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NIH grant 1R01HL185049-01: Subclinical kidney and cardiovascular indicators of transplant-associated thrombotic microangiopathy (TMA)
Institute: {'code': 'HL', 'abbreviation': 'NHLBI', 'name': 'National Heart Lung and Blood Institute', 'admin_org_id': '12500068', 'admin_funding_url': ''}. PI: Sonata Jodele. Award: $638652.
Start: 2026-09-05T00:00:00.
PROJECT SUMMARY/ABSTRACT
Transplant-associated thrombotic microangiopathy (TMA) is a life-threatening complication of hematopoietic
stem cell transplantation (HSCT) that occurs within the first 100 days of transplant. Over the last decade, our
research team has advanced understanding of the diagnosis and management of TMA. Standardized diagnostic
and risk stratification criteria for TMA, developed by our group, were recently adopted by international consensus.
High-risk (severe) TMA is analogous to an uncontrolled fire, leading to multi-organ injury and very high mortality.
Accordingly, established diagnostic criteria and targeted complement blockade have focused on improving
outcomes in patients with the highest risk TMA. Despite this past and ongoing work, knowledge gaps remain in
our understanding of the clinical significance of different TMA risk phenotypes. While using complement blockade
in patients meeting high-risk criteria is associated with increased survival, we need to determine the earliest time
to initiate therapy for TMA, as our long-standing experience and clinical data indicates that patients with less
than severe TMA also suffer from TMA-associated organ injury and have reduced post-transplant survival.
Identifying subclinical indicators of impending TMA or identifying patients at high-risk to develop TMA will inform
new diagnostic approaches to improve outcomes in patients with TMA before the fire burns out of control. We
hypothesize that sensitive or subclinical markers of kidney and cardiovascular injury are early indicators of
impending TMA after allogeneic HSCT. The objective of the current proposal is to identify early indicators of
impending TMA in an established cohort of children and young adults (N=300) undergoing HSCT. We are
focusing on the kidney and the cardiovascular system because this hypothesis is supported by our published
and preliminary data and because early TMA-associated kidney and cardiac injury can be identified by sensitive
biomarker monitoring. Specifically, our preliminary data support that soluble urokinase plasminogen activator
receptor (suPAR), a marker of kidney injury, measured in baseline plasma before HSCT, predicts TMA.
Furthermore, elevations of serum cystatin C and protein in the urine were also associated with a higher risk of
TMA. These biomarkers will be examined in Aim 1 focusing on subclinical kidney injury. Aim 2 will evaluate
cardiovascular injury biomarkers, such as ST2, CXCL8 and CXCL3 and also include comprehensive
assessments of blood pressure and echocardiograms. Our preliminary data supports that endothelial injury
presenting as systemic hypertension or pulmonary hypertension are also early indicators of impending TMA.
Finally, the knowledge gained from Aim 1 and Aim 2 will be applied to a new prospectively enrolled validation
cohort (N=100). The prospective cohort will test, during clinical care, how the identified biomarkers identify
impending TMA and its severity after HSCT. Our approach will inform the optimal timing to initiate therapy in the
most appropriate patients. This will aid in the design of future interventional trials to prevent, treat, or decrease
the severity of TMA after HSCT and improve patient survival for this high-risk population.document fetched 2026-09-13 02:46