Adele Rike | University of Cincinnati (original) (raw)

Papers by Adele Rike

Transplantation proceedings

Current antibody-mediated rejection (AMR) therapies (intravenous immunoglobulin, apheresis, ritux... more Current antibody-mediated rejection (AMR) therapies (intravenous immunoglobulin, apheresis, rituximab, polyclonal antibodies) do not target the primary antibody producing B cells, that is, the plasma cell. We report the preliminary results from the first clinical experience with plasma cell targeted therapy with bortezomib. Bortezomib is approved by the US Food and Drug Administration for the treatment of plasma cell tumors (multiple myeloma). Kidney transplant patients with mixed acute cellular rejection (ACR) and AMR episodes (by Banff '97 criteria, update 2005) were treated with bortezomib (1.3 mg/m(2) per dose x 4) at standard labeled doses. Patients were monitored by serial donor specific anti-HLA antibody (DSA) determinations [Luminex/Labscreen beads] and quantified by conversion to fluorescence intensity to molecules of equivalent soluble fluorescence (MESF). Five patients were treated with bortezomib. Each patient also had coexisting ACR. In each case, bortezomib treatme...

Clinical transplants, 2007

Elimination of corticosteroid-related morbidity has been a goal of transplant clinicians from the... more Elimination of corticosteroid-related morbidity has been a goal of transplant clinicians from the earliest days of renal transplantation more than 50 years ago. Over the past decade, this goal has begun to be realized. Herein, we describe our efforts to eliminate corticosteroid therapy from maintenance immunosuppression-efforts that have spanned 15 years and have included design and conduct of five multicenter trials and over ten single center trials with over 650 patients at the University of Cincinnati. These efforts have led to a near complete elimination of corticosteroid-related morbidity, and, importantly, a more precise definition of the risk/benefit assessments of corticosteroid withdrawal in individual patient populations, which has allowed individualization and tailoring of corticosteroid-free immunosuppression.

Clinical transplants, 2005

Over the past few years, significant progress has been made in the science and development of pai... more Over the past few years, significant progress has been made in the science and development of paired donation. With increasing awareness of paired donation and ready availability of the tools necessary to establish new consortia, paired donation can be made available to transplant programs and patients with increasing alacrity. Increasing registration of recipients and their donors for paired donation will lead to larger pools for matching and to transplantation of increasing numbers of patients via paired donation. As paired donation becomes common practice throughout the US and the international transplant community, its role in facilitating transplantation of sensitized patients will be better defined. Presently, paired donation remains an attractive alternative to desensitization and wait list paired donation for a majority of patients with preexisting humoral immunity to their donors.

Transplantation, 2008

ABSTRACT Purpose: Statin therapy has previously been shown to reduce acute rejection (AR) risk in... more ABSTRACT Purpose: Statin therapy has previously been shown to reduce acute rejection (AR) risk in cardiac transplant (txp). Moreover, statin therapy reduces risk for cardiovascular events (CVE) in the general population. The purpose of this study was to evaluate statin therapy on AR, CVE, and patient (pt) survival in kidney txp recipients. Methods: Pts were categorized by presence or absence of statin therapy post-txp. Univariate analysis (UVA) and multivariate analysis (MVA) were conducted by stepwise logistic regression (STATA v9.2) to determine significant risk factors for AR, CVE, and pt survival. Kaplan Meier analysis was conducted for pt survival and CVE rates. Results: 638 renal txp pts were analyzed from 1997-2007 (46% statin v. 54% no statin). Baseline characteristics and AR rates were similar between groups. Statin therapy post-txp was associated with increased pt survival (95% v. 90%, p< 0.02) and decreased incidence of CVE (15% v. 21%, p < 0.05). Individual factors for CVE evaluated by UVA and found to be insignificant included: current PRA > 25%, HDL < 40 mg/dL, African American recipient race, age, gender. Significant factors for CVE on UVA included: pre-txp diabetes (DM), statin therapy, repeat txp, deceased donor (DD), corticosteroid therapy (CS), and DR mismatch > 0. Significant factors on final MVA included: DM (OR 3.2, CI 2.0-4.9) and CS (OR 3.2, CI 2.0-4.9). Significant factors for pt survival on UVA included: pre-txp DM, statin therapy, DD, CS, delayed graft function, and DR mismatch > 0. Significant factors on final MVA included: DM, males, and CS. Statin therapy approaches significance in the MVA for decreasing risk of CVE (p=0.07) and death rates (p=0.08). Conclusions: This analysis indicates that CS increases CVE and death rates. Statin therapy offers a means for reducing cardiovascular risk in patients receiving CS. * * * *

Transplantation, 2010

Background. Rapid and complete elimination of donor-specific anti-human leukocyte antigen antibod... more Background. Rapid and complete elimination of donor-specific anti-human leukocyte antigen antibodies (DSA) during antibody-mediated rejection (AMR) is rarely achieved with traditional antihumoral therapies. Proteasome inhibitor-based therapy has been shown to effectively treat refractory AMR, but its use as a primary therapy for AMR has not been presented. Our initial experience with proteasome inhibition as a first-line therapy for AMR is presented. Methods. Adult kidney transplant recipients with AMR, diagnosed by Banff criteria, received a bortezomib-based regimen as the primary therapy. Bortezomib therapy was administered per package insert with plasmapheresis performed immediately before each bortezomib dose, and a single rituximab dose (375 mg/m 2 ) given with the first bortezomib dose. DSA were quantitated using single-antigen beads on a Luminex platform. Results. Two patients underwent bortezomib-based therapy for acute AMR occurring within the first 2 weeks after transplantation. High DSA levels and positive C4d staining of peritubular or glomerular capillaries were present at the time of diagnosis. Both patients experienced prompt AMR reversal and elimination of detectable DSA within 14 days of bortezomib-based therapy. Renal function remains excellent with normal urinary protein excretion at 5 and 6 months after AMR diagnosis. One patient experienced a repeated elevation of DSA (including two new human leukocyte antigen specificities) 2 months after initial bortezomib therapy, but without C4d deposition or histologic evidence of AMR. Retreatment with bortezomib provided prompt, complete, and durable DSA elimination. Conclusions. Proteasome inhibitor-based combination therapy provides a potential means for rapid DSA elimination in early acute AMR in renal transplant recipients.

Transplantation, 2008

Current antihumoral therapies in transplantation and autoimmune disease do not target the mature ... more Current antihumoral therapies in transplantation and autoimmune disease do not target the mature antibody-producing plasma cell. Bortezomib is a first in class proteosomal inhibitor, that is Food and Drug Administration approved, for the treatment of plasma cell-derived tumors that is multiple myeloma. We report the first clinical experience with plasma cell-targeted therapy (bortezomib) as an antirejection strategy. Eight episodes of mixed antibody-mediated rejection (AMR) and acute cellular rejection (ACR) in six transplant recipients were treated with bortezomib at labeled dosing. Monitoring included serial donor-specific antihuman leukocyte antigen antibody (DSA) levels and repeated allograft biopsies. Six kidney transplant patients received bortezomib for AMR and concomitant ACR. In each case, bortezomib therapy provided (1) prompt rejection reversal, (2) marked and prolonged reductions in DSA levels, (3) improved renal allograft function, and (4) suppression of recurrent rejection for at least 5 months. Moreover, immunodominant DSA (iDSA) (i.e., the antidonor human leukocyte antigen antibody with the highest levels) levels were decreased by more than 50% within 14 days and remained substantially suppressed for up to 5 months. One or more additional DSA were present at lower concentrations (non-iDSA) in each patient and were also reduced to nondetectable levels. Bortezomib-related toxicities (gastrointestinal toxicity, thrombocytopenia, and paresthesias) were all transient. Bortezomib therapy: (1) provides effective treatment of AMR and ACR with minimal toxicity and (2) provides sustained reduction in iDSA and non-iDSA levels. Bortezomib represents the first effective antihumoral therapy with activity in humans that targets plasma cells.

Transplantation, 2009

Few prospective trials in human leukocyte antigen (HLA) identical living donor (LD) renal transpl... more Few prospective trials in human leukocyte antigen (HLA) identical living donor (LD) renal transplantation exist. This prospective study evaluated a corticosteroid (CS)-free, calcineurin inhibitor (CNI) minimization immunosuppressive regimen in HLA-identical LD renal transplant recipients. Twenty HLA-identical LD recipients were prospectively enrolled. Immunosuppression included mycophenolate mofetil (MMF) (2 g/day), tacrolimus (target trough 4-8 ng/mL), sirolimus (target trough 6-10 ng/mL), and no pre- or postoperative steroids. In the absence of prior rejection, tacrolimus was discontinued at posttransplant day 120 and sirolimus at 1 year, leaving patients on MMF monotherapy. Tacrolimus was successfully withdrawn in 94% of patients (16/17). One hundred percent (15/15) of patients who reached 1-year posttransplant had sirolimus discontinued. Ninety-four percent (17/18) of patients remain off CSs. Mean serum creatinine at 6, 12, and 24 months were 1.38+/-0.32, 1.35+/-0.37, and 1.25+/-0.29 mg/dL; corresponding mean calculated creatinine clearance estimates were 70+/-18, 73+/-17, and 72+/-15 mL/min. Acute cellular rejection, chronic allograft nephropathy, and CNI toxicity were not observed. Death-censored graft survival was 100% at last follow-up. A CS-free, CNI minimization immunosuppressive regimen with weaning to MMF monotherapy provides excellent renal function, graft survival, and patient survival in HLA-identical LD renal transplant recipients.

Transplantation proceedings

Current antibody-mediated rejection (AMR) therapies (intravenous immunoglobulin, apheresis, ritux... more Current antibody-mediated rejection (AMR) therapies (intravenous immunoglobulin, apheresis, rituximab, polyclonal antibodies) do not target the primary antibody producing B cells, that is, the plasma cell. We report the preliminary results from the first clinical experience with plasma cell targeted therapy with bortezomib. Bortezomib is approved by the US Food and Drug Administration for the treatment of plasma cell tumors (multiple myeloma). Kidney transplant patients with mixed acute cellular rejection (ACR) and AMR episodes (by Banff '97 criteria, update 2005) were treated with bortezomib (1.3 mg/m(2) per dose x 4) at standard labeled doses. Patients were monitored by serial donor specific anti-HLA antibody (DSA) determinations [Luminex/Labscreen beads] and quantified by conversion to fluorescence intensity to molecules of equivalent soluble fluorescence (MESF). Five patients were treated with bortezomib. Each patient also had coexisting ACR. In each case, bortezomib treatme...

Clinical transplants, 2007

Elimination of corticosteroid-related morbidity has been a goal of transplant clinicians from the... more Elimination of corticosteroid-related morbidity has been a goal of transplant clinicians from the earliest days of renal transplantation more than 50 years ago. Over the past decade, this goal has begun to be realized. Herein, we describe our efforts to eliminate corticosteroid therapy from maintenance immunosuppression-efforts that have spanned 15 years and have included design and conduct of five multicenter trials and over ten single center trials with over 650 patients at the University of Cincinnati. These efforts have led to a near complete elimination of corticosteroid-related morbidity, and, importantly, a more precise definition of the risk/benefit assessments of corticosteroid withdrawal in individual patient populations, which has allowed individualization and tailoring of corticosteroid-free immunosuppression.

Clinical transplants, 2005

Over the past few years, significant progress has been made in the science and development of pai... more Over the past few years, significant progress has been made in the science and development of paired donation. With increasing awareness of paired donation and ready availability of the tools necessary to establish new consortia, paired donation can be made available to transplant programs and patients with increasing alacrity. Increasing registration of recipients and their donors for paired donation will lead to larger pools for matching and to transplantation of increasing numbers of patients via paired donation. As paired donation becomes common practice throughout the US and the international transplant community, its role in facilitating transplantation of sensitized patients will be better defined. Presently, paired donation remains an attractive alternative to desensitization and wait list paired donation for a majority of patients with preexisting humoral immunity to their donors.

Transplantation, 2008

ABSTRACT Purpose: Statin therapy has previously been shown to reduce acute rejection (AR) risk in... more ABSTRACT Purpose: Statin therapy has previously been shown to reduce acute rejection (AR) risk in cardiac transplant (txp). Moreover, statin therapy reduces risk for cardiovascular events (CVE) in the general population. The purpose of this study was to evaluate statin therapy on AR, CVE, and patient (pt) survival in kidney txp recipients. Methods: Pts were categorized by presence or absence of statin therapy post-txp. Univariate analysis (UVA) and multivariate analysis (MVA) were conducted by stepwise logistic regression (STATA v9.2) to determine significant risk factors for AR, CVE, and pt survival. Kaplan Meier analysis was conducted for pt survival and CVE rates. Results: 638 renal txp pts were analyzed from 1997-2007 (46% statin v. 54% no statin). Baseline characteristics and AR rates were similar between groups. Statin therapy post-txp was associated with increased pt survival (95% v. 90%, p< 0.02) and decreased incidence of CVE (15% v. 21%, p < 0.05). Individual factors for CVE evaluated by UVA and found to be insignificant included: current PRA > 25%, HDL < 40 mg/dL, African American recipient race, age, gender. Significant factors for CVE on UVA included: pre-txp diabetes (DM), statin therapy, repeat txp, deceased donor (DD), corticosteroid therapy (CS), and DR mismatch > 0. Significant factors on final MVA included: DM (OR 3.2, CI 2.0-4.9) and CS (OR 3.2, CI 2.0-4.9). Significant factors for pt survival on UVA included: pre-txp DM, statin therapy, DD, CS, delayed graft function, and DR mismatch > 0. Significant factors on final MVA included: DM, males, and CS. Statin therapy approaches significance in the MVA for decreasing risk of CVE (p=0.07) and death rates (p=0.08). Conclusions: This analysis indicates that CS increases CVE and death rates. Statin therapy offers a means for reducing cardiovascular risk in patients receiving CS. * * * *

Transplantation, 2010

Background. Rapid and complete elimination of donor-specific anti-human leukocyte antigen antibod... more Background. Rapid and complete elimination of donor-specific anti-human leukocyte antigen antibodies (DSA) during antibody-mediated rejection (AMR) is rarely achieved with traditional antihumoral therapies. Proteasome inhibitor-based therapy has been shown to effectively treat refractory AMR, but its use as a primary therapy for AMR has not been presented. Our initial experience with proteasome inhibition as a first-line therapy for AMR is presented. Methods. Adult kidney transplant recipients with AMR, diagnosed by Banff criteria, received a bortezomib-based regimen as the primary therapy. Bortezomib therapy was administered per package insert with plasmapheresis performed immediately before each bortezomib dose, and a single rituximab dose (375 mg/m 2 ) given with the first bortezomib dose. DSA were quantitated using single-antigen beads on a Luminex platform. Results. Two patients underwent bortezomib-based therapy for acute AMR occurring within the first 2 weeks after transplantation. High DSA levels and positive C4d staining of peritubular or glomerular capillaries were present at the time of diagnosis. Both patients experienced prompt AMR reversal and elimination of detectable DSA within 14 days of bortezomib-based therapy. Renal function remains excellent with normal urinary protein excretion at 5 and 6 months after AMR diagnosis. One patient experienced a repeated elevation of DSA (including two new human leukocyte antigen specificities) 2 months after initial bortezomib therapy, but without C4d deposition or histologic evidence of AMR. Retreatment with bortezomib provided prompt, complete, and durable DSA elimination. Conclusions. Proteasome inhibitor-based combination therapy provides a potential means for rapid DSA elimination in early acute AMR in renal transplant recipients.

Transplantation, 2008

Current antihumoral therapies in transplantation and autoimmune disease do not target the mature ... more Current antihumoral therapies in transplantation and autoimmune disease do not target the mature antibody-producing plasma cell. Bortezomib is a first in class proteosomal inhibitor, that is Food and Drug Administration approved, for the treatment of plasma cell-derived tumors that is multiple myeloma. We report the first clinical experience with plasma cell-targeted therapy (bortezomib) as an antirejection strategy. Eight episodes of mixed antibody-mediated rejection (AMR) and acute cellular rejection (ACR) in six transplant recipients were treated with bortezomib at labeled dosing. Monitoring included serial donor-specific antihuman leukocyte antigen antibody (DSA) levels and repeated allograft biopsies. Six kidney transplant patients received bortezomib for AMR and concomitant ACR. In each case, bortezomib therapy provided (1) prompt rejection reversal, (2) marked and prolonged reductions in DSA levels, (3) improved renal allograft function, and (4) suppression of recurrent rejection for at least 5 months. Moreover, immunodominant DSA (iDSA) (i.e., the antidonor human leukocyte antigen antibody with the highest levels) levels were decreased by more than 50% within 14 days and remained substantially suppressed for up to 5 months. One or more additional DSA were present at lower concentrations (non-iDSA) in each patient and were also reduced to nondetectable levels. Bortezomib-related toxicities (gastrointestinal toxicity, thrombocytopenia, and paresthesias) were all transient. Bortezomib therapy: (1) provides effective treatment of AMR and ACR with minimal toxicity and (2) provides sustained reduction in iDSA and non-iDSA levels. Bortezomib represents the first effective antihumoral therapy with activity in humans that targets plasma cells.

Transplantation, 2009

Few prospective trials in human leukocyte antigen (HLA) identical living donor (LD) renal transpl... more Few prospective trials in human leukocyte antigen (HLA) identical living donor (LD) renal transplantation exist. This prospective study evaluated a corticosteroid (CS)-free, calcineurin inhibitor (CNI) minimization immunosuppressive regimen in HLA-identical LD renal transplant recipients. Twenty HLA-identical LD recipients were prospectively enrolled. Immunosuppression included mycophenolate mofetil (MMF) (2 g/day), tacrolimus (target trough 4-8 ng/mL), sirolimus (target trough 6-10 ng/mL), and no pre- or postoperative steroids. In the absence of prior rejection, tacrolimus was discontinued at posttransplant day 120 and sirolimus at 1 year, leaving patients on MMF monotherapy. Tacrolimus was successfully withdrawn in 94% of patients (16/17). One hundred percent (15/15) of patients who reached 1-year posttransplant had sirolimus discontinued. Ninety-four percent (17/18) of patients remain off CSs. Mean serum creatinine at 6, 12, and 24 months were 1.38+/-0.32, 1.35+/-0.37, and 1.25+/-0.29 mg/dL; corresponding mean calculated creatinine clearance estimates were 70+/-18, 73+/-17, and 72+/-15 mL/min. Acute cellular rejection, chronic allograft nephropathy, and CNI toxicity were not observed. Death-censored graft survival was 100% at last follow-up. A CS-free, CNI minimization immunosuppressive regimen with weaning to MMF monotherapy provides excellent renal function, graft survival, and patient survival in HLA-identical LD renal transplant recipients.