During the follow-up, 376 HCV-positive and 333 HCV-negative recipients experienced graft failure. The 1-, 5-, and 10-year graft survival rate was 94.4%, 76.8%, and 57.0% in HCV-positive recipients and 94.0%, 81.1%, and 66.4% in HCV-negative recipients, respectively (Figure 2B). The difference between the 2 groups did not reach statistical significance (P = 0.15). Chronic rejection, acute rejection, and primary failure were most frequently reported causes of graft failure in both HCV-positive and negative groups (Table 2). The incidence of graft failure due to recurrent disease was significantly higher in HCV-positive than in HCV-negative recipients (0.38% vs 0.19% per year, respectively; HR, 2.00; 95% CI, 1.06-3.78).
Predictors of Death and Graft Failure
In the multivariable Cox proportional hazards regression analysis summarized in Table 3, recipient death was associated with recipient factors including age (HR, 1.04; 95% CI, 1.02-1.05) and diabetes (HR, 1.34; 95% CI, 1.04-1.73), donor factors including age (HR, 1.01; 95% CI, 1.00-1.01) and deceased status (HR, 1.64; 95% CI, 1.09-2.44), and a transplant factor of 5 or 6 HLA mismatches (HR, 1.50; 95% CI, 1.11-2.02). After adjusting for these variables, HCV was associated with a significant increase in the risk of death (HR, 1.50; 95% CI, 1.28-1.75).
In the multivariable Cox analysis predicting graft failure, HCV was found to be significantly associated with graft failure (HR, 1.26; 95% CI, 1.08-1.47). Other statistically significant factors in the model included African American race (HR, 1.56; 95% CI, 1.31-1.85), donor age (HR, 1.02; 95% CI, 1.01-1.02), deceased donor (HR, 1.78; 95% CI, 1.43-2.23), 2 to 4 HLA mismatches (HR, 1.87; 95% CI, 1.31-2.65), and 5 or 6 HLA mismatches (HR, 1.98; 95% CI, 1.40-2.82). In contrast, recipient age was inversely associated with risk of graft failure (HR, 0.98; 95% CI, 0.98-0.99).
When the analysis was repeated restricting the study to living donor KTx, among 14,025 primary living donor adult KTx recipients, 364 were HCV-positive (Figure S1, SDC,http://links.lww.com/TP/B494). PS-matching resulted in 335 pairs of HCV-positive and -negative recipients (Table S3, SDC,http://links.lww.com/TP/B494). Results of the recipient and graft survival analyses mirrored those of the overall results. For example, in the multivariable proportional hazards regression analyses, HCV-positivity was independently and significantly associated with recipient death (HR, 1.90; 95% CI, 1.33-2.74) and graft failure (HR, 1.54; 95% CI, 1.06-2.24) (Table S4, SDC,http://links.lww.com/TP/B494).
We examined whether the inferior outcome of HCV-positive recipients was attributable to the use of HCV-positive donor kidneys. In the PS-matched pairs, 375 (27.5%) HCV-positive recipients and 8 (0.6%) HCV-negative recipients were given a HCV-positive organ. In unadjusted analysis, patient and graft survival was indeed inferior in recipients with HCV+ donors (Figure S2A and S2B, SDC,http://links.lww.com/TP/B494). Then we repeated the multivariable analysis excluding pairs at least one of whom received a HCV-positive organ from a HCV+ donor. The HRs remained virtually unchanged (Table S5, SDC,http://links.lww.com/TP/B494), suggesting that recipient HCV serostatus remains an independent predictor of their outcome.
Finally, we analyzed whether the difference in liver failure mortality between HCV-positive and -negative patients may have been exaggerated because hepatitis B patients were excluded from the analysis. In the overall cohort, 560 patients (1.7%) were HBsAg-positive, including 50 who were HCV-positive and 510 HCV-negative. When HBsAg-positive patients were added back into the sample, there was only one additional death attributed to liver failure which occurred in HCV− patients. The incidence of liver failure deaths and HRs associated with HCV did not change (data not shown).
In this study, HCV infection was common among KTx recipients: 4.4% of KTx recipients were HCV-positive, highlighting the burden of HCV in KTx patients. More importantly, when HCV-positive and -negative KTx recipients were carefully matched, HCV was associated with significantly lower long-term recipient survival, which was attributable to infection and liver failure. Similarly, long-term death-censored graft survival was also lower in HCV-positive KTx recipients, in part as a result of higher incidence of recurrent disease. These results were similar between deceased donor and live donor recipients.
Although it makes intuitive sense that HCV infection would worsen the outcome of KTx, published data have been inconsistent. Earlier studies were inconclusive because of their small sample size and short-term follow-up.5,6,8,9 More recent papers began to incorporate better statistical power.10-22 Most, but not all, showed that HCV infection posed a negative impact on recipient survival,5,11,13-15,17,19-22 in part because very few directly addressed the substantial differences in demographic and clinical characteristics between HCV-positive and -negative patients. Given the known deleterious effects of immunosuppression on the progression of HCV liver disease and lack of safe and effective antiviral therapy until very lately, those recipients, if followed long enough, are expected to experience higher incidence of liver-related morbidity and mortality.
Data are less certain when the question is about the impact of HCV on survival of the renal graft, apart from the decrement in recipient’s outcome related to liver disease. Majority of studies assessing graft survival considered the recipient’s death as graft loss as well, making the interpretation of the data tricky.10-12,14,15,17-22 There have been 3 studies which considered death-censored graft survival and none of them showed significant impact of HCV on graft survival.16,18,19 None of these studies incorporated statistical matching of HCV-positive and -negative patients to account for the substantial differences between those patients. Finally, Kucirka et al23 investigated the impact of donor HCV-positivity. They found that the utilization of HCV-positive kidneys was associated with an increase in adverse liver outcomes, while there was a significant reduction in the waiting time. As discussed below, given the recent availability of effective antiviral therapy, these data will need to be updated in the near future.
Based on PS-matched comparisons, we demonstrated that survival of HCV-positive recipients is decreased significantly (multivariable hazards ratio = 1.5), which is likely driven by the progression of liver disease. Deaths from liver failure were only seen in HCV-positive recipients—which is also consistent with the fact that the survival curves in Figure 2 begin to separate after several years after KTx. Further, we suspect that the significantly increased mortality from infection and malignancy may also in part be explained by advanced liver disease, where sepsis and multiorgan failure and/or hepatocellular carcinoma are important causes of death. It is also noteworthy that cardiovascular mortality was increased, albeit marginally significantly, in HCV-positive KTx recipients. HCV infection may cause systemic inflammation which has been associated with accelerated atherosclerosis and cardiovascular morbidity and mortality.24
With regard to graft survival, while the difference between HCV-positive and -negative patients did not reach statistical significance in the unadjusted analysis, the multivariable Cox model incorporating other relevant predictors showed that HCV-positivity was associated with significantly increased risk of graft failure (multivariable HR, 1.26). Table 2 strongly indicates that an important driver of this difference is recurrence of the original renal disease. There are several renal diseases associated with HCV infection, including mixed cryoglobulinemia, membranoproliferative glomerulonephritis, membranous nephropathy and polyarteritis nodosa. Some of these lesions, such as membranoproliferative glomerulonephritis and membranous nephropathy, are known to recur in the allograft.25,26 In addition, certain de novo lesions such as renal thrombotic microangiopathy and transplant glomerulopathy are more frequently reported in HCV-positive recipients.27,28
Safe and highly effective anti-HCV agents are now available for patients with CKD, including grazoprevir/elbasvir and glecaprevir/pibrentasvir. With these agents, there has been a significant change in the treatment of HCV-positive patients with CKD. Moreover, essentially all of the currently available antiviral agents may be used in KTx recipients with satisfactory renal function with very high rates of cure.29-32 It is likely that data will accumulate soon which will demonstrate HCV-positive KTx recipients’ survival has improved. It is less clear, however, to what extent antiviral therapy will also improve graft survival. Although clearance of HCV may halt the generation of immune complexes, the natural course of post-KTx glomerulopathies remains uncertain. These data are urgently needed because it is a common policy to withhold anti-HCV therapy in patients awaiting KTx in the hopes of shortening the waiting time with utilization of HCV-positive organs.
We recognize some of the study’s limitations. First, HCV positivity was defined based on anti-HCV results, not true viremia (ie, HCV RNA-positivity). With modern anti-HCV assays, approximately 30% of individuals with positive anti-HCV antibodies do not have detectable HCV RNA in the serum and are considered to have spontaneously cleared the virus. In patients on HD, however, up to 20% with viremia may lack anti-HCV antibodies.33 Thus, in this study, it is likely that some proportion of patients were misclassified with regard to their HCV infection status. It is important to point out that misclassification of these patients would have tended to negate the differences between HCV-positive and -negative patients, making our observation more conservative. Second, as with any retrospective studies, this analysis was constrained by availability, completeness and quality of data. For example, the cause of death reported to OPTN was missing in approximately 30% of the decedents. Moreover, cause of death may be difficult to determine and inaccurately reported. We note, however, that these difficulties should affect both HCV-positive and -negative patient equally. Other variables such as antiviral therapy, detailed assessment of liver pathology (eg, liver biochemical data, cirrhosis status, and hepatocellular carcinoma) and socioeconomic status were unavailable. Given the various differences between HCV-positive and -negative patients, there may have been undetected confounders. While we attempted to minimize this effect by instituting PS matching, some of the potentially important data (eg, socioeconomic status) were not available in the database.
In conclusion, after careful matching of patients, HCV infection was associated with decreased long-term recipient and graft survival, largely as a result of HCV’s impact on the liver and the kidney graft, respectively. When highly effective and safe therapy against HCV is widely available, prospective, large scale studies are needed to define its impact on recipient and graft survival. Until such data become available, our data suggest that KTx recipients with HCV infection must be urgently treated, which may prevent progression of liver disease and potentially avert re-establishment of HCV-related glomerular disease.
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