1. health and fitness
2. disease

Q J Med 2005; 98:199–203
doi:10.1093/qjmed/hci036
Angiotensin-converting-enzyme inhibitors slow renal
decline in IgA nephropathy, independent of
tubulointerstitial fibrosis at presentation
Y. KANNO, H. OKADA, Y. YAMAJI1, Y. NAKAZATO1 and H. SUZUKI
Department of Nephrology, Saitama Medical School, and 1Kidney Center,
Saitama Social Insurance Hospital, Saitama, Japan
Received 9 July 2004 and in revised form 19 January 2005
Summary
pressure, serum creatinine, and urinalysis were
measured monthly, and 24-h endogenous creatinine clearance (CCr) at least once a year.
Results: In the CCB group, TIF was positively
correlated with the rate of decline in CCr
(dCCr), consistent with previous observations. In
the ACEI group, dCCr was lower (0.02 0.02
vs. 0.06 0.03), and the TIF-dCCr correlation was
absent.
Discussion: In the absence of post-treatment
histological data, it is not possible to say whether
ACEIs have an effect on TIF. However, ACEIs
appear to slow the progression of renal failure in
IgAN, regardless of the degree of TIF at presentation.
Introduction
In the last decade, much interest has focused on
renal fibrosis in the progression of renal diseases.1–3
Quantitative evaluation of tubulointerstitial fibrosis
(TIF) in the kidney can be the best predictor of
final outcome of a variety of primary and secondary
renal diseases.4–6 Data from the AIPRI (AngiotensinConverting-Enzyme Inhibition in Progressive Renal
Insufficiency) trial and the REIN (The Raminipril
Efficacy In Nephropathy) study show that angiotensin-converting-enzyme inhibitors (ACEIs) can
significantly slow the rate of decline in renal
function, in patients with non-diabetic glomerulopathy.7,8 In a recent review based on a series of
studies including the REIN study, Remuzzi et al.
concluded that urinary protein is one of the main
mediators of glomerular damage to the tubulointerstitium, and that an ACEI, ramipril, can confer
renoprotection via a reduction in urinary protein
excretion in progressive, non-diabetic, proteinuric
patients.9 ACEIs have also been shown to slow
the progression of nephropathy in type 1 diabetes
patients,10 but the effects of ACE inhibition in type 2
diabetes remain inconclusive, possibly due to its
heterogeneous nature.11 Since TIF has a significant
impact on the prognosis of a variety of renal
diseases, the results from these studies suggest that
Address correspondence to Dr H. Suzuki, Department of Nephrology, Saitama Medical School, 38 Morohongo,
Moroyama-cho, Irumagun, Saitama 350-0495, Japan. e-mail: [email protected]
! The Author 2005. Published by Oxford University Press on behalf of the Association of Physicians.
All rights reserved. For Permissions, please email: [email protected]
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Background: Tubulointerstitial fibrosis (TIF) is a
marker of progression of diabetic and non-diabetic
nephropathy, correlating with creatinine clearance (CCr), and functional outcome. Angiotensinconverting-enzyme inhibitors (ACEIs) slow the rate
of decline of renal function in proteinuric patients.
Aim: To examine whether ACEIs affect TIF, directly
or indirectly.
Design: Prospective 3-year follow-up study.
Methods: We enrolled 49 patients with IgA
nephropathy (IgAN), treating some with ACE
inhibitors (n ¼ 26, 1–2 mg/day temocapril or trandolapril) and some with calcium-channel blockers
(CCB, n ¼ 23, 2.5–5 mg/day amlodipine). Blood
200
Y. Kanno et al.
ACEIs may have direct and/or indirect effects on
TIF in non-diabetic and diabetic renal diseases.11
Although a number of animal studies suggest
that the renin-angiotensin-aldosterone-system (RAS)
involves TIF,12–14 few published clinical observations support this hypothesis. Some recent studies
have reported the efficacy of ACEIs in IgA nephropathy (IgAN),15,16 but it remains unknown
whether the effects of ACEIs on IgAN are mainly
by reducing proteinuria, or by other mechanisms.
We conducted a prospective study to determine
how an ACEI affected the functional prognosis
of patients with biopsy-proven IgA nephropathy
(IgAN), as a function of the degree of TIF.
Methods
fields were saved as graphic image files.18 Images
were analysed quantitatively with image analysis
software (MacScope, Mitani). As the blue-stained
collagenous area in MT stain was used as an index
of fibrosis19 in each image, TIF index was calculated
as (collagenous area in blue/non-glomerular and
arterial total area).20
Statistics
Data were expressed as mean SD. ANOVA and
Bonferroni/Dunnett’s test was used to determine the
significance of difference in multiple comparisons.
Spearman correlation coefficients (two-tailed) were
used to evaluate whether dCCr index was correlated
with TIF index. Values of p50.05 were considered
statistically significant.
Patients
Quantification of TIF
MT-stained kidney sections were examined under
a light microscope connected to a digital CCD
camera (HC-2500, Fuji Film Company). Whole sections were scanned at 100, and non-overlapping
Results
Clinical and pathological data
All enrolled patients completed the study, and the
baseline and the final data of patients are shown
in Table 1. Serum creatinine levels at the entry were
0.96–1.42 mg/dl. The two groups were comparable
at baseline. Blood pressure was well controlled,
and remained at or below the target level
(130/85 mmHg) in both groups. Proteinuria slightly
increased in the CCB group, and significantly
decreased in the ACEI group. Although there was
no significant difference in the level of serum
creatinine between the two groups at the end of
follow-up, CCr was slightly but significantly larger,
and dCCr index significantly smaller in the ACEI
group than in the CCB group (Table 1).
To evaluate TIF quantitatively, the fibrotic areas
that stained blue in the MT-stained biopsy sections
were counted using a computerized image analyser
(Figures 1a, 1b), and the TIF index was calculated
(Table 1). There was no significant difference in TIF
index between the two groups.
Clinical and pathological correlations
Other parameters that changed from baseline in
the two groups included TIF index, serum creatinine, CCr, and proteinuria, showing weak, positive
correlations (Figure 2a). However, no correlation
was observed between TIF index and age or blood
pressure. In the longitudinal evaluation, dCCr
index had a significant positive correlation with
TIF index in the CCB group (r ¼ 0.532, n ¼ 23,
p ¼ 0.0125), but there was no correlation in
the ACEi group (r ¼ 0.372, n ¼ 26, p ¼ 0.0631)
(Figure 2b). There was a significant difference
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After obtaining informed consents, 49 Japanese
patients with IgAN were enrolled in the study at
Saitama Medical School Hospital, and Saitama
Social Insurance Hospital, when they were about
to undergo renal biopsy. Histopathological diagnosis of IgAN was based on the demonstration
of prominent IgA deposition in the mesangial area
by immunofluorescence. Patients with diabetes
mellitus, hyperlipidaemia, liver diseases, systemic
lupus erythematosus, and Henoch-Schoenlein
purpura were excluded. Patients who had a past
history of treatment with ACEIs or steroids were
also excluded. Enrolled patients randomly assigned
to the ACEI group (n ¼ 26) were administered
1–2 mg/day of temocapril or trandolapril, and
those in the calcium channel blocker (CCB) group
(n ¼ 23) were administered 2.5–5 mg/day of amlodipine. The target blood pressure in the out-patient
clinic was 130/85 mmHg, and was achieved by
the administration of these antihypertensives, with
an additional 10–20 mg/day of arotinolol when
needed. The patients, whose blood pressures were
below 130/85 mmHg at registration, received a
minimum dose of each agent. Blood pressure,
serum levels of creatinine, and urinalysis were
measured on a monthly basis for at least 3 years.
We measured 24-h endogenous creatinine clearance (CCr) at least once a year. The index of
the decline in CCr over 3 years (dCCr index) was
calculated as (initial CCr–final CCr)/initial CCr.17
ACE inhibitors and IgA nephropathy
Table 1
201
Demographic data
Age (years)
Sex (M/F)
Systolic BP (mmHg)
Diastolic BP (mmHg)
Serum creatinine (mg/dl)
Proteinuria (g/day)
CCr (ml/min)
TIF index
dCCr index/year
ACEI group (n ¼ 26)
CCB group (n ¼ 23)
Year 0
Year 3
Year 0
Year 3
120 2*
73 2*
1.18 0.26
0.79 0.36*
85.5 5.5
–
0.02 0.02**
35 3
12/11
140 3
83 2
1.02 0.08
1.10 0.15
90.8 7.1
14.0 1.8
–
122 2*
74 2*
1.23 0.42
1.33 0.62
85.5 7.4
–
0.06 0.03
35 2
8/18
143 3
87 2
1.07 0.13
1.09 0.16
92.8 6.2
16.5 1.7
–
*p50.05 vs. year 0. **p50.05 vs. CCB group. ACEI, angiotensin-converting-enzyme inhibitor;
CCB, calcium channel blocker; CCr, creatinine clearance; TIF, tubulointerstitial fibrosis; dCCr, rate of
decline in CCr. Data are means SD, except sex ratios.
a
Figure 1. Representative renal histopathology of IgAN
with TIF. a TIF area is in blue on the MT-stained section
(100, MT). b Most of the blue area in a turns green, and
the green area is quantitatively evaluated by an image
analyser. The TIF index is 11.4% in this case (100, MT).
between the regression lines of the two groups
(p ¼ 0.003).
Discussion
In this study, RAS blockade by ACEI slowed the
rate of decline of renal function in IgAN patients,
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b
with or without TIF. Tubulointerstitial alterations
preceding advanced TIF (scarring) consisted of
interstitial monocytes infiltration, fibroblast proliferation, and extra-cellular matrix (ECM) protein
accumulation;1–3 a number of studies suggest the
involvement of Ang II in these alterations.12–14
A hallmark of renal injury is excessive urinary
protein excretion, which is not only an indicator
of glomerular damage, but may contribute to
tubulointerstitial alterations, regardless of the type
of glomerular injury.9 Proteins filtered from the
glomerulus are reabsorbed by the proximal tubular
epithelial cells (PTECs). An excess load of proteins in
PTECs may induce lysosomal rupture and phenotypic changes. These release or activate local
vasoconstrictors such as Ang II and endothelin,
chemotactic proteins such as MCP-1 and OPN,
and profibrotic growth factors such as TGF-b1,
leading to tubulointerstitial alterations.2,21 Thus RAS
blockade by ACEI probably attenuates TIF via two
different pathways. On the one hand, ACEIs may
reduce urinary protein-induced Ang II generation
and suppress subsequent increases in profibrotic
factors induced by Ang II, as described above.2,21
On the other, antiproteinuric effects of ACEIs via
their haemodynamic actions could reduce tubular
exposure to proteins, providing an additional mechanism for attenuating TIF.2,21 Both TIF and proteinuria are good prognostic indicators in most of the
progressive glomerulopathies, and in the AIPRI
and REIN studies, renoprotection by ACEIs correlated with the degree of reduction in urinary protein
excretion.8,9
However, in the present study, we found only
a weak negative correlation between the degree
of reduction in urinary protein excretion and dCCr
202
Y. Kanno et al.
a
2.5
(r = 0.096, N=49, p=0.5061)
Proteinuria (g/day)
2
1.5
1
0.5
0
0
10
20
30
40
TIF index
b
.4
dCCr index
.3
ACE
CCB
.2
.1
0
-.1
-.2
0
5
10
15
20
25
TIF index
30
35
40
Figure 2. Clinical and pathological correlations. a In both
groups at baseline, TIF index shows a weak, positive
correlation with urinary protein excretion. b At the end
of 3-year follow-up, in the CCB groups, TIF index was
positively correlated with dCCr index (r ¼ 0.532, n ¼ 23,
p ¼ 0.0125). By contrast, in the ACEI group, there was
no correlation between TIF index and dCCr index
(r ¼ 0.372, n ¼ 26, p ¼ 0.0631). There was a significant difference between the regression lines of the two
groups (p ¼ 0.003).
index (data not shown). This might be accounted
for by a difference in the patients studied. In the
AIPRI study and the REIN study, both groups
were large, and included a wide variety of proteinuric renal diseases,78 and the most significant
renoprotective effects were seen in patients with
urinary protein excretion 43 g/24 h, (measured as
the degree of reduction in the amount of protein
excreted).9 In our study, a relatively small number
of patients with IgAN were enrolled, and few had
urinary protein excretion 42 g/24 h. Thus the direct
effects of ACEIs on TIF might be more prominent
in our study than in the REIN study.
In this study, we demonstrated that interstitial
fibroblast-like cells were positive for AT1R in the
IgAN kidneys. Like human renal fibroblasts,
cultured rat renal fibroblasts (NRK 49F) also possess
functional AT1aR, and produce TGF-b1 and fibronectin in response to Ang II.14 Renal fibroblasts
Acknowledgements
A part of this study was presented at the 34th
annual meeting of American Society of Nephrology
(San Francisco, USA, 2001).
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dCCr index = - 0.001 x TIF index +0.038, r = -0.372 (ACE)
dCCr index = 0.008 x TIF index -0.046, r = 0.532 (CCB)
derived from fibrosing kidneys often bear profibrotic phenotypes such as hyperproliferative growth,
enhanced synthesis of collagen and production
of profibrotic cytokines, compared with those
derived from normal kidneys.22–25 In addition to
these phenotypes, fibrosis-derived fibroblasts have
enhanced profibrotic responsiveness to RAS,26
and this may account for our experience of
superior effectiveness of ACEIs on IgAN patients
with TIF.
This study has some limitations. First, changes in
RAS were not evaluated by plasma renin activity
or plasma aldosterone concentration, leaving some
uncertainty about systemic RAS status. This is
mainly because of the variation in these measurements with time, stature, meals, emotions, and so
forth.27 Secondly, recently ACE gene polymorphisms have attracted attention as a predictor of
efficacy of ACEIs in several renal diseases. Yoshida
et al. found a high frequency of the DD genotype
in IgAN with progressive renal deterioration,28
but subsequent studies have produced conflicting
results. Schena et al. concluded in their metaanalysis that the development of IgAN was not
associated with the presence of D allele in the
Asian and Caucasian populations.29 Therefore,
we did not determine ACE gene polymorphism of
patients at enrolment. Thirdly, we lack pathological
data after the treatment, because patients were
unwilling to have a repeat biopsy. Therefore our
conclusion are somewhat speculative, based on
the changes in physiological data, and the pathological findings at the start of the study. Lastly,
the allocation of patients to treatment groups
was not random, and this may have introduced
some bias.
In conclusion, ACEIs retarded the progression
of IgAN in kidneys with or without TIF.
Co-administration of ACEIs and ARB additively
reduced urinary protein excretion in these
patients,30 as in the COOPERATE study, in which
drug combination therapy retarded progression of
non-diabetic renal diseases more efficaciously than
either monotherapy.31 This suggests that inhibition
of RAS at multiple points is a promising approach
to retard the progression of diabetic and nondiabetic renal diseases, and should be investigated
using prospective clinical trials.
ACE inhibitors and IgA nephropathy
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