Treatment with Foscarnet after Allogeneic Hematopoietic-Cell Transplant (AlloHCT) Is Associated with Long-Term Loss of Renal Function
Authors: Foster Yevgeniya , Grant Michael J , Thomas Samantha M , Cameron Blake , Raiff Doug , Corbet Kelly , Ferreri Christopher , Horwitz Mitchell E. 
Published: October 2019

Abstract
Introduction: Despite a well-established risk of chronic kidney disease (CKD) in 20-30% of patients undergoing AlloHCT, the benefits of treating serious infections, such as cytomegalovirus (CMV), with nephrotoxic drugs often outweigh this risk. Given a lack of consensus on the optimal management of post-transplant Human-Herpes Virus 6 (HHV6) reactivation, our center has taken an aggressive stance toward screening for and treating HHV-6 viremia with foscarnet, a nephrotoxic drug with an unknown impact on long-term renal function.
Methods: To clarify the impact of foscarnet exposure on long-term renal function after transplant, we conducted a retrospective cohort study of all adult patients who underwent AlloHCT at Duke from June 2002 - Feb 2016 (n=997). HHV6 viral loads were checked weekly for the first 90 days after umbilical cord blood and haploidentical transplants, and as clinically indicated (e.g. cytopenias, encephalopathy) in others. Foscarnet treatment for HHV6 viremia was given at the physician's discretion. Data were abstracted with a web-based clinical research query tool and manual chart review. Estimated glomerular filtration rate (eGFR) was calculated with the CKD-EPI equation based on repeated measures of serum creatinine (Cr) values at baseline, 90 days (n=839), 6 months (n=720), and 12 months (n=491) after transplant. Acute Kidney Injury (AKI) and Acute Kidney Failure (AKF) were defined as 2 and 3x baseline Cr, or >50% and >75% decrease in eGFR, respectively. Multivariate logistic regression was used to estimate the association of foscarnet exposure on the probability of >30% decline in eGFR at 90 days, 6 months, and 12 months after adjustment for confounders.
Results: Of the 997 patients included in the study, 45% (n=448) were treated with foscarnet. Patients treated with foscarnet were slightly older (median age 52yrs vs. 49yrs), less likely to receive myeloablative conditioning, and more likely to be CMV positive, receive an alternative donor graft (umbilical cord blood or haploidentical), and experience acute GvHD. The most frequent indications for treatment were CMV (n=257, 57.4%) and HHV6 (n=140, 31.3%). In the first 90 days post-transplant, when most patients were treated with foscarnet, patients exposed vs. unexposed had similar rates of AKI/AKF: AKI 59.2% vs. 59.2%; p=0.99; AKF 26.1% vs. 27.3%; p=0.67. There was no difference in eGFR at 90 days, but patients treated with foscarnet had significantly lower eGFRs at 6 months and 12 months (Figure 1). There was a significant difference in the decline in eGFR from baseline to 12 months: median -29.1 (mL/min/1.73m2) (interquartile range (IQR) -50.8 to -10.7) vs. -22.2 (-37.4 to -7.4); p=0.002. After adjustment for age, race, acute and chronic GVHD, conditioning regimen, donor type, treatment with alemtuzumab, and HHV6 status, patients treated with foscarnet were more likely to experience a >30% decrease in eGFR from baseline to 12 months compared to those who were not (Odds Ratio 1.8 (95% CI 1.11-2.93); p=0.02). In this multivariate model, acute and chronic GVHD were not significant predictors of eGFR decline at 12 months. Unadjusted median survival was 11.9 months (95% CI; 10.1-14.0 months) and 20.8 months (95% CI; 15.8-25.4 months) for patients treated vs. not treated with foscarnet, respectively (p<0.001).
Conclusion: Foscarnet use post AlloHCT had a profound impact on long-term renal function independent of other transplant-related factors. As declines of >30% in eGFR are strongly associated with a 10-year risk of end-stage renal disease and mortality in >60% and 50% of patients in the general population, respectively, (Coresh, et al. JAMA 2014), this information should be considered as one weighs the risks vs. benefits of treating HHV6 viremia following AlloHCT.

Disclosures
Horwitz: Gamida Cell: Research Funding.