Abstract
Objective
To study the effect of ascorbic acid (AA) supplementation on urinary pH, metabolic stone workup parameters, and development of de novo urolithiasis in stone-forming patients.
Material and methods
A retrospective review of the patients followed-up at a tertiary stone centre between September 2009 and October 2015 was performed. Patients with recurrent urolithiasis who received AA supplementation as a urinary acidifying agent were included in the study. Detailed metabolic stone work-up, including two 24-hour urine collections obtained pre- and post-AA supplementation were compared. In addition, imaging studies were reviewed to assess the development of de novo urolithiasis.
Results
Twenty-four patients were included in the study with a mean age of 60.6 years and a median daily AA dose of 1000 mg (range: 500–2000 mg). Median follow-up period was 22.6 months (range: 19.7–32.1). After AA supplementation, there was a significant decrease in urinary pH (7.6 vs. 6.9, p=0.02). Although there was no significant increase in the daily oxalate excretion, two patients (8.3%) had their AA dose reduced or discontinued due to de novo hyperoxaluria (342.9 vs 510.2 umol/day; p=0.75). Other serum and urinary parameters did not show any significant changes. Eight (33.3%) patients developed de novo urolithiasis with struvite and carbonate apatite being the major components.
Conclusion
AA supplementation resulted in significantly lower urinary pH in patients with recurrent urolithiasis and alkaline urine pH. Prospective studies are needed to assess whether this reduction in urinary pH is associated with lower stone recurrence rates.
Keywords: Ascorbic acid, dietary supplements, urolithiasis
Introduction
Struvite stones are made of magnesium ammonium phosphate and calcium carbonate apatite. They are formed in alkaline urine through the action of urea-splitting organisms such as Proteus, Klebsiella and Pseudomonas.[1,2] This process is facilitated by the action of urease enzyme that breaks down urea into ammonia and carbon dioxide, which both respectively hydrolyze into ammonia and bicarbonate, thus alkalinizing the urine. This milieu favours formation of struvite and carbonate apatite stones.[1,2] As a potent irreversible inhibitor of bacterial urease, acetohydroxamic acid (Lithostat, Mission Pharmacal, San Antonio, USA), was described in 1965.[3] In a randomized clinical trial, Williams et al.[4] found that 7 patients (36.8%) who received placebo developed de novo urolithiasis when compared with none of the 18 patients who received acetohydroxamic acid (p<0.01).[4] Thus, acetohydroxamic acid could be used as a prophylactic agent against formation of struvite stones. However, this medication is not available in Canada possibly due to its adverse effects such as tremulousness and phlebothrombosis.[4]
According to the latest Canadian Urological Association guidelines, struvite stones do not require a detailed metabolic evaluation since only scarce number of metabolic abnormalities can be identified.[5] However, close radiological and bacteriological monitoring are recommended for those patients. [5] In fact, little could be offered to these patients other than surgical extraction of all struvite stones and antibiotic prophylaxis.
Ascorbic acid (AA) has been studied in the literature regarding to its effects at lowering urinary pH in patients with recurrent urinary tract infections.[6] Results have been controversial. While some studies refuted its acidifying effects, others showed significant reductions in urinary pH after AA supplementation.[7–10] However, none of these studies have examined the acidifying effects of AA in recurrent urolithiasis patients with alkaline urine. The aim of the present study was to assess the effects of AA supplementation on urinary parameters in patients with recurrent urolithiasis and alkaline urine. The primary endpoint was to determine whether AA supplementation lowers urinary pH. Secondary endpoint was to assess its effects on serum and 24-hour urine collection parameters and to assess any changes in stone composition or formation of de novo urolithiasis. The hypothesis of this study was that AA supplementation would result in lower urinary pH and higher urinary oxalate excretion.
Material and methods
Study design
After a review of all patients followed at a tertiary stone clinic between September 2009 and October 2015, 43 patients who received AA supplementation were retrospectively identified and 24 of them met the inclusion criteria and were included in the present study (Figure 1).
Figure 1.
Study design and patient selection
Patients who were prescribed AA supplementation were included. Exclusion criteria consisted of over-the-counter use of AA without prescription, no history of urolithiasis and missing data about urine collection parameters pre- or post-AA supplementation. Clinical, and demographic about patients’ age, gender, AA dosage and the concomitant use of mandelamine or prophylactic antibiotics were collected. Biochemical data about pre- and post-AA metabolic stone work-up including fasting morning urinalysis with pH, two 24-hour urine collections and stone analysis (if available) were collected. Twenty-four-hour urine collection parameters included urine volume, creatinine, calcium, sodium, oxalate, magnesium, phosphorus, potassium, urea nitrogen, uric acid and citrate. Since each metabolic work-up consisted of analysis of 24-hour urine collections obtained at two separate occasions, the worst value for each parameter was used for the present study. Serum parameters analyzed included intact parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH) VD], ionized normalized calcium, creatinine, potassium and uric acid. Patients were followed semiannually with imaging studies (abdominal ultrasound, plain abdominal radiography or abdominal computed tomography) to assess for de novo urolithiasis, defined as progression of already existing urolithiasis or appearance of new urolithiasis.
Statistical analysis
Version 22 of IBM Statistical Package for the Social Sciences Statistics for Windows (IBM SPSS Statistics Armonk, NY, USA) was used to perform statistical analyses. Descriptive data are presented in terms of means and 95% confidence intervals (CI) of the means, or medians and ranges. The Wilcoxon Signed -Rank Test was used to compare the mean (± SD) values for pre- and post-AA supplementation urinary parameters such as pH, volume, creatinine, sodium, calcium, oxalate, magnesium, phosphorus, potassium, urea nitrogen, uric acid, and citrate. In addition, the Wilcoxon Signed-Rank Test was used to compare the mean (± SD) of pre- and post-AA supplementation values for serum parameters such as intact PTH, 25(OH) VD, ionized normalized calcium, potassium, and uric acid. A two-tailed p value of <0.05 was considered statistically significant.
Results
The mean patients’ age was 60.6 years (95% CI: 52.7–68.5) including 11 (45.8%) females. All patients had recurrent urolithiasis and alkaline urine with mean baseline pH of 7.6. Patients were prescribed AA supplementation with a median daily dose of 1000 mg (range 500–2000 mg) to acidify urine. Fifteen patients (63%) were also on prophylactic antibiotics. In addition, 5 patients (21%) were also on mandelamine treatment. The median follow-up time was 22.6 months (range: 19.7–32.1 months). Two patients (8.3%) were not compliant with AA supplementation and another three patients (12.5%) had their total daily dose of AA decreased from the initial dosage to improve compliance. Two patients (8.3%) had their AA dose reduced or discontinued due to de novo hyperoxaluria. There was a statistically significant reduction in mean urinary pH post-AA supplementation (7.6 vs. 6.9; p=0.02) (Figure 2). Furthermore, the 24-hour urinary oxalate excretion increased post-AA supplementation. However, this increase was not statistically significant (342.9 umol/d vs. 510.2 umol/d; p=0.75). In addition, there were no significant differences in other urinary parameters measured (Table 1). Similarly, there were no statistically significant differences between pre- and post-AA serum parameters in terms of intact PTH (p=0.17), 25(OH) VD (p=0.80), ionized normalized calcium (p=0.5), serum creatinine (p=0.18), serum potassium (p=0.13), and serum uric acid (p=0.42) (Table 1).
Figure 2.
Urinary pH pre- and post-AA supplementation
Table 1.
Metabolic stone work-up before, and after ascorbic acid supplementation
| Variable [reference values] | Pre-ascorbic acid supplementation | Post-ascorbic acid supplementation | p | |
|---|---|---|---|---|
| Urinalysis | Urine pH | 7.6 (7.3–7.8) | 6.9 (6.5–7.3) | 0.02 |
| 24-hour | ||||
| Urinary parameters | Volume (mL/d) | 1667 (1299–2035) | 1290 (847–1733) | 0.93 |
| Creatinine (mmol/d) [7.1–17.7] | 8.92 (7.17–10.68) | 7.70 (5.33–10.07) | 0.16 | |
| Sodium (mmol/d) [40–220] | 128 (112–145) | 138 (102–174) | 0.14 | |
| Calcium (mmol/d) [2.5–7.5] | 3.62 (2.83–4.42) | 3.55 (2.53–4.58) | 0.05 | |
| Oxalate(umol/d) [100–480] | 342.9 (285–401) | 510.2 (170–851) | 0.75 | |
| Magnesium (mmol/d) [3.0–5.0] | 2.32 (1.71–2.93) | 2.72 (1.55–3.88) | 0.97 | |
| Phosphorus (mmol/d) [12.9–42.0] | 18.7 (15.7–21.7) | 17.0 (13.1–20.8) | 0.48 | |
| Potassium (mmol/d) [26–77] | 48.7 (40–57.3) | 38.2 (29.4–46.9) | 0.45 | |
| Urea nitrogen (mmol/d) [430–710] | 272 (230–314) | 263 (206–321) | 0.39 | |
| Uric acid (mmol/d) [1.5–4.4] | 2.43 (2.05–2.80) | 2.08 (1.62–2.55) | 0.59 | |
| Citrate (mmol/d) [1.6–4.5] | 1.69 (1.13–2.25) | 1.23 (0.68–1.78) | 0.67 | |
| Serum parameters | PTH intact (pmol/L) [1.60–6.90] | 5.32 (3.90–6.75) | 6.71 (4.54–8.88) | 0.17 |
| 25(OH) VD (nmol/L) [75–250] | 60.4 (47.8–73.0) | 60.0 (36.5–83.5) | 0.80 | |
| Ionized Normalized Calcium (mmol/L) [1.15–1.32] | 1.19 (1.16–1.21) | 1.21 (1.18–1.24) | 0.50 | |
| Creatinine (umol/L) [55–110] | 82 (63–101) | 70 (53–88) | 0.18 | |
| Potassium (mmol/L) [3.5–5.0] | 4.4 (4.2–4.6) | 4.3 (4.0–4.5) | 0.13 | |
| Uric acid (umol/L) [150–470] | 325 (296–354) | 321 (281–360) | 0.42 | |
Data are presented as means and 95% confidence interval. 25(OH) VD: 25-hydroxyvitamin D; AA: ascorbic acid; CI: confidence interval; PTH: parathyroid hormone; UTI: urinary tract infection
Over a median follow-up of 22.6 months, eight out of 24 patients (33.3%) had de novo urolithiasis. Six (75%) of these patients with de novo urolithiasis were also taking mandelamine, prophylactic antibiotics or both. Pre-, and post-AA supplementation stone analyses were available for 17 and 3 patients, respectively (Table 2). Except for 2 patients who formed calcium oxalate stones, pre-AA supplementation stone analysis showed that most patients had struvite or carbonate apatite stones. Interestingly, none of the patients developed uric acid stones or pure calcium oxalate after AA supplementation. Post-AA supplementation stone analyses for the three patients showed the presence of struvite and carbonate apatite stones.
Table 2.
Stone composition before and after ascorbic acid supplementation
| Stone composition | Pre-ascorbic acid supplementation (n=3) | Post-ascorbic acid supplementation (n=17) |
|---|---|---|
| Struvite | 9 (53%) | 2 (67%) |
| Carbonate apatite | 6 (35%) | 1 (33%) |
| Calcium oxalate | 2 (12%) | 0 |
| Uric acid | 0 | 0 |
Discussion
Ascorbic acid supplementation has been studied in the past with regards to its urinary acidifying effects. However, there has been conflicting evidence regarding its efficiency. Furthermore, previous studies mostly focused on AA supplementation in healthy subjects, calcium stone-formers, or patients with recurrent urinary tract infections. However, no study has been performed in patients with struvite stones. In the current study, AA supplementation was used in patients with recurrent urolithiasis and alkaline urine and it resulted in a significant decrease in urinary pH. Similarly, McDonald and Murphy[11] found a significant decrease in urinary pH of twelve patients with indwelling catheter and chronic urinary tract infections (Table 3). Although post-AA urine pH was as low as 5.3, AA supplementation was used only for one day. Furthermore, Murphy et al.[6] studied patients complaining of chronic urinary tract infections associated with chronic indwelling catheters, chronic intermittent catheterization or without catheter. They showed that AA was an effective urinary acidifying agent only in patients with uninfected urine. In patients with infected urine, AA supplementation alone did not result in significant reduction in urinary pH. However, when AA supplementation was combined with antibacterial therapy such as nalidixic acid (negGram), mandelamine, or nitrofurantoin (furadantin), it resulted in significant reduction in urinary pH. This was attributed to the eradication of urease-producing bacteria by the antibacterial agent.[6] While the results of the study by Murphy et al.[6] are congruent with the current study, they did not assess de novo urolithiasis. In another study, 47 calcium stone-forming patients were recruited to receive either 1 or 2 g of AA supplementation per day. There was no significant change in pre- and post-AA supplementation urinary pH with oral intake of either 1 g or 2g amino acid.[7] However, one could argue that the patient population in that study were calcium stone-forming patients who had acidic urinary pH prior to receiving AA. These patients were different from patients in the present study who were stone-forming patients with alkaline urine with mostly struvite or carbonate apatite stones.
Table 3.
Previous studies on ascorbic acid supplementation
| Author | Year | # of patients | Dose of ascorbic acid | Patient population | Baseline urinary pH | Final urinary pH | p | Remarks |
|---|---|---|---|---|---|---|---|---|
| Murphy et al.[6] | 1965 | 38 | 3–6 g/day | 19 patients with chronic catheter, 8 patients with intermittent catheter, 11 patients without catheter | - | - | - | Significant decrease in urinary pH in in patients with uninfected urine. AA was more effective in patients with chronic UTI on prophylactic antibiotics |
| Baxmann et al.[7] | 2003 | 47 | 1 g/day or 2 g/day, for 3 days | Calcium stone-forming patients | 5.8 | 5.8 | >0.05 | AA resulted in increased in urinary oxalate excretion. However, this was not the same population as struvite and carbonate apatite stone-formers in the present study |
| Castello et al.[8] | 1996 | 13 | 2 g/day | Spinal cord injury patients | 5.93 | - | 0.96 | Baseline pH was already acidic. This was randomized control trial |
| Barton et al.[9] | 1981 | 7 | 2 g IV | Healthy subjects | 5.93 | 6.39 | <0.05 | There was a significant rise in urinary pH. However, baseline pH was already acidic |
| Nahata et al.[10] | 1977 | 10 | 4 g/day and 6 g/day | Healthy subjects | 5.6 to 6.5 | Decreased by 0.24 | - | Baseline pH was already acidic |
| McDonald and Murphy[11] | 1959 | 15 | 2.5 g/day for 1 day | Chronic Urinary Tract Infection UTI patients, chronic indwelling catheter patients | 7.4 | 5.3 | <0.1 | - |
| Travis et al.[12] | 1965 | 12 | 2–8 g/m2/day | Pediatric hospitalized patients | 6.0 | >5.5 | - | There was no consistent lowering of urinary pH unless given mandelamine as an adjunct. However, baseline pH was already acidic |
| Hetey et al.[13] | 1980 | 20 | 4 g/day for 5 days | Spinal cord injury patients | 5.4 to 6.03 | Decreased by 0.58 | - | Baseline pH was already acidic. This was randomized control trial |
| Schmidt et al.[14] | 1981 | 4 | 10 g for 5 days | Healthy subjects | - | - | - | There was an increased urinary oxalate excretion from 555 to 966 umol/L/day |
| Takigushi et al.[15] | 1966 | 30 | 1 g/day for 90 days or 2 g/day for 180 days or 2 g/day for 90 days | Healthy subjects | - | - | - | There was no significant increase in urinary oxalate excretion. Oral AA was mostly excreted in the urine as reduced AA |
| Present study | 2017 | 24 | 500 mg–2000 mg/day | Stone-formers with alkaline urine | 7.6 | 6.9 | 0.02 | Patients were mainly struvite and carbonate apatite stone formers. There was no significant rise in urinary oxalate excretion |
Travis et al.[12] analyzed the effect of AA supplementation in hospitalized sick children. They couldn’t find any consistent decrease in urinary pH with high doses of AA (Table 3). However, they were particularly looking to obtain a pH less than 5.5 in order to optimize the effects of methanamine mandelate in the prophylaxis of urinary tract infections, since pH of 5.5 is recommended for optimal conversion of methanamine mandelate to formaldehyde, the active antiseptic moiety.[10,12] Similarly, they have not shown significant reduction in post-AA supplementation urinary pH (Table 3).[8–10,12,13] Similar to Baxmann et al.[7] all of these studies had baseline acidic urinary pH, which could explain lack of significant reduction in post-AA supplementation urinary pH. Unlike previously published papers, the present study has included stone-forming patients with alkaline urine. This could explain why this study showed a significant acidifying effect of AA supplementation.
Baxmann et al.[7] study found that AA supplementation in calcium-stone forming patients resulted in significant hyperoxaluria following both oral intake of 1 g/day and 2 g/day ascorbic acid. However, there was discrepancy in measuring urinary oxalate depending on the assay used. Therefore, urinary oxalate measurements may not have been accurate.[7] In another study, there was a significant increase in urinary oxalate. However, they used daily doses of 10 g AA whereas in the present study 2000 mg was the maximum dosage (Table 3).[14] In the current study, one patient had his AA supplementation discontinued due to de novo hyperoxaluria and another had his dose reduced for the same reason. However, there was no significant increase in mean 24-hour urinary oxalate excretion. This is similar to what Takigushi et al.[15] found. Finally, Schmidt et al.[14] found that at least 25% of AA is excreted in the urine and most AA is excreted in the urine as reduced AA. Therefore, 24-hour urine collections could be used to monitor the development of hyperoxaluria in patients receiving AA supplementation.
Recurrence rates of struvite stones have been reported to range from 30 to 85% within 6 months.[1,16] In this study, 8 (33.3%) patients had de novo stones after a median follow-up of 22.6 months. This is within the reported range of stone recurrence in patients with struvite stones.
Limitations of the present study include its small sample size as well as its retrospective design. Nonetheless, the present study is the first study to demonstrate significant reduction in urinary pH after AA supplementation in patients with recurrent urolithiasis and alkaline urine. In addition, there were no de novo pure calcium oxalate or uric acid stones.
In conclusion, AA supplementation resulted in significantly lower urinary pH in patients with recurrent urolithiasis and alkaline urine pH. Prospective studies are needed to assess whether this reduction in urinary pH is associated with lower stone recurrence rates.
Footnotes
Ethics Committee Approval: Ethics committee approval was received for this study from the ethics committee of McGill University Health Center (MUHC) (Study Code: 15-532-MUHC).
Informed Consent: No informed consent was needed as this was retrospective chart review for quality control study.
Peer-review: Externally peer-reviewed.
Author Contributions: Concept - Y.A.N., A.S., N.F., S.A.; Supervision – Y.A.N., N.F., S.A.; Data Collection and/or Processing - Y.A.N., A.S.; Writing Manuscript - Y.A.N., A.N., N.F., S.A.; Critical Review - Y.A.N., A.N., N.F., S.A.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: This work was supported in part by the Fond de Recherche en Santé du Québec (FRSQ) Research-Scholar Grant to Dr. Sero Andonian and by a grant from the Urology Care Foundation Research Scholars Program and the Boston Scientific Corporation, The Endourological Society, and the “Friends of Joe” to Dr Yasser Noureldin and the Canadian Urological Association Scholarship Foundation-Société Internationale d’Urologie (CUASF-SIU) International Scholarship grant to Dr Yasser Noureldin.
References
- 1.Griffith DP. Struvite stones. Kidney Int. 1978;13:372–83. doi: 10.1038/ki.1978.55. https://doi.org/10.1038/ki.1978.55. [DOI] [PubMed] [Google Scholar]
- 2.Rodman JS. Struvite Stones. Nephron. 1999;81(Suppl 1):50–59. doi: 10.1159/000046299. https://doi.org/10.1159/000046299. [DOI] [PubMed] [Google Scholar]
- 3.Fishbein WN, Carbone PP. Urease Catalysis: II. Inhibition of the enzyme by hydroxyurea, hydroxylamine, and acetohydroxamic acid. J Biol Chem. 1965;240:2407–14. [PubMed] [Google Scholar]
- 4.Williams JJ, Rodman JS, Peterson CM. A randomized double-blind study of acetohydroxamic acid in struvite nephrolithiasis. N Engl J Med. 1984;311:760–64. doi: 10.1056/NEJM198409203111203. https://doi.org/10.1056/NEJM198409203111203. [DOI] [PubMed] [Google Scholar]
- 5.Paterson R, Fernadez A, Razvi H, Sutton R. CUA Guidelines: Evaluation and medical management of the kidney stone patient. Can Urol Assoc J. 2010;4:375–9. doi: 10.5489/cuaj.10166. https://doi.org/10.5489/cuaj.10166. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Murphy FJ, Zelman S, Mau W. Ascorbic Acid as a urinary acidifying agent. 2. Its adjunctive role in chronic urinary infection. J Urol. 1965;94:300–3. doi: 10.1016/S0022-5347(17)63620-6. [DOI] [PubMed] [Google Scholar]
- 7.Baxmann AC, De O G Mendonça C, Heilberg IP. Effect of vitamin C supplements on urinary oxalate and pH in calcium stone-forming patients. Kidney Int. 2003;63:1066–71. doi: 10.1046/j.1523-1755.2003.00815.x. https://doi.org/10.1046/j.1523-1755.2003.00815.x. [DOI] [PubMed] [Google Scholar]
- 8.Castelló T, Girona L, Gómez MR, Mena Mur A, García L. The possible value of AA as a prophylactic agent for urinary tract infection. Spinal Cord. 1996;34:592–3. doi: 10.1038/sc.1996.105. https://doi.org/10.1038/sc.1996.105. [DOI] [PubMed] [Google Scholar]
- 9.Barton CH, Sterling ML, Thomas R, Vaziri ND, Byrne C, Ryan G. Ineffectiveness of intravenous AA as an acidifying agent in man. Arch Intern Med. 1981;141:211–2. https://doi.org/10.1001/archinte.1981.00340020073020. [PubMed] [Google Scholar]
- 10.Nahata MC, Shimp L, Lampman T, McLeod DC. Effect of AA on Urine pH in Man. Am J Hosp Pharm. 1977;34:1234–7. [PubMed] [Google Scholar]
- 11.McDonald DF, Murphy GP. Bacteriostatic and acidifying effects of methionine, hydrolyzed casein, and AA on the urine. N Engl J Med. 1959;261:803–5. https://doi.org/10.1056/NEJM195910152611608. [Google Scholar]
- 12.Travis LB, Dodge WF, Mintz AA, Assemi M. Urinary acidification with ascorbic acid. J Pediatr. 1965;67:1176–8. https://doi.org/10.1016/S0022-3476(65)80223-2. [Google Scholar]
- 13.Hetey SK, Kleimberg ML, Parker WD, Johnson EW. Effect of ascorbic acid on urine pH in patients with ınjured spinal cords. AM J Hosp Pharm. 1980;37:235–7. [PubMed] [Google Scholar]
- 14.Schmidt K, Hagmaier V, Hornig DH, Vuilleumier J, Rutishauser G. Urinary oxalate excretion after large intakes of ascorbic acid in man. Am J Clin Nut. 1981;34:305–11. doi: 10.1093/ajcn/34.3.305. [DOI] [PubMed] [Google Scholar]
- 15.Takiguchi H, Furuyama S, Shimazono N. Urinary Oxalic Acid Excretion by Man Following Ingestion of Large Amounts of Ascorbic Acid. J Vitaminol. 1966;12:307–12. https://doi.org/10.5925/jnsv1954.12.307. [Google Scholar]
- 16.Wong H, Riedl RL, Griffith DP. Medical management and prevention of struvite stones. In: Coe FL, Favis MJ, Pak CC, et al., editors. Kidney stones: Medical and surgical management. Lippincott-Raven; Philadelphia: 1996. pp. 941–50. [Google Scholar]