Background: Hypomagnesemia is a frequent complication of allogeneic hematopoietic cell
transplantation (HCT) and is related to cyclosporine-induced renal magnesium (Mg) loss.
Recently, a link between EGF, Mg, and cyclosporine (CSA) in renal transplant recipients has
been proposed through downregulation of EGF leading to inhibition of the Mg channel TRMP6
in the distal convoluted tubule, but similar associations have not been investigated postallogeneic HCT. We hypothesized that lower serum EGF would be associated with higher CSA
levels, grade III-IV acute graft versus host disease (GVHD) status, and more severe Mg wasting
after allogeneic HCT.
Patients and Methods: 107 adult allogeneic HCT recipients from the University of Minnesota
enrolled on an immune monitoring study had EGF levels measured by magnetic bead array at
day +100 post-allogeneic HCT. Clinical variables analyzed included patient age, sex, underlying
diagnosis, donor type, HCT conditioning regimen, maximum acute GVHD overall grade and
organ involvement prior to day +100, use of oral and intravenous supplemental Mg including
cumulative requirements over 2 weeks, and concurrent immunosuppressive drug therapy.
Results: 54 patients had acute GVHD (grade I-II n= 34, grade III-IV n =20) and 53 patients did
not have acute GVHD prior to the day +100 serum sample collection. The median serum EGF
in this cohort was 101 pg/mL. Levels of EGF at day +100 showed no relationship with age,
underlying diagnosis, donor type, or conditioning intensity. EGF was significantly lower in
patients who had acute GVHD grade III-IV prior to day +100 and nearly 3-fold lower in those
with upper GI GVHD involvement versus no upper GI GVHD involvement (median 43 pg/mL
versus 119 pg/ml, p=0.007). Serum EGF negatively correlated with CSA level (Spearman’s rho
= -0.34, p=0.007), but not with tacrolimus levels, sirolimus levels, prednisone dose, or serum
creatinine. Serum EGF levels > 100 pg/mL at day +100 were associated with improved 2-year
survival (RR 0.46, 95% CI 0.22 – 0.94, p=0.03).
Conclusions: Patients with prior grade III-IV acute GVHD, and in particular upper GI GVHD,
had lower EGF levels at day +100. This may be due in part to decreased EGF production from
Brunner’s glands in the duodenum versus excess EGF losses. The inverse relationship
between CSA and EGF may be direct or may represent patients with more severe acute GVHD
being maintained with higher drug levels. While studies in renal transplantation identified a
connection between urinary EGF, Mg wasting, and diminished renal function, circulating levels
of EGF in allogeneic HCT did not show a similar correlation. Differences in EGF post-allogeneic
HCT are predominantly due to grade III-IV GVHD status, although a potential contribution from
CSA effect on the kidney cannot be ruled out. The role of circulating EGF in the long-term
outcomes of allogeneic HCT should be further studied.