Clinical effects of the oral administration of Astragali Radix extract in patients with chronic kidney disease

Abstract

Background

The decline in glomerular filtration rate is an unfortunate consequence of chronic kidney disease (CKD). People diagnosed with CKD are limited to managing the illness with a combination of lifestyle changes and pharmaceutical agents that target the renin–angiotensin–aldosterone system pathway. Researchers are investigating the potential of herbal agents, such as Astragali Radix, as treatment options in CKD. However, few studies have investigated this compound, and even fewer have examined the oral administration of the compound concerning its significance in bioavailability, as well as realistic compliance of daily medicinal use among potential users. We investigated the clinical effects of the oral administration of Astragali Radix as a renoprotective medicinal agent.

Methods

A total of 16 participants with an estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m² (CKD stage 3b) were included in the study. Approximately 10 g per day of Astragali Radix was mixed with 200 mL of water and infused by heating until the volume was reduced to 100 mL, which was set as the daily dose. All patients continued to take the Western pharmacological agents after initiating adjunctive treatment with Astragali Radix. The Benjamini–Hochberg (false discovery rate (FDR) correction) method and paired t-test were used to compare each participant’s baseline eGFR with their follow-up eGFR at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and 5 years after adjunctive treatment with oral Astragali Radix extract.

Results

After starting Astragali Radix treatment, the mean eGFR of the subjects significantly increased from 34.3 ± 5.3 to 45.5 ± 10.7 mL/min/1.73 m² at 1 year (15 cases); 46.2 ± 10.5 mL/min/1.73 m² at 2 years (14 cases); 45.0 ± 10.0 mL/min/1.73 m² at 3 years (13 cases); and 42.2 ± 8.5 mL/min/1.73 m² at 5 years (11 cases). Only one case showed increased urine protein levels during the 5-year study period, while urine protein levels of other individuals did not increase. The major side effects of taking Astragali Radix were skin rash and an urticaria-like allergic reaction, which was observed in three excluded participants in the initial period.

Conclusions

These results suggest that Astragali Radix can preserve and potentially improve long-term eGFR in patients with CKD stage G3b or G4. Astragali Radix may be an option for treating CKD mainly caused by diabetes or hypertension.

Background

A person with a glomerular filtration rate (GFR) < 60 mL/min/1.73 m² or a urinary albumin-to-creatinine ratio > 30 mg/gCr meets the criteria for chronic kidney disease (CKD) diagnosis. The number of people diagnosed with this disease has increased internationally [1, 2]. The most common medical conditions that increase the risk of CKD development are diabetes (both types 1 and 2) and hypertension [3]. Currently, this disease is incurable. Management consists of pharmacological interventions and lifestyle changes to preserve kidney function and delay the necessity of dialysis or a kidney transplant.

Regarding pharmaceutical interventions, the class of drugs that target the renin–angiotensin–aldosterone system (RAAS) pathway or sodium–glucose cotransporter 2 (SGLT2) are the most effective in preserving renal function. The renin–angiotensin–aldosterone inhibitors have been established as renoprotective agents and are commonly prescribed to patients with CKD. Researchers have recently investigated the SGLT2 pathway and found that it initiates anti-inflammatory processes by targeting inflammasomes (innate immune system receptors and sensors that regulate caspase-1 activation and induce inflammation) that appear to protect kidney function, such as nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) [4]. The success of drugs that target SGLT2 has expanded the potential pharmaceutical options for CKD, which now includes medications that can potentially target inflammatory-inducing pathways [5].

Astragali Radix (AR, Huangqi in Chinese, also known as Astragalus) is a compound derived from the dried root of Astragalus membranaceus or A. mongholicus. The potential medicinal benefits of this genus were first documented in Shennong Emperor’s Classic of Materia Medica of the Qin or Han Dynasty, dating 221 B.C.–220 A.D. Today, Astragalus is one of the most commonly used medicinal herbs, particularly as adjunct treatment for upper respiratory infections, allergic rhinitis (hay fever), asthma, and chronic fatigue syndrome. The medicinal mechanism of action of AR is based on its being an immunomodulator that inhibits inflammatory pathways [6].

Previous clinical studies have described the renoprotective effects of AR, either alone or in combination with other Chinese herbs. However, most of these have reported the recovery of GFR in the relatively short term (weeks); few have investigated the effectiveness of long-term follow-up. In addition, AR was administered intravenously, not orally, in these studies, which is not the pattern that the general population consumes the herb.

In this 5-year study, we evaluated the clinical effects of adding oral AR extract to the pharmaceutical regimen of patients with CKD, especially interested in GFR.

Materials and methods

AR dosing

Nagasaka et al. [7] reported administering 15 g per day of AR as safe, considering that adverse effects were not observed at this dose. In our study, approximately 10 g per day of AR was mixed with 200 mL of water and infused by heating until the volume was reduced to 100 mL, which was set as the daily dose. Patients were instructed to take the concoction by dividing the daily dose into two smaller doses, without evaluation of diagnosis from oriental medicine, such as Qi, red liquid, liquid, hot, or cold; therefore, we thought that taking the decoction of the AR herbal medicine would be effective regardless of the diagnosis based on the Western and Oriental medicine evaluation. All patients continued to take the Western pharmacological agents after initiating adjunctive treatment with AR; thus, we thought that the effect of additional AR could be appreciated.

Inclusion criteria for patients

Approximately 100 patients with CKD taking various Western pharmacological agents, such as renin–angiotensin system (RAS) inhibitors and/or other antihypertensive agents, visited the Usuki Cardiovascular Clinic from 1 April 2007 to 30 November 2014. We selected 22 patients with CKD stage 3b, eGFR < 45 mL/min/1.73 m² at the serial 2 points before the start of the study. Because preparing a decoction of AR is a labor-intensive process, we selected patients with CKD stage 3b, which is a more severe form of CKD. Intervention for patients with CKD stage 3b is valuable in slowing the progression of CKD. After obtaining the consent of the patients, we added the AR extract treatment to the regimen and instructed patients on how to take it. Unfortunately, three participants had an allergic reaction, such as rash or urticaria, one complained about the distastefulness, and another had gait disturbance during the initial entry period. In addition, one participant suffered from acute myocardial infarction at 6 months from the start of the AR extract treatment. Thus, we selected 16 participants (Tables 1, 2) in the final analysis, excluding those 6 participants.

Table 1. Data of participants at baseline and after 5 years

Characteristics	Value (mean ± SD)
	Baseline (n = 16)	After 5 years (n = 11)
Age (years)	79 ± 9	81 ± 8
Female sex, n (%)	5 (31)	3 (27)
Body mass index (kg/m2)	24.8 ± 2.6	23.4 ± 3.3
Systolic blood pressure (mmHg)	130 ± 15	126 ± 14
Diastolic blood pressure (mmHg)	72 ± 9	68 ± 9
Hemoglobin (mg/dL)	11.9 ± 1.8	11.5 ± 2.1
Albumin (mg/dL)	4.0 ± 0.2	4.0 ± 0.3
HbA1c (%)	5.5 ± 0.6 (n = 15)	5.7 ± 0.5
BNP (pg/ml)	Not measured	109 ± 96 (n = 8)
Cardiothoracic ratio (%)	51 ± 6 (n = 14)	53 ± 5 (n = 10)
CRP (mg/dL)	0.24 ± 0.20 (n = 15)	0.15 ± 0.13 (n = 10)
eGFR (mL/min/1.73 m2)	34.3 ± 5.3	42.2 ± 8.5
Median (min, IQR, max)	34 (24, 31–39, 44)	44 (24, 39–45, 56)
G3a (45 ≤ eGFR < 60), n (%)	0 (0)	3 (27.3)
G3b (30 ≤ eGFR < 45), n (%)	13 (81.25)	7 (63.6)
G4 (15 ≤ eGFR < 30), n (%)	3 (18.75)	1 (9.1)
eGFR slope (mL/min/1.73 m2/year)	−4.44 ± 3.97 (n = 15) −4.44 ± 3.52 (n = 11)	1.50 ± 1.67 (n = 11)
Potassium (mmol/L)	4.7 ± 0.5 (n = 16) 4.9 ± 0.3 (n = 11)	4.6 ± 0.4 (n = 11)
Urea nitrogen (mg/dL)	26.8 ± 8.1 (n = 15)	28.5 ± 12.2 (n = 11)
Uric acid (mg/dL)	6.5 ± 1.3 (n = 14)	6.1 ± 1.0 (n = 11)
Distribution of urinary protein, n (%)
None	11 (68.75)	6 (54.5)
± 1	1 (6.25)	1 (9.1)
1 +	2 (12.5)	1 (9.1)
2 +	2 (12.5)	2 (18.2)
Missing data	0 (0.0)	1 (9.1)
Hematuria, n (%)
None	14 (87.5)	10 (90.9)
± 1	2 (12.5)	0 (0.0)
Missing data	0 (0.0)	1 (9.1)
Comorbidities, n (%)
Hypertension	15 (93.8)	11 (100)
Dyslipidemia	9 (56.9)	7 (63.6)
Previous myocardial infarction	5 (31.3)	5 (100)
Diabetes mellitus	4 (25.0)	4 (36.3)
Atrial fibrillation	4 (25.0)	3 (27.2)
Angina pectoris	4 (25.0)	2 (18.1)
Congestive heart failure	4 (25.0)	4 (36.3)
Carotid stenosis	2 (12.5)	0 (0.0)
Cerebrovascular accident	2 (12.5)	1 (9.0)
Valvular heart disease	2 (12.5)	1 (9.0)
Baseline medications, n (%)
Renin–angiotensin system inhibitor	14 (87.5)	11 (100.0)
Diuretic	13 (81.3)	10 (90.9)
Statin	9 (56.3)	7 (100.0)
Glucose-lowering therapy	4 (25.0)	4 (36.3)

AR, Astragali Radix; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; IQR, interquartile range; SD, standard deviation; min, minimum; max, maximum; BNP, B-type natriuretic peptide; CRP, C-reactive protein

Table 2. Etiology of CKD and oral medications of participants at baseline

Case	Etiology of CKD	Oral medications
1	CKD with HTN	Irbesartan 200 mg, azelnidipine 16 mg, doxazosin mesilate 1 mg, indapamide 2 mg, aliskien fumarate 150 mg, atorvastatin 10 mg, allopurinol 100 mg, warfarin 3.5 mg
2	CKD with HTN	Candesartan cilexetil 12 mg, cilnidipine 10 mg, indapamide 1 mg, aspirin 100 mg
3	CKD with HTN	Candesartan cilexetil 12 mg, amlodipine besilate 5 mg, atorvastatin 10 mg, aspirin 100 mg, sarpogrelate hydrochloride 100 mg
4	CKD with HTN	Irbesartan 200 mg, efonidipine hydrochloride ethanolate 10 mg, indapamide 0.5 mg, guanabenz acetate 1 mg, rosuvastatin calcium 2.5 mg, allopurinol 200 mg
5	DKD	Losartan potassium 62.5 mg, pravastatin 15 mg, aspirin 100 mg, warfarin 2.25 mg, azosemide 30 mg, denopamine 7.5 mg, nicorandil 15 mg, isosorbide dinitrate 40 mg, rapid-acting insulin from the Department of Diabetes
6	DKD	Irbesartan 100 mg, spironolactone 25 mg, indapamide 2 mg, furosemide 40 mg, digoxin 0.125 mg, warfarin 3.5 mg, pioglitazone 15 mg, glimepiride 2 mg, miglitol 225 mg, atorvastatin 10 mg, aspirin 100 mg, nicorandil 15 mg, allopurinol 200 mg
7	CKD with HTN	Candesartan 12 mg, nifedipine (slow release) 40 mg, doxazosin mesilate 7 mg, indapamide 2 mg, carvedilol 10 mg, atorvastatin 5 mg, allopurinol 100 mg, aspirin 100 mg, nicorandil 15 mg, isosorbide mononitrate 40 mg
8	DKD	Candesartan 8 mg, carvedilol 5 mg, furosemide 20 mg, pioglitazone 15 mg, gli-mepiride 1 mg, voglibose 0.9 mg, warfarin 7 mg, digoxin 0.25 mg, allopurinol 300 mg
9	Unknown	Rosuvastatin calcium 2.5 mg
10	CKD with HTN	Irbesartan 150 mg, cilnidipine 20 mg, indapamide 1 mg, metoprolol tartrate 80 mg, atorvastatin 5 mg, aspirin 81 mg, ticlopidine 200 mg, allopurinol 100 mg
11	CKD with HTN	Enalapril 10 mg, irbesartan 150 mg, amlodipine 5 mg, indapamide 2 mg, carvedilol 10 mg, atorvastatin 5 mg, cilostazol 200 mg, aspirin 100 mg, allopurinol 200 mg
12	CKD with HTN	Candesartan 12 mg, amlodipine 5 mg, carvedilol 2.5 mg, furosemide 20 mg, cilostazol 100 mg, warfarin 1.75 mg
13	CKD with HTN	Candesartan 12 mg, efonidipine hydrochloride 10 mg, doxazosin mesilate 2.5 mg, indapamide 1 mg, celiprolol 200 mg, cilostazol 100 mg, allopurinol 100 mg
14	CKD with HTN	Amlodipine 2.5 mg, aspirin 100 mg, allopurinol 100 mg
15	DKD	Telmisartan 80 mg, nifedipine (slow release) 40 mg, atenolol 50 mg, spironolactone 50 mg, furosemide 40 mg, aspirin 100 mg, ticlopidine 200 mg, nicorandil 15 mg, isosorbide mononitrate 40 mg, rapid-acting insulin from the Department of Diabetes
16	CKD with HTN	Losartan potassium 25 mg, nicorandil 10 mg, furosemide 20 mg, Goreisan 2.5 g, benzbromarone 25 mg

CKD, chronic kidney disease; DKD, diabetic kidney disease; HTN, hypertension

eGFR and proteinuria measurements

We measured eGFR and proteinuria every 6 months after participants started taking the AR. The eGFR was calculated with serum creatine using the revised formula recommended by the Japanese Society of Nephrology [8]. Urine samples were collected to evaluate proteinuria. The results were divided into the rapid (group R) and slow (group S) improvement groups in terms of eGFR. Rapid improvement was defined as an increase in eGFR by at least 10 mL/min/1.73 m² from the baseline within the first 6 months from the start of treatment (Table 3).

Table 3. Data of participants at baseline and after 5 years in the rapid and slow eGFR improvement groups

Characteristics	Value (mean ± SD)
	Group R		Group S
	Baseline (n = 10)	After 5 years (n = 7)	Baseline (n = 6)	After 5 years (n = 4)
Age (years)	77 ± 9	80 ± 7	82 ± 11	83 ± 10
Female sex, n (%)	2 (20)	1 (14)	3 (50)	2 (50)
Body mass index (kg/m2)	25.0 ± 2.9	23.5 ± 4.2	24.4 ± 1.6	23.1 ± 1.7
Systolic blood pressure (mmHg)	125 ± 11	128 ± 16	138 ± 19	123 ± 12
Diastolic blood pressure (mmHg)	74 ± 8	70 ± 10	70 ± 11	64 ± 5
Hemoglobin (mg/dL)	12.1 ± 1.6	11.5 ± 2.3	11.7 ± 2.2	11.6 ± 1.9
Albumin (mg/dL)	4.0 ± 0.2	4.0 ± 0.3	4.1 ± 0.3	4.1 ± 0.3
HbA1c (%)	5.8 ± 0.7 (n = 9)	6.0 ± 0.5	5.2 ± 0.2	5.4 ± 0.2
BNP (pg/ml)	Not measured	110 ± 120 (n = 5)	Not measured	109 ± 53 (n = 3)
Cardiothoracic ratio (%)	51 ± 7	53 ± 6	51 ± 2 (n = 4)	51 ± 4 (n = 3)
CRP (mg/dL)	0.20 ± 0.17 (n = 9)	0.17 ± 0.16 (n = 6)	0.30 ± 0.25	0.12 ± 0.05
eGFR (mL/min/1.73 m2)	33.8 ± 5.0	41.7 ± 9.8	35.0 ± 6.3	42.4 ± 6.3
Median (min, IQR, max)	33.5 (27, 29.5–37, 44)	43.9 (24, 42.9–44, 56)	38.0 (24, 27.5–39.5, 40)	42.0 (35.7, 39.1–44.9, 50)
G3a (45 ≤ eGFR < 60), n (%)	0 (0.0)	2 (28.6)	0 (0.0)	1 (25.0)
G3b (30 ≤ eGFR < 45), n (%)	8 (80.0)	4 (57.1)	5 (83.3)	3 (75.0)
G4 (15 ≤ eGFR < 30), n (%)	2 (20.0)	1 (14.3)	1 (16.7)	0 (0.0)
eGFR slope (mL/min/1.73 m2/year)	−4.88 ± 3.36 (n = 10) −5.20 ± 3.86 (n = 7)	1.74 ± 1.97 (n = 7)	−3.72 ± 5.10 (n = 6) −3.10 ± 2.79 (n = 4)	1.09 ± 1.08 (n = 4)
Potassium (mmol/L)	4.7 ± 0.5 (n = 10) 4.9 ± 0.3 (n = 7)	4.5 ± 0.4　(n = 7)	4.8 ± 0.4	4.7 ± 0.5
Urea nitrogen (mg/dL)	26.7 ± 8.8 (n = 9)	31.0 ± 14.8	27.0 ± 7.7	24.0 ± 4.2
Uric acid (mg/dL)	5.8 ± 0.9 (n = 8)	6.1 ± 0.7	7.3 ± 1.2	6.1 ± 1.5
Distribution of urinary protein, n (%)
None	7 (70.0)	3 (42.8)	4 (66.7)	2 (50.0)
± 1	1 (10.0)	0 (0.0)	0 (0.0)	1 (25.0)
1 +	1 (10.0)	1 (14.3)	1 (16.65)	0 (0.0)
2 +	1 (10.0)	2 (28.6)	1 (16.65)	0 (0.0)
Missing data	0 (0.0)	1 (14.3)	0 (0.0)	1 (25.0)
Hematuria, n (%)
None	8 (80.0)	6 (85.7)	6 (100)	3 (75.0)
± 1	2 (20.0)	0 (0.0)	0 (0.0)	0 (0.0)
Missing data	0 (0.0)	1 (14.3)	0 (0.0)	1 (25.0)
Comorbidities, n (%)
Hypertension	9 (90.0)	7 (100)	6 (100)	4 (100)
Dyslipidemia	4 (40.0)	4 (57.1)	4 (66.7)	3 (75.0)
Previous myocardial infarction	3 (30.0)	3 (42.9)	2 (33.3)	2 (50.0)
Diabetes mellitus	4 (40.0)	4 (57.1)	0 (0.0)	0 (0.0)
Atrial fibrillation	4 (40.0)	3 (42.9)	0 (0.0)	0 (0.0)
Angina pectoris	2 (20.0)	2 (28.6)	2 (33.3)	0 (0.0)
Congestive heart failure	4 (40.0)	4 (57.1)	0 (0.0)	0 (0.0)
Baseline medications, n (%)
Renin–angiotensin system inhibitor	8 (80.0)	6 (85.7)	6 (100)	4 (100)
Diuretic	7 (70.0)	7 (100)	5 (83.3)	3 (75.0)
Statin	4 (40.0)	4 (57.1)	4 (66.7)	3 (75.0)
Glucose-lowering therapy	4 (40.0)	4 (57.1)	0 (0.0)	0 (0.0)

Group R, fast improvement group; Group S, slow improvement group; AR, Astragali Radix; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; IQR, interquartile range; SD, standard deviation

Statistical methods

The paired t-test was used to compare each participant’s baseline eGFR with their follow-up eGFR at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and 5 years after adjunctive treatment with oral AR extract. We also appropriately used repeated measures analysis of variance (ANOVA), Benjamini–Hochberg (false discovery rate (FDR) correction) method, Mann–Whitney U test, and the chi-squared test.

The statistical significance level was set at p < 0.05.

Results

We were able to follow at least 11 of all 16 patients during 5 years. Figure 1 shows the eGFR changes in the 11 participants. The mean eGFR improved significantly with the AR extract, from 34.3 ± 5.3 mL/min/1.73 m² at baseline to 45.5 ± 10.7 mL/min/1.73 m² at 1 year (p < 0.02); 46.2 ± 10.5 mL/min/1.73 m² at 2 years (p < 0.02); 45.0 ± 10.0 mL/min/1.73 m² at 3 years (p < 0.03); and 42.2 ± 8.5 mL/min/1.73 m² at 5 years (p < 0.02).

[See PDF for image]

Fig. 1

The eGFR values before and every 6 months following prescription of Astragali Radix extract. Statistically significant improvement of estimated glomerular filtration rate (eGFR) at 0.5, 1, 1.5, 2, 2.5, 3, and 3.5 years (tested using Benjamini–Hochberg (FDR correction) method) and 5 years (tested using paired t-test) after prescription of Astragali Radix extract was confirmed

Repeated measures ANOVA was used to compare eGFR at each time point (0.5–5 years) with baseline eGFR. Statistically significant differences were observed between the groups (p < 0.05). We performed pairwise t-tests among groups, including the baseline group, and applied multiple comparison correction using the Benjamini–Hochberg (FDR correction) method. As a result, significant differences were observed between the baseline eGFR and the eGFR at 0.5, 1, 1.5, 2, 2.5, 3, and 3.5 years after taking AR. Moreover, a significant difference was observed between baseline eGFR and eGFR 5 years after taking AR, demonstrated with the paired t-test.

The eGFR slope of 11 patients who were followed up to 5 years after adding AR improved significantly compared with that before adding AR (1.50 ± 1.68 versus −4.44 ± 3.52 mL/min/1.73 m²/year, p < 0.05) (Table 1).

The eGFR slopes of the patients in groups R and S significantly improved in the 5 years after adding AR compared with those before the start of the study (1.74 ± 1.97 versus −5.20 ± 3.86, p < 0.05; 1.09 ± 1.08 versus −3.10 ± 2.79 mL/min/1.73 m²/year, p < 0.05, respectively) (Table 3).

A total of 3 of the 16 participants are taking AR now. Five participants stopped taking the AR decoction owing dural hematoma, general pain, and the complicated procedures required to prepare the decoction. After the withdrawal of AR, their eGFR showed a decrease of about 5–15 mL/min/1.73 m².

The qualitative urine protein tests were negative for ten participants and showed a result of +1 for one patient. Their levels were stable during 5 years. Two participants have missing follow-up data. In addition, in two participants, the urine protein level increased from +1 to +2, and in one participant, the urine protein level increased from + 2 to +3 at the last observational time. In one participant, the urine protein level decreased from +2 to ±, and in one participant, the urine protein level decreased from ± to negative at the last observational time.

No significant relationship was found between the duration of improved eGFR above the baseline and eGFR at baseline (r = 0.093).

No significant difference was observed between the groups with or without proteinuria at baseline in terms of duration of improved eGFR above the baseline (4.2 ± 2.2 years versus 6.1 ± 3.5 years, not significant).

Ten participants showed a rapid eGFR change > 10 mL/min/1.73 m² within 6 months (group R, rapid improvement group), whereas the other six participants were categorized as group S (slow improvement group). The comparison of these two groups is presented in Table 3. Four participants in group R had diabetes and congestive heart failure, whereas the S group had none.

No significant differences were observed between the two groups in terms of eGFR at baseline, age, sex, body mass index, blood pressure, and mean duration of eGFR improvement above the baseline (group R, 5.8 ± 3.6 years versus group S, 5.6 ± 2.8 years, not significant).

Discussion

Studies on the effectiveness of oral AR extract are limited. Previous systematic reviews on AR or A. membranaceus reported renoprotective potential for diabetic kidney disease (DKD) and CKD. Zhang et al. [9] summarized 66 studies, including 1 involving 4785 patients with DKD, and compared the effect of AR on albuminuria with that of conventional therapy. This particular study concluded that the intravenous injection of AR extract might be tolerated and effective for the reduction of albuminuria (mean difference: −0.25, 95% confidence interval (CI): −2.49 to −1.61), proteinuria (mean difference: −1.85, 95% CI: −2.34 to −1.37), and serum creatinine (mean difference: −14.78, 95% CI: −19.22 to −10.33). However, improvement in eGFR was only followed for up to 8 weeks.

The intravenous injection of AR extract is permitted in China and Taiwan; therefore, previous studies were almost entirely performed in these two countries. The problematic points were the short-term intervention and the unclear renal prognosis after the discontinuation of intravenous injection.

In Japan, only the oral prescription of AR extract is permitted as a modality for herbal medicine. The long-term effects of oral prescription needed to be established. Yoshino et al. [10] reported a case series study on the adjunctive prescription of AR to conventional treatment for patients with CKD G2 and G3. A total of 37 patients took the extract orally as powder or preparation for 6 months. The mean baseline eGFR was 66 ± 13 mL/min/1.73 m². Subsequently, 6 months later, the mean eGFR improved significantly to 70 ± 14 mL/min/1.73 m² (p < 0.01). No severe adverse events were reported. Our findings reveal that not only can oral administration of AR provide renoprotective benefits in CKD G3b and G4, but these benefits can also persist for years after the start of administration. There have been large-scale studies, but most of them were relatively short observation studies (less than 1 year) and limited to Astragalus root (AR) injections. There are very few studies that have been able to follow-up individuals for 5 years with oral AR medication.

Zhang et al. [11] observed astragaloside IV, a constituent of AR, induced vasorelaxation by upregulating aortic NOX and cGMP in the animal model of metabolic syndrome. This animal model originally exhibited mild hypertension and impaired endothelium-dependent vasorelaxation, among others. Administration of astragaloside IV reduced blood pressure and improved endothelium-dependent vasorelaxation. We thought these pharmacological effects contributed to the improvement of GFR in patients who were hypertensive with CKD. In our cases, a slight improvement of systolic and diastolic blood pressure was observed (before, 131 ± 7 mm Hg and 69 ± 10 mm Hg; 5 years later, 128 ± 16 mm Hg and 65 ± 5 mm Hg, respectively).

In our study, the potassium of 11 patients significantly decreased during 5 years after AR treatment (4.6 ± 0.4 versus 4.9 ± 0.3 mmol/L, p < 0.05). This result showed that the renal function was maintained because there was no apparent increase in potassium until at least 5 years after treatment with AR.

Sun et al. [12] observed that AR reduced oxidative stress in the diabetic model. These findings could help shed light on the physiological mechanism of eGFR improvement or the reduction of urine protein, particularly in diabetes cases. In our cases, a slight improvement of CRP was observed (before, 0.24 ± 0.20; 5 years later, 0.15 ± 0.13 mg/dL). However, we could not examine other inflammatory markers, such as IL-6 and TNF-α, in this study.

Zhang et al. [13] summarized ten randomized control studies with 640 participants with CKD. They concluded that Astragalus significantly decreased 24-h proteinuria at end of treatment (mean difference: −0.53 g/24 h, 95% CI: −0.79 to −0.26). We thought glomerular hyperfiltration due to improvement of the eGFR might worsen proteinuria after taking AR in some limited cases. However, hematuria appeared after taking AR in two participants. We also could not deny the possibility that worsening of glomerulonephritis affected proteinuria in these two participants. Proteinuria worsened 4 or 6 years later after the start of AR.

There were 3 participants who had increased qualitative proteinuria after taking AR out of 16 participants. The eGFR of case 1 and 6 improved and was maintained after 4 and 6 years when proteinuria worsened, respectively. Although the eGFR of case 15 decreased after 6 years when proteinuria worsened, the eGFR slope of this case improved from −14.8 to −10.5 mL/min/1.73 m²/year. From these results, we believe AR treatment is beneficial for preserving renal function even in the presence of worsening proteinuria. In the future, further long observational studies are necessary to confirm this point. Therefore, we think that the change in renal function over the observation period of this study is not known at this time.

The rapid eGFR change group (group R) had diabetes and congestive heart failure cases, while the slow eGFR change group (group S) had none. The vasorelaxation or antioxidant effects of AR might be related to the eGFR improvement in diabetes and heart failure cases. However, group S, consisting mainly of patients with hypertension without diabetic cases, showed increase of eGFR less than 10 mL/min/1.73 m². Age-related factors might have contributed to this result (mean age 77 ± 9 years versus 82 ± 11 years, not significant).

We noted an allergic reaction, such as rash or urticaria, in three of our participants. Gait disturbance (one participant) and acute myocardial infarction (one participant) are severe adverse effects. However, we could not find the causal relationship between these events and AR treatment. No studies in the PubMed database reported gait disturbance caused by AR treatment. AR was used for the treatment of acute myocardial infarction, and a meta-analysis concluded its efficacy and safety [14].

Limitations to our study

One limitation of our study was a small sample size. We intended to have 22 participants in the study; however, owing to the issues mentioned in the Methods and Results sections, only 16 participants were able to complete the study. Another potential reason for the issue with participant recruitment was the length of the study (years versus months in other studies). Regardless, our 5-year study demonstrated a significant improvement in eGFR in 11 out of 16 participants with CKD G3b and G4 (baseline, 34.3 ± 5.4 mL/min/1.73 m²; 5 years later, 42.2 ± 8.5 mL/min/1.73 m², p < 0.02). Another limitation was the arbitrary selection of participants for the study. Furthermore, we failed to evaluate proteinuria because of the lack of quantitative measurement. Finally, we could not avoid the adverse effects associated with the single dosage prescription of 10 g AR per day. A controlled study with a larger data set needs to be conducted in the future to address the limitations in our study. The evaluation of a lower dosage in a trial is also necessary to confirm the safety of AR.

This was a retrospective observational study; unfortunately a control group could not be established. In the future, we will perform a prospective control study.

Conclusions

Our study suggests that the oral administration of 10 g AR daily can initiate and maintain the long-term improvement of eGFR in patients with CKD stage G3b and G4 mainly caused by diabetes or hypertension.

Acknowledgements

This study was supported by Grants-in-Aid for Scientific Research 22K08352 from the Japan Society for the Promotion of Science.

Author contributions

S.U., N.O., Y.T., and T.F. collected data. K.I. and T.N. supervised this study. S.U. drafted the original article. S.N. acquired grants and edited the article.

Funding

Not applicable.

Data availability

The data concerning this study are not available publicly by the Ethics Review Committee of KOBE University Hospital Clinical & Translational Research Center (no. B2000278). The patients provided written consent to participate in this study. All data generated or analyzed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

The design of this study was approved by the Ethics Review Committee of Kobe University Hospital Clinical & Translational Research Center (no. B200027). Consent to participate was not applicable.

Consent for publication

Informed consent from the patients involved was obtained for the publication of this article.

Competing interests

The authors declare that they have no competing interests.

Abbreviations

AR

Astragali Radix

CKD

Chronic kidney disease

DKD

Diabetic kidney disease

eGFR

Estimated glomerular filtration rate

GFR

Glomerular filtration rate

Group R

Rapid improvement group

Group S

Slow improvement group

RAAS

Renin–angiotensin–aldosterone system

SGLT2

Sodium–glucose cotransporter 2

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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