Pharmacotherapy of Urolithiasis

Evidence From Clinical Trials

Orson W Moe; Margaret S Pearle; Khashayar Sakhaee

Kidney Int. 2011;79(4):385-392.

Abstract and Introduction

Abstract

Urolithiasis is a worldwide problem with significant health and economic burdens. Medical therapy that alters the course of stone disease has enormous medical and financial impact. Urolithiasis is a final manifestation of a broad range of etiologies and pathogenesis. The modest progress in understanding the pathophysiology has hampered successful development of targeted therapy. Current regimens are based mostly on rational alteration of urinary biochemistry and physical chemistry to lower the risk of precipitation. In terms of pharmacotherapy, there are drugs to successfully improve hypercalciuria, hypocitraturia, aciduria, hyperuricosuria, and hypercystinuria. These agents have been proven to be effective in randomized controlled trials in improving urinary biochemical and physicochemical risk factors, as well as clinical outcomes. Although our current regimens have clearly improved the management and lives of stone formers, there are still clearly identifiable immense voids in the knowledge of pathophysiology of stone disease that can be filled with combined basic science and clinical studies.

Introduction

Urolithiasis is a global problem spanning all geographic regions with an estimated annual incidence of 1%, prevalence of 3–5% and a lifetime risk of 15–25%. Once afflicted, urolithiasis tends to be recurrent in the majority of cases. According to data from the Urological Diseases in America Project, the total annual cost of nephrolithiasis in the United States in the year 2000 was about $5.3 billion. This underscores the toll taken by this disease on working-age individuals and society at large. Given the high cost of urgent medical treatment and/or surgical intervention, the attractiveness of a medical prophylactic program to reduce stone occurrences or increase the likelihood of successful conservative management of an acute-stone event is obvious. Indeed, simple medical management strategies utilizing inexpensive drug therapies have been shown to be efficacious and cost effective.^[1] A retrospective study of patients followed for up to 20 years has shown sustained efficacy of medical therapy in the improvement of biochemical parameters and clinical events.^[2]

Although there is steady improvement in therapy with shock-wave therapy and endourological techniques, the advance of medical therapy has been rather modest. From an etiological and pathophysiological point of view, it is important to emphasize that urolithiasis is a mere final manifestation of diverse and systemic etiological and pathogenic events. A major hurdle in this field in the past and present is the fact that the development of specific targeted therapy has been handicapped by the relative slow progress in unraveling pathophysiology. Current medical approaches are based on carefully constructed and rational modification of urinary biochemistry and physical chemistry to lower stone risk rather than etiology. This brief review is not meant to discuss the pathophysiology of urolithiasis, but rather provides a summary of the existing clinical data on medical therapy. Prospective randomized controlled trials will be highlighted, whereas uncontrolled and retrospective studies will be mentioned. Dietary and life style modifications and surgical therapy are not covered in this review. Because of the space limitation, complete and exhaustive citation is not possible.

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Table 1. Commonly used drugs in medical expulsive therapy
Type	Drug		Recommended dosage
Type	Generic name	Trade name	Recommended dosage
Calcium-channel blocker	Nifedipine	Adalat Adalat CC Procardia Procardia XL	30 mg/day
α₁-Selective α-blocker	Tamsulosin	Flomax Flomaxtra Urimax	0.4 mg/day
α₁-Selective α-blocker	Terazosin	Hytrin	5 mg/day
α₁-Selective α-blocker	Doxazosin	Cardura	4 mg/day
Corticosteroid	Deflazacort	Calcort Cortax Decortil Deflanil	30 mg/day
Glucocorticoid	Methylprednisolone	Medrol A-methaPred Depo-Medrol Medrol DosePak Solu-Medrol	16 mg/day

Table 2. Major clinical trial in pharmacotherapy of urolithiasis
	Author (ref.)	Drug	N	Design	Finding
Renal colic	Hollingsworth et al. ⁶	α-Blocker or calcium-channel blockers vs placebo or no Rx		Meta-analysis	Improved likelihood of stone passage
	Parsons et al. ⁸	α-Blocker vs no Rx	911	Meta-analysis	Improved likelihood of stone passage
Hypercalciuria	Brocks et al. ¹³	Bendroflumethiazide vs placebo	62	RCT	Both groups showed decrease in stone formation
	Scholz et al. ¹⁴	Hydrochlorothiazide vs placebo	51	RCT	Thiazides decreased calciuria but not stone events
	Laerum and Larsen¹⁵	Hydrochlorothiazide vs placebo	50	RCT	Decreased new stone formation Prolonged stone-free interval
	Ettinger et al. ¹⁶	Chlorthalidone vs Mg hydroxide vs placebo	124	RCT	Chlorthalidone more effective than Mg hydroxide or placebo in reducing stone events
	Ohkawa et al. ¹⁷	Trichlormethiazide vs no treatment	175	RCT	Decreased calciuria and stone formation rate
	Borghi et al. ¹⁸	Diet vs diet+indapamide vs diet+indapamide+allopurinol	75	RCT	Diet + pharmacotherapy better than diet alone.
Hypocitraturia	Barcelo et al. ³¹	Potassium citrate vs placebo	57	RCT	Decreased stone formation and increased urinary citrate
	Ettinger et al. ³²	Potassium magnesium citrate vs placebo	64	RCT	Decreased stone formation
	Hofbauer et al. ³³	Diet+sodium potassium citrate vs diet	50	RCT	No difference in stone formation
	Soygür et al. ³⁴	Potassium citrate vs no treatment after shockwave lithotripsy	110	RCT	Decreased stone recurrence
	Kang et al. ³⁵	Mix of potassium citrate, thiazide, allopurinol vs no treatment after percutaneous nephrolithotomy	226	NCT	Decreased stone recurrence
	Pak et al. ³⁶	Potassium citrate vs pretreatment in calcium and uric acid stone formers	89	NNT	Decreased stone events
Aciduria (uric acid stones)	Pak et al. ⁴²	Potassium citrate	18	NNT	Decreased stone events
Hyperuricosuria (calcium stones)	Ettinger et al. ⁴⁷	Allopurinol vs placebo	60	RCT	Decreased stone events
	Coe²⁰	Thiazide vs allopurinol vs both	202	RCT	Decreased stone events vs pretreatment
Cystinuria	Dahlberg et al. ⁵⁰	D-penicillamine	89	Retrospective	Decreased stone event and dissolution of stones
	Chow et al. ⁵¹	D-penicillamine or α-mercaptopropionylglycine vs conservative Rx	16	NNT	Decreased stone event
	Pak et al. ⁵²	D-penicillamine or α-mercaptopropionylglycine vs conservative Rx	66	Retrospective	Both drugs equally effective in reducing stone events
	Barbey et al. ⁵³	D-penicillamine or α-mercaptopropionylglycine vs conservative Rx	27	Retrospective	Decreased stone events

Abbreviations: N, number of patients; NCT, non-randomized controlled trial; NNT, non-randomized non-placebo controlled trial; RCT, randomized controlled trial; Rx, treatment.

Table 3. Commonly used drugs in the treatment of hypercalciuric calcium nephrolithiasis
Drug	Recommended dosage(s)	Comments
Hydrochlorothiazide	50 mg/day 25 mg twice/day	A single dosage is preferred since the twice a day dosage may cause frequent nocturia and consequent patient discomfort.
Chlorthalidone	25 mg/day 50 mg/day	Both dosages lower urinary calcium by the same degree. Because of its long action, this treatment may cause hypokalemia and hypocitraturia.
Indapamide	1.2 mg/day 2.5 mg/day	This treatment may have fewer side effects that hydrochlorothiazide, including the rare occurrence of hypokalemia and hypotension.
Amiloride	5 mg/day	This treatment is a potassium sparing diuretic that lowers urinary calcium, but to a lesser degree than hydrochlorothiazide.
Amiloride/Hydrochlorothiazide	5 mg/50 mg/day	Maintains the hypocalciuric effect of thiazide, whereas averting the development of severe hypokalemia.
Trichlormethiazide	2 mg/day 4 mg/day	This drug is not marketed in the United States.

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