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Mechanisms of Renal Disease in b-Thalassemia

Khaled M. Musallam* and Ali T. Taher
*Department of Medicine and Medical Specialties, IRCCS Ca Granda Foundation Maggiore Policlinico Hospital, Milan,
Italy, and Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon

Although advances in the care of patients with b-thalassemia translate into better
patient survival, this success has allowed previously unrecognized complications to
emerge, including several renal abnormalities. Clinical studies continue to show
that mild tubular dysfunction and abnormalities in GFR are common in patients
with b-thalassemia. Chronic anemia and iron overload are believed to lie behind
these abnormalities. Nonprogressive increases in levels of serum creatinine have
also been observed after exposure to some iron chelators. Longitudinal studies
are needed to understand the true burden of renal dysfunction in patients with
J Am Soc Nephrol 23: 12991302, 2012. doi: 10.1681/ASN.2011111070

As a group, the thalassemias are the most

common monogenetic disorders worldwide, presenting a signicant public health
concern for developing countries. Large
migrations from countries where the disease is prevalent have also increased the
number of patients in multiethnic western
cities.1 b-thalassemia is an inherited disorder of hemoglobin synthesis wherein
mutations of the b-globin gene lead to
various degrees of defective b-chain production, an imbalance in a/b-globin
chain synthesis, ineffective erythropoiesis,
and a spectrum of anemia.
Patients with b-thalassemia major present in the rst year of life with profound
anemia and subsequently require regular
blood transfusions for survival, as well as
iron chelation therapy to treat transfusional iron overload and prevent end-organ
damage. Some patients, however, present
later in life with a milder form of anemia
(hemoglobin level, 7090 g/L) and remain largely transfusion-independent:
the so-called b-thalassemia intermedia
phenotype.2 Patients with b-thalassemia
intermedia can also develop considerable
iron overload due to increased intestinal
J Am Soc Nephrol 23: 12991302, 2012

iron absorption triggered by the ongoing

ineffective erythropoiesis. 3 Chronic
anemia, iron overload, and the use of
specic iron chelators have all been linked
to renal manifestations in patients with
Evidence of proximal tubular damage
is observed in patients with b-thalassemia
major. Low-molecular-weight proteinuria
is found in almost all patients. Moreover,
several studies report increased urinary
excretion of several markers of proximal
tubular damage in a considerable number
of patients with b-thalassemia major, including N-acetyl-b-D-glucosaminidase
and b2-microglobulin (up to 60%); calcium (approximately 13%), phosphate
and magnesium (about 9%), uric acid
(30%40%), amino acids (approximately
30%), and malondialdehyde derived from
the destruction of membrane lipids by
peroxidation.4 A more recent study shows
that the secretion of such markers is signicantly reduced in patients with b-thalassemia
major who have undergone curative hematopoietic stem-cell transplantation
compared with age-matched patients
who have not had transplantation.5

Both iron overload and chronic anemia could explain tubular dysfunction in
patients with b-thalassemia, although
the two often coexist and the independent contribution of each risk factor has
not been widely investigated. Rats subjected to chronic iron loading develop
iron deposits that are clearly evident in
glomeruli and in proximal but not distal
tubules, as well as signs of signicant
glomerulosclerosis, tubular atrophy,
and interstitial brosis.6 Autopsy series
of patients with b-thalassemia major
show hemosiderin deposits in both the
terminal portion of proximal tubules
and the distal tubules. 7 In the acidic
proximal tubular uid, iron dissociates
from transferrin, resulting in the production of reactive oxygen species with
subsequent damage to the brush border
of the renal tubular membrane. If
iron enters proximal tubular cells along
with transferrin, it can be released from
transferrin inside the lysosomes to enter
the cytoplasm as free reactive iron, where
it also stimulates the production of reactive oxygen species and cellular injury.810
The mechanism of injury is mediated
by mitochondrial stress in proximal
tubular cells, as evidenced by increased
efux of cytochrome C, release of lactate

Published online ahead of print. Publication date

available at
Correspondence: Dr. Ali T. Taher, Department of
Internal Medicine, American University of Beirut
Medical Center, PO Box 11-0236, Riad El-Solh
1107 2020, Beirut, Lebanon. Email: ataher@aub.
Copyright 2012 by the American Society of

ISSN : 1046-6673/2308-1299



dehydrogenase, and reduction in adenosine triphosphate.11,12 This pathologic

and experimental evidence is supported
by clinical studies showing a good correlation between serum ferritin levels and
markers of tubular toxicity,13,14 and by reversal of tubular defects after iron chelation therapy.14,15 Chronic anemia and
hypoxia are also associated with oxidative
stress, lipid peroxidation, and functional
abnormalities in tubular cells.16,17 Damage to the proximal tubule and volume
increases of the peritubular space were
also demonstrated in one study on anemic rats.18 A good correlation between
the severity of anemia and markers of
tubular abnormalities are reported in
patients with b-thalassemia major.19
Abnormalities in GFR are also evident
in patients with b-thalassemia. In patients with b-thalassemia who do not
receive regular transfusion therapy (patients with b-thalassemia intermedia),
creatinine clearance and GFR are increased.20 Anemia may reduce systemic
vascular resistance, leading to a hyperdynamic circulation that increases renal
plasma ow and GFR.21 These changes
can eventually lead to stretching of the
glomerular capillary wall and subsequent endothelial and epithelial injury,
together with transudation of macromolecules into the mesangium associated with glomerular dysfunction.22 In
the long-term, such changes may lead
to a progressive decline in GFR. Moreover,
chronic hypoxia of tubular cells with
increased metabolic demand causes apoptosis or epithelial-mesenchymal transition, leading to the development of
tubulointerstitial injury and consequent
glomerulosclerosis and kidney brosis.4,23
In addition, tubular cell damage from
heavy iron overload may allow injured
cells to migrate into the interstitium, releasing cytokines and growth factors that
can cause tubulointerstitial scarring and
glomerular sclerosis and leading to further
decrease in GFR.24 A negative correlation
between serum ferritin levels and GFR,
evident from measurement of cystatin
C, has been reported in patients with
b-thalassemia major.25 Additional factors
that contribute to a decreased GFR in
these patients include transfusion-related

hepatitis B or C virus or HIV infections

leading to GN, as well as iron-induced
hepatic and cardiac dysfunction.4
Three iron chelators are available for
the management of iron overload in
b-thalassemia: parenteral deferoxamine
mesylate (Desferal, Novartis) and the oral
agents deferiprone (Ferriprox, Apotex;
Kelfer, Cipla) and deferasirox (Exjade,
Novartis) (Table 1). Renal manifestations
attributed to iron chelation therapy have
probably received the most attention from
investigators studying thalassemia. Acute
renal failure attributed to drug use is rare
but has also been reported. In some studies, deferoxamine overdose secondary to
administration-pump malfunction or inadequate dosage monitoring resulted in
acute renal failure necessitating dialysis.4
Findings on renal biopsy describe tubular

necrosis, which is the most likely cause

given the reversible nature of damage.26
Several cases of acute kidney injury have
also been reported in postmarketing surveillance of the oral chelator deferasirox.4
Recently, a boxed warning was added to
the deferasirox prescribing information in the United States, although this
amendment has not been adopted by
the European Health Authority or applied globally. The warning indicates
the drug may cause renal and hepatic impairment, including failure and gastrointestinal hemorrhage. In some cases, these
reactions were fatal. However, such reactions were more frequently observed in
patients with advanced age, high-risk
myelodysplastic syndromes, underlying
renal or hepatic impairment, or low
platelet counts.

Table 1. Available iron chelators for the management of transfusional iron

overload in patients with b-thalassemia
Usual dosage


2560 mg/kg per day
intravenous 812
hr, 5 d/wk
2030 min
Urinary, fecal


2040 mg/kg per day

Oral, once daily

34 h
Decreased cardiac
mortality, especially
in combination with

816 h
Ease of administration

Signicant reduction
in hepatic and
cardiac siderosis

Improved survival
in adherent
Adverse events

Local injection site

GI disturbances
Allergic reactions


Auditory disturbance
Bone abnormalities
Growth retardation


75 mg/kg per day

Oral, 3 times daily

Reddish-brown urine

GI disturbances

GI disturbances

Increased serum
creatinine levels

Increased appetite/
weight gain
Progression of liver

Renal and hepatic
GI hemorrhage

Cardiovascular events
Respiratory distress
Neurologic disturbance
GI, gastrointestinal.

Journal of the American Society of Nephrology

J Am Soc Nephrol 23: 12991302, 2012


Figure 1. Mechanisms of renal disease in patients with b-thalassemia.

Fluctuations in levels of serum creatinine with deferasirox therapy have also

been the subject of concern. In a multicenter randomized phase 3 registration trial
comparing deferasirox and deferoxamine
therapy in patients with b-thalassemia
major, mild, dose-dependent increases in
serum creatinine were observed in 38% of
patients receiving deferasirox at dosages
of 2030 mg/kg per day. These increases
were sometimes transient, were mostly
within the normal range, and did not exceed twice the upper limit of normal.
Dose reductions were required in only
13% of patients receiving deferasirox. In
about 25% of these patients, levels of
serum creatinine returned to baseline,
and in the remainder of patients it remained stable or uctuated between
baseline and the maximum increase observed before dose reduction.27 Safety
data with deferasirox in children and adults
with b-thalassemia major have now been
reported for up to 5 years of treatment and
conrm absence of progressive increases
in serum creatinine over longer-term
treatment, 28 even in patients with
heavy iron load who require dose escalation to .30 mg/kg per day.29 Studies
on levels of cystatin C in patients with
b-thalassemia major receiving deferasirox
for up to 9 months also conrm that changes
are stable over the treatment period.25
J Am Soc Nephrol 23: 12991302, 2012

The causes of this mostly reversible

nonprogressive increase in serum creatinine in patients treated with deferasirox
are still controversial. It has been hypothesized that the underlying mechanism is related not to a nephrotoxic effect
of the drug itself but to overchelation
leading to a relative depletion of iron
and reduction in GFR.4 This hypothesis
stems from observations of a similarly
high rate of serum creatinine increase in
the deferoxamine group (14% in patients
with b-thalassemia major and 22% in
those with sickle cell disease) during the
randomized trials,27,30 and the fact that
increases in serum creatinine are more
common in patients who showed dramatic decreases in liver iron concentration and serum ferritin level or those with
lower transfusion rate and baseline iron
The mechanisms used in alterations
of the GFR with relative iron depletion
include damage to mitochondrial function in tubular cells and production of
adenosine and adenosine triphosphate
(leading to activation of the tubuloglomerular feedback, vasoconstriction of
the afferent preglomerular arterioles,
and consequent reduction of GFR), and
interference with the arachidonic acid
cascade and the nal production of prostaglandins (leading to an imbalance

between vasodilating and vasoconstrictive prostaglandins, with consequent

changes in intrarenal hemodynamics
and GFR).4 In all cases, management of
increases in serum creatinine should be
individualized, although recommendations for dose reductions and monitoring
are available.31 The search for novel iron
chelators with more favorable renal
safety proles is ongoing.32
Despite expanding knowledge of renal manifestations in patients with bthalassemia (Figure 1), it should be
noted that most available studies are crosssectional and involve a small number
of patients. Longitudinal studies investigating the true incidence, mechanisms,
and consequences of renal abnormalities
in this patient population are warranted.
Investigations involving transfusionindependent patients with b-thalassemia
intermedia are also called for because
data in this latter group are lacking.

We would like to thank Professor Claudio
Ponticelli (Division of Nephrology, Humanitas
Scientic Institute, Milan, Italy) for insightful
interpretations of the mechanisms of renal
function in patients with b-thalassemia.
Thalassemia and the Kidneys



A.T.T. is a member of the Novartis Speakers

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