Introduction

Kidney stones or urolithiasis results from the buildup of solid mineral and salt deposits in the urinary system or kidneys. These deposits can induce severe pain and discomfort; potential problems, such as infection or urinary tract blockage, could arise if they are not addressed. The incidence and the prevalence of urolithiasis exhibit significant variation across different populations. According to some estimations, this condition might impact as much as 10–15% of the world’s population [1].

The burden of urolithiasis is substantial in terms of its impact on individual patients and its broader economic and healthcare costs. Kidney stones can cause severe pain and discomfort, often necessitating hospitalization or surgical intervention for removal. Beyond the direct costs of treatment, urolithiasis can also result in lost productivity and diminished quality of life for affected individuals. Moreover, emerging evidence links nephrolithiasis to an increased risk of chronic kidney disease (CKD) [2].

The etiology of urolithiasis is sophisticated and remains incompletely understood. The production of kidney stones is believed to be motivated by a mixture of factors, such as nutrition, genetics, underlying medical conditions, and specific drugs. Stones frequently result when urine gets concentrated, facilitating the crystallization and adhesion of minerals. After their formation, these crystals can undergo further growth, eventually forming more giant stones that can provoke pain and other symptoms [3].

Also, present therapies for urolithiasis incorporate both medicinal and surgical methods. Petite stones may pass naturally with pain medication and increased fluid consumption in certain circumstances. Nonetheless, larger stones or those causing troubles may demand more intrusive therapies such as shock wave lithotripsy or ureteroscopy for removal. While these therapies can effectively remove existing stones, recurrence is expected, and they do not state the fundamental causes of stone formation.

There are drawbacks to current treatments for urolithiasis. For instance, surgical interventions carry risks such as infection or bleeding and may not be appropriate for all patients. Medical treatments such as thiazide diuretics or potassium citrate can help counteract stone recurrence in some cases but may not be helpful for all types of stones. Furthermore, these treatments need continuing checking and may have side effects [4].

Given these limitations, there is considerable interest in using plant extracts and phytochemicals to prevent and treat urolithiasis. Many herbs have been traditionally utilized for their diuretic or antispasmodic qualities, which may help facilitate the transit of kidney stones. Additionally, several plant chemicals have been proven to decrease the crystallization or aggregation of minerals in the urine, potentially reducing the likelihood of stone formation [5]. Urolithiasis has traditionally been treated using a variety of herbal remedies, including Crataeva magna, Aerva javanica, Ipomoea eriocarpa, Peperomia tetraphylla, Punica granatum, Terminalia bellirica, Hibiscus rosa-sinensis, Moringa oleifera, and Costus spiralis [6]. To dissolve kidney stones and stop them from coming back, people have turned to anti-urolithiatic herbs in various forms, such as decoction, infusion, or juice. There are fewer side effects and lower costs when using medicinal plants, but their efficacy is lower, and the period of therapy is longer. Additional scientific investigations are required to investigate safe and natural anti-urolithiatic substances based on the ethnopharmacological data that is now accessible [7]. Phytochemicals contain complex molecular structures that work across various metabolic pathways to deliver desired medicinal effects. Some of these secondary metabolites are bioactive, with high selectivity for cellular targets. In contrast, some metabolites have several cellular targets that may cooperate to produce a specific biological activity. Also, phytochemicals can create biological activity through synergistic processes [8].

Current evidence-based guidelines for managing urolithiasis, such as those from the European Association of Urology (EAU), recommend increasing fluid intake, maintaining a balanced diet, and engaging in regular physical activity to prevent stone formation [9]. In addition, weight management is emphasized as a crucial factor in reducing the risk of stone recurrence [10]. While these lifestyle modifications are effective, they may only be sufficient for some patients, particularly those with recurrent stones or underlying metabolic disorders.

Herbal treatments can provide specific bioactive compounds that inhibit stone formation, reduce oxidative stress, and improve renal function. By integrating herbal treatments with conventional recommendations, we can offer a more comprehensive approach to managing urolithiasis. This combined strategy may enhance patient outcomes, particularly for those who do not respond adequately to lifestyle modifications alone.

In conclusion, urolithiasis is a frequent and significant disorder that can cause considerable pain and discomfort for affected individuals. While current therapies can help relieve existing stones, there are limits to these techniques, and recurrence is likely. This systematic review outlines the utilization of plant extracts and phytochemicals as a potential field of research for the prevention and treatment of urolithiasis to give specific references for further study.

Methodology

Search strategy

A comprehensive literature search was conducted using five databases: PubMed, Web of Science, Cochrane Database of Systematic Reviews, Medline, and Scopus. The search was limited to articles published in English between January 2021 and December 2023, as shown in Fig. 1. The search strategy aimed to include all research articles, whether in vivo, in vitro, or clinical trial studies. Plant names were verified using the Plant List and Royal Botanical Garden, Kew databases. The search included the following keywords: Plants OR Phytotherapy OR Pharmacognosy OR Ethnopharmacology OR Dietary Phytochemical OR Plant Bioactive Compound OR Plant-Derived Chemical OR Bioactive Compounds OR Plant OR Phytonutrient OR extract OR leaves OR seeds AND Nephrolithiasis OR Urolithiasis OR Kidney Calculi OR Urinary Lithiasis OR Ureterolithiasis OR Urinary Calculi OR Ureteral Calculi OR Urinary Bladder Calculi OR Kidney stone AND Treatment OR Therapeutic OR Therapy OR Therapies OR Prophylaxis OR Preventive therapy OR Prevention OR Control.

Fig. 1
figure 1

Search parameters and criteria. The schematic illustration summarizes all keywords used for database searches and criteria to retrieve articles for discussion in this review

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Study selection

Two authors independently screened the titles and abstracts of all articles identified from the search. Full-text articles were then assessed for eligibility based on the inclusion and exclusion criteria. Any disagreements were resolved through discussion. The inclusion criteria were studies that investigated the use of plants, dietary phytochemicals, phytotherapy, or plant bioactive compounds for the prevention or treatment of urolithiasis in in vivo, in vitro, or clinical trials. The exclusion criteria were non-original articles, duplicate publications, articles with inaccessible full text, irrelevant articles, studies focused on risk factors and mechanisms of urolithiasis without investigating anti-urolithic effects, and articles not in English.

Data extraction

Data extraction was performed independently by two authors using a standardized form. The extracted data included study design, type of stone, plant species, plant part used, solvent type, main findings, and study reference. Discrepancies were resolved through discussion. Data were analyzed using Microsoft Excel to summarize and synthesize the findings.

Data synthesis

Data were analyzed using the Excel program to summarize the data.

Results

The initial literature search used specified terms to identify 200 articles. After removing 62 duplicates, 138 articles remained. Upon further screening and reading, 21 articles were excluded due to the unavailability of full text. Additionally, 53 articles were excluded as they were either review articles, not written in English, or focused on mechanisms of urolithiasis risk factors without investigating anti-urolithic effects. Ultimately, 64 publications were included in this systematic review.

Our review identified several studies that focused on different types of kidney stones, including calcium oxalate, uric acid, and infectious stones (struvite stones). The majority of studies investigated the effects of herbal treatments on calcium oxalate stones, which are the most common type. However, we also found evidence supporting the efficacy of herbal remedies in managing other stone types.

For instance, uric acid stones, which form in acidic urine, may be prevented by plant extracts that alkalinize the urine. Plants like Cucumis melo var. inodorus have shown potential in increasing urinary pH, thereby reducing the risk of uric acid stone formation [16]. Similarly, infectious stones, often associated with urinary tract infections, may benefit from the antimicrobial properties of certain herbs. For example, Mentha piperita has demonstrated antibacterial activity against common uropathogens, which can help prevent the formation of struvite stones [75].

The relevant information from all suitable articles was extracted and organized into tables and figures. The retrieved data encompassed details such as the study’s methodology, the composition of the stone, the specific plant utilized, the plant part employed, the solvent type used for extraction, the nature of the study (in vivo, in vitro, clinical trial), the primary findings, and the study’s reference.

Tables 1 and 2 demonstrate experimental signs on plants that prevent and treat urolithiasis in in vivo and in vitro studies, respectively. Table 3 exhibits clinical evidence of plants used to prevent and treat urolithiasis, while Table 4 summarizes the phytochemicals of different plants used for the same purpose.

Table 1 In vivo investigations on the therapeutic benefits of Medicinal Plants against urolithiasis
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Table 2 In vitro studies on the therapeutic effects of Medicinal Plants against urolithiasis
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Table 3 Clinical trial research on the therapeutic efficacy of Medicinal Plants on urolithiasis
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Table 4 Therapeutic Effects of Phytochemicals on Urolithiasis
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Tables 1, 2, 3, and 4 present a comprehensive collection of pharmacological investigations on different types of extracts and formulations of medicinal plants and phytochemical substances, including aqueous, hydroalcoholic, alcoholic, and other varieties. The tables contain data on the cited study, the plant’s scientific name, the specific plant part employed, the kind of extract, the type of stones, the crystal-inducing agent/model, and the anti-urolithic activity/mechanism. The herbal extracts were found to exhibit anti-urolithic actions, as evidenced by the following effects: decreased crystal deposition, reduced oxidative stress, improved renal morphology, changes in urinary pH, decreased levels of lithogenic factors in urine, such as oxalate, calcium, and phosphate, improved renal function, increased urinary citrate, and altered protein expression.

The majority of studies used 0.75–1% ethylene glycol (EG) in drinking water alone (n = 16, 25%) [14, 16, 19, 22, 34] or in combination with ammonium chloride (AC) (n = 15, 23.43%) [11,12,13, 18, 26] (Fig. 2) to provoke calcium oxalate (CaOx) nephrolithiasis. A small number of studies retained other methods, such as intraperitoneal injection of sodium oxalate (NaOx) in Wistar rats or Drosophila [21, 24], implantation of zinc disks into the bladder of rats [25], or feeding rats with 3% glycolic acid mixed with food for seven days [27]. Additionally, certain plants were the subject of multiple studies, in contrast to other plants, while the majority of stones utilized were CaOx (n = 54, 84.4%) (Figs. 3 and 4).

Fig. 2
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Number of studies based on the methods used for crystal induction. NaOx sodium oxalate, EG ethylene glycol, AC ammonium chloride

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Fig. 3
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Number of studies discussed a certain plant name from 2021 to 2023

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Fig. 4
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Number of studies based on the types of stones studied. CaOx calcium oxalate, COM calcium monohydrate

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The most common studies used aqueous extracts (n = 20, 31.25%) [21,22,23, 42] and leaves (n = 23, 35.9%) [12, 18, 20, 37, 44] were the widely utilized herbal preparations, as shown in Figs. 5 and 6. Other botanical parts utilized involved fruits (n = 6, 9.4%) [13, 15, 22, 28], roots (n = 4, 6.25%) [31, 57], tea preparation [46], peel and pulp [40], pits [42], citrus waste peel [49], seeds (n = 12, 18.75%) [16, 19, 67], rhizomes [65], stems [14], and flowers (n = 4, 6.25%) [29]. Some studies utilized whole plants (n = 18, 28.1%) [21, 23, 24, 33, 35], herbal medications (Ningmitai capsule) [68], Daidzin (isoflavone compound) [70], and poly-herbal formulations such as Safoof-e-Pathar Phori [11].

Fig. 5
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Number of studies based on parts of the plants used

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Fig. 6
figure 6

Number of studies based on the types of solvents used in the extraction

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Other extraction methods included hydroalcoholic (n = 7, 10.9%) [15, 28, 30], methanolic (n = 10, 15.6%) [17, 19, 20], or ethanolic solvents (n = 18, 28.125%) [12, 13, 16, 18, 24, 29], although some studies applied formulations/constituents like triterpenoids extracted from plants [74] (Fig. 5). Numerous clinical trials have been conducted to explore the efficacy of various herbal treatments for urolithiasis. This systematic review inspected three clinical trials. In a randomized, single-blind clinical trial by Aryaeefar et al. (2022), a total of 126 patients with ureteral stones (0–10 mm) were randomly split into a control group and an intervention group that administered whole plant distillate of Alhagi maurorum for four weeks. Even though an insignificant difference in stone size or placement was detected between the groups, the time essential for stone removal was markedly shorter in the intervention group. Furthermore, a randomized, single-blinded study by Shakeri et al. (2022) evaluated the effects of Nigella sativa seeds and tamsulosin in 80 patients with kidney and ureteral calculi (4–10 mm). The two groups displayed a reduction in stone size and number, with a more considerable decrease in pain score noted in the Nigella sativa group. Wang et al. (2022) conducted a randomized clinical trial with 123 patients diagnosed with urinary stones (10–20 mm), where the Ningmitai capsule (a herbal formulation) group displayed significantly higher stone expulsion rates, stone-free rates, and shorter duration to complete a stone-free state compared to the control group.

The review systematically investigated six studies that searched the effects of plant-based compounds on kidney stones. These studies used in vitro and in vivo methods to investigate the impact on CaOx and calcium oxalate monohydrate (COM) crystals. The compounds examined included Quercetin, Daidzin, Trigonelline, Medicagenic Acid, Methyl Gallate, Gallic Acid, and Pentacyclic Triterpenoids (Lupeol and Ursolic acid). The studies’ results showed the effects of these substances on the development of stones, including alterations in urine characteristics, such as urine output volume, pH levels, protein concentrations, crystal features, such as size, number, and mass, as well as changes in levels of other biochemical markers. In rat models with CaOx nephrolithiasis circumstances were associated with modifications in components like oxalate and citrate levels together with variations in pH balance, oxidative stress markers, production of crystallization modulators and inflammatory molecules, Crystal formations in urine and deposition within the kidneys [12, 15]. Most studies have revealed enhancements in renal structure and function following the administration of these compounds. Moreover, it was frequently noted in the research that there were changes in the excretion levels of CaOx, magnesium, and phosphate.

Discussion

Nephrolithiasis, or the development of kidney stones, is a complex and multifactorial process that involves several steps and physicochemical changes in the urine environment. These changes result in the production of crystals, their growth, aggregation, and subsequent retention inside the kidneys [76, 77]. This process concerns interactions between many urinary ions and a range of crystallization modulatory macromolecules. Most idiopathic CaOx stones develop on a base of biological apatite called Randall’s plaque (RP). This plaque starts in the renal papillary interstitium and travels outward to the papillary surface. When the surface epithelium breaks down, the plaque becomes exposed to the urine in the pelvic area. Furthermore, some stones form joined to tubular crystal deposits, struggling the terminal collecting ducts [78, 79].

Herbal treatments can complement lifestyle changes by targeting specific pathways involved in stone formation. For example, many phytochemicals have anti-inflammatory and antioxidant properties that can mitigate the renal damage caused by oxidative stress, which is not directly addressed by lifestyle modifications [80]. Furthermore, some herbal remedies have diuretic and antispasmodic effects, which can aid in the expulsion of stones and provide symptomatic relief [81].

To investigate the pathogenesis of CaOx nephrolithiasis and develop therapeutic agents, various in vitro and in vivo models have been established [82, 83]. CaOx crystal nucleation, growth, and aggregation were investigated in vitro crystallization studies with and without crystallization modulators [51]. These methods afford a preliminary evaluation of crystallization modifying activity, probable modes of action, and anti-urolithic potential. Nonetheless, the biological system and pathogenesis of urolithiasis are complicated, and these in vitro results cannot be extrapolated to therapeutic effects [84].

As a result, in vivo animal models of CaOx nephrolithiasis have been established to understand the pathophysiology better and examine the anti-urolithic activities and potential of various medicines [29, 30]. Experimental nephrolithiasis is induced by administering hyperoxaluria-inducing agents through drinking water, diet, or injection [85, 86]. These in vivo models have considerably contributed to our understanding of human illnesses and remain a key tool for researchers to examine numerous physiological processes, biochemical events, and test novel pharmaco-therapeutic drugs [87].

The majority of the studies reviewed here have utilized the well-established and relatively economical rat model of nephrolithiasis by administering EG in drinking water, either alone [19, 20] or in combination with AC [15, 18]. EG, a precursor of oxalic acid, is quickly absorbed from the gastrointestinal system and converted to oxalic acid by hepatic enzymes. EG predominantly affects the kidneys, with substantial variations in sensitivity among strains, species, and sexes. In comparison to mice, rats are more sensitive, and male rats are more sensitive than female ones. While EG (0.75–1%) alone can induce CaOx deposition, its effects are variable [88]. In order to decrease the amount of time needed and attain a consistently high rate of renal crystal deposition, hypercalciuric, nephrotoxic, or pH-reducing procedures, such as AC [89], gentamicin [90], or a diet lacking in magnesium, has been combined with EG.

When rats are given EG at a concentration of 0.75% or more in drinking water, they develop hyperoxaluria, which leads to crystalluria and CaOx crystal deposition in the renal tubules [28]. The incidence of crystal deposition in the kidney varies from 80 to 100%, depending on the co-administered medicine, and nephrolithiasis develops in around 1–3 weeks [91]. Oxidative stress in the kidneys, increased water intake and polyuria, lower urinary pH, decreased urinary Ca2+, Mg2+, and citrate contents, increased CaOx crystalluria, phosphate excretion, renal hypertrophy, and weight loss are the main characteristics of hyperoxaluria-induced nephrolithiasis [35, 39]. Increased loss of urine protein, decreased clearance of creatinine, and raised levels of blood urea nitrogen (BUN) and creatinine in the serum are further indicators of renal impairment [30, 34].

Herbal therapies were prepared for assessment using a variety of plant parts in the examined research, including flowers, seeds, fruits, leaves, stems, roots, and rhizomes. The most popular component was leaves, which were extracted using alcoholic, hydroalcoholic, and aqueous solvents. The effectiveness of herbal administration was evaluated in relation to common biomarkers of nephrolithiasis, including renal CaOx crystal deposits, citrate, pH, oxalate, oxidative stress markers, urine calcium, phosphate, and improved renal structure and function. While some studies did not investigate every facet of nephrolithiasis, every therapy decreased the amount of CaOx crystals that were deposited in the kidneys. Most studies indicated that using herbal remedies improved the kidneys’ structure and function. Furthermore, research on oxidative stress showed that herbal remedies have antioxidant qualities.

The clinical trials in this review suggest potential benefits of herbal treatments like Alhagi maurorum, Nigella sativa, and the Ningmitai capsule (a Chinese herbal formulation) in facilitating stone passage, alleviating pain, promoting stone expulsion, and increasing stone-free rates in patients with urolithiasis. While these findings corroborate the traditional use of these herbs and provide preliminary evidence for their anti-urolithic properties, the number of trials is limited. Larger, well-designed clinical studies are warranted to further evaluate the efficacy and safety of these herbal treatments, including their potential interactions with conventional therapies, before recommending their use in clinical practice.

The studies investigating various phytochemicals highlight their potential as therapeutic agents for urolithiasis. Quercetin, Daidzin, trigonelline, medicagenic acid, methyl gallate, gallic acid, lupeol, and ursolic acid exhibited anti-urolithic effects by reducing crystal formation, adhesion, aggregation, and oxidative stress while improving renal function in experimental models. These findings suggest phytochemicals may target multiple pathways involved in stone formation and associated renal dysfunction. However, further research is warranted to elucidate their mechanisms of action, optimize dosing and formulations, evaluate safety profiles, and translate these findings into clinical applications to prevent and manage urolithiasis.

Differentiating between stone types is crucial for effective management. Herbal treatments can be tailored to target the specific pathophysiological mechanisms of different stones. For calcium oxalate stones, phytochemicals, such as quercetin and gallic acid, can inhibit crystal formation and aggregation. For infectious stones, the antimicrobial properties of herbs like Mentha piperita can help prevent stone formation by controlling urinary infections. This targeted approach allows for a more personalized treatment plan, potentially improving outcomes for patients with different types of kidney stones.

In conclusion, this systematic review critically evaluates the use of various phytochemical and natural herbal treatments in experimental models of nephrolithiasis, highlighting their potential as therapeutic agents for managing this complex condition. The findings underscore the need for further research to elucidate the underlying mechanisms and translate these findings into clinical practice.

Conclusion

This systematic review has provided a comprehensive overview of the current state of research on the use of plants in treating and preventing urolithiasis. The findings suggest that various plants and their components have significant potential in managing this condition. They reduce the size and number of stones and alter the levels of urinary oxalate, calcium, phosphate, and citrate, which are critical factors in stone formation. However, further well-designed clinical trials are needed to validate these findings and establish these plants’ optimal use in clinical practice. This research opens new avenues for developing safe and effective phytotherapeutic strategies for urolithiasis, and ongoing research is essential to translate these findings into clinical applications.