Managing Urinary Tract Stones: Improving Stone Dissolution and Patient Compliance with Potassium Citrate

Introduction

Urinary tract stones or calculi, referred to calcifications that form in the urinary system, are well-documented common occurrences in the general population with geographic, racial, and gender variations.¹Barnela SR, Soni SS, Saboo SS, Bhansali AS. Medical management of renal stone. Indian J Endocrinol Metab. 2012; 16(2): 236-239.   They affect up to 12% of men and 5% of women by the age of 70 years and a strong family history may be established in more than a third of affected individuals.²Steggall MJ. Urinary tract stones: causes, complications and treatment. Br J Nurs. 2001;10(22):1452-6.   Despite the introduction of several new drugs in the past few decades, urinary tract stones continue to challenge the clinicians across the globe. Owing to high recurrence rates and plummeting age of occurrence, management of this clinical condition, including pharmacotherapeutic treatment, warrants considerable attention. In this paper, we provide an update on the medical management of urinary tract stones, focusing our attention on potential role of alkalinizing agents, such as Potassium Citrate.

Pharmacotherapy for Urinary Tract Stones

As previously reported, medical management is imperative in patients with urinary tract stones, albeit with appropriate individualization. Given the high recurrence rate after a first time stone episode, an initial metabolic evaluation to search for underlying causes of stone is warranted. A risk assessment should be made to determine the extent of the evaluation in patients presenting with a single stone episode (Box 1). Medical management is initiated for small stones (< 7 mm) and uric acid stones. The objective of medical management includes the entire repertoire of

• Complete stone clearance
• Prevention of stone recurrence
• Preservation of renal function
• Control of urinary tract infections
• Correction of anatomical abnormalities
• Correction of the underlying metabolic disorders.

Past few decades have heralded an era of effective pharmacologic intervention in stone disease. Henceforth, drugs can control the pain associated with the disease, interfere at various levels in lithogenesis, and contribute to the expulsion of stones.³Micali S, Grande M, Sighinolfi MC, De Carne C, De Stefani S, Bianchi G. Medical therapy of urolithiasis. J Endourol. 2006;20(11):841-7.  

Lithogenesis or stone formation has been propounded to be a multifactorial process, and several factors have been implicated in the pathogenesis of urinary tract stones. Out of all, alteration in urinary pH appears to be the most important contributory mechanism. Additionally, environmental-nutritional factors (such as dehydration, low urinary volume, diet rich in animal protein) and metabolic alterations; including hypercalciuria, hyperuricosuria, and deficiency of stone-inhibiting factors (citrate, magnesium, glycosaminoglycans) may have an influence in the stone formation (Figure 1).⁴Ngo TC, Assimos DG. Uric Acid Nephrolithiasis: Recent Progress and Future Directions. Rev Urol. 2007; 9(1): 17-27.   Specific pharmaceutical agents, such as citrate, represent highly effective treatments for the promoting factors.3 Stone dissolution for uric acid and cystine calculi is a standard therapy adopted by physicians for the management of urinary tract stones, particularly those formed by hyperuricosuria which account for a significant percentage of urinary stones, second only to calcareous stones.⁴Ngo TC, Assimos DG. Uric Acid Nephrolithiasis: Recent Progress and Future Directions. Rev Urol. 2007; 9(1): 17-27.   In this regard, urinary alkalization with administration of alkali has been clinically established as an important treatment approach for dissolution of stones.⁵Trinchieri A, Esposito N, Castelnuovo C. Dissolution of radiolucent renal stones by oral alkalinization with Potassium Citrate/potassium bicarbonate. Arch Ital Urol Androl. 2009;81(3):188-91.  

Stone Dissolution: Role of Alkalinizing Agents

Barring the cases with severe obstruction, progressive azotemia, serious infection, or unremitting pain, medical dissolution therapy through alkalinization of the urine is generally supported as the initial management approach owing to success of this approach in the majority of cases (70% to 80%).⁴Ngo TC, Assimos DG. Uric Acid Nephrolithiasis: Recent Progress and Future Directions. Rev Urol. 2007; 9(1): 17-27.   Urinary alkalinization is the cornerstone of medical management of uric acid stones.⁶Hongshi Xu, Anna L. Zisman, Fredric L. Coe, and Elaine M. Worcester. Kidney stones: an update on current pharmacological management and future directions. Expert Opin Pharmacother. 2013; 14(4): 435-447.   Researchers have suggested that uric acid stone disease can be prevented and these are one of the few successfully dissolved urinary tract stones.⁷Ferrari P, Bonny O. Diagnosis and prevention of uric acid stones. Ther Umsch. 2004;61(9):571-4.   Urinary alkalinization with monitoring of urinary pH to ensure a pH greater than 6.0 can prevent uric acid stone formation and dissolution of in-situ stones.⁴Ngo TC, Assimos DG. Uric Acid Nephrolithiasis: Recent Progress and Future Directions. Rev Urol. 2007; 9(1): 17-27.  ⁸Paterson R, Fernandez A, Razvi H, Sutton R. Evaluation and medical management of the kidney stone patient. Can Urol Assoc J. 2010; 4(6): 375-379.   Therefore, patients with known uric acid stones without significant obstruction or infection can be optimized to receive a trial of oral medical dissolution, which will also serve as preventative therapy.⁶Hongshi Xu, Anna L. Zisman, Fredric L. Coe, and Elaine M. Worcester. Kidney stones: an update on current pharmacological management and future directions. Expert Opin Pharmacother. 2013; 14(4): 435-447.   However, irrespective of the pharmacological agent patient noncompliance or the intolerance of the prescribed medications typically result in failure of the medical therapy.⁴Ngo TC, Assimos DG. Uric Acid Nephrolithiasis: Recent Progress and Future Directions. Rev Urol. 2007; 9(1): 17-27.   In this regard oral medical therapy with Potassium Citrate is the ideal choice followed by alternative of sodium alkali. Literature suggests that alkalization of the urine is not only effective in preventing future uric acid stones from forming, but it can also potentially dissolve existing stones. The goal of alkalization is to maintain a urinary pH between 6.0 and 6.5 which is best achieved with Potassium Citrate.⁹Lipkin ME, Preminger GM. Demystifying the Medical Management of Nephrolithiasis. Rev Urol. 2011; 13(1): 34-38.  

Choosing Potassium Citrate Based Alkalizers Over Sodium Alkali and Herbal Products: Where are We?

Both potassium and sodium alkali treatment have been propounded to be effective in raising the urinary pH, nevertheless Potassium Citrate is usually preferred over Sodium Citrate because sodium loads increase urinary calcium excretion.⁶Hongshi Xu, Anna L. Zisman, Fredric L. Coe, and Elaine M. Worcester. Kidney stones: an update on current pharmacological management and future directions. Expert Opin Pharmacother. 2013; 14(4): 435-447.   Due to the avoidance of a high sodium load, Potassium Citrate is a preferred alkalizing agent which is usually employed because it may avoid the complication of calcium salt precipitation. The initial recommended dosage for Potassium Citrate is 30 to 40 mEq/day. Additionally, sodium-containing products are not recommended for some patients, including hypertensive patients, those with heart disease and pregnant women, in whom sodium intake should be restricted. Results of a wide array of clinical studies have suggested that Potassium Citrate therapy may retard the crystallization of calcium oxalate and may not cause calcium phosphate crystallization. Contrastingly, such effect may not be observed with Sodium Citrate which may sometimes accentuate the crystallization of calcium salts.¹⁰Preminger GM, Sakhaee K, Pak CY. Alkali action on the urinary crystallization of calcium salts: contrasting responses to Sodium Citrate and Potassium Citrate. J Urol. 1988;139(2):240-2.  

Sakhaee¹¹Sakhaee K, Nicar M, Hill K, Pak CY. Contrasting effects of Potassium Citrate and Sodium Citrate therapies on urinary chemistries and crystallization of stone-forming salts. Kidney Int. 1983 ;24(3):348-52.   and colleagues compared the contrasting effects of Potassium Citrate therapy (60 mEq/day) and Sodium Citrate treatment on urinary chemistries and crystallization. Five patients with uric acid lithiasis were randomly optimized to treatment with both alkali which resulted in significant increase in urinary pH from 5.35 +/- 0.18 SD to 6.68 +/- 0.14 for Potassium Citrate and 6.73 +/- 0.20 for Sodium Citrate. Nonetheless, significant decline in urinary calcium from 154 +/- 47 mg/day to 99 +/- 23 mg/day (P less than 0.01) was reported during Potassium Citrate therapy which also resulted in rise in urinary citrate from 398 +/- 119 mg/day to 856 +/- 103 mg/day (P less than 0.001). Additionally, urinary saturation (activity product ratio) of calcium oxalate decreased from 3.21-fold to 1.69fold saturation (P less than 0.01), and the inhibitor activity against calcium oxalate precipitation (formation product ratio) significantly increased. However, no significant decrease in urinary calcium (to 139 +/- 24 mg/day) was observed with Sodium Citrate therapy despite the fact that it increased urinary citrate substantially (to 799 +/- 89 mg/day, P less than 0.01). The result of the study is indicative of potential role of Potassium Citrate in preventing the complication of calcium nephrolithiasis in patients with uric acid stones, an effect which was not observed with Sodium Citrate therapy.

In addition, there is scarcity of good quality RCTs on diet / herbal supplements for prevention of urolithiasis. As a matter of fact herbal preparations have been shown to increase the stone burden rather than decreasing it.¹²Erickson SB, Vrtiska TJ, Lieske JC. Effect of Cystone on Urinary composition and Stone formation over a one year period. Phytomedicine 2015. 18(10): 863-867.   At times they may contain toxic heavy metals and may not have any effect on urinary composition which clearly delineates the importance of Potassium Citrate in management of this particular clinical condition. Potassium Citrate has a role in the treatment of cystine stones as well.⁹Lipkin ME, Preminger GM. Demystifying the Medical Management of Nephrolithiasis. Rev Urol. 2011; 13(1): 34-38.   Thus, oral Potassium Citrate is primarily employed for supplementation owing to its documented superior efficacy over sodium-containing salts.

Evidence Based Role of Potassium Citrate in Management of Urinary Tract Stones

Scientific research has established citrate as an important inhibitor of stone formation. It acts as a buffer thereby raising the urinary pH and also inhibits calcium salt crystallization.⁹Lipkin ME, Preminger GM. Demystifying the Medical Management of Nephrolithiasis. Rev Urol. 2011; 13(1): 34-38.   Potassium, on the other hand, maintains the urine pH above the pKa for uric acid thus promoting dissolution of uric acid crystals. Potassium Citrate thus acts mainly by inhibiting calcium salt crystallization by forming bicarbonate which binds to calcium, directly inhibiting calcium salt formation and promoting increased release of some urinary proteins that inhibits calcium salt crystallization.¹³Singh I, Bishnoi I, Agarwal V, Bhatt S. Prospective randomized clinical trial comparing phytotherapy with Potassium Citrate in management of minimal burden (≤8 mm) nephrolithiasis. Urol Ann. 2011; 3(2): 75-81.   Potassium Citrate is available in 3 formulations: tablets, crystals for dilution, and oral solution.¹⁴Zuckerman JM, Assimos DG. Hypocitraturia: Pathophysiology and Medical Management. Rev Urol. 2009; 11(3): 134-144.  

Therapy with Potassium Citrate has been associated with enhanced citraturic effect and may confer additional inhibitory action against calcium stone formation and is effective not only against calcium based stones but also against non-calcium stones as well.¹⁵Morgan MSC, Pearle MS. Medical management of renal stones. BMJ 2016;352:i52.   The European association of urology (EAU) guidelines recommend Potassium Citrate as the firstline agent for prevention of uric acid stone, with a target pH of 6.¹⁶Turk C, Knoll T, Petrik A, Sarica K, Skolarikos A, Straub M, Seitz C. Guidelines on Urolithiasis. European Association of Urology 2015. Available at: http://uroweb.org/wpcontent/ uploads/22-Urolithiasis_LR_full.pdf [Accessed on 2/5/2016].   Akin to that, Potassium Citrate is the ideal choice for patients with recurrent calcium stones and low or relatively low urinary citrate.¹⁷Pearle Ms, Goldfarb DS et al. American urological association guidelines 2014 for management of kidney stones. Available at: https://www.auanet.org/education/guidelines/ management-kidney-stones.cfm. Accessed on 12/5/2016.  

A plethora of clinical studies and trials have been conducted in the past to validate the efficacy of Potassium Citrate in patients with urinary tract stones. In a study conducted in private practice setting, Nicar, Hsu and Fetner¹⁸Nicar MJ, Hsu MC, Fetner C. Urinary response to oral Potassium Citrate therapy for urolithiasis in a private practice setting. Clin Ther. 1986;8(2):219-25.   assessed the response to one week of oral Potassium Citrate therapy (60 mEq/day), with respect to urinary risk factors for kidney stones. They observed a significant rise in urinary pH, citrate, and potassium excretion, accompanying a significant fall in calcium excretion in response to the therapy. Researchers also noticed a significant reduction in urinary saturation of calcium oxalate as some risk factors in urolithiasis were corrected with oral Potassium Citrate therapy. The study results support the propitious role of oral Potassium Citrate in amelioration of some of the risk factors in urolithiasis.

Likewise, in a long-term clinical trial Potassium Citrate has been demonstrated to reduce the stone formation rates by 96% in patients with hypocitraturia.¹⁹Preminger 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(4):658-61.   Additionally, significant reduction in stone formation rate was also demonstrated with Potassium Citrate supplementation (Figure 2).

Furthermore, in a retrospective review of patients on Potassium Citrate therapy Song²⁰Song Y, Hernandez N, Shoag J, Goldfarb DS, Eisner BH. Potassium Citrate decreases urine calcium excretion in patients with hypocitraturic calcium oxalate nephrolithiasis. Urolithiasis. 2016;44(2):145-8.   and colleagues evaluated the effects of Potassium Citrate on urinary calcium excretion. The investigators performed a retrospective review of a metabolic stone database at a tertiary care academic hospital. Patients with a history of calcium oxalate nephrolithiasis and hypocitraturia were identified who were on Potassium Citrate therapy for a minimum of 3 months. Change in urine potassium of 20 mEq/day or greater suggesting compliance with Potassium Citrate therapy was considered as the inclusion criteria. Potassium Citrate was administered orally at a daily dosage of 30-60 mEq. Therapeutic effect was compared by using paired t-test. Baseline 24-h urine values were reported as: citrate 280.0 mg/ day, potassium 58.7 mEq/day, calcium 216.0 mg/day, pH 5.87. Significant improvements were reported in each of the preceding parameters: citrate increased to 548.4 mg/day (p < 0.0001), potassium increased to 94.1 mEq/day (p < 0.0001), calcium decreased to 156.5 mg/day (p = 0.04), pH increased to 6.47 (p = 0.001) (Figure 3). No difference was reported in pre-and posttherapy levels of urine sodium excretion, however, urinary calcium excretion decreased by a mean of 60 mg/day on Potassium Citrate therapy-a nearly 30 % decrease in urine calcium excretion. The study findings validate the hypothesis that alkali therapy reduces urine calcium excretion.

Potassium Citrate for Dissolution of Stone

Pak, Sakhaee and Fuller²¹Pak CY, Sakhaee K, Fuller C. Successful management of uric acid nephrolithiasis with Potassium Citrate. Kidney Int. 1986;30(3):422-8.   sought to evaluate the response of long-term Potassium Citrate therapy in patients with stone. Researchers recruited 18 patients with uric acid nephrolithiasis (six with uric acid stones alone and 12 with both uric acid and calcium stones). The included patients were optimized to long-term treatment (1 to 5.33 years, mean of 2.78 years) with Potassium Citrate (30 to 80 mEq/day, usually 60 mEq/ day). Urinary pH increased from low (5.30 +/- 0.31 SD) to normal (6.19 to 6.46) during treatment. High urinary content of undissociated uric acid (204 +/- 82 mg/day) before the treatment declined to normal range (64 to 108 mg/day) following treatment. Urinary citrate rose from 503 +/- 225 mg/day to 852 to 998 mg/day along with decrease in new stone formation rate from 1.20 +/- 1.68 stones/year to 0.01 +/- 0.04 stones/year (P less than 0.001 by chi square). Importantly, remission was experienced in 94.4% of patients, and the group stone formation rate declined by 99.2% (Figure 4).

Potassium Citrate for Prevention of Recurrence

Randomized trials have shown that Potassium Citrate reduces the stone recurrence rates in calcium stone formers. In a study conducted by Soygur²²Soygur T, Akbay A, Küpeli S. Effect of Potassium Citrate therapy on stone recurrence and residual fragments after shockwave lithotripsy in lower caliceal calcium oxalate urolithiasis: a randomized controlled trial. J Endourol. 2002;16(3):149-52.   and colleagues efficacy of Potassium Citrate treatment was determined in preventing stone recurrences and residual fragments after shockwave lithotripsy (SWL) for lower pole calcium oxalate urolithiasis. The study recruited a total of 110 patients ( mean age 41.7 years) who underwent SWL because of lower caliceal stones and who were stone free or who had residual stone 4 weeks later. All included patients reportedly had simple calcium oxalate lithiasis without urinary tract infection and with normal renal morphology and function. Four weeks after SWL, sex, age, and urinary values of citrate, calcium, and uric acid matched patients who were stone free (N = 56) and patients who had residual stones (N = 34) were independently randomized into two subgroups. While oral Potassium Citrate 60 mEq per day was prescribed to one group, the other group served as controls. The study results reported 0 stone recurrence rate at 12 months in patients who were stone free after SWL and receiving medical treatment. However, untreated patients showed a 28.5% stone recurrence rate. Similarly, in the residual fragment group, the medically treated patients had a significantly greater remission rate than the untreated patients (44.5 vs. 12.5%; P < 0.05). The researchers corroborated the efficacy of Potassium Citrate therapy in significant alleviation of calcium oxalate stone activity after SWL for lower pole stones in patients who were stone free. The study results are indicative of beneficial effect of medical treatment on stone activity after SWL among patients with residual calculi.

Potassium Citrate for Improved Patient Compliance

As stated previously patient compliance is a major issue, expense convenience and palatability are all important and should result in individualization of therapy. Since long-term medical therapy is often required for prevention of recurrence, therefore, high palatability, pleasant taste, and tolerability hold accountability for enabling long-term adherence of patients to the drug. Although all oral citrate supplements may not have a pleasant taste, however, their taste can be improved without altering their beneficial effects and thus improved patient compliance is attainable in majority of cases.²³Mechlin C, Kalorin C, Asplin J, White M. Splenda® improves tolerance of oral Potassium Citrate supplementation for prevention of stone formation: results of a randomized double-blind trial. J Endourol. 2011;25(9):1541-5.   Tolerability of Potassium Citrate has been determined not only in adult but in pediatric population as well.²⁴Tekin A, Tekgul S, Atsu N, Bakkaloglu M, Kendi S. Oral Potassium Citrate treatment for idiopathic hypocitruria in children with calcium urolithiasis. J Urol. 2002;168(6):2572-4.  

References

1. Barnela SR, Soni SS, Saboo SS, Bhansali AS. Medical management of renal stone. Indian J Endocrinol Metab. 2012; 16(2): 236-239.
2. Steggall MJ. Urinary tract stones: causes, complications and treatment. Br J Nurs. 2001;10(22):1452-6.
3. Micali S, Grande M, Sighinolfi MC, De Carne C, De Stefani S, Bianchi G. Medical therapy of urolithiasis. J Endourol. 2006;20(11):841-7.
4. Ngo TC, Assimos DG. Uric Acid Nephrolithiasis: Recent Progress and Future Directions. Rev Urol. 2007; 9(1): 17-27.
5. Trinchieri A, Esposito N, Castelnuovo C. Dissolution of radiolucent renal stones by oral alkalinization with Potassium Citrate/potassium bicarbonate. Arch Ital Urol Androl. 2009;81(3):188-91.
6. Hongshi Xu, Anna L. Zisman, Fredric L. Coe, and Elaine M. Worcester. Kidney stones: an update on current pharmacological management and future directions. Expert Opin Pharmacother. 2013; 14(4): 435-447.
7. Ferrari P, Bonny O. Diagnosis and prevention of uric acid stones. Ther Umsch. 2004;61(9):571-4.
8. Paterson R, Fernandez A, Razvi H, Sutton R. Evaluation and medical management of the kidney stone patient. Can Urol Assoc J. 2010; 4(6): 375-379.
9. Lipkin ME, Preminger GM. Demystifying the Medical Management of Nephrolithiasis. Rev Urol. 2011; 13(1): 34-38.
10. Preminger GM, Sakhaee K, Pak CY. Alkali action on the urinary crystallization of calcium salts: contrasting responses to Sodium Citrate and Potassium Citrate. J Urol. 1988;139(2):240-2.
11. Sakhaee K, Nicar M, Hill K, Pak CY. Contrasting effects of Potassium Citrate and Sodium Citrate therapies on urinary chemistries and crystallization of stone-forming salts. Kidney Int. 1983 ;24(3):348-52.
12. Erickson SB, Vrtiska TJ, Lieske JC. Effect of Cystone on Urinary composition and Stone formation over a one year period. Phytomedicine 2015. 18(10): 863-867.
13. Singh I, Bishnoi I, Agarwal V, Bhatt S. Prospective randomized clinical trial comparing phytotherapy with Potassium Citrate in management of minimal burden (≤8 mm) nephrolithiasis. Urol Ann. 2011; 3(2): 75-81.
14. Zuckerman JM, Assimos DG. Hypocitraturia: Pathophysiology and Medical Management. Rev Urol. 2009; 11(3): 134-144.
15. Morgan MSC, Pearle MS. Medical management of renal stones. BMJ 2016;352:i52.
16. Turk C, Knoll T, Petrik A, Sarica K, Skolarikos A, Straub M, Seitz C. Guidelines on Urolithiasis. European Association of Urology 2015. Available at: http://uroweb.org/wpcontent/ uploads/22-Urolithiasis_LR_full.pdf [Accessed on 2/5/2016].
17. Pearle Ms, Goldfarb DS et al. American urological association guidelines 2014 for management of kidney stones. Available at: https://www.auanet.org/education/guidelines/ management-kidney-stones.cfm. Accessed on 12/5/2016.
18. Nicar MJ, Hsu MC, Fetner C. Urinary response to oral Potassium Citrate therapy for urolithiasis in a private practice setting. Clin Ther. 1986;8(2):219-25.
19. 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(4):658-61.
20. Song Y, Hernandez N, Shoag J, Goldfarb DS, Eisner BH. Potassium Citrate decreases urine calcium excretion in patients with hypocitraturic calcium oxalate nephrolithiasis. Urolithiasis. 2016;44(2):145-8.
21. Pak CY, Sakhaee K, Fuller C. Successful management of uric acid nephrolithiasis with Potassium Citrate. Kidney Int. 1986;30(3):422-8.
22. Soygur T, Akbay A, Küpeli S. Effect of Potassium Citrate therapy on stone recurrence and residual fragments after shockwave lithotripsy in lower caliceal calcium oxalate urolithiasis: a randomized controlled trial. J Endourol. 2002;16(3):149-52.
23. Mechlin C, Kalorin C, Asplin J, White M. Splenda® improves tolerance of oral Potassium Citrate supplementation for prevention of stone formation: results of a randomized double-blind trial. J Endourol. 2011;25(9):1541-5.
24. Tekin A, Tekgul S, Atsu N, Bakkaloglu M, Kendi S. Oral Potassium Citrate treatment for idiopathic hypocitruria in children with calcium urolithiasis. J Urol. 2002;168(6):2572-4.