Anaemia

Iron

  • Screen annually in CKD G3, biannually in CKD G4
  • Investigate - EPO def is dx of exclusion. “possible”” in eGFR <60, “probable” in <30

Iron studies

  • % HRC if able to process within 6 hours
  • Reticulocyte Hb count (CHr)
  • TSATS and ferritin ( if above not available or thalassaemia)
  • Ferritin & CRP
  • PTH & TFT ( can contribute to iron def)
  • Consider - b12/folate/haemolysis/plasma&urine electrophroesis, hb electrophoresis, LTC & Marrow
  • Scopes etc

Iron repletion

  • %HRC <6% / CHr >29 pg / ferritin and TSAT (>100 microgram/L and >20%).
  • Oral iron usually ok for CKD, ~PD. IV for HD.
  • If not in centre, high dose low frequency is good

Oral iron is viable in mild CKD

  • Interestingly alternate day dosing is higher in absorbtion to daily dosing per Lancet haematology
  • measuring the isotopic label abundance in erythrocytes 14 days after administration, and serum hepcidin.
  • iron deficient women who were not anaemia
  • shock, horror, no CKD included
  • hard to generalise this observation to our patients but it is intriguing imo

Iron Therapy

  • In HD proactive high-dose IV iron sucrose (venofer) 400 mg every month (or 100mg every week) should be given unless ferritin > 700 μg/L or TSAT>40% ( PIVOTAL)

  • Avoid in infection, probably

  • Monitor quarterly

  • Hb Targets: 100-120

  • Caution in malignancy

  • ferrinject (Ferrous carboxymaltose) has reports of hypophos fairly consistantly in trials

  • Limits Feritin =< 800. Review iron therapy when hits 500.

Iron

PIVOTAL


PIVOTAL

  • High dose IV iron vs low dose
  • High dose non inferior for compositive CV | death endpoint
  • Less CV composite events in high dose hazard ratio, 0.80; 95% CI, 0.64 to 1.00
  • Less Blood transfusions
  • Same infections
  • Starting dose: 600mg Iron sucrose IV each session for a week on month 1. Then 200mg IV fortnightly from month 2 onwards, adhering to safety limits. Stop if ferritin 700 or TSATS >40%. Hb target was 100-120.


ESA

Eprex (erythropoietin alpha) 50 U/kg three times /week - 70kg person: 3500units each HD session IV.

Neorecoromon ( EPO beta) is same dose.

EPREX weekly total / 240 = darbepoetin alfa IV weekly dose in mcg.

HB Targets

Tips

  • 90-115 probably reasonable, aim 110 mean.
  • Safe speed limit: 10 to 20 g/L per month.
  • Decrease in preference to withholding.
  • Adjust in 25-50% increments
  • Wait 2-4 weeks for dose change to have effect.
  • Consider trend, rather than absolute values to avoid constant changes
  • Red Flag: 300 IU/kg/week - treatment failure, assess for bleeding/deficiency
    • This is 7000 u/HD in a 70kg person. Review early at 5000 units/session.
  • Caution HTN - 175/95 as arbitrary cut off. review.
Guideline Year Target Iron
KDOQI 2012 90 - 115 g/L Tsats <30, Ferr <500 ug/L
KDIGO 2012 10 - 11.5 g/L Tsats <30, Ferr <500 ug/L
CARI 2010 100 - 120 g/L
Renal Assoc. 2017 100 - 120 g/L (aim 110) Tsats <20. Ferr 200-500
European BP 2010 110 - 120 g/L

Note the RA audit measures for future QI work

NORMAL HEAMATOCRIT TRIAL


NHT

  • Intervention: EPO-a :: target Hb 13-15, vs rescue Hb 9-11 on HD with CVD
  • Endpoint: Death & non-fatal MI
  • Results: N=1265 | risk ratio for the normal-hematocrit group as compared with the low-hematocrit group, 1.3; 95 percent confidence interval, 0.9 to 1.9
  • Stopped early due to safety concerns
  • mortality rates decreased with increasing hematocrit values in both groups.
  • The patients in the normal-hematocrit group had a decline in the adequacy of dialysis and received intravenous iron dextran more often than those in the low-hematocrit group.


CHOIR


CHOIR

  • Intervention: EPO-a :: target Hb 13.5 vs 11.3 in CKD eGFR >15

  • Endpoint: CV events including death, MI, hospitalizations for CHF, and stroke

  • Results: N=1432 | Composite of death, MI, hospitalization for CHF, or stroke 17.5% vs. 13.5% (HR 1.34; 95% CI 1.03-1.74; P=0.03) | More SAE 54.8% vs. 48.5% (P=0.02), CHF 11.2% vs. 7.4% (P=0.02) although less MI 1.5 vs. 2.8% (P=0.09)

  • Even though the study population was randomized, the high Hgb group had more comorbid conditions, including a greater percentage of HTN, history of CABG, and severe CHF.

  • The high-Hgb group was not able to reach the target Hgb level despite higher doses of erythropoietin.

  • The trial was open-label, not double-blinded.


TREAT


TREAT

  • Intervention: Darbo :: target Hb >10 vs rescue ESA if <9 in CKD eGFR >20, DM2,Hb<11, TSATS >15%

  • Endpoint: death or CV events and death or ESRD, stroke

  • Results: N=4038 | Death or CV: 31.4% vs. 29.7% (HR 1.05; 95% CI, 0.94 to 1.17; P=0.41), Death or ESRD 32.4% vs. 30.5% (HR 1.06; 95% CI, 0.95 to 1.19; P=0.29)

  • 5% vs. 2.5% (HR 1.92; 95% CI 1.38-2.68; P<0.001; NNH 40)

  • Less fatigue though!!

  • Did not target different hemoglobin levels for different sexes

  • Incomplete details pertaining to stroke

  • Unclear effect of iron administration in placebo group


CREATE


CREATE

  • Intervention: EPO-beta :: target Hb >13-15, vs rescue Hb 10.5-11.5 in CKD eGFR 15-30
  • Endpoint: composite of eight cardiovascular events; secondary end points included left ventricular mass index, quality-of-life scores, and the progression of chronic kidney disease.
  • Results: N=603 | OVer 3 years (58 events in group 1 vs. 47 events in group 2; hazard ratio, 0.78; 95% confidence interval, 0.53 to 1.14; P=0.20).
  • Dialysis was required in more patients in group 1 than in group 2 (127 vs. 111, P=0.03)
  • But slightly confusingly mean eGFR was the same ~24
  • General health and physical function improved significantly (P=0.003 and P<0.001, respectively, in group 1, as compared with group 2).
  • SAE similar but more HTN in higher hb


Resistance to ESA therapy

Failure to reach the target Hb level despite SC epoetin dose >300 IU/kg/week (450 IU/kg/week IV epoetin), or darbepoetin dose >1.5 microgram/kg/week. ( 70kg man = 7000 units/session)

Hyporesponsive patients who are iron replete should be screened clinically and by investigations for other common causes of anaemia.

Pure Red Cell Aplasia

Considered whenever a patient receiving long term ESA therapy (more than 8 weeks) develops all the following (2A):

  • sudden decrease in Hb concentration at the rate of 5 to 10g/L per week OR requirement of transfusions at the rate of approximately 1 to 2 per week
  • normal platelet and white cell counts,
  • absolute reticulocyte count less than 10,000/µl

ESA therapy should be stopped in patients who develop ESA induced PRCA.

Patients who remain transfusion dependent after withdrawing ESA therapy should be treated with immunosuppressant medications guided by the level of anti EPO antibodies

It was probably the rubber bungs on the old school EPREX syringes which were generating the antibodies, their removal from the market has essentially fixed the issue

HIF inhibitors

Roxadustat is suss

A Roxadustat paper is being retracted

  • compared roxadustat CV outcomes to EPO-alpha in non HD CKD - which its not really indicated for due to increased CV endpoints
  • post-hoc changes to the stratification factors
  • Failed to sort out the issues on review so all gone

HIMALAYAS

Risks - Tumour progression - PAH - Increased cysts in ADPKD