Residency · Residency · Nephrology

Anemia of Chronic Kidney Disease

Introduction

Anemia is a nearly universal complication of advanced CKD, with prevalence increasing as GFR declines: approximately 15 percent at an eGFR of 30 to 59, 50 percent at an eGFR below 30, and 90 percent in patients on dialysis. KDIGO defines anemia as a hemoglobin below 13 g/dL in men and below 12 g/dL in women. The anemia of CKD is primarily attributable to inadequate erythropoietin production by the failing kidneys, with iron deficiency serving as the most common treatable contributing factor. Beyond its symptomatic burden of fatigue and reduced quality of life, CKD anemia contributes to left ventricular hypertrophy, heart failure, and mortality.

Pathophysiology

Erythropoietin Deficiency

Erythropoietin is produced by peritubular fibroblast-like cells in the renal cortex in response to hypoxia, sensed through the HIF-2alpha pathway. In CKD, reduced functional renal mass leads to an inadequate EPO response relative to the degree of anemia. Serum EPO levels may be within the "normal" range but are inappropriately low for the severity of anemia, reflecting a blunted EPO response. The liver, which contributes approximately 10 percent of EPO production, provides insufficient compensation.

Iron Deficiency

Iron deficiency in CKD presents in two distinct forms. Absolute iron deficiency reflects truly depleted iron stores, with ferritin below 100 ng/mL in non-dialysis CKD or below 200 ng/mL in hemodialysis patients. Causes include reduced dietary intake, poor absorption from uremic gastritis and PPI use, and chronic blood loss from the hemodialysis circuit, frequent phlebotomy, uremic platelet dysfunction, and gastrointestinal losses.

Functional iron deficiency occurs when iron stores appear adequate but mobilization is impaired. This condition is driven by hepcidin excess: hepcidin, produced by the liver, is the master regulator of iron homeostasis that blocks ferroportin, the iron export channel on enterocytes and macrophages. When hepcidin is elevated, iron becomes trapped in the reticuloendothelial system despite adequate stores. In CKD, hepcidin is elevated due to chronic inflammation, reduced renal clearance, and iron supplementation itself. The result is a TSAT below 20 percent despite ferritin levels of 200 to 500 ng/mL.

Other Contributing Factors

Additional factors contributing to CKD anemia include uremic toxin-mediated suppression of erythropoiesis by indoxyl sulfate and p-cresyl sulfate, chronic inflammation with IL-6 and TNF-alpha driving hepcidin elevation, shortened red blood cell survival from the uremic milieu reducing RBC lifespan from 120 to 60 to 90 days, bone marrow fibrosis from severe secondary hyperparathyroidism, folate and B12 deficiency from losses during dialysis, a mild reduction in EPO and RBC production from ACE inhibitor/ARB use, and aluminum toxicity which is now rare.

<image>Pathophysiology diagram of CKD anemia showing three main pathways converging on reduced red blood cell production. Pathway 1 (EPO deficiency): declining renal mass → reduced peritubular fibroblast function → inadequate EPO → reduced erythroid progenitor stimulation in bone marrow. Pathway 2 (Iron dysregulation): show the hepcidin-ferroportin axis with elevated hepcidin in CKD (from inflammation and reduced clearance) blocking ferroportin on enterocytes (reduced iron absorption) and macrophages (iron trapping in reticuloendothelial system). Show absolute iron deficiency from blood losses. Pathway 3 (Uremic milieu): uremic toxins suppressing erythropoiesis, shortened RBC survival (60-90 days vs normal 120 days), chronic inflammation, and bone marrow fibrosis from hyperparathyroidism. Include drug targets: ESAs replacing EPO, IV iron bypassing hepcidin-blocked absorption, and HIF-PHIs stabilizing HIF to increase endogenous EPO.</image>

Evaluation

Initial Workup (When Hb <10 g/dL or Declining)

The initial evaluation includes a CBC with reticulocyte count, iron studies comprising serum iron, TIBC, TSAT (calculated as serum iron/TIBC times 100), and ferritin. Reticulocyte hemoglobin content (CHr or Ret-He) below 29 pg suggests iron-deficient erythropoiesis and is more responsive to acute iron status changes than ferritin. A peripheral blood smear should be reviewed to rule out hemolysis, microangiopathy, and myelodysplasia. Vitamin B12 and folate levels should be checked. An EPO level is usually not needed when eGFR is below 30, but haptoglobin and LDH should be considered if hemolysis is suspected, along with stool occult blood and CRP to assess inflammation.

Iron Status Interpretation in CKD

Ferritin is an acute phase reactant and is elevated in inflammatory states, potentially exceeding 500 ng/mL even with functional iron deficiency. A TSAT below 20 percent combined with a ferritin below 500 warrants a trial of iron supplementation per KDIGO 2012 guidelines. The PIVOTAL trial redefined upper thresholds as discussed below.

Iron Therapy

Oral Iron

Oral iron is first-line for CKD non-dialysis patients with mild iron deficiency. Ferrous sulfate at 325 mg providing 65 mg of elemental iron, given daily to three times daily, is the standard regimen. Absorption is limited in CKD due to hepcidin-mediated ferroportin blockade, uremic gastrointestinal changes, and PPI co-administration. Response rates are 30 to 50 percent in non-dialysis CKD, inferior to intravenous iron. Ferric citrate serves a dual role as both an iron supplement and phosphate binder, with superior absorption that improves iron stores while binding dietary phosphorus.

Intravenous Iron

Intravenous iron is preferred for dialysis patients due to the convenience of administration with hemodialysis sessions and for non-dialysis CKD patients with inadequate oral response. The PIVOTAL trial, published in 2019, demonstrated that a proactive high-dose IV iron strategy of 400 mg monthly when ferritin is below 700 and TSAT below 40 percent was superior to a reactive low-dose strategy of 200 mg only when ferritin falls below 200 or TSAT below 20 percent. The high-dose approach resulted in fewer cardiovascular events, reduced ESA requirements, and no increase in infection or mortality, establishing higher ferritin thresholds up to 700 and TSAT up to 40 percent as safe.

Available intravenous iron formulations include iron sucrose at 200 mg over 15 minutes, which is most commonly used in hemodialysis with a low anaphylaxis risk; ferric gluconate at 125 mg over 10 minutes with a slightly higher infusion reaction risk; ferric carboxymaltose at 750 mg over 15 minutes for 2 doses one week apart, which is convenient for outpatient non-dialysis CKD but carries a risk of hypophosphatemia from FGF-23 elevation; ferumoxytol at 510 mg over 15 minutes for 2 doses 3 to 8 days apart; and ferric derisomaltose which can be given as a single infusion of up to 1000 mg over 20 minutes with an excellent safety profile.

Iron targets during ESA therapy are a TSAT of 20 to 50 percent and ferritin of 200 to 500 ng/mL per KDIGO, with PIVOTAL supporting thresholds up to ferritin 700 and TSAT 40 percent. Iron should be held during active systemic infection, when ferritin is consistently above 800, or when TSAT exceeds 50 percent.

Erythropoiesis-Stimulating Agents (ESAs)

Available Agents

Available ESAs include epoetin alfa, a short-acting agent dosed at 2000 to 20,000 units subcutaneously or intravenously 1 to 3 times weekly; darbepoetin alfa, a longer-acting hyperglycosylated form dosed at 0.45 mcg/kg every 1 to 2 weeks; and methoxy polyethylene glycol-epoetin beta (CERA), a continuous erythropoietin receptor activator allowing monthly dosing.

KDIGO Targets and Guidelines

The KDIGO-recommended hemoglobin target is 10 to 11.5 g/dL, and hemoglobin should not be targeted above 13 g/dL. ESAs should be initiated when hemoglobin falls below 10 g/dL, though the decision should be individualized. Iron stores must be replete before or concurrent with ESA initiation, as iron-deficient erythropoiesis wastes ESA.

Key Trials Establishing Hb Targets

The Normal Hematocrit Study in 1998, targeting a hematocrit of 42 percent versus 30 percent in hemodialysis patients with cardiac disease, was stopped early due to increased mortality and vascular access thrombosis in the higher target group. The CHOIR trial in 2006, targeting hemoglobin 13.5 versus 11.3 in non-dialysis CKD, showed increased cardiovascular events with the higher target. The CREATE trial in 2006 found no difference in cardiovascular events between targets of 13 to 15 versus 10.5 to 11.5 but observed more dialysis in the higher target group. The TREAT trial in 2009, studying darbepoetin targeting hemoglobin 13 versus placebo with rescue at hemoglobin below 9 in diabetic CKD, showed no benefit in the cardiovascular composite but a 2-fold increase in stroke risk and increased venous thromboembolism. The collective conclusion from these trials is that higher hemoglobin targets with ESAs cause harm, and ESA dose matters more than hemoglobin level.

ESA Hyporesponsiveness

ESA hyporesponsiveness is defined as failure to reach target hemoglobin despite an ESA dose exceeding 300 IU/kg/week of epoetin or 1.5 mcg/kg/week of darbepoetin. The most common cause is iron deficiency. Other causes include inflammation or infection, hyperparathyroidism causing marrow fibrosis, aluminum toxicity, B12 or folate deficiency, hemoglobinopathy, myelodysplasia, pure red cell aplasia from anti-EPO antibodies, malignancy, and inadequate dialysis. ESA doses should not be escalated indefinitely; instead, the underlying cause should be investigated and treated.

Pure Red Cell Aplasia (PRCA)

Pure red cell aplasia is a rare but serious complication caused by anti-EPO neutralizing antibodies, usually IgG directed against EPO. It presents with sudden onset of severe anemia, very low reticulocyte count, and absent erythroid precursors on bone marrow biopsy. It was historically associated with subcutaneous Eprex formulated with polysorbate 80 as a stabilizer, though the incidence has decreased with manufacturing changes. Treatment requires stopping all ESAs due to cross-reactive antibodies, immunosuppression with cyclosporine or corticosteroids, and consideration of peginesatide or transfusions.

<image>Clinical algorithm for managing anemia in CKD. Start with Hb measurement: if Hb <10 g/dL, initiate workup. Check iron studies (TSAT, ferritin, CHr). If iron deficient (TSAT <20% or ferritin <100 in non-dialysis / <200 in dialysis): start iron therapy (IV preferred in dialysis, oral or IV in non-dialysis). Recheck iron studies in 1-3 months. If iron replete but Hb remains <10: initiate ESA (epoetin or darbepoetin) with target Hb 10-11.5 g/dL. Monitor Hb every 2-4 weeks during titration, then monthly. If ESA hyporesponsive (no response despite adequate dose and iron): investigate causes (inflammation, hyperparathyroidism, B12/folate, blood loss, malignancy, PRCA). Consider HIF-PHI as alternative. Include the PIVOTAL trial thresholds: proactive iron to ferritin <700 and TSAT <40% reduces CV events and ESA requirements.</image>

HIF-Prolyl Hydroxylase Inhibitors (HIF-PHIs)

Mechanism

HIF-prolyl hydroxylase inhibitors work by inhibiting the prolyl hydroxylase domain enzymes that normally target HIF-2alpha for degradation. By stabilizing HIF-2alpha, these agents simulate the hypoxic response, leading to increased endogenous EPO production as well as improved iron absorption and mobilization through reduced hepcidin levels. Their oral administration represents a significant advantage over injectable ESAs. HIF-PHIs upregulate EPO production, transferrin receptor expression, ferroportin, DMT1, and duodenal cytochrome b, while downregulating hepcidin.

Available Agents

Roxadustat has been approved in the EU, Japan, and China, though the FDA issued a Complete Response Letter citing safety concerns. Daprodustat received FDA approval in 2023 for dialysis patients, with the ASCEND-D and ASCEND-ND trials demonstrating non-inferiority to ESAs for hemoglobin maintenance. Vadadustat had its FDA application withdrawn after the INNO2VATE trial raised cardiovascular safety concerns in non-dialysis patients. Molidustat has been approved in Japan.

Potential Advantages

HIF-PHIs offer oral administration improving convenience particularly for non-dialysis CKD, a more physiologic EPO response with lower sustained EPO levels compared to the supra-physiologic peaks seen with ESAs, improved iron utilization through hepcidin suppression leading to better oral iron absorption and mobilization, and potentially reduced intravenous iron requirements.

Concerns

Cardiovascular safety data are conflicting across agents, and MACE endpoints require long-term surveillance. Theoretical risks related to HIF-mediated effects include potential tumor promotion through angiogenesis, pulmonary hypertension, and retinal neovascularization. Long-term safety data remain limited. KDIGO 2024 indicates that HIF-PHIs may be considered as an alternative to ESAs, particularly in non-dialysis CKD where oral administration offers clear practical advantages, but emphasizes the need for ongoing cardiovascular safety monitoring.

Key Clinical Pearls

• The PIVOTAL trial changed iron management: proactive high-dose IV iron (target ferritin <700, TSAT <40%) reduces cardiovascular events and ESA requirements compared to reactive low-dose iron
• Never target Hb >13 g/dL with ESAs: TREAT, CHOIR, and the Normal Hematocrit Study consistently show harm (stroke, cardiovascular events, death, VTE) with higher Hb targets
• Iron deficiency is the most common cause of ESA hyporesponsiveness; always ensure adequate iron stores (TSAT >20%, ferritin >200 in HD) before escalating ESA dose
• Ferric carboxymaltose causes hypophosphatemia through FGF-23 elevation; monitor phosphorus, especially with repeated dosing in CKD patients already prone to phosphorus derangements
• HIF-PHIs represent a paradigm shift with oral administration and physiologic EPO stimulation, but cardiovascular safety remains the key unanswered question for widespread adoption

References

1. Macdougall IC, White C, Anker SD, et al. Intravenous Iron in Patients Undergoing Maintenance Hemodialysis (PIVOTAL). N Engl J Med. 2019;380(5):447-458.
2. Pfeffer MA, Burdmann EA, Chen CY, et al. A Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease (TREAT). N Engl J Med. 2009;361(21):2019-2032.
3. Singh AK, Carroll K, Engstrom-Heidenby E, et al. Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis (ASCEND-D). N Engl J Med. 2021;385(25):2325-2335.
4. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int Suppl. 2012;2(4):279-335.
5. Babitt JL, Lin HY. Mechanisms of Anemia in CKD. J Am Soc Nephrol. 2012;23(10):1631-1634.

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