Abstract: Renal calculi are crystalline structures of calcium oxalate with associated risk factors like dehydration, high fat diet, animal protein, high salt intake and obesity. Crystals form in the distal tubule, nephron loop and/or collecting tubule have symptoms of severe pain and renal colic. Nephrolithiasis is a global problem affecting all geographical regions. This study compiles the epidemiology of renal calculi focusing on prevalence, occurrence and re-occurrence rate in global perspective. Literature of nephrolithiasis prevalence has been reviewed for Europe, Canada, American, East Asia, Gulf region, Japan, China and different parts of India. Etiology of nephrolithiasis was reviewed in detail for types, factors, symptoms, promoters and inhibitors. Renal calculi induction and progression mechanism was discussed with pathophysiology involved. Water and Food are directly related to occurrence of renal calculi, as a major concern correlation has been discussed. Depending on the type of renal stone, food which are to be avoided and preventive actions were discussed. Concise information was provided on the different experimental models of nephrolithiasis induction in animals. Understanding the pathophysiology of this disorder is necessary for the development of new therapeutic options and treatment. Nephrolithiasis is associated with chronic kidney dysfunction, bone loss and fractures, increased risk of coronary artery disease, hypertension, type 2 diabetes mellitus etc. and understanding the pathophysiology is necessary to develop highly effective drugs.
INTRODUCTION
The formation of kidney stone is also known as renal calculi or crystal. It is a serious though not life threatening disorder prevalent throughout the world. In medical terminology condition of having urinary calculi is termed as nephrolithiasis and urolithiasis where the root word "Lith" meaning "a stone"1. Nephrolithiasis is common worldwide, often debilitating that has different etiology and pathophysiology. Copiousness of promoter and inadequacy of inhibitors mainly promote production and retention of crystals in renal tubules2,3. Renal calculi are crystalline structures composed most commonly of calcium oxalate salts. They form when the concentrations of these ions, as well as solutes such as hydrogen ions, sodium ions and uric acid are present in the filtrate in higher than normal amounts. This condition is known as supersaturation and supersaturated ions are more likely to come out of solution and crystallize. Risk factors for supersaturation include dehydration, high fat diet, animal protein, high salt intake and obesity.
Typically, the crystals form in the distal tubule, nephron loop and/or in collecting system. Most crystals simply pass unnoticed into the urine. However, sometimes the crystals adhere to the epithelium of the tubules, particularly in the collecting system and form seed crystals that lead to the formation of stones. The stones may remain in the collecting system or may break off and lodge in the calyces, renal pelvis and ureter. Stones lodged within the urinary system cause occurrence of common symptom of nephrolithiasis, severe pain and renal colic that radiates from the lumbar region to the pubic region. Other symptoms include hematuria (blood in the urine), sweating, nausea and vomiting. Nephrolithiasis can be diagnosed in several ways, including computed tomography scans and an intravenous pyelogram. An IVP is a radiograph of the urinary system that uses a contrast medium such as iodine to reveal the structure of the renal pelvis, the major and minor calyces, the ureters and urinary bladder. The old Sanskrit literatures in India, the Vedas, the Puranas and the Samhita described first time about renal calculi and their remedies. The Chark Samhita had explained anatomy, physiology and pathology of renal calculi in Mutravahaashmari with diagnosis and its treatment. The Sushruta Samhita had also focused about surgery with descriptive explanation and type of renal calculi, characteristics of renal calculi, etiology and symptoms in Ashmari Nidana with scientific description and explained renal calculi treatment in Ashmari Chikitistia Sthanam4,5.
Renal calculi is perceived as acute disorder but the growing stage of urolithiasis is a systemic disease that can lead to end stage renal disorder. The prevalence is increasing due to environmental cause and genetic predisposition6. On an average 6% woman and 12% men are affected with renal stone7. Recurrence rate of nephrolithiasis is 70-80% in males and 47-60% in females, with majority 80% of calcium oxalate stones8,9.
URINARY SYSTEM
The urinary system is a group of organs that consists of two kidney and ureters with single bladder and urethra. This system mainly filters the blood stream excrete out the unwanted fluid and other substance through urine. Urine is liquid containing excess mineral or vitamins with waste product of metabolism. Urinary system along with other organ systems maintains homeostasis with acid base balance and water salt balance of blood.
Different function of urinary system:
| • | Excretion or elimination of metabolic waste product |
| • | Regulation of fluid volume |
| • | Regulation of different electrolytes |
| • | Maintain the pH of blood |
| • | Homeostasis maintenance |
| • | Elimination of toxins |
| • | Separation of urea and mineral salts |
| • | Mineral and salt balance |
RENAL CALCULI
A renal calculus is a solid crystalline mineral material that accumulate in the urinary system when one more crystal forming material separates from the supersaturated urine. Renal calculi results from the growth of crystal to form in to large lumps or aggregate of crystals or in to stone10. Primary component of renal calculi is salt, mineral and other constituents found in urine. Renal calculi grow slowly over several days to month. Renal calculi are found in different sizes, some are as small as like grain of sand or large as pearls and big as golf boll. Renal calculi sometime cover entire pelvis area of urinary system. They are smooth, spiky or asymmetric and jagged. Renal stone are mainly found in three colors as brown, yellow and reddish. Passing of renal calculi produces discomfort and the level of uneasiness depends upon the size of renal calculi. Tiny renal calculi may pass unnoticed with urine. Often renal calculi’s grows to large size, that passing through urinary tract is noticed with some discomfort but if it is renal stone with rough or sharp edges it can be painful white passing through the urinary system. In some cases of nephrolithiasis renal calculi cannot pass through the urinary system requiring medical intervention. If neglected it leads to substantial damage and produces several types of renal impairment11.
Epidemiology of renal calculi: Kidney stone is one of the oldest recorded disorder of human and one of the major health burden. Now a days large number of peoples are affected with this disorder all over the world. Three common terms used in epidemiological study of renal calculi is incidence, prevalence and life time prevalence. The definition of incidence is the number of new renal stone patients found in a selective population at a particular time point. Prevalence is the total number of renal stone patients in a selective population at a particular time point and life time prevalence is the presence of old nephritic stone in number of patient. Nephrolithiasis is a common disorder responsible for significant human suffering as per studies and surveys done over the last half century reporting steadily increasing cases7,12.
Nephrolithiasis is a global problem affecting all geographical regions throughout the globe. Annual approximate prevalence is 3-5% and approximate life time prevalence is 15-25%. Nephrolithiasis tend to be recurrent in most of the renal calculi patients. Recurrence rates of renal stone are approximately 10% year–1, 50% over a period of 5-10 years and 75% over 20 years period11. The incidence rate of nephrolithiasis varies with geographical region of an individual country. The rate of recurrence of renal calculi in patients after 1st time occurrence is 14% at 1st year, 35% in 5th year and 52% in 10th year13.
The comparative incidence of renal calculi in adults are higher in Western region as compared to Eastern region of the world. The risk rate of prevalence as reported throughout the globe is Saudi Arabia 20.1%, USA 13-15%, Canada 12% and Europe 5-9%14,15. This era of globalization is witnessing increase cases of acute renal injury and emerging epidemic of renal calculi among all age groups including children of East Asia mainly Macau, Taiwan, Hong Kong and China due to the use of different type of milk and milk product, like milk powder, melamine-tainted milk, cookies, candies and chocolates16. In the year 2008 approximate 2.9 lakhs cases were diagnosed with renal stones, including children below age of 3 year17. High incidence rate is reported in middle east (20-25%) due to hot climate with increased chances of dehydration18. In Japan, minimum 5.4% of the population have at least one time affected with renal calculi in their life time provided by the data of 1995-1987 nationwide survey on nephrolithiasis6.
The countries with alarming occurrence rate of nephrolithiasis is British island, central Europe, North Australia, Scandinavian and Mediterranean countries. The stone forming belt of the world is identified as Egypt, Sudan, Saudi Arabia, Iran, UAE, Philippines, India, Pakistan, Thailand, Myanmar and Indonesia with cases of renal calculi in all age group including child below 1 year of age and adults over 70 years with a male to female ratio19 of 2:1. Almost one million people in USA is affected with renal calculi and visit emergency department annually with an economic impact20 of approximately 2.1-5.3 billion US$. In last decades, an increase of almost 50% was observed in diagnosis and treatment cost of nephrolithiasis21. North American children have 5 time increased prevalence of pediatric nephrolithiasis in last 10 years. Incidence of nephrolithiasis varies in different region of USA but is mostly found in South Eastern states as like North Carolina, Virginia, Georgia, Tennessee and Kentucky and has a combined name as stone belt of North America22. Approximately 7.5 lakh cases of renal calculi were found in Germany between 1979-2000 suggesting a continuously increasing trend in renal stone occurrence and approximately three-fold prevalence in population aged between 50-64 years12,23. Studies in UK identified and suggested that due to change of life style and diet, a gradually upward tendency in annual incidence and downward in the age of onset for nephrolithiasis has been observed24. Swedish renal stone studies based on epidemiology, showed recurrence rate of 70% after 10 years on the patients previously having minimum two renal calculi before the follow up period25.
Approximate 2 million people in India is affected with nephrolithiasis every year and some parts of country has name denoted as a stone belt that is, Gujarat, Maharashtra, Punjab, Rajasthan, Delhi, Haryana and part of states on North East side26. Urinary stone are also found in south India due to high intake of tamarind in regular diet27. In upper urinary tract urolithiasis is found mainly in the form of pure calcium oxalate crystals as observed in case studies of AIIMS, New Delhi28,29. The Kutchchh and Saurashtra region of Gujarat also has higher prevalence of renal calculi. In India, approximate 50% of the population is affected with renal calculi, which may end up to renal damage or loss of kidney function30. The rate of nephrolithiasis incidence, mainly staghorn calculi is very high in Manipur and some reports indicates North Western region of India have also increased prevalence31. North Eastern part of Bihar in Purina division showed increase renal stone cases during 1999-200132. In the last few decades occurrence of pediatric renal calculi cases were observed in some epidemiological studies33.
ETIOLOGY OF RENAL CALCULI
Generally, nephrolithiasis is more common in male as compare to female, mainly six type of stones are found as calcium oxalate containing stone, calcium phosphate containing stone, cystine containing stone, uric acid stone, xanthine and struvite containing stone. Main causes of nephrolithiasis are hypercalciuria, hyperoxaluria, hypocitraturia, hyperuricosuria, hypomagnesuria, gouty diathesis, etc.
Type of renal calculi:
| • | Calcium oxalates stone are crystalline component of calcium oxalate monohydrate, calcium oxalate dihydrate and calcium oxalate trihydrate |
| • | Calcium phosphate stone have crystalline components like hydroxyapatite, calcium hydrogen phosphate, dihydrate, unusual form of calcium phosphate, tricalcium phosphate, ammonium magnesium, phosphate hexahydrate, ammonium magnesium, phosphate monohydrate, magnesium hydrogen, phosphate trihydrate, carbonate apatite and octacalcium phosphate. Calcium oxalate and calcium phosphate stones are prevalent with abnormality in urinary system like hypercalciuria, hypomagnesuria, hyperuricosuria, hyperoxolourea and hypocitraturia |
| • | Uric acid stone are crystalline components of uric acid anhydrous and uric acid dehydrate, usually 5-10% of analyzed population with renal stone are affected with uric acid stone. Uric acid is a metabolic product and around 25% of patients with this stone also suffer from gout disorder. Main reason of this type of stone is low urine volume, hyperuricosuria and acidic urine pH |
| • | Cystine stone are caused due to high level of essential amino acid, cystine in urine. Cystine stone usually occur in childhood and it is a rare inherited metabolic disorder affecting 1-3% analyzed population of renal stone |
| • | Struvite stone are infectious urinary stone of ammonium magnesium phosphate hexahydrate or struvite. It is a fascinating inorganic phosphate mineral closely associated with chronic urinary tract infection due to some microorganism such as urease-producing bacteria. This bacterium split urea in to ammonium which is combined with magnesium and phosphate |
| • | Medication caused renal stone are formation of renal calculi due to inappropriate large dose ingestion of drugs like ephedrine, ciprofloxacin, guaifenesin, indianvir, nelfinavir, oxypurinol, sulfa drug, topimarate and triamterene34 |
Urinary calculi promoters: Calcium, sodium, oxalate, uric acid, urate and cystine.
Urinary calculi inhibitors: Magnesium, potassium, pyrophosphate, citrate, glycosamino glycans kidney proteins such as nephrocalcin, osteopontin, tamm-horsfall protein, muco-protein, uropontin, crystal matrix protein, renal lithostathine, urinary prothrombin fragment 1, bikunin (inter-alpha inhibitor) and calgranulin. Citrate is the main complexer for calcium ions in the urinary track.
Nephrolithiasis induction: Nephrolithiasis get started with super saturation of urine caused by various reasons as age, sex, climate, diet, fluid intake, inheritance, etc. Super-saturation initiates abnormality in kidney morphology, change in urine flow, metabolic abnormality and urinary tract infection. The oxalate ion interacts with tubular cell of kidney and in this process mitochondria starts lipid signaling. Lipid signaling produces free radical provoking necrosis of renal cell, increase in stone formation and decrease in crystallization inhibitor induces nucleation process. Crystal are activated and a change in different physiochemical reactions produces aggregation and retention of crystal in renal tubule. Crystals are converted to osteoponin or concrete stone in chronic cases3.
Factor affecting nephrolithiasis occurrence
Age and sex: Most vulnerable age for nephrolithiasis occurrence is 20-70 years. It is widely occurred in men as compared to women.
Diet: High content of protein, sodium and low level of calcium increases the risk of nephrolithiasis.
History of family: Family history of nephrolithiasis increased risk of the nephrolithiasis occurrence.
Dehydration: Nephrolithiasis predisposes with excretion of concentrated urine.
Hypertension: Hypertension increases the risk of the nephrolithiasis.
Obesity: Increase in Body Mass Index (BMI) also has increased risk of kidney stone.
Inflammatory bowel diseases and gastric bypass surgery: They affect the absorption of the calcium ion and increases the precipitation of calcium and other stone forming substance which causes nephrolithiasis35.
Drug: Loop diuretics, antacids, acetazolamide, glucocorticoids, theophylline, vitamins D and C etc., has incidental correlation with occurrence of renal calculi.
Symptoms of renal calculi:
| • | Discomfort in the side and back and below the ribs. This discomfort usually occur only on the side of the renal calculi and does not cross over to the other side |
| • | Fluctuations in discomfort intensity, with periods of discomfort lasting 20-60 min |
| • | Discomfort waves radiating from the side and back to the lower abdomen and groin |
| • | Bloody, cloudy or foul-smelling urine |
| • | Discomfort, pain and inflammation on urination |
| • | Nausea and vomiting |
| • | Persistent urge to urinate |
| • | Fever and chills if an infection is present |
Nephrolithiasis that do not cause these expressions may show up on x-rays when the patients seek medical care for other complications, such as blood in the urine or reappearing urinary tract infections.
RENAL STONE FORMATION MECHANISM
Step 1-5: Initially homogeneous nucleation starts which progress to heterogeneous nucleation causing oxalates crystal formation following that membrane phospholipids redistribution occurs.
Step 6: Oxalate induces redistribution of phospholipid phosphatidy serine in renal cell surface. Macrophages remove and engulf damaged cells36. Which serves as a calcium oxalate crystal binding site triggering other membrane linked enzyme activity37 (Fig. 1).
Step 7: The cytosolic phospholipase A2 (cPLA2), is a highly attentive phospholipase enzyme that hydrolyze the acyl group in sn-2 position of phospholipids. Arachidonic acid and assorted lyso-phospholipids are some of the many by products of cytosolic phospholipaseA2 which can trigger other signaling pathways in the cell38. Arachidonic acid and assorted lyso-phospholipids implicate renal epithelial cell injury39. Patients suffering with active renal calculi show elevated plasma and red blood cell membrane arachidonic acid40.
Step 8-9: In the renal epithelial cell culture oxalate exposure directly causes activation of cytosolic phospholipase A2 (cPLA2) and implicate oxalate action like change in mitochondrial function and gene expression through by product of cytosolic phospholipase A2 (cPLA2) (arachidonic acid and lyso-phosphatidylcholine)41,42.
Step 10-11: Generation of ceramide depends upon activation of cytosolic phospholipase A2 and oxalate induced cytosolic phospholipaseA2 activation43. The following different cellular responses are membrane damage, cellular injury, proliferation, cytotoxicity and renal cell damage produced by signaling molecule44.
Step 12-15: Reactive Oxygen Species (ROS) also promote cell membrane damage unmasking additional crystal binding sites, attached crystals form centers for nucleation of new crystals favoring stone development. Crystals up taken by endocytosis exacerbate cell damage. Alternatively, crystals may dissolve within lysosomes or re-emerge at the basolateral surface, again providing centers for stone growth in the renal interstitium. Cell death produced by oxalate exposure may leave cellular debris that forms a nidus for additional crystal growth, also promoting stone formation42.
DIET IN RELATION TO KIDNEY STONE
Presence of highly concentrated calcium, oxalate and phosphorus containing substances in urine can cause formation of kidney stones. Waste products of the food in the bloodstream are carried to the kidneys and excreted in urine. Diet and fluid intake are important factors out of several other factors that can promote or inhibit kidney stone formation. In susceptible persons, certain foods can promote stone formation but commonly not related to people who are not susceptible. The first step in prevention of kidney stones is to understand the causes and types of stone formed. Laboratory analysis of stones as it passes in urine or retrieved surgically or with a scope inserted through the urethra intothe bladder or ureter gives direct indication of type of stone. Blood and urine are to be tested for unusual levels of chemicals, such as calcium, oxalate and/or sodium to determine type of kidney stone. The information related to type of stone helps the health care provider to suggest diet changes that can prevent future kidney stone growth. Depending on the type of kidney stone, changes in consumption of sodium, animal protein, calcium, citrate, potassium and oxalate are to done.
| Fig. 1: | Intracellular and extracellular events in calcium oxalate stone formation |
For example, limiting oxalate in the diet may help prevent calcium oxalate stones but may not be helpful in preventing uric acid stones. Following a special diet may be enough to prevent forming more kidney stones in early diagnosed cases and for chronic cases medications in addition to a special diet is needed.
High risk food: The risk of kidney stones increases with increased daily sodium consumption. High-sodium diet can trigger kidney stones as it increases the amount of calcium in urine as extra sodium causes to lose more calcium in urine. Low-sodium diet is recommended for the calcium oxalate or calcium phosphate stone prone. Instead of reducing calcium intake, focusing on limiting the sodium paired with calcium-rich and oxalate-rich foods will be beneficial. Current guidelines suggest limiting total daily sodium intake to 2,300 mg. Patients with calcium oxalate or calcium phosphate stones should limit their sodium intake to the U.S. RDA level, along with medications. Canned or commercially processed foods as well as restaurant-prepared and fast foods are sources of "Hidden" sodium. Getting too little dietary calcium can also cause oxalate levels to rise in blood. To prevent this, the amount of calcium should be appropriate to age group. More than 50 years older people should consume 1,000 mg calcium day–1, along with 800-1,000 IU of vitamin D to help the body absorb the calcium.
Animal protein, such as red meat, poultry, eggs and seafood have high concentrations of purine. High purine intake leads to a higher production of uric acid that can accumulate as crystals in the joints, or as stones in the kidneys. A high-protein diet also reduces levels of citrate, that helps prevent kidney stone forming. To prevent occurrence of common type of uric acid kidney stones, it is necessary to cut down high-purine foods and follow a healthy diet containing mostly vegetables, fruits, whole grains and low fat dairy products. Limiting sugar-sweetened foods and drinks containing high fructose corn syrup and alcohol is also helpful because these can increase uric acid levels in the blood. Eating less animal-based protein and eating more fruits and vegetables will help decrease urine acidity and this will help reduce the chance for stone formation.
Calcium oxalate kidney stones are the leading type of kidney stones. Oxalate is naturally found in many foods, including fruits and vegetables like beets, chocolate, spinach, rhubarb, tea and most nuts are rich in oxalate and colas are rich in phosphate, both of which can contribute to kidney stones. The persons prone to suffer from stones are advised to avoid these foods or to consume in smaller amounts. Some research suggests that limiting high oxalate foods may help reduce chance of forming further oxalate stone. Eating and drinking calcium and oxalate-rich foods together during a meal is a better approach than limiting oxalate entirely because oxalate and calcium are more likely to bind in the stomach and intestines before the kidneys begin processing thus making it less likely that kidney stones will form45.
Fluid consumption: Changes in fluid intake help prevent kidney stones. Drinking enough fluids each day is the best way to prevent most types of kidney stones by keeping urine diluted and flushing away materials that might form stones. Health care providers recommend 2-3 L of fluid intake per day but people with cystine stones may need to drink even more. Water is best but other fluids such as citrus drinks also help prevent kidney stones. Some studies suggest citrus drinks like lemonade and orange juice protect against kidney stones because they contain citrate, which stops crystals from growing into stones. Citrate in the urine may prevent the calcium from binding with other constituents that lead to stones. In hotter weather, patients are required to drink more water to make up for fluid loss from sweating. For normal population, particular foods and drinks are unlikely to trigger kidney stones unless consumed in extremely high amounts. Some studies have shown that consumption of high quantity vitamin C in the form of supplements put at slightly higher risk of kidney stones as body converts vitamin C into oxalate. Caution should be exercised with consumption of vitamin C, vitamin D, fish liver oils or mineral supplements containing calcium since these supplements can increase the chances of stone formation in some people. The B6 may actually help people with high urine oxalate46.
EXPERIMENTAL NEPHROLITHIASIS INDUCTION
Nephrolithiasis can be induced in rodents by induction of acute or chronic hypercalciuria, hyperoxaluria, hypocitraturia, hyperuricosuria or hypomagnesuria by using a variety of inducing agent like ethylene glycol with ammonium chloride, glycolic acid and sodium glyoxylate, ethylene glycol 0.75% v/v along with ammonium chloride 2% w/v oral–1 in drinking water is used as common nephrolithiasis inducing agent47,48. Diet containing 3% glycolic acid given for 28 days induces nephrolithiasis49. Glyoxylate induced calcium oxalate (CaOx) crystal in mouse kidney models is also reported by Liang et al. 50 and Peng et al. 51.
CONCLUSION
Nephrolithiasis remains life threatening disorder and cover almost all regions of the world. Exhaustive understanding of this disorder is necessary as lot of factors can induced this disease. Some drugs are associated with induction of nephrolithiasis. Understanding the pathophysiology of this disorder is also necessary for the development of new therapeutic options or treatment. This disorder is associated with chronic kidney dysfunction, bone loss and fractures, increased risk of coronary artery disease, hypertension, type 2 diabetes mellitus and the metabolic syndrome. In India though nephrolithiasis is a commonly prevalence disease but pharmacotherapy is neglected emphasizing the need to develop highly effective drugs for treatment of nephrolithiasis.
SIGNIFICANCE STATEMENTS
Nephrolithiasis is a global problem affecting all geographical regions. Renal calculi are crystalline structures associated risk factors i.e., dehydration, high fat diet, animal protein, high salt intake and obesity.
Literature reviewed for nephrolithiasis prevalence in Europe, Canada, American, East Asia, Gulf region, Japan, China and different parts of India.
Renal calculi induction and progression mechanism was discussed with pathophysiology involved. Fluid intake and diet has been correlated with type of renal stone, as well as the precautions and preventive action were also discussed.
Relation of fluid intake and diet has been correlated with type of renal stone, precaution and preventive actions were discussed.
Concise information was provided on experimental models of nephrolithiasis induction in animals.
Nephrolithiasis is associated with chronic kidney dysfunction, bone loss, coronary artery disease, hypertension and type 2 diabetes mellitus signifying necessity of understanding the pathophysiology.