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Anemia of CKD Diagnosis: Comprehensive Guide for Automotive Technicians

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Introduction

Anemia of chronic kidney disease (CKD), often referred to as renal anemia, is a common and significant complication in individuals suffering from impaired kidney function. As automotive technicians at xentrydiagnosis.store, understanding the intricacies of vehicle diagnostics often requires a systematic approach, much like diagnosing medical conditions. In the context of human health, anemia of CKD presents a diagnostic challenge, requiring a thorough evaluation to differentiate it from other forms of anemia and to manage it effectively. This article provides a detailed overview of the diagnosis of anemia of CKD, drawing parallels to our diagnostic expertise in automotive repair, and emphasizing the importance of accurate and timely identification for improved patient outcomes.

Anemia, generally defined as a reduction in hemoglobin levels below 13 g/dL in men and 12 g/dL in women, is a frequent comorbidity in patients with CKD. This specific type of anemia is normocytic and normochromic, meaning the red blood cells are of normal size and hemoglobin content, but hypoproliferative, indicating a reduced production rate. It is strongly associated with diminished quality of life, increased hospitalization rates, and higher mortality risks in CKD patients. Richard Bright, a pioneer in nephrology, first established the link between anemia and kidney disease in 1836, highlighting the long-recognized connection between renal function and hematological health.

The prevalence and severity of anemia escalate with the progression of CKD. It affects a substantial portion of patients in stage 3 CKD and nearly all patients with stage 5 CKD, who are dialysis-dependent. The primary drivers of anemia in CKD, including end-stage renal disease (ESRD), are multifaceted. A key factor is the impaired production of erythropoietin, a hormone primarily produced by the kidneys that stimulates red blood cell production in the bone marrow. Additionally, chronic inflammation associated with CKD disrupts iron metabolism and reduces gastrointestinal iron absorption, further contributing to the anemic state. A shortened red blood cell lifespan also plays a role in the pathophysiology of anemia of CKD.

Historically, blood transfusions were the primary treatment for anemia associated with kidney disease. However, this approach carries significant risks, including infections, iron overload (hemosiderosis), fluid overload, and transfusion reactions. Frequent transfusions can also lead to allosensitization, which can complicate kidney transplantation if it becomes a viable option. While androgens were briefly explored in the 1970s to mitigate transfusion needs, this practice is now discouraged due to limited efficacy and potential side effects.

A transformative advancement in the management of anemia of CKD emerged with the development of recombinant erythropoietin and erythropoiesis-stimulating agents (ESAs) in the late 1980s. ESAs revolutionized treatment by directly addressing the erythropoietin deficiency, the cornerstone of CKD anemia. Initially used to reduce transfusion dependence, ESAs were found to offer a range of benefits, including improved survival rates, enhanced quality of life, better cardiac function, fewer hospitalizations, and reduced healthcare costs. The introduction of ESAs led to a significant increase in the average hemoglobin levels in dialysis patients and a marked decrease in transfusion requirements.

However, the landscape of ESA therapy evolved with the Normal Hematocrit Trial in 1998, which raised concerns about potential adverse events associated with targeting higher hemoglobin or hematocrit levels. Subsequent clinical trials further investigated the optimal hemoglobin targets, revealing that aiming for “normal” hemoglobin levels with ESAs might not always translate to better patient outcomes and could, in some cases, increase risks. These findings prompted a re-evaluation of ESA usage and spurred the search for alternative and more refined management strategies for anemia of CKD.

The strong link between anemia of CKD and negative health outcomes, such as cardiovascular events and increased mortality, is well-established. Furthermore, the severity of anemia is directly correlated with a decline in quality of life and an increase in hospital admissions. Therefore, a deep understanding of the complex mechanisms underlying anemia of CKD, adherence to recommended diagnostic and treatment guidelines, and awareness of emerging therapeutic options are crucial for effectively managing this condition and improving patient well-being. Accurate and timely diagnosis is the first critical step in this comprehensive management approach.

Etiology

Anemia of chronic renal disease is a condition with multiple contributing factors, with the primary cause being the diminished production of erythropoietin by the kidneys. This hormonal deficiency is compounded by disruptions in iron metabolism, often stemming from chronic inflammation inherent in CKD. The reduced erythropoietin production is linked to the downregulation of hypoxia-inducible factor (HIF), a critical transcription factor that regulates the gene expression of erythropoietin. In essence, the body’s normal response to low oxygen levels, which should trigger erythropoietin production, is blunted in CKD.

Beyond erythropoietin deficiency, several other mechanisms contribute to anemia in CKD patients. Uremia, the buildup of waste products in the blood due to kidney dysfunction, can lead to red blood cell deformities and hemolysis (red blood cell destruction). Deficiencies in essential nutrients like folate and vitamin B12, which are crucial for red blood cell maturation, can also arise in CKD patients, either due to dietary factors, dialysate losses during dialysis, or anorexia. Dysfunctional platelets, another consequence of uremia, can increase bleeding risk, and blood loss during hemodialysis sessions can further exacerbate anemia.

Erythropoietin deficiency is a hallmark of kidney disease. This hormone is primarily synthesized by peritubular type 1 interstitial cells located in the renal cortex and outer medulla. Erythropoietin plays a vital role in erythropoiesis, the process of red blood cell production, by promoting the differentiation of erythroid progenitor cells in the bone marrow. Inadequate erythropoietin levels lead to programmed cell death (apoptosis) of these erythroid precursors, hindering red blood cell production. Furthermore, pro-inflammatory cytokines, elevated in chronic inflammatory states like CKD, can directly inhibit erythropoietin production and suppress the proliferation of erythroid progenitor cells, creating a double blow to red blood cell production.

Iron deficiency is another significant piece of the anemia of CKD puzzle. It manifests in two forms: absolute iron deficiency and functional iron deficiency. Absolute iron deficiency refers to a true depletion of total body iron stores, which can result from poor dietary intake, impaired iron absorption in the gastrointestinal tract, frequent blood draws for lab tests (phlebotomy), and blood losses during dialysis procedures. Functional iron deficiency, also known as relative iron deficiency, is characterized by an inability to effectively utilize stored iron. This occurs due to chronic inflammation, which impairs the release of iron from its storage sites, primarily in macrophages. In the context of CKD, the inflammatory milieu creates a “reticuloendothelial cell iron blockade,” preventing iron from being readily available for erythropoiesis. Exogenous administration of ESAs, while stimulating red blood cell production, can also exacerbate functional iron deficiency by rapidly consuming readily available iron stores, creating a supply-demand mismatch.

Iron homeostasis is tightly regulated by hepcidin, a hormone produced by the liver. Hepcidin acts as the master regulator of iron metabolism, controlling iron absorption from the gut and the release of stored iron from cells. Hepcidin reduces the expression of ferroportin, a protein responsible for exporting iron from cells, including enterocytes (intestinal cells that absorb iron) and macrophages. Hepcidin production is upregulated by inflammation, infection, and, notably, renal failure itself. As kidney function declines and the glomerular filtration rate (GFR) falls, hepcidin levels rise due to reduced renal clearance of this hormone. Elevated hepcidin in CKD contributes to reduced iron absorption, increased iron storage within cells (making it less available for erythropoiesis), and suppression of erythroid progenitor cell proliferation, further compounding the anemia.

HIF plays a crucial role in cellular responses to hypoxia, or low oxygen conditions. It’s a transcription factor composed of an oxygen-sensitive α-unit and a stable β-unit. HIF regulates the expression of erythropoietin (EPO) and genes involved in iron metabolism. Under normal oxygen levels, enzymes called prolyl-4-hydroxylase domain-containing proteins (PHD 1–3) hydroxylate HIF-α, marking it for degradation. However, in hypoxic conditions, HIF-α is stabilized, leading to increased erythropoietin transcription and production. Interestingly, HIF also indirectly reduces hepcidin levels by stimulating erythroblasts (immature red blood cells) to secrete erythroferrone, a hormone that suppresses hepcidin production. This intricate interplay between erythropoietin, hepcidin, and HIF highlights the complexity of iron regulation and erythropoiesis in the context of CKD.

Image alt text: Diagram illustrating iron metabolism and erythropoiesis. Key elements include erythropoietin stimulation of red blood cell production, hepcidin regulation of iron release from macrophages and iron absorption, and the interplay of these factors in anemia of chronic kidney disease.

Epidemiology

Anemia of CKD typically becomes clinically significant when the glomerular filtration rate (GFR), a measure of kidney function, falls below 60 mL/min/1.73 m2. Even at stage 3 CKD, a considerable proportion, up to 20%, of patients exhibit anemia. As CKD progresses, the prevalence of anemia dramatically increases. It is estimated that at least 90% of patients who progress to dialysis-dependent ESRD will develop anemia.

The severity and frequency of anemia are directly linked to the declining GFR. Data from the National Health and Nutrition Examination Survey (NHANES) spanning 2007-2010 revealed that anemia was twice as prevalent in individuals with CKD compared to the general population. Similar findings have been reported by the CKD Prognosis Consortium, underscoring the strong epidemiological association between CKD and anemia. These statistics emphasize the significant public health burden of anemia of CKD and the importance of effective diagnostic and management strategies.

Pathophysiology

The pathophysiology of anemia of CKD is complex and multifactorial, involving both absolute and functional iron deficiencies, as well as erythropoietin deficiency and other contributing factors. As previously discussed, erythropoietin deficiency and impaired iron metabolism are central to the development of this condition.

Absolute iron deficiency in CKD can arise from several sources. Poor nutritional intake, particularly in patients with reduced appetite or dietary restrictions related to CKD management, can contribute to inadequate iron stores. Decreased iron absorption in the gastrointestinal tract, often due to chronic inflammation and elevated hepcidin levels, further limits iron availability. Frequent phlebotomy for blood testing, a routine aspect of CKD care, can lead to cumulative iron losses over time. Intradialytic blood losses, estimated to be around 161 mg of iron annually, also contribute to absolute iron deficiency in patients undergoing hemodialysis.

Functional iron deficiency, on the other hand, is characterized by the body’s inability to effectively access and utilize stored iron. As mentioned earlier, chronic inflammation associated with CKD induces a reticuloendothelial cell iron blockade. This inflammatory state leads to iron sequestration within macrophages and other storage cells, limiting its release for erythropoiesis. This phenomenon is not unique to CKD; any inflammatory condition can induce functional iron deficiency. Furthermore, the administration of exogenous erythropoietin can exacerbate functional iron deficiency. ESA therapy stimulates erythropoiesis, increasing the demand for iron. If iron release from storage is impaired due to inflammation, a supply-demand mismatch occurs, leading to functional iron deficiency even when total body iron stores might be adequate.

Beyond erythropoietin and iron dysregulation, other mechanisms contribute to the pathogenesis of anemia in CKD:

  • Shortened Red Blood Cell Lifespan: Studies using radioisotope labeling have demonstrated a reduced lifespan of red blood cells in CKD patients. Uremia and other unidentified factors are believed to contribute to this accelerated red blood cell destruction.

  • Nutritional Deficiencies: Deficiencies in essential nutrients like vitamin B12 and folate can worsen anemia in CKD. Dialysis can lead to the loss of water-soluble vitamins, and anorexia, common in CKD, can reduce overall nutrient intake. Although routine supplementation with water-soluble vitamins is standard practice in hemodialysis patients, micronutrient deficiencies can still occur.

  • Fibroblast Growth Factor 23 (FGF23): FGF23, a hormone produced by bone cells (osteocytes and osteoblasts), is markedly elevated in CKD, primarily due to metabolic bone disease associated with kidney dysfunction. Emerging research indicates that FGF23 may directly suppress erythropoiesis and erythropoietin production. Animal studies have shown that FGF23 antagonists can improve renal anemia, suggesting a potential therapeutic target.

In summary, anemia of chronic renal disease is a complex condition arising from a combination of relative erythropoietin deficiency, uremia-induced inhibitors of erythropoiesis, shortened red blood cell lifespan, disordered iron homeostasis (both absolute and functional iron deficiency), and other contributing factors like FGF23. Understanding this multifactorial etiology is crucial for developing comprehensive diagnostic and therapeutic strategies.

History and Physical Examination

The clinical presentation of anemia of chronic renal disease often mirrors that of anemia from other causes. Patients may experience a range of non-specific symptoms, including:

  • Generalized weakness and fatigue: A pervasive feeling of tiredness and lack of energy is a hallmark symptom of anemia.
  • Dyspnea: Shortness of breath, particularly with exertion, can occur due to reduced oxygen-carrying capacity of the blood.
  • Decreased concentration: Anemia can impair cognitive function, leading to difficulty focusing and concentrating.
  • Dizziness: Lightheadedness or dizziness, especially upon standing, can result from reduced blood flow to the brain.
  • Chest pain: Angina or chest pain, more common in severe anemia, can occur due to reduced oxygen supply to the heart muscle.
  • Headaches: Anemia can sometimes trigger headaches.
  • Reduced exercise tolerance: Patients may notice a significant decrease in their ability to perform physical activities.

Observable signs during a physical examination may include:

  • Skin and conjunctival pallor: Pale skin and pale mucous membranes (such as the conjunctiva of the eyes) are visual indicators of reduced hemoglobin levels.
  • Respiratory distress: In more severe cases, patients may exhibit signs of respiratory distress, such as increased respiratory rate or labored breathing.
  • Tachycardia: An elevated heart rate (tachycardia) can be a compensatory mechanism to improve oxygen delivery to tissues.
  • Heart failure: In chronic and severe anemia, particularly in patients with pre-existing cardiac conditions, heart failure can develop or worsen due to increased cardiac workload.

It is important to note that these signs and symptoms are not specific to anemia of CKD and can be present in various other conditions. Therefore, a thorough evaluation, including laboratory testing, is essential for accurate diagnosis.

Evaluation and Diagnosis of Anemia of CKD

The diagnosis of anemia of chronic renal disease relies on a combination of clinical assessment and laboratory investigations. The primary focus of the diagnostic process is to confirm the presence of anemia, characterize its nature, and exclude other potential causes of anemia before attributing it to CKD. As automotive technicians, we understand the importance of a systematic diagnostic approach, using various tools and tests to pinpoint the root cause of a vehicle malfunction. Similarly, in diagnosing anemia of CKD, a step-by-step evaluation is crucial.

The initial step in evaluating suspected anemia of CKD involves a complete blood count (CBC) with differential. This fundamental blood test provides key information about red blood cells, white blood cells, and platelets. In anemia of CKD, the CBC typically reveals:

  • Reduced hemoglobin (Hgb): Below 13 g/dL in men and 12 g/dL in women, confirming the presence of anemia.
  • Normal mean corpuscular volume (MCV): Indicating normocytic anemia, where red blood cell size is normal.
  • Normal mean corpuscular hemoglobin concentration (MCHC): Indicating normochromic anemia, where red blood cell hemoglobin content is normal.
  • Low or inappropriately normal reticulocyte count: Reticulocytes are immature red blood cells, and a low count suggests hypoproliferative anemia, meaning the bone marrow is not adequately producing new red blood cells. In healthy individuals with anemia, the reticulocyte count would typically be elevated as the bone marrow attempts to compensate. In CKD anemia, this compensatory response is blunted due to erythropoietin deficiency.

A peripheral blood smear is another valuable diagnostic tool. Examining a stained blood smear under a microscope can provide visual confirmation of normocytic and normochromic red blood cells. It can also help rule out other causes of anemia, such as hemolytic anemias (where red blood cells are prematurely destroyed) or anemias with abnormal red blood cell morphology. In cases of coexisting iron deficiency, the peripheral smear might reveal hypochromia (paler red blood cells) and microcytosis (smaller than normal red blood cells).

To exclude other potential causes of anemia, particularly those that are treatable, several additional blood tests are typically performed:

  • Vitamin B12 and folate levels: These tests assess for deficiencies in these essential vitamins, which are crucial for red blood cell production. Deficiencies can cause macrocytic anemia (large red blood cells) but can also contribute to anemia in CKD patients.
  • Haptoglobin level: Haptoglobin is a protein that binds free hemoglobin in the blood. A decreased haptoglobin level can indicate hemolysis, suggesting a cause of anemia other than CKD or a contributing factor.
  • Thyroid studies (thyroid-stimulating hormone – TSH): Hypothyroidism can cause anemia. Checking thyroid function helps rule out this endocrine disorder as a primary or contributing cause of anemia.

Iron indices are critical in evaluating iron status and differentiating between absolute and functional iron deficiency in anemia of CKD. The standard iron panel includes:

  • Serum iron level: Measures the amount of iron circulating in the blood, bound to transferrin. Normal range: 60 to 170 mcg/dL for adults.
  • Serum ferritin level: Reflects the body’s iron stores. Ferritin is an acute phase reactant, meaning its levels can be elevated by inflammation, even in the presence of iron deficiency. Normal range: 11 to 300 ng/mL.
  • Total iron-binding capacity (TIBC): Measures the amount of transferrin in the blood, which indirectly reflects the availability of binding sites for iron. Normal range: 240 to 450 mcg/dL.
  • Transferrin saturation (TSAT): Calculated as (serum iron / TIBC) x 100. Represents the percentage of transferrin saturated with iron, indicating the availability of iron for erythropoiesis. Normal range: 20% to 40%.

In pure iron deficiency anemia (e.g., due to dietary deficiency or blood loss), typical iron indices are: decreased serum iron, decreased ferritin, elevated TIBC, and decreased TSAT.

However, in anemia of CKD, the iron indices are often more complex and influenced by chronic inflammation. Common findings include:

  • Decreased or normal serum iron: May be decreased due to reduced iron availability but can also be within the normal range.
  • Decreased or normal TIBC: Often decreased or in the low-normal range, reflecting the inflammatory state.
  • Elevated ferritin: Serum ferritin levels are often elevated in CKD due to chronic inflammation, even if functional iron deficiency is present. Thus, a high ferritin level does not rule out iron deficiency in CKD.
  • Decreased TSAT: Transferrin saturation is typically decreased, indicating reduced iron availability for erythropoiesis, despite potentially elevated ferritin levels.

The Dialysis Patients’ Response to IV Iron With Elevated Ferritin (DRIVE) study demonstrated that intravenous (IV) iron can be beneficial in hemodialysis patients even with ferritin levels as high as 1200 ng/mL, provided that the TSAT is less than 30%. This highlights the importance of TSAT in guiding iron therapy in CKD patients, even in the context of elevated ferritin. Low ferritin levels are highly suggestive of iron deficiency, but elevated ferritin should be interpreted cautiously in CKD, as it can be misleading due to inflammation.

Reticulocyte indices, beyond the basic reticulocyte count, can provide more refined measures of functional iron deficiency and the bone marrow’s response to iron supplementation. Reticulocyte hemoglobin content (CHr or Ret-He) indirectly measures the amount of hemoglobin in reticulocytes. This parameter reflects iron availability for erythropoiesis over the preceding 3-4 days, potentially providing a more accurate assessment of functional iron availability compared to serum iron, ferritin, or MCV. However, this test has limitations and may not be accurate in certain conditions like thalassemias. Percentage of hypochromic red blood cells can also be measured; values above 4.3% are suggestive of iron deficiency.

Serum erythropoietin levels are generally not routinely measured in the diagnostic workup of anemia of CKD. This is because treatment decisions are primarily guided by hemoglobin levels, iron status, and response to therapy, rather than by erythropoietin levels. The concept of “relative erythropoietin deficiency” in CKD implies that erythropoietin levels, while potentially measurable, are inappropriately low relative to the degree of anemia. In other words, the body’s erythropoietin response is insufficient to overcome the underlying erythropoiesis-suppressing factors in CKD. Similarly, hepcidin levels are not typically measured in clinical practice, as they do not directly influence current treatment options.

Bone marrow biopsy is rarely performed for the routine diagnosis of anemia of CKD. It is considered the gold standard for assessing iron stores but is invasive and usually reserved for complex or atypical cases, or when other hematologic disorders are suspected. In anemia of CKD, bone marrow biopsy may reveal erythroid hypoplasia (reduced erythroid precursors) or depleted iron stores, which can correlate with the reported resistance of bone marrow to erythropoietin stimulation in some CKD patients.

In summary, the diagnosis of anemia of CKD is typically established based on:

  1. Clinical context: Presence of chronic kidney disease.
  2. CBC findings: Normocytic, normochromic, hypoproliferative anemia.
  3. Peripheral smear: Normocytic, normochromic red blood cells, ruling out other morphological abnormalities.
  4. Exclusion of other causes: Normal vitamin B12, folate, thyroid function, and consideration of hemolysis.
  5. Iron indices: Characteristically low TSAT, elevated or normal ferritin (interpreting ferritin cautiously due to inflammation).
  6. Reticulocyte indices: Low reticulocyte count and potentially low reticulocyte hemoglobin content supporting hypoproliferative nature and functional iron deficiency.

This comprehensive evaluation, akin to a detailed automotive diagnostic process, allows for accurate diagnosis and guides appropriate management strategies for anemia of CKD.

Treatment and Management (Brief Overview relevant to Diagnosis Context)

While this article focuses on diagnosis, it’s important to briefly touch upon treatment as diagnostic findings directly influence management strategies. The primary goals of treatment for anemia of CKD are to alleviate symptoms, improve quality of life, reduce cardiovascular risk, and minimize the need for blood transfusions. Treatment strategies are guided by diagnostic parameters, particularly hemoglobin levels and iron status.

Erythropoiesis-Stimulating Agents (ESAs) and iron supplementation form the cornerstone of anemia of CKD treatment. ESAs, such as epoetin alfa and darbepoetin alfa, are synthetic forms of erythropoietin that stimulate red blood cell production. Iron supplementation is crucial to ensure adequate iron availability for erythropoiesis, especially when ESA therapy is initiated. Due to impaired oral iron absorption in CKD, intravenous (IV) iron is often the preferred route, particularly in hemodialysis patients and those with advanced CKD.

KDIGO guidelines recommend considering ESA therapy when hemoglobin levels fall below 10 g/dL in CKD patients. However, treatment decisions are individualized, taking into account factors like symptoms, rate of hemoglobin decline, transfusion requirements, and response to iron therapy. Target hemoglobin levels with ESA therapy are generally less than 11.5 g/dL, as higher targets have not shown to be beneficial and may increase cardiovascular risks. Iron supplementation is guided by TSAT and ferritin levels, with KDIGO recommending target ranges of TSAT 20-30% and ferritin 100-500 ng/mL. However, recent studies suggest that more liberal iron administration strategies, with higher ferritin and TSAT targets, may be beneficial in certain patient populations.

Novel therapies are emerging for anemia of CKD, including hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs), which stimulate endogenous erythropoietin production by stabilizing HIF. Other novel iron therapies, such as ferric citrate, ferric maltol, sucrosomial iron, and ferric pyrophosphate, offer alternative routes of iron administration and may address some of the limitations of traditional oral and IV iron formulations. Ziltivekimab, an anti-inflammatory antibody targeting interleukin-6, is also being investigated as a potential treatment for anemia of inflammation in CKD.

The choice of treatment strategy for anemia of CKD is directly linked to the diagnostic evaluation. Hemoglobin levels guide the initiation and adjustment of ESA therapy. Iron indices, particularly TSAT and ferritin, guide iron supplementation strategies, including the route of administration (oral vs. IV) and target iron parameters. Understanding the underlying pathophysiology and diagnostic findings is therefore essential for effective and personalized management of anemia of CKD.

Differential Diagnosis

When diagnosing anemia of chronic renal disease, it is crucial to consider and exclude other conditions that can cause anemia, as some may have overlapping clinical features or may coexist with CKD. The differential diagnosis of anemia in CKD includes:

  • Alcohol use disorder: Chronic alcohol abuse can lead to various forms of anemia, including macrocytic anemia and iron deficiency anemia.
  • Aplastic anemia: A rare condition characterized by bone marrow failure and pancytopenia (deficiency of all blood cell types).
  • Dialysis-related blood loss: Significant blood loss during dialysis can contribute to anemia.
  • Hypothyroidism: As mentioned earlier, hypothyroidism can cause anemia, typically normocytic or macrocytic.
  • Gastrointestinal losses: Chronic blood loss from the gastrointestinal tract, such as from ulcers or tumors, can lead to iron deficiency anemia.
  • Medication-induced anemia: Certain medications, such as ACE inhibitors and ARBs (commonly used in CKD management), can sometimes contribute to anemia. Other drugs can cause hemolytic anemia or aplastic anemia.
  • Methemoglobinemia: A rare condition where hemoglobin is unable to carry oxygen effectively.
  • Myelophthisic anemia: Anemia caused by bone marrow infiltration by abnormal cells, such as in metastatic cancer or myelofibrosis.
  • Sickle cell anemia: A genetic disorder causing hemolytic anemia and characteristic sickle-shaped red blood cells. While less common in older adults developing CKD, it should be considered in relevant populations.
  • Systemic lupus erythematosus (SLE): This autoimmune disease can cause anemia through various mechanisms, including anemia of chronic inflammation, hemolytic anemia, and bone marrow suppression.
  • Panhypopituitarism: Pituitary gland dysfunction can lead to deficiencies in hormones that stimulate erythropoiesis.
  • Primary and secondary hyperparathyroidism: While primarily affecting calcium and bone metabolism, hyperparathyroidism can sometimes contribute to anemia.

A thorough diagnostic evaluation, as outlined previously, including CBC, peripheral smear, iron studies, vitamin levels, and other relevant blood tests, is essential to differentiate anemia of CKD from these other potential causes. Clinical history, physical examination findings, and consideration of comorbidities are also crucial in narrowing down the differential diagnosis.

Prognosis and Complications (Briefly in Diagnostic Context)

While prognosis and complications are primarily relevant to the overall management of CKD and anemia, they have indirect implications for diagnosis. Patients with anemia of CKD who are unresponsive to erythropoietin therapy have a poorer prognosis and are at higher risk of adverse cardiac events. Identifying ESA hyporesponsiveness during the diagnostic and monitoring phase is therefore important. Iron deficiency and inflammation are key factors contributing to ESA hyporesponsiveness. Elevated levels of C-reactive protein (CRP), a marker of inflammation, are associated with resistance to erythropoietin in dialysis patients.

Anemia of CKD is a significant component of the cardiorenal anemia syndrome, highlighting the interconnectedness of kidney disease, heart disease, and anemia. The severity of anemia is associated with adverse cardiovascular outcomes. Studies have shown that for every 1 g/dL decrease in hemoglobin concentration, there is a significant increase in left ventricular dilatation in patients with stage 5 CKD, indicating increased cardiac stress. Cardiovascular disease remains the leading cause of mortality in CKD patients, and anemia contributes to this increased risk.

The Dialysis Outcomes Practice Pattern Study (DOPPS) has demonstrated that hemoglobin levels below 11 g/dL are associated with increased hospitalization and mortality in CKD patients. This underscores the importance of effective anemia management in improving overall outcomes.

Complications of untreated or poorly managed anemia of CKD are numerous and contribute to reduced quality of life and increased morbidity and mortality. Anemia is an independent risk factor for death in CKD patients. It can accelerate the progression of left ventricular hypertrophy, increase peripheral oxygen demand, and worsen cardiac outcomes. Other complications include depression, fatigue, stroke, reduced exercise tolerance, and increased risk of hospital readmission. Early and accurate diagnosis, followed by appropriate management, is crucial to mitigate these complications and improve patient prognosis.

Deterrence and Patient Education (Diagnostic Relevance)

While deterrence of CKD itself is a broader topic, patient education plays a crucial role in the diagnostic process and ongoing management of anemia of CKD. Healthcare providers should educate patients about the causes and consequences of anemia associated with CKD. Understanding the link between kidney disease and anemia can improve patient adherence to diagnostic testing and treatment plans.

Dietary counseling, often with the help of a dietitian, is important in addressing potential nutritional deficiencies that can contribute to anemia. Patients should be educated about iron-rich foods and strategies to optimize iron absorption, although oral iron may be less effective in advanced CKD. Patients should also be instructed to report any symptoms of anemia, such as fatigue, shortness of breath, or dizziness, to their healthcare providers promptly. Early reporting of symptoms can trigger timely diagnostic evaluation and intervention.

For patients receiving ESA therapy at home, proper education on medication storage and administration is essential. Some ESAs require refrigeration, and patients need to understand subcutaneous injection techniques if self-administering the medication. Adherence to prescribed medication regimens is crucial for effective anemia management, and patient education is a key component in achieving this adherence.

Pearls and Key Issues in Anemia of CKD Diagnosis

Key points to remember regarding the diagnosis of anemia of chronic renal disease:

  • Anemia of CKD is a prevalent complication primarily caused by decreased erythropoietin production and abnormal iron metabolism.
  • Typical iron indices in anemia of CKD are: normal or low serum iron and TIBC, low TSAT, and elevated ferritin (interpreting ferritin cautiously due to inflammation).
  • Reticulocyte hemoglobin content and percentage of hypochromic RBCs can provide more accurate assessments of recent iron availability than traditional iron indices.
  • Current KDIGO guidelines recommend initiating IV iron therapy when ferritin is less than 500 ng/mL and TSAT is less than 30%. However, newer studies suggest potential benefits of IV iron even with higher ferritin levels.
  • Serum erythropoietin levels are generally not helpful in routine diagnosis or treatment decisions.
  • A thorough diagnostic evaluation is essential to exclude other causes of anemia and guide appropriate management strategies.
  • Early and accurate diagnosis of anemia of CKD is crucial for improving patient outcomes and reducing complications.

Enhancing Healthcare Team Outcomes in Diagnosis

Effective diagnosis and management of anemia of CKD require a collaborative approach by an interprofessional healthcare team. This team typically includes nephrologists, primary care physicians, hematologists, nurse practitioners, physician assistants, nurses, pharmacists, dietitians, and dialysis technicians. Each member plays a vital role in the diagnostic process and ongoing patient care.

Nephrologists and primary care physicians are often the first to suspect anemia of CKD based on clinical presentation and CKD diagnosis. They initiate the diagnostic workup, order appropriate laboratory tests, and interpret the results. Hematologists may be consulted in complex cases or when there is diagnostic uncertainty. Nurses, particularly dialysis nurses, play a crucial role in monitoring patients for signs and symptoms of anemia, obtaining blood samples for laboratory testing, and administering medications. Pharmacists ensure appropriate medication management, including ESA and iron therapy, and monitor for drug interactions and adverse effects. Dietitians provide nutritional counseling to address dietary iron intake and optimize overall nutritional status. Dialysis technicians are essential in the dialysis setting, monitoring patients during dialysis, administering medications as prescribed, and reporting any relevant observations to the healthcare team.

Effective interprofessional communication and care coordination are paramount for optimal diagnostic and management outcomes. Regular team meetings, clear communication channels, and shared electronic health records facilitate information exchange and collaborative decision-making. A strategic approach to anemia management, guided by evidence-based guidelines and individualized patient needs, is essential. Ethical considerations, including informed consent and patient autonomy in treatment choices, should guide all aspects of care. By fostering a multidisciplinary approach, leveraging each team member’s expertise, and prioritizing patient-centered care, healthcare teams can enhance diagnostic accuracy, optimize treatment strategies, and improve outcomes for patients with anemia of CKD.

Review Questions (Example based on Diagnostic Content)

  1. Which of the following is a typical finding in the complete blood count (CBC) of a patient with anemia of chronic kidney disease?
    a) Macrocytic anemia
    b) Microcytic anemia
    c) Normocytic anemia
    d) Elevated reticulocyte count

  2. Which iron index is most helpful in differentiating functional iron deficiency from absolute iron deficiency in anemia of CKD?
    a) Serum iron
    b) Serum ferritin
    c) Total iron-binding capacity (TIBC)
    d) Transferrin saturation (TSAT)

  3. Elevated serum ferritin levels in a patient with CKD definitively rule out iron deficiency. True or False?

  4. Serum erythropoietin levels are routinely measured to guide treatment decisions in anemia of CKD. True or False?

  5. Which of the following is NOT typically part of the initial diagnostic evaluation for anemia of CKD?
    a) Complete blood count (CBC)
    b) Peripheral blood smear
    c) Bone marrow biopsy
    d) Iron indices (serum iron, ferritin, TIBC, TSAT)

Answer Key: 1-c, 2-d, 3-False, 4-False, 5-c

References

  1. Badura K, Janc J, Wąsik J, Gnitecki S, Skwira S, Młynarska E, Rysz J, Franczyk B. Anemia of Chronic Kidney Disease-A Narrative Review of Its Pathophysiology, Diagnosis, and Management. Biomedicines. 2024 May 27;12(6) [PMC free article: PMC11200696] [PubMed: 38927397]

  2. Babitt JL, Eisenga MF, Haase VH, Kshirsagar AV, Levin A, Locatelli F, Małyszko J, Swinkels DW, Tarng DC, Cheung M, Jadoul M, Winkelmayer WC, Drüeke TB., Conference Participants. Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference. Kidney Int. 2021 Jun;99(6):1280-1295. [PubMed: 33839163]

  3. Cases and Observations Illustrative of Renal Disease, Accompanied with the Secretion of Albuminous Urine. Med Chir Rev. 1836 Jul 01;25(49):23-35. [PMC free article: PMC5093576] [PubMed: 29918407]

  4. Fishbane S, Coyne DW. How I treat renal anemia. Blood. 2020 Aug 13;136(7):783-789. [PubMed: 32556307]

  5. DeGowin RL, Lavender AR, Forland M, Charleston D, Gottschalk A. Erythropoiesis and erythropoietin in patients with chronic renal failure treated with hemodialysis and testosterone. Ann Intern Med. 1970 Jun;72(6):913-8. [PubMed: 5448750]

  6. Richardson JR, Weinstein MB. Erythropoietic response of dialyzed patients to testosterone administration. Ann Intern Med. 1970 Sep;73(3):403-7. [PubMed: 5455991]

  7. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med. 1987 Jan 08;316(2):73-8. [PubMed: 3537801]

  8. Macdougall IC, Lewis NP, Saunders MJ, Cochlin DL, Davies ME, Hutton RD, Fox KA, Coles GA, Williams JD. Long-term cardiorespiratory effects of amelioration of renal anaemia by erythropoietin. Lancet. 1990 Mar 03;335(8688):489-93. [PubMed: 1968526]

  9. Perkins R, Olson S, Hansen J, Lee J, Stiles K, Lebrun C. Impact of an anemia clinic on emergency room visits and hospitalizations in patients with anemia of CKD pre-dialysis. Nephrol Nurs J. 2007 Mar-Apr;34(2):167-73, 182. [PubMed: 17486947]

  10. Maddux FW, Shetty S, del Aguila MA, Nelson MA, Murray BM. Effect of erythropoiesis-stimulating agents on healthcare utilization, costs, and outcomes in chronic kidney disease. Ann Pharmacother. 2007 Nov;41(11):1761-9. [PubMed: 17895328]

  11. Charytan DM, Pai AB, Chan CT, Coyne DW, Hung AM, Kovesdy CP, Fishbane S., Dialysis Advisory Group of the American Society of Nephrology. Considerations and challenges in defining optimal iron utilization in hemodialysis. J Am Soc Nephrol. 2015 Jun;26(6):1238-47. [PMC free article: PMC4446883] [PubMed: 25542967]

  12. Coyne DW. The health-related quality of life was not improved by targeting higher hemoglobin in the Normal Hematocrit Trial. Kidney Int. 2012 Jul;82(2):235-41. [PMC free article: PMC3388517] [PubMed: 22437411]

  13. Bernhardt WM, Wiesener MS, Scigalla P, Chou J, Schmieder RE, Günzler V, Eckardt KU. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J Am Soc Nephrol. 2010 Dec;21(12):2151-6. [PMC free article: PMC3014028] [PubMed: 21115615]

  14. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995 Jun 06;92(12):5510-4. [PMC free article: PMC41725] [PubMed: 7539918]

  15. Agarwal AK. Practical approach to the diagnosis and treatment of anemia associated with CKD in elderly. J Am Med Dir Assoc. 2006 Nov;7(9 Suppl):S7-S12; quiz S17-21. [PubMed: 17098634]

  16. Batchelor EK, Kapitsinou P, Pergola PE, Kovesdy CP, Jalal DI. Iron Deficiency in Chronic Kidney Disease: Updates on Pathophysiology, Diagnosis, and Treatment. J Am Soc Nephrol. 2020 Mar;31(3):456-468. [PMC free article: PMC7062209] [PubMed: 32041774]

  17. Lee KH, Ho Y, Tarng DC. Iron Therapy in Chronic Kidney Disease: Days of Future Past. Int J Mol Sci. 2021 Jan 20;22(3) [PMC free article: PMC7863960] [PubMed: 33498292]

  18. Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest. 2007 Jul;117(7):1933-9. [PMC free article: PMC1904317] [PubMed: 17607365]

  19. Nakai T, Iwamura Y, Kato K, Hirano I, Matsumoto Y, Tomioka Y, Yamamoto M, Suzuki N. Drugs activating hypoxia-inducible factors correct erythropoiesis and hepcidin levels via renal EPO induction in mice. Blood Adv. 2023 Aug 08;7(15):3793-3805. [PMC free article: PMC10393763] [PubMed: 37146271]

  20. St Peter WL, Guo H, Kabadi S, Gilbertson DT, Peng Y, Pendergraft T, Li S. Prevalence, treatment patterns, and healthcare resource utilization in Medicare and commercially insured non-dialysis-dependent chronic kidney disease patients with and without anemia in the United States. BMC Nephrol. 2018 Mar 15;19(1):67. [PMC free article: PMC5856223] [PubMed: 29544446]

  21. Inker LA, Grams ME, Levey AS, Coresh J, Cirillo M, Collins JF, Gansevoort RT, Gutierrez OM, Hamano T, Heine GH, Ishikawa S, Jee SH, Kronenberg F, Landray MJ, Miura K, Nadkarni GN, Peralta CA, Rothenbacher D, Schaeffner E, Sedaghat S, Shlipak MG, Zhang L, van Zuilen AD, Hallan SI, Kovesdy CP, Woodward M, Levin A., CKD Prognosis Consortium. Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium. Am J Kidney Dis. 2019 Feb;73(2):206-217. [PMC free article: PMC6348050] [PubMed: 30348535]

  22. KDOQI; National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis. 2006 May;47(5 Suppl 3):S11-145. [PubMed: 16678659]

  23. Tsukamoto T, Matsubara T, Akashi Y, Kondo M, Yanagita M. Annual Iron Loss Associated with Hemodialysis. Am J Nephrol. 2016;43(1):32-8. [PubMed: 26885949]

  24. Park MY, Le Henaff C, Sitara D. Administration of α-Klotho Does Not Rescue Renal Anemia in Mice. Front Pediatr. 2022;10:924915. [PMC free article: PMC9259788] [PubMed: 35813388]

  25. Eschbach JW. The anemia of chronic renal failure: pathophysiology and the effects of recombinant erythropoietin. Kidney Int. 1989 Jan;35(1):134-48. [PubMed: 2651751]

  26. Vos FE, Schollum JB, Coulter CV, Doyle TC, Duffull SB, Walker RJ. Red blood cell survival in long-term dialysis patients. Am J Kidney Dis. 2011 Oct;58(4):591-8. [PubMed: 21715072]

  27. Eschbach JW, Funk D, Adamson J, Kuhn I, Scribner BH, Finch CA. Erythropoiesis in patients with renal failure undergoing chronic dialysis. N Engl J Med. 1967 Mar 23;276(12):653-8. [PubMed: 6018456]

  28. Tessitore N, Solero GP, Lippi G, Bassi A, Faccini GB, Bedogna V, Gammaro L, Brocco G, Restivo G, Bernich P, Lupo A, Maschio G. The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin. Nephrol Dial Transplant. 2001 Jul;16(7):1416-23. [PubMed: 11427634]

  29. Mittman N, Sreedhara R, Mushnick R, Chattopadhyay J, Zelmanovic D, Vaseghi M, Avram MM. Reticulocyte hemoglobin content predicts functional iron deficiency in hemodialysis patients receiving rHuEPO. Am J Kidney Dis. 1997 Dec;30(6):912-22. [PubMed: 9398141]

  30. Coyne DW, Kapoian T, Suki W, Singh AK, Moran JE, Dahl NV, Rizkala AR., DRIVE Study Group. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) Study. J Am Soc Nephrol. 2007 Mar;18(3):975-84. [PubMed: 17267740]

  31. Mast AE, Blinder MA, Dietzen DJ. Reticulocyte hemoglobin content. Am J Hematol. 2008 Apr;83(4):307-10. [PubMed: 18027835]

  32. Karagülle M, Gündüz E, Sahin Mutlu F, Olga Akay M. Clinical significance of reticulocyte hemoglobin content in the diagnosis of iron deficiency anemia. Turk J Haematol. 2013 Jun;30(2):153-6. [PMC free article: PMC3878462] [PubMed: 24385778]

  33. Radtke HW, Claussner A, Erbes PM, Scheuermann EH, Schoeppe W, Koch KM. Serum erythropoietin concentration in chronic renal failure: relationship to degree of anemia and excretory renal function. Blood. 1979 Oct;54(4):877-84. [PubMed: 476305]

  34. Korte W, Cogliatti SB, Jung K, Riesen W. Mild renal dysfunction is sufficient to induce erythropoietin deficiency in patients with unexplained anaemia. Clin Chim Acta. 2000 Feb 25;292(1-2):149-54. [PubMed: 10686284]

  35. Phiri KS, Calis JC, Kachala D, Borgstein E, Waluza J, Bates I, Brabin B, van Hensbroek MB. Improved method for assessing iron stores in the bone marrow. J Clin Pathol. 2009 Aug;62(8):685-9. [PMC free article: PMC2709917] [PubMed: 19638538]

  36. Carrera F, Burnier M. Use of darbepoetin alfa in the treatment of anaemia of chronic kidney disease: clinical and pharmacoeconomic considerations. NDT Plus. 2009 Jan;2(Suppl_1):i9-i17. [PMC free article: PMC2638549] [PubMed: 19461859]

  37. Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Nephrol Dial Transplant. 2001;16 Suppl 3:3-13. [PubMed: 11402085]

  38. Fishbane S, Spinowitz B. Update on Anemia in ESRD and Earlier Stages of CKD: Core Curriculum 2018. Am J Kidney Dis. 2018 Mar;71(3):423-435. [PubMed: 29336855]

  39. Fishbane S, Singh B, Kumbhat S, Wisemandle WA, Martin NE. Intravenous Epoetin Alfa-epbx versus Epoetin Alfa for Treatment of Anemia in End-Stage Kidney Disease. Clin J Am Soc Nephrol. 2018 Aug 07;13(8):1204-1214. [PMC free article: PMC6086700] [PubMed: 29921734]

  40. Wish JB, Rocha MG, Martin NE, Reyes CRD, Fishbane S, Smith MT, Nassar G. Long-term Safety of Epoetin Alfa-epbx for the Treatment of Anemia in ESKD: Pooled Analyses of Randomized and Open-label Studies. Kidney Med. 2019 Sep-Oct;1(5):271-280. [PMC free article: PMC7380401] [PubMed: 32734207]

  41. Fishbane S, Spinowitz BS, Wisemandle WA, Martin NE. Randomized Controlled Trial of Subcutaneous Epoetin Alfa-epbx Versus Epoetin Alfa in End-Stage Kidney Disease. Kidney Int Rep. 2019 Sep;4(9):1235-1247. [PMC free article: PMC6734106] [PubMed: 31517143]

  42. Macdougall IC, Walker R, Provenzano R, de Alvaro F, Locay HR, Nader PC, Locatelli F, Dougherty FC, Beyer U., ARCTOS Study Investigators. C.E.R.A. corrects anemia in patients with chronic kidney disease not on dialysis: results of a randomized clinical trial. Clin J Am Soc Nephrol. 2008 Mar;3(2):337-47. [PMC free article: PMC2390949] [PubMed: 18287255]

  43. Panchapakesan U, Sumual S, Pollock C. Nanomedicines in the treatment of anemia in renal disease: focus on CERA (Continuous Erythropoietin Receptor Activator). Int J Nanomedicine. 2007;2(1):33-8. [PMC free article: PMC2673829] [PubMed: 17722510]

  44. Szczech LA, Barnhart HX, Inrig JK, Reddan DN, Sapp S, Califf RM, Patel UD, Singh AK. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int. 2008 Sep;74(6):791-8. [PMC free article: PMC2902279] [PubMed: 18596733]

  45. Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin DA. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998 Aug 27;339(9):584-90. [PubMed: 9718377]

  46. Bello NA, Lewis EF, Desai AS, Anand IS, Krum H, McMurray JJ, Olson K, Solomon SD, Swedberg K, van Veldhuisen DJ, Young JB, Pfeffer MA. Increased risk of stroke with darbepoetin alfa in anaemic heart failure patients with diabetes and chronic kidney disease. Eur J Heart Fail. 2015 Nov;17(11):1201-7. [PMC free article: PMC4703474] [PubMed: 26423928]

  47. Ye Y, Liu H, Chen Y, Zhang Y, Li S, Hu W, Yang R, Zhang Z, Lv L, Liu X. Hemoglobin targets for the anemia in patients with dialysis-dependent chronic kidney disease: a meta-analysis of randomized, controlled trials. Ren Fail. 2018 Nov;40(1):671-679. [PMC free article: PMC6282462] [PubMed: 30741617]

  48. Ku E, Del Vecchio L, Eckardt KU, Haase VH, Johansen KL, Nangaku M, Tangri N, Waikar SS, Więcek A, Cheung M, Jadoul M, Winkelmayer WC, Wheeler DC., for Conference Participants. Novel anemia therapies in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2023 Oct;104(4):655-680. [PubMed: 37236424]

  49. Fishbane S, Berns JS. Hemoglobin cycling in hemodialysis patients treated with recombinant human erythropoietin. Kidney Int. 2005 Sep;68(3):1337-43. [PubMed: 16105069]

  50. Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, Zwahlen M, Clarke MJ, Weingart O, Kluge S, Piper M, Napoli M, Rades D, Steensma D, Djulbegovic B, Fey MF, Ray-Coquard I, Moebus V, Thomas G, Untch M, Schumacher M, Egger M, Engert A. Erythropoietin or Darbepoetin for patients with cancer–meta-analysis based on individual patient data. Cochrane Database Syst Rev. 2009 Jul 08;2009(3):CD007303. [PMC free article: PMC7208183] [PubMed: 19588423]

  51. Badiu I, Diena D, Guida G, Ferrando C, Rapezzi D, Besso L. Cutaneous allergic reaction correlates with anti-erythropoietin antibodies in dialysis patient developing pure red cell aplasia. Clin Case Rep. 2022 Apr;10(4):e05554. [PMC free article: PMC8979157] [PubMed: 35414924]

  52. Casadevall N. Antibodies against rHuEPO: native and recombinant. Nephrol Dial Transplant. 2002;17 Suppl 5:42-7. [PubMed: 12091607]

  53. McKoy JM, Stonecash RE, Cournoyer D, Rossert J, Nissenson AR, Raisch DW, Casadevall N, Bennett CL. Epoetin-associated pure red cell aplasia: past, present, and future considerations. Transfusion. 2008 Aug;48(8):1754-62. [PMC free article: PMC2730535] [PubMed: 18482185]

  54. Macdougall IC, Casadevall N, Locatelli F, Combe C, London GM, Di Paolo S, Kribben A, Fliser D, Messner H, McNeil J, Stevens P, Santoro A, De Francisco AL, Percheson P, Potamianou A, Foucher A, Fife D, Mérit V, Vercammen E., PRIMS study group. Incidence of erythropoietin antibody-mediated pure red cell aplasia: the Prospective Immunogenicity Surveillance Registry (PRIMS). Nephrol Dial Transplant. 2015 Mar;30(3):451-60. [PMC free article: PMC4339685] [PubMed: 25239637]

  55. Fudin R, Jaichenko J, Shostak A, Bennett M, Gotloib L. Correction of uremic iron deficiency anemia in hemodialyzed patients: a prospective study. Nephron. 1998;79(3):299-305. [PubMed: 9678430]

  56. Markowitz GS, Kahn GA, Feingold RE, Coco M, Lynn RI. An evaluation of the effectiveness of oral iron therapy in hemodialysis patients receiving recombinant human erythropoietin. Clin Nephrol. 1997 Jul;48(1):34-40. [PubMed: 9247776]

  57. Mikhail A, Brown C, Williams JA, Mathrani V, Shrivastava R, Evans J, Isaac H, Bhandari S. Renal association clinical practice guideline on Anaemia of Chronic Kidney Disease. BMC Nephrol. 2017 Nov 30;18(1):345. [PMC free article: PMC5709852] [PubMed: 29191165]

  58. Wolf M, Rubin J, Achebe M, Econs MJ, Peacock M, Imel EA, Thomsen LL, Carpenter TO, Weber T, Brandenburg V, Zoller H. Effects of Iron Isomaltoside vs Ferric Carboxymaltose on Hypophosphatemia in Iron-Deficiency Anemia: Two Randomized Clinical Trials. JAMA. 2020 Feb 04;323(5):432-443. [PMC free article: PMC7042864] [PubMed: 32016310]

  59. Pergola PE, Fishbane S, Ganz T. Novel Oral Iron Therapies for Iron Deficiency Anemia in Chronic Kidney Disease. Adv Chronic Kidney Dis. 2019 Jul;26(4):272-291. [PubMed: 31477258]

  60. Fishbane SN, Singh AK, Cournoyer SH, Jindal KK, Fanti P, Guss CD, Lin VH, Pratt RD, Gupta A. Ferric pyrophosphate citrate (Triferic™) administration via the dialysate maintains hemoglobin and iron balance in chronic hemodialysis patients. Nephrol Dial Transplant. 2015 Dec;30(12):2019-26. [PMC free article: PMC4656038] [PubMed: 26175145]

  61. Fell LH, Fliser D, Heine GH. Ferric pyrophosphate: good things come to those who wait? Nephrol Dial Transplant. 2015 Dec;30(12):1942-4. [PMC free article: PMC4832995] [PubMed: 26203048]

  62. Singh AK, Carroll K, McMurray JJV, Solomon S, Jha V, Johansen KL, Lopes RD, Macdougall IC, Obrador GT, Waikar SS, Wanner C, Wheeler DC, Więcek A, Blackorby A, Cizman B, Cobitz AR, Davies R, DiMino TL, Kler L, Meadowcroft AM, Taft L, Perkovic V., ASCEND-ND Study Group. Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis. N Engl J Med. 2021 Dec 16;385(25):2313-2324. [PubMed: 34739196]

  63. Haider MU, Furqan M, Mehmood Q. Daprodustat: A potential game-changer in renal anemia therapy-A perspective. Front Pharmacol. 2023;14:1249492. [PMC free article: PMC10449327] [PubMed: 37637409]

  64. Xu Q, Huang J, Liu Q, Wang X, Liu H, Song Y, Dou F, Lv S, Liu G. Short-term effect of low-dose roxadustat combined with erythropoiesis-stimulating agent treatment for erythropoietin-resistant anemia in patients undergoing maintenance hemodialysis. Front Endocrinol (Lausanne). 2024;15:1372150. [PMC free article: PMC11246906] [PubMed: 39010898]

  65. Pergola PE, Devalaraja M, Fishbane S, Chonchol M, Mathur VS, Smith MT, Lo L, Herzog K, Kakkar R, Davidson MH. Ziltivekimab for Treatment of Anemia of Inflammation in Patients on Hemodialysis: Results from a Phase 1/2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial. J Am Soc Nephrol. 2021 Jan;32(1):211-222. [PMC free article: PMC7894678] [PubMed: 33272965]

  66. Pergola PE, Davidson M, Jensen C, Mohseni Zonoozi AA, Raj DS, Andreas Schytz P, Tuttle KR, Perkovic V. Effect of Ziltivekimab on Determinants of Hemoglobin in Patients with CKD Stage 3-5: An Analysis of a Randomized Trial (RESCUE). J Am Soc Nephrol. 2024 Jan 01;35(1):74-84. [PMC free article: PMC10786611] [PubMed: 38088558]

  67. Fishbane S, Block GA, Loram L, Neylan J, Pergola PE, Uhlig K, Chertow GM. Effects of Ferric Citrate in Patients with Nondialysis-Dependent CKD and Iron Deficiency Anemia. J Am Soc Nephrol. 2017 Jun;28(6):1851-1858. [PMC free article: PMC5461803] [PubMed: 28082519]

  68. Sarnak MJ, Levey AS. Epidemiology, diagnosis, and management of cardiac disease in chronic renal disease. J Thromb Thrombolysis. 2000 Oct;10(2):169-80. [PubMed: 11005939]

  69. Pisoni RL, Bragg-Gresham JL, Young EW, Akizawa T, Asano Y, Locatelli F, Bommer J, Cruz JM, Kerr PG, Mendelssohn DC, Held PJ, Port FK. Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2004 Jul;44(1):94-111. [PubMed: 15211443]

  70. Del Fabbro P, Luthi JC, Carrera E, Michel P, Burnier M, Burnand B. Anemia and chronic kidney disease are potential risk factors for mortality in stroke patients: a historic cohort study. BMC Nephrol. 2010 Oct 16;11:27. [PMC free article: PMC2973927] [PubMed: 20950484]

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