Timothy A. Horwedel
Washington University in St. Louis
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Clinical Transplantation | 2009
Christin C. Rogers; Scott R. Johnson; Didier A. Mandelbrot; Martha Pavlakis; Timothy A. Horwedel; Seth J. Karp; Ogo Egbuna; James R. Rodrigue; Robyn Chudzinski; Alexander S. Goldfarb-Rumyantzev; Douglas W. Hanto; Michael P. Curry
Abstract: The long‐term use of calcineurin inhibitors (CNI) leads to renal dysfunction in many liver transplant (LT) recipients. The purpose of this analysis is to evaluate renal function in patients converted from CNI to sirolimus (SRL). From May 2002–November 2006, 137 LT were performed in 125 patients, 72 of which were converted to SRL. Evaluation of SRL conversion was stratified by early conversion (<90 d from LT) (EC) vs. late conversion (LC). Renal function was evaluated using the six‐point modification of diet in renal disease formula (estimated glomerular filtration rate [eGFR]). Forty‐two patients on SRL and 40 on CNI had at least three months of follow‐up and are included in the eGFR evaluation. At all time points after conversion, the EC group demonstrated a significantly higher mean eGFR than those in the LC group. A significant improvement in eGFR was seen within the EC group when comparing eGFR at time of conversion to eGFR at three, six, nine, and 12 months after conversion and last follow‐up. The only improvement in the LC group was from conversion to the three‐month time point. We conclude that EC to SRL results in a profound improvement in eGFR that begins at three months and is sustained beyond one yr.
Journal of The American Society of Nephrology | 2017
Michael E. Seifert; Muthukumar Gunasekaran; Timothy A. Horwedel; Reem Daloul; Gregory A. Storch; Thalachallour Mohanakumar; Daniel C. Brennan
Humoral immune responses against donor antigens are important determinants of long-term transplant outcomes. Reactivation of the polyomavirus BK has been associated with de novo antibodies against mismatched donor HLA antigens in kidney transplantation. The effect of polyomavirus reactivation (BK viremia or JC viruria) on antibodies to kidney-specific self-antigens is unknown. We previously reported excellent 5-year outcomes after minimization of immunosuppression for BK viremia and after no intervention for JC viruria. Here, we report the 10-year results of this trial (n=193) along with a nested case-control study (n=40) to explore associations between polyomavirus reactivation and immune responses to the self-antigens fibronectin (FN) and collagen type-IV (Col-IV). Consistent with 5-year findings, subjects taking tacrolimus, compared with those taking cyclosporin, had less acute rejection (11% versus 22%, P=0.05) and graft loss (9% versus 22%, P=0.01) along with better transplant function (eGFR 65±19 versus 50±24 ml/min per 1.73 m2, P<0.001) at 10 years. Subjects undergoing immunosuppression reduction for BK viremia had 10-year outcomes similar to those without viremia. In the case-control study, antibodies to FN/Col-IV were more prevalent during year 1 in subjects with polyomavirus reactivation than in those without reactivation (48% versus 11%, P=0.04). Subjects with antibodies to FN/Col-IV had more acute rejection than did those without these antibodies (38% versus 8%, P=0.02). These data demonstrate the long-term safety and effectiveness of minimizing immunosuppression to treat BK viremia. Furthermore, these results indicate that polyomavirus reactivation associates with immune responses to kidney-specific self-antigens that may increase the risk for acute rejection through unclear mechanisms.
Transplantation | 2017
Tarek Alhamad; Andrew F. Malone; Daniel C. Brennan; Robert J. Stratta; Su-Hsin Chang; Jason R. Wellen; Timothy A. Horwedel; Krista L. Lentine
Background Successful pancreas transplantation requires surgical expertise and multidisciplinary medical management. The impact of transplant center volume on pancreas allograft survival remains unclear. Methods We examined Organ Procurement and Transplantation Network data on 11 568 simultaneous pancreas-kidney (SPK) and 4308 solitary pancreas (pancreas transplant alone and pancreas after kidney) transplants between 2000 and 2013. Results Average annual transplant center volume was categorized by tertiles into low, medium, and high volume, respectively, as follows: 1 to 6 (n = 3861), 7 to 13 (n = 3891), and 14 to 34 (n = 3888) for SPK, and 1 to 3 (n = 1417), 4 to 10 (n = 1518), and 11 to 33 (n = 1377) for solitary pancreas transplants. Favorable donor characteristics were seen in low-volume centers. For SPK transplantation, low (adjusted hazard ration [aHR], 1.55, 95% confidence interval [CI], 1.34-1.8) and medium (aHR, 1.24; 95% CI, 1.07-1.44) center volumes were associated with a higher risk of early pancreas graft failure at 3 months. The increased risk associated with low center volume extended to 1, 5, and 10 years. For solitary pancreas transplants, low, but not medium, center volume was associated with a higher risk of early pancreas graft failure at 3 months (aHR, 1.56; 95% CI, 1.232-1.976), and this risk persisted over 10 years. Patients transplanted at high-volume centers had better pancreas survival rates across all categories of the Pancreas Donor Risk Index. Conclusion On average, low center volume were associated with higher risk for pancreas failure. Future studies should seek to identify care processes that support optimal outcomes after pancreas transplantation irrespective of center volume.
Transplant International | 2017
Joseph G. Maliakkal; Daniel C. Brennan; Charles W. Goss; Timothy A. Horwedel; Howard Chen; Dennis K. Fong; Nikhil Agarwal; Jie Zheng; Kenneth B. Schechtman; Vikas R. Dharnidharka
Ureteral stent (UrSt) placement has been shown to be a significant independent risk factor for BK viruria, viremia, and BK virus nephropathy. We assessed whether this observation could be validated at our high volume kidney transplant center that has had a strong historical focus on BK virus nephropathy detection. We performed a retrospective case–control study of adults receiving a kidney‐only transplant and followed for 1 year between 2004 and 2011 with uniform immunosuppression and use of blood BK virus PCR screening protocol. Among 1147 patients, 443 (38.6%) received a UrSt and 17.2% with a UrSt had BK viremia versus 13.5% without stent (odds ratio 1.33; 95% CI: 1.00–1.78). We confirmed a previously reported association between immediate graft function (IGF) and higher rate of BK viremia (15.7% vs. 5.9% in patients without IGF). On multivariable competing risks Cox regression in patients with IGF, UrSt (adjusted hazard ratio [aHR] 1.35; 95% CI: 1.04–1.75) and African American race (aHR 1.47; 95% CI: 1.04–2.09) significantly increased the risk for BK viremia. In the largest sample size to date, we confirmed that UrSt placement during kidney transplant surgery is a risk factor for BK viremia within the first year post‐transplant and that IGF is associated with BK viremia.
American Journal of Nephrology | 2015
Michael L. Spinner; Lyndsey J. Bowman; Timothy A. Horwedel; Rowena Delos Santos; Christina L. Klein; Daniel C. Brennan
Background/Aims: Post-renal transplant recurrent glomerulonephritis (GN) contributes to allograft loss. Rituximab treatment has been used in a multidose strategy with variable efficacy and toxicity. We investigated a novel single-dose approach. Methods: A single center, retrospective, cohort study was conducted between January 1998 and April 2012 among renal allograft recipients with recurrent GN treated with rituximab (cases) or without (controls). The primary outcome was complete response (CR, urine protein/creatinine ratio (UP/C) <0.3). Secondary outcomes included partial response (PR >50% reduction in UP/C), response relapse, treatment-response by GN type, acute rejection incidence, time to graft loss, and infection incidence. Results: The median dose of rituximab was 200 mg per patient. Of 20 rituximab cases and 13 controls, CR was achieved in eight (40%) versus four (31%), respectively (p = 0.72). Three subjects in each group achieved PR (p = 0.66). Response relapse was similar between the two groups (p = 0.47). Significantly more subjects with recurrent membranous nephropathy (MN) achieved CR with rituximab treatment (p = 0.029). Acute rejection was lower in the rituximab group versus controls (n = 0 vs. 4; p = 0.046). The mean time to graft loss was much later in the rituximab group (35 months, (95% CI 33-37)) versus controls (29 months, (95% CI 24-35)) at 36 months (p = 0.04). There was no infection increase in rituximab-treated subjects (p = 0.16). Conclusion: Single-dose rituximab for treatment of recurrent GN was associated with less subsequent rejection and longer time to graft loss without increased infection, but was no more effective than regimens not using rituximab at 36-months except those with recurrent membranous GN.
Nephrology Dialysis Transplantation | 2017
Nicholas S. Britt; Jennifer C. Hagopian; Daniel C. Brennan; April A. Pottebaum; Carlos A. Q. Santos; Ara Gharabagi; Timothy A. Horwedel
Background Urinary tract infections (UTIs) are common following kidney transplantation (KT); however, the influence of recurrent post-KT UTI (R-UTI) is not well-characterized. Methods We compared graft outcomes, patient outcomes and multidrug-resistance rates between patients with no UTI, nonrecurrent UTI (NR-UTI) (urine sample containing >105 bacterial colony-forming units/mL) and R-UTI (≥2 UTIs in any 6-month period or ≥3 UTIs in any 12-month period) post-KT in a retrospective cohort study (1999-2014) at Barnes-Jewish Hospital (St Louis, MO). All adult KT recipients were included and those experiencing mortality within 30 days of KT were excluded. Results Of 2469 recipients included, 1835 (74.3%) had no UTI, 465 (18.8%) had NR-UTI and 169 (6.8%) had R-UTI. R-UTI was associated with poorer graft survival compared with NR-UTI [hazard ratio (HR) 1.45; 95% confidence interval (CI) 1.23-1.83; P < 0.001) and no UTI (HR 2.11; 95% CI 2.02-3.80; P < 0.001). This relationship persisted after adjusting for confounding factors in Cox regression (HR 2.01; 95% CI 1.53-2.66; P < 0.001). There was no difference in patient survival between no UTI and NR-UTI (HR 1.21; 95% CI 0.91-1.63; P = 0.181); however, R-UTI was associated with poorer patient survival compared with nonrecurrent cases (HR 1.87; 95% CI 1.21-2.89; P = 0.005). R-UTI were more likely to be caused by multidrug-resistant Gram-negative organisms (risk ratio 1.49; 95% CI 1.31-1.70; P < 0.001). Conclusions R-UTIs were associated with poorer graft and patient outcomes, as well as increased multidrug-resistance compared with nonrecurrent cases.
American Journal of Nephrology | 2013
Christin C. Rogers; Natalya Asipenko; Timothy A. Horwedel; Shiva Gautam; Alexander S. Goldfarb-Rumyantzev; Martha Pavlakis; Scott R. Johnson; Seth J. Karp; Amy Evenson; Khalid Khwaja; Douglas W. Hanto; Didier A. Mandelbrot
Background: Modern immunosuppression and rabbit antithymocyte globulin (rATG) have facilitated the success of early steroid withdrawal (ESW) protocols. Little data exist on optimal rATG dosing in ESW protocols. Methods: Rejection at 12 months in era 1 (four doses of rATG, 1.25 mg/kg) vs. era 2 (three doses of rATG, 1.25 mg/kg) was the primary endpoint. Secondary endpoints included patient and graft survival, renal function and infectious complications. Factors associated with rejection at 1 year were identified. Results: 199 patients received rATG induction and ESW: 102 in era 1 and 97 in era 2. Compared to era 1, era 2 was not associated with worse outcomes, including rejection, renal function, infection or graft survival. Rejection at 1 year and uncensored graft survival differed between the dosing groups. Rejection rates were significantly higher in the <4 mg/kg group compared to the 4-5.9-mg/kg and the ≥6-mg/kg groups, whereas uncensored graft survival was the lowest in the ≥6-mg/kg group. Factors associated with rejection at 12 months included: rATG dose received of 4-5.9 versus <4 mg/kg (OR 0.20, 95% CI 0.036-0.85, p = 0.026); recipient age (per year, OR 0.94, 95% CI 0.89-1.0, p = 0.038); panel reactive antibody 10-79.9 versus <10% (OR 5.4, 95% CI 1.2-25, p = 0.030) and rATG dose held (OR 4.0, 95% CI 1.0-15, p = 0.049). Conclusions: A comparison of rATG dosing based on era did not result in a significant difference in rejection, renal function, infection or graft survival. However, when evaluating the study population based on actual dose received there were notable differences in both rejection rates and uncensored graft survival.
Clinical Transplantation | 2018
April A. Pottebaum; Jennifer C. Hagopian; Daniel C. Brennan; Ara Gharabagi; Timothy A. Horwedel
Evaluation of potential kidney transplant recipients is important to identify and treat conditions that may influence graft or patient survival after transplantation. We performed a single‐center, observational cohort study to determine whether pretransplant midodrine use influences outcomes after kidney transplantation. We analyzed graft and patient outcomes for adult patients who underwent a kidney‐only transplantation at Barnes‐Jewish Hospital from January 1999 to December 2015. We quantified adjusted associations of pretransplant midodrine use with post‐transplant complications by multivariable Cox regression. Among the 2621 kidney transplant recipients analyzed, 37 (1.4%) were taking midodrine immediately prior to transplantation. Midodrine users were more commonly older (56.5 vs 50.4 years) and obese (67.6% vs 33.6%). Midodrine users were also more likely to be on hemodialysis (86.5% vs 59.2%), to have a longer duration of dialysis dependence (646 months vs 577 months), and to have higher levels of sensitization (peak panel reactive antibody >20%, 32.4% vs 15.8%) compared to nonusers. Pretransplant midodrine users had significantly higher rates of delayed graft function (DGF) (32.4% vs 6.7%, P < 0.001). No difference in the incidence of DGF was observed based on the midodrine dosing regimen. After multivariable adjustment for recipient and donor characteristics, pretransplant midodrine use was independently associated with graft failure at 1 year (adjusted hazard ratio, 5.11; 95% confidence interval, 2.09‐12.49).
Transplantation direct | 2017
Zaid Brifkani; Daniel C. Brennan; Krista L. Lentine; Timothy A. Horwedel; Andrew F. Malone; Rowena Delos Santos; Thin Thin Maw; Tarek Alhamad
Background White recipients of 2-haplotype HLA-matched living kidney transplants are perceived to be of low immunologic risk. Little is known about the safety of induction avoidance and calcineurin inhibitor withdrawal in these patients. Methods We reviewed our experience at a single center and compared it to Organ Procurement and Transplantation Network (OPTN) registry data and only included 2-haplotype HLA-matched white living kidney transplants recipients between 2000 and 2013. Results There were 56 recipients in a single center (where no induction was given) and 2976 recipients in the OPTN. Among the OPTN recipients, 1285 received no induction, 903 basiliximab, 608 thymoglobulin, and 180 alemtuzumab. First-year acute rejection rates were similar after induction-free transplantation among the center and induced groups nationally. Compared with induction-free transplantation in the national data, there was no decrease in graft failure risk over 13 years with use of basiliximab (adjusted hazard ratio [aHR], 0.86; confidence interval [CI], 0.68-1.08), Thymoglobulin (aHR, 0.92; CI, 0.7-1.21) or alemtuzumab (aHR, 1.18; CI, 0.72-1.93). Among induction-free recipients at the center, calcineurin inhibitor withdrawal at 1 year (n = 27) did not significantly impact graft failure risk (HR,1.62; CI, 0.38-6.89). Conclusions This study may serve as a foundation for further studies to provide personalized, tailored, immunosuppression for this very low-risk population of kidney transplant patients.
Transplantation | 2014
J. Maliakkal; H. Chen; D. Fong; N. Agarwal; J. Zheng; Timothy A. Horwedel; Daniel C. Brennan; Vikas R. Dharnidharka
B1011 Treatment of BK Viremia and Subsequent Graft Rejecttion – A Double-Edged Sword Clinical Decision. N. Elfadawy,1 S. Flechner,1 S. Mossad,2 R. Fatica,1 J. Schold,3 S. Nurko,1 B. Stephany,1 T. Srinivas,4 E. Poggio.1 1Glickman Urological and Kidney Institute, The Cleveland Clinic, Cleveland, OH; 2Department of Infectious Disease in the Medicine Institute, The Cleveland Clinic, Cleveland, OH; 3Department of Quantitative Health Science, The Cleveland Clinic, Cleveland, OH; 4Division of Nephrology, Medical University of South Carolina, Charleston, SC. Various reports have described clinical activity of lefl unomide (Lf) and ciprofl oxacin toward clearing BK viremia (BKV). Moreover, both drugs are thought to have immunosuppressive effect that might protect against graft rejection after reduction of standard immunosuppression. There are limited data comparing BKV clearance rates and incidence of subsequent graft rejection after using these drugs. The aim of this study was to compare the rate of BKV clearance and the incidence of subsequent graft rejection following the use of different BKV treatment protocols. We screened 609 kidney recipients from 2007 to 2011 for BKV using qPCR in blood. During 1-year following transplant, 130 patients (21.3%) had BKV. 91% of our cohort had protocol biopsy done (at 0, 3, or 12 months post-transplant). Moreover, patients with BKV and impaired graft function had for-cause biopsy. We classifi ed patients with BKV by the treatment received into: Observation (n=44); reduction in immunosuppression (RIS) (30-50% reduction) (n=43); RIS + Cipro (n=14); RIS + Lf (n=18); or RIS + Cipro + Lf (n=11). We compared the slopes of decline of BKV among the groups. We also recorded the incidence of biopsy proven acute graft rejection (BPAR) that occurred after initiating the treatment. The 5 slopes were parallel to each other with no signifi cant difference in the rate of BKV decline (p=0.16). Eleven of 130 (8.5%) patients with BKV developed BPAR within a median of 1.9 months after initiating BKV treatment (IQR 1.2-9.8) compared to 39/479 (8.1%) in patients without BKV (p=0.9). There was a trend toward graft rejection in the group who had RIS alone (11.6%), compared to the groups who had cipro (7%), Lf (5.8%), cipro + Lf (9%) or observation (6.6%) using the Cox survival model (p= 0.9). The evidence does not support increased viral clearance when Lf and/or cipro are added to RIS. Moreover, adding Lf and/or cipro to the RIS was not associated with a signifi cant lower risk of subsequent BPAR. Larger prospective studies are still needed to confi rm these results. Abstract# B1012 Inter-Institutional Evaluation of Prospective BK Virus Screening On Kidney Transplant Outcomes. A. Shields,1 S. Raabe,2 J. Kremer,2 D. Hanseman,1 E. Woodle,1 R. Alloway,1 B. Abu Jawdeh,1 A. Govil,1 M. Cardi.2 1Univ of Cincinnati; 2The Christ Hospital. Background: The evidence base supporting BK virus (BKV) screening is not robust and remains to be fi rmly established. The purpose of this study was to evaluate outcomes with and without prospective BKV screening in renal transplant (txp) recipients. Methods: 594 patients (pts) receiving a renal txp from 2008-2013 at 2 physically proximate centers were analyzed. For 15 years, the centers have worked collaboratively and use identical immunosuppressive, infection prophylaxis, and patient care protocols. Txp surgeons and clinical research teams are common to both centers. One center utilized a prospective BKV screening protocol, whereas the other measured BK viral loads when for cause allograft biopsies suggested BKV nephropathy (BKVN). Protocol biopsies were not performed. BKV screening protocol included urine and serum DNA PCR every month until one year posttxp. Most pts with a positive urine BKV load and all pts with a positive serum BKV load or with a biopsy demonstrating BKVN were treated using preemptive immunosuppression reduction. Results: Demographics were similar between groups; however, the screening group pts were older and had more HLA mismatches. Patient survival, graft survival, graft loss due to BKVN, and death censored graft survival were not different between groups. BK-related outcomes are in table. Screening (n=256) No Screening (n=338) p BKVN 2.7% 4.1% NS Mean time to BKVN Diagnosis (days) 185±169 261±132 <0.0001 BK Viremia 11% N/A Mean Time to BK Viremia (days) 124±98 N/A BK Viruria 25% N/A Mean time to BK Viruria (days) 106±94 N/A Renal function was not different between groups, except it was better in the screening group at 1 year (MDRD 59±13 vs 55±20 mL/min, p<0.002). Rejection was lower in the screening group as below. Screening (n=256) No Screening (n=338) p Acute Rejection (AR) 14% 21% 0.01 1 Year AR 11% 17% 0.04 Late AR > 6 Mths 3.5% 8.3% 0.02 AMR or Mixed AR 5% 5% NS Banff < 2A AR 6% 12% 0.01 Banff ≥ 2A AR 3% 5% NS Mean Time to 1st AR (days) 186±349 252±362 0.03 Conclusion: Prospective BK virus screening with urine and serum DNA PCR did not result in a statistically signifi cant reduction in BKVN incidence. BKVN was diagnosed earlier in screened pts, but did not infl uence allograft survival or patient survival but may have had some impact on renal function at 1 year post-txp. Despite preemptive reductions in immunosuppression due to positive BK screening, the screening group had less rejection. Abstract# B1013 Differences in BK Viral Clearance Kinetics across Recipient Race. D. Taber,1 N. Pilch,2 A. Posadas,3 C. Bratton,1 J. McGillicuddy,1 K. Chavin,1 P. Baliga,1 T. Srinivas.3 1Transplant, MUSC, Charleston, SC; 2Pharmacy, MUSC, Charleston, SC; 3Nephrology, MUSC, Charleston, SC. Clearance of BK viremia (BKV) among kidney transplant recipients (KTX) may be infl uenced by host immune responses. Despite known immunologic differences among races, data are limited on associations of race with BKV clearance and KTX outcome. METHODS: Retrospective longitudinal cohort study of all adult solitary KTX between 2005-12 that developed BKV, defi ned by at least two positive BK PCRs with one >2,000 copies/mL; all from a single lab. Cohorts were divided by race (AA vs. non-AA) and analyzed for BKV clearance kinetics and outcomes. RESULTS: 1,176 patients were eligible for inclusion, 103 (8.8%) developed signifi cant BKV. The incidence of BKV was similar between racial cohorts (9.3% AA vs 8.1% non-AA, p=0.536). Baseline characteristics were similar between groups; except non-AAs had a higher incidence of CV events, re-transplant, and lower HLA mismatches (Top Table 1). BK viral clearance kinetics demonstrated a two-phase clearance pattern in both cohorts (Figure 1), with AA patients having a more rapid initial clearance phase (median BK reduction per month AA: -9,711 vs. non-AA: -2,807 copies/mL, p=0.014; middle Table 1) with similar terminal clearance phase between groups. Immunosuppression dosing, levels and clinical outcomes were also similar across groups (bottom Table 1). CONCLUSION: The incidence of BKV is similar between AAs and non-AAs; AAs display a more pronounced initial BK viral clearance. Terminal clearance phase is similar across race. Understanding racial differences in BK viral clearance kinetics should allow optimal immunosuppression regimen titration during this high-risk time period. B1013 Differences in BK Viral Clearance Kinetics across Recipient Race. D. Taber,1 N. Pilch,2 A. Posadas,3 C. Bratton,1 J. McGillicuddy,1 K. Chavin,1 P. Baliga,1 T. Srinivas.3 1Transplant, MUSC, Charleston, SC; 2Pharmacy, MUSC, Charleston, SC; 3Nephrology, MUSC, Charleston, SC. Clearance of BK viremia (BKV) among kidney transplant recipients (KTX) may be infl uenced by host immune responses. Despite known immunologic differences among races, data are limited on associations of race with BKV clearance and KTX outcome. METHODS: Retrospective longitudinal cohort study of all adult solitary KTX between 2005-12 that developed BKV, defi ned by at least two positive BK PCRs with one >2,000 copies/mL; all from a single lab. Cohorts were divided by race (AA vs. non-AA) and analyzed for BKV clearance kinetics and outcomes. RESULTS: 1,176 patients were eligible for inclusion, 103 (8.8%) developed signifi cant BKV. The incidence of BKV was similar between racial cohorts (9.3% AA vs 8.1% non-AA, p=0.536). Baseline characteristics were similar between groups; except non-AAs had a higher incidence of CV events, re-transplant, and lower HLA mismatches (Top Table 1). BK viral clearance kinetics demonstrated a two-phase clearance pattern in both cohorts (Figure 1), with AA patients having a more rapid initial clearance phase (median BK reduction per month AA: -9,711 vs. non-AA: -2,807 copies/mL, p=0.014; middle Table 1) with similar terminal clearance phase between groups. Immunosuppression dosing, levels and clinical outcomes were also similar across groups (bottom Table 1). CONCLUSION: The incidence of BKV is similar between AAs and non-AAs; AAs display a more pronounced initial BK viral clearance. Terminal clearance phase is similar across race. Understanding racial differences in BK viral clearance kinetics should allow optimal immunosuppression regimen titration during this high-risk time period.