Cardiovascular disease in stable renal transplant patients in Norway: morbidity and mortality during a 5-yr follow-up

BACKGROUND: Although cardiovascular disease is a major cause of death after renal transplantation (Tx), predictors for cardiovascular events have not been well defined. Aims of this cross-sectional study were first to assess cardiovascular morbidity and mortality in stable renal Tx patients, and to identify predictors for cardiovascular events during long-term follow-up. METHODS: In all, 406 renal Tx patients (mean age: 47 yr, 60.1% males, 70.9% using cyclosporine A) commenced a baseline registration (median) 48 months after Tx, and 405 was thereafter followed in 5 yr. Kaplan-Meier plots and multivariate regression analysis (Cox proportional hazards model) were used to identify and characterize predictors for cardiovascular events. RESULTS: There were 88 deaths (average annual mortality: 4.4%), and 74% of these were cardiovascular. In age groups 40-49, 50-59, and 60-69 yr, odds ratio for cardiovascular mortality in patients vs. general population was 46.2, 20.1, and 8.0, respectively. Death from ischemic heart disease (IHD) was independently predicted by baseline congestive heart failure (relative risk: RR 5.33), diabetes (RR 2.28), systolic blood pressure (mmHg, RR 1.02), age (yr, RR 1.06), and high-density lipoprotein cholesterol (mmol/L, RR 0.36). Predictors for a major ischemic heart event (death from or onset of IHD) were in addition baseline total cholesterol (mmol/L, RR 1.18) and cerebrovascular disease (RR 2.98). CONCLUSIONS: Thus, IHD was the major cause of death late after renal Tx, and a major ischemic heart event was predicted by baseline congestive heart failure, diabetes, age, hypertension, and hypercholesterolemia.     

Cumulative risk of cardiovascular events after orthotopic liver transplantation

As survival after orthotopic liver transplantation (OLT) improves, cardiovascular (CV) disease has emerged as the leading cause of non-graft-related deaths. The aims of our study were to determine the cumulative risk of CV events after OLT and to analyze predictive risk factors for those experiencing a CV event after OLT. We identified all adult patients who underwent OLT at our institution for end-stage liver disease between October 1996 and July 2008. The cumulative risk of CV events after OLT was analyzed with the Kaplan-Meier method. Multivariate logistic regression analysis was used to identify factors independently associated with CV events after OLT. In all, 775 patients were included in our study cohort (mean age of 53.3 years, female proportion = 44%, Caucasian proportion = 84%, median follow-up = 40 months). The most common indications for OLT were hepatitis C virus (33.2%), alcohol (14.5%), and cryptogenic cirrhosis (12.7%). Eighty-three patients suffered 1 or more CV events after OLT. Posttransplant metabolic syndrome was more prevalent in patients with CV events versus patients with no CV events (61.4% versus 34.1%, P < 0.001). According to a multivariate analysis, independent predictors of CV events were an older age at transplantation [odds ratio (OR) = 1.2, addition of 95% confidence interval (CI) = 1.1-1.3, P = 0.006], male sex (OR = 2.0, 95% CI = 1.2-3.3, P = 0.01), posttransplant diabetes (OR = 2.0, 95% CI = 1.3-3.3, P = 0.003), posttransplant hypertension (OR = 1.8, 95% CI = 1.1-3.0, P = 0.02), and mycophenolate mofetil (OR = 2.0, 95% CI = 1.3-3.2, P = 0.003). Among post-OLT patients, the cumulative risk at 5 years of 13.5%, respectively. In conclusion, cardiac complications after liver transplantation are common (Approximately 10% of patients experience 1 or move cv events). Patients with posttransplant hypertension and diabetes, which are modifiable risk factors, are approximately twice as likely to experience a CV event.     

Explained and unexplained ischemic heart disease risk after renal transplantation

Whether the high incidence of ischemic heart disease (IHD) among renal transplant patients can be attributed to the same risk factors that have been identified in the general population is unclear. The risk for major IHD events occurring >1 yr after transplantation among 1124 transplant recipients was estimated by using the risk calculated from the Framingham Heart Study (FHS). The FHS risk predicted IHD (relative risk, 1.28; 95% confidence interval, 1.20 to 1.40; P: < 0.001); however, the FHS risk tended to underestimate the risk of IHD for renal transplant recipients. This was largely attributable to increased risks associated with diabetes mellitus and, to a lesser extent, age and cigarette smoking for renal transplant recipients. For men, the relative risks for diabetes mellitus were 2.78 (1.73 to 4.49) and 1.53 for the transplant recipient and FHS populations, respectively; the relative risks for age (in years) were 1.06 (1.04 to 1.08) and 1.05, respectively, and those for smoking were 1.95 (1.20 to 3.19) and 1.69, respectively. For women, the relative risks for diabetes mellitus were 5.40 (2.73 to 10.66) and 1.82, respectively. There was a tendency for the risk associated with cholesterol levels to be higher for transplant recipients, compared with the FHS population, but the risks associated with high-density lipoprotein cholesterol levels and BP appeared to be comparable. Independent of these and other risk factors, the adjusted risk of IHD for the transplant recipient population has decreased. Compared with the era before 1986, transplantation between 1986 and 1992 was associated with a lower relative risk of 0.60 (0.39 to 0.92); transplantation after 1992 was associated with an even lower relative risk of 0.27 (0.11 to 0.63) for IHD. Of concern was the fact that dihydropyridine calcium channel antagonists were associated with an increased risk for IHD (relative risk, 2.26; 95% confidence interval, 1.24 to 4.12; P: = 0. 008), and this association was independent of other antihypertensive agents and risk factors. Therefore, although the FHS risk predicts IHD after renal transplantation, it tends to underestimate the risks, especially the risk associated with diabetes mellitus. The unexpected finding that dihydropyridine calcium channel antagonists were associated with an increased IHD risk merits further evaluation.     

Is there disparity between risk and incidence of cardiovascular disease after liver transplant?

BACKGROUND: Hypertension and hypercholesterolemia are recognized complications of liver transplantation, but whether they contribute to the development of cardiovascular disease is uncertain. We aimed first to determine the prevalence of risk factors for coronary heart disease (CHD) after liver transplantation and second to study the effect of liver transplantation on the predicted 10-year risk of developing CHD and the incidence of cardiovascular events in comparison with a matched local population. METHODS: Data on blood pressure, serum lipids, weight, diabetes mellitus, smoking, and incidence of myocardial infarction (MI) and stroke were obtained retrospectively from the case notes of 181 consecutive adult liver transplant recipients (median follow-up 54 months). The Framingham coronary risk equations were used to calculate the 10-year probability of developing CHD. RESULTS: The prevalences of hypertension and hypercholesterolemia after transplantation were 77% and 62%, respectively. The predicted 10-year risk of CHD increased from 6.9% before transplantation to 11.5% at 1 year after transplantation, whereas that of a matched local population was 7%. Compared with a matched nontransplant population, the incidence ratios for MI and stroke were 0.55 (95% confidence interval, 0.01-3.06 ) and 1.45 (95% confidence interval, 0.18-5.22), respectively. No patients died from MI or stroke. CONCLUSIONS: Liver transplant recipients have a high prevalence of risk factors for cardiovascular disease, exceeding that of the general population, and have a higher predicted risk of developing CHD. Despite this, there were no deaths from CHD or stroke during the study period.     

Coronary event rates in liver transplant recipients reflect the increased prevalence of cardiovascular risk-factors

Increased prevalence of cardiovascular risk-factors in liver transplant recipients compared with pretransplant and standard population data has been acknowledged. The impact of risk-profiles on cardiovascular event rates or death, however, has not yet been established. Here we evaluate the development of risk-factors during a prospective follow-up of 10 years in 302 patients and compare numbers of coronary events with data from the German Prospective Cardiovascular Münster (PROCAM)-Score population. Prevalence of overweight (17% vs. 27%), hypertension (70% vs. 80%), and diabetes (21% vs. 25%) increased from early to late after transplantation, while elevated serum cholesterol (64% vs. 37%) and triglycerides (40% vs. 21%) became less frequent. Cardiovascular risk-profiles favoring tacrolimus over ciclosporin A based immunosuppression early after transplantation converged over time. Increased risk-scores in liver transplant recipients matched with score standardized event rates in the PROCAM population (ratio: 1.11, 95% CI: 0.53-2.03), nine events were predicted for the transplant population and oppose 10 events observed. Thus, indicating a reflection of increased cardiovascular risk-profiles in corresponding numbers of cardiovascular events.     

Renal disease burden following liver transplantation

Significant chronic kidney disease (CKD) occurs following orthotopic liver transplant (OLT). Since CKD is associated with increased cardiovascular events, mortality, and hepatic allograft dysfunction, early recognition of CKD and implementation of changes may improve the long-term outcome. The purpose of this study was to determine the burden of renal disease following OLT. PATIENTS AND METHODS: We retrospectively reviewed our OLT recipients from 1997 until 2004. We calculated glomerular filtration rates (GFR) using the Modification of Diet in Renal Disease study (MDRD) method. The GFRs were further subdivided into pre-MELD and post-MELD eras. RESULTS: During the study period, we performed 407 OLTs. We censored data from living donor liver transplants (n = 14), combined liver-kidney transplants (n = 12), and from patients whom we did not have complete data for 6 months after transplant (n = 40). Mean MELD score at the time of transplant was 18 +/- 7 (mean +/- standard deviation). The mean GFR at 6 months following OLT was 63.7 +/- 30.2 mL/min per 1.73 m(2). Only 14% (n = 47) of our patients had normal renal function at 6 months, while 78% (n = 266) of our patients had mild to moderate risk for renal failure. Eight percent (n = 28) had stage 4 or 5 CKD. There were no differences between the pre-MELD and post-MELD GFRs. CONCLUSIONS: The burden of renal disease is significant in our patient population at 6 months posttransplantation. It may be important to introduce CKD management as early as 6 months after transplant to impact the outcomes of OLT recipients.     

Decreased survival in liver transplant patients requiring chronic dialysis: a Canadian experience

BACKGROUND: Chronic kidney disease is associated with increased mortality among nonrenal organ transplant recipients. End-stage renal disease (ESRD) is a serious complication after orthotopic liver transplantation (OLT). It is unclear if the outcomes of these individuals are different from nontransplant patients requiring dialysis or a kidney transplant. METHODS: We report the incidence of ESRD in OLT recipients and compare their outcomes to matched dialysis controls. We analyzed 4186 patients who received an OLT in Canada between January 1981 and December 2002 and 228 matched, nontransplant, chronic dialysis controls. RESULTS: The incidence of ESRD after OLT was 2.9% (n=120). The unadjusted mortality rate for those who required chronic dialysis was 49.2% compared with 26.8% in those who did not develop kidney failure (P<0.0001). The survival of OLT recipients on dialysis was lower than the matched chronic dialysis cohort (log-rank test, P=0.01). A kidney transplant was performed in 24% of the OLT recipients and 21% of the matched dialysis cohort, and their overall survival was similar. The OLT patients who remained on dialysis had a significantly lower survival when compared with matched dialysis patients who did not receive a kidney transplant (log-rank test, P=0.0002). CONCLUSIONS: Mortality was greater for OLT recipients on dialysis than would be expected from a matched, nontransplant, dialysis cohort. Kidney transplantation may abrogate some of this increased mortality risk.     

Metabolic syndrome and cardiovascular risk after liver transplantation: a single-center experience

Excessive weight gain, hypertension, hyperlipidemia, and diabetes are frequently observed among orthotopic liver transplantation (OLT) patients. These alterations, which are probably multifactorial in origin, contribute to posttransplantation metabolic syndrome (PTMS), which increases the risk of cardiovascular events. We assessed the prevalence of PTMS (diagnosed according to modified NCEP Adult Treatment Panel III criteria) in 156 OLT patients undergoing regular follow-up after transplantation (median 68 months; range, 6 to 234 months). Several pre- and post-OLT data were collected to identify the factors associated with the presence of PTMS which was found in 28% of cases. The only independent predictive factors for PTMS were diabetes mellitus and patients who were overweight or obese before-OLT. The prevalence of PTSM was lower among patients on tacrolimus immunosuppression. In our population, 21% of patients showed a high cardiovascular risk score with a 4% incidence of cardiovascular events, which was higher among subjects with PTMS. Close follow-up is mandatory to prevent the development of PTMS mainly among overweight and diabetic patients before transplantation.     

Predicting coronary heart disease in renal transplant recipients: a prospective study

BACKGROUND: Current cardiovascular risk calculators, widely used in the general population, have not yet been validated in renal transplant recipients. We conducted a prospective study to determine the incidence and risk factors for ischemic heart disease in renal transplant recipients and to assess the relevance of the Framingham Heart Study risk calculator in this population. METHODS: Three hundred and forty four consecutive renal transplant recipients free of vascular disease were enrolled. Coronary events were registered and analyzed with respect to traditional and nontraditional cardiovascular risk factors. The risk of coronary events was assessed through the Framingham Heart Study formula and the relevance of this equation was then analyzed. RESULTS: The patients were followed for a mean duration of 72 +/- 14 months. Twenty seven coronary events occurred in 27 patients (7.8%). In addition to risk factors included in the Framingham Heart Study score, C-reactive protein (CRP) level (P= 0.009), and hyperhomocysteinemia (P= 0.01) were found to be independent risk factors for ischemic heart disease events in renal transplant recipients. The Framingham Heart Study model did not predict absolute ischemic heart disease risk in the transplant population as a whole. CONCLUSION: Nontraditional cardiovascular risk factors greatly contribute to increased incidence of ischemic heart disease events in renal transplant recipients. They should therefore be considered in preventive care of these patients which relies on reduction of overall absolute risk. Although the Framingham Heart Study score has an excellent predictive value in low-risk renal transplant recipients, it tends to underestimate the real cardiovascular risk in high-risk patients.     

Evolution of Causes and Risk Factors for Mortality Post‐Liver Transplant: Results of the NIDDK Long‐Term Follow‐Up Study

Although mortality rates following liver transplantation (LT) are well described, there is a lack of detailed, prospective studies determining patterns of and risk factors for long‐term mortality. We analyzed the multicenter, prospectively obtained The National Institute of Diabetes and Digestive and Kidney Diseases LT Database of 798 transplant recipients from 1990 to 1994 (follow‐up 2003). Overall, 327 recipients died. Causes of death >1 year: 28% hepatic, 22% malignancy, 11% cardiovascular, 9% infection, 6% renal failure. Renal‐related death increased dramatically over time. Risk factors for death >1 year (univariate): male gender, age/decade, pre‐LT diabetes, post‐LT diabetes, post‐LT hypertension, post‐LT renal insufficiency, retransplantation >1 year, pre‐LT malignancy, alcoholic disease (ALD) and metabolic liver disease, with similar risks noted for death >5 years. Hepatitis C, retransplantation, post‐LT diabetes, hypertension and renal insufficiency were significant risk factors for liver‐related death. Cardiac deaths associated with age, male gender, ALD, cryptogenic disease, pre‐LT hypertension and post‐LT renal insufficiency. In summary, the leading causes of late deaths after transplant were graft failure, malignancy, cardiovascular disease and renal failure. Older age, diabetes and renal insufficiency identified patients at highest risk of poor survival overall. Diligent management of modifiable post‐LT factors including diabetes, hypertension and renal insufficiency may impact long‐term mortality.     

Clinical epidemiology of cardiac disease in renal transplant recipients

Cardiovascular disease (CVD) is the major cause of death among renal transplant recipients (RTRs), accounting for 17-50% of deaths. Both cardiomyopathy (congestive heart failure [CHF] and left ventricular hypertrophy [LVH]) and ischemic heart disease (IHD) are important complications of renal transplantation, although the morbid impact of cardiomyopathy has been overlooked until recently. Echocardiographic disorders and clinical CHF occur far more frequently in RTRs than in the general population, suggesting that renal transplantation may be a state of accelerated heart failure. In contrast, the incidence of IHD in RTRs is similar to that in the Framingham cohort. Age, diabetes, and gender remain important markers of risk for both disorders. Smoking, hyperlipidemia, and hypertension appear to be the major reversible risk factors for IHD, while anemia and hypertension are major reversible risk factors for cardiomyopathy. Definitive evidence on optimal intervention is lacking. Clinical trials are needed to define optimum targets for treatment of these risk factors, especially hypertension and anemia.     

Hypertension is associated with hyperlipidemia, coronary heart disease and chronic graft failure in kidney transplant recipients.

BACKGROUND: Hypertension is a common concomitant condition in renal transplant recipients. There is accumulating evidence that this disorder is an important risk factor for chronic renal graft failure and other cardiovascular complications in these patients. SUBJECTS AND METHODS: The current retrospective study in 330 patients treated with cyclosporin or azathioprin covered 5 years and aimed to further characterize the interrelation between hypertension and renal graft failure. Furthermore, the association of hypertension with hyperlipidemia and the prevalence of coronary heart disease was evaluated. RESULTS: Altogether, before transplantation 182 patients were normotensive (no antihypertensive medication except diuretics) and 105 were hypertensive (blood pressure > 160/95 mmHg or patients requiring antihypertensive medication); for the remaining 43 patients no data were available. After transplantation the prevalence of hypertension in the cyclosporin group was 71, 76 and 70% after 1, 3 and 5 years, respectively. The respective numbers for the azathioprin group were 60, 59 and 58%. Hypertension was associated with graft dysfunction both in cyclosporin- and azathioprin-treated patients. Hyperlipidemia (cholesterol, triglycerides) was more severe in hypertensive than in normotensive patients. The prevalence for hypertension was higher in patients with coronary artery disease than in patients without the disease. CONCLUSION: The results further support the view that hypertension may be a risk factor for the development of chronic renal graft failure and coronary artery disease in this population. Furthermore, the association of hypertension with hyperlipidemia hints to an unfavorable accumulation of renal and cardiovascular risk factors in a large number of renal allograft recipients.     

A prospective analysis of oxidative stress and liver transplantation

BACKGROUND: Oxidative stress (OS) is a potential mechanism of injury in many deleterious complications of orthotopic liver transplantation (OLT). Therefore, we evaluated OS prospectively in a cohort of 50 adult patients before, during, and after OLT. METHODS: Urine, collected preoperatively, perioperatively, and at intervals for the first postoperative year, was analyzed for dinor-dihydro-isoprostane F2alpha-III (dinor-dihydro iPF2alpha-III), a well-characterized in vivo indicator of OS. Clinical events were extracted from the clinical records. RESULTS: One-year patient and graft survival were 86% and 80%, respectively. There were nine episodes of acute cellular rejection (ACR). Twenty patients each experienced at least one adverse event. Pretransplantation urinary dinor-dihydro iPF2alpha-III levels were elevated, compared to healthy volunteers, and rose significantly following reperfusion of the grafted liver. Levels fell sharply following OLT but never reached those of control subjects. Urinary dinor-dihydro iPF2alpha-III levels steadily increased thereafter, reaching preoperative levels within 12 months of transplantation. There was no significant difference in dinor-dihydro iPF2alpha-III excretion, with respect to hepatitis C virus (HCV) status, the development of ACR, or the presence or absence of a composite of predesignated adverse events. CONCLUSIONS: OLT recipients exhibit enhanced lipid peroxidation in vivo, which is augmented during intra-operative liver reperfusion. Although OS declines following OLT, it redevelops gradually, albeit without association with clinical events such as acute cellular rejection, organ failure, or infection of the allograft by HCV. We conclude that OS increases in the first year after liver transplantation, in a time-dependent fashion, but independent of clinical events affecting the allograft.     

The natural history of hepatitis C virus in pediatric liver transplant recipients.

Although rare in the pediatric population, the natural history of hepatitis C virus (HCV) recurrence in pediatric patients undergoing orthotopic liver transplantation (OLT) for end-stage liver disease secondary to HCV has not been well described. We performed an analysis of all 67 pediatric patients (< 17 years old) who have undergone OLT for HCV in the United States between 1/1988 and 6/2005. The 67 pediatric patients received a total of 83 OLTs for HCV. Following initial OLTs performed for HCV, the patient and allograft survival rates were 71.6% and 55.0%, respectively, at 5 years. Following retransplantation these rates decreased to 55.0% and 33.8%, respectively, following retransplantation. Recipients were listed for retransplantation after 31.3% of all OLTs, and overall recipients were retransplanted after 19.3% of OLTs. The overwhelming majority of retransplants were performed for HCV recurrence. A mean of 1.2 OLTs were performed per patient for HCV. The median time between OLTs for HCV was 290 days. In conclusion, the risk of HCV recurrence in pediatric OLT recipients is high and is associated with a high rate of retransplantation. Still, OLT represents the only treatment option that may achieve long-term survival in pediatric patients with end-stage liver disease secondary to HCV that is recalcitrant to medical management.     

Homocysteine,renal function,and risk of cardiovascular disease

BACKGROUND: Patients with renal impairment have markedly elevated homocysteine levels and are at particularly high risk of ischemic heart disease (IHD) and stroke, but the relevance of elevated homocysteine levels in this population is uncertain. METHODS: We examined the association with IHD from a meta-analysis of 30 population studies of differences in homocysteine concentrations (involving 5000 IHD and 1100 stroke events in apparently healthy individuals), and from a meta-analysis of 40 studies (involving 11,000 IHD events) of the association of methylene-tetrahydrofolate reductase (MTHFR) and homocysteine with IHD. We explored the association of renal function with homocysteine levels in a cross-sectional study of 1200 healthy elderly individuals. RESULTS: Among prospective studies, a 25% lower blood homocysteine level was associated with an 11% lower risk of IHD and about a 20% lower risk of stroke, after adjustment for known cardiovascular risk factors. Individuals who had the TT genotype for MTHFR compared with those with CC had 25% higher homocysteine levels and a 16% higher risk of IHD. Among individuals aged over 65 years, a 1% higher serum creatinine level was associated with about a 1% higher homocysteine concentration. CONCLUSIONS: The concordance of the IHD risks obtained in the studies of genetically determined differences in homocysteine and the population-based studies of homocysteine suggest that these associations are likely to be causal. Renal function is an important determinant of circulating homocysteine concentrations. Results of ongoing randomized trials of folic acid-based vitamins in patients with renal disease are required to clarify the relevance of lowering homocysteine for vascular disease.     

Chlamydia pneumoniae infection and ischemic heart disease in hemodialysis patients

INTRODUCTION: Ischemic heart disease and other atherosclerotic complications are the prominent causes of death among hemodialyzed end-stage renal disease (ESRD) patients and renal transplant recipients. Numerous articles in recent years have raised the possibility of an infective factor, especially Chlamydia pneumoniae, in the development of atherosclerosis and its complications. The aim of this study was to assess the incidence of chronic C pneumoniae infection and its association with ischemic heart disease and atherosclerosis in a population of patients with ESRD awaiting renal transplantation. MATERIAL AND METHODS: The studied group consisted of 164 subjects: 99 ESRD patients (heart disease [HD] group) who were hospitalized for vascular access creation (27), pretransplantation nephrectomy (47), or kidney transplantation (25), and a control group of 65 subjects consisting of 50 healthy blood donors and 15 multiorgan donors. C pneumoniae was detected in vascular wall fragments, kidney biopsy specimens and peripheral blood monocytes using real time polymerase chain reaction (PCR). Serum immunoglobulin IgG and IgA anti-C pneumoniae antibodies were detected using Enzyme-linked immunosorbent assay (ELISA) and a lipid profile (cholesterol, high-density lipoprotein [HDL], low-density lipoprotein [LDL], and triglycerides [TG]) was obtained. Data on cardiovascular disease events, smoking history, diabetes, hypertension, cause, and length of renal failure were collected and analyzed. The existence of atherosclerotic lesions was detected using ultrasound (US) Doppler examination of aortic bifurcation. Chronic C pneumoniae infection was diagnosed on the basis of detection of both IgA and IgG antibodies and/or the detection of C pneumoniae DNA in vascular wall fragments or peripheral blood monocytes. After a follow-up of 32 months, data on cardiovascular events and patient history were collected again. RESULTS: Chronic C pneumoniae infection affected 46.5% (46/99) of HD patients and 9% (6/65) of controls (P < .05). Among HD patients, 26.3% (26/99) had ischemic heart disease (IHD) versus 6% in the control group. Among C pneumoniae-infected HD patients, IHD was more frequent (39.1%) than in noninfected HD patients (15%; P < .05). Within the 32-month observation period of the HD group, cardiac pain was observed in 11 (24%; 11/46) infected patients versus 3 (5.7%; 3/53) patients without C pneumoniae infection (P < .05). Exacerbation of previously diagnosed IHD was observed in 8 (44%; 8/18) cases in the C pneumoniae-infected group versus 0 (0%; 0/8) in the uninfected patients (P < .05). CONCLUSIONS: Chronic C pneumoniae infection affects hemodialysis patients more frequently than healthy subjects. Hemodialysis patients with C pneumoniae infection are at the greater risk of exacerbation of existing IHD.     

Prospective interventional study to evaluate the efficacy and safety of liposomal amphotericin B as prophylaxis of fungal infections in high-risk liver transplant recipients

INTRODUCTION: Invasive fungal infections are a life-threatening complication in transplant recipients. The prevalence of fungal infection after orthotopic liver transplantation (OLT) is 5% to 42%. The most common isolated pathogens are Candida and Aspergillus species. High-risk liver transplant recipients are more susceptible to the development of invasive fungal infections, with prevalence >40% and mortality rates of 78% to 100%. The strategy for fungal prophylaxis in this population has not been defined. PATIENTS AND METHODS: Among 100 consecutive OLT followed for 28 months, 21 recipients (15 men, overall mean age of 48.5 years, range 23-65 years) were considered to be high risk for the development of fungal infections when they presented at least one of the following criteria: acute liver failure, assisted ventilation >7 days, retransplantation, relaparotomy, antibiotic therapy >14 days, transfusion requirements >20 red blood cells units, and/or biliary leakage. This group received intravenous liposomal amphotericin B (1 mg/kg/d for 7-10 days). RESULTS: One-year survival in the high-risk group was 80%. Prevalence of invasive fungal infection was 9.5%. No Candida infection was observed. Two patients developed Aspergillus infection: an abdominal aspergillosis treated with percutaneous drainage and liposomal amphotericin B (5 mg/kg/d) showed a favorable clinical outcome. The other patient who developed brain aspergillosis died 25 days after OLT. Adverse events related to the drug were hypokalemia (n = 2), back pain (n = 3), and renal dysfunction (n = 2). None of these events required withdrawal of the prophylaxis regimen. CONCLUSION: In our series, prophylaxis with liposomal amphotericin B in high-risk liver graft recipients showed a low rate of severe fungal infections. More studies are needed in order to determine the highest risk population and the best drug dosage.     

Recipients who receive a human leukocyte antigen-B compatible cadaveric liver allograft are at high risk of developing acute graft-versus-host disease

Acute graft-versus-host disease (GvHD) is an uncommon but often fatal complication after orthotopic liver transplantation (OLT). To determine whether there is an association between human leukocyte antigen (HLA) matching and the development of GvHD after cadaveric OLT, we undertook a retrospective, single-center analysis of 412 consecutive adult recipients where HLA typing data was available. Seven (1.7%) recipients developed acute GvHD, and six died from their disease. Donor compatibility at HLA-B but not at HLA-A or -DR was identified as a significant risk factor for the development of GvHD. Of 14 recipients with no HLA-B mismatches, 3 (21%) developed GvHD (odds ratio 27, P<0.001). Conversely, of 262 recipients mismatched at both HLA-B loci, only 1 (0.4%) developed GvHD (odds ratio 0.09, P<0.01). Our findings suggest that patients receiving a liver allograft with no HLA-B mismatched antigens are at increased risk of developing GvHD.     

Alcohol recidivism impairs long-term patient survival after orthotopic liver transplantation for alcoholic liver disease.

The aim of this study was to evaluate the rate of alcohol recidivism after orthotopic liver transplantation (OLT) for alcoholic liver disease (ALD) and its influence on the allograft and patient survival, as well as the development of comorbidities and de novo cancers. The study was performed on 54 subjects previously analyzed and transplanted in our center for ALD, whose follow-up was prolonged to a mean of 99.2 (SD 31.7) months (range, 14-155). Medical records were reviewed, and data on alcohol consumption, therapeutic compliance, graft evolution, rejection, infections, comorbidities, rates of de novo malignancies and other clinical events, and survival were collected. Comparisons between groups were performed by the Fisher's exact test, and survival was assessed by the Kaplan-Meier method. Survival curves were compared using the Mantel-Cox statistic. The risk of death resulting from alcohol recidivism was analyzed with a Cox proportional hazards model. Fourteen patients who underwent transplantation for ALD (25.9%) returned to alcohol use between 5.0 and 86.9 months after OLT (median, 47.5). There was no significant association between the presence or absence of alcohol recidivism and the occurrence of graft rejection, infections, associated comorbidities after OLT, or compliance. The 5- and 10-year survival rates for patients with alcohol recidivism were 92.9% and 45.1%, respectively, compared with 92.4% and 85.5%, respectively, for patients without alcohol recidivism. These figures show significantly lower survival rates in recidivistic patients after 10 years (P < 0.01, Mantel-Cox). The fact that patients who resumed alcohol consumption have a worse 10-year survival rate might be attributed to a higher frequency of deaths, primarily from cancer and cardiovascular events.