Background & aims

Renal dysfunction increases risk of death for patients with cirrhosis. We investigated whether mortality differs significantly among patients with acute kidney injury (AKI), chronic kidney disease (CKD), and both.

Methods

We performed a retrospective analysis of all non-status 1 adults on the waitlist for liver transplantation for at least 90 days, collected from the Organ Procurement and Transplantation Network registry from July 1, 2007 through July 1, 2014. We assigned patients to groups of AKI (an increase of ≥0.3 mg/dL or ≥50% in serum creatinine in the last 7 days or fewer than 72 days of hemodialysis), CKD (an estimated glomerular filtration rate <60 ml/min/1.73 m² for 90 days with a final rate ≥30 ml/min/1.73 m² or ≥72 days of hemodialysis), AKI and CKD (meet both definitions), or normal (meet neither definition). We performed competing risk analyses to associate patterns of renal dysfunction with waitlist mortality, accounting for liver transplantation, with renal pattern as a time-dependent covariate. Logistic regression for 6-month mortality determined the added benefit of including renal function pattern in the assessment.

Results

There were 22,680 patients in the cohort; they spent a median 1.6 years (range, 0.7-3.1 years) on the waitlist and a median 5 years (range, 2-9 years) undergoing assessments of renal function. In competing risk analysis, even after adjusting for confounders including final model for end-stage liver disease sodium (MELD-Na) scores, the pattern of renal function was significantly associated with waitlist mortality: AKI and CKD (subhazard ratio [SHR], 2.86; 95% CI, 2.65-3.10), AKI (SHR, 2.42; 95% CI 2.22-2.64), CKD (SHR, 1.56; 95% CI, 1.45-1.67) compared with normal. The area under the curve values, based on MELD-Na score at time of placement on the waitlist, were 0.80 with renal function pattern and 0.71 without (P < .001).

Conclusion

In competing risk analysis, even after adjusting for confounders including final MELD-Na score, we found the pattern of renal dysfunction to associate with mortality in patients with cirrhosis. Including information on type of renal dysfunction could improve risk analysis.

The burden of chronic kidney disease (CKD) is rising among patients with cirrhosis, though it is not known what impact this has had on outcomes after liver transplantation (LT). All patients listed for LT in the United States between 2002 and 2017 were analyzed, excluding those listed with Model for End-Stage Liver Disease (MELD) exceptions. The primary outcome was post-LT mortality. We defined pre-LT CKD as an estimated glomerular filtration rate <60 mL/minute for 90 days or ≥42 days of hemodialysis. Cox regression determined the association between pre-LT CKD and post-LT mortality. Of 78,640 LT candidates, the proportion with CKD among LT recipients increased from 7.8% in 2002 to 14.6% in 2017 (test for trend, P < 0.001). Among the 39,719 LT recipients, pre-LT CKD was significantly associated with post-LT mortality (hazard ratio [HR], 1.16; P < 0.001) even after adjusting for donor risk index (DRI), age, MELD, etiology, hepatic encephalopathy, simultaneous liver-kidney transplantation (SLKT), and diabetes. There was no mediating influence of SLKT on the effect of pre-LT CKD on post-LT survival (P > 0.05). Therefore, pre-LT CKD has a deleterious impact on post-LT outcomes, which is an impact that is not mediated through SLKT. These findings highlight the need for the identification of CKD when preventative measures are possible.

Background

Women with chronic liver disease have lower rates of hepatocellular carcinoma (HCC) as compared to men; it is unknown if there are sex-based differences in HCC recurrence postliver transplant.

Methods

We conducted an analysis of patients who underwent liver transplant for HCC in the United Network for Organ Sharing/Organ Procurement and Transplantation Network from January 1, 2012 through December 31, 2017.

Results

A total of 12 711 patients underwent liver transplant for HCC: 2909 (23%) women and 9802 (73%) men. Women had significantly lower rates of postliver transplant HCC recurrence than men (4.0% versus 5.4%, P = 0.002). A cox-regression analysis for postliver transplant HCC recurrence highlighted that even after accounting for etiology of cirrhosis, alpha-fetoprotein at liver transplant, tumor diameter, tumor pathology, and vascular invasion, female sex was associated with a 25% lower risk of postliver transplant HCC recurrence (95% confidence interval: 0.57-0.99). There were no interactions between female sex and the following variables: age, type of locoregional therapy, alpha-fetoprotein, donor sex, body mass index, or nonalcoholic steatohepatitis etiology (P > 0.05 for each).

Conclusions

This study demonstrates an independent effect of sex on risk for HCC recurrence postliver transplant. Our data highlight an opportunity to better understand HCC tumor biology by investigating the drivers of this sex-based difference in HCC recurrence.

Background

With the implementation of the "Safety Net," we aimed to determine the impact of simultaneous liver-kidney transplantation (SLKT), as compared to kidney transplant after liver transplant (KALT), on kidney allograft failure (KF).

Methods

An analysis of the UNOS database for all adult patients who received either an SLKT or KALT from 2002 to 2017. The outcomes were 90-day KF and 1-year KF (as reported to UNOS, at 90- and 365-day postkidney transplant, respectively). We compared the following groups of patients: SLKT <25 (SLKT with final model for end-stage liver disease [MELD] <25), SLKT25/35 (MELD ≥25/<35), and SLKT35 (MELD ≥35) to KALT.

Results

Of the 6276 patients, there were 1481 KALT, 1579 SLKT <25, 1832 SLKT25/35, and 1384 SLKT ≥35. The proportion of patients with 90-day and 1-year KF increased significantly among the KALT, SLKT <25, SLKT25/35, and SLKT ≥35 groups (P < 0.001; test for trend): 90-day KF: 3.3% versus 5.5% versus 7.3% versus 9.3% and 1-year KF: 5.1% versus 9.4% versus 12.3% versus 14.7%. After adjustment and compared with KALT, beginning at an MELD ≥25 those undergoing SLKT had significantly higher risk of 90-day and 1-year KF: 90-day KF: SLKT25/35: hazard ratio, 1.6(1.0-2.3); SLKT ≥35: 2.1(1.3-3.3); 1-year KF: SLKT25/35: hazard ratio, 1.7(1.2-2.4); SLKT ≥35: 2.1(1.5-3.0).

Conclusions

As compared to KALT recipients, SLKT recipients with an MELD ≥25 had significantly higher risk of early KF. Given the now well-established "Safety Net," KALT may serve as an opportunity to improve kidney outcomes in patients with an MELD ≥25.

Background and aims

We investigated the impact of the inclusion of kidney dysfunction type on the discrimination and calibration of the Model for End-Stage Liver Disease with sodium (MELD-Na-KT) score.

Approach and results

We included all adults listed for ≥90 days without exception points from January 1, 2008, through December 31, 2018. We defined kidney dysfunction types as follows: acute kidney disease (AKD; an increase of ≥0.3 mg/dL or ≥50% in serum creatinine in the last 7 days or fewer than 72 days of hemodialysis), chronic kidney disease (CKD; an estimated glomerular filtration rate <60 ml/min/1.73 m²  for 90 days or ≥72 days of hemodialysis), AKD on CKD (met both definitions), or none (met neither definition). We then developed and validated a multivariable survival model with follow-up beginning at the first assessment after 90 days from waitlist registration and ending at the time of death, waitlist removal, or 90 days from enrollment in this study. The predictor variables were MELD-Na and the derived MELD-Na-KT model. In the derivation cohort, kidney dysfunction type was significantly associated with waitlist mortality after controlling for MELD-Na. There was a significant linear interaction between kidney dysfunction type and MELD-Na score. In the validation cohort, we saw an improvement in the discrimination of the model with an increase in the c-index from 0.76 with MELD-Na to 0.78 with MELD-Na-KT (p = 0.002) and a net reclassification index of 10.8% (95% CI, 1.9%-11.4%). The newly derived MELD-Na-KT model had lower Brier scores (MELD-Na-KT 0.042 vs. MELD-Na 0.053).

Conclusions

This study demonstrates the feasibility and the potential for objectively defined kidney dysfunction types to enhance the prognostication of waitlist mortality provided by the MELD-Na score.

Despite the growth of transplant hepatology as a subspecialty over the past decade, data on professional roles and compensation models remain lacking. Furthermore, the prevalence of physician burnout and job satisfaction are unknown in this profession. We aimed to conduct a comprehensive assessment of early career transplant hepatologists to fill these voids in knowledge and to inform current and future transplant hepatologists. An online survey designed to quantify clinical and nonclinical roles, compensation and structure, job satisfaction, and burnout was sent to 256 early career transplant hepatologists. Respondents were divided into three practice settings: university hospital clinical (n = 79), non-university hospital clinical (n = 35), and research (n = 25). The median age of respondents was 38 (interquartile range [IQR] 36-40) years, and 44% were women. The median half-days/week spent in clinic was 4 (IQR 3-6) and in endoscopy was 1 (IQR 1-2). Most of the respondents provided inpatient care (88%) for a median of 9 (IQR 6.5-10) weeks/year. The median base compensation was $300,000 (IQR US $263,750-$326,250), and most (76%) had salary-based compensation. Although only 8% of respondents were dissatisfied with their position, the prevalence of burnout was high at 35%. Conclusion: This survey is a comprehensive assessment focusing on early career transplant hepatologists, is reflective of the current training paradigm and practice of transplant hepatology, and provides transparency to guide professional negotiations and empower both trainees pursuing careers in transplant hepatology and early career transplant hepatologists.

Background

In nontransplant patients with chronic hepatitis C virus (HCV), HCV genotype has been linked with a differential response to antiviral therapy, risk of steatosis and fibrosis, as well as all-cause mortality, but the role of HCV genotypes in posttransplant disease progression is less clear.

Methods

Using the multicenter CRUSH-C cohort, genotype-specific rates of advanced fibrosis, HCV-specific graft loss and response of antiviral therapy were examined.

Results

Among 745 recipients (605 [81%] genotype 1, 53 [7%] genotype 2, and 87 [12%] genotype 3), followed for a median of 3.1 years (range, 2.0-8.0), the unadjusted cumulative rate of advanced fibrosis at 3 years was 31%, 19%, and 19% for genotypes 1, 2, and 3 (P = 0.008). After multivariable adjustment, genotype remained a significant predictor, with genotype 2 having a 66% lower risk (P = 0.02) and genotype 3 having a 41% lower risk (P = 0.07) of advanced fibrosis compared to genotype 1 patients. The cumulative 5-year rates of HCV-specific graft survival were 84%, 90%, and 94% for genotypes 1, 2, and 3 (P = 0.10). A total of 37% received antiviral therapy, with higher rates of sustained virologic response in patients with genotype 2 (hazard ratios, 5.10; P = 0.003) and genotype 3 (hazard ratios, 3.27; P = 0.006) compared to patients with genotype 1.

Conclusion

Risk of advanced fibrosis and response to therapy are strongly influenced by genotype. Liver transplantation recipients with HCV genotype 1 have the highest risk of advanced fibrosis and lowest sustained virologic response rate. These findings highlight the need for genotype-specific management strategies.

Background and aims

Kidney dysfunction is associated with increased mortality among patients with cirrhosis. We investigated whether kidney dysfunction types [e.g., acute kidney injury (AKI), chronic kidney disease (CKD), and AKI on CKD] were differentially associated with inpatient mortality.

Methods

We utilized the nationwide inpatient sample, a nationally representative database, from 2007 to 2014. We included all hospitalizations with previously validated codes for cirrhosis or associated decompensated cirrhosis diagnoses. We defined kidney dysfunction types also from previously validated codes, and we grouped hospitalizations into the following diagnoses: normal, AKI, CKD, and AKI on CKD. Our primary outcome was inpatient mortality.

Results

There were 1,293,779 hospitalizations with cirrhosis sampled in this study. Of these hospitalizations, 849,193 (66%) had normal kidney function, 176,418 (14%) had AKI, 157,600 (12%) had CKD, and 110,568 (9%) had AKI on CKD. We found that the proportion of hospitalizations with AKI, CKD, and AKI on CKD increased significantly throughout the study period (p < 0.001, test for trend for all). Kidney dysfunction type was differentially associated with inpatient mortality, even after adjustment: as compared to those with CKD, normal kidney function: OR 0.75 [95 CI 0.73-0.78], AKI: OR 2.40 [95 CI 2.32-2.48], and AKI on CKD: OR 1.66 [95 CI 1.60-1.72].

Discussion

Using a nationally representative cohort of all hospitalizations with cirrhosis, our study highlights that the burden of kidney dysfunction, especially AKI, among hospitalizations with cirrhosis is rising, and the inclusion of kidney dysfunction type may be an opportunity to improve prognostication.

The severe acute respiratory syndrome coronavirus 2 pandemic has drastically altered all facets of clinical care and research. Clinical research in hepatology has had a rich tradition in several domains, including the discovery and therapeutic development for diseases such as hepatitis B and C and studying the natural history of many forms of chronic liver disease. National Institutes of Health, foundation, and industry funding have provided important opportunities to advance the academic careers of young investigators while they strived to make contributions to the field. Instantaneously, however, all nonessential research activities were halted when the pandemic started, forcing those involved in clinical research to rethink their research strategy, including a shift to coronavirus disease 2019 research while endeavoring to maintain their preexisting agenda. Strategies to maintain the integrity of ongoing studies, including patient follow-up, safety assessments, and continuation of investigational products, have included a shift to telemedicine, remote safety laboratory monitoring, and shipping of investigational products to study subjects. As a revamp of research is being planned, unique issues that face the research community include maintenance of infrastructure, funding, completion of studies in the predetermined time frame, and the need to reprogram career path timelines. Real-world databases, biomarker and long-term follow up studies, and research involving special groups (children, the homeless, and other marginalized populations) are likely to face unique challenges. The implementation of telemedicine has been dramatically accelerated and will serve as a backbone for the future of clinical research. As we move forward, innovation in clinical trial design will be essential for conducting optimized clinical research.

Background & aims

NS3/4A protease inhibitors, boceprevir or telaprevir, combined with peginterferon and ribavirin was the standard treatment for HCV genotype 1 and remains the only available direct antiviral drug based therapy in some countries. Efficacy and safety data in liver transplant recipients are limited.

Methods

This was a retrospective cohort study of 81 patients with genotype 1 HCV treated with boceprevir (10%) or telaprevir (90%) plus peginterferon and ribavirin at 6 US transplant centers (53% stage 3-4/4 fibrosis, 57% treatment experienced). The primary end point was undetectable HCV RNA 12 weeks after treatment completion (SVR12).

Results

The intent-to-treat SVR12 rate was 63% (51/81). Patients with an extended rapid virologic response, (undetectable HCV RNA at 4 and 12 weeks after starting boceprevir or telaprevir), had a higher rate of SVR12 than all other patients (85% vs. 15%, p<0.001). Adverse effects were common; 21% of patients experienced hemoglobin <8g/dl and 57% required blood transfusions during the first 16 weeks. Twenty seven percent were hospitalized and 9% died; all were liver-related.

Conclusions

The addition of boceprevir or telaprevir to peginterferon and ribavirin yields SVR12 of 63% in liver transplant recipients with genotype 1 recurrent HCV, despite a high prevalence of advanced fibrosis and prior non-response to peginterferon and ribavirin. Rapid virologic response predicted a high likelihood of SVR. Despite a doubling of SVR rates, poor tolerability and high rates of adverse events were frequent and pose barriers to its widespread application.