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Urolithiasis – A brief overview

Introduction

Urolithiasis refers to stones originating anywhere in the urinary tract, including the kidneys and bladder, from dissolved urinary minerals. These stones are solid concretions or calculi (crystal aggregations). However, the pathophysiological bases for the formation of kidney and bladder stones are entirely different.1Pearle MS, Calhoun E, Curhan GC. Urolithiasis. Available at http:// kidney.niddk.nih.gov/statistics/uda/Urolithiasis-Chapter08.pdf. Accessed on May 13, 2010.  

Prevalence

Urolithiasis is a problem that is generally increasing in tropical as well as most Western countries. In the tropics, it is mainly seen as bladder stones in children and upper urinary tract stones in adults. While the former has been decreasing in most countries due to gradual improvements in the levels of nutrition, the incidence of upper urinary tract stones in adults is ironically increasing as a result of improved living standards. The main factor implicated in the formation of bladder stones in children is a nutritionally poor diet that is acidogenic and low in animal protein, calcium, and phosphate, but high in cereal. This leads to the formation of urine with a relatively high content of ammonium and urate ions and consequently to the formation of ammonium acid urate crystals and stones. As nutrition improves, the formation of bladder stones gives way to upper urinary tract stones consisting of calcium oxalate, often mixed with calcium phosphate or uric acid, as happens in most Western countries.2Robertson WG. Renal stones in the tropics. Semin Nephrol. 2003 Jan;23(1):77-87.  

Pathophysiology

One or more of the following mechanisms can be responsible for causing stone disease:3Smith JK, Lockhart ME, Berland NW, Kenney P. Nephrolithiasis/Urolithiasis. Available at http://emedicine.medscape.com/article/381993-overview. Accessed on May 13, 2010.  

  • Presence or abundance of substances that promote crystal and stone formation
  • Absence of substances that inhibit crystal formation
  • Excessive excretion or concentration of salts in the urine, leading to supersaturation of the crystallizing salt. The greater the degree of supersaturation, the greater is the rate of growth of the calculi
  • Stasis or anatomic factors, such as ureteropelvic junction (UPJ) obstruction, horseshoe or ectopic kidney, autosomal dominant polycystic kidney disease, vesicoureteral reflux, calyceal diverticula, medullary sponge kidney

Etiology of kidney stones

The causes of kidney stones or calcium oxalate crystals in the kidney are:

  • Metabolic conditions
    • Renal tubular acidosis
    • Dent’s disease
    • Hyperparathyroidism
    • Primary hyperoxaluria
    • Medullary sponge kidney
  • Crohn’s disease
  • Water fluoridation
  • Skeletal fluorosis
  • Vitamin C – debatable
  • Increasing global temperatures
  • Drug intake
    • Indinavir
    • Sulfadiazine
    • Triamterene

Source: http://en.wikipedia.org/wiki/Kidney_stone

Types of kidney stones

There are several types of kidney stones based on the type of crystals they are made of.

Calcium

Calcium stones are the most common type of kidney stones, found in 75-85% of cases. Almost 50% of these are composed of a mixture of calcium oxalate and calcium phosphate. They demonstrate intermediate fragility to extracorporeal shock wave lithotripsy (ESWL). Approximately 36% of calcium stones are formed of only calcium oxalate dihydrate. These may be spiculated, dotted, mulberry, or jackstone in appearance. Usually, these stones are fragile in response to ESWL.

The remaining 14% of stones are composed of calcium phosphate (apatite) or calcium monohydrate. Being the densest, they are the least amenable to ESWL therapy.

Calcium stones can be attributable to multiple causes. Most of them are idiopathic, or primary. Calcium oxalate stones are usually associated with idiopathic hypercalciuria, in which increased absorption in individuals after a normal diet raises serum calcium levels and also inhibits parathyroid function as an abnormal response to vitamin D. Sometimes, primary hypercalciuria can occur due to the inability of the kidneys to conserve calcium, resulting in low serum calcium concentrations, which stimulate parathormone secretion.

A small proportion of calcium stones are secondary to some disease process, such as hyperparathyroidism (in which hypercalcemia and increased absorption lead to hypercalciuria), sarcoidosis (where the production of activated vitamin D by macrophages is abnormal) and renal tubular acidosis (where the distal tubule loses the ability to maintain the hydrogen-ion gradient, thereby raising the pH of the urine, causing hypercalciuria and hyperphosphaturia).

Patients with spinal cord injury are more prone to develop stones since their immobilization causes rapid skeletal calcium mobilization. Hyperoxaluria, resulting from inflammatory bowel disease, bowel surgery, vitamin C overdose, or renal failure, can also cause calcium stone formation.

Other conditions as sociated with calcium stones include milk-alkali syndrome, use of steroids, Cushing syndrome, hypervitaminosis D, paraneoplastic phenomenon, and multiple myeloma.3Smith JK, Lockhart ME, Berland NW, Kenney P. Nephrolithiasis/Urolithiasis. Available at http://emedicine.medscape.com/article/381993-overview. Accessed on May 13, 2010.  

Uric acid (urate)

Uric acid stones constitute around 5-10% of all urinary stones.4Moe OW. Kidney stones: pathophysiology and medical management. The Lancet 2006:367 (9507): 333-344.   Conditions that cause hyperuricosuria with or without hyperuricemia, and acid/base metabolism disorders where the urine is excessively acidic, result in uric acid precipitation. Uric acid stones are small, smooth and radiolucent on conventional radiographs but opaque on CT scans. They are associated with a persistently low urine pH and presence of uric acid crystals in fresh urine samples.5Halabe A, Sperling O. Uric acid nephrolithiasis. Mineral and Electrolyte Metabolism 1994:20 (6): 424-31.  

 

Struvite

Struvite stones are composed of magnesium, ammonium and phosphate, and are also known as infection stones, urease or triple-phosphate stones. About 10-15% of urolithiasis patients have struvite stones.6Jennette JC, Heptinstall RH. In: Jennette JC, Olson JL et al., eds. Heptinstall’s Pathology of the Kidney, 6th ed. Lippincott Williams & Wilkins, 2007: p. 1063.   These stones are radiolucent but form complexes with calcium phosphate. Sometimes they enlarge and branch (staghorn).

Struvite stones are always associated with urinary tract infections,6Jennette JC, Heptinstall RH. In: Jennette JC, Olson JL et al., eds. Heptinstall’s Pathology of the Kidney, 6th ed. Lippincott Williams & Wilkins, 2007: p. 1063.   with urea-splitting bacteria,7Rodman JS. Struvite Stones. Proceedings of the International ASTIF Meeting, New Frontiers in Renal Stone Disease, Rome, Italy, 1999.   such as Proteus mirabilis (most common), Klebsiella, Serratia and Providencia species, having a role in their formation. These organisms split urea into ammonia, which decreases the acidity of the urine, making conditions favorable for the formation of struvite stones. Obstruction and infection frequently combine to cause renal destruction and, potentially, renal failure, if both kidneys are affected.3Smith JK, Lockhart ME, Berland NW, Kenney P. Nephrolithiasis/Urolithiasis. Available at http://emedicine.medscape.com/article/381993-overview. Accessed on May 13, 2010.  

Cystine

Cystine stones account for only approximately 1% of urinary stones. They have a homogeneous, groundglass appearance, and are less opaque and fragile than other stones.3Smith JK, Lockhart ME, Berland NW, Kenney P. Nephrolithiasis/Urolithiasis. Available at http://emedicine.medscape.com/article/381993-overview. Accessed on May 13, 2010.   They are formed in people suffering from cystinuria, where cystine accumulates in the urine, as happens in conditions like Fanconi’s syndrome.

Recurrence of stones and its risk factors

The recurrence rate of renal stones is quite high, with a 30% to 50% chance of forming a second stone within 5 years of an initial episode. This high recurrence rate warrants an initial metabolic evaluation to determine the underlying cause(s). In patients presenting with a single stone episode, a risk assessment should be done (Fig. 1).8Lipkin ME, Preminger GM. Demystifying the medical management of nephrolithiasis. Rev Urol. 2011;13(1):34-8.  

A number of factors increase the risk of recurrent stone formation. They are:9Taylor EN, Stampfer MJ, Curhan GC. Obesity, weight gain, and the risk of kidney stones. JAMA. 2005;293:455-462.  

  • Family history of stones
  • Bone/gastrointestinal disease
  • Gout
  • Chronic urinary tract infection
  • Nephrocalcinosis
  • Obesity
  • Type 2 diabetes
  • Large/complex stones
  • Specific stone composition (uric acid or cystine)
  • Drugs, e.g., topiramate and guaifenesin

Presence of any of these risk factors calls for a standard metabolic evaluation (SME). SME should also be done in cases of recurrent stone formation (Fig. 1). If it is a first-time stone episode with no risk factors, a screening evaluation should be performed, consisting of a thorough history, basic serum chemistries, and a urinalysis (Fig. 1). Any collected stones should also be sent for analysis.

Medical management of urolithiasis
General principles of treatment

While pharmacological treatment is the preferred choice in patients with uric acid/urate, cystine or infection stones, those with calcium stones should be treated according to the severity of the disease.10Tiselius HG. Epidemiology and medical management of stone disease. BJU Int. 2003 May;91(8):758-67.  

The formation of calcium oxalate stones can be attributed to a wide range of dietary and metabolic factors. Dietary factors include a high intake of animal proteins, oxalate and sodium, and a low intake of fluids and potassiumcontaining citrus products. Some of the metabolic causes of stones are hypercalciuria, hypocitraturia, gouty diathesis, hyperoxaluria, and hyperuricosuria.11Pak YC. Medical Management of Urinary Stone Disease. Nephron Clin Pract 2004;98:c49-c53.  

Hence, irrespective of the underlying metabolic abnormality, certain dietary modifications should be recommended. They include:

When dietary modification fails to control stone formation or there are severe metabolic derangements, a pharmacological intervention may be necessary. In general, thiazide or indapamide with potassium citrate is recommended for patients with hypercalciuria, and potassium citrate alone for the remaining normocalciuric subjects.11Pak YC. Medical Management of Urinary Stone Disease. Nephron Clin Pract 2004;98:c49-c53.  

Aims of medical management

Once a metabolic abnormality is found, targeted medical therapy can be initiated (Fig. 2).14Pearle MS, Preminger GM, Goldfarb DS, et al. ABC’s of Medical Management of Stones, 2nd ed. San Antonio, TX: Mission Pharmacal Company; 2010. Available at StoneDisease.org.  

Medical management is best suited for small stones (< 7 mm) and uric acid stones. The aims of medical management are:15Bolong DT. Update on stone management for the family physician. Available at http://www.gls-lithotripsy.com/Stone%20management.html. Accessed on May 17, 2010.  

  • Pain control. Severe, colicky pain can be addressed by antiprostaglandins (e.g., sodium diclofenac, 75 mg deep IM or IV drip 1-2 mg – after a negative skin test), which are more effective than spasmolytics.
  • Inducing spontaneous passage. Although some studies have shown that the use of nifedipine and methylprednisone increases stone passage by 87%, there is no clinical evidence to this effect. For uric acid stones, alkalizing agents such as bicarbonate or potassium citrate have proved to be effective.
  • Stone dissolution. Only uric acid stones can be dissolved. This treatment aims to keep urinary pH between 6.0 and 6.5. Initially, 25 mg potassium citrate should be administered twice daily and urine pH monitored biweekly. If more alkali is needed, the intake should be increased to 3-4 times daily. Allopurinol is best used for patients with hyperuricemia, gout and myeloproliferative disorders.

Role of potassium citrate in urolithiasis

Citrate is an important inhibitor of stone formation. Hypocitraturia, defined as urinary citrate less than 500 mg/day, is a risk factor for calcium nephrolithiasis.16Preminger GM, Harvey JA, Pak CY. Comparative efficacy of “specific” potassium citrate therapy versus conservative management in nephrolithiasis of mild to moderate severity. J Urol. 1985;134:658-661.   Alkaline citrate is the preferred method to increase the excretion of urinary citrate. Due to the alkali load, the excretion of citrate increases, which reduces the tubular reabsorption of citrate in the kidneys. The simultaneous alkalinization and a high citrate excretion prevent the crystallization of both calcium oxalate and calcium phosphate.17Tiselius HG, Berg C, Fornander A-M, Nilsson M-A. Effects of citrate on the different phases of calcium oxalate crystallization. Scanning Microscopy 1993; 7: 381-91.   In addition to the direct inhibitory effects of citrate, an increased urinary pH results in dissociation of citrate and of the inhibitory macromolecules, which makes conditions unfavorable for crystallization to occur in the urine.

Citrate also helps by binding with calcium in the urine, thereby reducing the amount of calcium available to form calcium oxalate stones. In addition, it prevents tiny calcium oxalate crystals from growing and massing together into larger stones. Finally, it makes the urine less acidic, which inhibits the development of both calcium oxalate and uric acid stones.18Kidney Stones. Available at http://healthlibrary.epnet.com/GetContent.aspx?token=e0498803-7f62-4563-8d47-5fe33da65dd4&chunkiid=21459. Accessed on May 15, 2010.  

Potassium citrate was approved by the US FDA in 1985 for the prevention of calcium stones (including calcium oxalate stones) and uric acid stones.18Kidney Stones. Available at http://healthlibrary.epnet.com/GetContent.aspx?token=e0498803-7f62-4563-8d47-5fe33da65dd4&chunkiid=21459. Accessed on May 15, 2010.   Use of potassium citrate has been shown to reduce the stone formation rates by 96% in patients with hypocitraturia.16Preminger GM, Harvey JA, Pak CY. Comparative efficacy of “specific” potassium citrate therapy versus conservative management in nephrolithiasis of mild to moderate severity. J Urol. 1985;134:658-661.   The dosage of potassium citrate should be titrated with a goal of a urinary citrate level greater than 500 mg/day.

Potassium citrate has a role in the treatment of cystine stones as well. Patients with cystine stones should increase their fluid intake to maintain a urine volume greater than 4 L/day.8Lipkin ME, Preminger GM. Demystifying the medical management of nephrolithiasis. Rev Urol. 2011;13(1):34-8.   In addition, potassium citrate should be taken to maintain urinary pH between 6.0 and 6.5.

In a retrospective cohort study19Robinson MR, Leitao VA, Haleblian GE, Scales CD Jr, Chandrashekar A, Pierre SA, Preminger GM. Impact of long-term potassium citrate therapy on urinary profiles and recurrent stone formation. J Urol. 2009 Mar;181(3):1145-50.   with a median of 41 months follow-up, urinary pH and citrate levels remained significantly higher in patients treated with potassium citrate when compared with pretreatment values. Overall, a significant and durable change in urinary metabolic profiles was noted within 6 months of initiating the therapy. These changes included:

  • Increase in urinary pH (5.90 to 6.46)
  • Increase in urinary citrate (470 to 700 mg/day)
  • Significant decrease of 93% in stone formation rate (1.89 to 0.46 stones per year) (Fig. 3)
  • Remission rate of 68%

In a retrospective study,20Lee YH, Huang WC, Tsai JY, Huang JK. The efficacy of potassium citrate based medical prophylaxis for preventing upper urinary tract calculi: a midterm followup study. J Urol. 1999 May;161(5):1453-7.   313 patients with upper urinary calculi were divided into 3 groups as follows:

  • Group 1 (n= 64, 20.4%) – regular medical prophylaxis with potassium citrate for 24 to 42 months (mean 27.8)
  • Group 2 (n=80, 25.6%) – intermittent medical prophylaxis with potassium citrate for 1.5 to 19 months (mean 7.9)
  • Group 3 (n=169, 54%) – no medical prophylaxis

In group 1 (regular prophylaxis), the stone recurrence rate was 7.8%, which was significantly less than in groups 2 (30%) and 3 (46.2%). Similarly, new stone formation in patients with a history of multiple stone recurrence was less frequent in group 1 than in groups 2 and 3 (9.7, 47.4 and 52.2%, respectively). Fig. 4 graphically depicts these results.

This study showed that regular medical prophylaxis with potassium citrate may effectively prevent stone recurrence regardless of previous treatment modalities, stone composition, metabolic abnormalities and stone-free status. Patients with a history of multiple stone recurrence, calcium oxalate dihydrate stones, hypercalciuria and hyperuricosuria benefit from regular medical prophylaxis with potassium citrate.

In a 3-year, double-blind study21Barcelo P, Wuhl O, Servitge E, et al. Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis. J Urol. 1993;150:1761-1764.   of 57 people with a history of calcium stones and low urinary citrate levels, those given potassium citrate developed fewer kidney stones than they had previously. In comparison, the group given placebo experienced no change in their rate of stone formation.

Pak et al 22Pak CY, Sakhaee K, Fuller CJ. Physiological and physiochemical correction and prevention of calcium stone formation by potassium citrate therapy. Trans Assoc Am Physicians. 1983;96:294-305.   studied the long-term effects of potassium citrate therapy in 53 patients with renal stones, either alone or in combination with thiazide and/or allopurinol. The following results were obtained:

  • Significant increase in urinary citrate and pH
  • Significant decrease in urinary saturation of calcium oxalate
  • Decline in spontaneous nucleation of calcium oxalate
  • Prevention of new stone formation
  • Decrease of stone passage rate from 5.14-7.41 stones/patient year before potassium citrate treatment to 0.66-1.33 stones/patient year during treatment
  • Remission in 75.0-91.7% of patients
  • In patients who relapsed on other treatments (with passage of 5.14 stones/patient year), the addition of potassium citrate to the ongoing treatment reduced stone formation to 1.33 stones/patient year and caused remission in 91.7% of patients
  • In 14 of 33 patients with pre-existing radiopaque stones, there was radiological evidence of a reduced number of stones after potassium citrate treatment for 8 months to 2 years

The investigators concluded that potassium citrate restores normal urinary citrate, decreases saturation and tendency for spontaneous nucleation of calcium oxalate, and inhibits new stone formation.

Conclusion

Urolithiasis is a growing problem all over the world. Diet plays an important role in its genesis. Renal stones may be of various types, e.g., calcium oxalate, uric acid, struvite or cystine. Metabolic conditions like diabetes and obesity are among the factors associated with an increased risk of stone recurrence. Treatment consists of dietary modification and pharmacological intervention. Most of the drugs used to prevent stone recurrence are well tolerated and highly effective. In particular, potassium citrate can reduce stone formation rates by up to 96% and has durable long-term effects. For this reason, potassium citrate therapy has become one of the cornerstones of medical stone management.

References

  1. Pearle MS, Calhoun E, Curhan GC. Urolithiasis. Available at http://kidney.niddk.nih.gov/statistics/uda/Urolithiasis-Chapter08.pdf. Accessed on May 13, 2010.
  2. Robertson WG. Renal stones in the tropics. Semin Nephrol. 2003 Jan;23(1):77-87.
  3. Smith JK, Lockhart ME, Berland NW, Kenney P. Nephrolithiasis/Urolithiasis. Available at http://emedicine.medscape.com/article/381993-overview. Accessed on May 13, 2010.
  4. Moe OW. Kidney stones: pathophysiology and medical management. The Lancet 2006:367 (9507): 333-344.
  5. 5Halabe A, Sperling O. Uric acid nephrolithiasis. Mineral and Electrolyte Metabolism 1994:20 (6): 424-31.
  6. Jennette JC, Heptinstall RH. In: Jennette JC, Olson JL et al., eds. Heptinstall’s Pathology of the Kidney, 6th ed. Lippincott Williams & Wilkins, 2007: p. 1063.
  7. Rodman JS. Struvite Stones. Proceedings of the International ASTIF Meeting, New Frontiers in Renal Stone Disease, Rome, Italy, 1999.
  8. Lipkin ME, Preminger GM. Demystifying the medical management of nephrolithiasis. Rev Urol. 2011;13(1):34-8.
  9. Taylor EN, Stampfer MJ, Curhan GC. Obesity, weight gain, and the risk of kidney stones. JAMA. 2005;293:455-462.
  10. Tiselius HG. Epidemiology and medical management of stone disease. BJU Int. 2003 May;91(8):758-67.
  11. Pak YC. Medical Management of Urinary Stone Disease. Nephron Clin Pract 2004;98:c49-c53.
  12. Borghi L, Meschi T, Amato F, et al. Urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. J Urol. 1996;155:839-843.
  13. Pak YC, Griffith DP, Menon M, Preminger GM, Resnick MI. ABCs of Medical Management of Stones. Available at http://www.stonedisease.org/For_Health_Professionals/ABCs/ABCs_Slides.pdf. Accessed on May 14, 2010.
  14. Pearle MS, Preminger GM, Goldfarb DS, et al. ABC’s of Medical Management of Stones, 2nd ed. San Antonio, TX: Mission Pharmacal Company; 2010. Available at StoneDisease.org.
  15. Bolong DT. Update on stone management for the family physician. Available at http://www.gls-lithotripsy.com/Stone%20management.html. Accessed on May 17, 2010.
  16. Preminger GM, Harvey JA, Pak CY. Comparative efficacy of “specific” potassium citrate therapy versus conservative management in nephrolithiasis of mild to moderate severity. J Urol. 1985;134:658-661.
  17. Tiselius HG, Berg C, Fornander A-M, Nilsson M-A. Effects of citrate on the different phases of calcium oxalate crystallization. Scanning Microscopy 1993; 7: 381-91.
  18. Kidney Stones. Available at http://healthlibrary.epnet.com/GetContent.aspx?token=e0498803-7f62-4563-8d47-5fe33da65dd4&chunkiid=21459. Accessed on May 15, 2010.
  19. Robinson MR, Leitao VA, Haleblian GE, Scales CD Jr, Chandrashekar A, Pierre SA, Preminger GM. Impact of long-term potassium citrate therapy on urinary profiles and recurrent stone formation. J Urol. 2009 Mar;181(3):1145-50.
  20. Lee YH, Huang WC, Tsai JY, Huang JK. The efficacy of potassium citrate based medical prophylaxis for preventing upper urinary tract calculi: a midterm followup study. J Urol. 1999 May;161(5):1453-7.
  21. Barcelo P, Wuhl O, Servitge E, et al. Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis. J Urol. 1993;150:1761-1764.
  22. Pak CY, Sakhaee K, Fuller CJ. Physiological and physiochemical correction and prevention of calcium stone formation by potassium citrate therapy. Trans Assoc Am Physicians. 1983;96:294-305.
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