Medical Expulsion Therapy (MET) of urinary stones

Urolithiasis is known to be a burden to mankind from ancient eras and remains a major issue regarding health and well being today. Almost 20% of urinary tract stones are found in the ureters with majority (70%) being located in the lower third of the ureter.¹Ahmed AA, Al Syed AS. Korean J Urol 2010; 51:193.   The life time risk of developing urinary calculi is between 5 and 12%, affecting more men compared to women.²Smith RD, Shah M, Patel A. F1000 Med Reports 2009; 1:53.   The incidence is peaked in the third and fourth decades, and prevalence increased with age until approximately the age of 70 years.³Ranabir S, Baruah MP, Reetu Devi K Indian Journal of Endocrinology and Metabolism. Apr 2012;16(2).  

Indian prevalence

In India, 12% of the population is expected to have urinary stones, out of which 50% may end up with loss of kidneys or renal damage. Gujarat has higher prevalence of urinary stones.⁴ Ahamed J, Khalid N, and Jabeen E, Pak. J. Sci. Ind. Res., 1987;30:205-07.   Also, nearly 15% of the population of northern India suffers from kidney stones. Fewer occurrences of urinary calculi are found in southern India, which may be due to regular dietary intake of tamarind.⁵Rao, T.V.K and Mytreye Dass, Asian Journal of Chemistry, 2000;12: 719.  

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 darkcolored urine.

Management of urinary stones

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

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%.⁶Borghi 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 expulsion therapy

The management of patients having ureteral calculi has changed dramatically in this current era with minimal invasiveness being the primary focus of concern, so far selection of any treatment modality is concerned.

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 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 non-obstructing uric acid stones.⁷Trinchieri 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.⁸Singh 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.⁹Liu 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.

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.¹⁰Lipkin 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.¹¹Cervenakov I, Fillo J, Mardiak J, et al Int Urol Nephrol 2002;34:25-9.   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).¹²Dellabella 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.²⁴Yencilek 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.²⁵Speakman 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 nifedepine and tamsulosin reveals a better stone expulsion rate of 97.1% in tamsulosin versus 77.1% in nifedepine group. One study reported that tamsulosin was superior to nifedipine because of the decreased time to expulsion and slightly higher rate of expulsion.¹⁶Porpiglia 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.¹⁷Dellabella 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.

Kü hn et al found relaxing effects on potassium chloride-induced tension of ureteral smooth muscle by PDE4 inhibitors in vitro.²⁷Kühn R, ü ckert 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, ü 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 perinephric 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 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 gastro-intestinal ulceration and perinephric hematoma.

Several cases have been reported of a possible association between the use of 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.  

Minimally Invasive Surgical Management

• Extracorporeal shockwave lithotripsy (ESWL),
• Ureterorenoscopy (URS) or
• Percutaneous nephrolithotripsy (PCNL)

Extracorporeal shockwave lithotripsy (ESWL)

ESWL is performed as an outpatient procedure and is well tolerated. It has good stone-free rates; 82% in the upper ureter and 73% in the mid-ureter and 74% in the distal ureters. Lithotripsy is generally indicated for renal stones smaller than 2 cm (20mm), ³⁵A bdel-Khalek M, Sheir KZ, et al Scand J Urol Nephrol 2004; 38:161-167.   especially those not located in the calyx in the lower pole. Lithotripsy has the disadvantage of damaging nearly any structure in the trajectory of the shock wave, causing bleeding, inflammation, or perforation. Lithotripsy is more likely to fail if the skin to- stone distance is more than 10 mm, if the lower pole forms an acute angle with the ureter, or if the body mass index is greater than 30 kg/m2 (ie, if the patient is obese).³⁶Pareek G, Hedican SP, Lee FT Jr, Nakada SY. Urology 2005; 66:941-944.  

Steinstrasse is a well-known complication following extracorporeal shock wave lithotripsy (ESWL). It has been identified in 5-10% of patients with large stone burdens [> 2 cm (20mm)] and may necessitate surgical intervention if medical treatment fails.

A study was conducted to evaluate the efficacy of tamsulosin as a conservative management of steinstrasse.³⁷Moursy E, Gamal WM, Abuzeid A. Scand J Urol Nephrol. 2010 Nov;44(5):315-9.   This study was conducted on 88 patients who were treated with ESWL between January 2005 and December 2008. Patients were divided into two groups. Patients in group 1 (study group) received a single daily morning dose of tamsulosin (0.4 mg) for a maximum of 4 weeks, in addition to pain-relieving therapy. Patients in group 2 (control group) received only the pain-relieving therapy. Stone expulsion occurred in 32 of the 44 patients (72.7%) receiving tamsulosin and in 25 of the 44 patients (56.8%) in the control group. Patients receiving tamsulosin had a significantly higher stone expulsion rate (P = .017). This study supports the use of tamsulosin which significantly facilitates expulsion of retained ureteral stone fragments following ESWL with less need for hospitalization.

Percutaneous nephrolithotomy for large or staghorn stones

Percutaneous nephrolithotomy is highly effective for renal calculi but is associated with more complications than lithotripsy or ureteroscopy. Percutaneous nephrolithotripsy (PCNL) is usually reserved for large renal stones >20mm and staghorn calculi as well as large impacted upper ureteric stones > 15mm.

Percutaneous antegrade ureteroscopy

Percutaneous antegrade removal of ureteral stones can be performed in selected cases when SWL is not indicated or has failed and retrograde ureteroscopy is unsuitable, especially in those with urinary diversion or renal transplants. Studies have demonstrated that the antegrade approach is a safe and effective treatment option for ureteral calculi in selected patients. However, for large or impacted stones, the ureteral injury rate and ureteral stricture rate of the antegrade approach exceed those of retrograde ureteroscopy.³⁸Kim BS, Lee JN, Choi JY et al Korean J Urol 2010;51:800-802.  

Ureterorenoscopy (URS)

Ureterorenoscopic stone removal (URS) is a viable alternative for the removal of urinary stones. Miniaturization in ureteroscope design has allowed for small caliber semirigid and flexible ureteroscope to be developed with good optical quality. Holmium/YAG laser, which has a low penetration of only 0.5mm, helps in precise vaporization and fragmentation in turn increasing stone clearance. Complications associated with the procedure such as ureteral perforation is less than 5% while ureteric stricture is less than 2%.³⁹Johnson DB, Pearle MS. Urol Clin North Am 2004:31:157.  

Open surgery (Ureterolithotomy)

This method may be needed if other methods do not work or are not possible. With the advent of minimally invasive techniques, open surgery has assumed a distant role in the management of urolithiasis.

Conclusion

Urinary tract stone disease is a very common disease of urinary tract affecting humans. The approach to the management of these ureteral stones has seen significant change due to recent advances in the technology, but the conservative approach still holds the upper hand. Urine alkalization and pharmacological management is safe and cost effective method of managing the urinary stones. Tamsulosin an alpha blocker is a mostly studied and effective and safe drug in medical expulsion therapy. 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.

Surgical treatment should be promptly instituted on right indications or when medical management fails.

References

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26. Romics I, Molnár DL,Timberg G, et al BJU International 2003: 92-96.
27. Kühn R, ü ckert S, Stief CG, et al Urol Res 2000;28:110-5.
28. Gratzke C, ü 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. A bdel-Khalek M, Sheir KZ, et al Scand J Urol Nephrol 2004; 38:161-167.
36. Pareek G, Hedican SP, Lee FT Jr, Nakada SY. Urology 2005; 66:941-944.
37. Moursy E, Gamal WM, Abuzeid A. Scand J Urol Nephrol. 2010 Nov;44(5):315-9.
38. Kim BS, Lee JN, Choi JY et al Korean J Urol 2010;51:800-802.
39. Johnson DB, Pearle MS. Urol Clin North Am 2004:31:157.