Download Effects of calcium channel blockers on renal function, advanced

Effects of calcium channel blockers on renal function, advanced
glycation end products (AGEs) and soluble receptor for AGEs in
diabetic nephropathy
Yoshiko Sakamoto, MD1, Nobuharu Fujiwara, MD 1, 2, Tsukasa Nakamura, MD 1, 2,
Masayoshi Takeuchi, PhD3,Kazuhisa Kodama, MD 1, Yutaka Hikichi, MD1,
Jun-ichi Oyama, MD1, Sho-ichi Yamagishi, MD 4, Koichi Node, MD 1
1 Department of Cardiovascular Medicine, Saga University, Saga, Japan
2 Division of Nephrology, Department of Internal Medicine, Shinmatsudo Central General
Hospital, Matsudo, Chiba, Japan
3 Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical
University, Japan
4 Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications,
Kurume University School of Medicine, Kurume, Japan
Address for correspondence: Koichi Node, MD
Department of Cardiovascular Medicine, Saga University
5-1-1 Nabeshima, Saga 849-8501, Japan
Tel: +81-952-34-2364
Fax: +81-952-34-2089
E-mail:[email protected]
Short title: Renoprotection: Benidipine versus amlodipine
Source of support: none
We certify that there is no conflict of interest with any financial organization regarding the
material discussed in the manuscript.
Abstract
Objectives: This study was designed to compare the effects of the calcium channel blockers
(CCBs), benidipine and amlodipine, on renal function, advanced glycation end products
(AGEs) and the soluble receptor for AGE (RAGE) in patients with diabetic nephropathy
associated with hypertension and microalbuminuria.
Methods: Sixty patients who had been treated with angiotensin II receptor blockers (ARBs)
were assigned randomly to also receive either amlodipine 5 mg/day (n=30) or benidipine 8
mg/day (n=30). Urinary albumin excretion (UAE), urinary liver-type fatty acid binding
protein (L-FABP), serum AGEs, and serum soluble RAGEs were measured before and after
12 months of treatment.
Results: Prior to CCB therapy, serum AGEs (R=0.814, p<0.001) and soluble RAGEs
(R=0.696, p<0.001) correlated with urinary L-FABP, while serum RAGEs correlated with
serum AGEs (R=0.887, p<0.001). In addition, serum AGEs (R=0.892, p<0.001) and serum
RAGEs (R=0.787, p<0.001) correlated with UAE. After 12 months of treatment, systolic
and diastolic blood pressures showed similar reductions in the two groups. Serum
creatinine and estimated glomerular filtration rate (eGFR) showed no changes throughout
the study period. Benidipine caused a significant reduction in UAE (p<0.001), urinary
L-FABP (p<0.001), serum AGEs (p<0.001) and soluble RAGE (p<0.001), whereas
amlodipine did not.
Conclusions: These results suggested that L-FABP and the AGE/RAGE system are
associated with progression of diabetic nephropathy, and that the addition of benidipine, but
not of amlodipine, to an ARB ameliorated UAE, L-FABP and the AGE/RAGE system in
hypertensive patients with diabetic nephropathy.
Key words: chronic kidney disease, diabetic nephropathy, calcium channel blockers,
advanced glycation end products, soluble receptor for advanced glycation end products
Introduction
Although it has been established that angiotensin converting enzyme inhibitors (ACEIs)
and angiotensin receptor blockers (ARBs) reduce proteinuria/albuminuria and suppress the
reduction in glomerular filtration rate (GFR) in patients with diabetic nephropathy, the
renoprotective effects of calcium channel blockers (CCBs) remain to be established.
Kumagai et al. (2) reported that the L-type CCB, amlodipine, had very similar effects on
renal function to those of ACEIs, while Peng et al. (3) demonstrated that benidipine, an
inhibitor of T-type as well as L- and N-type calcium channels (1), caused an equivalent
reduction in proteinuria as the ARB, valsartan, in hypertensive patients with protein
excretion of 1-3 g/day. Several investigators have reported that benidipine has greater
beneficial effects than amlodipine on renal function in patients with either essential
hypertension (4) or chronic kidney disease (CKD) (5). These findings suggest that
benidipine may have potential benefits as an antihypertensive drug with a reno-protective
effect. However, only a few studies have compared the effects of benidipine and
amlodipine on renal function in patients with diabetic nephropathy, including urinary
albumin excretion (UAE) and urinary levels of liver-type fatty-acid binding protein
(L-FABP).
Advanced glycation end products (AGEs) are thought to be involved in the pathogenesis of
diabetic nephropathy as a consequence of multifactorial mechanisms such as oxidative
stress and overproduction of various cytokines (6). AGEs are heterogeneous sugar-derived
proteins which accumulate in the glomerular basement membrane, mesangial cells, and
podocytes in diabetic patients (6). Inhibition of AGE formation, blockade of the interaction
between AGEs and the receptor for AGE (RAGE) and suppression of RAGE expression or
its downstream pathways may therefore serve as therapeutic targets for treatment of
vascular complications in diabetes (7). Matsui et al. (8) suggested that blockade of the renin
angiotensin system (RAS) by ARBs may have a protective role against tubular injury in
diabetes by attenuating the deleterious effects of AGEs via down-regulation of RAGE.
However, the effects of CCBs on the AGE/RAGE axis in patients with diabetic
nephropathy are not well known.
In this study, we compared the effects of benidipine and amlodipine on renal function and
the AGE/RAGE axis in patients with diabetic nephropathy with microalbuminuria.
Patients and Methods
Patients
We enrolled 60 patients with diabetic nephropathy complicated by microalbuminuria and
poorly controlled hypertension despite receiving the maximum dose of ARBs. The patients
had a high systolic (>130 mmHg) and/or diastolic (>80 mmHg) blood pressure measured
on 2 different days within 4 weeks of the start of the study (9). Diabetic nephropathy was
diagnosed clinically as persistent microalbuminuria (20-200 g/min) in at least 2 of 3
consecutive 24-h urine samples in patients with diabetic retinopathy, but without kidney or
urinary tract diseases. In patients with no signs of retinopathy, a kidney biopsy was required
for the diagnosis of diabetic nephropathy (10). Exclusion criteria in the study were age
younger than 20 years and older than 70 years, renal impairment (serum creatinine >1.2
mg/dL for women or >1.5 mg/dL for men), valvular heart disease, chronic lung disease,
liver disease, collagen disease, recent stroke or myocardial infarction (within 1 year), or a
clinical contra-indication to CCBs.
Study design
The patients were assigned randomly to two groups in a blinded fashion to receive either
amlodipine 5 mg/day or benidipine 8 mg/day. These are the daily standard doses of both
agents approved in Japan (11). Any other anti-hypertensive therapy could be added during
the study in order to attain a blood pressure of < 130/80 mmHg, including alpha-blockers
and diuretics, but not ACEIs, other ARBs, or other CCBs. The doses of these extra drugs
were not changed during the study period. Table 1 summarizes the clinical and laboratory
findings of the subjects. Treatment with the CCBs was continued for 12 months, with
clinical and laboratory parameters being investigated every 3 months. The local ethical
committee approved the study protocol, and written, informed consent was obtained from
each patient at the start of the study.
Measurements
Blood pressure was measured 3 times with the patient in the sitting position, after 10 min of
rest, and the average blood pressure used in the analyses. Serum creatinine, HbA1c,
LDL-cholesterol, HDL-cholesterol, triglycerides, uric acid, and urinary creatinine were also
measured. The estimated glomerular filtration rate (eGFR) was calculated in accordance
with the Japanese Society of Nephrology CKD Practice Guidelines as; eGFR (mL/min/1.73
m2) = 194  (serum creatinine level [mg/dL])-1.094  (age [y])-0.287. The product of this
equation was multiplied by a correction factor of 0.739 for women (12). Urinary L-FABP
concentration was determined in duplicate using a specific enzyme immunoassay (CMIC,
Tokyo, Japan) according to the instructions provided by the manufacturer (13, 14). The
value was expressed as the ratio of L-FABP concentration to urinary creatinine
concentration. Serum AGEs were measured by a enzyme-linked immunosorbent assay
(ELISA), with one IU corresponding to 2 g of glyceraldehyde-derived AGE-bovine serum
albumin standard as described previously (15, 16). Soluble RAGEs were measured using a
commercially available ELISA kit (R & D System, Minneapolis, MN, USA) (17).
Statistics
The data were expressed as mean ± SE. Simple regression analysis was performed to assess
the linear relationship between two variables. Intergroup comparisons were performed
using unpaired t tests for parametric data or Mann Whitney’s U test for non-parametric data.
Intragroup comparisons were assessed using a paired t test for parametric data or the
Wilcoxon Rank Sum test for non-parametric data. The level of statistical significance was
set at p<0.05. All calculations were performed with SPSS version 11.0 software (SPSS, Inc.,
Chicago, IL, USA).
Results
The baseline characteristics and concomitant medications including the type of ARBs
were similar between the patients receiving either benidipine or amlodipine (Table 1). No
adverse effects were observed in any patient during the study period and the study protocol
was completed by all the patients.
Prior to the start of CCB treatment, both serum AGEs (R=0.814, p<0.001) and serum
soluble RAGEs (R=0.697, p<0.001) correlated with urinary L-FABP, while serum soluble
RAGEs correlated with serum AGEs (R=0.887, p<0.001) (Fig. 1). In addition, serum AGEs
(R=0.892, p<0.001) and serum soluble RAGEs (R=0.787, p<0.001) both correlated with
UAE.
Systolic and diastolic blood pressure both decreased after 12 months (p<0.001) in the
benidipine (152.6±7.4/91.8±3.8 to 130.6±3.1/81.6±1.7 mmHg, p<0.001) and amlodipine
(151.0±6.6/90.6±3.6 to 131.0±2.8/82.2±1.6 mmHg, p<0.001) groups. Serum creatinine and
eGFR showed no significant differences during the study period in the benidipine group
(creatinine, 0.763±0.082 to 0.771±0.066 mg/dL; eGFR, 74.71±8.11 to 75.12±7.40 mL/min)
nor in the amlodipine group (creatinine, 0.760±0.080 to 0.796±0.058 mg/dL; eGFR,
75.72±6.04 to 73.28±7.13 mL/min). Figure 3 shows the changes in UAE and urinary
L-FABP. UAE decreased significantly after 12 months in the benidipine group (124.9±24.8
to 86.2±28.4 g/min, p<0.001), whereas no significant change was observed in the
amlodipine group (125.3±25.7 to 121.6±22.1 g/min, p=0.72). The UAE values after 12
months were significantly lower in the benidipine group compared to the amlodipine group
(p<0.001). Urinary L-FABP levels decreased significantly after 12 months in the benidipine
group (25.32±6.00 to 19.76±5.22 g/g.crea, p<0.001), whereas they remained unchanged in
the amlodipine group (25.28±5.30 to 26.04±5.36 g/g.crea, p=0.82). The L-FABP levels
after 12 months tended to be lower in the benidipine group compared to the amlodipine
group (p=0.069). Serum AGE levels decreased significantly after 12 months in the
benidipine group (12.5±2.4 to 9.6±1.6 U/mL, p<0.001), whereas they showed no difference
in the amlodipine group (13.1±2.5 to 13.4±2.3 U/mL, p=0.84). The AGE levels after 12
months were lower in the benidipine group compared to the amlodipine group (p<0.001).
Serum soluble RAGE levels decreased after 12 months in the benidipine group
(2152.0±460.2 to 1680.6±266.6 pg/mL, p<0.001). However, this trend was not observed in
the amlodipine group (2148.7±337.8 to 2120.2±312.2 pg/mL, p=0.82). Soluble RAGE
levels in the benidipine group were also lower than in the amlodipine group (p<0.001) (Fig.
4).
Discussion
The role of CCBs on CKD has attracted considerable recent attention (18). Ichihara et al.
(19) reported that the addition of the CCB, amlodipine, to ARB therapy was beneficial for
vascular function and structure in hypertensive patients, with this effect occurring
independent of the blood pressure-lowering effect. Kumagai et al. (2) reported that the
effect of amlodipine on renal function was similar to that of the ACEI, enalapril, in patients
with chronic glomerulonephritis. In animal models, the potentially protective effect of
amlodipine against the loss of glomeruli in spontaneously hypertensive rats was shown to
be a major additional effect of hypertensive treatment, especially when the renal lesions
already existed (20). While amlodipine has only an L-type calcium channel blocking effect,
benidipine lowers glomerular capillary hydraulic pressure by reducing the resistance of
efferent arterioles due to its N-type and T-type calcium channel blocking effect, with a
subsequent reduction in UAE (21). Therefore, benidipine is considered to have a more
potent renoprotective effect than amlodipine, and therefore may be very effective for
treating hypertensive patients with diabetes (1). While some investigators have reported
favorable effects of benidipine on renal function in patients with hypertension or CKD (4,
5), Morikawa et al. (22) demonstrated that benidipine did not reduce proteinuria in patients
with non-diabetic nephropathy. In the present study, we demonstrated that the addition of
benidipine, but not of amlodipine, to an ARB ameliorated UAE and decreased urinary
L-FABP levels in hypertensive patients with diabetic nephropathy.
Urinary L-FABP is a novel urinary biomarker of renal tubulointerstitial function. Sasaki et
al. (23) reported that urinary L-FABP levels reflected free fatty acid-induced proximal
tubular stress that leads to tubulointerstitial damage. Kamijo-Ikemori et al. (24) showed that
renal L-FABP ameliorated tubulointerstitial damage in diabetic mice, suggesting that
L-FABP has a renoprotective effect. It was reported recently that urinary L-FABP may be a
novel biomarker of chronic intrarenal ischemia in type 2 diabetes (25). In the present study,
we demonstrated that urinary L-FABP level was associated with serum AGEs and soluble
RAGEs in patients with diabetic nephropathy. There is evidence that AGEs accumulate in
hypertrophied renal tubules of patients with diabetic nephropathy (26) and also modulate
extracellular matrix turnover, with RAGEs being expressed on the surface of cultured
mesangial cells. Therefore, the AGE/RAGE system may play an important role in the
pathogenesis of diabetic nephropathy (27). Recently, Kerm et al. (28) reported that
processing of AGE-modified proteins leads to renal tubular stress in patients with diabetic
nephropathy, while Nakamura et al. (29) demonstrated that serum soluble RAGEs
correlated positively with serum AGEs in patients with type 2 diabetes. Our finding of a
correlation between the baseline levels of AGEs and soluble RAGEs is in accordance with
these previous results. In addition, our study showed that baseline levels of serum AGEs
and soluble RAGEs both correlated with urinary L-FABP.
As pathophysiological crosstalk between the AGE/RAGE system and angiotensin II
is considered to be involved in the progress of diabetic nephropathy, inhibition of AGE
formation and/or their downstream pathway, in addition to inhibition of RAS, may be a
novel therapeutic option for diabetic nephropathy (6). Targeting of RAGEs may also be a
beneficial treatment strategy (30). Matsui et al. (31) showed a unique beneficial effect of
telmisartan as an anti-inflammatory agent on AGE inhibition in diabetic nephropathy, with
this effect being mediated by PPAR-gamma activation. In the present study, telmisartan had
already been administered to several patients in both groups (amlodipine group: n=3,
benidipine group: n=3). Matsui and coworkers (31) also demonstrated that irbesartan
protected against tubular injury in diabetes by attenuating the deleterious effects of AGEs
via down-regulation of RAGEs (8). In the present study, medication with ARBs was similar
in the amlodipine and benidipine groups. Therefore, our findings appeared to be dependent
on differences in the effects of amlodipine and benidipine. Matsui et al. (32) reported that
nifedipine, but not amlodipine, down-regulated RAGE mRNA and subsequently reduced
generation of reactive oxygen species in AGE-exposed mesangial cells. In our study, we
demonstrated that 12 months of treatment with benidipine reduced the levels of serum AGE
and soluble RAGEs in diabetic patients with microalbuminuria.
Limitations/conclusions
The present study had several limitations. First, the sample size was relatively small and
therefore a large-scale, multicentered, double-blind study is required to confirm our
findings. Second, whether the present results were a class effect of T-type CCBs or
alternatively were specific to benidipine also remains to be determined. Third, we did not
determine whether the effects were dose-dependent, as the standard doses of amlodipine
and benidipine approved in Japan were used in the study (11). Fourth, we did not determine
the effects of these drugs in diabetic patients with macroalbuminuria, and/or renal
insufficiency. It is therefore necessary in future studies to determine whether benidipine is
effective at different stages of diabetic nephropathy.
In conclusion, the present study indicates that benidipine is more effective than
amlodipine for ameliorating UAE, urinary L-FABP, and the AGE/RAGE system in patients
with hypertensive diabetic nephropathy and microalbuminuria.
Acknowledgements
We thank Dr. Shingo Yamada, Central Institute, Shino-Test Corp, Sagamihara, for
measuring serum HMGB1. We also thank Dr. Takeshi Sugaya, Department of Medicine, St.
Marianna University School of Medicine, Kawasaki, for helpful suggestions concerning
L-FABP, and Dr. Hikaru Koide, Department of Medicine, Koto Hospital, Tokyo, for helpful
suggestions about the manuscript in general. We certify that there is no conflict of interest
with any financial organization regarding the material discussed in the manuscript.
This
word was supported by Grant-in-Aid for Scientific Research on Priority Areas (C)
(No.21590901) from the Ministry of Education, Culture, Sports, Science and Technology,
Japan.
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Figure legends
Fig. 1.
Correlation between urinary liver-type fatty acid binding protein (L-FABP) and
serum advanced glycation end products (AGEs), and serum soluble receptor for AGEs
(soluble RAGEs); and between serum AGEs and serum soluble RAGEs. Significant linear
correlations were observed between these parameters.
Fig. 2. Effect of benidipine and amlodipine on blood pressure. Both drugs had a similar
blood pressure-lowering effect.
Fig. 3. Changes in urinary albumin excretion (UAE) and urinary L-FABP after 12 months.
UAE and urinary L-FABP decreased significantly in the benidipine group (p<0.001),
whereas no difference was observed in the amlodipine group. The levels of UAE and
urinary L-FABP after 12 months were significantly lower in the benidipine group than in
the amlodipine group (p<0.001).
Fig. 4. Changes in serum AGEs and serum soluble RAGEs after 12 months. Serum AGEs
and soluble RAGEs decreased significantly in the benidipine group (p<0.001), whereas
they remained unchanged in the amlodipine group. The levels of serum AGEs and soluble
RAGEs after 12 months were significantly lower in the benidipine group than in the
amlodipine group.