It is time to re-think 'extended criteria'.
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Adult↗
Biomedical subjects
G B Klintmalm
Publications and source records attributed to G B Klintmalm.
MELD scores do not predict patient morbidity while on the liver transplant waiting list.
The goals of this study were to assess waitlist morbidity in terms of the frequency of health care services utilized by patients while on the liver transplant (LTX) waiting list and to determine whether that utilization can be predicted by the Model for End-Stage Liver Disease (MELD). Sixty-three noncomatose subjects were followed from waitlist placement until death, change in status, LTX, or study discontinuance. Health care events included doctor/clinic visits, labs, outpatient/inpatient tests and procedures, and hospital/intensive care unit days. Listing MELD scores and LTX MELD scores were examined against the number of health care event occurrences within 60 days of listing and 60 days of LTX, respectively, as were changes in MELD scores between listing and LTX and differences in the number of occurrences between the two time points. The only significant correlations noted were between LTX MELD scores and number of hospital days near LTX (r = .360, P = .046) and between LTX MELD scores and the sum total number of occurrences near LTX (r = .370, P = .044). These results suggest that MELD scores do not appear to predict morbidity in terms of health care utilization in patients awaiting LTX. Developing a system capable of predicting waitlist morbidity may lead to the implementation of medical interventions aimed at circumventing foreseeable complications and/or crises in patients awaiting LTX.
Humans↗
Sirolimus conversion after liver transplantation: improvement in measured glomerular filtration rate after 2 years.
METHODS: We reviewed our prospectively maintained database of 2005 liver transplantations. Therapy was either started de novo or converted from calcineurin inhibitors (CNIs) to sirolimus as the main immunosuppressive agent for nephrotoxicity or rejection. Glomerular filtration rate (GFR) was determined with iodine 125-labeled sodium isthalamate (Glofil-125), and serum creatinine concentration was obtained before and 3 months after transplantation, and yearly in both groups. Sirolimus levels were 10 to 15 ng/mL in patients at less than 3 months after transplantations and 5 to 10 ng/mL in the remaining patients. All patients received mycophenolate mofetil as maintenance therapy. RESULTS: Data for 29 patients in the de novo group and 35 in the conversion group were reviewed. Patients in the de novo group demonstrated an acute cellular rejection rate of 17.2%, 40% of which were steroid resistant. In this group, 48.2% discontinuation of sirolimus was necessary because of adverse effects. Patients in the conversion group demonstrated an acute cellular rejection rate of 2.8% and a 34.3% rate of sirolimus discontinuation. Seventeen (56.7%) patients at 1 year and 8 (44.4%) patients at 2 years demonstrated continued improvement in GFR. In the conversion group, case-control analysis did not demonstrate a significant difference in GFR and serum creatinine concentration (P > .05) at 1 and 2 years after conversion. At the time of review, no patients in the conversion group required hemodialysis. CONCLUSIONS: Conversion to sirolimus therapy is an effective strategy in improving renal function in patients with CNI-induced nephrotoxicity and can be done without increased rejection. Most of our patients (65.7%) tolerated sirolimus conversion. Of these, 56.7% and 44.4% demonstrated continued increase in GFR with the CNI-free regimen at 1 and 2 years, respectively. Long-term, large-population, prospective, randomized, controlled studies should further validate these results.
Creatinine↗
Acute graft versus host disease after liver transplantation: patterns of lymphocyte chimerism.
The diagnosis of acute graft versus host disease (aGVHD) following liver transplantation can be difficult, since many of the clinical signs can be caused by drug reactions or viral infections. To establish criteria for the persistence of donor T-cells versus engraftment, we measured donor T-cells by short tandem repeat (STR) assays in 49 liver transplant patients for 8 or more weeks post-transplant. Donor CD3+ T-cells were detected in 38 of 49 patients, on POD 2 with a mean level of 5%. The top of the 99% confidence interval for weeks 1, 2, 3, 4 and 8 were 11, 6, 3, 2 and 3%. Donor CD8+ T-cells were measured in eight patients. The level of CD8+ T-cells was much less than that for CD3+ T-cells, except in two cases of apparent aGVHD. One patient developed severe aGVHD with donor T-cells as high as 84%. The other had 10% donor T-cells for more than 16 weeks associated with fever and neutropenia. We tested the sensitivity of PCR-ssp typing of HLA DR/DQ for donor T-cells. At least one donor type was detected in all samples with 1% or more donor DNA. Thus, higher levels of donor T-cell chimerism, particularly with a high proportion of CD8+ T-cells, strongly supports a diagnosis of aGVHD.
Acute Disease↗
Delay of hepatitis C recurrence in liver transplant recipients: impact of mycophenolate mofetil on transplant recipients with severe acute rejection or with renal dysfunction.
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Disease Progression↗
Recurrence of hepatitis C in liver transplant recipients treated with mycophenolate mofetil.
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Disease Progression↗
Role of alpha-1-antichymotrypsin deficiency in promoting cirrhosis in two siblings with heterozygous alpha-1-antitrypsin deficiency phenotype SZ.
BACKGROUND: Alpha-1-antitrypsin (A1AT) deficiency is the most common inherited metabolic disorder with the potential to cause injury in the lung and liver. Recent reports suggested that alpha-1-antichymotrypsin (A1AC) deficiency may also be a possible cause of chronic liver disease. However, it has received little attention and is rarely investigated in the clinical setting. AIMS: To assess the role of A1AC deficiency in the pathogenesis of chronic liver disease in two siblings with heterozygous A1AT phenotype Pi SZ. PATIENTS: Two adult siblings with an A1AT Pi SZ phenotype and reduced levels of A1AC consistent with heterozygosity who developed cirrhosis and underwent liver transplantation. METHODS AND RESULTS: A1AT and A1AC levels in plasma measured by electroimmunoassay were 74 mg/dl and 90 mg/dl (140-470) and 0.12 mg/ml and 0.14 mg/ml (0.173-0.46), respectively. Immunohistochemistry revealed an apparent accumulation of both A1AT and A1AC in hepatocytes. A previously reported point mutation in exon III (Pro(229) to Ala substitution) of the A1AC gene was not detected by polymerase chain reaction amplification and a single strand conformation polymorphism analysis. CONCLUSIONS: Our report represents the first case of two siblings with A1CA phenotype Pi SZ who developed cirrhosis and underwent liver transplantation. Both siblings were heterozygous for A1AT and A1AC deficiency suggesting that combined deficiency of these two major serine protease inhibitors may enhance the risk of developing liver disease.
Adult↗
End-stage renal disease (ESRD) after orthotopic liver transplantation (OLTX) using calcineurin-based immunotherapy: risk of development and treatment.
BACKGROUND: The calcineurin inhibitors cyclosporine and tacrolimus are both known to be nephrotoxic. Their use in orthotopic liver transplantation (OLTX) has dramatically improved success rates. Recently, however, we have had an increase of patients who are presenting after OLTX with end-stage renal disease (ESRD). This retrospective study examines the incidence and treatment of ESRD and chronic renal failure (CRF) in OLTX patients. METHODS: Patients receiving an OLTX only from June 1985 through December of 1994 who survived 6 months postoperatively were studied (n=834). Our prospectively collected database was the source of information. Patients were divided into three groups: Controls, no CRF or ESRD, n=748; CRF, sustained serum creatinine >2.5 mg/dl, n=41; and ESRD, n=45. Groups were compared for preoperative laboratory variables, diagnosis, postoperative variables, survival, type of ESRD therapy, and survival from onset of ESRD. RESULTS: At 13 years after OLTX, the incidence of severe renal dysfunction was 18.1% (CRF 8.6% and ESRD 9.5%). Compared with control patients, CRF and ESRD patients had higher preoperative serum creatinine levels, a greater percentage of patients with hepatorenal syndrome, higher percentage requirement for dialysis in the first 3 months postoperatively, and a higher 1-year serum creatinine. Multivariate stepwise logistic regression analysis using preoperative and postoperative variables identified that an increase of serum creatinine compared with average at 1 year, 3 months, and 4 weeks postoperatively were independent risk factors for the development of CRF or ESRD with odds ratios of 2.6, 2.2, and 1.6, respectively. Overall survival from the time of OLTX was not significantly different among groups, but by year 13, the survival of the patients who had ESRD was only 28.2% compared with 54.6% in the control group. Patients developing ESRD had a 6-year survival after onset of ESRD of 27% for the patients receiving hemodialysis versus 71.4% for the patients developing ESRD who subsequently received kidney transplants. CONCLUSIONS: Patients who are more than 10 years post-OLTX have CRF and ESRD at a high rate. The development of ESRD decreases survival, particularly in those patients treated with dialysis only. Patients who develop ESRD have a higher preoperative and 1-year serum creatinine and are more likely to have hepatorenal syndrome. However, an increase of serum creatinine at various times postoperatively is more predictive of the development of CRF or ESRD. New strategies for long-term immunosuppression may be needed to decrease this complication.
Adult↗
Renal replacement therapy and orthotopic liver transplantation: the role of continuous veno-venous hemodialysis.
BACKGROUND: The need for renal replacement therapy (RRT) either before or after orthotopic liver transplant (OLTX) has been reported to be a poor prognostic indicator for survival. Use of continuous veno-venous hemodialysis (CVVHD) for RRT has been reported in three series of OLTX patients with high 90-day mortality rates of 57-60%. We have examined our patient population to determine the effect of necessity and type of RRT on patient survival after OLTX. METHODS: We analyzed 1535 OLTX that were performed at our institution from 1985 through 1999, 1037 from 1985 to 1995 (period I) and 498 from 1996 to 1999 (period II). Combined liver-kidney transplants were excluded from analysis. Hospital dialysis unit records and a prospectively maintained database on all OLTX patients served as the source of data. Patients were classified into groups defined on whether or not they received RRT, when they received RRT, and the type of RRT. Groups were compared for preoperative intensive care unit status, time on the waiting list, laboratory variables, 90-day postoperative mortality, 1-year patient survival, and absolute survival. RESULTS: Use of RRT increased from 8.29% in period I to 12.45% in period II, along with increased median waiting times. In period I, patients receiving preoperative RRT had a 90-day mortality (0%) and a 1-year survival (89.5%) almost identical to those patients who never required RRT (1.7% and 90.6%). Patients who developed acute renal failure postoperatively requiring RRT, however, had a 90-day mortality of 28.6% and a 1-year survival of 55%. In period II, patients requiring RRT had a 90-day mortality of 39.7% and a 1-year actuarial survival of 54.5% compared with 6.9% and 88.6% in patients never requiring RRT. Patients treated with CVVHD had a 90-day mortality of 42% compared with 25% in patients treated with hemodialysis alone. However, patients receiving CVVHD both pre- and postoperatively had a 90-day mortality of 27.7% vs. 50% in those patients who only received CVVHD postoperatively. Patients who developed acute renal failure postoperatively, which required RRT, regardless of therapy, had a 1-year survival of only 41.0% compared with a 1-year survival of 73.6% in those patients started on RRT preoperatively, P=0.03. CONCLUSIONS: The need for RRT has increased along with waiting time in OLTX patients. Patients developing the need for RRT postoperatively have an increased 90-day mortality and lower 1-year survival with the highest being present in patients receiving CVVHD, which was started postoperatively. These findings may reflect a trend toward a sicker population awaiting OLTX and emphasize the negative impact of renal failure on survival after OLTX.
Acute Kidney Injury↗
Hepatocellular cancer in liver transplantation.
Hepatocellular carcinoma (HCC) is a malignant epithelial tumor that accounts for over 80% of primary liver tumors. It affects males more than females, and is responsible for over 1 million yearly deaths worldwide. HCC tends to be relentless in nature and of rapid evolution. Most cases of HCC are associated with cirrhosis, usually caused by chronic viral hepatitis or alcohol ingestion. In cases of established cirrhosis, HCC develops with an annual incidence of 3%-10%. Hepatocellular carcinoma may present in a generalized way with overall clinical deterioration and malaise, as a palpable liver mass, or as an asymptomatic lesion that is discovered incidentally. Alpha-fetoprotein (AFP) measurements allow for the differentiation of HCC in cirrhotics, and can act as predictive markers. Patients with cirrhosis and small tumors (up to 3 cm, or 5 cm if solitary), no more than three nodules, and no portal vein involvement were found to benefit more from orthotopic liver transplantation (OLTx) than from resection. Tumors under 3 cm in size were unlikely to recur, while those over 5 cm posed the greatest risk. An incidental HCC in a transplant patient should be treated as seriously and aggressively as if the transplant had been undertaken for HCC.
Carcinoma, Hepatocellular↗
Cannulation of the aorta in organ donors with infrarenal aortic pathologies.
Retrograde embolization of atherosclerotic arterial plaque remains a threat at the time of organ perfusion in elderly donors. In order to circumvent this potential procurement complication, we describe a technique with two variations. This technique allows for perfusion with UW solution without having to cannulate through severely atherosclerotic distal aortic walls.
Adenosine↗
Cannulation of the aorta in organ donors with aortic and caval injuries at the time of procurement.
Injuries sustained by major vessels during procurement pose a major threat to organ viability. Aortic and inferior vena cava lacerations produce rapid hemorrhage associated with hypoperfusion and ischemic damage. We describe a technique that will prevent such damage in the event of vascular mishaps.
Aorta, Abdominal↗
Post-transplant lymphoproliferative syndrome in the pediatric liver transplant population.
Post-transplant lymphoproliferative disease remains a complication with a high morbidity and mortality. The present study examined 291 pediatric liver transplants performed in 263 children from October 1984 to December 1999. Post-transplant lymphoproliferative disease has an overall incidence of 12%. Tacrolimus and cyclosporine had a similar incidence of post-transplant lymphoproliferative disease. Fifty-six per cent of patients who developed post-transplant lymphoproliferative disease were Epstein-Barr virus negative at the time of transplantation. Mean time of conversion to Epstein-Barr virus positivity was 1.1 years after liver transplantation. Ten per cent of those who developed post-transplant lymphoproliferative disease never had Epstein-Barr virus detected. Mean time from Epstein-Barr virus positivity to detection of post-transplant lymphoproliferative disease was 2.68 years, and 3.13 years from liver transplantation (OLTx) to post-transplant lymphoproliferative disease. There was a 35% incidence of mortality. Deaths occurred a mean of 0.76 years after diagnosis of post-transplant lymphoproliferative disease. Most cases of post-transplant lymphoproliferative disease had extranodal location. There was one recurrence in 10% of patients, and two in 3%. All recurrent cases were seen in recipients who became Epstein-Barr virus positive after transplantation. There has been a decrease in the incidence of post-transplant lymphoproliferative disease from 15% to 9% to 4%. Post-transplant lymphoproliferative disease should be diagnosed promptly and treated aggressively. The best treatment, however, seems to be prevention, starting in the immediate postoperative period. Survivors should be monitored for both recurrence of post-transplant lymphoproliferative disease and acute cellular rejection.
Adolescent↗
The elderly liver transplant recipient: a call for caution.
OBJECTIVE: To determine whether liver transplantation is judicious in recipients older than 60 years of age. SUMMARY BACKGROUND DATA: The prevailing opinion among the transplant community remains that elderly recipients of liver allografts fare as well as their younger counterparts, but our results have in some cases been disappointing. This study was undertaken to review the results of liver transplants in the elderly in a large single-center setting. A secondary goal was to define, if possible, factors that could help the clinician in the prudent allocation of the donor liver. METHODS: A retrospective review of a prospectively maintained single-institution database of 1,446 consecutive liver transplant recipients was conducted. The 241 elderly patients (older than 60 years) were compared with their younger counterparts by preoperative laboratory values, illness severity, nutritional status, and donor age. Survival data were stratified and logistic regression analyses were conducted. RESULTS: Elderly patients with better-preserved hepatic synthetic function or with lower pretransplant serum bilirubin levels fared as well as younger patients. Elderly patients who had poor hepatic synthetic function or high bilirubin levels or who were admitted to the hospital had much lower survival rates than the sicker younger patients or the less-ill older patients. Recipient age 60 years or older, pretransplant hospital admission, and high bilirubin level were independent risk factors for poorer outcome. CONCLUSIONS: Low-risk elderly patients fare as well as younger patients after liver transplantation. However, unless results can be improved, high-risk patients older than 60 years should probably not undergo liver transplantation.
Age Factors↗
Readmission to the intensive care unit after liver transplantation.
OBJECTIVE: We undertook this study to understand the factors at our transplant center that contribute to patients' return to the ICU after their liver transplant and their initial discharge from that unit. Patients who, after liver transplantation, fail discharge from the Intensive Care Unit (ICU) and must be readmitted to that unit may well utilize many more resources than those patients who are well enough to stay out of the ICU. DESIGN: A retrospective review of a prospectively maintained liver transplant research database followed by a retrospective review of (a subgroup) patient charts and contemporaneous controls. SETTING: A large metropolitan tertiary care center and adult liver transplant center. PATIENTS: A total of 1,197 consecutive adult patients who underwent their initial liver transplantation from 1984 to 1996. INTERVENTION: Readmission to the intensive care unit after adult liver transplantation and discharge from that unit. MAIN RESULTS: Only recipient age, pretransplant synthetic function labs (protime and albumin), bilirubin levels, and intraoperative blood product requirements could be statistically linked to the group requiring ICU readmission. The primary etiology for ICU readmission was cardiopulmonary deterioration. Readmission was associated with significantly lower patient and graft survivals. A detailed review of 23 patients transplanted from October 1994 to June 1996 was made, with special emphasis on cardiopulmonary status (hemodynamics, respiratory variables, and chest radiograph findings). This subgroup was compared with 30 temporally matched controls who were not readmitted to the ICU. Intravascular fluid overload and lower inspiratory capacity were significant factors related to ICU readmission. Readmitted patients had a longer hospitalization with higher hospital charges than the control group. CONCLUSIONS: We conclude that the most important means of preventing ICU readmission in liver transplantation patients is to optimize cardiopulmonary function and status. Close monitoring of fluid balance to avoid hypervolemia is essential. Readmitted patients have a greater resource utilization and have lower survival rates.
Adult↗
Veno-venous bypass in liver transplantation: heparin-coated perfusion circuits reduce the activation of humoral defense systems in an in vitro model.
We studied the effects of bypass circuit surface heparinization on kallikrein-kinin, coagulation, fibrinolytic and complement activation in a closed model system for simulating veno-venous bypass (WBP) in orthotopic liver transplantation (OLT). The circuits were identical to those in routine use during clinical OLT in our institution. Fresh whole human blood diluted 1:2 with Ringer's acetate was circulated at a non-pulsatile flow (2 l/min) and at a constant temperature (37.5 degrees C) for 12 h. In 10 experiments, the entire inner surface of the circuits was coated with end-point attached heparin (HC). In the remaining 10, non-treated PVC tubing was used (NC). Components of the plasma kallikrein-kinin, coagulation, fibrinolytic and complement systems were analyzed using functional techniques (chromogenic peptide substrate assays) and enzyme immunoassays at baseline, 3 and 12 h. Significant activation of the initial (C3bc) and terminal (TCC) components of the complement system were found in both the NC and HC groups after 3 and 12 h: C3bc: NC: baseline = 4 (3.5-7.7), 3 h = 17.3* (12.5-27), 12h = 31* (17.7-63.6), HC: baseline = 4.9 (3.2-6.8), 3h = 9* (6-14.4), 12h = 13.7* (7.4-18.1). TCC: NC: baseline = 0.4 (0.2-0.6), 3h = 5*(0.8-11.9), 12 h: 13.1* (4.2-25.7). HC: baseline = 0.5 (0.1-0.6), 3 h = 0.6* (0.1-0.8), 12 h = 1.2* (0.3-2) AU/ml; median and range (*: p < 0.05). The C3bc and TCC concentrations were significantly higher in the NC group at 3 and 12 h, compared to the HC group: C3bc (NC vs. HC group): 3 h, p < 0.001; 12 h, p < 0.001. TCC (NC vs. HC group): 3h, p < 0.001; 12 h, p < 0.001. Significant increases in the values of thrombin-antithrombin complexes (p = 0.003), prothrombin fragment 1 + 2 (p = 0.006) and plasmin-alpha2-antiplasmin complexes (p = 0.016) were found in the non-coated group, but not in the heparin-coated group during the observation period, showing that the coagulation and fibrinolytic systems were activated in the non-coated circuits. We conclude that heparin-coating of the internal surface of the extracorporeal perfusion circuit used for WBP reduces activation of the plasma cascade systems in a closed venous system in vitro.
Blood Coagulation Factors↗
Liver allotransplantation after extracorporeal hepatic support with transgenic (hCD55/hCD59) porcine livers: clinical results and lack of pig-to-human transmission of the porcine endogenous retrovirus.
BACKGROUND: Whole organ extracorporeal perfusion of a genetically modified humanized (transgenic) pig liver has been proposed as a technology that may sustain patients with severe liver failure while awaiting human liver transplantation. METHODS: We report on two cases of successful extracorporeal perfusion of a transgenic pig liver in patients awaiting transplantation for fulminant hepatic failure. The pig livers used were transgenic for human CD55 (decay-accelerating factor) and human CD59. These transgenic modifications are designed to reduce or eliminate the hyperacute rejection inherent in pig-to-primate xenotransplants. We also report on the results of serial surveillance testing for presence of the porcine endogenous retrovirus (PoERV) in these two patients. RESULTS: Extracorporeal perfusion in two patients was performed for 6.5 and 10 hr, respectively, followed by the successful transplantation of a human liver and resultant healthy patients (18 and 5 months later as of this writing). The porcine livers showed evidence of synthetic and secretory function (decreasing protime and bilirubin, bile production). Serial polymerase chain reaction analysis of these patients' peripheral blood mononuclear cells has failed to show presence of PoERV DNA sequences. CONCLUSIONS: The CD55/CD59 transgenic porcine liver appears capable of safely "bridging" a patient to liver transplantation. Human PoERV infection from these livers has yet to be demonstrated.
Adolescent↗
Comparing quality of life following liver transplantation for Laennec's versus non-Laennec's patients.
The overall success of orthotopic liver transplantation (OLTX) includes not only survival, but quality of life (QOL) as well. We studied one controversial group of OLTX recipients, patients transplanted for alcoholic liver disease (Laennec's), to determine if their post-OLTX QOL was similar to that of patients transplanted for non-alcoholic liver disease (non-Laennec's). Over a 10-yr period, patients undergoing OLTX at our institution were asked to complete a QOL questionnaire addressing a wide range of topics from demographics and employment to symptom distress/frequency, activities of daily living, and effect of loss of health on daily life. Twenty-four Laennec's and 100 non-Laennec's OLTX recipients completed the questionnaire at both their 2- and 5-yr follow-up visits at our institution. Both groups were well-matched in age, race, and patient location status at the time of OLTX. No significant differences could be detected between Laennec's and non-Laennec's scores regarding overall QOL, including one's ability to function, health perception, and self-perception at 2 and 5 years post-OLTX, and between 2 and 5 years post-OLTX. Although not between groups, a significant difference was noted regarding patients' satisfaction with life, with less satisfaction reported at the 5-yr versus the 2-yr time point post-OLTX. Rates of current/recent employment between both groups were also similar at 2 years post-OLTX, and again at 5 years post-OLTX. We conclude that overall QOL and employment levels appear similar between patients transplanted for alcoholic and non-alcoholic liver disease. This similarity appears to extend to 5 years post-OLTX.
Activities of Daily Living↗