ESAs are widely used agents to manage CKD-related anemia. ESA resistance, or , is a definition used to recognize ptns not achieving their target

 

EPO Hyporesponsiveness

 

Abbreviations:

o   A/V: arteriovenous.

o   ACEi: angiotensin-converting enzyme inhibitors

o   AMI: myocardial infarction.

o   ARBs: angiotensin II receptor antagonists.

o   CHOIR: Outcomes in Renal Insufficiency trial

o   CKD: chronic kidney disease.

o   CVS MR: cardiovascular mortality.

o   Depoa: Darbepoietin a.

o   DX: dialysis.

o   Dzt: dialysate.

o   EPO: erythropoietin.

o   ESAs: erythropoiesis-stimulating agents.

o   ESKD: end-stage kidney disease.

o   HB: Hemoglobin.

o   Hct: haematocrit.

o   HDX: haemodialysis.

o   HIV: human immunodeficiency virus infection

o   Hrsp hyporesponsiveness

o   KDIGO: Kidney Disease: Improving Global Outcomes.

o   KDOQI: The Kidney Disease Outcomes Quality Initiative.

o   MM: multiple myeloma.

o   OFC: osteitis fibrosis cystica

o   PD: peritoneal dialysis.

o   PRCA: Pure red cell aplasia.

o   TREAT: Trial to Reduce Cardiovascular Events with Aranesp Therapy study

o   URR: urea reduction ratio.

 

 

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 450 units/kg/wk IV EPO or 300 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: 45,000 units/wk of epoetin corresponds roughly to 100 mcg/wk of Depoa. Other criteria given by European Best Practice Guidelines & KDIGO may include the following:

1)    Failure to attain or maintain desired HB with 300 units/kg/wk of EPO (= 20,000 units/wk) & 1.5 mcg/kg/wk of Depoa (about 100 mcg/wk).

2)    Lack of rise in HB after 1^st 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 <10 g/dL with EPO >7700 units/dose, in 12.5 % 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.

 

Aetiology: the 2 most common factors: Iron deficits & infection and/or inflammation

1)    Iron deficiency:  commonly seen cause of EPO resistance. It could be “absolute” (e.g., external blood loss) or “functional” (related to EPO or anemia of CKD). EPO resistance assessment should include both categories of iron deficiency. 

2)    Infection/inflammation: Chronic inflammatory states are commonly seen in HDX and are crucial causes of EPO resistance. DX catheter is a common cause of chronic inflammation. Other causes may include skin/wound infection; failed KTx; hidden infected old, non-functioning A/V graft; and HIV infection.  

3)    Inadequate DX: Old study: 20 stable HDX ptns moderately under-dialyzed (mean URR: 60.7 %), augmenting DX dose has led to raised Hct with the same dose of EPO. Difference in DX membrane can impact EPO response as expanding urea clearance can be achieved by providing larger dialyzer with a better membrane.

4)    Increasing DX dose is not likely to increase EPO response in ptns with fairly adequate DX (i.e., Kt/V ≥1.0-1.2). Only changing in DX modality may impact EPO response. Providing ultrapure Dzt can improve HB & decreasing EPO needs that can be explained by a limited inflammatory process (Ultrapure Dzt = properly maximized micro-biological purification).

5)    Other: causes may include severe hyperparathyroidism with OFC, bone aluminium intoxication (rare), cancer, bone marrow diseases e.g., myelodysplastic syndrome, MM, and hemoglobinopathies, e.g., sickle cell disease, B₁₂ & folate deficits.

6)    PRCA, can induce complete EPO resistance, seen with SC EPO, no longer seen. ACEi/ARBs may induce relative EPO resistance (genetic background assumed).  

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.

OUTCOME

Mortality: ESA resistance can be associated with higher MR. Observational study: HDX ptns (US), ptns with HB <9.5 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 (>20,000 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 1^st 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 1^st 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 > 30,000 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 2002 & 2006. Ptns were categorized as poor, intermediate, & good responders according to the response to the 1^st 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 1^st visit after given EPO and at baseline, resp; time refers to the duration between visits; and EPO dose is the 1^st weekly provided dose. ESA responsiveness was expressed as g/dL/mo., 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.