Medical expulsion of urinary stones

Introduction

Urolithiasis, a worldwide disease, has affected humans from ancient eras to modern times.¹Yung-Tai Chen. Urological Science 2012;23(1):5-8.   Indeed, the disease is quite common with a high recurrence rate²Knoll T. European urology supplements. 2010; 9:802-806.  ; and over a lifetime can affect up to 10-15% of the population.³Itoh Y, Kojima Y, Yasui T, et al. Int J Urol. 2007;14(8):749-53.  ^,4Spernat D, Kourambas J. BJU Int. 2011;108 Suppl 2:9-13.   Essentially, the process of lithogenesis, i.e., the formation of stones in the urinary tract, is multifactorial, and influenced by environmental nutritional factors (low urinary volume, diet rich in animal protein, etc.) and metabolic alterations; i.e., hypercalciuria, hyperuricosuria, and deficiency of stone-inhibiting factors [citrate, magnesium, glycosaminoglycans (GAGs)]. ⁵Moe OW. Lancet. 2006 Jan 28;367(9507):333-44.  ^,6Micali S, Grande M, Sighinolfi MC, et al. J Endourol. 2006 Nov;20(11):841-7   Obese people are known to have a higher risk of stone formation.1

Symptoms

These urinary stones often present with pain, hematuria or infection. Symptoms include a frequent urge to urinate, painful urination, hematuria, and dysuria. In some cases, stones can cause potentially serious complications. There also may be abdominal pain, pain in the penis, and dark colored urine.

Diagnosis in practice – through imaging

The stone formed may get impacted at multiple sites along the course of urinary tract (Figure 1). There are many useful tools for diagnosing urolithiasis, including conventional plain radiography, intravenous urography, ultrasonography, computed tomography (CT), and nuclear medicine. Particularly, nonenhanced CT has high sensitivities and specificities, and can be rapidly performed without intravenous administration of contrast material; and, therefore, it can be used in patients with severely impaired renal function. Beyond that, it can also reveal extraurinary causes of flank pain. However, there are associated concerns about radiation exposure and costs.¹Yung-Tai Chen. Urological Science 2012;23(1):5-8.  

Management of urinary stones

Clinical presentation, proper history, and laboratory tests help to identify whether one needs urgent surgical or medical treatment. Management of

stone disease needs individualization. In most cases, medical management in urolithiasis is indicated for clinically stable patients with nonobstructive urinary stones, recurrent stone formers, and the patients with underlying systemic diseases. Here, it is vital to obtain detailed history of patient illness including family history, drug history, and history of previous similar illness and previous interventions, besides assessing risk factors for stone disease.⁷Barnela SR, Soni SS, Saboo SS, et al. Indian Journal of Endocrinology and Metabolism, 2012;16(2):236-239.  

Management of kidney stones includes

• Dietary management
• Disease-specific therapies and
• Medical expulsion therapy (MET) of stones

Medical therapies are divided into three broad groups:

• Observation and medical therapy
• Shock wave lithotripsy (SWL) and ureteroscopy [Rigid and flexible (RIRS)] and
• Open surgery, laparoscopic stone removal or percutaneous nephrolithotomy (PCNL)/antegrade ureteroscopy

Dietary management

For preventing recurrence of kidney stones, fluid intake and dietary changes are important measures. Many trials have shown that increasing urine volume to at least 2 lit/day can reduce the recurrence of stone disease by up to 40-50%.⁸Borghi L, Meschi T, Amato F, et al J Urol 1996;155:839-43.   Fluid intake mainly should include water. Oxalate-rich foods like cucumber, green peppers, beetroot, spinach, soya bean, chocolate, popcorn, and sweet potato should be avoided, as small reduction in urinary oxalate has been found to be associated with significant reduction in the formation of calcium oxalate stones.

Medical expulsive therapy

Medical expulsion therapy, i.e., treatment with drugs which facilitates the spontaneous passage of ureteric calculi, has recently emerged as an efficacious and safe option for the initial management of ureteral stones as demonstrated by the increased stone expulsion rate, decreased expulsion time, and reduced need for analgesic therapy. In fact, it is a cost-effective strategy for the management of distal ureteral stones providing another incentive for initial “facilitated observation” before embarking on surgical intervention.⁹Bensalah K, Pearle M, Lotan Y. et al. Eur Urol. 2008; 53(2):411-8.   It decreases the incidence of adverse events by 29% and decreases the total cost associated with ureteral stones by 24%.¹⁰Brede C, Hollingsworth JM, Faerber GJ, et al. J Urol. 2010; 183(2):585-9.  

Urinary alkalization for dissolution of urinary stones

Uric acid and cystine calculi can be dissolved with medical therapy. Patients with uric acid stones who do not require urgent surgical intervention for reasons of pain, obstruction, or infection can often have their stones dissolved with alkalization of the urine. The dosage of the alkalizing agent should be adjusted to maintain the urinary pH between 6.5 and 7.0. Urinary pH of more than 7.5 should be avoided because of the potential deposition of calcium phosphate around the uric acid calculus, which would make it undissolvable. Both uric acid and cystine calculi form in acidic environments.

Potassium citrate is a preferred alkalizing agent, because of the availability of slow-release tablets and the avoidance of a high sodium load. Potassium citrate should be preferred because it may avoid the

complication of calcium salt precipitation. Studies have proved that urinary alkalization with potassium citrate/bicarbonate is a well tolerated and highly effective treatment, resulting in dissolution of nonobstructing uric acid stones.¹¹Trinchieri A, Esposito N, Castelnuovo C. Arch Ital Urol Androl. 2009 Sep;81(3):188-91.  

Potassium citrate helps in chemo-dissolution of uric acid and cystine stones and is useful in prevention of stone recurrence in general and in those who have undergone SWL or percutaneous nephrolithotomy.¹²Singh SK, Agarwal MM, Sharma S. BJU Int. 2011 Feb; 107(3):356-68.  

Pharmocotherapy

MET is a treatment with combination of drugs which facilitates the spontaneous passage of ureteric calculi. Ureteric colic is an emergency and management depends upon the severity of obstruction and degree of renal function deterioration. Approximately 90% of stones < 5 mm and 15% of stones between 5 and 8 mm pass spontaneously within 4 weeks, while 95% of those larger than 8 mm require urological intervention.¹³Liu M, Henderson SO. Can J Emerg Med 2007;9:463-5.  

AUA and European guidelines have also approved MET as one of the safe and effective treatment approach for the ureter stone management.

European and US guidelines recommend, MET as an option when following conditions are met

1. Newly diagnosed uretral stone < 10 mm
2. well controlled pain
3. good renal function
4. periodic imaging to monitor stone position and assess hydronephrosis

Glyceryl trinitrate, calcium channel antagonists, corticosteroids, parasympatholytic agents and alphablockers have all been evaluated as therapies to promote ureteral stone expulsion, with inconsistent results.

Alpha-blockers

Alpha-blockers are a particularly promising class of stone-expulsive agents.¹⁴Lipkin M, Shah O Rev Urol. 2006; 8(Suppl 4): S35-42.   Tamsulosin has been the most commonly studied alpha-1 blocker in the treatment of ureteral stones with increased spontaneous stone expulsion. Alpha adrenergic receptors are densely located in the smooth muscles of ureter. Alpha-1a-receptors predominate in bladder outlet, prostate, and proximal urethra, whereas

alpha-1d-receptors are seen in lower ureter and detrussor muscle of bladder.¹⁵   Drugs which block these receptors cause smooth muscle relaxation and inhibits peristalsis and relieves spasm.

Tamsulosin is effective in expulsion therapy as it increases the passage rate and reduces the passage time for stones up to 10 mm. In a study of tamsulosin in renal colic, 100% expulsion rate was seen in the treatment group and 70% in the control group. The mean expulsion time in the treatment group was 65.7 hours (range 2-288 hours) compared with 111.1 hours for the control group (range 12-240 hours).¹⁶Dellabella M, Milanese G, Muzzonigro G. J Urol 2003; 170:2202-5.   In this study, the mean stone size was 6.7 (SD 2.1) mm in the treatment group, compared with 5.8 mm in control subjects (P=0.047).

Mode of action of tamsulosin – Tamsulosin stimulates α-adrenergic receptors which are present in the ureter. Stimulation of the α receptors increases the force of ureteral contraction and the frequency

of ureteral peristalsis. This stimulation induces an increase in the intraureteral pressure gradient around the stone, that is an increase in the urine bolus above the stone (and consequently an increase intraureteral pressure above the stone) as well as decreased peristalsis below the ureter (and consequently a decrease in intraureteral pressure below the stone) in association with the decrease in basal and micturition pressure even at the bladder neck. For these reasons there would be a stronger urge to expel the stone.

Several trials have been conducted to evaluate the efficacy of alpha blockers in the management of ureteral stones. Some of the recent studies supporting the efficacy of tamsulosin in the management of ureteral stones are summarized in Table.1

Tamsulosin is effective in the management of distal ureteral stones, but its role in managing proximal stones is unclear. A study was conducted to evaluate the efficacy of tamsulosin on the spontaneous passage of proximal ureteral calculi ≤ 10 mm. This study was conducted on 92 patients, who were randomly divided into two groups.²²Yencilek F, Erturhan S, Canguven O, et al. Urol Res. 2010;38(3):195-9.   Group1- were given classical conservative approach, Group 2 additionally received tamsulosin, 0.4 mg/day during 4 weeks follow-up. Stone expulsion rate was significantly better and also higher spontaneous passage rate of stone was seen with tamsulosin group. This study supported the use of tamsulosin in the proximal ureter stone management.

Tamsulosin with ADS technology

Unlike conventional tamsulosin formulations that depend on the presence of water in the gastrointestinal tract (GIT) to release the active ingredient, the innovative ADS technology ensures continuous and consistent tamsulosin release throughout the entire length of the GIT including the colon where water is poorly available. This results in a more constant exposure to tamsulosin over 24 hours with a smaller peak-to-trough fluctuation (PTF) than the conventional formulations; and, also reduces/eliminates the dependency on food. In fact, the innovation appears superior to conventional MR formulation of tamsulosin that has a variable absorption profile dependent on when it is taken in relation to food and gastrointestinal transit time. Furthermore, as not all patients comply with the dosing recommendations in the patient leaflet, the independence of food intake might considerably improve the tolerability of Tamsulosin.²³Speakman M. Efficacy and safety of tamsulosin OCAS. BJU international 2006;98(2): 13-17.   Consequently, the ADS advantage equates with less adverse effects on physiologic parameters.

Calcium channel blockers

The use of calcium channel antagonists such as nifedipine has also proved useful. Calcium-channel blockers suppress smooth muscle contraction and reduce ureteral spasm. Studies comparing nifedipine against tamsulosin seem to indicate that both drugs are useful, but tamsulosin is more efficacious. A comparative study between nifedipine and tamsulosin reveals a better stone expulsion rate of 97.1% in tamsulosin versus 77.1% in nifedipine group. One study reported that tamsulosin was superior to nifedipine because of the decreased time to expulsion and slightly higher rate of expulsion.²⁴Porpiglia F, Ghignone G, Fiori C, Fontana et al. J Urol 2004; 172:568-71.   Another study reported that tamsulosin was shown to have significantly improved quality of life variables such as mobility, capacity to perform usual activities, pain and discomfort, and anxiety.²⁵Dellabella M, Milanese G, Muzzonigro G J Urol 2005; 174:167-72.   Hence, although calcium channel blockers are also indicated in medical expulsion therapy, alpha adrenergic blockade may be the preferential mode of therapy.

Corticosteroids

Steroids are also found to be useful as medical expulsive agents in distal ureteric stones. This is because calculus in distal ureter causes inflammation and submucosal edema which further aggravates the obstruction due to the stone per se; and being anti-inflammatory agents, steroids reduce the inflammation and neutrophil-induced damage. In effect, in combination with other agents, steroids improve stone passage and reduce stone expulsion time.

According to a study conducted to assess the clinical role of corticosteroids in the medical expulsive therapy of symptomatic distal ureteral stones, stone expulsion rate was 85% in combination therapy of corticosteroids and tamsulosin when compared to that of corticosteroids alone (37.5%). This study concluded that when the medical expulsive therapy for symptomatic distal ureteral stones is considered, the use of steroids (deflazacort) proves efficient only when administered together with alpha(1)-blockers (tamsulosin).

Phosphodiesterases (PDEs) inhibitors

Phosphodiesterases (PDEs) regulate intracellular cyclic nucleotide turnover influencing smooth muscle tension. Drotaverine inhibits phosphodiesterases

hydrolyzing cAMP, thereby increasing cAMP concentration, decreasing Ca uptake of the cells and changing the distribution of calcium among the cells.²⁶Romics I, Molnár DL,Timberg G, et al BJU International 2003: 92-96.   Drotaverine is an effective spasmolytic, inhibiting phosphodiesterase type IV in the smooth muscle cells, accompanied by a mild Ca-channel blocking effect with no anticholinergic effect.

Kuhn et al found relaxing effects on potassium chloride- induced tension of ureteral smooth muscle by PDE4 inhibitors in-vitro.²⁷Kuhn R, Uckert S, Stief CG, et al Urol Res 2000;28:110-5.   Gratzke et al demonstrated the ureteral smooth muscle relaxing effects of different PDE5 inhibitors in vitro. Results were similar to those reported for tamsulosin, suggesting the potential of using PDE inhibitors in the treatment of ureteral colic.²⁸Gratzke C, U ckert S, Reich O, et al Der Urologe 2007; 46:1219-23.   Recently a randomized, single-blind study comparing single intramuscular doses of drotaverine hydrochloride (PDE4) (80 mg) vs. diclofenac sodium (75 mg) on 100 patients (50 in each arm) presenting to the emergency department (ED) with renal colic was conducted.²⁹Dash A, Maiti R, et al Pain Med 2012 Mar;13(3):466-71.   Pain intensity was recorded using a visual analog scale (VAS), which is the primary outcome measure of this study, before drug administration and 30 and 60 minutes afterwards. VAS decreased significantly (P < 0.001) with both drotaverine (52.4%) and diclofenac (49%) at 30 minutes. Reduction of VAS at 60 minutes was 61.3% with drotaverine in comparison to 60.4% with diclofenac (Figure 2).

Nonsteroidal Anti-Inflammatory Drugs

Nonsteroidal anti-inflammatory drug (NSAID) agents that inhibit cyclo-oxygenase (COX), an enzyme involved in prostaglandin synthesis from fatty acids; have been used extensively in the management of patients with renal colic. But according to a study, oral diclofenac, a nonselective COX inhibitor, did not increase stone expulsion rate compared to placebo. However, diclofenac significantly decreased pain and hospital admissions.³⁰Laerum E, Ommundsen OE, Gronseth JE, et al Eur Urol 1995;28:108-111.   Perinephric hematoma is one of the post ESWL complication. Patients who are taking aspirin or NSAIDs, or those with untreated kidney infection or poorly controlled hypertension are at particular risk of developing perineprhic hematoma. NSAIDs are associated with mild gastrointestinal disturbances, occasional hypersensitivity reactions, and sometimes coagulation disorders because of cyclo-oxygenase inhibition.³¹Power I, Chambers WA, Greer IA, Ramage D, Simon E. Anesthesia.1990;45:916-9   They have antithrombocytic effects because they block the synthesis of thromboxane A2, slow down hemostasis, and may cause a prolonged bleeding time. They reduce renal blood flow, renin release, and the glomerular filtration rate by inhibiting the synthesis of prostaglandin E2.³²British National Formulary. 2008; 56: 543-51. available from: http://www.bnf.org/bnf   To avoid this complication NSAIDs are preferably avoided during treatment phase.

According to Martindale, caution is advised while using tamsulosin with diclofenac, as elimination of tamsulosin is increased leading to reduced effect of tamsulosin.³³Sean C, Sweetman, (ed). Martindale: The Complete Drug Reference. 37th edition. London pharmaceutical press: 2011.   Also NSAIDs like diclofenac do not have any effect on stone expulsion rate and should be used with caution in patients at risk of renal impairment, cardiac failure and gastric ulceration. Drotaverine is a better option to NSAIDs because of superior pain relief, no drug interaction with tamsulosin and no risk of gastrointestinal ulceration and perinephric hematoma.

Several cases have been reported of a possible association between the use of non-steroidal antiinflammatory drugs (NSAIDs) and the development or aggravation of necrotizing fasciitis. A case fatal necrotizing fasciitis occurring in association with intramuscular injections of diclofenac in a patient who was admitted for the symptoms of a urinary stone was reported. Intramuscular injections caused a locally aseptic necrosis. Hence avoid the use of intramuscular injections of diclofenac and other NSAIDs in cases of potentially infectious diseases.³⁴Verfaillie G, Knape S, Corne L. Eur J Emerg Med 2002 Sep;9(3):270-3.  

Urology referral

Surgical intervention should be instituted immediately in patients with intractable pain, severe obstruction, signs of infection, or failure of stones progression after 3 to 4 weeks, significant symptoms prompting several office visits, or for patients with specific occupational requirements (i.e. a pilot).³⁵Gettman MT, Segura JW. BJU International 2005;95(2):85-93   Even for small stones, if passage has not happened after this period, spontaneous passage is unlikely and therefore surgical intervention will likely be required.³⁶Ricardo Beduschi, J. Stuart Wolf Jr. Braz J Urol, 2001; 27:120-127.  

Larger and more proximal ureteral stones are less likely to pass spontaneously and are more likely to require urologic intervention. Most urologists prefer to wait several days before intervention unless there is evidence for infection, low likelihood of spontaneous passage (e.g., size is >10 mm), the presence of an anatomic abnormality that would prevent passage, or unrelenting pain.

Drug therapy is highly effective in stone expulsion; however, it is imperative that an appropriate urology referral be made in cases of patients receiving medical expulsion therapy, who do not pass their stones within 4 weeks since delay in definitive management may increase the rate of complications, including renal dysfunction, urosepsis, and intractable pain.⁷Barnela SR, Soni SS, Saboo SS, et al. Indian Journal of Endocrinology and Metabolism, 2012;16(2):236-239.   Such patients can be treated by minimally invasive surgical procedures including ESWL, ureteroscopy, and percutaneous nephrolithotomy. While each procedure has its own advantages and disadvantages, the choice of treatment largely depends on the size and location of stones. Furthermore, in order to select the most appropriate surgical treatment, location, composition, and size of the stone(s), the anatomy of the collecting system, and the presence of obstruction along with the presence of infection of the urinary tract should be considered.³⁷Sarica K. Arch Ital Urol Androl. 2008 Jun;80(2):43-9.  

Still, even though minimally invasive treatments for ureteral stones are efficacious, they are not free of complications and are associated with high cost. Consequently, medical expulsive therapy would be the favored alternative strategy for the initial management of small distal ureteral stones.³⁸Tzortzis V, Mamoulakis C, Rioja J, et al. Drugs. 2009; 69(6):677-92.  

MET should be considered for ureterolithiasis without complication post ESWL, percutaneous nephrolithotomy and ureteroscopy.³⁹Tiselius H-G, Alken P, Buck C, et al. European Association of Urology 2008. Available at: http://www.uroweb.org/fileadmin/user_upload/Guidelines/Urolithiasis.pdf  

Conclusion

As correct use of prophylactic and therapeutic medications can decrease the morbidity associated with ureteric calculi, medical expulsive therapy should be the routine in the treatment of ureteral calculi before ureteroscopy or extracorporeal lithotripsy. In general, small stones in the lower ureter can pass out spontaneously in a few weeks, and this likelihood of spontaneous passage can be increased with use of tamsulosin, which has been found efficacious in medical expulsion of stones up to 10 mm; allowing complete home patient treatment. Combination therapy of tamsulosin and potassium citrate for the treatment of uric acid stones has shown the better results. Drotaverine can be used for the analgesic effect rather than NSAIDs, to avoid the adverse effects of NSAIDs. Yet, treatment decisions should always be individualized, and should the stone remain despite medical expulsion therapy; a urology referral for other more definite treatment options should be considered without delay.

References

1. Yung-Tai Chen. Urological Science 2012;23(1):5-8.
2. Knoll T. European urology supplements. 2010; 9:802-806.
3. Itoh Y, Kojima Y, Yasui T, et al. Int J Urol. 2007;14(8):749-53.
4. Spernat D, Kourambas J. BJU Int. 2011;108 Suppl 2:9-13.
5. Moe OW. Lancet. 2006 Jan 28;367(9507):333-44.
6. Micali S, Grande M, Sighinolfi MC, et al. J Endourol. 2006 Nov;20(11):841-7
7. Barnela SR, Soni SS, Saboo SS, et al. Indian Journal of Endocrinology and Metabolism, 2012;16(2):236-239.
8. Borghi L, Meschi T, Amato F, et al J Urol 1996;155:839-43.
9. Bensalah K, Pearle M, Lotan Y. et al. Eur Urol. 2008; 53(2):411-8.
10. Brede C, Hollingsworth JM, Faerber GJ, et al. J Urol. 2010; 183(2):585-9.
11. Trinchieri A, Esposito N, Castelnuovo C. Arch Ital Urol Androl. 2009 Sep;81(3):188-91.
12. Singh SK, Agarwal MM, Sharma S. BJU Int. 2011 Feb; 107(3):356-68.
13. Liu M, Henderson SO. Can J Emerg Med 2007;9:463-5.
14. Lipkin M, Shah O Rev Urol. 2006; 8(Suppl 4): S35-42.
15. Cervenakov I, Fillo J, Mardiak J, et al Int Urol Nephrol 2002; 34:25-9.
16. Dellabella M, Milanese G, Muzzonigro G. J Urol 2003; 170:2202-5.
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22. Yencilek F, Erturhan S, Canguven O, et al. Urol Res. 2010;38(3):195-9.
23. Speakman M. Efficacy and safety of tamsulosin OCAS. BJU international 2006;98(2): 13-17.
24. Porpiglia F, Ghignone G, Fiori C, Fontana et al. J Urol 2004; 172:568-71.
25. Dellabella M, Milanese G, Muzzonigro G J Urol 2005; 174:167-72.
26. Romics I, Molnár DL,Timberg G, et al BJU International 2003: 92-96.
27. Ku¨hn R, U¨ckert S, Stief CG, et al Urol Res 2000;28:110-5.
28. Gratzke C, U¨ ckert S, Reich O, et al Der Urologe 2007; 46:1219-23.
29. Dash A, Maiti R, et al Pain Med 2012 Mar;13(3):466-71.
30. Laerum E, Ommundsen OE, Gronseth JE, et al Eur Urol 1995;28:108-111.
31. Power I, Chambers WA, Greer IA, Ramage D, Simon E. Anesthesia.1990;45:916-9
32. British National Formulary. 2008; 56: 543-51. available from: http://www.bnf.org/bnf
33. Sean C, Sweetman, (ed). Martindale: The Complete Drug Reference. 37th edition. London pharmaceutical press: 2011.
34. Verfaillie G, Knape S, Corne L. Eur J Emerg Med 2002 Sep;9(3):270-3.
35. Gettman MT, Segura JW. BJU International 2005;95(2):85-93
36. Ricardo Beduschi, J. Stuart Wolf Jr. Braz J Urol, 2001; 27:120-127.
37. Sarica K. Arch Ital Urol Androl. 2008 Jun;80(2):43-9.
38. Tzortzis V, Mamoulakis C, Rioja J, et al. Drugs. 2009; 69(6):677-92.
39. Tiselius H-G, Alken P, Buck C, et al. European Association of Urology 2008. Available at: http://www.uroweb.org/fileadmin/user_upload/Guidelines/Urolithiasis.pdf