CJASN ePress. Published on May 11, 2015 as doi: 10.2215/CJN.12181214

Article

GFR in Patients with b-Thalassemia Major Gai Milo,*† Revital Feige Gross Nevo,*† Idit Pazgal,†‡ Anat Gafter-Gvili,†‡ Ofer Shpilberg,†‡ Uzi Gafter,†‡ Arie Erman,†‡ and Pinhas Stark†‡

Abstract Background and objectives Patients with b-thalassemia major (TM) may have tubular dysfunction and glomerular dysfunction, primarily hyperfiltration, based on eGFR. Assessment of GFR based on serum creatinine concentration may overestimate GFR in these patients. This study sought to determine GFR by using inulin clearance and compare it with measured creatinine clearance (Ccr) and eGFR. Design, setting, participants & measurements Patients followed up in an Israeli thalassemia clinic who had been regularly transfused for years and treated with deferasirox were included in the study. They were studied by inulin clearance, Ccr, the CKD Epidemiology Collaboration and the Modification of Diet in Renal Disease equations for eGFR, and the Cockcroft–Gault estimation for Ccr. Expected creatinine excretion rate and tubular creatinine secretion rate were calculated. Results Nine white patients were studied. Results, given as medians, were as follows: serum creatinine was 0.59 mg/dl (below normal limits); GFR was low (76.6 ml/min per 1.73 m2) and reached the level of CKD; Ccr was 134.9 ml/min per 1.73 m2, higher than the GFR because of a tubular creatinine secretion rate of 30.3 ml/min per 1.73 m2 (this accounted for 40% of the Ccr); and eGFR calculated by the CKD Epidemiology Collaboration and Modification of Diet in Renal Disease equations and Cockcroft–Gault–estimated Ccr were 133, 141, and 168 ml/min per 1.73 m2, respectively. These latter values were significantly higher than the GFR, reaching the hyperfiltration range, and indicated that the estimation techniques were clinically unacceptable as a method for measuring kidney function compared with the GFR according to Bland and Altman analyses. Conclusions Contrary to previous reports, patients in this study with TM had normal or reduced GFR. The estimating methods showed erroneous overestimation of GFR and were clinically unacceptable for GFR measurements in patients with TM by Bland and Altman analysis. Therefore, more accurate methods should be used for early detection of reduced GFR and prevention of its further decline toward CKD in these patients. Clin J Am Soc Nephrol 10: ccc–ccc, 2015. doi: 10.2215/CJN.12181214

Introduction

b-Thalassemias are a group of recessively autosomal hereditary hemoglobinopathies, characterized by reduced or absence of synthesis of the b-globin chains, ineffective erythropoiesis, and anemia. Patients with b-thalassemia major (TM) present in their first year of life with severe anemia and subsequently require blood transfusions for survival. The repeated transfusions, together with ineffective erythropoiesis and the increased intestinal iron absorption, lead to iron overload, which necessitates chelation therapy to prevent organ damage (1). Blood transfusions with concomitant iron chelation therapy prolong survival of patients with TM (2). Iron overload in these patients affects internal organs, such as the heart, liver, lungs, and endocrine glands (3). Its effect on the kidneys is less known, yet anemia, iron overload, and treatment with certain iron chelators have been linked to kidney dysfunction (3). Kidney dysfunction mainly includes various tubular abnormalities (4–11). Several studies calculated eGFR in patients with TM by using the Schwartz www.cjasn.org Vol 10 August, 2015

*Department of Nephrology and Hypertension, Rabin Medical Center, Petah-Tikva, Israel; † Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel; and ‡Institute of Hematology, Rabin Medical Center, Petah-Tikva, Israel Correspondence: Dr. Uzi Gafter, Department of Nephrology and Hypertension, Rabin Medical Center, Sackler School of Medicine, Tel Aviv University, 7 Keren Kayemet Street, PetahTikva 49372, Israel. Email: gafter@post. tau.ac.il

equation for children and adolescents (12) and the Modification of Diet in Renal Disease (MDRD) equation for adults (13). The eGFR was high, with hyperfiltration in most of the patients (3,5–7). However, these equations, which are based on the measurement of serum creatinine (Scr), may be inaccurate. Therefore, Quinn et al. (14) studied, for the first time, renal function in a large population of patients with TM by measuring creatinine clearance (Ccr). They also calculated eGFR by the Schwartz equation and compared it to the Ccr. They found that the Ccr in most of the regularly transfused patients with TM was within the normal range; however, it was high in 17.8% and low in 8.3% of the patients. The mean eGFR by the Schwartz equation was significantly higher than the mean Ccr, overestimating GFR in most patients. However, as the author stated, one of the study’s limitations was failure to obtain a gold standard measurement of GFR (14). Economou et al. (11) determined kidney function in patients with TM treated with iron chelation, using serum cystatin C as a marker for GFR (11). The cystatin C Copyright © 2015 by the American Society of Nephrology

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serum level was significantly elevated compared with the level in controls, suggesting reduced GFR in those patients. These results warrant determination of GFR by an accurate method. Recently, Piga et al. (15) reported normal GFR measured by 51Cr EDTA in patients with TM naive to iron chelating therapy with deferasirox. Treatment with deferasirox for up to 2 years was associated with reduction in GFR of 17.7%–17.2%, which did not progress during 2 years of follow-up and reversed after a 4-week washout period (15). The aim of the current study was to measure GFR in patients with TM receiving deferasirox as a chelating agent through use of inulin clearance (Cin), the gold standard method for determining GFR (16). In addition, we aimed to measure Ccr, calculate eGFR and estimated Ccr (eCcr), and compare these values to GFR (Cin indexed for body surface area [BSA]).

Materials and Methods Study Patients We screened all adult patients with TM who underwent regular transfusion and were treated with iron chelation in the Comprehensive Center of Thalassemia, Hemoglobinopathies and Rare Anemias at the Institute of Hematology at the Rabin Medical Center, a tertiary center. Patients who received 8 or more units of packed red blood cells per year were defined as having undergone regular transfusion (14). They were treated with chelating drugs, including deferoxamine, deferiprone, or a combination of both, or with deferasirox (Exjade). Treatment with deferoxamine has caused acute renal failure requiring dialysis in patients with TM (3) and reduced GFR (3,17). Deferasirox treatment in patients with TM has caused mild, dose-dependent increases of Scr (18). These increases were transient and generally within the normal range. In some patients, Scr returned to baseline after dose reduction or interruption of treatment with deferasirox; however, even in patients who continued to have an elevated Scr, no progressive rise occurred (18). Furthermore, treatment with deferasirox for up to 5 years in patients with TM (19) showed no progressive rise in Scr. Therefore, we included in this study regularly transfused patients with TM who received only deferasirox as a single drug for at least 1 year. We excluded patients who received other iron chelating therapies (such as deferoxamine, deferiprone, or a combination of both) that were associated with acute renal failure or reduction in GFR (3,17). The files of all patients were reviewed for demographic, clinical, and biochemical characteristics. Each patient underwent a Cin study, as previously described (20,21), 1 week after a timed-collected Ccr test using a 24-hour urine collection. Treatment with deferasirox was not interrupted during the studies. Studies were performed not less than 3 weeks after the last blood transfusion to avoid potential hemodynamic effects. Creatinine was determined by an enzymatic measurement. We estimated the expected urinary creatinine excretion rate (22) and calculated tubular creatinine secretion rate (TScr) (23). In addition, we calculated the eGFR by using the CKD Epidemiology Collaboration (CKD-EPI) (24) and MDRD equations and eCcr by the Cockcroft–Gault (CG) equation (25), using their Scr level. The study was conducted according to the Declaration of Helsinki and was approved by the Rabin Medical Center

Institutional Review Board. All participants provided informed consent. Statistical Analyses Data are presented as median and range, unless otherwise specified. A Wilcoxon signed rank test for related samples, the graphical Bland and Altman method (26), and Pearson correlations were performed using GraphPad software. A two-tailed P value ,0.05 was considered to represent a statistically significant difference.

Results Thirty-three patients who had regular transfusion and received iron chelation therapy were screened. Twentythree patients who received combinations of iron chelation drugs (deferoxamine, deferiprone, or a combination of both) were excluded. Ten patients who received deferasirox as a single iron chelation drug for at least 1 year were included in the study. One of these patients dropped out because of technical failure in the inulin clearance test. Five women and four men completed the study; all were white. Their median age was 30 (21–37) years. They were of short stature (median height, 1.54 [1.4–1.7) m and low body weight (median, 55 [41–66] kg). Their median BSA was 1.52 (1.25–1.71) m2 and their median body mass index was 22.6 (range, 17.3–29.3) kg/m2. All patients were diagnosed at infancy. Individual hematologic and renal data are given in Table 1. They received transfusion with 15 units of packed red blood cells in the year before the study. They were treated with iron chelating drugs for 27 years; in the last 4 of which, they received a median daily dose of 30.3 (18.2–41.7) mg/kg deferasirox only. Their hemoglobin and ferritin levels and the number of transfusions are given in Table 1. As shown in this table, the patients had a low Scr level of 0.59 mg/dl, which is below the normal limits in our laboratory. Their 24-hour urinary creatinine excretion was 19.9% less than expected (P,0.004). They had mild proteinuria. Table 2 presents the results of kidney function tests. The patients had a low Cin of 72 ml/min, lower than the Cin measured in our laboratory in healthy young adults (20,21). When indexed for BSA, the GFR (Cin/1.73 m2 BSA) was 76.6 (46.9–119.8) ml/min per 1.73 m2, lower than the normal GFR in young men of 130 ml/min per 1.73 m2 and 120 ml/min per 1.73 m2 in young women (27). Four of the patients had a GFR between 46.9 and 65.4 ml/min per 1.73 m2. The measured Ccr was significantly higher than the Cin (P,0.004). The TScr was 30.3 ml/min per 1.73 m2, accounting for 40% of the Ccr. The patients’ GFRs inversely correlated with their age (r=20.5), just shy of significance, suggesting that a longer survival may be associated with reduced GFR. Figure 1 compares GFR and the estimating equations. The eGFR as calculated by the CKD-EPI formula was 133.0 (94–162) ml/min per 1.73m2, higher than the GFR (P,0.004) and slightly over the normal upper limit of 130 ml/min per 1.73 m2. The eGFR calculated by the MDRD formula was 141.0 (97–256) ml/min per 1.73m2, higher than the GFR (P,0.004); the eCcr by the equation CG was 168 (72–247) ml/min per 1.73 m2, also higher than

1195.3 1072.8 1201.2 1402.8 1014.8 751.9 1007.2 1008.2 1468.3 1072.8a (751.9–1468.3) 952.2 858.8 1150.5 1200.5 671.0 820.5 1040.0 656.0 697.5 858.8 (671.0–1040.0)

Inulin Clearance in b-Thalassemia Major, Milo et al.

Discussion

4 4.5 4 5 4 1 5 5 2.5 4 (1–5) a

P,0.004 urinary creatinine versus expected urinary creatinine.

27 28 28.5 24.5 27 30 20 18 19.5 27 (18–30) 15 17 15 15 12 15 16 13 15 15 (12–17) 1646 1460 635 1114 1391 348 2750 1770 3883 1460 (348–3883) 10.1 10.9 9.5 9.4 10.6 10.2 10.5 10.8 9.7 10.2 (9.4–10.9) 1 2 3 4 5 6 7 8 9 Median (range)

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the GFR (P,0.008). The latter two were in the hyperfiltration range. Figure 2 illustrates the Bland and Altman analyses for agreement between GFR and CKD-EPI eGFR, MDRD eGFR, and CG eCcr. The best agreement was seen with CKD-EPI eGFR. However, even this estimating method would be a clinically unacceptable method for GFR measurement given the difference between the upper and lower 95% limits of agreement (26).

0.53 0.74 0.80 0.40 0.66 0.83 0.51 0.36 0.59 0.59 (0.36–0.83)

Expected Urinary Creatinine (mg/ 24 hr) Ferritin (ng/ml) Hemoglobin (g/dl) Patient No.

Table 1. Hematologic and renal variables

No. of Transfusions

Duration of Iron Chelation Therapy (yr)

Duration of Deferasirox Therapy (yr)

Serum Creatinine (mg/dl)

Urinary Creatinine (mg/24 hr)

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To our knowledge, this is the first study to measure GFR in patients with TM by using inulin clearance, the gold standard method for GFR measurement (16). The GFR was lower than that in normal healthy young adults (20,21,27). Moreover, four of the nine patients had mild to moderate CKD. Piga et al. (15) recently reported normal GFR measured by plasma sampling of 51Cr EDTA in patients with TM who were had regular transfusion and were naive to deferasirox therapy. They showed reduction of 9.5% in GFR after 8 weeks of treatment with 30 mg/kg deferasirox per day, which reversed completely after a 2-week washout. Then they treated five patients similarly for 2 years. In this case, GFR decreased by 19.1 ml/min (17.7%) to 89.4 ml/min shortly after commencement of treatment. No progressive decline occurred thereafter, and when deferasirox treatment was interrupted after 2 years, GFR recovered almost completely after a 4-week washout. The higher GFR found by Piga et al. compared with our findings may be attributed to the following reasons: First, measurement of GFR by 51CrEDTA using plasma sampling overestimates true renal clearance by 10% (28). Second, Piga et al. excluded patients with Scr above the upper normal limit, CG-calculated eCcr ,60 ml/min, proteinuria, a history of nephrotic syndrome, or the use of drugs with a potential effect on renal parameters. Thus, a priori they selected patients with normal kidney function. Third, the patients in our study were treated with iron chelation for 27 years (and for the last 4 had received deferasirox), a longer period compared with Piga and colleagues’ patients. In addition, Piga et al. also excluded patients with serum levels of alanine aminotransferase five times the upper normal limit, a marker of hepatic iron overload. The median Ccr in our study of 134.9 (mean, 133.3) ml/min per 1.73 m2 was significantly higher than the GFR (P,0.008). Interestingly, it was similar to the Ccr of 136 ml/min per 1.73 m2 (n=106) found by Quinn et al. in their regularly transfused adult patients with TM (14). The overestimation of GFR by the Ccr in our study was in large part due to the proximal tubular secretion of creatinine. Urinary creatinine excretion is composed of filtered creatinine and proximal tubular secretion of creatinine. As GFR decreases, the relative contribution of the tubular secretion of creatinine to the GFR increases (23). Shemesh et al. (23) showed that at an inulin clearance of 40–80 ml/min per 1.73 m2, TScr accounts for 57% of the GFR. In our study, TScr accounted for 40% of the GFR. Assessment of kidney functions by estimating equations based on Scr overestimated GFR significantly. The eGFR calculated by the CKD-EPI formula was slightly above the upper normal limit, suggesting hyperfiltration, whereas the

mCcr, measured creatinine clearance; Ccr, creatinine clearance; TScr, tubular creatinine secretion rate; Pr, protein; Cr, creatinine; NA, not available. a GFR=inulin clearance/1.73 m2 body surface area. b Ccr=mCcr/1.73 m2 body surface area. c P,0.004 inulin clearance versus mCcr; GFR versus Ccr.

172 122 181 261 194 NA 232 332 215 204.5 (122–332) 15.1 30.3 103.4 134.9 27.2 23.6 65.6 75.5 7.4 30.3 (7.4–134.9) 134.9 94.9 150.3 221.2 81.5 89.0 168.9 175.1 84.0 134.9c (81.5–221.2) 119.8 64.6 46.9 86.3 54.3 65.4 103.3 99.6 76.6 76.6 (46.9–119.8) 124.8 80.6 99.9 208.4 71.6 68.9 141.6 126.5 82.1 99.9c (68.9–208.4) 110.8 54.9 40.9 81.3 47.7 50.4 86.6 72.0 74.8 72.0 (40.9–110.8) 1 2 3 4 5 6 7 8 9 Median (range)

Patient No.

Inulin Clearance (ml/min)

mCcr (ml/min)

GFR (ml/min per 1.73 m2)a

Ccr (ml/min per 1.73 m2)b

TScr (ml/min per 1.73 m2)

Pr/Cr (mg/g)

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Table 2. Kidney function test results

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eGFR calculated by the MDRD formula and eCcr calculated by the CG formula reached the hyperfiltration range. These results suggest that the previous studies, which found hyperfiltration in patients with TM (3,5–7,14), probably overestimated GFR. Indeed, Quinn et al. have shown that eGFR calculated by the Schwartz equation overestimated the Ccr measured in their study by 30 ml/min per 1.73 m2; most of the patients had hyperfiltration, especially those with lower Scr values (14). The overestimation of GFR by the various estimating equations based on Scr results from the low Scr levels in patients with TM. Several factors may contribute to the low Scr levels: first, urinary creatinine excretion was significantly lower than expected. Because in healthy individuals urinary creatinine excretion is expected to equal creatinine generation (29,30), most of which is generated by muscle metabolism (30), the lower creatinine excretion by these patients with TM indicates a decreased generation by their muscles. Indeed, previous studies found reduced muscle mass in patients with TM (31), and muscle biopsies revealed variations in muscle fibers and muscle fiber atrophy (32). Of note, iron deposits were not found in these muscle biopsy specimens (32). On the basis of detailed clinical and electrophysiologic studies, muscular disease in patients with TM was considered to be of a neurogenic origin (33). The second possible factor contributing to low Scr levels stems from the fact that the reduction in GFR was compensated by increased tubular creatinine secretion, which prevented the appropriate rise in Scr. A third factor could be extrarenal excretion of creatinine, especially when kidney function is reduced (34). Finally, variation in measurement of Scr (30), especially at the lower levels, may also contribute to overestimation of GFR (14,30). Recently, Ziyadeh et al. (35) described hyperfiltration in patients with thalassemia intermedia by using eGFR (CKD-EPI formula). However, their Scr level was 0.5 mg/dl, suggesting a possible overestimation of GFR. Overestimation of GFR by estimating methods was also reported in patients with sickle cell anemia (36). Iron overload and chronic anemia appear to be the main factors responsible for tubular damage and, consequently, interstitial fibrosis, glomerulosclerosis, and GFR reduction in patients with TM. Autopsies of patients with TM revealed hemosiderin deposits in the proximal and distal tubules (37). Similarly, iron overload in rats led to mild proteinuria with iron deposits in glomeruli, proximal tubules, and interstitium associated with glomerulosclerosis, tubular atrophy, and interstitial fibrosis (38). Several studies reported correlation between serum ferritin levels and markers of tubular toxicity, which iron chelation therapy reversed (7,39). Other studies have shown renal tubular abnormalities related to duration of chelation, duration of transfusions, amount of transfusions, and body iron content, as measured by magnetic resonance imaging (5,7,8). Iron can cause oxidative lipid peroxidation and mitochondrial stress in proximal tubules (40,41), thereby contributing to GFR decline. The degree of tubular abnormalities was correlated with the severity of anemia (5,10). Anemia may cause oxidative stress (3,42), leading to lipid peroxidation (3) and DNA damage (43). Hemolysate and hemoglobin were found to ameliorate oxidation-induced DNA damage (44). The

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Figure 1. | Comparison between GFR and estimating equations: CKD Epidemiology Collaboration (CKD-EPI) eGFR, Modification of Diet in Renal Disease (MDRD) eGFR, and Cockcroft-Gault (CG)– estimated creatinine clearance. Median is depicted by a horizontal line. P,0.004, CKD-EPI and MDRD equations compared with GFR; P,0.008, CG-estimated creatinine clearance compared with GFR.

findings of markers of oxidative damage to tubules (4–10) favor a role for both anemia and iron overload in kidney dysfunction of patients with TM. Treatment with iron chelators was also linked to renal function disturbances (3). Acute renal failure requiring dialysis treatment was reported in patients with TM who were treated with large doses of deferoxamine (3). In a phase 3 trial comparing deferasirox and deferoxamine therapy in patients with TM, a mild dose-dependent rise in Scr was observed in 38% of the patients. This reversed spontaneously or with reduction or interruption of treatment in most patients (18). However, this study showed no progressive rise in Scr. Furthermore, treatment with deferasirox for 5 years in patients with TM (19) did not cause any progressive rise in creatinine either. Recently, Piga et al. (15) showed a reduction in GFR that paralleled a reduction in renal plasma flow in five patients treated with 30 mg/kg deferasirox per day. These changes were nonprogressive for 2 years, after which interruption of treatment led to almost complete reversal of the renal plasma flow and the GFR. This suggests a hemodynamic cause for the GFR rather than parenchymal damage. However, because the study included only five patients, a largerscale study is required to fully validate this suggestion. In interpreting the results of our study, it is plausible to infer that the reduction in GFR is related in part to deferasirox treatment. Yet, reduction in GFR in our patients was of a greater magnitude than that reported by Piga et al. (15) and was associated with mild proteinuria, suggesting chronic tubulointerstitial nephritis (4–11). Furthermore, Economou et al. (11), who used cystatin C in patients with TM, also described a reduction in GFR. In addition, adult patients with TM had a lower GFR than children with TM (14). Finally, in a long-term study, Lai et al. (45) showed that the mean eGFR (calculated by MDRD formula) in adult patients with TM decreased significantly over 10 years of follow-up. In 66 of 81 patients, the decline was within the normal limits, but in 15 of them (.18%), it decreased to CKD levels ,90 ml/min per 1.73 m2.

Figure 2. | Agreement assessment between GFR and estimating equations by Bland and Altman method. Graphical Bland and Altman measurement of agreement among (A) GFR and CKD Epidemiology Collaboration (CKD-EPI) eGFR, (B) GFR and Modification of Diet in Renal Disease (MDRD) eGFR, and (C) GFR and Cockcroft-Gault (CG) estimated creatinine clearance (eCcr). Bias=mean difference between GFR and estimating methods.

Our study’s main contribution is due to the novel finding of a low GFR and CKD by inulin clearance in patients with TM receiving deferasirox. Furthermore, our finding

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of an inverse correlation of GFR with age supports the results of Lai et al. (45) and the studies that reported association between duration of transfusions, duration of chelation, and iron content with tubular dysfunction (5,7,8). Our results contrast with the findings of studies that used eGFR and reported hyperfiltration (3,5–7,14). Our findings suggest that a larger population of patients with TM may ultimately develop CKD following their prolonged longevity. The limitations of our study are the fact that it is a cross-sectional study and has a relatively small number of participants. Thus, a longitudinal study with more patients and preferably with a washout period of chelation therapy is required to validate our results. As shown, the estimating methods for determination of GFR are not clinically reliable; thus, the use of a more accurate method to assess GFR is warranted. Such a method may enable early detection of GFR decline and prevention or attenuation of its deterioration to CKD and the need for RRT. An important practical issue relates to the treatment of patients with TM with iron chelation drugs, antibiotics, cytotoxic drugs, and other medications that need adjustment according to GFR because the use of estimated methods for GFR may cause erroneous dosing. In conclusion, patients with TM who receive deferasirox may have reduced GFR, which is masked when Scr or eGFR are used for its assessment. The use of a more accurate method may lead to early detection of reduced GFR and slow the progressive deterioration to CKD. Acknowledgments We wish to thank Dr. Michal Herman-Edelstein for her help with the statistical analyses and graphical representations and Mrs. Ruth Miller for her linguistic assistance. Disclosures None. References 1. Steinberg MH, Forget BG, Higgs DR, Weatherall DJ: Disorders of Hemoglobin: Genetics Pathophysiology and Clinical Management, Cambridge, Cambridge University Press, 2009 2. Borgna-Pignatti C, Rugolotto S, De Stefano P, Zhao H, Cappellini MD, Del Vecchio GC, Romeo MA, Forni GL, Gamberini MR, Ghilardi R, Piga A, Cnaan A: Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 89: 1187–1193, 2004 3. Ponticelli C, Musallam KM, Cianciulli P, Cappellini MD: Renal complications in transfusion-dependent beta thalassaemia. Blood Rev 24: 239–244, 2010 4. Sumboonnanonda A, Malasit P, Tanphaichitr VS, Ong-ajyooth S, Sunthornchart S, Pattanakitsakul S, Petrarat S, Assateerawatt A, Vongjirad A: Renal tubular function in beta-thalassemia. Pediatr Nephrol 12: 280–283, 1998 5. Sumboonnanonda A, Malasit P, Tanphaichitr VS, Ong-ajyooth S, Petrarat S, Vongjirad A: Renal tubular dysfunction in alphathalassemia. Pediatr Nephrol 18: 257–260, 2003 6. Aldudak B, Karabay Bayazit A, Noyan A, Ozel A, Anarat A, Sasmaz I, Kilinc¸ Y, Gali E, Anarat R, Dikmen N: Renal function in pediatric patients with beta-thalassemia major. Pediatr Nephrol 15: 109–112, 2000 7. Koliakos G, Papachristou F, Koussi A, Perifanis V, Tsatra I, Souliou E, Athanasiou M: Urine biochemical markers of early renal dysfunction are associated with iron overload in beta-thalassaemia. Clin Lab Haematol 25: 105–109, 2003 8. Mohkam M, Shamsian BS, Gharib A, Nariman S, Arzanian MT: Early markers of renal dysfunction in patients with beta-thalassemia major. Pediatr Nephrol 23: 971–976, 2008

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GFR in Patients with β-Thalassemia Major.

Patients with β-thalassemia major (TM) may have tubular dysfunction and glomerular dysfunction, primarily hyperfiltration, based on eGFR. Assessment o...
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