Keywords

19.1 Introduction

Chronic kidney disease (CKD) is a significant cause of morbidity and mortality worldwide, which imposes a high economic cost to the healthcare systems [1]. CKD has a direct correlation with increased risks of cardiovascular morbidity, premature death, hospitalization, cognitive dysfunction, and decreased quality of life [1,2,3,4]. A recent meta-analysis indicated a high global prevalence of CKD (11–13% with the majority in stage 3) [1]. End-stage renal disease (ESRD) occurs when the glomerular filtration rate (GFR) is substantially decreased and accompanied by signs and symptoms of kidney failure that necessitate replacement therapy [5].

Today, diabetes and hypertension are the primary cause of ESRD [6]. The ever-increasing high prevalence of type 2 diabetes has led to a significant rise in the number of patients with CKD and the number requiring end-stage renal failure management, particularly with the need for dialysis [6].

It has been demonstrated that inflammation plays a central role in the etiology of chronic diseases such as CKD, cardiovascular disease, diabetes, metabolic syndrome, and hypertension [7,8,9,10,11]. Increased inflammation and reduced antioxidant capacity is a common complication among CKD and hemodialysis patients [11, 12]. One of the significant factors involved in the development and progression of nondiabetic or diabetic proteinuric CKD and its related complications is increased oxidative stress among patients with renal disorders [13, 14]. Controlling proteinuria and delaying the progression of CKD in adults are the main targets of the current treatment of kidney diseases [15, 16]. Likewise, although dialysis and transplantation are an effective way of managing end-stage renal failure, these approaches are not optimal therapies for kidney failure since they are associated with several adverse effects [5]. In CKD and hemodialysis patients, it has been shown that high levels of inflammatory and hyperlipidemic factors are associated with the increased risk of cardiovascular disease [17,18,19,20].

Finding new, safe, and practical therapeutic approaches to treat kidney diseases as one of the strategies or complementary therapy, with an emphasis on reducing inflammation, has recently attracted significant attention. In this regard, medicinal plants and herbal bioactive compounds with antidiabetic, antilipidemic, anti-hypertension, and anti-inflammatory properties could be potential candidates to consider as an alternative or complementary medicine in the treatment of renal diseases [21,22,23,24,25].

Curcumin is the main active ingredient in turmeric with several proven health benefits [26,27,28,29,30,31]. It has been shown that this natural bioactive compound has several unique properties such as anti-tumor, anti-inflammatory, antioxidant, antithrombotic, chemosensitizing and chemopreventive, neuroprotective and cardioprotective, lipid-modifying, analgesic, and antirheumatic activities [22, 32,33,34,35,36]. Recently, the favorable effects of curcumin on kidney diseases were shown in preclinical studies [37,38,39]. In addition, the results of these medicinal herbs on kidney diseases have been assessed in clinical trials [40,41,42].

Although the effects of curcumin/turmeric on renal diseases were assessed in some clinical trials, to our knowledge, there has been no review of the main findings of these studies. Thus, the main aim of this systematic review was to assess the effects of curcumin or turmeric supplementation on kidney diseases in clinical trials.

19.2 Methods

This systematic review was designed and reported based on the guidelines of the preferred reporting items for systematic reviews and meta-analyses (PRISMA) [43].

19.2.1 Search Strategy

ISI web of science, Scopus, PubMed, and Google Scholar databases systematically searched up to April sixth, 2020 without any limitation for language and date using the following keywords: (“curcumin” OR “curcuminoids” OR “turmeric”) AND (“hemodialysis” OR “Chronic Kidney Disease” OR “Acute Kidney Disease” OR “nephritis” OR “renal diseases” OR “kidney diseases” OR “nephro” OR “Nephrotic syndrome”) AND (“Intervention Study” OR “Intervention Studies” OR “Controlled trial” OR “Randomized controlled trial” OR “Randomised clinical trial” OR “Non-Randomized Controlled Trials” OR “Clinical Trial” OR “Non-Randomized Controlled Trials” OR “Cross-Over study” OR “Cross-Over trial” OR “Cross Over trial” OR “Cross Over study” OR “Double-Blind Method” OR “Double-Blind” OR “Double-Blind trial” OR “Double-Blind study”). Whenever possible, Medical Subject Headings (MESH) terms were also used. Finally, a direct search was performed of the reference lists of the included original papers and review articles to identify other relevant works for inclusion in the current review.

19.2.2 Study Selection

Two independent authors (MB and GA) reviewed the title and abstract of all papers found in the first stages of the search. Articles were excluded if they did not meet the inclusion criteria using a screen form with a hierarchical approach based on study design, population, exposure, and outcome, and reference lists of relevant review articles were reviewed to explore additional studies. The full texts of eligible citations were considered. Any disagreements were discussed and a final agreement made.

19.2.3 Inclusion and Exclusion Criteria

The main aims of the search were to identify articles investigating the effects of curcumin/turmeric supplementation alone or in combination with other herbs or nutrients on kidney or renal diseases. Original articles were included in the present systematic review which followed these criteria: (1) use of a clinical trial design; (2) curcumin or turmeric supplementation was applied; and (3) the study was conducted on patients with kidney or renal diseases as a primary disease or secondary condition.

Studies were excluded if they (1) were uncontrolled; (2) reported duplicate data; or (3) were reviews, letters, editorial articles, study protocol, or case reports.

19.2.4 Data Extraction

Relevant articles were selected after screening records from the initial search. The following information was extracted from eligible studies and reported in Table 19.1: publication information including the first author’s last name, publication date, study location, details of the clinical trial including sample size, patients, mean age (years), study design, intervention (treatment), control, duration of the study, findings of the studies including main results, side effects, and study quality using Jadad Scores.

Table 19.1 Summary of studies included in the systematic review
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19.2.5 Quality Assessment

Two independent reviewers (MB and GA) evaluated the quality of the included studies using the Jadad scale, which contained three domains as follows: (1) randomization (0-2 points); (2) blinding (0-2 points); and (3) dropouts and withdrawals (0-1 points) [44]. According to the mentioned domains, the overall quality of each study was considered as low or high quality if the scores were less than or equal to 2 or greater than or equal to 3, respectively [45].

19.3 Results

The online search yielded in 679 non-duplicated records, of which, after reading the title and abstracts, 660 irrelevant records were omitted. Nineteen articles were selected for a full assessment, of which 12 records were appropriate (Fig. 19.1). Thus, data extraction was performed on 12 articles [40,41,42, 46,47,48,49,50,51,52,53,54]. The characteristics of each selected paper are shown in Table 19.1. The studies were published between 2011 and 2020 and comprised a total of 631 patients. Eight studies were conducted in Iran [40, 42, 47, 48, 51,52,53,54], two in Mexico [46, 50], one in Brazil [41], and one in the United States of America [49]. Six studies worked on hemodialysis patients [41, 42, 50,51,52,53], three studies were conducted on CKD patients (with or without diabetes) [40, 46, 49], and one of these articles worked on contrast-induced nephropathy patients [40]. One study was conducted on patients with overt type 2 diabetic nephropathy [47], one in patients with type 2 diabetes mellitus with overt albuminuria [54], and one in patients with relapsing or refractory biopsy-proven lupus nephritis [48]. All of the studies were conducted on both male and females, except for two studies which did not mention the gender of the participants [49, 53]. The mean age of the participants varied from 33.6 to 63.8 years. All of the included studies were conducted in the context of randomized controlled trials, all applied randomization, and all had a placebo group. One study used nano-curcumin (120 mg/day) [42], six studies used turmeric (500 mg–2.5 g daily) [41, 47, 48, 51,52,53], three studies used curcumin (320–1500 mg daily) [40, 46, 54], one applied curcumin and Boswellia serrata (each capsule contained 824 mg of purified turmeric extract, 95% curcuminoids, and 516 mg of Boswellia serrata extract; 2 capsules/day) [49], and one study used curcumin (500 mg/daily) in combination with resveratrol (500 mg/day) [50]. The duration of the studies was in the range of 8–16 weeks [41, 42, 46,47,48,49,50,51,52,53,54]. One study used curcumin two days before coronary angiography or angioplasty to three days afterwards in CKD patients [40].

Fig. 19.1
figure 1

Flowchart of the process of study selection

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19.3.1 Quality Assessment

Overall , ten studies out of 12 were categorized as high quality [40,41,42, 47,48,49, 51,52,53,54], and two had a low-quality methodological approach [46, 50].

19.3.2 Effects of Curcumin on the Inflammatory and Stress Oxidative Status of Patients

In three studies, curcumin/turmeric consumption significantly reduced high-sensitivity C-reactive protein (hs-CRP) compared with placebo [41, 42, 52]. In one study, hs-CRP levels were significantly reduced after turmeric consumption, although no differences were found compared with the placebo group [53]. In one study, curcumin and Boswellia serrata did not affect CRP levels [49]. Four studies assessed the effects of curcumin/turmeric on serum interleukins (ILs), and one of these found that IL-6 levels were significantly reduced in response to treatment [49]. However, no significant difference was found than in placebo groups. In other studies, curcumin/turmeric had no significant effects on IL-6 [53], IL-8 [47], and IL-1β [41] compared with the placebo group. Likewise, in comparison to the placebo, curcumin/turmeric had no significant effects on TNF-α levels [47, 49, 53]. In one study, turmeric treatment significantly decreased nuclear factor kappa B (NF-κb) mRNA expression. However, mRNA expression of nuclear factor erythroid factor 2-related (Nrf2), Nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome did not significantly change [41]. In one study, plasma malondialdehyde (MDA) was significantly decreased, and red blood cell catalase (CAT) activity was increased in the turmeric group compared with placebo, and glutathione peroxidase (GPX) and glutathione reductase (GR) were increased in both intervention and control groups. However, differences between groups were not significant [51]. One study showed that curcumin and resveratrol did not affect thiobarbituric acid reactive substance (TBARS) levels [50]. Another investigation showed that curcumin attenuated lipid peroxidation in individuals with nondiabetic proteinuric CKD and enhanced the antioxidant capacity in subjects with diabetic proteinuric CKD [46]. In the study of Ortiz et al., ferritin levels were significantly decreased in the curcumin and resveratrol group compared with placebo in patients with CKD and iron overload undergoing hemodialysis [50]. The adhesion molecules, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion protein 1 (VCAM-1) , were significantly decreased after 12 weeks of intervention with nano-curcumin in hemodialysis patients compared with the placebo [42].

19.3.3 Effects of Curcumin on the Clinical and Biochemical Parameters of the Kidney

Blood urea nitrogen (BUN) was assessed in five studies [47,48,49, 52, 54]. In all of these studies, curcumin/turmeric had no significant effect on this parameter compared with placebo. Likewise, creatinine was assessed in six studies, and curcumin/turmeric did not affect this in comparison to the control group [40, 47,48,49, 52, 54]. In the study conducted by Hami et al., serum creatinine was increased after 72-h intervention in both groups, but there was no difference between the groups [40]. In another study, curcumin treatment did not affect proteinuria in nondiabetic or diabetic proteinuric CKD [46]. However, turmeric treatment remarkably reduced proteinuria in relapsing or refractory lupus nephritis and overt type 2 diabetic nephropathy patients compared with placebo [47, 48]. Glomerular filtration rate (GFR) did not improve after curcumin/turmeric supplementation in nondiabetic or diabetic proteinuric CKD [46] and relapsing or refractory lupus nephritis patients [48]. After turmeric supplementation, serum albumin was significantly increased compared with placebo in a study conducted in hemodialysis patients [51]. However, there was no significant effect in five studies conducted on hemodialysis patients [41, 53], CKD patients [49], patients with relapsing or refractory lupus nephritis [48], and diabetic patients with overt albuminuria [54]. In the study of Vanaie et al., curcumin supplementation for 16 weeks resulted in a substantial reduction in albuminuria among diabetic patients with overt albuminuria in comparison to the placebo [54]. Other biochemical factors, such as serum uric acid [50], urea [41], phosphorus [41], potassium [41, 53], and hemoglobin [41, 51], were evaluated in a few studies, which found no significant effects. Moreover, compared with placebo, turmeric treatment had no effects on systolic and diastolic blood pressure, as assessed in two studies in patients with overt type 2 diabetic nephropathy and relapsing or refractory lupus nephritis [47, 48].

19.3.4 Effects of Curcumin on Lipid Profile, Glycemic Indices, and Liver Functional Tests

Curcumin/turmeric supplementation had no significant effects on lipid profile [41, 42, 46, 47, 51, 54], except for one study in which 12 weeks’ treatment with curcumin and resveratrol led to decreased triglycerides, very low density lipoprotein (VLDL), and cholesterol compared with placebo [50]. Fasting blood sugar (FBS) [42, 47, 50, 54] and hemoglobin A1C (HbA1c) [41, 54] levels did not change in response to curcumin/turmeric treatment. Likewise, after curcumin/turmeric supplementation, liver function tests such as measurement of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) did not change in the study groups [49, 53].

19.3.5 Effects of Curcumin/Turmeric on Other Outcomes and Adverse Effects

In their study, Ortiz et al. showed that 12 weeks’ intervention with curcumin and resveratrol significantly increased body mass index (BMI), muscle mass (kg), and bone mass (kg). At the same time, the percentage of fat and subjective global evaluation were significantly decreased (data of the control group were not reported) in patients with CKD and iron overload undergoing hemodialysis [50]. In the study conducted by Alvarenga et al., turmeric did not affect BMI or waist circumference [41]. Overall supplementation with curcumin/turmeric had no adverse side effects in renal diseases, although two studies stated that a few patients reported some adverse effects [49, 54] (Table 19.1).

19.4 Discussion

To the best of our knowledge, this is the first review which systematically assessed the effects of curcumin/turmeric supplementation on renal diseases. The main findings were that curcumin/turmeric supplementation had some favorable effects on renal diseases, particularly in terms of inflammation and stress oxidative, although the effects on clinical parameters such as BUN, creatinine, GFR, and serum albumin were weak and insignificant.

Atherosclerotic cardiovascular disease is the common and important cause of morbidity and mortality among patients with CKD. This appears to be a consequence of abnormalities of lipid metabolism, and a systemic increase in inflammation and oxidative stress in CKD patients [55]. Clinical evidence has documented that consumption of curcumin and turmeric can improve endothelial function and serum lipid profiles among patients with cardiovascular disease by modulating several pathways involved in lipid metabolism, including lipoprotein lipase (LPL), cholesteryl ester transfer protein (CETP), peroxisome proliferator-activated receptor gamma (PPAR-γ), and PPAR-α [56, 57]. In addition, it has well-established anti-inflammatory and anti-oxidative properties [29,30,31,32].

Both preclinical and clinical evidence suggests that curcumin can interfere with multiple signaling pathways linked to tissue injury, including the NF-κB signaling pathway, arachidonic acid (AA) metabolism, and the damaging effects of reactive oxygen species (ROS) [58]. NF-κB is the most critical transcriptional activator protein in the inflammatory cascade. Clinical evidence on hemodialysis patients showed that turmeric supplementation resulted in significant reduction in NF-kB mRNA expression [41]. In vivo and in vitro studies have shown that curcumin down-regulates NF-κB expression through inhibition of the c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (p38 MAPK), and extracellular signal-regulated kinase (ERK) pathways in response to pro-inflammatory stimuli and redox status [59,60,61,62]. Also, curcumin appears to inhibit nuclear NF-κB translocation through IκB kinase (IKK) activation and prevent NF-κB binding to the promoter region of inflammation-relevant genes [63].

Some effects of curcumin on inflammation can also be attributed to modulation of leukocyte recruitment into injured tissue, thereby altering AA metabolism and down-regulating NF-κB target genes, such as CXCL1, CXCL2, ICAM-1, and VCAM-1 [64, 65]. In line with this, a nano-formulation of curcumin has been found to reduce the levels of ICAM-1 and VCAM-1 adhesion molecules in hemodialysis patients after 12 weeks’ intervention [42]. AA metabolites, such as leukotrienes, have been implicated in the inflammatory cascade through increasing endothelial membrane permeability and leukocyte recruitment. Curcumin switches AA metabolism through inactivation of phospholipase A2 (PLA2G2A) and arachadonate 5-lipoxygenase (ALOX5) and down-regulation of cyclooxygenase-2 (PTGS2) gene expression via the NF-κB pathway [66]. This is consistent with findings which have shown that curcumin could act as a selective COX-2 inhibitor [67].

Patients with renal diseases have consistently exhibited an imbalance between oxidants and antioxidants status. Elevated free radical levels not only cause damage to DNA and increase lipid peroxidation, but also stimulate signaling pathways that switch on inflammation-relevant gene expression. Curcumin as the main phenolic compound in turmeric directly scavenges free radicals. In addition, increasing evidence supports its roles in enhancing both endogenous enzymatic and non-enzymatic antioxidants, perhaps due to induction of the Nrf2 transcription factor [68,69,70].

One of the major drawbacks of curcumin use is its poor absorption and bioavailability, which has severely limited its applications [71]. To overcome this limitation, one of the studies reviewed here used nano-curcumin [42]. The use of new formulations of curcumin such as curcumin-piperine or phospholipid curcumin with greater bioavailability may lead to better results in treatment outcomes for kidney disease patients [72].

Although this systematic review comprehensively assessed the effects of curcumin and turmeric supplementation on renal diseases based on randomized clinical trials, several limitations should be acknowledged. First, the small number of included studies and corresponding low numbers of participants made it difficult to draw robust evidence-based conclusions on its efficacy. Second, it was difficult to make comparisons across the studies due to their heterogeneous nature, regarding use of different forms of curcumin, different dosages, and treatment durations, as well as dissimilar outcome measures. Finally, more than a half of the studies (eight studies) were conducted in Iran, which restricts the ability to extend the findings to other populations.

19.5 Conclusions

Within the limitations of this review, it can be concluded that curcumin or turmeric supplementation might have some beneficial effects on inflammatory and stress oxidative parameters of patients with renal diseases. However, curcumin/turmeric had no considerable positive impact on clinical outcomes of kidney diseases apart from alleviation of proteinuria. The patients reported no serious adverse effects following curcumin/turmeric supplementation, supporting the case that these natural products are relatively safe. Thus, more randomized controlled trials using larger patient numbers and standardized protocols are needed for more accurate testing of the effects of curcumin supplementation on renal diseases.