Effect of KSPtabs Supplementation on Key Urine Parameters Associated
with Kidney Stone Formation (2016)

Allison D. Barger PharmD, Andrew P. Barger CNS, Michael D. Trotter MD

Background
In the United States, the prevalence of nephrolithiasis has doubled since 1972, affecting approximately 1 in 10 people1,2. Most commonly diagnosed in patients 18-74 years of age, the incidence and prevalence of nephrolithiasis is escalating globally and this increase is evident across sex, race, and age2. Nephrolithiasis is a persistent disease, with up to 50% of stone formers developing recurrence after their initial event. The prevalence of nephrolithiasis represents a significant economic burden, with annual estimates exceeding $5 billion (3). This toll includes both treatment costs and also indirect costs associated with loss of patient productivity, as it primarily affects the working-age population. The Healthcare Cost and Utilization Project reported that, in 2009, there were 1.3 million Emergency Department visits for kidney stones, with numbers increasing significantly from year to year3. The direct cause of this increase is unclear, and though global warming is thought to have a role in stone development, changes in dietary practices appear to be a clear driving force influencing these trends (1).

The pathophysiological mechanism responsible for nephrolithiasis is due to disruption in the fine balance between urinary concentrations of certain minerals and salts and the body’s ability to excrete them. Stones form when these compounds that are typically soluble in the urine accumulate as solid crystals within the kidney. As urinary concentrations of these compounds increase, so does the opportunity for stone development, which is why dehydration is a risk factor for the disease. However, this crystal formation is also driven by a chemical component.  Normal urine contains elements and exhibits properties, such as a basic pH, that innately inhibit the development of stones. Some of these inhibitory components are acquired through diet, such as citrate, magnesium and pyridoxine, while others are produced intracellularly during normal metabolic processes. When natural inhibitory components are outweighed by stone-promoting factors (i.e. dehydration, low pH, etc), renal calculi are more likely to form and will continue to grow if the environment for stone formation remains favorable.

Approximately 75% of stones are made up of calcium oxalate; another 5-10% are composed of uric acid. When excreted in urine, citrate and magnesium are known inhibitors of calcium oxalate stones 3. Dietary potassium citrate chelates calcium ions in the urine, increases urine pH, decreases calcium availability and reduces calcium oxalate stones as a result2. Dietary magnesium displaces calcium and directly binds to oxalate in the urine, inhibiting the ability for crystal formation (2). Lemon, lime and orange juices naturally contain high amounts of citrate but low amounts of magnesium, and in combination with increased hydration, are thought to prevent kidney stones. However, these juices have strong disadvantages including taste, patient access, negative effects on tooth enamel and high quantities of vitamin C, which can lead to higher oxalate absorption and acidic urine- properties that actually increase stone formation. Therefore, a safe, alternative kidney stone prophylaxis is required.

Prevention of recurrent nephrolithiasis is key to a patient’s quality of life and can be accomplished with dietary manipulation including increased hydration, reducing salt, animal protein and oxalate intake, while increasing citrate intake1,2. We explored these recommendations and created a supplement, KSP effervescent tablets, to theoretically prevent kidney stone development by increasing urine pH, increasing urinary concentrations of citrate and magnesium while also encouraging overall hydration.

Methods
In this prospective study, participants were chosen out of a population of patients from a Urology practice in Austin, Texas who were known to have a history of nephrolithiasis. Total number of patients in study was 35. Both male and female patients were utilized for the study with an average age of 62 years. Participants were provided KSP supplements and testing materials at no expense. Study participants were not compensated for their time and no travel was required as the urine collection was performed at the participant’s home. The 24-hour urine collection testing kits were provided by Litholink LabCorp specialty testing group (4). The collection kits contained antimicrobial preservatives to maximize sample integrity at room temperature4. Study participants were instructed to urinate in the provided kit and collect each urination for a period of 24-hours and return the kit to LabCorp for analysis. For the control arm of the study, participants were asked to perform a 24-hour urine test prior to utilizing KSP tablets. For the study arm, participants were asked to repeat the 24-hour urine while supplementing with KSP tablets. Participants were provided 5 tubes of supplements, each containing 12 individual tablets, and were asked to dissolve 1 tablet for each 16 ounces of water, three times daily. Participants were instructed to complete a 24-hour urine while utilizing the third tube of effervescent tablets. An end study questionnaire was also utilized. In order to control for dietary influences, participants were asked to maintain a similar diet throughout both arms of the study. Results of each testing period were calculated by LabCorp and provided to the authors for comparison.

Results and Discussion
Several parameters were used for comparison including: overall urine output, urine pH, oxalate, citrate, magnesium, phosphorus, and calcium. Other incidental metabolic changes were compared including urine potassium and ammonium, which were noted, but not intended as study end-points. After comparing pre- and post- KSP supplementation study participants were found to have increased urine output. Prior to KSP supplementation study participants averaged 1.96 liters of urinary output in a 24-hour period. In the follow-up analysis participants averaged 2.94 liters of output, which represents an increase of 50%. Urine pH showed an increase, becoming less acidic, with a 14.5% increase. One study participant was an outlier with more acidic urine after supplementation with KSP tablets. Urine citrate had the largest improvement within the study and post-analysis results showed an average increased citrate output of 128%. Magnesium also increased after supplementation demonstrating a 36% average increase. Noteworthy decreases were obtained in both urine calcium and super saturation of uric acid (ssUA). Urine calcium decreased by 25% and ssUA reduced by 74%. Other metabolic parameters evaluated showed an increase in urinary output of Potassium (37%) and a decrease in both Phosphorus (-26%) and Ammonium (-40%). After study completion and analysis, participants showed increased urine output, increased urine pH, and increased urine citrate, and urine magnesium. Decreased urine calcium and decreased super saturation of uric acid were also observed with KSP supplementation. Overall, study participants did not exhibit significant adverse events (AE) and KSP effervescent tablets were tolerated very well.

Conclusions
KSP effervescent tablets demonstrate a positive impact on stone-inhibiting factors, which in turn could lead to a reduction in urinary crystallization. There was also a significant increase in fluid consumption seen with use of KSPtabs. Patient feedback questionnaire demonstrated a 78% increase in “drinkability” of water. Difficult variables to control in the study obviously include other dietary intake and comorbidities of each individual. KSPtabs has continued to monitor outcomes and is still compiling additional data for analysis. Study parameters included 3 tablets per day and new data is being collected with 2 and 4 tablet use respectively. KSPtabs will continue to update the study to provide further evidence-based information on the product.

References
(1) Romero, V., Akpinar, H., & Assimos, D. (2010). Kidney Stones: A Global Picture of Prevalence, Incidence, and Associated Risk Factors. Reviews in Urology, 12(2-3), E86-E96. Retrieved February 4, 2017, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931286.
(2) Scales, C., Smith, A., Hanley, J., & Saigal, C. (2012). Prevalence of kidney stones in the United States. Eur Urol, 62(1), 160-5. Retrieved February 5, 2017, from https://www.ncbi.nlm.nih.gov/pubmed/22498635.
(3) Hyams, E. S., & Matlaga, B. R. (2014). Economic impact of urinary stones. Transl Androl Urol, 3(3), 278–283. Retrieved February 4, 2017, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4708578.
(4) Laboratory Corporation of America. “Scientific Expertise”. https://www.litholink.com/scientific-expertise.