Anemia in Chronic Kidney Disease

Introduction

Anemia commonly arises in cases of chronic kidney disease (CKD), leading to a decline in quality of life and heightened morbidity and mortality rates. The underlying mechanisms contributing to anemia in CKD are intricate and varied. Termed as anemia of chronic kidney disease (CKD), it manifests as a type of normocytic, normochromic, hyperproliferative anemia. Its presence often correlates with adverse outcomes in CKD patients and amplifies the risk of mortality. Hence, treatment primarily focuses on enhancing renal function, where feasible, and promoting red blood cell production. Therapeutic approaches typically involve using erythropoiesis-stimulating agents and iron supplementation as preferred options for managing anemia associated with chronic renal disease.

Anemia frequently arises in individuals with chronic kidney disease (CKD), leading to diminished quality of life, poorer renal outcomes, heightened morbidity and mortality, and increased financial burdens. Various studies examining anemia rates among non-dialysis dependent CKD patients have shown a wide range of prevalence, reaching up to 60 %. As kidney function, measured by estimated glomerular filtration rate (eGFR), decreases, the prevalence and severity of anemia tend to escalate.

Analysis of data from the National Health and Nutrition Examination Survey (NHANES) in 2007–2008 and 2009–2010 uncovered that anemia affected CKD patients at twice the rate of the general population (15.4% vs. 7.6%), with its prevalence escalating from 8.4% at CKD stage 1 to 53.4% at stage 5. Recent findings from the CKD Prognosis Consortium corroborate these trends, additionally noting a higher prevalence of anemia among diabetic CKD patients, irrespective of their eGFR and albuminuria levels.

What Are Causes of Anemia in Chronic Kidney Disease?

Anemia associated with chronic kidney disease has a complex origin involving multiple factors, with the primary cause often attributed to reduced production of erythropoietin (EPO), the hormone essential for stimulating the generation of red blood cells. Recent research has linked this decrease in erythropoietin to the suppression of hypoxia-inducible factor (HIF), a transcription factor governing the expression of erythropoietin.

Other contributing mechanisms include uremia-induced red blood cell deformities leading to hemolysis, deficiencies in folate and vitamin B12, insufficient iron levels, bleeding tendencies due to platelet dysfunction, and occasionally, blood loss during hemodialysis.

Furthermore, in specific conditions such as glomerulopathy and malignant hypertension, red blood cell fragmentation by damaged blood vessel lining in the kidneys worsens anemia. This explains why anemia can be particularly severe in renal glomerulopathies, encompassing conditions like glomerulonephritis and diabetic nephropathy, correlating with the extent of kidney function decline.

What Are Symptoms Of Anemia in Chronic Kidney Disease?

The symptoms of anemia arising from chronic kidney disease are similar to those stemming from other causes.

Typical manifestations consist of:

Difficulty breathing (dyspnea)

• The feeling of tiredness (fatigue)

• Overall weakness

• Headaches

• Decreased ability to focus

• Dizziness

• Reduced capacity for physical activity.

Observable indicators often include:

• Paleness of the skin and conjunctiva

• Difficulty breathing (respiratory distress)

• Rapid heartbeat (tachycardia)

• Chest discomfort (more common in severe cases of anemia)

• Heart failure (typically in cases of long-standing severe anemia).

What Is the Treatment Of Anemia in Chronic Kidney Disease?

The approach to treating anemia associated with chronic kidney disease focuses on enhancing renal function, where feasible, and promoting the production of red blood cells. This typically involves the administration of erythropoiesis-stimulating agents (ESAs) along with iron supplementation. In the past, managing anemia in CKD primarily relied on blood transfusions, which were fraught with various complications such as infections, fluid overload, and transfusion reactions.

The use of androgens in the 1970s marked an initial attempt to avoid transfusions in CKD patients. However, the introduction of recombinant erythropoietin (EPO) in the 1980s, followed by ESAs, revolutionized anemia management in CKD. These treatments aimed to reduce the need for transfusions and yielded numerous benefits, including improved survival, enhanced quality of life, better cardiac function, decreased hospitalizations, and reduced costs.

The following are the treatment options for anemia in chronic kidney disease:

• Recombinant human erythropoietin and darbepoetin alfa are the primary ESAs for managing CKD-related anemia. While they exhibit similar efficacy and side effect profiles, darbepoetin alfa boasts a longer half-life, allowing for less frequent dosing.

• According to KIDGO guidelines, in non-dialysis CKD patients, ESAs are typically considered when hemoglobin levels drop below 10 g/dl, with individualized treatment plans based on factors such as anemia symptoms, transfusion dependency, rate of hemoglobin decline, and response to iron therapy.

• In dialysis patients, ESAs are generally reserved for hemoglobin levels between 9 and 10 g/dL, administered with each dialysis session for erythropoietin or once weekly for darbepoetin alfa.

• Although the peak increase in red blood cell production in response to ESAs occurs within 8 to 12 weeks, about 10% to 20% of cases may exhibit ESA resistance. Common adverse effects of ESAs include seizures, hypertension exacerbations, dialysis access clotting, cancer progression, and increased mortality in cancer patients.

• Regardless of dialysis status, all CKD patients' target hemoglobin level with ESA therapy is typically maintained below 11.5 g/dL.

• Several trials have demonstrated adverse outcomes associated with higher hemoglobin targets, including increased mortality and cardiovascular events.

• Consequently, there is a growing interest in exploring alternative management strategies for CKD-related anemia.

• Iron deficiency is prevalent in CKD patients due to impaired iron absorption, chronic bleeding, and ESA-induced depletion of iron stores. Therefore, iron supplementation is fundamental to managing anemia in CKD, with intravenous iron preferred in hemodialysis patients due to reduced oral absorption.

• KIDGO recommends specific target levels for transferrin saturation and ferritin, depending on CKD status and iron supplementation.

• Unlike the general population, high serum ferritin levels do not reliably indicate hemoglobin responsiveness in CKD patients, and routine measurement of erythropoietin levels is not recommended for evaluating renal anemia.

Conclusion

In conclusion, anemia in chronic kidney disease represents a multifaceted challenge with significant implications for patient well-being and clinical management. While the primary etiology often involves reduced erythropoietin production and impaired iron metabolism, various factors, including uremia, comorbidities, and treatment-related complications, contribute to its complexity.

The advent of erythropoiesis-stimulating agents (ESAs) and advancements in iron supplementation have substantially improved anemia management in CKD, offering opportunities to enhance quality of life, reduce transfusion dependency, and mitigate adverse outcomes. However, carefully considering individual patient factors, including dialysis status, hemoglobin levels, and response to therapy, is essential to tailor treatment strategies effectively. Furthermore, recent studies underscore the importance of maintaining conservative hemoglobin targets to mitigate risks associated with ESA therapy, highlighting the need for ongoing research and refinement in clinical practice guidelines.