Early Acute Kidney Injury Post Allogeneic Hematopoetic Progenitor Cell Transplant Is Associated with Increased Risk of Gvhd, Higher Mortality and Reduced Survival

Introduction:Although acute kidney injury (AKI) is associated with poor outcomes post allogeneic Hematopoetic Progenitor Cell Transplant (HPCT), the timing of AKI development potentially confounds any associated clinical impact, including via presence of concomitant GVHD and requirement for immunosuppression modification.

Aims: To define rates, risk factors and clinical significance of early AKI (occurring prior to day 14) post allogeneic HPCT.

Methods: Consecutive allogeneic HPCT performed at a single Australian transplant centre between January 2008 and December 2013 were identified from an institutional database. Clinical characteristics and outcomes were then retrospectively determined by review of individual patient records. Those patients receiving haplo-identical transplants and cord blood transplants were excluded. Baseline serum creatinine was defined by day 0 value, with maximum relative increase in creatinine before day 14 graded from 0-3 using the Kidney Disease Improving Global Outcomes (KDIGO) score. A KDIGO score >=2 was used to define AKI. Non-relapse mortality (NRM) was defined as any non-relapse related death; PFS and OS were calculated from day 0 till relapse or death respectively. Analysis of categorical variables was made using Fisher's exact test; survival analyses were performed using the Kaplan-Meier method. A p value <0.05 was used to identify variable for inclusion in multivariate analysis.

Results: A total of 479 consecutive transplants were reviewed; median follow-up for the whole cohort was 69mths (range 36-108mths). Of these patients, 57 (12%) developed >=grade 2 acute kidney injury <=day 14 (early AKI cohort), including 41 patients with grade 2 (9%) and 16 (3%) with grade 3 AKI. Patients who developed early AKI were significantly more likely to be female (56.4% vs 40.5% respectively; p=0.018) and have undergone ABO-minor mismatched (33.3% vs 20.4% respectively; p=0.044) and unrelated donor SCT (73.7% vs 58.5% respectively; p=0.019). Clinical outcomes were significantly inferior in patients who developed early AKI, with increased incidence of grade III-IV acute GVHD (72% vs 52% respectively; p=0.004), increased NRM (40% vs 21% respectively; p=0.001) and reduced OS (median 21mths vs 118mths respectively; p=0.0001); PFS was similar irrespective of development of early AKI or not (4yr PFS 67% vs 69% respectively; p=0.7). Multivariate analysis revealed early AKI, development of grade III-IV acute GVHD and unrelated donor transplantation as independent predictors of mortality. For patients with early AKI, requirement for dialysis (n=10) and significant dose reduction / omission of calcineurin inhibitor and / or methotrexate based immunosuppression (n=29) prior to day 14 were both associated with significantly inferior OS.

Conclusion: AKI prior to day 14 post allogeneic HPCT is associated with significantly increased rates of NRM, decreased OS, and increased rates of severe acute GVHD. Requirement for haemodialysis or significant modification of immunosuppression amongst patient with AKI is also associated with significantly inferior OS. Novel immunosuppression approaches for patients who develop early AKI to limit further renal injury and reduce risk of subsequent development of GVHD are required.