Kidney Tubular Damage Secondary to Deferasirox: Systematic Literature Review

Deferasirox is a first-line therapy for iron overload that can sometimes cause kidney damage. To better define the pattern of tubular damage, a systematic literature review was conducted on the United States National Library of Medicine, Excerpta Medica, and Web of Science databases. Twenty-three reports describing 57 individual cases could be included. The majority (n = 35) of the 57 patients were ≤18 years of age and affected by thalassemia (n = 46). Abnormal urinary findings were noted in 54, electrolyte or acid–base abnormalities in 46, and acute kidney injury in 9 patients. Latent tubular damage was diagnosed in 11 (19%), overt kidney tubular damage in 37 (65%), and an acute kidney injury in the remaining nine (16%) patients. Out of the 117 acid–base and electrolyte disorders reported in 48 patients, normal-gap metabolic acidosis and hypophosphatemia were the most frequent. Further abnormalities were, in decreasing order of frequency, hypokalemia, hypouricemia, hypocalcemia, and hyponatremia. Out of the 81 abnormal urinary findings, renal glucosuria was the most frequent, followed by tubular proteinuria, total proteinuria, and aminoaciduria. In conclusion, a proximal tubulopathy pattern may be observed on treatment with deferasirox. Since deferasirox-associated kidney damage is dose-dependent, physicians should prescribe the lowest efficacious dose.


Introduction
Iron overload secondary to regular blood transfusions may result in injury and dysfunction of the heart, liver, anterior pituitary, pancreas, and joints. Both parenteral iron chelation with deferoxamine and oral chelation with deferiprone or deferasirox have been shown to reduce iron overload and organ damage [1,2]. Due to its efficacy and ease of use, deferasirox 20-30 mg/kg once-daily is currently the first-line therapy for iron overload secondary to blood transfusions [1,2]. It has been known for about 10 years that an increase in circulating creatinine occurs in about one out of ten cases [3]. This tendency is most likely to occur in well-chelated patients with circulating ferritin 1000 µg/L or less [4]. The pattern of kidney tubular damage that occurs with deferasirox therapy, however, is poorly defined. To address this issue, we performed a systematic review of the individually reported cases of kidney tubular damage that have been associated with deferasirox.
Patients with pre-existing conditions other than the blood transfusion-dependent disease, patients on other drugs with a potential to induce acid-base or electrolyte disturbances, patients affected by intercurrent infectious disease, and pregnant women were excluded.

Data Extraction-Classification
Data were extracted using a piloted form and transcribed into a predefined spreadsheet. From each case meeting the mentioned inclusion criteria demographics, the underlying transfusion-dependent disease, information on deferasirox therapy before the onset of kidney damage, laboratory values (including urinary findings, acid-base balance, electrolytes, and blood creatinine values), and time to resolution after withdrawing deferasirox were extracted. The possible occurrence of kidney damage after reintroducing deferasirox was also addressed. Finally, since metabolic acidosis is categorized as anion gap and non-anion gap acidosis, this information was collected in patients with this acid-base abnormality. If needed, attempts were made to contact original authors to obtain missing data. The clinical features associated with the kidney damage were poorly documented and were consequently not extracted.
Circulating creatinine was used to classify acute kidney injury [8] as stage I (rise in creatinine by ≤1.9 times baseline), stage II (rise in creatinine by 2.0-2.9 times baseline), and stage III (rise in creatinine by ≥3.0 times baseline, rise in creatinine by ≥354 µmol/L, or the start of kidney replacement therapy).

Completeness of Reporting
Completeness of included cases was judged using the following two components: 1. description of diagnosis and drug treatment (including dose), duration of therapy, and time to recovery of kidney damage (rating 0 to 4); and 2. description of laboratory data in blood and urine (rating 0 to 4). The reporting completeness was graded according to the sum of each item as excellent (≥6), good (4)(5), satisfactory (2)(3)(4), or poor (<2).

Analysis-Statistics
The pairwise deletion was used to handle missing data. Categorical data are given as frequency and were analyzed using the Fisher's exact test. Continuous data are given as a median and interquartile range and were analyzed using the Kruskal-Wallis test and the Dunn posttest. Significance was set at p < 0.05.

Findings
The majority (61%) of the 57 patients were ≤18 years of age (Table 1). Three-quarters of the cases were affected by a thalassemia syndrome. Laboratory features consistent with kidney damage were mostly observed >6 months after starting a standard dose deferasirox therapy, although this information was not available in more than half of the cases. A recurrence of the kidney damage was noted in nine of the 18 patients, who were again exposed to deferasirox (usually in a reduced dose). Abnormal urinary findings were noted in 54 (95%), electrolyte o malities in 46 (81%), and an acute kidney injury in 9 (16%) cases (Table nary findings without any electrolyte or acid-base abnormality and wi injury were noted in 11 (19%) cases. The diagnosis of latent tubular da these cases. Nine (16%) cases presented with abnormal urinary find acid-base abnormalities, and acute kidney injury. The diagnosis of a accompanied by tubular damage was made in these cases. The remain presented with abnormalities in the electrolyte or acid-base balance bu ney injury (abnormal urinary findings were also observed in 34 out of th the diagnosis of overt kidney tubular damage was made in these case acute kidney injury (20 [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] years) were male. Furthermore, they w significantly older than patients with latent (14 [11][12][13][14][15][16][17][18][19] years) or overt tubulopathy.
A total of 117 acid-base and electrolyte disorders were reported in the 48 patients ith either isolated overt tubular injury or acute kidney injury ( Table 2). Metabolic acidois (with a normal anion gap) and hypophosphatemia were reported in more than threeuarters of cases. Further disorders were, in decreasing order of frequency, hypokalemia, ypouricemia, hypocalcemia, and hyponatremia. Metabolic alkalosis, hyperkalemia,   ◆ non-hereditary hemochromatosis, Ewing's sarcoma, sideroblastic anemia; ☩ informat available in 4 cases; ✙ information not available in 32 cases; * deferasirox therapy was n in 17 cases.
A total of 117 acid-base and electrolyte disorders were reported in the 48 patients with either isolated overt tubular injury or acute kidney injury ( Table 2). Metabolic acidosis (with a normal anion gap) and hypophosphatemia were reported in more than three-information not available in 32 cases; * deferasirox therapy was not stopped in 17 cases.
A total of 117 acid-base and ele with either isolated overt tubular inju sis (with a normal anion gap) and hyp quarters of cases. Further disorders w hypouricemia, hypocalcemia, and h ing's sarcoma, sideroblastic anemia; ☩ information not available in 32 cases; * deferasirox therapy was not stopped ere noted in 54 (95%), electrolyte or acid-base abnoridney injury in 9 (16%) cases (Table 2). Abnormal urite or acid-base abnormality and without acute kidney s. The diagnosis of latent tubular damage was made in ented with abnormal urinary findings, electrolyte or e kidney injury. The diagnosis of acute kidney injury as made in these cases. The remaining 37 (65%) cases e electrolyte or acid-base balance but without any kidgs were also observed in 34 out of the 37 cases). Hence, lar damage was made in these cases. All patients with rs) were male. Furthermore, they were slightly but not ith latent (14 [11][12][13][14][15][16][17][18][19] years) or overt (11 [5.6-20] years) electrolyte disorders were reported in the 48 patients jury or acute kidney injury (Table 2). Metabolic acidohypophosphatemia were reported in more than threes were, in decreasing order of frequency, hypokalemia, hyponatremia. Metabolic alkalosis, hyperkalemia,  Table 2. Abnormal urinary findings and electrolyte-acid-base disorders were detected in 57 patients (27 females and 30 males 3 to 78, median 15 years of age) on therapy with oral deferasirox. Data are presented as median and interquartile range or as absolute numbers, as appropriate. Patients with latent tubulopathy, overt tubulopathy without acute kidney injury, and acute kidney injury are presented separately.

All
Tubulopathy without Kidney Injury * Stage I in 3, stage II in 5 and stage III in 1 case; ✿ anion gap normal in all cases (N = 13) with this information; ✙ acute kidney injury significantly more common in males than in females (p < 0.02); ☩ ß2-microglobulin excretion in all 21 cases.

Discussion
The present systematic review points out that the kidney tubular damage associated with oral deferasirox therapy may present in three ways: (a) abnormal urinary findings consistent with latent tubular damage; (b) overt acid-base or electrolyte abnormalities; and (c) acute kidney injury (always associated with abnormal urinary findings and with an electrolyte or acid-base imbalance).
The kidney tubular damage caused by deferasirox characteristically presents with renal glucosuria, excessive ß2-microglobulin excretion, generalized aminoaciduria, nongap metabolic acidosis, hypophosphatemia, and hypouricemia. Hence, these data suggest the existence of a proximal tubular disturbance. Proximal tubular defects are typically observed on treatment with aminoglycosides, nucleotide reverse transcriptase inhibitors, or platinum compounds and result from mitochondrial toxicity [30,31]. No kidney damage was so far reported on treatment with other iron chelators such as deferiprone or deferoxamine [2,32]. These clinical observations are supported by in vitro studies: it was found that deferasirox, but not other chelators, induces a dramatic swelling of mitochondria and decreases the cellular ATP content [33]. Iron being essential for kidney tubular cells, it is currently assumed that deferasirox associated tubular damage results from excessive chelation of iron within these cells, which is likely superior to that observed with other chelators [34]. Furthermore, the kidney damage caused by deferasirox is likely dose-dependent [34]. Finally, pharmacogenetics might be a relevant determinant of deferasirox toxicity [34,35]. A total of 81 abnormal urinary findings were detected. Renal glucosuria was the most frequently detected urinary abnormality, followed by tubular proteinuria, total proteinuria, and generalized aminoaciduria. Table 2. Abnormal urinary findings and electrolyte-acid-base disorders were detected in 57 patients (27 females and 30 males 3 to 78, median 15 years of age) on therapy with oral deferasirox. Data are presented as median and interquartile range or as absolute numbers, as appropriate. Patients with latent tubulopathy, overt tubulopathy without acute kidney injury, and acute kidney injury are presented separately.
A total of 81 abnormal urinary findings were detected. Renal glucosuria was the most frequently detected urinary abnormality, followed by tubular proteinuria, total proteinuria, and generalized aminoaciduria.

Discussion
The present systematic review points out that the kidney tubular damage associated with oral deferasirox therapy may present in three ways: (a) abnormal urinary findings consistent with latent tubular damage; (b) overt acid-base or electrolyte abnormalities; and (c) acute kidney injury (always associated with abnormal urinary findings and with an electrolyte or acid-base imbalance).
The kidney tubular damage caused by deferasirox characteristically presents with renal glucosuria, excessive ß 2 -microglobulin excretion, generalized aminoaciduria, non-gap metabolic acidosis, hypophosphatemia, and hypouricemia. Hence, these data suggest the existence of a proximal tubular disturbance. Proximal tubular defects are typically observed on treatment with aminoglycosides, nucleotide reverse transcriptase inhibitors, or platinum compounds and result from mitochondrial toxicity [30,31]. No kidney damage was so far reported on treatment with other iron chelators such as deferiprone or deferoxamine [2,32]. These clinical observations are supported by in vitro studies: it was found that deferasirox, but not other chelators, induces a dramatic swelling of mitochondria and decreases the cellular ATP content [33]. Iron being essential for kidney tubular cells, it is currently assumed that deferasirox associated tubular damage results from excessive chelation of iron within these cells, which is likely superior to that observed with other chelators [34]. Furthermore, the kidney damage caused by deferasirox is likely dose-dependent [34]. Finally, pharmacogenetics might be a relevant determinant of deferasirox toxicity [34,35].
In this analysis, most cases with acid-base or electrolyte abnormalities simultaneously presented with urinary abnormalities. Furthermore, all cases with kidney injury concurrently presented with an acid-base or electrolyte imbalance and with urinary abnormalities. It is therefore tempting to assume that the latent tubulopathy represents the early stage, the overt tubulopathy the middle stage, and finally the manifest acute kidney injury the advanced stage of damage induced by deferasirox (Figure 2). This hypothesis deserves confirmation in longitudinal studies. It has been speculated but not proven that iron overload may per se induce kidney damage [1,2]. Furthermore, sickle cell disease and perhaps also some other transfusiondependent conditions may cause kidney abnormalities [36]. In the present analysis, however, patients affected by sickle cell disease or with pre-existing kidney disease were not included.
The present analysis has four major limitations. First, we found no more than 57 individually documented cases of kidney tubular damage caused by deferasirox. Second, the reporting completeness was excellent only in a minority of cases. Third, it has been suggested that the assessment of tubular proteinuria, which consists of low-molecularweight proteins such as retinol-binding protein or ß 2 -microglobulin and enzymes such as N-acetyl-ß-glucosaminidase, might be an early and accurate marker of tubular dysfunction [37]. Regrettably, we currently have no data to support or infirm this recommendation. Fourth, available data do not allow to estimate the prevalence of the tubular damage unassociated with acute kidney injury caused by deferasirox. Future work is necessary to address these issues.

Conclusions
Aminoglycoside-class antimicrobials, nucleotide reverse transcriptase inhibitors, and platinum compounds occasionally cause a dose-and time-related kidney disease. Similar damage may be observed on treatment with the iron-chelating agent deferasirox but not with deferoxamine or deferiprone. Deferasirox-associated kidney damage is dosedependent and more likely to occur when iron stores are low. It has therefore been recommended [4,34] that physicians prescribe the lowest possible dose to achieve a satisfactory iron burden and consider discontinuing therapy if circulating ferritin is 1000 µg/L or less.