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NDT Advance Access published April 5, 2012
Nephrol Dial Transplant (2012) 0: 1–7
doi: 10.1093/ndt/gfs053
Original Article
Tonsillectomy has beneficial effects on remission and progression of IgA
nephropathy independent of steroid therapy
Isseki Maeda1,2, Tomoshige Hayashi1, Kyoko Kogawa Sato1, Mikiko Okumoto Shibata2,
Masahiro Hamada2, Masatsugu Kishida2, Chizuko Kitabayashi2, Takashi Morikawa2, Noriyuki Okada2,
Michiaki Okumura2, Masayo Konishi3, Yoshio Konishi2, Ginji Endo1 and Masahito Imanishi2
1
Department of Preventive Medicine and Environmental Health, Osaka City University Graduate School of Medicine, Osaka, Japan,
Department of Nephrology and Hypertension, Osaka City General Hospital, Osaka, Japan and 3Department of Nephrology, Wakakusa
Daiichi Hospital, Osaka, Japan
2
Abstract
Background. Indication of tonsillectomy in IgA nephropathy is controversial. The purpose of this study was to
examine the efficacy of tonsillectomy on remission and
progression of IgA nephropathy.
Methods. We conducted a single-center 7-year historical
cohort study in 200 patients with biopsy-proven IgA nephropathy. Study outcomes were clinical remission defined as
disappearance of urine abnormalities at two consecutive
visits, glomerular filtration rate (GFR) decline defined as
30% GFR decrease from baseline and GFR slope during
the follow-up.
Results. Seventy of the 200 patients received tonsillectomy.
Tonsillectomy was associated with increased incidence of
clinical remission (P < 0.01, log-rank test) and decreased
incidence of GFR decline (P ¼ 0.01, log-rank test). After
adjustment for age and gender, hazard ratios in tonsillectomy
were 3.90 (95% confidence interval 2.46–6.18) for clinical
remission and 0.14 (0.02–1.03) for GFR decline. After
further adjustment for laboratory (baseline mean arterial
pressure, GFR, 24-h proteinuria and hematuria score), histological (mesangial score, segmental sclerosis or adhesion,
endocapillary proliferation and interstitial fibrosis) or treatment variables (steroid and renin–angiotensin system inhibitors), similar results were obtained in each model. Even after
exclusion of 69 steroid-treated patients, results did not
change. GFR slopes in tonsillectomy and non-tonsillectomy
groups were 0.60 6 3.65 and 1.64 6 2.59 mL/min/1.73
m2/year, respectively. In the multiple regression model, tonsillectomy prevented GFR decline during the follow-up period (regression coefficient 2.00, P ¼ 0.01).
Conclusion. Tonsillectomy was associated with a favorable renal outcome of IgA nephropathy in terms of
clinical remission and delayed renal deterioration even in
non-steroid-treated patients.
Keywords: clinical remission; IgA nephropathy; renal deterioration;
steroid therapy; tonsillectomy
Introduction
IgA nephropathy is the most common type of primary glomerulonephritis. Clinical course of this disease depends on
clinical manifestations and is greatly varied by patient.
Ten-year renal survival was estimated ~80–85% [1]. In
patients at high risk for progressive disease, such as those
with severe proteinuria or arterial hypertension, treatment
with renin–angiotensin system (RAS) inhibitors or corticosteroid to resolve urine abnormalities and prevent renal
deterioration is established with support from a growing
body of evidence [2–7]. However, the therapeutic effect
of tonsillectomy in IgA nephropathy is controversial [8].
Although IgA nephropathy has highly variable clinical
presentations, gross hematuria at the time of tonsillitis is
one of the typical clinical features of this disease. Chronic
and recurrent tonsillitis are considered to play an important
role in new onset and progression of IgA nephropathy.
Although several previous studies have examined whether
tonsillectomy had a beneficial effect on IgA nephropathy in
regard to clinical remission or renal deterioration, the results were inconsistent [9–12]. Some of the studies showed
that tonsillectomy normalized urine abnormalities (clinical
remission) in patients with IgA nephropathy, but failed to
show that tonsillectomy prevented renal deterioration in the
same patients [9, 10]. Because of the slowly progressive
nature of IgA nephropathy, renal deterioration could not be
detected as study outcomes including end-stage renal disease (ESRD) or need for renal replacement therapy in relatively short-term studies. As the therapeutic target of
early-stage IgA nephropathy is delaying loss of renal function, the therapeutic efficacy of tonsillectomy should be
measured by continuous values such as glomerular filtration rate (GFR) slope. In addition, because steroid therapy
has a strong effect on clinical manifestation of IgA
nephropathy, a study in patients who mainly received combination therapy with tonsillectomy and steroid therapy
might be inappropriate to evaluate the independent efficacy
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Correspondence and offprint requests to: Tomoshige Hayashi; E-mail: [email protected]
2
of tonsillectomy. Two retrospective studies examined the
effect of tonsillectomy on kidney outcome in the 1970s,
when the indication of corticosteroid therapy for IgA
nephropathy was limited. However, the results were inconclusive [11, 12]. The main reasons for the discrepancy were
the difference of patient characteristics and indication for
renal biopsy and treatment.
We therefore performed a longitudinal study using historical
data from a single center to elucidate the effect of tonsillectomy
on the remission and progression of IgA nephropathy.
Materials and methods
Site and setting
Therapeutic intervention
Of the 200 patients, 70 patients received tonsillectomy. Indication of tonsillectomy was decided after consultation with otolaryngologists. Standard
indications of tonsillectomy were recurrent tonsillitis three times or more
per year, repeated episodes of gross hematuria at the time of tonsillitis or
chronic tonsillitis with pus in tonsillar crypt [9, 13, 14]. Tonsillectomy was
performed within 6 months from the renal biopsy. There were 69 patients
who received oral or pulse steroid therapy as their initial treatment. Main
indications for steroid therapy were if patients had symptoms of progressive diseases such as high-grade proteinuria, erythrocyte cast, acute renal
failure or advanced histological findings including glomerular sclerosis,
crescent formation, endocapillary proliferation or interstitial infiltration. In
oral steroid therapy, the initial dose of prednisolone was 0.6–0.8 mg/kg/
day. In pulse steroid therapy, 500 mg of methylprednisolone was administered intravenously on three consecutive days followed by oral prednisolone (30 mg/day) on four consecutive days. This course was repeated
three times. After that, prednisolone at a dose of 30 mg/day was given
orally on alternative days. In both therapies, prednisolone was gradually
tapered and finished over 1 year. The protocol of the pulse therapy was
established by Hotta et al. [9].
Data collection
Clinical, laboratory and histological data were recorded in our database.
Patient characteristics included age at biopsy, gender, time of onset, type
of onset (gross hematuria, urine abnormalities in medical checkup or
other symptoms), history of recurrent tonsillitis, evidence of enlarged
tonsils and anthropometric and laboratory data. Blood pressure was
measured using a mercury manometer in a supine position after a few
minutes of rest. Twenty-four-hour urine collection was performed on
three consecutive days. Baseline blood pressure, serum creatinine, 24h proteinuria and hematuria score were calculated as the average of the
three measurements. The results of dipstick urinalysis were interpreted as
(), (), (1), (21) or (31). Results of () or less in dipstick urinalysis
were regarded as normal. To assess the degree of hematuria, the dipstick
results were converted into scores: () to 0, () to 0.5, (1) to 1, (21) to
2 and (31) to 3. We calculated estimated GFR using a modified threevariable equation for Japanese, which was validated by the standard
inulin clearance techniques, as follows: estimated GFR ¼ 194 3
Age0.287 3 serum creatinine1.094 (mg/dL) 3 0.739 (if female) [15].
Histological evaluation was made according to the Oxford classification
of IgA nephropathy [16, 17]. The following pathological variables were
evaluated: mesangial hypercellularity score, presence or absence of segmental sclerosis or adhesion, endocapillary hypercellularity and tubular
atrophy/interstitial fibrosis. Interstitial lesion was graded as 0: 0–25%, 1:
26–50% and 2: 51% or more. These variables were described as having
predictive value for renal outcome in previous articles [16, 17]. During
the follow-up period, patients underwent a medical checkup every 1–3
months. Blood pressure, dipstick urinalysis and serum creatinine were
measured at every visit. Treatments with oral or intravenous steroids,
RAS inhibitors, other anti-hypertensive medications or tonsillectomy
were also recorded.
Outcomes
Clinical remission of IgA nephropathy was defined as normal dipstick
examination of hematuria and proteinuria on two consecutive visits at least
3 months apart. GFR decline was defined as >30% loss of estimated GFR
from the baseline value. GFR slope of each patient during the follow-up
period was obtained by a linear regression model and the principle of least
squares. To calculate GFR slope, we used values of estimated GFR at
every visit during the entire follow-up period of each patient even if the
patient had experienced clinical remission or 30% GFR decline earlier.
This value indicated annual GFR loss (mL/min/1.73 m2/year) and was not
dependent on the follow-up length of patients.
Statistics
Baseline characteristics are presented separately according to the presence
or absence of tonsillectomy. The values are expressed as mean SD,
median (interquartile range) or %. Paired analysis between the groups
was performed using unpaired t-test, Mann–Whitney test or chi-square
test. To assess the effect of tonsillectomy on clinical remission or GFR
decline, we used Kaplan–Meier plot, log-rank test and Cox’s proportional
hazards models. Follow-up of each patient for Cox’s proportional hazards
models was continued until the date of the first occurrence of each outcome of interest, the final visit or 7 years from diagnostic biopsy, whichever came first. Because we had a limited number (n ¼ 30) of incident
cases of GFR decline, adjustment for all baseline variables in one model
might cause inaccurate estimation [18]. To avoid this problem, we examined four models in which tonsillectomy was adjusted for the following
variables: in Model 1, age and gender; in Model 2 (laboratory variables),
mean arterial pressure, GFR, 24-h proteinuria and hematuria score in
addition to Model 1; in Model 3 (histological variables), mesangial score,
segmental sclerosis or adhesion, endocapillary proliferation and interstitial
fibrosis in addition to Model 1 and in Model 4 (treatment variables), RAS
inhibitors and steroid therapy in addition to Model 1. Proportional hazard
assumption was confirmed by log-log plot.
We also examined risk factors affecting GFR slope using multiple
linear regression analysis. In this model, we included factors that had a
P-value <0.2 in univariate analyses or had clinical relevance. We included
age, gender, mean arterial pressure, GFR, 24-h proteinuria, hematuria
score, mesangial score, segmental sclerosis or adhesion, interstitial fibrosis, RAS inhibitors and tonsillectomy in the multiple linear regression
model. Multicollinearity was tested using variance inflation factor. In both
Cox proportional hazards models and multiple linear regression models,
non-linear effects of continuous independent variables were evaluated by
inserting quadratic and log transformations into the multiple-adjusted
models. Because 24-h proteinuria showed a non-linear effect, we converted it into log-transformed form. We calculated 95% confidence
Downloaded from http://ndt.oxfordjournals.org/ by guest on April 7, 2012
From April 1997 to December 2007, 1034 patients underwent renal biopsy
in the Department of Nephrology and Hypertension, Osaka City General
Hospital, Osaka, Japan. In our clinical policy, main indication for performing a renal biopsy was asymptomatic urine abnormalities (persistent microscopic hematuria and mild to moderate proteinuria), recurrent episodes
of gross hematuria, nephrotic syndrome or acute renal insufficiency of
unknown origin without obvious urological abnormalities. Of these
1034 patients, 340 patients had a diagnosis of IgA nephropathy. Diagnosis
of IgA nephropathy was made by detection of mesangial proliferative
glomerulonephritis with deposits of immune complex staining predominantly for IgA in light microscopic and immunofluorescence studies. Patients were eligible for the current study if the following criteria were all
satisfied: age 15–65 years at study entry; newly diagnosed IgA nephropathy; no clinical or biological evidence of systemic diseases such as Henoch–Schonlein purpura nephritis, systemic lupus erythematosus, other
collagen diseases, viral hepatitis, diabetes or malignancy; no previous treatment with corticosteroids or immunosuppressive drugs; baseline serum creatinine level <176.8 mmol/L (2.0 mg/dL) and at least 12 months follow-up
at our institute. Of the 340 patients, 99 patients were excluded because of
age criteria (n ¼ 18), non-initial biopsy or previous treatment (n ¼ 13),
concomitant disease (n ¼ 28), elevated serum creatinine (n ¼ 3) and/or loss
to follow up before 12 months (n ¼ 43). Eligible patients consisted of 241
men and women. Then, we further excluded 41 subjects because of incomplete clinical data (n ¼ 18), normal range of hematuria and proteinuria (n ¼
11) or insufficient biopsy specimen containing less than eight glomeruli (n ¼
12). Therefore, the cohort for current analyses consisted of 200 men and
women. We also performed additional analyses to assess independent effectiveness of tonsillectomy after exclusion of 69 patients who had received
steroid therapy as their initial treatment. The protocol of this research was
reviewed and approved by the local ethical committee.
I. Maeda et al.
Tonsillectomy and IgA nephropathy
3
intervals for each hazard ratio and coefficient. P-values were two-tailed.
Statistical analyses were performed using PASW Statistics 17.0 (SPSS
Inc., Chicago, IL).
Results
Baseline characteristics
Baseline characteristics of study participants are shown in
Table 1. Most of the clinical and histological factors were
comparable between tonsillectomy and non-tonsillectomy
groups. Endocapillary hypercellularity in biopsy specimens
was seen more often in patients who received tonsillectomy
than in those who did not. The tonsillectomy group received treatment with steroid and RAS inhibitors more
frequently than the non-tonsillectomy group. The tonsillectomy group showed more active and less advanced
histological changes and was administered aggressive treatments compared to the non-tonsillectomy group.
Incidence rates of clinical remission were 9.3 per 100
person-years in the non-tonsillectomy group and 34.2 per
100 person-years in the tonsillectomy group. Tonsillectomy
showed a significant positive association with clinical remission (P < 0.01, Figure 1A). In Cox’s proportional hazards
models, patients with tonsillectomy revealed a 3.90 times
higher hazard ratio for clinical remission than those without
tonsillectomy after adjustment for age and gender. This relationship remained after adjustment for laboratory, histological or treatment variables; multiple-adjusted hazard ratios
for tonsillectomy were 4.03 (95% confidence interval
2.52–6.44), 3.71 (2.30–5.98) and 3.06 (1.74–5.40), respectively. Lower hematuria score and steroid therapy were also
associated with clinical remission (Table 2).
GFR decline
Incidence rates of GFR decline were 4.8 per 100 person-years
in the non-tonsillectomy group and 0.5 per 100 person-years
Non-steroid-treated patients
To eliminate the therapeutic effect of corticosteroid therapy,
we excluded an additional 69 patients who underwent steroid
therapy as their initial treatment. Characteristics of the patients
without steroid therapy are presented in Table 3. The tonsillectomy group had fewer cases of males, lower 24-h proteinuria and lower mesangial score than the non-tonsillectomy
Table 1. Baseline characteristics according to patients with or without tonsillectomy who had IgA nephropathya
Age, years
Gender, male
History of recurrent tonsillitis, yes
Gross hematuria, yes
Body mass index, kg/m2
Mean arterial pressure, mmHg
IgA, mg/dL
Estimated GFR, mL/min/1.73 m2
24-h proteinuria, mg/dL
Hematuria score
Mesangial score
Glomeruli with segmental sclerosis or adhesion, %
Endocapillary hypercellularity, yes
Interstitial fibrosis, 0–25/26–50/51%1
Steroid therapy
RAS inhibitor
GFR slope, mL/min/1.73 m2/year
Tonsillectomy (n ¼ 70)
No tonsillectomy (n ¼ 130)
31.0 (25.2–36.7)
19 (27.1%)
51 (72.9%)
26 (37.1%)
21.3 (19.5–24.6)
87.5 (81.8–94.0)
319.0 (267.0–385.3)
89.6 6 25.2
349.7 (129.4–1006.8)
2.00 (1.92–2.38)
0.50 (0.33–0.74)
11.1 (5.4–25.9)
37 (52.9%)
66/3/1
50 (71.4%)
49 (70.0%)
0.03 6 6.03
32.1 (23.0–48.5)
48 (36.9%)
85 (65.4%)
49 (37.7%)
21.9 (19.9–24.2)
87.8 (81.7–98.0)
325.7 (250.4–442.5)
85.4 6 23.2
341.7 (127.9–842.7)
2.50 (1.79–3.00)
0.57 (0.37–0.83)
15.4 (7.0–30.0)
45 (34.5%)
116/9/5
19 (14.6%)
58 (44.6%)
1.31 6 2.73
P-value
0.25
0.21
0.34
1.00
0.40
0.44
0.46
0.25
0.95
0.09
0.18
0.07
0.02
0.46
<0.01
0.01
0.10
a
Values are expressed as mean 6 SD, median (interquartile range) or % and compared using unpaired t-test, Mann–Whitney’s U-test or chi-square test,
respectively.
Downloaded from http://ndt.oxfordjournals.org/ by guest on April 7, 2012
Clinical remission
in the tonsillectomy group. Tonsillectomy was associated
with a lower incidence of GFR decline (P ¼ 0.01, Figure
1B). In Cox’s proportional hazards models, patient who received tonsillectomy had a lower risk for GFR decline. After
adjustment for laboratory, histological or treatment variables,
multiple-adjusted hazard ratios were 0.12 (0.02–0.89), 0.12
(0.02–0.89) and 0.10 (0.01–0.85), respectively. Proteinuria
was associated with an unfavorable renal outcome. Treatment
with RAS inhibitors showed a significantly higher hazard
ratio for GFR decline (Table 2).
As shown in Table 1, the tonsillectomy group revealed a
higher proportion of patients receiving steroid and RAS
inhibitor therapy. Since these treatments are known to delay progression of IgA nephropathy, we conducted additional analyses. After further adjustment for the treatments
of steroid and RAS inhibitor therapy in Models 1–3 (shown
in Table 2), which did not include these treatments, the
results did not change (data not shown). Similarly, distributions of segmental glomerulosclerosis and endocapillary
hypercellularity differ by groups. When we performed additional analyses to use these histological factors as independent variables in Models 1, 2 and 4 of Table 2 which did
not include them, the results did not change (data not
shown). Furthermore, even when we defined a rapid disease
evolution if a patient had a GFR slope <5.12 mL/min/1.73
m2/year, which was the lowest 10th percentile value of the
analytic cohort (n ¼ 200), the proportion of the patients who
underwent tonsillectomy was not different between patients
with or without rapid disease progression (40.0 versus
34.4%, in patients with or without rapid disease evolution,
P ¼ 0.62 in chi-square test).
4
I. Maeda et al.
Fig. 1. (A) Kaplan–Meier plot illustrating the probability of clinical remission among all patients who had IgA nephropathy according to tonsillectomy.
(B) Kaplan–Meier plot illustrating the probability of renal survival for all patients who had IgA nephropathy according to tonsillectomy.
Clinical remissionb
HR (95% CI)
Model 1 (age- and gender-adjusted model)d
Tonsillectomy
Model 2 (clinical factor-adjusted model)d
Tonsillectomy
Mean arterial pressure, 10 mmHg
Baseline GFR, 10 mL/min/1.73 m2
Log 24-h proteinuria, mg/dL
Hematuria score
Model 3 (histological factor-adjusted model)d
Tonsillectomy
Mesangial score
Segmental sclerosis or adhesion
Endocapillary proliferation
Interstitial fibrosis
26–50%
51%1
Model 4 (treatment factor-adjusted model)d
Tonsillectomy
Steroid
RAS inhibitor
GFR declinec
P
HR (95% CI)
P
0.05
3.90 (2.46–6.18)
<0.01
0.14 (0.02–1.03)
4.03 (2.52–6.44)
0.95 (0.73–1.23)
0.92 (0.80–1.05)
0.66 (0.42–1.05)
0.64 (0.48–0.85)
<0.01
0.68
0.21
0.08
<0.01
0.12 (0.02–0.89)
1.26 (0.81–1.94)
1.26 (0.98–1.60)
5.93 (2.02–17.42)
1.00 (0.61–1.63)
3.71 (2.30–5.98)
0.55 (0.26–1.16)
1.00 (0.53–1.88)
1.30 (0.84–2.00)
<0.01
0.12
1.00
0.24
0.12 (0.02–0.89)
1.57 (0.55–4.48)
0.57 (0.16–1.95)
1.78 (0.80–3.97)
0.04
0.40
0.37
0.16
1.14 (0.46–2.81)
0.86 (0.20–3.65)
0.78
0.83
1.86 (0.59–5.86)
2.67 (0.58–12.19)
0.29
0.21
3.06 (1.74–5.40)
2.35 (1.38–4.02)
0.58 (0.36–0.93)
<0.01
<0.01
0.02
0.10 (0.01–0.85)
1.01 (0.32–3.16)
2.61 (1.12–6.06)
0.03
0.99
0.03
0.04
0.30
0.07
<0.01
1.00
a
CI, confidence interval; HR, hazard ratio.
Clinical remission was defined as normal dipstick examination of hematuria and proteinuria on two consecutive visits at least 3 months apart.
GFR decline was defined as >30% loss of estimated GFR from baseline.
d
Age and gender were also adjusted in models 1–4.
b
c
group. The non-tonsillectomy group presented a steeper GFR
slope than the tonsillectomy group (1.64 2.59 versus 0.60
3.65, P < 0.01). Incidence rates of clinical remission were
21.8 per 100 person-years in the tonsillectomy group and 8.3
per 100 person-years in the non-tonsillectomy group. The
tonsillectomy group showed a higher incidence of clinical
remission than the non-tonsillectomy group (P < 0.01,
Figure 2A). Although the incidence rate of GFR decline
was lower in the tonsillectomy group than in the non-tonsillectomy group, the difference did not reach statistical significance (P ¼ 0.10, Figure 2B). In Cox’s proportional hazards
models, the hazard ratio for clinical remission was about three
times higher in patients with tonsillectomy than in those with-
out tonsillectomy even after adjustment for potential confounders. Lower proteinuria was also associated with a
higher incidence of clinical remission (Table 4).
Because no patients with tonsillectomy reached the end
point of GFR decline during the follow-up, we could not
estimate hazard ratios in Cox’s proportional hazards model.
Instead, we calculated GFR slope during mean follow-up
of 5.2 0.2 years (2.7 0.4 years in tonsillectomy and 5.6
0.2 years in non-tonsillectomy group) and assessed factors relevant to GFR slope. In the multiple linear regression
model, tonsillectomy indicated a delaying effect on renal
function decline (regression coefficient 2.00, 95% confidence interval 0.58–3.42, P ¼ 0.01). A higher baseline
Downloaded from http://ndt.oxfordjournals.org/ by guest on April 7, 2012
Table 2. Multivariable-adjusted hazard ratio for clinical remission or GFR decline in all patients with IgA nephropathy (n ¼ 200)a
Tonsillectomy and IgA nephropathy
5
Table 3. Baseline characteristics according to patients with or without tonsillectomy who had IgA nephropathy and who did not receive initial steroid
therapya
Age, years
Gender, male
History of recurrent tonsillitis, yes
Gross hematuria, yes
Body mass index, kg/m2
Mean arterial pressure, mmHg
IgA, mg/dL
Estimated GFR, mL/min/1.73 m2
24-h proteinuria, mg/dL
Hematuria score
Mesangial score
Glomeruli with segmental sclerosis or adhesion, %
Endocapillary hypercellularity, yes
Interstitial fibrosis, 0–25/26–50/51%1
RAS inhibitor
GFR slope, mL/min/1.73 m2/year
Tonsillectomy (n ¼ 20)
No tonsillectomy (n ¼ 111)
P-value
31.7 (24.5–38.5)
3 (15.0%)
17 (85.0%)
7 (35.0%)
21.5 (19.7–24.2)
87.7 (83.3–95.0)
319.0 (267.0–385.3)
98.5 (71.3–116.3)
138.6 (59.9–461.7)
2.00 (1.67–2.33)
0.37 (0.25–0.50)
9.0 (0.0–26.6)
4 (20.0%)
19/1/0
8 (40.0%)
0.60 6 3.65
34.3 (23.0–49.6)
43 (38.7%)
72 (64.9%)
43 (38.7%)
21.9 (20.0–24.3)
89.3 (82.9–98.0)
325.7 (250.4–442.5)
88.7 (69.5–104.7)
307.7 (119.5–790.2)
2.50 (1.67–3.00)
0.56 (0.38–0.80)
15.4 (6.7–25.0)
31 (27.9%)
100/6/5
49 (44.1%)
1.64 6 2.59
0.36
0.04
0.12
0.81
0.70
0.57
0.17
0.17
0.05
0.07
0.01
0.10
0.59
0.62
0.81
<0.01
a
Values are expressed as median (interquartile range) or % and compared using Mann–Whitney’s U-test or chi-square test.
GFR was associated with faster renal deterioration
(Table 5). Multicollinearity did not affect the result because
the variance inflation factor in each variable was <5.
Operative findings
Although of the 70 patients who received tonsillectomy, 12
patients had no clinical symptoms of recurrent tonsillitis or
gross hematuria following tonsillitis before tonsillectomy, a
substantial amount of pus attachment to re-sected tonsils
was detected among the operative findings in 11 patients. In
tonsils of the other one case, inflammatory response was
confirmed histologically.
Adverse event
Serious adverse events were not observed throughout the
study. Only one patient experienced hyperglycemia that
needed temporary insulin injection.
Discussion
In this single-center historical cohort study among patients
with biopsy-proven IgA nephropathy, we demonstrated
that tonsillectomy was significantly associated with favorable renal outcomes such as clinical remission and delayed
renal deterioration. Even in patients who did not receive
initial steroid therapy, tonsillectomy was significantly associated with clinical remission and a smaller annual GFR
loss during the follow-up. This reno-protective effect was
independent of the known risk factors including blood pressure, proteinuria and histological findings.
Although several reports examined the therapeutic effect
of tonsillectomy in IgA nephropathy, the results were not
consistent [9–12]. Hotta et al. [9] reported that treatment
with tonsillectomy and steroid therapy was associated with
clinical remission in 329 patients with IgA nephropathy.
Similar results were described in a report by Komatsu et al.
Downloaded from http://ndt.oxfordjournals.org/ by guest on April 7, 2012
Fig. 2. (A) Kaplan–Meier plots illustrating the probability of clinical remission among patients who had IgA nephropathy and did not receive initial
steroid therapy according to tonsillectomy. (B) Kaplan–Meier plots illustrating the probability of renal survival among patients who had IgA nephropathy
and did not receive initial steroid therapy according to tonsillectomy.
6
I. Maeda et al.
[10] that combination therapy of tonsillectomy and pulse
steroid was superior to pulse steroid alone with regard to
remission of proteinuria. However, they failed to demonstrate the delaying effect of the combination therapy on
renal deterioration. Since corticosteroid therapy has strong
effects on resolution of urine abnormalities and sustention
of renal function, evaluating the efficacy of tonsillectomy
as combination therapy with steroids might cause indistinguishable results. Two retrospective observations were per-
Table 4. Multivariable-adjusted hazard ratio for clinical remission in
patients with IgA nephropathy who did not receive initial steroid
therapy (n ¼ 131)a
Clinical remissionb
HR (95% CI)
3.29 (1.53–7.08) <0.01
3.05 (1.37–6.79)
0.90 (0.63–1.29)
0.84 (0.69–1.03)
0.43 (0.22–0.85)
0.70 (0.49–1.00)
0.01
0.56
0.10
0.01
0.05
3.22 (1.41–7.36)
0.47 (0.18–1.26)
0.78 (0.33–1.88)
0.82 (0.41–1.63)
0.01
0.14
0.58
0.58
0.87 (0.19–4.08)
0.49 (0.07–3.73)
0.86
0.49
3.73 (1.68–8.28) <0.01
0.65 (0.35–1.20)
0.17
a
CI, confidence interval; HR, hazard ratio.
Clinical remission was defined as normal dipstick examination of hematuria and proteinuria on two consecutive visits at least 3 months apart.
c
Age and gender were also adjusted in models 1–4.
b
Table 5. Regression coefficients for GFR slope among patients with IgA nephropathy who did not receive initial steroid therapy (n ¼ 131)a
GFR slope (mL/min/1.73 m2/year)b
b
Tonsillectomy, yes
Age, per 5 years
Gender, male
Mean arterial pressure, per 10 mmHg
Baseline GFR, per 10 mL/min/1.73 m2
Log 24-h proteinuria, mg/dL
Hematuria score, per L
Mesangial score, per L
Segmental sclerosis or adhesion, yes
Interstitial fibrosis
26–50%
51%1
RAS inhibitor, yes
a
Standardize b
P-value
2.00 (0.58–3.42)
0.11 (0.41 to 0.19)
0.57 (1.66 to 0.52)
0.35 (0.96 to 0.26)
0.40 (0.73 to 0.07)
1.21 (2.56 to 0.13)
0.10 (0.57 to 0.77)
0.06 (1.66 to 1.79)
0.20 (1.81 to 1.41)
0.25
0.11
0.09
0.13
0.35
0.22
0.03
0.01
0.02
0.01
0.48
0.30
0.26
0.02
0.08
0.78
0.94
0.81
0.45 (2.93 to 2.03)
0.08 (2.54 to 2.70)
0.02 (1.28 to 1.17)
0.04
0.01
0.01
0.72
0.95
0.97
b, regression coefficient.
GFR slope was obtained using linear regression model and values of estimated GFR at every visit during the follow-up (up to 7 years) even if the patient
had experienced clinical remission or 30% GFR decline earlier.
b
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Model 1 (age- and gender-adjusted model)c
Tonsillectomy
Model 2 (clinical factor-adjusted model)c
Tonsillectomy
Mean arterial pressure, 10 mmHg
Baseline GFR, 10 mL/min/1.73 m2
Log 24-h proteinuria, mg/dL
Hematuria score
Model 3 (histological factor-adjusted model)c
Tonsillectomy
Mesangial score
Segmental sclerosis or adhesion
Endocapillary proliferation
Interstitial fibrosis
26–50%
51%1
Model 4 (treatment factor-adjusted model)c
Tonsillectomy
RAS inhibitor
P
formed in the 1970s when the indication of corticosteroid
in IgA nephropathy was limited. Rasche et al. [11] described that tonsillectomy had no beneficial effect on preventing ESRD. This might be partly because they included
patients with relatively advanced stages: 55% of the participants had hypertension, 35% had elevated serum creatinine (>150 mmol/L) and 62% had high-grade proteinuria
(>1.5 g/day). Consequently, they observed that 25% of
their subjects reached ESRD in 2.3 years and failed to
detect a beneficial effect of tonsillectomy. On the other
hand, Xie et al. [12] reported effectiveness of tonsillectomy
in a long-term observational study. They included patients
with a relatively mild stage of IgA nephropathy: mean
serum creatinine was 94.7 mmol/L and 38% of the patients
had proteinuria of 0.5 g/day or less at baseline. Therefore,
tonsillectomy might indicate a beneficial effect on renal
function decline in an early and mild stage of IgA nephropathy. Strength of our study was to demonstrate tonsillectomy was associated with not only amelioration of urinary
finding but also delaying renal deterioration in patients
treated with both combination therapy and tonsillectomy
alone in a large number of subjects with a variety of clinical
and histological manifestations.
The mechanisms explaining how tonsillectomy improves
renal outcome are unclear. As acute deterioration of urinary
findings is frequently observed at the time of upper respiratory
tract or gastrointestinal infections, IgA nephropathy has been
thought to be a disease of mucosal immune system. Because
patients with recurrent tonsillitis showed an elevated level
of serum immunoglobulin (IgA, IgG and IgM), increased
IgA synthesis has been thought to play an important part
in the pathogenesis of IgA nephropathy [19]. In addition,
anomaly in the glycosylation of IgA molecules may play
another important part in the pathogenesis [20]. Altered glycosylation leads to a decrease in the clearance of IgA1 molecules by the liver [21] and increases binding of IgA1 to
glomerular mesangium [22]. These two mechanisms are related, and elevated synthesis and reduced clearance of
Tonsillectomy and IgA nephropathy
Conflict of interest statement. None declared.
References
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18. Peduzzi P, Concato J, Feinstein AR et al. Importance of events per
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Received for publication: 22.7.11; Accepted in revised form: 2.2.12
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abnormal IgA1 may form a vicious circle. Tonsillectomy may
provide resolution upstream of the pathogenesis and induce
remission of the disease.
Our study had several limitations. Firstly, participants of
the current study had relatively mild cases of IgA nephropathy compared with those of previous reports. Because all
students at schools and subjects at worksites are required to
undergo annual health screenings by Japanese law, a mild
and early stage of IgA nephropathy might be diagnosed
more frequently in Japan than in countries without such a
screening system. IgA nephropathy is a slowly and gradually
progressive disease with repeated episodes of ‘flare-ups’ at
each occurrence of upper respiratory infection. Tonsillectomy can be a useful therapeutic option especially in an early
stage of IgA nephropathy with preserved renal function.
Secondly, because this study was a historical cohort study,
tonsillectomy was not randomly assigned. Tonsillectomy
and steroid therapy were frequently performed after 2001,
which was the year of publication by Hotta et al. [9]. Their
concept was that combination therapy of steroids and tonsillectomy was associated with clinical remission, and a patient
who achieved clinical remission sustained renal function
over a long period of time. In our institute, tonsillectomy
was administered as a part of the combination therapy if a
patient wished to undergo this therapeutic option to achieve
clinical remission of IgA nephropathy even if their clinical
manifestations were not so severe. Relatively recent cases
tended to undergo tonsillectomy. This decision-making
process could cause the difference of follow-up length between the two groups and substantial selection bias. Thirdly,
a significant relationship was not observed between histological findings and renal outcomes. In addition, patients
who were prescribed RAS inhibitors showed a higher risk
for renal function decline. Mild histological findings and
treatment with RAS inhibitors are known as factors associated with favorable renal outcome. They might reflect referral bias. Patients who revealed advanced disease in biopsy
specimen or had hypertension or high-grade proteinuria
would undergo aggressive treatment. Even if we applied a
multivariable analysis, we might not be able to control for
these confounders entirely. Finally, difference of the incidence of 30% GFR decline between tonsillectomy and
non-tonsillectomy group among non-steroid-treated subjects
did not reach a statistical significance in log-rank test. We
thought that this was due to the limited number of subjects
treated with tonsillectomy alone.
In conclusion, tonsillectomy was associated with favorable renal outcomes of clinical remission and delayed renal
deterioration. This association was observed not only in
patients with combination therapy but also in patients with
tonsillectomy alone. This GFR preservation effect was independent of other known factors including treatment with
RAS inhibitors. Tonsillectomy should be considered in
patients with IgA nephropathy, especially at a mild or early
stage, to prevent future renal deterioration.
7