Markers of Renal Complications in Beta Thalassemia Patients with Iron Overload Receiving Chelation Agent Therapy: A Systematic Review

Figures & data

Figure 1 PRISMA flow chart.

Table 1 Chelation Therapy and Marker Reported from Study of Beta Thalassemia

No.	Authors	Year of Publication	Study Type	Age (Years)	Chelation of Therapy (Number of Patients)	Markers Reported
1	Aldudak 2000^Citation17	2000	Cross-sectional	9.6 ± 5.0; 10 ± 4.7	Deferoxamine (70)	BUN
						S Cr
						S Na
						S K
						S Ua
						S Phosp
						Ccr
						TRP
						uVolume
						uOsmolality
						uP/Cr
						uNAG/Cr
						uMDA/Cr
2	Smolkin 2008^Citation16	2008	Cross-sectional	10.8 ± 6.2; 11.2 ± 3.4; 10.2±4.5	Deferoxamine (n/a)	BUN
						Serum creatinine
						Serum uric acid
						GFR
						FENa
						FEK
						Urine Ca/Cr
						Uric acid excretion
						Tubular phosphorus reab
						Urine osmolality
						uNAG
						uNAG/Cr
3	Economou 2010^Citation25	2010	Case-control	13.66 ± 5.11; 12.66 ± 4.2	Deferasirox (28) group A	Serum creatinine
					Deferiprone + deferoxamine (14) group B	Urea
						Cystatin-C
						U Protein
						U Ca
						U FeNa
						u Phoshor, rabsorbtion
						uβ2 MG
						CrC
						eGFR
4	Hamed 2010^Citation5	2010	Case-control	8.72±3.7; 8.4±4.1	Deferoxamine (34);	Cystatin-C
					w/o chelation (35)	Creatinine
						eGFRSchwartz
						Uric acid
						Calcium
						Inorganic phosphate
						Total antioxidant capacity
						Albumin/Cr
						NAG/Cr
						β2MG/Cr
						Inorganic phosphorus
						MDA/Cr
5	Mansi, 2013(belum ada)	2013	Case-control		Deferoxamine (42)	Glucose
						Urea
						Creatinine
						Uric acid
						Sodium
						Potassium
						Chloride
6	Ali 2014^Citation21	2014	Cross-sectional	9.67± 1.35; n/a	Deferoxamine (62) group IA	Cystatin-C
					No chelating (38) group IB	Serum creatinine
					Control (50) group II	eGFRSchwartz
						CrC
						Albumin/Cr
7	Sen 2015^Citation11	2015	Cross-sectional	9.14 ± 4.4; 8.8 ± 4.0	Deferasirox (59)	U Na/Cr
						U K/Cr
						U Ca/Cr
						U P/Cr
						U Mg/Cr
						U Protein/Cr
						U Uric acid/Cr
						uNAG/Cr
						uNGAL/Cr
						uKIM1/Cr
						uL-FABP/Cr
8	Behairy 2017^Citation24	2017	Case-control	10.41±3.86, 8.6±3.47	Deferoxamine (60%)	Urea
					Deferasirox (32.9%)	Creatinine
					Hydra (7.1%)	Urea/Cr
						Urine volume
						CrC
						Cystatin-C
						β2MG
						uAlbumin/Cr
						eGFRSchwartz
9	Bekhit 2017^Citation19	2017	Case-control	8.5 ± 3.5; n/a	Deferasirox (21)	S Urea
					Deferiprone (8)	S Cr
					Deferoxamine (3)	U Creatinine
						U Ca/Cr
						U uric acid
						GFR
						uNAG
10	Annayev 2018^Citation23	2018	Case-control	18.4 ± 11.8; n/a	Deferasirox (38)	FENa
					Deferiprone (8)	Na
					None (4)	K
						Ca
						P
						Mg
						U Ca/Cr
						Urea
						Creatinine
						Albumin
						GFR based on age
						SCystatin-C
						uβ2 MG
11	ElAlfy 2018^Citation20	2018	Cross-sectional	12.8 ± 3.2	Deferoxamine (2)	Urea
					Deferasirox (9)	Uric acid
					Deferiprone (3)	Serum creatinine
					Combined (36)	Cystatin-C
						Urinary β2 microglobulin
						uAlbumin/Cr
						uβ2 M/albumin
12	Badelli 2019^Citation10	2019	Case-control	n/a	Deferoxamine (19)	GFR
					Deferasirox (21)	BUN
						Creatinine
						Cystatin-C
						GFR based on Cystatin
						uNGAL
						uKIM1
						uIL-18
						uCreatinine
						uAlbumin
						uNGAL/Cr
						uIL-18/Cr
						uKIM1/Cr
						uAlbumin/Cr
13	Fouad 2019^Citation15	2019	Case-control	29±9; 28±5	Deferasirox (11),	Albumin/Cr
					Deferipone(3)	eGFR
						NGAL
						uNGAL/Cr
14	Nafea 2019^Citation3	2019	Cross-sectional	14.7 ± 4.3	Deferasirox (26)	Serum K
					Desferoxamine (14)	Serum Na
					Deferiprone(26)	Serum Ca total
						Seurm P
						Serum Mg
						Serum creatinine
						U K/Cr
						U Na/Cr
						U P/Cr
						U Mg/Cr
						Urinary creatinine
						eGFR
						U KIM-1/Cr
15	Bilir 2020^Citation22	2020	Cross-sectional	12.63 ± 4.58; 11.44 ± 4.37	Deferasirox (47)	Creatinin
						S Sodium
						S Potassium
						S Calcium
						S Phosphorus
						eGFR
						Cystatin-C
						Total antioxidant capacity
						Total oxidant capacity
						U Ca/Cr
						U Protein/Cr
						uβ2MG/Cr
						uRBP/Cr
						uNAG/Cr
						MDA/Cr
16	Capolongo 2020^Citation45	2020	Case-control	34 ± 12; 33 ± 14	Deferoxamine (40)	Serum creatinine
						eGFR
						S Na
						S K
						S Ca
						S Chlorine
						S Bicarbonate
						FENa
						U Ca
						U Phosp
						uAlbumin/Cr
						uOsmolarity
						uOsmolality
						pH
17	Mahmoud 2021^Citation42	2021	Case-control	9.58±4.07	Deferasirox (100)	Urea
						Creatinine
						eGFR
						U protein/Cr
						UNa/Cr
						UK/Cr
						UCa/Cr
						Uuric acid/Cr
						uNAG
						uNAG/Cr
						uKIM1
						uKIM1/Cr
						SCystatin-C
18	Tanous 2021^Citation18	2021	Cross-sectional	20.92± 9.7	Deferasirox (26)	Serum creatinine
					Deferiprone + deferoxamine (6)	Serum Na
					Deferoxamine (4)	Serum K
						Serum uric acid
						eGFR
						uNAG <12
						Abnormal uNAG (>12)
						Abnormal urine Ca/Cr (>0.14)
						Urine osmolality

Table 2 Result and conclusion from Study of Beta Thalassemia with Iron Overload and Receiving Chelation Agent Therapy

No	Authors	Results-Conclusions
1	Aldudak 2000	Administration of chelating agents in beta thalassemia patients actuates a damage to the proximal tubular kidney.
2	Smolkin 2008	In beta thalassemia patients, UNAG and UNAG/creatinine ratio markers can be used as markers to determine the frequency of transfusion and the effect of chelating agent therapy on ferritin levels.
3	Economou 2010	Glomerular and tubular dysfunction in iron overload beta thalassemia patients receiving chelating agents was observed through the elevation of cystatin C, proteinuria, hypercalciuria and beta2-microglobulin.
4	Hamed 2010	Chelating agents in beta thalassemia patients have been shown stimulate glomerular and tubular dysfunction.
5	Smolkin 2008	In beta thalassemia patients, UNAG and UNAG/creatinine ratio markers can be used as markers to determine the frequency of transfusion and the effect of chelating agent therapy on ferritin levels.
6	Mansi 2013	Kidney damage occurs in beta thalassemia patients receiving chelating agents characterized by increased urea, creatinine, uric acid, urinary sodium and potassium.
7	Ali 2014	Elevated cystatin C, serum creatinine, and serum ferritin and high uACR indicate kidney damage in beta thalassemia
8	Sen 2015	NAG and NGAL can be used as markers of renal injury in beta thalassemia patients experiencing iron overload and receive therapeutic chelating agents.
9	Behairy 2017	Cystatin-C and beta-2 microglobulin are specific and sensitive early biomarkers for monitoring glomerular and tubular dysfunction in children with beta-TM.
10	Bekhit 2017	NAG is excreted following renal damage, hence used as marker of the toxicity index in beta thalassemia patients receiving chelating agents.
11	Annayev 2018	Kidney damage was concluded after an increase in Cystatin C and beta microglobulin in beta thalassemia patients receiving iron chelating agents.
12	ElAlfy 2018	Iron overload in beta thalassemia patients with long-term use of chelating agents revealed differences in serum cystatin C, uACR, and urinary B2 microglobulin, and B2 microglobulin/albumin ratio values.
13	Badeli 2019	Administration of deferasirox led to kidney damage, characterized by an increase in uNGAL, inflammatory factors, sort of IL18, in beta thalassemia patients.
14	Fouad 2019	uNGAL levels, uNGAL/creatinine ratio, eGFR and urinary albumin creatinine ratio were distinctive between group with iron overload and added chelating agents.
15	Nafea 2019	UKIM-1 is a biomarker used to detect worsening eGFR in beta-thalassemia patients with iron overload and routine deferasirox.
16	Bilir 2020	Iron overload marked by high serum ferritin, is associated with proteinuria, increased cystatin C, and urinary protein/Cr in beta thalassemia patients routinely receiving chelating agents.
17	Capolongo 2020	The administration of chelating agents in patients with beta thalassemia iron overload induced renal tubular damage and required early detection to prevent further kidney damage.
18	Mahmoud 2021	Serum cystatin-C is a good predictive marker in the evaluation of glomerular dysfunction. Urine concentrations of NAG and KIM-1 represent sensitive, specific, and highly predictive early biomarkers for acute renal injury in patients with beta TM when subclinical kidney injury or dysfunction is expected before serum creatinine increases.
19.	Tanous 2021	The use of deferasirox for approximately 10 years induced the decline of eGFR and was negatively correlated with uNAG in beta thalassemia patients with iron overload.

Aldudak B, Karabay Bayazit A, Noyan A, et al. Renal function in pediatric patients with beta-thalassemia major. Pediatr Nephrol. 2000;15(1–2):109–112. doi:10.1007/s004670000434

 PubMed Web of Science ®Google Scholar

Smolkin V, Halevy R, Levin C, et al. Renal function in children with β-thalassemia major and thalassemia intermedia. Pediatr Nephrol. 2008;23(10):1847–1851. doi:10.1007/s00467-008-0897-8

 PubMed Web of Science ®Google Scholar

Economou M, Printza N, Teli A, et al. Renal dysfunction in patients with beta-thalassemia major receiving iron chelation therapy either with deferoxamine and deferiprone or with deferasirox. Acta Haematol. 2010;123(3):148–152. doi:10.1159/000287238

 PubMed Web of Science ®Google Scholar

Bakr A, Al-Tonbary Y, Osman G, El-Ashry R. Renal complications of beta-thalassemia major in children. Am J Blood Res. 2014;4(1):1–6.

 PubMedGoogle Scholar

Ali BA, Mahmoud AM. Frequency of glomerular dysfunction in children with Beta thalassaemia major. Sultan Qaboos Univ Med J. 2014;14(1):e88–94. doi:10.12816/0003341

 PubMedGoogle Scholar

Şen V, Ece A, Uluca Ü, et al. Urinary early kidney injury molecules in children with beta-thalassemia major. Ren Fail. 2015;37(4):607–613. doi:10.3109/0886022X.2015.1007871

 PubMed Web of Science ®Google Scholar

Behairy OG, Abd Almonaem ER, Abed NT, et al. Role of serum cystatin-C and beta-2 microglobulin as early markers of renal dysfunction in children with beta thalassemia major. Int J Nephrol Renovasc Dis. 2017;10:261–268. doi:10.2147/IJNRD.S142824

 PubMed Web of Science ®Google Scholar

Bekhit OE, El Dash HH, Ahmed MS. Early detection of kidney dysfunction in Egyptian patients with beta-thalassemia major. Egypt Pediatr Assoc Gazette. 2017;65(3):85–89. doi:10.1016/j.epag.2017.02.002

 Google Scholar

Annayev A, Karakaş Z, Karaman S, Yalçıner A, Yılmaz A, Emre S. Glomerular and tubular functions in children and adults with transfusion-dependent thalassemia. Turk J Haematol. 2018;35(1):66–70. doi:10.4274/tjh.2017.0266

 PubMed Web of Science ®Google Scholar

ElAlfy MS, Khalil Elsherif NH, Ebeid FSE, et al. Renal iron deposition by magnetic resonance imaging in pediatric β-thalassemia major patients: relation to renal biomarkers, total body iron and chelation therapy. Eur J Radiol. 2018;103:65–70. doi:10.1016/j.ejrad.2018.04.007

 PubMed Web of Science ®Google Scholar

Badeli H, Baghersalimi A, Eslami S, et al. Early kidney damage markers after deferasirox treatment in patients with thalassemia major: a case-control study. Oxid Med Cell Longev. 2019;2019:5461617. doi:10.1155/2019/5461617

 PubMed Web of Science ®Google Scholar

Fouad IZ, ElNahid MS, Youssef MF, Amroussy YM. Urinary neutrophil gelatinase-associated lipocalin as a marker of kidney injury in Egyptian patients with thalassemia. Egypt J Intern Med. 2019;31(3):343–352. doi:10.4103/ejim.ejim_114_18

 Google Scholar

Nafea OE, Zakaria M, Hassan T, El Gebaly SM, Salah HE. Subclinical nephrotoxicity in patients with beta-thalassemia: role of urinary kidney injury molecule. Drug Chem Toxicol. 2022;45(1):93–102. doi:10.1080/01480545.2019.1660362

 PubMed Web of Science ®Google Scholar

Arman Bilir Ö, Kirkiz S, Fettah A, et al. Renal function and the oxidative status among children with thalassemia major and healthy controls: a cross-sectional study. Transfus Apher Sci. 2020;59(4):102746. doi:10.1016/j.transci.2020.102746

 PubMed Web of Science ®Google Scholar

Capolongo G, Zacchia M, Beneduci A, et al. Urinary metabolic profile of patients with transfusion-dependent β-thalassemia major undergoing deferasirox therapy. Kidney Blood Press Res. 2020;45(3):455–466. doi:10.1159/000507369

 PubMed Web of Science ®Google Scholar

Mahmoud AA, Elian DM, Abd El Hady NM, et al. Assessment of subclinical renal glomerular and tubular dysfunction in children with beta thalassemia major. Children. 2021;8(2):100. doi:10.3390/children8020100

 PubMedGoogle Scholar

Tanous O, Azulay Y, Halevy R, et al. Renal function in β-thalassemia major patients treated with two different iron-chelation regimes. BMC Nephrol. 2021;22(1):418. doi:10.1186/s12882-021-02630-5

 PubMed Web of Science ®Google Scholar