Beta-thalassemia: renal complications and mechanisms: a narrative review

Figures & data

Table 1. Renal disease in beta-thalassemia.

Renal manifestation	Etiology	Mechanism	Evaluation/Biomarkers
Hematuria	Nephrolithiasis	Hypercalciuria, hyperuricosuria, cystinuria, struvite stones	Dipstick urinalysis
Tubular dysfunction	Chronic anemia/hypoxia	Oxidative stress, lipid peroxidation, endothelial damage and loss of peritubular capillaries	Serum β2-Μ Urine calcium/creatinine Urine β2-M/creatinine UrinaryNAG Urinary NAGL Urinary a1-microglobulin Urinary RBP
	Iron overload	Oxidative stress, lipid peroxidation
	Iron chelators	Nephrotoxicity
	Aminoglycoside, intravenous radiocontrast agents, NSAIDs	Cytotoxicity, renal vasoconstriction, acute tubular necrosis.
	Beta-lactames	Mitochondrial dysfunction, lipid peroxidation, acute tubular necrosis
	Ampicillin, ciprofloxacin, sulfonamides, acyclovir	Crystal precipitation within the distal tubular lumen
Glomerular dysfunction	Chronic anemia/hypoxia	Reduced vascular resistance, elevated RPF	Urine dipstick Serum creatinine Urine protein/creatinine Serum cystatin CrCl eGFR
		Damage and loss of peritubular capillaries, epithelial-mesenchymal transdifferentiation of tubular cells to myofibroblasts, tubulointerstitial injury, glomerulosclerosis
	Iron overload	Damage and loss of peritubular capillaries, epithelial-mesenchymal transdifferentiation of tubular cells to myofibroblasts, tubulointerstitial injury, glomerulosclerosis
	Infections (e.g. HIV, HCV, HBV)	Glomerulonephritis
	Iron chelators	Relative iron depletion, mitochondrial dysfunction in tubular cells, tubuloglomerular feedback, vasoconstriction of the afferent arteriole
	NSAIDs, COX-2 inhibitors	Vasoconstriction of the afferent arteriole
	ACE inhibitors, ARBs	Vasodilation of the afferent and efferent arterioles
Nephrolithiasis	Vitamin D, calcium supplementation, deferasirox, tubular dysfunction	Hypercalciuria, calcium stones	Urine dipstick Serum electrolytes Serum creatinine 24-hour urine collection Radiographic studies
	Tubular dysfunction	Cystinuria, cystine stones
	Splenectomy increased red cell turnover, tubular dysfunction	Hyperuricosuria, uric acid stones
	Urinary tract infections by urease-producing bacteria (e.g. Proteus spp, Klebsiella spp, S.epidermidis, Mycoplasma spp, yeast species)	Struvite stones

Note: β2M: β2 microglobulin; NAG: N-Acetyl-beta-D-glucosaminidase; NAGL: neutrophil gelatinase-associated lipocalin; RBP: Retinol binding protein; RPF: Renal plasma flow; HIV: Human immunodeficiency virus; HBV: Hepatitis B virus; HCV: Hepatitis C virus; NSAIDs: Nonsteroidal anti- inflammatory drugs; COX2: Cyclooxygenase-2; ACE: Angiotensin-converting enzyme; ARBs: Angiotensin receptor blockers; CrCl: Creatinine clearance; eGFR: estimated glomerular filtration rate.

Table 2. Studies indicated or no tubular dysfunction in patients with beta-thalassemia.

Authors	Study type	Number of patients	Age (years)	Chelation therapy	Biomarkers	Results-conclusions
Koliakos et al, 2003 [25]	observational	91 TM with no evidence of renal disease	17.2 ± 7.2	DFO	Urine NAG, Urine IgG	- high incidence of renal proximal tubular dysfunction. - iron overload as the main cause of this dysfunction
Papassotiriou et al, 2010 [66]	observational	150 TM with no evidence of renal disease	29.2 (6.4–44.2)	DFX	Plasma NGAL, Cys C	Cys C concentration may be influenced by hemodynamic parameters as a result of therapy with DFX. Any changes in cys C do not reflect renal impairment.
Ahmadzadeh et al, 2011 [14]	case-control study	140 TM with no evidence of renal disease	7–16	DFO	Urine NAG, blood sample for biochemical and ferritin tests	- Kidney dysfunction in thalassemia increases with increasing age, duration, and levels of bloodtransfusion andhypercalciuria. - The presence of severe renal dysfunction in thalassemic patients should be investigated using sensitive and specific tests, mainly NAG, to prevent progress
Mohkam et al, 2008 [20]	cross-sectional study	103 TM with no evidence of renal disease	12.5+/−5.53	DFO	Urine sodium (Na), potassium (K), calcium (Ca), creatinine (Cr), phosphate, uric acid (UA), NAG and amino acids	Urinary NAG excretion can be a reliable index of the tubular toxicity and a possible predictor of proteinuria, aminoaciduria and eventual renal impairment in these patients.
Michelakakis et al, 1997 [24]	case-control study	36 TM with no evidence of renal disease	5–22	DFO	Urine specimens. Urine NAG, a-Mannosidase, ferritin	Iron overload resulted in increased urinary levels of the lysosomal enzyme NAG. Reduction of iron load, achieved by regular DFO infusion, resulted in normalization of the urinary enzyme levels.
Smolkin et al, 2008 [21]	case-control study	37 TM and 11 TI	2.4–27	DFO	Urine and blood samples, Urine NAG	Renal tubular function is impaired in children with TM and TI. It is not known whether these functional abnormalities would have any long-term effects on the patients.
Tantawy et al, 2014 [32]	cross-sectional, case-control study	66 TM and 26 TI	2.5–16	DFP	Serum ferritin, bicarbonate, plasma osmolality and urinary total proteins, microalbuminuria, NAG, RBP, α-1 microglobulin, bicarbonate, osmolality, creatinine clearance (CrCl)	Asymptomatic renal dysfunctions are prevalent in young β-TM and β-TI patients that necessitate regular screening
Ong-ajyooth et al, 1998 [13]	case-control study	95 beta-thal/Hb E	na	na	Urine NAG, β2Μ Plasma and urine MDA	This is the first report of renal tubular defects found associated with beta-thal/Hb E disease. The mechanism leading to the damage is not known but it might be related to increased oxidative stress secondary to tissue deposition of iron, as indicated by the raised levels of serum and urine MDA.
Patsaoura et al, 2014 [17]	case-control study	35 TI	8–63	-	Plasma NGAL, STfR, NTBI,	The increased NGAL levels reported for the first time in TI patients in agreement with the elevated expression of NGAL observed in TI mouse models. The induction of NGAL may represent either a survival response, facilitating the survival of the less damaged thalassemic erythroid precursors, or a consequence of the abnormal iron regulation in TI.
Roudkenar et al, 2008 [18]	case-control study	25 adults TM and 9 pediatric TM	24.33 ± 7.09 and 8.28 ± 1.49	na	Plasma NGAL with PCR and ELISA	- In all adult cases, except one sample, NGAL protein was expressed more compared to the controls - Positive correlation with ferritin - Negative correlation with sex, age - NGAL upregulation was not found in pediatric beta-thalassemia patients. Iron overload and oxidative status in beta-thalassemia patients induce NGAL/Lcn2 expression. Upregulation of NGAL in this disorder may play a beneficial role in decreasing ROS or chelating iron. Obviously, chelating of iron is one of the major therapeutic goals in b-thalassemia.

Note: TM: Thalassemia major; TI: Thalasemia intermedia; TMin: Thalassemia minor; DFO: Desferrioxamine; DFX: Deferasirox NAG: N-Acetyl-beta-D-glucosaminidase; β2M: β2 microglobulin; NAGL: Neutrophil gelatinase-associated lipocalin; IgG: Immunoglobulin G; Cys C: Cystatin C; NT-proBNP: N-terminal pro b-type natriuretic peptide; RBP: Retinol binding protein; MDA: malondialdehyde; STfR: Soluble Transferrin Receptor; NTBI: Non-transferrin-bound serum iron; hs-CRP: high-sensitivity C-reactive protein; PCR: Polymerase chain reaction; ELISA: Enzyme-linked Immunosorbent Assay; Lcn-2: Lipocalin-2; ROS: Reactive oxygen species.

Table 3. Deferasirox induced Fanconi syndrome.

Authors	Study design	Patient population	Comorbidities/other potentially nephrotoxic medications	Dose and duration of treatment	Clinical picture	Outcome
Chuang et al, 2015 [73 ]	Cohort study, single center, evaluating the incidence of DFX- related FS and its risk factors.	57 patients with TDT, aged 7.8 ± 4.4 years old	None	9299 ± 1774 mg/kg/year for 6.9 ± 1.8 years	Non-anion gap metabolic acidosis, hypophosphatemia, glucosuria	DFX was stopped. All features of proximal tubular dysfunction resolved.
Rafat et al, 2009 [81]	Case report	78-year-old male with sideroblastic anemia	DM, CLL, aortic valve replacement, and essential hypertension/ perindopril, glibenclamide, metformin	24 mg/kg/d for 1 month	Non-anion gap metabolic acidosis, hypophosphatemia, glycosuria, proteinuria, hypourichemia, increased β2-microglobulin urinary level. Increase in serum creatinine from 0.9–2 mg/dl.	DFX was stopped. Resolution of tubulopathy apart from minimal proteinuria. Serum creatinine 1.2 mg/dl
Murphy et al, 2013 [79]	Case report	21-year-old male with Ewing sarcoma	Ifosfamide	1125 mg/d for 9 months	Hypophosphatemia, hypokalemia, glycosuria, proteinuria, kaliuresis. Increase in serum creatinine from 1.1–2.5 mg/dl. Kidney biopsy revealed severe tubular injury with tubular epithelial cells demonstrating isometric vacuolization consistent with drug toxicity	DFX was stopped. Fluid and electrolyte supplementation. SCr fell to 1.5 mg/dL and bicarbonate normalized. Persistent hypokalemia, hypophosphatemia, proteinuria, and glycosuria
Shah et al, 2017 [89]	Case report	20-year-old male with TDT admitted for a scheduled allogenic stem cell transplant	Fludarabine	20–30 mg/kg/d for 8 years. Due to dispensing error he received a one-time dose of 90 mg/kg.	Acute onset, following high dose administration. Metabolic acidosis, glycosuria, hematuria, phosphaturia, kaliuresis and elevated β2- microglobulinuria	DFX was stopped. Fluid and electrolyte supplementation. Plasmapheresis. All features of proximal tubular dysfunction resolved.
Papneja et al, 2016 [87]	Two Case reports, two centers	16-year-old male with DBA	None	30 mg/kg/d for 6 years with a transient increase to a maximum of 45 mg/kg/day during the last year.	Non-anion gap metabolic acidosis hypokalemia, hypophosphatemia, phosphaturia, glucosuria, and proteinuria	DFX was stopped. Fluid and electrolyte supplementation. FS was resolved. DFX was restarted.
		14-year-old male with DBA	None	36 mg/kg/d for 10 months	Non-anion gap metabolic acidosis hypokalemia, hypophosphatemia, hyperphosphaturia, glucosuria, and proteinuria. Increase in SCr from 59 μmol/l to 204 μmol/l.	DFX was stopped. Fluid and electrolyte supplementation. SCr was normalized. All features of proximal tubular dysfunction resolved. DFX was restarted.
Dee et al, 2014 [75]	Cohort study, single center, evaluating the incidence of DFX- related FS.	9 patients with TDT, aged 2.6–23.8 years old	One patient had influenza virus H3N2 and developed severe hypokalemia while on DFX. Another patient had Echovirus type 6 infection 10 months before the onset of renal tubular dysfunction	Dose was not indicated. Cumulative incidence was estimated at 11% at 2 months and about 90% at 6 years of DFX therapy	Metabolic acidosis (33%), elevated urine β2M [Odds ratio (OR) = 35.29, P = 0.0009], hypokalaemia (OR = 23.22, P = 0.015), hypophosphataemia (OR = 57.00, P = 0.001), hypocalcaemia (OR = 23.22, P = 0.015)	Normalized after reduction or withdrawal of DFX.
Tunc et al, 2012 [88]	Cohort study, single center, evaluating the incidence of DFX- related adverse events.	8 patients with Fanconi anemia aged 12.8 ± 3.6 years old	All patients were receiving oxymethalone.	10–30 mg/kg/d for 13.6 ± 5.8 months	Proteinuria (87.5%). Increase in SCr (37.5%) in: a patient with unilateral renal agenesis (from 1.03 mg/dL to 1.44 mg/dL), a patient who undergone surgery for cellulitis (SCr 1.28 mg/dL), a patient with congenital abnormality of the right duplicated collecting system during sepsis (SCr 1.26 mg/dL)	SCr was normalized in 2/3 of patients after transient cessation of DFX. Other information is not provided.
Rheault et al, 2011 [82]	Two case reports	7.5-year-old-male with TDT	None	30 mg/kg/d for 18 months.	Normal-anion gap metabolic acidosis, hypokalemia, phosphaturia, glucosuria, aminoaciduria hypercalciuria.	DFX was stopped. Fluid and electrolyte supplementation. Features FS were improved. DFX was restarted at 20 mg/kg/d with evidence of mild FS (elevated urine β2M, hypercalciuria).
		8.5-year-old-female with TDT	None	30 mg/kg/day for 12 months.	Elevated protein to creatinine ratio (0.38), urine calcium to creatinine ratio (0.46) and urine β2M.	Stable without intervention.
Wei et al, 2011 [83]	Case report	18.75-year-old male with TDT	Secondary hypothyroidism and hypogonadotropic hypogonadism/ oral thyroxine, intramuscular testosterone cypionate	28.9–35.3 mg/kg/d for 27 months.	Proteinuria, glycosuria, hypophosphatemia, hypocalcemia, hyponatremia, hypokalemia, metabolic acidosis, low serum uric acid, elevated urinary β2M. Increase in SCr from 0.5–1.74 mg/dL. Also developed coma, hepatic dysfunction and thrombocytopenia.	Fluid and electrolyte supplementation. DFX was stopped and patient had full recovery.
Yacobovich et al, 2010 [84]	Four case reports	8.5-year-old female with TDT	None	30 mg/kg/d for 8 months.	Metabolic acidosis, glycosuria, hypokalemia, hypophosphatemia.	DFX was stopped. Fluid and electrolyte supplementation. FS was resolved.
		11-year-old female with TDT	None	30 mg/kg/d for 24 months.	Metabolic acidosis, glycosuria, low serum uric acid, hypokalemia, hypophosphatemia and elevated urine lysozyme. Also had gastroenteritis.	DFX was stopped. Fluid and electrolyte supplementation. FS was resolved.
		8-year-old male with TDT	None	30 mg/kg/d for 36 months.	Metabolic acidosis, glycosuria, low serum uric acid, hypokalemia, hypophosphatemia and elevated urine lysozyme. Also had gastroenteritis.	DFX was stopped. Fluid and electrolyte supplementation. FS was resolved.
		32-year-old female with TDT	Calcium plus vitamin D supplement. Also, on ofloxacin and phenazopyridine HCL for a recently diagnosed urinary tract infection	38 mg/kg/d for 33 months.	Metabolic acidosis, glycosuria, low serum uric acid, hypokalemia, hypophosphatemia, kaliurisis.	DFX was stopped. Fluid and electrolyte supplementation. FS was resolved.
Grange et al, 2010 [78]	Case report.	77-year-old male with non- hereditary hemochromatosis.	Hypertension/ irbesartan, HCTZ, ursodesoxycholic acid	1500 mg/day for 1 month.	Glycosuria, hypokalemia, hypophosphatemia, hypocalcemia, kaliurisis, phosphaturia, aminoaciduria. Increase in SCr at 180 μmol/L.	DFX was stopped. Fluid and electrolyte supplementation. FS was resolved. SCr was normalized.
Even-Or et al, 2009 [77]	Two case reports.	18-year-old male with pure red cell aplasia.	None.	20 mg/kg/d for 6 months.	Glycosuria, uricosuria, phosphaturia, kaliuria, aminoaciduria, low serum uric acid, hypokalemia, hypophosphatemia. Increase in SCr from 0.6–1.07 mg/dL.	DFX was stopped. FS and SCr were resolved. DFX was restarted and mild hypouricemia, hypophosphatemia, phosphaturia and increased urinary β2M within a few weeks, while on 10 mg/kg/day of DFX. He continued treatment with increasing doses with no further deterioration.
		11-year-old female with TDT.	Acute graft rejection after AHSCT at the age of 4 years, splenectomy.	30 mg/kg/d for 6 months.	Glycosuria, uricosuria, phosphaturia, kaliuria, aminoaciduria, low serum uric acid, hypokalemia, hypophosphatemia., increased urinary β2M	DFX was stopped. Electrolyte supplementation. FS was resolved.

Note: DFX: Deferasirox; FS: Fanconi syndrome; Scr: Serum creatinine; DBA: Diamond-Blackfan anemia, β2M: β2 microglobulin; HCTZ: Hydrochlorothiazide; AHSCT: Allogeneic hematopoietic stem cell transplantation.

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