The cornerstone of urolithiasis management in most clinical settings is the surgical removal of stone burden even though it is well documented that prevention is better than treatment. Certain metabolic abnormalities are associated with a higher occurrence of stone diseases, such as hyperoxaluria, hypercalciuria, and hyperuricosuria. Medical dissolution therapy along with preventive measures is available, but long-term adherence is difficult, and efficacy is not well-proven. Although guidelines on urolithiasis management are available for many years, there is no standard pathway for follow-up of stone patients (primary and recurring), therefore the main goal of our paper is to establish a well-documented algorithm. The aim of this review is to summarize the latest advances in medical dissolution therapy for stone disease and monitoring of this condition.
Materials and Methods
A literature search in Medline was conducted between 2019 and 2021, to identify all relevant titles to stone medical dissolution therapy. Our search algorithm consisted of the terms: Urolithiasis, medical dissolution therapy, potassium citrate, sodium bicarbonate, alkalizing agents. Reference lists of included articles were also searched for any relevant studies. Abstract/full-text screening was performed independently by two authors (L. T., A. S.) and disagreements were resolved on consensus.
Urine pH and metabolic composition alterations are some of the main contributing factors in the formation and establishment of stone disease. Acidic pH can lead to crystallization of CaOx monohydrate and injury of renal cells while alkaline pH facilitates the formation of CaOx dehydrate, which is considered less pathogenic. Potassium citrate is an alkalizing agent which goal is to increase urinary pH and citrate levels while reducing stone formation in patients with CaOx or urate stones with hypocitraturia, but long-term patient compliance is difficult due to gastrointestinal adverse events. It is also not advised for patients at risk for hyperkalemia or renal failure. Boydston et al. examined whether sodium bicarbonate and potassium bicarbonate are effective as alkalizing agents, compared to potassium citrate and concluded that both agents increase urinary citrate, pH and CaP supernaturation, while CaOx supernaturation was reduced only with potassium citrate. Patients taking sodium/potassium bicarbonate showed a greater 3-month adherence of nearly 70% versus 58% with potassium citrate with lesser cost. Medullary sponge kidney (MSK) is often complicated by nephrolithiasis, which affects quality of life in these patients. Cicerello et al. report a clinically significant increase of urinary pH in patients with MSK and normal urine composition which was accompanied by a decreased need for invasive procedures during the follow-up of these patients. To study this context, Doizi et al., designed a randomized controlled trial (RCT) where patients with CaP stones and no hypercalciuria were administered potassium citrate or citric acid, which offers the citrates but is not accompanied by increase in urinary pH. The authors reported no significant increase in urinary citrate, pH, or ammonium with no difference in CaP crystal growth or saturation, between citric acid and placebo.
Dietary advice are simple and applicable measures for stone recurrence prevention and there are present in nearly all urological guidelines worldwide. Citrate is a known stone formation inhibitor since it binds to calcium ions and prevents high urinary concentrations. Cheng et al. tested two types of lemonade (diet and regular), which is a natural source of citrates, in patients with kidney stones, in a randomized trial. Patients in both groups showed increased urine output with no changes in urinary composition, except citrate which increased in diet and decreased in regular group. Superannuation of CaOx decreased in diet group at an excess of nearly 800 calories daily for regular lemonade. At a similar manner, Sromicki and Hess evaluated the efficacy of simple dietary tips (increased fluid intake, limited consumption of oxalate and concurrent intake of calcium up to 1200 mg/day, limited intake of meat/poultry and sufficient amounts of fruits/vegetables) and reported increased urinary volume and calcium concentration, while urinary oxalate/urate and CaOx supernaturation were decreased by 21.5%.
Uric acid stones account for nearly 10% of stone composition and the main contributing factor for their formation is acidic urinary pH. The increased rates of obesity, metabolic syndrome, and its components like diabetes mellitus are believed to further increase the occurrence of this type of stone. The European Association of Urology Guidelines suggest oral chemolysis for uric acid stone management, but the level of existing evidence is low. Elbaset et al. designed a RCT to compare efficacy of oral dissolution therapy with oral potassium citrate and ultrasound-guided safe working load or combination, for the management of radiolucent stones 1–2.5 cm and detected a better stone free rate and stone volume reduction in group receiving both treatments during a 3-month follow-up. Gridley et al. assessed efficacy of potassium citrate with or without allopurinol in renal urate stones and reported that 67% had complete response, 33% partial response with a median reduction of 68% in stone burden, while only 13% of patients underwent an axillary surgical intervention during a 3-month follow-up. Similarly, Salem et al. report a response rate of 65%, while Tsaturyan et al. found a complete response at 61% of patients with a 22.1% requiring a surgical procedure during the 3-month period of follow-up.
Another trial evaluated the role of febuxostat 40 mg or 80 mg versus the standard treatment of allopurinol 300 mg for urate stones and detected that greater stone size reduction of serum uric acid level, occurred to the group of febuxostat 80 mg with a similar safety profile. Theobromine exhibits a suspensory effect on uric acid crystal aggregation, therefore Hernandez et al. designed a RCT to compare citrate versus citrate combined with theobromine for the treatment of urate or CaOx monohydrate/urate stones and found no statistically significant differences in clinical efficacy. Finally, Elsawy et al. found a stone free rate of 53.2% at 3 and 83% at 6 months. Despite a reported response rate of 53%–83% for oral chemolysis in urate stones, it is important to identify predictors of this response. Lower stone density, smaller stone size, and initial clinical response with higher urine pH at 3 months, seem to independently predict success, while presenting did not offer additional information at regression analysis.
Traditional herbs are currently used in many countries and are considered complementary to modern medicine. Several studies have demonstrated the potential role of different plant extracts to stone disease management. Plyllanthus niruri combined with B6 and magnesium, led to a stone-free rate (SFR) of 25% at 3 months whereas patients who received black seeds (Nigella sativa L.) and suffered from stones 5–6.9 mm were most likely to experience stone expulsion or stone burden reduction compared to placebo.
Since recurrence rates are high in urolithiasis, monitoring of patients is very important. Castiglione et al., assessed whether dephosphorylated and uncarboxylated Matrix-Gla-protein (dpucMGP) could predict recurrence at 5 years and concluded that it is not predictive of either stone formation or recurrence. Lee et al. tried to identify patient characteristics that led to the completion of a 24-h urine test and concluded that increasing age, family history of nephrolithiasis and renal colic as initial presentation increased the likelihood, while public insurance and neurogenic bladder led to a decreased proportion. Yang et al., assessed the efficacy of kidney injury test on a spot urine sample for detection of nephrolithiasis and detected a higher score in patients with stones compared to healthy controls with a 95% accuracy, while obstructive disease led to an even higher score.
During the last years, major advances have been made in medical treatment of stone disease, which showed encouraging results for new molecules in stone era (tolvaptan, a-La, herbs) and enhanced the strength of evidence for older practices, like oral dissolution therapy for uric acid stones. However, these should be further tested in larger-scale trials, before incorporating them into clinical practice.
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