Kidney involvement and anemia in COVID-19 infection

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.

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.

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.