US Pharm. 2020;45(9):34-36.

Urolithiasis—the formation of stones (calculi) in the kidney, bladder, and/or urethra—is increasingly common, with a rate of approximately 12% worldwide, and it is associated with an enhanced risk of end-stage renal disease. The most common form of kidney stone is calcium oxalate (CaOx) on the renal papillary surface.1,2

Stone formation involves a complex process that results from a number of physicochemical occurrences—namely, supersaturation, nucleation, growth, aggregation, and stone retention within tubular cells. Additionally, cellular injury furthers the retention of particles on the renal papillary surface. No medication exists at present that prevents or cures the formation of kidney stones. A greater knowledge of kidney stone pathophysiology is required in order to foster a better understanding of therapeutic approaches as well as the clinical indications for these approaches.1,2

Etiology

Urolithiasis is a complex, multifactorial process involving intrinsic factors (e.g., age, sex, heredity) and extrinsic factors (e.g., geography, climate, diet [i.e., oxalate-rich foods], mineral composition, water intake). Kidney stones are a common cause of blood in the urine and pain in the abdomen, groin, or back. Stone development is related to decreased volume of urine or increased excretion of components such as calcium, urate, cystine, oxalate, phosphate, and xanthine. The calculi, which form in the urine-collecting area of the kidneys, range in size from tiny to as large as the renal pelvis. Kidney stones occur in one in 20 people at some point in life (approximately 0.5%/year in North America and Europe).3,4

Chemical Composition

Abnormalities in the urine composition of a number of different chemicals are responsible for the chemical composition of kidney stones. The size, shape, and chemical composition of stones are varied. Kidney stones are typically classified into the following five types according to differences in mineral composition and pathogenesis1,2,4:

CaOx: Calcium stones, which account for roughly 80% of all urinary stones, consist of pure CaOx (50%), calcium phosphate (5%), or a combination of these (45%). The chief component of calcium stones is calcium hydrogen phosphate or hydroxyapatite. Found in the majority of kidney stones, CaOx occurs as CaOx monohydrate (COM), CaOx dihydrate (COD), or a mixture of both (the mixed form accounts for more than 60% of occurrences). COM is found more often than COD in clinical stones, and it is the most thermodynamically stable type of stone.1,2,4 CaOx stone formation involves many elements, such as hyperuricosuria, hyperoxaluria, and hypercalciuria. CaOx stone formation is promoted by a urinary pH between 5.0 and 6.5, and calcium phosphate stones develop when the pH exceeds 7.5. Calcium stones have a higher recurrence rate than other kinds of kidney stones.1,2,4

Magnesium Ammonium Phosphate: These stones, accounting for 10% to 15% of all urinary stones, develop in patients with chronic, urease-producing urinary tract infections. Urease is required to split urea into ammonia and carbon dioxide; this renders urine more alkaline, which elevates the pH. Phosphate is less soluble with alkaline pH than with acidic pH; therefore, phosphate precipitates onto insoluble ammonium products, leading to a large stone formation. Women are more likely than men to develop this kind of stone.1,2

Uric Acid: Uric acid stones, which occur more often in men, represent approximately 3% to 10% of all stones. A diet high in purines, particularly a diet high in meat and fish, can lead to hyperuricosuria, low urine volume, and low urinary pH (< 5.05), and these conditions may result in the formation of uric acid stones. These stones may form in the kidneys of persons with gouty arthritis. Usually, the cause of uric acid nephrolithiasis is idiopathic.1,2

Cystine: Constituting less than 2% of all stones, this type of calculus is caused by cystinuria, a genetic disorder in which the amino acid cystine builds up in the urine, resulting in stone formation. Each day, persons who are homozygous for cystinuria excrete more than 600 mmol of insoluble cystine. The presence of urinary cystine is the only clinical manifestation of cystine stones.1,2,4

Drug-Induced: Approximately 1% of all stones are induced by medications such as triamterene, guaifenesin, atazanavir, and sulfa drugs. These agents may induce the formation of calculi through their metabolic actions of interfering with the metabolism of CaOx or purine.1,2

Mechanism and Risk Factors

The pathogenesis of urolithiasis is a complex biochemical process that is not fully understood.  The formation of kidney stones is a biological process encompassing physicochemical changes and urine supersaturation. Supersaturation causes solutes to precipitate in urine, leading to nucleation and the formation of crystal concretions. The transformation from liquid to solid is affected by pH and specific concentrations of excess substances. The level of urinary saturation with respect to stone-forming constituents such as calcium, phosphorus, uric acid, oxalate, cystine, and low urine volume is a risk factor for crystallization. The crystallization process thus depends on the thermodynamics and kinetics of a supersaturated solution. Lithiasis can be prevented by avoidance of supersaturation. Most of the time, urolithiasis depends on the amount of imbalance between urinary inhibitors and promoters of crystallization.2,5

Factors Influencing Kidney Stone Characteristics

In a healthy person, urine contains chemicals that prevent crystal formation. Inhibitors of stone formation reduce the initiation of supersaturation, nucleation, crystal growth, aggregation rate, and other processes necessary for formation. Types of inhibitors are small organic anions (e.g., citrate), small inorganic anions (e.g., pyrophosphates), multivalent metallic cations (e.g., magnesium), and macromolecules (e.g., glycosaminoglycans, glycoproteins). These inhibitors appear not to work equally well in everyone, leading some people to form stones. Tiny crystals usually pass through the urinary tract and out of the body without being noticed.2,6

In contrast, promoters are substances that facilitate stone formation by various means. These include cell-membrane lipids (e.g., phospholipids, cholesterol, glycolipids), calcitriol hormone enhancement via parathyroid-hormone stimulation, oxalate, cystine, calcium, sodium, and low urine volume. Among patients with recurrent stone formation, urinary oxalate excretion was found to be higher, whereas citrate excretion was lower. It has been suggested that an imbalance between urinary stone inhibitors and promoters is, in general, the cause of stone formation.2,6

Prevention and Treatment

For effective prevention, it is necessary to address the reason for stone formation. Generally, prevention of the first and second episodes of urolithiasis requires proper diet as well as medication use. Nutritional management is the optimal preventive strategy for kidney stones.2

Patients should increase their intake of water and other liquids sufficiently to achieve a daily urine output of at least 2 L. Adequate fluid intake reduces urinary saturation and dilutes promoters of CaOx crystallization. High-oxalate foods such as spinach, nuts, potato chips, french fries, and beets should be limited.2

It is important to reduce the amount of sodium consumed. Sodium increases the risk of stones by lessening renal tubular calcium reabsorption and increasing urinary calcium. It is also advisable to restrict animal proteins, which increase the acid load because of their high level of sulfur-containing amino acids. High protein intake reduces urine pH and the level of citrate, thereby enhancing urinary calcium excretion via bone reabsorption. Patients with highly acidic urine may need to eat less meat, poultry, and fish and avoid foods containing vitamin D. Increased intake of vegetables and fruits that are rich in potassium is recommended.2,7

Reduced calcium intake results in enhanced intestinal absorption of oxalate, which may cause an increased risk of stone formation. Limiting vitamin C intake is recommended based on the in vivo conversion of ascorbic acid to oxalate.2 To prevent cystine, CaOx, and uric acid stones, the urine should be alkalinized through consuming a lot of vegetables and fruits, taking supplemental or prescription citrate, or drinking alkaline mineral waters. Gout must be controlled in patients who form uric acid stones, and intake of sodium and protein must be restricted in those who form cystine stones. To prevent calcium phosphate stones, the urine should be acidified.2 Cranberry juice has been found to have an effect on the prevention and treatment of urinary tract disorders, but most urologists do not recommend it for stone formers because of its acidifying effects and oxalate content.1

There is no drug treatment for urolithiasis, but some medications may provide pain relief. Alpha-blockers, such as tamsulosin, and the combination of dutasteride and tamsulosin relax the muscles of the ureter, helping the patient pass the stone more quickly with less pain. Calcium channel blockers (nifedipine) and phosphodiesterase-5 inhibitors (tadalafil) are also believed to act by relaxing the ureteral smooth muscles to reduce ureteral contractions.8 For severe pain, IV narcotics and anti-inflammatory drugs may be given in the emergency department. Stones that are less painful may be managed with ibuprofen, but it should be used under physician supervision, as it can cause kidney failure.8

Procedures such as extracorporeal shock wave lithotripsy and laparoscopic ureterolithotomy have revolutionized the treatment of urinary and renal lithiasis. These techniques have high efficiency of stone disintegration, less anesthesia exposure, shorter hospitalizations, and fewer complications.9

Percutaneous nephrolithotomy, a minimally invasive procedure performed under general anesthesia, is another technique for removal of staghorn calculi and kidney stones greater than 2 cm near the pelvic region. The risk of complications with percutaneous nephrolithotomy is higher than for other endoscopic procedures and must be performed by an experienced physician.9

REFERENCES

1. Kumar SBN, Kumar KG, Srinivasa V, Bilal S. A review on urolithiasis. Int J Universal Pharmacy Life Sci. 2012;2:269-280.
2. Alelign T, Petros B. Kidney stone disease: an update on current concepts. Adv Urol. 2018;2018:3068365.
3. Singh KB, Sailo SL. Understanding epidemiology and etiologic factors of urolithiasis: an overview. Sci Vis. 2013;13:169-174.
4. Sofia NH, Manickavasakam K, Walter TM. Prevalence and risk factors of kidney stone. Global J Res Analysis. 2016;5:183-187.
5. Chhiber N, Sharma M, Kaur T, Singla SK. Mineralization in health and mechanism of kidney stone formation. Int J Pharm Sci Invention. 2014;3:25-31.
6. Basavaraj DR, Biyani CS, Browning AJ, Cartledge JJ. The role of urinary kidney stone inhibitors and promoters in the pathogenesis of calcium containing renal stones. EAU-EBU Update Series. 2007;5:126-136.
7. Frassetto L, Kohlstadt I. Treatment and prevention of kidney stones: an update. Am Fam Physician. 2011;84:1234-1242.
8. Stöppler MC. Kidney stone treatment. www.medicinenet.com/kidney_stone_treatment/views.htm. Accessed June 1, 2020.
9. Shafi H, Moazzami B, Pourghasem M, Kasaeian A. An overview of treatment options for urinary stones. Caspian J Intern Med. 2016;7:1-6.

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