Open Journal of Organ Transplant Surgery, 2011, 1, 8-13
doi:10.4236/ojots.2011.11002 Published Online August 2011 (
Copyright © 2011 SciRes. OJOTS
Conversion from Calcineurin Inhibitors to Sirolimus
Maintenance Therapy in Renal Allograft Recipients
with Risk Factors
Shuming Ji1, Jiqiu Wen1, Do ngr ui Cheng1, Qiquan Sun1, Jinsong Chen1, Zhihong Liu2*
1Research Institute of Nephrology, Department of Nephropathy, Jinling Hospital, Nanjing, China
2Nanjing University Schoo l of Medicine, Nanjing, China
E-mail: *
Received July 31, 2011; revised August 17, 2011; accepted August 23, 2011
Background: The efficacy and safety of conversion treatment with sirolimus in renal transplant recipients
using the calcineurin inhibitor (CNI) with one or more risk factors was evaluated. Methods: Ninety-three
renal transplant recipients were prospectively enrolled. CNIs(CsA and FK506) as main immunosuppressant
were converted to SRL immunosuppressant protocol. Rapid conversion with sirolimus was performed in all
patients. The CNI withdrawal was in 2 weeks. At 4 hours after oral administration of cyclosporin A or tac-
rolimus, the patients took sirolimus. Initial dose of sirolimus was 6 mg, and repeated maintenance dose is 1.0 -
2.0 mg/d. The first concentration of sirolimus was detected at 5 - 7 days after first oral administration, and
the target concentration was 6 - 10 μg/L. Results: The symptoms were markedly improved in patients with
CNI induced renal toxicity and CNI induced liver toxicity, and the concentration of sirolimus were main-
tained at (5.1 ± 1.2) μg/L. Serum creatinine levels decreased from (297.72 ± 150.28) μmol/L to (123.76 ±
44.2) μmol/L, and the liver function were recovery in 24 (92.3%) patients. 9 patients with high glucose re-
turned to normal, and 2 patients were improved. Serum creatinine levels decreased more than 25% of pri-
mary level in 17 patients, and the effective rate was 51.5%. 10 patients with tumor were appeared 6 - 43
months after renal transplantation, no recurrence was found in 8 of them and 2 patients were dead. Acute
rejections were occurred in 3 patients at 6 months after conversion treatment. The complications were in-
cluded hyperlipidemia and proteinuria. 3 patients were dead, 6 patients returned to dialysis treatment, and 2
patients were removal of grafts. At 3 years after conversion treatment, the survival rates of patients and grafts
were 90.9% and 75.8%, respectively. Conclusion: The conversion treatment with SRL and MMF may be a
better option for the renal transplant recipients using the CNI with risk factors appeared.
Keywords: Renal Transplant, Calcineurin, Inhibitor, Conversion, Sirolimus
1. Introduction
Over the past two decades, the progress in renal trans-
plantations has been focused much on the ways of re-
ducing acute rejection. Incidence of acute rejections in
the majority of renal transplant recipients has fallen be-
low 20% and 1-year graft survival rate was as high as
90%. This is resulted mainly from the use of calcineurin
inhibitor (CNI), which could effectively prevent acute
renal allograft rejection. However, the long-term survival
of renal transplant recipients has not shown any im-
provement. [1] CNI-induced-nephrotoxicity, CNI-asso-
ciated hepatotoxicity, post-transplant diabetes mellitus
(PTDM), chronic allograft nephropathy(CAN), malig-
nancy incidence rate as well as other adverse reactions
resulted from CNI in renal transplant recipients, are the
major risk factors. [2] In recent years, substituting the
use of CNI with sirolimus (SRL) in part of the immuno-
suppression scheme for renal transplant recipients have
been increasingly focused upon. [3] We had applied the
newly revised immunosuppressive scheme, where SRL
conversion was used instead of CNI when one or more
risk factors had been identified to evaluate the efficacy
and safety of conversion calcineurin inhibitor to siro-
S. M. JI ET AL.9
limus in the renal transplant recipients.
2. Methods
2.1. Patients
Ninety-three renal transplant recipients who had received
conversion-to-SRL-based immunosuppressive therapy
were prospectively enrolled at Jinling Hospital from June
2002 to December 2005. Patient demographics data are
listed in Table 1. Criteria for inclusion were: I. Patients
with CNI-induced nephrotoxicity is characterized by
irreversible tubulointerstitial fibrosis in a striped pattern
beginning in the medulla and progressing to the me-
dullary rays of the cortex, generally accompanied by
some degree of renal dysfunction; [4] II. Patients with
CNI-associated-hepatotoxicity: [5] Bilirubin and transa-
minases increased significantly,but,bilirubin and transa-
minases decreased significantly within 2 weeks after
withdrawal CNIs, and liver function normalized; III.
Post-transplant diabetes mellitus was defined as the un-
interrupted need for glucose-lowering medication for at
least 3 months. [6] IV. Chronic allograft nephropathy
characterized by progressive renal dysfunction accompa-
nied by chronic interstitial fibrosis, tubular atrophy, vas-
cular occlusive changes,and glomerulosclerosis. [7] V.
Patients with concurrent post-transplant malignancy.
Any patients of the following had not been included in
this study: Those who had resumed back to their conven-
tional immunosuppressive therapy due to disease pro-
gression or financial reasons; Those who had already
hyperlipidemia (blood cholesterol >6 mmol/L, or triacyl-
glycerol >2 mmol/L); urine protein >0.8 g/24 h; periph-
eral blood WBC <3.5 × 109/L, platelet count <80 × 109/L.
All the clinical data collected in the paper for research is
strictly complied with the Regulation of Human Organ
Transplantation in China, and no prisoners or organs
from prisoners were used in the collection of data for this
2.2. Switch Scheme from CNI to Sirolimus
SRL conversion course, applies fast conversion, [8] the
two drugs are overlapped for a shorter period, between
one and two weeks, generally reducing CNI by 50%
starting from the day that SRL is introduced. The objec-
tive of this approach would be to maintaining CNI until
being sure that SRL levels are sufficient. Initial single
oral loading dose was given at 6 mg, followed by main-
tenance dose given 1 - 2 mg/day. SRL target trough lev-
els were 6 - 10 ug/L (high-performance liquid chroma-
tography). The first level is usually measured between 5
and 7 days after initiating SRL, and if it is within or close
to the target range, CNI is then discontinued. If the level
is still low, the SRL dose is increased and CNI is main-
tained until measuring a second level a week later. After
conversion, mycophenolate mofetil (MMF,750 mg, twice
per day) adjusted by AUC 0-12, and maintained at 35 -
45 mg·h/L. Steroid therapy was unchanged. The study
was approved by the committee of ethics at Jinling Hos-
pital. All patients gave their written informed consent.
2.3. Clinical Design
Serum creatinine levels, rate of acute rejection, renal
graft loss, pulmonary infection and mortality rate were
monitored dynamically after SRL conversion had been
initiated. Those specific criteria for observations include
liver and renal function, blood cholesterol, triacylglyc-
erol, blood sugar, urine protein and routine peripheral
blood tests. In the meantime, SRL blood trough concen-
trations were monitored.
Table 1. Clinical parameters at SRL conversion.
CNI-nephrotoxicity CNI-hepatotoxicity PTDM CAN Tumor
n 13 26 11 33 10
Gender (man/female) 8/5 20/6 8/3 21/12 3/7
Age (year) 38.2 ± 11.1 36.7 ± 14.1 40.2 ± 8.0 34.2 ± 9.9 41.0 ± 6.4
Basal immunosuppressive drugs at conversion (n)
CsA 10 21 2 32 7
FK506 3 5 9 1 3
MMF 13 26 11 33 9
Transplantation time (mons) 22 ± 6 23 ± 4 25 ± 9 30 ± 9 36 ± 3
Followed-up time (mons) 37 ± 6 36 ± 4 37 ± 9 38 ± 3 38 ± 7
CNI: calcineurin inhibitor, PTDM: Post-transplantation diabetes mellitus, CAN: Chronic allograft nephropathy.
Copyright © 2011 SciRes. OJOTS
Copyright © 2011 SciRes. OJOTS
2.4. Statistical Analysis
Values before and after conversion were compared with
a Wilcoxon signed rank test. SPSS (version 11) software
was used to make the calculations. Values of P < 0.05
were considered to be significant.
3. Results
3.1. Demographic Characteristics
Patient demographics data are listed in Table 1. CNI-
induced nephrotoxicity (13,13.9%), CNI-associated heap-
totoxicity (26,28.0%), PTMD(11,11.8%), CAN(33,35.5%)
and post-transplantation tumor (10,10.8%). Follow-up
arrangements were conducted at 36.9 ± 1.2(35 - 38)
months post-SRL therapy, mean SRL dose was 2.6 ± 0.4
mg/d, SRL target trough levels were 7.3 ± 2.3 ug/L.
3.2. Clinical Outcomes after SRL Conversion
CNI-induced nephrotoxicity was reported in 13 patients
(10 from CsA and 3 from FK506), average CNI mainte-
nance time given before conversion was 11 ± 6 months
and average blood trough levels were 213.9 ± 19.3 ug/L
and 10.3 ± 3.7 ug/L respectively. Meanwhile other clini-
cal complications such as hirsutism, gingival hypertro-
phy and elevated blood pressure were noted. After SRL
conversion, the above symptoms as mentioned showed
significant improvement, where blood SRL concentra-
tion was maintained at 7.1 ± 1.2 ug/L, and serum crea-
tinine level was reduced from 3.3 ± 1.7 mg/dl to 1.4 ±
0.5 mg/dl.
CNI-associated hepatotoxicity was reported in 26 pa-
tients (21 from CsA and 5 from FK506). Serum alanine
aminotransferase (ALT) was 102.2 ± 24.3U/L, total bili-
rubin (TB) was 38.2 ± 9.8 umol/L.After conversion,
ALT was 30.1 ± 13.3U/L, TB was 11.8 ± 7.2 umol/L,and
the period of liver functioning restoration after conver-
sion took 11.3 ± 1.9 days; ALT was noted reduced but
not reaching its normal level in two cases, in which con-
current hepatitis C was noted in one patient whose blood
direct bilirubin levels showed progressive elevation, and
succumbed to liver failure 6 months after SRL conver-
Hyperglycemia had been reported in 11 patients (2
from CsA and 9 from FK506) where blood glucose lev-
els have returned to normal in 9 cases within 6 months
after conversion. Oral hypoglycemic drugs had been
stopped and glycosylated hemoglobin returned to normal
from 9.2 ± 0.6 to 5.4 ± 0.3%. The other two patients had
switched from insulin to oral hypoglycemics in control
of blood glucose levels efficiently.
CAN was confirmed on allograft pathology 38 ± 3
months after SRL conversion. In 17 cases, fall of serum
creatinine exceeded 25% compared with their original
level with an efficacy rate of 51.5%. Among the other 16
cases which were SCr >2.5 mg/dl before SRL conversion,
improvement in renal functioning was achieved in 2
cases, whereas no improvement shows in the other 14
cases. Serum creatinine levels in the 14 patients showed
slow-progressive rise, in which performing dialysis was
necessary in 5 patients, and allograft removal was man-
aged in one patient.
Tumor occurrences were noted around 6 - 43 months.
Among them, bladder cancer was reported in 3 cases,
breast cancer in 3 cases, colon cancer, esophageal cancer,
thyroid cancer and lymphoma in 1 case each. In the 3
patients with bladder transitional cell carcinoma (T2,
grade-II), transurethral resection of tumor was managed
followed by regular bladder instillation chemotherapy.
Patients were followed-up for 36 - 38 months, no recur-
rences were reported in 2 cases. However, recurrence
was reported in one case after 11 months. A second op-
eration of transurethral resection of tumor had been ar-
ranged and no further recurrence has been detected till
today.; Among the 3 patients with breast cancer, 2 pa-
tients presented with grade III invasive ductal carcinoma
of the right breast, where cancerous growth was detected
near the base region plus ipsilateral axillary lymph node
metastasis (immunohistochemistry: E-cad+++, EMC+++).
Surgical resection followed by standard chemotherapy
had been managed and no recurrence was reported after
37 months of follow-up. One patient with colon cancer
had been managed with chemotherapy alone, however,
the patient succumbed to massive gastrointestinal tract
hemorrhage 8 months after SRL conversion. Esophageal
cancer and thyroid cancer, 1 patient of each had received
surgical resection of tumor only, and no recurrence was
reported after 37 months and 38 months follow-up re-
spectively; One patient who had been diagnosed with
lymphoma was treated with intermittent chemotherapy.
The patient survived for 36 months and succumbed to
pulmonary infection subsequently.
3.3. Adverse Reactions
Acute rejection occurred within 6 months after SRL
conversion in 3 cases (9.1%), which were in the third
month in 1 case and the fourth month in the other 2 re-
spectively. Methylprednisolone pulse therapy was man-
aged and blood SRL and MMF concentrations were re-
adjusted. One month later, total recovery from acute re-
jection was achieved in one patient, SCr level had re-
turned to normal (1.1 mg/dl). The other 2 cases were
beyond control and had to be managed with hemodialy-
S. M. JI ET AL.11
sis, in which allograft removal was managed in one pa-
tient. Pulmonary infections were reported in 3 cases 6
months after SRL conversion (9.1%), which were from
the PTDM, CAN and tumor conversion groups. Among
them, one patient with lymphoma succumbed to infec-
tion (mixed pulmonary infection: cytomegalovirus plus
staphylococcus and fungal agents), whereas recovery
was achieved in the other 2. Mild nausea and vomiting
and severe diarrhea were 9 cases (27.3%), and they were
all alleviated when drug doses had been reduced. Hy-
percholesterolemia was 11 cases (33.3%), hypertriacy-
glycerolemia in 12 cases (36.4%), hyperuricemia in 9
cases (27.3%), liver dysfunction in 8 cases (24.2%), leu-
kopenia in 8 cases (24.2%), thrombocytopenia in 6 cases
(18.2%) and oral ulcers in 5 cases (15.2%). After 36
months of follow-up, proteinuria (3.2 ± 0.5 g/24 h.) was
reported in 13 cases (39.4%). Tripterygium Wilfordii
Hook f. (60 mg/d) was concomitantly added into treat-
ment, [9] and full recovery was achieved in 9 cases
3.4. Survival Rates
Within 3 years of follow-up, death was reported in 3
cases, where their causes of death include liver failure,
severe pulmonary infection and massive gastrointestinal
tract hemorrhage one of each case. Serum creatinine in 8
patients showed progressive elevation (CAN 6 cases,
acute rejection 2 cases), in which 6 of them had to re-
sume dialysis and 2 required allograft removal. The
3-year kidney graft and patient survival rates with SRL
conversion were 75.8% and 90.9% respectively.
4. Discussion
Sirolimus, as a new generation, highly-effective immu-
nosuppressive agent, has little nephrotoxicity along with
anti-proliferative as well as anti-tumor effects. [10] Ap-
plication of SRL has provided the opportunity for renal
allograft recipients to withdraw from the use of CNI,
thus becoming the clinical research hotspot of how to
prevent post-transplantation long-term complication, and
improve the long-term survival of renal transplants. [11]
The question on how to select the most appropriate indi-
vidual for safe and effective conversion on renal allograft
recipients from one immunosuppressive agent to another
has brought aroused concerns from many patient.
4.1. Suitability for Conversion to SRL Therapy
In our study, the efficacy rate of conversion treatment in
CAN patients was 51.5%, but of course, the renal func-
tion on some patients did not show any improvement on
schedule, or was even deteriorated. From our study, we
have discovered that the mean initial serum creatinine
level before conversion in patients with no renal function
improvement after conversion to SRL, was high. There-
fore, the therapeutic efficacy of conversion treatment is
rising if applying to CAN patients with initial serum
creatinine <2.5 mg/dl. Hence, early intervention is a
leading factor towards successful conversion treatment.
[12] So giving early conversion treatment before renal
impairment develops should be considered. Our experi-
ence tells us that conversion treatment shouldn’t be in-
tervened when serum creatinine levels are high (>2.5
mg/dl), which means that we shouldn’t wait until crea-
tinine reaches to this level. [13]
In our case studies, restoration of hepatic function was
reported in 24 patients after conversion treatment. In
spite of the presence of hepatic dysfunction resulted from
SRL as reported in our study, the mechanism may not be
similar to CNI-induced hepatic function impairment.
Besides, dose-related adverse reaction could be an essen-
tial factor, so as long as timely dose adjustment is as-
sured by giving a rational dosage which corresponds to
the desired target concentration of 6 - 10 ug/L, hepatic
damage can be reduced or even avoided. Therefore, for
some renal allograft recipients who have developed he-
patic dysfunction upon receiving CNI-based treatment,
switching to SRL may be a good choice.
In patients who’ve developed impaired glucose toler-
ance or diabetes mellitus after transplantation are suitable
for SRL conversion and withdraw from CNI at the same
time (particularly, FK506). Regardless of gradual steroid
withdrawal done before or after conversion, a series of
data have shown good results which was obtained from
our conversion treatment. In our study, 9 PTDM patients
who’d received conversion treatment achieved better
control, which could have been associated with the
elimination or reduction of CNI damage to pancreatic
islets. This prompts the use of SRL does not increase
glucose tolerance impairment in renal recipients, which
makes immunosuppressive conversion to be the best op-
tion for the treatment of certain hyperglycemic recipi-
The arise of malignant tumor during the stable phase
of post-transplantation has become an extremely promi-
nent problem, which affects graft and recipient’s long-
term survival rates. [14] The classical strategies of con-
trolling post-transplant malignancy include reducing the
dose of administrated immunosuppressive agent, or even
withdrawal. However, this could also impact immune
responses significantly, and as a result, increases the risk
of allograft impairment/loss. Conversion to SRL therapy
may, in one hand, prevent the increase of immune re-
sponse risk which brings rise to rejection; and on the
Copyright © 2011 SciRes. OJOTS
other hand, as shown from some conversion treatment
results, it has a suppressive effect on primary tumors as
well as on metastasis theoretically.
4.2. Safety of SRL Conversion
The main adverse reactions noted from SRL conversion
were hyperlipidemia, proteinuria, leucopenia, anemia
and pulmonary infection in severe cases. These manifes-
tations occurred mostly with the standard dose admini-
stration and blood trough levels (10 - 15 ug/L) recom-
mended by foreign experts, and as we know that the ad-
verse reactions are associated with its doses and concen-
tration given, by lowering SRL doses and concentration
should be able to reduce or prevent from these adverse
reactions to occur; therefore, we think that there could
possibly be differences between pharmacokinetic and
drug metabolism gene polymorphism as well as genetic
background variation in immune system between the
Western and Asian population, [15,16] i.e. similar to the
administration of cyclsporine, we must not adopt the C2
monitoring standards of European of American renal
recipients. To determine the appropriate SRL plasma-
dose concentration at variable intervals after transplanta-
tion in the Chinese population of renal transplant recipi-
ents will be the clinical research issue that requires a
solution from now on.
In conclusion, Ninety-three renal transplant recipients
were prospectively enrolled. CNIs(CsA and FK506) as
main immunosuppressant were converted to SRL im-
munosuppressant protocol.These observations support
the conversion treatment with sirolimus in renal trans-
plant recipients using the calcineurin inhibitor (CNI)
with one or more risk factors was effective and safe. At 3
years after conversion treatment, the survival rates of
patients and grafts were 90.9% and 75.8%, respectively.
The results from this clinical trial suggest the conversion
treatment with SRL and MMF may be a better option for
the renal transplant recipients using the CNI with risk
factors appeared.
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