Herbs with Potential Nephrotoxic Effects According to

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REVIEWARTICLE

Herbs with Potential Nephrotoxic Effects According to the Traditional Persian Medicine: Review and Assessment of Scientific Evidence Fatemeh Kolangi1, Zahra Memariani1,2,*, Mahboubeh Bozorgi3, Seyyed Ali Mozaffarpur1,2 and Mohaddeseh Mirzapour1 1

School of Traditional Medicine, Babol University of Medical Sciences, Babol, I.R Iran; 2Traditional Medicine & Medical History Research Center, Health Research Center, Department of Persian Medicine, Babol University of Medical Sciences, Babol, I.R.Iran; 3 School of Traditional Medicine, Tehran University of Medical Sciences, Tehran, Iran Abstract: Background: The increased use of herbal remedies particularly in patients with kidney diseases indicated the importance of studies, which focused on nephrotoxic plants. Objective: The present study aimed to review and assess the kidney-damaging herbs mentioned in the Persian medicine [PM] books. ARTICLE H ISTORY Received: September 10, 2017 Revised: January 04, 2018 Accepted: February 18, 2018 DOI: 10.2174/1389200219666180404095849

Methods: The main PM books were searched for nephrotoxic herbs and their relevant reformers traditionally proposed for preventing renal damage. PubMed, Scopus and Google Scholar were investigated for evaluation of the scientific evidence relating to the nephrotoxicity of herbs. Results: A total of 64 plants with kidney damage potential and their reformer medicaments were recorded in 7 sources included in this review. Allium schoenoprasum and Marrubium vulgare were the most repeated and emphasized nephrotoxic plants in PM books, but there was no relevant scientific evidence. Despite the lack of clinical studies, some evidence was found for 38% of plants that were related to renal damage. The most repeated reformers for reducing the renal side effects mainly consisted of gum tragacanth, gum Arabic, mastic gum, anise, jujube and honey and some evidence was found for their nephroprotective activities. Conclusion: The present study reviewed and assessed the herbs with adverse renal effects in the main PM books. Some evidence was in line with the potential nephrotoxicity of plants and their reformers. Despite the lack of clinical research for evaluation of their renal damage, the herbs may be focused in term of their nephrotoxicity; and there is a need for further studies on the scientific basis of their nephrotoxicity.

Keywords: Combination therapy, kidney, medicinal plants, nephrotoxicity, renal injury, traditional medicine. 1. INTRODUCTION For centuries, people have used plants for the treatment of different ailments and there have been strong historical relationships between plants and the human health [1]. Traditional medicines have been widely used around the world so that more than 80% of people use different traditional remedies for treatment in some populations [2]. It is estimated that up to 80% of Africans [3], more than 60% of the Chinese [4], and a significant percentage of the rural population in India [5] use traditional and indigenous medicines in their health care. Natural products were the most common forms of CAM therapy in the USA from 2002 to 2007 [6]. Use of herbal medicines in Iran is reported to be 56% and 68% among general and women populations respectively [7]. Despite the need for more scientific evidence, plant products have been often considered as natural and safe alternatives to conventional synthetic pharmaceuticals by general public [1, 8]. A significant increase in the use of herbal remedies especially in patients with kidney diseases may increase the probability of renal injuries [1]. High surface area and flow, high metabolic activity, and active secretion and reabsorption mechanisms make kidneys sensitive to toxic *Address correspondence to this author at the School of Traditional Medicine, Traditional Medicine and History of Medical Sciences Research Center, Health Research Institute Babol University of Medical Sciences, Babol, Iran; Tel: +98 1132194728; Fax: +98 1132194728; E-mail: [email protected]

1389-2002/18 $58.00+.00

substances [9]; However, since current therapies are limited in chronic kidney diseases, many kidney patients seek alternative therapies [10]. The use of traditional medicine among the patients with kidney diseases has been higher than any other patients in northern Tanzania and Australia [11, 12]. Due to the renal vulnerability to toxic substances, the improper use of herbal remedies might lead to various kidney conditions such as electrolyte abnormalities, proteinuria, acute and chronic kidney diseases and even kidney failure [8, 13]. Valuable books have been written about the PM which has a long history of herbal treatment. As a traditional medicine system, many medicinal plants are described in PM manuscripts; in monographs of all plants, PM scholars -according to their clinical experiences- have specified daily doses and target organs of some plants and then warned of the probable adverse effects of some herbs, precautions and contraindications in people or vulnerable patients. They have also explained that a combination therapy with some other medicaments, namely reformers (Mosleh), can be effective for reforming or reducing the plants' side effects [14]. Some herbs have been specified with potential harmful effects on kidneys through investigation of the symptoms based on the PM scholars' clinical observations and experience by diagnosing the kidney diseases including functional impairment, structural disorders and/or disruption, and the other specific disorders such as stones and inflammation, and renal weakness and atrophy [15]. The © 2018 Bentham Science Publishers

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herbs with adverse renal effects are specified by terms such as "Mozer-e-Gordeh" and "Moz'ef-e-Gordeh" which mean "harmful for the kidney" in PM books. Following the introduction of these plants, some other medicaments have been recommended for simultaneous use as reformers in order to prevent the adverse potential effects [16, 17]. Considering the importance of scientific documentation about renal damaging plants and effective solutions to prevent or reduce these potential adverse effects, the present study aimed to introduce these herbs according to the Traditional Iranian Practitioners and evaluated them by searching the related scientific evidence. The present research can be the basis for future studies to explore plants and phytochemicals which have not been studied in terms of renal toxic effects and relevant protective combination therapies. 2. RESEARCH METHOD We reviewed the main PM manuscripts during the 9th to 18th centuries. These references included Jame-ol-mofradat al adviahval-aghziyah Ibne Baitar (12th-13th century) [18], Al-Hawi Al-Kabir Fi-Tebb (Rhazes 9th-10th century) [19], Canon of Medicine (Avicenna, 10th-11th century) [20], Tohfat-ol-Moemenin (Tonekaboni, 17th century) [16], Tazkira-uli-albab (Antaki 16th century)-[21], Makhzan-ol-advie (Aghili Shirazi, 18th century) [17], and Alabnieh an haghaegh-ol-advieh (Heravi AM, 10th century) [22], and then we collected the relevant data. Three first references are in Arabic and others are Persian. Our literature review model for finding the renal toxic plants was in accordance with previous studies [23]. We searched the Persian and Arabic terms such as "Gordeh", "Koleye" (which mean the kidney), "Alat-e-boul" (which mean the urinary track), and "Mazerrat", "Zarar", "Ziyan", "Mozer" (which means injury) in the aforementioned references. In addition to the renal toxic plants, we also explored the introduced medicaments in the references for prevention of side effects. We then collected, categorized and analyzed the obtained data [23]. We searched the additional reports about current pharmacological adverse effects of the medicinal plants on kidneys in databases such as PubMed, Scopus and Google Scholar in order to evaluate relationships between traditional knowledge and current findings. 3. RESULTS AND DISCUSSION We found about 64 medicinal plants with kidney damage potential in PM reference books which proposed the combination therapy with some other herbs to prevent the adverse renal effects. Table 1 presents herbs with adverse renal effects, which are mentioned in PM books, as well as their related protective agents for preventing the adverse renal effects. Among all the aforementioned herbs as renal damaging agents, Allium schoenoprasum and Marrubium vulgare were respectively the most repeated and emphasized plants in PM books. In the case of M. vulgare, the excessive consumption might lead to renal damage and hemorrhage. Despite the PM scholars' views about the high possibility of renal injury by M. vulgare, there was not any evidence for its direct or indirect renal or urinary system toxicity. Scientific evidence including experimental toxicity studies, case reports, events in animals, adverse effects in clinical trials, and phytochemical content with renal damage potential were found for nearly 38% of plants with potential harm to kidneys based on the PM. 3.1. Plants with Evidence for Both Adverse and Therapeutic Effects on Kidneys According to the PM books, some of these plants such as asafetida, garlic, saffron, wormwood and raisin also have some therapeutic effects on kidneys in addition to their potential kidney damage [16, 17, 21, 22]. Their medicinal properties are confirmed by current scientific evidence [24-29]. Based on the PM scholars' experience, their potentially harmful effects are considered due to the

Kolangi et al.

continued exposure to high doses of herb or because of kidney specific tendency of some plants such as asafetida, garlic, saffron, wormwood and raisin [16, 17, 21, 22] among which the herbs with scientific evidence of dose-dependent nephrotoxicity are as follows: 3.1.1. Ferula Assa Foetida According to a research, the oral administration of F. assa foetida oleo-gum-resin in rats resulted in dose-dependent renal tubular necrosis despite the fact that there was no sign of prominent pathological changes in the cortex and medulla [24]. 3.1.2. Allium Sativum An animal study reported that the chronic use of low dose of garlic had a potential cytoprotective effect. However, higher doses caused cell damage; and nephrotoxic effects could be significant. The aforementioned study indicated the histopathologically-marked interstitial nephritis with acute and chronic inflammation in a dose of 1000 mg/kg [27]. 3.1.3. Crocus Sativus It is reported that Saffron increases the serum urea nitrogen in neonates of lactating mice at the end of the lactating period. The histopathology evaluations of kidneys indicated some changes and abnormalities in 1000 and 2000 mg/kg/day of saffron and it was along with the presence of Glomeruli disappearance in some areas of the cortical region in 2000 mg/kg/day [30]. 3.2. Plants with Direct Nephrotoxic Effects Potential kidney-damaging mechanisms of studied plants could be classified into several categories. Some herbs or their active noxious components were directly nephrotoxic as described below. 3.2.1. Cymbopogon spp. Hepatotoxic and nephrotoxic effects of the ethanol extract of Cymbopogon citraus were observed in rats according to an acute toxicity study [31]. 3.2.2. Urtica dioica Infusion of U. dioica leaves has been shown to cause kidney damage via degenerative alterations and hyperaemia in proximal and distal tubules of the kidneys in rats [32]. 3.2.3. Amaranthus spp. An animal case report indicated that poisoning occurred in cattle in areas with severe invasion by A. blitum and A. hybridus at the seeding stage. Their kidneys were oedematous, with increased consistency and sometimes yellow in color. The severe toxic nephrosis was considered as the main histological lesion [33]. 3.2.4. Artemisia absinthium There is a report about rhabdomyolysis and acute renal failure via A. absinthium essential oil ingestion as a medication [34]. Furthermore, some evidence like basophilic tubules, hyaline cast, and calcification of kidneys were found in histopathology examination in a 13-week repeated dose-toxicity study in rats which orally received the extract of A. absinthium [35]. 3.3. Plants with Alteration of Serum Potassium Levels Some studied herbs such as Glycyrrhiza glabra and Areca catechu can cause kidney damage via alteration of serum potassium levels [36-38]. According to the reports about human cases, the licorice root contained glycyrrhizic acid which could cause hyperaldosteronismlike syndrome with hypokalemia, metabolic alkalosis and high blood pressure. In high doses and long application, Licorice caused sodium retention and high blood pressure and might lead to hypokalemia and rhabdomyolysis with acute renal failure [36, 37]. In the case of A. catechu, a retrospective study reported that the Chronic Kidney Disease (CKD) was more common in patients who previously consumed Betel nut. The long-term consumption of this

Herbs with Potential Nephrotoxic Effects According to the Traditional Persian Medicine

herb caused hypercalcemia, metabolic alkalosis, hypokalemia, and eventually CKD [38]. 3.4. Plants with Remarkable Oxalic Acid Content Oxalic acid is associated with renal damage such as the inflammation, fibrosis, and even progressive renal failure. The rate of oxalate in the urine is an important risk factor in the development of calcium oxalate crystals in kidneys. An increase in the plasma oxalate content may occur due to the reduced Glomerular Filtration Rate (GFR) in the Chronic Kidney Disease (CKD), which may lead to the increased renal inflammation and more rapid progression of CKD [38]. According to the reports, most medicinal or edible plants have high oxalate content which may play an important role in the renal damage [39]. High rate of oxalic acid content is reported in some studied herbs including Prunus domestica, Pennisetum spp, Portulaca oleracea, Rumex sp. [40-44] and Amaranthus sp. [45]. Some evidence for their noxious effects on kidneys is described as follows: 3.4.1. Pennisetum spp. There have been some reports on the high mortality of cattle and buffalo calves feeding on Napier grass (P. purpureum cv. Pusa giant) with higher levels of oxalic acid (3.01%) and lower levels of calcium than other varieties of Napier grass [40]. Furthermore, some histopathological observations were reported in the kidneys of 5 Nubian goats which were daily fed 0.25 or 1g / kg of millet (P. typhoides) for 62 days [41]. 3.4.2. Portulaca oleracea Significant liver and kidney damage and even death were reported in goats which were fed a diet containing only Purslane [42]. 3.4.3. Rumex spp. Acute oxalate toxicosis was reported in 10% (100) of mature ewes within 40 hours after being temporarily penned in a lot containing considerable growing R. crispus (curly dock). Perirenal edema and renal tubular degeneration were clearly observable in ewes which were euthanatized on the third day of toxicosis. Diagnosis of oxalate toxicosis was confirmed by histopathologic findings [44]. It was also reported that a patient showed acute Tubulointerstitial Nephritis (TIN) after digesting a sort of herbal medicine called R. patientia in the retrospective review of medical records of 19 acute TIN [43]. 3.5. Active Noxious Compounds of the Studied Plants Active compounds of studied plants include sesquiterpene coumarin, oxalates, -myrcene, thujone, limonene, tannin, saponin, cyanogenic glycosides, safranal, cinnamaldehyde, salicin (salicylates), glycyrrhizic acid (Table 2). These substances might cause direct injury while being concentrated or causing renal ischemia, hemoglobinuria or myoglobinuria [34, 37]. Other than the nephrotoxic chemicals of plants, the kidney damage may be due to some mycotoxin nephrotoxins such as Pennisetum spp cases in which the toxic fungi isolate produce toxic metabolites as reported in some studies [46, 47]. 3.6. Ancillary Medication for Prevention of Renal Side Effects The most repeated ancillary or reformer medications -as combination therapy for correcting, modifying or lessening the probable renal side effects mentioned for each plant- mainly consist of gum tragacanth (Astragalus spp.), gum Arabic (Acacia arabica L.), honey, Jujube (Ziziphus jujuba), anise (Pimpinella anissum) and mastic gum (Pistacia lentiscus) (Table 1). By searching scientific databases, some evidence was found for the nephroprotective activities of these plants including P. lentiscus [48], Corylus avellana [49], Cichorium intybus [50], P. anisum [51], and Quercus robur [52].

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P. lentiscus essential oil affected the fasting glucose and some functional parameters of liver and kidney in rabbits. It was safe with no adverse effect on renal functions and with possible antiglycogenesis activities [48]. Ethanolic extract of P. anisum seeds protected the kidneys in a gentamicin-induced nephrotoxicity model in rats. It also improved tubular damage and decreased plasma concentrations of renal function markers such as creatinine, BUN, MDA as well as the absolute excretion of sodium and potassium [51]. According to the conducted studies, the caffeoylquinic acidrich extract from chicory seeds improved glycaemia, increased blood antioxidant status, and reduced the content of thiobarbituric acid-reactive substances in kidneys and heart tissues [50]. Q. robur and C. avellana could affect the renal protection by their antioxidant activities against free radicals through decreasing the serum levels of Advanced Oxidation Protein Products (AOPP) and Lipid Peroxides (LP), and increasing activities of antioxidant enzymes [49, 52]. In general, scientific evidence was found for 38% of PM kidney-damaging herbs. There is a need for further studies on probable nephrotoxicity for most of these plants especially for M. vulgare and the seeds of A. schoenoprasum as two emphasized and repeated kidney-damaging herbs in the PM. There is limited evidence on medicinal or toxic effects of M. vulgare. It also has vasodilator and diuretic effects in some studies [53]. Despite the lack of evidence, precautions should be taken while prescribing M. vulgare, as a diuretic and vasodilator plant, in kidney diseases patients. Some herbal diuretic supplements may cause kidney irritation or damage [54, 55]. The present study found evidence mostly of experimented animals or animal case reports. Despite the fact that the "case report” got a low rank at the evidence levels, it was probably able to detect novelties as a way to present unusual and uncontrolled observations such as the side effects of herbs and drugs [56]. Despite the fact that some herbs are not harmful for human but show toxicity in some animals, rare or never been observed phenomenon, might be important for the medical community and might sensitize them for some precautions especially in patients with kidney disease. In recent years, the increased consumption of medicinal plants as an alternative therapy may cause some health problems despite its benefits probably due to the lack of the herbs safety evidence. Kidneys, as vulnerable organs, are at the risk of improper consumption of nephrotoxic herbs. There is often a short interval between the plant consumption and clinical demonstration of renal damage in acute renal failure cases; and patients can remember the consumption time. Therefore, the acute nephrotoxicity by herbs is going to be diagnosed more than ever, but it is more difficult to diagnose the chronic renal damage because of its slow progress [57]. This problem is practically remarkable as a warning issue about the potential toxicity of herbal treatment indicating the importance of reporting the renal damage due to herbal remedies by clinicians and precautions through prescribing herbal remedies in the case of any kidney damage. CONCLUSION The present study reviewed renal damaging plants from the PM scholars' viewpoint by searching the selected major PM literature. Some scientific evidence was relatively found at different levels to confirm their opinions via several underlying mechanisms. Despite the lack of strong clinical evidence, their precautions could be taken into account for appropriate prescription of introduced herbs in patients with chronic kidney diseases. Furthermore, the introduced reforming medications for reducing adverse potential renal effects may be studied in future pharmacological studies. The present study can be the basis for further investigation in order to explore plants and phytochemicals that have not been studied in terms of their renal toxic effects.


Table 1.

Kolangi et al.

Herbs with renal damaging effect mentioned in the main selected PM books and their relevant protective agents which prevent the adverse renal effects. *: Plants in the first column have been repeated in PM books that are mentioned in the method. ND: not determined.

No.

*Scientific Name

Traditional Name

Plant Part

Protective Combination Therapy

References

1.

Ajuga chamaepitys (L.) Schreb.

Komafitus

Aerial parts

Pistacia lentiscus L.

[22]

2.

Alhagi mannifera Jaub. & Spach

Aghool

Aerial parts

Gum tragacanth

[17, 21]

3.

Allium sativum L.

Som

Bulb

ND

[17, 21]

4.

Allium schoenoprasum L.

Korras

Seeds

Honey

[17-20, 22]

5.

Amaranthus spp.

Baghle-Yamaanieh

Leaves

ND

[17, 21]

A.blitum 6.

Cymbopogon spp.

Ezkher

Roots

ND

[19, 20]

7.

Anethum graveolens L.

Shebet

Aerial parts

Lime juice, oxymel in hot temperaments

[17, 21]

Honey, Syzygium aromaticum and Cinnamomum zeylanicum in cold temperaments. 8.

Arbutus unedo L.

Ghotlob

Fruits

ND

[22]

9.

Arctium lappa L.

Arghitoon

10.

Areca catechu L.

Fufel

Leaves

ND

[16, 21]

Fruits

Gum tragacanth

[17]

11.

Artemisia absinthium L.

12.

Artemisia spp.

Afsantin

Aerial parts

Pimpinella anisum

[22]

Berenjasf

Aerial parts

Pimpinella anisum

[16, 17, 21]

13.

Astracantha arnacantha (M.Bieb.) Podlech.

Navares

Seeds

Corylus avellana L.

[16, 17, 21]

14.

Capparis spinosa L.

Kabar

Fruits

Pimpinella anisum

[17, 22]

Roots

Honey Alpinia officinarum

15.

Ammoides pusilla (Brot.) Breistr.

Atrilal

Seeds

Gum tragacanth

[17, 21]

16.

Centaurea spp.

Ghantariun

Aerial parts

Gum Arabic

[22]

17.

Chelidonium majus L.

Mamiran

Rhizome

Honey

[16, 17, 21]

18.

Cinnamomum spp.

Salikhah

Bark

Gum tragacanth

[16, 17]

19.

Crataegus orientalis Pall. ex M.Bieb.

Zaaroor

Fruits

Pimpinella anisum L.

[16, 17, 21]

20.

Crocus sativus L.

Zaferan

Stigma

Pimpinella anisum L.

[17]

21.

Cuminum cyminum L.

Keravia

Fruits

Gum tragacanth

[16, 17, 21]

22.

Cynodon dactylon (L.) Pers.

Aghsoon

Aerial part

Papaver somniferum

[16, 17, 21]

23.

Delphinium staphisagria L.

Zabib-ol-jabal

Seeds

Gum Arabic

[21]

24.

Dorema ammoniacum D.Don

Oshagh

Gum resin

Hyssopus officinalis

[16, 17, 21]

Pimpinella anisum 25.

Dracaena cinnabari Balf.f.

Dam-ol-Akhaveyn

Gum resin

Gum tragacanth

[16, 17, 21]

26.

Dryopteris juxtaposita Christ.

Sarakhs

ND

Aerial parts

[17]

27.

Ferula assa foetida L.

Oshtorghar

Rhizome

Honey

[16, 17, 21]

Rheum ribes Unripe grapes 28.

Ferula persica Willd.

Sakbinaj

Gum resin

Gum tragacanth

[16, 17, 21]

29.

Glycyrhiza glabra L.

Sus

Rhizome

Gum tragacanth

[16, 17, 21]

30.

Gossypium spp.

Ghoton

Seeds

Viola odorata

[17]

31.

Helleborus niger L.

Kharbagh Asvad

Roots

Daucus carota.

[16, 17]

Pistacia lentiscus Gum tragacanth. Zataria multiflora Mentha pulegium Table (1) contd….


Traditional Name

Plant Part


No.

*Scientific Name

Protective Combination Therapy

References

32.

Lepidium sativum L.

Horf

Seeds

Cucumis stivus

[17]

33.

Lonicera spp.

Sarimat-ol-jadie

Leaves

Zizyphus jujuba Mill.

[16, 17]

34.

Marrubium vulgare L.

Farasiun

Aerial part

Gum tragacanth. Foeniculum vulgare Mill.

[16-18, 21]

Honey Nardostachys jatamansi (D.Don) DC 35.

Mentha spp.

Foodanage Nahri

Leaves

36.

Morinda officinalis F.C.How.

Asabeol-sofr

Root

Gum tragacanth

[16, 17]

Oak seeds

[16, 17]

Myrtus communis L. 37.

Morus alba L.

Toot

Fruits


[22]

38.

Nigella sativa L.

Shooniz

Seeds

Gum tragacanth

[16, 17, 21]

39.

Origanum majorana L.

Marzangush

Aerial parts

Cichorium intybus

[16, 17, 21]

Portulaca oleracea L. 40.

Papaver somniferum L.

Afiun

Opium Latex

Crocus sativus L.

[17]

Cinammomum cassia. Piper nigrum 41.

Pennisetum spp.

Samam

Seeds

Gum tragacanth

[16, 17, 21]

42.

Piper nigrum L.

Felfel

Fruits

ND

[16, 17, 21]

43.

Polypodium vulgare L.

Basfayaj

Rhizome

Adiantum capillus veneris.

[16, 17, 21]

Terminalia chebula 44.

Salix spp.

Gharab

Leaves

Gam Arabic

[16, 17, 21]

45.

Portulaca oleracea L.

Baghlatol-hamgha

Leaves


[21]

46.

Prunus domestica L.

Ejjas

Fruits

Zizyphus jujube Mill.

[16, 17, 21]

47.

Rubus spp.

Olaygh

Fruits

ND

[17]

48.

Rumex spp.

Hommaaz

Fruits

Foeniculum vulgare Mill.

[16, 17]

49.

Salvia officinalis

Lesanol-Ebel

Aerial parts

Gum Arabic

[16, 17, 21]

50.

Sandarac

Sandrus

Gum resin

Gum Arabic

[16, 17, 21]

51.

Sarcostemma viminale (L.) R.Br.

Hormolah

Seeds

Cucumbers

[16]

52.

Stick lac, shellac

Lok

Gum


[22]

53.

Symphytum spp.

Samghuten

Flower

Gum tragacanth

[21]

54.

Syzygium aromaticum (L.) Merr. & L.M.Perry

Gharanfol

Buds

Gum Arabic

[16, 17, 21]

55.

Tamarix gallica L.

Tarfa

Leaves

Gum Arabic

[21]

56.

Teucrium chamaedrys L.

Kamadaryus

Aerial part

Gum tragacanth

[16, 21]

57.

Tragopogon pratensis L.

Lahiyatol-tis

Leaves

Zizyphus jujuba Mill.

[16, 17, 21]

58.

Trifolium spp.

Terefolon

Seeds, leaves

Gum tragacanth

[16, 17]

59.

Urtica dioica L.

Anjoreh

Seeds

Gum tragacanth

[16, 17]

Teucrium polium L.

Gum Arabic 60.

Valeriana spp.

Sonbol

Rhizome

Gum tragacanth

[16, 17, 21]

61.

Verbascum spp.

Bavacira

Aerial part

Gum tragacanth

[21]

62.

Verbena officinalis L.

Ray-ol-hamam

Aerial part

Gum tragacanth

[16, 17, 21]

63.

Vitex agnus-castus L.

Aslagh

Leaves

Gum Arabic

[16, 17]

64.

Vitis vinifera L.

Zabib

Fruits

Ziziphus jujuba Mill.

[16, 17, 21]

Raisin

5


Table 2.

Kolangi et al.

Scientific evidence related to the renal damaging potential of herbs mentioned in PM books. *ND: not determined in the study.

Scientific Name lium sativum L.

Plant Part

Active Component Focused by Study

Bulb

Alicin, allicindiallyl sulfide

Study Type Animal study: Administration of 1000 mg/kg fresh garlic homogenate daily for 30 days in rats.

Evidence

References [27]

Organosulfur compounds (Allicin, ajoene, vinyldithin and diallyl disulfide, and trisulfide) [27]

[33]

Amino acids, amarantin [58]

- Chronic kidney disease (CKD) was more common in patients previously consumed betelnut (P = 0.003).

[38]

Alkaloids, tannins, flavones, triterpenes, steroids [59].

- Rhabdomyolysis Renal Failure.

Acute

[34]

alpha- and beta-thujone, sesquiterpene lactones [58].

-

Basophilic tubules, hyaline cast, calcification of the kidney (in 2% extract treatment group).

[35]

alpha- and beta-thujone, sesquiterpene lactones [58].

-

Increased BUN (Blood Urea Nitrogen) and Creatinine (in doses 400 and 800 mg/kg)

[60]

Glucosinolates, glucocapparin, sinigrin, glucocleomin and glucocapangatin, Rutin, Stachydrine [58].

Decreased kidney weights, and many pathological changes of kidney.

[61]

Cinnamaldehyde [58].

- Multisystem hypersensitivity reaction and progressive acute renal failure.

[63]

phenolics, tannins, and alkaloids [62]

-

Serum urea nitrogen was increased;

[30]

-

Histopathology evaluations of the kidney showed some changes and abnormalities.

crocin, picrocrocin, crocetin, carotenoids [58]

-

Interstitial nephritis with acute and chronic inflammation.

- Active tubulitis with loss of tubules. - Mild to moderate increase in mesangial cellularity in glomeruli, with focal neutrophil infiltration.

Amaranthus spp.

Leaves

Oxalate

Areca catechu L.

Animal case report: Poisoning of cattle with A. hybridus and A. blitum (respectively 339.88 and 492.25 g/kg.).

A.blitum

Seeds

Alkaloids (namely arecoline, arecaidine, guvacoline and guvacine)?


Essential oil

Thujone


Extract

Thujone

Capparis spinosa L.

Fruits

Retrospective study: Investigation of the relationship between chronic kidney disease (CKD) and use of betelnut among 3,552 people. Case report

Animal study :

-

Cinnamomum spp.

Bark

Cinnamaldehyde

Crataegus orientalis Pall. ex M.Bieb.

Fruits and leaves

ND*

Crocus sativus L.

Stigmas

ND

Animal study: Doses of 200, 400 and 800 mg/kg of methanolic extract were administrated by oral gavages for 7 days in rats. Animal study:

Case report:

Animal study: Nephrotoxicity and hepatotoxicity study in neonates of lactating mothers in mice, by administration of 500, 1000 or 2000 mg/kg/day of saffron from the delivery day until the end of lactating period.

and

- Evidence of renal toxicity at doses of 400 and 800 mg/kg in the histopathologic studies.

-

Rats treated with cinnamaldehyde at the dose level of 73.5 mg/ kg body weight / day for 90 days.

A 68-year-old man eats 1/2 kg of raw Crataegus orientalis fruits and drinking five cups of tea made from its leaves 3 days before the onset of the symptoms.

Oedematous kidneys with increased consistency and sometimes yellow in colour.

- Severe toxic nephrosis.

A 13-week repeated dose toxicity study of 0, 0.125, 0.5, or 2% wormwood extract was performed in rats. Alkaloids (tetrahydroquinoline, stachydrin, capparisine), glucosinolates, flavonoids (quersetin, kaempferol).

Major Bioactive Phytochemicals

Table (2) contd….


Scientific Name

Plant Part

Crocus sativus L. Safranal

Cymbopogon spp.

Leaves

Active Component Focused by Study Safranal

â- myrcene, limonene

Dryopteris Leave of juxtaposita Christ the fern

Ferula assa foetida L.

Oleogumresin

ND

Sesquiterpene coumarin

Study Type


Evidence

Animal study:

-

Increased serum urea nitrogen.

Acute and sub acut toxicity study of safranal in mice and rats (via administration of 0.1, 0.25 or 0.5 mL/kg/day, orally) for 21 days.

-

Pathological changes in the kidney.

References


[29]

crocin, picrocrocin, crocetin, carotenoids, [58]

Animal study: Acute toxicity study of the oral administration of Cymbopogon citraus ethanol extracts at the concentration of 143, 286, 572, 1716 and 2828 mg / kg body weight for the 30% extract and 150, 300, 375, 412 and 450 mg / Kg body weight for the 80% extract.

- 30% and 80% extracts demonstrated hepatotoxic and nephrotoxic effects in animals.

[31]

piperitone, borneol, cadinene, camphene, camphor, farnesene, geraniol, alpha-and betapinene, limonene [58].

Animal study: Rabbits were orally received fern as a part of their diet (%25). Compared with two other groups as a control.

- Increase in kidney weight, urea and creatinine levels were observed after 90 days.

[65]

Flavonoids and quercetin [64].

-

No signs of prominent pathological changes in the cortex and the medulla, but little renal tubular necrosis was seen dose-dependently.

[24]

Asaresionotannols, farnesiferols, ferulic acid, sulphated terpenes, pinene, cadinene, vanillin, sesquiterne coumarins [58].

-

Acute renal failure, intense degeneration in renal biopsy.

[36]

Glycyrrhizin Glycyrrhetinic acid [58].

-

Vacuolation of tubules with a normal glomerulus which was consistent with hypokalemic nephropathy.

- Suppressed plasma aldosterone concentration [1.6 pg/ml (normal;38.1-300 pg/mL)]; hypokalemic rhabdomyolysis and acute renal failure.

[37]

Glycyrrhizin, Glycyrrhetinic acid [58].

Animal study: Acute toxicity study: Oral administration of 250, 500, and 1,000 mg/kg body weight of the rats. Chronic toxicity study: Administration of asafetida (25, 50, 100, and 200 mg/kg body weight) for 6 weeks.

Glycyrrhiza glabra L.

Rhizome

glycyrrhizic acid

Case report: A 39-year-old female ingested 50-100 g herbal products contained licorice, every day for 8 weeks.

Glycyrrhiza glabra L.

Rhizome

Glycyrrhizic acid

Lepidium sativum L.

Seed

ND

Animal study: Rats received diets containing 2%, 10%, 50% (w/w) of the ground L. sativum seeds as test diets for 6 weeks.

- Degeneration and necrosis of the renal tubular cells with lymphocytic infiltration in the renal cortex (in 50% w/w group).

[66]

Glucotropaeolin, sinapin, sinapic acid, mucilaginous matter [58].

Mentha spp.

Aerial part

ND

Animal study: Administration of Mentha spicata L., (20 g/L; and 40 g/L tea ) for 30 days in rats.

- Histopathological lesions correlated with dose and markedly nephrotoxic changes in rats.

[67]

Carvone, limonene, cireole [58].

Papaver somniferum L.

Latex (opium)

ND

Cross-sectional study: 279 opium poisoned patients referred to the emergency department were studied and presence of renal failure was recorded.

-

[68]

Morphine, narcotine, codeine, papaverinethebaine [58].

Table (2) contd….

7

Case report: A 49-year-old male consumed herbal medication included 16 gr licorice root powder (~600750 mg glycyrrhizic acid) per 100 gr. for 1.5 years

Renal failure was reported in 25.1% of patients exposed to opium as the highest chance of causing renal failure among other poisonous agents.


Kolangi et al.

Scientific Name

Plant Part

Active Component Focused by Study

Pennisetum spp.

Leaves

Oxalate, tannin, saponin, cyanogenic glycosides

Animal study: 5-9-month-old Nubian goats were fed 0.25 or 1g per kg per day for 62 days by millet (Pennisetum typhoides).

Leaves

Oxalate

Animal case report

Piper nigrum L.

Fruits

ND

Animal study: Injection or orally administration to Egyptian toads

Portulaca oleracea L.

Leaves

Oxalate

Prunus domestica L.

Fruit

Rumex spp.

Fruits

Study Type

Evidence

-

References


Fatty change, Congestion, gelatinization of renal pelvis was found in kidney histopathology.

[41]

- Higher mortality in cattle and buffalo calves has been reported following feeding on Napier grass (Pennisetum purpureum cv. Pusa giant) that contained high levels of oxalic acid (3.01%) and low levels of Ca, when compared to other varieties of Napier grass.

[40]

- Kidney tumor was observed.

[69]

Piperine, piperatine, piperidine [58].

Animal case report

- Goats fed a diet containing only purslane showed significant liver and kidney damage and died within 15 to 45 days of commencing the diet.

[42]

Protein, l-noradrenaline, dopamine and l-dopa, catechol [58].

Oxalates

Review article

- Plums are known to contain considerable levels of oxalates, which occur naturally and may increase the risk of kidney stone formation.

[70]

Malic acid [58].

Oxalate

Animal case report

-

[44]

Anthraquinone derivatives [58].

Ten of 100 mature ewes were afflicted with acute oxalate toxicosis within 40 hours after being temporarily penned in a lot contained Rumex crispus.

Oxalate, tannin, saponin, cyanogenic glycosides [41].

- Perirenal edema and renal tubular degeneration, oxalate toxicosis. Rumex spp.

-

Oxalate

Case series: Retrospective review of the medical records of 19 acute TIN patients.

- 1 Of 19 person, was developed acute TIN after digestion of a sort of herbal called Rumex patientia.

[43]

Anthraquinone derivatives [57].

Salix spp.

Bark, leaves

Salicin (salicylates)

Case reports

- Willow bark (Salix daphnoides) contains salicylates, which can contribute to ischemic renal injury through induction of vasoconstriction.

[2,71,72]

Salicin (salicylates) [58].

Teucrium chamaedrys L.

Aerial part

Neoclerodane diterpenoids,

Animal study: Rats received 50, 100, 150, 200 mg/kg extracts for 28 days via ip injection.

- Nephrotoxic effects including degeneration, destruction and vacuolization were observed in the second five groups.

[73]

Harpagide, acetyl harpagide; clerodane, neoclerodane diterpenes; phenylpropanoids; caryophyllene [58].

Urtica dioica L.

Leaves

ND

Animal study: The effect of 0.5% infusion of the leaf of U. dioica was studied in diabetic rats induced by streptozotocin.

- The proximal and distal tubules of the kidneys exhibited degenerative alterations and hyperaemia.

[32]

Acetylcholine, histamine, hydroxytryptamine [58]

Vitis vinifera L.

Grape skin extract

ND

Animal study:

- Renal proximal tubules of the cortex and medulla in kidney of female rats were slightly calcified. In group which received 5.0% diet, more calcified tubules were observed.

[74]

Tartaric and malic acids, pectin, tannin, flavone glycosides, vitamins, minerals [58].

Teucrium polium L.

Raisin

Oral toxicity was investigated in rats using diet containing 0%, 0.2%, 1.0% or 5.0% the extract for 13 weeks.


CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise.

[24]

[25]

ACKNOWLEDGEMENTS Declared none.

[26]

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