Natural products for the prevention of antibiotic-associated kidney injury

Abstract

Drug-induced acute kidney injury (AKI), especially from exposure to antibiotics, has a high prevalence secondary to their frequent prescription. Typically, drug-induced AKI results from acute tubular necrosis or acute interstitial nephritis. While some risk factors for the development of AKI in individuals treated with antibiotics are modifiable, others such as concomitant drug therapies to treat comorbidities, age, and pre-existing chronic kidney disease are not modifiable. As such, there is an urgent need to identify strategies to reduce the risk of AKI in individuals requiring antibiotic therapy. Natural products, especially those rich in active constituents possessing antioxidant properties are an attractive option to mitigate AKI risk. Given that mitochondrial dysfunction precedes AKI and natural products can restore mitochondrial health and counter the oxidative stress secondary to mitochondrial damage investigating their utility warrants further attention. The following review summarizes the available preclinical and clinical evidence that provides a foundation for future study.

Introduction

Globally, 13.3 million cases of acute kidney injury (AKI) are diagnosed per year [1,2]. Drugs are responsible for up to 26% of AKI cases, and antibiotics are implicated in approximately 50% of these events [3]. The use of antibiotics in hospitalized patients is common, with roughly 60% of hospitalized patients receiving at least one antibiotic during their hospital course. Hospitalized patients frequently require multiple antibiotics raising the risk of AKI [4–6]. Some risk factors for antibiotic-induced AKI are modifiable, but many are not, including advanced age, obesity, heart failure, hypertension, and diabetes. Moreover, while concomitant nephrotoxic drugs are modifiable, many are essential for clinical management.

Given the frequency of individuals managed with antibiotics, the identification of therapies to reduce iatrogenesis is critical. Natural products are an attractive option for the prevention of AKI given their over-the-counter availability, patient willingness to consume, and safety profiles. From a mechanistic perspective, a variety of natural products may target the inciting factors leading to AKI. Oxidative stress is thought to be a key driver of antibiotic-induced AKI, and various natural products have antioxidant properties, including activation of nuclear factor-erythroid factor 2-related factor 2 (NRF2) and the master regulator of antioxidant response. This review summarizes the available evidence supporting natural products as reno-protective agents.

Proposed antibiotic-induced nephrotoxicity pathophysiology

The pathophysiology of antibiotic-induced nephrotoxicity (Table 1) can generally be separated into two main categories of injury, acute tubular necrosis (ATN) and acute interstitial nephritis (AIN) (Figure 1). ATN is precipitated by the exposure of the proximal tubule to toxic substances. This exposure can occur in several ways, including apical drug transport or basolateral (peritubular) drug transport into the proximal tubular cells [7]. Although the intrinsic toxicity of antibiotics against proximal tubule cells is not entirely known, mitochondrial injury is commonly cited as a potential cause because mitochondria are highly abundant in the kidney and work as the primary energy source for kidney cell function [8,9]. Changes to kidney mitochondrial integrity are often seen prior to the clinical manifestation of AKI [9]. A proposed mechanism involves the uptake of antibiotics into lysosomes, which subsequently leak into the cell cytoplasm and cause injury to multiple organelles, including the mitochondria [10]. During normal homeostasis, the mitochondrion is responsible for producing reactive oxygen species, including superoxide, hydroxyl, and hydrogen peroxide radicals. However, these reactive oxygen species can induce cellular apoptosis, lipid peroxidation, and calcium imbalance if not protected by mitochondrial antioxidant mechanisms [11]. Ischemic reperfusion injury (IRI) is also implicated in aminoglycoside-associated injury via worsened reperfusion cellular energetics [12]. IRI ultimately recruits proinflammatory cytokines and increases the production of reactive oxygen species that lead to lipid peroxidation to further damage renal tubule cells [13].

Table 1.

Summary of commonly prescribed antibiotics and their proposed mechanism of drug injury [10,73–77].

Drug class	Select medications within drug class	Proposedpathophysiology	Proposed mechanism of drug injury
Aminoglycosides	Gentamicin, tobramycin, neomycin, amikacin, streptomycin	ATN	Mitochondrial toxicity and subsequent free radical generation in addition to decreased proximal tubule protein synthesis
Beta lactams (penicillins, cephalosporins, carbapenems)	Cephaloridine, cephaloglycin, imipenem	ATN	Damage to mitochondrial transport and substrate uptake through the production of oxidative products
Rifamycin	Rifampin	AIN + ATN	Formation of drug-antibody complexes that deposit in either the tubular epithelium or interstitium
Sulfonamides	Sulfamethoxazole	AIN	Immune-mediated hypersensitivity and cytotoxic T-cell injury
Glycopeptide	Vancomycin	ATN + AIN	Oxidative stress and generation of ROS in proximal tubule cells

Abbreviations: AIN = acute interstitial nephritis; ATN = acute tubular necrosis; ROS = reactive oxygen species.

Figure 1.

Medications may cause acute kidney injury by a variety of mechanisms. The pathophysiology can be categorized into two main categories – acute interstitial nephritis (AIN) and acute tubular necrosis (ATN). Right panel: AIN results secondary to T-cell mediated hypersensitivity. Toxin deposits in the interstitium bind to proteins forming haptens and activating the immune cascade. Macrophages present the antigens to T-cells resulting in their activation. In turn, the infiltrating activated immune cells release chemokines and cytokines resulting in damage to the nephron. Left panel: ATN is precipitated by exposure of the proximal tubule cells to a toxin. This exposure triggers mitochondrial stress, production of reactive oxidative species (ROS), activation of the inflammasome, and chemokine and cytokine release. Ultimately, mitochondrial dysfunction, cell apoptosis, lipid peroxidation, and calcium imbalance lead to the manifestation as acute kidney injury. Natural products may mitigate the cascade of events through NRF2 activation and restoration of mitochondrial health.

AIN is believed to be a T-cell-mediated hypersensitivity reaction [14]. Drugs within the kidney can become immunogenic through the binding to specific proteins forming haptens, acting directly as antigens, or forming neo-antigens. These drugs are believed to subsequently deposit in the interstitium. Following the immunogenicity of these molecules, renal dendritic cells and macrophages present these antigens to T-cells activating them. The effector T-cells increase the production of chemokines and cause the localization of inflammatory cells. The hypersensitivity reaction typically results in renal infiltration with lymphocytes, macrophages, and other immune cells, causing nephron damage [15]. Furthermore, the long-term activation of this process can lead to fibroblast activation through tumor growth factor (TGF)-β, causing fibrosis and chronic kidney disease [16]. When comparing the two potential mechanisms of toxicity, natural products may be more effective at preventing AKI resulting from the ATN variety since many of these compounds support mitochondrial health through antioxidative properties – a key inciting factor in ATN.

Mechanism of action of natural products in the context of AKI

Natural products are commonly used to treat various ailments, although their mechanisms of action are not always completely understood. Traditionally, natural products are divided into categories based on their molecular structure. These products can also be organized by their mechanism, which involves their action on cellular transport, DNA damage, apoptosis, oxidative stress, inflammation, and autophagy [17]. Due to the oxidative stress induced by nephrotoxic drugs during kidney injury, there is reason to believe that certain natural products with action against oxidative stress may prove beneficial.

Flavonoids can be widely found in many plants, consumed primarily through fruits, vegetables, and medicinal plants [18]. The protective effect of flavonoids against oxidative stress can be attributed to their ability to decrease free radicals. Some flavonoids can directly scavenge ${\text{O}}_2^{-}$. Other flavonoids achieve this effect by the potential inhibition of xanthine oxidase [19]. Xanthine oxidase is present in a variety of tissues, including the kidney. Due to its high output of superoxide anions, the inhibition of xanthine oxidase results in a similar decrease in free radical production [20]. There are data suggesting that flavonoids can suppress cyclooxygenase, lipoxygenase, mitochondrial succinoxidase, and nicotinamide adenine dinucleotide + hydrogen (NADH) oxidase enzymes which also play a role in reactive species production [21]. Total flavonoids have also been discovered to decrease levels of inflammatory markers, such malondialdehyde (MDA), as well as upregulate levels of silent information regulator factor 2-related enzyme 1 (SIRT1) and nuclear factor erythroid 2-related factor-2 (NRF2), which play integral roles in the regulation of antioxidant genes in kidney injury caused by IRI¹³. Saponins are another class of natural products commonly found within traditional medicines [22]. Specific isolated triterpene saponins were tested as free radical scavengers and were shown to have activity against superoxide, hydroxyl, and hydrogen peroxide free radicals [22,23]. Certain alkaloids found within natural medicines have also been documented to have antioxidant characteristics. Berberine, an isoquinoline alkaloid found within several plant species, including Berberis vulgaris, Berberis thunbergii, and Berberis aquifolium, was shown to decrease the expression of enzymes of 4-hydroxy-2-nonenal (4-HNE), a lipid peroxidation product that propagates oxidative stress [24]. Collectively, natural products possess properties that may alleviate oxidative stress and protect the kidney from antibiotic-induced kidney injury. Several preclinical studies have investigated natural products and are summarized below.

Preclinical evidence

Drug-induced nephrotoxicity is a result of various factors, such as the innate toxicity profile of a compound, patient characteristics, and the pharmacokinetic and pharmacodynamic characteristics of a drug [25]. Several antibiotics carry an inherent risk of nephrotoxicity and are cleared through the kidney, presenting a toxicity risk.

Gentamicin is an aminoglycoside that is commonly used in combination with other antibiotics to treat serious gram-negative bacillary or gram-positive coccal infections [26]. However, gentamicin is also a well-known nephrotoxic agent proposed to cause tubular, glomerular, and vascular effects on the kidney [27]. Furthermore, gentamicin has also been proposed to cause kidney damage through oxidative stress [28], [29] which has been supported by various studies using experimental natural antioxidants such as trans-resveratrol [30], rutin [31], vitamins E and C [32] to prevent gentamicin-induced kidney damage. Another proposed mechanism involves the upregulation of myo-inositol oxygenase (MIOX), which may augment the production of lipoxygenase-12 (ALOX-12) and subsequently 12-hydroxyeicosatetraenoic acid (12-HETE). Both ALOX-12 and 12-HETE increase inflammatory cytokines, such as TNF-α, IL-1β, and IL-6. Furthermore, in MIOX-overexpressed transgenic mice, there was increased production of 4-hydroxynonenal (4-HNE), a major biomarker of reactive oxygen species and lipid hydroperoxidation. Usage of ML355, an experimental ALOX-12 inhibitor showed decreased expression of tubular apoptosis and inflammatory mediators, as well as decreasing albumin excretion demonstrating functional improvement [33]. While not investigated for kidney protection, there are natural products (i.e., baicalein and Traumeel) that inhibit ALOX-12 or interrupt the arachidonic acid pathway [34,35].

Vancomycin is a glycopeptide antibiotic effective against gram-positive infections, and it is hypothesized to cause AKI with prolonged and higher doses [36–38]. Though the exact mechanism of vancomycin-induced AKI is not clearly defined, preclinical data suggest that vancomycin can induce oxidative stress in the proximal tubule, causing acute renal damage [78,79]. The reactive oxygen species generated by vancomycin compromise renal cellular membrane integrity by inducing lipid peroxidation and cause poly [ADP-ribose] polymerase 1 (PARP-1) overactivity from DNA damage, jointly leading to cellular apoptosis and acute renal tubule cell damage. The leakage of proteases from lysosomes damaged by reactive oxygen species may also instigate cell death [39]. Well-established antioxidants such as caffeic acid phenethyl ester (CAPE), vitamin C, vitamin E, and N-acetylcysteine have all been studied in animal models to assess the reno-protective capacity against vancomycin-induced AKI with promising results [40].

Colistin, a polymyxin E, is used to treat infections caused by multidrug-resistant (MDR) gram-negative bacteria [41,42]. Nevertheless, the high rate of colistin-associated nephrotoxicity reported in the recent meta-analysis has limited its use in clinical practice [43]. The mechanism of colistin-associated nephrotoxicity is still not clearly identified. It was hypothesized that colistin directly interacts with tubular epithelial cell membrane which leads to increased membrane permeability and eventually cell death [44,45]. However, recent research proposes that the oxidative stress caused by intracellularly accumulated colistin may be one of the critical factors related to colistin-associated nephrotoxicity [44]. Several preclinical studies support the efficacy of natural products with antioxidant properties to reduce the risk of kidney injury, such as ascorbate [46], alpha-tocopherol [47], melatonin [48], and black garlic [49] with promising results.

Various plant and fruit extracts have been studied in preclinical studies for their reno-protective effects against antibiotic-induced nephrotoxicity. The results of select preclinical studies are summarized in Table 2 [49–68].

Table 2.

Select preclinical studies evaluating natural products for the prevention of antibiotic-associated acute kidney injury.

Antibiotic	Study (Author, Year)	Natural products	Rationale	Active constituents	Animal model and exposure	Results
Gentamicin	Uzun-Goren et al., 2022	Curcumin	Curcumin is an antioxidant and has been evaluated in numerous studies.	Curcumin, demethoxycurcumin, and bisdemethoxycurcumin	Male Wistar rats exposed to gentamicin 80 mg/kg/day intraperitoneal for 10 days following curcurmin. Curcumin 100 mg/kg/day orally for 15 days or control.	Curcumin attenuated nephrotoxicity by suppressing p38 MAPK and NFκβ and activating NRF2.
	Laorodphun et al., 2022	Curcumin	Curcumin acts as antioxidant to inhibit free radical generation and scavenges reactive oxygen species.	Curcumin, demethoxycurcumin, and bisdemethoxycurcumin	Male Sprague-Dawley rats exposed to gentamicin 100 mg/kg/day for 15 days. Curcumin (100, 200, and 300 mg/kg/day) concomitantly or control for 15 days.	Pre-treatment with curcumin resulted in reversed nephrotoxicity hallmarks (serum creatinine, blood urea nitrogen, and augmented creatinine clearance) and normalized markers of oxidative stress (malondialdehyde), and increased antioxidant molecules (superoxide dismutase, glutathione).
	Sarwar et al., 2022	Water Spinach and red grape	Red grape and water spinach contain compounds necessary to scavenge free radical and promote renal tubule regeneration.	Polyphenolic compounds	Female Wistar albino rats exposed to gentamicin 80 mg/kg/day for 7 days. Water spinach (20 g/rat/day) or red grape (5 mL/rat/day) or control for 7 days.	Administration of red grape and water spinach has been shown to ameliorate gentamicin-induced nephrotoxicity through histological and biochemical findings and improving kidney function by decreasing uremic toxins (serum creatinine, uric acid).
	Hassanein et al., 2021	Umbelliferone	Umbelliferone (UBF) is a coumarin derivative that has potent antioxidant and anti-inflammatory activity.	Coumarin phenolic compound	Adult male Wistar rats exposed to gentamicin 100 mg/kg intraperitoneal for 8 days. UMB 50 mg/kg for 7 days prior to gentamicin and continued concomitantly for 8 days or control.	Administration of UMB prior to and concomitantly with gentamicin decreased serum creatinine and urea, decreased expression of ERK1/ERK2, TLR-4, and p38 MAPK renal proteins and suppression of NF-κB-p65/NLRP-3, and JAK1/STAT-3.
	Ersegkin et al., 2020	Ferulic acid	Ferulic acid has antioxidant properties, as well as protective effect in various kidney diseases.	Phenolic acid	Female Wistar albino rats exposed to gentamicin 80 mg/kg/day intraperitoneally for 8 days. Ferulic acid 50 mg/kg orally given concomitantly for8 days or control.	Administration of ferulic acid was shown to decrease urea, creatinine, malondialdehyde, advanced protein products, IL-6, and TNF-α.
	Beshay et al., 2020	Resveratrol	Resveratrol is widely known compound with antioxidant and anti-inflammatory properties and has been previously studied for its nephroprotective ability.	Polyphenol	Male albino mice exposed to gentamicin 225 mg/kg intraperitoneal for 15 days. Resveratrol 50 mg/kg intraperitoneal for 7 days prior to gentamicin and continued concomitantly for 15 days or control.	Administration of resveratrol was shown to decrease serum creatinine, BUN, and malondialdehyde and increase GSH and glutathione catalase activity.
	Salama et al., 2018	Troxerutin	Troxerutin found in coffee/tea and several vegetables shown to have antioxidant properties.	Flavonoid	Male Wistar rats exposed to gentamicin 50 mg/kg intraperitoneal for 15 days. Troxerutin 50 mg/kg/day orally for 15 days concomitantly or control.	Co-administration with troxerutin was shown to significantly improve renal function (increased GFR and decreased urinary albumin) and decreased nephrotoxic findings (albumin to creatinine ratio, serum creatinine, and BUN), renal tubule injury markers (KIM-1), and inflammatory cytokines (IL-10, IL-6, TNF- α).
	Mahmoud et al., 2017	Kiwifruit	Kiwifruit alleviates oxidative stress and gentamicin induces nephrotoxicity by forming free radicals.	Flavonoids, polyphenols, serotonin, and vitamins C and E	Male CD1 albino mice exposed to gentamicin100 intramuscular 100 mg/day for 10 days. Kiwifruit 70 mg/day for 10 days or control.	Co-administration of kiwifruit with gentamicin had reduced improved histochemical findings and near a complete recovery.
	Moreira Galdino et al., 2017	Rudgea viburnoides	Rudgea viburnoides was historically used for multiple purposes medically (hypotensive, blood depurative, anti-rheumatic, diuretic) including kidney pain.	Tannins, flavonoids, triterpenes, sterols, and saponins	Adult male Wistar rats exposed to gentamicin 80 mg/kg twice daily for 5 days. Plant extract 50 or 200 mg/kg twice daily for 7 days or control.	Administration of Rudgea viburnoides plant extract decreased the serum creatinine and polyuria, reversed gentamicin-induced proteinuria, and altered the morphology of the kidneys in comparison with the control arms.
	Jose et al., 2016	Coconut inflorescence sap powder	Coconut inflorescence sap powder is used traditionally for multiple medical conditions as it is proposed to work as a detoxifying agent.	Endogenous antioxidants (exact compounds unknown) contains carbohydrates, minerals, vitamins, and amino acids	Adult male Wistar rats exposed to gentamicin 80 mg/kg for 16 days. Coconut inflorescence sap powder 20 mg/kg for 16 days or control.	Administration of Coconut inflorescence sap powder was associated with a significant improvement in all biochemical parameters (antioxidant enzymes, GSH, creatinine, uric acid, urea, inflammatory markers, and lipid peroxidation) suggesting reduced of kidney injury.
	Aldahmash et al., 2016	Propolis	Propolis has been studied in multiple medical conditions and is a substance formed from plants that consist mostly of antioxidating agents.	Eight different flavonoids have been reported	Swiss albino mice exposed to gentamicin 80 mg/kg for 7 days. Propolis 500 mg/kg for 7 days or control.	Coadministration of propolis decreased BUN and significant histological findings, however, there was an insignificant difference in serum creatinine levels to the control.
	Cekmen et al., 2013	Pomegranate extract	Pomegranate extract displays antioxidant properties, and gentamicin-induced kidney injury is proposed to facilitate through reactive oxygen species.	Vitamin C, flavonoids (anthocyanins)	Adult male Wistar albino rats exposed to gentamicin 100 mg/kg for 14 days. Pomegranate extract 100 μ/L for 14 days or control.	Administration of pomegranate extract resulted in a statistically significant lower serum creatinine and BUN along with a significantly greater GSH and reduced kidney damage via analysis of histologic parameters.
	Hussain et al., 2012	Solanum xanthocarpum fruit extract	Solanum xanthocarpum fruit extract is used traditionally for multiple medical conditions.	Steroidal alkaloids, flavonoids, and glycosides	Wistar rats were exposed to gentamicin 100 mg/kg for 8 days. Solanum xanthocarpum fruit extract 200 or 400 mg/kg for 8 days or control.	Administration of the Solanum xanthocarpum fruit extract significantly lowered serum creatinine, BUN, and renal lipid peroxidation along with an increase in renal antioxidants. Histological parameters were concurrent with these findings.
	Hsu et al., 2011	Sesame oil	Iodinated contrast used with aminoglycosides works synergistically to cause kidney damage through oxidative stress and sesame oil works as an antioxidant.	Potent antioxidants	Sprague-Dawley rats exposed to gentamicin 100 mg/kg/day for 5 days with or without a single dose of 4 ml/kg contrast. Sesame oil 0.5 ml/kg as a single dose or control.	Administration of sesame oil showed statistical significance in preventing the rise in BUN and serum creatinine levels. This was also evidence in histological and oxidative findings.
	Shirwaikar et al., 2004	Aerva lanata	Aerva lanata was historically used for kidney protection in a multitude of ailments.	Flavonoids, alkaloids, steroids, polysaccharides, tannins, saponins	Adult male Wistar albino rats exposed to gentamicin 40 mg/kg for 13 days or cisplatin 5 mg/kg once. Ethanol extract of Aerva lanata 75, 150 or 300 mg/kg for 5 days or control for cisplatin group or for 10 days or control for gentamicin group.	A dose-dependent reduction of acute tubular necrosis was seen when administering ethanol extract treatment (displayed by the BUN and serum creatinine). In the preventative groups, there was a reversal of some of the damage as seen with the BUN and serum creatinine.
Colistin	Worakajit et al., 2022	Panduratin A	Panduratin A has shown to attenuate oxidative damage and inhibit activity against lipid peroxidation.	A bioactive flavonoid	C57BL/6 male mice exposed to colistin 15 mg/kg for 7 days. Panduratin A 2.5 mg/kg or 25 mg/kg for 7 days or control.	Administration of Panduratin A attenuated colistin nephrotoxic effects which was demonstrated through BUN, and histologic findings.
	Dumludag et al., 2022	Silymarin	Historically used to treat liver and gallbladder diseases along with poisoning due to its known hepatoprotective effects. Proposed to have Anti-inflammatory, antifibrotic and anti-apoptotic effects.	silibinin, isosilybinin, taxifolin, silychristine, dihydrosilibinin and silydianine	Sprague–Dawley male rats exposed to colistin 750,000 IU/kg/day for 7 days. Silymarin100 mg/kg/day for 7 days or control.	Administration of silymarin displayed improvement in tubular necrosis and a significant increase in antioxidant capacity, as seen through glutathione peroxidase and superoxide dismutase levels, when co-administered with colistin.
	Wang et al., 2020	7-Hydroxycoumarin	Previous experimental studies that demonstrated protective effects of 7-hydroxycoumarin (7-HC) against renal injury caused by cisplatin and methotrexate	Coumarin phenolic compound	Adult Kunming mice exposed to colistin 15 mg/kg/day for 7 days. 7-hydroxycoumarin 50 mg/kg/day for 7 days or control.	Administration of 7-HC decreased malondialdehyde and increased superoxide dismutase and catalase activities. 7-HC attenuated oxidative stress by promoting NRF2 signaling.
	Colistin Lee et al., 2019	Aged black garlic	Aged black garlic contains constituents that possess antioxidant and anti-inflammatory properties that could help ameliorate kidney injury from colistin.	Phytochemical compounds (phenolic compounds, flavonoids, pyruvate, and thiosulfate), and the major organosulfur compounds (SAC and S- allylmercaptocysteine)	Male Sprague-Dawley rats exposed to colistin 10 mg/kg for 6 days. 1% Aged black garlic (100 μL) or control for 6 days.	Administration of aged black garlic reduced the serum creatinine and BUN in a statistically significant manner, and histological findings were consistent with less renal damage.
	Ghlissi et al., 2018	Vitamins E and C	Known antioxidant activity which can work synergistically together.	Vitamin E and C	Male Wistar rats exposed to colistin methane sulfonate 450,000 IU/kg/day for 7 days. 100 mg/kg/day of Vitamin C plus 100 mg/kg of Vitamin E or control for 7 days.	Coadministration of vitamins E and C improved histopathological damage and restored all biochemical parameters, such as superoxide dismutase, catalase, and glutathione peroxidase.
Vancomycin	Qu et al., 2020	Chlorogenic acid	Chlorogenic acid has been studied and shown to have antioxidant effects through free radical scavenging.	Phenolic compound	Rats were exposed to vancomycin 200 mg/kg intraperitoneal twice daily for 7 days. Chlorogenic acid 150 mg/kg orally 2 h prior to vancomycin dosing for 7 days or control.	Administration of chlorogenic acid prior to vancomycin resulted in decreased malondialdehyde and nitric oxide, decreased pro-inflammatory mediators, and prevented the decrease of glutathione reductase, peroxidase, and catalase.

Abbreviations: BUN = blood urea nitrogen, GFR = glomerular filtration rate, GSH = glutathione, IL = interleukin, JAK = Janus kinase, KIM-1 = kidney injury molecule-1, MAPK = mitogen-activated protein kinases, NFkβ = nuclear factor kappa β, NRF2 = nuclear factor-erythroid factor 2-related factor 2, STAT = signal transducer and activator of transcription protein, TLR-4 = toll-like receptor 4, TNF-α= tumor necrosis factor α

Clinical evidence

As described in the previous sections, numerous preclinical studies evaluate the reno-protective effects of the natural products against antibiotic-induced kidney injury. However, there are few published human studies that translate the findings of preclinical evidence. A small randomized controlled clinical trial (n = 28) investigated the effects of ascorbic acid on the risk of kidney injury secondary to colistin and did not identify any benefits [69]. The small sample of this study makes drawing conclusions difficult. In another randomized controlled trial enrolling 179 subjects receiving vancomycin with 84 receiving concomitant N-acetylcysteine (NAC), individuals receiving NAC had significantly improved serum creatinine and creatinine clearance but did not find statistically significant differences in the incidence of AKI between groups [70]. Similarly, a small matched-group interventional study (30 vitamin E + vancomycin vs. 60 vancomycin alone) reported that exposure to vitamin E significantly reduced the incidence of AKI with improvements in serum blood urea nitrogen (BUN), while other markers of kidney functions such as serum creatinine, creatinine clearance, and urine output were not significantly improved [71]. Lastly, a recent retrospective cohort study (101 melatonin + vancomycin vs. 202 vancomycin alone) evaluating the reno-protective effects of melatonin against vancomycin-induced nephrotoxicity found that melatonin was associated with a reduced incidence of AKI in hospitalized patients after accounting for confounding in a multivariable analysis [72]. Collectively, the available data are derived from small samples and limited in the assessment strategies of kidney injury. Confirmation in large randomized controlled trials is essential to identify the utility of natural products in preventing AKI in the clinical setting. An ongoing clinical trial investigating melatonin for the prevention of vancomycin-associated kidney injury will provide additional evidence on the prospect of using natural products as reno-protective agents (NCT05084196).

Challenges and concerns with natural products

Numerous preclinical studies suggest that natural products may have a role in the prevention of antibiotic-associated AKI; however, definitive data from human studies are lacking. Few studies have investigated the benefits of natural products as preventative therapies for AKI in humans. Those that have been completed are primarily observational in nature and require confirmation in additional larger randomized controlled trials. There are several important considerations when evaluating the current state of the evidence and future directions for research. First, AKI is not exclusively caused by oxidative stress, and the pathophysiology of injury may be immune-mediated which would not respond to antioxidants. Second, the active constituent and its consistency in the natural product must be identified to choose a source appropriately. Third, the dose of active constituents in the natural product must be attainable in humans. Doses used in cell culture and animal studies may be outside the limit of possibility in humans. In such cases, novel formulations with concentrated active constituents may require development and further study. Finally, many natural products have not undergone extensive toxicologic evaluations to determine off-target effects nor evaluations for impurities. In summary, enthusiasm for using natural products to prevent AKI must be tempered with careful evaluation in preclinical models and controlled human studies.

Summary and conclusions

Data from preclinical models suggest that natural products may help reduce AKI. While these data have been corroborated in observational human clinical studies, additional larger randomized controlled trials are essential to determine the safety and efficacy of using natural products as reno-protective agents.