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Received for publication: 13.10.2014; Accepted in revised form: 14.11.2014
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doi: 10.1093/ndt/gfu273
Advance Access publication 20 August 2014
Antiproteinuric effect of add-on paricalcitol in Fabry
disease patients: a prospective observational study
Antonio Pisani1, Massimo Sabbatini1, Giovanni Duro2, Paolo Colomba2 and Eleonora Riccio1
Nephrology, Department of Public Health, University Federico II, Naples, Italy and 2Institute of Biomedicine and Molecular Immunology
“A. MONROY”, National Research Council, Palermo, Italy
Correspondence and offprint requests to: Eleonora Riccio; E-mail: [email protected]
A B S T R AC T
Background. Proteinuria is the predominant risk factor for
renal disease progression in Fabry disease (FD). When urine
protein excretion is controlled to <0.50 g/24 h, the rate loss of
glomerular filtration rate (GFR) is not significantly different
from 0. However, enzyme replacement therapy (ERT) alone
does not decrease proteinuria and it has been recommended
that patients receiving ERT also receive anti-renin–angiotensin
system (RAS) therapy. Emerging evidence show that paricalcitol (PCT) reduces proteinuria in the presence of intensified
inhibition of RAS; however, there is no evidence in FD. We
evaluated the antiproteinuric effect of PCT in FD patients with
proteinuria >0.50 g/24 h persisting despite ERT and anti-RAS
therapy titrated to maximum tolerated dosage.
Methods. Fifteen FD patients were selected and studied in the
first 6 months of add-on oral PCT (1 µg/day) and, in order
to verify the dependence of proteinuria reduction on PCT,
3 months after drug withdrawal.
Results. At baseline, proteinuria was 1.3 ± 0.6 g/24 h. Six
months of add-on PCT significantly decreased proteinuria to
0.4 ± 0.3 g/24 h, with levels <0.50 g/24 h achieved in four patients at Month 1, six at Month 3, and in 12 by Month 6, in
the absence of changes to BP and GFR. Proteinuria recovered
to basal value after drug withdrawal.
© The Author 2014. Published by Oxford University Press
on behalf of ERA-EDTA. All rights reserved.
Conclusions. In conclusion, our study is the first evidence that
PCT is effective in reducing proteinuria in FD patients in the
presence of ERT and anti-RAS therapy.
Keywords: enzyme replacement therapy, Fabry disease, paricalcitol, proteinuria
INTRODUCTION
Fabry disease (FD) is an X-linked disorder caused by lysosomal α-galactosidase A deficiency, with subsequent deposition of undegraded glycosphingolipid products in multiple
organs. Progressive nephropathy is one of the main features of
FD [1]. The decline in renal function in FD is adversely affected by male gender, advanced chronic kidney disease
(CKD), hypertension and, in particular, severe proteinuria.
Studies of patients with FD have identified proteinuria as a
major risk factor for renal disease progression. Therefore treatment of proteinuria is one of the goals in management of FD
patients. When urine protein excretion is controlled to <0.50
g/24 h, the rate of loss of estimated glomerular filtration rate
(eGFR) was not significantly different from 0 [2].
Currently, enzyme replacement therapy (ERT) is the only
specific treatment for FD patients, which has been shown to
slow the progression of Fabry nephropathy [3]. However, ERT
alone does not appear to reduce proteinuria [4, 5] and it has
been recommended that patients receiving ERT also receive
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ORIGINAL ARTICLE
1
ORIGINAL ARTICLE
angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers (ACEi/ARBs). Multiple blockade of renin–
angiotensin system (RAS) allows an additional decrement of
proteinuria which is, however, still limited and heterogeneous,
with many patients being left with significant residual proteinuria [6]; therefore, novel ways of proteinuria treatment are
being studied.
Recent studies have shown broad-ranging activities of
vitamin D that extend beyond the regulation of calcium and
phosphorus metabolism mediated by vitamin D receptor [7].
These so-called non-calcemic activities include regulation of
renal and cardiovascular functions and modulation of immune
responses. Several data have shown that paricalcitol (PCT)
reduces proteinuria in several models of kidney disease, likely
through the nuclear factor κB pathway and the RAS [8–12].
However, the effects of these strategies in patients with FD
nephropathy are unknown.
The aim of our study was to evaluate the effect of PCT on
proteinuria in FD patients with proteinuria >0.5 g/24 h persisting despite the ERT and anti-RAS therapy titrated to
maximum tolerated dosage.
M AT E R I A L S A N D M E T H O D S
Study population
This is a prospective, observational study. Between December
2011 and December 2013, 49 patients with FD were seen at the
Fabry Center of the Federico II University of Naples and considered for recruitment. The inclusion criteria were: (i) genetically
proven FD, (ii) stable dose of ERT for at least 12 months, (iii)
stable dose of ACEi or ARB titrated to maximum tolerated
dosage for at least 6 months and (iv) persistent proteinuria
>0.50 g/24 h despite the use of ERT and ACEi/ARBs in two
consecutive samples within 12 weeks. Exclusion criteria were:
steroid/immunosuppressive treatment, eGFR changes >30% in
the past 3 months, parathormone (PTH) levels <20 pg/mL,
serum phosphorus >5.0 mg/dL, serum calcium (adjusted for
albumin) >10.0 mg/dL, active malignancy. On the basis of such
criteria, 15 patients were enrolled in the study and written
informed consent was obtained from all of them (Figure 1). The
study was approved by the local medic ethics committee and
was in adherence with the Declaration of Helsinki.
Study procedures
In patients identified by the inclusion criteria, data were
collected at enrolment ( prior to ACEi/ARB maximum dosage
therapy), at baseline ( prior to first administration of PCT),
during administration of oral PCT (after 1, 3 and 6 months)
and 3 months after PCT withdrawal.
At baseline, 15 FD patients were selected and studied in the
first 6 months of add-on oral PCT (1 µg/day) and, in order
to verify the dependence of proteinuria reduction on PCT,
3 months after drug withdrawal. None of the patients had received a vitamin D analogue at least 1 month before beginning
enrolment in the study.
662
F I G U R E 1 : Flow chart of patients selection.
Intensification of anti-RAS therapy
To achieve remission of proteinuria, anti-RAS therapy was
titrated during enrolment to the full dose suggested by manufacturer’s recommendations, or at the highest tolerated dose
( presence of symptomatic hypotension, acute eGFR decrease
>30% or serum potassium >5.5 mmol/L). The patients were
first administered a single anti-RAS agent (either ACEi or
ARB), opportunely titrated; if proteinuria still persisted above
the target, ACEi with ARB were combined. In case of low
blood pressure (BP) levels, antihypertensive drugs other than
anti-RAS were downtitrated or eliminated.
Add-on PCT
PCT was administered at a dosage of 1 µg/day; this dosage
was chosen as it is not associated with excessive decline of
PTH levels in most patients [9, 11].
Data collection
Demographic and clinical data were obtained at baseline
(Tables 1 and 2). At each control a complete clinical evaluation
was performed, including body weight, BP and adjustments of
therapy. Moreover, we evaluated 24-h urinary proteins, and in
venous plasma or serum the following chemistries: creatinine,
calcium, phosphate, albumin and PTH. Renal function was expressed as eGFR, calculated with Modification of Diet in Renal
Disease equation.
Standard laboratory procedures were used for blood and
urinary measurements.
Urine collections were considered inaccurate, and repeated,
if the value of measured creatinine excretion rate fell outside
the normal range.
Statistics
Variables are reported as mean and standard deviation
(SD) or as median and interquartile range. Means are
A. Pisani et al.
Table 1. Main characteristics of patients at enrolment
Age (years)
Gender (M/F)
ERT (agalsidase alfa/beta)
Body mass index (kg/m2)
Diabetes (%)
25-OH-Vitamin D (ng/mL)
eGFR (mL/min/1.73 m2)
Serum albumin (g/dL)
Proteinuria (g/24 h)
Systolic BP (mmHg)
Diastolic BP (mmHg)
Antihypertensive drugs (n)
Anti-RAS per patient (n)
42.7 ± 10.5
8/7
7/8
28.2 ± 7.4
7
22.17 ± 11.2
79.5 ± 25
4.1 ± 0.4
2.1 ± 0.6
124 ± 8
74 ± 8
1.1 ± 0.6
0.7 ± 0.5
Data are expressed as mean ± SD.
ERT, enzyme replacement therapy; eGFR, estimated glomerular filtration rate; BP, blood
pressure; Anti-RAS, angiotensin-converting enzyme or angiotensin receptor blockers.
compared by paired or unpaired Student t-test and McNemar
or chi-square test for categorical variables. ANOVA for repeated measures with Bonferroni as post hoc test are also used
where appropriate. A two-tailed P-value of <0.05 is considered
significant. Data are analysed using SPSS 20.0 (SPSS, Inc.,
Chicago, IL, USA).
Data at enrolment
We studied 15 patients identified by the inclusion criteria
(Tables 2 and 3).
At time of enrolment (9 months prior to study baseline),
the median age for the eight men and the seven women was
42.7 ± 10.5 years. Eight families with distinct mutations were
represented; the clinical manifestations were different, with
multiple organ involvement in addition to Fabry nephropathy
(Table 2). All patients were treated with a stable dose of ERT
for at least 12 months. Eight patients were treated with agalsidase beta and seven with agalsidase alfa, and the mean duration of ERT was 72.1 ± 36.8 months (median 60 months).
Most patients were on antihypertensive therapy before
Data at baseline
At baseline, the mean number of antihypertensive drugs
was 1.7 ± 0.7. The increase in number of BP lowering drugs,
observed at baseline versus enrolment visit, was due to the
larger use of anti-RAS agents. At baseline, in fact, all patients
were treated with anti-RAS therapy at full dose: nine patients
were under multiple blockade of RAS, and the remaining
six were under a single anti-RAS agent. Intensification of RAS
therapy was also obtained in these six patients administered a
single anti-RAS agent; at enrolment, in fact, these drugs were
not used in five patients or used at low dosage in the remaining
patients, while at baseline all patients were treated with RAS
blockers at full dose. In these six patients, combined therapy
was considered unfeasible because adding the second antiRAS agent had been associated with hypotension (n = 5) and
hyperkalaemia (n = 1). Intensification of RAS was associated
with a significant decrease in proteinuria (1.34 ± 0.6 mg/24 h,
P < 0.001 versus enrolment), which still remained >0.5 g/24 h,
and of BP (108/63 ± 6/4 mmHg, P < 0.001 versus enrolment),
without changes in GFR (P = 0.3) (Table 3).
Data at follow-up
As reported in Table 4, add-on PCT was associated with a
progressive decline in PTH levels that, however, did not decrease below the lower limit of normal range (20 pg/mL) in
any patient. Serum calcium and phosphate remained within
normal range in all patients (Tables 3 and 4).
Add-on PCT induced a progressive decrease of proteinuria
to 0.4 ± 0.3 g/24 h (P < 0.001) (Table 4). The individual values
at enrolment, at baseline and at the end of follow-up period
are shown in Table 3 and in Figure 2. Remission of proteinuria
to values <0.5 g/24 h was achieved in four patients at Month 1
(26.7%), six at Month 3 (40%) and in 12 at Month 6 (80%).
The mean reduction of proteinuria after 6 months of PCT was
68%. No correlation was found between percentage change in
proteinuria, BP and eGFR (r = 0.16, P = 0.34).
Table 2. Genetic and clinical characteristics of the patients at enrolment
ID
Age (gender)
Family group (mutation)
Clinical manifestations of FD
ERT (Mo)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
45 (M)
53 (F)
54 (F)
32 (M)
36 (F)
49 (M)
18 (M)
52 (F)
53 (M)
36 (F)
32 (M)
33 (M)
44 (F)
51 (F)
53 (M)
1 (c.1066C>T)
2 (p.R35W)
3 (c.901C>T)
3 (c.901C>T)
1 (c.1066C>T)
4 (p.A288D)
5 (IVS4+5G>T)
6 (c.740G>A)
4 (p.A288D)
1 (c.1066C>T)
7 (c.680G>C)
2 (p.R35W)
1 (c.1066C>T)
8 (c.1133C>G)
1 (c.1066C>T)
ACR; CKD
LVH
ANG, CKD
ACR, ANG, LVH
ACR, CKD
ACR, ANG, CAD, CKD, CVA, LVH
LVH
CAD, CKD, LVH
ACR, ANG, CAD, CVA, LVH
CAD, CKD, LVH
ACR, LVH
ACR, ANG, CW, LVH
CKD, LVH
ANG, CKD, CVA, LVH
ACR, LVH
Agalsidase alfa (61)
Agalsidase beta (20)
Agalsidase beta (108)
Agalsidase beta (108)
Agalsidase alfa (55)
Agalsidase beta (57)
Agalsidase alfa (41)
Agalsidase beta (131)
Agalsidase alfa (50)
Agalsidase alfa (60)
Agalsidase alfa (121)
Agalsidase beta (17)
Agalsidase beta (58)
Agalsidase alfa (132)
Agalsidase beta (63)
ACR, acroparesthesias; ANG, angiokeratomas; CAD, coronary artery disease; CKD, chronic kidney disease; CVA, cerebrovascular accident; CW, corneal whirls; LVH, left ventricular
hypertrophy.
Paricalcitol in Fabry disease
663
ORIGINAL ARTICLE
R E S U LT S
enrolment; the mean number of antihypertensive drugs was
1.1 ± 0.6; ACEi/ARBs, however, were not used in five patients
or used at low dosage in the remaining 10 patients (Table 3).
Table 3. Individual modifications of proteinuria, glomerular filtration rate (eGFR), use of angiotensin-converting-enzyme inhibitor (ACEi), angiotensin
receptor blocker (ARB) and blood pressure (BP) during the different phases of the study
ID Enrolment
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
a
Baseline
Final visit
Withdrawal
Proteinuria
(g/24 h)
eGFR
(mL/
min)
BP
Antihypertensive
(mmHg) drugsa (ACEi/
ARBs)
Proteinuria
(g/24 h)
eGFR
(mL/
min)
BP
Proteinuria
(mmHg) (g/24 h)
eGFR
(mL/
min)
BP
Proteinuria
(mmHg) (g/24 h)
eGFR
(mL/
min)
BP
(mmHg)
2.1
2.4
1.4
2.7
0.7
2.5
1.4
2.1
1.9
2.3
2.3
1.7
1.7
3.6
2.5
73
90
52
101
68
61
135
70
96
69
93
105
50
34
95
120/80
120/70
120/80
130/80
100/60
130/80
125/80
130/80
135/80
120/60
120/70
130/70
120/60
130/70
130/85
1.2
1.6
0.6
2
0.8
2
0.6
1.3
1.3
1.4
1.4
0.9
0.9
2.8
1.3
70
93
50
104
67
60
138
68
94
69
92
103
48
34
94
110/70
110/60
105/70
115/70
100/60
120/65
110/70
110/70
115/60
105/55
100/60
110/55
100/50
115/60
120/70
70
91
51
106
67
61
137
67
93
68
90
103
51
36
93
100/65
110/65
100/65
115/70
105/65
120/60
100/65
110/65
110/60
110/55
100/70
105/60
105/60
115/60
115/65
68
91
50
104
67
63
137
66
94
68
91
105
50
35
93
105/70
110/65
105/65
110/70
100/65
120/65
115/70
110/60
105/65
110/60
100/70
100/55
100/60
120/60
120/65
2 (2)
1 (1)
2 (2)
1 (1)
1 (1)
3 (2)
1 (1)
2 (2)
2 (2)
2 (2)
1 (1)
2 (2)
3 (2)
2 (2)
1 (1)
0.4
0.6
0
1
0
0.4
0.2
0.5
0.3
0.4
0.5
0.2
0.2
1
0.4
1.1
2
0.6
1.8
0.8
1.9
0.6
1.2
1.1
1.3
1.4
1
1
2.4
1.4
Numbers in brackets refer to number of ACEi and/or ARBs at patients’ highest tolerated doses.
ORIGINAL ARTICLE
Table 4. Overall changes of main clinical and laboratory data before PCT treatment (enrolment, baseline), during PCT treatment (Month 1–6) and 3
months after PCT withdrawal
SBP/DBP (mmHg)
eGFR (mL/min/1.73 m2)
PTH (pg/mL)
ALP (U/L)
Serum calcium (mg/dL)
Serum phosphorus (mg/dL)
Proteinuria (g/24 h)
Enrolment
Baseline
Month 1
Month 3
Month 6
Withdrawal
124 ± 8/74 ± 8
79.5 ± 25
74 ± 21
85 ± 33
9.2 ± 0.7
3.9 ± 0.6
2.1 ± 0.6
110 ± 6/63 ± 6b
78.9 ± 26
72 ± 25
84 ± 31
9.3 ± 0.6
3.9 ± 0.7
1.3 ± 0.6b
112 ± 9/64 ± 7
79.2 ± 25.4
67 ± 22a
77 ± 35
9.3 ± 0.6
3.9 ± 0.8
0.9 ± 0.4a
110 ± 9/64 ± 8
78.7 ± 24.2
54 ± 21a
73 ± 21
9.4 ± 0.5
4.0 ± 0.7
0.7 ± 0.4a
108 ± 6/63 ± 4
78.9 ± 25.2
45 ± 19a
67 ± 17
9.4 ± 0.4
4.0 ± 0.7
0.4 ± 0.3a
109 ± 7/64 ± 4
78.8 ± 25.6
61 ± 23a
71 ± 19
9.4 ± 0.3
4.0 ± 0.7
1.3 ± 0.5
Data are expressed as means ± SD.
SBP/DBP, systolic/diastolic blood pressure; eGFR, estimated glomerular filtration rate; PTH, parathormone; ALP, alkaline phosphatase.
a
Significantly different versus baseline (P < 0.05, minimum value).
b
Significantly different versus enrolment (P < 0.05, minimum value).
The first dose of PCT (1 µg/day) did not change throughout
the 6 months of follow-up in all the patients.
Data after PCT withdrawal
To verify the dependence of proteinuria reduction on PCT,
we evaluated the change of proteinuria 3 months after drug
withdrawal. In all the patients, proteinuria recovered to baseline (Tables 3 and 4 and Figures 2 and 3).
DISCUSSION
This study has shown that treatment with 1 µg PCT significantly reduces proteinuria in patients with FD nephropathy
who were on a stable dose of ACEi and/or ARBs titrated to
maximum tolerated dosage.
Early observational studies of vitamin D supplementation
in patients have indicated the capacity of activators of the
vitamin D receptor (VDRA) to decrease proteinuria (range
17–61%) in a number of kidney disease, irrespective of the
level of renal insufficiency (stage 2–5), of its primary diagnosis
664
and of the previous or concomitant use of anti-RAS agents
[8–12]. Of note, higher doses of PCT (2 versus 1 µg/day) in
diabetic CKD patients further decreased urinary protein excretion with no additional metabolic or clinical side effects, suggesting the possibility of safely increasing PCT doses, if
needed.
However, the exact effect of PCT in patients with FD nephropathy was undefined. The presence of proteinuria >0.5
g/24 h identifies a subgroup of FD patients which carries the
highest risk of renal disease progression. In these patients,
minimizing RAS activity is a main target of treatment. Moreover, recent evidence highlighted the very high prevalence
of vitamin D insufficiency and deficiency in FD patients
[13]. In fact, due to symptoms such as heat intolerance and
the inability to sweat, Fabry patients tend to avoid sunlight
exposure. Often, patients also suffer from malabsorptive
gastrointestinal disease. Both conditions may contribute to a
deficiency in vitamin D. It has been recently evidenced,
moreover, that vitamin D deficiency is strongly associated
with cardiomyopathy and adverse clinical symptoms in FD
patients [14].
A. Pisani et al.
F I G U R E 2 : Proteinuria levels for individual patients at enrolment,
before (baseline), after 1-, 3- and 6-month add-on PCT (T1, T3 and
T6, respectively), and after 3-month drug withdrawal. Each patient is
shown as an individual regression line.
evidence that low-dose PCT, given in the absence of exogenous
calcium loading, is not associated to excessive suppression of
bone turnover [19].
Interpretation of results is limited by the small sample size
and the absence of control group; nevertheless, the remarkable
antiproteinuric response and the recovery of proteinuria to
baseline after 3 months of drug withdrawal support the validity of our observations. Regarding the recovery of proteinuria
after drug withdrawal, however, we cannot exclude some
degree of escape of proteinuria which is not an uncommon
finding when inhibition of RAS is intensified [20, 21]. Furthermore, more prolonged follow-up is required to verify efficacy
and safety of this approach over the long term. Finally, we did
not assess systemic RAS activity.
In conclusion, our study suggests that, in patients with FD
and persisting proteinuria despite ERT and maximal tolerated
anti-RAS therapy, add-on PCT safely allows a reduction of
proteinuria with a remarkable achievement of levels <0.5 g/24 h
in more than two-thirds of cases. PCT therefore represents a
potential additional therapeutic option to be considered when
intensified anti-RAS treatment is not completely efficacious or
unfeasible because of adverse effects. Whether the antiproteinuric effect of PCT translates into improvement of prognosis
of these high-risk patients is worth investigating.
None declared.
F I G U R E 3 : Proteinuria levels measured in patients before
(baseline), after add-on PCT (Month 6), and after 3-month drug
withdrawal. Data are mean ± SD.
VDRAs appear to mediate antiproteinuric effects by several
mechanisms. First, in cultured human podocytes, VDRA prevented lyso-Gb-3-induced, TGFβ1-mediated, up-regulation of
extracellular matrix proteins [15]. Experimental studies have
shown that vitamin D acts as a strong negative endocrine
regulator of the RAS and functions mainly to suppress renin
production [14]. Therefore, the effects on RAS inhibition represent an important target in the treatment of patients with
FD nephropathy. Nonetheless, our data show that RAS inhibition in our patients was not optimal, since its maximization
determined a significant decrease in urinary protein excretion;
this strongly suggests that medical intervention in these patients should be more aggressive.
Another important conclusion of our study is that PCT
does not affect BP; this means that the reduction of proteinuria
is not BP dependent.
The significant antiproteinuric effect of PCT was not impaired by major adverse effects, thus extending to this subgroup of high-risk and poly-treated patients the favourable
safety profile of PCT previously reported [8–12, 16–18]. PTH
and alkaline phosphatase (ALP) remained in the normal range
in most patients. This finding supports the experimental
Paricalcitol in Fabry disease
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