Download Conversion from calcineurin inhibitors to sirolimus in chronic

Nephrol Dial Transplant (2006) 21: 488–493
doi:10.1093/ndt/gfi266
Advance Access publication 9 November 2005
Original Article
Conversion from calcineurin inhibitors to sirolimus in
chronic allograft dysfunction: changes in glomerular
haemodynamics and proteinuria
Anna Saurina1, Josep M. Campistol2, Carlos Piera3, Fritz Diekmann2, Begoña Campos4,
Nieves Campos3, Xavier de las Cuevas1 and Federico Oppenheimer2
1
Nephrology Department, Hospital de Terrassa, 2Renal Transplant Unit, Hospital Clı́nic de Barcelona,
Nuclear Medicine Department, Hospital Clı́nic de Barcelona and 4Statistics Department,
Universitat de Barcelona, Spain
3
Abstract
Background. The study was conducted in order to
describe possible intraglomerular haemodynamic
changes inducing proteinuria after 14 patients with
chronic allograft dysfunction were converted from
calcineurin inhibitors (CIs) to sirolimus without changing concomitant immunosuppression or antihypertensive treatment.
Methods. Creatinine, glomerular filtration rate (GFR),
proteinuria, renal functional reserve (RFR) and
effective renal plasma flow (ERPF) were determined
before and 8 months after conversion. Intraglomerular
pressure (PG), afferent arteriolar resistance (AAR) and
efferent arteriolar resistance (EAR) were calculated
using Gomez’s formula.
Results. Creatinine (1.97 vs 2.075 mg/dl; P ¼ 0.270)
and GFR (40 vs 43 ml/min; P ¼ 0.505) remained
unchanged, proteinuria increased (338 vs 1146 mg/
24 h; P ¼ 0.006), RFR decreased (34.84 vs 13.47%;
P ¼ 0.019), ERPF (248 vs 310.6 ml/min; P ¼ 0.0625)
and PG (42.72 vs 46.17 mmHg; P ¼ 0.0625) tendentially
increased and AAR tendentially decreased (14.12 vs
10.28 dyne/s/cm5; P ¼ 0.0625).
Conclusion. After conversion, PG shows a tendency to
increase and RFR decreases significantly—characteristics of hyperfiltration, which could possibly partially
explain the increase of proteinuria. Therefore, the application of angiotensin-converting enzyme inhibitors or
angiotensin II receptor blockers seems promising. To
avoid hyperfiltration, conversion should be performed
early when renal insufficiency is still moderate.
Correspondence and offprint requests to: Josep M. Campistol,
Unidad de Trasplante Renal, Hospital Clı́nic, Villarroel 170,
E-08036 Barcelona, Spain. Email: [email protected]
Keywords: calcineurin inhibitors; CAD; hyperfiltration;
proteinuria; sirolimus
Introduction
The clinical phenomenon of chronic allograft dysfunction (CAD) most often finds its histopathologic
correlate in chronic allograft nephropathy (CAN) as
defined by the BANFF 97 classification. CAN is the
most prevalent cause of late transplant failure [1] and is
characterized by a slow loss of renal function often in
combination with proteinuria and hypertension. None
of the clinical manifestations are specific and other
causes of graft dysfunction such as acute rejection, drug
toxicity or other glomerulopathies must be excluded to
diagnose CAN [2]. Although several risk factors have
been implicated, the pathophysiology and aetiology of
CAN are not completely understood. Both immunological and non-immunological factors play a role in
the development of CAN. With the introduction of
calcineurin inhibitors (CIs) in the early 1980s, the
incidence of acute rejection episodes decreased, and
1-year survival improved. However, the rate of loss of
renal function in long-term kidney transplant patients
>1 year after transplantation has not significantly
changed over the past decades [1]. CI therapy can cause
functional and histological renal impairment and has
been suggested to be an important cause of the
development of CAN [1,3]. The use of these agents at
therapeutic doses, sufficient to prevent allograft rejection, generally reduces the glomerular filtration rate
(GFR) by 15–25% and may lead to tubulointerstitial
fibrosis. A recent publication by Nankivell et al.
demonstrated that CI nephrotoxicity is increasingly
prevalent and is even virtually universal 10 years after
ß The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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Proteinuria after conversion from calcineurin inhibitors to sirolimus
transplantation. Despite slight to moderate reductions
in CI doses, the nephrotoxicity is progressive and is the
chief cause of late histological injury and ongoing
decline of renal function [3].
Sirolimus (SRL) is a new agent with lymphocytespecific features similar to those of CIs but with a
different mechanism of action and side effect profile.
SRL does not appear to be nephrotoxic and might
protect against chronic rejection and graft vascular
disease. The ability of SRL to inhibit cytokine- and
growth factor-stimulated proliferation of non-immune
cells appears to account for the effects observed in
animals. Given the proliferative processes predominant
in chronic rejection, the inhibitory effects of SRL might
be useful in preventing chronic rejection.
In 1983, Bosch and colleagues [4] demonstrated that
GFR is submaximal under normal conditions and
that the difference between the baseline value and the
maximum value after protein load represents the
so-called ‘renal functional reserve’ (RFR). The RFR
is directly correlated with the number of properly
functioning glomeruli and inversely correlated with the
number of destroyed glomeruli, and represents the
capacity of the kidney to increase its level of activity
under demanding conditions.
Several studies of conversion from CI-based to SRLbased immunosuppression in patients with CAD have
demonstrated that conversion improves renal function.
However, in some patients, conversion is associated
with a significant increase of proteinuria [5,6]. The exact
aetiology of proteinuria is not completely known,
but haemodynamic changes may play a significant
causative role.
The aim of this study was to describe and investigate
if substitution of CI with SRL in renal transplant
patients with CAD induces changes in glomerular
haemodynamics that can explain the increase of urinary
protein excretion often accompanied by CI withdrawal
and introduction of SRL.
Patients and methods
Patients
Fourteen renal transplant patients were included in our study
>1 year after renal transplantation. All patients were treated
with CIs and had clinical signs of CAD. In all patients, a
transplant biopsy was scheduled to confirm the diagnosis
histologically. In six patients, transplant biopsies could be
performed, all of them showing signs of CAN. Four patients
were classified as Banff grade I, and the remaining two
patients were classified as Banff grade II and III, respectively.
Inclusion criteria were: transplantation performed >1 year
previously, moderate renal insufficiency (creatinine level:
1.5–2.5 mg/dl) without an increase of >25% in the previous
year, and proteinuria <1.5 g/24 h. Patients with other
causes of renal dysfunction, diabetes or hypertension
due to renal artery stenosis were excluded from the
study. All patients provided written informed consent,
and the ethics committee of our hospital approved the
protocol.
489
Study design
Serum creatinine, proteinuria/24 h, effective renal plasma
flow (ERPF) and GFR before and after a protein infusion to
calculate RFR were determined. After these studies, the CI
was withdrawn in all patients and was replaced with SRL.
Co-adjuvant immunosuppressive treatment was maintained
throughout the study period. On day 1 of conversion, SRL
was introduced at a dose of 2 mg/day and changed according
to SRL target trough concentrations of 8–12 ng/ml.
Simultaneously, the CI dose was reduced by 50%. After
achieving the SRL target trough concentration, CIs were
progressively eliminated within 6 weeks. Eight months after
withdrawal of CIs, the above-mentioned studies were
repeated. In order to study proteinuria, the mean of three
independent measurements separated by 4 weeks each both
before and after conversion was calculated. In order to avoid
other influences on glomerular haemodynamics, no changes
were made to baseline antihypertensive treatment nor
angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) treatment during the study
period.
Measurement methods
Measurements of serum creatinine, total protein (TP),
haematocrit (Hct), 24 h proteinuria and urine electrophoresis
were performed by routine techniques.
SRL blood trough concentrations were measured using a
high-performance liquid chromatography assay with double
mass spectrometry.
GFR and ERPF were studied using the open bicompartmental method of Sapirstein and Blaufox [7] with
[99mTc]DTPA and [131I]orthoiodohippurate, respectively.
After 48 h, GFR was determined again during an amino
acid infusion (Aminoplasmal L-10 without electrolytes, B.
Braun Medical SA, Rubı́, Barcelona). To study RFR, saline
alone was administered intravenously during the first hour
to compensate for osmotic diuresis after the beginning of the
amino acid infusion. In the second hour, the amino acid
infusion was started at 4.5 mg/kg/min and the application
of intravenous saline was maintained at 20% of the total
volume/h of amino acid infusion. The volume of saline
infusion during the first hour is the total saline and amino
acid volume of 1 h. At the beginning of the third hour,
we started the study of GFR and ERPF with infusion of
[99mTc]DTPA and [131I]orthoiodohippurate.
Gomez’s equations were used to calculate glomerular
hydrostatic pressure (PG), afferent arteriolar resistance
(AAR) and efferent arteriolar resistance (EAR) [8]. The
filtration coefficient (KFG) of glomerular capillaries was
assumed to be 0.0812 (ml/s)/mmHg and the PG in
Bowman’s space (HT) to be 10 mmHg. Measurements such
as mean arterial pressure (MAP), GFR, ERPF, renal blood
flow (RBF), Hct and TP were used to estimate the intrarenal
haemodynamics quantitatively. RBF was calculated as RBF
(ml/min) ¼ ERPF/(1 – Hct). The filtration fraction (FF) was
calculated as FF ¼ (GFR/ERPF) 100.
Statistical analysis
Values before and after conversion were compared with a
Wilcoxon signed rank test. SPSSÕ (version11) software was
used to make the calculations. Asymptomatic P-values <0.05
490
A. Saurina et al.
Table 1. Patients
Age Sex Aetiology of renal disease
Transplant Origin
Time after transplantation Treatment before
(months)
conversion
Follow-up
32
44
55
56
55
72
31
47
66
30
68
67
34
42
Second
First
First
First
First
First
First
First
First
First
First
First
First
First
78
50
92
25
145
78
204
175
103
94
162
84
101
192
Yes
Yes
Yes
Yes
Yes
Yes
Lost
Yes
Yes
Lost
Yes
Yes
Yes
Yes
M
F
M
F
F
M
F
M
M
M
M
F
M
F
Unknown
FSGN
Unknown
Chronic GN
Interstitial nephropathy
IgA nephropathy
Membranoproliferative GN
Unknown
Nephroangiosclerosis
Membranoproliferative GN
Nephroangiosclerosis
FSGN
IgA nephropathy
Unknown
Cadaveric
Cadaveric
Cadaveric
Cadaveric
Cadaveric
Cadaveric
Living donor
Cadaveric
Cadaveric
Cadaveric
Cadaveric
Cadaveric
Cadaveric
Cadaveric
CsA þ AZA þ steroids
Tacrolimus þ MMF þ steroids
CsA
Tacrolimus þ MMF þ steroids
CsA
CsA
CsA
CsA þ steroids
CsA
CsA
CsA
CsA þ steroids
CsA þ AZA
CsA
AZA ¼ azathioprin; CsA ¼ cyclosporin A; MMF ¼ mycophenolate mofetil; FSGN ¼ focal segmentary glomerulonephritis; GN ¼
glomerulonephritis.
were considered to be significant, except in the case of n<6
where an alpha error of <10% was applied according to
critical values tables [9]. All analyses of significance were
based on a two-tailed distribution.
GFR (mL/min)
80
p=n.s.
Proteinuria (mg/day)
2500
RFR (%)
p=0.006
p=0.019
60
2000
Results
60
1500
Fourteen kidney transplant recipients were included in
this study, but only 12 completed it: one patient decided
to terminate SRL treatment due to clinical intolerance
and another presented a rapid decline of renal function
and lost the graft before the end of the study (Table 1).
Of the 12 patients who finished the study, there
were seven men and five women aged between 32
and 72 years. All patients received a cadaveric
graft. The follow-up period after transplantation was
25–192 months (mean: 107 months). All patients
had been treated with CIs before conversion to SRL
(Table 1).
Renal function
No significant differences were found in serum creatinine before and after conversion (1.97 vs 2.075 mg/dl;
P ¼ 0.270). GFR showed a slight but non-significant
increase (40 vs 43 ml/min; P ¼ 0.505). The results of
renal function are shown in Figure 1. After withdrawal of CI and the introduction of SRL, proteinuria
increased significantly (338 vs 1146 mg/24 h; P ¼ 0.006)
and RFR decreased significantly (34.84 vs 13.47%;
P ¼ 0.019).
Urine electrophoresis was performed after conversion in five patients. In these patients, mean total urinary protein excretion was 1621±758 mg/day and
mean albumin excretion 1304±800 mg/day (76%).
Mean percentages in the a1, a2, b and g fractions
were 3.98, 2.94, 7.22 and 9.88%, respectively; the
IgG/albumin ratio was 0.15. This corresponds to
proteinuria of a predominantly glomerular source.
40
40
1000
20
20
500
0
0
0
before conversion
after conversion
Fig. 1. This figure depicts functional parameters (n ¼ 12). The
glomerular filtration rate (GFR) remained unchanged after
conversion from calcineurin inhibitor to sirolimus. However, after
conversion, proteinuria significantly increased while renal functional reserve (RFR) significantly decreased.
Haemodynamic data
The results of functional studies are shown in Figure 2.
Data on intrarenal haemodynamics were obtained in
five patients. ERPF (248 vs 310.6 ml/min; P ¼ 0.0625)
and RBF (337.71 vs 455.63 ml/min; P ¼ 0.0625) are
suggestive of an increase after conversion. A tendency
towards a decrease of AAR was observed (14.12 vs
10.28 dyne/s/cm5; P ¼ 0.0625), whereas EAR remained
unchanged (1.83 vs 1.84 dyne/s/cm, P ¼ 0.68), leading
to a trend towards an increase in PG (42.72 vs
46.17 mmHg; P ¼ 0.0625). Furthermore, the filtration
fraction (FF) also remained unchanged (14.65 before vs
14.80 after conversion; P ¼ 0.686).
Proteinuria after conversion from calcineurin inhibitors to sirolimus
RBF (ml/min)
600
GP (mm Hg)
p=0.0625
p=0.0625
50
AAR
491
(dyne.sec.cm-5)
18
p=0.0625
EAR
3
(dyne.sec.cm-5)
p=n.s.
16
14
500
40
12
2
400
30
300
8
20
200
100
10
10
6
1
4
2
0
0
0
0
before conversion
after conversion
Fig. 2. Haemodynamic parameters (n ¼ 5). After conversion, afferent arterial resistance (AAR) significantly decreased, leading to a
significant increase in renal blood flow (RBF) and intraglomerular pressure (GP). Efferent arteriolar resistance (EAR) remained
unchanged.
SRL trough concentrations after conversion
The mean SRL trough concentration 8 months after
conversion was 9.59±3.58 ng/ml.
Safety profile
Analysis of MAP before and after conversion showed
no differences during the study period (98±5 before vs
96±7 mmHg after conversion; P ¼ 0.9). The systolic
(135±9 vs 136±7 mmHg; P ¼ 0.9) and the diastolic
pressure (80±7 vs 76±9 mmHg; P ¼ 0.2) did not show
any differences. Five patients were treated with an
ARB, three with an ACEI. During the study period, no
changes of ACEI or ARB, or any other antihypertensive treatment were made. There was no correlation
between ACEI or ARB treatment on the one hand and
increase in proteinuria or change of RFR on the other
hand. After withdrawal of CI, plasmatic lipid levels
(cholesterol and triglycerides) increased (cholesterol,
176.5 mg/dl before vs 228.83 mg/dl after conversion;
P ¼ 0.0001; triglycerides, 124.5 mg/dl before vs
176 mg/dl after conversion; P ¼ 0.019), but only two
patients required addition of a new lipid-lowering
agent. The Hct level decreased non-significantly
(33.4 vs 30.5% before and after conversion, respectively; P ¼ 0.088), and five patients started treatment
with darbepoetin.
Discussion
This is the first study that describes a loss of renal
functional reserve and possible haemodynamic changes
simultaneously with the increase of urinary protein
excretion that accompanies the conversion from CI to
SRL treatment in patients with CAD. This suggests
these changes to be a possible pathophysiological factor
contributing to an increase of proteinuria in these
patients. The changes have the potential to explain at
least partially the increase of proteinuria after conversion in these patients.
Although our study lacks the proof due to failure of
achieving allograft biopsies in the majority of patients,
we assume that chronic graft dysfunction in our
patients is closely linked with the histological changes
proprietary to CAN. Recently, in a not perfectly
comparable, but similar group of patients with CAD
(n ¼ 59, all with graft biopsies), we could show that all
but one had signs of CAN [6]. The causes of the
development of CAN are multifactorial, immunological and non-immunological. CI-related nephrotoxicity
is one of the major causes. In a recent article, Nankivell
and colleagues [3] describe the natural course of CAN.
In this study, nephrotoxicity, implicated in late ongoing
injury, was almost universal after 10 years [3].
As early as 1981, Hostetter and colleagues showed
that reduced nephron mass in rats was associated with
hyperfiltration [10]. In a recent study, Estorch and
colleagues [11] showed that hyperfiltration is prevalent
in a considerable number of transplant patients, is
associated with proteinuria and can be measured using
[51Cr]EDTA and o-[131I]iodohippurate. It is already
known that hyperfiltration in association with proteinuria is seen in chronic graft dysfunction and acts as an
additional progression factor [12].
Conversion from CI to SRL was accompanied by an
increase of urinary protein excretion without significant
changes of serum creatinine or GFR. An increase of
proteinuria in conversion patients with CAN has also
492
been observed in other studies in adult patients who
were converted for CAD, as well as in paediatric kidney
transplant patients converted as part of a rescue
therapy [6,13]. Butani describes that his patients react
favourably to ARB treatment. The present study shows
that the change from CI to SRL with a consequent
increase of urinary protein excretion is associated with
a significant decrease of RFR. Loss of RFR with
maintained GFR is observed in states of glomerular
hyperfiltration. In order to investigate whether loss of
RFR was accompanied by changes of glomerular
haemodynamics ERPF, RBF and PG were determined
and demonstrated to have a tendency to increase after
conversion, whereas AAR decreased. This corresponds
to the characteristics of hyperfiltration in the remnant
kidney mass model described by Hostetter and colleagues [10]. Cyclosporin produces vasoconstriction in the
afferent glomerular arteriole, which increases AAR.
The observed decrease of AAR and increase in PG and
RBF can be attributed to CI withdrawal. As already
stated, CAN patients have reduced functional nephron
mass and severe glomerular and tubulointerstitial
damage. If AAR decreases in this pathophysiological
condition, then PG increases, leading to hyperfiltration
and increased urinary protein excretion. Urinary
electrophoresis data collected post-conversion suggest
that the proteinuria in our patients is of predominantly
glomerular origin. An observational study by Ruiz
et al. confirms that the proteinuria observed after
conversion from CI to SRL is glomerular, which also
supports the concept of its glomerular and possibly
haemodynamic origin [14].
The therapeutic benefits of CI (cyclosporin and
tacrolimus) are limited by acute and chronic nephrotoxicity. Whereas CI treatment for the prevention of
rejection alters glomerular haemodynamics and leads to
fibrosis and scarring, SRL has a different mechanism of
action and exhibits antiproliferative properties [15]
without deleterious effects on GFR or RBF [16,17].
Therefore, conversion to SRL treatment is a promising
concept in patients with CAD and CI treatment, as
shown in a previous study by our group [6], which
demonstrated that conversion is only successful in
terms of stabilized or improved renal function after
1 year in patients with moderate renal insufficiency
and low proteinuria at the time of conversion as a
parameter for the degree of structural damage.
Therefore, cautious evaluation of patients is required.
The data that were collected in this study do not allow
any conclusion on the clinical benefit of conversion for
the patients reported here. However, long-term outcome beyond 3 years after conversion has not become
available yet. Thus, it still remains a field for future
studies to determine if short-term improvement of renal
function also translates into the long-term benefit of
improved graft survival.
The study is limited by the fact that direct
haemodynamic data are only available in five patients,
which renders careful statistical evaluation difficult.
However, the data on RFR—available in all patients
that completed the study—also support the concept of
A. Saurina et al.
haemodynamic changes. This study was not designed to
evaluate the influence of ACEIs or ARBs on the process
of proteinuria in conversion patients. This needs to
be determined in another study.
The study design does not permit the gathering of
long-term data in a large number of patients in order to
study the overall safety of conversion to SRL. A large
international conversion study is under way and will be
published shortly.
This study was not designed to exclude that other
pathophysiological mechanisms contribute to SRLassociated proteinuria. There are experimental as well
as clinical data showing that high lipid levels might be
associated with the development or progression
of proteinuria [18,19]. Thus, a potential influence of
SRL-induced hyperlipidaemia on proteinuria cannot be
excluded.
In conclusion, the present study describes an
association between conversion from CI to SRL treatment in patients with CAD and possible haemodynamic glomerular changes. These changes could explain
hyperfiltration and a certain increase in proteinuria
after CI withdrawal in patients with CAD. We suggest
that—at least until further evidence is available—
conversion be performed early and with extreme
caution in patients with CAD and pre-existing proteinuria, when glomerular and tubulointerstitial damage is
still limited, in order to avoid hyperfiltration, increase
of urinary protein excretion and further decline of renal
function.
Acknowledgements. This study was partially financed by ‘Redes
Tematicas de Investigación cooperativa: V-2003-REDC03’ and by
‘Marató TV3 TV 3610’.
Conflict of interest statement. None declared.
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Received for publication: 3.3.05
Accepted in revised form: 17.10.05