Gustaf Herlenius | Göteborg University (original) (raw)
Papers by Gustaf Herlenius
Scandinavian Journal of Gastroenterology
BACKGROUND Acute kidney injury (AKI) is frequent after liver transplantation (LT), with impact on... more BACKGROUND Acute kidney injury (AKI) is frequent after liver transplantation (LT), with impact on graft function, morbidity and mortality. Although multifactorial, the pathophysiology of perioperative kidney injury remains unclear. Our aims were to analyze the frequency, evolution and risk factors for kidney impairment during the peri- and early post-operative period. METHODS In a prospective, single-center study of 27 adult patients undergoing first single-organ LT, we analyzed measured glomerular filtration rate (mGFR) pre-transplant, at post-operative day (POD) 10, and at 1, 3, 12 and 36 months. Kidney and liver graft biopsies were performed during LT. RESULTS A median mGFR decline of 45% was detected from pre-transplant to POD 10, correlating strongly with the mGFR evolution from baseline to 12 months (rs = 0.80, p<.001) and baseline to 36 months (rs = 0.82, p<.001). AKI occurred in 59% of recipients within 48 h of LT, notably before the introduction of calcineurin inhibitors on POD 3. AKI was strongly associated with mGFR at 12 and 36 months. Kidney and liver graft biopsies showed only minor histological changes. Donor and recipient body mass index, recipient age, model of end-stage liver disease score, diagnosis of hepatitis C, donor cause of death, as well as bleeding, transfusions and duration of the anhepatic phase correlated with early kidney dysfunction. CONCLUSION The greatest decline in mGFR was evident within 10 days and AKI within hours of LT, irrespective of baseline mGFR and before introduction of calcineurin inhibitors. Very early post-LT kidney injury has substantial consequences for long-term kidney function.
International Journal of Molecular Sciences
Acute kidney injury (AKI) is frequent after liver transplantation (LT) and correlates with later ... more Acute kidney injury (AKI) is frequent after liver transplantation (LT) and correlates with later development of chronic kidney disease. Its etiology is multifactorial and combines pre-, intra-, and postoperative factors. Additionally, the liver graft itself seems an important element in the development of AKI, yet the detailed mechanisms remain unclear. We hypothesized that grafts of LT recipients developing significant early AKI may show distinct proteomic alterations, and we set out to identify proteome differences between LT recipients developing moderate or severe AKI (n = 7) and LT recipients without early renal injury (n = 7). Liver biopsies obtained one hour after reperfusion were assessed histologically and using quantitative proteomics. Several cytokines and serum amyloid A2 (SAA2) were analyzed in serum samples obtained preoperatively, 2–4 h, and 20–24 h after graft reperfusion, respectively. LT induced mild histological alterations without significant differences between ...
Transplantation Proceedings, 2006
We report 12 cases of pseudoaneurysm hepatic artery (PA) among 825 liver transplantations (OLT) p... more We report 12 cases of pseudoaneurysm hepatic artery (PA) among 825 liver transplantations (OLT) performed between January 1985 and December 2005. In the early period (1985 to 1995), the incidence was 2.6% and in the later period (1996 to 2005), 0.9%. Median time to onset was 39.5 days post-OLT (range 14 days to 5 years). Six patients presented with rupture into the peritoneum (n ϭ 4) or gastrointestinal tract (n ϭ 2), while five patients presented with gastrointestinal bleed due arteriobiliary fistulation with hemobilia. The twelfth PA was found incidentally during retransplantation. PAs were detected with radiological imaging (n ϭ 4), exploratory laparotomy (n ϭ 6), at autopsy (n ϭ 1) or at retransplantation (n ϭ 1). We performed immediate revascularization, after surgical excision was performed in three and endovascular embolization in one patient. In six patients hepatic artery ligation without revascularization was inevitable with subsequent successful retransplantation in four patients. No PA-specific treatment was attempted in two cases due to the poor prognosis or diagnostic ambiguity. In 10 cases microbial pathogens were cultured in the blood, subhepatic abscesses, or from the wall of the hepatic artery. A hepaticojejunostomy was performed for biliary reconstruction in six patients and two had a hepaticojejunostomy conversion due to biliary leak. Survival in the early period (1985 to 1995) was 14%, whereas during the later period (1996 to 2005), the survival increased to 100% with a 4.2-year median follow-up (range 7.4 months to 6.9 years). Infrequently PA complicates OLT, becoming evident primarily after rupture with hemoperitoneum or a gastrointestinal bleed. Early recognition with angiography is important but acute hemorrhage often requires immediate exploration with ligation of the PA, although surgical or endovascular exclusion of the PA followed by revascularization provides a feasible treatment option.
Transplantation Proceedings, 2010
Background. Chronic kidney disease (CKD) has emerged as a significant cause of morbidity and a ri... more Background. Chronic kidney disease (CKD) has emerged as a significant cause of morbidity and a risk factor for mortality after orthotopic liver transplantation (OLT). The use of calcineurin inhibitor (CNI)-based immunosuppression is an important etiologic factor for developing CKD. CNI discontinuation or minimization protocols with replacement of the CNI with non-nephrotoxic drugs, such as mycophenolate mofetil (MMF) or sirolimus (SRL), may have the potential to preserve or recover renal function. Patients and Methods. In this prospective, randomized, single-center study with CNI discontinuation, OLT recipients with CKD (measured glomerular filtration rate [GFRm] 15-45 mL/min/1.73 m 2) were randomized to either SRL or MMF-based immunosuppression. The main objective was to study the effect of CNI discontinuation on renal function. Secondary aims were to assess the frequency of biopsy-proven acute rejection episodes (BPAR) and adverse events (AE). Renal function was followed with GFRm using 51-Chromium EDTA clearance at baseline, 3 months, and 1 year. Patients were stratified according to baseline GFRm Ͼ versus Ͻ30 mL/min/1.73 m 2. The 25 patients were enrolled for MMF (n ϭ 13) or SRL (n ϭ 12). The median age at inclusion was 59 years (range, 25-66) and the median number of years after OLT was 4.4 (range, 1-13). Twenty-two patients were followed up for a year; MMF (n ϭ 12) and SRL (n ϭ 10). Results. Mean GFRm for the whole cohort (n ϭ 25) was 31ϩ/Ϫ8 mL/min/1.73 m 2 at baseline. After 3 months the GFRm (n ϭ 23) increased to 40ϩ/Ϫ10 mL/min/1.73 m 2 (P ϭ .0001) and at 1 year 42 ϩ/Ϫ 11 mL/min/1.73 m 2 (n ϭ 22). There was not significant difference between the MMF and the SRL study arms. The cohort (n ϭ 8) with baseline GFRm Ͻ30 mL showed a 63% (P ϭ .003) increased filtration after 1 year. There was no significant difference in the frequency or severity of AE between the study arms with the exception of oral ulcerations and persistent hypertriglyceridemia in the SRL group. Two deaths occurred, 1 in each study arm, both probably unrelated to the change in immunosuppression. There were no BPAR episodes. Conclusion. CNI discontinuation and replacement with either MMF or SRL resulted in a significant improvement in renal function even in those patients with severe CKD. The protocol was effective with no acute rejection episodes. The SRL arm showed a higher frequency of oral apthous ulcerations and hypertriglyceridemia. Future studies addressing long-term renal function after CNI discontinuation are needed.
Transplantation, 2010
Background. Intestinal preservation injury consists of progressive submucosal edema, with fluid o... more Background. Intestinal preservation injury consists of progressive submucosal edema, with fluid originating both from the lumen and the interstitium. Although vascular flushing aims to control electrolyte shifts in the tissue, the lumen is not addressed, and luminal water and electrolytes enter the tissue during ischemia. Because macromolecular solutions may retain water and electrolytes intraluminally, we investigated whether these solutions administered intraluminally may alleviate preservation injury. Methods. Sprague-Dawley rat intestines were perfused with University of Wisconsin solution. After excision of the intestines, we intraluminally introduced solutions containing polyethylene glycol 3350 with high (125 mEq) or low (65 mEq) sodium before cold preservation. Controls underwent only vascular flush. After 8, 14, or 20 hr of cold storage, the intestines were analyzed for extent of tissue injury, water retention, brush-border maltase, and tight junction proteins zonula occludens-1 and claudin-3. Results. Intraluminal composition changed over time, indicating sodium absorption and potassium secretion. After 8 and 14 hr of cold storage, intestines from the low-sodium group had the best morphology and least edema, followed by the controls. Maltase activity slightly decreased in all groups over time and was not affected by the intraluminal polyethylene glycol solutions. Various degrees of delocalization and degradation of zonula occludens-1 and claudin-3 were recorded within the tight junctions, with the most significant effects in intestines from the high-sodium group. Conclusions. Intraluminal macromolecular solutions may modulate the preservation injury in University of Wisconsinperfused intestines. Low-sodium solutions administered immediately before preservation may improve preservation injury, but high-sodium solutions may be detrimental.
Liver Transplantation, 2007
Liver transplantation can be a therapeutic option for individual patients with neuroendocrine tum... more Liver transplantation can be a therapeutic option for individual patients with neuroendocrine tumors metastatic only to the liver. In this consecutive series of 15 patients (5 multivisceral and 10 orthotopic liver transplantations) with well-differentiated carcinoids, or endocrine pancreatic tumors, we allowed higher proliferation rate (Ki67 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;10%), large tumor burden, and higher age than previous studies. Liver transplantation offered good relief of symptoms, long disease-free intervals, and potential cure in individual patients. The survival of grafts and patients compared well with transplantation for benign disease. The overall 5-year survival was 90%. The recurrence-free survival of both multivisceral and liver transplantation related to the time after transplantation (about 20% at 5 years) despite inclusion of patients with higher risk. In conclusion, the critical prognosticators for long-term outcome still remain to be defined. The experience with multivisceral transplantation for patients with endocrine tumors of the pancreatic head is still limited.
American Journal of Transplantation, 2012
Rapidly progressing mucosal breakdown limits the intestinal preservation time below 10 h. Recent ... more Rapidly progressing mucosal breakdown limits the intestinal preservation time below 10 h. Recent studies indicate that intraluminal solutions containing polyethylene glycol (PEG) alleviate preservation injury of intestines stored in UW-Viaspan. We investigated whether a low-sodium PEG solution is beneficial for intestines stored in histidine-tryptophane-ketoglutarate (HTK) preservation solution. Rat intestines used as control tissue (group 1) were perfused with HTK, groups 2 and 3 received either a customized PEG-3350 (group 2) or an electrolyte solution (group 3) intraluminally before cold storage. Tissue injury, brush-border maltase activity, zonula occludens-1 (ZO-1) and claudin-3 expression in the tight junctions (TJ) were analyzed after 8, 14 and 20 h. We measured epithelial resistance and permeability (Ussing chamber) after 8 and 14 h. Group 2 had superior morphology while maltase activity was similar in all groups. TJ proteins rapidly decreased and decolocalized in groups 1 3; these negative events were delayed in group 2, where colocalization persisted for about 14 h. Intestines in group 2 had higher epithelial resistance and lower permeability than the other groups. These results suggest that a customized PEG solution intraluminally reduces the intestinal preservation injury by improving several major epithelial characteristics without negatively affecting the brush-border enzymes or promoting edema.
Transplantation, 2008
Background. Chronic kidney disease after organ transplantation is a serious complication that neg... more Background. Chronic kidney disease after organ transplantation is a serious complication that negatively impacts on long-term patient survival. We describe long-term renal function after intestinal transplantation by serial measurements of glomerular filtration rates (GFR) with 51 Chromium EDTA clearance. Materials and Methods. Ten patients with at least 6 months survival form the basis of this report. Glomerular filtration rate measurements were performed at baseline, 3 months posttransplantation, and yearly thereafter. Median follow-up time for the cohort was 1.5 years (0.5-7.8 years). Tacrolimus (Prograf) was discontinued in four patients because of impaired renal function. These four patients were switched to sirolimus (Rapamune) at 11, 18, 24, and 40 months posttransplantation. Results. Median baseline GFR was 67 (22-114) mL/min/1.73 m 2. In the adult patients, GFR 3 months posttransplantation had decreased to 50% of the baseline. At 1 year, median GFR in the adult patients was reduced by 72% (nϭ5). Two patients developed renal failure within the first year and required hemodialysis. One of the pediatric patients fully recovered her renal function, the second pediatric patient lost 20% of her baseline GFR at 6 months posttransplantation. Glomerular filtration rate calculated with the modified diet in renal disease formula consistently overestimated GFR by approximately 30% compared with measured GFR. Conclusion. Chronic kidney disease and renal failure are common after intestinal transplantation. These two factors significantly contribute to poor long-term survival rates. Measurements of GFR may help to identify those individuals at risk for developing chronic kidney disease to implement renal sparing strategies.
Encyclopedia of Gastroenterology
Lakartidningen, 2004
Outcome after intestinal transplantation has improved dramatically since the introduction of nove... more Outcome after intestinal transplantation has improved dramatically since the introduction of novel immunosuppressive agents and refined surgical techniques. Small bowel transplantation is now considered to be the best treatment modality for patients with life threatening complications of intestinal failure and parenteral nutrition. We hereby review the international experience as well as the first ten cases of intestinal transplantation performed in Sweden.
Transplantation
Microscopic examination of endoscopic biopsies is the mainstay of acute rejection (AR) surveillan... more Microscopic examination of endoscopic biopsies is the mainstay of acute rejection (AR) surveillance after intestinal transplantation. However, biopsies require time for processing and may entail risks. The endoscopic features encountered during AR are quite well defined yet there are no established endoscopic criteria for diagnosing AR or any grading system for the severity of the endoscopic findings. In theory, a grading system could allow a faster preliminary diagnosis of AR based on endoscopic findings.Moreover, such scoring systemwould reduce interobserver variability and allow for more objective intraand interpatient comparisons. We designed a five-stage grading score based on previously described endoscopic features of AR (erythema, edema, ulcerations, friability, villous alterations). Two investigators retrospectively reviewed the endoscopy reports of 26 patients (19 adults and 7 pediatric) receiving 27 intestines containing grafts and graded the examinations using the score. Results were correlated with the pathology findings with regard to the presence and degree of AR. Five hundred four ileoscopies were reviewed: 374 examinations (74%) were considered normal (G0), 59 had mild alterations (erythema, edematous villiG1), moderate changes (erosions, blunted villi-G2) were found in 36 endoscopies, 17 ileoscopies revealed advanced changes (ulcerations, villus loss G3) while in 18 occasions the changes were estimated as severe (mucosal lossG4). Inter-reviewer agreement was very good (kappa=0,815, p<0.001). AR was found in biopsies from 86 endoscopy sessions (17%) and in 63 cases AR was considered moderate or severe. For the cases with low-degree AR the sensitivity of this new grading score was 66% and the specificity was 86% whereas the positive and negative predictive values were 45% and 93% respectively. During advanced AR the sensitivity of the score was 90% and the specificity was 86% whereas the positive and negative predictive values were 40% and 98% respectively. We herein suggest a novel grading score that both summarizes the findings and allows comparisons between intestinal graft endoscopies. Its prospective evaluation is ongoing. 205.5
Transplantation
Mihai Oltean, Chiara Zanfi, Laurens J. Ceulemans, Pablo Farinelli, Jacques Pirenne, Augusto Lauro... more Mihai Oltean, Chiara Zanfi, Laurens J. Ceulemans, Pablo Farinelli, Jacques Pirenne, Augusto Lauro, Gustaf Herlenius, Gabriel Gondolesi The Transplant Center, Sahlgrenska University Hosptal, Gothenburg, Sweden; Liver and Multiorgan Transplant Center, St. Orsola University Hospital, Bologna, Italy; Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium; Institute of Multiorgan Transplantation, Favaloro Foundation, Buenos Aires, Argentina.
Läkartidningen, 2004
Outcome after intestinal transplantation has improved dramatically since the introduction of nove... more Outcome after intestinal transplantation has improved dramatically since the introduction of novel immunosuppressive agents and refined surgical techniques. Small bowel transplantation is now consi ...
A randomized, double-blind, placebo-controlled study to determine safety, tolerance, and prelimin... more A randomized, double-blind, placebo-controlled study to determine safety, tolerance, and preliminary pharmacokinetics of ascending single doses of orally administered sirolimus (rapamycin) in stable r
Background: Chronic kidney disease (CKD) after liver (LT) or intestinal (IT) transplantation may ... more Background: Chronic kidney disease (CKD) after liver (LT) or intestinal (IT) transplantation may decrease patient survival. Calcineurin inhibitors (CNI) play a major role in its development. Aims: Describe long term renal function and risk factors for developing CKD in adults and children after LT and IT. Investigate if CNI discontinuation in adults after LT improves renal function. Methods: GFR was measured (GFRm) with either Iohexol or 51-Cr EDTA-clearance in both adults and children at different intervals before and after LT and IT. Results: After LT in adults (n=152) (I), GFRm decreased with 42% after10 years. Prevalence of CKD increased over time: 12% at 5 years and 29% at 10 years. Eight patients (5%) required renal replacement therapy (RRT). Baseline GFRm correlated poorly with late renal function. GFRm at 3 months post-LT correlated well with GFRm at 5 years and GFRm below30 ml/min/1.73m2 at 3 months was a risk factor for CKD at 5 years. After IT (II) CKD was almost universa...
Transplant International
Intestinal transplantation (ITx) is a life-saving procedure for complicated intestinal failure. I... more Intestinal transplantation (ITx) is a life-saving procedure for complicated intestinal failure. It is still characterized by a high risk of infection and rejection(1). Of all organs, the intestine is the most vulnerable to ischemia reperfusion injury (IRI) and the associated crosstalk between the innate and adaptive immune response can trigger rejection(2). A crucial factor in limiting IRI is the organ preservation phase. Currently, static cold storage with University of Wisconsin (UW) solution is the gold standard, although other solutions such as HTK (Histidine-Tryptophan-Ketoglutarate) have also been reported (3). Due to low numbers, randomized controlled trials are difficult to organize in this field.
Scandinavian Journal of Gastroenterology
BACKGROUND Acute kidney injury (AKI) is frequent after liver transplantation (LT), with impact on... more BACKGROUND Acute kidney injury (AKI) is frequent after liver transplantation (LT), with impact on graft function, morbidity and mortality. Although multifactorial, the pathophysiology of perioperative kidney injury remains unclear. Our aims were to analyze the frequency, evolution and risk factors for kidney impairment during the peri- and early post-operative period. METHODS In a prospective, single-center study of 27 adult patients undergoing first single-organ LT, we analyzed measured glomerular filtration rate (mGFR) pre-transplant, at post-operative day (POD) 10, and at 1, 3, 12 and 36 months. Kidney and liver graft biopsies were performed during LT. RESULTS A median mGFR decline of 45% was detected from pre-transplant to POD 10, correlating strongly with the mGFR evolution from baseline to 12 months (rs = 0.80, p<.001) and baseline to 36 months (rs = 0.82, p<.001). AKI occurred in 59% of recipients within 48 h of LT, notably before the introduction of calcineurin inhibitors on POD 3. AKI was strongly associated with mGFR at 12 and 36 months. Kidney and liver graft biopsies showed only minor histological changes. Donor and recipient body mass index, recipient age, model of end-stage liver disease score, diagnosis of hepatitis C, donor cause of death, as well as bleeding, transfusions and duration of the anhepatic phase correlated with early kidney dysfunction. CONCLUSION The greatest decline in mGFR was evident within 10 days and AKI within hours of LT, irrespective of baseline mGFR and before introduction of calcineurin inhibitors. Very early post-LT kidney injury has substantial consequences for long-term kidney function.
International Journal of Molecular Sciences
Acute kidney injury (AKI) is frequent after liver transplantation (LT) and correlates with later ... more Acute kidney injury (AKI) is frequent after liver transplantation (LT) and correlates with later development of chronic kidney disease. Its etiology is multifactorial and combines pre-, intra-, and postoperative factors. Additionally, the liver graft itself seems an important element in the development of AKI, yet the detailed mechanisms remain unclear. We hypothesized that grafts of LT recipients developing significant early AKI may show distinct proteomic alterations, and we set out to identify proteome differences between LT recipients developing moderate or severe AKI (n = 7) and LT recipients without early renal injury (n = 7). Liver biopsies obtained one hour after reperfusion were assessed histologically and using quantitative proteomics. Several cytokines and serum amyloid A2 (SAA2) were analyzed in serum samples obtained preoperatively, 2–4 h, and 20–24 h after graft reperfusion, respectively. LT induced mild histological alterations without significant differences between ...
Transplantation Proceedings, 2006
We report 12 cases of pseudoaneurysm hepatic artery (PA) among 825 liver transplantations (OLT) p... more We report 12 cases of pseudoaneurysm hepatic artery (PA) among 825 liver transplantations (OLT) performed between January 1985 and December 2005. In the early period (1985 to 1995), the incidence was 2.6% and in the later period (1996 to 2005), 0.9%. Median time to onset was 39.5 days post-OLT (range 14 days to 5 years). Six patients presented with rupture into the peritoneum (n ϭ 4) or gastrointestinal tract (n ϭ 2), while five patients presented with gastrointestinal bleed due arteriobiliary fistulation with hemobilia. The twelfth PA was found incidentally during retransplantation. PAs were detected with radiological imaging (n ϭ 4), exploratory laparotomy (n ϭ 6), at autopsy (n ϭ 1) or at retransplantation (n ϭ 1). We performed immediate revascularization, after surgical excision was performed in three and endovascular embolization in one patient. In six patients hepatic artery ligation without revascularization was inevitable with subsequent successful retransplantation in four patients. No PA-specific treatment was attempted in two cases due to the poor prognosis or diagnostic ambiguity. In 10 cases microbial pathogens were cultured in the blood, subhepatic abscesses, or from the wall of the hepatic artery. A hepaticojejunostomy was performed for biliary reconstruction in six patients and two had a hepaticojejunostomy conversion due to biliary leak. Survival in the early period (1985 to 1995) was 14%, whereas during the later period (1996 to 2005), the survival increased to 100% with a 4.2-year median follow-up (range 7.4 months to 6.9 years). Infrequently PA complicates OLT, becoming evident primarily after rupture with hemoperitoneum or a gastrointestinal bleed. Early recognition with angiography is important but acute hemorrhage often requires immediate exploration with ligation of the PA, although surgical or endovascular exclusion of the PA followed by revascularization provides a feasible treatment option.
Transplantation Proceedings, 2010
Background. Chronic kidney disease (CKD) has emerged as a significant cause of morbidity and a ri... more Background. Chronic kidney disease (CKD) has emerged as a significant cause of morbidity and a risk factor for mortality after orthotopic liver transplantation (OLT). The use of calcineurin inhibitor (CNI)-based immunosuppression is an important etiologic factor for developing CKD. CNI discontinuation or minimization protocols with replacement of the CNI with non-nephrotoxic drugs, such as mycophenolate mofetil (MMF) or sirolimus (SRL), may have the potential to preserve or recover renal function. Patients and Methods. In this prospective, randomized, single-center study with CNI discontinuation, OLT recipients with CKD (measured glomerular filtration rate [GFRm] 15-45 mL/min/1.73 m 2) were randomized to either SRL or MMF-based immunosuppression. The main objective was to study the effect of CNI discontinuation on renal function. Secondary aims were to assess the frequency of biopsy-proven acute rejection episodes (BPAR) and adverse events (AE). Renal function was followed with GFRm using 51-Chromium EDTA clearance at baseline, 3 months, and 1 year. Patients were stratified according to baseline GFRm Ͼ versus Ͻ30 mL/min/1.73 m 2. The 25 patients were enrolled for MMF (n ϭ 13) or SRL (n ϭ 12). The median age at inclusion was 59 years (range, 25-66) and the median number of years after OLT was 4.4 (range, 1-13). Twenty-two patients were followed up for a year; MMF (n ϭ 12) and SRL (n ϭ 10). Results. Mean GFRm for the whole cohort (n ϭ 25) was 31ϩ/Ϫ8 mL/min/1.73 m 2 at baseline. After 3 months the GFRm (n ϭ 23) increased to 40ϩ/Ϫ10 mL/min/1.73 m 2 (P ϭ .0001) and at 1 year 42 ϩ/Ϫ 11 mL/min/1.73 m 2 (n ϭ 22). There was not significant difference between the MMF and the SRL study arms. The cohort (n ϭ 8) with baseline GFRm Ͻ30 mL showed a 63% (P ϭ .003) increased filtration after 1 year. There was no significant difference in the frequency or severity of AE between the study arms with the exception of oral ulcerations and persistent hypertriglyceridemia in the SRL group. Two deaths occurred, 1 in each study arm, both probably unrelated to the change in immunosuppression. There were no BPAR episodes. Conclusion. CNI discontinuation and replacement with either MMF or SRL resulted in a significant improvement in renal function even in those patients with severe CKD. The protocol was effective with no acute rejection episodes. The SRL arm showed a higher frequency of oral apthous ulcerations and hypertriglyceridemia. Future studies addressing long-term renal function after CNI discontinuation are needed.
Transplantation, 2010
Background. Intestinal preservation injury consists of progressive submucosal edema, with fluid o... more Background. Intestinal preservation injury consists of progressive submucosal edema, with fluid originating both from the lumen and the interstitium. Although vascular flushing aims to control electrolyte shifts in the tissue, the lumen is not addressed, and luminal water and electrolytes enter the tissue during ischemia. Because macromolecular solutions may retain water and electrolytes intraluminally, we investigated whether these solutions administered intraluminally may alleviate preservation injury. Methods. Sprague-Dawley rat intestines were perfused with University of Wisconsin solution. After excision of the intestines, we intraluminally introduced solutions containing polyethylene glycol 3350 with high (125 mEq) or low (65 mEq) sodium before cold preservation. Controls underwent only vascular flush. After 8, 14, or 20 hr of cold storage, the intestines were analyzed for extent of tissue injury, water retention, brush-border maltase, and tight junction proteins zonula occludens-1 and claudin-3. Results. Intraluminal composition changed over time, indicating sodium absorption and potassium secretion. After 8 and 14 hr of cold storage, intestines from the low-sodium group had the best morphology and least edema, followed by the controls. Maltase activity slightly decreased in all groups over time and was not affected by the intraluminal polyethylene glycol solutions. Various degrees of delocalization and degradation of zonula occludens-1 and claudin-3 were recorded within the tight junctions, with the most significant effects in intestines from the high-sodium group. Conclusions. Intraluminal macromolecular solutions may modulate the preservation injury in University of Wisconsinperfused intestines. Low-sodium solutions administered immediately before preservation may improve preservation injury, but high-sodium solutions may be detrimental.
Liver Transplantation, 2007
Liver transplantation can be a therapeutic option for individual patients with neuroendocrine tum... more Liver transplantation can be a therapeutic option for individual patients with neuroendocrine tumors metastatic only to the liver. In this consecutive series of 15 patients (5 multivisceral and 10 orthotopic liver transplantations) with well-differentiated carcinoids, or endocrine pancreatic tumors, we allowed higher proliferation rate (Ki67 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;10%), large tumor burden, and higher age than previous studies. Liver transplantation offered good relief of symptoms, long disease-free intervals, and potential cure in individual patients. The survival of grafts and patients compared well with transplantation for benign disease. The overall 5-year survival was 90%. The recurrence-free survival of both multivisceral and liver transplantation related to the time after transplantation (about 20% at 5 years) despite inclusion of patients with higher risk. In conclusion, the critical prognosticators for long-term outcome still remain to be defined. The experience with multivisceral transplantation for patients with endocrine tumors of the pancreatic head is still limited.
American Journal of Transplantation, 2012
Rapidly progressing mucosal breakdown limits the intestinal preservation time below 10 h. Recent ... more Rapidly progressing mucosal breakdown limits the intestinal preservation time below 10 h. Recent studies indicate that intraluminal solutions containing polyethylene glycol (PEG) alleviate preservation injury of intestines stored in UW-Viaspan. We investigated whether a low-sodium PEG solution is beneficial for intestines stored in histidine-tryptophane-ketoglutarate (HTK) preservation solution. Rat intestines used as control tissue (group 1) were perfused with HTK, groups 2 and 3 received either a customized PEG-3350 (group 2) or an electrolyte solution (group 3) intraluminally before cold storage. Tissue injury, brush-border maltase activity, zonula occludens-1 (ZO-1) and claudin-3 expression in the tight junctions (TJ) were analyzed after 8, 14 and 20 h. We measured epithelial resistance and permeability (Ussing chamber) after 8 and 14 h. Group 2 had superior morphology while maltase activity was similar in all groups. TJ proteins rapidly decreased and decolocalized in groups 1 3; these negative events were delayed in group 2, where colocalization persisted for about 14 h. Intestines in group 2 had higher epithelial resistance and lower permeability than the other groups. These results suggest that a customized PEG solution intraluminally reduces the intestinal preservation injury by improving several major epithelial characteristics without negatively affecting the brush-border enzymes or promoting edema.
Transplantation, 2008
Background. Chronic kidney disease after organ transplantation is a serious complication that neg... more Background. Chronic kidney disease after organ transplantation is a serious complication that negatively impacts on long-term patient survival. We describe long-term renal function after intestinal transplantation by serial measurements of glomerular filtration rates (GFR) with 51 Chromium EDTA clearance. Materials and Methods. Ten patients with at least 6 months survival form the basis of this report. Glomerular filtration rate measurements were performed at baseline, 3 months posttransplantation, and yearly thereafter. Median follow-up time for the cohort was 1.5 years (0.5-7.8 years). Tacrolimus (Prograf) was discontinued in four patients because of impaired renal function. These four patients were switched to sirolimus (Rapamune) at 11, 18, 24, and 40 months posttransplantation. Results. Median baseline GFR was 67 (22-114) mL/min/1.73 m 2. In the adult patients, GFR 3 months posttransplantation had decreased to 50% of the baseline. At 1 year, median GFR in the adult patients was reduced by 72% (nϭ5). Two patients developed renal failure within the first year and required hemodialysis. One of the pediatric patients fully recovered her renal function, the second pediatric patient lost 20% of her baseline GFR at 6 months posttransplantation. Glomerular filtration rate calculated with the modified diet in renal disease formula consistently overestimated GFR by approximately 30% compared with measured GFR. Conclusion. Chronic kidney disease and renal failure are common after intestinal transplantation. These two factors significantly contribute to poor long-term survival rates. Measurements of GFR may help to identify those individuals at risk for developing chronic kidney disease to implement renal sparing strategies.
Encyclopedia of Gastroenterology
Lakartidningen, 2004
Outcome after intestinal transplantation has improved dramatically since the introduction of nove... more Outcome after intestinal transplantation has improved dramatically since the introduction of novel immunosuppressive agents and refined surgical techniques. Small bowel transplantation is now considered to be the best treatment modality for patients with life threatening complications of intestinal failure and parenteral nutrition. We hereby review the international experience as well as the first ten cases of intestinal transplantation performed in Sweden.
Transplantation
Microscopic examination of endoscopic biopsies is the mainstay of acute rejection (AR) surveillan... more Microscopic examination of endoscopic biopsies is the mainstay of acute rejection (AR) surveillance after intestinal transplantation. However, biopsies require time for processing and may entail risks. The endoscopic features encountered during AR are quite well defined yet there are no established endoscopic criteria for diagnosing AR or any grading system for the severity of the endoscopic findings. In theory, a grading system could allow a faster preliminary diagnosis of AR based on endoscopic findings.Moreover, such scoring systemwould reduce interobserver variability and allow for more objective intraand interpatient comparisons. We designed a five-stage grading score based on previously described endoscopic features of AR (erythema, edema, ulcerations, friability, villous alterations). Two investigators retrospectively reviewed the endoscopy reports of 26 patients (19 adults and 7 pediatric) receiving 27 intestines containing grafts and graded the examinations using the score. Results were correlated with the pathology findings with regard to the presence and degree of AR. Five hundred four ileoscopies were reviewed: 374 examinations (74%) were considered normal (G0), 59 had mild alterations (erythema, edematous villiG1), moderate changes (erosions, blunted villi-G2) were found in 36 endoscopies, 17 ileoscopies revealed advanced changes (ulcerations, villus loss G3) while in 18 occasions the changes were estimated as severe (mucosal lossG4). Inter-reviewer agreement was very good (kappa=0,815, p<0.001). AR was found in biopsies from 86 endoscopy sessions (17%) and in 63 cases AR was considered moderate or severe. For the cases with low-degree AR the sensitivity of this new grading score was 66% and the specificity was 86% whereas the positive and negative predictive values were 45% and 93% respectively. During advanced AR the sensitivity of the score was 90% and the specificity was 86% whereas the positive and negative predictive values were 40% and 98% respectively. We herein suggest a novel grading score that both summarizes the findings and allows comparisons between intestinal graft endoscopies. Its prospective evaluation is ongoing. 205.5
Transplantation
Mihai Oltean, Chiara Zanfi, Laurens J. Ceulemans, Pablo Farinelli, Jacques Pirenne, Augusto Lauro... more Mihai Oltean, Chiara Zanfi, Laurens J. Ceulemans, Pablo Farinelli, Jacques Pirenne, Augusto Lauro, Gustaf Herlenius, Gabriel Gondolesi The Transplant Center, Sahlgrenska University Hosptal, Gothenburg, Sweden; Liver and Multiorgan Transplant Center, St. Orsola University Hospital, Bologna, Italy; Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium; Institute of Multiorgan Transplantation, Favaloro Foundation, Buenos Aires, Argentina.
Läkartidningen, 2004
Outcome after intestinal transplantation has improved dramatically since the introduction of nove... more Outcome after intestinal transplantation has improved dramatically since the introduction of novel immunosuppressive agents and refined surgical techniques. Small bowel transplantation is now consi ...
A randomized, double-blind, placebo-controlled study to determine safety, tolerance, and prelimin... more A randomized, double-blind, placebo-controlled study to determine safety, tolerance, and preliminary pharmacokinetics of ascending single doses of orally administered sirolimus (rapamycin) in stable r
Background: Chronic kidney disease (CKD) after liver (LT) or intestinal (IT) transplantation may ... more Background: Chronic kidney disease (CKD) after liver (LT) or intestinal (IT) transplantation may decrease patient survival. Calcineurin inhibitors (CNI) play a major role in its development. Aims: Describe long term renal function and risk factors for developing CKD in adults and children after LT and IT. Investigate if CNI discontinuation in adults after LT improves renal function. Methods: GFR was measured (GFRm) with either Iohexol or 51-Cr EDTA-clearance in both adults and children at different intervals before and after LT and IT. Results: After LT in adults (n=152) (I), GFRm decreased with 42% after10 years. Prevalence of CKD increased over time: 12% at 5 years and 29% at 10 years. Eight patients (5%) required renal replacement therapy (RRT). Baseline GFRm correlated poorly with late renal function. GFRm at 3 months post-LT correlated well with GFRm at 5 years and GFRm below30 ml/min/1.73m2 at 3 months was a risk factor for CKD at 5 years. After IT (II) CKD was almost universa...
Transplant International
Intestinal transplantation (ITx) is a life-saving procedure for complicated intestinal failure. I... more Intestinal transplantation (ITx) is a life-saving procedure for complicated intestinal failure. It is still characterized by a high risk of infection and rejection(1). Of all organs, the intestine is the most vulnerable to ischemia reperfusion injury (IRI) and the associated crosstalk between the innate and adaptive immune response can trigger rejection(2). A crucial factor in limiting IRI is the organ preservation phase. Currently, static cold storage with University of Wisconsin (UW) solution is the gold standard, although other solutions such as HTK (Histidine-Tryptophan-Ketoglutarate) have also been reported (3). Due to low numbers, randomized controlled trials are difficult to organize in this field.