Part Ⅰ Efficacy And Safety Of A Low-sodium Diet And Spironolactone in Patients With Stage 1-3a Chronic Kidney Disease: A Pilot Study

Abstract

1. Background

Excessive salt intake is associated with the deterioration of chronic kidney disease (CKD). Aldosterone is also known as an independent risk factor for kidney injury. Dietary sodium intake acts as a main stimulator in aldosterone-mediated kidney injury. Hence, this study aimed to further investigate the renal protective effects and safety of a low-sodium diet in combination with spironolactone (SPL) in stage 1-3a CKD.

2. Methods

This single-center, SPL-blinded randomized controlled trial recruited patients with stage 1-3a CKD, randomized into three groups, low-sodium (3g/d salt)+placebo, medium-sodium (5g/d salt)+SPL, and low-sodium (3g/d salt)+SPL. Patients received 12 weeks of intervention. The primary and secondary endpoints were 24-h urine protein and estimated glomerular filtration rate (eGFR) at the end of the intervention, respectively.

3. Results

A total of 74 patients were analyzed eventually. Significantly decreased 24-h urine protein was found in all three groups, from 0.37 to 0.23g/d (P=0.004) in the low-sodium+placebo group, from 0.44 to 0.29g/d (P=0.020) in the medium-sodium+SPL group, and from 0.35 to 0.31g/d (P=0.013) in the low-sodium +SPL group. There were no significant differences among the three groups in 24-h urine protein amount change after intervention from pretreatment values (P=0.760, ITT set). The results of the 24-h urine protein by using PP set analysis were similar to the ITT set. No significant differences in eGFR, nutritional, metabolic, inflammatory, and other biomarkers were observed across all three groups (P>0.05). No safety signal was observed.

4. Conclusion

No additional benefit was observed when SPL was prescribed to patients already on a low-sodium diet (3.0g/d). Still, small doses of SPL may benefit patients with poor sodium restriction. A combination of short-term low-dose SPL and ARB is safe for patients with stage 1-3a CKD, but blood potassium must be regularly monitored.

Keywords

Low-sodium diet, Mineralocorticoid receptor antagonist, Chronic kidney disease, Spironolactone, Safety, Cistanche benefits.

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Background

Chronic kidney disease (CKD) incidence is growing worldwide. The USRDS in 2018 revealed that CKD prevalence in adults reached 14.8% in 2013–2016 [1]. An epidemiological survey in China in 2012 indicated a CKD prevalence of 10.8% in adults over 18 years old [2]. For patients with CKD, early intervention is of great importance in controlling CKD progression and reducing mortality.

High salt intake is closely associated with the progression of CKD. When the urine sodium-to-creatinine ratio increases by 100mmol/L, the risk of CKD developing into end-stage renal disease (ESRD) increases by 1.61 times [3, 4]. High salt intake leads to renal impairment in various ways, including increasing transforming growth factor (TGF)-β1 production and enhancing oxidative stress and inflammatory response in the kidney [5–7]. Salt restriction reduces the effects of the above adverse factors, protecting the kidney and enhancing the antiproteinuric and antihypertensive effects of the renin-angiotensin-aldosterone system (RAAS) antagonists such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) [8, 9]. Heeg et al. [9] found that the effectiveness of ACEI lisinopril in reducing albuminuria greatly depends on dietary sodium intake. The ACEI could not decrease albuminuria when sodium intake from food increased from 50 to 200mmol/d, while the decreasing effect of the ACEI on albuminuria recovered accordingly when sodium intake was reduced back to 50mmol/d. Vogt et al. [10] showed that proteinuria was reduced by 30% with losartan monotherapy alone. The reduction increased to 55% with the addition of salt restriction and to 56% with the addition of hydrochlorothiazide (HCT). The enhancing effects of salt restriction on ARB activity appeared similar to the addition of diuretics. Slagman et al. [11] reported that moderate dietary sodium restriction is more effective than the maximal dose of angiotensin receptor blocker in controlling proteinuria and blood pressure in patients with renal disease on a maximal dose of ACEI.

Aldosterone is a steroid hormone with mineralocorticoid activity. Historically, aldosterone has been shown to act mainly on the distal convoluted tubules of the kidney, regulating extracellular fluid capacity and potassium metabolism. However, in the past 20 years, studies have revealed an extensive role played by aldosterone [12–16]. Mounting evidence has been observed that aldosterone could affect the heart, blood vessels, the central nervous system, and the kidney, promoting vascular remodeling, collagen formation, and endothelial dysfunction [15, 16]. These interactions play important roles in the pathophysiology of progressive renal dysfunction. Moreover, aldosterone/mineralocorticoid receptors (MR) could also damage podocytes. The enhanced MR effect is closely associated with protein leakage in the kidney [17–20], leading to CKD progression. With these new insights, mineralocorticoid receptor antagonists (MRAs) as a new treatment strategy are of particular interest. The discovery of the “aldosterone escape” phenomenon has made MRAs even more attractive for the treatment of CKD [21]. Multiple studies have evaluated the effects of MRAs on blood pressure control and proteinuria reduction, as well as their possible role in delaying the progression of CKD [14, 22, 23].

Aldosterone has been recognized as an independent risk factor mediating renal injury. However, another important parameter, sodium intake, cannot be ignored. More than 70 years ago, a pioneering study by Hans Selye showed that when desoxycorticosterone acetate (DOCA) is used in a rodent model of partial nephrectomy, improper salt intake (3% saltwater) is required for inducing significant vasculitis changes in the heart and kidney [24]. A study of Dahl salt-sensitive rats also showed that high salt could induce oxidative stress and promote MR activation in the kidney [20]. These studies helped to understand the pathogenesis of MR-induced renal injury and establish reasonable treatment plans for CKD. Relevant research data also demonstrated that salt intake could affect the balance of the beneficial and adverse effects of aldosterone [25]. In case of improper salt intake, acute administration of aldosterone reduces the levels of phosphorylated extracellular nitric oxide synthase (eNOS; vascular protection), increases the amounts of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase C (adverse to blood vessels). Conversely, salt intake reduction increases phosphorylated eNOS levels, reduces ERK1/2 and protein kinase C amounts, and minimizes or reverses the response to acute aldosterone administration. Plasma aldosterone levels unsuitable for intake of diet salt would amplify the above phenomenon. Hattori et al. [26] found that under low-salt conditions, MRA can completely suppress the expression of RAS-related genes in the myocardium of rats, alleviate myocardial oxidative stress and inflammatory response, and delay myocardial hypertrophy and fibrosis; meanwhile, MRA is only partly effective under high-salt conditions.

Based on the above, salt restriction is not only beneficial for renal protection but also can enhance the proteinuria-reducing effect of ACEI/ARB while alleviating aldosterone-associated renal damage. So far, the main treatment delaying CKD progression and reducing the risk of end-stage renal disease is RAAS antagonists, including ACEI and ARB medications, as well as direct renin inhibitors. These medications are the current standard treatment options for CKD patients with proteinuria [27–31]. However, these medications only decrease the risk of proteinuria and ESRD by 20–30%. Additional new therapies are needed given the huge cost burden of CKD as well as the associated physiological and psychological damage to patients [32, 33]. Therefore, this study aims to investigate the renal protective effects and safety of a low-sodium diet combined with an MRA, spironolactone (SPL), in patients with stage 1-3a CKD.

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Methods

1. Participants

Patients with stage 1-3a CKD were consecutively recruited from the outpatient Department of Nephrology at Hangzhou Hospital of Traditional Chinese Medicine from September 2014 to April 2017. According to K-DOQI guidelines [3, 4], the diagnostic criteria for CKD include: 1) renal injury (abnormal renal structure or function) for ≥ 3 months, with or without glomerular filtration rate (GFR) decreases; 2) GFR<60ml/(min·1.73 m2 ) for ≥3months, with or without evidence of renal injury. Inclusion criteria were 1) primary chronic glomerular disease with positive urinary protein or albumin, 2) estimated GFR (eGFR)≥45ml/min/1.73 m2, 3) aged 18–70years, 4) no clinical evidence of acute injury, and 5) no mental disorder and ability to cooperate

Exclusion criteria were 1) treatment with glucocorticoids, immunosuppressants, or nonsteroidal anti-inflammatory medications (NSAIDs) for more than one week in the past three months, 2) serious primary diseases affecting organs such as the heart, brain, lung, liver, or hematopoietic system, 3) malignant tumors, tuberculosis, and/ or other acute infectious diseases, 4) pregnancy, lactation or pregnancy planning shortly in women, 5) hypersensitivity to MRAs such as SPL, and 6) participation in other medication-based clinical trials.

2. Study design

This was a single-center, double-blinded (SPL-blinded), randomized controlled trial. Patients were randomized into three groups and received the assigned intervention for 12 weeks. The random numbers were produced using a random number table in advance and were kept in an opaque envelope. After the intervention, blinding was uncovered. The current study was approved by the ethics committee of Hangzhou Hospital of Traditional Chinese Medicine (2013LL065), and written informed consent was obtained from the patients.

3. Grouping and treatment

Eligible patients were randomly assigned to three groups before the run-in period started. (1) Lowsodium+placebo group. Patients underwent strict control of daily dietary salt intake. The salt bag (3g/bag) and salt control spoon were provided, and the salt bag was replaced at the return visit. The appearance, size, weight, smell, and color of the placebo (Zhejiang Conba Pharmaceutical Co., Ltd) were the same as those of SPL, and it was administered orally at 40mg the first week and 20mg thereafter, once a day, 30min after breakfast. (2) Medium-sodium+SPL group. The salt bag (5 g/bag) and salt control spoon were provided, and SPL (20mg tablets; Hangzhou Minsheng Pharmaceutical Co., Ltd) was taken. SPL was administered orally at 40mg the first week and 20mg thereafter, once a day, 30min after breakfast. (3) Low-sodium+SPL group. Patients underwent strict control of daily dietary salt intake. Supplies and medications such as SPL were provided, and the salt bag was replaced at each visit. The intervention lasted for 12 weeks.

In the run-in period (0–4 weeks), patients received training in optimal blood pressure and blood lipid control, salt intake assessment, and high-quality dietary choice with proper protein intake. Basic treatment during this period included the following: 1) Dietary guidance according to Chinese expert consensus on protein nutrition therapy for chronic kidney disease: dietary protein intake is 0.8g/kg/d-1.0g/kg/d with 50% high biological value protein, and dietary energy intake is 30–35kcal/ kg/d, and education of adult patients for low-fat diet during treatment. 2) Blood pressure control: the ARB dose was stable for more than 3months at the time of enrollment and maintained throughout the study. Among the patients, 79.7% used ARBs (Irbesartan at 75–150mg or Cozaar at 50–100mg), 10.8% used calcium channel blocker (CCB), and 1 patient used β blocker. CCB and other antihypertensive medications were added to patients showing increased blood pressure during the study. However, the ARB dosage remained unchanged. No diuretics were used in the study. The target blood pressure was below 130/80mmHg.

All patients received routine diet and nutrition guidance to correctly record diet diaries (including food types and quantities), and regular outpatient follow-up was performed. During the study period, patients were visited by assigned investigators, who distributed medications, recovered medications, and exchanged salt bags to ensure patient compliance and safety.

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4. Biomarker assessment

The follow-up visits occurred at 0, 4, 8, and 12 weeks after treatment initiation. During each follow-up visit, blood pressure measurements and laboratory tests (blood and urine) were performed. Self-reported dietary intake and adverse events were documented. During visits at 0 and 12 weeks, an electrocardiogram (ECG) and renal ultrasound were also performed as a safety assessment.

The primary endpoint was 24-h urine protein at the end of the intervention in the intent-to-treat (ITT) set and per-protocol (PP) set. The secondary endpoint was eGFR at the end of the intervention and was analyzed in the PP set. Nutritional, metabolic, and inflammatory biomarkers including serum albumin (ALB), serum pre-albumin (PA), blood uric acid (UA), total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and C-reactive protein (CRP) were checked regularly. Besides ECG and renal ultrasound, safety indicators including blood routine, liver function, serum creatinine (Scr), blood urea nitrogen (BUN), and blood potassium were monitored regularly. Adverse events such as gynecomastia and sexual dysfunction were also monitored. Other indicators included 24-h urinary sodium (24h-UNa), urine potassium (UK), blood pressure, and estimated dietary protein intake (eDPI) [34]. 24h-UNa were monitored at 0, 4, 8, and 12 weeks.

5. Statistical analysis

The last observation carried forward (LOCF) and a regression-based multiple imputation procedure was used to manage the missing data. Data were analyzed with SPSS 19.0 (IBM Corp, Armonk, NY, USA). Continuous variables with a normal distribution were presented as means ± standard deviation (SD) and compared by one-way analysis of variance (ANOVA) among three groups. Paired t-test was used to compare results between two-time points in each group. Continuous variables with skewed distribution were presented as median and interquartile range and were compared by the Kruskal-Wallis test among three groups. The Wilcoxon rank-sum test was used to compare results between two-time points in each group. Categorical variables were presented as frequency and percentage and were compared by Pearson Chi-squared test. P<0.05 was considered statistically significant.

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Hongmei Zhang, Bin Zhu, Liyang Chang, Xingxing Ye, Rongrong Tian, Luchen He, Dongrong Yu, Hongyu Chen, and Yongjun Wang.