Proteasome inhibition with bortezomib: an effective therapy for severe antibody mediated rejection after renal transplantation.

Antibody-mediated rejection (AMR) following renal transplantation is less responsive to conventional anti-rejection therapies. Plasmapheresis (PP), intravenous immunoglobulin (IVIg), rabbit antithymocyte globulin (rATG) and rituximab deplete immature B-cells but not mature plasma cells. The proteasome inhibitor bortezomib has activity against mature plasma cell, the source of damaging donor-specific antibody (DSA).We present the successful use of bortezomib in 2 patients who developed AMR following kidney transplantation. The first patient was a 54-year-old white female who received living-unrelated kidney transplantation from her husband. She developed severe AMR early after transplantation with rising DSA titers consistent with an anamnestic immune response by memory cells to the donor antigens. Renal function deteriorated despite treatment with pulse methylprednisolone (MP), PP and IVIg. After initiation of therapy with bortezomib, DSA titers became negative and serum creatinine returned to baseline with histological resolution of AMR. The second patient was a 19-year-old white male who received deceased donor kidney transplantation and developed AMR within 2 weeks, refractory to therapy with pulse MP, PP and IVIg with rising DSA. Bortezomib use resulted in disappearance of DSA and renal function improvement. Both patients tolerated the treatment well with stable renal function at last follow-up. The novel mechanisms of action and preliminary results with bortezomib are encouraging, but require larger studies and longer follow-up.

Predictors of infection requiring hospitalization in patients with systemic lupus erythematosus: a time-to-event analysis.

OBJECTIVES: To evaluate the predictors of serious infection in patients with systemic lupus erythematosus (SLE). METHODS: Serious infections were identified in SLE patients in a prospectively-followed single centre cohort. Associations of serious infection with disease-related variables and medication use were analysed using Cox and related regression models. RESULTS: 346 patients were followed for a mean (SD) of 6.6 (3.7) years. 86 episodes of serious infection were observed, with an incidence rate of 3.8 episodes per 100 person-years. Patients who had serious infection had higher baseline SLE Damage Index (SDI) and Charlston Comorbidity Index (CCI); they were also more likely to have high disease activity status (HDAS), and higher disease activity in multiple clinical domains, higher flare rates, higher time-adjusted prednisolone dose exposure, and less time in lupus low disease activity state (LLDAS). Patients who have received cyclophosphamide, rituximab and mycophenolate were more likely to have experienced serious infection. After multivariable adjustment in Cox regression analysis, cyclophosphamide, higher SDI score, and higher disease activity were associated with an increased hazard of first serious infection. History of previous serious infection conferred the highest risk. Lymphopenia was also a modest but statistically significant predictor of serious infection. CONCLUSION: History of previous serious infection was the strongest predictor of serious infection in our SLE cohort. This study also suggests that clinical factors such as damage accrual, disease activity, and choice of immunosuppressant, can each have an independent risk in predicting serious infection particularly the first episode.

SARS-COV-2 vaccine acceptance in patients with rheumatic diseases: a cross-sectional study.

OBJECTIVES: To evaluate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine acceptance among patients with rheumatic diseases (RMD). METHODS: All rheumatology patients attending a large suburban health network were invited to participate in an anonymized online survey. The primary outcome of interest was SARS-COV-2 vaccine acceptance. RESULTS: The mean (SD) age of respondents (n = 641) was 52.7 (15.1) years and 74.4% (n = 474) were female. Sixty-five percent were willing to have a SARS-COV-2 vaccine, while 34.4% were vaccine-hesitant (unwilling or undecided). On multivariate analysis, vaccine acceptance was associated with smoking (OR: 2.25 [95% CI: 1.22-4.15; p = .009]), history of malignancy (OR: 2.51 [95% CI: 1.19-5.26; p = .015]), influenza or pneumococcal vaccination in the preceding year (OR: 2.69 [95% CI: 1.78-4.05; p < .001]) and number of COVID-Safe measures practiced (OR: 1.54 [95% CI: 1.05-2.26; p = .027]). Vaccine acceptance correlated with positive beliefs regarding vaccine efficacy (r = 0.40; p < .001) and safety (r = 0.36; p < .001). Vaccine acceptance correlated negatively with concerns regarding side-effects (r = -0.30; p < .001) and vaccine-associated RMD flare (r = -0.21; p < .001). In vaccine-hesitant respondents, 39.2% were more likely to accept vaccination if given a choice of which vaccine they receive and 54.5% if their rheumatologist recommended it. Twenty-seven percent of patients on immunomodulators were willing to withhold medications while 42.1% were willing if advised by their rheumatologist. CONCLUSION: SARS-COV-2 vaccine hesitancy is prevalent amongst RMD patients and associated with concerns regarding vaccine safety, efficacy, side effects and RMD flare. Clinician recommendation, vaccine choice and communications targeting patient concerns could facilitate vaccine acceptance.Significance and Innovations Vaccine hesitancy is prevalent in RMD patientsVaccine acceptance is associated with beliefs regarding vaccine safety and efficacy and concerns regarding RMD flare and vaccine-associated side effectsVaccine choice and clinician recommendation have the potential to improve vaccine acceptance in patients who are hesitant.

A Description of the Type, Frequency and Severity of Infections Among Sixteen Patients Treated for T-Cell Lymphoma.

BACKGROUND: Infections are an important cause of morbidity and mortality in T-cell lymphomas. Factors contributing to increased risk of infection include the nature of the underlying disease, as well as treatment-associated immunosuppression. Currently there are few reports describing the types of infections, including preventable infections, in this cohort of patients. The aim of the study was to identify the type, frequency and severity of infection in patients with T-cell lymphoma undergoing treatment. METHODS: A case series was performed on all patients with T-cell lymphoma over a 5-year period from 2011 to 2016 at a tertiary Australian hospital. Information was collected from medical record review regarding patient demographics, lymphoma treatment and outcomes, and infectious outcomes. Severe infections were recorded, defined as infection requiring hospitalization. RESULTS: Sixteen patients were identified with a diagnosis of T-cell lymphoma who received treatment at our institution. There were 42 discrete episodes of severe infections in total. Severe infections occurred in 81% of patients, with over 40% having more than one infection. The median length of hospital stay was 13 days, 33% required intensive care admission and 14% of infectious episodes resulted in death. Only 50% of infectious episodes were microbiologically proven, with the most common etiology being bacterial. The most commonly isolated organism overall was Staphylococcus aureus, with the most common source of infection being skin and soft tissue. There was one case of cytomegalovirus (CMV) infection and five cases (12%) of invasive fungal infection. The highest rates of infection occurred during progressive disease. Rates of prophylaxis were highest with antiviral agents, and comparatively lower with antibacterial and antifungal agents. CONCLUSION: Infections are frequent, opportunistic and severe in patients with T-cell lymphoma. Our data suggests that fungal prophylaxis may be indicated with T-cell lymphoma.

Clinical outcome of hypertension management.

OBJECTIVE: This study aimed to investigate the association between inadequately controlled hypertension, medication use pattern and the incidence of cardiovascular events (CVEs) over 5 years. The cost of hospitalisation associated with inadequately controlled hypertension was estimated. METHODS: This was a retrospective observational study of patients who were diagnosed with hypertension with at least one blood pressure reading recorded at baseline (year 2000), reviewed from 2001-2005. Primary endpoints were the extent, duration and prevalence of blood pressure deviation from treatment goals. Secondary endpoints were incidence of CVEs and the number of days of hospitalisation associated with inadequately controlled hypertension. RESULTS: In total, the medical records of 210 patients were reviewed. Statistically significant positive associations were found between inadequately controlled systolic blood pressure with the incidence of CVEs (p=0.018) and increased cardiovascular drugs (p<0.001), non-cardiovascular drugs (p=0.019) and total drug usage (p<0.001). Similar observations were observed between inadequately controlled diastolic blood pressure and increased cardiovascular (p<0.05) and total (p=0.007) drug usage. Patients with uncontrolled blood pressure at all times during the study period were associated with a higher incidence of CVEs (p=0.026). The mean cost of hospitalisation due to CVEs was estimated to be HK$42,584.0 +/- 36,670.0 (US$1 = HK$7.8) and it accounted for 3.3% of the total healthcare expenditure during 2005. CONCLUSION: Inadequately controlled blood pressure is positively associated with an increased incidence of CVEs and polypharmacy in Hong Kong Chinese hypertensive patients.

Steroid avoidance in renal transplant patients maintained on a cyclosporine-based protocol.

OBJECTIVE: The aim of this study was to analyze the effect of steroid avoidance, as compared with our pre-existing protocol that contained steroids, on renal allograft and patient survival. Secondary outcomes included body weight, diabetes, hyperlipidemia, and infection. MATERIALS AND METHODS: This retrospective chart review of the results of steroid avoidance was performed in 169 patients who had undergone renal transplant between January 2000 and March 2002 and had received an immunosuppression regimen of cyclosporine, mycophenolate mofetil, and prednisone; and 148 patients who had undergone transplant between November 2002 and November 2004 who had received induction immunosuppression with a steroid taper by postoperative day 4 and were maintained on cyclosporine and mycophenolate mofetil. RESULTS: One-year allograft survival rates, rejection-free graft survival rates, and patient survival rates were 88%, 76%, and 97%, respectively, in the steroid-maintenance group compared with 90%, 74%, and 96%, respectively, in the steroid-avoidance group (P = NS). No differences were detected in multiple secondary variables related to the metabolic effects of steroid therapy. CONCLUSIONS: These data suggest that steroid avoidance can be performed safely and effectively in patients on a cyclosporine-based protocol of immunosuppression. Longer follow-ups are suggested to determine the effects of limited steroid exposure on the metabolic profiles of patients.

Outcomes of Early Steroid Withdrawal in Recipients of Deceased-Donor Expanded Criteria Kidney Transplants in the Era of Induction Therapy.

OBJECTIVES: This study explored the safety of early steroid withdrawal in recipients of expanded criteria deceased-donor kidney transplants. MATERIALS AND METHODS: Using the Organ Procurement and Transplant Network-United Network of Organ Sharing database, we identified patients who underwent expanded criteria deceased-donor kidney transplant between January 2000 and December 2008 after receiving induction with rabbit-antithymocyte globulin (n = 3717), alemtuzumab (n = 763), or interleukin 2 blocking agent (n = 2600) followed by calcineurin inhibitor and mycophenolate mofetil-based maintenance with and without steroid therapy. RESULTS: Adjusted overall graft survival (hazard ratio 1.32; 95% confidence interval, 1.1-1.56; P = .002) and patient survival (hazard ratio 1.46, 95% confidence interval, 1.16-1.83, P = .001) were inferior, whereas death-censored graft survival (hazard ratio 1.13; 95% confidence interval, 0.87-1.47; P = .35) was similar for chronic steroid maintenance versus early steroid withdrawal groups in rabbit-antithymocyte globulin-induced patients. Graft and patient outcomes were similar for chronic steroid maintenance versus early steroid withdrawal groups among alemtuzumab and interleukin 2 blocking agent-induced patients. Among rabbit-antithymocyte globulin-induced patients, adjusted overall graft survival (hazard ratio 1.57; 95% confidence interval, 1.2-2.0; P < .001) and patient survival (hazard ratio 1.5; 95% CI, 1.15-2.1; P = .004) were inferior, whereas death-censored graft survival (hazard ratio 1.5; 95% confidence interval, 0.97-2.43; P = .07) trended inferior for chronic steroid maintenance versus early steroid withdrawal groups in recipients > 60 years old (n = 1729). CONCLUSIONS: Our study showed safety of early steroid withdrawal in recipients of expanded criteria deceased-donor kidney transplants who underwent perioperative induction followed by calcineurin inhibitor and mycophenolate mofetil maintenance. Among rabbit-antithymocyte globulin-induced patients, chronic steroid maintenance was associated with inferior graft and patient outcomes, an effect limited to older recipients.

Impact of steroid maintenance on the outcomes in first-time deceased donor kidney transplant recipients: Analysis by induction type.

AIM: To analyze the impact of steroid maintenance on the outcomes in kidney transplant recipients stratified by induction agent received. METHODS: Patients who underwent first-time deceased donor kidney transplantation between 2000 and 2008 after receiving induction therapy with rabbit-antithymocyte globulin (r-ATG), alemtuzumab or an interleukin-2 receptor blocker (IL-2B) and discharged on a calcineurin inhibitor (CNI)/mycophenolate mofetil (MMF)-regimen along with or without steroids were identified from the Organ Procurement and Transplant Network/United Network of Organ Sharing database. For each induction type, adjusted overall and death-censored graft as well as patient survivals were compared between patients discharged on steroid vs no steroid. Among r-ATG induced patients, analysis was repeated after splitting the group into low and high immune risk groups. RESULTS: Among the 37217 patients included in the analysis, 17863 received r-ATG (steroid = 13001, no-steroid = 4862), 3028 alemtuzumab (steroid = 852, no-steroid = 2176) and 16326 IL-2B (steroid = 15008, no-steroid = 1318). Adjusted overall graft survival was inferior (HR = 1.16, 95%CI: 1.06-1.27, P = 0.002) with similar death-censored graft survival (HR = 0.99, 95%CI: 0.86-1.14, P = 0.86) for steroid vs no-steroid groups in r-ATG induced patients. Both adjusted overall and death-censored graft survivals for steroid vs no-steroid groups were similar in alemtuzumab (HR = 0.92, 95%CI: 0.73-1.15, P = 0.47 and HR = 0.87, 95%CI: 0.62-1.22, P = 0.43 respectively) and IL-2B (HR = 1.05, 95%CI: 0.91-1.21, P = 0.48 and HR = 0.94, 95%CI: 0.75-1.18, P = 0.60 respectively) induced groups. Adjusted patient survivals were inferior for steroid vs no-steroid groups in r-ATG induced (HR = 1.31, 95%CI: 1.15-1.49, P < 0.001) but similar in alemtuzumab (HR = 1.02, 95%CI: 0.75-1.38, P = 0.92) and IL-2B (HR = 1.17, 95%CI: 0.97-1.40, P = 0.10) induced patients. Among the r-ATG induced group there were 4346 patients in the low immune risk and 13517 patients in the high immune risk group. Adjusted overall graft survivals were inferior for steroid vs no steroid groups in both low immune (HR = 1.34, 95%CI: 1.09-1.64, P = 0.001) and high immune (HR = 1.18, 95%CI: 1.07-1.30, P = 0.005) risk groups. Adjusted death-censored graft survivals for steroid vs no steroid groups were similar in both low (HR = 1.06, 95%CI: 0.78-1.45, P = 0.70) and high (HR = 1.04, 95%CI: 0.98-1.20, P = 0.60) immune risk groups. Adjusted patient survivals were inferior for steroid vs no steroid groups in both low immune (HR = 1.54, 95%CI: 1.18-2.02, P < 0.001) and high immune (HR = 1.32, 95%CI: 1.16-1.51, P = 0.002) risk groups. Overall, there were significantly higher deaths from infections and cardiovascular causes in patients maintained on steroids. CONCLUSION: Our study showed an association between steroid addition to a CNI/MMF-maintenance regimen and increased death with functioning graft in patients receiving r-ATG induction for first-time deceased donor kidney transplantation.

Influence of induction modality on the outcome of deceased donor kidney transplant recipients discharged on steroid-free maintenance immunosuppression.

BACKGROUND: Over last several years, alemtuzumab induction has been increasingly used in kidney transplantation especially in patients maintained on steroid-free immunosuppression. It is unclear which induction agent is associated with better graft and patient outcomes in these patients. METHODS: Using Organ Procurement and Transplant Network/United Network of Organ Sharing database, graft and patient survivals were compared with multivariate analysis for deceased donor kidney transplant recipients from January 2000 to December 2008 who received induction with rabbit-antithymocyte globulin (r-ATG), alemtuzumab, or an interleukin-2 (IL-2) receptor blocker and were discharged on a calcineurin inhibitor/mycophenolate mofetil/steroid-free immunosuppression. RESULTS: When compared with r-ATG (n=5348), adjusted graft survival was inferior with alemtuzumab (n=2428, hazards ratio [HR] 1.26, 95% confidence interval [CI] 1.10-1.43, P=0.001) and IL-2 receptor blocker (n=1396, HR 1.19, 95% CI 1.01-1.39, P=0.04) inductions and patient survival was inferior with alemtuzumab (HR 1.29, 95% CI 1.08-1.55, P=0.006). Alemtuzumab induction was associated with higher adjusted graft failure risks in patients with panel reactive antibody more than 20% (HR 1.30, 95% CI 1.01-1.68, P=0.04), recipients of expanded criteria donor kidneys (HR 1.58, 95% CI 1.23-2.02, P<0.001), and kidneys with cold ischemia time more than 24 hr (HR 1.31, 95% CI 1.04-1.65, P=0.02) and higher patient death risks in recipients of expanded criteria donor kidney (HR 1.66, 95% CI 1.20-1.30, P=0.002) and kidneys with cold ischemia time more than 24 hr (HR 1.44, 95% CI 1.04-2.00, P=0.03). Adjusted graft survival rates were similar for different induction agents in the low-immune risk group. CONCLUSIONS: When compared with alemtuzumab and IL-2 receptor blocker, r-ATG induction seems to be associated with superior outcomes in deceased donor kidney transplant recipients maintained on calcineurin inhibitor/mycophenolate mofetil/steroid-free regimen.

Treatment of antibody-mediated rejection in kidney transplant recipients: a single-center experience with a bortezomib-based regimen.

OBJECTIVES: Antibody-mediated rejection after kidney transplant is less responsive to conventional antirejection therapies. The proteasome inhibitor bortezomib has activity against mature plasma cells that produce damaging donor-specific antibodies. We present our experience of using a bortezomib-based regimen in patients with severe antibody-mediated rejection. MATERIALS AND METHODS: A retrospective chart review was performed on patients with biopsy-proven antibody-mediated rejection after kidney transplant at our institution over 12 months. Diagnosis of antibody-mediated rejection was made on the basis of positive peritubular capillary C4d staining along with either histologic evidence of acute rejection or positive donor-specific antibody titers. Treatment for antibody-mediated rejection included plasmapheresis, intravenous immunoglobulin, steroids, single-dose rituximab (375 mg/m²) along with bortezomib (1.3 mg/m²) on days 1, 4, 8, and 11. Antibody-mediated rejection was diagnosed in 6 patients. Patients received induction with either alemtuzumab (n=4) or rabbit-antithymocyte globulin (n=2) and were maintained on a tacrolimus/mycophenolate mofetil/early steroid withdrawal protocol. RESULTS: Four of 6 patients responded to treatment. Patients had stable kidney function during followup (median 14 months) after bortezomib therapy. CONCLUSIONS: In this series, we demonstrated the effectiveness of a bortezomib-based treatment regimen in achieving reduction of donor-specific antibody titers and stable renal function in patients experiencing severe antibody-mediated rejection.

Effect of high-dose erythropoietin on graft function after kidney transplantation: a randomized, double-blind clinical trial.

BACKGROUND AND OBJECTIVES: Delayed graft function (DGF) is associated with adverse long-term outcomes after deceased-donor kidney (DDK) transplantation. Ischemia-reperfusion injury plays a crucial role in the development of DGF. On the basis of promising animal data, this study evaluated any potential benefits of erythropoietin-alfa (EPO-α) given intra-arterially at the time of reperfusion of renal allograft on the degree of allograft function, as well as tubular cell injury measured by urinary biomarkers in the early post-transplant period. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A prospective, randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the influence of EPO-α administered intraoperatively on the outcomes of DDK transplantations performed at the study center between March 2007 and July 2009. RESULTS: Seventy-two patients were randomly assigned to EPO-α (n=36) or placebo (n=36). The incidences of DGF, slow graft function, and immediate graft function did not significantly differ between the treatment and control groups (41.7% versus 47.2%, 25.0% versus 36.1%, and 33.3% versus 16.7%, respectively; P=0.24). The groups had similar levels of urinary biomarkers, including neutrophil gelatinase-associated lipocalin and IL-18 at multiple times points soon after transplantation; urinary output during the first 3 postoperative days; 1-month renal function; and BP readings, hemoglobin, and adverse effects during the first month. CONCLUSIONS: This study did not show any clinically demonstrable beneficial effects of high-dose EPO-α given intra-arterially during the early reperfusion phase in DDK transplant recipients in terms of reducing the incidence of DGF or improving short-term allograft function.

Transplantation and the primary care physician.

Increasing appreciation of the survival benefits of kidney transplantation, compared with chronic dialysis, has resulted in more patients with kidney disease being referred and receiving organs. The evolving disparity between a rapidly increasing pool of candidates and a smaller pool of available donors has created new issues for the physicians who care for kidney patients and their potential living donors. This article outlines current efforts to address the growing number of patients who await transplantation, including relaxation of traditional donation criteria, maximization of living donation, and donation schemas that permit incompatible donor-recipient pairs to participate through paired donation and transplantation chains. New ethical issues faced by donors and recipients are discussed. Surgical advances that reduce the morbidity of donors are also described, as is the role of the primary physician in medical issues of both donors and recipients.

Sorbent hemodialysis: clinical experience with new sorbent cartridges and hemodialyzers.

To recycle spent dialysate, a sorbent hemodialyzer uses a purification cartridge, adapted from water reclamation systems originally designed for the aerospace program. Increasing interest in home hemodialysis has driven a renewed examination of sorbent dialyzer technology, resulting in the development of a modern sorbent hemodialyzer and an array of new sorbent cartridges. Initial clinical experience with the Allient Hemodialysis System and the new sorbent cartridges is presented, with an emphasis on achievable clearances and ultrafiltration, as well as information about symptom profile and electrolyte balance.