Opposite effects of urea on hemoglobin-oxygen affinity in anemia of chronic renal failure

Abstract

We studied the action of urea on the spin-spin relaxation rate of 2,3-diphosphoglycerate (2,3-DPG) phosphorus atoms in normal and uremic erythrocytes. At concentrations from 10 to 60 mM, urea increased the relaxation rates of 2,3-DPG P-3 phosphorus atoms. This evidenced a stronger binding of 2,3-DPG to hemoglobin (Hb), suggesting that the deoxyform of Hb was stabilized. This hypothesis was confirmed by measurements of the association constant of oxygen to hemoglobin (K) in normal erythrocytes in presence of urea concentrations in the range of those observed in uremic patients (30 mM). Indeed, the observed decrease in K suggests that the T structure of hemoglobin is stabilized. By contrast, with higher urea concentrations (120 mM), measurements of P50 showed an increase in the hemoglobin affinity for oxygen (decrease in P50). Moreover, the relaxation rates of 2,3-DPG P-3 phosphorus atoms were not modified, which is consistent with the simultaneous increase of K. This may be attributed to the formation of carbamylated hemoglobin in presence of urea. These results suggest two opposite effects of urea on Hb-O2 affinity: the first reinforces 2,3-DPG-Hb binding and leads to a decrease in O2 affinity; the second, mediated by carbamylation of Hb, hinders the binding of 2,3-DPG and increases the O2 affinity. These findings are consistent with the fact that, despite the presence of carbamylated hemoglobin, uremic patients do not present increased Hb-O2 affinity.

Sex, haemoglobin and kidney disease: new perspectives

“…Of note, uraemia in CKD may also impact on 2,3-DPG levels and oxygen affinity in a similar manner. The relationship between sex hormones, EPO production and effect, uraemia and haematopoiesis are complex and not well-studied [24]. Given the ability of the human body to adapt to lower Hgb chronically, there may be some common elements regarding CKD and female gender with respect to the adaptation to low Hgb.…”

Towards Erythropoietin Equations That Estimate Oxygen Delivery rather than Static Hemoglobin Targets

“…Urea has been investigated as a factor in that phenomenon and while urea does appear to modify the binding of the available 2,3DPG [30], the effect varied and only became significant at levels higher than what is usually seen in chronic dialysis patients (120 m M or 336 mg/dl).…”

Carbamylated Proteins and Peptides in Health and in Uremia

“…This is illustrated by the fact that the binding of oxygen in carbamylated hemoglobin is such that O 2 is not given up by the red cell as readily, so that tissue pO 2 falls. However, this is not significant in vivo, because the effect of uremia on DPG cancels out the effect of carbamylated hemoglobin on oxygen retention in the red cell [15]. …”

“…Carbamylated hemoglobin gives up its oxygen with difficulty when compared to noncarbamylated hemoglobin, and this has been the subject of some study with regard to uremic patients [15]. In sickle cell disease, in addition carbamylated hemoglobin reduces the chance of sickle cell hemoglobin precipitating in the sickle cell patient, particularly in anoxic conditions, so that its presence is a benefit to the patient threatened by frequent sickle cell crises [9, 13, 14, 16].…”

“…Although carbamylated hemoglobin gives up its oxygen with greater difficulty than the non-carbamylated hemoglobin, and tissue PO 2 falls in inverse proportion to the concentration of carbamylated hemoglobin, this is offset in uremic patients by the effect of carbamylated hemoglobin on 2,3 diphosphoglycerate [15]. …”