Influence of the period between onset of IgA nephropathy and medical intervention on renal prognosis

doi:10.4236/health.2011.38086

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Vol.3, No.8, 518-523 (2011)

doi:10.4236/health.2011.38086

Health

Influence of the period between onset of IgA

nephropathy and medical intervention on renal

prognosis

Keiko Okazaki, Yusuke Suzuki, Takashi Kobayashi, Fumiko Kodama, Satoshi Horikoshi,

Yasuhiko Tomino*

Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan;

*Corresponding Author: yasu@juntendo.ac.jp

Received 12 May 2011; revised 8 July 2011; accepted 28 July 2011.

ABSTRACT

Background. The clinical course of IgA neph-

ropathy (IgAN) is highly variable. In order to

verify the necessity of early medical interven-

tion in IgAN patients, the present study inves-

tigated the clinical impact of the duration be-

tween disease onset and first medical interven-

tion on renal prognosis. Methods. We enrolled

57 patients diagnosed with IgAN on the basis of

biopsy performed at our hospital. The medical

records of these patients were traceable to the

last 10 years, during which they had not un-

dergone dialysis or treatment at any other hos-

pital. On the basis of histological assessmen t of

prognosis, these patients were classified ac-

cording to the Japanese guidelines into the fol-

lowing groups: groups I, good progn osis; gr oup

II, relatively good prognosis; group III, relatively

poor prognosis; and group IV, poor prognosis.

We investigated the correlation between the

duration of disease onset and the first consul-

tation with a nephrologist and the rate of in-

crease in serum creatinine ov er a 10 year period.

In addition to the abovementioned patients, 6

patients with IgAN who underwent dialysis with-

in the 10 y ears were separately ev aluated. These

patients came under the poor prognosis cate-

gory; i.e., they belonged to group IV. Results.

The duration between disease onset and medi-

cal consultation was significantly longer in

younger patients or in those w ith asymptomatic

proteinuria at onset when compared to that in

older patients or in those with other urinary

abnormalities. There was a significant correla-

tion between this duration and renal prognosis,

particularly in group III patients. Although the

duration between onset and consultation was

not correlated to the serum creatinine level at

the time of first medical intervention, urinary

protein level among group IV patients at the

time of first consultation was significantly higher

in patients with dialysis than that in those with-

out dialysis. Conclusions. Early medical inter-

vention may lead to a better renal prognosis,

particularly in group III patients, who form a

major portion of the IgAN population. It there-

fore appears that early diagnostic screening

and subsequent intervention are important for a

good prognosis in IgAN patients.

Keywords: IgA Nephropathy; Medical Intervention;

Diagnosis; Prognosis

1. INTRODUCTION

The number of patients with end stage renal disease

(ESRD) requiring renal replacement therapy continues to

increase worldwide. At the end of 2008, the number of

patients with ESRD in Japan had risen to 282,622 [1].

This number continues to increase by approximately 7%

every year [2]. The increase in the number of such pa-

tients presents serious problems, not only for public

health, but also in terms of socioeconomic issues. The

concept of chronic kidney disease (CKD) has therefore

attracted considerable recent attention, and it has been

reported that CKD is one of the most important risk fac-

tors for not only ESRD, but also for cardiovascular dis-

ease [3,4]. Immediate measures for the prevention of

CKD are therefore required.

Until 1996, chronic glomerulonephritis was the most

frequent primary renal disease leading to ESRD in Japan.

Although a transition was noted in the main cause of

ESRD, which changed to diabetic nephropathy from

chronic glomerulonephritis after 1998, 24.0% newly

developed ESRD cases in 2007 were a result of chronic

K. Okazaki et al. / Health 3 (2011) 518-523

519

glomerulonephritis [1]. In particular, IgA nephropathy

(IgAN) is the leading cause of primary glomerulonephri-

tis in Japan.

In Japan, approximately 70% IgAN patients are iden-

tified by abnormalities detected in annual urinalysis car-

ried out at schools or offices [5]. Because most patients

are asymptomatic, doctors may not be consulted for a

long time even after abnormalities are detected in the

urinalysis. In fact, in 1995 a Joint Committee of the Spe-

cial Study Group on Progressive Glomerular Disease,

Ministry of Health, Labor and Welfare of Japan, reported

an average of more than 3 years as the time period be-

tween estimated onset and first consultation and subse-

quent diagnosis of IgAN by renal biopsy [6].

Follwing the onset of IgAN, approximately 5% - 10%

patients develop ESRD within 5 years and approxima-

tely 30% develop the disease within 15 - 20 years [5,7,8].

Conversely, approximately 60% patients do not develop

ESRD. Notably, some of these patients achieve sponta-

neous natural remission or maintain a clinically stable

condition without any treatment [8,9]. Owing to the va-

riable clinical course of IgAN, specific indications for

medical intervention have not been established.

The present study aimed to verify the necessity of

early medical intervention in IgAN patients and to iden-

tify the patients requiring immediate medical interven-

tion by retrospectively evaluating the influence of the

duration from onset to first medical intervention on renal

prognosis. These findings may provide guidance in es-

tablishing a standard management strategy, both clini-

cally and socially, for IgAN.

2. SUBJECTS AND METHODS

2.1. Stud y Design

We first investigated the correlation between renal

prognosis and the period between estimated onset and

first medical intervention. We defined the estimated on-

set as the time point of detection of the first abnormality

in urinalysis, or when macrohematuria first appeared.

The first consultation with a nephrologist at our hospital

was considered the first medical intervention. The rate of

increase in serum creatinine over a 10 year period was

calculated as follows: Cr = [S − Cr (after 10 years) − [S

− Cr] (at first consultation)] / S − Cr (at first consulta-

tion). The correlations among the duration from onset to

first intervention, sex, age at onset, and urinalysis ab-

normalities at onset were also examined.

2.2. Patients

The main study group comprised 57 patients diag-

nosed with IgAN on the basis of renal biopsy between

1990 and 2002 at Juntendo University Hospital. The me-

dical records of these patients were traceable for 10

years after the first medical examination; in addition,

these patients had not undergone dialysis during this

period. Patients who had been treated with antiplatelet

and/or anticoagulant agents, angiotensin converting en-

zyme inhibitors (ACE I), angiotensin II receptor block-

ers (ARB), or adrenocortical steroids in other hospitals

were excluded from the study. Patients who had experi-

enced events causing aggravation of the disease, such as

pregnancy, in the 10 year follow-up period were also

excluded.

In addition, 6 patients with IgAN who had undergone

dialysis therapy during the 10 year follow-up period

were evaluated separately.

2.3. Data Collection

Patient data were obtained by reviewing medical re-

cords at our hospital. The data collected included sex,

age at estimated onset and at first visit to our hospital,

urinary abnormalities at onset, and the period between

onset and first hospital visit. The therapeutic modality

for each patient in the 10 year follow-up period was re-

viewed. The histological prognostic groups (groups I-IV)

were formed according to the clinical guidelines for

IgAN revised by the Joint Committee of the Special

Study Group on Progressive Glomerular Disease, Minis-

try of Health, Labor and Welfare of Japan, in 2002 [10]:

good prognosis (group I), relatively good prognosis

(group II), relatively poor prognosis (group III), and

poor prognosis (group IV) (Table 1).

2.4. Statistical Analysis

All data were expressed as mean ± standard deviation.

In this study, statistical analysis was performed by Stat

View (SAS Institute Inc., Cary, NC). Pearson’s correla-

tion coefficient analysis was used to examine the rela-

tionship between the duration from onset to first medical

intervention and renal prognosis, as well as between the

duration from onset to first medical intervention and age

at onset. Fisher’s PLSD test was used to compare the

durations from onset to first hospital visit between the

four histological groups, and also between the urinalysis

groups. The Mann–Whitney U test was also used to

compare the mean duration between males and females.

P values < 0.05 were considered statistically significant.

3. Results

3.1. Patient Characteristics

The characteristics of the 57 patients (34 males and 23

females; mean age at estimated onset, 27.91 ± 10.48

K. Okazaki et al. / Health 3 (2011) 518-523

520

Table 1. Histological prognostic stage (clinical guidelines for IgA nephropathy in Japan, 2nd version).

Grade Mesangial proliferation

and increased matrix

Glomerulosclerosis, crescent

formation or adhesion to

Bowman’s capsule

Interstitial

cellular

infiltration

Tubular

atrophy

Changes of

blood vessels

I: Good prognosis slight - - - -

II: Relatibly good prognosis slight <10% - - -

III: Relatively poor prognosis moderate, diffuse 10% - 30% slight slight mild sclerosis

IV: Poor prognosis severe, diffuse 30%< + + hyperplasia,

degeneration

between the four histological groups (group I, 104.5 ±

125.4 months; group II, 53.6 ± 50.6 months; group III,

80.0 ± 108.4 months; and group IV, 59.4 ± 70.6 months).

A significant correlation between the duration until

medical intervention and renal prognosis was observed

only in group III (r = 0.55, P = 0.004) (Figure 2).

years) are summarized in Table 2. The mean age at onset

was significantly higher in male patients than that in

female patients (31.79 ± 11.10 vs. 22.17 ± 6.09 years) (P

= 0.0004). As shown in Table 2, the onset of disease in

most patients was incidentally detected by abnormal

findings in routine annual urinalysis. Of the 57 patients,

56 were classified histologically into group I (n = 4),

group II (n = 14), group III (n = 25), and group IV (n -

13).

3.3. Factors for Early Consultation with a

Nephrologist

The mean duration from estimated onset to the first

medical intervention was 74.62 ± 99.78 months in males

and 60.87 ± 70.15 months in females (P = 0.57). As

shown in Figure 3, there was a significant correlation

between the duration until medical intervention and age

at onset (r = −0.3, P = 0.050). The duration from onset to

first medical intervention was significantly longer in

patients with asymptomatic proteinuria as the initial uri-

nalysis abnormality compared to that in patients with

other abnormalities such as asymptomatic hematuria (P

= 0.01) or asymptomatic hematuria and proteinuria (P =

0.003) (Figure 4).

3.2. Correlation between the Duration from

Onset to First Medical Intervention and

Renal Prognosis

There was a significant correlation between the dura-

tion from estimated onset to first medical intervention

and renal prognosis over the 10 year follow-up period (r

= 0.42, P = 0.0011) (Figure 1). There was no significant

difference in duration from estimated onset to renal biopsy

Table 2. Patients characteristics.

Male:female 34:23

Average age at onset

(years old)

27.91 ± 10.48 (10 – 57)

(male : 31.79 ± 11.1, female: 22.17 ± 6.1)

Urinary abnormality

at the onset

Chance proteinuria/hematuria 26

Chance proteinuria 16

Chance hematuria 11

Macrohematuria 3

Other 1

Reason for first

consultation with a

nephrologist

Chance proteinuria/hematuria 30

Chance proteinuria 8

Chance hematuria 6

Macrohematuria 6

Edema 2

Others 5

Average age at first

medical intervention

(years old)

33.67 ± 11.17 (16 – 61)

(male: 37.94 ± 11.4, female : 27.35 ± 7.3)

Histological

prognostic st ag es

Group I 4 (7.1%)

Group II 14 (25.0%)

Group III 25 (44.6%)

Group IV 13 (23.2%)

Unknown 1(1.8%)

3.4. Treatment s in Each Group Classified o n

the Basis of Histological Prognostic

Criteria

The treatment regimes in each histological group are

Figure 1. Significant correlation between the duration from

onset to the first medical intervention and rate of increase in

serum creatinine levels over the 10 year follow-up period.

Openly accessible at

K. Okazaki et al. / Health 3 (2011) 518-523

521

Figure 2. Correlation between the duration from onset to the first medical intervention and the rate

of increase in serum creatinine levels over 10 years in patients grouped according to histological

prognostic criteria. A significant correlation is observed in group III (c) (r = 0.55, P = 0.004), but not

in groups I (a) (P = 0.54), II (b) (P = 0.26), and IV (d) (P = 0.29).

Figure 3. Significant correlation between duration from on-

set to the first medical intervention and age at onset (r =

−0.3, P = 0.05).

summarized in Table 3. Of the 57 patients, 54 were

treated with antiplatelet agents, 12 with anticoagulants

(group II, n = 1; group III, n = 7; and group IV, n = 4),

37 with an ACE I or ARB (group I,n = 2; group II, n = 7;

group III, n = 18; and group IV, n = 10), and 6 with

adrenocortical steroids (group II, n = 1; group III, n = 3;

and group IV, n = 2). Three patients underwent tonsil-

lectomy (1 patient each from groups I, III, and IV). Only

2 patients in group I did not receive any treatment over

the 10 year follow-up period. The number of patients

treated with anticoagulants in group II was less than that

in groups III and IV.

Figure 4. Comparison of the duration from onset to the

first medical intervention among groups classified by uri-

nalysis abnormalities at onset. Patients with asymptomatic

proteinuria visited a nephrologist after a longer period from

onset than did those with asymptomatic hematuria (P = 0.01)

or asymptomatic hematuria and proteinuria (P = 0.003).

3.5. Analysis of Dialysis Cases

All 6 patients (4 males and 2 females) who had under-

gone dialysis within the 10 year follow-up period were

classified histologically into Group IV. In this group,

there was no significant difference in the duration from

estimated onset to the first medical intervention between

dialysis (104.0 ± 110.4 months) and nondialysis patients

K. Okazaki et al. / Health 3 (2011) 518-523

522

Table 3. Treatments in each group classified by histological prognostic criteria.

Group I (N = 4) Group II (N = 14) Group III (N = 25) Group IV (N = 13)

Average period from estimated onset to start of

medicatio n (months) 138.3 ± 136.2 60.3 ± 51.9 84.5 ± 108.7 65.3 ± 72.0

Average period from first consultation to start of

medicatio n (months) 3.0 ± 2.7 3.9 ± 4.2 4.4 ± 6.7 6.3 ± 7.5

Antiplatelet 2 (50.0%) 14 (100%) 25 (100%) 12 (100%)

Anticoagulant 0 1 (7.1%) 7 (28%) 4 (30.7%)

ACEI or ARB 2 (50.0%) 7 (50%) 18 (72%) 10 (76.9%)

Adrenocort ical steroids 0 1(7.1%) 3 (12%) 2 (15.3%)

Tonsillectomy 1 (25.0%) 0 1 (4%) 1 (7.7%)

(59.0 ± 70.6 months). Serum creatinine level at first me-

dical intervention was also not significantly different be-

tween dialysis (1.25 ± 0.63 mg/dl) and non- dialysis pa-

tients (0.96 ± 0.34 mg/dl). However, urinary protein lev-

els at first consultation were significantly higher in the

dialysis patients (3.0 ± 2.5 g/day) than those in nondia-

lysis patients (1.3 ± 1.3 g/day) (P = 0.05).

4. DISCUSSION

IgAN is a disease with poor prognosis. Approximately

40% patients with IgAN develop ESRD within 20 years

of observation. However, 60% patients do not develop

ESRD, with some achieving natural remission [8,9]. It is

therefore important to evaluate the necessity of medical

intervention in patients with IgAN, a condition charac-

terized as CKD.

In general, patients in histological groups III and IV

require long-term treatment, while patients in groups I

and II do not. Therefore, patients in the latter 2 groups

tend to withdraw from treatment within 10 years. In the

current study, we enrolled only those patients whose

medical records could be traced for longer than 10 years;

therefore, the proportion of patients with seriously im-

paired renal function would be higher. In fact, the pro-

portion of patients in groups III and IV in our study was

slightly greater than that reported in the Japanese popu-

lation of IgAN patients [6] (group I, 7.1 vs. 24.4%;

group II, 25 vs. 33.2%; group III, 44.6 vs. 32.8%; group

IV, 23.2 vs. 10.0%). As a result, the data from this pa-

tient group with a marginally worse prognosis may not

be representative of the overall IgAN patient population.

However, a positive correlation between renal prognosis

and the duration from estimated onset to the first medi-

cal intervention was demonstrated in these patients as

well. Subgroup analysis also revealed that this signifi-

cant correlation was observed only in histological group

III, emphasizing that early medical intervention may

lead to an improved renal prognosis for a majority of

patients with IgAN.

On the other hand, there was no difference in the du-

ration until medical intervention between nondialysis

and dialysis patients in Group IV. This finding suggests

that early medical intervention may have little influence

on the prognosis of patients with severe renal impair-

ment, which is reflected by higher levels of urinary pro-

tein at the time of first intervention. However, even in

group IV, 68% patients (13/19) survived without dialysis

over the 10 year follow-up period, indicating the impor-

tance of early medical intervention. Accordingly, our

present analysis highlighted that early medical interven-

tion may be more important for patients in histological

groups III and IV. However, in order to identify these

patients with a histologically poor prognosis, early scree-

ning and subsequent renal biopsy are required. Urinaly-

sis is one of the best methods for early screening of

CKDs such as IgAN [11]. In Japan, under the auspices

of local governments and the Ministry of Health, Labor

and Welfare, a dipstick urine examination has been avai-

lable annually for all school children since 1973, for all

working adults since 1972, and for all residents older

than 40 years of age since 1982 [12]. The Japanese

screening system has certainly contributed to the preven-

tion of CKD progression. However, the 2nd screening

session for patients with hematuria and/or proteinuria

depends on each school or company. The majority of

patients with mild to moderate hematuria and/or pro-

teinuria are followed-up by school or company doctors.

Only when progression or continuing abnormalities in

urinalysis are detected, do these doctors refer the pa-

tients to a nephrologist. This is a major reason why the

mean period from estimated onset to first medical inter-

vention was greater than 6 years in our study. Several

reports concerning the effects and outcome of this scree-

ning are available. For example, the positive rates of

proteinuria (0.4% - 4.9%) and hematuria (1.2% - 21.2%)

in subjects measured by dipstick screening are extremely

high according to one such report [13], suggesting that

false positive patients may also be included. This fact

may also partially influence the delay in initiating medi-

cal consultation.

K. Okazaki et al. / Health 3 (2011) 518-523

523

The present study demonstrated that asymptomatic pa-

tients with proteinuria at onset visited the hospital after a

longer period from onset. As macrohematuria is a strong

motivation for consultation, one reason for this delay

may be that patients with asymptomatic hematuria at

initial urinalysis had macrohematuria more frequently

than patients with asymptomatic proteinuria alone. In

fact, all 6 patients, who first consulted a doctor because

of macrohematuria, did not have asymptomatic protein-

uria at onset. However, in the present study, patients with

macrohematuria accounted for only 10.5% of the study

group, and the number of other patients with macr-

ohematuria may be limited. Accordingly, in addition to

the present screening system, disease-specific methods

are required, at least for IgAN. There are several candi-

dates that may serve as clinical diagnostic markers of

IgAN. For example, more than 75% patients can bepre-

dicted to have IgAN when they have 3 or more of the

following 4 clinical markers: 1) more than five red blood

cells in the urinary sediment, 2) persistent proteinuria

(urinary protein level of more than 0.3 g/day), 3) serum

IgA levels of more than 315 mg/dl, and 4) serum IgA/C3

ratio of 3.01 [14,15]. It has been reported that increased

production of aberrantly glycosylated polymeric IgA1

may be involved in the pathogenesis of IgAN. Therefore,

measurement of serum and urinary alactose-deficient

IgA1 levels is a potential noninvasive test for diagnosis

of IgAN [16].

In conclusion, this study demonstrated that early me-

dical intervention by a nephrologist may improve renal

prognosis, particularly in histological group III patients

and a portion of group IV patients, both of whom form

the major population of IgAN. Therefore, early screen-

ing and subsequent early pathological diagnosis is needed

in all IgAN patients in order to provide early medical

intervention. Because IgAN is a major cause of CKD,

early diagnosis and intervention in patients with this

disease is important from a socioeconomic perspective.

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