Oral Dissolution Therapy of Uric Acid Stones: A Systematic Review

Abstract

Background/Objectives: Uric acid stones are the second most common type of kidney stones worldwide. Despite being cost-effective and widely available, pharmacological management for these stones is less utilized compared to surgical approaches. Therefore, we conducted a systematic review of the literature to assess the efficacy and shortcomings of oral dissolution therapy for uric acid stones. Methods: Embase, Scopus, PubMed, and Cochrane library databases were searched for English language studies on adults who were diagnosed with uric acid kidney stones and treated with oral dissolution therapy. Results: Twelve studies met our inclusion criteria. Potassium citrate was the primary agent used for dissolution in 10 of the studies and demonstrated a 50% or higher success rate for complete dissolution of uric acid stones. Treatment time for successful dissolution varied, with an average of 3 months minimum and an average of 2.78 years maximum. Overall, 11 of the studies recommended that oral dissolution therapy should be used for either treatment or prevention of uric acid stones. Conclusions: The available evidence demonstrates benefit of oral dissolution therapy for patients with uric acid stones. However, future rigorous studies are required to determine the optimal treatment regimen.

1. Introduction

Urolithiasis affects about 12% of the world population and is increasing in prevalence [1]. Uric acid stones comprise 3–10% of all urinary tract stone types, making them the third most common [2]. Risk factors for uric acid stone formation are predominantly decreased urinary pH and hyperuricosuria [3]. Persistently low urinary pH has been hypothesized to be associated with uric acid nephrolithiasis, primarily as a consequence of acid-base chemistry. In an acidic environment, urate that has been excreted in urine turns into the insoluble form of uric acid and eventually precipitates into stones [4]. Increased uric acid in the urine (>800 mg in men and >750 mg in women) or bloodstream (>7 mg/dL in men and >6 mg/dL in women) can be caused by diet, certain medications, metabolic disorders, or genetic conditions [5]. Uric acid is one of the metabolized byproducts of purines. [6] Purine-rich dietary sources include animal proteins such as red meats, poultry, and fish and have been shown to both increase urinary uric acid and decrease urine pH [6].

Gout is another risk factor that has been strongly associated with uric acid stone formation. This relationship is proposed to be due to both hyperuricemia as well as a defect in renal ammonia production which subsequently increase urine uric acid [7]. Additionally, myeloproliferative disorders can increase cell turn over and release of nucleic acids that lead to hyperuricemia, hyperuricosuria, and, ultimately, uric acid stone formation [5,8]. Drug-induced hyperuricemia can also be caused through different mechanisms by diuretics, anti-tubercular drugs, immunosuppressive agents, and others [9].

Although the etiology of uric acid stones is relatively well understood, optimal treatment modalities are still the subject of ongoing research. Currently, the American Urological Association and European Association of Urology recommendations for treatment of uric acid stones include lifestyle changes, pharmacological management, and/or surgical management [10,11]. Uric acid stones are the only type of kidney stones that have shown success with oral pharmacologic therapy through urinary alkalinization. These agents are typically oral alkaline citrate such as potassium or sodium bicarbonate [12]. As oral citrate is metabolized, it undergoes proton consumption, resulting in alkalosis that inhibits citrate reabsorption by the sodium dicarboxylate cotransporter in the proximal tubule [13]. Potassium salts also aid in citrate urinary excretion, leading to an overall increased urinary citrate and thus higher urine pH [14]. Similarly, oral sodium bicarbonate is excreted into the urine, making it more alkaline [12]. Elevating urinary pH to a target pH between 6.5 and 7.0 creates unfavorable conditions for uric acid stone growth and promotes dissolution [3]. Urate-lowering agents, such as allopurinol and febuxostat, may also be prescribed for stone patients with concurrent hyperuricemia and gout, but are not primarily prescribed to address their uric acid stone burden [15]. Despite being a noninvasive and accessible option, oral dissolution therapy (ODT) is not commonly prescribed. This is particularly noteworthy, given patients typically prefer conservative treatments over surgical management [16]. An effective, standardized oral pharmacotherapy option for uric acid stones could be beneficial for both patients and providers. Currently, there is limited information on the efficacy, optimal dosing, and duration of available dissolution treatments. In this systematic review, we aim to investigate the different types of oral dissolution treatments available and their efficacy in treating uric acid stones.

2. Materials and Methods

2.1. Search Strategy

Cochrane guidelines and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist were utilized to perform this review. The databases searched included Embase, Scopus, PubMed, and Cochrane library (latest search June 18, 2021). The search terms included: ‘uric acid kidney stones’, ‘uric acid kidney stone treatment’, ‘uric acid nephrolithiasis’, ‘uric acid nephrolithiasis treatment’, ‘citrate treatment for uric acid kidney stones’, ‘sodium bicarbonate treatment for uric acid stones’, ‘urine alkalization and uric acid stones’, ‘potassium citrate and uric acid stones’, ‘low purine diet and uric acid stones’, ‘allopurinol and uric acid stones’, ‘hydration and uric acid stones’. Terms were combined using Boolean operators. Two review authors (RT and BL) independently reviewed the search results and identified studies that appeared to meet the inclusion criteria, and any discrepancy was resolved after discussion with the senior author (KS). Research was limited to studies done in English on patients 18 years old or older who were diagnosed with uric acid kidney stones and treated with ODT.

2.2. Assessment of Risk of Bias in Included Studies

We used the Cochrane Risk of Bias Tool (RoB 2) [17] to assess risk of bias for the randomized controlled trials. The five Rob 2 domains assessed for each study included: bias arising from the randomization process, bias due to deviations from intended intervention, bias due to missing outcome data, bias in measurement of the outcome, and bias in selection of the reported result. For each domain and for an overall assessment, the study was rated as ‘low’, ‘some concern’, ‘high’, or ‘unclear’ risk of bias. For non-randomized studies, the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) [18] assessment tool was used. Each of the identified non-randomized studies was assessed against seven ROBINS-I domains: bias due to confounding, bias due to selection of participants, bias in classification of interventions, bias due to deviations from intended interventions, bias due to missing data, bias in measurement of outcomes, and bias in selection of the reported result. For each risk domain and for an overall assessment, the study was rated as ‘low’, ‘moderate’, ‘serious’, ‘critical’, or ‘no information’. The Risk of Bias Visualization Tool (ROBVIS) [19] was used to display the results.

2.3. Protocol Registration

This protocol was registered on the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) database [20].

3. Results

From the database searches, 5426 articles were identified (Figure 1). After screening all abstracts, 5412 were excluded for being out of the scope of this review. 18 articles were read in full and 12 met the inclusion criteria.

Figure 2 and Figure 3 display the risk of bias domain ratings for each study. The overall risk of bias for non-randomized studies was judged to be as ‘low’ or ‘moderate’ across all studies. Similarly, the overall risk of bias for the one randomized controlled study was determined to be ‘some concerns’.

3.1. Participant Characteristics

In total, the 12 studies involved 957 participants. Overall, the sample sizes were small—only 42% of the studies had more than 50 participants [21,22,23,24,25]. The mean age of participants, recorded in eight of the studies, was 57 years [21,23,26,27,28,29,30,31]. Median age was reported in two studies as 63 [24] and 46 [25]. Age was not reported in two studies [22,32]. Other baseline characteristics of the articles reviewed are reported in Table 1.

Of the 12 studies included, eight were retrospective [22,24,25,26,27,29,30,32], three were prospective [21,23,31] cohort studies, and one was a randomized controlled trial [28].

3.2. Interventions

3.2.1. Potassium Citrate

Potassium citrate therapy was used as a primary oral dissolution agent in 10 studies [21,22,23,24,25,27,29,30,31,32], often supplemented with allopurinol in cases of hyperuricemia, hyperuricosuria, or history of gout [22,24,25,27,29,30]. Treatment regimens and results for all studies are outlined in Table 2.

Increased fluid intake to 2L or more per day alongside dietary recommendations to reduce intake of purine-rich foods were explicitly prescribed in adjunct to treatment in several studies [21,22,24,29,32]. Elsawy et al. [21] conducted a large prospective cohort study in which they treated 182 patients with solitary or multiple stones in the kidney with Uralyt-U (potassium citrate 20 mEq) and supplemental allopurinol for hyperuricemia. All patients were treated for 3 to 6 months, until stone-free status was achieved. At 3 months post treatment, 53.3% of subjects had complete dissolution, 35.7% had partial, and 11.1% had none. Notably, by 6 months, 83% of subjects achieved complete stone dissolution.

Another prospective cohort study by Salem et al. [23] evaluated the efficacy of Uralyt-U (potassium sodium hydrogen citrate) and the role of ureteral double J (DJ) stents in 139 patients with solitary uric acid renal calculi. 47 patients required ureteral stents due to residual stones after percutaneous nephrolithotomy, migrated stone after ureteroscopy, pyelonephritis, painful impaction, or elevated creatinine. After an average of 3 months of treatment, 64.1% of patients without stents and 66% with stents achieved complete stone dissolution.

In a smaller prospective study, Trinchieri et al. [31] enrolled eight patients with renal uric acid stones. Initially, all patients were instructed to maintain 1500 mL of daily water intake for 6 weeks. For another 6 weeks, patients received potassium citrate 40 mEq and potassium bicarbonate 20 mEq in addition to the water. Following treatment, complete dissolution occurred in three (37.5%) patients and partial dissolution occurred in the remaining five (62.5%).

The effect of urinary alkalization was also evaluated through several retrospective studies. Tsaturyan et al. [24] conducted a large retrospective study on 216 patients with renal or ureteral uric acid stones who were treated with potassium citrate, sodium bicarbonate, or magnesium bicarbonate ODT. Potassium citrate 20 mEq three times daily was prescribed for patients with good renal function and adapted based on urine pH. Stent or nephrostomy was placed prior to treatment for patients with acute renal function impairment, intolerable pain, or pyelonephritis from stone obstruction. Alternatively, sodium bicarbonate or magnesium bicarbonate was given to patients with chronic renal insufficiency or those who could not tolerate potassium citrate. After 3 months of treatment, complete dissolution was observed for 58.5% of patients.

Petritsch et al. [22] also performed a retrospective study, looking at 140 patients with known uric acid stones in the kidney or ureter who were given a mixture of Uralyt-U (sodium + potassium citrate + citric acid) to alkalinize their urine pH to between 6.2 to 7. Although precise treatment duration was not specified, patients were monitored by intravenous urogram every 6–8 weeks until complete dissolution was shown. Overall, complete dissolution rate was 80%.

Table 1. Patient and stone characteristics in all studies.

Study	Country	Design	N *	Patient Age (Years)	Gender Distribution	Weight or BMI	Number of Stones	Stone Size	Stone Density (HU)	Location of Stone	Definition of Treatment Success, Partial Success, or Failure
Alsinnawi et al. 2016 [26]	UK	Retrospective	23	Mean: 59; range: 21–78	18 M; 9 F	Mean weight: 97 kg; range: 70–127 kg	>/=1	Mean: 9.8 mm, median: 7 mm, range: 4–40 mm	N/A	Renal	Success: >50% dissolution partial: <50% dissolution failure: no dissolution
Elsawy et al. 2019 [21]	Egypt	Prospective	182	Mean: 51 +/− 11	M and F, exact count N/A	Mean BMI (success and failure): 35 +/− 7	>/=1	Mean surface area: 1.3 cm3, range: 0.16–11.84 cm3	N/A	Renal	Success: complete stone dissolution Partial: any reduction in stone surface area Failures: no change or increased surface area
Gridley et al. 2019 [27]	USA	Retrospective	21	Mean: 55.8; range: 42–70	13 M; 8 F	Mean BMI: 43.7; range: 23.9–69.8 mean BMI: 41.1 (complete responders), 48.4 (partial)	>/=1	Mean: 30.9 mm; range: 8–66 mm	Mean: 403.9 (SD = 17.9)	Renal or ureteric	Success: complete stone clearance or punctate stones (1–2 mm) on imaging Partial: reduction in total stone burden yet persistence of kidney stones
Hernandez et al. 2020 [28]	Spain	Prospective, RCT	47	Mean: 60.4 +/− 10.1	42 M; 5 F	Mean BMI: 30.2 +/− 4.7	N/A	N/A	N/A	Renal	N/A
Moore et al. 2021 [29]	USA	Retrospective	27	Mean: 64.8 (complete or partial responders), 62.3 (non-responders)	23 M; 4 F	Mean BMI: 32.2 (responders), 34 (non-responders); range: 22–84	>/=1	Range: 4.5–40.5 mm	Mean (partial/complete responders): 375 (SD 58.5); range 264–455 non-responders: mean 458 (SD 172); range 248–900	Renal or ureteric	Success: stone no longer visible on CT Partial: residual stone at end of follow-up Failure: stone burden increased or remained stable
Petrisch et al. 1977 [22]	Austria	Retrospective	140	N/A	M and F, exact count N/A	N/A	>/=1	N/A	N/A	Renal or ureteric	Success: complete dissolution and patient free of symptoms
Salem et al. 2019 [23]	Egypt	Prospective	139	Mean: 45.1 +/− 10.5 range: 22–70	74 M; 65 F	N/A	1	Mean: 17 ± 5.7 mm (responders), 19.2 ± 6.1 mm (nonresponders); range 5–30 mm	<600 HU; mean (responders): 347.3 (SD 68.5); mean (nonresponders): 428.9 (SD 84)	Renal	Success: complete stone dissolution or residual that measures up to 2 mm in max length
Sinha et al. 2013 [32]	India	Retrospective	48	N/A	N/A	Mean weight: 58 kg (success); 68.9 (failure)	N/A	Range: 14.8–15.67 mm	N/A	N/A	Success: complete or partial dissolution Partial: at least a 50% reduction in stone size Failure: no change, inadequate reduction, increase in stone size and those refusing to take the tablets due to upper gastrointestinal side effects
Sterrett et al. 2008 [30]	USA	Retrospective	10	Mean: 57	5 M; 5 F	N/A	N/A	N/A	N/A	N/A	Success: no radiographic evidence of significant stone burden (>3 mm) on KUB or noncontract CT Noncompliance: missing > 50% of appts in 1 year or noncompliant with medications
Trinchieri et al. 2009 [31]	Italy	Prospective	8	Mean: 66	4 M; 4 F	N/A	N/A	≤15 mm	N/A	Renal	Success: complete dissolution Partial: not defined
Tsaturyan et al. 2020 [24]	Switzerland	Retrospective	216	Median: 63; range: 52–74	162 M; 54 F	Median BMI: 29.4; range: 25.9–33.8	>/=1	Median: 9.0 mm; range: 7.0–15.0 mm	<450 HU; median: 430; IQR: 360–500	Renal and ureteric	Success: absence of any visible stone fragments on non-contrast CT Failure: partial (median 36.6% reduction of stone IQR 20.0–61.8) and no response
Yunhua et al. 2020 [25]	China	Retrospective	96	Median: 46; range: 23–76	49 M; 47 F	Mean BMI: 23.1; BMI < 30 kg/m	>/=1	Mean: 13 mm; range: 6–29 mm	N/A	Renal	Success: >50% decrease in or the number of stones with diameter >5 mm decreased

* Number of patients who completed treatment. BMI: Body Mass Index; CT: Computerized Tomography; F: Female; HU: Hounsfield Units; IQR: Interquartile Range; KUB: Kidney Ureter Bladder X-Ray; M: Male; N/A: Not available; RCT: Randomized Control Trial; UK: United Kingdom; USA: United States of America.

Table 1. Patient and stone characteristics in all studies.

Study	Country	Design	N *	Patient Age (Years)	Gender Distribution	Weight or BMI	Number of Stones	Stone Size	Stone Density (HU)	Location of Stone	Definition of Treatment Success, Partial Success, or Failure
Alsinnawi et al. 2016 [26]	UK	Retrospective	23	Mean: 59; range: 21–78	18 M; 9 F	Mean weight: 97 kg; range: 70–127 kg	>/=1	Mean: 9.8 mm, median: 7 mm, range: 4–40 mm	N/A	Renal	Success: >50% dissolution partial: <50% dissolution failure: no dissolution
Elsawy et al. 2019 [21]	Egypt	Prospective	182	Mean: 51 +/− 11	M and F, exact count N/A	Mean BMI (success and failure): 35 +/− 7	>/=1	Mean surface area: 1.3 cm3, range: 0.16–11.84 cm3	N/A	Renal	Success: complete stone dissolution Partial: any reduction in stone surface area Failures: no change or increased surface area
Gridley et al. 2019 [27]	USA	Retrospective	21	Mean: 55.8; range: 42–70	13 M; 8 F	Mean BMI: 43.7; range: 23.9–69.8 mean BMI: 41.1 (complete responders), 48.4 (partial)	>/=1	Mean: 30.9 mm; range: 8–66 mm	Mean: 403.9 (SD = 17.9)	Renal or ureteric	Success: complete stone clearance or punctate stones (1–2 mm) on imaging Partial: reduction in total stone burden yet persistence of kidney stones
Hernandez et al. 2020 [28]	Spain	Prospective, RCT	47	Mean: 60.4 +/− 10.1	42 M; 5 F	Mean BMI: 30.2 +/− 4.7	N/A	N/A	N/A	Renal	N/A
Moore et al. 2021 [29]	USA	Retrospective	27	Mean: 64.8 (complete or partial responders), 62.3 (non-responders)	23 M; 4 F	Mean BMI: 32.2 (responders), 34 (non-responders); range: 22–84	>/=1	Range: 4.5–40.5 mm	Mean (partial/complete responders): 375 (SD 58.5); range 264–455 non-responders: mean 458 (SD 172); range 248–900	Renal or ureteric	Success: stone no longer visible on CT Partial: residual stone at end of follow-up Failure: stone burden increased or remained stable
Petrisch et al. 1977 [22]	Austria	Retrospective	140	N/A	M and F, exact count N/A	N/A	>/=1	N/A	N/A	Renal or ureteric	Success: complete dissolution and patient free of symptoms
Salem et al. 2019 [23]	Egypt	Prospective	139	Mean: 45.1 +/− 10.5 range: 22–70	74 M; 65 F	N/A	1	Mean: 17 ± 5.7 mm (responders), 19.2 ± 6.1 mm (nonresponders); range 5–30 mm	<600 HU; mean (responders): 347.3 (SD 68.5); mean (nonresponders): 428.9 (SD 84)	Renal	Success: complete stone dissolution or residual that measures up to 2 mm in max length
Sinha et al. 2013 [32]	India	Retrospective	48	N/A	N/A	Mean weight: 58 kg (success); 68.9 (failure)	N/A	Range: 14.8–15.67 mm	N/A	N/A	Success: complete or partial dissolution Partial: at least a 50% reduction in stone size Failure: no change, inadequate reduction, increase in stone size and those refusing to take the tablets due to upper gastrointestinal side effects
Sterrett et al. 2008 [30]	USA	Retrospective	10	Mean: 57	5 M; 5 F	N/A	N/A	N/A	N/A	N/A	Success: no radiographic evidence of significant stone burden (>3 mm) on KUB or noncontract CT Noncompliance: missing > 50% of appts in 1 year or noncompliant with medications
Trinchieri et al. 2009 [31]	Italy	Prospective	8	Mean: 66	4 M; 4 F	N/A	N/A	≤15 mm	N/A	Renal	Success: complete dissolution Partial: not defined
Tsaturyan et al. 2020 [24]	Switzerland	Retrospective	216	Median: 63; range: 52–74	162 M; 54 F	Median BMI: 29.4; range: 25.9–33.8	>/=1	Median: 9.0 mm; range: 7.0–15.0 mm	<450 HU; median: 430; IQR: 360–500	Renal and ureteric	Success: absence of any visible stone fragments on non-contrast CT Failure: partial (median 36.6% reduction of stone IQR 20.0–61.8) and no response
Yunhua et al. 2020 [25]	China	Retrospective	96	Median: 46; range: 23–76	49 M; 47 F	Mean BMI: 23.1; BMI < 30 kg/m	>/=1	Mean: 13 mm; range: 6–29 mm	N/A	Renal	Success: >50% decrease in or the number of stones with diameter >5 mm decreased

* Number of patients who completed treatment. BMI: Body Mass Index; CT: Computerized Tomography; F: Female; HU: Hounsfield Units; IQR: Interquartile Range; KUB: Kidney Ureter Bladder X-Ray; M: Male; N/A: Not available; RCT: Randomized Control Trial; UK: United Kingdom; USA: United States of America.

Table 2. Study characteristics and results.

Study	N *	Duration of Treatment	Treatment	N in Each Group	Results N (%) of Each Treatment Group
Alsinnawi et al. 2016 [26]	23	Mean: 9 weeks			Complete dissolution	Partial dissolution	No dissolution
			Sodium bicarbonate 2 g TID increased to 2 g QD, according to urinary pH		9 (39%)	2 (9%)	10 (43%)
Elsawy et al. 2019 [21]	182	3–6 months			Complete dissolution	Partial dissolution	No dissolution
			Uralyt-U (PC 20 mEq) TID + AP 300 mg QD for hyperuricemia	N/A	At 3 months: 97 (53.3%) At 6 months: 151 (83%)	65 (35.7%)	20 (11%)
Gridley et al. 2019 [27]	21	Median: 20 months; range 2–72			Complete dissolution	Partial dissolution	No dissolution
			PC 20 mEq TID	10	7 (70%)	3 (30%)
			PC 30 mEq BID	3	2 (66.7%)	1 (33.3%)
			PC 30 mEq TID	8	5 (62.5%)	3 (37.5%)
			PC + AP 100 mg QD	3	2 (66.7%)	1 (33.3%)
			PC + AP 300 mg QD	13	9 (69.2%)	4 (30.8%)
Hernandez et al. 2020 [28]	47	14-day treatment + 7-day washout + 14-day alternate treatment			Risk of uric acid crystallization
			Citrate BID (0.653 mmol K-Cit + 0.933 mmol Mg-Cit)	N/A	Lower than baseline
			Citrate + theobromine BID (0.653 mmol K-Cit + 0.933 mmol Mg-Cit + 0.333 mmol theobromine extract)	N/A	Lower than baseline and lower than citrate alone
Moore et al. 2021 [29]	27	Median: 154 days; range 41–312			Complete or partial dissolution	No Response
			PC	14	4 (28.6%)	10 (71.4%)
			Sodium bicarbonate	2	1 (50%)	1 (50%)
			PC + sodium bicarbonate	10	5 (50%)	5 (50%)
			Any AP	8	3 (37.5%)	5 (62.5%)
Petritsch et al. 1977 [22]	140	Until dissolution (monitored every 6–8 wks)			80% complete dissolution
			Sodium + PC + citric acid (Uralyt U)	N/A
			Sodium + PC + citric acid (Uralyt U) + AP for uricemia	N/A
Salem et al. 2019 [23]	139	Mean: 3 months			Complete dissolution	No dissolution
			Potassium sodium hydrogen citrate (Uralyt-U) TID, evening dose doubled	92	59 (64.1%)	33 (35.9%)
			Potassium sodium hydrogen citrate (Uralyt-U) + double J stent	47	31 (66%)	16 (34%)
Sinha et al. 2013 [32]	48	Mean: 103.6 ± 89 days			Complete dissolution	Partial dissolution	No dissolution
					10 (20.8%)	13 (27%)	25 (52%)
			Potassium magnesium citrate (7 mEq potassium, 3.5 mEq magnesium and 10.5 mEq of citrate) 2 tablets TID	39
			Potassium magnesium citrate (7 mEq of potassium, 3.5 mEq of magnesium and 10.5 mEq of citrate) 1 tablet TID	5
			Potassium magnesium citrate (7 mEq of potassium, 3.5 mEq of magnesium and 10.5 mEq of citrate) 9 tablets QD	3
			Potassium magnesium citrate (7 mEq of potassium, 3.5 mEq of magnesium and 10.5 mEq of citrate) 15 tablets QD	1
Sterrett et al. 2008 [30]	10	Mean: 46.1 months; range: 11–86
			PC (20 mEq TID) + AP 600 mg	1	Development of new stone
			PC (20 mEq TID) + AP 600 mg	1	Multiple stones and interventions required
			PC (20 mEq TID) + AP 300 mg + Acetazolamide (500 mg QHS)	1	No further stones after starting acetazolamide
			PC (20 mEq TID) + Acetazolamide (250mg qAM + 500 mg QHS)	1	Slight growth of previous stone while taking acetazolamide
			PC (20 mEq TID) +Acetazolamide (500 mg QHS)	1	Slight growth and calcification of previous stone on acetazolamide
Trinchieri et al. 2009 [31]	8	3 months			Complete dissolution	Partial dissolution
			1500 mL water QD for 6 weeks	8	0%	0%
			1500 mL water QD + (PC 20 mEq + potassium bicarbonate 10 mEq) BID	8	3 (37.5%) had complete stone dissolution at 6 weeks; 2 (25%)% had complete dissolution after 4 and 6 months	5 (62.5%) at 6 weeks
Tsaturyan et al. 2020 [24]	216	3 months			Complete dissolution	Partial or no dissolution
					127 (58.8%)	89 (41.2%)
			PC 20 mEq TID	202
			Sodium bicarbonate	22
			Magnesium bicarbonate	1
			ODT + AP 100–300 mg/day for hyperuricemia or history of gout	N/A
Yunhua et al. 2020 [25]	90	6 months			Maximum stone diameter decreased by >50%
			PC + AP 300 mg/d (100 mg TID)	31	16 (51.6%)
			PC + febuxostat 40 mg/d (40 mg QD, F40 group)	29	17 (58.6%)
			PC + febuxostat 80 mg/d (40 mg BID, F80 group)	30	22 (73.3%)

* Number of patients who completed treatment. AP: Allopurinol; BID: two times a day; F40: Febuxostat 40 mg); F80: Febuxostat 80 mg; N/A: Not available; PC: Potassium citrate; TID: three times a day; qAM: every morning; QD: once a day; QHS: once a day at bed time.

Table 2. Study characteristics and results.

Study	N *	Duration of Treatment	Treatment	N in Each Group	Results N (%) of Each Treatment Group
Alsinnawi et al. 2016 [26]	23	Mean: 9 weeks			Complete dissolution	Partial dissolution	No dissolution
			Sodium bicarbonate 2 g TID increased to 2 g QD, according to urinary pH		9 (39%)	2 (9%)	10 (43%)
Elsawy et al. 2019 [21]	182	3–6 months			Complete dissolution	Partial dissolution	No dissolution
			Uralyt-U (PC 20 mEq) TID + AP 300 mg QD for hyperuricemia	N/A	At 3 months: 97 (53.3%) At 6 months: 151 (83%)	65 (35.7%)	20 (11%)
Gridley et al. 2019 [27]	21	Median: 20 months; range 2–72			Complete dissolution	Partial dissolution	No dissolution
			PC 20 mEq TID	10	7 (70%)	3 (30%)
			PC 30 mEq BID	3	2 (66.7%)	1 (33.3%)
			PC 30 mEq TID	8	5 (62.5%)	3 (37.5%)
			PC + AP 100 mg QD	3	2 (66.7%)	1 (33.3%)
			PC + AP 300 mg QD	13	9 (69.2%)	4 (30.8%)
Hernandez et al. 2020 [28]	47	14-day treatment + 7-day washout + 14-day alternate treatment			Risk of uric acid crystallization
			Citrate BID (0.653 mmol K-Cit + 0.933 mmol Mg-Cit)	N/A	Lower than baseline
			Citrate + theobromine BID (0.653 mmol K-Cit + 0.933 mmol Mg-Cit + 0.333 mmol theobromine extract)	N/A	Lower than baseline and lower than citrate alone
Moore et al. 2021 [29]	27	Median: 154 days; range 41–312			Complete or partial dissolution	No Response
			PC	14	4 (28.6%)	10 (71.4%)
			Sodium bicarbonate	2	1 (50%)	1 (50%)
			PC + sodium bicarbonate	10	5 (50%)	5 (50%)
			Any AP	8	3 (37.5%)	5 (62.5%)
Petritsch et al. 1977 [22]	140	Until dissolution (monitored every 6–8 wks)			80% complete dissolution
			Sodium + PC + citric acid (Uralyt U)	N/A
			Sodium + PC + citric acid (Uralyt U) + AP for uricemia	N/A
Salem et al. 2019 [23]	139	Mean: 3 months			Complete dissolution	No dissolution
			Potassium sodium hydrogen citrate (Uralyt-U) TID, evening dose doubled	92	59 (64.1%)	33 (35.9%)
			Potassium sodium hydrogen citrate (Uralyt-U) + double J stent	47	31 (66%)	16 (34%)
Sinha et al. 2013 [32]	48	Mean: 103.6 ± 89 days			Complete dissolution	Partial dissolution	No dissolution
					10 (20.8%)	13 (27%)	25 (52%)
			Potassium magnesium citrate (7 mEq potassium, 3.5 mEq magnesium and 10.5 mEq of citrate) 2 tablets TID	39
			Potassium magnesium citrate (7 mEq of potassium, 3.5 mEq of magnesium and 10.5 mEq of citrate) 1 tablet TID	5
			Potassium magnesium citrate (7 mEq of potassium, 3.5 mEq of magnesium and 10.5 mEq of citrate) 9 tablets QD	3
			Potassium magnesium citrate (7 mEq of potassium, 3.5 mEq of magnesium and 10.5 mEq of citrate) 15 tablets QD	1
Sterrett et al. 2008 [30]	10	Mean: 46.1 months; range: 11–86
			PC (20 mEq TID) + AP 600 mg	1	Development of new stone
			PC (20 mEq TID) + AP 600 mg	1	Multiple stones and interventions required
			PC (20 mEq TID) + AP 300 mg + Acetazolamide (500 mg QHS)	1	No further stones after starting acetazolamide
			PC (20 mEq TID) + Acetazolamide (250mg qAM + 500 mg QHS)	1	Slight growth of previous stone while taking acetazolamide
			PC (20 mEq TID) +Acetazolamide (500 mg QHS)	1	Slight growth and calcification of previous stone on acetazolamide
Trinchieri et al. 2009 [31]	8	3 months			Complete dissolution	Partial dissolution
			1500 mL water QD for 6 weeks	8	0%	0%
			1500 mL water QD + (PC 20 mEq + potassium bicarbonate 10 mEq) BID	8	3 (37.5%) had complete stone dissolution at 6 weeks; 2 (25%)% had complete dissolution after 4 and 6 months	5 (62.5%) at 6 weeks
Tsaturyan et al. 2020 [24]	216	3 months			Complete dissolution	Partial or no dissolution
					127 (58.8%)	89 (41.2%)
			PC 20 mEq TID	202
			Sodium bicarbonate	22
			Magnesium bicarbonate	1
			ODT + AP 100–300 mg/day for hyperuricemia or history of gout	N/A
Yunhua et al. 2020 [25]	90	6 months			Maximum stone diameter decreased by >50%
			PC + AP 300 mg/d (100 mg TID)	31	16 (51.6%)
			PC + febuxostat 40 mg/d (40 mg QD, F40 group)	29	17 (58.6%)
			PC + febuxostat 80 mg/d (40 mg BID, F80 group)	30	22 (73.3%)

* Number of patients who completed treatment. AP: Allopurinol; BID: two times a day; F40: Febuxostat 40 mg); F80: Febuxostat 80 mg; N/A: Not available; PC: Potassium citrate; TID: three times a day; qAM: every morning; QD: once a day; QHS: once a day at bed time.

Similarly, Yunhua et al. [25] conducted a retrospective study of 90 patients with radiolucent nephrolithiasis and hyperuricemia at a single institution in China. All patients were given potassium citrate in combination with either: allopurinol 100 mg three times daily for the control group, febuxostat 40 mg daily (F40), or febuxostat 80 mg daily (F80). After 6 months of treatment, maximum stone diameter was decreased by more than 50% in 73.3% patients in the F80 group, 58.6% of the F40 group, and 51.6% of the control group.

In a smaller single-institution retrospective study, Gridley et al. [27] examined dissolution of stones in a cohort of 21 patients with nonobstructive uric acid calculi in the renal pelvis or ureter who were treated with potassium citrate alone or in combination with allopurinol. Patients were treated for a median of 20 months (range 2–72 months). Notably, 7 (70%) of the patients taking potassium citrate 20 mEq TID and 9 (69.2%) of the patients on combined potassium citrate and allopurinol 300 mg daily experienced complete dissolution.

Moore et al. [29] conducted a retrospective study on 27 patients who were given ODT for uric acid stones in the kidney and/or ureter. Treatments included potassium citrate alone, sodium bicarbonate alone, their combination, or allopurinol. Sodium bicarbonate was only given if patients had a history of hyperkalemia or renal dysfunction or as a second line therapy for intolerance to higher doses of potassium citrate. Potassium citrate was started at 20–30 mEq split over 2–3 doses daily, and titrated based on tolerance, pH, and side effects to achieve a target treatment pH of 6.5–7.0. Treatment duration was a median of 154 days (range 41–312 days). Out of the fourteen patients taking potassium citrate alone, four (28.6%) experienced complete or partial dissolution. The other group sizes were smaller and complete or partial dissolution was seen in 1 (50%) patient taking sodium bicarbonate alone, 5 (50%) on potassium citrate and sodium bicarbonate combined, and 3 (37.5%) taking allopurinol.

In a retrospective analysis of a single institution in India, Sinha et al. [32] examined 48 patients who were given potassium citrate and magnesium oxide tablets to treat uric acid calculi in unspecified areas of the urinary tract. Patients were started on 978 mg tablets and the dose was adjusted to maintain a urine pH between 6 and 7. Treatment duration was a mean of 103.6 days. Overall complete dissolution and partial dissolution rates were 20.8% and 27.0%, respectively.

Through a retrospective chart review, Sterrett et al. [30] identified 10 patients treated with acetazolamide in adjunction to potassium citrate for uric acid or cystine stones, with only half having uric acid stones relevant for this review. The medical regimen included 20 mEq potassium citrate three times daily, with acetazolamide 500 mg added for patients whose urine pH remained below 6.5 after two follow-up appointments using potassium citrate alone. Adverse effects of acetazolamide (i.e., nocturia, paresthesia, gastrointestinal intolerance, nausea) prompted discontinuation of acetazolamide in two individuals. The exact treatment regimens are reported in Table 2. On average, patients received therapy for 46.1 months (range 11–86 months). Only one patient with a uric acid stone achieved stone free status.

3.2.2. Bicarbonate

Although some studies looked at sodium bicarbonate in adjunct to other ODTs, Alsinnawi et al. [26] performed a retrospective study of 23 patients with renal uric acid stones who were treated with sodium bicarbonate therapy alone. Sodium bicarbonate was initiated at a dose of 2 g three times daily and titrated to five times daily to maintain a urine pH of at least 7. After an average of 9 weeks post treatment, 9 (39%) of patients attained complete dissolution while 2 (9%) had partial dissolution.

3.2.3. Citrate

A double blind, randomized cross over trial was performed by Hernandez et al. looking at the efficacy of citrate alone or citrate with theobromine in patients with a history of renal uric acid lithiasis [28]. A risk of uric acid crystallization (RUAC) test was used to measure the ability of urine to inhibit the crystallization of uric acid. Patients were randomly assigned to one group for 14 days, underwent a 7-day washout period, then crossed over to the alternate treatment for an additional 14 days. Citrate tablets (0.653 mmol K-Cit + 0.933 mmol Mg-Cit) or citrate theobromine tablets (0.653 mmol K-Cit + 0.933 mmol Mg-Cit + 0.333 mmol theobromine extract) were given twice daily. The total duration of the study was 35 days, with 28 days of active treatment. Patients’ urine was added to wells and hydrochloric acid and/or uric acid were added to the wells to promote the crystallization of uric acid. They found that the combination of citrate and theobromine was more effective at reducing uric acid crystallization than citrate monotherapy.

3.3. Effects of Interventions Summarized

3.3.1. Primary Outcomes

Urinary pH was measured across all studies throughout the treatment course to measure alkalinization progress. The metrics for success, partial success, and failure for each study are summarized in Table 1. Seven of the ten studies using potassium citrate combination therapy were found to have a greater than 50% success rate for complete dissolution of uric acid stones [21,22,23,24,25,27,29], with two surpassing 80% success [21,22]. Notably, both high success rate studies included patients who were given allopurinol in addition to the potassium citrate therapy, though the amount of allopurinol was not specified [21,22]. It is also important to note that three studies with over 50% full or partial success rate had small cohorts with fewer than 30 participants [27,29,31]. Only two studies using potassium citrate combination therapy reported minimal improvement in dissolution [30,32]. Treatment with sodium bicarbonate monotherapy resulted in complete dissolution for 39% of patients who completed treatment [26]. One study showed that treatment with citrate and citrate theobromine reduced the risk of uric acid crystallization [28].

3.3.2. Secondary Outcomes

There were conflicting findings from the studies with regards to secondary outcomes.

Alsinnawi et al. associated higher serum uric acid levels with better dissolution response while Sinha et al. found that lower serum uric acid levels significantly improved dissolution rates [26,32].

When considering patient characteristics, Sinha et al. found that the gender of the patient did not affect success rate. Elsawy et al. found that higher HbA1c after ODT predicted a poor response to ODT [21]. Three studies found that lower weight/BMI correlated with successful results [27,29,32], and Sinha et al. confirmed it was a significant predictor for success rate [32]. In contrast, two studies found that there was no association between BMI and success rate of oral chemolysis [21,24].

Outcomes regarding stone size were also mixed. Two studies indicated that larger uric acid stones were correlated with better treatment outcomes [26,32], while two studies reported that smaller stones correlated with better outcomes [23,24]. Moore et al. proposed that total stone volume is a better predictor of stone dissolution rate than mean diameter [29].

Some studies evaluated whether pH affected ODT success [21,25,31,32]. Elsawy et al. found that higher urine pH (6.7 +/− 0.4 vs. 6.4 +/− 0.7, p = 0.02) measured at 8 weeks of treatment was significantly associated with stone-free status at 6 months [21]. Trinchieri et al. demonstrated that potassium citrate/bicarbonate significantly increased mean urinary pH in comparison to water only (morning 6.60 +/−1.06 vs. 5.53 +/− 0.51, p = 0.030; afternoon 6.53 +/− 0.70 vs. 5.63 +/− 0.41, p = 0.007; night 6.57 +/− 0.51 vs. 5.98 +/− 0.80, p = 0.092) [31]. Meanwhile, Yunhua et al. suggested that although potassium citrate successfully alkalinized urine (p < 0.001), there were no significant differences among the groups in pH at baseline or at the 6th month after treatment (p = 0.659 and 0.987), therefore differences were attributed to urate-lowering drugs (febuxostat or allopurinol) [25]. Sinha et al. found that study participants with successful dissolution had more acidic urine at presentation, but that urine pH did not significantly affect dissolution (p = 0.11) [32].

Some studies looked at how additional instruments played a role in oral dissolution management. Sinha et al. found that stenting before alkalinization significantly improves dissolution rate (p = 0.039) [32], but Salem et al. found no significant effect (p = 0.832) [23].

Regarding calcium crystallization with dissolution therapy use, Hernandez et al. found that using low dose citrate prevented the crystallization of insoluble calcium phosphates [28].

Side effects and adverse reactions were also an important component of treatment efficacy. Hernandez et al. found that using citrate ODT led to fewer undesirable side effects [28]. Gastrointestinal upset was the most commonly mentioned side effect throughout eight of the studies [21,22,23,25,27,29,30,32]. Other commonly reported side effects reported were: bad taste [23], difficulty swallowing the pill, electrolyte imbalances [23,24,29], renal colic [29], or UTI/Acute pyelonephritis [27]. Some side effects were only reported in single studies: liver dysfunction, nonobstructive renal dysfunction, abnormal complete blood count, hyperlipidemia, abnormal myoenzymes, hypersensitivity [25], nocturia, paresthesia in upper extremities, malaise, and mixed uric acid calcium oxalate stone formation [30]. Two studies reported that no adverse effects were reported [28,31] and one did not assess for side effects [26].

3.3.3. Study Conclusions

Ten studies recommended ODT to treat uric acid stones [21,22,23,24,25,26,27,29,31,32]. Meanwhile, one study recommended ODT to prevent uric acid stones [28]. Sterrett et al. concluded that acetazolamide in combination with potassium citrate is effective in increasing urinary pH but did not address if this therapy is recommended for dissolution or prevention of stones [30].

4. Discussion

The main findings of this systematic review are that ODTs are an effective potential option for either treating or preventing uric acid stones. This finding is supported by the risk of bias tool which evaluated the rigor of the primary studies in this review and demonstrated that there were no studies with high or serious concerns. However, due to the heterogeneity in treatment regimens and criteria for treatment success (Table 1 and Table 2), direct comparison of these regimens is challenging.

Despite the lack of consensus on the optimal therapeutical regimen, solutions containing potassium citrate, especially Uralyt-U, were the most commonly used therapy and showed effective dissolution. However, it is important to note that Uralyt-U formulations exhibit slight variations depending on the manufacturer. In general, the most successful outcomes were observed in studies that had used potassium citrate 20 mEq three times daily. Interestingly, some of the studies in this systematic review demonstrated that when potassium citrate was combined with other drugs such as allopurinol, tamsulosin, or febuxostat, there were better outcomes. Overall, these studies demonstrated that at least half of patients with uric acid stones may benefit from ODT—however the small size of some of the studies must also be considered.

This finding has implications for general patient management as it can decrease the number of patients who undergo surgery for treatment of uric acid stones. An effective medical option could be beneficial for both providers and patients. This would help institutions facing challenges with high operating room expenses, limited operating room availability, and personnel shortages. It would also allow patients a more affordable and less invasive option that would not require them to skip work or family obligations for a procedure. Furthermore, ODT could be an especially helpful solution for patients who are low-income or in low-resource settings. In a study comparing the cost effectiveness of medical dissolution treatment versus surgical treatment, Nevo et al. found that when dissolution was achieved, the cost was approximately 10% of that of surgical treatment [33]. However, it is important to note that only one third of their patients were able to successfully use ODT alone.

Poor adherence to medication is a common problem with ODT [34]. In this systematic review, gastrointestinal upset was found to be the main complaint while using ODT, which is a common side effect of many drugs. However, since this side effect caused noncompliance for many participants across the studies, it will be important to address gastrointestinal issues either prophylactically or immediately once symptomatic while starting this treatment. Another challenging aspect of ODT is patients having to monitor their own urinary pH and adjust their treatment dose accordingly for optimal results. This step could be time-consuming and impractical for some participants, making perfect use unlikely. In addition, having to take multiple timed doses per day creates additional challenges for perfect compliance. Therefore, standardized treatment protocols could be a possible way to effectively overcome this barrier.

While results varied regarding the time required for dissolution, many of the studies with at least 50% success rate took an average treatment duration of a minimum of 3 months to a maximum of 2.78 years. The extended treatment time necessary for dissolution may be impractical for patients with obstructing ureteral stones. Furthermore, only one study specifying the presence of stones in the ureter indicated that these stones were nonobstructive, making it challenging to assess the impact of longer treatment durations on patients with painful obstruction. In some of the studies in this review, ureteral stents were inserted along with medical management to prevent obstruction. While one study showed that stents aided in dissolution rate, another found they have no effect. Until further studies can clarify their utility in dissolution, stent use or indwelling time should be minimized since prolonged use carries the risk of encrustation and infection [35].

Overall, we suggest that for patients with known or suspected nonobstructive uric acid stones in the renal pelvis, ODT with potassium citrate may be considered as an initial course of treatment. This option is worthwhile to try to minimize stone size or allow full dissolution before more costly and higher-risk surgical interventions are attempted. Although there is not an established surveillance protocol for patients with uric acid stone burden, unenhanced CT has high sensitivity and can help determine if further treatment is needed after a trial of ODT [36].

5. Limitations

Most of the 12 studies had retrospective study designs and only one was a randomized controlled trial, making it difficult to assess the cause and effect of ODT clearly. Additionally, the article by Petritsch was written over 40 years ago from the time of this systematic review and may have not met some of the rigorous requirements expected now for scientific reporting.

6. Conclusions

Despite the limitations in some of the studies, overall, our analysis suggests that ODT should be considered in clinical practice to treat uric acid stones, particularly for patients with comorbidities such as diabetes and obesity that place them at higher risk for surgical treatment. To clarify an optimal ODT regimen and enhance the rigor of the analysis, future multi-institutional randomized control trials should be carried out.