While “personalized medicine” approaches have dramatically enhanced the treatment of some diseases, their efficacy in the treatment of kidney stones has been called into question. Current AUA guidelines encourage biochemical testing and tailored therapies for patients with recurrent kidney stone disease. However, there is emerging evidence that empiric treatment for kidney stone disease may have equivalent outcomes to personalized regimens.^1-5 Empiric therapies should assume kidney stones are calcium-based, given that these represent 90% of all kidney stones. This review will compare the data for personalized and empiric approaches to calcium-based kidney stone prevention.

Empiric versus Personalized Treatment

Among 3 contemporary studies, there was no evidence that either 24-hour urine studies or selective preventative pharmacological therapy lowered the rate of kidney stone recurrence when compared to empiric therapy. Possible explanations include differences in physicians’ interpretation or recommendations based on 24-hour urine studies.

Hsi et al in 2021 evaluated stone recurrence among patients who received selective versus empiric preventative pharmacological therapy.³ Selective therapy patients underwent 24-hour urine studies before treatment while empiric therapy patients did not. Among 10,125 patients followed for 2 years after their first stone event, 27% received selective therapy and 73% received empiric therapy. Overall stone recurrence was 11%, and there was no difference between the groups (p=0.25). The empiric cohort had a higher prevalence of hypertension, and thus, may not have received preventative pharmacological therapy (eg thiazide diuretics) primarily for stone prevention. The authors claim that this should bias the results to favor the selective therapy group, who were more likely exposed to intentional pharmacological therapy for stone prevention (ie the “stone-clinic effect”), which would increase the strength of their findings. The study was primarily limited by the short followup period.³

Song et al in 2021 examined the effects of 24-hour urine studies and pharmacological therapy on the risk of recurrence in a cohort of 130,129 stone-forming veterans.⁵ Patients already receiving preventative therapy were excluded. Of the patients, 7.1% completed 24-hour urine studies within 6 months of their initial stone event. Surprisingly, 24-hour urine studies were associated with an increased risk of stone recurrence (HR 1.17, 95% CI 1.12–1.22). This study had a 5-year followup and was better controlled for inadvertent preventative pharmacological therapy, mitigating the “stone-clinic effect.” The study findings were primarily limited by the mostly older male veteran patients.⁵

Samson et al evaluated recurrent stone episodes in 434,055 patients with and without 24-hour urine studies and a minimum of 3-year followup.⁶ Of the patients, 6.9% had 24-hour urine studies completed within 6 months of their initial stone events, and 24-hour urine studies were associated with higher 3-year stone recurrence (OR 1.15, 95% CI 1.12–1.19). While this was a large study, it was limited by its less conservative definition of stone recurrence (event within 90 days vs 120 days in the other studies) and its lack of uninsured/unemployed patients.⁶

Empiric Diet and Lifestyle Changes

The following interventions are evidence-based, effective, inexpensive and target modifiable risk factors that influence stone formation (see figure).

Fluid Intake

The AUA guidelines recommend drinking enough liquid to produce 2.5 liters of urine daily. A “timed water bottle” can help track and distribute fluid intake throughout the day. The ongoing PUSH (Prevention of Urinary Stones with Hydration) trial will elucidate how increased fluid intake can reduce the risk of stone progression.⁷ While water is the ideal liquid, other noncalorie containing beverages are effective. For patients with soda addiction, consider switching to a lemon-lime, citrate-containing beverage.

Figure. Simplified guide to calcium stone prevention.

Diet

Limiting salt intake to less than 100 mEq or 2,300 mg per day has been shown to lower the risk of stone formation. The protective effect of dietary calcium can be counterintuitive for patients; the recommended 1.2 grams of calcium per day reduces the risk of stone formation by binding oxalate in the intestines and preventing its absorption. Risk of kidney stone events is significantly lower in vegetarian, low-meat, low-oxalate and high-fiber diets.^7-9

Medications for Stone Prevention

The risk of kidney stone formation can be described through drivers of crystallization (low urine pH, high excretion of calcium/oxalate and low citrate excretion) and inhibitors of crystallization (neutral urine pH, low calcium/oxalate excretion and high citrate excretion). The 2 major classes of empiric medications, alkali therapy and anti-hypercalciuria therapy, function by modifying these drivers and inhibitors. Both classes are effective at reducing the recurrence of kidneys stones, irrespective of metabolic laboratory results. Choice of empiric therapy should be informed by patient comorbidities and side effect tolerability.

Alkali Therapy

Alkali therapies work by alkalinizing the urine, increasing urine citrate excretion and decreasing crystallization of calcium salts. They can prevent calcium, cystine, leucine, tyrosine and uric acid stones. The relative risk of recurrent stone formation with the administration of potassium citrate was 0.25 when compared with placebo.⁴ The recommended starting dosage of potassium citrate is between 15–30 mEq twice a day, taken with meals.² Primary care physicians should measure serum potassium in 1–2 months after first prescription. Frequency of monitoring should change as indicated by the patient’s comorbidities. Potassium bicarbonate at 25 mEq twice a day works similarly to potassium citrate and may have fewer gastrointestinal side effects; however, it is slightly less effective.²

Anti-Hypercalciuria Therapy

Thiazide diuretics work by blocking the sodium chloride cotransporter in the distal convoluted tubule. Thiazides are effective against most calcium-containing stones. The relative risk of recurrent stone formation was 0.53 for thiazides when compared with placebo.⁴ The recommended starting dosage of chlorthalidone is 25 mg once a day.² Baseline creatinine and electrolytes should be checked before administration, then periodic monitoring by primary care physicians is appropriate.

Bisphosphonates decrease calcium loss from bones by interfering with osteoclast interactions with bone, inhibiting the development of osteoclasts and inducing apoptosis. The medications can effectively reduce serum and urinary calcium levels, preventing kidney stones.¹⁰ The recommended starting dosage of alendronate is 70 mg once a week.² Serum calcium and creatinine should be checked before administration. If there is risk of hypocalcemia, periodically monitor calcium, magnesium and phosphate levels.

Conclusions

Recent studies have called into question the efficacy of personalized treatments for calcium-based kidney stone disease. Certainly, specific scenarios like cystinuria, stones from medical comorbidities and medication-related stones require a tailored approach. However, for many routine calcium-based stone formers advanced workup may not be required. Empiric diet and lifestyle recommendations accompanied with preventative medications can significantly reduce the risk of stone disease, decrease the burden on patients and save significant health care costs.