Leukemia and Iron Overload

This may be why iron chelating drugs are used to prevent transplant
rejection.
----------------------
Pediatric Transplantation
Chotsampancharoen T, Gan K, Kasow KA, Barfield RC, Hale GA, Leung W.
Iron overload in survivors of childhood leukemia after allogeneic
hematopoietic stem cell transplantation.
Pediatr Transplantation 2008. (c) 2008 Blackwell Munksgaard
Abstract
Abstract: Iron overload has not been studied extensively and
prospectively in pediatric survivors of allogeneic hematopoietic stem
cell transplantation (HSCT); therefore, we conducted a prospective
long-term study of 133 survivors of childhood leukemia to assess the
incidence of and risk factors for iron overload and to investigate its
association with organ dysfunction.
One yr after HSCT, the mean serum ferritin level was 1158 ng/mL
(range, 22-3264 ng/mL), with 124 patients (93.2%) having a serum
ferritin level that exceeded the upper limit of the normal range (110
ng/mL).
Thereafter, the serum ferritin level declined over time.
There was a positive correlation between the level of serum ferritin
and that of total bilirubin (r = 0.21, p < 0.001) and glutamate
pyruvate transaminase (r = 0.17, p < 0.001).
A high concentration of serum ferritin was associated with low cardiac
fractional shortening (r = -0.15, p = 0.047).
In addition, patients with hypothyroidism and GH deficiency had a
higher level of serum ferritin than those without (p < 0.02).
We conclude that iron overload is common after HSCT and is associated
with hepatic, cardiac, and endocrine dysfunction.

-----------------------------------

NEWS FROM THE LITERATURE

Hepatic Iron Overload Reduces Liver Transplant Survival
Research in August's issue of Gastroenterology has confirmed that
one-
and five-year survival after liver transplant is lower in patients
with
hepatic iron overload, presenting with or without HFE-associated
hemochromatosis.


Previous uncontrolled studies have suggested that patients with
hepatic
iron overload have a poor outcome after liver transplantation.
Researchers examined the effect of HFE mutations on
post-transplantation survival in patients with hepatic iron overload.
The researchers enrolled 260 patients with end-stage liver disease
and
hepatic iron overload from 12 liver transplantation centers. The team
recorded hepatic iron concentration, hepatic iron index, HFE mutation
status and survival after liver transplantation.


HFE-associated hemochromatosis was defined in 14 patients as
homozygosity for the C282Y mutation. In 11 patients, the team defined
HFE-associated hemochromatosis as compound heterozygosity for the
C282Y/H63D mutation. The HFE-associated hemochromatosis mutations
were
identified in 13 percent of patients. The researchers found that
survival post-liver transplantation was significantly lower among
patients with HFE-associated hemochromatosis. The one-, three- and
five-year survival rates in these patients were 64 percent, 48
percent
and 34 percent, respectively compared with simple heterozygotes or
wild-type patients. The researchers observed that patients with
HFE-associated hemochromatosis had a hazard ratio for death of three
after adjustment for age. The hazard ratio for mortality remained the
same after adjusting for United Network for Organ Sharing status,
year
of transplantation and either elevated hepatic iron index or iron
concentration. The team noted that non-HFE-associated hemochromatosis
patients with hepatic iron overload had decreased survival versus the
overall population undergoing liver transplantation. - Newsfeed from
GastroHep.com


Gastroenterology; 2005: 129(2): 494-503

-------------------------
Source: University of California, San Diego Health Sciences
Released: Fri 30-May-2008, 17:00 ET

Transplant Research: Drug May Prolong Kidney Life


Newswise -- New research from the University of California, San Diego
Department of Medicine, Division of Nephrology, shows that the anti-
rejection drug sirolimus (brand name Rapamune) may help prolong the
clinical benefit of transplanted kidneys and delay rejection,
especially in patients who do not regularly take their prescribed
medications (are "non-compliant"). While the transplant field has
been
highly successful at reducing rejection and graft loss in the first
year, post-transplant, reducing risk for graft rejection in the long-
term has proved more difficult.


The findings are being presented at the 2008 American Transplant
Congress (ATC), in Toronto on Saturday, May 31, 2008, by Cheri Ye,
M.D., who was mentored by Robert Steiner, M.D., professor of
medicine,
and Director of Transplant Nephrology.


"No one is perfect at taking medications," explained Steiner. "But
missing doses of immunosuppression, or not taking full doses each
day,
will bring about gradual rejection of kidney transplants that is
almost impossible to detect in its early stages. Long acting drugs
like sirolimus may help with this problem."


A team of five UC San Diego investigators reported a careful
assessment of immune function at "trough" levels (lowest daily
levels)
of the three most commonly used immunosuppressive drugs, using an
assay (ImmuKnow(R)/ Cylex) designed specifically to measure the degree
of immunosuppression at any given time. Lower "mitogenic response"
meant better immunosuppression and more protection from rejection. On
average, the participants, 160 kidney transplant patients, were 6.4
years out from their transplant.


At these trough levels of drug in the blood stream, the assay
demonstrated that sirolimus caused a significantly lower level of
mitogenic response, and results appeared to be stable in individual
patients over time.


"At least half of transplanted kidneys are lost through chronic graft
rejection, usually within 10 years. When patients do not have those
rejection problems, they can go for 20 to 30 years before kidney
rejection or other serious problems. This is an especially important
issue now because of our nationwide donor-organ shortage," said
coauthor, David Perkins, M.D., Ph.D., professor of medicine &
surgery,
and Director of Research for Transplantation.


"This study was not commercially funded," added Steiner. "We just
wanted to confirm what we suspected from experience in our transplant
clinic, where we focus on compliance in many ways to help our
patients
keep their kidneys functioning well. We showed that when the daily
dose is wearing off and another dose is due to be taken, patients
taking sirolimus could be more protected against rejection than other
commonly used agents."


The assay used is the only commercially available of its kind, and
potentially valuable, but researchers emphasized that experience and
understanding of it is limited.


"Our ATC abstract is a report of clinical experience, but real
progress is often made at the level of basic science. My laboratory
is
studying this intensively at a basic level in several ways, including
looking at the genetics associated with various responses to the
assay," said Perkins.


The researchers believe that this new study may help develop tools to
monitor patients in the long-term, and also contribute to a protocol
for using sirolimus in less compliant patients. Steiner pointed out
that, "The best results will occur if we prevent rejection, because
once rejection is established the threat to graft survival is much
greater, no matter what we do."


Co-authors of the study, "Sirolimus (SRL) Blunts Mitogen Response at
Trough (C0) Levels More Than Cyclosporin (CSA) or Tacrolimus (TAC): A
Safeguard for Our Many Long Term Noncompliant Kidney Transplant
Patients (KTPs)" include UC San Diego School of Medicine physicians
Nitin Khosla M.D., and Rodolfo Batarse, M.D., assistant professor of
medicine.


About ATC
The ATC is the premier educational event in the field of basic and
clinical transplantation, with the widest range of educational
opportunities. Topics range from toll-like receptors and composite
limb grafts to recent immuno-suppression trials and issues in the
globalization of transplantation.


The American Society of Transplant Surgeons (ASTS) was founded in
1974
in an effort to unite surgeons involved in the fledgling field of
transplantation. Since then, the Society has established a strong
presence in transplantation research, education and training, and
advocacy.


The American Society of Transplantation (AST) was founded in 1982 and
is an organization of more than 2,600 transplant professionals
dedicated to research, education, advocacy and patient care in
transplantation. AST's goal is to offer a forum for the exchange of
knowledge, scientific information and expertise in the field of
transplantation.


About UCSD Center for Transplantation
The UCSD Center for Transplantation at UCSD Medical Center performed
San Diego County's first kidney transplant in 1968 and has since
performed more than 2,000 kidney transplants on patients of all ages.
In 1999, the kidney transplant program began using a new, less
invasive technique for living kidney donation, using endoscopic
instruments through very small incisions. In addition, UC San Diego
Medical Center's clinical research programs are at the forefront of
discovering new information on the biology of organ rejection, organ
preservation and long-term medical management for transplant
recipients.


(c) 2008 Newswise. All Rights Reserved.


---------------------------------------------------------------------------------


"Influence of sirolimus on iron homeostasis"


Transplantation. 2006 Oct 15;82(7):908-12. Links


Comment in:
Transplantation. 2007 May 15;83(9):1283; author reply 1284.
Sirolimus interferes with iron homeostasis in renal transplant
recipients.Maiorano A, Stallone G, Schena A, Infante B, Pontrelli P,
Schena FP, Grandaliano G.
Division of Nephrology, Department of Emergency and Transplantation,
University of Bari, Italy.


BACKGROUND:
Sirolimus is an immunosuppressive drug whose use is frequently
associated with anemia. A pathogenic link between sirolimus-induced
anemia and the appearance of an inflammatory state was recently
suggested. Because inflammation-related anemia is characterized by a
functional iron deficiency, we investigated whether sirolimus may
influence iron homeostasis and serum levels of hepcidin, a key
mediator of inflammation-related anemia.
METHODS:
To this purpose, 42 consecutive transplanted patients with biopsy-
proven chronic allograft nephropathy were randomized (2:1 ratio) to
receive either a 40% cyclosporine reduction (group A, 14 patients) or
immediate cyclosporine withdrawal and sirolimus introduction (group
B,
28 patients). Hemoglobin levels and iron status were evaluated 6
months before and after randomization.
RESULTS:
The two groups had similar hemoglobin levels and iron status at
baseline. We did not observe any significant change in hemoglobin and
iron status in group A patients after randomization. On the contrary,
we observed a significant reduction of hemoglobin without any change
of red blood cell count after sirolimus introduction, with a
significant reduction of mean corpuscular volume and mean corpuscular
hemoglobin. Serum iron and transferrin saturation (TSAT) levels were
markedly reduced after the switch, while ferritin serum
concentrations
remained stable. Although sirolimus-induced anemia was recently
suggested to resemble inflammation-related anemia, hepcidin serum
levels were similar in the two groups after randomization. None of
group A and eight of group B patients presented a TSAT <20 and were
given iron supplementation after randomization, in all of them oral
iron therapy did not influence either hemoglobin or serum iron
levels.
CONCLUSION:
We demonstrated that sirolimus-induced anemia is independent of the
drug antiproliferative effect and does not present the features of
inflammation-related anemia. This event may be due to the direct
influence of sirolimus on iron homeostasis.


PMID: 17038905 [PubMed - indexed for MEDLINE]


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