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Nephrolithias is a common problem in populations around the world, and contribute significantly to the development of end stage renal disease. It is a matter of debate whether the metabolic factors responsible for renal stone formation are similar or variable in different populations around the globe. This review discusses the influence of different metabolic and dietary factor, and some other co-morbid conditions on the etiopathogenesis Nephrolithiasis. Evaluation and medical management of Nephrolithiasis is summarized in the later part of the article.
Nephrolithiasis is a common problem with the life-time risk around 12% in men and 6% in women, in the United States.[1,2] The overall prevalence of inpatient nephrolithiasis remained stable around 5% in the US from 1998 to 2003, but the male : female ratio decreased from 1.6 : 1 to 1.2 : 1. Scales et al., also reported a dramatic increase in prevalence among females. The incidence peaked in the third and fourth decades, and prevalence increased with age until approximately the age of 70 years. Importantly, kidney stones were a recurrent disorder, with lifetime recurrence risks reported to be as high as 50%.[5,6] It may lead to end-stage renal disease in around 0.6 - 3.2%.[7–9]
Numerous factors determine the prevalence of stones, including age, race, and geographic distribution. In the United States (US), African Americans, Latin Americans, and Asian Americans are much less likely to have stones than whites.
However, all racial groups demonstrate a remarkable similarity in the incidence of the underlying metabolic abnormalities. The geographical location also appears to influence stone formation. Sun exposure can lead to more concentrated urine by increasing insensible fluid losses due to sweating and can also stimulate vitamin D production, resulting in intestinal calcium absorption and urinary calcium excretion. The geographic location and genetic predisposition can also influence the type of stone formed.[10,12]
In the US the various types of renal stones seen are, mixed calcium oxalate and calcium phosphate (37%), Calcium oxalate (26%), Calcium phosphate (7%), Uric acid (5%), Struvite (22%), and Cystine (2%). Calcium oxalate is also the most common stone reported in India.[14–16]
Risk factors for urolithiaisis are generally divided into non-dietary, dietary, and urinary.
Family history — The risk of urolithiaisis is greater in individuals with a family history of stone disease. It is estimated to be more than 2.5 times greater in those individuals. A combination of genetic predisposition as well as similar environmental exposures may be the cause for it. A polygenic inheritance has been proposed to account for the familial tendency. However, there is limited information on the genes that contribute to the risk of the common forms of stone disease.
Anatomic abnormalities that result in urinary stasis such as ureteropelvic junction obstruction, horseshoe kidney or polycystic kidney may precipitate or worsen stone formation.
Systemic disorders such as primary hyperparathyroidism are associated with an increased risk of formation of calcium containing stones. Primary hyperparathyroidism may be found in 5% of the stone formers.
A number of other common conditions have also been linked to nephrolithiasis [Table 1]. Increasing body mass index (BMI) is associated with an increasing risk of stone formation, independent of other risk factors, including diet. The magnitude of increase in the risk from BMI is higher in women than in men. Those with BMI ≥ 30 kg / m2have 30% higher risk among men, but there is nearly a two-fold higher risk among women compared to those with a BMI of 21 – 23 kg / m2.
A history of gout increases the likelihood of forming kidney stones, both uric acid and calcium oxalate. In the National Health and Nutrition Examination Survey (NHANES) III, a prevalence of previous kidney stones in subjects with reported gout was 13.9%. When examined prospectively, a history of gout was associated with a doubling of the risk of forming a stone, independent of diet, weight, and medications.
Diabetes mellitus also increases the risk of stone formation, independent of diet and body size. In a prospective epidemiological study that involved three large cohorts in the United States, the Nurses’ Health Studies I and II, and the health Professionals Follow-Up study in men, a higher prevalence of a history of kidney stones was observed in patients with diabetes compared to those without diabetes. In a cross-sectional study, Meydan et al., observed a prevalence of stone disease of 21% in patients with diabetes, as compared to 8% in patients without diabetes. The insulin-resistance results in defective renal ammonia genesis and low urine pH,[27,28] therefore, may be expected to favor the production of uric acid stones, as low urine pH has been shown to be a major lithogenic factor in idiopathic uric acid nephrolithiasis.[29–31] Insulin has been shown to enhance uric acid and sodium reabsorption in the proximal convoluted tubule, resulting in hyperuricemia, decreased uric acid, and sodium excretion.[32–34]
Environmental factors — Individuals working in a hot environment appear to be at a higher risk for kidney stone formation. Situations leading to a lower fluid intake have a higher risk of stone formation.
Several dietary factors have been proposed to modify the risk of Nephrolithiasis [Box 1]. The nutrients that have been implicated include calcium, animal protein, oxalate, sodium, sucrose,[39,40] fructose, fluoride, and a deficiency of magnesium,[43,44] and potassium.
Calcium — In a prospective study of dietary factors and the risk of incident stone disease performed in a cohort of more than 50,000 male health professionals aged 40 to 75 years, men with a higher intake of dietary calcium had a lower risk of incident nephrolithias independent of other risk factors. A similar finding has been reported in other studies.[47,48]
Low calcium intake is known to increase oxalate absorption and urinary excretion. Furthermore, low dietary calcium intake may increase the risk of stone formation, even among individuals with a family history of stones.
In a randomized trial, Borghi et al., compared a low calcium diet (400 mg / d) to a diet containing1200 mg of calcium, along with low sodium and low animal protein intake, in men with hypercalciuria and calcium oxalate stones. The recurrence of nephrolithiasis was reduced by 50% in the higher calcium intake group.
The Nurses’ Health Study I showed intake of dietary calcium was inversely associated with risk for kidney stones and intake of supplemental calcium was positively associated with the risk. The differential effect may be due to the timing of calcium ingestion relative to oxalate consumption. However, the Nurses’ Health Study II reported that supplemental calcium did not increase the risk of stone formation.
Oxalate – Up to one-third of the patients with calcium oxalate nephrolithiasis may have increased absorption of dietary oxalate, and in some cases a deficiency of oxalate degradation by the bacterium Oxalobacter formigenes in the gut, may be the culprit.
Other nutrients — Several other nutrients have been implicated in the development of stone formation. High animal protein intake leads to increased calcium and uric acid excretion as well as decreased urinary citrate, all of which increase the risk of stone formation. An increased risk of stone formation has been observed for higher animal protein intake, only among men with BMI < 25 kg / m2. Prospective studies demonstrate that sucrose is associated with an increased risk in women[39,40] and higher dietary potassium intake is associated with a decreased risk.[43,48] Low potassium levels can promote hypocitraturia. Of late, phytate has also been found to substantially reduce the likelihood of stone formation.[47,54]
Magnesium complexes with oxalate, thereby potentially reducing oxalate absorption in the gastrointestinal (GI) tract and decreasing calcium oxalate supersaturation in the urine. Low magnesium levels are found in up to 18 of the stone formers. In prospective observational studies, higher dietary magnesium is associated with a 30% lower risk of stone formation in men, but not in women.[40,47]
Vitamin C can be metabolized to oxalate and higher vitamin C intake can increase the risk of calcium oxalate stone formation. An observational study in men has found that those who consume 1000 mg or more per day of vitamin C have a 40% higher risk of stone formation compared to men who consume less than 90 mg / day, after accounting for dietary potassium intake. However, the study by Curhan et al., does not support an association between the intake of vitamin C and kidney stones.
Vitamin B6 is a cofactor in oxalate metabolism, and vitamin B6 deficiency increases oxalate production and urine oxalate excretion. Observational data have shown that a high intake of vitamin B6 may reduce the risk of kidney stone formation in women, but not in men.
Inadequate fluid intake leading to low urine volume less than one liter per day may be seen in 12 – 25% of first-time stone formers. A randomized trial confirmed the value of increasing the urine volume. Observational studies have found that coffee, tea, beer, and wine are associated with a reduced risk of stone formation.[61,62] Citrus juices can reduce the risk of stone formation, and grapefruit juice intake is associated with a higher risk.
Abnormal levels of several substances in the urine have been implicated in the pathogenesis of urolithiasis.
Hypercalciuria — Idiopathic hypercalciuriais is the most common metabolic abnormality in patients with calcium-related kidney stones, seen in up to 40% of the patients with calcium stone disease. It is defined as 24 hours of urinary calcium more than 300 mg in males and 250 mg in females. Other common causes of hypercalciuria include hyperparathyroidism and granulomatous diseases.
Hyperoxaluria (urinary oxalate excretion > 45 mg / d) may be present in up to 40% of the male stone formers and in up to 10% of then female stone formers. Although the mean urinary oxalate levels may not differ between cases and controls, the oxalate does appear to be an important independent risk factor for stone formation. Primary hyperoxaluria is a hereditary condition that is associated with stone disease. Enteric hyperoxaluria can also occur for many different reasons, but malabsorption and malnutrition are the most common causes.
Hyperuricosuria (> 800 mg in men and > 750 mg in women per day) is present in up to 35% of the metabolic evaluations, although it is also coexistent with other abnormalities. Up to 20% of these patients will have calcium oxalate calculi. In NHANES III, the prevalence of previous kidney stones in subjects with reported gout was 13.9%.
Hypocitraturia (< 450 mg in men, < 550 mg in women per day) is present in over 30% of the stone patients. In 50% of the cases it coexists with other metabolic abnormalities and in up to 10% of the cases it exists alone. Citrate is protective against stone formation because it forms soluble complexes with calcium, which inhibit crystal nucleation and growth.[68,69] Hypocitraturia is often idiopathic, although other disease states, such as, distal renal tubular acidosis (RTA), hypokalemia, chronic diarrhea, urinary tract infection, thiazide medication, and a low-alkali, high-protein diet can induce this disorder.
Urine pH — An abnormal urinary pH is another risk factor for nephrolithiasis. High urinary pH leads to increased saturation of calcium phosphate predisposing to nephrolithiasis. Also high urinary pH can lead to the formation of struvite stones due to a low solubility of phosphate, when there is excessive ammonia production by urea splitting organisms. However, a low urinary pH predisposes to uric acid nephrolithiasis.
Kidney stones form when the urine becomes oversaturated with respect to the specific components of the stone. Saturation is dependent on chemical free ion activities of the stone constituents, which are affected by urinary ion concentration, pH, and combination with other substances. Low urinary pH increases the free ion activity of uric acid ions, but decreases the activity of calcium and phosphate ions. Citrate combines with calcium ions to form soluble complexes and can thereby decrease their free ion activity.[68,69]
Although formation of stones can occur through either homogeneous or heterogeneous nucleation, heterogeneous nucleation on a pre-existing surface, such as, cellular debris or another crystal is more common.
The crystals must then aggregate into clinically significant stones. For stone formation to occur before the crystals are eliminated, the crystals anchor at the renal papillae, over areas of interstitial calcium phosphate, in the form of apatite, termed Randall's plaques.[74,76,77] The apatite crystals form in the interstitium around the thin limbs of the loop of Henle. A combination of the apatite crystal and organic material extends from the loop of the Henle tubular basement membrane to the papillary uroepithelial surface, where calcium oxalate crystals or other crystals can adhere and form stones.
Several endogenously produced substances such as uropontin, pyrophosphate, and nephrocalcin have been shown to inhibit calcium crystallization. Differences in the concentration or activity of these inhibitors might account for the differing risk of stone formation among people with similar degrees of urinary oversaturation.
Various imaging modalities are available for the diagnosis of urolithiasis. They can also help determine the location and extent of the stone burden and might elucidate the genitourinary abnormalities contributing to stone formation.
A plain radiograph of the abdomen that includes the kidneys, ureter, and bladder (KUB) is a cheap and readily available tool. The sensitivity and specificity of plain abdominal radiography are 58% and 69%.
The renal ultrasound is a useful test for patients who must avoid exposure to radiation or contrast, such as pregnant women and children. Ultrasound can detect calculi in 93% of the patients, but detect all stones in only 60% of the patients. An ultrasound can miss 30% of papillary-calyceal stones. Another study showed a poor sensitivity of 24% and specificity of 90% with the ultrasound. Visualization of the ureteral stones is poor with ultrasound (19%).
Intravenous urography (IVU) is useful in detecting certain genitourinary abnormalities that can predispose to nephrolithiasis, such as, pelvicaliceal abnormalities that cannot be visualized adequately with ultrasonography. Another advantage of an intravenous pyelogram (IVP) is that the osmotic diuresis generated by the contrast agent administered may flush out the offending stone during an episode of acute renal colic. A major disadvantage of IVP is exposure to radiographic contrast material.
A helical CT has a high sensitivity of 97% and specificity of 96% for detecting genitourinary calculi. It has proved to be more effective than IVU in detecting urolithiasis. The sensitivity for detecting ureteral stone is 98.5% for unenhanced CT and 59.1% for IVU. The helical CT takes less time to perform, 30 minutes, including time for curved, multiplanar, reformatted, reconstruction, compared to an average of 108 minutes for an IVU. However, because of a higher radiation dose and cost, some authors recommend that it should be reserved for cases where ultrasonography and IVU cannot visualize the calculi. Scout CT has been shown to be inferior to plain radiography by some authors.[87–89]
Although it is uniformly accepted that patients with multiple stones merit a thorough investigation into the cause of nephrolithiasis, evaluation of the patient with a single stone is controversial. The National Institutes of Health Panels determined that all patients, even those with a single stone, should undergo at least a basic evaluation in order to rule out a systemic etiological mechanism. Patients less than 25 years of age or those with multiple stones, bilateral stones, uric acid stones, staghorn calculi, nephrocalcinosis, a single kidney or a history of recurrent stones, undergoing workup as a kidney donor or renal impairment should undergo detailed metabolic screening. The relevant tests are included in Box 2, and discussed in more detail in the underlying text.
The evaluation of the stone former includes a stone history and a thorough review of diet, fluid intake, and lifestyle. The evaluation proceeds with a thorough review of the patient's diet and fluid intake. Particular attention is paid to ingestion of foods high in sodium and the quantity of animal protein consumed.
Determination of stone composition will facilitate appropriate diagnosis and medical management. Patients with uric acid and cystine stones often have higher recurrence than patients with calcium stones, therefore, stone analysis may make it possible to inhibit residual stone growth or recurrence. Patients with calcium stones are heterogeneous with regard to metabolic disorders, but there is a significant likelihood of renal tubular acidosis in those with calcium phosphate calculi. X-ray diffraction, infrared spectroscopy, and polarization microscopy are common techniques for stone analysis. Dual-energy multidetector CT may also be used.
Blood screening tests should be a routine component of the diagnostic evaluation for all stone formers. Serum electrolyte, calcium, carbon dioxide, uric acid measurements as well as measurement of serum creatinine should be obtained, to assess the renal function. These tests are generally inexpensive, and will effectively screen for metabolic abnormalities that may contribute to recurrent stone formation.
Primary hyperparathyroidism may manifest with hypercalcemia. This disorder can be confirmed by determining the patient's serum parathyroid hormone level and serum phosphorous, as an elevated parathyroid hormone level and depressed phosphorous supports the diagnosis. Ionized calcium values must be evaluated if serum albumin levels are abnormal. Moreover, if the diagnosis is suspected, but the calcium level is normal, the administration of a short course of a thiazide-type diuretic can ‘unmask’ occult cases with resultant hypercalcemia.
Distal renal tubular acidosis may be suspected in the setting of low potassium and carbon dioxide values. Patients with distal RTA generally form calcium phosphate stones.
Less-commonly encountered conditions may require alternative blood tests for diagnosis. Elevated serum oxalate levels and vitamin D levels can diagnose primary hyperoxaluria and hypervitaminosis D, respectively.
A simple clean catch urinalysis can be very informative and should be performed for all stone formers. The specific gravity of urine reflects the general state of hydration of a patient; chronically volume-depleted patients will demonstrate an elevated specific gravity, thereby implying an elevated stone risk. Microscopic examination of the urine sediment can identify crystals that can predict the stone composition. A simple urinalysis will also measure urinary pH. There is a significant variability between fasting urine and 24 hours urine, and 24 hours collection is favored.
Infection is supported with the concomitant presence of pus cells, nitrites, leukocyte esterase, and bacteria. Urine culture can demonstrate the presence of a urea-splitting organisms, such as Proteus, Pseudomonas or Klebsiella, all of which may be associated with the formation of struvite calculi.
The 24-hour urine collection test is the mainstay of the comprehensive metabolic evaluation. A commonly encountered concern when performing a 24-hour urine study is whether one or two collections should be performed. Pak et al., have recommended a single 24-hour collection, as it is more convenient for the patient. They reported a high reproducibility of stone risk factors in repeated samples. However, Parks et al., compared two separate 24-hour urine collections and found disparities in around 70% of the patients.
Any urinary tract infection should be treated prior to collection, as it could induce hypocitraturia and an elevated urinary pH, potentially confounding the test results. In general, a 24-hour urine collection should not be performed in the course of an acute stone event, as the patient's routine lifestyle and dietary habits are altered. Decisions regarding the management of medical therapy during the 24-hour urine collection should be patient- and drug-specific.[64,66]
Nephrolithiasis is a common medical problem worldwide with a significant social and financial burden. The recurrence of this disease is high, so appropriate metabolic evaluation of stone formers is warranted in certain situations. A complete endocrine and metabolic workup is necessary in order to provide appropriate medical treatment.
Source of Support: Nil
Conflict of Interest: None declared.