Anemia of CKD

• Iron deficiency - seen commonly in HD patients since there is small chronic blood loss on HD machine. But also seen due to chronic disease.

  • Target transferrin saturation (Tsat) >20%

    • Patients with a Tsat ≤15% have worse outcomes [Cho et al 2019]

  • Target ferritin 100-300

  • There are various repletion doses for HD patients (can give IV Venofer on HD)

  • Enteral iron and iron rich foods for the remaining kids

• Epogen/ESAs - see dosing below. Typically given IV 3x/week on HD or SQ weekly-2x weekly on PD.

  • Target Hgb 11-12

  • There is a full flowsheet available during HD clinic on when to hold or change doses (and by how much). Typically, don’t want Hgb > 13 without some intervention (hold and reduce dose).

• Adverse effects of iron excess

  • Evidence from patients with hereditary hemochromatosis

    • Excess iron deposits in the liver, heart and endocrine glands lead to organ dysfunction

    • Iron-loading anemias: mutations in beta-globin gene lead to ineffective erythropoiesis and anemia

    • Transfusions and dietary iron hyperabsorption lead to iron overload, a major cause of morbidity and mortality

  • Diabetes mellitus

  • Cardiovascular disease

  • Neurodgenerative disorders

  • AKI

  • Malignancy

  • Infection

• Systemic iron

History of erythropoietin stimulating agents (ESAs)

• Before the advent used Cobalt salts, androgens, frequent blood transfusions, which were associated with significant adverse effects:

  • Chronic cobalt use: cardiomyopathy, neuropathy, thyroid dysfunction

  • Transfusions: infection, sensitization, iron overload

Types of ESAs

• Epoetin alfa (EPO)

• Darbepoetin alfa

  • EPO with two added sialic acid-containing carbohydrate side chains to extend duration of effect

• CERA (methoxy propylene glycol-epoetin beta)

  • EPO + large methoxy propylene glycol polymer chain, which greatly slows the association with the EPO receptor

  • Result is significantly longer half-life (up to 130 hours when given subcutaneously and 90 hours when given IV) which allows for a monthly dosing regimen

ESA initiation and maintenance

• As a general rule, initiate if Hb is persistently <10 g/dL

  • Individualize initiation and maintenance targets based on potential benefits (improvement in symptoms, school attendance/performance, avoidance of transfusion) and potential harms

• Initial dosing (see ESA dosing for more details)

  • Epoetin: 20-50 IU/kg/dose IV/SQ three times weekly

  • Darbepoetin: weekly or every 2 weeks [Warady et al., 2018]

    • 0.45 µg/kg IV/SQ weekly

    • 0.75 µg/kg IV/SQ every two weeks

  • Conversion to CERA: (Fischbach et al., 2018)

    • [***] 4 µg every 4 weeks for each 125 IU of epoetin alfa/beta or 0.55 ug of darbepoetin alfa

  • After initiation, repeat Hb in 2-4 weeks

    • Goal rate of Hb increase: 1-2 g/dL/month

      • Exceeding this rate can increase risk of adverse effects

• Maintenance (see ESA dosing for more details)

  • Typically target Hb 11-12 g/dL

    • Check Hb and adjust medications no more frequently than every 2 weeks

    • Prefer to dose adjust rather than hold altogether to avoid rebounding[***]

    • For long-acting ESAs, use a lower starting dose and less frequent adjustments to avoid overshooting Hb targets [***]

  • Typical epoetin requirements:

    • 275-350 units/kg/week in infants [Koshy et al., 2008]

    • 200-250 units/kg/week in older children [Koshy et al., 2008]

    • Maintenance ESA requirements in children may be higher than adults despite lower body weight [Bamgbola et a., 2009]

      • Proposed mechanism: May be due to [***] increased drug clearance with growth

• [***LEFT OFF HERE]

• Iron deficiency

  • Correction of ID reduces severity of anemia of CKD

  • Untreated ID is frequent cause of ESA hyporesponsiveness

  • Risk factors in dialysis patients include: blood loss (in circuits, phlebotomy), inflammation, poor absorption of enteral iron (exacerbated by phosphate binders, gastric acid suppressants)

  • Absolute iron deficiency

  • Functional iron deficiency

    • Rapid utilization due to erythropoiesis

    • Inflammation decreases iron availability

      • more resistant to iron therapy

      • more difficult to utilize iron in the body

  • Biomarkers:

    • Ferritin (serum)

      • Intracellular iron-storage protein

      • Increased by inflammation, iron overload

    • Transferrin saturation (TSAT)

      • Transferrin binds to iron in plasma

      • Carrier protein, transports iron from storage site to bone marrow

  • Targets

    • Iron supplementation to maintain:

      • Ferritin ≥100 ng/mL

      • TSAT ≥20%

    • Ferritin has important limitations as a marker of accessible stored iron

      • Hepcidin-mediated iron blockade

      • Low ferritin does indicate iron deficiency but high ferritin does not rule out iron blockade

    • No routine iron supplementation for ferritin >500 or TSAT >30%

      • Adult data supports the use of IV iron even in patients with high ferritin levels

  • Goals:

    • Avoid depletion of iron stores

    • Prevent iron-restricted erythropoiesis

    • Intracellular iron stored in ferritin is exported by ferropoietin, oxidized, then loaded onto transferrin where it is carried to the bone marrow

      • Interrupted by hepcidin, but IV iron can bypass this [***]

  • Treatments:

    • Oral/enteral:

      • Pros: inexpensive, available, few adverse effects

      • Cons: poorly absorbed, adherence

    • IV:

      • Pros: shown to decrease PRBC transfusion, adherence is guaranteed as it is administered in dialysis unit [***]

      • Cons: anaphylaxis, oxidative stress, cost

      • Safety: carbohydrate (sucrose) shell means reduced oxidative stress by non-transferrin-bound IV iron

    • Selecting treatment:

      • In children not on an ESA and not on HD, treat with oral iron unless "intolerant" or target Hb is not reached within 3 months

      • On ESA and not on HD -> trial of oral iron

      • Offer IV iron to children on HD

  • Novel treatments:

    • Intradialysate soluble ferric pyrophosphate citrate (FPC) - Triferic (R)

      • Can be added to the bicarbonate concentrate at each hemodialysis session, results in dialysate with 100 ug/L if iron

      • Crosses membrane and donates to transferrin

        • Immediately bioavailable

      • FDA approved in adults

      • Has been studied in children on dialysis (Pratt, pediatric nephrology, 2018)

        • Older patients received larger doses, likely because

        • Increasing blood flow rate increases delivery up until plateau of Qb of 300 mL/min

      • Also available in IV formulation

      • Doses

        • [***]

    • Ferric citrate

      • Phosphorus binder that can also act as an iron supplement

      • Some of the ferric ions dissociated from ferric citrate are reduced by the bowel mucosa to ferrous iron and absorbed through the duodenal brush border [***]

      • Studies in children (Hanudel, ped neph, 2018)

        • Decreased time averaged serum phosphate

    • Small molecule HIF stabilizers

      • [***] mechanism

      • Administered orally in highly bioavailable preparations

        • Stabilize HIF and modulate HIF-controlled gene products

        • Stimulate endogenous EPO synthesis

          • Works even in the absence of kidneys by increasing liver production

      • Trials ongoing in children: vadadustat, daprodustat, roxadustat

Downsides of EPO: injection

• Hypoxia-inducible factors (HIF)

  • Family of oxygen-sensitive proteins that regulate the cell's transcriptional response to hypoxia

    • [***]

  • Central regulator of erythropoiesis in response to hypoxia

    • EPO production

    • Indirect suppression of hepcidin by promotion of erythropoiesis

    • Augmentation of enteric iron absorption and transport

    • Mobilization of endogenous iron stores to erythroid marrow

• Under normoxia [***]

• Different actions

  • 3 prolyl hydroxylase isoforms

    • HIF-PHIs vary in their ability to inhibit these isoforms

  • Expression of HIF-regulated genes

• Different dosing

  • Daily except for roxadustat, which is 3 days per week

• Different pharmacokinetics

  • All rapidly absorbed

  • Halflives vary

  • Metabolism

    • cytochrome P450 (roxadustat, daprodustat, enarodustat)

    • ***

• Efficacy

  • Multiple randomized clinical trials in adults, including dialysis-dependent and non-dialysis-dependent CKD

  • Consistently effective when compared to traditional ESAs

    • Improved Hb change and fewer transfusions in some studies with dialysis dependent patients

• Decreased hepcidin

  • Hepcidin suppressed by low iron stores and erythropoiesis

    • All ESAs (including traditional ESAs) decrease hepcidin

  • HIF effects vs traditional ESA

    • One study showed that molidustat led to a greater decrease in hepcidin than darbepoetin

• Iron utilization

  • Some studies suggest decreased IV iron use

  • May make oral iron more effective

• Potential benefits

  • Oral medication

    • Downside: increases medication burden to patients who are on hemodialysis and getting ESAs IV

    • Downside: needs to be given much more frequently compared to medications like darbepoetin which can be given every ~2 weeks

  • Improve iron metabolism and decrease need for IV iron

    • ***

  • Work in patients with functional iron deficiency

    • Improve iron metabolism

    • Directly suppress inflammation

  • Avoid high levels of erythropoietin (EPO level is ~10% of that seen in ESAs)

    • Mechanisms:

      • Direct effects on erythroid progenitor and the bone marrow

      • Iron utilization may reduce need for EPO

      • Endogenous EPO may be superior to rEPO

• Safety

  • Why would you use a medication that has multiple effects vs just the effect(s) that you are seeking?

  • Why is the HIF pathway not usually active?

    • Other pathways that are selectively activated: complement, inflammation, coagulation

      • Constitutive activation of these pathways (e.g., atypical HUS) is deleterious

  • Rationale

    • Beneficial side effects

    • Erythropoietin effect occurs at lower HIF activity than other effects

• CV safety data

  • Most studies have no revealed any significant safety signals, however some studies have shown conflicting signals for cardiovascular events:

    • Thromboembolic events in pooled analysis of HD patients

      • Roxadustat: 11.3%

      • Darbepoetin: 3.9%

    • Roxadustat vs epoetin alfa in DD CKD (pooled analysis of 3 studies)

      • Major adverse cardiovascular events (MACE): no difference

      • MACE+ (heart failure or unstable angina requiring hospitalization): HR favors roxadustat (HR: 0.84, p=0.02)

    • Vadadustat vs darbepoetin in NDD CKD (PRO2TECT)

      • MACE (primary outcome): vadadustat did not meet noninferiority outcome (HR 1.14)

    • Vadadustat vs darbepoetin in DD CKD (INNO2VATE)

      • MACE: no difference (HR 0.96)

  • CKD progression more common with molidustat than darbepoetin

    • 13.4% vs 6.3% (ESA naive)

    • 12.2% vs 7.3% (ESA treated)

  • Hyperkalemia increased in Chinese phase 3 studies (NDD CKD and DD CKD), perhaps due to increased metabolic acidosis or effects on glycolytic pathways

  • Vascular endothelial growth factor (VEGF)

    • Anti-VEGF used to treat macular degeneration

    • No evidence of increased eye disease in clinical trials

  • Cancer

    • Growing tumors experience hypoxia and use the HIF pathway to adapt and promote angiogenesis (target of anti-cancer therapy)

    • No human or animal data supports increased risk

  • Other concerns: small studies or theoretical risks

    • Pulmonary hypertension: HIF increased pulmonary artery vascular tone

      • Chronic hypoxia has been used as a model of pulmonary hypertension

    • Glucose and liver metabolism

    • Profibrogenic effects

    • Vascular calcifications

    • FGF23 levels

    • Obesity (mitochondrial dysfunction)

    • Hyperglycemia

    • Liver fibrosis

    • Pulmonary fibrosis

    • Kidney fibrosis

    • Concerns regarding acceleration of cyst growth in predialysis patients with ADPKD

• Unanswered questions

  • Safety and efficacy in children

  • Effect on iron metabolism and whether it reduces need for IV iron

  • Whether there is extra benefit if inflammation/EPO-resistant

  • Whether higher doses required in anephric patients

  • Side effects

    • CV risk (heart, stroke, mortality)

    • Progression of CKD

    • Off-target effects