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REVIEW ARTICLE
Ahead of print publication  

The biological roles of urea: A review of preclinical studies


1 Department of Physiology, Faculty of Basic Medical Sciences, University of Medical Sciences, Ondo City, Nigeria
2 Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University Ado-Ekiti, Ekiti State, Nigeria

Date of Submission28-Feb-2021
Date of Acceptance08-Jul-2022
Date of Web Publication22-Nov-2022

Correspondence Address:
Olorunsola I Adeyomoye,
Department of Physiology, Faculty of Basic Medical Sciences, University of Medical Sciences, Ondo City
Nigeria
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijn.ijn_88_21

  Abstract 


Urea is an organic compound that has been reported to be effective against many pathological conditions. However, many other studies have reported the toxic effects of urea. These controversies on the biological roles of urea remain unresolved. This review aims to evaluate the biological roles of urea in experimental animals from data published in peer-reviewed journals. A PubMed search was conducted using the phrase, “urea application in experimental animals.” A total of 13 publications that met the inclusion criteria were evaluated. The test substance, animal model, number of animals, doses, duration of treatment, and effects were recorded. Regarding the toxic effect, urea caused decreased excretion of other nitrogenous compounds, increased oxidative stress, decreased insulin, and impairment of beta-cell glycolysis. Furthermore, it caused endothelial dysfunction, loss of synapsis, and decreased olfaction. Regarding the therapeutic effects, urea caused increased growth, increased digestion, and decreased hepatic dysfunction. It also induced apoptosis of tumor cells and exerted neuroprotective properties. Products containing urea should be used with caution, especially in individuals with symptoms of chronic kidney disease. However, more studies are needed to elucidate the mechanisms of its therapeutic effects.

Keywords: Biological Roles, experimental animals, therapeutic effects, toxic effects, urea



How to cite this URL:
Adeyomoye OI, Akintayo CO, Omotuyi KP, Adewumi AN. The biological roles of urea: A review of preclinical studies. Indian J Nephrol [Epub ahead of print] [cited 2022 Dec 10]. Available from: https://www.indianjnephrol.org/preprintarticle.asp?id=361728




  Introduction Top


Urea is an organic compound with the chemical formula CO (NH2)2. It is produced in the liver and serves as the metabolic by-product of protein and nitrogen metabolism.[1] It helps in the excretion of most nitrogen-containing compounds and is highly soluble in water; it has a molecular weight of 60 g/mol. It is colorless, odorless, and neutral in solution. Exogenous urea is usually taken up by specific urea transporters (UT-A and UT-B).[2]

Dating back to the 19th century, the role of urea has been studied extensively. The findings from these studies have, however, remained controversial. The major issue surrounding the role of urea has been its effects on macromolecules within the cells, tissues, and organs of the body. Some studies reported that urea is toxic, especially at a high concentration,[3],[4],[5] while other studies claim that urea is nontoxic and even has therapeutic effects.[6],[7],[8],[9]

When urea is produced, it is normally excreted into the urine through the kidneys. When urea gets to the kidneys (carried in the bloodstream), it plays an important role in urine formation and urine concentration, alongside with urea transporters. The first stage of urine formation is glomerular filtration. The other processes of urine formation are tubular reabsorption and secretion. In the renal tubules, 99% of the filtrate gets reabsorbed into the extracellular fluid, thus maintaining the fluid volume in the body. Urea filtered across the glomerulus enters the proximal tubule. Absorption depends on the permeability of different parts of the nephron, and absorption of some substances might be passive, actively transported, or co-transported.[10] In tubular secretion, urea and other waste products like uric acid, drugs, hydrogen, and bicarbonate ions are moved out of the peritubular capillaries to the filtrate. This is to maintain the pH and remove unwanted wastes.[11] After the filtrate has undergone the above processes of urine formation, the urine proceeds into the collecting duct, then to the calyces, and finally to the renal pelvis which joins with the ureter.

Principal and intercalated cells are located in the distal part of distal convoluted tubule and collecting duct and are responsible for reabsorption of sodium ions and water and the secretion of potassium ions. In addition, the intercalated cells are responsible for secretion of hydrogen and bicarbonate ions.[12] Tubular processes are mainly controlled by local factors such as starling forces and glomerulotubular balance. Tubular processes are also controlled by a central mechanism, that is, hormones such as vasopressin, aldosterone, natriuretic peptides, angiotensin II, parathyroid hormone, and sympathetic nervous system.[13] Urine is about 95% water and 5% waste products, in which urea constitutes 2% of the waste product excreted. In certain conditions, when the kidney functions are compromised, there is a buildup of urea in the blood. The concentration of urea in the blood could also increase when there is an increased or high consumption of protein.[14] The abundance of urea has customarily become a substitute marker of renal function, protein intake, and dialysis.[15] One major condition that affects the kidney function is chronic kidney disease (CKD), a major public health problem[16],[17] Individuals with diabetes mellitus, hypertension, cardiovascular diseases, and many more conditions are more predisposed to having CKD.[18],[19],[20] Urea concentration has been shown to increase in CKD.[21],[22],[23] Although urea is generally believed to be nontoxic, studies have shown that the buildup of urea in CKD could cause devastating effects to cellular structures and functions.[24],[25],[26],[27] Furthermore, CKD patients who undergo dialysis have shown great improvements and a decrease in the symptoms associated with renal functions.[28] Research has shown that urea is not the final end product of protein metabolism, and since it is soluble in water, it can release its nitrogen to form other compounds that are highly toxic (uremic toxins).[29],[30] These derivatives of urea are as well toxic and have damaging effects on the tissues.[31]

On the other hand, urea and its derivatives are said to have beneficial effects.[32] Many publications, both old and recent, have supported the claim that urea and its derivatives have therapeutic actions.[33],[34] It is also important to mention that urea products can be produced or synthesized in the laboratory for commercial purposes, and its role in plants has been widely studied and established.[35] It is used in fertilizers as a source of nitrogen and as an important material for chemical industries.[36]

Many studies have reported both the toxicological and therapeutic effects of urea and its derivatives. The need to have a clear understanding of the role of urea cannot be overemphasized. This would help the clinicians and other researchers to know when not to use urea for therapeutic purposes. In this article, we present a review to help elucidate the scientific relevance of urea in experimental animals. This would provide data to clinicians on how to recommend the use of these urea products for clinical research.


  Biosynthesis of Urea (Urea Cycle) Top


The urea cycle is a series of reactions that result in the production of urea from ammonia. It was discovered in 1932 by Hans Krebs and Henseleit. Protein catabolism produces ammonia, which is highly toxic to the body organs. Most organisms eliminate ammonia directly to the external environment. However, in some animals including humans, ammonia is converted to urea before its clearance.[37] The production of urea is controlled by a series of enzymes within the cytosol and the mitochondria of cells.[38],[39] In the mitochondria, ammonia combines with CO2 using energy from adenosine triphosphate (ATP) to form carbamoyl phosphate. This combines with ornithine to form citrulline. Citrulline diffuses out of the mitochondria into the cytosol, where it combines with aspartate to form arginine succinate, which breaks down to form arginine and fumarate. Arginine receives water to form ornithine and urea. Ornithine re-enters the mitochondria to initiate another cycle, while urea is excreted in urine.


  Uremia Top


This occurs when there is a high level of urea in the blood. The causes of elevated urea in the blood could be classified into three different categories, which include prerenal, renal, and postrenal causes. In prerenal causes, an increased production of urea in the liver through high-protein diets can lead to uremia. More so, a decreased blood pressure, shock, and dehydration could also reduce the clearance of urea, thereby increasing its blood concentration.[40] The renal causes may be due to a decrease in kidney functions, and the factors may include acute kidney disease and CKD, tubular necrosis, and many other related kidney diseases.[41] The post-renal causes occur due to the obstruction in the urinary outflow of urea. This could be due to enlarged prostate tumor of the bladder or severe infection of the urinary tract.[42]


  Assessment of Urea Top


Urea is the primary metabolite of dietary protein and turnover of tissues. To determine its blood concentration, the whole urea is assayed and in some cases, only the nitrogen components of urea are measured. The normal range of urea nitrogen is between 5 and 20 mg/dL. This range varies due to several factors which include protein content of the diet, protein catabolism, water content of the body, liver urea biosynthesis, and urea excretion in the kidney.[43] Several methods exist for analyzing urea. The recent techniques are automated, and they produce reproducible and reliable results. Urea nitrogen can be measured using a diacetyl or Fearon reaction, which produces a yellow chromogen product when added to urea.[44] The quantification occurs through photometry procedure. Urea concentration can also be assayed using the enzymatic procedure which involves the breakdown of urea to ammonia and carbonic acid by the enzyme urease.[23] The absorbance is then measured at a specific wavelength. Blood urea nitrogen (BUN) test measures the amount of nitrogen in the blood that is derived from the waste product urea; however, the assay could be performed using serum and not whole blood.[45]


  Literature Search Top


A PubMed search was carried out for articles published before 2019 using the phrase, “urea application in experimental animals.” A total number of 1142 articles were screened using the title and abstract. Thirteen articles met the inclusion criteria, while 1129 articles were excluded [Figure 1]. The search was mainly for research articles, and no clinical trials, case reports, and case series were reviewed. The information recorded from these publications included the test substance, amount injected, animal model, number of animals, duration of treatments, and effects. The research publications were categorized based on the following:
Figure 1: A systematic guide for the selection of articles

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  1. The toxicity of urea in experimental animals
  2. The therapeutic effects of urea in experimental animals.



  Urea Toxicity in CKD Top


Urea concentration increases during CKD. [46],[47],[48] Many studies administered urea in nephrectomized or CKD animals to further increase its concentration in order to study its effects.[46],[47],[18],[49],[50],[51],[52] [Table 1] gives a list of seven articles which were reviewed, and the following observations were made. Different nitrogenous compounds (arginine, aspartic acid, and urea) were administered to experimental rats of different sample sizes. The results showed retention of nitrogen compounds in the blood, and this may likely imply a buildup of toxic products that should be excreted in urine.[46] However, using animals of the same sample size would have guaranteed more valid and reliable results. We observed that urea induces the production of intracellular reactive oxygen species (ROS) in cells such as renal tubular cells, vascular endothelial cells, adipocytes, vascular smooth muscle cells, and beta cells in CKD mice.[47],[48] Most of the parameters were investigated using modern experimental techniques, which ensures validity of the studies. These ROS are highly reactive radicals that can damage cellular components. Increased ROS production in excess of antioxidants leads to oxidative stress, which has been reported in the etiology and pathogenesis of many diseases like diabetes, cancer, Alzheimer's disease, and many more.[53],[54],[55] Many of the effects reported in [Table 1] are due to increased ROS production, which occurs in animals with chronic diseases. The high concentration of urea in the plasma (uremia), which occurs in CKD, could result in a defect in carbohydrate, protein, and lipid metabolism.[56] ROS production has been shown to increase modification of insulin-signaling molecules and reduce insulin-stimulated insulin receptor substrate (IRS) and Akt phosphorylation and glucose transport in uremic animals, which therefore creates a state of insulin resistance.[48],[57] Uremia has also been reported to cause carbamylation of intracellular proteins which are responsible for the altered mitochondria ROS production. Trecherel et al.[58] studied in vitro expression of proapoptotic proteins (Bcl-2–associated death [BAD] promoter) in smooth muscle cells exposed to urea, and it was confirmed that urea has the potential to induce apoptosis and cell death in smooth muscle cells and plays a role in atherogenesis and progression of atherosclerosis, thus promoting cardiovascular disease. We observed that a high urea concentration administered to nephrectomized dogs was lethal and sufficient to cause death of animals. The symptoms exhibited by the animals included gastrointestinal disturbances like vomiting, diarrhea, nausea, weakness, and others.[49] There was also electrolyte imbalance, which has been reported to play a critical role in the pathogenesis of many diseases.[49] The hypernatremia, hyperkalemia, and hyperchloremia observed may be due to the inability of the kidney to excrete these ions. Although these ions are necessary for nerve and muscle functions, their excess concentration in the blood could be deleterious. In addition, the excess bicarbonate ions caused by urea could result in metabolic acidosis, which is characterized by increase in blood pH. In one of the studies conducted using CKD zebrafish, a decrease in the volume of the olfactory epithelium was shown to occur in uremic fish [Table 1], even though the mechanisms of this have not been ascertained.[50] The decrease may be due to olfactory cell degeneration or apoptosis induced by high urea level. The olfactory epithelium is the sensory system of smell, and therefore, any disruption to the olfactory cells may interfere with the ability to detect airborne substances in the environment.
Table 1: Toxicity of urea in experimental animals

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Patients with CKD suffer from depression due to the accumulation of urea. This observation was further confirmed in mice and could be as a result of inhibition of the mTORC1-S6k signaling pathway and loss of synapses in the medial prefrontal cortex of the brain.[51] Furthermore, other studies on urea showed that it is capable of causing disruption of the intestinal barrier and proposed that the mechanism of this effect involves diffusion of urea into the gut and its conversion by microbial urease to ammonia.[53],[59] The impaired integrity of the intestinal epithelia potentially supports leakage of bacterial intestinal toxins into the body fluid and systemic inflammation. The deposition of extracellular cell matrix (ECM) by increased ROS production and protein kinase C activation has widely been reported in CKD.[60] The ECM causes endothelial dysfunction and disturbances in the ultrafiltration processes of the renal tubular cells, as reported in the wild-type CKD mice exposed to urea.[52] This causes an increase in blood urea with increase in signs of toxicity. This elevated urea level may be because of carbamylation reaction, a posttranscriptional modification where urea derived from its catabolism (isocyanic acid) tampers with the function and structural integrity of proteins.


  Therapeutic Actions of Urea in Experimental Animals Top


According to a study conducted by Sweeny et al.[61], urea was shown to improve animal feed supplementation. It was reported to increase nutritional value and aids the digestion of low-energy crop stubbles. Emmanuel et al.[62] also studied the effects of different levels of urea supplementation on nutrient intake and growth performance in growing camels fed roughage-based complete pellet diets and urea was confirmed to influence digestibility, feed intake, growth rate, feed efficiency, and economics.[63],[64],[65] Urea has been confirmed to have an effect on plasma sodium lower than 135 mEq/L (hyponatremia), according to a clinical research trial performed by Rondon-Berrios et al.[66] Patients who had syndrome of inappropriate ADH secretion (SIADH) as the only cause of hyponatremia were treated with oral urea as the sole drug therapy for hyponatremia[67] The mechanism of effectiveness of urea on hyponatremia caused by SIADH is based on the pharmacokinetics of urea; it is a partially effective due to its permeability into the muscle tissues, connecting tubule, cortical collecting duct, and medullary collecting duct. Urea has been shown to create a positive sodium balance, which contributes to improvement of plasma sodium.[68] This study was further supported by Van Reeth and Decaux[69] who reported that urea administration ameliorates hyponatremia and decreases brain damage in rats. Thiourea, a regulator of leptin hormone secretion from adipocytes, plays an important role in the progression of obesity and hepatic steatosis. In a study carried out by Liang et al.,[70] administration of thiourea (a similar compound to urea) in animals was observed to modulate triglyceride metabolism and decrease body weights, total cholesterol, high- and low-density lipoproteins.[70] Even though urea and its derivatives have been reported to have many therapeutic effects, their antitumor effects have also been widely reported [Table 2]. In a study carried out by Vedarethinam et al.,[71] it was reported that 1,3-bis-((3-hydroxynaphthalen-2-yl) phenylmethyl) urea (1,3-BPMU) has cytotoxic and growth inhibitory effects on hepatocellular carcinoma cells (HEP-G2).[71] They also stated that a flow cytometry analysis shows that 1,3-BPMU causes early and late apoptosis. This compound is a derivative of urea, and the effects are mediated by urease. Another urea derivative, URD12, has been confirmed to exhibit cytotoxic activity against the K562 human leukemia and KB human mouth epidermal carcinoma cell lines. Wang et al.[72] further studied URD12 in in vivo and in vitro assays using BGC-823 human gastric carcinoma, SMMC-7721 human hepatoma, and HepG2 human hepatocellular carcinoma cell lines [Figure 2]. URD12 was confirmed to inhibit the growth of tested tumor cell lines with no effects on the weight, spleen, and thymus. Several other studies have also reported that urea has therapeutic applications. Evidence suggest that topical urea may impact epidermal permeability and barrier function. Rawlings et al.[73] Susanne et al.[73] confirmed this myth by conducting a placebo-controlled, double-blinded study in healthy human volunteers, after which urea significantly improved cutaneous barrier function as there was a significant decrease in transepidermal water loss. Dermal therapists have shown considerable interest in urea due to its properties. Urea has been confirmed to have a great effect on xerosis.[74] It has a good hydrating effect by improving the water-holding capacity of the stratum corneum and the skin barrier function and regulates skin surface pH. With appropriate urea concentration, reduction of stratum corneum integrity together with decreased protease activity was not observed.[75] According to a comparative study conducted by Kiane de Kleijne et al., Caduff et al.,[76] urea showed great environmental benefits. Urea production from basic oxygen furnace gas (BOFG) avoids greenhouse gas emissions, and net emission savings could be achieved especially when combined with excess carbon-dioxide transport and storage.
Figure 2: Summary of findings on the biological roles of urea

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Table 2: Therapeutic actions of urea in experimental animals

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  Conclusions Top


The scientific role of urea remains controversial; however, we have been able to analyze some of the toxicological and therapeutic effects of urea in this review. In most of the articles reviewed, we observed that the toxicity of urea was mainly reported in CKD and other related pathological conditions. We also observed that urea plays a significant role in inhibiting the growth and causing apoptosis of cancerous cells, even though it has several other therapeutic functions.

Ethical approval and consent to participate

Not Applicable.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Adeyomoye OI, Adewoye EO. Preliminary assessement and antioxidative properties of Methanol extract of Parquetina nigrescens in alloxan induced diabetic rats. Asian J Res Med Pharm Sci 2018;3:1-10.  Back to cited text no. 1
    
2.
Anderson MO, Zhang J, Liu Y, Yao C, Phuan PW, Verkman AS. Nanomolar potency and metabolically stable inhibitors of kidney urea transporter UT-B. J Med Chem 2012;55:5942-50.  Back to cited text no. 2
    
3.
Vanholder R, Baurmeister U, Brunet P, Cohen G, Glorieux G, Jankowski J, et al. A bench to bedside view of uremic toxins. J Am Soc Nephrol 2008;19:863-70.  Back to cited text no. 3
    
4.
Massy ZA, Pietrement C, Touré F. Reconsidering the lack of urea toxicity in dialysis patients. Semin Dial 2016;29:333-7.  Back to cited text no. 4
    
5.
Johnson WJ, Hagge WW, Wagoner RD, Dinapoli RP, Rosevear JW. Effects of urea loading in patients with far-advanced renal failure. Mayo Clin Proc 1972;47:21-9.  Back to cited text no. 5
    
6.
Symmers W, Kirk TS. Urea as a bactericide, and its application in the treatment of wounds. Lancet 1915;4;186:1237-9.  Back to cited text no. 6
    
7.
Kligman AM. Dermatologic uses of urea. Acta Derm Venereol 1957;37:155-9.  Back to cited text no. 7
    
8.
Serup J. A three-hour test for rapid comparison of effects of moisturizers and active constituents (urea). Measurement of hydration, scaling and skin surface lipidization by noninvasive techniques. Acta Derm Venereol Suppl (Stockh) 1992;177:29-33.  Back to cited text no. 8
    
9.
Sasaki Y, Tadaki T, Tagami H. The effects of a topical application of urea cream on the function of pathological stratum corneum. Acta Dermatol-Kyoto 1989;84:581-6.  Back to cited text no. 9
    
10.
David Weiner, William E. Mitch and Jeff M. Sands. Urea and ammonia metabolism and control of renal nitrogen excretion. Clin J Am Soc Nephrol 2015;10:1444-58.  Back to cited text no. 10
    
11.
Suchy-Dicey AM, Laha T, Hoofnagle A, Newitt R, Sirich TL, Meyer TW, et al. Tubular secretion in CKD. J Am Soc Nephrol 2016:2148-55.  Back to cited text no. 11
    
12.
Roy A, Al-bataineh MM, Pastor- Soler NM. Collecting duct intercalated cell function and regulation. Clin J Am Soc Nephrol 2015;10:305-24.  Back to cited text no. 12
    
13.
Dusikova K, Mad'a P, Fontana J. Functions of cells and human body: Urine formation. Multimedia Textbook. Word Press; 2013.  Back to cited text no. 13
    
14.
Kimmel PL, Patel SS. Quality of life in patients with chronic kidney disease: Focus on end-stage renal disease treated with hemodialysis. Semin Nephrol 2006;26:68-79.  Back to cited text no. 14
    
15.
Perl J, Unruh ML, Chan CT. Sleep disorders in end-stage renal disease: 'Markers of inadequate dialysis'? Kidney Int 2006;70:1687-93.  Back to cited text no. 15
    
16.
Williams M. Diabetic kidney disease in elderly individuals. Med Clin North Am 2013;97:75-89.  Back to cited text no. 16
    
17.
Stevens PE, Levin A. Evaluation and management of CKD: Synoposis of the KDIGO 2012 clinical pracztice guidelines. Ann Intern Med 2013;158:825-30.  Back to cited text no. 17
    
18.
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-305.  Back to cited text no. 18
    
19.
Eknoyan G, Lameire N, Barsoum R, Eckardt KU, Levin A, Levin N, et al. The burden of kidney disease: Improving global outcomes. Kidney Int 2004;66:1310-4.  Back to cited text no. 19
    
20.
Menon V, Wang X, Sarnak MJ, Hunsicker LH, Madero M, Beck GJ, et al. Long-term outcomes in nondiabetic chronic kidney disease. Kidney Int 2008;73:1310-5.  Back to cited text no. 20
    
21.
Bauer JH, Brooks CS, Burch RN. Renal function studies in man with advanced renal insufficiency. Am J Kidney Dis 1982;11:30-5.  Back to cited text no. 21
    
22.
Dosseter JB. Creatininemia versus uremia. Ann Intern Med 1966;65:1287-99.  Back to cited text no. 22
    
23.
Kassirer JP. Clinical evaluation of kidney function: Glomerular function. N Engl J Med 1971;285:355-89.  Back to cited text no. 23
    
24.
Madero M, García-Arroyo FE, Sánchez-Lozada LG. Pathophysiologic insight into Meso American nephropathy. Curr Opin Nephrol Hypertens 2017;26:296-302.  Back to cited text no. 24
    
25.
Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 2003;41:1-12. doi: 10.1053/ajkd. 2003.50007.  Back to cited text no. 25
    
26.
Levey AS, Coresh J. Chronic kidney disease. Lancet 2012;379:165-80.  Back to cited text no. 26
    
27.
Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM. Hyperfiltration in remnant nephrons: A potentially adverse response to renal ablation. J Am Soc Nephrol 2001;12:1315-25.  Back to cited text no. 27
    
28.
Hounkpatin HO, Fraser SDS, Glidewell L, Blakeman T, Lewington A, Roderick PJ. Predicting risk of recurrent acute kidney injury: A systematic review. Nephron 2019;142:83-90.  Back to cited text no. 28
    
29.
Toyohara T, Akiyama Y, Suzuki T, Takeuchi Y, Mishima E, Tanemoto M, et al. Metabolomic profiling of uremic solutes in CKD patients. Hypertens Res 2010;33:944-52.  Back to cited text no. 29
    
30.
Kabanda A, Jadoul M, Pochet JM, Lauwerys R, van Ypersele de Strihou C, Bernard A. Determinants of the serum concentrations of low molecular weight proteins in patients on maintenance hemodialysis. Kidney Int 1994;45:1689-96.  Back to cited text no. 30
    
31.
Hamburger J. Electrolyte disturbances in acute uremia. Clin Chem 1957;3:332-43.  Back to cited text no. 31
    
32.
Javid M. Urea-new use of an old agent. Reduction of intracranial and intraocular pressure. Surg Clin North Am 1958;38:907-28.  Back to cited text no. 32
    
33.
Buckell M. Blood changes on intravenous administration of mannitol or urea for reduction of intracranial pressure in neurosurgical patients. Clin Sci 1964;27:223-7.  Back to cited text no. 33
    
34.
Kleeman CR, Daison H, Levin E. Urea transport in the central nervous system. Am J Physiol 1962;203:739-47.  Back to cited text no. 34
    
35.
Bremner JM, Krogmeier MJ. Elimination of the adverse effects of urea fertilizer on seed germination, seedling growth, and early plant growth in soil. Proc Natl Acad Sci U S A 1988;85:4601-4.  Back to cited text no. 35
    
36.
Eskew DL, Welch RM, Cary EE. Nickel: An essential micronutrient for legumes and possibly all higher plants. Science 1983;222:621-3.  Back to cited text no. 36
    
37.
Keshet R, Szlosarek P, Carracedo A, Erez A. Rewiring urea cycle metabolism in cancer to support anabolism. Nat Rev Cancer 2018;18:634-45.  Back to cited text no. 37
    
38.
Wild KT, Ganetzky RD, Yudkoff M, Ierardi-Curto L. Hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome causing severe neonatal hyperammonemia. JIMD Rep 2019;44:103-7.  Back to cited text no. 38
    
39.
Barmore W, Azad F, Stone WL. Physiology, urea cycle. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK513323.  Back to cited text no. 39
    
40.
Zemaitis MR, Foris LA, Katta S, Bashir K. Uremia. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020. [Updated on 2020 Aug 16].  Back to cited text no. 40
    
41.
Meyer TW, Hostetter TH. Approaches to uremia. J Am Soc Nephrol 2014;25:2151-8.  Back to cited text no. 41
    
42.
Depner TA. Uremic toxicity: Urea and beyond. Semin Dial 2001;14:246-51.  Back to cited text no. 42
    
43.
Duranton F, Cohen G, De Smet R, Rodriguez M, Jankowski J, Vanholder R, et al. Normal and pathologic concentrations of uremic toxins. J Am Soc Nephrol 2012;23:1258-70.  Back to cited text no. 43
    
44.
Hosten AO. BUN and creatinine. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston: Butterworths; 1990. Chapter 193.  Back to cited text no. 44
    
45.
Gounden V, Bhatt H, Jialal I. Renal Function Tests. StatPearls Publishing; 2020.  Back to cited text no. 45
    
46.
Burton D. Cohen uremic toxins. Bull N Y Acad Med 1975;51:11.  Back to cited text no. 46
    
47.
D'Apolito M, Du X, Zong H, Catucci A, Maiuri L, Trivisano T, et al. Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure. J Clin Invest 2010;120:203-13.  Back to cited text no. 47
    
48.
Koppe L, Nyam E, Vivot K, Manning Fox JE, Dai XQ, Nguyen BN, et al. Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease. J Clin Invest 2016;126:3598-612.  Back to cited text no. 48
    
49.
Grollman Ef, Grollman A. Toxicity of urea and its role in the pathogenesis of uremia. J Clin Invest 1959;38:749-54.  Back to cited text no. 49
    
50.
Bettini S, Lazzari M, Ferrando S, Gallus L, Franceschini V. Histopathological analysis of the olfactory epithelium of zebrafish (Danio rerio) exposed to sublethal doses of urea. J Anat 2016;228:59-69.  Back to cited text no. 50
    
51.
Wang H, Huang B, Wang W, Li J, Chen Y, Flynn T, et al. High urea induces depression and LTP impairment through mTOR signalling suppression caused by carbamylation. EBioMedicine 2019;48:478-90.  Back to cited text no. 51
    
52.
Vaziri ND, Yuan J, Norris K. Role of urea in intestinal barrier dysfunction and disruption of epithelial tight junction in chronic kidney disease. Am J Nephrol 2013;37:1-6. doi: 10.1159/000345969.  Back to cited text no. 52
    
53.
Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, et al. Oxidative stress: Harms and benefits for human health. Oxid Med Cell Longev 2017;2017;8416763. doi: 10.1155/2017/8416763.  Back to cited text no. 53
    
54.
Halliwell B. Role of free radicals in neurodegenerative diseases: Therapeutic implications for antioxidant treatment. Drugs Aging 2001;18:685-716.  Back to cited text no. 54
    
55.
Singh RP, Sharad S, Kapur S. Free radicals and oxidative stress in neurodegenerative diseases: Relevance of dietary antioxidants. J Indian Acad Clin Med 2004;5:218-25.  Back to cited text no. 55
    
56.
Institute of Medicine (US) Committee on Diet and Health, Woteki CE, Thomas PR, editors. Eat for Life: The Food and Nutrition Board's Guide to Reducing Your Risk of Chronic Disease. Washington (DC): National Academies Press (US); 1992. Chapter 7, Protein, Carbohydrates, and Chronic Diseases.  Back to cited text no. 56
    
57.
Freeman AM, Pennings N. Insulin Resistance. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507839/.  Back to cited text no. 57
    
58.
Trecherel E, Godin C, Louandre C, Benchitrit J, Poirot S, Mazière JC, et al. Upregulation of BAD, a pro-apoptotic protein of the BCL2 family, in vascular smooth muscle cells exposed to uremic conditions. Biochem Biophys Res Commun 2012;417:479-83.  Back to cited text no. 58
    
59.
Madara JL, Dharmsathaphorn K. Occluding junction structure-function relationships in a cultured epithelial monolayer. J. Cell Biol 1985;101:2124-33.  Back to cited text no. 59
    
60.
Li J, Gobe G. Protein kinase C activation and its role in kidney disease. Nephrology (Carlton) 2006;11:428-34.  Back to cited text no. 60
    
61.
Sweeny JPA, Surridge V, Humphry PS, Pugh H, Mamo K. Benefits of urea supplementation methods on the production performances of merino sheep. Vet J 2014;200:398-403.  Back to cited text no. 61
    
62.
Emmanuel N, Patil NV, Bhagwat SR, Lateef A, Xu K, Liu H. Effects of diferent levels of uea supplementation on nutrient intake and growth performance in growing camels fed roughage based complete pellet diets. Anim Nutr 2015;1:356-61.  Back to cited text no. 62
    
63.
Xu Y, Li Z, Moraes LE, Shen J, Yu Z, Zhu W. Effects of incremental urea supplementation on rumen fermentation, nutrient digestion, plasma metabolites, and growth performance in fattening lambs. Animals (Basel) 2019;9:652. doi: 10.3390/ani9090652.  Back to cited text no. 63
    
64.
Saro C, Mateo J, Andrés S, Mateos I, Ranilla MJ, López S, et al. Replacing soybean meal with urea in diets for heavy fattening lambs: Effects on growth, metabolic profile and meat quality. Animals (Basel) 2019;9:974. doi: 10.3390/ani9110974.  Back to cited text no. 64
    
65.
Pan M, Heinecke G, Bernardo S, Tsui C, Levitt J. Urea: A comprehensive review of the clinical literature. Dermatol Online J 2013;19:20392.  Back to cited text no. 65
    
66.
Rondon-Berrios H, Tandukar S, Mor MK, Ray EC, Bender FH, Kleyman TR, Weisbord SD. Urea for the treatment of hyponatremia. Clin J Am Nephrol 2018;13:1627-32.  Back to cited text no. 66
    
67.
Verbalis JG. Whole body volume regulation and escape from antidiuresis. Am J Med 2006;119 (7 Suppl 1):s21-9.  Back to cited text no. 67
    
68.
Verbalis JG, Baldin EF, Neish PN, Robinson AG. Effect of protein intake and urea on sodium excretion during inappropriate antidiuresis in rats. Metabolism 1988;37:46-54.  Back to cited text no. 68
    
69.
Van Reeth O, Decaux G. Rapid correction of hyponatraemia with urea may protect against brain damage in rats. Clin Sci (Lond) 1989;77:351-5.  Back to cited text no. 69
    
70.
Liang X, Pei H, Ma L, Ran Y, Chen J, Wang G, et al. Synthesis and biological evaluation of novel urea- and guanidine-based derivatives for the treatment of obesity-related hepatic steatosis. Molecules 2014;19:6163-83.  Back to cited text no. 70
    
71.
Vedarethinam V, Dhanaraj K, Ilavenil S, Arasu MV, Choi KC, Al-Dhabi NA, et al. Antitumor effect of the mannich base (1,3-bis-((3-Hydroxynaphthalen-2-yl) phenylmethyl) urea) on hepatocellular carcinoma. Molecules 2016;21:632.  Back to cited text no. 71
    
72.
Wang A-Y, Lu Y, Zhu H-L, Jiao Q-C. URD 12: A urea derivative with marked antitumor activities. Oncol Lett 2012;3:373-6.  Back to cited text no. 72
    
73.
Verbrugge FH, Tang WH, Hazen SL. Protein carbamylation and cardiovascular disease. Kidney Int 2015;88:474-8.  Back to cited text no. 73
    
74.
Weber TM, Kausch M, Rippke F, Schoelermann AM, Filbry AW. Treatment of xerosis with a topical formulation containing glyceryl glucoside, natural moisturizing factors, and ceramide. J Clin Aesthet Dermatol 2012;5:29-39.  Back to cited text no. 74
    
75.
Rawlings AV, Scott IR, Harding CR, Bowser PA. Stratum corneum moisturization at the molecular level. J Invest Dermatol 1994;103:731-41.  Back to cited text no. 75
    
76.
Caduff M, Huijbregts MA, Althaus HJ, Koehler A, Hellweg S. Wind power electricity: The bigger the turbine, the greener the electricity?. Environ Sci Technol 2012;46:4725-33.  Back to cited text no. 76
    


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   Abstract
  Introduction
   Biosynthesis of ...
  Uremia
  Assessment of Urea
  Literature Search
  Urea Toxicity in CKD
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