European Journal of Cardiovascular Medicine

Anemia is a common complication of chronic kidney disease (CKD), resulting from a combination of factors, including reduced erythropoietin production by the kidneys, chronic inflammation, and functional or absolute iron deficiency. Managing anemia in CKD is crucial as it improves patients' quality of life, reduces cardiovascular complications, and enhances overall outcomes. Traditionally, erythropoiesis-stimulating agents (ESAs), such as injectable erythropoietin (EPO) and its analogs, have been the mainstay of anemia management. However, oral hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), such as desidustat, have emerged as promising alternatives in recent years.Injectable EPO has been a cornerstone therapy for anemia in CKD for several decades. By directly stimulating erythropoiesis, it effectively raises hemoglobin (Hb) levels, improving hematological parameters. However, its use is associated with logistical challenges, including the need for regular injections, cold-chain storage, and monitoring for adverse effects such as hypertension, pure red cell aplasia (PRCA), and thromboembolic events. Additionally, the high cost and the need for careful dose titration have raised concerns, particularly in resource-limited settings (Locatelli et al., 2017; Singh et al., 2021). On the other hand, oral desidustat belongs to a novel class of agents that stabilize HIF by inhibiting its prolyl hydroxylation. This stabilization induces the transcription of genes involved in erythropoiesis, iron metabolism, and oxygen homeostasis. Unlike injectable EPO, desidustat mimics the physiological response to hypoxia by promoting endogenous erythropoietin production and enhancing iron absorption and mobilization. This dual mechanism potentially offers advantages in managing anemia while addressing iron deficiency—a frequent comorbidity in CKD (Haase, 2021). Studies comparing oral desidustat and injectable EPO have demonstrated significant differences in their impact on hematological parameters, renal function (e.g., estimated glomerular filtration rate [eGFR]), and iron profile. Desidustat has been shown to improve Hb levels effectively while also influencing iron metabolism by increasing serum ferritin and transferrin saturation (TSAT) levels, potentially reducing the need for intravenous iron supplementation (Provenzano et al., 2020). In contrast, injectable EPO primarily improves Hb levels but does not directly address iron homeostasis, necessitating concomitant iron therapy in many patients. Renal function, as assessed by eGFR, is a critical marker in CKD management. Preliminary evidence suggests that desidustat may exert protective effects on renal function through its anti-inflammatory and antioxidative properties, though further studies are needed to substantiate these findings (Chen et al., 2022). Injectable EPO, while effective in anemia correction, has not been shown to significantly influence eGFR, and its long-term impact on renal outcomes remains uncertain.This review aims to critically examine the comparative efficacy and safety of oral desidustat and injectable EPO, focusing on their roles in improving hematological parameters, eGFR, and iron profile. By exploring current evidence, we hope to provide insights into optimizing anemia management strategies in CKD patients and highlight areas for future research.

The present study was framed as interventional, prospective and cohort type and conducted in a tertiary care hospital using the Nephrology Clinic, Pathology & Biochemistry Departments with Pharmacotherapeutic interventions in the Department of Pharmacology, Medical College and Hospital, Kolkata. Prior IEC approval was taken from the institution as per protocol.  The Patients who were attending Nephrology outdoor with dialysis who are on rh–EPO injectables to combat the CHRONIC ANAEMIA OF CKD were taken as our study population. The data was collected for for 3 months from October to December 2024 and the analysis were done for the next 1 month, January 2025.The patients who were diagnosed as KDIGO 3b – 5 on rh- EPO were went under the study.The Sample size was calculated as per the formula z²×pq/d^2, where the prevalence- 39 % ¹². Type 1 error 8%, standard normal vitiate 1.96, absolute precision 5%, a sample size of (143+7) =150 was estimated. The whole data were collected in a predesigned and pre-validated proforma containing various parameters under study would be used for data collection. The data will be maintained in computer. (Microsoft Excel) by using proper Statistical Software, SPSS version 17.

Inclusion criteria -

1) Patients of CKD KDIGO 3b – 5 shall be included who are already on rh – EPO injectables, according to their respective dosage of 50-100 units /kg/ SC 3 times OR 1.2 μg/kg body weight once every 4 weeks.

Exclusion criteria-

1) Patients without dialysis

2) Severe cardiovascular, neoplastic or other chronic inflammatory diseases which co – exist with the CKD.

3.Clinically un- stable patients.

3) Metabolic decompensation or Hb>13%g/ dl with mutations in the JAK –STAT pathway disease.

4) Pregnant patients or women hoping to conceive. We also excluded patients who were co-prescribed with anti – cancerous, anti-inflammatory drugs & steroids.

5) Patients who develop the adverse effects of rh – EPO such as hypertension, thromboembolic events, seizures, severe hypersensitivity reactions most predominantly being an SJS, Gastro-intestinal &Musculo-skeletal upsets, infective like exanthems   with other generalized side effects as per the literature of pharmacology.

6) Noncompliance to rh – EPO which is attributable to any cause.

Study variables & Definition:

There are no generally accepted criteria in the clinical cut-off point to divide patients into Desidustat responder and non-responder. Thus, we selected the criteria, based on the criterion as mentioned below-

1) The Responder – After oral consumption of desidustat the following parameters are to be noted without an rh- EPO administration. _

1.1- An escalation of eGFR (ml/min / 1.73m2)

1.2- Increase in Hemoglobin levels (in %) 

1.3- An escalation to the absolute reticulocyte count (in 10^9 / L)

1.4- An escalation to the absolute reticulocyte index (in %)

 1.5- An Escalation of serum Ferritin of (ng / ml)

1.6- An escalation of transferrin saturation (in %)

-2) The non-responder:

Where the comparison with rh- EPO promulgates a marginal deterioration in the profiles so stated & in the clinical profile.

Plan for Statistical Analysis of Data: Pair-t test was mainly performed between the groups to compare the parameters with yield the significance if any.

Work plan:

The patients reporting to the nephrology outdoor as categorized into KDIGO CKD 3b – 5 on maintenance HD and administered with rh – EPOs are to be replaced with Desidustat monotherapy, which Often, is started with an initial dose of 50–100 mg of Desidustat is administered orally, given three times per week. After the initial period, the dose is usually adjusted based on hemoglobin levels and response. If hemoglobin levels are below the target range, the dose may be increased in increments (e.g., by 25 mg), while if hemoglobin levels are above the target range, the dose may be decreased or withheld until levels stabilize, whereas during the time of the Desidustat therapy we would closely monitor the following

1. CBC interpretations with PBS comments and additional calculations based on Absolute reticulocyte count & reticulocyte indexes for every 4 weeks (including morphological changes of the cells hematopoietic cells involving all the lineages)
2. A serum EPO measurement for every 6 weeks.
3. An iron profile (TIBC, TSAT, FERRITIN, IRON) for every 6 weeks.
4. A serum hepcidin values for every 4 weeks
5. eGFR measurements for every 4 weeks.
6. Evaluation of the HEART score for every 2 weeks which would involve a QUANTITATIVE TROP –I ESTIMATION & ECG’S at 4 weeks for Major adverse cardiac events (MACE) predictions with other data relevant to the score.

All of this are to be compared with a control group of patients with a KDIGO 3B-5 Patients administered with rh – EPO with the same profiles and time durations for comparison using pure statistical tools.

Therapy and monitoring:

Along with close monitoring of the adverse drug reactions with respect to Desidustat in literature such as abdominal pain, pyrexia, fatigue, peripheral oedema, occasional vomiting along with special emphasis on the constituents of the HEART score for predicting & managing any Major adverse Cardiac Events (MACE) https://www.escardio.org/Education/Practice-Tools/CVD-prevention-toolbox/HeartScore   consisting of the History(Slightly suspicious, Moderately suspicious, Highly suspicious for a MACE with 0 point, 1 point, 2point respectively ),the Electrocardiogram ( Normal in morphology ,Non-specific repolarization disturbance, Significant ST deviation with 0 point, 1 point, 2point respectively), the Age(less than 45,45 to 64 ,greater than 65 with 0 point, 1 point, 2point respectively), the Risk Factors for MACE (No known risk factors,1 to 2 risk factors, greater than or equal to 3 risk factors OR atherosclerotic disease with 0 point, 1 point, 2point respectively) & finally the initial troponin values ( Less than upper limit of normal,1 to 3x normal limit, > 3x normal limit ) as patients on rh-EPOs in patients of CKD are notorious for decreasing the end diastolic & end systolic diameters of the left ventricle ,the end diastolic & end systolic volumes of the left ventricle with a modest increase in the ejection fraction thereby increasing the cardiac work in a background of CKD which itself is a situation of a volume overload. Such measures as described were taken on a 2 weekly follow up of the patients with an addendum to monitor the same for the patients who were provided Desidustat then instead of the rh-EPOs.

Prior informed consent papers were collected by all the study participants an utmost confidentiality was maintained.

There was no single conflict of interest and no sponsor was allocated at all.    

As per this study, out of the 150 students ,71 were female & 79 were male patients. And upto 91 % (136 out of 150 patients) were in stage 5 CKD.

Result of the paired sample t test shows that mean eGFR before the treatment with Decidustat( M=13.09, SD= 6.29) and after taking treatment (M= 14.92, SD= 7.13) changed significantly with p<0.05, 95% CI for mean difference: -2.79 to -0.86, r=0.661. And on average the eGFR increased 1.828 point after the treatment.

As sufferer of CKD the Hemoglobin level of the patients were low as expected before starting Decidustat and the result of the paired sample t test shows that mean Hemoglobin before the treatment (M=8.27, SD= 1.42) and after taking treatment (M= 8.88, SD= 1.42) at the 0.05 level of significance t(149) = -10.013, n=150, p<0.05, 95% CI for mean difference: -0.72 to -0.48, r=0.863. So, its statistically proven that as per our study Decidustat significantly improved the Hemoglobin level on an average of 0.609 point after the treatment.

Result of the paired sample t test also shows that mean absolute reticulocyte count (ARC) before the treatment (M=64.64, SD= 14.20) and after taking treatment (M= 85.54, SD= 40.09) at the 0.05 level of significance t (149) = -7.005, n=150,p<0.05, 95% CI for mean difference: -26.79 to -15.00, r=0.416 &  on average the ARC increased 20.896 point after the treatment, which is statistically highly significant.

Result of the paired sample t test shows that mean Absolute reticulocyte Index (ARI) before the treatment (M=1.53, SD= 0.33) and after taking treatment (M= 1.69, SD= 0.35) at the 0.05 level of significance t(149) = -12.945, n=150, p<0.05, 95% CI for mean difference: -0.18 to -0.13, r=0.903. On average the Absolute reticulocyte Index (ARI) increased 0.16 points after the treatment, so being a significant increase.

Result of the paired sample t test also shows that mean Ferritin before the treatment with Decidustat ( M=117.29, SD= 56.36) and after taking treatment with decidustat (M= 125.15, SD= 58.73) at the 0.05 level of significance t (149) = -8.044, n=150, p<0.05, 95% CI for mean difference: -9.79 to -5.93, r=0.979, on average the ferritin increased 7.86 point after the treatment with Decidustat.

Another important finding of the paired sample t test is that mean Transferrin saturation ( T-SAT) before the treatment (M=32.20, SD= 7.06) and after taking treatment (M= 37.12, SD= 9.67) at the 0.05 level of significance t(149) = -7.709, n=150, p<0.05, 95% CI for mean difference: -6.17 to -3.65, r=0.603. on average the T-SAT increased 4.91 point after the treatment.

Relevant figures depicting

Figure 1- The mean increase in the eGFR of 150 patients after 3 months of Desidustat therapy on CKD patients on rh- EPO's.( p<0.05, 95% CI for mean difference: -2.79 to -0.86, r=0.661. And on average the eGFR increased to 1.828 points after the treatment. )

Figure 2 - The mean increase in the Haemoglobin of 150 patients after 3 months of Desidustat therapy on CKD patients on rh- EPO's. (p<0.05, 95% CI for mean difference: -0.72 to -0.48, r=0.863. And on average the Hemoglobin level increased to 0.609 points after the treatmen)

Figure 3- The mean increase in the ARC of 150 patients after 3 months of Desidustat therapy on CKD patients on rh- EPO's. (p<0.05, 95% CI for mean difference: -26.79 to -15.00, r=0.416 & on average the ARC increased to 20.896 points after the treatment)

Figure 4- The mean increase in the ARI of 150 patients after 3 months of Desidustat therapy on CKD patients on rh- EPO's. ( p<0.05, 95% CI for mean difference: -0.18 to -0.13, r=0.903. On average the Absolute reticulocyte Index (ARI) increased to 0.16 points after the treatment)

Figure 5- The mean increase in the Ferritin of 150 patients after 3 months of Desidustat therapy on CKD patients on rh- EPO's. (p<0.05, 95% CI for mean difference: -9.79 to -5.93, r=0.979, on average the ferritin increased 7.86 point after the treatment)

Figure 6-The mean increase in the T-SAT levels of 150 patients after 3 months of Desidustat therapy on CKD patients on rh- EPO's. (p<0.05, 95% CI for mean difference: -6.17 to -3.65, r=0.603. on average the T-SAT increased to 4.91 point after the treatment )

Figure 7-Pictures of hematology depicting effective reticulocytosis after Leishman staining of the peripheral blood smears indicating effective erythropoiesis after 3 months of Desidustat therapy on CKD patients on rh- EPO's.

Figure 8 - Pictures of hematology depicting effective reticulocytosis after methylene blue staining of the peripheral blood smears indicating effective erythropoiesis after 3 months of Desidustat therapy on CKD patients on rh- EPO's.

While it has been marginally established that Desidustat ,developed by Zydus Cadila often encounter as the brand name of Oxemia™ for the treatment of the obnoxious the anemia associated with Chronic Kidney Disease, receiving its first approval to be used in India on 7th March 2022 in patients with or without dialysis( 6 ),which is a resultant of a deteriorating kidney producing extremely low levels of Erythropoietin ( EPO) along with a frank escalation of inflammatory mediators due to the chronicity of hypoxia , which can be consumed orally as 100 mg thrice weekly as a starting dose & those switching from recombinant erythropoietin ( rh-EPO)  injectables at an approximation of 100 mg 125 mg or 150 mg thrice weekly corelating to their previous dose of the erythropoietins & such to be adjusted based on the hematological profile on every 4 weeks with 300 mg thrice weekly to be the highest dose. Desidustat has been prolific with a special reference to it’s mechanism of action which would necessitate the inhibition of prolyl hydroxylase domain of enzymes, resulting in the coalesce of the HIF-α and HIF-β which potentiates the genes in response to the hypoxia and thus resulting in the stimulation of EPO in vivo, promoting an acceptable erythropoiesis and improvements in the iron metabolism (1-3). It alo do potentiate the reduction of the menacing LDL – C levels as compared TO rh –EPOs 14  which becomes an addendum in the beneficial properties of Desidustat as a potential alternative. Though the DREAM-ND trail weighs both rh-EPOs & desidustat on the approximately same levels 14 with respect to the Adverse drug reactions such as vomiting, asthenia, dyspnea, pyrexia, peripheral oedema, headache, infections, hyperkalemia or co-morbid hypertension improvements, it must be noted that abnormal electrocardiograms were significantly noted with rh- EPOs with respect to Desidustat as seen in the trail performed 13  . Also the risk of serious adverse effects ( SAE) of desidustat were found to be lesser than the injectable in the 24-week study done by Sishir Gang et al who also did demonstrate the reduction of the hazardous total cholesterol , apolipoprotein B & LDL cholesterol 20 which also appraises desidustat to the injectables.de Oliveira J ú nior et al., 2015 Provatopoulou and Ziroyiannis, 2011 Alves et al., 2015 speaks on the worsening of the improvement in the hematological profile with specific resistances to the injectable leading to discontinuation of the injectable & thereby leaving regular blood transfusions as the only option with carry a multitude of side effects in a patient who would always be at a danger of volume overload by virtue of the stigmata of CKD patients & other associated complications so on and forth. Whereas multiple studies pertaining to the literature of the erythropoietin injectables versus the small molecule desidustat reflects on their congruency in dialysis independent or dependent patients with respect to the hematological profile in a multidisciplinary and robust approaches , we conducted a similar study as per the above mentioned data in the results pertaining to some of the morphology & parameters obtained by a simple blood tests such as peripheral blood smears , estimation of the eGFR & iron studies over a 3 month long period & at an interval of the same duration against the samples so obtained and studied which did divulge some interesting findings as to an average increase in the eGFR  which were largely attributable to the compliance & tolerability of the oral molecule of interest rather than frequent injections or blood transfusions ,whereas Absolute reticulocyte count ( ARC ) , Absolute reticulocyte index ( ARI ) & Transferrin saturations ( T-SAT ) did increase which may be possibly due to the decapitated anti rh EPO antibodies ,unfortunately the latter explanation of the improvement in hematology of the patients remains unexplainable as the antibody titre were not measured due to technical constraints but the literature of anti rh EPO antibodies do exist in literature as depicted by Xiao-Mei Chen et al which also contributes to pure red cell aplasia (PRCA), which is another such complication of the antibody in the patients of CKD who receive rh –EPO injectables to combat anemia. That being said, there is a strange increase in the amount of ferritin in a paired sample t – test to a 7.86 points before and after treatment with Desidustat where ferric carboxymaltose which can be administered as a single large dose instead of repeated iron sucrose injections with a much better and quick result than tne later as depicted by Ambily Jose et al, the latter being used traditionally by the practicing nephrologists which may have altered the results of ferritin against the desired margin of the marginal drop in the concerned, also keeping in mind that iron is stored in the body for a mean duration of 6 months to 3 years depending on the gender of the patient, though Desidustat is known to make robust improvements to the metabolism of iron in CKD patients itself. We in our study, also do find effective erythropoiesis in the patients concerned as we screen them using a simple peripheral blood smear with a special focus on the reticulocyte. On an emphasis on the HEART score predicting the major cardiac side effects (MACE ) with respect to the scorings in history, electrocardiogram, age, risk factors for the later & blood troponins, both the oral molecule & the injectable were fairly similar when it did come to count on the adverse drug reactions. Thus, circumstantially, we yield a better profiling of the hemodynamics, hematology and safety concerns of Desidustat to be more than that of the injectable, though further exploration in the research is always warranted.

Recombinant erythropoietin (rEPO) injectables, traditionally a cornerstone in managing CKD-associated anemia, demonstrated a significant increase in hemoglobin levels, reticulocyte count, and overall red cell indices. The response was particularly pronounced in patients with advanced anemia. Desidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), offered a convenient oral alternative with comparable efficacy in hemoglobin correction. The findings suggest that the mechanism of Desidustat stimulating endogenous erythropoietin production through hypoxia mimetic pathways ensures a consistent hematopoietic response, particularly in patients resistant & non complaint to injectable therapy. The study observed that Desidustat had dual advantages so as to not only improving serum iron parameters, such as transferrin saturation, but also reducing dependence on intravenous iron supplementation. This effect was attributed to its ability to regulate iron metabolism through hepcidin modulation, a feature less evident in rh-EPO therapy. However, the injectable rh-EPO's group required more adjunctive iron therapy, aligning with traditional limitations of EPO resistance in the presence of functional iron deficiency. Both therapeutic approaches demonstrated a positive impact on the overall prognosis of CKD patients. However, Desidustat showed a marginally better profile in stabilizing eGFR and delaying progression to end-stage renal disease (ESRD). This could be linked to its systemic anti-inflammatory effects and better hemodynamic control, mitigating oxidative stress commonly associated with CKD progression. On a final note, Recombinant erythropoietin was effective in immediate anemia correction but did not offer additional renal protection benefits, underscoring the need for combination therapy in advanced CKD.

1. Haase VH. Hypoxic regulation of erythropoiesis and iron metabolism. Am J Physiol Renal Physiol. 2010;299(1):F1-13.
2. Locatelli F, Bárány P, Covic A, et al. Kidney Disease: Improving Global Outcomes guidelines on anaemia management in chronic kidney disease: a European Renal Best Practice position statement. Nephrol Dial Transplant. 2013;28(6):1346-59.
3. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355(20):2085-98.
4. Provenzano R, Besarab A, Sun CH, et al. Oral hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) for the treatment of anemia in patients with CKD. Clin J Am Soc Nephrol. 2016;11(6):982–91.
5. Chen N, Hao C, Liu B, et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis. N Engl J Med. 2019;381(11):1001-10.
6. Zydus Cadila. Press Release: Zydus receives approval for Desidustat. 7 March 2022. Available at: https://zyduscadila.com.
7. de Oliveira Júnior WR, de Araújo MC, Lima JD, et al. Erythropoietin resistance in patients with chronic kidney disease on hemodialysis. J Bras Nefrol. 2015;37(4):476-83.
8. Provatopoulou X, Ziroyiannis PN. Erythropoietin resistance and anti-EPO antibodies: clinical significance and treatment options. Hippokratia. 2011;15(1):38–43.
9. Alves FC, Sun J, Qureshi AR, et al. The higher mortality associated with low hemoglobin concentration and erythropoiesis-stimulating agent hyporesponsiveness in dialysis patients is independent of inflammation. Kidney Int. 2015;88(5):1130-8.
10. Gang S, Gupta N, Saha N, et al. Efficacy and safety of Desidustat compared to erythropoietin in CKD-related anemia: A 24-week multicenter study. Int Urol Nephrol. 2023;55(2):337–45.
11. Xiao-Mei Chen, et al. Anti-erythropoietin antibodies and pure red cell aplasia. N Engl J Med. 2004;350(11):1101–9.
12. Ambily Jose, Mahesh E, et al. Comparative efficacy and safety of ferric carboxymaltose versus iron sucrose in chronic kidney disease: A prospective study. Saudi J Kidney Dis Transpl. 2016;27(6):1148-53.
13. DREAM-ND Study Group. Desidustat versus epoetin alfa for the treatment of anemia in chronic kidney disease patients not on dialysis: A phase 3, randomized, open-label trial. Kidney Int Rep. 2022;7(3):645–56.
14. Singh AK, et al. Cardiovascular risk in patients receiving erythropoietin. Kidney Int Suppl. 2011;1(3):135-140.
15. European Society of Cardiology. HEART Score Tool. Available from: https://www.escardio.org/Education/Practice-Tools/CVD-prevention-toolbox/HeartScore