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.

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.

Combining novel technologies with improved logistics to reduce hemodialysis vascular access dysfunction.

Hemodialysis (HD) vascular access dysfunction is currently a huge clinical problem for which there are no effective therapies. There are, however, a number of promising technologies that are currently at the experimental or clinical trial stage. We believe that the application of these novel technologies in combination with better clinical protocols for vascular access care could significantly reduce the current problems associated with HD vascular access.

Reducing de novo donor-specific antibody levels during acute rejection diminishes renal allograft loss.

The effect of de novo DSA detected at the time of acute cellular rejection (ACR) and the response of DSA levels to rejection therapy on renal allograft survival were analyzed. Kidney transplant patients with acute rejection underwent DSA testing at rejection diagnosis with DSA levels quantified using Luminex single-antigen beads. Fifty-two patients experienced acute rejection with 16 (31%) testing positive for de novo DSA. Median follow-up was 27.0 +/- 17.4 months postacute rejection. Univariate analysis of factors influencing allograft survival demonstrated significance for African American race, DGF, cytotoxic PRA >20% (current) and/or >50% (peak), de novo DSA, C4d and repeat transplantation. Multivariate analysis showed only de novo DSA (6.6-fold increased allograft loss risk, p = 0.017) to be significant. Four-year allograft survival was higher with ACR (without DSA) (100%) than mixed acute rejection (ACR with DSA/C4d) (65%) or antibody-mediated rejection (35%) (p < 0.001). Patients with >50% reduction in DSA within 14 days experienced higher allograft survival (p = 0.039). De novo DSAs detected at rejection are associated with reduced allograft survival, but prompt DSA reduction was associated with improved allograft survival. DSA should be considered a potential new end point for rejection therapy.

Proteasome inhibition reduces donor-specific antibody levels.

BACKGROUND: 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). METHODS: 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). RESULTS: Five patients were treated with bortezomib. Each patient also had coexisting ACR. In each case, bortezomib treatment led to prompt ACR and AMR rejection reversal. DSA levels decreased significantly in all patients (except 1 patient who had short follow-up). Observed toxicities from bortezomib included a transient grade III thrombocytopenia (1 patient) and mild-to-moderate nausea, vomiting, and/or diarrhea (3/5 patients). Opportunistic infections were not observed. CONCLUSIONS: Bortezomib therapy provides effective reduction in DSA levels with long-term suppression. These preliminary results indicate that proteasome inhibition provides an effective means for reducing HLA antibody levels in transplant recipients.

Measurement of hemodynamic and anatomic parameters in a swine arteriovenous fistula model.

PURPOSE: Although arteriovenous fistulae (AVFs) are currently the preferred mode of permanent hemodialysis access they do have significant problems due to initial non-maturation and a later venous stenosis. These problems appear to have been exacerbated following a push to increase AVF prevalence in the US. The reasons for both AVF non-maturation and the later venous stenoses are unclear but are thought to be related to abnormal hemodynamic wall shear stress (WSS) profiles. This technical note aims to describe the successful development of measurement techniques that can be used to establish a complete hemodynamic profile in a pig model with two different configurations of AVF. METHODS AND RESULTS: The curved and straight AVF configurations were created in an in vivo pig model. Flow and pressure in the AVFs were measured using the perivascular flow probes and Doppler flow wires while the pressure was recorded using a pressure transducer. The anatomical configuration was obtained using two different approaches: a) combination of intravascular ultrasound (IVUS) and angiograms, (b) 64 slice CT angiography. 3D models were reconstructed using image processing and computer modeling techniques. Numerical calculations were then performed by applying the measured flow and pressure data into the configurations to obtain the hemodynamic WSS profiles. CONCLUSION: The described methodologies will allow the calculation and optimization of WSS profiles in animal models. This information could then be translated to the clinical setting where it would have a positive impact on improving the early maturation rates of AVFs as well as reducing the late venous stenoses.

The native arteriovenous fistula in 2007. Surveillance and monitoring.

In the past 5 years, some clinical trials have questioned the value of surveillance in managing vascular accesses. Although prolongation of access life span is an important end point, reduction of thrombotic events reduces patient risks resulting from loss of access patency. Most of the available evidence suggests that detection of stenosis and prevention of thrombosis is valuable. When a test indicates the likely presence of a stenosis, then venography or fistulography should be used to definitively establish the presence and degree of the stenosis. In most but not all cases, angioplasty should be performed if the stenosis is greater than 50% by diameter. The value of routine use of any surveillance technique for detecting anatomic stenosis alone, without concomitant functional assessment by measurement of access flow, venous pressure, recirculation or other physiologic parameters, has not been established. Stenotic lesions should not be repaired merely because they are present. If such correction is performed, then intraprocedural or periprocedural measurement of access flow (QA) or intra-access pressure should be conducted to demonstrate a functional improvement with a successful percutaneous transluminal angioplasty.

The native arteriovenous fistula in 2007. Research needs.

Several research questions are open in the field of vascular access for hemodialysis. The present paper reviews both prognostic issues, such as the identification of factors for patient stratification before access insertion, and intervention questions, such as comparison of the advantages and disadvantages of different surgical solutions, the effects of different medications on vascular pathology, the different cannulation practices to prevent vessel wall lesions and technologies for early diagnosis of access dysfunction. Given that the quality of the available literature in nephrology is often suboptimal, nephrologists need to pay special attention to methodology issues before embarking on expensive multicenter studies.

In vitro paclitaxel and radiation effects on the cell types responsible for vascular stenosis: a preliminary analysis.

Hemodialysis vascular access dysfunction as a result of venous neointimal hyperplasia in dialysis access grafts and fistulae is currently a huge clinical problem. The aim of this study was to assess the effects of paclitaxel and radiation, both singly and in combination on the proliferation of cell types present within the lesion of venous neointimal hyperplasia (vascular smooth muscle cells, fibroblasts and endothelial cells within the neointimal microvessels). Vascular smooth muscle cells, fibroblasts and endothelial cells were plated onto 96-well plates and exposed to different concentrations and doses of paclitaxel and radiation, respectively (both individually and in combination). Growth inhibition was assessed with an MTT assay. Both paclitaxel and radiation resulted in significant growth inhibition of all three cell types. However, even small doses of paclitaxel appeared to attenuate the antiproliferative effect of radiation on these cell types. Further experiments to elucidate the mechanism behind these findings could result in a better understanding of combination antiproliferative therapies.

BRAVO I: A pilot study of vascular brachytherapy in polytetrafluoroethylene dialysis access grafts.

Hemodialysis vascular access dysfunction owing to stenosis and thrombosis in polytetrafluoroethylene dialysis access grafts is a huge clinical problem for which there are currently no long lasting durable therapies. Vascular brachytherapy has been used successfully for the prevention of coronary restenosis following angioplasty and stent placement. The Beta Radiation for Treatment of Arterial-Venous Graft Outflow I study was a pilot study of vascular brachytherapy in hemodialysis patients with patent but dysfunctional grafts. Twenty-five patients were randomized to receive either radiation therapy (a single dose of 18.4 Gy) or sham radiation, following angioplasty. The primary efficacy end point of the study was target lesion primary patency at 6 months. The primary safety end point was a composite of death, emergency surgery on the graft, venous rupture, or aneurysm formation. Forty-two percent of the radiated grafts achieved the target lesion primary patency end point at 6 months as compared to 0% of the control group (P = 0.015), but this did not translate into an improvement in secondary patency at either 6 or 12 months. Radiation therapy was found to be safe in the setting of hemodialysis vascular access dysfunction. Our results suggest that vascular brachytherapy is an intervention that is worthy of further examination in the setting of non-thrombosed dialysis access grafts.

Early corticosteroid withdrawal under modern immunosuppression in renal transplantation: multivariate analysis of risk factors for acute rejection.

UNLABELLED: Early corticosteroid withdrawal has been shown to be effective in low-risk patient populations in a number of US and European multicenter trials. However, patient populations traditionally considered to be at high risk for acute rejection (eg, African Americans, repeat transplant recipients, sensitized patients) are usually excluded from these trials. Since our initial experience with early withdrawal almost 10 years ago, we have included high-immunologic-risk patients. We have accumulated enough high-risk patients with early withdrawal to allow the first multivariate analysis of risk factors for acute rejection in early withdrawal under modern immunosuppression. METHODS: Early withdrawal was performed under prospective IRB-approved protocols. Statistical analysis included chi square test and logistic regression. All rejection episodes were biopsy proven and graded by Banff 1997 criteria. RESULTS: A total of 164 patients underwent early withdrawal: 82% had at least one mismatched DR antigen, 17% had delayed graft function, 33% were African American, and 18% were repeat transplant recipients. Multivariate analysis of risk factors for acute rejection indicated that two factors induced a statistically significant alteration in acute rejection risk: repeat transplant recipients (4.3-fold increased risk) and thymoglobulin induction (0.30 risk (ie, 70% reduction in risk compared to patients not receiving thymoglobulin induction). Sensitized recipients and African Americans were also at increased risk but did not quite reach statistical significance. These data strongly support the use of T-cell depleting antibody induction therapy in high-risk patients undergoing early withdrawal under modern immunosuppression.

Corticosteroid avoidance ameliorates lymphocele formation and wound healing complications associated with sirolimus therapy.

INTRODUCTION: Sirolimus (RAPA) and corticosteroids (CS) both inhibit wound healing. To evaluate the possibility that RAPA and CS have additive effects on wound healing, we evaluated the effects of corticosteroid avoidance (CSAV) on wound healing complications in patients treated with RAPA. METHODS: One hundred nine patients treated with a CSAV regimen (no pretransplantation or posttransplantation CS) were compared with a historical control group (n = 72) that received cyclosporine (CsA), mycophenolate mofetil (MMF), and CS. The CSAV group received low-dose CsA, MMF, RAPA, and thymoglobulin induction. Complications were classified as follows: wound healing complications (WHC) or infectious wound complications (IWC). WHC included lymphocele, hernia, dehiscence, diastasis, and skin edge separation. IWC included wound abscess and empiric antibiotic therapy for wound erythema. RESULTS: The CSAV group was largely CS-free: 11% of patients received CS for rejection, 12% of patients received CS for recurrent disease, and 85% of patients are currently off CS. The CSAV group had a significantly lower incidence of WHC (13.7% vs 28%; P = .03) and lymphoceles (5.5% vs 16%; P = .02) than the control group. There was no difference in the incidence of IWC between the 2 groups. Patients who received CSAV were 18% less likely (P = .57) to develop any type of complication, 41% less likely (P = .20) to develop a WHC, and 71% less likely (P = .018) to develop a lymphocele. CONCLUSIONS: CSAV in a RAPA-based regimen results in a marked reduction in WHC and lymphoceles. Therefore, CSAV provides a promising approach for addressing WHC associated with RAPA therapy.

Body weight alterations under early corticosteroid withdrawal and chronic corticosteroid therapy with modern immunosuppression.

UNLABELLED: Weight gain is a well-known complication of corticosteroid maintenance therapy. The purpose of our study was to compare patterns of weight gain under chronic corticosteroid therapy (CCST) to those observed under early corticosteroid withdrawal (CSWD) in renal transplant recipients. METHODS: Renal transplant recipients who underwent early CSWD in IRB-approved prospective trials were compared to a historical control group of patients receiving CCST who were matched for age, sex, and race. RESULTS: One hundred sixty-nine patients with early CSWD were compared to 132 patients who received CCST. Mean population weight gain was significantly higher in CCST patients at 12 months (5.52 kg vs 3.05 kg, P < .05) posttransplant. Caucasian CSWD patients demonstrated a greater reduction in weight gain with CSWD than African Americans (mean weight decrease 2.9 vs 1.9 kg/patient, P < .05). Patients who were overweight (body mass index [BMI] 25-30) or obese (BMI > 30) demonstrated a greater reduction in weight gain with CSWD at 1 year (mean reduction in weight gain with CSWD 5.3 kg/patient and 4.4 kg/patient) than did patients of normal weight (BMI < 25; 0.1 kg/patient, P < .01 and <.05 versus BMI < 25). CONCLUSIONS: Early CSWD patients gain significantly less weight than CCST patients following transplantation. Marked variations in the effect of early CSWD on weight gain may be observed due to race and pretransplant BMI. Caucasians and overweight patients demonstrate greater benefits from CSWD than African Americans and patients with normal BMI.

A prospective, pilot study of early corticosteroid cessation in high-immunologic-risk patients: the Cincinnati experience.

BACKGROUND: The first prospective trial of steroid withdrawal dedicated to high-immunologic-risk patients is reported herein. METHODS: Twenty-five patients were enrolled prospectively in an IRB-approved HIPAA-compliant protocol. Immunosuppression included corticosteroid withdrawal (CSWD) at 7 days, tacrolimus (target trough level 4 to 8 ng/mL), sirolimus (target trough level 8 to 12 ng/mL), and Mycophenolate Mofetil (2 g/d). Induction with daclizumab (2 mg/kg) on posttransplant days (PTD) 0 and 14 was administered to the first 10 patients. The protocol for the next 15 patients was modified because of high acute rejection rates to include received T-cell-depleting antibody induction therapy with thymoglobulin (1.5 mg/kg) on PTDs 0 and 2 followed by daclizumab on Postoperative day (POD) 14. Recipient inclusion criteria included: (1) repeat transplant recipients; or (2) patients with a peak PRA > or =25%. All rejection episodes were diagnosed by biopsy and graded using Banff '97 criteria. RESULTS: Twenty-five patients were enrolled and median follow-up was 402 days. Forty percent of recipients were black, 68% of patients were repeat transplant recipients, 68% received deceased donor kidneys, and 36% had a peak flow PRA >25%. Overall acute rejection, graft survival, and patient survival rates of 40%, 88%, and 96%, respectively, were observed for the duration of the study. Acute rejection occurred in 6 of 10 patients (60%) with daclizumab induction; however, acute rejection rates fell to 27% when thymoglobulin was introduced (P = .1). CONCLUSIONS: This study supports our previous observations in a multivariate analysis of early CSWD patients, wherein polyclonal antibody induction therapy reduced acute rejection. High-immunologic-risk patients may be able to undergo early CSWD with acceptable rates of acute rejection.

Histocompatibility testing predicts acute rejection risk in early corticosteroid withdrawal regimens.

UNLABELLED: Histocompatibility testing has been shown to predict acute rejection risk in steroid-based immunosuppression. However, little evidence exists of its ability to predict acute rejection risk in corticosteroid-free patients, with no evidence in early corticosteroid withdrawal (CSWD) under modern immunosuppression. The purpose of this study was to evaluate the ability of histocompatibility testing to identify patients at high risk for acute rejection after early CSWD. METHODS: One hundred eighty-one patients were entered into six IRB-approved early CSWD regimens. Histocompatibility testing included serologic PRA, flow cytometric PRA testing by Class I and Class II MHC beads, and B cell crossmatching with pronase treatment. All rejection episodes were biopsy proven, and grading was assigned using Banff criteria. Influence of individual tests was examined using Chi square univariate and multivariate logistic regression analysis. RESULTS: Median follow-up was 23.5 months (range 7-48 months). Of 181 patients, 16% were repeat transplant recipients, 36% received deceased donor renal transplants, 48% received living related donor renal transplants, and 16% received living unrelated transplants. Overall patient survival was 97%, and death-censored graft survival was 96.5%. Acute rejection rates in the entire follow-up period were 17.7%. 12.4% in primary transplant recipients and 37% in repeat transplant recipients. Multivariate analysis revealed that HLA AB and DR locus mismatching were associated with increased acute rejection risk. Similarly, serologic PRA analysis predicted acute rejection risk; however, flow cytometry crossmatching did not predict acute rejection risk. The greatest single influence on acute rejection risk appeared to be a flow cytometric B cell crossmatch (7.94-fold increased risk). In conclusion, histocompatibility testing can identify patients at high risk for acute rejection following early CSWD. HLA matching, serologic PRA testing, and flow cytometry-based B cell crossmatching can all be used to predict acute rejection risk.

Global cardiovascular risk under early corticosteroid cessation decreases progressively in the first year following renal transplantation.

UNLABELLED: A primary reason to eliminate corticosteroids from immunosuppressive regimens in solid organ transplant recipients is improved cardiovascular risk profiles. Although a number of studies have documented that corticosteroid withdrawal (CSWD) regimens reduce hypertension, hyperlipidemia, diabetes, and weight gain, global assessments of cardiovascular risk under CSWD have not been reported. The purpose of this study was to document cardiovascular risk under CSWD using a global risk assessment by Framingham risk assessment. METHODS: Framingham global cardiovascular risk assessments were performed at baseline and 3, 6, and 12 months posttransplant on patients enrolled in prospective, IRB-approved early (<7 days of corticosteroids) CSWD trials. Framingham score was based on age, sex, presence of diabetes, HDL and total cholesterol, and systolic blood pressure. All patients were nonsmokers. Left ventricular hypertrophy assessment by EKG criteria was not available at all time points and therefore were not included. RESULTS: One hundred eighty-three patients were included in the analysis. Fourteen percent of patients had evidence of coronary heart disease (prior MI, CABG, PTCA, or significant cardiovascular disease as evidenced by angiography) prior to transplant. Complete information was available for 160 patients at baseline, 132 at 1, 3, and 6 months, and 93 at 12 months posttransplant. Mean 10-year risk (expressed as percent) for developing coronary heart disease decreased over time: 8.03 at baseline, 8.31 at 3 months, 7.40 at 6 months, and 7.20 at 12 months, indicating that global cardiovascular risk fell at 1 year posttransplant by about 10% in renal transplant recipients undergoing early CSWD. CONCLUSIONS: Estimation of cardiovascular risk by Framingham risk factor assessment allows incorporation of several cardiovascular risk factors into a single estimate, thereby accounting for differential effects of each individual factor on global cardiovascular risk. This experience indicates that global cardiovascular risk decreases by approximately 10% at 1 year posttransplant in renal transplant recipients who undergo early corticosteroid withdrawal (CSWD).

African American renal transplant recipients benefit from early corticosteroid withdrawal under modern immunosuppression.

African Americans have historically been considered high-risk renal transplant recipients due to increased rejection rates and reduced long-term graft survival. Modern immunosuppression has reduced rejections and improved graft survival in African Americans and may allow successful corticosteroid withdrawal. Outcomes in 56 African Americans were compared to 56 non-African Americans enrolled in early withdrawal protocols. Results are reported as African American versus non-African American. Acute rejection at 1 year was 23% and 18% (P = NS), while patient and graft survival was 96% versus 98% and 91% versus 91% (P = NS), respectively. In conclusion, early withdrawal in African Americans is associated with acceptable rejection rates and excellent patient and graft survival, indicating that the risks and benefits of early withdrawal are similar between African Americans and non-African Americans. Additional followup is needed to determine long-term renal function, graft survival, and cardiovascular risk in African Americans with early steroid withdrawal.

Early steroid withdrawal does not increase risk for recurrent focal segmental glomerulosclerosis.

UNLABELLED: Experience with early corticosteroid withdrawal (CSWD) in renal transplant recipients with focal segmental glomerulosclerosis (FSGS) has not been previously reported. Since corticosteroids are used to treat primary FSGS, concern exists as to whether early CSWD regimens will be associated with an increased risk of FSGS recurrence posttransplant. The purpose of the present study was to evaluate the results of early CSWD in FSGS recipients and compare these results to a historic control group of FSGS patients who underwent renal transplantation under corticosteroid-based immunosuppression. METHODS: Forty-three patients with FSGS underwent renal transplantation with early CSWD. Results in these patients were compared to FSGS patients that underwent renal transplantation with chronic corticosteroid therapy. All rejection episodes were biopsy proven with grading by Banff criteria. Statistical analyses included Student's t test and chi square tests. RESULTS: Results in 43 patients with a median follow-up of 569 days were analyzed and compared to control patients. There was no significant difference in recurrent FSGS, time to recurrence, or graft loss. CONCLUSION: CSWD does not increase risk for recurrence of FSGS. These observations indicate that ECSW can be achieved in FSGS patients, thereby affording them the benefits of steroid elimination.

Outcomes of patients with rejection post-polyomavirus nephropathy.

INTRODUCTION: We sought to determine the effects of rejection in renal transplant recipients with polyomavirus nephropathy (PVN). METHODS: SCr, biopsy findings, BKV serum and urine loads (Taqman PCR), and BKV antibody titers (HA inhibition assay) were analyzed by two-sample median tests and z tests in 11 patients with median follow-up of 7.3 (2.0 to 31.5) months post-PVN. All patients underwent immunosuppression reduction (ISR) as PVN treatment. RESULTS: Post-PVN, 3 (27%) patients had five rejection episodes, with 80% being mild. Median time to rejection was 18 (2 to 60) weeks. One hundred percent of patients who experienced post-PVN rejection also experienced rejection pre-PVN. Rejection episode treatments consisted of: none in one, increased tacrolimus in two, IVIG in one, IVIG and increased tacrolimus in one. Median viral loads in patients with post-PVN rejection versus those without rejection were not different in serum (2.01 x 10(4) vs 9.00 x 10(4) BKV copies/mL; P = .22) or urine (5.37 x 10(5) vs 8.93 x 10(6) BKV copies/mL; P = .28). Median BKV antibody titers were slightly lower (16384 vs 32768 HA units; P = .02) and median SCr values were significantly higher (2.7 vs 1.9 mg/dL, P = .0003) in patients who had experienced post-PVN rejection. Graft losses occurred in one rejection-free patient (chronic allograft nephropathy) and in one patient who experienced multiple acute rejection episodes, humoral rejection, and worsening PVN. CONCLUSIONS: Patients who experience rejection prior to PVN are at high risk of developing rejection post-ISR and post-PVN; however, low graft loss rates may still be achieved.