PhysiologyTier 1Medical Sciences concept

Erythropoietin production - stimulus and site

Core concept

Site: renal peritubular interstitial fibroblasts of the deep cortex and outer medulla (~90%)
- ~10% hepatic (the fetal site, and the reason anephric patients are not completely EPO-deficient)
- Not the tubular cells, not the glomerulus - the interstitial fibroblast**
Stimulus: tissue hypoxia, sensed through the HIF pathway
- Normoxia: prolyl hydroxylase (PHD) enzymes, using O2, iron and 2-oxoglutarate, hydroxylate HIF-2alpha
  - -> recognised by VHL E3 ubiquitin ligase -> proteasomal degradation
- Hypoxia: PHD cannot work without O2 -> HIF-2alpha stabilised -> dimerises with HIF-1beta -> binds the hypoxia response element
  - -> inc EPO transcription (plus VEGF, transferrin, transferrin receptor, and suppressed hepcidin)
EPO acts on the erythroid burst/colony-forming units in marrow -> JAK2/STAT5 -> prevents apoptosis of erythroid progenitors
- Response takes ~5 days to a reticulocytosis, weeks for a haemoglobin rise

The kidney is an ideal oxygen sensor because renal O2 consumption is coupled to GFR: inc GFR -> inc Na reabsorption -> inc O2 use, so cortical PO2 tracks the oxygen carrying capacity, not the blood flow
Where the pathway fails

Problem	Effect
CKD	dec EPO from loss of interstitial fibroblasts (they transdifferentiate to myofibroblasts) -> normocytic normochromic anaemia, low reticulocytes
VHL disease	Constitutive HIF -> erythrocytosis; haemangioblastoma, RCC, phaeochromocytoma
Chuvash polycythaemia	VHL germline mutation -> HIF stabilised -> congenital secondary erythrocytosis
EPOR mutation	Primary familial polycythaemia - low EPO with a high haematocrit
JAK2 V617F	Polycythaemia vera - EPO-independent signalling -> SUPPRESSED EPO
PHD2 (EGLN1), HIF2A gain of function	Congenital erythrocytosis

The EPO level separates the polycythaemias
- LOW/suppressed EPO with a high Hct -> polycythaemia vera (confirm JAK2 V617F, then exon 12)
- HIGH or inappropriately normal EPO -> secondary
  - Hypoxic: chronic lung disease, OSA, right-to-left shunt, high altitude, smoking (carboxyhaemoglobin), high-affinity haemoglobin
  - Non-hypoxic (autonomous EPO secretion): renal cell carcinoma, hepatocellular carcinoma, cerebellar haemangioblastoma, uterine leiomyoma, phaeochromocytoma, renal cysts, post-transplant erythrocytosis
  - Exogenous: testosterone, anabolic steroids, EPO doping, SGLT2 inhibitors (modest rise)
Anaemia of CKD is not only EPO deficiency - also hepcidin-mediated functional iron deficiency, uraemic inhibitors, shortened RBC survival, blood loss with dialysis

Correct iron before, and during, ESA therapy - the commonest cause of ESA hyporesponsiveness is iron deficiency; then consider infection/inflammation, hyperparathyroidism, B12/folate, blood loss, malignancy, PRCA
- Investigate hyporesponsiveness if the dose has doubled without effect
Do not normalise the haemoglobin - target 100-115 g/L (do not exceed ~130)
- Trials targeting normal Hb (CHOIR, CREATE, TREAT) showed increased stroke, thrombosis, vascular access loss and death
HIF prolyl hydroxylase inhibitors (roxadustat, daprodustat, vadadustat) - oral, stabilise HIF -> inc endogenous EPO and dec hepcidin (better iron mobilisation)
- Concerns: thrombosis, and theoretical tumour and retinal risk from broad HIF activation
Pure red cell aplasia from anti-EPO antibodies - rare, with subcutaneous epoetin; sudden loss of response with reticulocytopenia -> stop all ESAs, test for antibodies
ESAs are contraindicated or used cautiously in active malignancy - shortened survival and tumour progression signals in several cancers
A polycythaemic patient needs an EPO level and a JAK2 before being labelled with polycythaemia vera; do not just venesect
Post-renal-transplant erythrocytosis - occurs 8-24 months post-transplant; treat with ACEi or ARB

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