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Abstract
Background and objectives Current therapy for IgA nephropathy mainly includes renin-angiotensin system
inhibitors and adding steroids for patients with persistent proteinuria. This study aimed to evaluate kidney
disease progression and its risk factors in a Chinese cohort under current therapy.
Design, setting, participants, & measurements Patients with IgA nephropathy followed up for at least 12
months from a prospective database were involved. Renal survival and the relationship between clinical
parameters and composite kidney failure events (dened as end stage kidney failure or eGFR halving) were
assessed.
Results Overall, 703 patients between 2003 and 2011 were enrolled in this study, with a mean follow-up time of
45 months. Mean eGFR was 84.0 ml/min per 1.73 m2, systolic BP was 124 mmHg, and time-averaged mean
arterial pressure was 90.0 mmHg. Median proteinuria at baseline was 1.60 g/d, and time-averaged proteinuria
was 0.80 g/d. The mean rate of eGFR decline was 23.12 ml/min per 1.73 m2 per year (95% condence interval,
219.07 to 11.80), and annual end stage kidney failure rate was 2.3%. Multivariate Cox regression analyses
revealed that baseline eGFR (hazard ratio, 0.76 per 10 ml/min per 1.73 m2; 95% condence interval, 0.66 to 0.91),
proteinuria at 6 months (hazard ratio, 1.53 per g/d; 95% condence interval, 1.27 to 1.84), and systolic BP control
at 6 months (hazard ratio, 1.36 per 10 mmHg; 95% condence interval, 1.05 to 1.77) were associated with composite kidney failure events. Baseline eGFR (regression coefcient, 20.06; 95% condence interval, 20.07
to 20.04), time-averaged proteinuria (regression coefcient, 20.21; 95% condence interval, 20.25 to 20.16),
and time-averaged mean arterial pressure (regression coefcient, 20.15; 95% condence interval, 20.21 to 20.09)
were independent predictors of the slope of eGFR by linear regression.
Conclusion Lower proteinuria and lower BP were associated with slower eGFR decline and lower risk of end
stage kidney failure in patients currently being treated for IgA nephropathy.
Clin J Am Soc Nephrol 9: 484489, 2014. doi: 10.2215/CJN.01990213
Introduction
IgA nephropathy (IgAN) was described by Berger and
Hinglais in 1968 (1), and it is now the most common
form of primary GN worldwide, especially in the
Asian-Pacic region (2). IgAN is characterized by a
highly variable clinical course ranging from a completely benign incidental condition to rapidly progressive renal failure. Most affected individuals
develop chronic, slowly progressive renal injury,
and many patients develop end stage kidney disease
(ESKD) (3). It is estimated that 1%2% of all patients
with IgAN will develop ESKD within 1 year from the
time of diagnosis (4). Studies (57) have conrmed
the prognostic value of some clinical and biochemical
parameters for the long-term outcome of patients
with IgAN. Among them, impaired renal function,
sustained hypertension, persistent proteinuria (especially proteinuria over 1 g/d), and severe renal lesions at initial biopsy constitute poor prognostic
markers. Other risk factors are numerous and
484
*Renal Division,
Peking University First
Hospital, Beijing,
China; Peking
University Institute of
Nephrology, Beijing,
China; Key
Laboratory of Renal
Disease, Ministry of
Health of China,
Beijing, China; Key
Laboratory of Chronic
Kidney Disease
Prevention and
Treatment (Peking
University), Ministry
of Education, Beijing,
China; and
|
Department of
Nephrology, Affiliated
Hospital of Weifang
Medical College,
Shandong, China
Correspondence:
Dr. Jicheng Lv, Renal
Division, Peking
University First
Hospital Institute of
Nephrology, Peking
University, No. 8,
Xishiku St, Xicheng
District, Beijing,
China. Email:
jichenglv75@gmail.
com
using renin-angiotensin system (RAS) inhibitors and suggest adding steroids in patients with persistent proteinuria,
regardless of supportive therapy (20). However, few studies
have evaluated the progression and risk factors of IgAN under current therapy.
In this observational study, we aim to evaluate if therapy
with RAS inhibitors and sequential addition of steroids or
other immunosuppressive agents were associated with
proteinuria reduction and BP control. We also investigate
kidney disease progression and its risk factors for IgAN
under current therapy.
485
inhibitors; a 6- to 8-month course of the oral dose of prednisone or equivalent was started at 0.81.0 mg/kg per day
for 8 weeks, and the dose was then tapered by 510 mg
every 2 weeks. (3) Other immunosuppressive agents
would be considered in patients with impaired kidney
function (SCr.1.5 mg/dl) or rapidly progressive kidney
function decline (SCr increase.15% in the year before entry) (24). Renal lesions were graded according to the Haas
classication at the time that the database was established
(25).
Statistical Analyses
Data were analyzed using SPSS 16.0 software. Continuous variables were expressed as means6SDs. All categorical variables were expressed as frequencies or
percentages. The relationship between variables and composite kidney failure events dened as ESKD or eGFR
halving was assessed by Cox regression. Parameters signicantly associated with composite kidney failure events
by univariate analysis were included in the multivariate
models. For proteinuria and BP, which was the time-varying
covariate, we have used the values at month 6 to predict
kidney failure events in the Cox model when patients had
entered a relative stable condition (26). Univariate followed
by multivariate linear regression was used to determine independent predictors of slope of eGFR (15,21). P,0.05 was
considered statistically signicant.
Results
Clinical Characteristics
Clinical characteristics at baseline and during follow-up
are summarized in Table 1. Mean age at biopsy was
33.9611.9 years, and 361 (51.4%) patients were men.
Mean systolic BP and diastolic BP at baseline were
124615 and 79612 mmHg, respectively. Mean eGFR
was 84.0629.1 ml/min per 1.73 m2, and baseline MAP
was 93.8612.2 mmHg. The median and interquartile range
(IQR) of initial proteinuria were 1.60 and 0.873.09 g/d.
Patients were followed for 45.0628.8 months. Seven patients died, and six of these patients died before reaching
ESKD, because of infection (n=3), cardiovascular disease
(n=2), and lymphoma (n=1).
Treatment and Proteinuria Response
In total, 676 (96.2%) patients received ACEi and/or ARB
therapy, and 316 (45%) patients received steroids or
steroids plus other immunosuppressive agents. Overall,
262 (37.3%) patients with a median peak proteinuria of 1.33
g/d (IQR=0.891.86 g/d) achieved a remission of proteinuria (TA proteinuria,1 g/d) with RAS blockade therapy
alone. Steroids were added in 91 (12.9%) patients with
persistent proteinuria (.1 g/d), regardless of supportive
therapy. The median time of RAS inhibition before adding
steroids was 4.4 months (IQR=3.07.0 months), and 55
(60.4%) patients achieved proteinuria remission. The combination of steroids with other immunosuppressive agents,
such as cyclophosphamide, mycophenolate mofetil, and
leunomide, was used in 195 patients with impaired kidney function (n=68) or rapidly progressive kidney function
decline (n=127), and 79 (40.5%) patients achieved remission of proteinuria. Overall, 111 patients did not receive
486
Characteristics
Value
IQR, interquartile range; SBP, systolic BP; DBP, diastolic BP; MAP, mean arterial pressure; TA proteinuria, time-averaged proteinuria;
TA MAP, time-averaged MAP; RAS, renin-angiotensin system; ESKD, end stage kidney disease.
a
CKD stages 1, 2, 3a, 3b, and 4 were divided by eGFR$90, 6089, 4559, 3044, and 1529 ml/min per 1.73 m2, respectively.
steroid therapy despite persistent proteinuria.1 g/d, including 7 patients with diabetic mellitus, 2 patients with
tuberculosis, 7 patients with hepatitis B virus infection, 2
patients with unstable angina, and 93 patients who refused
steroid therapy. Thirty patients had steroids added who
presented with nephrotic syndrome or had glomerular necrosis ndings in renal biopsy. Fourteen patients received
no therapy (namely, patients who were planning pregnancy, were intolerant of RAS inhibitors, or received traditional Chinese medicine treatment).
Among 32 patients with stage 4 CKD, 26 patients were
treated with RAS inhibitors and immunosuppressive
agents for active lesions in kidney biopsy; the remaining
six patients with dominant chronic pathologic lesions were
managed with only supportive therapy.
Kidney Progression and Risk Factors
During follow-up, the median of TA proteinuria reduced
from 1.60 (0.873.09) to 0.80 (0.441.47) g/d. Mean TA
MAP was 90.068.7 mmHg. By the last visit, 91 (12.9%)
composite kidney failure events were observed, including
62 ESKD and 29 halving of eGFR events. Patients were
followed for 31,635 person-years; the event rate of ESKD
487
Table 2. Factors at presentation and during follow-up influencing composite kidney failure events (ESKD or eGFR halving) by
univariate and multivariate Cox regression
Univariate
Multivariate
Characteristic
Age (per 10 yr)
Sex (women versus men)
Haas classication
I/II
III
IV
V
Baseline eGFR (per 10 ml/min per 1.73 m2)
Baseline proteinuria (per g/d)
Proteinuria at month 6 (per g/d)
Baseline SBP (per 10 mmHg)
SBP at month 6 (per 10 mmHg)
Immunosuppressive therapy (yes or no)
Uric acid (per mg/dl)
HR
95% CI
P Value
1.10
0.79
0.93 to 1.30
0.53 to 1.18
0.26
0.24
1
2.61
5.02
18.87
0.67
1.13
1.85
1.31
1.64
2.37
1.28
Reference
0.89 to 7.62
1.76 to 14.37
6.50 to 54.74
0.62 to 0.73
1.07 to 1.18
1.64 to 2.09
1.17 to 1.48
1.38 to 1.95
1.55 to 3.60
1.17 to 1.40
0.10
0.01
,0.001
,0.001
,0.001
,0.001
,0.001
,0.001
,0.001
,0.001
HR
95% CI
P Value
1
0.59
1.99
3.04
0.76
1.02
1.53
0.81
1.36
1.73
1.09
Reference
0.11 to 3.27
0.43 to 9.24
0.61 to 15.28
0.66 to 0.91
0.92 to 1.13
1.27 to 1.84
0.64 to 1.03
1.05 to 1.77
0.88 to 3.38
0.92 to 1.30
0.54
0.38
0.18
0.002
0.79
,0.001
0.09
0.02
0.11
0.34
Table 3. Factors at presentation and during follow-up influencing decline in renal function (ml/min per 1.73 m2 per year) by
univariate and multivariate linear regression
Univariate
Characteristic
Regression
Coefcients
0.05
0.03
Multivariate
P
Value
95% CI
0.01 to 0.09
20.07 to 0.13
0.01
0.58
1
20.01
20.01
20.19
20.02
Reference
20.16 to 0.15
20.21 to 0.18
20.39 to 0.01
20.04 to 20.01
0.94
0.88
0.06
0.01
20.01
20.02 to 0.02
0.78
20.21
20.02
20.26 to 20.17
20.06 to 0.02
20.19
0.04
20.24 to 20.13
20.05 to 0.15
20.01
20.04 to 0.02
Regression
Coefcients
0.01
95% CI
20.03 to 0.05
P
Value
0.63
20.06
20.07 to 20.04
,0.001
,0.001
0.40
20.21
20.25 to 20.16
,0.001
,0.001
0.34
20.15
20.21 to 20.09
,0.001
0.38
95% CI, 95% condence interval; TA proteinuria, time-averaged proteinuria; MAP, mean arterial pressure.
Discussion
In this large prospective cohort study with more than 700
patients, we evaluated kidney disease progression and its
risk factors under current therapy. Nearly all patients
received RAS inhibitors. Sequential steroids were considered in patients with persistent proteinuria, and other
immunosuppressive agents were considered in those patients with impaired kidney function or rapidly progressive
kidney function decline. Proteinuria declined by approximately 50%, and BP was well controlled among patients
treated with our current therapy regimen. Proteinuria and
BP were strong risk factors of kidney failure events or the
rate of GFR decline. However, the risk of kidney failure
events for patients with IgAN remained high, with about
2.3% of patients reaching ESKD each year and an annual
rate of GFR decline greater than 3 ml/min per 1.73 m2.
488
Parameter
Intercept
Baseline eGFR (per 10
ml/min per 1.73 m2)
TA proteinuria (per
g/d)
TA MAP (per
10 mmHg)
Regression
Coefcients
Standardized
b-Coefcients
1.73
20.06
20.25
20.21
20.33
20.15
20.19
These ndings suggest that new therapy strategies are urgently needed to reduce kidney burden and the high risk
of kidney failure events in this population.
Similar to prior reports, baseline eGFR, proteinuria, and
poor BP control during follow-up were the strongest risk
factors for the rate of eGFR decline. As in the Toronto GN
cohort, we developed a formula to predict GFR decline
using eGFR, proteinuria, and BP. This model could explain
18% of all variability shown in the GFR slope based on the
adjusted R2 of our model, which suggests that the discrimination capacity of current biomarkers for IgAN progression is limited. New biomarkers should be developed to
improve the ability to predict kidney disease progression.
Recent studies have shown that serum galactose-decient
IgA1 level (27) and anti-glycan autoantibodies (28) were
strongly associated with kidney failure events in patients
with IgAN. Additional study is needed to conrm their
roles in IgAN progression.
Data from this study suggest current therapy regimen for
IgAN was associated with a slower kidney function progression as compared with those in history (9,15). A longterm cohort from the Toronto Glomerulonephritis Registry
(15) had recruited a population with similar baseline proteinuria and kidney function; only 53% of patients received RAS inhibitors, and 12.5% of patients were
treated with steroids. Urine protein excretion during follow-up was reduced from 2.37 to 2.17 g/d compared with
from 2.49 to 1.12 g/d in our cohort. The rate of GFR decline was 24.8 ml/min per 1.73 m2 per year, and the annual kidney failure rate of 4.3% was also much higher than
the rate in this cohort. Another interesting nding from
this study was that higher baseline GFR was associated
with a faster rate of GFR decline. This result contrasts
with the Toronto Equation (15,29). Patients with kidney
impairment would receive more intensive care in current
clinical practice, including more frequent follow-up and
higher doses of RAS inhibitors and immunosuppressive
agents, which partially explains why patients with lower
GFR showed a slower rate of GFR decline.
Another large cohort from south China included 1155
patients, with 90% of patients receiving RAS inhibitors. In
that study, the rate of GFR decline was 21.7 ml/min per
1.73 m2 per year, and the ESKD rate was 1.7/100 personyears; however, the median proteinuria at presentation
was only 0.89 g/d (14). The largest cohort was from Japan,
with 2283 patients followed for 87 months. Only 28.2% of
patients received RAS inhibitors. The ESKD rate was 1.7/
100 person-years (9). The cohort of IgAN patients from the
area of Saint-Etienne comprised 332 homogenous patients
from the Saint Etienne area of France, and it included patients with mild proteinuria (0.97 g/d). More than 70% of
patients with proteinuria.1 g/d or hypertension received
RAS inhibitors, and the annual ESKD rate was only 0.75%
(5). Thus, the importance of this study is proven risk and
progression of IgAN under current therapy, including
RAS inhibition and sequential steroids or other immunosuppressive agents. Most of these cohorts with relatively
good prognoses mainly recruit patients with mild proteinuria (less than 1 g/d in more than 50% of patients), which
may represent a lead time bias because of different biopsy
indications.
In this study, we have shown the association between
proteinuria reduction, BP control, and kidney protection in
patients with IgAN. Similar to the Toronto Glomerulonephritis Register and the Glasgow cohort, we quantied the
association of the rate of GFR decline with baseline eGFR,
proteinuria, and BP control. After aggressive therapy,
annual ESKD rate declined but was still as high as 2.3%.
Therefore, novel therapeutic targets must be conrmed that
have already been used in human or animals, such as
vitamin D (30,31), a-tocopherol (3234), and pentoxifylline
(35), to slow the rate of renal function decline with time.
Other strategies are worth considering, such as selective
correction of the intracellular glycosylation pathway, targeted deletion of a small population of Gd-IgA1producing
cells (27), blocking IgA1 interaction with mesangial transferrin receptor (36), or inhibiting production of autoantibodies targeting galactose-decient IgA1 (28).
The strengths of this study include a large sample size,
uniform therapy strategy, and robust database, for which
all data were collected at regular 3- to 6-month intervals.
One of the major limitations was that this cohort logically
included sicker people or those patients on more intensive
treatment regimen, and, therefore, the analyses have inherent selection bias for disease severity or treatment
choice. Other limitations were the relatively short followup and single center study. Thus, more studies are needed
to evaluate progression of IgAN in patients under the
current therapy regimen.
In summary, our data clearly showed that lower proteinuria and lower BP were associated with slower eGFR
decline and lower risk of ESKD event in patients currently
being treated for IgAN. However, the risk of kidney failure
remained high. New treatment regimens are still needed to
retard residual kidney progression in individuals with
IgAN.
Acknowledgments
This work was supported, in part, by National Natural Science
Foundation (NSF) of China Grants 81322009 and 81270795, Major
State Basic Research Development Program of China 973 Program
No. 2012CB517700, Program for New Century Excellent Talents
in University from the Ministry of Education of China Grant
NCET-12-0011, Capital Clinical Research Grant Z12110700100000
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Received: February 19, 2013 Accepted: November 15, 2013
X.L. and Y.L. contributed equally to this work.
Published online ahead of print. Publication date available at www.
cjasn.org.