Transplant-Associated Renal Microangiopathy Is Associated with a High Risk of Refractory Gvhd and Characterized By a Specific Biomarker Signature
Authors: Zeisbrich Markus , Beimler Jörg , Zeier Martin G. , Falk Christine S. , Ho Anthony D , Dreger Peter , Luft Thomas 
Published: October 2019

Abstract
Introduction
There is increasing evidence that endothelial damage is involved in the pathogenesis of steroid-refractory graft-versus-host disease (refGVHD). Recently, serum soluble ST2 (suppressor of tumorigenicity,IL-33 receptor), an independent risk factor of cardiovascular death, has been identified as a risk factor of refractory GVHD. However, the pathomechanism of endothelial cell dysfunction which is associated with mortality from GVHD is yet poorly characterized. Renal transplant-associated microangiopathy (TMA) is another endothelial complication of alloSCT, and its association with severe GVHD and with biomarkers of endothelial damage (ST2, sCD141 (soluble thrombomodulin)), and endothelial function (VEGF) is investigated in this study.
Methods
Evidence for renal TMA was studied in a cohort of 508 patients who underwent alloSCT between 2002 and 2013 at our institution and who have provided informed consent for this observational study. Criteria to diagnose renal TMA included an otherwise unexplained 50% rise in creatinine and lactate dehydrogenase (LDH) levels (or a pre-existing LDH above 400 U/L), a 50% drop in platelet counts (or a pre-existing platelet count below 50/nl) and at least 4% schistocytes. Cytokines were measured in sera taken prior to alloSCT and on the indicated days thereafter and stored at minus 80C. ST2 and sTM were measured by Duo Set ELISA (R&D) whereas VEGF was quantified by the multiplex protein array technology (Luminex). Statistical analyses were performed using SPSS19 and included a cumulative incidence analysis of cause-specific hazards and the non-parametrical median test of independent probes.
Results
Both renal TMA and refGVHD were rare complications after alloSCT but were significantly associated with each other (TMA only 18/508 (3.5%), refGVHD only 26/508 (5.1%), both 20/508 (3.9%), chi2 0.000). Median time intervals from alloSCT to renal TMA and refGVHD were 1.93 (0.23-60.16) months and 1.23 (0.16-12.4) months respectively. In the overlap group, GVHD onset usually occurred before renal TMA (-0.69 months, -55.4 to 11.2) NRM rates were significantly increased in all three cohorts but approached 100% in patients with both complications (Figure 1).
Serum sTM levels as well as soluble ST2 levels increased between transplantation and day 100/day 200 after alloSCT in all cohorts, refGVHD, TMA and both. In contrast, VEGF levels (day 100) were significantly lower specifically in patients with TMA with or without refGVHD, but not in patients with refGVHD without TMA (Table 1).
Conclusions
This study identifies renal TMA as an endothelial cell dysfunction associated with extremely high mortality rates in the context of GVHD. The absence or presence of renal TMA defines two separate subsets of refGVHD with a different prognosis. Biomarkers of endothelial damage or vulnerability, such as sTM, ST2, and VEGF can help to dissect TMA and refGVHD, and might be useful to identify and guide management of patients with endothelial dysfunction who are at high risk of fatal complications after alloSCT.
Table 1 p=0.000
Figure 1 NRM in patients suffering from renal TMA, refractory GVHD, or both. P=0.000. Figure 1. NRM in patients suffering from renal TMA, refractory GVHD, or both. P=0.000.
Cytokines on days 100 (sTM and VEGF) or day 200 (ST2) in patients with renal TMA, refractory GVHD, or both
Median (range) in pg/ml
Table 1. Cytokine/condition no GVHD no TMA TMA only refGVHD only both Chi2 sTM d100 11.7 (0-40.0) 15.0 (9.1-19.6) 14.0 (9.8-31.2) 20.4 (12.3-40.0) 0.000 sST2 d200 550.0 (0-20000) 1719.8 (143-11968) 2268.6 (506-20000) 6718.1 (429-20000) 0.000 VEGF d100 111.7 (7,8-753.3) 66.1 (42.1-156.6) 114.12 (34.9-497.3) 74.8 (19.8-576.6) 0.035

Disclosures
No relevant conflicts of interest to declare.