Shinshu M ed J, 62⑵ :89 〜97, 2014

The Traditional Japanese Medicine (Kampo)Boiogito has a Dual Beneﬁt in
Cardiorenal Syndrome:A Pilot Observational Study
M ilan GAUTAM , Atsushi IZAWA ＊ , Tatsuya SAIGUSA , Saeko YAMASAKI
Hirohiko MOTOKI , Takeshi TOMITA , Yusuke MIYASHITA , Jun KOYAMAMinoru HONGO and Uichi IKEDA
1) Department of Cardiovascular Medicine, Shinshu University School of Medicine
2) Department of Cardiovascular Medicine, Shinshu University School of Health Sciences

Background : Conventional treatment for cardiorenal syndrome (CRS) is frequently associated with drug
resistance and limited clinical success. We aimed to explore a new approach utilizing Boiogito (TJ‑20), a
traditional Japanese medicine (Kampo), in combination with conventional treatment for patients with CRS.
Methods and Results:We enrolled 26 patients with CRS (18 men ;mean age,77±8.4 years;mean serum brain
natriuretic peptide (BNP),241.5±196.6 pg/mL ;mean estimated glomerular ﬁltration rate(eGFR),40.02±10.54
mL.min .1.73 m ). Treatment with TJ‑20 was started at an average dose of 4.6±1.5 g/day, which wasincreased to 5.2±1.2 g/day at 3.5 months and to 5.9 ±1.5 g/day at 9.4 months. TJ‑20 treatment signiﬁcantly
increased mean eGFR (mL.min .1.73 m )to 44.60±10.76 at 3.5 months (P＝0.001), and to 45.93±11.57 at 9.
4 months (P＝0.0004). In addition, the New York Heart Association functional classiﬁcation improved (P＝0.
019),and serum BNP levels decreased signiﬁcantly to 195.5±145.7 pg/mL at 3.5 months (P＝0.008)and to 163.
3±130.2 pg/mL at 9.4 months (P＝0.007).The increase in eGFR had no correlation with the decrease in BNPlevel, indicating independent eﬀects on both renal function and heart failure status.
Conclusions:TJ‑20 can beneﬁt both renal function and heart failure status in patients with CRS.Alternative
medicine utilizing TJ‑20 may provide a novel and useful strategy for the diﬃcult management of patients with
CRS. Shinshu Med J 62 : 89 ―97, 2014
(Received for publication December 2, 2013;accepted in revised form January 8, 2014)
Key words:chronic heart failure, renal insuﬃciency, renal function, brain natriuretic peptide

Introduction

failure (CHF) and is associated with adverse outcomes in these patients. Ronco et al described

Cardiorenal syndrome(CRS)is characterized bya

the bidirectional pathophysiology of CRS as fol-

combination of cardiac and renal dysfunction. Its

lows: “acute or chronic dysfunction in one organ

incidence is increasing, because of shared risk fac-

may induce acute or chronic dysfunction in thetors such as hypertension, diabetes mellitus, ather-other organ” . Complex and poorly understoodosclerosis,and renovascular disease .CRS has beencardiorenal interactions in CRS make patient man-identiﬁed in 30‑60% of patients with chronic heart

agement a clinical challenge. In addition, mostCorresponding author:Atsushi Izawa

medications used in CHF may be either underused

Department of Cardiovascular M edicine,Shinshu Univer-or understudied in patients with renal insuﬃciency,sity School of M edicine,3‑1‑1 Asahi,M atsumoto,Nagano

because patients with renal dysfunction are often

390‑8621 JapanE‑mail:izawa611＠shinshu‑u.ac.jp

excluded from clinical heart failure trials. The

Milan Gautam and Atsushi Izawa contributed equally toevidence base is, therefore, limited regarding thethis work.

optimal management of patients with CRS

No. 2, 2014

. In
89

Gautam.Izawa.Saigusa et al.

addition,conventional treatment with diuretics andinotropes has not shown any beneﬁt in relation to

failure) , along with renal insuﬃciency (estimatedglomerular ﬁltration rate, eGFR ＜ 65 mL.min .1.

the long‑term survival of patients with CRS ;there-

73 m ) were enrolled in the study. Our enrolled

fore, alternative therapeutic approaches are ofpatients fell under either CRS type 2 or CRS type 4

major clinical importance.

categories, as described by Ronco et al . Patients

Kampo prescription, a variation of ancientwith intravascular volume depletion,indications for

Chinese medicine, comprises several elemental

hemodialysis or acute kidney injury, sepsis or on-

herbs . These agents are available for ethical use

going infection, alcohol and/or drug abuse, hepaticand are included in the Japanese National Healthinsuﬃciency,known allergy to the study medication

Insurance Drug List . The combination of herbs isor any of its components, or enrollment in otherthought to increase the eﬀectiveness and decrease

clinical trials involving medical or device‑based

the adverse reactions of each individual herb . Ininterventions, were excluded from the study.

addition, Kampo prescription can be added to con-Patients received standard medications including

ventional medications in clinical practice as theseangiotensin II receptor blockers, angiotensin‑

agents have been shown to produce little inhibition

converting enzyme inhibitors,β‑blockers,and diur-on the activity of drug‑metabolizing major cyto‑

etics (Table 1).TJ‑20 treatment at a dose of 2.5 g,5.

chrome enzymes and the major drug transporter P‑

0 g, or 7.5 g per day was added to the standard

glycoprotein .

medications in each patient and the dose of TJ‑20

Boiogito (TJ‑20, Tsumura & Co., Tokyo, Japan)
elicits moderate diuretic eﬀects and has been used

was modiﬁed within the conventional dose according to the patientʼs acceptance and adherence.

to control imbalance of the distribution of body

The institutional ethics committee of Shinshu

ﬂuids in patients presenting with easy fatigability,

University School of M edicine approved the proto-

lower limb edema, or renal dysfunction in

col.The protocol has been registered at the Univer-rheumatoid arthritis. An interesting ﬂuid con-sity Hospital M edical Information Network

trol eﬀect of TJ‑20 has been reported to decrease(UM IN000012762). All enrolled patients received ajoint eﬀusion in osteoarthritis of the knee ,where-

full explanation of the treatment agents and gave

as no study has investigated its eﬃcacy in CRS.

their informed written consent prior to the study.

Based on these previous ﬁndings and reports, we

The study was performed in accordance with the

hypothesized that the moderate diuretic eﬀects of

Declaration of Helsinki and with Good Clinical

TJ‑20 added to standard treatment for heart failure

Practice. Patients were managed based on themight beneﬁt CRS patients, who require body ﬂuid

recommended guidelines from the Japanese Circula-control.We here report the ﬁndings of a preliminarytion Society,and in accordance with the 2013 Amer-observational studythat evaluated the eﬀects ofTJ‑

ican College of Cardiology Foundation/American

20 in combination with the standard therapy forHeart Association guidelines for the management

CHF in patients with CRS.

of heart failure .

M ethods
Study design

Laboratory analyses
During the follow‑up period, levels of serum
creatinine (sCr), eGFR, blood urea nitrogen (BUN),

This was a prospective, observational study.

brain natriuretic peptide (BNP),and serum electro-

Twenty‑six patients with CHF, New York Heartlytes including sodium (Na ), potassium (K ), andAssociation (NYHA)functional class I‑III,Stage B

chloride (Cl ) ions, were measured using routine(structural heart disease but without signs or symp-

laboratory tests. Levels of eGFR were calculated

toms of heart failure) or Stage C (structural heart

using the Modiﬁed Diet in Renal Disease (MDRD)

disease with prior or current symptoms of heart

study equation,modiﬁed for Japanese patients with90

Shinshu M ed J Vol. 62

Boiogito in cardiorenal syndrome
Table 1 Baseline characteristics of the study
patients (n＝26)
Characteristicsn (%)

Gender, maleAge, years (n±SD)

18 (69)77±8.4

NYHA class I/II/III
Stage B/C

5/17/4
11/15

Etiology and risk factors

ground treatment agents. All tests were two‑sided
and P＜0.05 was considered statistically signiﬁcant.
Statistical analyses were performed using GraphPad Prism version 5.0f,GraphPad Software,San
Diego, California.
Results
Clinical characteristics

Diabetes mellitus
Hypertension
Hypertensive heart disease
Cerebrovascular disease

7 (27)
22 (85)
10 (39)5 (19)

Ischemic heart disease
Peripheral arterial disease
Arrhythmias
Cardiomyopathy
Valvular heart disease

7 (27)0
18 (69)4 (15)
6 (23)

77±8.4 years, and 18 patients (69 %) were men.

Dyslipidemia

11 (42)

No patient was lost during the follow‑up period.
The mean eGFR at baseline was 40.02±10.54 mL.

M edications

In total,26 patients aged between 57 and 93 years
were studied,with follow‑up examinations after 3.5
and 9.4 months. The mean age of the patients was
Treatment with TJ‑20 was started at an average
dose of 4.6±1.5 g/day, increasing to 5.2±1.2 g/day
at 3.5 months and to 5.9 ±1.5 g/day at 9.4 months.

ARBs

17 (65)

min .1.73 m , corresponding to stage 3 CKD.The

ACEIs
β‑blockers
Diuretics

9 (35)

baseline characteristics are summarized in Table 1.

22 (85)16 (62)

Laboratory evaluations before and after
treatment

Abbreviations: NYHA, New York Heart Association ;ARBs, angiotensin II receptor blockers;ACEIs,
angiotensin‑converting enzyme inhibitors

The eGFR levels improved signiﬁcantly from 40.
02±10.54 mL.min .1.73 m
to 44.60±10.76 mL.

chronic kidney disease (CKD):eGFR＝194×Serum×Agecreatinine(×0.739 if female) mL.

0004, Fig. 1). As shown in Fig. 1, mean sCr levels

min .1.73 m. Laboratory parameters were

23±0.50 mg/dL at 3.5 months (P＜0.0001), and to 1.

averaged from 2‑3 outpatient visits for each of 3

21±0.51 mg/dL at 9.4 months(P＝0.0002).The mean

points as follows:1) before initiation of the treat-

BUN levels also decreased signiﬁcantly from 25.

ment (3±1.8 months), and followed at mean inter-67±6.68 mg/dL to 24.20±6.48 mg/dL at 3.5 months

vals of 2) 3.5±1.8 and 3) 9.4±2.3 months after(P＝0.047), and to 23.96±6.83 mg/dL at 9.4 months

starting the treatment.

(P＝0.029,Fig.1).There were no signiﬁcant changes

Statistical analyses

in the levels of serum sodium (141.4±1.93 meq/L vs.

min .1.73 m

at 3.5 months (P＝0.001), and to 45.
93±11.57 mL.min .1.73 m at 9.4 months (P＝0.
decreased signiﬁcantly from 1.40±0.67 mg/dL to 1.

Data were expressed as mean±standard devia-

141.6±1.67 meq/L,and 141.2±1.59 meq/L ;P＞0.05;

tion (SD)for continuous variables, such as age andFig. 2),serum chloride (106±2.43 meq/L vs.106.2±

laboratory parameters. Treatment eﬃcacy at 3.5

2.84 meq/L,and 105.8±2.45 meq/L ;P＞0.05;Fig.2)

months and 9.4 months from baseline was analyzed

or serum potassium (4.54±0.35 meq/L vs.4.52±0.36

by comparing the means using the Wilcoxon mat-meq/L,and 4.42±0.38 meq/L ;P＞0.05;Fig.2)fromched‑pairs signed‑rank test. Spearmanʼ
s correla-baseline to 3.5 and 9.4 months, respectively. Meantion was used to show the association between

BNP levels decreased progressively from 241.5±

continuous variables. One‑ or two‑way ANOVA

196.6 pg/mL to 195.5±145.7 pg/mL at 3.5 months

tests were used to determine changes in eGFR and(P＝0.008),and to 163.3±130.2 pg/mL at 9.4 months

BNP levels in the presence or absence of back-(P＝0.007;Fig. 3). No signiﬁcant changes in eGFR,

No. 2, 201491

Gautam.Izawa.Saigusa et al.

Fig. 1Signiﬁcant improvements in serum estimated glomerular ﬁltration rate(eGFR),creatinine(sCr),and blood urea nitrogen (BUN)in patients with cardiorenal syndrome treated with TJ‑20(n＝26).
Data are expressed as mean ± SD.

Fig. 2

No signiﬁcant interval changes were observed in levels of serum sodium,chloride,or potassiumin patients treated with TJ‑20 (n＝26).

BUN, sCr, and BNP levels were observed between

The NYHA classiﬁcation of the patients is shownthe 3.5‑month and 9.4‑month follow‑up examina-

in Fig. 3.Six out of 26 patients (23%)treated with

tions (P＞0.05). The eﬀects were observed consis-

TJ‑20 demonstrated an improvement in NYHA

tently in all patients followed up at 9.4 months (Fig.

functional class at 3.5 months from baseline (mean

1 and Fig. 3). To evaluate eﬀects of backgroundfrom 2.0±0.63 to 1.76±0.58; P＝0.019). This

treatment agents, we calculated the changes in

improvement was maintained in all patients who

eGFR and BNP levels at baseline, 3.5 and 9.4

were followed up at 9.4 months (1.76±0.58; P＝0.

months between patents with and without receiving019).

angiotensin II receptor blockers, angiotensin‑

D

Correlations between changes in eGFR andconverting enzyme inhibitors, β‑blockers, or diur-

BNP levels

etics (Table 2).No signiﬁcant changes in eGFR andNo signiﬁcant correlations were found between

BNP levels in the presence or absence of these

the increase in eGFR and the decrease in BNP

background treatment agents were observed (P＞0.

levels at either 3.5 or 9.4 months (Spearman r＝0.

05).

033, P＝0.876 and r＝0.061, P＝0.766, respectively;
Changes in NYHA functional class

92

Fig. 3).
Shinshu M ed J Vol. 62

Boiogito in cardiorenal syndrome

Fig. 3Time courses of brain natriuretic peptide (BNP) levels and New York Heart Association(NYHA)functional class in patients with cardiorenal syndrome treated with TJ‑20 (n＝26). No
correlations were observed between the changes in estimated glomerular ﬁltration rate (ΔeGFR)
and BNP (ΔBNP)at 3.5 months (green circles)or at 9.4 months (blue circles).

Table 2 Changes in eGFR and BNP levels in the presence or absence of background treatment agents
Laboratory
parameters

Treatment
agentsNumberofpatients

Baseline

3.5 months

9.4 months

P value

P value

ARB＋
ARB−

17
9

42.25±8.5935.42±12.77

46.71±9.09
40.63±13.02

48.33±10.69
40.60±11.61

0.187
0.601

0.964

ACEI＋
ACEI−

9

39.07±14.71
40.52±8.03

43.93±14.48
44.96±8.70

46.27±14.07
45.33±10.22

0.565

17

β‑blockers＋
β‑blockers−

22440.64±11.02
36.59 ±7.5245.13±11.22
41.72±8.43

46.68±12.04
40.03±4.63

0.199
0.595

0.920

Diuretics＋
Diuretics−

16
10

41.21±10.73
38.12±10.49

45.23±10.32
43.61±11.93

46.27±10.99
44.66±12.62

0.375
0.418

0.964

ARB＋
ARB−

17
9

232.5±189.3
258.7±221.3

183.5±123.1
215.6±182.6

166.1±120.8
184.0±166.1

0.413
0.711

0.989

ACEI＋
ACEI−

9
17

205.2±130.5
260.8±225.7

186.7±118.0
199.9 ±161.2

147.3±97.39
185.5±152.4

0.566
0.452

0.908

β‑blockers＋
β‑blockers−

224

250.4±210.8
193.0±90.55

206.4±153.3
141.0±95.76

172.3±136.0
172.3±150.3

0.319
0.818

0.853

Diuretics＋
Diuretics−

16

289.4±233.7
164.9 ±77.88

213.8±162.8
158.9 ±103.4

201.6±154.6
125.4±82.63

0.363

eGFR

0.235

0.925

BNP

10

0.565

0.745

Results are expressed as mean±SD ; One‑way ANOVA and Two‑way ANOVA. Abbreviations:eGFR, estimatedglomerular ﬁltration rate;ARBs,angiotensin II receptor blockers;ACEIs,angiotensin‑converting enzyme inhibitors;
BNP, brain natriuretic peptide
No. 2, 201493

Gautam.Izawa.Saigusa et al.

Safetyloop diuretics have been associated with sudden

There were no signiﬁcant adverse events resulting

death or death from pump failure. Moreover,in discontinuation of TJ‑20 treatment at the end of

CHF patients are likely to have a delicate balance

our study.No cardiovascular events were observed ;between dehydration and overhydration, i.e., a nar-however,2 patients (8%)developed pseudoaldoster-row therapeutic window for optimal ﬂuid balance .

onism with hypokalemia.The TJ‑20 administration

Therefore, the use of diuretics can be a double‑

was discontinued when their serum potassium levels

edged sword, and the dose should be kept to thedecreased to 2.4 meq/L and 2.6 meq/L,at 16 and 17

minimum needed to achieve and maintainmonths, respectively.

euvolemia .
Hydrostatic modulating eﬀects of Saireito (TJ‑

Discussion114) , Goreisan (TJ‑17) , and of TJ‑20

haveThis is the ﬁrst report that clearly demonstrates

been reported to control body ﬂuid imbalances inthe beneﬁcial eﬀects of Japanese Kampo medicine

patients suﬀering from edema, thirst, spontaneous(TJ‑20), in combination with conventional treat-

sweating, or oliguria. These agents elicit moderatement,for CHF patients with renal insuﬃciency.The

diuretic eﬀects in patients with excess body water

administration of TJ‑20 signiﬁcantly ameliorated

but not in euvolemic patients; therefore, Kampo

renal function,decreased BNP levels,and improved

medicine may prevent dehydration and/or renal

NYHA functional class from baseline. In the gen-insuﬃciency. Although changes in diuretic agentseral population,GFR decreases at a constant rate of
3.73 and 7.53 mL.min .1.73 m per decade in peo-(loop, thiazide, and potassium sparing) during theple aged under 45 years and over 45 years, respec-

study (data not shown), we speculate that the addi-

tively ; therefore, the improvement in eGFRtion of TJ‑20 has the potential to optimize diuresis

demonstrated in this study for up to 9.4 months wasand prevent renal dysfunction.

course of treatment were not signiﬁcant in thisremarkable. Although the study had no control

Although the mechanisms of action of individual

group,we can compare the results with the naturalcomponents of TJ‑20 are beyond the scope of thishistory of patients with CRS .

study, the following potential mechanisms derived

An intravenous loop diuretic is recommended asfrom various studies suggest the beneﬁcial eﬀects of

the ﬁrst‑line choice in patients with acute pulmo-

TJ‑20. Oral treatment with TJ‑20 in rats withnary congestion or edema without shock (class I

puromycin aminonucleoside ‑induced nephrosis

recommendation, level of evidence B) . Despite

signiﬁcantly suppressed proteinuria and urinary

their ubiquitous use in acute settings,the safety andexcretion of thromboxane B (TXB ),and increased

eﬃcacy of loop diuretics are limited, and manythe 6‑keto‑prostaglandin F /TXB

concerns have been raised. First, the use of loop

kidney . This indicates a renal release ofdiuretics may decrease GFR by impairing renal

vasodilatory prostaglandins.Treatment with TXA

perfusion and glomerular ﬁltration pressure,and by(the precursor of TXB ) synthase inhibitor in rats

activating both the renin‑angiotensin‑aldosterone

with subtotal nephrectomy prevented renal

system and the sympathetic nervous system .Sec-

insuﬃciency and increased the renal synthesis ofond, possible adverse eﬀects of loop diuretics arevasodilatory prostacyclin . Astragalus, one of the

hypokalemia, hyponatremia, and hypomagnesemia,

components of TJ‑20,induces natriuresis,partly bywhich maylead to cardiac arrhythmias and increaseenhancing the response to endogenous atrial natriur-

the risk of sudden cardiac deathetic peptide in rats with experimental CHF.Third,diuretic

ratio in theand inresistance can be seen in CRS patients,because thehealthy humans . Astragalus also attenuateddose‑response curve may shift to the lower right as

myocardial inﬂammation and ﬁbrosis in a rat modela result of the CRS status .Importantly,high‑doseof experimental autoimmune myocarditis . These

94

Shinshu M ed J Vol. 62

Boiogito in cardiorenal syndrome

reports are consistent with the beneﬁcial eﬀects ofFirst, this hospital‑based observational study can-TJ‑20 in improving renal function and CHF status

not prove the mechanisms of action of TJ‑20 or thein our study.

roles of each component of the agent. Second, thisA post hoc analysis from the Scandinavian

study was a preliminary observational study andSimvastatin Survival Study has demonstrated renal

had only 26 patients with no controls.Third,eGFR

protective eﬀects of simvastatin in patients withcalculation may involve inaccurate estimation,

coronary heart disease . Similarly, atorvastatinbecause the MDRD formula was derived from atreatment for patients with metabolic syndromecohort of relatively young patients with establishedincreased eGFR levels, especially in patients with

CKD. Fourth, neither echocardiography nor any

stage 3 CKD .Based on these reports,statins haveother means of assessing cardiac function was avail-been proposed as an option to treat patients withable. Finally, the follow‑up period of 9.4 months

CKD and cardiovascular disease.In this study,there

was not suﬃcient to draw conclusions regarding thewas no change in statin therapy during the study

long‑term eﬀects of TJ‑20.Further research will be

period.

required to understand the precise role of each

Serum BNP levels can be partly dependent on thepatientʼ
s renal function . However, we found nocomponent of TJ‑20,and the potential mechanisms
underlying the beneﬁcial eﬀects on CRS.

correlation between the changes in eGFR and BNP

Conclusionlevels after TJ‑20 treatment, suggesting that the

The addition of TJ‑20, the Japanese Kampo

decrease in BNP levels could be distinct from the

Boiogito, to standard heart failure treatment clear-

increase in eGFR levels. Although we could notly demonstrated beneﬁcial eﬀects on the status ofclearly separate the beneﬁcial eﬀects of TJ‑20 onrenal function and heart failure.The observations inrenal function and the status of heart failure, ourthis study may suggest new strategies for utilizing

results suggest that these eﬀects could have a dual

traditional Japanese medicine in the management of

beneﬁt for cardiorenal protection.

CRS.

Study limitations
There were several limitations to this study.

Conﬂict of Interest :None declared

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No. 2, 201497