NephrologyTier 2Disease (DEADMAN)

Chronic renal failure - anaemia

Description

Normochromic, normocytic, hypoproliferative anaemia with an inappropriately low reticulocyte count
Multifactorial - EPO deficiency is only part of it
Appears from CKD G3a, near-universal by G5 (~51% at eGFR <30)
*Anaemia of CKD is a diagnosis of exclusion* - always exclude iron, B12/folate deficiency, blood loss, haemolysis and myeloma first

Prevalence rises with stage: ~10% at G3a, ~50% at G4-5, >90% on dialysis
More severe at any eGFR in diabetic nephropathy
Aboriginal and Torres Strait Islander patients: higher burden, earlier onset (paralleling earlier CKD)

Why the anaemia

1. Relative erythropoietin deficiency - peritubular interstitial fibroblasts fail
- EPO is not absent, it is inappropriately low for the haemoglobin
2. Functional iron deficiency - inflammation -> IL-6 -> inc hepcidin -> ferroportin internalised
- -> iron trapped in macrophages and enterocytes
- -> low serum iron and low TSAT despite normal or high ferritin
- Hepcidin is renally cleared, so it accumulates in CKD - a double hit
3. Absolute iron deficiency - GI losses, blood loss in the dialysis circuit (1-3 g iron/yr on HD), frequent blood tests, poor absorption
4. Shortened red cell survival - uraemic environment, mechanical trauma in the circuit
5. Uraemic inhibitors of erythropoiesis; secondary hyperparathyroidism -> marrow fibrosis
6. Nutritional - B12, folate; aluminium (historical)

This is why iron must be corrected before, not after, giving an ESA - a hyporesponsive patient is usually iron deficient

Define and investigate

Anaemia: Hb <130 g/L (M), <120 g/L (F)
Investigate every CKD patient with anaemia - do not assume it is the CKD
- FBE, reticulocyte count, iron studies (ferritin + TSAT), B12 and folate
- SPEP + serum free light chains (myeloma mimics CKD anaemia exactly)
- Blood film, LDH, haptoglobin, DAT if haemolysis suspected
- Faecal occult blood / GI evaluation if iron deficient
- CRP, PTH, TSH

Interpreting iron studies in CKD

Ferritin is an acute phase reactant and is falsely reassuring
TSAT reflects supply to the marrow - it is the more useful number
Iron deficiency in CKD: ferritin <100 microgram/L, OR ferritin 100-300 with TSAT <20%

Monitoring frequency

1. Iron first - always

Correct iron before starting an ESA
- Pre-ESA targets: ferritin >100 microgram/L and TSAT >20%
- On ESA: ferritin 200-500 microgram/L and TSAT 20-30%
IV iron is preferred in dialysis patients (poor oral absorption from high hepcidin, plus ongoing circuit losses)
- Ferric carboxymaltose or iron polymaltose/sucrose; watch for hypophosphataemia with ferric carboxymaltose
Oral iron reasonable in non-dialysis CKD; alternate-day dosing improves absorption
*Proactive high-dose IV iron in HD reduces ESA dose and cardiovascular events (PIVOTAL)* without excess infection
Do not check ferritin within 4-8 weeks of IV iron - it is falsely elevated

2. Erythropoiesis-stimulating agents

Epoetin alfa/beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta (monthly)
Indication: symptomatic anaemia after iron repletion, usually Hb <100 g/L
Target Hb 100-115 g/L
- Some Australian units accept up to 120; do not exceed 130 and do not target normalisation
- *Higher targets increase stroke, thrombosis, vascular access thrombosis, and mortality* - CHOIR, CREATE, TREAT
- TREAT (darbepoetin in diabetic CKD): almost doubled stroke risk, and worse outcomes with a history of malignancy
ESAs improve symptoms, exercise tolerance and quality of life, and reduce transfusion. They do NOT improve mortality
Adjust dose by no more than ~25% every 4 weeks; chasing the Hb causes cycling

ESA hyporesponsiveness - the checklist

Iron deficiency (much the commonest)
Infection or inflammation, underdialysis, severe hyperparathyroidism, aluminium toxicity
B12/folate deficiency, haemolysis, blood loss, malignancy, myeloma, ACEi/ARB (mild)
*Pure red cell aplasia from anti-EPO antibodies - rare; abrupt Hb fall, reticulocytes near zero. Stop all ESAs permanently*

3. HIF prolyl-hydroxylase inhibitors

Daprodustat, roxadustat, vadadustat - oral; stabilise HIF -> endogenous EPO production and improved iron mobilisation (dec hepcidin)
Non-inferior to ESAs for Hb; thrombotic and cardiovascular safety signals in some trials; limited Australian availability

4. Transfusion

Avoid unless necessary - allosensitisation compromises future transplantation, plus iron loading and volume overload
Reserve for symptomatic acute anaemia, active bleeding, or ESA failure
If transfusion is unavoidable in a transplant candidate, discuss with the transplant unit

5. The rest

Adequate dialysis, control secondary hyperparathyroidism, minimise blood draws and circuit losses
Treat the GI source of any iron deficiency

CKD-MBD and secondary hyperparathyroidism - marrow fibrosis worsens the anaemia
LVH and heart failure - anaemia contributes; correcting it does not reverse LVH (CREATE)
Reduced quality of life, exercise tolerance, cognition; fatigue
Iron deficiency, GI angiodysplasia, occult malignancy
Myeloma and MGRS - the mimic to exclude
Malnutrition-inflammation complex; hepcidin-driven functional iron deficiency
Aluminium toxicity (historical), lead
Allosensitisation from transfusion - reduces transplant access

Progressive as eGFR falls; partially reversible after transplantation - EPO production resumes within weeks
- Post-transplant anaemia persists in ~20-40% from graft dysfunction, mycophenolate, valganciclovir, trimethoprim, parvovirus B19
Post-transplant erythrocytosis can occur instead (~10-20%) - treated with ACEi/ARB or venesection
Untreated anaemia is associated with more hospitalisation, worse quality of life, LVH progression and higher mortality
- *But correcting it to normal levels does not improve those outcomes and causes harm* - the central lesson of the ESA trials
Monitor Hb monthly on dialysis, iron studies 3-monthly; reassess for a new cause whenever an established patient becomes hyporesponsive

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