Nephrolithiasis continues to account for a large portion of the urologist’s practice. Yet metabolic stone evaluation and medical treatment remains an enigma to many practitioners. Nephrolithiasis has been the topic of only 2 previous Lattimer lectures. Yet instead of rehashing basic metabolic evaluation and selective medical therapy of stone disease, I want to highlight what I consider major advances in medical stone management that should have a significant impact on one’s ability to prevent recurrent stone formation in our patients.

Empiric Therapy

Evaluation of urine chemistry and selective medical therapy is useful but not accessible to all urologists. Therefore, empiric prescriptions based on stone composition may be more important to reduce stone recurrence in many of the world’s stone formers. Increased fluid intake, generic dietary manipulation, and prescriptions of potassium citrate and thiazides have been proposed for patients with calcium and uric acid calculi. In addition, general dietary advice is currently recommended in our calcium oxalate (CaOx) stone formers specifically to reduce dietary sodium intake, as well as moderate the intake of dairy products, foods high in oxalate and animal protein. Recent data from the PUSH (Prevention of Urinary Stones with Hydration) trial supported by the Urinary Stone Disease Research Network provide innovative methods (eg smart water bottle) for patients to increase their fluid intake.

Dietary Supplements

Over the years, dietary supplements have been proposed to reduce the risk of recurrent stone formation. Yet a recent evidence-based evaluation of 27 dietary supplements for the management of nephrolithiasis demonstrated that over two-thirds of the supplements claiming to treat stones contain ingredients with conflicting or no evidence to support their claims. Certain natural beverages have been touted to impact stone information. Lemon juice mixed with water to create homemade lemonade can significantly increase urinary citrate and impact recurrent stone formation. Yet, when compared to orange juice (OJ), lemonade has no impact on urine pH, while there is an alkali effect with a large volume of OJ. However, cost and tolerance limit the usefulness of OJ as a dietary supplement. Most recently, an over-the-counter drink mix has been introduced to provide increased alkali to stone formers. Moonstone, 1 packet twice a day, and water can increase urinary citrate and pH as well as decrease the supersaturation of CaOx in stone formers. Thus, newer dietary supplements may ultimately prove to be beneficial in managing patients not only with calcium oxalate, but also with uric acid and cystine calculi.

Alternative Alkalizing Agents

Citrate has long been demonstrated to be perhaps the most important inhibitor of CaOx stones and useful to alkalinize urine in patients with uric acid and cystine calculi. While potassium citrate was originally introduced in the early 1980s and can significantly reduce the risk of recurrence stone formation, current formulations of potassium citrate may be difficult to tolerate in some patients and have become extremely expensive for many. Alternative alkali therapy with either sodium bicarbonate or potassium bicarbonate has been demonstrated to provide adequate alkali in patients unable to tolerate or afford potassium citrate. The citraturic and pH effects of these alternative alkali medications appear to be similar to that of potassium citrate, with an almost 75% reduction in cost. Sodium and potassium bicarbonate should be considered in those individuals unable to afford or tolerate standard potassium citrate therapy.

Reduction in Urinary Oxalate

The supersaturation of CaOx in urine is impacted by many factors. Urinary oxalate remains one of the most misunderstood yet important drivers of CaOx stone formation. Recently, a number of treatments to reduce urinary oxalate have been developed, including Oxalobacter formigenes and oxalate decarboxylase (ALLN-177). Some have even suggested that reduction of “normal” urinary oxalate can decrease the risk of recurrent CaOx stone formation.

Genetic Diagnosis and Therapy of Nephrolithiasis

Monogenic mutations causing nephrolithiasis and chronic kidney disease have been identified in 11% of adults and almost 30% of patients who are diagnosed with stones before the age of 25. Genetic sequencing has now identified at least 10 monogenic causes of kidney stones including cystinuria, distal renal tubular acidosis and primary hyperoxaluria. Currently, the Rare Kidney Stone Consortium suggests that all pediatric patients should be evaluated to treat recurrent nephrolithiasis and prevent renal disease. Various genetic panels for managing these conditions are available to test those individuals considered to be at high risk for a genetic cause of their stones, including pediatric patients and those with a strong family history of stones or nephrocalcinosis, as well as stone patients with chronic kidney disease.

Mutations of 2 genes underlie the genetic basis of cystinuria. Both proteins encoded by these genes are subunits of the transport system responsible for reabsorption and absorption of cystine and dibasic amino acids at the apical membranes of the proximal renal tubule and small intestines. Knockout animal models have been used for drug development.

Recently, the field of small interfering RNA (siRNA)-based therapeutics has been introduced to treat a number of monoclonal medical conditions. siRNA is a natural mechanism by which short strands of RNA cause targeted gene suppression with the opportunity to selectively target and silence the mRNA products of genes. Nowhere has the use of siRNA therapeutics had a greater effect on disease management than in those patients with primary hyperoxaluria. Two new liver-directed RNA interference agents have been introduced to reduce hepatic oxalate production by degrading the mRNA that encodes glycolate oxidase. In fact, recent Phase III trials have demonstrated a substantial reduction in urinary and plasma oxalate levels, with most patients reaching the normal or near normal range.

Ultimately, more empiric management or dietary supplements may play an increasing role in managing our patients with recurrent stones. Newer medications will be introduced to correct metabolic defects and reduce the risk for new stone formation. Yet it may be genetic diagnosis and gene-based therapeutics that ultimately offer our patients long-standing relief of their recurrent stone disease.