Timing and Determinants of Erythropoietin Deficiency in Chronic Kidney Disease

Abstract

on behalf of the NephroTest Study Group Summary Background and objectives Anemia in patients with CKD is highly related to impaired erythropoietin (EPO) response, the timing and determinants of which remain unknown.Design, setting, participants, & measurements This study measured EPO levels and studied their relation to GFR measured by 51Cr-EDTA renal clearance (mGFR) in 336 all-stage CKD patients not receiving any erythropoiesis-stimulating agent.Results In patients with anemia defined by World Health Organization criteria (hemoglobin [Hb] ,13 g/dl in men and 12 g/dl in women), EPO response to Hb level varied by mGFR level. EPO and Hb levels were negatively correlated (r=20.22, P=0.04) when mGFR was .30 ml/min per 1.73 m 2 , whereas they were not correlated when mGFR was ,30 (r=0.09, P=0.3; P for interaction=0.01). In patients with anemia, the ratio of observed EPO to the level predicted by the equation for their Hb level decreased from 0.72 (interquartile range, 0.57-0.95) for mGFR $60 ml/min per 1.73 m 2 to 0.36 (interquartile range, 0.16-0.69) for mGFR ,15. Obesity, diabetes with nephropathy other than diabetic glomerulopathy, absolute iron deficiency, and high C-reactive protein concentrations were associated with increased EPO levels, independent of Hb and mGFR.Conclusions Anemia in CKD is marked by an early relative EPO deficiency, but several factors besides Hb may persistently stimulate EPO synthesis. Although EPO deficiency is likely the main determinant of anemia in patients with advanced CKD, the presence of anemia in those with mGFR .30 ml/min per 1.73 m 2 calls for other explanatory factors.

Physiology of the Renal Interstitium

“…Decreased Epo levels in patients with CKD are obvious only when anemia is present but cannot be adequately elevated when hematocrit drops, suggesting that part of the Epo production capacity (i.e., through loss of Epo-producing cells) is irreversibly lost (53)(54)(55). In general, decreased Epo levels (typically assessed by ELISA in serum) correlate with severity of decreased excretory kidney function.…”

“…While Epo levels are better preserved in glomerular diseases than in interstitial diseases, suggesting that impaired Epo production is a direct consequence of interstitial disease (56), there is one exception as polycystic kidney disease is often associated with increased Epo production and polycythemia, due to aberrant HIF1a accumulation around cysts due to local hypoxia (57). Nevertheless, circulating Epo levels have been suggested as diagnostic marker of the extent of tubulointerstitial involvement in diabetic nephropathy (58), but due to superimposed regulating factors (including anemia, systemic inflammation, and reduced iron availability), utility of Epo levels as valid diagnostic marker for interstitial fibrosis could not be validated (53). Impaired Epo production as cause of anemia is not limited to CKD but is also increasingly being recognized as a cause of anemia in patients with diabetes mellitus.…”

Increased Synthesis of Liver Erythropoietin with CKD

“…3 Surprisingly, in a large cohort of patients with CKD and anemia, circulating Epo levels were only moderately suppressed at early stages of disease compared with expected values. 4 In addition to kidney fibroblasts, liver cells and astrocytes may also synthesize Epo and thereby, contribute to circulating Epo levels. 5,6 This contribution may increase when the kidneys are unable to secrete sufficient Epo to maintain erythropoiesis, and an experimental report suggested that liver Epo synthesis is activated in mice suffering from chronic GN.…”

“…8 Several patients with CKD displayed higher Epo levels than expected for their [Hb], suggesting that other factors than Epo deficiency may contribute to anemia of CKD. 4 Glycosylation changes may influence both Epo binding to its receptor and its half-life. 10,11 A higher PMI suggests less glycosylated Epo.…”

“…4 This suggests that the liver may reactivate Epo synthesis with CKD but without compensating fully for deficient kidney Epo when it is beyond a given threshold. This may be related to the maximal capacity of the liver to produce Epo in adults, a shorter half-life of the produced Epo, or altered hypoxia sensing in liver as suggested by previous observations.…”