graft survivals were 95% and 93%, respectively. There were 25 episodes of biopsy-proven or clinically presumed rejection in 22 patients in the first year. Of the 17 biopsy-proven episodes, 12 were antibody-mediated rejection and five were acute cellular rejection. Of the patients with antibody-mediated rejection (biopsy proven or empiric), two patients (12%) lost their graft by 1 year. The median modification of diet in renal disease at 6 and 12 months was 55 mL/min (range 9–104 mL/min) and 48 mL/min (range 8–99), respectively. Conclusions. Despite increased rejection rates, graft and patient survivals indicate that desensitization of positive crossmatch patients is a reasonable alternative for a sensitized patient who could potentially wait 10 or more years for a suitable cadaveric kidney.

Novel Once-Daily Extended-Release Tacrolimus Versus Twice-Daily Tacrolimus in De Novo Kidney Transplant Recipients: Two-Year Results of Phase 3, Double-Blind, Randomized Trial

BACKGROUND 1-year data from this trial showed the noninferiority of a novel once-daily extended-release tacrolimus (LCPT; Envarsus XR) to immediate-release tacrolimus (IR-Tac) twice daily after kidney transplantation. STUDY DESIGN Final 24-month analysis of a 2-armed, parallel-group, randomized, double-blind, double-dummy, multicenter, phase 3 trial. SETTING & PARTICIPANTS 543 de novo kidney recipients randomly assigned to LCPT (n=268) or IR-Tac (n=275); 507 (93.4%) completed the 24-month study. INTERVENTION LCPT tablets once daily at 0.17 mg/kg/d or IR-Tac twice daily at 0.1 mg/kg/d; subsequent doses were adjusted to maintain target trough ranges (first 30 days, 6-11 ng/mL; thereafter, 4-11 ng/mL). The intervention was 24 months; the study was double blinded for the entirety. OUTCOMES & MEASUREMENTS Treatment failure (death, transplant failure, biopsy-proven acute rejection, or loss to follow up) within 24 months. Safety end points included adverse events, serious adverse events, new-onset diabetes, kidney function, opportunistic infections, and malignancies. Pharmacokinetic measures included total daily dose (TDD) of study drugs and tacrolimus trough levels. RESULTS 24-month treatment failure was LCPT, 23.1%; IR-Tac, 27.3% (treatment difference, -4.14% [95% CI, -11.38% to +3.17%], well below the +10% noninferiority criterion defined for the primary 12-month end point). Subgroup analyses showed fewer treatment failures for LCPT versus IR-Tac among black, older, and female recipients. Safety was similar between groups. From month 1, TDD was lower for LCPT; the difference increased over time. At month 24, mean TDD for LCPT was 24% lower than for the IR-Tac group (P<0.001), but troughs were similar (means at 24 months: LCPT, 5.47 ± 0.17 ng/mL; IR-Tac, 5.8 ± 0.30 ng/mL; P=0.4). LIMITATIONS Trial participant eligibility criteria may limit the generalizability of results to the global population of de novo kidney transplant recipients. CONCLUSIONS Results suggest that once-daily LCPT in de novo kidney transplantation has comparable efficacy and safety profile to that of IR-Tac. Lower TDD reflects LCPTs improved bioavailability and absorption.

Therapeutic Monitoring of Mycophenolic Acid: Is There Clinical Utility?

Mycophenolate mofetil (MMF) is the ester prodrug of the active immunosuppressant mycophenolic acid (MPA), an uncompetitive, selective and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). The pharmacokinetic profile of MPA is complex. MPA, as opposed to most other agents utilized in transplantation, undergoes glucoronidation as the first step in its metabolism. In addition, it undergoes extensive enterohepatic recirculation and its clearance is highly dependent on protein binding (restrictive clearance). Thus, interpretation of any monitoring strategy can be confounded by these complex processes. As an example, MPA does not have dose linearity over the first several months of administration. Therefore, at any given dose, exposure is lower in the very early posttransplant period than at later time points. These lower MPA concentrations in the immediate posttransplant period may be the result of renal dysfunction and uremia which results in decreased binding of MPA to serum albumin and increased clearance of free MPA. In addition, it is unclear if early steroid usage and changes in enterohepatic recirculation may also contribute to this ‘adaptation’ over time.

Cell population in spleens during antibody-mediated rejection: Pathologic and clinical findings

Background In the treatment of refractory antibody-mediated rejection (AMR), splenectomy has been associated with surprisingly rapid recovery of renal function. The mechanism is still unclear. Methods We review 11 recipients, who underwent rescue splenectomy (RS) as a treatment of AMR within 3 months after kidney transplantation. At transplantation, all patients had undergone desensitization for initially positive crossmatch to their prospective donors. The cellular populations of the spleen were analyzed by immunohistochemistry. For comparison, we obtained spleen specimens from eight controls who were nontransplantation patients. Results Rejection occurred in all the patients early after transplantation (mean [SD], 7.1 [5.7] days). One graft was lost 4 weeks after kidney transplantation. A significantly higher number of plasma cells (PCs) (P=0.049) and lower number of T and B lymphocytes (P=0.02 and P=0.005, respectively) were detected in the RS group compared with the control group. By analyzing the PC variations in the RS group, significantly lower numbers of PCs were detected in the spleens of patients who received rituximab before splenectomy (P=0.0004). In contrast, a higher number of PCs were found in patients (n=3) who did not respond to splenectomy and subsequently underwent bortezomib treatment and recovered their renal function (P=0.02). Conclusions Splenectomy may reverse AMR by debulking PCs. Our analysis suggests that patients with a very high load of PCs may not be rescued by splenectomy alone and may need additional treatments.

Results of Positive Cross-Match Transplantation in African American Renal Transplant Recipients

Positive cross‐match (PXM) renal transplantation has been utilized to address the issue of the increasing demand for transplantation with the shortage of suitable organs. Our primary objective was to analyze the outcomes of African American (AA) PXM renal transplant recipients utilizing AA negative cross‐match (NXM) renal transplant recipients as a comparator group. This was a retrospective study consisting of all PXM patients who underwent a desensitization protocol and all AA NXM transplant recipients at the University of Illinois at Chicago from July 2001 to March 2007. We found that AA PXM recipients had significantly lower estimated glomerular filtration rate (eGFR) at 1 year than AA NXM (46.2 vs. 60.6, p = 0.007). AA PXM who experienced acute rejection within the first year were more likely to have an eGFR less than 30 mL/min/1.73 m2 at 1 year compared to their NXM counterparts (45.5% vs. 12.5%, p = 0.034). Positive cross‐match renal transplantation in AA seems to be associated with a high degree of AR and severe renal compromise at 1 year. Larger studies are needed to determine if protocols that are associated with good short‐term outcomes in non‐AA need to be modified for the AA population.

Reported isolated pancreas rejection is associated with poor kidney outcomes in recipients of a simultaneous pancreas kidney transplant.

Background. We hypothesized that many reported and presumed isolated pancreas acute rejection episodes in simultaneous pancreas kidney patients may in fact be missed concordant kidney acute rejection episodes. Methods. To test this hypothesis, we undertook an analysis of the Organ Procurement and Transplant Network database from 1995 to 2006 to assess the impact of reported isolated pancreas rejection on kidney allograft outcomes. The primary outcome of interest was kidney graft status beyond the first posttransplant year. Results. For overall graft survival, we found that when pancreas alone rejection was compared with no rejection there was a significant difference between the curves (log-rank P<0.0001). In addition, this endpoint was also significant for death censored graft survival (log-rank P=0.0036). For both overall and death censored graft survival the multivariate analyses demonstrated an increased risk (adjusted hazards ratio: 2.46, 3.22, respectively) for patients reported to have pancreas alone rejection. Conclusions. These results indicate that patients with isolated pancreas rejection have worse renal allograft survival than patients reported as having no acute rejection and fare at least as poorly as those with reported kidney graft rejection supporting the concept of concordance of acute rejection in the majority of patients.

LCPT once‐daily extended‐release tacrolimus tablets versus twice‐daily capsules: a pooled analysis of two phase 3 trials in important de novo and stable kidney transplant recipient subgroups

African‐American and elderly kidney transplant recipients (KTR) have increased risk for poor clinical outcomes post‐transplant. Management of immunosuppression may be challenging in these patients and contribute to worse outcomes. A novel once‐daily formulation of tacrolimus (LCPT) has demonstrated noninferiority, similar safety, improved bioavailability, a consistent concentration time profile, and less peak and peak‐trough fluctuations vs. tacrolimus twice‐daily (Tac BID). This pooled analysis of two phase 3 randomized, controlled trials, including 861 (LCPT N = 428; Tac BID N = 433; 38% of patients were stable KTR, and 62% were de novo KTR) patients, examined the efficacy of LCPT in KTR subgroups (blacks, females, and age ≥65). Overall, treatment failure [death, graft failure, centrally read biopsy‐proven acute rejection (BPAR), or lost to follow‐up] at 12 months was as follows: LCPT: 11.9%, BID Tac: 13.4% [−1.48% (−5.95%, 2.99%)]. BPAR rates were as follows: LCPT: 8.2%, Tac BID: 9.5% [−1.29% (−5.14%, 2.55%)]. Numerically, fewer treatment failure events with LCPT were found in the majority of subgroups, with significantly less treatment failure associated with LCPT among black KTR [−13.82% (−27.22%, −0.31%)] and KTR ≥65 [−13.46% (−25.27%, −0.78%)]. This pooled analysis suggests numerically lower efficacy failure rates associated with LCPT among high‐risk subgroups, in particular black KTR and KTR ≥65 years old.

Combined Robot-assisted Kidney Transplantation and Sleeve Gastrectomy in a Morbidly Obese Recipient

Background Kidney transplantation confers a well-documented survival advantage for patients with end-stage renal disease (ESRD) over dialysis, regardless of body mass index (BMI). However, obese patients with ESRD have limited access to kidney transplantation. In most transplant centers, a patient with a BMI above 35 to 40 kg/m2 is either completely excluded from transplantation or is required to lose weight before being considered for transplantation. Materials and Methods Herein, we present the first case of a 35-year-old woman with a BMI of 42 kg/m2 (96.8 kg) and ESRD, who underwent combined robot-assisted kidney transplant and sleeve gastrectomy. Results The total operative time was 318 minutes with an estimated blood loss of 125 mL. At 24 months after transplantation, the patient’s weight, BMI, creatinine, and estimated glomerular filtration rate were 81.9 kg, 35.1 kg/m2, 0.79 mg/dL, and 81.2 mL/min per 1.73 m2, respectively. Conclusions Combined robot-assisted kidney transplant and sleeve gastrectomy is feasible in morbidly obese patients and adds little additional operative time.

ABO incompatible renal transplantation in an HIV-seropositive patient.

To date, there have been no reports of successful ABO blood group incompatible renal transplantation in HIV patients. We describe a case of a 47-year-old African American man with end-stage renal disease secondary to HIV-induced nephropathy who underwent a live unrelated (spouse) donor ABO blood group incompatible transplant using an intravenous immunoglobulin/plasmapheresis preconditioning regimen with interleukin-2 receptor antagonist induction along with tacrolimus and mycophenolate mofetil maintenance. The postoperative course was complicated by two acute cellular rejection (Banff Ia) episodes that were successfully managed with corticosteroid boluses and the addition of corticosteroids to maintenance immunosuppression. Antibody-mediated rejection was not observed on biopsy. The patient reached a serum creatinine nadir of 2.0 mg/dL on postoperative day 20, which has now been maintained for 170 days. His current CD4 count was 410 cells/microL.

Eculizumab for Prevention of Antibody-Mediated Rejection in Blood Group-Incompatible Renal Transplantation

Antibody-mediated rejection (AMR) is one of the leading causes of allograft failure especially in patients undergoing ABO-incompatible (ABOi) renal transplantation. We hypothesized that complement inhibition with eculizumab, a C5 inhibitor, would protect against AMR and maintain graft function in ABOi renal transplant recipients. Four patients undergoing living donor kidney transplant from ABOi donors were treated with a 9-week eculizumab course without therapeutic plasma exchange, intravenous immunoglobulin, or splenectomy. All patients had successful transplants and have normal graft function at the time of last follow-up. There were no cases of AMR or acute cellular rejection. Of note, 2 patients were transplanted despite persistent ABO antibody titers of 1:32, conventionally considered a contraindication to proceed in standard protocols. Eculizumab is a promising option to prevent AMR with ABOi renal transplantation without the need for splenectomy, post-transplant therapeutic plasma exchange, and intravenous immunoglobulin. Future multicenter studies are needed to determine long-term efficacy and safety.