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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Sprache: Englisch
- Veröffentlichungsjahr: 2006
The kidneys are a vital organ present in humans and vertebrate animals. Various toxic chemicals, present in food and water adversely affect the kidneys. Plants and plant-derived compounds have been a major source for the treatment and cure of diseases since ancient times. Even today, almost 25% of the prescription drugs for renal problems are sourced from plants. An Introduction to Nephroprotective Plants gives an overview of nephrotoxicity and medicinal plants used for protecting the kidney and reducing the effect of kidney toxicity and managing renal diseases. This book is an answer to the current gaps in knowledge resources on nephroprotective plants. The reader is introduced to the basic physiology of the renal excretory system and its disorders. The introduction is followed by chapters which give information on medicinal plants used in traditional systems of medicine (both codified and noncodified). Information about plant parts used, method of use and dosage is provided along with references. Key Features- Simple structured presentation in six chapters- Includes an introduction to the urinary system and its diseases- Includes information about codified and noncodified medicinal plants used for neuroprotection- Covers phytochemicals extracted from medicinal plants which are screened and used in modern medicine for nephroprotection in detail.- Covers ethnobotanical and polyherbal formulations- References for further reading An Introduction to Nephroprotective Plants serves as a convenient desk reference for all researchers (pharmacologists, medicinal chemists, ethnobotanists) and healthcare professionals (physicians, pharmacists, nurses and medical students) who require complete information on nephroprotective plants. Audience: Researchers (pharmacologists, medicinal chemists, ethnobotanists) and healthcare professionals (physicians, pharmacists, nurses and medical students) who require complete information on nephroprotective plants, readers in traditional medicine.
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PREFACE
The kidney is a vital organ present in humans and vertebrate animals. Various toxic chemicals being used in food and water are causing toxicity to the kidney. There is a necessity to know about the methods of protecting this vital organ and the medicinal plants that are being used to protect it. The book An Introduction to Nephroprotective Plants gives an overview of nephrotoxicity and medicinal plants used for protecting the kidney and curing kidney toxicity and related diseases. Plants and plant-derived compounds have been a major source for the treatment and cure of diseases since ancient times. Even today, 25% of prescription drugs are sourced from plants. There is no comprehensive information on the plants that are used, both in traditional medicine and in modern medicine, for nephroprotection and curing kidney diseases. This book is an answer to this. It gives information on medicinal plants used in traditional medicine (both codified and noncodified) and ethnomedicine. Plant parts used, method of use and dosage, and references are given. Phytochemicals extracted from medicinal plants, screened and used in modern medicine for nephroprotection, and curing kidney problems are given in detail. Description of medicinal plants screened for nephroprotection and methods of screening are given. Methods of the assay for screening the medicinal plants for kidney protection and kidney toxicity cure are also given.
This book is a single point of reference for all researchers who require complete information on nephroprotective plants. It also gives information on phytochemicals used for kidney protection. Simply it will be a desk reference on herbal kidney protection.
The book will be useful for researchers working on kidney disorders and diseases, physicians treating patients with kidney problems, hospitals, pharmacy institutions, pharmacy students, pharmacy researchers, and ethnobotanists or people working on traditional medicine.
Since it is a voluminous subject, we might have missed some references. Readers are requested to bring such omissions to our notice so that the same can be included in future editions.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The author declares no conflict of interest, financial or otherwise.
ACKNOWLEDGEMENTS
Declared none.
Urinary System, Its Functions and Disorders
T. Pullaiah,M. RamaiahAbstract
Kidneys (2), ureters (2), urinary bladder (1), and urethra (1) constitute the urinary system. Man is exposed to in the form of medicines, industrial and environmental chemicals, and a variety of naturally occurring substances and kidney is adversely affected by these chemicals. An acute injury is the result of this exposure that may lead to renal failure and renal malignancies. In this chapter, kidney functions, urinary system disorders, nephrotoxicity, nephrotoxic chemical substances, diabetic nephropathy, and urolithiasis are given.
Introduction
A pair of fist-sized organs, called kidneys, are located outside the peritoneal cavity on each side of the spine. A kidney of an adult human is 10-12.5 x 5-7.5 x 3 cm in size (length x breadth x thick) and weighs 135-150 g. The functional unit of kidneys is nephrons and each human kidney contains about 0.8-1.2 x 10-6 nephrons. Extra water and wastes from the blood are removed by the kidney and converted to urine. Kidneys also keep a stable balance of salts and other substances in the blood. Kidneys (2), ureters (2), urinary bladder (1), and urethra (1) constitute the urinary system. Ureters carry urine from the kidneys a triangle-shaped to the bladder in the lower abdomen. The bladder’s elastic walls stretch and expand like a balloon to store urine. Urine is emptied through the urethra to outside the body when the walls of the bladder flatten together. By selectively excreting or retaining various substances according to specific body needs, the kidneys maintain the body’s homeostasis.
Functions of the Kidneys
Jayasudha [1], has given a detailed account of the functions and urinary system disorders.
The kidneys help regulate the blood levels of sodium ions, potassium ions, calcium ions, chloride ions and phosphate ions.A variable amount of hydrogen ions (H-) are excreted by the kidneys into the urine and conserve bicarbonate ions (HCO3-). These two activities help regulate blood pH.Kidneys adjust blood volume by conserving or eliminating water in the urine.By secreting the enzyme rennin, the kidneys help regulate blood pressure which activates the rennin-angiotensin-aldosterone pathway. Increased rennin causes an increase in blood pressure.The kidneys help excrete waste substances by forming urine.The kidneys maintain a relatively constant blood osmolarity close to 300 millimoles per litre by separately regulating loss of water and loss of solutes in the urine.Two hormones, calcitriol, the active form of vitamin D and erythropoietin are produced by the kidneys. Calcitrol helps regulate calcium homeostasis and erythropoietin stimulates the production of red blood cells.The kidney can use the amino acid glutamine in the synthesis of new glucose molecules. The kidneys then release glucose into the blood to help maintain a normal blood glucose level.Disorders of Urinary System
Urinary system disorders range from easy to treat, to life-threatening in severity. These include Renal calculi or kidney stones (calcium oxalate, uric acid or calcium phosphate crystals), Cessation of glomerular filtration or renal failure [2], acute renal failure (ARF), chronic renal failure (CRF) [3], Glomerulonephritis, polycystic kidney disease (PKD), hydronephrosis, nocturnal enuresis, painful bladder syndrome/interstitial cystitis, urinary retention or bladder-emptying problems and urinary incontinence.
Nephrotoxicity
Toxic chemicals and medication may be poisonous to the kidney, which result in renal dysfunction or nephrotoxicity (Greek: nephros=kidney). Nephropathy is one of the progressive complications that arise due to the detrimental effects of metabolites created due to various metabolic and physiological reactions.
Because of high blood supply and the presence of cellular transport systems that cause accumulation of toxic compounds within the nephron epithelial cells, kidney becomes susceptible. Many drugs have been shown to induce significant
nephrotoxicity. Aminoglycoside antibiotics have been widely used for gram-negative infections. However, their nephrotoxicity is a major limitation in clinical use. Among aminoglycosides, the grade of nephrotoxicity is in the following order, neomycin > GM > tobramycin.
The kidney is adversely affected by an array of chemicals that man is exposed to in the form of medicines, industrial and environmental chemicals, and a variety of naturally occurring substances. The level of exposure varies from minute quantities to very high doses. Exposure may be over a long period of time or limited to a single event, and it may be due to a single substance or to multiple chemicals. The circumstances of exposure may be an inadvertent, accidental, or intentional overdose or therapeutic necessity. Some chemicals cause an acute injury, while others produce chronic renal changes that may lead to end-stage renal failure and renal malignancies [4].
The kidney has several features that allow nephrotoxicants to accumulate [5]. It is highly vascular, receiving about 25% of the resting cardiac output (CO). The proximal renal tubule presents a large area for nephrotoxicant binding and transport into the renal epithelium. Reabsorption of the glomerular filtrate progressively increases intraluminal nephrotoxicant concentrations. It is the major organ of excretion and homeostasis for water-soluble molecules; because it is a metabolically active organ, it can concentrate certain substances actively [6]. In addition, its cells have the potential to convert chemicals and metabolically activate a variety of compounds [4].
GM mainly causes tubular toxicity, both lethal and sub-lethal alterations in tubular cells handicap reabsorption and, in severe cases, may lead to significant tubular obstruction [7]. Tubular cytotoxicity is the consequence of many interconnected actions triggered by drug accumulation in epithelial cells. An excessive concentration of the drug over an undetermined threshold destabilizes intracellular membranes and the drug redistributes throughout the cytosol. It then acts on mitochondria to unleash the intrinsic pathway of apoptosis [8].
A large number of chemicals in common usage nowadays are renal toxins. Administration of such toxins into the body may cause mechanical trauma to the kidneys and selectively interfere with certain functions of the renal tubules. Proximal renal tubular cells are particularly susceptible to acute injury by these substances and the exposure may be followed by acute tubular necrosis [9-11]. Certain food dyes are known to cause renal toxicity [12].
Some of the chemical nephrotoxicants and their activities are given below:
Cyclophosphamide (CP) is one of the most popular alkylating anticancer drugs despite its toxic side effects, including nephrotoxicity, hematotoxicity, mutagenicity, and immunotoxicity.Deltamethrin, a pyrethroid insecticide, showed toxicity in mammalian animals.GM-induced nephrotoxicity is a major contributor to Acute Kidney Injury (AKI) resulting from free radicals induced oxidative stress. GM nephrotoxicity, which occurs in about 15-30% of treated subjects, is manifested clinically as nonoliguric renal failure, with a slow rise in serum creatinine and hypoosmolar urinary output developing after several days of treatment.Cisplatin (cis-diamminedichloroplatinum (II)) is an effective agent against various solid tumours. Despite its effectiveness, the dose of cisplatin that can be administered is limited by its nephrotoxicity. Hundreds of platinum compounds (e.gl., carboplatin, oxaliplatin, nedaplatin and the liposomal form lipoplatin) have been tested over the last two decades in order to improve the effectiveness and to lessen the toxicity of cisplatin.Overdose of Paracetamol (PCM) can cause nephrotoxicity.Aminoglycosides, commonly used antibiotics against Gram negative bacteria, are nephrotoxic.Amikacin, a valuable aminoglycoside, is associated with undesirable renal toxicity.Cadmium, a known industrial pollutant, accumulates in the kidney and leads to nephrotoxicity.Acute kidney injury (AKI) has become increasingly prevalent in both developed and developing countries, and is associated with severe morbidity and mortality, especially in children. Cerda et al. [13] have reviewed recent literature on AKI, identified differences and similarities in the condition between developed and developing areas, analyzed the practical implications of the identified differences, and made evidence-based recommendations for study and management.
Diabetic Nephropathy
Das et al. [14] have given a detailed account of Diabetic Nephropathy (DN). DN is characterized by an increase in various things viz. kidney size, urinary albumin excretion, glomerular volume and kidney function chased by the accumulation of glomerular extracellular matrix, glomerular sclerosis and tubular fibrosis. Diabetic kidney disease is reported in about 15%–25% of type I diabetes patients and 30%–40% of patients with type II diabetes. Health problems associated with diabetic nephropathy have been discussed by Baig et al. [15], Fioretto ad Mauer [16] and Sheela et al. [17]. The pathophysiology of DN comprises of hyperfiltration and development of microalbumin urine which is followed by deterioration of kidney functions associated with extracellular and cellular disruption in both places that is glomerular and tubulo-interstitial regions of kidney [18]. It also includes hypertrophy/hyperplasia of glomerulus and the tubules, thickening of tubular basement membranes, thickening of glomerular, and expansion of tubulo-interstitial as well as mesangial compartments [19].
Kidney Stones
Aggarwal et al. [20] and Das et al. [14] have discussed in detail kidney stones and herbal treatment of kidney stones. Renal colic is the first manifestation of renal stone disease. The formation of solid phases in urinary passages is described as “Nephrolithiasis,” whereas the accumulation and aggregation of salts in renal parenchyma is termed as “Nephrocalcinosis”. Nephrocalcinosis is very common and can develop or cannot into nephrolithiasis. Formation of kidney stone is a complex process including chronicle events, viz. crystal nucleation, its growth, aggregation, and crystal retention inside the renal tubules [14, 21].
Mankind is known to be afflicted by urinary stone disease first reported in Egyptian Mummies dated 4000 BC and references are being made in early Sanskrit documents in India between 3000 and 200 BC [20]. Urolithiasis is a common multi-factorial disease that has been recognized and documented in medical literature even by Greek and Roman physicians. In the light of these historical clues, it appears that humankind has been afflicted by urinary stones since antiquity. Depending on the socio-economic conditions and subsequent changes in dietary habits, the overall probability of stone formers differs in various parts of the world. Urolithiasis is affecting 5-9% in Europe, 4-8% in the UK, 12% in Canada, 15% in the US, 20% in Gulf countries and 11% population in India with a relapse rate of 50% in 5–10 years and 75% in 20 years [22-24]. The stone belts of the world are located in the countries of the Middle East, North Africa, Mediterranean regions, Southern states of USA, and North-western states of India. In India, with a prevalence rate of 15%, too high incidence of stone belts has been found to occur. Marangella et al. [25] discussed about the drugs for the treatment of nephrolithaisis, while Butterweck et al. [26] gave an account of herbal medicines in the management of nephrolithiasis.
Urolithiasis encompasses all the renal, bladder and ureteric stones [27]. Kidney stones are composed of inorganic and organic crystals amalgamated with proteins. Urinary stones can be classified according to stone composition as calcium stone, uric acid stone, struvite stone and cystine stone. Some of the other types are calcium phosphate stone, xanthine stone, DHA stone, and crixivan stone. Approximately 80% of kidney stones are primarily composed of calcium oxalate [28-30]. The major predisposing factors that create an imbalance between levels of promoters and inhibitors of stone formation are low urine volumes, diet, hypercalciuria, hyperoxaluria, hyperuricosuria, hypocitraturia, hypomagnesuria, low urinary pH, cystinuria, and distal renal tubular acidosis [31]. Presently, the available drug therapy for the treatment of urinary stone includes, antibiotics (for struvite stones), allopurinol (for uric acid stone), opiates and NSAID’S (for relieving pain), and diuretics (for renal stone removal) [29]. For kidney stones that do not pass on their own by pharmacological management, the most widely preferred technique is lithotripsy. In this procedure, shock waves are used to break up a large stone into smaller pieces that can then pass through the urinary system. In case of failure with all other treatments, surgical invasive techniques have also been used like percutaneous nephrolithotomy or through ureteroscopy [27, 32].
The formation of a urinary stone, known as nephrolithiasis, urolithiasis, renal calculi or kidney stone is a serious, debilitating problem throughout the world. Struvite or Ammonium Magnesium Phosphate Hexahydrate (AMPH) is one of the components of urinary stone (calculi). Struvite stones are commonly found in women. Struvites form in humans as a result of urinary tract infection with urolithic urea splitting microorganisms. These stones can grow rapidly forming “staghorn-calculi”, which is a more painful urological disorder. Therefore, it is of prime importance to study the growth and inhibition of Struvite crystals.
Urolithiasis/nephrolithiasis are commonly referred to as stone formation in any part of the urinary tract, such as kidneys, ureters, urinary bladder, and urethra. Kidney stones are generally caused by bacterial infection, while kidney stones form as a result of physicochemical or genetic derangements leading to supersaturation of the urine with stone-forming salts or, less commonly, from recurrent urinary tract infection with urease producing bacteria [33]. Stone formation is a complex process that occurs due to successive physiochemical events such as supersaturation, nucleation, growth, aggregation, and retention within the renal tubules [23].
Types of Stones
Vamsi and Latha [35] have given a detailed account of urolithiasis wherein they discussed the types of stones in the urinary system.
Physiologically
Physiologically the renal calculi differentiated as tissue attached and unattached.
1. Attached stones tend to have the detectable site of attachment to papillae with the composition of calcium oxalate (CaOx) monohydrate.
2. While the unattached calculi are distinguished by having different compositions and lack of detectable site [36].
Clinically
Based on the composition of the stone forming element in the calculi, clinically, these calculi are categorized as the following types.
• Calcium stones (CaOx alone/with calcium phosphate)
• Struvite stones (Magnesium ammonium phosphate)
• Uric acid stones
• Cystine stones
• Drug induced stones
• 2,8-Dihydroxyadenine stones
Among the kidney stones, CaOx stones constitute about 75%, struvite stones of 15%, uric acid stones of about 6%, and cystine stones of about 1-2% [37].
Calcium Stones
The Idiopathic causes are absorptive hypercalciuria, renal hypercalciuria, and resorptive hypercalciuria. The metabolic causes are hypercalcemia due to primary hyperparathyroidism, hyperoxaluria, hyperuricosuria, hypocitraturia, and hypomagnesuria. In explaining the detailed cause of each event. i. Hyperoxaluria arises due to primary hyperoxaluria of genetic disorder which enhances the hepatic oxalate production and enteric hyperoxaluria, where the colon is made to diffuse more oxalate. ii. Hyperuricosuria is evident from excessive purine intake. iii. Hypocitraturia arises due to metabolic acidosis induced by inflammatory bowel disease and chronic diarrhea. iv. Hypomagnesuria due to malabsorption of magnesium from the gut because of inflammatory bowel disease and chronic diarrhea [35].
In hypercalciuria, calcium promotes the ionization and saturation of crystallization of calcium salts and also binds with stone inhibiting substances such as citrates and glycosaminoglycans there by the events of hypercalciuria induced uroliths. The renal leak from the kidney, resorption from bone and absorption from the gut tends to be key defects in implicating the hypercalciuria individually or in combination with each other. On the other hand, excessive dietary sodium intake predisposes to uroliths by hypercalciuria and hypocitraturia. Moreover, there exists a linear relationship between urinary sodium and calcium levels, which establish a strong relationship to confer the risk of hypercalciuria induced uroliths. In addition to the above all etiological factors, protein overload, and metabolic acidosis are the other possible etiological factors in the pathogenesis of hypercalciuria induced calcium nephrolithiasis. In metabolic acidosis, the high urinary pH favors the formation of calcium-containing uroliths. The excess protein intake can predispose to calcium nephrolithiasis which was evident from the animal, metabolic and epidemiological studies [35].
Hypocitraturia corresponds to about 20-60% of calcium nephrolithiasis. As it is a major inhibitory component of calcium oxalate and calcium phosphate, lowered levels of citrate favours the risk of hypercalciuria induced calcium uroliths. Furthermore, the citrate tends to complex with calcium to form a soluble complex to prevent crystal growth. Hyperoxaluria, is another etiological factor of equal importance with hypercalciuria for inducing calcium nephrolithiasis by promoting the CaOx supersaturation in the urine. It occurs as a result of the dietary intake of oxalate-rich foods of spinach, rhubarb, beetroot, almond, nuts, etc. Hyperuricosuria, as a result of high dietary intake of protein, can attribute CaOx uroliths by the heterogeneous nucleation of uric acid [35].
Struvite Stones
These are also called infectious stones, as a consequence of persistent urease producing bacterial infections. Generally, these urease infections are caused by certain species of bacteria like E. coli, P. mirabilus, Pseudomonas species, Staphylococcal species, and Ureaplasma urealyticum. By secreting the urease enzyme, these bacterial species hydrolyse the urea to carbon dioxide and ammonia which can raise the urinary pH to favour the struvite stones formation. Infectious stones induced by these bacterial infections are caused by urinary tract obstructions due to ureteropelvic junction stenosis, urinary catheters, neurogenic bladder dysfunctioning, vesical ureteral reflux, medullary sponge kidney and distal renal tubular acidosis [35].
Uric Acid Stones
Uric acid stones are clinically evident when there is increased hyperuricosuria, acidic urine, and reduced volume of urine. Indeed the hyperuricosuria along with the aciduria clinically manifests the uric acid stones significantly. While elevated levels of uric acid within normal pH can be tolerated. But hyperuricosuria seems to be the sole cause for uric acid uroliths in rare conditions. The common etiological factors in inducing uric acid uroliths are dietary intake of excess protein food, gout, and recurrent monoarthritis along with acidic urine. Also, high body-mass index, type 2 diabetes, and glucose intolerance are most commonly seen in patients with uric acid uroliths [35].
In particular, obesity and type 2 diabetes conditions, impaired renal ammonium excretion and increased net acid production resulting in aciduria can favor the uric acid uroliths formation when it is associated with hyperuricosuria. The other causative factors like chronic diarrhea, gastroenterostomy, exercise-induced lactic acidosis, and high consumption of animal protein can predispose to acidic urine. Reduced urinary volume occurs as a result of chronic diarrhoea, excessive perspiration and intestinal ostomies can act as contributing factors in attributing the uric acid uroliths. The congenital enzymatic deficiencies, uricosuric agents, gout, myeloproliferative disorders, hemolytic anemia, and chemotherapy-induced tumor lysis acts as the risk factors of hyperuricosuria induced uric acid stones [35].
Cystine Stones
It constitutes of about only the least amount in all types of stones which occurs in individuals having cystinuria, an autosomal recessive disease that affects proximal tubular absorption of cystine. The solubility of cystine is about 243mg/l in normal urinary pH, while the solubility greatly increases by increasing the urinary pH. Moreover, cystine being a poorly soluble amino acid forms, tends to form cystine stones more at lower urinary acidic pH. It has also occurred as an autosomal recessive disorder of ornithine, arginine, and lysine. It affects about 1 in 20,000 individuals especially at the age of 20-30 years. They are presented as staghorn stones which are multiple and radio-opaque [35].
Drug Induced Stones
These constitute the rare forms of stones which are drug induced forms that result from various drugs like indinavir, triamterene, fluoroquinolones, primidone, tetracyclines, magnesium trisilicate, and sulfonamides. In addition to this, other drugs like calcitriol, corticosteroids, furosemide, and acidifiers can predispose the individual to hypercalciuria induced calcium uroliths. In other cases like ascorbic acid and allopurinol therapy, there exist implications of hyperoxaluria and hyperxanthuria induced lithogenesis. Topiramate, a new anti-epileptic drug also implicates the calcium uroliths by its renal tubular acidosis induced by its carbonic anhydrase enzyme. HIV-positive patients are more prone to develop these drugs induced stones when they are treated with lithogenic drugs like indinavir and sulfamides (sulfamethoxazole and sulfadiazine) [35].
2, 8-Dihydroxyadenine Stones
A rare form of stones that results from a very rare form of adenine phosphoribosyl-transferase (APRT) deficiency imherits renal stone disease, progressively ending with renal failure. In APRT deficiency condition, it accumulates large amounts of adenine which then metabolized to nephrotoxic 2, 8-dihydroxyadenine by xanthine oxidase enzyme. Since it is life-threatening, early diagnosis and treatment with allopurinol are needed [38].
Urolithiasis is a consequence of an imbalance between promoters and inhibitors of crystallization in urine [34]. Stone promoters include low urine volume, low urine pH, calcium, sodium, oxalate, and urate while stone inhibitors are citrate, magnesium (inorganic inhibitors) prothrombin fragment, glycosaminoglycans and osteopontin (organic inhibitors) [39].
Prevention
The following measures are opted to be the best suitable preventive measures in the management of urolithiasis [35].
• Increase uptake of water up to 2L daily.
• Maximizing the urinary output.
• Limiting the use of drugs that induce uroliths.
• Minimizing the intake of animal protein.
• Low intake of sodium.
• Lowering the dietary intake of purine and oxalate rich food.
• Limitation of dietary intake of calcium.
CONCLUSION
The urinary system, in any case, is called the renal structure. Kidneys assume such fundamental parts in eliminating unwanted materials and poisons and keeping up with body- wide homeostasis that issues of the kidneys might be dangerous. The steady loss of ordinary kidney work usually happens with various problems, including nephrotoxicity, diabetic nephropathy, polycystic kidney illness (PKD), kidney failure, kidney stones, bladder diseases, urolithiasis, urinary incontinence, and high BP.
ABBREVIATIONS
ARF – Acute Renal Failure
CRF – Chronic Renal Failure
GM - Gentamicin
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In vitro inhibition and dissolution of calcium oxalate by edible plant Trianthema monogyna and pulse Macrotyloma uniflorum extracts. J Cryst Growth 2005; 273: 546-54.[http://dx.doi.org/10.1016/j.jcrysgro.2004.09.038][38]Osborne CA, Lulich JP, Swanson LL, Albasan H. Drug-induced urolithiasis. Vet Clin North Am Small Anim Pract 2009; 39(1): 55-63.[http://dx.doi.org/10.1016/j.cvsm.2008.09.004] [PMID: 19038650][39]Santhoshi B, Chidrawar VR, Rao VUM. A brief review on the potential medicinal plants and screening models of urolithiasis. Int J Appl Biol Pharm Technol 2015; 6(1): 37-45.Screening Models of Nephroprotection, Nephrocurative and Antiurolithiatic Plants
T. Pullaiah,M. RamaiahAbstract
Renal issue stay persistent among the exceptional worldwide medical issues. It's a gradually reformist issue which may cause end-stage renal disease (ESRD). Till date, different screening models have been effectively evolved to reenact human infections, including chronic kidney disease (CKD). In this chapter, screening models for evaluating the biological activity of plant extracts in nephroprotection, nephrocuration and antiurolithiasis are given. This is a single point reference to the researchers.
Introduction
Throughout the most recent forty years, it has become progressively clear that the kidney is antagonistically influenced by a variety of synthetics that man is presented to as prescriptions, modern and ecological synthetic substances, and an assortment of normally happening substances. The degree of openness shifts from minute amounts to exceptionally high portions. Openness might be over a significant stretch or restricted to a solitary occasion, and it very well might be because of a solitary substance or to different synthetics. The conditions of openness might be a coincidental, unplanned, or purposeful excess or remedial need. A few synthetic compounds cause an intense physical issue, while others produce chronic renal changes that may prompt end-stage renal disappointment and renal malignancies. Nephrotoxicants (as remedial medications, mechanical or ecological synthetics) may represent roughly half of all instances of intense and persistent renal disappointment. The essential proportion of kidney work is glomerular filtration rate which springs from serum and urine creatinine fixations. Decrease of glomerular filtration rate (GFR) by half, characterizes CKD in animal models. In any case, GFR can't be dependably assessed in animal models. Consequently, in animal investigations of CKD, huge changes in biomarkers of renal capacity, including blood urea nitrogen (BUN) and creatinine are not just
adequate to evaluate the kidney work. What's more, urinary protein discharge, presence of common entanglements identified with CKD in people like normochromic sickliness, hyperphosphatemia, hyperparathyroidism, hyper kalemia and so forth are the highlights evaluated in animal models of CKD [1].
Different animal models are created utilizing various strategies inside the space of CKD to inexact the human illness. The accompanying subtleties have practical experience in key data on in vivo models of CKD created through unconstrained, obtained and hereditary strategies.
In vivo Animal Models
Spontaneous Models [1]
These models could be created by different metabolic or immunological techniques.
Lupus Nephritis
Advancement of Lupus nephritis by resistant complex-interceded glomerulonephritis is one such model. Mouse models including MRL/lpr and NZB/W have the ability to foster lupus nephritis unexpectedly looking like human histological discoveries identified with CKD. Studies in mouse models of lupus nephritis have been helpful in understanding the essential pathogenesis of immune system kidney infection. Demise because of renal disappointment has been distinguished as a significant end-point of these examinations.
Aging
Since aging can cause movement of renal disability and scarring, rodents of more than two years of age could be utilized as a model of CKD. It is liked to utilize male rodents of this model because of right on time and extreme side effects of scarring than in females.
Spontaneously Hypertensive Rats
These types of rodents are another trial model that can be utilized in research purposes identified with CKD. Biochemical and histopathological highlights identified with CKD could be noticed beginning from the sixth week in immediately hypertensive rodent model.
CKD as a Result of Intense Kidney Injury
The general danger of CKD after a serious scene of ischemic intense kidney injury is valuable in creating animal models of CKD. Long haul interstitial fibrosis and reformist renal inadequacy are the trademark highlights of this model. This model is researched most usually in rodents and mice. Renal fibrosis is clear during the chronic period of the infection.
Intrinsic Insufficiency of Nephrons
Munich Wistar Frömter rodent is a hereditary model with intrinsic insufficiency in nephron number. Their nephron number is 30–50%, not exactly ordinary. These animals are inclined to foster hypertension in adulthood. Munich Wistar Frömter rodents foster proteinuria at ten weeks old enough and display critical glomerulosclerosis by nine months
Acquired Models [1]
Animal models of CKD have been created for utilizing surgical and chemical strategies causing nephrotoxicity.
Surgical Methods
5/6 Nephrectomy
Decrease in renal mass tentatively by subtotal nephrectomy causes reformist glomerulosclerosis and tubulointerstitial fibrosis, related to CKD. It is a simple technique for prompting sickness in bigger creatures like rodents and rabbits. A few strategies are accessible to foster CKD utilizing this model. One methodology is the uninephrectomy followed by ligation of polar parts of the renal supply route. It is a strategy regularly acted in rodents. Another methodology is the careful extraction of around half of the leftover kidney, fourteen days after uninephrectomy. This methodology can be utilized both in rodents and mice. A blend of the over two models, which ties at least one part of the mouse renal vein, and afterward eliminates extra renal mass to accomplish an absolute 5/6 nephrectomy.
The nephrectomy technique is exceptionally subject to careful mastery and consequently the accessibility of working facilities. Since the movement of renal disappointment is firmly connected with the amount of tissue infarcted or extracted, it's identified with moderately enormous between individual and between lab varieties.
Unilateral Ureteral Obstruction (UUO)
This is an in vivo model helpful in analyzing the components of tubulointerstitial fibrosis related to human renal illness. It is feasible to incite this model both in rodents and mice without explicit strain reliance. Decrease in the renal blood stream and glomerular filtration rate is commented inside 24 hrs following kidney deterrent. Interstitial irritation tops at 2–3 days and rounded widening, cylindrical decay and fibrosis start from multi week after UUO. The test model would arrive at the end stage by around fourteen days following the technique.
Animal Models of Chronic Nephrotoxicity [1]
Thinking about the limitations in surgical models, the usage of non-surgical choices that utilize nephrotoxic specialists appear to be gainful. Following are not many models for the animal models created utilizing nephrotoxicants.
Adenine Induced CKD
The advancement of an animal model for CKD dependent on the admission of adenine, was first proposed by Yokowaza in 1982 [2]. Oral intake of adenine blended in with the food at 0.75% w/w was performed for the advancement of the trial model. Adenine and its metabolite, 2, 8-dihydroxyadenine, accelerate in the renal tubules and structure precious stones causing degenerative changes in renal tubules and the interstitium. The utilization of oral adenine causes impediment of renal tubules, which hinders the discharge of nitrogenous substances. This prompts morphological, biochemical and histopathological changes in kidneys looking like CKD in people. Grown-up creatures create hyperphosphatemia, auxiliary hyperparathyroidism, bone infection, and vascular calcification following oral administration of adenine.
High dreariness and mortality were seen in the above cases because of starvation and unhealthiness as opposed to renal disappointment in animals. As an answer, Adenine is blended in a casein-based chow, in which the casein successfully eliminates the natural smell and taste of adenine.
Another new model is for the enlistment of CKD by means of intraperitoneal adenine to defeat the high bleakness and mortality. It is by all accounts a better model than oral adenine administration for the acceptance of CKD since it is more common-sense, advantageous and exact because of the direct passage of the medication to the fundamental course. Adenine model is a superior option for the careful models of CKD because of a few reasons. It is a helpful strategy which can be utilized to initiate renal disappointment, with almost no between singular varieties throughout a brief timeframe. The level of decrease in renal capacity is additionally generally homogeneous.
Adriamycin Induced CKD
Adriamycin (doxorubicin) is an anthracycline drug utilized in malignant growth chemotherapy. It is a cytotoxic anti-infection secluded from societies of Streptomyces peucetius var. caesius. It is a notable inducer of renal injury in rodents, which mirrors the highlights in human CKD. Adriamycin isn't fundamentally used and is collected mostly in the kidney causing nephrotoxicity. The ideal portion of Adriamycin which may demonstrate nephrotoxicity relies upon species, strain, sexual orientation, age, source and bunch of the exploratory creatures. The ideal course of administration in a large portion of the examinations is intravenous utilizing the tail vein. Not withstanding, skin putrefaction in case of tissue extravazation is a fundamental entanglement related to tail vein infusion. Substernal intracardiac approach, intrarenal course, direct infusion of the renal vein and intraperitoneal organization are different courses of organization. Despite the fact that intraperitoneal organization is a simple technique to manage the medication, because of variable assimilation through the peritoneal layer and irregularity in acceptance of renal injury contrasted and the intravenous course makes this strategy less ideal. Male rodents are more helpless than female rodents to Adriamycin prompted nephropathy. Adriamycin actuated nephropathy model is an exceptionally reproducible model of renal injury with adequate mortality and dismalness.
Diabetic Nephropathy
Diabetic nephropathy is a significant reason for human CKD. A few mouse models have been created to summarise the pathogenesis of diabetic nephropathy. The pancreatic β-cell poison streptozotocin (STZ) is regularly used to display Type 1 diabetes to foster nephropathy in trial models. Primary similitude among glucose and STZ brings about transportation of STZ into pancreatic β-cells, with ensuing obliteration prompting hyperglycaemia. Mice are infused with a higher portion of STZ on sequential days because of their protection from STZ than in rodents. Further, Akita mice are utilized to foster type 1 diabetes mellitus. An unconstrained point change in the Akita mice prompts misfolding of insulin, coming about in pancreatic β-cell disappointment. This may bring about supported hyperglycaemia with significant degrees of albuminuria and nephropathy related renal histopathological changes.
Other Models of Chronic Nephrotoxicity
Poisons, heavy metals and natural medications are accounted for as possible reasons for CKD in people. Backing for the above discoveries came as few animals considered were incited by nephrotoxic renal illness. Folic corrosive and aristolochic corrosive nephropathy are two such models which cause intense kidney injury which will arrive at interstitial fibrosis. Intraperitoneal administration of nutrient folic corrosive during a high measurement (250ug/g BW) might be a typical strategy for prompting inconsistent interstitial fibrosis inside the persistent stage (28–42 days). Intraperitoneal infusion of aristolochic corrosive week after week has prompted reformist fibrosis and renal disappointment seriously in male mice inside the investigations, including this model. The outcomes were practically similar to the discoveries in adenine initiated models. Future utilization of cyclosporine A can prompt renal fibrosis in humans. On the side of this hypothesis, a rodent model has been created by controlling cyclosporin A (7.5 mg/kg/day and 15 mg/kg/day s.c.) for multi day time frame inside the examinations including CKD.
Cisplatin (cDDP; cisdiamminedichloroplatinum II) is another powerful antitumor specialist utilized in the treatment of strong tumors. Nephritic impedance is the principal genuine antagonistic outcome revealed in patients treated with cisplatin. These discoveries have intersection rectifier to the occasion of cisplatin inspired harmful models for the trials on CKD. The salt eating routine evoked model is another solid decision. Dislike in oral purine organization, salt is immediately ingested by mice. Further, the proportion of urinary salt discharge is useful in exact watching of dietary admission. A brief period of time (one to three weeks) for the enlistment of cutting edge CKD might be an additional benefit of this model.
Radiation Nephropathy
Animal models with nephropathy could be produced by therapeutic irradiation. Nonetheless, the chance of instigating illness is less (20%) contrasted with different techniques for acceptance. Intense endothelial wounds, persistent reformist optional sclerosis with corresponding tubulointerstitial fibrosis are the trademark highlights of radiation nephropathy.
Model for Assessing the Nephroprotective Activity
Adesia [3] has given details of methods for assessing the nephrotoxicity, which are given below.
Biochemical Parameters
The nephroprotective action can be evaluated utilizing different biochemical parameters like ALT, AST, ALP, total protein, serum bilirubin, and serum antioxidant enzymes alongside histopathological investigations of kidney tissue which are given underneath.
Experimental Animals
Male or female Wistar rats, weighing somewhere in the range of 150 and 200 g are to be utilized for the nephroprotective action. The rats are housed in polypropylene confines and kept up at 24 ± 2 °C under 12 h light/dull cycle and took care of not indispensable with standard pellet diet and ought to have free admittance to water. They are at first accustomed for the investigation convention and study convention is to be supported by the Institutional Ethical Committee according to the necessities of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), India or according to the Organisation for Economic Co-operation and Development (OECD/OCDE) or NIH guidelines. Prior to directing the trial, ethical clearance must be gotten from the Institutional Animal Ethical Committee of the Institution where the work is being completed.
Acute Oral Toxicity Studies
Wistar male albino rats 150–200 g are kept up under standard husbandry conditions, and are utilized for all arrangements of trials. The acute oral toxicity study is to be completed according to the OECD rules, got draft rules 423, got from CPCSEA, Ministry of Social Justice and Empowerment, Government of India. Animals are permitted to take standard research center feed and faucet water.
Evaluation of Nephroprotective Activity by Animal Model
In the Paracetamol-initiated kidney injury model, Paracetamol (2 g/kg) suspension utilized 0.1% Tween 80, is regulated to all animals with the exception of cotrol group. Cystone (100 mg/kg p.o.) is utilized as a norm. The animals are isolated into six gatherings of six each. Group 1, which filled in as should be expected control getting 1.5% Tween 80. Gathering/group 2 got paracetamol (2 g/kg, p.o.) single portion on sixth day. Gathering 3 got synthetic (2 g/kg, p.o.) single portion and cystone (100 mg/kg, p.o.) all the while for 7 days. Gathering 4, 5, and 6 got substance (2 g/kg, p.o.) various dosages and plant separate (100, 200, 300mg/kg, p.o.) all the while for 7 days. On the seventh day of the beginning of separate treatment, the rodents are anesthetized by light ether sedation and the blood is removed from retro orbital plexus. It is permitted to coagulate for 30 min and serum is isolated by centrifugation at 2500 rpm. The serum is utilized to appraise serum glutamate pyruvate transaminase, serum glutamate oxaloacetate transaminase, and ALP.
Assortment of Blood Tests and Planning of Post-Mitochondrial and Microsomal Parts of Kidney Samples
Prior to the end of the investigations, rodent feed is removed to quick the rodents and their sheets changed. Be that as it may, drinking water is given not indispensable. Rodents are forfeited by cervical disengagement. Blood tests are gathered via cardiovascular cut into heparinized cylinders and kidneys promptly eliminated, washed in super cold 1.15% KCl, smudged, and gauged. The kidneys are then minced with scissors in 3 volumes of super cold 100 mM potassium phosphate cradle, pH 7.4 and homogenized in a Teflon homogenizer. The homogenates are later centrifuged at 12,500 g for 15 minutes at 4oC and the supernatants termed the postmitochondrial fractions (PMF) is taken and recentrifuged at 100,000g for 1hr using the L5-50B ultracentrifuge Beckman to get the microsomal pellets which are resuspended in 0.25M sucrose solution. Aliquots of this suspension are stored at -20oC and thawed before use.
Renal Function Tests
Plasma Creatinine Estimation
Creatinine responds with basic picric acid to the structure a red tautomer of creatinine picrate. Absorbance is corresponding to concentration of creatinine [4]. 3.5 mL of picric acid in a test tube is added 0.5 mL of plasma test. The blend is centrifuged for 5 minutes. To 3 mL of the supernatant is added 0.2 mL of 4N NaOH. This response blend is hatched for 10 minutes and the absorbance is then perused at 520 nm and the creatinine concentration decided.
Blood Urea Nitrogen Estimation
Measurement of plasma urea is by the technique for Weatherburn [5] utilizing diagnostic Randox Kit. The standard of this response depends on the condensation of diacetyl with urea to frame the chromogen, diazine. Since diacetyl is unsteady, it is normally produced in the response framework from diacetyl monoxime. The response of diacetyl and urea gives diazine which absorbs firmly at 540 nm. Thiosemicarbazide and Fe (III) are added to the framework to upgrade and settle the shading. Test in copy, (0.1 mL) is added into a widespread container containing 19.9 ml of distilled water and the combination is shaken quite well. Aliquot of the combination is moved into a test tube and to it is added 1 mL of shading reagent followed by 1 mL of acid reagent. The blend is warmed in bubbling water shower for 20 minutes. It is then cooled and the absorbance read at 520 nm against blank. The concentration of urea in mg/100 mL is then calculated from a calibration curve.
Determination of Catalase Activity
Catalase activity is measured by the technique for Sinha [6]. This strategy depends on the way that dichromate in acetic acid is reduced to chromic acetic acid derivation when warmed within the sight of H2O2, with the development of perchromic acid as an unsteady transitional. The chromic acetic acid derivation at that point created is estimated colorimetrically at 570-610 nm. The catalase arrangement is permitted to part H2O2 for various periods. The response is halted at a specific time by the expansion of dichromate/acidic corrosive blend and the leftover H2O2 is controlled by estimating chromic acetic acid derivation colorimetrically subsequent to warming the response combination.
Colorimetric determination of H2O2: Various volumes of H2O2, going from 10 to 100 mmoles are taken in little test tubes and 2 mL of dichromate/acetic acid is added to each. The expansion of the reagent momentarily delivered a flimsy blue accelerates of perchromic acid. Resulting warming for 10 minutes in a bubbling water shower changed the shade of the answer for stable green because of the development of chromic acetic acid derivation. Subsequent to cooling at room temperature, the volume of the response blend is made to 3 mL and the optical density estimated with a spectrophotometer at 570 nm. The concentrations of the standard Vs absorbance were plotted.
Determination of catalase activity of samples: 1 mL of the test sample is mixed with 49 mL of distilled H2O2 to produce 1 in 50 dilutions of the sample. The test combination contained 4 mL of H2O2 (800 µmoles) and 5 mL of phosphate buffer in a 10 mL flat bottom flask. Mix rapidly, diluted enzyme preparation (1 mL) with the reaction mixture by a twirling movement. The response is had at room temperature. A 1 mL segment of the response combination is removed into 2 mL dichromate/acetic acid reagent at 60 seconds spans. The hydrogen peroxide substance of the removed sample is measured by the technique depicted previously.
Determination of Superoxide Dismutase (SOD) Activity
Superoxide dismutase activity is determined by the method of Misra and Fridovich [7]. This technique is based on the inhibition by superoxide dismutase, of the spontaneous autoxidation of adrenaline to adrenochrome at pH of 10.2 [8]. The reaction is performed at 30oC in 1 mL of 50 nM sodium carbonate buffer, pH of 10.2 having 0.3 mm adrenaline and 0.1 mm EDTA. The amount of enzyme required to block the change in absorbance at 480nm by 50%. 1 mL of sample diluted in 9 mL of distilled water to produce a 1 in 10 dilution is known as one unit of activity. 0.2 mL of the diluted sample is mixed with a 2.5 mL of 0.05M carbonate buffer at a pH of 10.2 to equilibrate in the spectrophotometer and the reaction initiated by the adding a freshly prepared 0.3 mL adrenaline to the mixture which is quickly mixed by inversion. Blank having 0.3 mL of adrenaline substrate, and 0.2 mL of distilled water. The increment in absorbance at 480 nm is checked at regular intervals for 150 seconds.
Determination of Reduced Glutathione Level
The technique for Beutler et al. [9] can be adopted in determining the degree of diminished glutathione (GSH). The diminished type of glutathione involves in many occasions the heft of cell non-protein sulfhydryl groups. This technique is hence founded on the advancement of a generally steady (yellow) shading when 5′, 5′-dithiobis - (2-nitrobenzoic corrosive) (Ellman's reagent) is added to sulfhydryl compounds. The chromophoric item coming about because of the response of Ellman's reagent with the diminished glutathione, 2 – nitro-5-thiobenzoic corrosive has a molar assimilation at 412 nm. 0.2 mL of test is added to 1.8 mL of distilled water and 3 mL of the precipitating solution is blended in with test. The combination is then permitted to represent around 5 minutes and afterward separated. Toward the finish of the fifth moment, 1 ml of filtrate is added to 4 mL of 0.1M phosphate support. At long last 0.5 mL of the Ellman's reagent is added. A clear is set up with 4 mL of the 0.1M phosphate support, 1 mL of diluted precipitating solution (3 sections to 2 pieces of refined water) and 0.5 mL of the Ellman's reagent. The optical density is estimated at 412 nm. GSH fixation is relative to the absorbance at that frequency and the gauge is acquired from the GSH standard.
Estimation of Glutathione-S-Transferase Activity
The estimation can be done by the method proposed by Habig et al. [10]. The rule depends on the way that all known glutathione-S-transferase exhibit a generally high action with 1-chloro-2, 4,- dinitrobenzene as the subsequent substrate, thusly, the customary measure for glutathione-S-transferase activity uses 1-chloro-2, 4,- dinitrobenzene as a substrate. At the point when this substance is formed with diminished glutathione, its ingestion greatest movements to a more extended frequency. The ingestion increments at the new frequency of 340nm give an immediate estimation of the enzymatic response. The mechanism for the assessment is arranged and the response is permitted to run for 1 moment each time before the absorbance is perused against the blank at 340 nm. The absorbance is estimated utilizing UNICAM Spectrophotometer.
Determination of Lipid Peroxidation
As per the method of Varshney and Kale [11
