Anthraquinones in Kidney Disease: Therapeutic Efficacy and Nephrotoxic Implications

Abstract

Broad classes of naturally occurring polyphenolic chemicals, anthraquinones are present in medicinal plants like Rheum, Cassia, and Aloe species. They have a complicated pharmacological profile that includes both toxicological and therapeutic aspects. Growing interest in their potential uses for renal diseases such as diabetes-related nephropathy, renal fibrosis, and ischemia–reperfusion injury has been sparked by their pleiotropic bioactivities, which include anti-inflammatory, antioxidant, antifibrotic, and cytoprotective properties. Anthraquinones can reduce both inflammation and oxidative stress by modifying glomerular and tubular functioning, enhancing redox balance, and controlling important signaling pathways like NF-?B, MAPK, and TGF-? at pharmacologically relevant dosages. However, prolonged or excessive exposure, especially from laxatives containing anthraquinone, has been linked to nephrotoxicity, which is characterized by oxidative damage, mitochondrial dysfunction, and tubular apoptosis. These substances are deemed inappropriate for long-term use by regulatory bodies including the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) because of the possibility of kidney impairment and cancer. Developments in prodrug design, targeted drug delivery, formulation science, and combined administration with nephroprotective adjuncts present viable ways to maximize therapeutic effectiveness while reducing renal toxicity. This review integrates clinical and translational evidence, discusses current gaps and future directions for safer therapeutic exploitation of this double-edged phytochemical class, and provides a thorough summary of the chemical structure, pharmacokinetics, pharmacodynamics, and molecular principles underpinning the dual renal effects of anthraquinones.

Keywords

Introduction

Table 1: The main naturally occurring anthraquinones

Compound	Structure	Major source	Reported pharmacological/ Renal relevance	References
Emodin		Rheum palmatum, Aloe vera	Anti-inflammatory, anti-fibrotic, antioxidant; mitigates renal fibrosis via inhibition of the TGF-β signalling pathway.	12
Chrysophanol		Rheum officinale	Antioxidant and nephroprotective; reduces oxidative stress and inflammation in diabetic nephropathy models.	13
Physcion		Cassia tora	Exhibits anti-inflammatory effects; ameliorates liver fibrosis	14,15
Sennoside A/B		Cassia angustifolia	Laxative glycosides; chronic exposure or misuse associated with renal tubular damage and electrolyte imbalance.	16
Alizarin		Rubia cordifolia	Displays antioxidant, anti-fibrotic and anti-calcific activities in renal tissue; prevents calcium oxalate deposition.	17
Aloe emodin		Aloe and Rhubarb	Helps suppressing renal fibrosis progression; exerts hepatoprotective, anti-viral and anti-inflammatory activity.	18,19
Rhein		Rheum paltatum	Antioxidant and anti-inflammatory activity; reduce kidney damage; decrease kidney inflammation by reducing oxygen free radical levels	6,20,21
Diacerein		Aloe vera and Rhubarb	Anti-inflamamtory, help prevent elevated blood glucose levels	22

3. Pharmacokinetics aspects of anthraquinones

Fig.1: Effects of anthraquinones in renal pharmacology

6. Anthraquinones in renal disorders

Anthraquinones are now recognized as significant phytochemicals that may be used to treat a range of renal conditions. Their main impact is ascribed to their capacity to reduce oxidative stress, inflammation, and fibrosis—three important mechanisms that underlie the development of kidney injury. Rhein, emodin, aloe-emodin, and chrysophanol are the anthraquinones that have been studied the most for their renoprotective qualities in a variety of disease settings.

6.1 Diabetic Nephropathy (DN)

Glomerular hypertrophy, thickening of the basement membrane, and interstitial fibrosis brought on by persistent hyperglycemia and inflammation are the hallmarks of diabetic nephropathy. Rheum palmatum is the source of Rhein, an anthraquinone that has been demonstrated to dramatically enhance renal function in diabetic animals (45). It decreases extracellular matrix deposition by inhibiting the production of fibronectin, connective tissue growth factor (CTGF), and TGF-β1.Rhein also reduces macrophage infiltration in renal tissue by blocking NF-κB activation (46,47). Proteinuria and serum creatinine levels in individuals with early DN were shown to improve in clinical settings when rhein-containing preparations were used (50).Similarly, emodin prevents DN by enhancing glucose metabolism, inhibiting mesangial growth, and activating AMPK and mTOR (48).

6.2 Acute Kidney Injury (AKI)

Abrupt loss of renal function brought on by ischemia, toxins, or inflammation is known as acute kidney injury. Renal ischemia/reperfusion injury has been shown to be lessened by anthraquinones such as emodin and aloe-emodin. They accomplish this by inhibiting tubular apoptosis, lowering lipid peroxidation, and activating the Nrf2/HO-1 pathway (49,5).Additionally, Rhein protects against cisplatin-induced nephrotoxicity by downregulating the production of TNF-α and IL-1β and restoring antioxidant enzyme activity (SOD, GSH-Px) (50). These results demonstrate anthraquinones' potential as adjuncts to lessen chemotherapy's nephrotoxic adverse effects.

6.3 Chronic Kidney Disease (CKD) and renal fibrosis

Mostly found in Rheum species (rhubarb), anthraquinones including rhein, emodin, aloe-emodin, and chrysophanol have drawn interest from researchers due to their potential to alter key pathways involved in the development of renal fibrosis and chronic kidney disease (CKD). One of the main factors influencing the progression of chronic kidney disease (CKD) to end-stage renal disease is renal fibrosis, which is defined by excessive extracellular matrix (ECM) deposition triggered by profibrotic signaling. By improving mitochondrial homeostasis through the upregulation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), emodin has demonstrated significant antifibrotic effects in preclinical models. This is linked to decreased expression of fibrosis markers and attenuated histopathological renal damage in unilateral ureteral obstruction (UUO) models, indicating that mitochondrial stabilization may be a significant antifibrotic mechanism (36,51,52,53).Rhein has been shown to decrease the advancement of fibrosis by blocking TGF-β1/Smad3 signaling, which is a key factor in the creation of ECM proteins and the activation of myofibroblasts (6). Chrysophanol and other anthraquinones inhibit NF-κB-mediated inflammatory pathways, which are intimately associated with profibrotic signaling in chronic kidney disease (CKD) (54). Numerous anthraquinones have been found to interact with CKD-related targets through network pharmacology and experimental validation. They reduce renal fibrosis and inflammation by inhibiting the activation of the NF-κB pathway and downregulating pro-inflammatory cytokines like IL-6, IL-1β, and TNF-α (51).Although there is still a lack of direct histological data in humans, clinical randomized controlled trials and observational studies of rhubarb-containing preparations in CKD patients have shown improvements in renal biochemical markers and decreases in proteinuria, outcomes that correlate with slowed fibrotic progression. All of these results point to the possibility that anthraquinones may target several signaling pathways (such as TGF-β/Smad, NF-κB, and mitochondrial regulation) to provide renoprotective and antifibrotic effects, which would warrant further research into them as CKD management adjuncts(6,55).

6.4 Drug-induced nephrotoxicity

A number of nephrotoxic substances cause oxidative and inflammatory kidney damage, including cyclosporine, gentamicin, and cisplatin. By blocking MAPK signaling and preserving mitochondrial integrity, emodin lessens the nephrotoxicity caused by gentamicin (56). Anthraquinones also inhibits endoplasmic reticulum stress and caspase-12 activation to prevent cyclosporine-induced kidney injury (57). The use of anthraquinones as nephroprotective adjuvants is supported by these findings.

6.5 Renal carcinoma and other disorders

Recent research suggests that anthraquinones may have anticancer potential against renal cell carcinoma (RCC), albeit limited. Emodin suppresses PI3K/Akt signaling and triggers death in RCC cells through ROS-mediated mitochondrial pathways (58). Furthermore, the antioxidant and anti-inflammatory effects of anthraquinones have shown promise in glomerulonephritis and renal cystic diseases, though more clinical data are required (59).

7. Anthraquinone induced nephrotoxicity

Anthraquinones have potential nephrotoxic effects despite their promise therapeutic uses, especially when used in large quantities or for an extended length of time. Although their redox-active quinone structure has numerous therapeutic advantages, it can also produce reactive oxygen species (ROS), which can result in renal dysfunction, tubular cell damage, and oxidative stress. The necessity of dose standardization and safety assessment in both pharmaceutical and herbal formulations is highlighted by this paradoxical result.

7.1 Mechanisms underlying anthraquinone-induced nephrotoxicity

The main mechanisms by which anthraquinones cause nephrotoxicity are oxidative stress, mitochondrial damage, and renal tubular epithelial cell death. ROS can be produced by redox cycling when anthraquinone metabolites, such as rhein anthrone and aloe-emodin anthrone, accumulate excessively (60). Tubular necrosis results from lipid peroxidation, intracellular glutathione (GSH) depletion, and caspase-3 activation (61).Additionally, through intrinsic apoptotic pathways, anthraquinones can promote cell death by reducing ATP and impairing mitochondrial oxidative phosphorylation. By fragmenting DNA and depolarizing the mitochondrial membrane, some derivatives, like danthron and chrysazin, directly cause cytotoxicity in proximal tubular cells (62).Modification of renal transporters, such as organic anion transporter 1 (OAT1) and OAT3, which are in charge of drug and metabolite clearance, is another contributory factor. These transporters are competitively inhibited by high anthraquinone dosages, which may cause hazardous intermediates to accumulate intracellularly (63).

7.2 Histopathological and experimental evidence

Research on animals has shown that long-term use of rhubarb extracts or laxatives containing anthraquinone causes tubulointerstitial fibrosis and pigment nephropathy. Histological observations include the development of brown pigment granules in renal tissue, interstitial inflammation, and tubular epithelial degradation (64).  Long-term administration to rhein (≥100 mg/kg/day) in mice caused mitochondrial enlargement, tubular dilatation, and increased serum creatinine (6). Similarly, emodin confirmed oxidative damage by causing localized tubular necrosis and elevated renal malondialdehyde (MDA) levels at high dosages (65).

7.3 Clinical Reports and Human Observations

Long-term use of herbal laxatives based on anthraquinone, such rhubarb, cascara, and senna, has been associated in a number of clinical case reports with melanosis coli and chronic kidney damage, which can occasionally lead to renal papillary necrosis (37). In a few cases, people who consumed herbal mixes containing emodin and rhein derivatives also experienced acute interstitial nephritis (37). These symptoms emphasize the thin safety margin between therapeutic and dangerous doses, even though they are usually reversible upon cessation. A case report published in the Hong Kong medical journal gives one of the most convincing clinical observations in humans that connects anthraquinone derivatives to renal disease. After using a patented herbal slimming pill that contained anthraquinone derivatives derived from rhubarb for an axtended period of time , a 23 year old lady experienced acute renal failure. Although renal function improved after stopping the medication , minor interstitial fibrosis and tubular atrophy remained histologically four months later, according to renal biopsy that revealed hypocellular interstitial fibrosis (66).

7.4 Structure–Toxicity Relationship

The pattern of chemical substitution in anthraquinones affects their potential for nephrotoxicity. Because of their increased redox cycling potential, hydroxylated anthraquinones (such as emodin and aloe-emodin) tend to produce more ROS, while their methylated or glycosylated equivalents are less hazardous (67). Conjugation by sulfation or glucuronidation increases renal excretion and decreases cytotoxicity, indicating that structural changes may provide safer compounds for medicinal application.

7.5 Strategies to Mitigate Toxicity

Researchers have suggested the following to reduce the risk of nephrotoxicity,regulated dosage and brief anthraquinone administration,co-administration of antioxidants to counteract ROS, such as quercetin and N-acetylcysteine,creation of focused medication administration methods that improve kidney selectivity,CYP450 and OAT interaction screening prior to clinical use (30).

8. Strategies to enhance therapeutic efficacy and minimize toxicity:

A multifaceted approach is advised to maximize the beneficial effects of anthraquinones in renal illness while reducing nephrotoxicity. First, pro-drug design or structural change can increase solubility, decrease unwanted renal tubular absorption, and promote localized activation of the active ingredient (68). Second, sustained release, decreased peak plasma concentrations, and less off-target renal exposure are made possible by targeted drug delivery methods and nanoparticle formulations (38). Third, the therapeutic window is further expanded and tubular damage caused by oxidative stress and apoptosis is decreased by co-administration of nephroprotective drugs, such as antioxidant or anti-inflammatory adjuncts, and optimization of dosage regimens (avoiding high Cmax, lowering frequency or dose) (69). Fourth, early monitoring employing sensitive renal biomarkers (e.g., KIM-1, NGAL) and modification of pertinent metabolic pathways (e.g., favoring glucuronidation over oxidative activation) aid in the detection of renal injury prior to overt toxicity (70). Individualized treatment and enhanced safety are made possible by patient selection and continuous renal function monitoring, particularly in individuals with pre-existing CKD or concurrent nephrotoxins. Last but not least, incorporating "safety-by-design" principles—like PK/PD modeling, mechanism-based toxicology (e.g., ferroptosis via Nrf2/GPX4 pathways, mitochondrial malfunction) and early in-vitro renal tubular cell screening—supports translation into the clinic with a lower risk of nephrotoxicity (71).

9. Clinical and Translational Evidence

Although there is still a lack of human clinical evidence, emerging translational research supports the renoprotective potential of important anthraquinones including rhein and emodin. While emodin reduces high-glucose-induced podocyte damage and renal fibrosis by activating AMPK/mTOR-mediated autophagy and Nrf2-driven antioxidant responses, rhein has been demonstrated to improve urinary albumin excretion and renal histopathology in diabetic nephropathy (DN) models by blocking TGF-β1/Smad signaling and oxidative stress (50). These drugs have poor oral bioavailability but high renal tissue accumulation, according to pharmacokinetic modeling, indicating both a therapeutic possibility and the necessity for rigorous safety investigation (72).As a result, kidney-targeted rhein liponanoparticles and other nanoparticle-based delivery systems have been created to improve renal selectivity and lower systemic exposure, and they have shown promise in animal DN models (42). These translational developments highlight a feasible route toward clinical testing of anthraquinones for renal disease, even though regulatory agencies advise against long-term use of anthraquinone-based laxatives due to possible nephrotoxicity, as long as standardization, formulation optimization, and early biomarker-guided safety monitoring are put into place.

CONCLUSION

A pharmacologically diverse class, anthraquinones have been shown to have renoprotective effects in a variety of experimental animals. Compounds like rhein and emodin are intriguing lead scaffolds for kidney-directed therapies because of their ability to inhibit fibrotic development, control inflammatory cascades, and reduce oxidative stress. Translational developments, such as better formulations and focused delivery methods, present encouraging approaches to boost effectiveness while reducing systemic toxicity.However, safety concerns limit the clinical translation of anthraquinones: in animal studies and case reports from human herbal product use, prolonged or high-dose exposure has been linked to tubular injury and interstitial fibrosis, highlighting the necessity of thorough toxicokinetic profiling and carefully planned clinical trials. In order to identify early benefits or harm, future research should focus on randomized clinical trials that include sensitive renal biomarkers (e.g., NGAL, KIM-1, and cystatin C), standardized botanical preparations or synthetic analogs with improved therapeutic indices, and structure–activity relationship (SAR) studies. Anthraquinones may replace conventional treatments as logically formulated medicines in renal pharmacotherapy with proper optimization and safety assessment.

CONFLICT OF INTEREST

No

FUNDING

No

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