LETTERS TO THE EDITOR
Everolimus and Minimization of Cyclosporine in Renal Transplantation:
24-Month Follow-Up of the EVEREST Study
The association of cyclosporine A
(CsA) with everolimus can exert synergistic effects on the alloimmune response. CsA inhibits the synthesis of
interleukin-2 while everolimus inhibits
the response to interleukin-2. Moreover, the interaction with CsA increases
the bioavailability of everolimus (1).
These data suggest that it is possible to
reduce the doses of both drugs when
given in combination.
Previously, we reported the 1-year
results of a randomized trial in 285 de
novo renal transplants, 278 from deceased
donors (2). Patients of group A received
low-concentration CsA (C2 maintenance
levels 350 –500 ng/mL) plus everolimus
(C0 levels 3– 8 ng/mL), while patients of
group B received very low-concentration
CsA (C2 maintenance levels 150 –300 ng/
mL) and everolimus at higher target levels
(C0 8 –12 ng/mL). One-year graft survival
rate was better in group B (98% vs. 90%;
P⫽0.007). The mean serum creatinine levels at 1 year were, respectively, 1.51⫾0.55
mg/dL and 1.55⫾0.62 mg/dL.
After the 1-year study was completed, 215 patients (110 in group A and
115 in group B) accepted to enter the
extension study and to continue the study
treatment up to 2 years. At 24 months, the
mean everolimus dosages were 1.45⫾0.6
mg/day in group A (blood levels 6.17⫾2.1
ng/mL) and 2.24⫾1.1 mg/day in group B
(blood levels 8.15⫾3.5 ng/mL), and the
dosages of CsA were 1.62⫾0.5 mg/kg/
day (C2 levels 407.6⫾159 ng/mL) and
1.38⫾0.7 mg/kg/day (C2 blood levels
330.7⫾159 ng/mL), respectively; the
prednisone dosages were 5.14⫾1.28 mg/
day in group A and 4.91⫾1.10 mg/day in
group B.
Four deaths (two in group A and
two in group B) occurred within 6
months since transplantation; another
patient of group A died after the first
year because of myocardial infarction.
Fifteen grafts were lost in group A and
six in group B (P⫽0.043). In group A,
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only one graft was lost after the first year
because of recurrent focal glomerular
sclerosis. In group B, three failures occurred in the second year; two because of
chronic rejection and one because of infection. The 24-month graft survival, including death as a cause of graft failure,
was 87.4% in group A and 94.4% in
group B (P⫽0.048).
Acute rejection after the first year
occurred in just one patient of group B.
The cumulative probability of biopsyproven rejection at 2 years was 15.0% in
group A and 15.7% in group B. The
mean levels of serum creatinine at 24
months were 1.45⫾0.5 mg/dL in group
A and 1.52⫾0.7 mg/dL in group B (P⫽not
significant [NS]). Mean glomerular filtration rate according to Nankivell et al. (3)
was 65.8⫾19.7 mL/min in group A versus
61.8⫾22.0 mL/min in group B. The slopes
of serum creatinine and glomerular filtration rate between 6 months and 2 years
were practically flat (data not shown).
At 24 months, systolic blood pressure was 135.6⫾16.1 mm Hg in group A
and 135.8⫾18.8 mm Hg in group B; diastolic blood pressure was 81.2⫾9.8 mm
Hg in group A versus 81.7⫾10.4 mm Hg
in group B. Most patients were on antihypertensive medication. Mean hemoglobin levels were 13.1⫾1.6 g/dL in group
A and 13.0⫾1.7 g/dL in group B. Plasma
cholesterol levels were 228.0⫾41 mg/dL in
group A and 235.1⫾54.5 mg/dL in group
B (P⫽NS). Triglycerides levels were
193.3⫾84.9 mg/dL versus 224.4⫾120.6
mg/dL (P⫽NS). 3-hydroxy-3-methylglutaryl-Co (HMG-CoA) reductase inhibitors were administered in 83% of patients in
both groups. Proteinuria more than 0.2
g/day occurred in 13 patients of group A
(9.1%) and in 20 of group B (14.1%).
The overall incidence of infections
requiring hospitalization was similar in
the two groups (10.5% in group A and
14.5% in group B). Diabetes was diagnosed in 7 (4.9%) patients in group A
and in 13 patients (9.2%) in group B
(P⫽NS). One patient (0.7%) in group A
and three patients in group B (2.1%) developed nonmelanoma skin cancer. Twelve
patients (four in group A and eight in
group B) discontinued treatment because of adverse events after the first year
(Table 1).
TABLE 1. Adverse events leading to discontinuation of treatment between
the first and the second year
Patients who discontinued everolimus (total)
Increase in serum creatinine
Abdominal abscess
Pancreatitis
Edema-arthralgias
Proteinuria
Gum hyperplasia
Mucositis
Transplant glomerulopathy
Interstitial pneumonia
Anemia
Severe urinary tract infection
Calcineurin toxicity
Group A
(112 patients)
Group B
(111 patients)
4 (3.6%)
0
0
0
0
2
1
0
0
1
0
0
8 (7.2%)
2
1
1
1
0
1
1
0
1
Transplantation • Volume 91, Number 10, May 27, 2011
Letters to the Editor
© 2011 Lippincott Williams & Wilkins
From these results, it is possible to
conclude that minimal doses of CsA in
association with everolimus may offer
excellent graft survival and stable renal
function at 2 years.
Claudio Ponticelli1
Maurizio Salvadori2
Maria Piera Scolari3
Franco Citterio4
Paolo Rigotti5
Antonella Veneziano6
Marta Bartezaghi6
on behalf of EVEREST Study
1
Division of Nephrology
Humanitas Scientific Institute
Rozzano (Milano), Italy
2
Division of Nephrology
Careggi Hospital
Firenze, Italy
3
Renal Transplant Unit
S. Orsola Malpighi University Hospital
Bologna, Italy
4
Department of Surgery
Catholic University Hospital
Roma, Italy
5
Surgery Division
Policlinic University Hospital
Padova, Italy
6
Medical Department
Novartis Italy
Origgio (Varese), Italy
C.P. is a consultant to Novartis Farma, Italy.
A.V. and M.B. are employees of Novartis
Farma, Italy.
Address correspondence to: Claudio Ponticelli, via
Ampere 126,20131 Milano, Italy.
E-mail: claudio.ponticelli@fastwebnet.it
C.P. designed the research and wrote the article;
M.S., M.P.S., F.C., and P.R. participated in the
performance of the research; A.V. participated
in the writing of the article; and M.B. com-
e73
puted statistical calculations and participated
in the writing of the article.
Received 19 January 2011.
Accepted 21 February 2011.
Copyright © 2011 by Lippincott Williams &
Wilkins
ISSN 0041-1337/11/9110-72
DOI: 10.1097/TP.0b013e318216c1db
REFERENCES
1.
2.
3.
Kovarik JM, Dantal J, Civati G, et al. Influence
of delayed initiation of cyclosporine on everolimus pharmacokinetics in de novo renal transplant patients. Am J Transplant 2003; 3: 1576.
Salvadori M, Scolari MP, Bertoni E, et al.
Everolimus with very low-exposure cyclosporine A in de novo kidney transplantation:
A multicenter, randomized, controlled trial.
Transplantation 2009; 88: 1194.
Nankivell BJ, Chapman JR, Allen RD. Predicting glomerular filtration rate after simultaneous pancreas and kidney transplantation. Clin
Transplant 1995; 9: 129.
Successful ABO Incompatible Kidney Transplant After an Isolated
Intestinal Transplant
To our knowledge, we herein report the first case in the literature of a
living unrelated ABO incompatible
(ABOi) renal transplantation after successful isolated small bowel and colon
transplantation. This case illustrates several interesting immunologic findings.
The patient is a 50-year-old
woman with a history of hypertension
and cholecystectomy who suffered with
complicated endometriosis, which lead
to multiple intestinal resections for recurrent obstruction and enterocutaneous fistulae. These ultimately led to
short gut syndrome and total parenteral
nutrition dependence for 5 years. The
patient underwent an ABO identical isolated intestinal transplant (small bowel
and right colon) with systemic venous
drainage and basiliximab and steroid
induction. Posttransplant maintenance
included tacrolimus, sirolimus, and
prednisone. No rejection was encountered, parenteral nutrition was discontinued, and her ileostomy was reversed
18 months later. Because of poor wound
healing and wound infection, sirolimus
was discontinued thereafter.
One year after small bowel transplantation, the patient experienced
progressive renal insufficiency presumed because of tacrolimus toxicity.
Despite diuretic therapy, volume management ultimately led to hemodialysis 16 months after transplant. Her
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only potential live kidney donor was
ABOi; the patient was blood group O;
and her donor was blood group A. She
subsequently underwent an ABOi renal
transplant 24 months after her intestinal
transplant. The desensitization protocol
consisted of pretransplant and posttransplant tacrolimus and mycophenolate mofetil with four preoperative
and two postoperative rounds of plasmapheresis and intravenous cytomegalovirus immune globulin. Induction
therapy also included 1.5 mg/kg rabbit
antithymocyte globulin intraoperatively
and on the first 4 postoperative days
along with methylprednisolone. Her
baseline anti-A antibody titer was 1:64.
After plasmapheresis, it decreased to 1:8
below the threshold of 1:32, necessary for
successful ABOi renal transplantation (1).
It is now 46 months after intestinal
transplant and 26 months after her kidney
transplant. She continues on a low fat diet
with no nutritional support. In addition,
she has a good kidney function and a serum creatinine level of 1.8. She is maintained on tacrolimus, mycophenolate
mofetil, and prednisone for immunosuppression. The patient has had no evidence of
rejection of graft or opportunistic infection.
DISCUSSION
Intestinal transplantation has improved in the past decade, achieving
1-year patient and graft survival rates in
excess of 90% at several centers (2). It
has been associated with a 30% to 40%
risk of rejection in the first 3 months (3).
Ojo et al. (4) report rates of renal failure
as high as 21.3% in recipients of intestinal transplants, likely related to aggressive immunosuppression protocols.
In this case, we successfully performed an isolated intestinal transplant
with an excellent functional outcome using an aggressive immunosuppressive
protocol including rabbit antithymocyte
globulin induction and maintenance tacrolimus, sirolimus, and prednisone.
Eventually the patient developed chronic
renal failure, and we followed up this
with an ABOi living donor kidney transplant. Despite the exposure to a second
set of non-self-human leukocyte antigens and crossing the ABO barrier, there
was no episode of rejection of either
allograft. We hypothesize that her previous immunosuppression and our desensitization protocol would decrease the
likelihood of such an occurrence.
At our center, we use sirolimus as a
part of our strategy for maintenance immunosuppression for intestinal transplantation, because this has been shown to
be of benefit in combating acute rejection
(5). She did not have evidence of rejection
but did develop a wound infection and
poor wound healing necessitating discontinuation of sirolimus. After 1 year, the
patient ultimately developed progressive