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Ifosfamide nephrotoxicity

Author: Roderick Skinner, PhD, MBChB, FRCPCH

Section Editor: Richard H Sterns, MD
Deputy Editor: Albert Q Lam, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2017. | This topic last updated: Jul 24, 2015.

INTRODUCTION Ifosfamide is a synthetic structural isomer of cyclophosphamide that has been approved
for concurrent use with other drugs (usually cisplatin, etoposide, or vinblastine) in the treatment of metastatic
germ-cell testicular cancer and some (especially pediatric) sarcomas.

Nephrotoxicity due to direct tubular injury is a prominent complication of ifosfamide therapy; glomerular
toxicity may also occur. Issues related to ifosfamide nephrotoxicity will be reviewed here.

PATHOGENESIS Many in vitro studies suggest that the metabolite chloroacetaldehyde is directly toxic to
the tubular cells, rather than the parent drug or another metabolite acrolein [1-3]. This relationship could
explain why cyclophosphamide, although structurally similar to ifosfamide, has virtually no nephrotoxicity. At
equivalent doses, the rate of chloroacetaldehyde generation with ifosfamide is much greater than with
cyclophosphamide, although there is considerable variability from patient to patient in the amount of
chloroacetaldehyde produced after ifosfamide administration [1]. Other toxic metabolites specific to ifosfamide
but not cyclophosphamide may contribute to nephrotoxicity, such as isophosphoramide mustard, although in
vitro studies have given conflicting results [4]. On the other hand, acrolein is believed to be the major cause of
the bladder toxicity (hemorrhagic cystitis) seen with both ifosfamide and cyclophosphamide.

Cellular oxidative stress may be the mechanism of injury, leading to energy depletion via mitochondrial
damage, a mechanism similar to that observed with the mitochondrial cytopathies [5]. Disruption of cell
membrane function is another possible mechanism of toxicity.

Mesna, which is used concurrently with ifosfamide to prevent bladder toxicity, might also be expected to
reduce renal damage due to chloroacetaldehyde or other nephrotoxic metabolites of ifosfamide. However,
mesna has a complex intrarenal pharmacology and association with intratubular glutathione. Thus, it has not
been possible to demonstrate a clear role for mesna in prevention of ifosfamide nephrotoxicity [1].

CLINICAL MANIFESTATIONS Ifosfamide-induced renal injury is primarily manifested by the onset of one
or more of the following signs of tubular dysfunction [1,6-11]:

Hypophosphatemia induced by decreased proximal tubular phosphate reabsorption, which can lead to
rickets in children and osteomalacia in adults [6-10,12]

Impairment in proximal tubular function (Fanconi syndrome) as manifested by renal glucosuria,

bicarbonaturia, aminoaciduria, tubular proteinuria (ie, low-molecular-weight proteins but not albumin),
potassium wasting, and a marked increase in urinary beta-2-microglobulin excretion [1,6,8,10,12]

Renal potassium wasting, which may cause severe hypokalemia [7,11,12]

Metabolic acidosis with a normal anion gap (hyperchloremic) acidosis due to type 1 (distal) or type 2
 (proximal) renal tubular acidosis [12]

Polyuria due to nephrogenic diabetes insipidus (ie, resistance to antidiuretic hormone), which appears to
be relatively rare [7,9,12,13]; when polyuria does occur, it is more often an appropriate response to
isotonic saline therapy (see 'Etiology of polyuria' below)

The time of onset of tubular dysfunction is variable. In a report of 27 patients with manifestations of tubular
dysfunction, the diagnosis was made during ifosfamide therapy in 9 patients and after the cessation of
therapy in 18 patients at a median of 13 months [6].

In addition to tubular dysfunction, ifosfamide therapy can lead to a reduction in glomerular filtration rate (GFR)
[7,8]. In most patients, the decline in GFR is mild (usually no more than 20 to 30 percent below the baseline
level) unless given in combination with another nephrotoxin such as cisplatin [7,8,12]. (See 'Risk factors'
below and 'Long-term prognosis' below.)

The clinical manifestations of ifosfamide nephrotoxicity are different from the major manifestations of
nephrotoxicity induced by cisplatin. Cisplatin primarily affects the S3 segment of the proximal tubule and the
distal nephron, leading to acute renal failure and hypomagnesemia due to urinary magnesium wasting.
Glucosuria and aminoaciduria can occasionally occur. (See "Cisplatin nephrotoxicity".)

Etiology of polyuria As noted in the preceding section, ifosfamide can induce nephrogenic diabetes
insipidus. However, it is an uncommon complication that typically occurs in patients who have other signs of
tubular toxicity, such as glucosuria, aminoaciduria, and hypophosphatemia [13].

A more frequent problem is the marked polyuria that may complicate the administration of high-dose
ifosfamide-based chemotherapy protocols. The cause of the polyuria in almost all such cases is a sodium
diuresis (not a dilute water diuresis as in diabetes insipidus) that results from the volume expansion induced
by saline therapy given to maintain a high urine output during chemotherapy administration, particularly if
ifosfamide, cisplatin, or carboplatin is part of the regimen. Thus, the diuresis is appropriate and resolves if
sodium intake is reduced and excretion of the excess fluid is permitted. In addition, the urine osmolality tends
to be similar to that of plasma, not dilute as in diabetes insipidus. (See "Diagnosis of polyuria and diabetes
insipidus", section on 'Solute diuresis'.)

A confounding factor is the presence of orthostatic (postural) hypotension. Although this finding may suggest
possible volume depletion, it may also be due to chemotherapy-induced autonomic neuropathy. Volume
expansion may minimize orthostasis by maximizing the intravascular volume, but it also leads to persistence
of the polyuria.

RISK FACTORS The risk factors for ifosfamide nephrotoxicity are cumulative dose, age under four to five
years, and prior or concomitant cisplatin therapy. Prior nephrectomy, presumably as a consequence of
reduced renal excretory capacity, has also been shown to increase the risk of ifosfamide nephrotoxicity in
children with cancer.

Cumulative ifosfamide dose Clinically significant nephrotoxicity has been described in children, mostly at
a total dose above 60 g/m2 [6-8,10,12,14], with severe nephrotoxicity primarily occurring at a total dose of
120 g/m2 or more [7]. The signs of nephrotoxicity are initially transient but become persistent in some patients
as the cumulative dose increases.

The high frequency of transient nephrotoxicity was demonstrated in a prospective study of 23 children and
young adults who were treated with high-dose ifosfamide (9 g/m2 given over five days for 11 cycles at three-
to six-week intervals) [10]. Acute tubular dysfunction occurred in all patients and was characterized by
increases in the excretion of beta-2-microglobulin, glucose, phosphate, and amino acids. These abnormalities
generally disappeared by day 0 of the next cycle. Only three patients (13 percent) developed persistent
Fanconi-like syndrome or requirement for oral electrolyte (potassium and phosphate) supplementation. The
cumulative dose was 70 g/m2 in one and over 90 g/m2 in the other two.

The differences in risk of persistent nephrotoxicity according to cumulative dose were illustrated in a series
of 76 children and young adults in which grading criteria were used to define the severity of ifosfamide
nephrotoxicity [7]. The criteria included the glomerular filtration rate (GFR), the renal threshold for phosphate
excretion (to evaluate for phosphaturia), the serum bicarbonate concentration (to evaluate for metabolic
acidosis), and the early morning osmolality (to evaluate urinary concentrating ability).

The following findings with respect to moderate and severe nephrotoxicity were noted at a median follow-up
of six months:

At a cumulative ifosfamide dose below 84 g/m2, there were no cases of severe nephrotoxicity, and 5 of
45 (11 percent) had moderate nephrotoxicity

At a cumulative ifosfamide dose 84 to 119 g/m2, 1 of 16 had severe nephrotoxicity, and 4 of 16 had
moderate nephrotoxicity (6 and 25 percent, respectively)

At a cumulative ifosfamide dose 120 g/m2 or more, 5 of 15 had severe nephrotoxicity, and 6 of 15 had
moderate nephrotoxicity (33 and 40 percent, respectively)

Lower doses are safer but may occasionally be associated with persistent tubular injury. At a median follow-
up of 19 months in a series of 593 children and adolescents with sarcoma who were treated with ifosfamide,
the incidence of tubulopathy (defined as at least two of hypophosphatemia, glucosuria, and proteinuria on at
least two examinations) was 0.4 and 6.5 percent in those exposed to an ifosfamide dose of 24 g/m2 and
between 24 to 60 g/m2, respectively [6].

Young children Children under four to five years of age are at increased risk of ifosfamide nephrotoxicity
[6,14]. In a multivariate analysis of the above study of 593 children and adolescents, children who were less
than four years of age at diagnosis had an 8.7-fold higher rate of tubulopathy, compared with an 18.6
increased risk with ifosfamide doses 60 g/m2 [6]. A possible mechanism is increased activity in young
children of CYP3A, the enzyme responsible for the generation of chloroacetaldehyde, which appears to
mediate ifosfamide nephrotoxicity [15]. However, some very long-term studies have failed to show a
relationship between young age and a higher risk of persistent nephrotoxicity [8,16]. (See 'Pathogenesis'
above.)

Prior nephrectomy A study of 120 children, 10 of whom had previously undergone nephrectomy as part
of their anti-cancer treatment, found that nephrectomized children were much more likely to develop
ifosfamide nephrotoxicity [17]. Subclinical nephrotoxicity (defined by phosphaturia and aminoaciduria) and
clinically evident nephrotoxicity (Fanconi syndrome) each occurred in three patients (30 percent). In contrast,
in the remaining 110 children, subclinical and clinically evident nephrotoxicity occurred in 4 and 12 patients,
respectively (4 and 11 percent). As suggested above, this is presumably due to reduced renal excretory
capacity caused by previous nephrectomy. Although not investigated specifically in the published literature, it
is likely that children with other causes of impaired renal function will also have a higher risk of developing
nephrotoxicity after ifosfamide treatment.

Prior or concomitant cisplatin therapy Concurrent administration of ifosfamide and cisplatin may have
additive nephrotoxicity [14,17-19], and ifosfamide nephrotoxicity can occur at lower cumulative doses in
patients with appreciable cisplatin exposure [18]. This potentiating effect may not occur in patients treated
with low doses of ifosfamide (24 g/m2) [6]. (See "Cisplatin nephrotoxicity".)
Carboplatin is a less toxic analog of cisplatin, and it is not clear if concurrent carboplatin therapy is a risk
factor for ifosfamide nephrotoxicity [6]. (See "Cisplatin nephrotoxicity", section on 'Cisplatin analogs'.)

PREVENTION The major method to prevent ifosfamide nephrotoxicity is to limit the cumulative dose.
Other preventative strategies, such as coadministration of mesna or N-acetylcysteine (NAC), have been
evaluated, but efficacy is unproven.

Limit ifosfamide dose As noted above, the risk of nephrotoxicity is low at cumulative ifosfamide doses of
60 g/m2 or less and, when toxicity does occur, it is usually mild to moderate in severity and more likely to be
transient [7,8,14,16]. Limiting the cumulative ifosfamide dose may be especially important in patients with
additional risk factors for toxicity, such as young children (age four to five years), those who have undergone
prior nephrectomy or have other causes of renal dysfunction, and those treated with cisplatin. (See 'Risk
factors' above.)

Therapies of unproven efficacy

Mesna Mesna is a synthetic sulfhydryl compound that can detoxify ifosfamide metabolites. The main
clinical benefit of mesna is to prevent the accumulation of the metabolite acrolein, which causes hemorrhagic
cystitis. As a result, all patients treated with ifosfamide in modern chemotherapy regimens also receive
mesna. (See "Cystitis in patients with cancer", section on 'Mesna'.)

Whether the coadministration of mesna also reduces renal dysfunction remains unproven [1,20]. In
experimental studies, in vivo mesna did not prevent in vitro nephrotoxicity induced by chloroacetaldehyde, the
metabolite that appears to be responsible for ifosfamide nephrotoxicity [20]. It is unclear whether alternative
mesna administration schedules are more likely to prevent ifosfamide nephrotoxicity. (See 'Pathogenesis'
above.)

N-acetylcysteine N-acetylcysteine (NAC), which is used in the treatment of acetaminophen

(paracetamol) intoxication, has been effective in an animal model for the prevention of ifosfamide
nephrotoxicity [21,22]. Clinical studies in humans have not been reported.

LONG-TERM PROGNOSIS The long-term impact of ifosfamide-induced renal injury in children has been
addressed in a small number of studies [6-8,12,16,23]. The best long-term data following moderate
ifosfamide exposure were provided in a report of 183 childhood cancer survivors who had been treated with a
median cumulative ifosfamide dose of 54 g/m2, with only 17 receiving more than 60 g/m2; none of the
patients received concurrent therapy with cisplatin or carboplatin [8].

At an average follow-up of 10 years, 90 percent had normal tubular function, and 79 percent had a normal
glomerular filtration rate (GFR), defined as greater than 90 mL/min per 1.73 m2. Almost all of the abnormal
findings were mild:

All but one of the 39 patients with a reduced GFR had a value between 60 and 89 mL/min per 1.73 m2
Two patients had mild hypomagnesemia
Two patients had hypophosphatemia (although 24 percent had a reduced threshold for phosphate
excretion)
One patient had a low serum bicarbonate concentration (19 meq/L)
Significant renal glucosuria was present in eight patients

Using a combined nephrotoxicity score in 81 evaluable patients, 63 percent had no nephrotoxicity, 36 percent
had mild nephrotoxicity, and one percent had moderate nephrotoxicity. No patients had severe nephrotoxicity.
No patient required long-term treatment with bicarbonate, phosphate, calcium, or vitamin D. In multivariate
analysis, the length of follow-up and older age at diagnosis were independent predictors of a reduction in
GFR. Thus, the authors concluded that ongoing evaluation for progressive nephrotoxicity is warranted.

The risk of moderate to severe nephrotoxicity is higher at cumulative doses 84 g/m2. (See 'Cumulative
ifosfamide dose' above.)

There are few data on long-term renal function in adults who have received ifosfamide. The best data come
from a retrospective cohort of 259 adults who received ifosfamide chemotherapy [24]. The mean estimated
GFR fell from 82 to 67 mL/min per 1.73 m2 after five years; most of this reduction occurred during the course
of chemotherapy (likely reflecting acute kidney injury), although renal function continued to decline thereafter.
No patient developed end-stage renal disease (ESRD).

SUMMARY AND RECOMMENDATIONS

Ifosfamide is a synthetic structural isomer of cyclophosphamide that is used to treat metastatic germ-cell
testicular cancer and some (especially pediatric) sarcomas. Nephrotoxicity due to direct tubular injury is
a prominent complication of ifosfamide therapy. (See 'Introduction' above.)

Renal injury is manifested by signs of tubular dysfunction including glucosuria, aminoaciduria, tubular
proteinuria (ie, low-molecular-weight proteins but not albumin), a marked increase in beta-2-
microglobulin excretion, and rarely, polyuria due to nephrogenic diabetes insipidus. Patients may have
hypophosphatemia due to decreased proximal phosphate reabsorption, hypokalemia due to potassium
wasting, and a normal anion gap metabolic acidosis. (See 'Clinical manifestations' above.)

In addition to tubular dysfunction, ifosfamide can lead to a reduction in glomerular filtration rate (GFR).
The reduction in GFR is generally mild unless ifosfamide is given in combination with another
nephrotoxin such as cisplatin. (See 'Clinical manifestations' above.)

Risk factors for ifosfamide nephrotoxicity include cumulative dose, age under four to five years, prior
nephrectomy (and probably other causes of renal dysfunction), and prior or concomitant cisplatin
therapy. Clinically significant nephrotoxicity is more likely to occur at a total dose above 60 g/m2 and
severe nephrotoxicity above 120 g/m2. (See 'Risk factors' above.)

The cornerstone of prevention of ifosfamide nephrotoxicity is to limit the cumulative dose. Other
modalities, such as mesna and N-acetylcysteine (NAC), have not been proven to be effective. (See
'Prevention' above.)

Limited studies suggest that the long-term prognosis of moderate ifosfamide nephrotoxicity is good with
the majority of patients recovering normal tubular function and GFR during the first 10 years after
completing treatment. (See 'Long-term prognosis' above.)

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REFERENCES

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Contributor Disclosures
Roderick Skinner, PhD, MBChB, FRCPCH Nothing to disclose Richard H Sterns, MD Nothing to
disclose Albert Q Lam, MD Nothing to disclose

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