Randeep Kashyap

Long-term survival after liver transplantation in 4,000 consecutive patients at a single center

ObjectiveTo evaluate the long-term survival outcomes of a large cohort of liver transplant recipients and to identify static and changing factors that influenced these outcomes over time. Summary Background DataLiver transplantation has been accepted as a therapeutic option for patients with end-stage liver disease since 1983, with continual improvements in patient survival as a result of advances in immunosuppression and medical management, technical achievements, and improvements in procurement and preservation. Although many reports, including registry data, have delineated short-term factors that influence survival, few reports have examined factors that affect long-term survival after liver transplantation. MethodsFour thousand consecutive patients who underwent liver transplantation between February 1981 and April 1998 were included in this analysis and were followed up to March 2000. The effect of donor and recipient age at the time of transplantation, recipient gender, diagnosis, and year of transplantation were compared. Rates of retransplantation, causes of retransplantation, and cause of death were also examined. ResultsThe overall patient survival for the entire cohort was 59%; the actuarial 18-year survival was 48%. Patient survival was significantly better in children, in female recipients, and in patients who received transplants after 1990. The rates of retransplantation for acute or chronic rejection were significantly lower with tacrolimus-based immunosuppression. The risk of graft failure and death was relatively stable after the first year, with recurrence of disease, malignancies, and age-related complications being the major factors for loss. ConclusionSignificantly improved patient and graft survival has been observed over time, and graft loss from acute or chronic rejection has emerged as a rarity. Age-related and disease-related causes of graft loss represent the greatest threat to long-term survival.

What Have We Learned About Primary Liver Transplantation Under Tacrolimus Immunosuppression?: Long-Term Follow-up of the First 1000 Patients

OBJECTIVE To summarize the long-term efficacy and safety of tacrolimus in orthotopic liver transplant (OLT) recipients, as well as to examine the factors that influence long-term morbidity and mortality rates. BACKGROUND Tacrolimus (FK506, Prograf) was introduced as primary immunosuppression for primary liver transplantation in 1989; many subsequent trials have verified the association of tacrolimus with decreased rates of acute rejection and steroid-resistant rejection after OLT. Cumulative experience with tacrolimus has also defined its short- and intermediate-term toxicity. METHODS One thousand consecutive patients undergoing primary OLT at a single center from August 1989 to December 1992, under tacrolimus immunosuppression, were followed until January 1999. Patients were categorized by age. Mean follow-up was 93.4+/-11 months after OLT. Patient survival, graft survival (with corresponding causes of death and retransplantation), and rejection rates (and corresponding doses of immunosuppression) were examined as efficacy parameters. Hypertension, renal function, incidence of malignancies, incidence of diabetes, and other toxicities were examined as safety parameters. RESULTS Actual 6-year overall patient survival rate was 68.1% and graft survival rate was 62.5%, with significant differences in the patterns of survival among the different age groups. After the first post-OLT year, infection, recurrence of disease, de novo malignancies, and cardiovascular events were the main causes of graft loss and death during the long-term follow-up. Graft loss related to either acute or chronic rejection was rare. The rate of acute rejection beyond 2 years was approximately 3% per year, and most were steroid-responsive. Approximately 70% of the patients were receiving tacrolimus monotherapy beyond year 1; at the latest follow-up, 74.2% were maintained on tacrolimus alone. In 6.1% of the survivors, end-stage renal disease developed during the follow-up period, requiring either dialysis or kidney transplantation. Hyperkalemia and hypertension was observed in approximately one third of the patients. Insulin-dependent diabetes mellitus (including patients who had diabetes before the transplant) was observed in 14% in year 1, dropping to 11% in year 7. In 82 patients, de novo malignancies developed; in 41 patients, lymphoproliferative disorders developed during the entire follow-up period. CONCLUSIONS Long-term patient and graft survival rates are excellent under tacrolimus immunosuppression. Pediatric patients have a better long-term outcome than adults, in part because of the limited recurrence of the original disease, which was the most common cause of late graft loss (other than patient death, most commonly the result of late de novo malignancies and cardiovascular events). Graft loss from late rejection was rare.

Pediatric liver transplantation: A single center experience spanning 20 years

BACKGROUND Survival after liver transplantation has improved significantly over the last decade with pediatric recipients faring better than adults. The 20-year experience of pediatric liver transplantation at Childrens Hospital of Pittsburgh is reported in terms of patient survival; graft survival in relation to age, gender, and immunosuppressive protocols; causes of death; and indications for retransplantation. METHOD From March 1981 to April 1998, 808 children received liver transplants at Childrens Hospital of Pittsburgh. All patients were followed until March 2001, with a mean follow-up of 12.2+/-3.9 years (median=12.6; range=2.9-20). There were 405 female (50.2%) and 403 male (49.8%) pediatric recipients. Mean age at transplant was 5.3+/-4.9 years (mean=3.3; range 0.04-17.95), with 285 children (25.3%) being less than 2 years of age at transplant. Cyclosporine (CsA)-based immunosuppression was used before November 1989 in 482 children (50.7%), and the subsequent 326 recipients (40.3%) were treated with tacrolimus-based immunosuppression. Actuarial survival was calculated using the Kaplan-Meier statistical method. Differences in survival were calculated by log-rank analysis. RESULTS Overall patient survival at 1, 5, 10, 15, and 20 years was 77.1%, 72.6%, 69.4%, 65.8%, and 64.4%, respectively. There was no difference in survival for male or female patients at any time point. At up to 10 years posttransplant, the survival for children greater than 2 years of age (79.5%, 75.7%, and 71.6% at 1, 5, and 10 years, respectively) was slightly higher than those at less than 2 years of age (72.6%, 66.9%, and 65.3% at 1, 5, and 10 years, respectively). However, at 15 and 20 years posttransplant, survival rates were similar (>2 years=67.3% and 65.8%; <2 years=64.1% and 64.1%). A significant difference in survival was seen in CsA-based immunosuppression (71.2%, 68.1%, 65.4%, and 61%) versus tacrolimus-based immunosuppression (85.8%, 84.7%, 83.3%, and 82.9%) at 1, 3, 5, and 10 years, respectively (P=0.0001). The maximum difference in survival was noted in the first 3 months between CsA and tacrolimus; thus, indicating there may have been other factors (nonimmunological factors) involved in terms of donor and recipient selection and technical issues. The mean annual death rate beyond 2 years posttransplant was 0.47%, with the mean annual death rate for patients who received tacrolimus-based immunosuppression being significantly lower than those who received CsA-based immunosuppression (0.14% vs. 0.8%; P=0.001). The most common etiologies of graft loss were hepatic artery thrombosis (33.4%), acute or chronic rejection (26.6%), and primary nonfunction (16.7%). Of note, retransplantation for graft loss because of acute or chronic rejection occurred only in those patients who received CsA-based immuno-suppression. CONCLUSION The overall 20-year actuarial survival for pediatric liver transplantation is 64%. Survival has increased by 20% in the last 12 years with tacrolimus-based immunosuppression. Although this improvement may be the result of several factors, retransplantation as a result of acute or chronic rejection has been completely eliminated in patients treated with tacrolimus.

Long-term follow-up after liver transplantation for alcoholic liver disease under tacrolimus.

BACKGROUND Liver transplantation (LTx) for alcohol-related liver disease (ALD) is an accepted modality of treatment and is one of the most common indications for LTx in the United States. The present report examines the long-term patient survival, graft survival, rates of recidivism, and development of de novo cancers in this group, and compares these results with a contemporaneous group of patients who were transplanted for non-ALD indications. METHODS Between August 1989 and December 1992, 185 adults received LTx for ALD (group I). During the same time interval, 649 adults received LTx for non-ALD (group II). The mean follow-up time was 94+/-10.7 months for group I vs. 92+/-11 months for group II. Kaplan-Meier survival estimates and the incidence of cancers using Surveillance Epidemiologic End Result data were compared in both groups. RESULTS At 5 years after orthotopic LTx, the overall patient survival and graft survival for group I were 72.0% and 66.5% vs. 66.5% and 60.3% for group II, respectively. After 5 years, the patient survival and graft survival for the alcoholic group were significantly lower (P=0.001) compared to the non-alcoholic group. The rate of de novo oropharyngeal cancer and lung cancer was 25.5 times and 3.7 times higher, respectively, in ALD group compared with the general population matched for age, sex, and length of follow-up (P=0.001), whereas this was not higher in the non-ALD group. Prior pretransplant length of sobriety and alcohol rehabilitation was not associated with the rate of post-LTx rate of recidivism, which was 20%. Out of 79 deaths in group I, only 1 was attributed to recidivism and 3 to noncompliance with recidivism. The other deaths occurred from de novo cancer (n=13), posttransplant lymphoproliferative disorder (n=5), age-related complications (n=23), and other infection or miscellaneous causes (n=34). CONCLUSIONS Patient and graft survival past 5 years after orthotopic LTx is significantly lower for ALD for a variety of reasons (P=0.001). The rate of upper airway malignances was significantly higher in ALD patients than for non-ALD post-LTx patients and the general public. Graft loss/death related to recidivism or chronic rejection was extremely low. More attention is needed for early diagnosis of de novo cancer and prevention of cardiorespiratory and cerebrovascular complications.

Nephrogenic Systemic Fibrosis Among Liver Transplant Recipients: A Single Institution Experience and Topic Update

Nephrogenic systemic fibrosis (NSF) is a recently characterized systemic fibrosing disorder developing in the setting of renal insufficiency. NSFs rapidly progressive nature resulting in disability within weeks of onset makes early diagnosis important. Two reports of NSF after liver transplantation are known of. We present three cases of NSF developing within a few months after liver transplantation and review the current literature. Loss of regulatory control of the circulating fibrocyte, its aberrant recruitment, in a milieu of renal failure and a recent vascular procedure appear important in its development. Known current therapies lack consistent efficacy. Only an improvement in renal function has the greatest likelihood of NSFs resolution. Delayed recognition may pose a significant barrier to functional recovery in the ubiquitously deconditioned liver transplant patient. Early recognition and implementation of aggressive physical therapy appear to have the greatest impact on halting its progression.

COMPARATIVE LONG-TERM EVALUATION OF TACROLIMUS AND CYCLOSPORINE IN PEDIATRIC LIVER TRANSPLANTATION

Background. In this report, we compare the long-term outcome of pediatric liver transplantation (LTx) patients maintained with tacrolimus-based and with cyclosporine (CsA)-based immunosuppressive therapy. We examine long-term patient and graft survival, the incidence of rejection, and immunosuppression-related complications. Method. There were 233 consecutive primary LTx in children (ages <18 years) performed between October 1989 and December 1994 with tacrolimus-based immunosuppressive therapy (Group I). These were compared with 120 consecutive primary LTx performed with CsA-based immunosuppressive therapy between January 1988 and October 1989(Group II). Children in both groups were followed until July 1999. Mean follow-up was 91.41±17.7 months (range 55.6–117.8) for Group I, and 128±6.1 months (range 116.7–138.6) for Group II. Results. At 9 years of follow-up, actuarial patient and graft survival were significantly improved (patient survival 85.4% in Group I vs. 63.8% in Group II, P =0.0001; graft survival Group I 78.9% vs. 60.8% Group II, P =0.0003) and the rate of re -transplantation was significantly lower among patients in Group I (12% in Group I vs. 22.5% in Group II P =0.01). Children in Group I also experienced a significantly reduced incidence of acute rejection (0.97 per patient Group I vs. 1.5 per patient Group II P =0.002) and significantly less steroid resistant acute rejection episodes (3.1% in Group I vs. 8.6% in Group II P =0.0001). The mean steroid dose was significantly lower in Group I compared with Group II at all time points (P =0.0001) after LTx. Freedom from steroid was also significantly higher in Group I compared with Group II at all time points after LTx (ranging from 78% to 84% in Group I and 9% to 32% in Group II during a 1- to 7-year posttransplant period P =0.0001). The rate of hypertension was significantly lower in Group I than Group II (P =0.0001), and the severity of hypertension (need for more than one anti-hypertensive medication) was also significantly lower in Group I than Group II (P =0.0001). Although the rate of posttransplant lymphoproliferative disorder (PTLD) was not significantly different (13.7% Group I vs.8.3% Group II, P =0.13), the survival after PTLD was significantly better for Group I at 81.2% than for Group II at 50% after 5 years (P =0.034). Conclusion. The results suggest that tacrolimus-based therapy provides significant long-term benefit to pediatric LTx patients, evidenced by significantly improved patient and graft survival, reduced rate of rejection, and hypertension with lower steroid doses.

Living-Donor Liver Transplantation in the United States: Identifying Donors at Risk for Perioperative Complications

Donor safety has been scrutinized by both the medical community and the media. Variability exists in reported donor complications and associated risk factors are ill defined. Use of administrative data can overcome the bias of single‐center studies and explore variables associated with untoward events. A retrospective cohort study identifying living liver donors in two large healthcare registries yielded 433 right and left lobe donors from 13 centers between 2001 and 2005. Perioperative complications were identified using International Classification of Diseases, 9th Revision (ICD‐9) coding data and classified according to the Clavien system. Logistic regression models identified factors associated with complications. There was one perioperative death (0.23%). The overall complication rate was 29.1% and major complication rate defined by a Clavien grade ≥3 was 3.5%. Center living‐donor volume (OR = 0.97, 95% CI = 0.95–0.99) and the ratio of living‐donors to all donors (living and deceased) (OR = 0.94, 95% CI = 0.92–0.96) were associated with a lower risk of all complications. Donor age >50 years (OR = 4.25, 95% CI = 1.22–14.87) was associated with a higher risk of major complications. Living liver donation is currently performed with a low risk of major morbidity. Use of administrative data represents an important tool to facilitate a better understanding of donor risk factors.

Long-term results after conversion from cyclosporine to tacrolimus in pediatric liver transplantation for acute and chronic rejection.

UNLABELLED Tacrolimus is beneficial in liver transplantation for reversing steroid-resistant acute rejection, and for controlling the process of chronic rejection in allograft recipients receiving Cyclosporine- (CyA) based regimens. Very little is known about the long-term efficacy of tacrolimus in pediatric transplantation after conversion from CyA. Our study examines the long-term outcome after conversion to tacrolimus for acute or chronic rejection in pediatric liver transplant (LTx) recipients. METHOD Seventy-three children (age < 18 years) receiving their primary LTx under CyA between August 1989 and April 1996 were converted to tacrolimus for ongoing acute rejection (n=22, group I) or chronic rejection (n=51, group II). Mean age at the time of conversion was 10.2+/-5.5 years with a mean interval from LTx to conversion of 3.5+/-2.9 (range 0.5-10.1 years). There were 33 boys and 40 girls. All patients were followed until June 1999. Mean follow-up was 97.3+/-17.4 months (range 62.4-118.9 months). RESULTS Overall 5-year actual patient survival was 78.1% and 8-year actuarial survival was 74.6%. Patients converted to tacrolimus therapy to resolve acute rejection (group I) experience significantly better patient and graft survival at 5 and 8 years than those converted to resolve chronic rejection (group II). Eight-year patient survival and graft survival was 95.5 and 90.9% for group I compared to 74.6 and 53.5% for group II, respectively (long rank P=0.035 and 0.01, respectively). Nearly 75% of children were weaned off steroids after conversion. There was a marked improvement in hypertension, gum hyperplasia, hirsutism, and cushingoid appearance. One child in group I (4.5%) and four children in group II (7.8%) developed posttransplant lymphoproliferative disorder after conversion. There was an improvement in growth in children who were less than the age of 12 years at the time of conversion and who were weaned off steroids; more significantly girls responded more favorably than boys. CONCLUSION The benefit of transplantation is maintained long-term after conversion to tacrolimus for acute or chronic rejection. The response rate was significantly better in group I as compared with group 11. Marked improvement in growth, hypertension, and reversal of the brutalizing effects of CyA was noted after conversion to tacrolimus. The results suggest that early conversion of pediatric liver transplant patients is warranted for the treatment of acute and chronic rejection, and for improvements in quality of life.

Survival outcomes in liver transplantation for hepatocellular carcinoma, comparing impact of hepatitis C versus other etiology of cirrhosis

The incidence of hepatocellular carcinoma (HCC) is on the rise worldwide as the most common primary hepatic malignancy. In the US approximately one half of all HCC is related to Hepatitis C virus (HCV) infection. The relationship between the primary disease and HCC recurrence after liver transplantation is unknown. We hypothesized that the primary hepatic disease underlying the development of cirrhosis and HCC would be associated with the risk of recurrent HCC after transplantation. A retrospective review was conducted of all primary liver transplants performed at the University of Rochester Medical Center from May 1995 through June 2004. The pathology reports from the native livers of 727 recipients were examined for the presence of HCC. There were 71 liver transplant recipients with histopathological evidence of HCC. These patients were divided in two groups on the basis of HCV status. Group 1 consisted of 37 patients that were both HCV and HCC positive, and Group 2 consisted of 34 patients that were HCC positive but HCV negative. Patient characteristics were analyzed, as well as number of tumors, tumor size, presence of vascular invasion, lobe involvement, recipient demographics, donor factors, pretransplantation HCC therapy, rejection episodes, and documented HCC recurrence and treatment. There were no statistically significant differences between the 2 groups, with the exception of recipient age and the presence of hepatitis B coinfection. The tumor characteristics of both groups were similar in numbers of tumors, Milan criteria status, vascular invasion, incidental HCC differentiation, and largest tumor size. The HCV positive population had a far lower patient survival rate with patient survival in Group 1 at 1, 3, and 5 years being 81.1%, 57.4%, and 49.3% respectively, compared with 94.1%, 82.8%, and 76.4% in Group 2 (p = 0.049). Tumor‐free survival in Group 1 at 1, 3, and 5 years was 70.3%, 43%, and 36.8% respectively, vs. 88.1%, 73%, and 60.8% in Group 2. In a subgroup analysis, tumor‐free survival was further examined by stratifying the patients on the basis of Milan criteria. Group 1 patients outside of Milan criteria had a statistically lower tumor‐free survival. By contrast, there was no statistical difference in tumor‐free survival in Group 2 patients stratified according to Milan criteria. Cox regression analysis identified HCV and vascular invasion as significant independent predictors of tumor‐free survival. Our results suggest that Milan selection criteria may be too limiting and lose their predictive power when applied to patients without HCV infection. Liver Transpl 13:807–813, 2007.

Minimizing Morbidity of Organ Donation: Analysis of Factors for Perioperative Complications After Living-Donor Nephrectomy in the United States

Background. Expansion of living kidney donation through liberalizing acceptance criteria invites a renewed focus on safety and outcomes. Wide variability exists in reported donor complications, and associated risk factors are ill defined. Use of administrative data can overcome the bias of single-center studies and identify variables associated with untoward events. Methods. The study population consisted of 3074 living kidney donors from 28 centers during 2004 and 2005. Data from a large healthcare registry were used to retrospectively identify the study cohort. Perioperative complications were identified using ICD-9-CM coding and classified according to the Clavien system. Logistic regression models were constructed to identify donor and center factors associated with complications. Results. There were no perioperative deaths. The overall complication rate was 10.6% and major complications defined by Clavien grade ≥3 was 4.2%. The prevalence of tobacco use, obesity, and hypertension, was 7.8%, 2.4%, and 2.3%, respectively. Age >50 (odds ratio [OR]=1.81, 95% confidence interval [95% CI]=1.25–2.61), tobacco use (OR=1.41, 95% CI=1.02–1.94), obesity (OR=1.92, 95% CI=1.06–3.46), and annual center volume ≤50 (OR=2.28, 95% CI=1.68–3.09), were significantly associated with overall morbidity, however only annual center volume ≤50 (OR=2.07, 95% CI=1.27–3.37) was significantly associated with a risk of major complications. Conclusions. The inclusion of donors with tobacco abuse, obesity, and age >50 increases complications; however, the risk of major morbidity is small. Use of administrative data represents an important tool to facilitate the reconciliation of an increased need for organ donors with the concern for donor safety.