Role of seaweeds in drug induced nephrotoxicity

Kidney is an important organ which is necessary for the body to perform various important functions which include blood purification, expelling metabolic wastes and managing water and electrolytes balance in the body. In this era of modern science, many synthetic drugs are used on patients to examine their therapeutic properties. Unfortunately, some drugs cause negative effects resulting in renal damage. Drug induced nephrotoxicity results in serious clinical syndromes, such as chronic kidney disease (CKD) and acute kidney injury (AKI). Synthetic drugs not only cure diseases but also cause some side effects in the human body. Instead of looking for synthetic drugs to cure diseases, it is necessary to consider natural drugs that maximize side effects of synthetic drugs and reduce therapeutic consequences with the most effective and dynamic healing effects. Research and utilization of marine algae have increased markedly from the last several decades. Seaweeds have also been used as drugs or drug sources over a large number of years going back into folk medicine. Since consumption of seaweeds as human food or animal feeds is increasing rapidly. In the current review, we have summarized the information regarding the drugs which cause nephrotoxicity and marine algae as seaweeds used for the treatment of nephrotoxicity.


Introduction
The presence of any kidney injury caused by medication directly or indirectly is called drug induced nephrotoxicity.Symptoms vary from acute or chronic in which decreased Glomerular Filtration Rate (GFR) to nephrotic syndrome and Hydro Electrolytic Disorders (HED) associated with tubular that can cause kidney damage (Sales & Foresto, 2020;Sohail et al., 2021).It is estimated that 20% of nephrotoxicity is raised by drugs and 66% increased by the extent of drug usage (Kim & Moon, 2012;Yousaf et al., 2022).Numerous renal toxicities include acute and chronic interstitial nephritis, proximal renal tubular acidosis (Patel & Sapra, 2020).

Metabolic Functions of Kidney
Kidney is an important organ in our body which performs several important functions like blood purification, expelling metabolic wastes and managing water and electrolytes balance in the body (Ekinci Akdemir et al., 2017).Kidney dysfunction causes decline in the kidney by many aspects like an infectious disease, abnormal functioning of the immune system, high sugar level, malignant growth etc. (Chielle et al., 2015;Nisha et al., 2017).Besides their excretory role, their role in drug and chemical biotransformation is also crucial because drug elimination and detoxification both are main functions of the kidney which makes it an important organ (Garza et al., 2022).The transport mechanisms in the kidney are well known by electrolyte and acid-base disorders are also interrupted by drugs.If a person is already suffering from kidney diseases, then their medication should be carefully examined in order to prevent them from further nephrotoxic agents.Hence, precaution for kidney harm should be at forefront for methodologies to fight against drug-induced nephrotoxicity (Patel & Sapra, 2020).Despite nephrotoxicity, hepatotoxicity is also caused by a number of drugs i.e.; acetaminophen (AAP), methotrexate (Yan et al., 2018;Sajith et al., 2020) that ultimately cause liver damage (Rane et al., 2016).Liver also significantly contributes in biotransformation of drugs and toxins for the fulfillment of many functions such as carbohydrate, fat and protein metabolisms.Liver is also the main site of drug-induced damage.From ages, an upward trend has been witnessed in kidney and liver diseases worldwide (Ekinci Akdemir et al., 2017).Nephrotoxicity and hepatotoxicity are the two major concerns to the pharmaceutical companies and also to the Food and Drug Administration (FDA) (Beger et al., 2010;Zhang et al., 2012).

Role of Drugs in Nephrotoxicity
Researchers reported in literature that a lot of synthetic drugs with wide range of antibiotics or chemicals which causes nephrotoxicity and hepatic failure (Figure 1) (Perazella, 2018) including, cisplatin, acetaminophen (AAP), and, carbon tetrachloride (CCl4) (Zamzami et al., 2019;Sohail et al., 2019Sohail et al., , 2021)).The most significant class of antibiotics executing toxic effects on kidney function is aminoglycosides which include gentamicin.Nephrotoxicity occurs in 10% to 25% of the cases who take gentamicin for 3 to 5 days (Saleh et al., 2016).Moreover, it decreases antioxidant enzyme activity and raises the reactive oxygen species (ROS) production (Erjaee et al., 2015).Vancomycin is an antimicrobial drug which causes nephrotoxicity in 10% to 20% of patients.Similarly, Cisplatin, (cis-diammine-dichloroplatinum (II), CDDP) is also the most significant nephrotoxic drug which is filtered at the glomerulus freely and absorbed into tubular cells of the kidney via transport-mediated process (Ciarimboli, 2014).It is normally used for the treatment of solid tumors that causes acute kidney damage after assemblage in the renal tubules (Sherif, 2015).For more than 25 years, it has been recognized that cisplatin causes nephrotoxicity and may cause various diseases including AKI, inadequate reabsorption in the proximal renal tubules, chronic kidney damage, deficiency of magnesium and calcium (Miller et al., 2010;Sohail et al., 2021).Although, from both clinical observations and animal experiments there is evidence which indicates that AKI is an independent risk for CKD as well (Shi et al., 2018).Commonly, the beginning of renal inadequacy starts after a few days of cisplatin dosage, evident by increased kidney profile (urea, creatinine & BUN).Another common occurrence is hypomagnesaemia, especially after dosage of cisplatin; nephrotoxicity has been identified even in the complete absence and reduction in glomerular filtration rate which is a high risk factor for cisplatin (Miller et al., 2010).As the dose of cisplatin increases the rate of nephrotoxicity also increases (Glezerman & Jaimes, 2016).Likewise, doxorubicin is another anti-cancer nephrotoxic drug which imbalances the functions between free radicals and antioxidants and therefore causes injuries in renal tissue (Ayla et al., 2011).Even though, usage of non-steroidal anti-inflammatory drugs (NSAIDs) i.e., AAP is linked with adverse renal effects which are approximately 1 to 5% among all patients (Solomon et al., 2017).The pharmacological effects of NSAIDs are dose and duration dependent, which predisposes the involvement of specific organs, and after liver the second one most affected is the kidney (Lucas et al., 2019).AAP is usually available as an over the counter drug and is widely available over the counter (OTC) in the UK and Australia (Lau et al., 2016).It is useful in mild to moderate pain of headache, myalgia and postpartum pain (Fokunang et al., 2018).It causes acute renal failure in 1-2% of patients (Canayakin et al., 2016;Hiragi et al., 2018).It is one of the most commonly consumed medications and its toxicity causes acute liver failure (ALF) which is reported in the United States (Rubin et al., 2018).NAPQI (N-Acetyl-pbenzoquinone) is present in the microsomal P450 enzyme system, which oxidize the major part of AAP taking away by Figure 1.A prescribed mechanism of drug factors associated with increased risk for nephrotoxicity (Perazella, 2018).GSH (intracellular glutathione) in therapeutic doses (Athersuch et al., 2018).The main symptom of acute kidney injury is acute necrosis in renal tubules caused by AAP toxicity by examining the level of kidney parameters (urea & creatinine) (Mazhar & Akram, 2016).When the drug toxicity is elevated in any organism, the free radicals are produced and oxidative stress performs a significant act in AAP which causes progressive kidney failure and also severe liver damage (Kheradpezhouh et al., 2010;Wang, 2017).Although these effects, warnings, and associations have been documented, acetaminophen remains a safe and effective medication when used correctly.The current manufacturer dose recommendation is limited to between 3 and 3.25 grams in 24 hours, depending on the formulation.However, toxicity is rare at less than 150 mg/kg for an adult or 200 mg/kg for a child (Gerriets et al., 2018).

Biomarkers of kidney toxicity
Creatinine, urea and blood urea nitrogen (BUN) are the basic kidney parameters for the detection of nephrotoxicity in clinical laboratories.Healthy kidneys filter creatinine and other waste items which leave from our body in the form of urine.Therefore, determination on level of serum creatinine is necessary whether acute or chronic kidney diseases evaluation (Ostermann & Joannidis, 2016).BUN occurs in the liver as an end product and 15% excreted in the gastrointestinal (GI) tract and remaining through the kidney.The raising in BUN can also show kidney injury (Zachariah et al., 2019).
Beside these parameters, electrolytes also perform main functions in the kidney.The balance of electrolytes and fluidity is controlled by the kidney but if there is any dysfunction it causes acute or chronic kidney failure.Electrolytes include magnesium (Mg), phosphorus (P), potassium (K), sodium (Na) and calcium (Ca) which can be affected and lead to a range of side effects (Dhondup & Qian, 2017).Patients with CKD and ESRD experience both hyperkalemia and hypokalemia (Clase et al., 2020).The Na concentration is important for maintaining balance between acid-base and fluid and for neuromuscular function.The imbalance of Na level particularly those who have CKD, because kidneys have the ability to manage dilution and concentration level that gets damaged and finally causes kidney disease (Lim et al., 2016).Hyponatremia could also be a consequence of diuretic usage in these patients (Wolfe et al., 2010).Mg concentrations are also maintained by the kidney.The magnesium levels deteriorate when renal function does not perform properly (Cunningham et al., 2012).However, those patients who have CKD and ESRD have normally low magnesium levels (hypomagnesaemia) (Alhosaini et al., 2014).
Furthermore, Ca and P have reciprocal connection between each other and get imbalance during kidney injury.The symptoms associated with hypocalcemia include; Muscle cramp, disturbance in the brain, removal of mineral salts from bones, congestive heart failure etc. (Garrard & Jones, 2018).
On the other hand, it is not only possible that nephrotoxic drugs have a toxic effect on the kidney only but it also ultimately causes hepatotoxicity including hepatocellular damage, cholestasis and even tumor production (Patel et al., 2016).List of blood markers for estimating hepatotoxicity is given below:

Biomarkers of liver toxicity
Liver markers include enzymes in which Lactate dehydrogenase (LDH), Aspartate aminotransferase (AST), Alanine aminotransferase (ALAT), Alkaline phosphatase (ALP) and bilirubin (Total bilirubin & direct bilirubin).ALAT is found in various organs like kidneys, liver, heart, and muscles.It occurs in cytoplasmic form and breaks the transamination reaction.Any sort of hepatic damage can increase the level of ALAT (Aulbach & Amuzie, 2017).It may be because of hepatitis, ischemic hepatic damage that causes liver damage.AST function is to replace the amino groups from glutamate to oxaloacetate to form aspartate which is used in the urea cycle as a by-product of nitrogen.Aspartate is utilized in the urea cycle and it's rising in patients with cirrhosis and even in hepatic injury that usually raise ALAT (Fikry & Ahmed, 2019).ALP is an enzyme which is found in renal tubules, liver etc.The main function of ALP is transport of the lipid in small intestines and bones calcification.Bones around 50% activate the ALP.The raise level of ALP usually occurs by acute viral hepatitis and others include; hepatic injury etc. Conversely, if ALP level is low then it causes hypothyroidism, zinc (Zn) deficiency, hypophosphatasia etc. (Fikry & Ahmed, 2019).LDH is an enzyme which performs a function to break the conversion of lactate to pyruvate.This enzyme is present in a vast variety of cells in the body.LDH content is present in various organs like; heart, kidney, liver, and muscle.Its production has been shown to be increased under hypoxic conditions in different cell lines (Yada et al., 2016).
Bilirubin is present in every person's blood and feces in the form of yellow pigment which proceeds by the liver.The liver can't process the bilirubin in case of an excess amount of bilirubin or inflammation in the liver.It is also reported that disturbance in bilirubin might increase the chances of certain heart diseases (Kwak et al., 2012;Fujiwara et al., 2018).
Beside these markers, lipid profile (Triglyceride & total cholesterol) and glucose are also key biochemical markers of nephrotoxicity and hepatotoxicity (Gill, 2016).The metabolism of lipids is actually the catabolic and anabolic of lipids in cells either to break down or store the fats.These fats are relatively consumed from food or they are synthesized in animal's liver for energy purposes.In the human body, excess amounts of lipid are present in the form of triglycerides and total cholesterol (Baynes, 2014).Furthermore, the system of kidney filtration can be damaged by raised levels of glucose because it goes into the bloodstream that may cause the kidneys to filter an excessive amount of blood (Triplitt, 2012).

Antioxidants markers
Antioxidants can mediate at first in the pathogenesis of renal damage by completely removing ROS.The research study in cells and tubules of nephrons and AKI in animal models have recognized nephron-defensive agents with antioxidant activities that decrease oxidative harm in the kidney (Panizo et al., 2015;Ratliff et al., 2016).In animal models the research clearly showed the increased level of oxidative stress and reduced tissue antioxidant status after nephrotoxicity (Dennis & Witting, 2017).Moreover, oxidative stress and ROS are considered to be driving factors in other chronic diseases that introduce the AKI include heart disease and diabetes (Ratliff et al., 2016).

Inflammatory cytokine in drug induced nephrotoxicity
Inflammation is the body's immune response which performs a significant function in progression of AKI (Black et al., 2019).Cytokines are nonstructural proteins which include interferon, chemokines, interleukins and tumor necrosis factors (Ferreira et al., 2018) which are transported in the form of paracrine and autocrine pathways.They are involved in different forms of diseases and disturbance in the immune system by anti and pro-inflammatory systems (Spangler et al., 2015).The pro-inflammatory effects in cytokines include TNFα (tumor necrosis factor), , IFN-y (interferon) and anti-inflammatory cytokines effect includes IL-4, IL-1ra and IL-10 and (Su et al., 2012).The inhibition in cytokines is linked with recovery of cisplatin which causes nephrotoxicity (Perse & Veceric-Haler, 2018).In this manner, new molecules are searched out that regulate kidney injury which is an important research zone that may lead to therapies to inhibit cisplatin-induced kidney injury (Humanes et al., 2017).Pro and anti-inflammatory cytokine relations work alone and sometimes merge with different types of cytokines responsible for up or down regulation of the rest of cytokines and some cytokines may have both inflammatory effects.It is typical for various cell types to emit a similar cytokine or for a single cytokine to follow up on a few diverse cell types (Pleiotropy) (Monastero & Pentyala, 2017).

Role of Medicinal Plant in Nephrotoxicity
God created everything on this earth which has a positive effect in contrast to humans who made things/medicines.To consider the side effect of drugs causes nephrotoxicity so researchers are looking for alternatives particularly coming from natural sources.There are some medicinal plants which are utilized to reduce the multiple illnesses for a very long time while they are being acceptable, reasonable, safe and accessible (Kasole et al., 2019).Natural or herbal therapeutics field has become one of the most famous trends because herbal products not only contain multicomponent therapeutics rather it also achieved a significant role in the health system for both humans and animals throughout the world (Pathak & Das, 2013).Numbers of evidence have reported that supplements from herbal medicine have potential to become a valuable complementary therapy in the treatment of various renal diseases (Roozbeh et al., 2013;Vahekeni et al., 2019).
Chinese herbal medicine (CHM) is a Traditional Chinese medicine (TCM), which has begun to attract academic attention in the world of western medicine.In past years, CHM aimed to develop new drugs for different varieties of diseases which affect human beings (Gu & Pei, 2017).China and other countries usually use CHM and it is ready to use in both the traditional and modern world (Pan et al., 2011).TCM theory is generally utilized in Asia and progressively worldwide to avoid CKD.The theoretical system of CHM is clearly different from conventional medicine and based on the differentiation of syndromes and patterns.The prescriptions are structured independently according to the patient's constitution and disease progression (Huang et al., 2018).
Medicines have many side effects which are used for the treatment of kidney damage, so herbal medicine performed a pivotal role in the prevention of many kidney diseases which are given in Table 1.

Role of Seaweeds in Drug Induced Nephrotoxicity
Over the last decade, researchers have developed an interest to focus on the significant role of algae which is a main source of a wide range of metabolites.Marine algae utilization and research have increased significantly in recent decades (Milledge et al., 2019).Marine algae have begun to gain attention as rich sources of various bioactive compounds with biomedical potential and great pharmaceuticals.It produces various compounds with great pharmacological activities such as anti-inflammatory, anticancer, antifungal, antimicrobial, antiviral etc. (Wali et al., 2019).Marine organisms survive in complex communities and live in close association with other organisms in competitive and hostile environments (Martins et al., 2014).They produce complex secondary metabolites as a response to ecological pressures such as predation and tide variations, competition for space.They serve as a source of natural products with therapeutic and nutritional properties.Moreover, the biomedical efficacy of several bioactive compounds derived from marine organisms has been experimentally demonstrated.Nowadays, researchers have demonstrated the various therapeutic properties of marine algae, which are verified in-vivo as well as in-vitro (Martins et al., 2014;Kim et al., 2018).

Phaeophyceae (Brown seaweed)
Brown seaweeds have the potential to provide an alternate source for solving many biomedical problems, including oxidative damage (Gomez-Zavaglia et al., 2019).Sargassum, a genus of brown seaweed, commonly known as sea holly or gulfweed belongs to the family Sargassaceae and contains approximately 400 species (Kanimozhi et al., 2015).Fucoxanthin is the main pigment in brown seaweeds, which is one of the most abundant carotenoids in nature (10% of estimated total carotenoid production) (Pangestuti & Kim, 2011).However, different strains of brown seaweed have different profiles and compositions of fucoxanthin.Previous studies reported that fucoxanthin has anti-cancer, anti-diabetic, anti-oxidation, anti-carcinogenic, anti-inflammatory, antiobesity and hepato-protective activities as well as cerebrovascular and cardiovascular protective effects (D'Orazio et al., 2012;Zhang et al., 2015).

Rhodophyta (Red seaweed)
The Rhodophyta (red algae) are a distinct eukaryotic lineage.
The red color of these algae is due to the pigments; phycoerythrin and phycocyanin.It characterizes other pigments, chlorophyll a (without chlorophyll b), beta-carotene, and other unique xanthophylls (Barkia et al., 2019).Abundantly cultivated edible red seaweed, Eucheuma cottonii, contains large amounts of polyunsaturated fatty acids, minerals, polyphenols, dietary fiber, vitamins, proteins, antioxidants and phytochemicals and has medicinal properties (Kania et al., 2013).E. cottonii showed the highest in-vivo antioxidant and anti-hyperlipidemic activities, elevated erythrocyte GSH-Px, and reduced plasma lipid peroxidation of high-fat diet rats toward the values of normal rats.Gracilaria birdiae (GB) is grown in northeast Brazil and used for food.However, little research has been done on the economic potential of this alga.
birdiae protects both the kidney and liver of rats from CCl4 which cause nephrotoxicity and hepatotoxicity possibly due to their antioxidant capacity (Barros-Gomes et al., 2018).

Chlorophyta (Green seaweed)
Ulva is a green alga, commonly known as sea lettuce, is widely distributed beyond coastal regions of the world and is widely used in the biotechnology, food and pharmaceutical industries (Torres et al., 2019).Green seaweeds contain high amounts of polyphenols such as epigallocatechin gallate, epicatechin, catechin, and gallic acid (Vinayak et al., 2011).Some beneficial green edible seaweed is; Ulva reticulata, Ulva lactuca, etc. Ethyl acetate extract of U. lactuca showed the highest antifungal activity than that of other extracts against filamentous fungi and yeast.Ulva reticulata is widely distributed in the Indo-west Pacific region, Southwest Asia, Northern Pacific Ocean, Southeast Asia and Western and Eastern Indian Ocean.In southern India, U. reticulata is highly concentrated along the coastline of Tamil Nadu, especially Mannar Bay, Rameshwaram to Kanyakumari (Lalitha & Dhandapani, 2018).
Pharmacological studies indicate that fucoidan is a sulfated polysaccharide extracted from brown seaweeds that inhibits renal fibrosis and glomerular sclerosis by reducing the accumulation of extracellular matrices.It also maintains the glomerular basement membrane and glomerular structural integrity, improves glomerular filtration function, and protects renal glycosaminoglycans from abnormal degradation (Wang et al., 2019).Josephine et al. (2006Josephine et al. ( , 2007) ) reported that isolated sulphated polysaccharide reduced blood urea nitrogen and serum creatinine level and attenuated renal tubular damage in renal glomerular injury in rats.Polysaccharides from green seaweeds, Caulerpa racemose (sea grapes) have been reported to be the kidney protective effects in diabetic models (Cao et al., 2021).The chemical constituents like fatty acids, alkaloids, phenolic compounds, terpernoids, were identified by GC-MS from green seaweeds like Ulva fasciata has nephroprotective activity (Abd El Raouf et al., 2017).The protective roles of seaweeds in nephrotoxicity are given in Table 2.

Conclusion
Worldwide kidney diseases have become a major cause for disability and even leading to death in the worst circumstances.Drugs which are usually used to treat diseases but its overdosing causes side effects and complications in the kidney and liver so there is a vast interest to search for alternative medicine which especially comes from natural sources without any side effects.The World Health Organization (WHO) reported that 80% of people rely on natural sources for some part of their primary health management needs.The main sources of these successful compounds are plants and microbes from the marine and terrestrial environments.Thereby, researchers are working on marine based natural products particularly edible seaweeds such as sea lettuce showed a promising role in attenuation of drug induced nephrotoxicity.In-addition they might be considered as potential candidates for natural based drug therapy as they minimize adverse effects of drugs particularly cisplatin and AAP.Further works are currently underway on seaweeds and other plants to discover effective medicines with fewer consequences.

Table 1 .
Effective role of medicinal plants used for the treatment of nephrotoxicity • Amelioration in kidney histology Ezejiofor et al. (2014) Elaeocarpus ganitrus Seeds Rat • Amelioration in urine and blood biochemical parameters • Improvement in oxidative stress • Amelioration in kidney histology Kakalij et al. (2014) Myristica fragran Fruits Rat • Amelioration in blood biochemical parameters • Improvement in oxidative stress

Table 2 .
Protective role of seaweeds for the treatment of nephrotoxicity in rats