Combined Effects of Hematopoietic Cell Transplantation Associated Thrombotic Microangiopathy and Acute Graft-Versus-Host Disease on Requiring Renal Replacement Therapy in US Patient Population – a Secondary CIBMTR Analysis

Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a significant contributor to increased morbidity/mortality following allogeneic hematopoietic cell transplantation (allo-HCT). The impact of TA-TMA on overall survival (OS) and renal health was evaluated using TA-TMA as a time-dependent covariate and published by the Center for International Blood and Marrow Transplant Research (CIBMTR) (Epperla et al., BJH. 2020). Acute Graft-Versus-Host Disease Grade 2-4 (aGVHD24) is a recognized risk factor for TA-TMA in both children and adults (Schoettler et al., BJH. 2024). This CIBMTR data was used to evaluate the effects of time-varying risk factors, TA-TMA, and aGVHD24 on the need for renal replacement therapy (RRT) in patient populations characterized by age and pre-HCT kidney health.

Methods: Allo-HCT recipients between 2008-2016 were included in this secondary analysis of an existing CIBMTR data. In the absence of any specific diagnostic criteria during this timeframe, TA-TMA was identified by presence or absence of the condition as judged by the treating physicians. The multivariate analysis model included TA-TMA and aGVHD24 as time-dependent covariates, with age groups (children age <18 years and adults age ≥18 years) and pre-HCT renal health (decreased kidney function defined as GRF <60 mL/min for adults and <90 mL/min for children) as fixed covariates. The proportional hazard assumption was not met for disease groups and as such, its effects were adjusted through stratification in the Cox multivariable regression model for the need for RRT. Interactions of TA-TMA, age groups and pre-HCT renal function were evaluated. Cumulative hazards of RRT were estimated for various group of patients.

Results: There was a significant association (p<0.001) between TA-TMA and aGVHD24 incidence, controlling for the age groups and pre-HCT kidney function. Interactions between acute GVHD and age groups with pre-HCT kidney function were significant (p=0.002 and 0.044, respectively). Interactions between TA-TMA with age groups and pre-HCT kidney function were not significant.

Patients with TA-TMA were at 3.6-fold higher risk (HR 3.62, 95% CI 2.67, 4.90) than patients with no TA-TMA for requiring RRT post-HCT. Adults as compared to children, with pre-HCT normal or decreased kidney function were at higher adjusted risk (HR 1.19, 95% CI 1.00, 1.42) and (HR 1.66, 95% CI 1.21, 2.28) respectively, for requiring RRT post-HCT.

Patients with pre-HCT normal kidney function and with post-HCT acute GVHD Grade 2-4 complications as compared to no or grade 1 acute GVHD, were at significantly higher adjusted risk (HR 2.14, 95% CI 1.89, 2.41) of requiring post-HCT renal replacement therapy.

Cumulative hazards averaged over all disease groups, at 6 months post-HCT, of requiring RRT in children with decreased (normal) pre-HCT kidney function, were estimated at 6.2% [5.3%, 7.2%] (5.4% [4.8%, 6.1%]) for patients with aGVHD24, 17.4% [14.6%, 20.2%] (8.9% [7.6%, 10.3%] for patients with TA-TMA, and 22.1% [18.1%, 26.1%] (19.0% [16.0%, 21.9%]) for patients with TA-TMA and aGVHD24 as compared to 4.9% [4.2%, 5.6%] (2.6% [2.2%, 2.9%]) for patients without aGVHD24 and TA-TMA.

Discussion: Our results demonstrate that while the incidence of TA-TMA and patients requiring RRT after HCT was similar in the children and adults, the adjusted HRs of requiring RRT were significantly much higher in adult patients. The onset of TA-TMA and aGVHD24 were also significant factors in requiring RRT. TA-TMA demonstrated greater effects in requiring RRT than the effects of aGVHD24. The combined effects of aGVHD24 and TA-TMA in children and adult patients, with decreased or normal pre-HCT kidney function are significantly much higher than the effects of aGVHD24 or TA-TMA alone. This study adds to the growing research on the effects of TA-TMA on kidney function. This information is important as it allows providers to better assess risk of requiring RRT in TA-TMA patients.