Date written: January 2025 – Public comment

Authors: CARI Kidney Stones Working Group

GUIDELINE RECOMENDATIONS
Practice Points

    • Nutrition therapy should be considered before pharmacological interventions, except for patients with the following conditions, who may benefit from simultaneous nutrition and pharmacological therapy (LINK):
      • Uric acid stones where alkali therapy has a primary role
      • Profound hypocitraturia (<0.5mmoL/24 hours)
      • Severe hypercalciuria (>10mmoL/24 hours)
      • Cystinuria
      • High symptom burden

Potassium citrate

  1. We recommend potassium citrate for people with recurrent kidney stones with hypocitraturia and/or low urine pH that persists despite nutrition therapy.
    (Strong recommendation, moderate certainty of the evidence)

Practice Points

    • Tablet formulations of potassium citrate are preferred due to improved tolerability and ease of use.
    • Potassium citrate is used to increase both urine citrate and pH.
    • Urine pH and citrate should be assessed after treatment is established to tailor dosing.
    • Recommended starting doses for potassium citrate:
  • Liquid: 3mmoL per mL, 5mL dose twice per day
  • Tablet: 1080mg, 1.5 tablets twice per day
  • For severe hypocitraturia, a higher dose of 2160mg three times daily may be required
    • Guidance for target urine citrate and urine pH levels:
Parameter Stone type Recommendation
Target urine citrate All stone types (excluding struvite/infection-related) >2.0 mmol/24 hours
Target urine pH Calcium oxalate/unknown 5.8 – 6.2
Uric acid 6.0 – 7.0
Calcium phosphate <6.0 and readdress indication
Cystine 7.0 – 8.0 (1, 2)
Struvite/infection-related Avoid alkalinisation
    • Potassium citrate should be avoided in the management of struvite stones and infection-related kidney stones.
    • Sodium bicarbonate is an appropriate alternative when potassium citrate is contraindicated or poorly tolerated. Monitor for potential increases in urine sodium and, consequently, calcium.
    • Over-alkalinisation of the urine with either potassium citrate or sodium bicarbonate increases the risk of calcium phosphate stones and should prompt a reduction in dose or cessation of therapy.
    • Monitoring for hyperkalaemia with potassium citrate may be necessary for patients with CKD. A single check may be sufficient once a maintenance dose has been established and the kidney function is stable.

Thiazide diuretics

  1. We suggest the use of thiazide diuretic for people with recurrent kidney stones and persistent hypercalciuria following nutrition therapy focused on fluid intake, sodium restriction, and normal calcium intake.
    (Conditional recommendation, low certainty of the evidence)

Practice Points

    • Long-acting thiazide diuretics (chlorthalidone) are preferred over short-acting thiazide diuretics (hydrochlorothiazide).
    • Repeat 24-hour urine collection after treatment commencement and/or dose adjustment is necessary to assess response.
Titrate thiazide diuretics to reduce urine calcium excretion to within reference intervals and considering baseline results. The minimum effective dose should be used and consideration given to potential side-effects.
24-hour urinary sodium is a reliable marker to assess sodium intake and efficacy of nutrition therapy.
Effectiveness of thiazides is optimised when combined with dietary sodium restriction.

Xanthine oxidase inhibitors

  1. We suggest against the routine use of xanthine oxidase inhibitors in people with recurrent kidney stones, unless indicated for prevention of gout.
    (Conditional recommendation, low certainty of the evidence)

Practice Points

  • Urinary alkalinisation is the main strategy for uric acid kidney stone prevention, with nutrition intervention first-line, and potassium citrate if additionally needed to reach target pH.
  • Xanthine oxidase inhibitors can be considered for individuals with recurrent uric acid stones and hyperuricosuria despite optimising urine pH.
  • Management of gout should take precedence over kidney stone prevention when considering the indication for xanthine oxidate inhibitors.

Other pharmacological treatments

Cystinuria

Practice Points

    • Nutrition therapy and potassium citrate are suggested as parallel first-line strategies for cystinuria management. Nutrition therapy focuses on a high urine volume and reduced sodium intake to decrease urine cystine concentration. (LINK).
    • The addition of potassium citrate aims to alkalinise the urine and increase cystine solubility for patients with cystinuria.
    • Currently, pharmacological treatment to manage cystinuria is available in Australia and New Zealand (thiol drugs) but should only be considered when nutrition therapy is insufficient.

Hyperoxaluria

Practice points

    • First-line nutrition strategies for management of hyperoxaluria are detailed in the nutrition therapy guidelines subtopic (LINK).
  • Currently pharmacological treatment to manage hyperoxaluria is not available in Australia and New Zealand.

Scope of the guidelines

These guidelines deal with pharmacological prevention of kidney stones in adults. Other clinical practice guidelines should guide pharmacological prevention of kidney stones in children.

Background

The incidence and prevalence of stones in the kidney and urinary tract is increasing worldwide (3), and the limited data from Australia and Aotearoa New Zealand, also indicates similar trends (4-6). Interventions to ablate or surgically remove kidney stones have increased in our region (7). In contrast, the rates of pharmacological interventions to prevent kidney stones are unknown despite being recognised as a cost-effective method for preventing stone recurrence (8). Pharmacological interventions for the prevention of recurrent kidney stones are recommended by urology societies globally (9, 10); a recent observational study in a large Veterans Affairs population demonstrated that the use of preventative pharmacological therapy is associated with a lower risk of acute stone episodes (11). However, a recent large RCT raises doubts about the efficacy of short-acting thiazide diuretics in the prevention of kidney stones (12). There is a need for updated guidance on managing kidney stones in the Australian and Aotearoa New Zealand context. Please note that the guideline development methods are available in Appendix 1, and the search strategy is detailed in Appendix 2.

Implementation and audit

All pharmacological medication for the management of kidney stone recurrence should be considered in a shared decision-making process between clinicians and people with lived experience of kidney stones. Using potassium citrate is an important foundation of management in people with kidney stones due to its low cost and efficacy in reducing kidney stone recurrence. The prescription of potassium citrate tablets rather than potassium citrate solutions is preferred due to greater tolerability and as an indicator of appropriate clinical care.

Guideline recommendations

Practice Points

Nutrition therapy should be considered before pharmacological interventions, except for patients with the following conditions, who may benefit from simultaneous nutrition and pharmacological therapy (LINK):

Uric acid stones where alkali therapy has a primary role

Profound hypocitraturia (<0.5mmoL/24 hours)

Severe hypercalciuria (>10mmoL/24 hours)

Cystinuria

High symptom burden

Rationale
  • Further details on first-line nutrition therapy can be found in Nutrition Therapy section of the guidelines (LINK).

Potassium citrate

We recommend potassium citrate for people with recurrent kidney stones with hypocitraturia and/or low urine pH that persists despite nutrition therapy.
(Strong recommendation, moderate certainty of the evidence)

Rationale

The evidence indicates that citrate therapy, compared to control, decreases the risk of recurrence for people with calcium-containing stones. However, the treatment is not well tolerated, and many participants of clinical studies withdrew due to adverse effects. The poor tolerability of powdered potassium citrate was highlighted at the CARI Guidelines Kidney Stones Workshops in Auckland and Whangārei, New Zealand, in May 2021. The tolerability of therapy needs to be carefully considered when implementing potassium citrate therapy to ensure the best outcomes for people at risk of recurrent stone formation. Potassium citrate is most commonly used in Australia and New Zealand, while alternatives, such as sodium bicarbonate and citro-tartrate powder, may increase urine sodium and calcium (13). Considering the evidence of benefits and manageable harms of therapy, as well as the ease of access to potassium citrate over the counter, the Working Group agreed upon a strong recommendation for treatment.

Benefits and harms

The CARI evidence review identified two relevant systematic reviews of RCTs (14, 15). Phillips et al. 2015 (15), a Cochrane review, assessed the safety and efficacy of citrate therapy for preventing recurrence in people with calcium-containing kidney stones. Across the seven RCTs that met inclusion criteria (477 participants), citrate therapy (potassium citrate, potassium-sodium, potassium-magnesium) compared to control decreased new stone formation (6 studies; RR = 0.24, 95% CI: 0.15, 0.41; I2 = 0%) and was associated with a reduction in stone size (4 studies; RR = 1.97, 95% CI: 1.19, 3.26; I2 = 0%). There were no differences between subgroups in terms of types of citrate used; however, more studies examined potassium citrates than any other types of citrate. Contrastingly, the review found that withdrawal due to adverse events was increased with citrate therapy compared to control (4 studies; RR = 4.45, 95% CI: 1.28, 15.50; I2 = 0%). Carvalho et al. 2017 (14) examined the effectiveness of citrate supplements for preventing nephrolithiasis recurrence in people undergoing extracorporeal shock wave lithotripsy (ESWL) across four RCTs with 374 participants. The review found that potassium citrate therapy after ESWL compared to ESWL alone decreased stone recurrence (4 studies; RR = 0.21, 95% CI: 0.13, 0.31; I2 = 29.7%).

Additionally, we identified four RCTs (13, 16-18) that were not included in the identified systematic reviews because their duration of follow-up was less than 6 months. The studies mainly examined changes in urinary concentration of uric acid, urate and calcium, and only one study reported no difference in clinical outcomes of stone recurrence (18).

Certainty of the evidence

The overall certainty of the evidence was moderate. All the included studies in the Cochrane review (15) demonstrated methodological limitations for unclear reporting of allocation concealment. Carvalho et al. 2017 had insufficient information to assess the risk of bias in the included studies (14). The additional identified studies were all small trials with limitations in study design, according to our Cochrane Risk of Bias assessment.

Preferences and values

The participants in the CARI Guidelines kidney stones workshops in New Zealand unanimously described how the unpleasant taste of the liquid form of potassium citrate solution negatively impacted adherence. In addition to the taste, the liquid was difficult to administer, as the prescription would only be a few millilitres per dose and, often, the potassium citrate liquid would become viscous and sticky over time with storage. The liquid form is also inconvenient from a portability perspective. If readily available, tablets rather than liquid form should be prescribed in Australia and New Zealand to improve patients’ tolerability and the practicality of adhering to this therapy. Alternative citrates, including sodium bicarbonate and citro-tartrate powder are much more tolerable, though often clinically avoided for calcium stone producers because of their high sodium content. Sodium bicarbonates have been shown to increase urine sodium and urine calcium compared to potassium citrate in a cross-over randomised controlled trial of people at risk of recurrent calcium containing kidney stones (13).

Equity

The guideline recommendation has been developed using well-established equity frameworks in guidelines and evidence synthesis (19, 20), as described previously. The included RCTs are small and have had little examination of important subgroups across the PROGRESS-Plus checklist. However, the Working Group recognises that, uniquely in Australia and New Zealand, rural and remote communities experience lower access to healthcare, including kidney health (21, 22). Potassium citrate is available at most pharmacies and online, as there is no scheduling requirement for their use. Despite the limited data, the Working Group does not consider that inequity will be entrenched based on the recommendation for potassium citrate use.

Resources and other considerations

To the Working Group’s knowledge, there has been no evaluation of the cost-effectiveness of potassium citrate for managing recurrent kidney stones. The government does not schedule potassium citrate for use in Australia and Aotearoa New Zealand; they are freely available over the counter. As a result, there are out-of-pocket costs for consumers associated with these therapies.

Practice Points
Tablet formulations of potassium citrate are preferred due to improved tolerability and ease of use.

Rationale

The consumer involvement workshops conducted in Aotearoa New Zealand highlighted that the liquid form of potassium citrate were unpalatable and difficult to administer. The participants described storage issues and lack of portability of the liquid form, and there was a preference for tablet form of potassium citrate, which are currently unavailable (January 2025) in Aotearoa New Zealand, but widely available in Australia.

Potassium citrate is used to increase both urine citrate and pH.
Urine pH and citrate should be assessed after treatment is established to tailor dosing.
Recommended starting doses for potassium citrate:
Liquid: 3mmoL per mL, 5mL dose twice per day
Tablet: 1080mg, 1.5 tablets twice per day
    • For severe hypocitraturia, a higher dose of 2160mg three times daily may be required.
Guidance for target urine citrate and urine pH levels:
Parameter
Stone type
Recommendation
Target urine citrate
All stone types (excluding struvite/infection-related)
>2.0mmoL/24 hours
Target urine pH
Calcium oxalate/unknown

Uric acid

Calcium phosphate

Cystine

Struvite/infection-related

5.8 – 6.2

6.0 – 7.0

<6.0 and readdress indication

7.0 – 8.0 (1)

Avoid alkalinisation

Potassium citrate should be avoided in the management of struvite stones and infection-related kidney stones.
Sodium bicarbonate is an appropriate alternative when potassium citrate is contraindicated or poorly tolerated. Monitor for potential increases in urine sodium and, consequently, calcium.

Rationale

A cross-over randomised controlled trial found that both potassium citrate and sodium bicarbonate effectively increased urine citrate and pH. However, the sodium bicarbonate in comparison does increase urine sodium and urine calcium (13). The increase of urine sodium and urine calcium may increase the risk of recurrence for people with calcium-containing kidney stones.

Over-alkalinisation of the urine with either potassium citrate or sodium bicarbonate increases the risk of calcium phosphate stones and should prompt a reduction in dose or cessation of therapy.

Rationale

It is important that first-line nutrition therapy includes healthy eating patterns (23, 24), following the recommended dietary intake of calcium to prevent formation of calcium phosphate stones. Additionally, it is important to balance acid load to prevent over alkalinisation of the urine. Please see the Nutrition therapy guidelines (LINK).

Monitoring for hyperkalaemia with potassium citrate may be necessary for patients with CKD. A single check may be sufficient once a maintenance dose has been established and the kidney function is stable.

Thiazide diuretics

We suggest the use of thiazide diuretic for people with recurrent kidney stones and persistent hypercalciuria following nutrition therapy focused on fluid intake, sodium restriction, and normal calcium intake. (Conditional recommendation, low certainty of the evidence)

Rationale

Thiazide diuretics decrease calcinuria by increasing calcium reabsorption at the proximal tubule; the decreased urine calcium may lead to reduced formation of kidney stones (25). The synthesised evidence on thiazide diuretics demonstrated a benefit in decreasing recurrent kidney stones (26). However, trials prior to 2023 were conducted with largely unknown dietary recommendations and unclear reporting of randomised controlled trials (RCTs) methods. In a large RCT (12), where participants were prescribed concomitant adequate fluid and low sodium intake in line with current recommendations, thiazide diuretics had little to no benefit on symptomatic or radiological stone recurrence, and were associated with increased harm.

Although there was a decrease in radiological recurrence of kidney stones, there were concerns regarding the NOSTONE participants’ adherence to recommended diets. Around half of the participants in this trial exhibited high urinary sodium excretion, i.e., greater than 168 mmol per day, at baseline, while the mean urinary sodium excretion at the end of follow up was even higher, i.e., greater than 181 mmol per day; this may have diminished the potential positive effect of hydrochlorothiazide (27).

In our meta-analysis, when the results of the NOSTONE trial were combined with those of previous studies, thiazides continued to demonstrate a decrease in kidney stone recurrence, with the effect evident in long-acting thiazides but not short-acting thiazides (28). Additionally, we found that, in studies where high fluid and low sodium diets were recommended for participants, thiazide diuretics had little to no effect compared to control. Thiazide diuretics are widely available at a low cost to people with recurrent kidney stones and are the second most cost-effective method, outside of nutrition, for the prevention of recurrent kidney stones. Given the low certainty of the evidence, especially considering recent evidence of no effect of thiazide diuretics on kidney stone recurrence, the Working Group agreed on a conditional recommendation for the use of thiazide diuretics in managing kidney stone recurrence.

Benefits and harms

The literature identified one relevant systematic review of RCTs comparing thiazide diuretics to placebo or no treatment in people with kidney calculi or hypercalciuria (26). The review included eight RCTs with 571 participants. Compared to placebo, thiazide diuretics may decrease the incidence of recurrent kidney stones (RR = 0.44, 95% CI: 0.33, 0.58; I2 = 21%). Seventy percent of participants were people with recurrent kidney stones, with a larger proportion of people with first-time kidney stones in the control group (42%) compared to the intervention group (19%). The systematic review also demonstrated that thiazide diuretics, compared to control, decreased 24-hour urinary calcium (SMD = –18.59, 95% CI: –25.11, –12.08; I2 = 99%). The review also reported on side-effects such as such as fatigue, dizziness, and muscle soreness, while hypotension and hypokalemia resulted in participants in the treatment group withdrawing from the study.

Our search also identified two additional RCTs not included in the published systematic review (26). Tehranchi et al. 2013 (29), a single-centre RCT conducted in Iran with 52 participants with a history of nephrolithiasis surgery found a probable increase in the stone-free rate for participants receiving thiazide treatment within 3 months and no difference in side effects. Dhayat et al. 2023 (12) conducted a double-blind RCT with 416 people with recurrent calcium-containing kidney stones across 12 centres in Switzerland. The study found that hydrochlorothiazide (12.5 mg, 25 mg, 50 mg) compared to placebo after 2.9 years resulted in no difference in symptomatic or radiological recurrence of kidney stones. Compared to placebo, hydrochlorothiazide resulted in more events of hypokalemia, gout, and new-onset diabetes mellitus. Importantly, Dhayat et al. 2023 was conducted in modern settings with clear reporting of randomisation and allocation concealment, as well as current recommendations of increased fluid intake and lower sodium intake; however, participant adherence to these recommendations has been questioned, with low urine outputs and high urine sodium indicated throughout the trial.

Our review of the findings from Dhayat et al. 2023 (12), when combined with data from the Li et al. 2020 systematic review (26), found that there may be a decrease in symptomatic recurrence of kidney stones for patients prescribed thiazide diuretics (9 studies, n = 997, RR = 0.64, 95% CI: 0.29, 0.84; I2 = 68%; absolute effects: 203 fewer per 100,000 people, 95% CI: 284 fewer, 72 fewer) (28). The effect was similar between studies that reported >50% of participants with hypercalciuria and those without; however, sensitivity analyses demonstrated effect modification. Short-acting thiazides demonstrated no effect compared to placebo, while long-acting thiazides reduced recurrence (test for subgroup differences p = 0.02, I2 = 82.8%). The long-acting thiazides decreased kidney stone recurrence by over 60% (4 RCTs, n = 382, RR = 0.38, 95% CI: 0.25, 0.57).

Additionally, studies that compared thiazide diuretic to no treatment may have overestimated the treatment effect, when examined against studies that compared thiazides to placebo (test for subgroup differences; p = 0.002, I2 = 68%). Studies that reported appropriate allocation concealment methods found no effect of thiazides on kidney stone recurrence, while studies with unclear reporting demonstrated a benefit of thiazide diuretics (test for subgroup differences p = 0.02, I2 = 82.8%).

Certainty of the evidence

The certainty of the evidence is low. There is inconsistency across the studies, with the systematic review (26) identifying a benefit of thiazide diuretic compared to placebo in stone recurrence, while Dhayat et al. 2023 RCT (12) demonstrated no difference compared to placebo for stone recurrence. The sensitivity analyses further illustrate the low certainty of the evidence, with effect modification evident across multiple characteristics and risk of bias domains. The systematic review included RCTs of variable quality, with many having unclear ratings for risk of bias across the domains, indicating methodological limitations of the included studies.

Preferences and values

A qualitative study examining the experiences of people with kidney stones (30), which included 33 adults (22–85 years of age) of primarily Irish descent, the majority being men (58%) and people with recurrent kidney stones (63%), reported patients’ ongoing experiences of frustration, primarily due to living with a condition characterised by unknown occurrence and high frequency of symptomatic episodes, which requires a state of constant vigilance about potential recurrence. Some study participants described pharmacological management as the only means of managing symptoms like renal colic. However, no specific effects of pharmacological management on recurrence were described. Further, the study highlighted the role of self-management strategies in increasing one’s control, such as changing diet and fluid intake, alongside healthcare professional support to manage medication adherence.

The key findings from the consumer workshops conducted by CARI Guidelines in Aotearoa New Zealand also supported the Irish qualitative study. Participants shared the psychological burden of constant underlying anxiety and stress attached to the ‘unknown’.

“You feel like you’re going back to square one [when another episode happens]. You start the cycle again. You’ll be absolutely fine, and you forget all about it… It takes a toll…”

Equity

The Working Group considered the GRADE equity framework in developing these guidelines (19). The PROGRESS PLUS checklist (20) considers of residence, socioeconomic status, age, race, ethnicity, culture, and language; however, importantly, many of these factors are interrelated and cannot be dealt with in isolation. The RCTs included in the systematic reviews and the additional RCTs have mainly been conducted in high-income countries and male populations, with the recent trial conducted in a majority white population (12). Although kidney stones have historically had a higher prevalence in men, there is a growing prevalence in females (31). Additionally, at our kidney stones workshops held in Aotearoa New Zealand, female participants described often being dismissed, as they did not present as the typical kidney stones patients.

“I actually struggled to get care initially. It was really hard to get anyone to help me. I couldn’t get any care.”

“Because I didn’t fit the criteria, they were like, “You don’t have any of the… [another participant] “… you’re not a 60-year-old man…” “… Quite a few doctors said to me, “Oh, you know, I might think kidney stones, but you just don’t fit the demographic…”

The included studies have not examined any gender differences. Additionally, limited reporting of other important socioeconomic variables provides insufficient information with which to analyse these differences. However, the Working Group recognises that, uniquely in Australia and New Zealand, rural and remote communities experience lower access to healthcare, including kidney health (21, 22). Furthermore, CARI Guidelines recognise the importance of culture, inclusion of family, and kinship in health-related decision-making for Māori in Aotearoa New Zealand and Aboriginal and Torres Strait Islander Peoples in Australia, and have developed guidelines specifically focused on improving equity of access (32, 33). Despite the limited data available for assessment, the Working Group considers that the recommendation will not entrench inequities across these demographics due to relatively suitable access to the treatment via public subsidy. However, these subgroups, particularly gender, must be considered in implementing thiazide diuretics for people with recurrent kidney stones.

Resources and other considerations

It is well established that, outside of treatment via nutrition therapy, medical management (including thiazide diuretics) is the second most cost-effective treatment of kidney stone recurrence (8). Importantly, thiazide diuretics, such as hydrochlorothiazide, are available via the general schedule in the Pharmaceutical Benefits Scheme in Australia, while other thiazides and longer-acting diuretics, including chlorthalidone, are subsidised under Pharmac in New Zealand and under the general schedule in Australia.

Practice Points
Long-acting thiazide diuretics (chlorthalidone) are preferred over short-acting thiazide diuretics (hydrochlorothiazide).

Rationale

Our review (28) found that there may be a decrease in symptomatic recurrence of kidney stones for participants taking long-acting thiazides compared to short-acting thiazides (test for subgroup differences p = 0.02, I2 = 82.8%). The long-acting thiazides decreased kidney stone recurrence by over 60% (4 RCTs, n = 382, RR = 0.38, 95% CI: 0.25, 0.57) while short-acting thiazides found no effect. Long-acting thiazides, such as chlorthalidone, are widely available and used in Australia and New Zealand.

Repeat 24-hour urine collection after treatment commencement and/or dose adjustment is necessary to assess response.
Titrate thiazide diuretics to reduce urine calcium excretion to within reference intervals and considering baseline results. The minimum effective dose should be used and consideration given to potential side-effects.

Rationale

Thiazide diuretics should be titrated to the minimally effective dose because of their potential side-effects, which include:

  • Hypokalemia
  • Hyperuricemia
  • Increased cholesterol and triglycerides
  • Hyperglycemia and increased HbA1c
24-hour urinary sodium is a reliable marker to assess sodium intake and efficacy of nutrition therapy.
Effectiveness of thiazides is optimised when combined with dietary sodium restriction.

Xanthine oxidase inhibitors

We suggest against the routine use of xanthine oxidase inhibitors in people with recurrent kidney stones, unless indicated for prevention of gout.
(Conditional recommendation, low certainty of the evidence)

Rationale

Due to limited evidence for the effectiveness of xanthine oxidase inhibitors in managing recurrent stone formation, the Working Group suggests against their use in patients without comorbid gout. Analysis of reported adverse drug reactions from a global World Health Organisation database indicated that, in patients treated for conditions including kidney stones and gout, xanthine oxidase inhibitors are more frequently associated with acute kidney injury (RR (febuxostat) = 5.67, 95% CI: 5.05, 6.36; RR (allopurinol) = 3.25, 95% CI: 3.05, 3.47) than any other drugs (34). Similarly, among patients with kidney stones, medical claims data indicates that allopurinol, compared to thiazides, is associated with 32% greater odds of kidney stone recurrence (p < 0.001; OR = 0.68, 95% CI: 0.53, 0.88) (35). Additionally, there is limited evidence on the safety and efficacy of xanthine oxidase inhibitors for people with uric acid stones. Some xanthine oxidase inhibitors are publicly subsidised in Australia and Aotearoa New Zealand, and the Working Group recognises that our conditional recommendation is unlikely to increase inequity in access and outcomes for people with experience of recurrent kidney stones and gout.

Benefits and harms

Our evidence review identified two relevant RCTs (36, 37). Goldfarb et al. 2013 (36) compared two xanthine oxidase inhibitors: febuxostat (80 mg/d) with allopurinol (300 mg/d) and placebo, in a six-month double-blind RCT. In this RCT, most participants at risk of recurrent calcium containing kidney stones were over 45 years of age (61.6%), 45% with hypertension and 42.4% with hyperlipidaemia. The participants’ mean BMI was 32.8 Kg/m2. After six months, febuxostat decreased urinary uric acid, compared to allopurinol or placebo, in people with hyperuricosuria and calcium nephrolithiasis. However, there was no change in the number or size of stones, nor in kidney function, between therapies. Allopurinol, compared to placebo, decreased serum creatinine (MD = –517.00, 95% CI: –985.46, –48.54 mg/dL) at 6 months, but there was no difference between febuxostat and allopurinol, or between febuxostat and placebo for serum creatinine. The study reported too few events to determine if there were any differences in adverse events between treatment conditions. The most frequently reported treatment-emergent adverse events were musculoskeletal and connective tissue pain and discomfort (12.1%), renal lithiasis (8.1%), upper respiratory tract infections (8.1%), headache (6.1%), and oedema (5.1%).

Ettinger et al. 1986 (37) conducted a double-blind RCT comparing allopurinol to placebo in 60 participants at risk of recurrent calcium containing kidney stones across multiple centres in northern California. The study found that allopurinol had reduced kidney stone calculus events in people with hyperuricosuria and normocalciuria after 2 years of follow-up (81.2% fewer compared to 63.4% fewer). Additionally, the allopurinol treated (33.3 months, SE = 1.8 months) group had a longer time to recurrence compared to placebo (27.4 months, SE = 1.8 months; p = 0.02) (MD = 5.90 months, 95% CI: 4.00, 6.81). However, the evidence provided in this trial has not been replicated in subsequent investigations, thus limiting the reliability of these findings. There were too few adverse events to determine a difference between allopurinol and placebo.

Certainty of the evidence

The overall certainty of the evidence was low. Only two relevant RCTs with a small number of participants were included. Additionally, the studies demonstrated high and unclear risk of bias across many domains, with particular concern around allocation concealment and blinding.

Preferences and values

The Irish qualitative study of adults with kidney stones (n = 33) (30) and the CARI Guidelines consumer involvement workshops (n = 28) found that people with kidney stones described the need for support with medication adherence. However, the participants provided no further description about experiences with xanthine oxidase inhibitor therapy.

Equity

The included RCTs are small and have had little examination of important subgroups across the PROGRESS-Plus checklist (20). However, the Working Group recognises that, uniquely in Australia and New Zealand, rural and remote communities have limited access to healthcare, including in kidney health (21, 22), which may include access to xanthine oxidase inhibitors.

Resources and other considerations

Xanthine oxidase inhibitors reduce uric acid and are often prescribed to treat gout. To the Working Group’s knowledge, no cost-effectiveness evaluation of xanthine oxidase inhibitors in managing recurrent kidney stones and gout has been undertaken. Allopurinol is available in Aotearoa New Zealand and publicly subsidised via Pharmac. Other xanthine oxidase inhibitors (benzbromarone, febuxostat, etc.) are available via special authority. Similarly, allopurinol is available via the PBS General Schedule in Australia, and other xanthine oxidase inhibitors are available via the special authority.

Practice Points
Urinary alkalinisation is the main strategy for uric acid kidney stone prevention, with nutrition intervention first-line, and potassium citrate if additionally needed to reach target pH.
Xanthine oxidase inhibitors can be considered for individuals with recurrent uric acid stones and hyperuricosuria despite optimising urine pH.
Management of gout should take precedence over kidney stone prevention when considering the indication for xanthine oxidase inhibitors.

Other pharmacological treatment

Cystinuria

Practice Points
Nutrition therapy and potassium citrate are suggested as parallel first-line strategies for cystinuria management. Nutrition therapy focuses on a high urine volume and reduced sodium intake to decrease urine cystine concentration (LINK).
The addition of potassium citrate aims to alkalinise the urine and increase cystine solubility for patients with cystinuria.

Rationale

Cystine kidney stones are formed by a high concentration of cystine in the urine, which has low solubility in low urine pH environments (2, 38, 39). The solubility of cystine stones is low (<250 mg/l or 1.05 mmol/L) when pH is below 6 but increases substantially (500 mg/l or 2.1 mmol/L) at pH 7.5 (38, 39). Increasing urine pH by increasing fluid intake and reducing sodium intake should be considered the first line treatment of low urine pH for patients with cystine kidney stones.

Currently, pharmacological treatment to manage cystinuria is available in Australia and New Zealand (thiol drugs) but should only be considered when nutrition therapy is insufficient.

Rationale

Current available therapies, e.g., thiol drugs, to manage cystinuria in Australia and Aotearoa New Zealand are limited. Therapies such D-penicillamine and Tiopronin are available but are expensive and require management within a hospital setting.

Hyperoxaluria

Practice points
First-line nutrition strategies for management of hyperoxaluria are detailed in the nutrition therapy guidelines subtopic (LINK).
Currently pharmacological treatment to manage hyperoxaluria is not available in Australia and New Zealand.

Suggestions for future research

  • Further trials examining the role of thiazide diuretics and nutrition therapy in managing hypercalciuria and prevention of kidney stone recurrence are required due to the imprecision evident in treatment effects.
  • Further trials of long-term thiazide diuretics are required to demonstrate their safety and efficacy for people with recurrent kidney stones.
  • In forthcoming trials, it is imperative to ensure that participants are provided with and follow suitable first-line nutritional strategies for managing kidney stones. This includes close monitoring and regulation of sodium intake, as it has been shown to reduce calcium reabsorption, thereby influencing the recurrence of stones.

CARI Guidelines Kidney Stones Working Group

Andrew J Mallett1,2,3,

David J. Tunnicliffe4,5

Lyn Lloyd6

Adam Mullan7

Ieuan Wickham8

Brydee Cashmore4,6

Alex Currie8

Edward Smith

Hicham Hassan 9, 10*

Matthew Jose12, 13*

*Authors have contributed equally as Co-Convenors of the Guideline Working Group.

Affiliations

  1. Department of Renal Medicine, Townsville University Hospital, Douglas, Queensland, Australia
  2. College of Medicine and Dentistry, James Cook University, Douglas, Queensland, Australia
  3. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
  4. Sydney School of Public Health, The University of Sydney, Sydney, NSW, Australia
  5. Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, NSW, Australia
  6. Nutrition and Dietetics, Te Toka Tumai, Auckland, New Zealand
  7. Northland Renal Services, Te Tai Tokerau, Northland, New Zealand
  8. Consumer partner
  9. Graduate School of Medicine, University of Wollongong, Wollongong, NSW, Australia
  10. School of Medicine, Lebanese American University School of Medicine, Beirut, Lebanon
  11. School of Medicine, University of Tasmania, Hobart, Tasmania, Australia
  12. Department of Renal Medicine, Royal Hobart Hospital, Hobart, Tasmania, Australia

Conflict of interest

The CARI Kidney Stones Working Group have no relevant conflicts of interests to report.

Funding

CARI Guidelines receives funding from the Australian and New Zealand Society of Nephrology, the Australian Living Evidence Collaboration, and the National Health and Medical Research Council Emerging Leadership 1 Investigator grant (APP1197337).

References

1. Skolarikos A JH, Neisius, A, Petřík A, Somani B, Tailly T, Gambaro G. EAU Guidelines. Edn. EAU Annual Congress; Paris2024.

2. Servais A, Thomas K, Dello Strologo L, Sayer JA, Bekri S, Bertholet-Thomas A, et al. Cystinuria: clinical practice recommendation. Kidney Int. 2021;99(1):48-58.

3. Raheem OA, Khandwala YS, Sur RL, Ghani KR, Denstedt JD. Burden of Urolithiasis: Trends in Prevalence, Treatments, and Costs. Eur Urol Focus. 2017;3(1):18-26.

4. Du J, Johnston R, Rice M. Temporal trends of acute nephrolithiasis in Auckland, New Zealand. N Z Med J. 2009;122(1299):13-20.

5. Lo SS, Johnston R, Al Sameraaii A, Metcalf PA, Rice ML, Masters JG. Seasonal variation in the acute presentation of urinary calculi over 8 years in Auckland, New Zealand. BJU Int. 2010;106(1):96-101.

6. Lee MC, Bariol SV. Evolution of stone management in Australia. BJU Int. 2011;108 Suppl 2:29-33.

7. Perera M, Papa N, Kinnear N, Wetherell D, Lawrentschuk N, Webb D, Bolton D. Urolithiasis Treatment in Australia: The Age of Ureteroscopic Intervention. J Endourol. 2016;30(11):1194-9.

8. Lotan Y, Cadeddu JA, Pearle MS. International comparison of cost effectiveness of medical management strategies for nephrolithiasis. Urol Res. 2005;33(3):223-30.

9. Pearle MS, Goldfarb DS, Assimos DG, Curhan G, Denu-Ciocca CJ, Matlaga BR, et al. Medical management of kidney stones: AUA guideline. J Urol. 2014;192(2):316-24.

10. Skolarikos A JH, Neisius, A, Petřík A, Somani B, Tailly T, Gambaro G. . EAU Guidelines Edn. Presented at EUA Annual Congress Milan2023.

11. Arivoli KV, A. N.; Oerline, M. K.; Hsi, R. S.; Patel, S. R.; Hollingsworth, J. M.; Shahinian, V. B. Preventive Pharmacological Therapy and Risk of Recurrent Urinary Stone Disease. Clin J Am Soc Nephrol. 2024;19(5):7.

12. Dhayat NA, Bonny O, Roth B, Christe A, Ritter A, Mohebbi N, et al. Hydrochlorothiazide and Prevention of Kidney-Stone Recurrence. N Engl J Med. 2023;388(9):781-91.

13. Pinheiro VBB, A. C.; Tiselius, H. G.; Heilberg, I. P. The effect of sodium bicarbonate upon urinary citrate excretion in calcium stone formers. Urology. 2013;82(1):33-7.

14. Carvalho M EB, Kuwaki EY, Pontes HP, Liu JWTW, Boros LH, Asinelli MO, Baena CP. . Effect of potassium citrate supplement on stone recurrence before or after lithotripsy: systematic review and meta‑analysis. Urolithiasis. 2017;45(5):449-55.

15. Phillips R HV, Myatt A, Somani B, Nabi G, Biyani CS. . Citrate salts for preventing and treating calcium containing kidney stones in adults (Review). Cochrane Database Syst Rev. 2015;2015(10):CD010057.

16. Aras B KN, Tuğcu V, Kemahli E, Ozbay B, Polat H, Taşçi AI. Can lemon juice be an alternative to potassium citrate in the treatment of urinary calcium stones in patients with hypocitraturia? A prospective randomized study. Urol Res. 2008;36(6):313-7.

17. Tosukhowong P YC, Sasivongsbhakdi T, Ratchanon S, Chaisawasdi S, Boonla C, Tungsanga K. Citraturic, alkalinizing and antioxidative effects of limeade-based regimen in nephrolithiasis patients. Urol Res. 2008;36(3-4):149-55.

18. Singh IB, 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.

19. Hultcrantz M, Rind D, Akl EA, Treweek S, Mustafa RA, Iorio A, et al. The GRADE Working Group clarifies the construct of certainty of evidence. J Clin Epidemiol. 2017;87:4-13.

20. O’Neill J, Tabish H, Welch V, Petticrew M, Pottie K, Clarke M, et al. Applying an equity lens to interventions: using PROGRESS ensures consideration of socially stratifying factors to illuminate inequities in health. J Clin Epidemiol. 2014;67(1):56-64.

21. Chondur R, Li SQ, Guthridge S, Lawton P. Does relative remoteness affect chronic disease outcomes? Geographic variation in chronic disease mortality in Australia, 2002–2006. Aust N Z J Public Health. 2014;38(2):117-21.

22. Bello AK, Hemmelgarn B, Lin M, Manns B, Klarenbach S, Thompson S, et al. Impact of remote location on quality care delivery and relationships to adverse health outcomes in patients with diabetes and chronic kidney disease. Nephrol Dial Transplant. 2012;27(10):3849-55.

23. Health Mo. Eating and Activity Guidelines for New Zealand Adults: Updated 2020. Wellington, New Zealand: Ministry of Health; 2020.

24. National Health and Medical Research Council. Australian Dietary Guidelines. Canberra, Australia: National Health and Medical Research Council; 2013.

25. Nijenhuis T, Vallon V, van der Kemp AW, Loffing J, Hoenderop JG, Bindels RJ. Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest. 2005;115(6):1651-8.

26. Li DF, Gao YL, Liu HC, Huang XC, Zhu RF, Zhu CT. Use of thiazide diuretics for the prevention of recurrent kidney calculi: a systematic review and meta-analysis. J Transl Med. 2020;18(1):106.

27. Brazier F, Cornière N, Eladari D. Leave NOSTONE unturned: are thiazides useless in preventing kidney stone recurrence? Kidney Int. 2023;104(4):640-3.

28. Tunnicliffe DJ, Mallett A, Cashmore B, Mullan A, Lloyd L, Yip A, et al. Update Thiazide Diuretic Evidence Review for CARI Guidelines Kidney Stones Recommendations. Kidney Int Rep. 2024;9(5):1145-8.

29. Tehranchi A, Rezaei Y, Mohammadi-Fallah M, Mokhtari M, Alizadeh M, Abedi F, et al. Effects of hydrochlorothiazide on kidney stone therapy with extracorporeal shock wave lithotripsy. Urol Ann. 2014;6(3):208-11.

30. E NN, Richards HL, Hennessey D, Fortune DG. ‘Like a ticking time bomb’: A qualitative study exploring the illness experiences of adults with kidney stone disease. Br J Health Psychol. 2023.

31. Nouvenne A, Meschi T, Prati B, Guerra A, Allegri F, Vezzoli G, et al. Effects of a low-salt diet on idiopathic hypercalciuria in calcium-oxalate stone formers: a 3-mo randomized controlled trial. Am J Clin Nutr. 2010;91(3):565-70.

32. Tunnicliffe DJ, Bateman S, Arnold-Chamney M, Dwyer KM, Howell M, Jesudason S, et al. Recommendations for culturally safe kidney care for First Nations Australians. Sydney, Australia: CARI Guidelines; 2022.

33. Walker C RS, White C, Lusis L, Jones M, Walker R, Collins J, Rodenburg R, Kara T, Palmer SC. Clinical practice guidelines for management of chronic kidney disease for Māori in Aotearoa/New Zealand. Sydney, Australia: CARI Guidelines; 2023.

34. Rey A, Batteux, B., Laville, S. M., Marienne, J., Masmoudi, K., Gras-Champel, M., & Liabeuf, S. Acute kidney injury associated with febuxostat and allopurinol: A post-marketing study. Arthritis Research and Therapy. 2019;21.

35. Hsi R, S., Yan, P. L., Crivelli, J. J., Goldfarb, D. S., Shahinian, V., & Hollingsworth, J. M. Comparison of empiric preventative pharmacologic therapies on stone recurrence among patients with kidney stone disease. Urology. 2022;166:8.

36. Goldfarb DS, MacDonald PA, Gunawardhana L, Chefo S, McLean L. Randomized controlled trial of febuxostat versus allopurinol or placebo in individuals with higher urinary uric acid excretion and calcium stones. Clin J Am Soc Nephrol. 2013;8(11):1960-7.

37. Ettinger B, Tang A, Citron JT, Livermore B, Williams T. Randomized trial of allopurinol in the prevention of calcium oxalate calculi. N Engl J Med. 1986;315(22):1386-9.

38. Dolin DJ, Asplin JR, Flagel L, Grasso M, Goldfarb DS. Effect of cystine-binding thiol drugs on urinary cystine capacity in patients with cystinuria. J Endourol. 2005;19(3):429-32.

39. Bouzidi H, Daudon M. [Cystinuria: from diagnosis to follow-up]. Ann Biol Clin (Paris). 2007;65(5):473-81.