Urolithiasis medical therapies

Transcription

1 Urolithiasis medical therapies Daniel Spernat and John Kourambas Department of Urology, Monash Medical Centre, Victoria, Australia SUMMARY This review paper provides a summary of medical therapies available for urolithiasis. The summary includes general medical advice, prophylactic medications, dissolution therapy and medical expulsion therapy. The paper is designed to provide a management strategy for all physicians who treat urolithiasis, from general practitioners, to emergency physicians, to urologists. OBJECTIVE To provide an up to date review of the literature in relation to the medical management of stone disease. This will encompass prophylaxis, dissolution therapy and medical expulsion therapy. What s known on the subject? and What does the study add? The medical management of urolithiasis is complex. There are many papers written on the topic and many conflicting views. It can be difficult for physicians to interpret these data and have a stepwise approach to the medical treatment of stones. Thus this study provides a framework and a review of the literature to allow physicians to practise evidence-based medicine when medically managing urolithiasis. due to the low incidence of a reversible metabolic cause. However, stone disease is common and over a lifetime urolithiasis can affect up to 10 15% of the population. RESULTS CONCLUSIONS Recurrent stone formers should have dietary optimization to decrease the risk of further stones. Furthermore, the correct use of prophylactic and therapeutic medications can decrease the morbidity associated with ureteric calculi. PATIENTS AND METHODS First-time stone formers do not regularly have a full urine and electrolyte evaluation Medical management of stone disease encompasses preventative measures, medical dissolution and medical expulsion therapy. KEYWORDS urolithiasis, prophylaxis, dissolution therapy, medical expulsion therapy INTRODUCTION Stone disease is common and affects 0.131% of the population at any time [1 ]. Over a lifetime urolithiasis can affect up to 10 15% of the population [2 ]. After passage of a first stone, the risk of recurrence is 40% at 5 years and 75% at 20 years [3 ]. First-time stone formers do not regularly have a full urine and electrolyte evaluation due to the low incidence of a reversible metabolic cause. However, a reversible metabolic abnormality can be identified in over 90% of recurrent stone formers [2 ]. Here we will focus on prophylactic management of urolithiasis, dissolution therapy of urolithiasis and medical management of ureteric colic. PROPHYLACTIC MANAGEMENT IN A URINARY STONE FORMER GENERAL MEDICAL ADVICE All patients presenting with renal colic should be given general medical advice to decrease the risk of a future stone episode. This advice includes increasing fluid intake so that urine output is >2 L/day. Furthermore, the best estimation of urine output is clear looking urine. This prevents urine stagnation, and thus decreases stone risk. Patients should increase their urinary citrate level through increased consumption of citric juices. Urinary citrate is a potent stone inhibitor. Citrate binds calcium in the urine, decreasing supersaturation and reducing the growth of crystals [3 ]. Furthermore, an increase in urinary citrate level even in patients with normal urinary citrate helps prevent stone recurrence [4 ]. Purine intake (animal meat) should be moderated as it increases urinary calcium, oxalate and uric acid secretion. Restricting animal protein and salt while maintaining a normal calcium intake decreases stone recurrence rates compared with a low calcium diet [5 ]. A high sodium load can increase the risk of calcium oxalate stone formation and thus salt restriction is also advised. Furthermore, obesity increases the risk of stone disease by increasing urinary acidity, hypocitraturia and hyperuricosuria. Consequently, weight loss and a low fat diet should be encouraged , SUPPLEMENT 2,

2 SPERNAT and KOURAMBAS This is especially important in patients with bowel disease or malabsorptive conditions. Calcium intake within dietary recommendations should be continued even in patients with calcium oxalate stones. Low dietary calcium leads to increased unbound oxalate to be reabsorbed in the gut and thus further increases the risk of calcium oxalate stones [6 ]. The relationship between dietary and urinary oxalate is complex. When Holmes et al. [7 ] varied the amount of dietary oxalate and calcium they found that urinary oxalate excretion increased as dietary oxalate intake increased. Furthermore as the dietary calcium decreased the urinary oxalate also increased. Thus we recommend avoiding large quantities of oxalate especially with low calcium diets [7 ]. Patients should also avoid excessive (maximum daily dose 2 g) vitamin C supplements, as this can increase oxalate excretion [8 ]. PROPHYLACTIC MEDICATIONS Thiazide diuretics Thiazides stimulate calcium reabsorption in the distal nephron while promoting excretion of sodium. This decreases urinary calcium excretion but may lead to hypokalemia. Hypokalemia can in turn cause hypocitraturia. Thus potassium citrate supplementation (40 60 meq/day) is recommended with thiazide diuretics. A recent Cochrane review has demonstrated that, in patients with idiopathic hypercalciuria and recurrent stones, the addition of thiazides to a normal or modified diet decreases stone recurrence and formation rate [9 ]. has several features. First it maintains the urine ph above the p K a for uric acid thus promoting dissolution of uric acid crystals. This decreases uric acid and calcium stone formation by decreasing formation of a nidus. Second, citrate also directly prevents the complexation of calcium. In patients with either hypocitraturia or acidic urine ph, treatment with this medication increases urinary citrate levels, ph and potassium [ 10 ]. This is associated with a remission rate of stone disease of up to 91% [10 ]. Allopurinol Allopurinol inhibits xanthine oxidase converting xanthine to uric acid, and therefore decreases uric acid production and hyperuricosuria. This in turn reduces the spontaneous nucleation of calcium oxalate. Randomized controlled trials have demonstrated that allopurinol decreases stone recurrence in patients with idiopathic calcium oxalate stones who had hyperuricosuria [11 ]. Allopurinol is therefore effective in decreasing pure uric acid calculi and calcium based calculi. UroPhos-K UroPhos-K is a slow release neutral form of potassium phosphate. It produces a sustained hypocalciuric response and maintains bone mass in patients with absorptive hypercalciuria. This effect is achieved by directly impairing the renal tubular reabsorption of calcium and by binding calcium in the gut. It also raises the urine ph. UroPhos-K causes a sustained and marked reduction in urinary calcium [12 ]. This effect occurs by a combination of reduced intestinal absorption, bone reabsorption and improved renal calcium reabsorption. The drug is well tolerated compared with placebo [13 ]. Sodium bicarbonate The major goal of sodium bicarbonate therapy is to increase the urine ph above 5.5 and preferably to This treatment enhances dissociation of uric acid and inhibits uric acid stone formation. However, treatment may be complicated by calcium oxalate (due to the sodium load) or calcium phosphate (due to ph above 7.0) stone formation. Thus potassium citrate is preferable as it avoids the sodium load that may precipitate calcium oxalate stone formation [14 ]. D penicillamine D penicillamine is used in cystinuria to enhance the solubility of the cystine by formation of a mixed disulfide bond. That is, the cystine binds to the medication instead of itself [15 ]. D penicillamine is very effective but has a significant side effect profile including nephrotic syndrome, dermatitis and pancytopenia. Use must be closely monitored with regular full blood counts, urea and electrolytes, and vitamin B 6 (pyridoxine) must be replaced. Alpha mercaptopropionylglycine Alpha mercaptopropionylglycine was introduced because of the poor tolerance of D penicillamine. It has a sulfhydryl group that forms a disulfide bond with cystine thus increasing its solubility. Common side effects include asthenia, gastrointestinal tract upset, rash, joint aches, and mental state changes. It is much better tolerated than D penicillamine [16 ]. However, alpha mercaptopropionylglycine is less effective than D penicillamine at lowering the cystine crystal volume in urine specimens of cystinuric patients [17 ]. Thus it is an arguably less effective agent in preventing recurrent cystine stones. Moreover, it is not easily available. Sodium cellulose phosphate Sodium cellulose phosphate is largely outdated by the above listed medications. It has become a medication of last resort due to its significant gastrointestinal side effects. It is a non-absorbable ion exchange resin that binds calcium and inhibits calcium absorption, and is used in patients with absorptive hypercalciuria type 1. Acetohydroxamic acid Acetohydroxamic acid is a urease inhibitor. It reduces the urine saturation of struvite and therefore retards stone formation in patients with chronic urea-splitting infections. It is given at a dose of 250 mg three times per day. Acetohydroxamic acid effectively inhibits the growth of struvite stones in the short term [18 ]. However, thrombosis has been observed with unusual frequency in patients receiving acetohydroxamic acid. It was subsequently determined that this medication causes a low grade intravascular coagulability [19 ]. Up to 15% of patients may develop a deep vein thrombosis. DISSOLUTION THERAPY ORAL MEDICATIONS Sodium bicarbonate Sodium bicarbonate may be used to increase the urinary ph to the target range of It is an effective agent for the

3 UROLITHIASIS MEDICAL THERAPIES TABLE 1 Spontaneous stone passage at one month Control Tamsulosin Terazosin Doxazosin Alfuzosin 53.57% 79.31% 78.57% 75.86% 70.5% dissolution of uric acid calculi [20 ] and the most commonly used agent in Australia. However, sodium bicarbonate increases calcium excretion and reduces citrate. These mitigate some of the benefits of increased urinary ph. Consequently potassium citrate is the preferred agent. However, potassium citrate is not appropriate for some patients due to poor renal function or high baseline serum potassium levels. Further, the gastrointestinal side effects of potassium citrate can limit its application. In this situation sodium bicarbonate or sodium citrate are the preferred agents. One must be careful of the sodium load in patients with congestive heart failure or poorly controlled hypertension [21 ]. has been demonstrated to be effective in the dissolution of uric acid calculi [ 22 ]. It is the preferred agent over sodium bicarbonate as monopotassium urate is more soluble than monosodium urate [ 21 ]. Further, it avoids the increase in calcium excretion and reduction in citrate excretion associated with sodium loading. PERCUTANEOUS INSTILLATION Calcium oxalate stones are resistant to dissolution therapy. However, struvite calculi have been associated with (limited) successful dissolution therapies since 1943 (Suby s solution G) [ 23 ]. The following two solutions are still used in limited cases. Hemiacidrin/renacidrin Hemiacidrin/renacidrin is no longer in routine use. After surgical removal of the bulk of the stone residual struvite stone fragments can be dissolved with this agent. Prior to treatment infection and bacterial colonization must be treated. Further, the renal pelvis is irrigated initially with saline to ensure no leakage or fever. The renal pelvis washout continues for h. If the patient s condition remains haemodynamically stable then irrigation with hemiacidrin is commenced. The flow is continued at 120 ml per hour. The stone burden is assessed at regular intervals and the chemolysis continues for h after the last radiographic stone is visible. Research suggests that concurrent use with shock wave lithotripsy may provide a useful adjunctive measure for improving the efficacy of stone comminution [24 ]. Tham E Tham E is the most efficacious agent for the dissolution of cystine stones [25 ]. Its use is limited by the need to place nephrostomy tubes and then instil the agent. While this treatment has been reported on an outpatient basis [26 ], most patients require prolonged inpatient care which limits its desirability as a treatment. MEDICAL EXPULSION THERAPY Medical expulsion therapy (MET) is beneficial for distal ureteric calculi. There is no evidence that MET improves the spontaneous stone passage rate of proximal ureteric calculi. However, tamsulosin has been shown to significantly increase the passage of stones between 5 and 10 mm from the proximal to the distal ureter [27 ]. High fluid intake A large diuresis that pushes the stone into the bladder sounds plausible; however, studies have demonstrated that it is actually more likely to counteract the passage of the stone and to cause more pain. A Cochrane database review from 2005 found no evidence to support diuresis as a method of pain relief or stone expulsion [28 ]. Alpha blockers Alpha blockers inhibit ureteral muscle contraction, reduce the basal tone, and decrease peristaltic frequency and colic pain facilitating ureteral stone expulsion. Meta-analysis has demonstrated an advantage to alpha blocker use that it increases spontaneous stone passage rate by 14 29% which is statistically significant. This is the recommended MET (combined AUA and European Association of Urology (EAU) guidelines 2007). Tamsulosin is the most commonly used and studied agent. A study comparing the efficacy of tamsulosin to terazosin and doxazosin has not demonstrated any significant difference. Furthermore, a study comparing the efficacy of tamsulosin to alfuzosin has not shown any significant difference [29 31 ]. While there has not been a head-to-head comparison of terazosin or doxazosin to alfuzosin, it would appear that these alpha blockers are equally efficacious at MET. Table 1 demonstrates the combined data on spontaneous stone passage at 1 month. Calcium channel blockers Nifedipine has been extensively studied as an agent for MET. Nifedipine is effective at increasing the spontaneous stone passage rate. Meta-analysis has demonstrated an increase in the spontaneous stone passage rate of 9%. This is not statistically significant and the combined AUA and EAU guidelines (2007) have described the positive effect of nifedipine as marginal. Further, a multicentre, prospective, randomized trial comparing the efficacy of tamsulosin and nifedipine in MET for distal ureteric stones has demonstrated that tamsulosin was significantly better than nifedipine in relieving renal colic and facilitating ureteric stone expulsion [32 ]. Corticosteroids Corticosteroids have been reported to facilitate stone expulsion compared with placebo [30 ]. Compared with alpha blockers, steroids demonstrate a lower rate of spontaneous stone expulsion (37.5% vs 60%) [34 ]. However, the combination of steroids (deflazacort) and alpha blockers (tamsulosin) demonstrates a statistically significant advantage over tamsulosin alone [33,34 ]. Common medications that do not improve spontaneous stone passage It is important to mention that antimuscarinics such as buscopan have no role in MET. Randomized controlled trials involving buscopan have shown not only no

4 SPERNAT and KOURAMBAS TABLE 2 First-line agents in routine use Uric acid stone prevention Calcium stone prevention with hypercalciuria Cystine stone prevention Uric acid stone dissolution Medical expulsion therapy Struvite stones analgesic benefit for ureteric obstruction [35 ] but no increases in stone expulsion rates [36 ] either. NSAIDs lead to decreased ureteral contractility, inflammation, glomerular filtration rate and intrarenal pressure [37 ]. Therefore, they provide excellent analgesic benefit in renal colic. In fact, a Cochrane review has reported that lower pain scores have been demonstrated in patients receiving NSAIDs compared with opioid analgesia. Further, patients treated with NSAIDs were significantly less likely to require rescue medication [38 ]. However, stone expulsion rates were not affected in double-blinded placebo-controlled trials [39,40 ]. Thus, the recommended first line agents in routine use have been summarised in Table 2. 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