ESAs are widely used agents to manage CKD-related anemia. ESA resistance, or , is a definition used to recognize ptns not achieving their target
ESAs are widely used agents to manage CKD-related anemia. ESA resistance, or (Hrsp), is a definition used to recognize ptns not achieving their target HB levels despite the administration of higher doses of ESAs or requiring persistently higher ESA doses to preserve their HB levels. ESA resistance is generally relative rather than complete. ESA resistance is also referred to as Hrsp. The criteria of ESAs resistance still not well determined. KDOQI criteria include failure to achieve/maintain a target HB with a maximum dose of units/kg/wk IV EPO or units/kg/wk SC EPO. Criteria of Depoa & methoxy polyethylene glycol-epoetin beta, not well defined yet, as the exact dose conversion is not well-determined. Package inserts include: 100 mcg/wk of units/wk of epoetin corresponds roughly to Depoa. Other criteria given by European Best Practice Guidelines & KDIGO may include the following:
1) Failure to attain or maintain desired HB with units/kg/wk of EPO (= 1.5 mcg/kg/wk of units/wk) & Depoa (about mcg/wk).
2) Lack of rise in HB after 1st mo of proper weight-based dosing and/or requiring 2 rises in EPO dosage up to 50 % above the original dose in a stable ptn. Also, EPO-resistant = higher dose requirement than that given to 90 % of other ptns.
EPIDEMIOLOGY: retrospective report: ESA Hrsp = 2 consecutive HB levels < g/dL with EPO > units/dose, in % of HDX ptns. ESA resistance in PD has not been well identified but much less commonly seen than HDX ptns as PD ptns usually show higher HB levels, requiring less ESA dosages.
: the 2 most common factors: &
SUGGESTED APPROACH: It is recommended to assess EPO-resistant cases thoroughly as EPO resistance is commonly associated with higher MR:
o Exclude absolute & functional iron deficiency and manage accordingly.
o Assure adequate DX, modify DX prescription to achieve appropriate Kt/V.
o Thorough physical testing to exclude hidden infection, esp. thrombosed A/V graft.
o Observational studies: old graft excision leas to better EPO response. Also does HDX catheter removal with A/V fistula placing improve EPO response.
o Severe hyperparathyroidism: optimize PTH levels either medical or surgical. Hyperparathyroidism control will improve EPO response.
With persistent EPO resistance, EPO can be held or continued with low doses to limit transfusion requirement that can be provided to limit anemia-associated Sms. New agents of ESA in DX ptns resistant to EPO needs more evaluations. Non-iron factors have been assessed as EPO adjuvants e.g., L-carnitine, ascorbic acid, pentoxifylline.
Mortality: ESA resistance can be associated with higher MR. Observational study: HDX ptns (US), ptns with HB < g/dL + higher ESA dose increments along 11-mo duration showed higher MR risk. Another study: data from the “Normal Hct Cardiac Trial”, a higher EPO-responsiveness measure (= ratio of weekly Hct alteration per ESA dose rise) a lowered MR has been observed. The impact of EPO resistance on MR with PD is not well assessed. Korean study: EPO resistance was associated with increasing MR with HDX but not with PD ptns. However, other reports comparing HDX with PD have not assured this link.
The higher MR seen with EPO resistance could be attributed to the underlying factor of EPO resistance. However, some reports assumed that the higher MR could be attributed to the higher EPO doses provided to these ptns. Unadjusted analysis of the Corrected HB in the CHOIR study, the higher risk of the primary endpoint (death, AMI, HF, or stroke) at 4 mo. was related to both the inability to achieve targets and the high doses of EPO administration (> units/wk).
On the other hand, adjusted analysis: only higher doses of EPO agents resulted in an independent higher risk of the primary endpoints. This elevated risk was seen in both high- & low-target HB groups, especially among ptns unable to achieve target HB. Whilst most reports were focusing on Hrsp during ongoing chronic EPO therapy, the relation between primary HB response to Depoa was evaluated in the TREAT trial. Ptns not responding to the 1st 2 doses of Depoa had higher rate of CVS endpoint & death as compared to those with a better initial therapeutic response.
Meta-regression analysis: 31 trials (12,956 ptns): all-cause MR was associated with elevated 1st 3-mo. & total-study-duration mean EPO doses independent of HB level. A similar trending for CVS MR that was statistically insignificant. The elevated total-study-duration mean ESA dosing was associated with a higher rate of HT, stroke, and thrombotic sequelae, including A/V vascular access-related thrombotic sequelae. However, the associated increased ESA dosing to MR has not been observed in all reports. Observational report: older HDX ptns, EPO dosing > units/wk were NOT associated with any harm or benefit.
Progression of CKD: EPO resistance could be complicated by more rapid progress to ESKD. Study: 194 consecutive CKD ptns started EPO between . Ptns were categorized as poor, intermediate, & good responders according to the response to the 1st provided EPO dose. Responsiveness was assessed according to the formula: (Hb1-Hb0)/time/EPO dose where Hb1 and Hb0 correspond to HB values at the 1st visit after given EPO and at baseline, resp; time refers to the duration between visits; and EPO dose is the 1st weekly provided dose. ESA responsiveness was expressed as ., standardized to 10 mcg/wk. During a medium following-up for 3 y., poor responsiveness was complicated by an increased risk of ESKD. The underlying mechanism still uncertain.