Aim: Lower urinary tract dysfunction (LUTD), despite surgical intervention, may progress to end-s... more Aim: Lower urinary tract dysfunction (LUTD), despite surgical intervention, may progress to end-stage renal disease (ESRD). Urologic pathology may damage a transplanted kidney, limiting patient and graft survival. We analyzed outcomes of renal transplant recipients with LUTD versus control recipients. Method: We identified kidney transplant recipients treated between 2001 and 2010; group 1 had ESRD due to LUTD with intervention prior to transplant, group 2 had ESRD secondary to LUTD without intervention, and group 3 had ESRD due to polycystic kidney disease (chosen as a relatively healthy control cohort without comorbid burden of other causes of ESRD e.g. diabetes). The primary outcome measured, graft survival, was death censored. Secondary outcomes included patient survival and graft function. Results: In 150 study patients (16 patients in group 1, 64 in group 2, and 70 in group 3), 5-year death-censored graft survival was 93.75%, 90.6%, and 92.9%, respectively, No significant differences in graft failure among groups (Cox proportional hazards model). Five-year patient survival was 100%, 100%, and 94.3%, respectively. Conclusions: Individuals with a history of LUTD had graft and patient survival rates similar to the control group. When appropriately treated, LUTD is not a barrier to successful renal transplant.
INTRODUCTION AND OBJECTIVE: Complicated urinary tract infections (cUTI) are a significant burden ... more INTRODUCTION AND OBJECTIVE: Complicated urinary tract infections (cUTI) are a significant burden on individual health and healthcare resources. They are often caused by polymicrobial infections where interactions between bacteria can change the antibiotic resistance of the pool of organisms. Guidance UTI is a urine-based test that combines PCR and Pooled Antibiotic Susceptibility (P-AST), which tests for antibiotic susceptibility against the combined pool of organisms. This study sought to determine rates of adverse outcomes, medical resource utilization, and costs with Guidance UTI compared to standard urine culture (SUC). METHODS: Using a randomized 5% sample of Medicare Parts AþB beneficiaries enrolled in 2017-19 (nw1.5M in each year), we compared 2 cohorts matched on sex, diabetes, and propensity score, based on whether outpatient UTI diagnosis was made with SUC (N [678) or Guidance UTI (N[69) initially, and for the year following their first cUTI after a 12-month baseline. UTI-related utilization and Medicareallowed cost was acquired from professional and facility claims. RESULTS: The rate of outpatient emergency visits was 13% lower and inpatient admissions was 67% lower when using Guidance UTI compared to SUC. For every 1,000 patients there were zero urosepsis, urgent care and skilled nursing facility admissions with Guidance UTI vs 13, 31 and 7 events respectively with SUC. For the composite outcome, Guidance UTI testing was associated with a 42% reduction compared to SUC (Figure 1). These reductions translate to $463.46 saving per cUTI patient tested with Guidance UTI (p[0.043), a saving of $11.6 million for 25,000 cUTI cases (Table 1). CONCLUSIONS: Guidance UTI testing is associated with reductions in critical adverse outcomes, healthcare resource utilization and cost for cUTI cases as compared to standard urine culture. cUTI cases may benefit from Guidance UTI's combination of increased sensitivity, reduced time to results, and P-AST results.
in 0-hr biopsy, the prevalence increased to almost 50% at 1-month after KT, and it was maintained... more in 0-hr biopsy, the prevalence increased to almost 50% at 1-month after KT, and it was maintained at the similar levels for 1-year. Meanwhile, the prevalence of stage II TLTs increased more gradually, from 2% at 1-month to 18% at 1-year post-transplantation. When patients are divided by their TLT staging, those with stage II TLTs in 6or 12month biopsies showed progressive decline in graft function over the next 5-years, while those with no or stage I TLTs did not. The use of preoperative rituximab was not associated with the prevalence of overall TLTs, however, it associated with dramatic reduction in the prevalence of both stage II TLT and B cell clusters regardless of biopsy time point. Patients with stage II TLTs in 6and/or 12-month biopsies showed more severe tubulitis and tubular atrophy scores despite of comparable degree of interstitial inflammation. In subgroup analysis of patients with Banff i score of 0 or 1, the patients with stage II TLTs exhibited progressive graft dysfunction even though the overall degree of interstitial inflammation was mild. CONCLUSIONS: Stage II TLTs predicted progressive graft dysfunction independent from Banff i scores, and finally the use of preoperative rituximab administration was associated with significant reduction in stage II TLT and B cell clusters.
INTRODUCTION AND OBJECTIVE: In May 2016 we performed the first successful penis transplant in the... more INTRODUCTION AND OBJECTIVE: In May 2016 we performed the first successful penis transplant in the United States in a patient with a history of subtotal penectomy for penile cancer. Here, we report 5-year follow-up outcomes specifically related to erectile function. Until recently he had been using daily Tadalafil 5 mg with good effect but had subsequently noted 30e40% decline in erectile quality. Here we report erectile function since the introduction of intraurethral gels (IUG). METHODS: Our patient was evaluated using penile doppler ultrasound with use of both audio/visual stimulation (AVS) and Trimix IUG. His erection response was graded by rigidity on 0e100% scale bymen's health urologists. Right and left cavernosal velocities were documented as well as SHIM score at each visit. All post-application measurements were taken from 0 to 20 minutes. Given his surgical transplant history, intracavernosal injections were avoided to ensure not injuring the vascular anastomoses. The Trimix IUG are composed of 7.5 mg Papaverine, 1 mg Phentolamine, and varying amounts of Alprostadil (250 mcg to 1000 mcg). The patient was exposed to AVS alone as a control followed by AVS and Trimix IUG at subsequent office visits. RESULTS: At 5-years follow-up after penis transplant, our patient was initially maintained on 5 mg daily Tadalafil; however, he noted poor erectile quality. Due to the complexity of his graft and risk of injury, intracavernosal injections were deemed potentially unsafe and he was prescribed intraurethral Trimix gel. Our results demonstrate 60% rigidity using 1000 mg Alprostadil Trimix intraurethral gel in the office with our patient noting superior erectile quality at home. His SHIM score was noted to be 20 when using daily Tadalafil combined with on demand Trimix intraurethral gel (500 mcg or 750 mcg Alprostadil). There were initial venous leak demonstrable; however, at higher doses, there is diminished venous leak and greater rigidity achieved. CONCLUSIONS: Our data is the first to demonstrate and characterize successful achievement of erectile function 5-years after Genito-urinary composite allotransplantation. Source of Funding: None
Hospital stay was longer with transplant only (6.5 vs 4.2 d, p ϭ 0.014). There were 4 intraoperat... more Hospital stay was longer with transplant only (6.5 vs 4.2 d, p ϭ 0.014). There were 4 intraoperative complications with transplant only, none in transplant with nephrectomy. Both had 4 postoperative complications. The laparoscopic bilateral and unilateral nephrectomy groups were similar in median age, BMI, and kidney length: 50.8 vs 56.3 yr (p ϭ 0.281), 27.8 vs 32.9 kg/m2 (p ϭ 0.838), 20.4 vs 19.8 cm (p ϭ 0.281). Bilateral nephrectomies had greater blood loss and operative time: 150 vs 50 ml (p ϭ 0.001), 302.8 vs 170.2 min (pϽ0.001). Median hospital stay (3d) and postoperative creatinine (1.3 mg/dl) were similar. There were 4 open conversions, 3 intraoperative and 4 postoperative complications with bilateral nephrectomy, and 0 with unilateral. Median kidney length was longer in open conversions: 27.3 vs 19.4 cm, p ϭ 0.003. CONCLUSIONS: Nephrectomy at the time of transplant had outcomes similar to transplant alone. A staged nephrectomy had better outcomes than bilateral laparoscopic nephrectomy.
Clinics and Research in Hepatology and Gastroenterology, 2019
Background: Paediatric liver allografts sometimes are allocated to adult recipients when there ar... more Background: Paediatric liver allografts sometimes are allocated to adult recipients when there are no suitable paediatric recipients on the waiting list. However, debate exits regarding the reported outcomes of liver transplants using such small grafts.
Journal of Clinical and Translational Science, 2019
OBJECTIVES/SPECIFIC AIMS: Objective: To summarize the diagnosis and management of two acute rejec... more OBJECTIVES/SPECIFIC AIMS: Objective: To summarize the diagnosis and management of two acute rejection (AR) episodes in the first penis transplant patient in the U.S. Background: Vascularized composite allotransplantation (VCA) has been utilized for state-of-the-art reconstruction of devastating craniofacial defects, limb loss, and recently, severe genitourinary defects. To date, more than 200 VCA’s have been performed, of which four successful penis transplants have been achieved worldwide (Two in the U.S.). However, despite the technical success of VCAs in general, acute rejection episodes remain a significant postoperative management problem, with 80-85% experiencing at least one episode in the first-year post-transplantation. The incorporation of skin in VCAs, which is highly immunogenic, allows early visible recognition of rejection but requires prompt management to prevent allograft failure as well as the progression of chronic rejection, which has been associated with the freq...
Background. Spleen transplantation (Tx) between some strains of rodents can lead to donor-specifi... more Background. Spleen transplantation (Tx) between some strains of rodents can lead to donor-specific tolerance either spontaneously or after a short course of immunosuppression. This study developed a surgical technique for spleen Tx in miniature swine to investigate its immunologic impact in a large animal model. Methods. The preferred surgical technique of spleen Tx (n)8؍ involved excision of the donor spleen with its vascular pedicle to the aorta and portal vein. Carrel patches of donor aorta and portal vein were anastomosed to the abdominal aorta and inferior vena cava, respectively, of the (splenectomized) recipient. The results in four major histocompatibility complexmatched pairs that were mismatched for the porcine allelic antigen are reported. Two recipients were untreated, one received a 12-day course of cyclosporine A (CsA) alone, and one received thymic irradiation (700 cGy) and CsA. Hematopoietic cell chimerism was followed by fluorescence-activated cell sorter, and graft survival was assessed by histology. Results. Spleen Tx was technically successful. In two untreated pigs, chimerism was detected in the blood (maximum 5% for 17 and 25 days) and lymph nodes (maximum 6% for 28 and 56 days), but both grafts showed histologic rejection by day 28. In two treated pigs, chimerism was present in the blood for 47 and 57 days, and rejection was prevented, with follow-up for 57 and 217 days, respectively. Conclusion. Spleen Tx in major histocompatibility complex-matched pairs treated with CsA؎thymic irradiation results in prolonged chimerism and is associated with the development of in vivo unresponsiveness to the transplanted spleen.
Introduction. There is a paucity of data on long-term outcomes of older kidney recipients. Our ai... more Introduction. There is a paucity of data on long-term outcomes of older kidney recipients. Our aim was to compare the early and long-term outcomes of deceased donor kidney transplantation in patients aged Ն60 years with outcomes in younger recipients. Materials and Methods. From 1998 to 2005, we performed 271 deceased donor kidney transplants. There were 76 recepients (28.1%) Ͼ60 years old. Older candidates were carefully selected based on their physiologic, cardiac, and performance status. Demographic data, including clinical characteristics, early complications, mortality, and patient and graft survival rates, were collected and analyzed. Results. Older patients had comparable perioperative mortality and morbidity, incidence of delayed graft function (DGF), length of stay, and readmissions compared with younger patients. The rates of acute rejection and major infections were also comparable between the 2 study groups. Among older recipients, 25/76 (32.1%) patients received extended criteria donor kidneys compared with only 35/195 (17.9%) of younger patients (P Ͻ .001). Nevertheless, equivalent 1-, 3-, and 5-year allograft survival rates were observed in elderly and young patients; 91.5% versus, 92.5%, 78.5% versus 81.9%, and 75.6% versus 78.5%, respectively. Overall patient survival was also comparable in both groups. Conclusion. Kidney transplantation in appropriately selected elderly recipients provides equivalent outcomes compared with those observed in younger patients. These observations support the notion that older recipients should not lose access to deceased donor kidney transplantation in the effort to achieve a perceived gain in social utility.
In several rodent models spleen allotransplantation has been shown to be associated with donorspe... more In several rodent models spleen allotransplantation has been shown to be associated with donorspecific tolerance to allo-antigens [1]. To study the tolerogenic capacity of the spleen in a systematic manner in large animals with known major histocompatibility (MHC) barriers, we have developed an allogeneic spleen transplantation (Tx) model in MHC-defined miniature swine [2]. One of the goals of investigating spleen Tx as a potential for tolerance induction was its extrapolation to xenoTx. In our allogeneic spleen Tx experiments, we have observed that all recipients develop hematopoietic cell chimerism in the blood. Across full MHC barriers, when recipients were treated with 100 cGy of whole body irradiation, 700 cGy thymic irradiation, and a 45-day course of cyclosporine, multilineage chimerism was present in the blood and lymphoid tissues, and in some cases resulted in engraftment of donor cells in recipient bone marrow (BM). This was associated with in vitro donor-specific hyporesponsiveness in mixed leukocyte reaction (MLR) and cell-mediated lympholysis (CML) assays. Long-term survivors demonstrated evidence for donor-specific regulatory T-cell activity, as peripheral blood mononuclear cells from these pigs contained a cell population that was able to suppress anti-donor responses of cells from naı̈ve recipient MHCmatched pigs in suppressor CML and suppressor MLR assays (F.J.M.F. Dor, unpublished data). We have performed xenogeneic pig spleen Tx in two baboons, in the first of which we established that the surgical technique used in our pig alloTx model was also feasible in the pig-to-baboonmodel. The second baboon (B221) also received donorspecific BM Tx 4 h later. We here report our observations in B221 and compare them with those in a baboon (B219) that received BM Tx only (with no spleen Tx). Both baboons were conditioned with a fairly complex regimen based on the pig-to-baboon BM Tx regimen reported previously [3,4]. Both donor pigs were miniature swine generated by nuclear transfer/embryo transfer with greatly reduced expression of a1,3-galactosyltransferase RNA, associated with reduced levels of Gala1–3Gal (Gal) when compared with wild-type swine; some Gal was detectable by flow cytometry on hematopoietic cells. No measures were taken to deplete natural anti-Gal antibodies, but complement depletion was performed using cobra venom factor, which was administered for the first 21 days. Spleen Tx was carried out in B221 in the abdomen using the previously-described technique [2]. BM was harvested from the donor pigs and prepared for infusion into the baboon as previously described [5]. BM cells (1.33 and 0.8 10/ kg in B221 and B219, respectively) were infused intravenously without untoward effect (in B221 4 h after spleen Tx). Blood was drawn at intervals to determine the extent of hematopoietic cell chimerism by flow cytometry. The maximum percentage of pig cells (using a ‘pan-pig’ antibody) in the blood of B221 was 16.8% (2 h after spleen Tx), but only 1.9 % in B219 (on day 2) (Fig. 1], and the duration of pig cell macrochimerism was 12 days in B221 compared with only 5 days in B219. In B221, the absolute number of pig cells was 689/ll after spleen Tx and 876/ll after BM Tx, respectively (Fig. 2] (2 h after spleen Tx and BM Tx); in contrast, in B219 the peak absolute number of pig cells 2 h after the BM Tx was 85/ll (Fig. 2). In both cases, loss of chimerism was most likely related to phagocytosis of pig cells by host macrophages [3,6].
Introduction Human cadaver allograft (HCA) is the current standard of care for temporary wound cl... more Introduction Human cadaver allograft (HCA) is the current standard of care for temporary wound closure of large burns, but a critical need for high-quality alternatives exists. Porcine skin shares many similarities with human skin, and hyperacute rejection is prevented via a single genetic modification. Like human skin, non-terminally sterilized porcine skin contains viable dermal and epidermal cells and intact vasculature that enables restoration of barrier function. These characteristics are distinct from those of traditional, terminally sterilized “xenografts” and may offer greater therapeutic capability. We report here key efficacy outcomes specific to severe burn care from a first-in-human clinical trial to assess the capability of genetically engineered porcine skin xenotransplants to provide temporary wound closure for severe and extensive deep-partial and full-thickness burn wounds, compared to HCA. Methods Split-thickness skin containing epidermal and dermal layers was harv...
The effects of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activit... more The effects of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice have been investigated using a versatile procedure for encapsulating doxorubicin inside liposomes. In this procedure, vesicles exhibiting transmembrane pH gradients (acidic inside) were employed to achieve drug trapping efficiencies in excess of 98%. Drug-to-lipid ratios as high as 0.3:1 (wt:wt) could be obtained in a manner that is relatively independent of lipid composition and vesicle size. Egg phosphatidylcholine (EPC)/cholesterol (55:45; mol/mol) vesicles sized through filters with a 200-nm pore size and loaded employing transmembrane pH gradients to achieve a doxorubicin-to-lipid ratio of 0.3:1 (wt/wt) increased the LD»of free drug by approximately twofold. Removing cholesterol or decreasing the drug-tolipid ratio in EPC/cholesterol preparations led to significant decreases in the LO»of liposomal doxorubicin whereas, the ID«,increased 4to 6fold...
Aim: Lower urinary tract dysfunction (LUTD), despite surgical intervention, may progress to end-s... more Aim: Lower urinary tract dysfunction (LUTD), despite surgical intervention, may progress to end-stage renal disease (ESRD). Urologic pathology may damage a transplanted kidney, limiting patient and graft survival. We analyzed outcomes of renal transplant recipients with LUTD versus control recipients. Method: We identified kidney transplant recipients treated between 2001 and 2010; group 1 had ESRD due to LUTD with intervention prior to transplant, group 2 had ESRD secondary to LUTD without intervention, and group 3 had ESRD due to polycystic kidney disease (chosen as a relatively healthy control cohort without comorbid burden of other causes of ESRD e.g. diabetes). The primary outcome measured, graft survival, was death censored. Secondary outcomes included patient survival and graft function. Results: In 150 study patients (16 patients in group 1, 64 in group 2, and 70 in group 3), 5-year death-censored graft survival was 93.75%, 90.6%, and 92.9%, respectively, No significant differences in graft failure among groups (Cox proportional hazards model). Five-year patient survival was 100%, 100%, and 94.3%, respectively. Conclusions: Individuals with a history of LUTD had graft and patient survival rates similar to the control group. When appropriately treated, LUTD is not a barrier to successful renal transplant.
INTRODUCTION AND OBJECTIVE: Complicated urinary tract infections (cUTI) are a significant burden ... more INTRODUCTION AND OBJECTIVE: Complicated urinary tract infections (cUTI) are a significant burden on individual health and healthcare resources. They are often caused by polymicrobial infections where interactions between bacteria can change the antibiotic resistance of the pool of organisms. Guidance UTI is a urine-based test that combines PCR and Pooled Antibiotic Susceptibility (P-AST), which tests for antibiotic susceptibility against the combined pool of organisms. This study sought to determine rates of adverse outcomes, medical resource utilization, and costs with Guidance UTI compared to standard urine culture (SUC). METHODS: Using a randomized 5% sample of Medicare Parts AþB beneficiaries enrolled in 2017-19 (nw1.5M in each year), we compared 2 cohorts matched on sex, diabetes, and propensity score, based on whether outpatient UTI diagnosis was made with SUC (N [678) or Guidance UTI (N[69) initially, and for the year following their first cUTI after a 12-month baseline. UTI-related utilization and Medicareallowed cost was acquired from professional and facility claims. RESULTS: The rate of outpatient emergency visits was 13% lower and inpatient admissions was 67% lower when using Guidance UTI compared to SUC. For every 1,000 patients there were zero urosepsis, urgent care and skilled nursing facility admissions with Guidance UTI vs 13, 31 and 7 events respectively with SUC. For the composite outcome, Guidance UTI testing was associated with a 42% reduction compared to SUC (Figure 1). These reductions translate to $463.46 saving per cUTI patient tested with Guidance UTI (p[0.043), a saving of $11.6 million for 25,000 cUTI cases (Table 1). CONCLUSIONS: Guidance UTI testing is associated with reductions in critical adverse outcomes, healthcare resource utilization and cost for cUTI cases as compared to standard urine culture. cUTI cases may benefit from Guidance UTI's combination of increased sensitivity, reduced time to results, and P-AST results.
in 0-hr biopsy, the prevalence increased to almost 50% at 1-month after KT, and it was maintained... more in 0-hr biopsy, the prevalence increased to almost 50% at 1-month after KT, and it was maintained at the similar levels for 1-year. Meanwhile, the prevalence of stage II TLTs increased more gradually, from 2% at 1-month to 18% at 1-year post-transplantation. When patients are divided by their TLT staging, those with stage II TLTs in 6or 12month biopsies showed progressive decline in graft function over the next 5-years, while those with no or stage I TLTs did not. The use of preoperative rituximab was not associated with the prevalence of overall TLTs, however, it associated with dramatic reduction in the prevalence of both stage II TLT and B cell clusters regardless of biopsy time point. Patients with stage II TLTs in 6and/or 12-month biopsies showed more severe tubulitis and tubular atrophy scores despite of comparable degree of interstitial inflammation. In subgroup analysis of patients with Banff i score of 0 or 1, the patients with stage II TLTs exhibited progressive graft dysfunction even though the overall degree of interstitial inflammation was mild. CONCLUSIONS: Stage II TLTs predicted progressive graft dysfunction independent from Banff i scores, and finally the use of preoperative rituximab administration was associated with significant reduction in stage II TLT and B cell clusters.
INTRODUCTION AND OBJECTIVE: In May 2016 we performed the first successful penis transplant in the... more INTRODUCTION AND OBJECTIVE: In May 2016 we performed the first successful penis transplant in the United States in a patient with a history of subtotal penectomy for penile cancer. Here, we report 5-year follow-up outcomes specifically related to erectile function. Until recently he had been using daily Tadalafil 5 mg with good effect but had subsequently noted 30e40% decline in erectile quality. Here we report erectile function since the introduction of intraurethral gels (IUG). METHODS: Our patient was evaluated using penile doppler ultrasound with use of both audio/visual stimulation (AVS) and Trimix IUG. His erection response was graded by rigidity on 0e100% scale bymen's health urologists. Right and left cavernosal velocities were documented as well as SHIM score at each visit. All post-application measurements were taken from 0 to 20 minutes. Given his surgical transplant history, intracavernosal injections were avoided to ensure not injuring the vascular anastomoses. The Trimix IUG are composed of 7.5 mg Papaverine, 1 mg Phentolamine, and varying amounts of Alprostadil (250 mcg to 1000 mcg). The patient was exposed to AVS alone as a control followed by AVS and Trimix IUG at subsequent office visits. RESULTS: At 5-years follow-up after penis transplant, our patient was initially maintained on 5 mg daily Tadalafil; however, he noted poor erectile quality. Due to the complexity of his graft and risk of injury, intracavernosal injections were deemed potentially unsafe and he was prescribed intraurethral Trimix gel. Our results demonstrate 60% rigidity using 1000 mg Alprostadil Trimix intraurethral gel in the office with our patient noting superior erectile quality at home. His SHIM score was noted to be 20 when using daily Tadalafil combined with on demand Trimix intraurethral gel (500 mcg or 750 mcg Alprostadil). There were initial venous leak demonstrable; however, at higher doses, there is diminished venous leak and greater rigidity achieved. CONCLUSIONS: Our data is the first to demonstrate and characterize successful achievement of erectile function 5-years after Genito-urinary composite allotransplantation. Source of Funding: None
Hospital stay was longer with transplant only (6.5 vs 4.2 d, p ϭ 0.014). There were 4 intraoperat... more Hospital stay was longer with transplant only (6.5 vs 4.2 d, p ϭ 0.014). There were 4 intraoperative complications with transplant only, none in transplant with nephrectomy. Both had 4 postoperative complications. The laparoscopic bilateral and unilateral nephrectomy groups were similar in median age, BMI, and kidney length: 50.8 vs 56.3 yr (p ϭ 0.281), 27.8 vs 32.9 kg/m2 (p ϭ 0.838), 20.4 vs 19.8 cm (p ϭ 0.281). Bilateral nephrectomies had greater blood loss and operative time: 150 vs 50 ml (p ϭ 0.001), 302.8 vs 170.2 min (pϽ0.001). Median hospital stay (3d) and postoperative creatinine (1.3 mg/dl) were similar. There were 4 open conversions, 3 intraoperative and 4 postoperative complications with bilateral nephrectomy, and 0 with unilateral. Median kidney length was longer in open conversions: 27.3 vs 19.4 cm, p ϭ 0.003. CONCLUSIONS: Nephrectomy at the time of transplant had outcomes similar to transplant alone. A staged nephrectomy had better outcomes than bilateral laparoscopic nephrectomy.
Clinics and Research in Hepatology and Gastroenterology, 2019
Background: Paediatric liver allografts sometimes are allocated to adult recipients when there ar... more Background: Paediatric liver allografts sometimes are allocated to adult recipients when there are no suitable paediatric recipients on the waiting list. However, debate exits regarding the reported outcomes of liver transplants using such small grafts.
Journal of Clinical and Translational Science, 2019
OBJECTIVES/SPECIFIC AIMS: Objective: To summarize the diagnosis and management of two acute rejec... more OBJECTIVES/SPECIFIC AIMS: Objective: To summarize the diagnosis and management of two acute rejection (AR) episodes in the first penis transplant patient in the U.S. Background: Vascularized composite allotransplantation (VCA) has been utilized for state-of-the-art reconstruction of devastating craniofacial defects, limb loss, and recently, severe genitourinary defects. To date, more than 200 VCA’s have been performed, of which four successful penis transplants have been achieved worldwide (Two in the U.S.). However, despite the technical success of VCAs in general, acute rejection episodes remain a significant postoperative management problem, with 80-85% experiencing at least one episode in the first-year post-transplantation. The incorporation of skin in VCAs, which is highly immunogenic, allows early visible recognition of rejection but requires prompt management to prevent allograft failure as well as the progression of chronic rejection, which has been associated with the freq...
Background. Spleen transplantation (Tx) between some strains of rodents can lead to donor-specifi... more Background. Spleen transplantation (Tx) between some strains of rodents can lead to donor-specific tolerance either spontaneously or after a short course of immunosuppression. This study developed a surgical technique for spleen Tx in miniature swine to investigate its immunologic impact in a large animal model. Methods. The preferred surgical technique of spleen Tx (n)8؍ involved excision of the donor spleen with its vascular pedicle to the aorta and portal vein. Carrel patches of donor aorta and portal vein were anastomosed to the abdominal aorta and inferior vena cava, respectively, of the (splenectomized) recipient. The results in four major histocompatibility complexmatched pairs that were mismatched for the porcine allelic antigen are reported. Two recipients were untreated, one received a 12-day course of cyclosporine A (CsA) alone, and one received thymic irradiation (700 cGy) and CsA. Hematopoietic cell chimerism was followed by fluorescence-activated cell sorter, and graft survival was assessed by histology. Results. Spleen Tx was technically successful. In two untreated pigs, chimerism was detected in the blood (maximum 5% for 17 and 25 days) and lymph nodes (maximum 6% for 28 and 56 days), but both grafts showed histologic rejection by day 28. In two treated pigs, chimerism was present in the blood for 47 and 57 days, and rejection was prevented, with follow-up for 57 and 217 days, respectively. Conclusion. Spleen Tx in major histocompatibility complex-matched pairs treated with CsA؎thymic irradiation results in prolonged chimerism and is associated with the development of in vivo unresponsiveness to the transplanted spleen.
Introduction. There is a paucity of data on long-term outcomes of older kidney recipients. Our ai... more Introduction. There is a paucity of data on long-term outcomes of older kidney recipients. Our aim was to compare the early and long-term outcomes of deceased donor kidney transplantation in patients aged Ն60 years with outcomes in younger recipients. Materials and Methods. From 1998 to 2005, we performed 271 deceased donor kidney transplants. There were 76 recepients (28.1%) Ͼ60 years old. Older candidates were carefully selected based on their physiologic, cardiac, and performance status. Demographic data, including clinical characteristics, early complications, mortality, and patient and graft survival rates, were collected and analyzed. Results. Older patients had comparable perioperative mortality and morbidity, incidence of delayed graft function (DGF), length of stay, and readmissions compared with younger patients. The rates of acute rejection and major infections were also comparable between the 2 study groups. Among older recipients, 25/76 (32.1%) patients received extended criteria donor kidneys compared with only 35/195 (17.9%) of younger patients (P Ͻ .001). Nevertheless, equivalent 1-, 3-, and 5-year allograft survival rates were observed in elderly and young patients; 91.5% versus, 92.5%, 78.5% versus 81.9%, and 75.6% versus 78.5%, respectively. Overall patient survival was also comparable in both groups. Conclusion. Kidney transplantation in appropriately selected elderly recipients provides equivalent outcomes compared with those observed in younger patients. These observations support the notion that older recipients should not lose access to deceased donor kidney transplantation in the effort to achieve a perceived gain in social utility.
In several rodent models spleen allotransplantation has been shown to be associated with donorspe... more In several rodent models spleen allotransplantation has been shown to be associated with donorspecific tolerance to allo-antigens [1]. To study the tolerogenic capacity of the spleen in a systematic manner in large animals with known major histocompatibility (MHC) barriers, we have developed an allogeneic spleen transplantation (Tx) model in MHC-defined miniature swine [2]. One of the goals of investigating spleen Tx as a potential for tolerance induction was its extrapolation to xenoTx. In our allogeneic spleen Tx experiments, we have observed that all recipients develop hematopoietic cell chimerism in the blood. Across full MHC barriers, when recipients were treated with 100 cGy of whole body irradiation, 700 cGy thymic irradiation, and a 45-day course of cyclosporine, multilineage chimerism was present in the blood and lymphoid tissues, and in some cases resulted in engraftment of donor cells in recipient bone marrow (BM). This was associated with in vitro donor-specific hyporesponsiveness in mixed leukocyte reaction (MLR) and cell-mediated lympholysis (CML) assays. Long-term survivors demonstrated evidence for donor-specific regulatory T-cell activity, as peripheral blood mononuclear cells from these pigs contained a cell population that was able to suppress anti-donor responses of cells from naı̈ve recipient MHCmatched pigs in suppressor CML and suppressor MLR assays (F.J.M.F. Dor, unpublished data). We have performed xenogeneic pig spleen Tx in two baboons, in the first of which we established that the surgical technique used in our pig alloTx model was also feasible in the pig-to-baboonmodel. The second baboon (B221) also received donorspecific BM Tx 4 h later. We here report our observations in B221 and compare them with those in a baboon (B219) that received BM Tx only (with no spleen Tx). Both baboons were conditioned with a fairly complex regimen based on the pig-to-baboon BM Tx regimen reported previously [3,4]. Both donor pigs were miniature swine generated by nuclear transfer/embryo transfer with greatly reduced expression of a1,3-galactosyltransferase RNA, associated with reduced levels of Gala1–3Gal (Gal) when compared with wild-type swine; some Gal was detectable by flow cytometry on hematopoietic cells. No measures were taken to deplete natural anti-Gal antibodies, but complement depletion was performed using cobra venom factor, which was administered for the first 21 days. Spleen Tx was carried out in B221 in the abdomen using the previously-described technique [2]. BM was harvested from the donor pigs and prepared for infusion into the baboon as previously described [5]. BM cells (1.33 and 0.8 10/ kg in B221 and B219, respectively) were infused intravenously without untoward effect (in B221 4 h after spleen Tx). Blood was drawn at intervals to determine the extent of hematopoietic cell chimerism by flow cytometry. The maximum percentage of pig cells (using a ‘pan-pig’ antibody) in the blood of B221 was 16.8% (2 h after spleen Tx), but only 1.9 % in B219 (on day 2) (Fig. 1], and the duration of pig cell macrochimerism was 12 days in B221 compared with only 5 days in B219. In B221, the absolute number of pig cells was 689/ll after spleen Tx and 876/ll after BM Tx, respectively (Fig. 2] (2 h after spleen Tx and BM Tx); in contrast, in B219 the peak absolute number of pig cells 2 h after the BM Tx was 85/ll (Fig. 2). In both cases, loss of chimerism was most likely related to phagocytosis of pig cells by host macrophages [3,6].
Introduction Human cadaver allograft (HCA) is the current standard of care for temporary wound cl... more Introduction Human cadaver allograft (HCA) is the current standard of care for temporary wound closure of large burns, but a critical need for high-quality alternatives exists. Porcine skin shares many similarities with human skin, and hyperacute rejection is prevented via a single genetic modification. Like human skin, non-terminally sterilized porcine skin contains viable dermal and epidermal cells and intact vasculature that enables restoration of barrier function. These characteristics are distinct from those of traditional, terminally sterilized “xenografts” and may offer greater therapeutic capability. We report here key efficacy outcomes specific to severe burn care from a first-in-human clinical trial to assess the capability of genetically engineered porcine skin xenotransplants to provide temporary wound closure for severe and extensive deep-partial and full-thickness burn wounds, compared to HCA. Methods Split-thickness skin containing epidermal and dermal layers was harv...
The effects of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activit... more The effects of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice have been investigated using a versatile procedure for encapsulating doxorubicin inside liposomes. In this procedure, vesicles exhibiting transmembrane pH gradients (acidic inside) were employed to achieve drug trapping efficiencies in excess of 98%. Drug-to-lipid ratios as high as 0.3:1 (wt:wt) could be obtained in a manner that is relatively independent of lipid composition and vesicle size. Egg phosphatidylcholine (EPC)/cholesterol (55:45; mol/mol) vesicles sized through filters with a 200-nm pore size and loaded employing transmembrane pH gradients to achieve a doxorubicin-to-lipid ratio of 0.3:1 (wt/wt) increased the LD»of free drug by approximately twofold. Removing cholesterol or decreasing the drug-tolipid ratio in EPC/cholesterol preparations led to significant decreases in the LO»of liposomal doxorubicin whereas, the ID«,increased 4to 6fold...
Uploads
Papers by Dicken Ko