Kidney involvement and anemia in COVID-19 infection

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for coronavirus disease 2019 (COVID-19), has infected > 700 million people and led to > 7 million deaths worldwide. Although COVID-19 primarily affects the lungs, it can also affect the kidneys through various pathways. SARS-CoV-2 affects the kidney via several common mechanisms, such as dysregulation of angiotensin-converting enzyme 2, transmembrane serine protease 2 and tissue proteinase L expression in kidney tissue. People with chronic kidney disease (CKD) and COVID-19 have an increased risk of mortality and hospitalization in the intensive care unit. Anemia, a common consequence of CKD, is also associated with worsening outcomes in COVID-19 patients. In these patients with multiple comorbidities, there is a sharp increase in D-dimers, inflammatory parameters, creatinine and blood urea nitrogen. COVID-19 patients also present with resistance to erythropoietin (EPO)-stimulating agents, which necessitates elevated dosages even several months post-infection. In CKD, anemia is exacerbated by decreased EPO production, red blood cell (RBC) fragmentation due to impairment of the renovascular endothelium in situations such as glomerulopathy and malignant hypertension. Other factors include iron and/or folic acid deficiency, bleeding due to platelet dysfunction, inflammation, reduced RBC lifespan, poor iron utilization, uremia, and atypical blood loss after dialysis. Excessive hepcidin synthesis impairs the absorption of dietary iron and the mobilization of iron from endogenous reserves, thus contributing significantly to anemia and poor iron regulation in CKD. These findings suggest that CKD may contribute to the occurrence of anemia in COVID-19 patients, especially in older people with comorbidities. Our review aims to explore the complex relationship between CKD, COVID-19 and anemia to improve our understanding of the underlying mechanisms of the disease and the potential cofactors that worsen outcomes in these patients.

Key Words: COVID 19; Hemodialysis; Renal transplant; Erythropoietin; Peritoneal dialysis; Iron deficiency; Renal anemia; Systemic inflammation; Renal replacement therapy

Core Tip: Severe acute respiratory syndrome coronavirus 2, the causative agent of coronavirus disease 2019 (COVID-19) infection, has had a major impact worldwide. People with chronic kidney disease (CKD) and COVID-19 have an increased risk of mortality and hospitalization, with anemia, which is common in CKD, exacerbating outcomes. Patients with CKD show resistance to erythropoietin (EPO)-stimulating agents and require higher doses even after infection. Anemia in CKD is exacerbated by factors such as decreased EPO production, red blood cell fragmentation, iron or folic acid deficiency, platelet dysfunction and excessive hepcidin synthesis. These factors contribute to poor iron regulation, which further complicates anemia in COVID-19 patients.

INTRODUCTION

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the highly transmissible virus that is responsible for the coronavirus disease 2019 (COVID-19) pandemic, has had a profound impact on global health, causing millions of deaths worldwide[1]. Its rapid transmission has disproportionally affected the most vulnerable populations with pre-existing conditions, including patients with chronic kidney disease (CKD). As of 2024, CKD is estimated to affect 850 million people worldwide, which represents > 10% of the world's population, with an average prevalence of 9.5%[2]. Systemic inflammation and immune deficiency are often found in patients with CKD and predispose patients to an increased risk of COVID-19 and its adverse outcomes, including further kidney function decline, cardiovascular events, hospitalization, and death. Infection risk is higher among patients undergoing both peritoneal dialysis (PD) and hemodialysis (HD)[3-5], who tend to be also at increased risk of poor outcomes due to COVID-19. Strengthening the immune response against SARS-CoV-2 is crucial for CKD patients, especially those whose immune systems are weakened by kidney disease progression, such as dialysis patients or those receiving immunosuppressive therapy for glomerulonephritis or kidney transplants (KTx)[6]. These groups of patients often exhibit a decreased humoral immunity to COVID-19 vaccines, which can affect their ability to mount effective immune responses. However, coexistence of COVID-19 and CKD of any severity is often associated with adverse outcomes and complications that significantly impact individual quality of life and contribute to overall mortality[7,8].

Anemia, a common and serious complication of CKD, can lead to cardiovascular events, hospitalization, and death. In addition, this condition adversely affects quality of life, emotional well-being, and work productivity[9].

Recent research has highlighted the complex interplay between CKD, anemia, and COVID-19 severity, particularly in the context of acute respiratory distress syndrome (ARDS) and thrombotic complications. On the one hand, in patients with COVID-19, anemia and dysregulated iron metabolism are associated with worse clinical outcomes, including increased disease severity and complications such as ARDS. Reduction in circulating hemoglobin (Hb) levels and consequently lower oxygen availability to cells tend to exacerbate tissue hypoxia and accelerate the onset of COVID-19-induced acute ARDS[5]. On the other hand, both CKD and COVID-19 patients have an increased susceptibility to anemia and impaired iron metabolism[6]. While the exact mechanisms of COVID-19 remain incompletely elucidated, patients with severe cases often exhibit a prothrombotic condition and a pronounced inflammatory response. The inflammatory response triggered by SARS-CoV-2, characterized by increased levels of proinflammatory cytokines, may stimulate the hepcidin production. Elevated hepcidin levels impede intestinal iron absorption and promote iron binding in macrophages, resulting in reduced serum iron levels despite normal to high iron stores; a condition known as functional iron deficiency. Similar to other inflammatory conditions, acute inflammation and reduced iron availability can lead to inhibition of erythropoietin (EPO) production and reduce bone marrow responsiveness[7]. Targeting iron metabolism pathways may offer potential therapeutic benefits, although direct interventions remain to be fully explored. However, since iron is essential for viral replication[8], iron overload is associated with worse prognosis; conversely, restricting iron supplementation may prove advantageous for patients with severe COVID-19, but additional research is required to elucidate this matter.

Management of anemia in CKD patients with COVID-19 may be complicated by potential associations between the infection and EPO resistance. The efficacy of erythropoiesis-stimulating agents (ESAs) in these patients is limited, especially during severe COVID-19 due to the inflammatory response and prothrombotic state, which may render ESA therapy potentially harmful. Some experts recommended maintaining ESA medication at the same dose but decreasing the Hb target (8-9 g/dL) for patients undergoing maintenance dialysis[9]. However, recent data suggest that higher ESA may be necessary due to increased resistance to therapy in COVID-19 patients. Novel approaches using hypoxia-inducible factor (HIF) stabilizers show promise in reducing ESA requirements. In this review, we evaluate the factors linking COVID-19, anemia, and CKD, and explore the underlying mechanisms that contribute to this complex relationship.

IMMUNE DYSFUNCTION IN COVID-19

Immune dysfunction is a well-documented consequence of COVID-19 infection[10]. Systemic inflammatory responses induced by chronic low-grade inflammation caused by SARS-CoV-2 have provided valuable insights to our understanding of the inflammatory pathways[11]. Patients with prolonged COVID-19 often exhibit elevated levels of proinflammatory cytokines[12], which can persist for up to a year post-infection[13,14]. While the exact casual relationships remain unclear, the frequency and supporting evidence suggest a strong association between persistent inflammation and prolonged disease symptoms Table 1.

Table 1 Typical timeline of inflammation in COVID-19¹.

Phase	Days post-infection	Features	Key inflammatory markers
Viral replication phase	1-5	Mild symptoms (fever, cough, fatigue); inflammation is usually low to moderate	CRP, IL-6, ferritin may be slightly elevated
Early inflammatory phase	5-10	Worsening symptoms (dyspnea, hypoxia); immune system response intensifies	Rising CRP, IL-6, ferritin, D-dimer, LDH
Hyperinflammatory phase (if occurs)	7-14+	Cytokine storm in severe cases; respiratory failure, organ dysfunction	Very high IL-6, CRP, ferritin, D-dimer; lymphopenia
Resolution/recovery	After day 14 (mild/moderate)	Symptoms improve; inflammation resolves gradually	Inflammatory markers decrease over weeks

¹In mild COVID-19, the inflammation remains limited and subsides quickly. In severe or critical illnesses, it is the hyperinflammatory response that often leads to complications such as acute respiratory distress syndrome, coagulation disorders, or multiple organ failure. In patients with chronic diseases (e.g., chronic kidney disease), the inflammatory response may be attenuated or prolonged, which complicates the interpretation of markers such as ferritin or C-reactive protein.

CRP: C-reactive protein; IL-6: Interleukin-6; LDH: Lactate dehydrogenase.

As well as anti-SARS-CoV-2 IgG antibodies, COVID-19 patients also develop autoantibodies against inflammatory cytokines. A higher prevalence of autoantibodies against extractable nuclear antigens and antinuclear antibodies has been linked to symptoms such as dyspnea and fatigue in long-term COVID-19 cases[15-18]. Finally, reduced ocular peripapillary vascular density, an indicator of microcirculatory function, has been associated with the presence of G-protein-coupled receptor autoantibodies in individuals experiencing prolonged COVID-19 symptoms[19]. Persistent inflammation and lingering COVID-19 symptoms result from slowed viral clearance, often due to immune system dysfunction[20]. This proinflammatory environment may promote the formation of autoantibodies through interactions with the microbiome, leading to prolonged immunological activation or dysregulation. Emerging studies suggest that gut dysbiosis may influence immune responses and contribute to neuroinflammation, which is linked to mood disorders and cognitive issues in long COVID patients.

COVID-19 patients frequently experience symptoms commonly observed in immune-mediated diseases, such as fatigue, cognitive impairment and mental exhaustion, and gastrointestinal complaints. Recognizing these immune-related manifestations is crucial for developing targeted treatment strategies, whether addressing the underlying etiology or managing long-term post-COVID sequelae[21].

The Delta wave, which was characterized by the longest hospital stays and the highest rates of severe cases and mortality, showed significant increases in inflammatory biomarkers.

C-reactive protein (CRP), fibrinogen, ferritin, interleukin (IL)-6, D-dimer, and lactate dehydrogenase increased from the Wuhan to the Delta waves and decreased in the Omicron wave, with the exception of procalcitonin, which increased from the Alpha to the Omicron wave. The median values of leukocytes and neutrophils increased from the Wuhan to the Delta waves and decreased in the Omicron wave, while an inverse pattern was observed for lymphocytes, monocytes, and basophils[22].

Increased IL-6 Level is regarded as a marker of systemic inflammation and unfavorable prognosis in COVID-19. IL-6 activates the hepatocytes to induce CRP and fibrinogen secretion. Studies published at the beginning of the pandemic supported a cut-off value > 55 pg/mL for serum IL-6 when identifying patients at high risk for severe COVID-19, and mortality was found to be associated with an IL-6 value of ≥ 100 pg/mL. we described an increase in IL-6 from the Wuhan to Alpha and Delta waves, with a decrease in the Omicron wave[23].

In addition, IL-6 stimulates the production of hepcidin, another important proinflammatory molecule involved in iron homeostasis. A high level of hepcidin reduces iron absorption and release, while a low level promotes iron availability. Elevated hepcidin levels have been found in hospitalized COVID-19 patients and have been associated with poorer outcomes, including the need for mechanical ventilation, renal replacement therapy (RRT) and increased mortality[24].

Consequently, iron homeostasis disorders such as hypoferremia and hyperferritinemia are common. Despite low serum iron, transferrin, the primary iron transport protein, and transferrin saturation (TSAT), a key index of iron availability, are downregulated in COVID-19. This reduction in transferrin may also contribute to the prothrombotic state observed in severe COVID-19 cases. These findings emphasize the link between inflammation and iron dysregulation in the pathophysiology of COVID-19.

SARS-CoV-2 also determines the activation of an inflammatory response with the associated activation of the JAK-STAT pathway (a pathway that is also involved in the mechanism of erythropoiesis)[25].

The JAK-STAT pathway is a cellular signaling pathway that transmits signals from the cell surface to the cell interior and activates the transcription of certain genes[26]. Cytokines bind to their receptors on the cell surface and activate the Janus kinases (JAKs). JAKs phosphorylate and activate signal transducer and activator of transcription (STAT) proteins, which then migrate to the cell nucleus and regulate gene expression. In the case of EPO, the EPO receptor associates with JAK molecules. The most important enzyme involved is JAK2, which determines the activation of the EPO-EPOR-JAK2 complex, which in turn phosphorylates and activates STAT proteins. The phosphorylated STATs migrate into the cell nucleus and activate the transcription of genes involved in erythropoiesis, with STAT5 being the most important.

RENAL INVOLVEMENT IN COVID-19 INFECTION

As the COVID-19 pandemic spread, the link between pre-existing kidney disease and severe outcomes became widely recognized. Renal dysfunction increases the likelihood of complications in these patients and can increase the incidence of serious outcomes such as intensive care unit (ICU) admission and death. Additionally, individuals receiving RRT are particularly vulnerable due to their increased susceptibility to infections and the need for stringent infection control measures in medical facilities. A deeper understanding of how viral infections affect kidney health is essential for developing more effective treatment and prevention strategies.

COVID-19 and kidney disease share several common pathogenetic mechanisms. Several studies have detected the presence of SARS-CoV-2 RNA and protein in the kidneys of infected patients[27,28], with electron microscopy confirming the presence of virions[29,30]. The angiotensin-converting enzyme (ACE)2 receptor, which facilitates SARS-CoV-2 entry into host cells, is highly expressed in proximal tubule cells[31]. These cells also express the transmembrane protease serine 2 and other proteases that enhance the S protein cleavage and viral entry into the kidney[32], suggesting that this organ may be directly susceptible to SARS-CoV-2 infection.

ACE2 plays a crucial role in linking two major pathways: The renin-angiotensin-aldosterone system and the kallikrein-kinin system. SARS-CoV-2 infection downregulates ACE2, leading to increased angiotensin II levels and accumulation of bradykinin-derived metabolites, with proinflammatory, cardiovascular, and pulmonary implications[33]. Another potential therapeutic approach sees the use of recombinant ACE2, with the aim of maintaining the ACE/ACE2 ratio in a state of equilibrium[34].

In a study involving 62 COVID-19 patients, SARS-CoV-2 was found in all kidney samples analyzed via reverse transcriptase-polymerase chain reaction, with the nucleocapsid protein identified in all tested samples. Viral RNA was detected in renal tubule cells and podocytes, and these infected cells showed increased expression of genes associated with damage, inflammation, and fibrosis[35]. While direct viral infection of kidney cells may contribute to kidney disease progression, the exact incidence of COVID-19-related kidney infections remains uncertain[36]. Additionally, inflammatory responses triggered by the virus can exacerbate kidney dysfunction, leading to a higher risk acute kidney injury (AKI), even in individuals with mild pre-existing renal impairment.

AKI is a common complication of COVID-19, especially in hospitalized older patients. Proteinuria and hematuria frequently occur in individuals with COVID-19 and AKI, alongside an abrupt reduction in estimated glomerular filtration rate (eGFR) and/or urine output[37,38]. While AKI is a common complication of COVID-19, its incidence varied significantly across geographical regions, including China, the USA, and Europe; in general, the incidence of AKI in hospitalized COVID-19 patients is reported to be > 20% in many studies, with some findings suggesting rates as high as 29% in European countries and varying from 0.5% to 80.3% globally during hospital admission. Conversely, Chinese studies found a significantly lower rate of 5.5%. Advanced age, male sex, ARDS, and/or mechanical ventilation as well as comorbidities such as CKD, hypertension, and diabetes mellitus, are recognized risk factors for AKI development in COVID-19[39].

Several pathogenic factors contribute to development of AKI in COVID-19, such as reduced renal perfusion, heightened systemic and local cytokine production, endothelial injury, and direct damage from nephrotoxic drugs[40]. Pulmonary changes during infection may worsen renal function, and vice versa. Acute lung injury increases systemic cytokine levels and local expression of damage-associated molecular patterns, which can bind to renal receptors, such as Toll-like receptors, triggering innate immune responses and increasing inflammation and renal damage[41]. Recent research highlights the role of endothelial dysfunction as a central mechanism in COVID-19-related AKI, suggesting that targeting this dysfunction may offer new therapeutic strategies. The etiology of AKI in patients with COVID-19 is thus complex and involves both indirect mechanisms resulting from the systemic effects of the viral infection and its consequences on distant organs such as the lungs, as well as the direct viral effects on the kidneys (Figure 1).

Figure 1 Severe acute respiratory syndrome coronavirus 2 spike (S1) protein binds to the angiotensin converting enzyme 2 receptor on the surface of podocytes. The transmembrane serine protease 2 facilitates viral entry by cleaving S1. Viral internalization leads to angiotensin-converting enzyme 2 (ACE2) degradation, reducing its ability to convert angiotensin (AT)II into Ang 1-7. This results in excess ATII, which is associated with proinflammatory and vasoconstrictive effects. ACE2 downregulation promotes accumulation of bradykinin-derived mediators, further enhancing inflammation. ATII: A key component of the renin-angiotensin-aldosterone system. ATII induces inflammatory cascades by increasing adhesion molecules, cytokines, and chemokines release; it also promotes reactive oxygen species production, cell growth, and extracellular matrix remodeling. ATII/AT1R pathway activates protein phosphatase 2A, which in turn downregulates endothelial NO synthase phosphorylation, decreasing levels of NO and leading to endothelial dysfunction. Kinins, such as bradykinin (BK) and kallidin: Bioactive proinflammatory peptides that are released by kallikreins (serum proteases) from their precursors, kininogens, following tissue injury. ACE2: Inhibits conversion of ATII into Ang 1-7, and blocks breakdown of des-Arg9 bradykinin (des-Arg9 BK, an active metabolite of BK) into inactive fragments. Des-Arg9 BK exerts its biological effects, mainly the release of proinflammatory cytokines and recruitment of immune cells, as well as the increase in vascular permeability, by activating B1 receptors. The inflammatory response extends beyond the kidneys, contributing to acute lung injury, a key complication of severe coronavirus disease 2019. Infected lung cells release viral particles and inflammatory cytokines, which enter circulation and exacerbate systemic inflammation. These circulating factors further stimulate toll-like receptors on podocytes, triggering innate immune responses, inflammation and kidney injury. SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.

A large US cohort study showed that 20.6% of COVID-19 ICU patients required RRT[42]. Machine learning approaches may help predict the need for RRT, as demonstrated in a Brazilian cohort[43]. Continuous RRT often suits hemodynamically unstable patients requiring prone positioning, while PD may be advisable in patients with coagulopathies/clotting of the HD circuit and/or contraindications to anticoagulants[44]. Fluid management in patients with COVID-19 and AKI is challenging clinicians must prevent both volume depletion and excessive volume resuscitation, which can exacerbate oxygenation issues in ARDS[45].

Patient outcomes reveal a concerning trend. Survivors of severe COVID-19 displayed an increased incidence of long-term renal complications, prompting investigation into whether the virus may help initiate these conditions. Although most individuals recover renal function after resolving the infection, 35%-40% exhibit persistent AKI for > 7 d, and 30% of those who required RRT still need dialysis after hospital discharge[46]. The severity of AKI correlates with the likelihood of developing new-onset renal failure, progression of CKD, and with increased mortality rate[47-50].

COVID-19 IN RRT

The high transmissibility of SARS-CoV-2 means that it spreads rapidly among vulnerable populations, including individuals undergoing RRT. A recent study found that, across 12 countries, the total pooled prevalence of COVID-19 in RRT patients was 22 times higher than in the general population[51]. Patients on RRT are at elevated risk of infection because of compromised innate and adaptative immunity and increased proinflammatory response[52]. A high clinical suspicion of COVID-19 is crucial in this setting, given that > 50% of RRT patients have a silent infection and only 47% present with fever (vs 90% in the general population)[53]. Approximately 50% of RRT patients diagnosed with COVID-19 required hospitalization in the early stages of the pandemic, and the mortality rate ranged from 20% to 30%[54]. Furthermore, individuals receiving inpatient HD were three to four times more likely to be hospitalized for COVID-19 compared with those on PD[55].

A Japanese retrospective cohort study conducted during the first three waves of COVID-19, and examining patients hospitalized for COVID-19 or other types of pneumonias, found that patients with COVID-19 and on dialysis had a higher risk of death compared to patients without COVID-19 and without need for dialysis. Additionally, isolation and prolonged length of stay contributed to functional decline among these patients[56]. Risk factors associated with higher mortality in RRT patients mirror those in the general population but are magnified in individuals undergoing RRT[57].

Besides a severely weakened immune system, advanced age, and multiple comorbidities (e.g., diabetes mellitus, hypertension, and cardiovascular diseases) increase these patients’ vulnerability. Black race and Hispanic ethnicity have also been identified as risk factors, as well as residing in residential neighborhoods[58,59]. Patients on outpatient dialysis face additional logistical challenges, traveling to and from the dialysis center multiple times week; most centers also lack adequate isolation spaces or ventilation systems to contain an epidemic. This forced close proximity with other patients and medical staff for at least 3-4 h per session, which became particularly problematic early in the pandemic, due to the inability to isolate patients when ill. All these factors amplified the risk of indirect infection and viral spread among these patients[60]. In contrast, patients on home dialysis had a lower risk of developing COVID-19.

As regards vaccination strategies, HD patients generally initiated active immunization during the Beta wave, receiving their first and second doses before the Delta variant emerged. Although they were shown to have a lower immunological response compared to healthy populations[61], the vaccine efficacy was ~80% in patients with CKD and dialysis[62] and may reduce clinical severity in those on HD[63]. However, these results must be interpreted alongside less pathogenic virus variants with lower pathogenicity and partial protection from prior SARS-CoV-2 infections.

In September and October 2021, patients were offered a third or booster vaccine, yet research suggests that, despite up to three doses, infection rates rose due Omicron variants. One study reported that 39% of doubly vaccinated HD patients developed COVID-19, and the booster vaccination did not significantly reduce the infection rate, which was 38%[64-70]. Goodlad et al[70] described 795 cases of infection in 710 dialysis patients, with 85 individuals infected two or three times. However, data on patients undergoing PD are insufficient[66,67], but an early study in the Wuhan region found infection rates of < 1% in PD patients[68], likely reflecting the early stage of the pandemic. Another analysis by Yavuz et al[71] found no significant differences in SARS-CoV-2 positivity, hospitalization, need for intensive care and ventilatory support, or all-cause mortality between patients undergoing HD and those receiving continuous ambulatory PD. While few studies have examined antibody levels in PD patients, one prospective observational study found a level of protection of 73% in a cohort of 88 individuals undergoing PD[70].

As previously reported, HD patients are more prone to contract airborne infections than PD patients are. This results from crowded waiting areas, public transportation usage, and poor ventilation in certain HD facilities[72]. Most HD clinics have now reinforced infection control measures and increased the use of personal protective equipment to lower risks. Alongside these measures and vaccination strategies, lockdown restrictions and other government regulations helped reduce infection rates among HD patients to levels similar to those of PD patients during the Alpha and Beta waves. By contrast, the Delta and Omicron variants precipitated a surge in infections among HD patients, likely due to more contagious virus strains and a loosening of some of strict infection-control protocols[73].

At the onset of the pandemic, HD patients with COVID-19 were significantly more prone to hospitalization, ICU admission, and higher mortality compared to those on PD. Over time, lockdowns, more robust control measures, vaccination, prior exposures, pharmacological treatment of infection, and varying viral virulence diminished hospitalizations, ICU admissions, and mortality rates. Nevertheless, even during later stages of the pandemic, HD patients consistently displayed elevated hospitalization and ICU admissions rates vs the general population[74].

Meanwhile, KTx recipients faced high risk of severe SARS-CoV-2 infection due to use of immunosuppressants, which can delay viral shedding and lead to atypical or complicated clinical presentations. Differentiating between rejection and viral infection in KTx patients requires a multidisciplinary team involving nephrologists, infectious disease experts, and pathologists[75]. Despite widespread vaccination, the mortality rate among KTx recipients nearly doubled during the COVID-19 period (6.40 deaths per 100 person-years compared to 3.54 pre-COVID). Mortality also increased across all ethnic and racial groups, but Native American, Hispanic, and African American populations showed the sharpest rises relative to non-Hispanic Caucasians[76].

Overall, individuals undergoing RRTs faced a substantially increased risk of moderate-to-severe COVID-19 due to several factors. They exhibit more complex clinical trajectories, greater ICU admission rates, and higher mortality than the general population[77].

CKD AND ANEMIA

According to World Health Organization thresholds, anemia is defined as Hb concentration < 13 g/dL in adult men and < 12 g/dL in adult women[78]. In CKD, anemia is typically normocytic and normochromic, arising primarily from reduced EPO production and/or a decreased responsiveness to it[79]. This condition is highly prevalent among individuals with CKD, adversely impacting quality of life and leading to worse clinical outcomes and increased mortality[80].

EPO, a glycoprotein hormone produced by peritubular interstitial cells in the renal cortex and outer medulla, is essential for red blood cell (RBC) production. A decrease in EPO secretion in CKD is partly attributed to the transdifferentiation of EPO-producing cells into myofibroblasts[81] and the downregulation of HIF; a key nuclear transcription factor for EPO gene expression[82]. Iron deficiency, whether from bleeding (e.g., gastrointestinal) or inadequate dietary intake, represents another major contributor to anemia in CKD. Moreover, persistent systemic inflammation associated with CKD raises hepcidin levels, thereby hindering intestinal iron absorption and release from storage sites[83]. Additional factors include vitamin B12 and folate deficits, shortened RBC lifespan associated with the uremic state, bleeding due to platelet dysfunction and blood loss during HD[84].

Anemia manifests with fatigue, weakness, shortness of breath, dizziness, and lightheadedness, all of which negatively affect functional status and health-related quality of life[9]; therefore, regular monitoring and, if necessary, treatment are vital. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines represent the standard of care for managing CKD-related anemia. According to these guidelines[85], complete blood count, reticulocytes, ferritin, and TSAT should be regularly measured every 3 mo in non-dialysis-dependent anemic patients and in those on PD, and at least monthly in CKD G5 anemic patients undergoing HD. If needed, additional tests like peripheral blood smear, vitamin B12 and folate dosage, and stool analysis[8], can further aid in diagnosis.

Iron deficiency is a common and treatable cause of anemia in CKD, and may contribute to diminished ESA therapy effectiveness[86]. Iron supplementation, given orally or intravenously, can increase Hb concentration to desired levels and possibly lower the required ESA dose[87]. The administration route is chosen based on several factors such as possible side effects (gastrointestinal symptoms with oral compounds, hypotension or hypersensitivity for IV infusions), accessibility, patient adherence, and cost-effectiveness[88]. While oral iron is generally preferred in non-dialysis-dependent patients, IV administration remains standard in CKD patients undergoing dialysis[89]. The PIVOTAL trial further supported a high-dose proactive IV approach to maximize clinical benefits and long-term outcomes in HD while being an optimal ESA-sparing strategy[90].

Nonetheless, addressing reduced EPO production is crucial to treat CKD-related anemia as this is considered the most widely recognized pathogenetic mechanism[91]. ESAs, namely epoetin, darbepoetin, and methoxy polyethylene glycol-epoetin β, are synthetic EPO analogs produced through recombinant DNA technology in cell cultures. Their use in CKD can increase Hb levels, reduce transfusion needs[92], and alleviate fatigue[89]. ESAs are when Hb falls below 10 g/dL, with dosing kept as low as possible to maintain Hb levels above the threshold that would necessitate RBC transfusion. In line with KDIGO guidelines, raising Hb above 11.5 g/dL is not recommended, since higher targets correlate with increased adverse effects, such as worsening hypertension, thromboembolism, thrombosis of vascular access, and malignancy[93].

A new class of oral medications, named HIF prolyl hydroxylase inhibitors (HIF-PHIs), function by stabilizing HIF, mimicking a condition of transient hypoxia and thus increasing endogenous EPO transcription[94]. They offer ancillary benefits due to pleiotropic effects on iron homeostasis and lipid profile, with increased intestinal uptake and release of iron from cellular deposits, reduced LDL cholesterol, and inhibition of hepcidin production[95,96]. These effects can be particularly valuable in non-dialysis-dependent CKD patients who exhibit hyporesponsiveness to ESA treatment due to iron deficiency and systemic inflammation. In this population, HIF-PHIs could serve as an alternate strategy to rise and maintain Hb levels, independently of the inflammatory state, while improving iron utilization profile and reducing the need for iron supplementation[97]. While HIF-PHIs have shown noninferiority to ESAs in both efficacy and major adverse events risk, long-term safety, especially regarding cardiovascular events and potential effects on tumor growth and cancer recurrence[98,99], remains under investigation, with several trials ongoing.

COVID-19 AND ANEMIA

A robust host immune response, both innate and adaptive components, is essential for containing and eliminating SARS-CoV-2. COVID-19 severity appears to be linked to excessive proinflammatory cytokine production, often termed a cytokine storm, which can precipitate ARDS. After SARS-CoV-2 infection, immune system hyperactivation and autoantibody production may lead to various autoimmune manifestations, including hemolytic anemia, thrombocytopenia, vasculitis, prothrombotic syndrome, and systemic coagulopathy[100,101].

Anemia in the setting of COVID-19 has been associated with poorer clinical outcomes, including increased mortality rates and prolonged hospital stays. A meta-analysis of 57 563 patients showed that lower Hb correlates with more severe COVID-19 symptoms and worse prognosis[102]. A more recent meta-analysis covering 573 928 subjects substantiated the value of anemia as a prognostic biomarker for COVID-19 severity[103]. Likewise, a study of 3092 hospitalized COVID-19 patients reported a significant link between anemia and increased risk for critical illness, ICU admission, and death[104]. Hypothetically, the reduced RBC oxygen-carrying capacity seen with low Hb levels exacerbates tissue hypoxia especially in high-risk patients, who already have enhanced peripheral oxygen demands due to a hypermetabolic state in response to infection, which can worsen respiratory distress in COVID-19[10]. Given the strong correlation between anemia and COVID-19 severity, Hb level may serve as an independent risk factor for COVID-19, aiding risk stratification in both outpatient and inpatient settings[105].

COVID-19 itself can trigger or aggravate anemia via multiple pathways. Hemolytic anemia typically arises from autoantibody formation, whereas inflammatory anemia may develop in post-acute COVID-19, driven by disruption of iron metabolism and erythropoiesis. Notably, low iron availability may further affect antiviral immunity, perpetuating symptoms and prolonging infection[106].

Although the iron sequestration of iron within macrophages serves as a defense against iron-dependent pathogens, it compromises iron availability for RBC production during erythropoiesis (HYPERLINK https://en.wikipedia.org/wiki/Erythropoiesis). Iron starvation has been demonstrated in the erythroid compartment as well as in leukocytes, and may affect T-cell effector function, humoral immunity, natural killer cell activation, and neutrophil antimicrobial activity. Patients with moderate to severe COVID-19 show decreased serum iron, TSAT, and Hb, alongside increased ferritin, hepcidin, and IL-6. These findings suggest that these patient groups need additional iron supplementation, although care must be taken to avoid iron overload, which can promote reactive oxygen species (ROS)-mediated damage to monocytes. Markers such as zinc-protoporphyrine IX, heme-CO₂, and CO-Hb are elevated, reflecting Fe-heme degradation. Furthermore, iron-laden macrophages in the bone marrow and excessive iron in the ventricular myocardium and liver have been observed in fatal COVID-19 cases, contributing to organ failure[107].

SARS-CoV-2 may also target erythroid precursor cells directly, disrupting Hb and iron metabolism. Studies of long-COVID patients have revealed low serum iron and TSAT, as well as high mean corpuscular Hb and CO binding, resulting in tissue hypoxia. Elevated CO-Hb is found in sepsis, hemolysis, and severe inflammation. Both decreased oxygen supply and increased CO-Hb may be responsible for several symptoms of long-COVID patients: Chronic fatigue syndrome, shortness of breath, dyspnea, neurocognitive deficits, myocardial depression, which exacerbate the anemia-related symptoms (Table 2).

Table 2 Use of erythropoiesis-stimulating agents and hypoxia-inducible factor prolyl hydroxylase inhibitor in patients with chronic kidney disease.

Agent	Initiation threshold	Hb target	Dosing	Maximum recommended doses	Monitoring
ESAs
	ND-CKD: Carefully weigh risks and benefits. Individualized initiation threshold; for most people, Hb 80-10.0 g/dL; DD-CKD: Hb concentration ≤ 9.0-10.0 g/dL	Hb level < 11.5 g/dL	ND-CKD: 4000 or 10 000 U weekly or every 2 wk; DD-CKD: 50-100 U/kg, 3 times weekly	-	Following initiation: Every 2-4 wk. During maintenance phase: At least once every 3 mo
			ND-CKD: 40-100 µg every 2-4 wk; DD-CKD: 0.45 μg/kg weekly or 0.75 μg/kg every 2 wk	-
Methoxy polyethylene glycol-epoetin beta			ND-CKD: 50-120 µg every 2 wk or 120-200 µg every month; DD-CKD: 0.6 µg/kg every 2 wk	-
HIF-PHIs
Advantages and benefits (vs ESAs): Reduction in hepcidin; improved iron bioavailability and utilization; decreased serum cholesterol levels; oral route of administration. HIF-PHIs are more likely to improve anemia in patients with chronic inflammation and ESAs hyporesponsiveness, while reducing the need for intravenous iron supplementation
Limitations and cautions (vs ESAs): Higher incidence of cancer events and related deaths (daprodustat); higher risk of MACEs (vadadustat)
Roxadustat (China, Chile, Egypt, EU, Iceland, Japan, Kuwait, Lichtenstein, Mexico, Norway, Russia, Saudi Arabia, South Africa, South, Korea, Turkey, United Arab Emirates, UK)	ND-CKD: Carefully weigh risks and benefits. Individualized initiation threshold; for most people, Hb 80-10.0 g/dL, DD-CKD: Hb concentration ≤ 9.0-10.0 g/dL	Hb level < 11.5 g/dL	70 mg for body weight < 100 kg, 100 mg for body weight ≥ 100 kg, 3 times weekly (ESA-naïve); 70-200 mg 3 times per week (switch from ESA) (EU). 50 mg 3 times per week (ESA-naïve), 70-100 mg 3 times per week (switch from ESA) (Japan)	ND-CKD: 3 mg/kg or 300 mg, thrice a week (EU); DD-CKD: 3 mg/kg or 400 mg, thrice a week (EU)	2-4 wk after initiation; every 4 wk during therapy
Vadadustat only DD-CKD: Australia, Europe (EU), Korea, Taiwan, and USA ND-CKD and DD-CKD: Japan			300 mg daily	600 mg/d (EU)
Daprodustat (Japan)			ND-CKD: 2-4 mg daily (ESA- naïve), 4 mg daily (switch from ESA). DD-CKD 4 mg daily	24 mg/d
Enarodustat (China, Japan, South Korea)			ND-CKD: 2 mg daily. DD-CKD: 4 mg daily. PD-CKD: 2 mg daily	8 mg/d (Japan)
Molidustat (Japan)			ND-CKD: 25 mg daily (ESA- naïve), 25-50 mg daily (switch from ESA). DD-CKD: 75 mg daily	200 mg/d
Desidustat (India)			100 mg 3 times per week (ESA- naïve), 100-150 mg 3 times per week (switch from ESA)	150 mg three times weekly

CKD: Chronic kidney disease; DD-CKD: Dialysis-dependent chronic kidney disease; ESA: Erythropoiesis-stimulating agent; Hb: Hemoglobin; HIF-PHI: Hypoxia-inducible factor prolyl hydroxylase inhibitor; MACEs: Major adverse cardiovascular events; ND-CKD: Non-dialysis-dependent chronic kidney disease; PD-CKD: Peritoneal dialysis chronic kidney disease.

RENAL ANEMIA AND SARS-COV-2 INFECTION

CKD, anemia and SARS-CoV-2 infection

The clinical manifestations of SARS-CoV-2 infection span a broad spectrum, from presentations to fatal disease[108]. Comorbidities such as cardiovascular disease, diabetes, cancer, hypertension, and CKD are key considerations in determining clinical outcomes.

CKD patients infected with SARS-CoV-2 face a high risk of developing anemia, primarily due to reduced EPO secretion, shortened RBC lifespan, and a chronic and persistent inflammatory milieu[12,109-115]. A retrospective study by Ramdani et al[115] offers valuable evidence for the heightened anemia risk in CKD patients with SARS-CoV-2 infection[110]. Out of 65 CKD patients (52.3% on dialysis, 4.6% on PD, and 43.1% without maintenance therapy), a significant portion were anemic, primarily due to insufficient EPO production, and elevated inflammatory markers: 38.5% of them experienced complications, with 60% requiring transfer to ICU, while 8% died. These findings underscore the need for close monitoring of both anemia and inflammation in CKD patients with COVID-19 to mitigate poor outcomes.

Similarly, in a study by Branco et al[116], analyzing adults with CKD who tested positive for SARS-CoV-2, fever, cough, and dyspnea emerged as the most common symptoms, while anemia, significantly tied to worse prognosis, was the principal laboratory abnormality.

Anemia is related to the acute phase of infection and can persist in the post-acute phase. A report by Bergamaschi et al[117], involving 83 patients evaluated 1 year post-infection, found that ~80% continued to exhibit anemia linked to CKD. These patients had more complications and a greater need for hospitalization compared to patients without SARS-CoV-2 infection[112].

The KDIGO guidelines for the treatment of anemia recommend monitoring Hb and iron metabolism markers every 1-3 mo in patients not treated with ESA and every 2-4 wk in treated patients. Unfortunately, no specific indication is given for patients with Sars-CoV-2 infection, but the guidance provided is limited to unspecified infections. In particular, it recommends temporarily suspending iron infusions in patients with an infection and not applying the recommendation to start iron therapy if ferritin is < 500 ng/mL or TSAT is < 30% in these patients. Thus, the only evidence that can be derived from this comes from clinical experience. In our center, patients admitted to the hospital with acute SARS-CoV-2 infection had daily or every other day blood count checks, while convalescent patients were examined according to the frequency of follow-up examinations; usually every 4-6 wk. Future research could focus on early changes in various biomarkers such as reticulocytes or serum ferritin in patients with SARS-CoV-2, even before anemia manifests with a decrease in Hb. Table 3 shows treatment strategies for anemia in patients with kidney disease (all CKD stages, dialysis, transplantation) who also have COVID-19 infection/systemic inflammation.

Table 3 Anemia treatment strategies in renal disease patients (all chronic kidney disease stages, dialysis, transplant) who also have COVID-19 infection/systemic inflammation.

CKD stage/modality	eGFR range (mL/min/1.73 m²)	Iron therapy	ESAs/HIFi	Anemia assessment monitoring frequency	Target Hb (g/dL)	Additional notes
Stage 1	≥ 90	Not routinely required unless iron deficiency is confirmed	Rarely indicated	Annually	11-12	Investigate other causes of anemia. Also evaluate: Blood smear review, haptoglobin, LDH, CRP, vitamin B12, folate, liver enzymes, SPEP with immunofixation, serum-free light chains, urinary Bence-Jones protein. TSH and stool analysis
Stage 2	60-89	Oral iron if ferritin < 100 ng/mL or TSAT < 20%. Withhold iron if ferritin ≥ 700 ng/mL (≥ 700 µg/L) or TSAT ≥ 40%	Usually not required	2times/yr	11-12	Nutritional assessment recommended
Stage 3	30-59	Oral or IV iron if ferritin < 100 ng/mL (< 100 µg/L) and transferrin saturation (TSAT) < 40%, or ferritin ≥ 100 ng/mL (≥ 100 µg/L) and < 300 ng/mL (< 300 µg/L), and TSAT < 25%. Withhold iron if ferritin ≥ 700 ng/mL (≥ 700 µg/L) or TSAT ≥ 40%	Consider if Hb < 10 g/dL	2-3 times/yr	10-11.5	Start addressing potential ESA/HIF-PHIi need
Stage 4	15-29	IV iron preferred, start therapy if ferritin < 100 ng/mL (< 100 µg/L) and transferrin saturation (TSAT) < 40%, or ferritin ≥ 100 ng/mL (≥ 100 µg/L) and < 300 ng/mL (< 300 µg/L), and TSAT < 25%. Withhold iron if ferritin ≥ 700 ng/mL (≥ 700 µg/L) or TSAT ≥ 40%	Initiate if Hb < 10 and iron replete	Quarterly	10-11.5	Monitor for ESA/HIF-PHIi resistance, inflammation
Stage 5 (non-dialysis)	< 15	Oral or IV iron. Withhold iron if ferritin ≥ 700 ng/mL (≥ 700 µg/L) or TSAT ≥ 40%	Usually required	Monthly to quarterly	10-11.5	Prepare for dialysis transition. Monitor for ESA/HIF-PHIi resistance, inflammation
Peritoneal dialysis	N/A	Oral or IV iron if ferritin < 100 ng/mL (< 100 µg/L) and transferrin saturation (TSAT) < 40%, or ferritin ≥ 100 ng/mL (≥ 100 µg/L) and < 300 ng/mL (< 300 µg/L), and TSAT < 25%. Withhold iron if ferritin ≥ 700 ng/mL (≥ 700 µg/L) or TSAT ≥ 40%	Commonly required	Monthly	10-11.5	Monitor for ESA/HIF-PHIi resistance, inflammation
Hemodialysis	N/A	IV iron (standard of care). Initiating iron therapy if ferritin ≤ 500 ng/mL (≤ 500 µg/L) and TSAT ≤ 30%. Withhold iron if ferritin ≥ 700 ng/mL (≥ 700 µg/L) or TSAT ≥ 40%	Required regularly	Monthly	10-11.5	Blood losses during HD contribute to anemia. Monitor for ESA/HIF-PHIi resistance, inflammation
Kidney transplant	N/A	Iron supplementation if deficiency persists. Withhold iron if ferritin ≥ 700 ng/mL (≥ 700 µg/L) or TSAT ≥ 40%	Rare post-transplant unless chronic graft dysfunction	Every 3-6 mo	11-12	Anemia often improves, but monitor for graft rejection or chronic disease recurrence, pharmacological interactions

The table focuses on the modifications needed due to inflammation and infection, including ESAs resistance, iron metabolism changes, and safety considerations. CRP: C-reactive protein; CKD: Chronic kidney disease; CRP: C-reactive protein; ESAs: Erythropoiesis-stimulating agents; eGFR: Estimated glomerular filtration rate; HD: Hemodialysis; Hb: Hemoglobin; HIF-PHI: Hypoxia-inducible factor prolyl hydroxylase inhibitor; IV: Intravenous; LDH: Lactate dehydrogenase; SPEP: Serum protein electrophoresis; TSH: Thyroid-stimulating hormone; TSAT: Transferrin saturation.

Social implications and blood transfusion

CKD, especially in the advanced stages, is a key risk factor for severe anemia. Standard primary treatment approaches include ESAs, HIF-PHIs, and IV iron supplementation; however, in certain cases, blood transfusions are necessary and become the mainstay therapeutic strategy[113]. Unfortunately, transfusions are not always feasible as they are logistically challenging, especially, in low-income settings, lacking donor availability or reliable blood testing infrastructures[114]. In addition, transfusions can increase allosensitization, thus reducing the chances of finding a compatible donor in patients undergoing KTx.

During the COVID-19 pandemic, demand for blood components such as RBCs, plasma, and platelets, rose among patients with renal insufficiency[115]. This surge in demand was primarily driven by a decline in the number of blood donors, driven by fear of contagion, and limited mobility due to restrictions and lockdown measures[116].

A retrospective study comparing transfusion rates during the pre-pandemic, pandemic, and post-pandemic periods showed a substantial reduction in blood transfusions during the pandemic, largely due to a decrease in hospital admissions, a lower number of available donors, and the postponement of nonurgent surgical interventions. Additionally, the research observed an increase in blood transfusions in the post-pandemic period compared to the pre-pandemic period, suggesting that the clinical manifestations and laboratory abnormalities - particularly Hb levels - associated with SARS-CoV-2 infections were more severe in this patient population[117].

HD, anemia and SARS-CoV-2 infection

HD patients had a higher infection risk due to a variety of factors, including shared waiting areas, communal transportation to and from the dialysis centers, indirect transmission through contaminated surfaces within the dialysis room and prolonged exposure to healthcare workers. In addition, many HD patients were older nursing home residents[118,119], thus adding another layer of susceptibility. Furthermore, uremia-related immune dysfunction may foster a proinflammatory state that weakens immune defense mechanisms[120].

In HD patients, SARS-CoV-2 infection can present with a range of clinical symptoms, including fever, respiratory insufficiency, and an increased risk of anemia[121]. The pathophysiology of anemia in these patients is multifactorial, involving reduced EPO secretion, iron deficiency, blood loss in the HD circuit, and infection-driven inflammation. Proinflammatory mediators suppress RBC differentiation and proliferation, as well as the expression of EPO receptors. In this context, anemia is worsened also by decreased EPO production; resistance to EPO stimulating agents is frequently encountered and necessitates elevated dosages even months post-infection[12]. Additionally, SARS-CoV-2 infection increases hepcidin levels, which further restrict iron mobilization from storage sites, further exacerbating the iron deficiency[122].

A Romanian retrospective study of 37 hospitalized HD patients with COVID-19 reported mortality in those with hypoalbuminemia and anemia, the former pointing to malnutrition/inflammation and the latter often linked to cardiovascular complications[123,124]. Another study comparing HF vs non-HD patients with COVID-19, showed lower Hb and albumin levels, and elevated urea concentration in the HD group, correlating with worse outcomes[125].

Although previous research[126] has shown no significant correlation between ESA use and mortality in HD patients with COVID-19, methodological constraints, such as the potential presence of asymptomatic SARS-CoV-2-positive patients, the retrospective design and single-time measurements, limit firm conclusions. Nevertheless, multiple reports have underscored the impact of anemia on COVID-19 prognosis, particularly in frail patients, highlighting its role as a critical determinant of patient prognosis[127-130].

PD, anemia, and SARS-CoV-2 infection

Anemia also poses a significant burden in patients undergoing PD[131-135]. In a study conducted by Yang et al[136] in 2024, including 125 PD patients infected with SARS-CoV-2, there was a reduction in Hb levels 1 mo after infection. Patients treated with roxadustat showed a faster recovery compared to those treated with EPO[131]. In the context of anemia management, one promising avenue yet to be fully explored is the potential therapeutic benefit of HIFs in this patient population. Among the few studies investigating the use of HIFs in patients undergoing RRT and affected by COVID-19, Bao et al[137] assessed the efficacy of roxadustat in PD patients with COVID-19 and underlined how this drug could effectively alleviate anemia while being also well-tolerated in patients who encounter difficulties with EPO administration. The study also found that medication adherence during the COVID-19 pandemic was superior with roxadustat compared to EPO.

Sachdeva et al[138] conducted an analysis of PD patients who were SARS-CoV-2 positive and required hospitalization. The most prevalent clinical manifestations included fever, cough, and dyspnea, with ~50% of patients also experiencing diarrhea. Hematological assessments revealed significant alterations in Hb levels, with 72% of patients presenting with anemia and 50% having severe anemia. The anemia associated with SARS-CoV-2 infection further complicated the recovery process in these patients. In this cohort, 27% of PD patients with SARS-CoV-2 who were hospitalized ultimately succumbed to the infection[139,140].

KTx, anemia, and SARS-CoV-2 infection

SARS-CoV-2 infection has played an important role in patients with KTx. In the pre-vaccination period, these patients were at high risk for more complications and mortality. Therefore, the incidence of infection-related complications is high[134,135]. To reduce the risk of infection in transplant patients, Liew et al[141] demonstrated the effectiveness of telemedicine for their follow-up care. The study included 81 transplant patients who tested positive for SARS-CoV-2; 70 of whom made a full recovery and 11 of whom required hospitalization. Anemia and reduced eGFR were found in all 11 of these patients. The study highlighted that parameters such as anemia and reduced eGFR were associated with a poorer prognosis in transplant patients infected with SARS-CoV-2.

Ghazanfar et al[142] examined various clinical parameters in SARS-CoV-2 positive transplant patients. They found that 29 transplant patients tested positive for SARS-CoV-2 and eight of them died. The study found significant changes in several laboratory parameters, including eGFR, serum albumin levels and particularly anemia.

Another study of 60 transplant patients who tested positive for SARS-CoV-2, 34 of whom developed severe disease and eight of whom died, showed that one of the most common laboratory changes was anemia, which occurred in 82% of cases. In addition, 78% of patients showed a reduction in Hb levels of ~1 g/dL compared to baseline values, and four patients required blood transfusions[138,143]. In this analysis, anemia was confirmed as a negative prognostic indicator. Therefore, timely and accurate diagnosis together with appropriate treatment is crucial to prevent potential complications and improve patient outcomes.

CONCLUSION

The impact of COVID-19 on the global population highlights the intricate links between different comorbidities and emphasizes the critical need for appropriate prevention strategies combined with a comprehensive treatment approach. A deep understanding of the impact of COVID-19 on people with pre-existing conditions such as anemia and CKD helps in the development of tailored treatment protocols, and raises awareness of the broader health impact of infectious diseases. The link between systemic inflammation and anemia in kidney patients with COVID-19 is an area of research that awaits answers that require further investigation. Future research directions should focus on longitudinal studies examining the chronic effects of COVID-19 on kidney function, biomarker development for early detection of complications, and personalized treatment approaches based on individual risk factors and comorbidity profiles.