Abigail R. Smith

Defining long-term outcomes with living donor liver transplantation in North America

OBJECTIVES To compare long-term survival of living donor liver transplant (LDLT) at experienced transplant centers with outcomes of deceased donor liver transplant and identify key variables impacting patient and graft survival. BACKGROUND The Adult-to-Adult Living Donor Liver Transplantation Cohort Study is a prospective multicenter National Institutes of Health study comparing outcomes of LDLT and deceased donor liver transplant and associated risks. METHODS Mortality and graft failure for 1427 liver recipients (963 LDLT) enrolled in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study who received transplant between January 1, 1998, and January 31, 2014, at 12 North American centers with median follow-up 6.7 years were analyzed using Kaplan-Meier and multivariable Cox models. RESULTS Survival probability at 10 years was 70% for LDLT and 64% for deceased donor liver transplant. Unadjusted survival was higher with LDLT (hazard ratio = 0.76, P = 0.02) but attenuated after adjustment (hazard ratio = 0.98, P = 0.90) as LDLT recipients had lower mean model for end-stage liver disease (15.5 vs 20.4) and fewer received transplant from intensive care unit, were inpatient, on dialysis, were ventilated, or with ascites. Posttransplant intensive care unit days were less for LDLT recipients. For all recipients, female sex and primary sclerosing cholangitis were associated with improved survival, whereas dialysis and older recipient/donor age were associated with worse survival. Higher model for end-stage liver disease score was associated with increased graft failure. Era of transplantation and type of donated lobe did not impact survival in LDLT. CONCLUSIONS LDLT provides significant long-term transplant benefit, resulting in transplantation at a lower model for end-stage liver disease score, decreased death on waitlist, and excellent posttransplant outcomes. Recipient diagnosis, disease severity, renal failure, and ages of recipient and donor should be considered in decision making regarding timing of transplant and donor options.Clinical Trials ID: NCT00096733.

Acute Rejection Increases Risk of Graft Failure and Death in Recent Liver Transplant Recipients

BACKGROUND & AIMS Acute rejection is detrimental to most transplanted solid organs, but is considered to be less of a consequence for transplanted livers. We evaluated risk factors for and outcomes after biopsy‐proven acute rejection (BPAR) based on an analysis of a more recent national sample of recipients of liver transplants from living and deceased donors. METHODS We analyzed data from the Adult‐to‐Adult Living Donor Liver Transplantation Cohort Study (A2ALL) from 2003 through 2014 as the exploratory cohort and the Scientific Registry of Transplant Recipients (SRTR) from 2005 through 2013 as the validation cohort. We examined factors associated with time to first BPAR using multivariable Cox regression or discrete‐survival analysis. Competing risks methods were used to compare causes of death and graft failure between recipients of living and deceased donors. RESULTS At least 1 BPAR episode occurred in 239 of 890 recipients in A2ALL (26.9%) and 7066 of 45,423 recipients in SRTR (15.6%). In each database, risk of rejection was significantly lower when livers came from biologically related living donors (A2ALL hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.43–0.76; and SRTR HR, 0.78; 95% CI, 0.66–0.91) and higher in liver transplant recipients with primary biliary cirrhosis, of younger age, or with hepatitis C. In each database, BPAR was associated with significantly higher risks of graft failure and death. The risks were highest in the 12 month post‐BPAR period in patients whose first episode occurred more than 1 year after liver transplantation: HRs for graft failure were 6.79 in A2ALL (95% CI, 2.64–17.45) and 4.41 in SRTR (95% CI, 3.71–5.23); HRs for death were 8.81 in A2ALL (95% CI, 3.37–23.04) and 3.94 in SRTR (95% CI, 3.22–4.83). In analyses of cause‐specific mortality, associations were observed for liver‐related (graft failure) causes of death but not for other causes. CONCLUSIONS Contrary to previous data, acute rejection after liver transplant is associated with significantly increased risk of graft failure, all‐cause mortality, and graft failure–related death, regardless of primary liver disease etiology. Living donor liver transplantation from a biologically related donor is associated with decreased risk of rejection.

Complications and Their Resolution in Recipients of Deceased and Living Donor Liver Transplants: Findings From the A2ALL Cohort Study

The purpose of this study was to explore long‐term complications in recipients of deceased donor liver transplant (DDLT) and living donor liver transplant (LDLT) in the Adult‐to‐Adult Living Donor Liver Transplantation Cohort Study (A2ALL). We analyzed 471 DDLTs and 565 LDLTs from 1998 to 2010 that were followed up to 10 years for 36 categories of complications. Probabilities of complications and their resolutions were estimated using the Kaplan–Meier method, and predictors were tested in Cox proportional hazards models. Median follow‐up for DDLT and LDLT was 4.19 and 4.80 years, respectively. DDLT recipients were more likely to have hepatocellular carcinoma and higher disease severity, including Model for End‐Stage Liver Disease score. Complications occurring with higher probability in LDLT included biliary‐related complications and hepatic artery thrombosis. In DDLT, ascites, intra‐abdominal bleeding, cardiac complications and pulmonary edema were significantly more probable. Development of chronic kidney disease stage 4 or 5 was less likely in LDLT recipients (hazard ratio [HR] 0.41, p = 0.02). DDLT and LDLT had similar risk of grade 4 complications (HR 0.89, p = 0.60), adjusted for other risk factors. Once a complication occurred, the time to resolution did not differ between LDLT and DDLT. Future efforts should be directed toward reducing the occurrence of complications after liver transplantation.

Interstitial fibrosis scored on whole-slide digital imaging of kidney biopsies is a predictor of outcome in proteinuric glomerulopathies

Background Interstitial fibrosis (IF), tubular atrophy (TA) and interstitial inflammation (II) are known determinants of progression of renal disease. Standardized quantification of these features could add value to current classification of glomerulopathies. Methods We studied 315 participants in the Nephrotic Syndrome Study Network (NEPTUNE) study, including biopsy-proven minimal change disease (MCD = 98), focal segmental glomerulosclerosis (FSGS = 121), membranous nephropathy (MN = 59) and IgA nephropathy (IgAN = 37). Cortical IF, TA and II were quantified (%) on digitized whole-slide biopsy images, by five pathologists with high inter-reader agreement (intra-class correlation coefficient >0.8). Tubulointerstitial messenger RNA expression was measured in a subset of patients. Multivariable Cox proportional hazards models were fit to assess association of IF with the composite of 40% decline in estimated glomerular filtration rate (eGFR) and end-stage renal disease (ESRD) and separately as well, and with complete remission (CR) of proteinuria. Results IF was highly correlated with TA (P < 0.001) and II (P < 0.001). Median IF varied by diagnosis: FSGS 17, IgAN 21, MN 7, MCD 1 (P < 0.001). IF was strongly correlated with baseline eGFR (P < 0.001) and proteinuria (P = 0.002). After adjusting for clinical pathologic diagnosis, age, race, global glomerulosclerosis, baseline proteinuria, eGFR and medications, each 10% increase in IF was associated with a hazard ratio of 1.29 (P < 0.03) for ESRD/40% eGFR decline, but was not significantly associated with CR. A total of 981 genes were significantly correlated with IF (|r| > 0.4, false discovery rate (FDR) < 0.01), including upstream regulators such as tumor necrosis factor, interferon gamma (IFN-gamma), and transforming growth factor beta 1 (TGF-B1), and signaling pathways for antigen presentation and hepatic fibrosis. Conclusions The degree of IF is associated with risk of eGFR decline across different types of proteinuric glomerulopathy, correlates with inflammatory and fibrotic gene expression, and may have predictive value in assessing risk of progression.

Early Postoperative Pain and its Predictors in the Adult to Adult Living Donor Liver Transplantation Cohort Study.

Background Little is known about how well postoperative pain is managed in living liver donors, despite pain severity being the strongest predictor of persistent pain with long-lasting disability. Methods We conducted a prospective multicenter study of 172 living liver donors. Self-reported outcomes for pain severity, activity interference, affective (emotional) reactions, adverse effects to treatment, and perceptions of care were collected using the American Pain Society Patient Outcomes Questionnaire-Revised. Mixed-effects linear regression was used to identify demographic and psychosocial predictors of subscale scores. Results Donors were young (36.8 ± 10.6) and healthy. Of 12 expert society analgesic recommendations for postoperative pain management, 49% received care conforming to 3 guidelines, and only 9% to 4 or 5. More than half reported adverse effects to analgesic treatment for moderate to severe pain that interfered with functional activity; however, emotional distress to pain was unexpectedly minimal. Female donors had higher affective (&bgr; = 0.88, P = 0.005) and adverse effects scores (&bgr; = 1.33, P < 0.001). Donors with 2 or more medical concerns before surgery averaged 1 unit higher pain severity, functional interference, adverse effects, and affective reaction subscale scores (&bgr; range 1.06-1.55, all P < 0.05). Receiving information about pain treatment options increased perception of care subscale scores (&bgr; = 1.24, P = 0.001), whereas depressive symptoms before donation were associated with lower scores (&bgr; = -1.58, P = 0.01). Conclusions Donors have a distinct profile of pain reporting that is highly influenced by psychological characteristics. Interventions to improve pain control should consider modifying donor behavioral characteristics in addition to optimizing pain care protocols.

Predictors of donor follow‐up after living donor liver transplantation

Donor safety in living liver donation is of paramount importance; however, information on long‐term outcomes is limited by incomplete follow‐up. We sought to ascertain factors that predicted postdonation follow‐up in 456 living liver donors in the Adult‐to‐Adult Living Donor Liver Transplantation Cohort Study. Completed donor follow‐up was defined as physical, phone, or laboratory contact at a given time point. Univariate and multivariate mixed effects logistic regression models, using donor and recipient demographic and clinical data and donor quality‐of‐life data, were developed to predict completed follow‐up. Ninety percent of the donors completed their follow‐up in the first 3 months, and 83% completed their follow‐up at year 1; rates of completed follow‐up ranged from 57% to 72% in years 2 to 7 and from 41% to 56% in years 8 to 10. The probability of completed follow‐up in the first year was higher for white donors [odds ratio (OR) = 3.27, 95% confidence interval (CI) = 1.25‐8.58] but lower for donors whose recipients had hepatitis C virus or hepatocellular carcinoma (OR = 0.34, 95% CI = 0.17‐0.69). After the first year, an older age at donation predicted more complete follow‐up. There were significant center differences at all time points (OR range = 0.29‐10.11), with center variability in both returns for in‐center visits and the use of phone/long‐distance visits. Donor follow‐up in the first year after donation was excellent but decreased with time. Predictors of follow‐up varied with the time since donation. In conclusion, adapting best center practices (enhanced through the use of telephones and social media) to maintain contact with donors represents a significant opportunity to gain valuable information about long‐term donor outcomes. Liver Transpl 20:967‐976, 2014.

Baseline Lower Urinary Tract Symptoms in Patients Enrolled in the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN): a Prospective, Observational Cohort Study

Purpose: We described and compared the frequency and type of lower urinary tract symptoms reported by men and women at the time that they were recruited from urology and urogynecology clinics into the Symptoms of Lower Urinary Tract Dysfunction Research Network multicenter, prospective, observational cohort study. Materials and Methods: At 6 research sites treatment seeking men and women were enrolled who reported any lower urinary tract symptoms at a frequency more than rarely during the last month on the LUTS (Lower Urinary Tract Symptoms) Tool. At baseline the study participants underwent a standardized clinical evaluation and completed validated questionnaires. Urological tests were performed, including pelvic/rectal examination, post‐void residual urine measurement and urinalysis. Results: A total of 545 women and 519 men were enrolled in the study. Mean ± SD age was 58.8 ± 14.1 years. At baseline nocturia, frequency and a sensation of incomplete emptying were similar in men and women but men experienced more voiding symptoms (90% vs 85%, p = 0.007) and women reported more urgency (85% vs 66%, p <0.001). Women also reported more of any type of urinary incontinence than men (82% vs 51% p <0.001), which was mixed incontinence in 57%. Only 1% of men reported stress incontinence but they had other urinary incontinence, including post‐void dribbling in 44% and urgency incontinence in 46%. Older participants had higher odds of reporting symptoms of nocturia and urgency. Conclusions: In this large, treatment seeking cohort of men and women lower urinary tract symptoms varied widely by gender and age. Men reported more voiding symptoms and nonstress or urgency urinary incontinence while women reported more incontinence overall and urgency. Older participants had greater odds of urgency and nocturia.

Social and Financial Outcomes of Living Liver Donation: A Prospective Investigation Within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study 2 (A2ALL-2)

Because results from single‐center (mostly kidney) donor studies demonstrate interpersonal relationship and financial strains for some donors, we conducted a liver donor study involving nine centers within the Adult‐to‐Adult Living Donor Liver Transplantation Cohort Study 2 (A2ALL‐2) consortium. Among other initiatives, A2ALL‐2 examined the nature of these outcomes following donation. Using validated measures, donors were prospectively surveyed before donation and at 3, 6, 12, and 24 mo after donation. Repeated‐measures regression models were used to examine social relationship and financial outcomes over time and to identify relevant predictors. Of 297 eligible donors, 271 (91%) consented and were interviewed at least once. Relationship changes were positive overall across postdonation time points, with nearly one‐third reporting improved donor family and spousal or partner relationships and >50% reporting improved recipient relationships. The majority of donors, however, reported cumulative out‐of‐pocket medical and nonmedical expenses, which were judged burdensome by 44% of donors. Lower income predicted burdensome donation costs. Those who anticipated financial concerns and who held nonprofessional positions before donation were more likely to experience adverse financial outcomes. These data support the need for initiatives to reduce financial burden.

Psychological Outcomes of Living Liver Donors From a Multicenter Prospective Study: Results From the Adult-to-Adult Living Donor Liver Transplantation Cohort Study2 (A2ALL-2)

Although single‐center and cross‐sectional studies have suggested a modest impact of liver donation on donor psychological well‐being, few studies have assessed these outcomes prospectively among a large cohort. We conducted one of the largest, prospective, multicenter studies of psychological outcomes in living liver donors within the Adult‐to‐Adult Living Donor Liver Transplantation Cohort Study2 (A2ALL‐2) consortium. In total, 271 (91%) of 297 eligible donors were interviewed at least once before donation and at 3, 6, 12, and 24 mo after donation using validated measures. We found that living liver donors reported low rates of major depressive (0–3%), alcohol abuse (2–5%), and anxiety syndromes (2–3%) at any given assessment in their first 2 years after donation. Between 4.7% and 9.6% of donors reported impaired mental well‐being at various time points. We identified significant predictors for donors’ perceptions of being better people and experiencing psychological growth following donation, including age, sex, relationship to recipient, ambivalence and motivation regarding donation, and feeling that donation would make life more worthwhile. Our results highlight the need for close psychosocial monitoring for those donors whose recipients died (n=27); some of those donors experienced guilt and concerns about responsibility. Careful screening and targeted, data‐driven follow‐up hold promise for optimizing psychological outcomes following this procedure for potentially vulnerable donors.

National Assessment of Hospitalization Rates for Incident End-Stage Renal Disease After Liver Transplantation.

Background We examined the association of incident end-stage renal disease (ESRD) after liver transplantation (LT) and resource utilization using a data linkage between the Scientific Registry of Transplant Recipients and claims data from the Centers for Medicare and Medicaid Services. Methods The study cohort consisted of patients aged ≥18 years who underwent deceased donor LT between January 1, 2003, and December 31, 2010, with Medicare as primary or secondary insurance and were discharged alive from the index LT hospitalization (n = 7019). The association of ESRD and post-LT hospitalization was assessed by sequential stratification, which entailed prognostic score matching of ESRD-free patients to each LT recipient at ESRD onset. The prognostic score was developed from a model of time to hospitalization and included baseline factors and hospitalization history as predictors. Results The overall hospitalization rates for LT recipients with and without ESRD were 2.7 and 1.1 per patient-year at risk, respectively. The total number of days hospitalized patient per year was 23 in ESRD and 7 in non-ESRD LT recipients. The adjusted post-LT hospitalization rate was 97% higher after reaching ESRD compared to non-ESRD (hazard ratio, 1.97; P < 0.0001). Conclusions Hospitalization rates increased significantly for LT recipients after ESRD onset. Early risk factor modification efforts targeting patients who are at high ESRD risk may reduce post-LT ESRD incidence and hence decrease morbidity and cost among LT recipients.