Twelve-month Kidney and Liver Outcomes of Kidney Transplantation from Hepatitis C Viremic Deceased Donors to Aviremic Recipients

Abstract

Introduction:

Utilization of Hepatitis C viremic (HCV+) deceased donor kidneys (DDKT) for aviremic recipients increases opportunities for transplantation with excellent short-term outcomes. Our primary aim was to understand longer-term outcomes, specifically assessing kidney and liver function in the first year posttransplant.

Methods:

This was a retrospective single-center study of adult DDKT recipients of HCV+ kidneys (cases) matched 1:1 to recipients of HCV- kidneys (comparators). Between-group outcomes were analyzed using comparisons of means and proportions, survival analysis methods, and multivariable mixed effects models.

Results:

Sixty-five cases and 65 comparators had statistically comparable demographic and clinical characteristics. There were no between-group differences in serum creatinine or estimated glomerular filtration rate at month 12 (p=0.662) or in their trajectories over months 1–12 (p>0.292). Within the first 60 days, rates of liver function values >3 times upper limit of normal among cases were comparable to comparators for aspartate aminotransferase (AST) (14% vs 6%, p=0.242) and higher for alanine transaminase (ALT) (23% vs 6%, p=0.011). AST declined during the first 8 weeks (p=0.005) and stabilized for both groups (p=0.406) during the following 10 months. ALT declined during the first 8 weeks (p<0.001), continued to decline over months 3–12 (p=0.016), and the trajectory was unrelated to antiviral therapy initiation among cases.

Conclusions:

Aviremic recipients of HCV+ kidneys had comparable kidney outcomes to matched recipients of HCV- kidneys. Despite more HCV+ recipients having an elevation in ALT within the first 60 days, ALT values normalized with no identified liver complications attributed to HCV.

Graphical Abstract

A study comparing 12-month kidney and liver outcomes in HCV+ kidney transplant recipients and matched HCV- comparators found similar SCr and eGFR at 12-months posttransplant and similar trajectories in eGFR. There were no long-term adverse liver outcomes attributed to HCV infection despite early transient elevation of ALT in HCV+ recipients.

Introduction

Direct-acting antiviral agents (DAA) for the treatment of hepatitis C (HCV) have allowed for increased utilization of organs from HCV-infected donors for transplantation.^1–3 Pilot studies showed 100% cure rates among HCV viremic kidneys transplanted into aviremic individuals (HCV D+/R−) with early DAA initiation posttransplant. ^4–6 Subsequent studies utilizing early or prophylactic DAA treatment showed good allograft outcomes.^7–9 However early treatment is not feasible when transplant centers rely on insurance approval to cover the cost of DAA.¹⁰ “Real-world” studies have illustrated >98% cure rates and excellent allograft outcomes at 6- and 12-months posttransplant by implementing DAA therapy after HCV viremia with a start time of 26–76 days posttransplant.^11–14 National database studies found no significant difference in 3-year or 5-year allograft survival for recipients of HCV+ kidneys compared to HCV- kidneys.^15,16 Not all studies included a matched comparator group and the database studies lacked granular data such as graft function and rejection rates. Therefore, additional data are needed on longer-term graft outcomes and kidney function in HCV D+/R− kidney transplant recipients.

A concern in the practice of HCV D+/R− kidney transplantation is the risk of liver injury, particularly with delayed DAA therapy. Fibrosing cholestatic hepatitis has been reported in both the pre-DAA and DAA eras among kidney transplant recipients infected with HCV posttransplant and is associated with high morbidity and mortality. ^13,17,18 To date, there has not been a study comparing liver outcomes in HCV D+/R− kidney transplant recipients to a comparator group of HCV D−/R− recipients to assess for potential hepatotoxicity when DAA initiation is delayed.

To address these knowledge gaps, our primary aim was to compare kidney and liver function in the first 12 months posttransplant between HCV D+/R− kidney transplant recipients (cases) and matched HCV D−/R− comparators. Our hypothesis was that outcomes would not be different between the two groups. This work expands on our prior study which reported on 6-month outcomes.¹¹

Materials and Methods

Study Design

This was a single center study at Vanderbilt University Medical Center (VUMC) that followed previously-described criteria and included deceased donor kidney transplant recipients between January 1, 2008 and August 30, 2020. ¹¹ The cohort of HCV+ recipients (cases) was transplanted from October 18, 2018 to August 30, 2020. Patients who received HCV D−/R− transplants (comparators) were matched as previously described.¹¹

Data were collected from VUMC transplant dataset and electronic medical records, stored and managed in the Research Electronic Data Capture tool at Vanderbilt University.^19,20 Labs, including liver enzymes, were collected at regular intervals as standard of care for all patients. The lab frequency is at a minimum weekly for 6 weeks, every two weeks until month 3 and then monthly until month 12. The study was approved by the Vanderbilt Institutional Review Board (#191146).

The HCV consent process, donor acceptance criteria, immunosuppression protocol, HCV screening and treatment protocol, and DAA application and approval process have been previously described.¹¹

Outcomes

Primary outcomes were kidney and liver function measured by the trajectories of serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) between posttransplant months 1 and 12, the trajectories of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) during the first posttransplant year, and whether there was evidence of abnormal liver function based on AST >3 times the upper limit of normal (ULN) (≥120 units/L), ALT >3 times ULN (≥165 units/L), and total bilirubin (Tbili) >1.2 mg/dL within the first 60 days posttransplant. Secondary outcomes were whether a sustained virologic response was achieved 12 weeks after completing DAA treatment (SVR-12), development of fibrosing cholestatic hepatitis, acute rejection episodes, rejection-free and death-censored graft survival, and patient survival over the first posttransplant year.

Statistical Analysis

Summary statistics are reported as mean (±SD), median (IQR), or frequencies (percentages). Outcomes of cases and comparators were compared using analysis of variance, chi-squared, and survival analysis methods. Multivariable mixed effects models that adjusted for delayed graft function evaluated the effects of HCV kidney status on the trajectories of SCr and eGFR between months 1 and 12 (days 31 through 379) with time by donor type interaction effects reflecting whether temporal trajectories differed based on HCV kidney status. Similarly, multivariable mixed effects models evaluated the effects of HCV kidney status on the trajectories of AST and ALT over the first year (days 1 through 379). Secondary piecewise mixed effects models determined temporal effects of HCV kidney status on liver function over the first 8 weeks and over the following 10 months (≥8.01 weeks through week 54).

Results

Recipient and Donor Characteristics

Sixty-five cases and 65 comparators had statistically comparable demographic and clinical characteristics with the exception of more comparators preemptively transplanted and maintained on a steroid-sparing regimen (Table S1). Pre-transplant recipient Fibrosis-4 index mean value was 1.6 +/− 1.18 (p=0.750). There were 64 and 43 unique donors for the comparators and cases with comparable characteristics.

Kidney Function

After adjusting for delayed graft function (p≤0.02), SCr increased marginally (p=0.045) and eGFR was stable (p=0.464) between posttransplant months 1 and 12, with no between-group differences in trajectories (time by group interaction p>0.292) or overall values (p>0. 346) (Figure S1, Table S2). At 12 months posttransplant, kidney function did not differ between cases and comparators. Specifically, mean eGFR was 58.6±17.3 ml/min/1.73m² and 56.3±15.4 ml/min/1.73m² (p=0.470) (Table 1).

Table 1.

Key Kidney and Liver Outcomes

		HCV+ donor (n=65)a	HCV- donor (n=64)a	p-value
Delayed Graft Function		2 (3.1)	8 (12.5)	0.054
Kidney Function at Approximately 1 Yearb	SCr (mg/dL)	1.29 (0.49)	1.34 (0.64)	0.662
	eGFR (ml/min/1.73m2)	58.6 (17.3)	56.3 (15.4)	0.470
Abnormal Liver Function within 60 Days	ALT ≥ 165 units/L	15 (23.1)	4 (6.3)	0.011
	AST ≥ 120 units/L	9 (13.8)	4 (6.3)	0.242
	Total Bilirubin > 1.2 mg/dL	8 (12.3)	7 (10.9)	1.000
Death-Censored Graft Survival	6 months	0.985 (0.015)	0.938 (0.030)	0.053
	12 months	0.985 (0.015)	0.908 (0.036)
Patient Survival	6 months	1.000	0.954 (0.026)	0.093
	12 months	0.985 (0.015)	0.923 (0.033)
Rejection-Free Graft Survival	6 months	0.908 (0.036)	0.891 (0.039)	0.824
	12 months	0.862 (0.043)	0.857 (0.041)

Note: Table entries are mean (SD), frequency (%), or cumulative proportion survival point estimates (SE).

^aUnless noted, one mortality at a week posttransplant reduced the group size for HCV- donors to 64 for all analyses except for patient and death-censored graft survival.

^b107 persons (52 cases and 55 comparators) had kidney function data at approximately the 12-month mark based on the last observation occurring between weeks 44 and 54.

Liver Function

Liver Function Test Abnormalities

Occurrences of liver function abnormalities within 60 days among cases and comparators are outlined in Table 1. Rates of AST and Tbili elevation did not differ between cases and comparators. Fifteen cases (23.1%) experienced elevated ALT compared to 4 (6.3 %) comparators (p=0.011). No patients developed fibrosing cholestatic hepatitis or complications attributable to HCV.

Liver Transaminase Trajectories Over Time

Longitudinal models of liver function showed a decline in AST and ALT over the first year, and significant group by time interaction effects (p≤0.032). Thus, the rates of change in liver function measures over the first year were likely higher (less negative) among comparators compared to cases (Figure 1, Table S2).

Figure 1.

Linear mixed-effects model of AST (A) and ALT (B)

Piecewise models reflecting the first 8 posttransplant weeks demonstrated a significant decline in AST (p=0.005), no difference in the trajectories of AST between cases and comparators (group by time interaction p=0.807), and no difference between in model-estimated mean AST values (p=0.991) (Figure 1). ALT declined during the first 8 weeks (p<0.001), the rate of change was more pronounced among the cases (group by time interaction p=0.031), and model-estimated ALT among cases was higher during this period (p<0.001).

Piecewise models reflecting the latter 10 months demonstrated that AST was stable (p=0.416), did not differ between cases and comparators (p=0.406), and the trajectories of AST did not differ over this period (group by time interaction p=0.822) (Figure 1). Model-estimated AST was 25.4 (95%CI 22.7, 28.2) units/L. ALT continued to decline over the last 10 months (p=0.016), was slightly lower in the comparators (p=0.034), and the trajectories of ALT did not differ between cases and comparators during this period (group by time interaction p=0.109). Model-estimated mean ALT was 29.8 (95%CI: 24.6, 35.0) units/L and 24.5 (95%CI: 19.2, 29.8) units/L for the cases and comparators, respectively. Thus, while the main effect of group was statistically significant in the multivariable model, confidence intervals for the model estimated means during the last 10 months overlapped.

Acute Rejection

Allograft biopsies were performed for-cause. All cases of rejection were biopsy-proven except one HCV D+/R− recipient was treated for presumed acute antibody mediated and cellular rejection. Seven cases (11%) and 4 (6%) comparators had 1 rejection episode each, and 2 cases (3%) and no comparators had 2 rejection episodes each (all column wise p>0.05) (Table S3).

Patient and Graft Survival

There was no significant difference between cases and comparators over the first posttransplant year in patient survival (p=0.093), death-censored graft survival (p=0.053), or rejection-free graft survival (p=0.824) (Table 1).

HCV+ Characteristics and Treatment

Two of 65 cases did not develop HCV viremia. Median time of DAA initiation was 28 days posttransplant (IQR 22–40) and there was no relationship between the declining trajectory (p<0.001) of ALT over the first year and whether DAA was initiated prior to or after day 28 (interaction p=0.856) (Table S4). Cox proportional hazards regression demonstrated there was no time dependent relationship between DAA treatment initiation and the likelihood of rejection (p=0.80). Sixty-one patients who developed viremia achieved SVR-12 after the first course of DAA (Table S5). Two cases failed the first course of DAA and required a second course of treatment to achieve SVR-12.

Discussion

In our study of HCV D+/R− kidney transplant recipients and matched HCV D−/R− comparators, there was no difference in kidney function within the first 12 months posttransplant. Regarding liver function, there were more cases with an elevation in ALT values ≥165 unit/L in the first 60 days posttransplant but no significant difference for elevation of AST or Tbili values. Despite this early difference in ALT, model-estimated mean values between days 60 and 365 were not significantly different.

The 12-month kidney outcomes of the HCV D+/R− cases in our study are consistent with prior studies. In comparison to the mean eGFR of 58.6 ml/min/1.73m² in our study, Molnar et al. reported a mean eGFR of 64 ± 16 ml/min/1.73m² in HCV D+/R− kidney transplant recipients with delayed DAA initiation. ¹⁴ In studies with early initiation of DAA, median eGFR ranged from 54–72.8 ml/min/1.73m² in HCV D+/R−recipients after 12 months.^7–9 Our finding of no significant difference in death-censored graft survival or patient survival between cases and comparators is consistent with other reports.^9,14 Acute rejection occurred in 9 (14%) of our HCV D+/R− cases and in 4 (6%) of the comparators (p>0.05). The rate of rejection is slightly higher compared to other similar-sized studies that had rejection in 10–11% in HCV D+/R− recipients.^9,14 However, similar to our findings, in the studies utilizing comparator groups, neither reported differences in rejection rates.^7,14 Additionally, we showed that timing of DAA initiation was not associated with likelihood of rejection. These results add to the growing literature in support that excellent 12-month graft outcomes and patient survival in HCV D+/R− kidney transplant recipients can be achieved despite delayed DAA initiation posttransplant.

No prior study to our knowledge has analyzed liver outcomes between HCV D+/R− patients and matched controls/comparators. Transient elevations in aminotransferases in the early postoperative period with no clinically significant liver disease are consistent with previous reports of HCV D+/R− recipients with delayed or early DAA initiation. ^5,7,9,14 These studies, however, did not include liver function data on HCV D−/R− recipients for comparison. Although early transaminitis can be attributed to HCV viremia, other factors exist such as medications and hypoperfusion. Importantly, based on our findings, these early abnormalities do not persist and appear to have minimal clinical significance.

There have been three reports of fibrosing cholestatic hepatitis when there was delayed DAA initiation.^14,17 In our cohort, where the median time to DAA initiation was 28 days, there were no cases of fibrosing cholestatic hepatitis within 12 months posttransplant. Regardless, patients should be informed of this rare complication, particularly when DAA initiation is delayed. We had excellent HCV cure rates with 96.8% of patients achieving SVR-12 with the first course of DAA. Two patients required a second course of DAA and subsequently achieved SVR-12. Previously published studies also report excellent cure rates with delayed or early DAA initiation.^7–9,14

To our knowledge, this is the only study that has reported liver outcomes in matched comparators to better assess risk of hepatotoxicity of HCV viremia in transplant recipients. Limitations of our study include that it is retrospective and conducted at a single center. Larger, multi-center studies are warranted to better assess outcomes as different transplant centers vary in posttransplant management.

Conclusion

Overall, our study adds to the collective literature, supporting the use of HCV + kidneys for aviremic recipients. Our data demonstrates no significant difference in kidney outcomes at 12 months post-transplant. In addition, despite early elevations in liver transaminases, there was no significant difference in liver function at 12 months despite having delayed DAA initiation after transplant. This is reassuring, that with successful treatment of HCV viremia, we did not identify liver complications attributable to HCV.

Supplementary Material

Tab S1

Table S1. Recipient and Donor Characteristics

Tab S2

Table S2. Longitudinal Models of Kidney and Liver Function over the First Posttransplant Year

Tab S3

Table S3. Acute rejection episodes

Tab S4

Table S4. Effect of DAA Therapy Initiation Time on ALT (units/L) over the First Posttransplant Year

Tab S5

Table S5. HCV+ characteristics and treatment

Fig S1

Figure S1. Linear mixed-effects model of eGFR

Supplemental Methods and Results

Supplemental Methods and Results. Effect of Timing of DAA Initiation Among Cases

Abbreviations

ALT

alanine transaminase

AST

aspartate aminotransferase

cPRA

calculated panel reactive antibody

DAA

direct antiviral agents

DDKT

Deceased donor kidney transplant

eGFR

estimated glomerular filtration rate

HCV

Hepatitis C virus

IQR

interquartile range

KDPI

Kidney donor profile index

SCr

Serum creatinine

SD

standard deviation

SVR

Sustained virologic response

VUMC

Vanderbilt University Medical Center