ENDOUROLOGY AND STONE DISEASE Efficacy of Medical Expulsive Therapy in Renal Calculi Less than or Equal to 5 Millimetres in Size Sudarshan Daga, Vinayak Wagaskar*, Harshawardhan Tanwar, Umesh Shelke, Bhushan Patil, Sujata Patwardhan Purpose: Natural history and modality of treatment for asymptomatic renal calculi less than or equal to 5 milli- metres in size is still unknown. Many options are available ranging from medical expulsive therapy to minimally invasive surgery. Till date no study has focussed on this very common but asymptomatic issue. Hence, this study is undertaken to evaluate efficacy of medical expulsive therapy in renal calculi less than or equal to 5mm in size. Materials and Methods: A prospective, parallel group, randomized study was carried out from 1st June 2014 to 31st May 2015, with total of 100 patients, 50 patients in each group. Patients with renal stones less than or equal to 5mm were included in the study. Group A Patients were administered medical expulsive therapy which includ- ed tamsulosin 0.4 mg daily at night time, furosemide 20mg, spironolactone 50mg in a single morning dose, and syrup potassium magnesium citrate 20Meq per dose three times a day for 12 weeks while group B patients were given placebo. The primary outcome variable was number of patients achieving clearance of stone during 12-week treatment period in both groups. Results: No statistically significant differences in age, gender, stone size, and calyceal stone location was found between the two treatment arms. A spontaneous stone expulsion rate of 50% (at 6 weeks) and 86 %( at 12 weeks) was noted in group A versus 28% (at 6 weeks) and 38 % (at 12 weeks) in group B. Less number of pain episodes and less analgesic medication was required in group A as compared to group B. Conclusion: Medical Expulsive therapy for 12 weeks significantly improves stone free rates in renal calyceal calculi less than or equal to 5mm. Key words: diclofenac sodium; furosemide; spironolactone; tamsulosin; urolithiasis. INTRODUCTION Urolithiasis affects almost varied population all over world (1,2). Estimated world risk is 10%-25%(1, 3). Natural history, progression and best modality of treat- ment for asymptomatic renal calculi less than 5mm is still not known. Occupations like Air force, Navy, Army and Bus Drivers, requires stone free status to join duty. Available treatment options are observation, medical expulsive therapy (MET), Shockwave Litho- tripsy (SWL), retrograde intra-renal surgery (RIRS), Micro-percutaneous nephrolithotomy (PCNL), ultra mini-PCNL. Cost of operative treatment is higher than non operative modalities like observation and MET(4). Several medications have being evaluated over the last 10 years for medical management of renal stones(5). Meta-analysis have demonstrated effectiveness of MET in post SWL procedure with added analgesic effect(6,7,8). Medline searches did not yield any published study re- lating to use of medical expulsive therapy for asymp- tomatic renal calyceal calculi less than 5mm in size. Karabacak et al. demonstrated presence of α1 recep- tors and their subtype in renal pelvis and calyces(9). They suggested that use of α1 blockers (tamsulosin) for treatment of renal cayceal stones may be impli- cated(9). After search of Medline data base, we did not find any study performed with respect to MET for particularly asymptomatic renal calyceal calculi and hence this is among the first prospective, randomized single institutional studies to evaluate efficacy of med- ical expulsive therapy for asymptomatic renal calyceal calculi ≤5mm in size. The purpose of this study was to evaluate efficacy of medical expulsive therapy for asymptomatic renal calyceal calculi ≤5mm in size. MATERIALS AND METHODS A prospective, parallel group, randomized study was carried out from 1st June 2014 to 31st May 2015. With a total of 100 patients, 50 patients in each group. Institu- tional Ethical Committee approval (EC-OA-105/2013) was taken. Patients who fulfilled our inclusion/exclu- sion criteria during study period were included and assigned into two groups by simple random method. Each patient was chosen entirely by a chance and had equal chance of being included in either group. A writ- ten informed consent was taken from all the patients. Inclusion criteria: All patients with asymptomat- ic or history of a single episode of renal colic with well controlled pain by analgesics, age >18 years, and stone size ≤5 mm in renal calyces were includ- ed in the study. These asymptomatic patients came to us with ultrasonography Kidney-Ureter-Blad- der (USG KUB) performed outside for other reasons Department of Urology, King’s Edward Memorial Hospital, Mumbai, India*Correspondence: King’s Edward Memorial Hospital, Mumbai, India. *Correspondence: King’s Edward Memorial Hospital, Mumbai India. Tel: +91-9890906273 Email: vinayakwagaskar@kem.edu. Received May 2016 & Accepted October 2016 Vol 13 No 06 November-December 2016 2893 and were incidentally detected to have renal calculi. Exclusion criteria: Patients with stone greater than 5mm, solitary kidney, ureteric stone, distal ureter- ic stricture or subtle ureteric stricture like those with history of prior ureteroscopy or history of Bilharzia- sis, bladder stone, pregnant female, recurrent stone formers, chronic renal failure, aberrant ureteral anato- my (e.g., ureteral ectopia, ureterocele and mega ureter), sensitivity to the drugs used in MET, presence of renal stones more than 3 in number and patients with uri- nary tract infection were excluded from the study. We also excluded patients with recurrent stone formers as these patients usually have underlying metabolic ab- normality and their treatment would have an influence on the results of our study. We did not include patients with clinical insignificant residual fragments (CIRF). Each patient was evaluated with history, physical ex- amination, and laboratory investigations like haemo- globin, complete blood count, blood urea nitrogen level, serum creatinine, serum electrolyte, urine C/S, X-Ray Kidney-Ureter-Bladder (KUB) and ultrasonog- raphy (USG) KUB. Literature supports that there is no significant difference in evaluation of urolithia- sis by USG and computed tomography KUB10. USG KUB was done by the same physician in all patients. CT KUB Plain was done only when stone was visu- alized on ultrasound and was not seen on X-ray KUB. Group A Patients were given medical expulsive ther- apy which included capsule tamsulosin 0.4 mg daily at night time, tablet furosemide 20mg, spironolactone 50mg single morning dose, and syrup potassium mag- nesium citrate 20Meq per dose three times a day for 12 weeks while group B patients were given placebo. Both groups were given dietary advice including wa- ter intake >3litre/day and tablet diclofenac sodium 50mg as per severity of pain. The primary outcome variable was number of patients achieving clearance of stone during the 12-week treatment period in both groups. Secondary variables included expulsion rate for different calyceal location, and incidence of pain in both groups. Expulsion rate was measured objec- tively by performing USG KUB after 6 weeks and af- ter 12 weeks. Side effects were evaluated from start of study till completion. Side effects such as dizziness, nausea, headaches and retrograde ejaculation (in male patients) in patients taking tamsulosin; muscle weak- ness and lethargy in patients taking furosemide and altered bowel habits, nausea and vomiting in patients taking potassium magnesium citrate syrup were ex- plained to them. All patients were asked to follow up at 6 and 12 weeks. These patients were also informed to refer if they experienced any of above side effects. Primary and secondary variable were evaluated at each visit. Primary physician evaluated the patients during study time. He was concealed about the group of the pa- tients. Outcome variables such as pain or stone free-rate was measured separately each time and measured again in the next follow-up visits. Imaging techniques includ- ed USG KUB, X-ray Kidney-Ureter-Bladder (KUB) at 6 and 12-week follow up visit. Imaging data were re- corded for noting variables like stone size and location. Statistical Analysis Since no data was available for sample size calculation, a universal sampling method was used. According- ly, 50 patients in each group were selected. The Null hypothesis assumed there was no difference between MET and placebo group on the effect of stone passage. Data was recorded on Microsoft excel 2010. Chi-square test with two tail distribution was used to compare two groups, P-value < .05 was considered as significant. RESULTS No statistically significant differences in age, gen- der, stone size, and calyceal stone location were found between the two treatment arms (Table 1). Median stone size in entire study group was 4.7 mm (inter-quartile range [IQR]: 2.0-5mm). Table 1. Distribution of patients in the groups with respect to age, sex, side affected and size of stone. GROUP A(MET) GROUP B (PLACEBO) P value Age, years; mean±SD(range) 35.14 ± 11.43 (17-68) 32.66 ± 10.24 (16-70) 0.443 Sex Male 31 32 0.8 Female 19 18 0.8 Side Right 38 36 0.25 Left 24 34 0.25 Stone Size, mm; mean ± SD 4.274 ± 1.06 4.49 ± 0.99 0.634 Table 2. Percentage of stone clearance achieved in the two groups at 6 weeks and at 12 weeks No. of patients achieved complete Group A(MET) Group B(Placebo) P value Clearance at 6 weeks 25(50%) 14(28%) 0.04 12 weeks 43(86%) 19(38%) <0.01 MET in renal stone < 5 mm- Daga et al. Endourology and Stone Diseases 2894 A spontaneous stone expulsion rate (Table 2) of 50% (at 6 weeks ) and 86 %( at 12 weeks) was noted in group A and 28% (at 6 weeks) and 38 % (at 12 weeks) in group B. Expulsion rate noted for different calyceal lo- cation at 6 weeks and 12 weeks are shown in Table 3. With significant less number of pain episodes in group A as compared to group B, only 8 patients(16%) in group A required analgesic as compared to 19(38%)in group B which was statistically significant (P < .05). Patients were asked to bring back empty strips of med- ication to evaluate compliance with medication at each visit. Expulsion rates in respect to number of patients achieving stone free status achieved statistical signifi- cance at 6 weeks (P = .04) and 12 weeks (P < .01) (Table 2). However, clearance rate in respect to number of stone from each calyx achieved statistical significance at 12 weeks only for superior and middle calyces (Table 3). DISCUSSION Many patients with renal calculi ≤5mm remain asymp- tomatic. Evaluation of ureteral smooth muscle physi- ology and obstruction caused by urinary stones signi- fies that α-blockers can facilitate stone expulsion(11-13). Distribution of α1 receptors and their subtypes has been confirmed by Karabacak et al. in human pel- vis and calyces(9). Meta-analysis has confirmed use of α-blockers (tamsulosin) to achieve clearance of residual stone in post surgical cases(14-16). Use of diu- retics like furosemide has been shown to be effective in expulsion of the calcium fragments and also diure- sis would further fasten expulsion of small stones(17). Expectant management is followed for renal calculi less than 5 mm in size which are likely to pass spontane- ously by follow up every 6 month(8). However, there is level IIb/B evidence that for small ≤5mm calculi after SWL when followed expectantly, a significant number would require intervention or have symptomatic ep- isodes during follow-up. Burgher and co-workers has described that stone > 4mm were 26 % more likely to fail observation than patients with smaller solitary cal- culi(18). Hubner et al. reported that 83% of 62 patients with asymptomatic calyceal stone required interven- tion within 5 years of diagnosis. Only 10% remained symptom free after 10 years(19). Karabacak et al.(9) had described density expression of α-1 receptor subtypes for renal pelvis and calyces which were α-1D>α- 1A>α-1B. No difference was observed in the receptor expressions in pelvis with calyces. However, receptor MET in renal stone < 5 mm- Daga et al. Stone free rate at Calyceal Location Group A(MET) Group B(placebo) P value 6 weeks Superior Calyx 66.66%(10/15) 45.46%(10/22) 0.3 Medial Calyx 63.41%(26/41) 47.83%(22/46) 0.2 Inferior Calyx 50%(9/18) 50%(9/18) 0.7 12 weeks Superior Calyx 93%(14/15) 45.46%(10/22) <0.01 Medial Calyx 90.25%(37/41) 60.87%(28/46) <0.01 Inferior Calyx 78%(13/18) 55.56%(10/18) 0.4 Table 3. Calyceal-wise stone clearance rates in the two groups. Figure 1. Patients' flow diagram. Vol 13 No 06 November-December 2016 2895 density for each calyx was not mentioned in study, which would have helped in predicting whether infe- rior calyx had less density of receptors which might be the reason for lower expulsion rate in our study. Soy- gur et al. have concluded that use of potassium citrate in post SWL lower pole calculi aided in spontaneous passage of stone and increasing clearance rates(20). Gravina and colleagues studied the efficacy of tam- sulosin as an adjunctive therapy after SWL for renal stones(21). At 12 weeks, clinical success was achieved in 78.5% of patients receiving tamsulosin and 60% of patients not receiving tamsulosin (P =.037). The stones ranged in size from 4 mm to 20 mm(19). However low- er pole calculi were not included in the study group. Mean stone size in our study was 4.7 mm and the most commonly reported stone location was middle calyx (65.9%) followed by superior calyx (31.66%) and inferi- or calyx (27.27%). On subgroup analysis, expulsion rate of above 90% was achieved after 12 weeks for superior and middle calyceal calculi and 78 % for inferior calyceal calculi. Overall number of patients achieving complete clearance of stone at 12 weeks was 43 out of 50(86%) which was statistically significant. Stone expulsion was significantly (P < .05) better with MET than with pla- cebo (86% vs. 38%); with an absolute benefit (AB) of 48%; number needed to treat (NNT) was 4 in our study. Four studies showed a beneficial effect for a-block- ade for renal stones treated with SWL(21-24). Han et al. demonstrated a significant expulsion rate and de- creased analgesic requirement with use of tamsulosin for upper ureteral stones after SWL(25). In a prospec- tive study of 70 patients performed by Arrabal-Martin M et al.(26), it was found that tamsulosin significantly increases stone expulsion rate (85.7%) as compared to hydration therapy (54.3%) in patients with distal ure- teric calculi less than 10 mm. Three double-blinded RCTs did not demonstrated significant differences in expulsion rate for MET using alfuzosin or tamsulosin for lower ureteral stone versus placebo(27-29). Howev- er average stone size in these 3 study group were 3.8 mm in Pedro et.al.(27), (2.9mm -3.2mm) in Vincendeau et al.(27) and (3.8mm -4.1 mm) in Hermanns et al.(29). With stone size less than 4mm there is higher chances of stone passing spontaneously(8), therefore decreased efficacy of MET is expected. In these studies, a-block- ers still reduced time to stone passage, pain scores, and need for analgesia(28). Similarly, Ferre et al.(30) failed to demonstrate a significant higher expulsion rate in the tamsulosin group. Again, mean stone size was 3.6 mm. Meta-analysis of 33 trials (3105 patients) examined a-blockers (most often tamsulosin) or calcium chan- nel blockers (nifedipine) in patients with renal stones (primarily < 10 mm; frequently distal ureter)(31). Stone expulsion was significantly (P < .001) better with MET than with placebo (80% vs. 54%); absolute benefit (AB) of 26%; number needed to treat (NNT) of four31.The more distal the stone, the lesser time required for expul- sion. Skolarikos A et al.(32) performed meta-analysis and demonstrated efficacy of a-blockers in stone clearance. They have also concluded that a-blockers significantly reduce the time to stone elimination, the intensity of pain, the formation of steinstrasse, and the need for auxiliary procedures. Similarly, efficacy of α-1D receptor block- ers in clearance of distal ureteric stones has been proven by other studies(33). European(34) and US(35) guidelines for urolithiasis recommend MET as an option when the fol- lowing criteria are met: newly diagnosed ureteral stone < 10 mm in patients without need for urgent urologic intervention; and well-controlled pain, no sepsis, good renal function, and following with periodic imaging to monitor stone position and assess hydronephrosis. The secondary variable of number of events of pain was significantly lower in MET group versus place- bo. Patients in MET arm required less analgesia than patients in the placebo arm. No serious complications were recorded in both groups. The common side ef- fects of tamsulosin are dizziness, nausea, diarrhoea, headache and retrograde ejaculation. In our study the only adverse effect noted was dizziness in 4 patients and nausea in 3 patients in MET group over a period of 12 weeks which was well tolerated. Patients with residual calculi in both groups after 12 weeks were managed with other modalities like SWL, or RIRS. With recent understanding of distribution of alpha adrenoreceptors in renal calyces and pelvis, the pres- ent study is one of the first to compare the efficacy between MET and placebo on renal calyceal calculi ≤5mm in size. The results suggest that treatment with use of MET in patients with ≤5mm renal calculi when taken for 12 weeks is effective in achieving stone clear- ance, implying a higher number of patients achiev- ing complete clearance and better pain management. Being an initial step to address small renal calculi and use of medical therapy which is better than observation and less morbid than invasive procedure certain limi- tations of this study are: single institutional study and small population size; a multicenter placebo controlled double blind study will be able to validate results ob- served in our study. Other limitations include the use of X-ray KUB and USG KUB to detect residual cal- culi when CT Scans should be the imaging of choice to detect the calculus. MET as a combine treatment of alpha blocker with diuretics and potassium citrate therapy was given to treatment group which has a confounding effect, however MET achieved a signifi- cant expulsion rate and better patient tolerability of all drugs with minimal side effects. Stone composition and metabolic evaluation was not addressed which would have been helpful to evaluate patients completely and starting specific medical therapy according to stone composition and addressing and minimizing future recurrences. Our study fails to address difference be- tween spontaneous passage and MET for small stones. CONCLUSIONS Medical Expulsive therapy for 12 weeks significant- ly improves stone free rates in renal calyceal calcu- li less than or equal to 5mm. However, further rand- omized studies are required to document these findings. CONFLICTS OF INTEREST None declared. REFERENCES 1. Moe OW. Kidney stones: pathophysiology and medical management. Lancet 2006; 367:333–44. 2. Romero V, Akpinar H, Assimos DG. Kidney stones: a global picture of prevalence, incidence, and associated risk factors. Rev Urol 2010; 12:e86–96. MET in renal stone < 5 mm- Daga et al. Endourology and Stone Diseases 2896 3. Lee YH, Huang WC, Tsai JY, Lu CM, Chen WC, Lee MH, et al. Epidemiological studies on the prevalence of upper urinary calculi in Taiwan. Urol Int 2002; 68:172–7. 4. Saigal CS, Joyce G, Timilsina AR. Direct and indirect costs of nephrolithiasis in an employed population: opportunity for disease management? Kidney Int 2005; 68:1808–14. 5. Moe OW, Pearle MS, Sakhaee K. Pharmacotherapy of urolithiasis: evidence from clinical trials. Kidney Int 2011; 79:385– 92. 6. Gravina GL, Costa AM, Ronchi P, et al. Tamsulosin treatment increases clinical success rate of single extracorporeal shock wave lithotripsy of renal stones. Urology 2005; 66:24-8. 7. Naja V, Agarwal MM, Mandal AK, et al. Tamsulosin facilitates earlier clearance of stone fragments and reduces pain after shockwave lithotripsy for renal calculi; results from an open-label randomized study. Urology 2008; 72:1006-11. 8. Zheng S, Liu LR, Yuan HC, et al. Tamsulosin as adjunctive treatment after shockwave lithotripsy in patients with upper urinary tract stones: a systematic review and meta-analysis. Scand J Urol Nephrol 2010;44:425-32. 9. Karabacak OR, Yilmazer D, Ozturk U, Sener NC, Saltas H, Karabacak Y, et al. The presence and distribution of alpha adrenergic receptors in human renal pelvis and calyces. Urolithiasis. 2013; 41: 385–8. 10. Carlo Passerotti, Chow JS, Silva A, Schoettler CL, Rosoklija I Perez-Rossello J et al. Ultrasound Versus Computerized Tomography for Evaluating Urolithiasis. The J Urol 182: 1829–1834. 11. Sigala S, Dellabella M, Milanese G, Fornari S, Faccoli S, Palazzolo F, et al. Evidence for the presence of alpha1 adrenoceptor subtypes in the human ureter. Neurourol Urodyn 2005; 24:142–8. 12. Tomiyama Y, Kobayashi K, Tadachi M, Kobayashi S, Inada Y, Kobayashi M, et al. Expressions and mechanical functions of alpha1-adrenoceptor subtypes in hamster ureter. Eur J Pharmacol 2007; 573:201–5. 13. Morita T, Wada I, Suzuki T, Tsuchida S. Characterization of alpha-adrenoceptor subtypes involved in regulation of ureteral fluid transport. Tohoku J Exp Med 1987; 152:111–8. 14. Vicentini FC, Mazzucchi E, Brito AH, Chedid Neto EA, Danilovic A, Srougi M. Adjuvant tamsulosin or nifedipine after extracorporeal shock wave lithotripsy for renal stones: a double blind, randomized, placebo-controlled trial. Urology 2011; 78:1016–21. 15. Hussein MM. Does tamsulosin increase stone clearance after shockwave lithotripsy of renal stones? A prospective, randomized controlled study. Scand J Urol Nephrol 2010; 44:27–31. 16. John TT, Razdan S. Adjunctive tamsulosin improves stone free rate after ureteroscopic lithotripsy of large renal and ureteric calculi: a prospective randomized study. Urology 2010; 75:1040–2. 17. Suki WN, Yium JJ, Von Minden M, Saller- Hebert C,Eknoyan G and Martinez-Maldonado M. Acute Treatment of Hypercalcemia with Furosemide.N Engl J Med 1970; 283:836-840. 18. Bugher A, Beman M, Holtzman JL, Monga M. Progression of nephrolithiasis: long-term outcomes with observation asymptomatic calculi. J Endourol. 2004;18:534–539. 19. Hübner W, Porpaczy P. Treatment of caliceal calculi. British journal of urology. 1990 1;66:9-11. 20. Soygur T, Akbay A, Kupeli S. Effect of potassium citrate therapy on stone recurrence and residual fragments after shockwave lithotripsy in lower calyceal calcium oxalate urolithiasis: a randomized controlled trial. J Endourol. 2002;16:149–52. 21. Gravina GL, Costa AM, Ronchi P, et al. Tamsulosin treatment increases clinical success rate of single extracorporeal shock wave lithotripsy of renal stones. Urology. 2005;66:24-28. 22. Bhagat SK, Chacko NK, Kekre NS, Gopalakrishnan G, Antonisamy B, Devasia A. Is there a role for tamsulosin in shock wave lithotripsy for renal and ureteral calculi? J Urol 2007;177:2185–8. 23. Naja V, Agarwal MM, Mandal AK, et al. Tamsulosin facilitates earlier clearance of stone fragments and reduces pain after shockwave lithotripsy for renal calculi: results from an open-label randomized study. Urology 2008;72:1006–11. 24. Hussein MM. Does tamsulosin increase stone clearance after shockwave lithotripsy of renal stones? A prospective, randomized controlled study. Scand J Urol Nephrol 2010;44:27–31. 25. Han MC, Jeong WS, Shim BS. Additive expulsion effect of tamsulosin after shock wave lithotripsy for upper ureteral stones. Korean J Urol 2006;47:813–7. 26. Arrabal-Martin M, Valle-Diaz de la Guardia F, Arrabal-Polo MA, Palao-Yago F, Mijan-Ortiz JL, Zuluaga-Gomez A. Treatment of ureteral lithiasis with tamsulosin: literature review and meta-analysis. Urol Int. 2010;84:254-9. 27. Pedro RN, Hinck B, Hendlin K, Feia K, Canales BK, Monga M. Alfuzosin stone expulsion therapy for distal ureteral calculi: a double-blind, placebo controlled study. J Urol 2008;179:2244–7, discussion 2247. MET in renal stone < 5 mm- Daga et al. Vol 13 No 06 November-December 2016 2897 28. Vincendeau S, Bellissant E, Bansalah K, et al. Lack of efficacy of tamsulosin in the treatment of distal ureteral stones. Eur Urol Suppl 2008;7:149. 29. Hermanns T, Sauermann P, Rufibach K, Frauenfelder T, Sulser T, Strebel RT. Is there a role for tamsulosin in the treatment of distal ureteral stones of 7 mm or less? Results of a randomised, doubleblind, placebo-controlled trial. Eur Urol 2009;56:407–12. 30. Ferre RM, Wasielewski JN, Strout TD, Perron AD. Tamsulosin for ureteral stones in the emergency department: a randomized controlled trial. Ann Emerg Med 2009;54:432– 9. 31. Seitz C, Liatsikos E, Porpiglia F, Tiselius HG, Zwergel U. Medical therapy to facilitate the passage of stones: what is the evidence? Eur Urol 2009;56:455-71. 32. Skolarikos A, Grivas N, Kallidonis P, Mourmouris P, Rountos T, Fiamegos A, Stavrou S, Venetis C; Members of RISTA Study Group. The Efficacy of Medical Expulsive Therapy (MET) in Improving Stone-free Rate and Stone Expulsion Time, After Extracorporeal Shock Wave Lithotripsy (SWL) for Upper Urinary Stones: A Systematic Review and Meta-analysis. Urology. 2015 ;86:1057-64. 33. Wang CJ, Tsai PC, Chang CH. Efficacy of Silodosin in Expulsive Therapy for Distal Ureteral Stones: A Randomized Double- blinded Controlled Trial. Urol J. 2016 28;13:2666-71. 34. Tiselius HG, Alken P, Buck C, Gallucci M, Knoll T, Sarica K, et al. Guidelines on urolithiasis. Arnhem, The Netherlands: European Association of Urology; 2009. 35. American Urologic Association. 2007 guideline for the management of ureteral calculi. Rockville, MD: Agency for Healthcare Research and Quality; 2007. MET in renal stone < 5 mm- Daga et al. Endourology and Stone Diseases 2898