Parameters of Protein Metabolism and Thyroid Function As Predictors in a Scoring System for Acute and Chronic Graft-Versus-Host Disease
Authors: Skert Cristina , Turra Alessandro , Malagola Michele , Perucca Simone , Cancelli Valeria , Daffini Rosa , Ribolla Rossella , Bergonzi Cesare , Filì Carla , Pagani Chiara , Di Palma Andrea , Cattina Federica , Bernardi Simona , Russo Domenico 
Published: October 2019

Abstract
Background Graft versus host disease (GVHD) is a common complication of allogeneic stem cell transplantation (allo-SCT), and represents its major cause of morbidity and mortality. Some “classical” patient-, donor- and transplant characteristics, such as age, gender disparity, donor type, HLA-match, and source of stem cells, have been reported as predictors for acute and chronic GVHD. However, no studies analysed these “classical” variables together with parameters of metabolic and endocrine functions, which may potentially influence the immune system. Thus, patient-and transplant variables together with index of liver and thyroid function, and some parameters of protein and lipid metabolism were retrospectively evaluated at different time points after transplantation, in order to identify possible predictors of acute and chronic GVHD and to calculate a risk score.
Methods Clinical and transplant characteristics, number and type of infections before and after SCT were analysed in 161 patients. The following variables were also analysed pre-SCT, at day +7,+14,+21,+28, at + 3 and +6 months: LDH, parameters of liver function; parameters of protein and lipid metabolism (serum albumin, urea, total protein, cholesterol, triglycerides); thyroid function tests; autoimmune parameters (anti-nuclear, anti-DNA, anti-cardiolipin antibodies); body mass index. A 2-step multivariate analysis was performed using principal component analysis (PCA) and Cox regression analysis, in order to solve the problem of the high number of variables (metabolic, patients- and transplant related) in comparison with the relatively limited and heterogeneous pool of patients. Based on the regression coefficient of Cox analysis for each significant predictor, a scoring system for acute and chronic GVHD was calculated.
Results In multivariate analysis, diagnosis of Myelodisplastic Syndrome or Chronic Myeloid Leukemia (HR 4,9; p=0.0004), conditioning regimen including Total Body Irradiation (HR 3,3; p=0.0003), and pre transplantation urea > 34 mg/dl with +21 day urea > 54 mg/dl (HR 2,6; p=0.0008) were evidenced as predictors for acute GVHD. Score values for each factor are 2, 1, and 1, respectively. Hence, the score, obtained by the sum of the three score values, ranged from 0 to 4. The probability of acute GVHD ranged from 8% (score 0) to 98% (score 4). Female donor (HR 5,1; p=0.0008), pre-SCT TSH values ≥ 2 mU/L with +28 day urea ≥ 39 mg/dl (HR 3,3; p=0.02), +6 month total protein < 5,5 g/dl with gamma-GT ≥ 347 U/L (HR 7,8, p=0.0001) resulted predictors for moderate/severe chronic GVHD, with score values of 1, 1, and 2 respectively. Risk of chronic GVHD at +6,5 month ranged from 3% (score 0) to 97% (score 4).
Discussion Our study evidenced that factors other than “classical” ones may be associated to GVHD. Our scoring system includes routine-parameters (urea, total protein, gamma-GT,TSH), which are easily available in clinical practice. Urea levels depend on the balance between protein intake, endogenous catabolism and urinary excretion. The inflammatory microenvironment of GVHD promotes muscle catabolism, hence, urea levels do increase. Increased urea levels could be an indirect index of increased uremic toxins as well, which may stimulate the production of pro-inflammatory cytokines and the activation of leukocytes. On the other hand, increased urea levels and uremic toxins could derive from a dysregulated metabolism of the gut microbiome, which may influence immune system. Our findings, which require a prospective validation, suggest the usefulness a deeper study of the complex network between metabolic/endocrine functions and immune system, in order to develop a holistic approach of the transplant management.

Disclosures
No relevant conflicts of interest to declare.