Anemia in Chronic Kidney Disease

Article written and reviewed by Dr Luca Moretti

Anemia in chronic kidney disease (CKD) is one of the paradigmatic forms of anemia of chronic disease, combining the typical inflammatory abnormalities with specific mechanisms secondary to the progressive loss of kidney function. It is a common complication of chronic kidney disease whose prevalence increases as glomerular filtration declines and is particularly high in advanced stages, with an impact on morbidity, physical performance, cognitive function and quality of life.

Epidemiology and clinical relevance

Anemia is one of the most common complications of CKD: prevalence increases as glomerular filtration declines and is particularly high in advanced stages and in patients on dialysis, but varies according to the population, the definition used, iron status and treatment with ESAs or iron. Frequency and severity increase with progression of kidney damage, age, the presence of comorbidities such as diabetes, cardiovascular disease and malnutrition, and the duration of kidney disease.
Anemia in CKD is independently associated with a worse prognosis and an increased risk of heart failure, myocardial ischemia, hospitalization, cognitive impairment and overall worsening of functional status.

Pathophysiology and molecular mechanisms

Anemia in CKD is a complex syndrome supported by multiple interacting mechanisms:

• Erythropoietin (EPO) deficiency: reduced renal EPO production, a hormone crucial for maturation of bone marrow erythroid precursors, is the primary cause. Tubulointerstitial damage and fibrosis lead to loss or repression of the EPO-producing phenotype in peritubular interstitial cells, resulting in production that is inadequate for the degree of anemia.
• Chronic inflammation and immune dysregulation: CKD is a chronic proinflammatory state. IL-6 promotes increased hepcidin synthesis, worsening functional iron deficiency and iron sequestration; TNF-α and other cytokines contribute mainly to suppression of erythropoiesis and alterations in iron metabolism through distinct mechanisms.
• Accumulation of uremic toxins: some uremic toxins, including indoxyl sulfate, may inhibit the erythropoietic response, interfere with erythroid progenitor function and contribute to oxidative stress; the role of individual uremic solutes is neither uniform nor completely defined.
• Reduced red blood cell survival: red blood cell lifespan decreases progressively as CKD advances; studies have reported mean values close to 120 days in early stages and around 60 days in stage G5. The uremic milieu and oxidative stress contribute to this reduction; in dialysis patients, blood loss or hemolysis related to the extracorporeal circuit may also occur in selected situations.
• Chronic blood loss: gastrointestinal microbleeding, bleeding at vascular access sites, repeated blood sampling and uremic platelet dysfunction contribute to cumulative iron deficiency.
• Associated nutritional deficiencies: protein calorie malnutrition and documented vitamin B12 or folate deficiencies aggravate ineffective erythropoiesis.

This complex pathophysiology produces hypoproliferative, normocytic and normochromic anemia in most cases, with possible phenotypic variations in the presence of superimposed iron or vitamin deficiencies.

Clinical features and systemic impact

The clinical picture of anemia in CKD is often insidious and worsens progressively as kidney function declines. The most common symptoms are:

• Asthenia, fatigue, reduced exercise tolerance
• Pallor of the skin and mucous membranes
• Dyspnea, palpitations, worsening arrhythmias or angina in predisposed individuals
• Sleep disturbances, mood changes, cognitive impairment
• Worsening physical performance and work capacity

In more advanced cases, especially in frail patients or those with heart disease, heart failure, myocardial ischemia and neurocognitive abnormalities may occur.
Anemia is associated with left ventricular hypertrophy, diastolic dysfunction, arrhythmias and greater cardiovascular risk; these associations do not demonstrate a direct causal effect of anemia on cardiovascular mortality.

Diagnosis and specific investigations

Diagnosis of anemia in CKD is based on an integrated assessment:

• Medical history and physical examination: assessment for symptoms and signs of anemia, CKD history, comorbidities and use of nephrotoxic drugs.
• Laboratory tests:
  • Complete blood count: normocytic, normochromic anemia, sometimes microcytic in iron deficiency, with low or borderline reticulocytes.
  • Ferritin and transferrin saturation must be interpreted together. According to KDIGO 2026, criteria for starting iron are: in hemodialysis, ferritin ≤500 ng/mL and TSAT ≤30%; in patients not receiving hemodialysis or receiving peritoneal dialysis, ferritin <100 ng/mL with TSAT <40%, or ferritin ≥100 and <300 ng/mL with TSAT <25%.
  • During iron therapy, it is reasonable to withhold iron if ferritin is >700 ng/mL or TSAT is ≥40%, except in selected specialist circumstances.
  • Inflammatory markers: CRP, ESR and fibrinogen may be elevated, especially when concomitant inflammation is present.
  • Exclusion of other causes of anemia: measurement of vitamin B12, folate, thyroid hormones and hemolysis profile.
  • Assessment of kidney function: serum creatinine, calculated GFR and indices of uremia.
• Advanced tests, when indicated: soluble transferrin receptor (sTfR), hepcidin measurement, which is not routine, integrated nutritional assessment; albumin and prealbumin may primarily reflect inflammatory status and must not be used in isolation as markers of malnutrition; imaging studies if occult blood loss is suspected.
• Differential diagnosis: it is essential to exclude pure iron deficiency anemia, anemia due to malabsorption, chronic hemolysis, myelodysplastic syndromes and hematologic complications of dialysis.

Failure to respond to oral iron or a high ESA requirement warrants reassessment of adherence, blood loss, inflammation, dialysis adequacy and other correctable causes; this finding does not identify a single etiology.

Principles of treatment and integrated management

Treatment of anemia in CKD aims to correct pathophysiologic deficits, improve symptoms and functional performance and reduce the need for transfusions. The main pillars of treatment are:

• Correction of iron deficiency: intravenous iron is generally preferred in hemodialysis. In patients not receiving hemodialysis, the choice between oral and intravenous iron depends on preferences, tolerability, response, venous access and likelihood of absorption; the oral route is not limited solely to mild CKD without inflammation.
• Erythropoietic stimulation: recombinant erythropoietins (rHuEPO, darbepoetin alfa, epoetin beta) are the cornerstone of treatment, to be titrated according to KDIGO recommendations and international guidelines, using the lowest effective dose and without maintaining Hb at values ≥11.5 g/dL, with an individualized target and avoidance of overcorrection because of thromboembolic and cardiovascular risk.
• Management of inflammation and comorbidities: control of infections, optimization of fluid and electrolyte balance, reduction of uremic toxins and correction of nutritional deficiencies.
• Correction of vitamin deficiencies: targeted supplementation with vitamin B12, folate and other water soluble vitamins in cases of documented deficiency.
• HIF-PHIs: HIF prolyl hydroxylase inhibitors are available in some jurisdictions and may be considered according to authorization, risk profile and guidelines; they are not simply experimental drugs and are not interchangeable without clinical assessment.

Regular monitoring of the complete blood count, iron parameters and kidney function is essential to adjust therapy and prevent complications.

Complications, prognosis and long term outcomes

Anemia in CKD is associated with greater morbidity and mortality, particularly cardiovascular mortality; beyond improvement in quality of life and reduction in transfusion requirements, it has not been demonstrated that correction of anemia reduces these outcomes. Clinical outcomes associated with anemia and treatment related complications include:

• Heart failure, arrhythmias and left ventricular hypertrophy
• Increased thromboembolic risk, especially with high Hb levels or inappropriate use of erythropoietin
• Neurocognitive impairment, mood disorders, worsening quality of life

A multidisciplinary, evidence based approach can improve symptoms, reduce the need for transfusions and optimize the use of iron and ESAs; normalization of hemoglobin has not been shown to improve overall mortality and major cardiovascular outcomes, and high Hb targets with ESAs may increase adverse events.

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