anemia in ckd patients anemia in ckd treatment guidelines anemia in ckd pathophysiology anemia and ckd progression how to treat anemia in ckd patients

 

ANEMIA IN NON-DX CKD

 

Abbreviations:

o   BTx: blood transfusions

o   CBC: complete blood count.

o   CI: contraindications.

o   CKD: chronic kidney disease.

o   CVS: cardiovascular

o   Depo: darbepoetin

o   DX: dialysis

o   eGFR: the glomerular filtration rate.

o   EPO: Epoetin, erythropoietin

o   ESAs: erythropoiesis-stimulating agents.

o   ESKD: end-stage kidney disease.

o   FDA: US Food and Drug Administration.

o   HB: haemoglobin.

o   HDX: haemodialysis

o   HF: heart failure

o   HIF PHIs: Hypoxia-inducible factor prolyl hydroxylase inhibitors.

o   KDIGO: Global Outcomes guidelines.

o   MI: myocardial infarction.

o   MR: mortality rate.

o   NHANES: National Health and Nutrition Examination Survey.

o   NICE: National Institute for Health and Care Excellence

o   PD: peritoneal dialysis

o   RBCs: red blood cell.

o   Retics: reticulocyte count

o   SC: subcutaneous

o   Sms: symptoms.

o   TIBC: total iron-binding capacity.

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

o   TSAT: transferrin saturation.

o   WHO: The World Health Organization.

Anemia is commonly observed among CKD ptns. Anemia is underlying many of the Sms reflecting the decline in renal function and commonly complicated by a higher MR & hospitalization.

 

Definition: Anemia was defined by WHO as:

o   HB <13.0 g/dL for (adult men & post-menopausal ladies) &

o   HB <12.0 g/dL for pre-menopausal ladies.

The WHO definition does not recognize the goals of therapy among CKD ptns. So, even despite properly treated, many CKD ptns will be anaemic as per this definition. Anemia therapy includes ESAs; several reports have now documented that targeting a normal HB via ESAs therapy potentiates the risk of an adverse outcome.  

Prevalence: Prevalence of anemia in non-DX CKD ptns is increasing with the eGFR decline. Analysis of 15,000 ptns in the NHANES, prevalence of anemia HB<12 g/dL in males & <11 g/dL in women) was increasing as follows:

o   1 % with eGFR of 60 mL/min/1.73 m2 .. to

o   9 % with eGFR of 30 mL/min/1.73 m2 & .. to

o   33-67 % at an eGFR of 15 mL/min/1.73 m².

 

Screening: Primarily, all ptns should be assessed for anemia, once they are 1^st evaluated for CKD with a CBC. Anaemic ptns should be assessed for its aetiology. The latter could be related to CKD, however, there is considerable risk for several causes of anemia seen in general population. Primary evaluation of anemia is generally similar in CKD ptns to general population including CBC, RBCs indices, Retics, s. iron, TIBC, % TSAT, s. ferritin, s. folate & B₁₂ level, as well as occult blood in stool.  

Monitoring: After primary assessment, continuous routine monitoring of CKD ptns for anemia is recommended and, if present, iron deficits should be evaluated. Monitoring of anemia can be accomplished via HB levelling. Frequency of monitoring varied according to the presence of anemia on the initial assessment, trends in HB levels, whether ptns treated with ESAs, and the relation to the degree of CKD severity. The following approach is greatly considering the KDIGO guidelines:

Ptns without anemia:  For CKD ptns without anemia, monitor the following:

o   eGFR: ≥45 mL/min/1.73 m²: monitor these ptns for evolution of anemia on annual bases. Assess for the cause of anemia if diagnosed.  

o   eGFR <45 mL/min/1.73 m²: screening at least twice yearly for anemia development. Evaluation for anemia aetiology as above if anemia have been diagnosed.  

Moreover, in all CKD ptns, checking HB is advised if clinically indicated (e.g., after major surgery, hospitalized ptns, or bleeding events).

Ptns with anemia not on an ESA: For anaemic CKD ptns on initial evaluation but did not started ESAs yet, monitor HB levels every 3-6 mo according to the eGFR, HB levels, and previous alterations in HB level:

o   eGFR ≥45 mL/min/1.73 m₂: Ptns with eGFR 45-60 mL/min/1.73 m2 + mild anemia > monitor every 6 mo. With progressive decline in HB or with moderate/severe anemia (i.e., HB <10 g/dL) monitor every 3 mo.

o   eGFR <45 mL/min/1.73 m₂: Ptns usually monitored every 3 mo, may be more frequently.  

These ptns usually screened for iron deficiency on 3 monthly bases. Ptns having marginal iron levels, or with lowered s. ferritin or TSAT levels at initial evaluation, should be assessed every 2-3 mo. The 2012 KDIGO & NICE guidelines suggest the assessment of iron status at least every 3 mo. during ESA therapy and more frequently with higher ESA dosing or monitoring the impact of I.V. iron or if there’s recent blood losses or with other urgent events (e.g., hospitalization) where iron stores could be depleted. No data supporting monitoring with this rate of frequency, and some physicians monitor CKD ptns on less frequent bases.

Ptns on iron therapy: Whether commencing an ESA or not, iron is typically assessed every 3 mo with oral iron therapy. Ptns receiving IV iron should check their iron stores after having their course completed. No data available supporting monitoring this rate of frequency, and some physicians monitor CKD ptns on less frequent bases.

Therapy of anemia: Primarily, therapeutic tools of anaemic ptns with CKD may include iron, ESAs, and, rarely, RBCs Tx according to severity of anemia and the associated iron deficits:

[1] Iron: Anaemic ptns with iron deficits should be treated with iron supplements before commencing ESAs therapy.  

[2] Erythropoiesis-stimulating agents:  ESAs should be provided to most CKD ptns with HB level <10 g/dL, providing: TSAT of >20 % & s. ferritin >200 ng/mL. Exceptions of these rules may include:

1)    Active cancer (particularly with expected cure) or with recent history of malignancy. Avoid ESAs to avoid triggering the risk of progressed/recurrence of cancer.

2)    Ptns with stroke: Avoid ESAs to avoid augmented risk for untoward effects (e.g., recurrence of stroke) due to ESAs therapy.

3)    Specific co-morbidities (e.g., being bedridden or with extremely limited capacity, dementia, etc) making them unlikely to get similar benefit from ESAs to active ptn & symptomatizing from anemia.

Avoid ESAs in these situations unless better HB is warranted for certain clinical goal (e.g., minimizing hospitalized timing for BTx, optimized therapy for HF) that is unachievable via iron supplements only. Ptns with TSAT ≤20 % & ferritin ≤500 ng/mL, provide iron before commencing an ESA, as they may respond to iron alone with a rising HB. If they respond to iron supplements adequately, then no need to add ESAs. The possibility of symptomatic anemia in younger ptns having CKD with little co-morbidities, whilst Sms of anemia may be observed at higher HB > we can start ESAs at HB level of 10 g/dL or even higher after explaining the potential risks/benefits in each case.

ESAs have greatly limiting the requirements for RBCs Tx (with risk limiting of Tx-related sequalae). The exact HB level at which to commence ESAs still uncertain, and the safety of these agents, ESAs, in severe anemia has not been accurately assessed in large RCT. The 2012 KDIGO that the potential benefits of reducing BTx and anemia-related Sms should be evaluated against their harmful impacts in individual bases (e.g., risk of stroke, vascular access thrombosis, & HT).

Route: for CKD ptns, an ESA, whether EPO or Depo, should be provided SC. Available reports have shown that SC dose of EPO needed to get the target HB is about 30 % less than that with IV route. IV & SC Depo are similarly effective. For non-DX CKD ptns, SC route is more convenient to be self-administrated. Avoiding IV route provide better veins preservation for future A/V access creation.

Dosages:  Starting dose for EPO = 50-100 units/kg/wk. However, lower dosage may be accepted with pre-therapy HB level approaching 10 g/dL. Practically wise, ptns mostly dosed by unit dosage (e.g., a vial), rather than strictly based unit/kg. So, we commence therapy with 4000- or 10,000-units SC once wkly or 10,000-20,000 units SC every other wk.

Weekly or less frequently dosing plans have been observed to be safe and efficacious, despite the lack of long-term trials. Meta-analysis of 7 RCT reported no difference in HB levels if EPO was provided every 2-4 wks as compared to more frequently given dose intervals. Depo is typically commenced with 60-200 mcg SC every 2-4 wks. If required, subsequent dose adjustment could be made in intervals and/or doses. Lowest effective ESA dose should be provided. Of note, higher ESA dosing (mainly EPO of > 10,000 units/wk or equivalent Depo dosing) could be complicated by a higher MR & CVS events regardless of HB level.  

Methoxy polyethylene glycol-epoetin beta: has also been approved for CKD ptns with an initially started dose of 0.6 mcg/kg by IV or SC routes with bi-weekly and subsequent monthly dosing. EPO alfa-epbx is the 1^st EPO "biosimilar" agent approved in the US; as with other EPO(s), the associated packages recommend thrice/week dosing that is NOT practical and its place in the therapy of anaemic CKD ptns not on DX remains to be recognized.  

Target HB value:  non-DX CKD ptns managed with ESAs can be mostly maintaining HB level between 10-11.5 g/dL via the lowest achievable ESA dosing. EPO therapy should be individualized with better quality of life at the level of HB ≥11.5 g/dL with ptn prepared to accommodate the possible risk(s) with higher HB target. However, DO NOT target the HB level of >13 g/dL.

The optimum target HB level for CKD ptns still uncertain. The FDA have warned on ESAs therapy: for non-DX CKD ptns, ESA therapy can be considered only if the HB level is <10 g/dL and the ESA dosing should be decreased or interrupted if the HB level was exceeding 10 g/dL. Among DX as well as non-DX CKD ptns, many reports have shown that HB levels exceeding ≥13 g/dL can be complicated with an increasing risk of adverse events. A variety of RCT comparing HB target levels for pre-DX ptns with CKD with the best data emerged from TREAT trial: 4038 ptns with type 2 DM & CKD (eGFR: 20-60 mL/min/1.73 m²) were randomly receiving Depo to get a target HB of 13 g/dL or to placebo, with Depo provided if the HB declined to <9 g/dL. Trial endpoints were the composite outcome of death or a CVS events (non-fatal MI, HF, stroke, and hospitalization for IHD) and death or ESKD. The mean targeted HB was 12.5 g/dL & 10.6 g/dL in the Depo & placebo g.s, resp. Following after 29 mo, both g.s showed the same risk of death, CVS events, death or ESKD. There was also rising risk of fatal/non-fatal stroke with Depo, while RBCs Tx were significantly more common in the placebo g. Fatigue was less commonly seen with Depo. A rising risk of death related to malignancy in the Depo g., mainly in ptns with previous history of malignancy. In the TREAT trial and other trials that compare lower & higher HB levels in CKD ptns, the ptns were mostly diabetics, with prior CVS disease that contributes to a higher rate of adverse events. These data are supporting the recommended practice of HB target level up to 11 g/dL in CKD ptns.  

Adverse effects:  observed with EPO therapy in pre-DX ptns are simulating those seen with HDX ptns. A crucial issue in this cohort is the higher risk of adverse CVS sequalae with higher degree of HB levels. However, EPO-induced HT is less observed in pre-DX ptns.

Investigational agents: 

ORAL ESAs

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHIs): The advent of a novel category of oral ESAs have been assessed as a new therapeutic agent for anemia in non-DX CKD ptns. Unlike other ESAs agents that are replacing to certain degree the endogenous EPO, HIF PHIs trigger renal and hepatic transcription of the EPO gene that results in a higher level of endogenous EPO. Efficacy of HIF PHIs was evaluated in a phase 3 trial of > 2700 non-DX CKD ptns & anemia (mean HB 9 g/dL) and were randomly receiving the HIF PHI, Roxadustat, or placebo 3 times weekly, to target an HB of at least 11 g/dL. Compared to placebo, ptns on roxadustat were more prone achieving the target HB (77 vs 9 %) and achieving an HB level between 10-12 g/dL for a higher % of time (82 vs 28 %).

 

See also, Anemia in HDX patients.