Background. Monitoring cyclosporine microemulsion (CsA-ME; Neoral) exposure 2 hours postdose (C2)... more Background. Monitoring cyclosporine microemulsion (CsA-ME; Neoral) exposure 2 hours postdose (C2) has been reported to optimize the efficacy and safety of CsA-ME therapy. The addition of induction therapy to a maintenance regimen including CsA-ME C2 monitoring has not been evaluated. Methods. In all, 123 adult renal transplant recipients were recruited at 14 U.S. centers for this 6-month study. CsA-ME dose was to be titrated to attain C2 targets of 1700 and 1500 ng/ml during posttransplant months 1 and 2, respectively. After 2 months, patients were randomized to one of two groups with different, decreasing C2 targets. Basiliximab, mycophenolate mofetil, and corticosteroids completed the study immunosuppression. Results. Of the 119 evaluable patients, 76% were male, 22% African American, and 66% deceased donor recipients. Biopsy-proven acute rejection occurred in 10 patients (9.3%); there were two failed grafts and one death. Serum creatinine and calculated GFR values suggest good renal function, with month 6 medians of 1.5 ng/ml and 67 ml/min/ 1.73 m 2 . Safety and tolerability assessments revealed no unexpected outcomes. Observed C2 levels were generally lower than protocol targets, particularly in the first weeks posttransplantation. Conclusions. The striking efficacy and outcomes may have been achieved in this study with lower C2 levels of CsA-ME because of the addition of basiliximab induction.
These data demonstrate excellent long-term patient and graft survival rates when cytolytic induct... more These data demonstrate excellent long-term patient and graft survival rates when cytolytic induction therapy is combined with sequential addition of CsA. OKT3 and MAG produce virtually indistinguishable outcomes with low rates of rejection and DGF. The frequency of serious posttransplant complications, infection, rejection, and malignancy was low. Although both MAG and OKT3 are effective, each has its drawbacks. Problems associated with MAG therapy are leukopenia, thrombocytopenia, cumbersome administration, and difficulty monitoring the patient's specific level of induced immunosuppression. OKT3 is simpler to administer, easy to monitor, but first dose reactions may produce additional graft injury. Furthermore, OKT3 may not protect completely against all mechanisms of cellular rejection. In our patient population, the best results occurred when kidneys functioned immediately, when CsA was introduced promptly, and when there were several days of overlap, with MAG or OKT3, especially when OKT3 was used as the induction agent.
Purpose Mammalian target of rapamycin (mTOR) inhibitors were previously considered a potential th... more Purpose Mammalian target of rapamycin (mTOR) inhibitors were previously considered a potential therapy for autosomal dominant polycystic kidney disease (ADPKD), but prior studies remained controversial about their efficacy. We performed an updated meta-analysis regarding the therapeutic and adverse effects of mTOR inhibitors in patients with ADPKD. Methods We systematically searched Cochrane Library, PubMed, EMBASE, and Medline for randomized controlled trials (RCTs) comparing mTOR inhibitors to placebo in ADPKD patients up to August 2019. We calculated weighted mean differences (WMDs) for total kidney volume (TKV), estimated glomerular filtration rates (eGFRs), and weighted odds ratios (ORs) for treatment-related complications between the treatment and the placebo groups, using the random effects model. Results We retrieved a total of 9 RCTs enrolling 784 ADPKD patients receiving rapamycin, sirolimus, or everolimus between 2009 and 2016. The WMDs of TKV and eGFR from baseline to the last measurement were − 31.54 mL (95% confidence interval [CI] − 76.79 to 13.71 mL) and 2.81 mL/min/1.73 m 2 (95% CI − 1.85 to 7.46 mL/min/1.73 m 2), respectively. Patients receiving mTOR inhibitors had a significantly increased risk of any adverse effects (OR 5.92, 95% CI 3.53-9.94), with the most common ones being aphthous stomatitis (OR 15.45, 95% CI 9.68-24.66) and peripheral edema (OR 3.49, 95% CI 1.31-9.27) compared to placebo users. Conclusions mTOR inhibitors did not significantly influence renal progression in patients with ADPKD, but were associated with a higher risk of complications. Whether mTOR inhibitors can be an add-on option or second-line agents remain undetermined.
Background Hepatic stellate cells (HSC) are involved in hepatic fibrogenesis. Cell signaling asso... more Background Hepatic stellate cells (HSC) are involved in hepatic fibrogenesis. Cell signaling associated with an insult to the liver affects an HSC transdifferentiation to fibrogenic myofibroblast-like cells. Aims To investigate the transcriptional expression distinguishing HSC and myofibroblast-like cells between livers with and without cirrhosis. Methods Tissue from ten cirrhotic livers (undergoing transplant) and four non-cirrhotic livers from the National Disease Research Interchange underwent cell separation to extract HSC and myofibroblast-like cell populations. Separated cell types as well as LI-90 cells were subjected to microarray analysis. Selected microarray results were verified by quantitative real-time PCR. Results Differential expression of some genes, such as IL-1b, IL-1a, and IL-6, was associated with both transdifferentiation and disease. Other genes, such as fatty acid 2-hydroxylase only show differential expression in association with disease. Functional analysis supported these findings, indicating some signal transduction pathways (IL-6) are involved in disease and activation, whereas retinoid X receptor signaling in HSC from cirrhotic and non-cirrhotic livers varies in scope and quality. Conclusions These findings indicate distinct phenotypes for HSC from cirrhotic and non-cirrhotic livers. Furthermore, coordinated differential expression between genes involved in the same signal transduction pathways provides some insight into the mechanisms that may control the balance between fibrogenesis and fibrolysis.
Journal of Trauma-injury Infection and Critical Care, May 1, 1989
This study analyzed age as a univariate factor in survival in a national group of 46,613 major tr... more This study analyzed age as a univariate factor in survival in a national group of 46,613 major trauma patients and compared 180 elderly major trauma patients (greater than or equal to 65 years) to a similarly injured group of 3,918 younger patients (less than 65 years). In the national group, mortality rose sharply between age 45 (10%) and 55 (15%) and doubled at age 75 years (20%). This age-dependent survival decrement occurred at all Injury Severity Score values, for all mechanisms of injury, and for all body regions. In the comparison study, mortality in the elderly group was nearly double that of mortality in the younger group (27% vs. 14%). The older patients had a markedly higher complication death rate, especially for pulmonary (14/100 vs. 6.1/1100) and infectious complications (4.6/100 vs. 0.7/100). The median length of stay was twice as long for the older patients (14 days vs. 7 days). Cost data showed that the DRG prospective payment system grossly underestimated the cost of care for these patients (mean loss of $2,177.14 per patient). To minimize mortality and morbidity, triaging elderly trauma victims to trauma centers at a much lower threshold than similarly injured younger patients is recommended. The current DRG system should be altered to account for age-dependent morbidity. Further study is needed to determine whether more rigorous infection prophylaxis, immunomodulation, and pulmonary therapy will augment survival in elderly patients.
Immunosuppression TMA is a complication that is still not fully understood. The contribution of i... more Immunosuppression TMA is a complication that is still not fully understood. The contribution of immunosuppressive medications, especially sirolimus, to its pathogenesis needs further investigation. Development of TMA in the setting of combined sirolimus and calcineurin inhibitor immunosuppression should prompt consideration of discontinuing sirolimus. 4. deMattos AM, Olyaei AJ, Bennett WM. Nephrotoxicity of immunosuppressive drugs: long term consequences and challenges for the future. Am J
Objectives: The method for drainage of exocrine secretions in pancreas transplantation remains a ... more Objectives: The method for drainage of exocrine secretions in pancreas transplantation remains a matter of debate. Different methods have evolved over time. Most data on these methods are from single-center studies with small sample sizes. Larger studies have yielded conflicting results. Methods: Data from the United Network for Organ Sharing database on all adult subjects who received pancreas and kidney-pancreas transplants between 1996 and 2012 were analyzed (n = 19,934). Subjects were divided into 3 groups: enteric drainage with Roux-en-Y (n = 4308), enteric drainage without Roux-en-Y (n = 11,145), and bladder drainage (n = 4481). Primary end points were patient and graft survival at 1, 3, 5, 10, and 15 years. Results: There was a patient and graft survival advantage with enteric drainage without Roux-en-Y reconstruction compared with the other methods. This was consistent at 1, 3, 5, 10, and 15 years. Conclusions: Our study demonstrated increased graft and patient survival when comparing enteric drainage of the transplanted pancreas without Roux-en-Y reconstruction to enteric drainage with Roux-en-Y and bladder drainage at 1, 3, 5, 10, and 15 years. Based on this study, we recommend enteric drainage without Roux-en-Y reconstruction as the method of choice in pancreas transplantation.
Malny Inlll~s :1 i',rccL~ diaguosis is iUllhlrtlln[ [0 predict the outcome ifl folminan[ hcl~atlc... more Malny Inlll~s :1 i',rccL~ diaguosis is iUllhlrtlln[ [0 predict the outcome ifl folminan[ hcl~atlc I'ailnrc (l:l IF) Wc have cvahlalcd the contribution of Iransjngular bvcr biopSY (T[,14) in the dlagu~ms and the pn.~gnosis iuclnding Ihc uscl'uncs.s m considenng for hvcr Iransl~lan~alLon It)LT) or iu cxcluding mmtc fmticnts from OI.]" In Ii 55 m,.mth f+criod. 33 FltF pat(cuts tpL';) were evllluated by the Liv~ Transplant Tam to decide the pnlative no.'d tbr ()I.T, or other appropriate trealmcnts in cc'rtain etiologic Ihcl.rs t Irg.,.-nl t)[.]" was indicated according to several criteria: clinical (King's College. Clichy) aud hist.h,gica[. .~ix(CCll pallCnls ~.~.crc f¢lnalc alld their age rallged bctwc~:n 4 ll|onlhs and 67 .'.'ears Euologic-~ wcpz di:,.l~bulcd us Ibllows Fuhniuant B (6)+ NANBNC (4). B Della (I) aculc Wils, afs (3). annie fany liver ol'prcgu,'mcy (2). drug toxicity (5): cesta%, I. IV drugs (2) Annanihl IXfis(ming (3). Budd.Chiari (I), auhfinuounc hepatitis (3). NSAID (I). halogcnalcd agcuts (2) spotted li:vur (I) aud Icptosl)irosis (I). lu all. encephalopadly 'Jcvclupl~Cd Icx'~ Ihan 2 ',',cks al'lcr janndic¢ (reset and progrcsse,J Io grade IV un 6 pl In 22/28, bilirubiu rose lu values ab(wc 18 ing/d], and prolhronlbin time was abt,','c S0 sccunds I,iver bi.psy (via Iransjognlar route) was perf.ru'w:d iu 19133 l/lcvcn i)ls (3]°/,,)~av Irmt~l}lanted. ;rod [he other 20 did uot n:ccivc (}LT because orcithcr apparent rapid impn~vcmcul (13 pts). presancc of contraindicaliou-(iucluding lack of :.u.,cial (,r I~lnuly sop]~{q~-~+ ])is) tW bccau~ of organ unavailability (2 pts) TI.13 alhmcd in all 19 caascs [o ass¢.~.'.; tile p,..'rcentag¢ of hepatocellular n¢cr.ms and Ichcuiar cullal~se+ aud wlicu u,.'cdcd. 1. quantitatc liver torquer 'there ;',as grcal cunc~wdancc between climcal dccisiOlt and inst,,Iogical lindings Furthcrul(llc. II did ilol shll%% reticular c,Jllapsc ill acuic fally liver of prcgnaocy pallenL, i.
Background. Monitoring cyclosporine microemulsion (CsA-ME; Neoral) exposure 2 hours postdose (C2)... more Background. Monitoring cyclosporine microemulsion (CsA-ME; Neoral) exposure 2 hours postdose (C2) has been reported to optimize the efficacy and safety of CsA-ME therapy. The addition of induction therapy to a maintenance regimen including CsA-ME C2 monitoring has not been evaluated. Methods. In all, 123 adult renal transplant recipients were recruited at 14 U.S. centers for this 6-month study. CsA-ME dose was to be titrated to attain C2 targets of 1700 and 1500 ng/ml during posttransplant months 1 and 2, respectively. After 2 months, patients were randomized to one of two groups with different, decreasing C2 targets. Basiliximab, mycophenolate mofetil, and corticosteroids completed the study immunosuppression. Results. Of the 119 evaluable patients, 76% were male, 22% African American, and 66% deceased donor recipients. Biopsy-proven acute rejection occurred in 10 patients (9.3%); there were two failed grafts and one death. Serum creatinine and calculated GFR values suggest good renal function, with month 6 medians of 1.5 ng/ml and 67 ml/min/ 1.73 m 2 . Safety and tolerability assessments revealed no unexpected outcomes. Observed C2 levels were generally lower than protocol targets, particularly in the first weeks posttransplantation. Conclusions. The striking efficacy and outcomes may have been achieved in this study with lower C2 levels of CsA-ME because of the addition of basiliximab induction.
These data demonstrate excellent long-term patient and graft survival rates when cytolytic induct... more These data demonstrate excellent long-term patient and graft survival rates when cytolytic induction therapy is combined with sequential addition of CsA. OKT3 and MAG produce virtually indistinguishable outcomes with low rates of rejection and DGF. The frequency of serious posttransplant complications, infection, rejection, and malignancy was low. Although both MAG and OKT3 are effective, each has its drawbacks. Problems associated with MAG therapy are leukopenia, thrombocytopenia, cumbersome administration, and difficulty monitoring the patient's specific level of induced immunosuppression. OKT3 is simpler to administer, easy to monitor, but first dose reactions may produce additional graft injury. Furthermore, OKT3 may not protect completely against all mechanisms of cellular rejection. In our patient population, the best results occurred when kidneys functioned immediately, when CsA was introduced promptly, and when there were several days of overlap, with MAG or OKT3, especially when OKT3 was used as the induction agent.
Purpose Mammalian target of rapamycin (mTOR) inhibitors were previously considered a potential th... more Purpose Mammalian target of rapamycin (mTOR) inhibitors were previously considered a potential therapy for autosomal dominant polycystic kidney disease (ADPKD), but prior studies remained controversial about their efficacy. We performed an updated meta-analysis regarding the therapeutic and adverse effects of mTOR inhibitors in patients with ADPKD. Methods We systematically searched Cochrane Library, PubMed, EMBASE, and Medline for randomized controlled trials (RCTs) comparing mTOR inhibitors to placebo in ADPKD patients up to August 2019. We calculated weighted mean differences (WMDs) for total kidney volume (TKV), estimated glomerular filtration rates (eGFRs), and weighted odds ratios (ORs) for treatment-related complications between the treatment and the placebo groups, using the random effects model. Results We retrieved a total of 9 RCTs enrolling 784 ADPKD patients receiving rapamycin, sirolimus, or everolimus between 2009 and 2016. The WMDs of TKV and eGFR from baseline to the last measurement were − 31.54 mL (95% confidence interval [CI] − 76.79 to 13.71 mL) and 2.81 mL/min/1.73 m 2 (95% CI − 1.85 to 7.46 mL/min/1.73 m 2), respectively. Patients receiving mTOR inhibitors had a significantly increased risk of any adverse effects (OR 5.92, 95% CI 3.53-9.94), with the most common ones being aphthous stomatitis (OR 15.45, 95% CI 9.68-24.66) and peripheral edema (OR 3.49, 95% CI 1.31-9.27) compared to placebo users. Conclusions mTOR inhibitors did not significantly influence renal progression in patients with ADPKD, but were associated with a higher risk of complications. Whether mTOR inhibitors can be an add-on option or second-line agents remain undetermined.
Background Hepatic stellate cells (HSC) are involved in hepatic fibrogenesis. Cell signaling asso... more Background Hepatic stellate cells (HSC) are involved in hepatic fibrogenesis. Cell signaling associated with an insult to the liver affects an HSC transdifferentiation to fibrogenic myofibroblast-like cells. Aims To investigate the transcriptional expression distinguishing HSC and myofibroblast-like cells between livers with and without cirrhosis. Methods Tissue from ten cirrhotic livers (undergoing transplant) and four non-cirrhotic livers from the National Disease Research Interchange underwent cell separation to extract HSC and myofibroblast-like cell populations. Separated cell types as well as LI-90 cells were subjected to microarray analysis. Selected microarray results were verified by quantitative real-time PCR. Results Differential expression of some genes, such as IL-1b, IL-1a, and IL-6, was associated with both transdifferentiation and disease. Other genes, such as fatty acid 2-hydroxylase only show differential expression in association with disease. Functional analysis supported these findings, indicating some signal transduction pathways (IL-6) are involved in disease and activation, whereas retinoid X receptor signaling in HSC from cirrhotic and non-cirrhotic livers varies in scope and quality. Conclusions These findings indicate distinct phenotypes for HSC from cirrhotic and non-cirrhotic livers. Furthermore, coordinated differential expression between genes involved in the same signal transduction pathways provides some insight into the mechanisms that may control the balance between fibrogenesis and fibrolysis.
Journal of Trauma-injury Infection and Critical Care, May 1, 1989
This study analyzed age as a univariate factor in survival in a national group of 46,613 major tr... more This study analyzed age as a univariate factor in survival in a national group of 46,613 major trauma patients and compared 180 elderly major trauma patients (greater than or equal to 65 years) to a similarly injured group of 3,918 younger patients (less than 65 years). In the national group, mortality rose sharply between age 45 (10%) and 55 (15%) and doubled at age 75 years (20%). This age-dependent survival decrement occurred at all Injury Severity Score values, for all mechanisms of injury, and for all body regions. In the comparison study, mortality in the elderly group was nearly double that of mortality in the younger group (27% vs. 14%). The older patients had a markedly higher complication death rate, especially for pulmonary (14/100 vs. 6.1/1100) and infectious complications (4.6/100 vs. 0.7/100). The median length of stay was twice as long for the older patients (14 days vs. 7 days). Cost data showed that the DRG prospective payment system grossly underestimated the cost of care for these patients (mean loss of $2,177.14 per patient). To minimize mortality and morbidity, triaging elderly trauma victims to trauma centers at a much lower threshold than similarly injured younger patients is recommended. The current DRG system should be altered to account for age-dependent morbidity. Further study is needed to determine whether more rigorous infection prophylaxis, immunomodulation, and pulmonary therapy will augment survival in elderly patients.
Immunosuppression TMA is a complication that is still not fully understood. The contribution of i... more Immunosuppression TMA is a complication that is still not fully understood. The contribution of immunosuppressive medications, especially sirolimus, to its pathogenesis needs further investigation. Development of TMA in the setting of combined sirolimus and calcineurin inhibitor immunosuppression should prompt consideration of discontinuing sirolimus. 4. deMattos AM, Olyaei AJ, Bennett WM. Nephrotoxicity of immunosuppressive drugs: long term consequences and challenges for the future. Am J
Objectives: The method for drainage of exocrine secretions in pancreas transplantation remains a ... more Objectives: The method for drainage of exocrine secretions in pancreas transplantation remains a matter of debate. Different methods have evolved over time. Most data on these methods are from single-center studies with small sample sizes. Larger studies have yielded conflicting results. Methods: Data from the United Network for Organ Sharing database on all adult subjects who received pancreas and kidney-pancreas transplants between 1996 and 2012 were analyzed (n = 19,934). Subjects were divided into 3 groups: enteric drainage with Roux-en-Y (n = 4308), enteric drainage without Roux-en-Y (n = 11,145), and bladder drainage (n = 4481). Primary end points were patient and graft survival at 1, 3, 5, 10, and 15 years. Results: There was a patient and graft survival advantage with enteric drainage without Roux-en-Y reconstruction compared with the other methods. This was consistent at 1, 3, 5, 10, and 15 years. Conclusions: Our study demonstrated increased graft and patient survival when comparing enteric drainage of the transplanted pancreas without Roux-en-Y reconstruction to enteric drainage with Roux-en-Y and bladder drainage at 1, 3, 5, 10, and 15 years. Based on this study, we recommend enteric drainage without Roux-en-Y reconstruction as the method of choice in pancreas transplantation.
Malny Inlll~s :1 i',rccL~ diaguosis is iUllhlrtlln[ [0 predict the outcome ifl folminan[ hcl~atlc... more Malny Inlll~s :1 i',rccL~ diaguosis is iUllhlrtlln[ [0 predict the outcome ifl folminan[ hcl~atlc I'ailnrc (l:l IF) Wc have cvahlalcd the contribution of Iransjngular bvcr biopSY (T[,14) in the dlagu~ms and the pn.~gnosis iuclnding Ihc uscl'uncs.s m considenng for hvcr Iransl~lan~alLon It)LT) or iu cxcluding mmtc fmticnts from OI.]" In Ii 55 m,.mth f+criod. 33 FltF pat(cuts tpL';) were evllluated by the Liv~ Transplant Tam to decide the pnlative no.'d tbr ()I.T, or other appropriate trealmcnts in cc'rtain etiologic Ihcl.rs t Irg.,.-nl t)[.]" was indicated according to several criteria: clinical (King's College. Clichy) aud hist.h,gica[. .~ix(CCll pallCnls ~.~.crc f¢lnalc alld their age rallged bctwc~:n 4 ll|onlhs and 67 .'.'ears Euologic-~ wcpz di:,.l~bulcd us Ibllows Fuhniuant B (6)+ NANBNC (4). B Della (I) aculc Wils, afs (3). annie fany liver ol'prcgu,'mcy (2). drug toxicity (5): cesta%, I. IV drugs (2) Annanihl IXfis(ming (3). Budd.Chiari (I), auhfinuounc hepatitis (3). NSAID (I). halogcnalcd agcuts (2) spotted li:vur (I) aud Icptosl)irosis (I). lu all. encephalopadly 'Jcvclupl~Cd Icx'~ Ihan 2 ',',cks al'lcr janndic¢ (reset and progrcsse,J Io grade IV un 6 pl In 22/28, bilirubiu rose lu values ab(wc 18 ing/d], and prolhronlbin time was abt,','c S0 sccunds I,iver bi.psy (via Iransjognlar route) was perf.ru'w:d iu 19133 l/lcvcn i)ls (3]°/,,)~av Irmt~l}lanted. ;rod [he other 20 did uot n:ccivc (}LT because orcithcr apparent rapid impn~vcmcul (13 pts). presancc of contraindicaliou-(iucluding lack of :.u.,cial (,r I~lnuly sop]~{q~-~+ ])is) tW bccau~ of organ unavailability (2 pts) TI.13 alhmcd in all 19 caascs [o ass¢.~.'.; tile p,..'rcentag¢ of hepatocellular n¢cr.ms and Ichcuiar cullal~se+ aud wlicu u,.'cdcd. 1. quantitatc liver torquer 'there ;',as grcal cunc~wdancc between climcal dccisiOlt and inst,,Iogical lindings Furthcrul(llc. II did ilol shll%% reticular c,Jllapsc ill acuic fally liver of prcgnaocy pallenL, i.
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