LITHUANIAN UNIVERSITY OF HEALTH SCIENCES MEDICAL ACADEMY
FACULTY OF MEDICINE DEPARTMENT OF UROLOGY
THE EFFECTIVENESS OF EXTRACORPOREAL SHOCKWAVE
LITHOTRIPSY IN TREATING URINARY TRACT STONES
Nouran Karim
MASTER THESIS
Supervisor: M.D. Povilas Aniulis
2 TABLE OF CONTENTS 1. SUMMARY ... 3 Aim:... 3 Objectives: ... 3 Methods: ... 3 Results: ... 4 Conclusions: ... 4 2. ACKNOWLEDGEMENTS ... 5 3. CONFLICT OF INTEREST... 6 4. BIOTHETICS APPROVAL ... 6 5. ABBREVIATIONS ... 7 6. TERMS ... 8 7. INTRODUCTION ... 9
8. AIMS AND OBJECTIVES ... 10
Aim:... 10
Objectives: ... 10
9. LITERATURE REVIEW ... 11
9.1 Urolithiasis... 11
9.2 Extracorporeal shock wave lithotripsy definition ... 12
9.3 Treatment choice according to size and location of stone ... 13
9.4 Predictors of success ... 16
9.5 SWL effectiveness for treatment of renal stones ... 18
9.6 SWL effectiveness for treatment of ureteral stones ... 20
9.7 Complications post extracorporeal shockwave therapy... 22
9.8 Effect of Tamsulosin as adjuvant treatment on effectiveness of shock wave lithotripsy ... 25
10. RESEARCH AND METHODOLOGY ... 26
11. RESULTS AND DISCUSSION ... 28
12. CONCLUSION ... 36
13. LIMITATIONS OF STUDY ... 37
14. REFERENCES ... 38
1. SUMMARY
Author: Nouran Karim
Title: The Effectiveness of Extracorporeal Shockwave Lithotripsy in Treating Urinary Tract Stones.
Aim: To provide a review of literature assessing the effectiveness and complications of extracorporeal shockwave lithotripsy in treating urinary tract stones and to compare these results with other widely used methods used for the treatment of urolithiasis.
Objectives:
1. To assess success rates of extracorporeal shockwave lithotripsy in treating renal and ureteral calculi by examining stone free rates of this procedure.
2. To evaluate complications and the rate of complications after extracorporeal shockwave lithotripsy.
3. To compare extracorporeal shockwave lithotripsy effectiveness with other methods of urinary tract stone removal: retrograde intrarenal surgery (rigid, semi-rigid and flexible ureteroscopy) and percutaneous nephrolithotomy,
4. To assess the effect that adjuvantly using Tamsulosin has on the effectiveness of extracorporeal shockwave lithotripsy.
Methods: Research was conducted following the preferred approach to reporting items for systemic reviews and meta-analysis (PRISMA) method. Research databases such as
4 Results: A review of literature has found that extracorporeal shockwave lithotripsy is
effective at treating urinary tract stones with a success rate of 64-100% with minimal
complication rates compared to other treatment modalities. The use of adjuvant therapy after shockwave lithotripsy significantly increases success rates. A total of 23 articles were
selected to be included in this review. 5 articles evaluated effectiveness in renal stones, 4 articles assessed effectiveness in ureteral calculi, 5 articles evaluated complications, 6 articles evaluated the effect of adjuvant therapy, 2 articles evaluated other predictors of success and 1 study assessed effectiveness for renal and ureteral stones and complications.
Conclusions:
1. Extracorporeal shockwave lithotripsy is most effective for smaller stones in the renal pelvis and distal ureter and is least effective for larger stones (>10mm), stones of higher density and stones in complex ureteral or renal areas such as inferior pole calyx or middle and proximal ureter.
2. The majority of the complications that occur due to extracorporeal shockwave lithotripsy are benign and occur less than alternative treatment modalities. The most common complications that occur are colicky pain, macroscopic haematuria and obstruction due to steinstrasse.
3. Retrograde intrarenal surgery (RIRS) and percutaneous nephrostolithotomy techniques (PNL) are more effective at managing renal and ureteral stones and require more repeat or auxiliary procedures, however, they result in higher complication rates than extracorporeal shockwave lithotripsy.
2. ACKNOWLEDGEMENTS
I would like to express my deepest appreciation to Dr. Povilas Aniulis for his patience, constant guidance, attention and encouragement throughout my final master thesis project.
6 3. CONFLICT OF INTEREST
I, Nouran Karim, the author report no conflicts of interest.
4. BIOTHETICS APPROVAL
5. ABBREVIATIONS
SWL- Extracorporeal Shock Wave Lithotripsy
PNL- Percutaneous nephrolithotomy
RIRS - Retrograde Intrarenal Surgery
URS- Ureteroscopy
fURS- Flexible Ureteroscopy
EUS- Endoscopic Ureterolithotripsy Surgery
SFR- Stone free rate
EAU- European Association of Urology
MET- Medical Expulsion Therapy
HU- Hounsfield units
HTN- Hypertension
8 6. TERMS
Calvien Grade: A method used to classify the grade of complications after urologic surgical procedures.
7. INTRODUCTION
The presence of stones in the urinary tract- urolithiasis, is a worldwide medical problem which is fairly common, with a worldwide prevalence of 2-3%. In 50% of cases, urinary stones will reoccur for patients with a history of calculi. [1]
The probability of developing these stones varies depending on gender, age, race or ethnicity, geography, occupation and climate.[1,2]
Urinary tract stones may lead to pain, infection, haemorrhage, haematuria, diminished kidney function and renal failure [1], therefore, require expulsion or removal.
With recent technological advancements, the management of urolithiasis has changed drastically. Choice of treatment depends on the condition of the patient, experience of surgeon, patient’s preference and availability of technology [3]. However, there are several other factors which alter the treatment options, including the size, location, and composition of the stone. The best and most effective treatment method is still debated.[4]
Open stone surgery has become obsolete with the introduction of minimally invasive options, which include: extracorporeal shockwave lithotripsy (SWL), percutaneous nephrostolithotomy techniques (PNL), retrograde intrarenal surgery (RIRS), intracorporal lithotripsy devices and endoscopic ureterolithotripsy surgery (EUS). [4]
10 8. AIMS AND OBJECTIVES
Aim: To provide a review of literature assessing the effectiveness and complications of extracorporeal shockwave lithotripsy in treating urinary tract stones and to compare these results with other widely used methods used for the treatment of urolithiasis.
Objectives:
1. To assess success rates of extracorporeal shockwave lithotripsy in treating renal and ureteral calculi by examining stone free rates of this procedure.
2. To evaluate complications and the rate of complications after extracorporeal shockwave lithotripsy.
3. To compare extracorporeal shockwave lithotripsy effectiveness with other methods of urinary tract stone removal: retrograde intrarenal surgery (rigid, semi-rigid and flexible ureteroscopy) and percutaneous nephrolithotomy.
9. LITERATURE REVIEW
9.1 Urolithiasis
Urolithiasis is the formation of stones within the urinary tract (in the kidney, ureter, bladder or urethra). It is the third most common urinary tract disease in humans. [5]
Classification according to location: [5] I. Nephrolithiasis (renal calculi)
II. Ureterolithiasis (ureteral stones) III. Cystolithiasis (bladder stones) IV. Uretherolithiasis (urethral stones)
Classification according to composition:
Table 1: Classification of calculi by etiology [2,6,7]
Stone Frequency Risk factors
Non-infection stones
Calcium oxalate 70-80% Calcium binds with oxalates to form the stone. Occurs due to: low urine volume, high urine calcium, low urine citrate or high urine oxalate.
Calcium phosphate 15% Calcium binds with phosphorus to form the stone. Occurs due to: low urine volume, high urine calcium, low urine citrate or high urine pH.
Uric acid 8% They occur due conditions which cause acidic urine: low urine output, excessive intake of proteins (red meat), alcohol intake, IBD, gout.
Are not visible on a plain X-ray.
Occur more frequently in men than women. Infection stones
Magnesium ammonium phosphate (Struvite)
1% They form in alkaline urine. Usually caused by a
bacterial urinary tract infection which raises urine pH to neutral or alkaline. These stones may become very large in size.
Genetic causes
Cystine 1-2% They occur in patients suffering from Cystinuria, a hereditary disease affecting both genders.
Drug stones
e.g. Atazanavir, Indinavir, Sulphadiazine, Uncontrolled Calcium supplementation
12 9.2 Extracorporeal shock wave lithotripsy definition
SWL was introduced in the 1980’s as an alternative to open surgery. It pulverises stones in the kidney and upper urinary tract through the use of shock waves propagated through the body and focused onto a small area, into smaller fragments which can be passed through urine spontaneously. [Figure 1] The procedure lasts approximately 45 to 60 minutes and does not require the use of anaesthesia. [8,9]
Three levels of frequencies may be used during this procedure; [10] i. High-frequency (100–120 sws/minute),
ii. Intermediate-frequency (80–90 sws/minute), iii. Low-frequency (60–70 sws/minute).
The contraindications for SWL treatment are: [6,10]
• Pregnancy, due to the effects on the fetus
• Hypo-coagulability state
• Uncontrolled infections of the urinary tract
• Serious skeletal malformations and severe obesity, which prevent the stone from being targeted
• Arterial aneurysm in the area of the stone (aortic or renal artery)
• Urinary tract obstruction distal to the stone.
9.3 Treatment choice according to size and location of stone
The European Association of Urology (EAU) Urolithiasis Guidelines for the treatment of renal stones suggest that the primary treatment of renal stones <10 mm should include SWL and RIRS as second line. The first line treatment for renal stones >20 mm should be PNL.
For 10-20mm renal stones (bar those that present in the lower pole), primary treatment includes SWL or Endourological techniques (RIRS/PNL). In cases of 10–20 mm lower pole renal stones, Endourology is recommended as second line if there are unfavourable factors for SWL. [Figure 2]
In the case of ureteric calculus: SWL or Ureteroscopy (URS) can be used for the treatment of those present in the proximal and distal ureter and are <10mm, however, for those >10mm, URS is the primary management tactic. [Figure 3] [6]
Fig. 2:A proposed treatment algorithm for kidney stones according to the 2020 update of the EAU Guideline on
14 Nevertheless, unlike the EAU guidelines, nowadays, SWL is used as first line to treat most cases since it can be performed easily without hospitalization with fewer subsequent
complications. [11,13] However, SWL often requires multiple treatments because of the lower stone free rate which leads to surgical delays or increased costs. [11,12]
Fig. 3: A proposed treatment algorithm for ureteral stones according to the 2020 update of the EAU Guideline on
Although the use of SWL, URS, RIRS and PNL are definitive treatments, conservative management is always first line and is important for symptom management, to correct the underlying cause and prevent recurrence.
A number of treatments may correct the underlying metabolic defects responsible for stone formation. These include a high fluid intake for all types of stones, thiazide diuretics for
hypercalciuria, potassium citrate for hyperuricosuria, hypocitraturia and uric acid stones. [14]
Non-steroidal anti-inflammatory drugs (NSAIDs) e.g. Metamizole or alternatively,
paracetamol, are used as first line treatment in the case of renal or ureteral colic. If greater analgesic effect is required, the addition of Ketamine produces a larger reduction in pain scores with fewer side effects, compared to opioid (pethidine) use. [6]
Stones <4mm in diameter are likely to pass spontaneously. Medical expulsion therapy (MET) is used to facilitate stone passage for ureteral stones >5mm and <10mm.
Several different medications increase the passage rate of ureteral stones, including alpha blockers (Tamsulosin), calcium channel blockers (Nifedipine), and antispasmodic agents. [14] Oral chemolysis causes alkalinisation of urine by the use of alkaline (potassium) citrate or sodium/magnesium bicarbonate. The optimal pH should be 7.0-7.2. Stones composed of uric acid, can be dissolved by oral chemolysis, however, this may promote calcium phosphate stone formation. [14]
16 9.4 Predictors of success
A number of factors can influence the outcomes of SWL; mainly factors related to the stone (size, location, composition, density (Hounsfield units (HU)), factors related to anatomy (obstruction/stasis, horseshoe kidney) and patient-related factors (age, sex, body mass index (BMI), skin to stone distance). [15]
Efficacy of SWL is measured by the stone-free rate (SFR), usually within 3 months of the procedure, allowing time for passage of the stone fragments. [2]
The SFR’s of SWL are inversely proportional to the size of the stone. [15,16] A study [18] showed the success rates of SWL in treating renal and ureteral stones of different sizes were 90.4%, 72.09%, 66.02% and 43.66% for stones 4-9mm, 10-19mm, 20-29mm and >30mm respectively. [Figure 4]
Another review [19] compared SFR for lower pole renal stones: 100%, 93% and 86% for calculi of <1 cm, 1–2 cm and >2cm, respectively.
Location of the stone also plays a factor is success of SWL. SFR for renal stones was 77.5% for renal pelvic and 47.4% for renal calyx stones.
Stone free (SF) status was seen in 77.2% of patients with proximal, 78.3% with mid and 84% with distal ureteric stones. [18]
90.40% 72.09% 66.02% 43.66% 0.00% 10.00% 20.00% 30.00% 40.00% 50.00% 60.00% 70.00% 80.00% 90.00% 100.00%
4-9mm stones 10-19mm stones 20-29mm stones >/=30mm stones
Success rates of SWL
Khalifa, B.B. et al. in a retrospective study of 68 patients [20] concluded that density of the
stone was an independent predictor of stone free outcome. For every 100 HU increase in stone there was significantly lower odds of becoming stone free. (Odds ratio [OR] 7.1, 95% CI 2.521–16.812, p = 0.013). Stones < 1000 HU had a higher chance of being treated successfully with SWL than stones > 1000 HU.
Calcium oxalate monohydrate stones (highest density) had the lowest SFR following SWL, while the patients with uric acid stones (lowest density) were stone free. SFR was 100%, 83% and 38% for stones <500HU, 500-1000HU and >1000HU respectively.
18 9.5 SWL effectiveness for treatment of renal stones
Various trials have been conducted to compare the effectiveness of SWL to RIRS and PNL. [22-26]
B. Resorlu et al. analysed 437 patients who had 10-20mm sized renal stones in a
retrospective analysis, in which 251 underwent SWL, 140 underwent PNL and 46 underwent RIRS.
The success rates were 66.5%, 91.4%, and 87% for SWL, PNL, and RIRS respectively (p < 0.001). Those who underwent SWL required auxiliary procedures more often (21.9%) compared to PNL (5.7%) and RIRS (8.7 %) (p < 0.001).
The complication rates, however, for the SWL (7.6%) were comparatively less than after PNL (22.1%) and RIRS (10.9 %) (p < 0.001). [Figure 5] [22]
The effectiveness of these methods to treat medium sized (10-20mm) renal pelvic stones was assessed in a retrospective study of 149 patients. 52 underwent SWL, 47 underwent flexible ureteroscopy (fURS) and 50 underwent PNL. SFR after an average of 2.6 sessions of SWL was 86 % (45/52). For those who underwent fURS and PNL, SFR was 91.4 % (43/47) after fURS, and 98 % (49/50) after PNL. Complication rates after SWL, fURS and PNL were 7.6 % (4/52), 6.3 % (3/47) and 12 % (6/50), respectively. [23] 66.50% 91.40% 87% 21.90% 5.70% 8.70% 7.60% 22.10% 10.90% 0.00% 10.00% 20.00% 30.00% 40.00% 50.00% 60.00% 70.00% 80.00% 90.00% 100.00% SWL PNL RIRS
Success rates Auxiliary procedures Complication rates
A prospective randomised trial of 135 patients, compared the three modalities for the
treatment of 10-20mm inferior calyceal calculi. 45 underwent SWL, 45 underwent RIRS and 45 underwent PNL (miniperc). The SFR after 3 months of shock wave lithotripsy, retrograde intrarenal surgery and PNL was 73.8%, 86.1% and 95.1% respectively (p = 0.01). The re-treatment rate (63.4% vs 2.1% and 2.2%, p <0.001) and the auxiliary procedure rate (20.2% vs 8.8% and 6.6%, p = 0.02) were significantly higher for shock wave lithotripsy than for RIRS and miniperc, respectively. [24]
The most effective treatment for smaller stones (<10mm) is still debatable. In a prospective trial of 140 patients (70 underwent SWL and 70 underwent RIRS), after 7 days, 34/70 patients (48.6 %) treated by SWL were stone free, while 38/70 patients (52.3%) treated by fURS group were stone free.
At 3 months evaluation, all patients who underwent fURS had no residual fragments. In the SWL group, the patients received an average of 2.7 ± 0.4 sessions of SWL, in this group, 64/70 patients (91.5 %) were stone free at 3 months. 4 of those who underwent SWL experienced complications (3 Calvien grade I, 1 Calvien Grade IIIa), 3 patients who
underwent fURS experienced complications, however all of these were Calvien grade I). [25]
The first line treatment for renal stones >20 mm is percutaneous nephrolithotomy (PNL) as the success rate is significantly higher after PNL. This is described in a retrospective study of 337 patients (167 underwent SWL, 170 underwent PNL). The SFR was 95% vs. 75%, for PNL and SWL respectively, (p < 0.001). The total required number of procedures (3 vs.1), the re-treatment rate (75% vs. 5%) and the need for auxiliary procedures (25% vs. 4.7%) were significantly higher in those who underwent SWL (p < 0.001). However, the
20 9.6 SWL effectiveness for treatment of ureteral stones
The size and location of stone in the ureter affects success rates of SWL treatment. SWL is generally more effective at treating smaller stones (<10mm) than larger stones (>10mm) . Demirbas et al. In a retrospective study of 2836 patients compared the success rates of SWL in treating stones in the proximal, mid, and distal parts of the ureter of different sizes (<10mm, >10mm). The success rates for calculi located in the proximal, mid, and distal ureter were 85.1%, 83.9%, and 88.4%, respectively. The success rates for patients with stones ≤ 10 mm in the proximal, mid, and distal ureter were 90%, 85.8%, and 90.4%,
respectively (p = .07). This rate for individuals with larger stones (> 10 mm) was significantly lower: 75.3% in the proximal ureter, 81.3% in the mid ureter, and 81.6% in the distal ureter. (p =.09).[Figure 6] [27]
In another retrospective study of 153 patients, the success rates were 90.2% and 68.6% in patients with stones <10mm and >10mm who underwent SWL, respectively. [28]
URS is an alternative method used to treat ureteral calculi. In a trial of 150 patients with proximal ureteral stones of < 20mm, In which half underwent URS and SWL each, showed that URS produced larger success rates. SFR after the first, second, and third sessions of SWL were 64%, 77.3%, and 94.7%, respectively, whereas for URS stone-free rates after the first, second, and third sessions were 86.7%, 92%, and 100%, respectively. [29]
90% 85.80% 90.40% 85.10% 83.90% 88.40% 80% 82% 84% 86% 88% 90% 92%
Proximal ureter stones Mid ureter stones Distal ureter stones
Stones </=10mm Stones >10mm
22 9.7 Complications post extracorporeal shockwave therapy
Despite the procedure being non-invasive, SWL is not complication free. Complications after an SWL arise from: [Table 2] [6,10]
1. Fragments, their formation and passage; 2. Infections;
3. The effects on tissues (renal and nonrenal).
Table 2: Complications of shockwave lithotripsy [6,10,17,18,43]
Complication % Stone fragments Steinstrasse - 1-4%, 5-10% if >2cm Residual fragments regrowth 21 – 59% Renal colic 2-4%
Infections Bacteriuria in stones of non-infectious origin
- 7.7-23.5%
Sepsis 1%
Effects on tissues
Renal Symptomatic haematoma,
(perirenal, subcapsular, or intrarenal)
<1%
Asymptomatic haematoma 4-19% Microscopic haematuria
Macroscopic haematuria All cases.
(if this does not occur, it indicates an issue with the delivery of shock waves)
Cardiovascular Arrhythmia 11-59%
Incident hypertension 8% Gastrointestinal e.g. Bowel perforation,
liver/spleen hematoma
The majority of cases that occur are limited and minor. Salem, et.al, in a prospective study of 3,241 patients with urinary calculi ≥4 mm who underwent SWL and were monitored for 3 months, reported 4,075 complications. Colicky pain (40%) was the most common, followed by macroscopic haematuria (32%) , obstruction (30.9%) – of which steinstrasse caused the majority of cases (78.5%). Symptomatic bacteriuria developed in 9.7% of cases; in which
Escherichia coli (30.4%) was the most common organism. Perirenal or subcapsular
hematomas occurred in 4.6% of patients, 11.9% of which were symptomatic. Pain was successfully managed using antispasmodics, anti-inflammatory agents, hydration with or without intervention. Those presenting with gross haematuria resolved spontaneously within 48 hours in 86.5% of cases and almost all cases (98%) resolved in 10 days. Infections were treated with appropriate antibiotics after antibiogram. [18] Without risk factors, antibiotic prophylaxis is usually not justified as the incidence of infections complications post SWL is low. [31]
Serious complications were also reported, a 35-year-old woman who died on day 10 post-SWL due to cerebral artery aneurysm rupture and bleeding. Another reported case was a 55-year-old woman without any underlying diseases who died due to cardiac arrest 6 hours post treatment. [18]
The EAU suggests that lowering shock wave frequency decreases the tissue damage caused by the shock waves. [6]
24 The long term complications of SWL are still debated, and there exists conflicting evidence of hypertension (HTN), diabetes and chronic kidney disease (CKD) as possible outcomes.[33]
In a population-based retrospective study of 11,570 participants with urolithiasis and 127,464 without urolithiasis, Michelle R.Denburg et al. evaluated the risk of developing HTN and CKD post SWL compared to the general population. Urolithiasis itself was associated with a
hazard ratio (HR) of 1.42 (95% CI: 1.35, 1.51) for HTN, so an individual who undergoes SWL to the kidney has a significantly increased risk for developing HTN (HR=1.96, 95% CI: 1.67, 2.29) compared with an individual without urolithiasis. When comparing SWL to the kidney or ureter, only SWL to the kidney was significantly and independently associated with HTN (HR=1.40, CI: 1.19, 1.66). Neither SWL nor URS were associated with new onset CKD. [34]
9.8 Effect of Tamsulosin as adjuvant treatment on effectiveness of shock wave lithotripsy
Medical expulsion therapy (MET) has recently been utilised to improve outcomes after SWL therapy. Examples of drugs that may be used are Tamsulosin, Doxazosin, Terazosin and Nifedipine [39,40]. Among these, Tamsulosin seems to have superiority in facilitating stone passage. [40]
Tamsulosin is a selective alpha-1A and alpha-1B adrenoceptor antagonist. It functions by inhibiting smooth muscle contraction in the ureter, facilitating stone passage into the bladder.[42]
Steinstrasse is a common complication, occurring in up to 10% of patients [Table 2].
Tamsulosin may be effective in improving stone free rate by facilitating the passage of stone fragments, reducing pain and decreasing the number of auxiliary requirements after SWL therapy. [37,39]
Several trials with control (where no adjuvant therapy was administered post SWL therapy) and case groups (in which Tamsulosin was given after treatment with SWL) were conducted to evaluate if Tamsulosin increased SWL success rate. [36,41]
S. Falahatkar et. al [36] found that compared to the placebo group, for those who received Tamsulosin, stone clearance rate was significantly increased, 60% to 71.4% (by 11.4%) and stone passage time was decreased, stone passage of 32.6% of patients between the 20th
and 30th day post treatment vs stone passage of 50% of patients between the 10th and 20th
day after SWL. In another study [41], however, there was no improvement in stone clearance between the placebo and case group in the case of ureteric stones treated by SWL.
Although, it reduced the incidence of renal colic among patients and henceforth reduced need for analgesic administration.
26 10. RESEARCH AND METHODOLOGY
Inclusion Criteria
Full text articles that were in English, included human adult models and within 10 years of the search date were manually sorted according to the inclusion and exclusion criteria: Studies in which urolithiasis (and not extra urinary tract stones) treatment was discussed, studies in which effectiveness of SWL was discussed, studies in which complications of SWL was discussed. Various study types were utilized to conduct this review (clinical studies,
randomized control trials, cohort studies, literature reviews, meta-analysis, systemic reviews & meta-analysis). This review was prepared in compliance with the Preferred approach to Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) method. Figure 7 shows the process of PRISMA for data collection and analysis.
Search Strategy
A literature search of publications between April 2010 and April 2020 was conducted using PubMed, Google Scholar, Cochrane library and UpToDate. A combination of the following terms were used to formulate the search; Extracorporeal shockwave lithotripsy, shock wave lithotripsy, urolithiasis, effectiveness, complications, reliability, stone free rate, success rate, renal stones, ureteric stones.
Data Extraction
A review of these articles was performed on the basis of title and abstract and any duplicates were removed. After extensive reviewing, a number of articles were deemed appropriate to be included in the literature review after the full article was assessed. The relevant
information was extracted according to specific objective.
Assessment of Studies
Studies identified from initial search in other sources
n= 4312
Papers deemed appropriate after titles and abstracts
assessed n= 83
Selected abstracts n= 30
Papers considered eligible after full article has been assessed:
n=16
Exclusion criteria
• Not in English, • Not within 10 years, • Animal model, • Paediatric cases,
• Non urinary tract stones, • Non full text articles.
Inclusion criteria
• Studies in which effectiveness of SWL was discussed,
• Studies in which complications of SWL was discussed,
• Studies in which urolithiasis treatment was discussed • Clinical studies,
• Randomized control trials, • Cohort studies,
• Literature reviews, • Meta-analysis,
• Systemic review & meta-analysis.
Duplicates, n= 4 Studies identified from
initial search in PubMed n= 2074
Papers deemed appropriate after abstracts
and summaries assessed n= 21
Papers considered eligible after full article has been assessed:
n= 7
Selected abstracts n= 10
Total no. of articles and scientific reviews included in the study
n= 23 Clinical studies, n= 12 Randomized control trials, n= 2 Cohort studies, n= 2 Literature reviews, n= 2 Meta-analysis, n= 2 Systemic review &
meta-analysis n= 3
28 11. RESULTS AND DISCUSSION
Table 3: Characteristics of studies on renal lithiasis
Author Date Type of Study Techniques Number of patients Size of lithiasis Location of stone Definition of SFR/ Success
Conclusion and notes
Resorlu, B. et al.[22] 2013 Retrospective study SWL, PNL, RIRS 437 (251,140,46) 10-20mm Kidney <3mm residual fragments
SWL was the least effective compared to PNL and RIRS
(SFR: 66.5%, 91.4%, and 87% for SWL, PNL, and RIRS respectively) and
required secondary procedures more often (SWL (21.9%), PNL (5.7%) and RIRS (8.7 %)) Complication rates for SWL were less than after PNL or RIRS. ( SWL (7.6%), PNL (22.1%) and RIRS (10.9 %) Bas, O. et al.[23] 2014 Retrospective study SWL, RIRS (fURS), PNL 149 (52,47,50) 10-20mm Renal pelvis No stones present
Kumar, A. et al.[24] 2015 Prospective randomised trial SWL, RIRS, PNL (miniperc) 135 (45, 45, 45) 10-20mm Inferior calyx
Not stated SWL was the least effective compared to RIRS and PNL (SFR: 73.8%, 86.1% and 95.1% respectively) and required re-treatment (63.4% vs 2.1% and 2.2% respectively) and secondary procedures (20.2% vs 8.8% and 6.6%) more often. Sener, N.C et al.[25] 2014 Prospective randomised trial SWL, RIRS 140 (70,70) <10mm Lower pole No residual fragments
After less sessions (1 vs 2.7 ± 0.4) fURS management yielded a higher SFR than SWL (52.3% vs 48.6%) with comparable complications ( 3 vs 4 complications) for stones <10mm. Mohammed Hassan et al.[26] 2015 Retrospective study SWL, PNL 337 (167, 170) 20-30mm Renal pelvis <4mm residual fragments
30 Table 4: Characteristics of articles on ureteric lithiasis
Author Date Type of Study Techniques Number of patients Size of lithiasis Location of stone Definition of SFR/ Success
Conclusion and notes
Demirbas, M. et al.[27] 2012 Retrospective study SWL 2836 5-15mm Proximal, mid, distal ureter Radiologically confirmed fragmentation and spontaneous passage of stone
The effectiveness of SWL was not significantly different according to size and location of ureteric stone.( The success rates for calculi
located in the proximal, mid, and distal ureter were 85.1%, 83.9%, and 88.4%, respectively)
Success rates were highest for distal <10mm (90.4%) stones and lowest for proximal >10mm stones (75.3%). Choi JW et al.[28] 2012 Retrospective study SWL 153 <10mm, >10mm Ureter <4mm residual fragments
Ur Rehman MF et al.[29] 2020 Prospective randomised trial SWL, URS (pneumatic lithotripsy) 150 (75,75) <20mm Proximal ureter <4mm residual fragments
URS is more effective at treating proximal ureteric stones than SWL. ( SFR after the first, second, and third sessions of SWL were 64%, 77.3%, and 94.7%,
respectively, whereas for URS stone-free rates after the first, second, and third sessions were 86.7%, 92%, and 100%, respectively.) Muhammad Islam and Asif Malik. [30] 2012 Randomised trial SWL, URS (pneumatic lithotripsy) 136 (68,68)
5-25mm Lower ureter completely free of stones
SFR after URS was significantly higher than SWL. (92.6% vs 73% at 3 months post procedure). 19.1% of those who underwent SWL required more than 1 session to establish a SF status.
32 Table 5: Characteristics of articles on SWL complications
Author Date Type of Study Techniques Number of patients Size of lithiasis Location of stone Number of complications
Conclusion and notes
Salem, S. et al. [18] 2010 Prospective study SWL 3241 ≥4 mm Urinary tract (kidney, ureter, bladder)
4,075 Majority of complications were minimal and treatable. Colicky pain was the most
common complication(40%), followed by gross haematuria(32%) and
obstruction(30.9%) – of which steinstrasse caused the majority of cases.
Moreno, A.M. et al.[31] 2014 Prospective cohort study SWL 366 - Kidney and ureter
20 After SWL urine culture was abnormal in 20 patients (5.8%), 4 (1.2%) were symptomatic. the remaining 4.6% were asymptomatic. Urosepsis did not develop for any patient. Without risk factors antibiotic prophylaxis is usually not justified as the incidence of infections complications post SWL is low Kumar, A. et al.[32] 2015 Prospective randomized comparison SWL, RIRS 195 (97,98) <20mm Lower pole 16 (6-SWL, 10-RIRS)
Lawler, A.C. et al.[33]
2017 Review SWL - - - - The long-term complications of SWL are still
debated and there exists conflicting evidence of hypertension (HTN), diabetes and chronic kidney disease (CKD) as possible outcomes. Michelle R.Denburg et al.[34] 2016 population-based retrospective study SWL, URS 139,034 - Kidney and ureter 2018 (1423-HTN, 595-CKD)
An individual who undergoes SWL to the kidney has a significantly risk for developing HTN compared with an individual without urolithiasis. (HR=1.96, 95% CI: 1.67, 2.29) When comparing SWL to the kidney or ureter, only SWL to the kidney was
significantly and independently associated with HTN. (HR=1.40, CI: 1.19, 1.66). Krambeck, A.E. et al.[35] 2011 Cohort Study SWL 4,782 - Kidney and ureter 983 (New onset HTN)
34 Table 6: Characteristics of articles on effectiveness of adjuvant therapy
Author Date Type of Study Techniques Number of patients
Size and location of lithiasis
Conclusion and notes
Falahatkar, S. et al.[36] 2011 Placebo-controlled, randomized, double-blind prospective clinical trial SWL + Tamsulosin 150 (71-control / 70-case) 4–20 mm
Kidney and ureter
Tamsulosin facilitated the clearance rate of
fragments (60% without adjuvant therapy to 71.4% post Tamsulosin) and decreased stone passage time post SWL. (stone passage of 32.6% of patients between the 20th and 30th day post treatment vs
stone passage of 50% of patients between the 10th
and 20th day after SWL)
Chen, K. et al.[37] 2015 Systematic Review and Meta-Analysis of Randomized Controlled Trials SWL + Tamsulosin 2093 (21 studies) 4-24mm
Kidney and ureter
Tamsulosin is effective at speeding up stone
expulsion and reduced incidence of steinstrasse and renal colic.
Most effective for ureteral stones and larger calculi. Li, M. et
al.[38]
2015 Meta-analysis SWL + Tamsulosin
- - Tamsulosin facilitated the clearance of fragments and decreased stone passage time post SWL and was effective at reducing pain.
Skolarikos, A. et al.[39] 2015 Systematic review and meta-analysis SWL + alpha-blocker
- - Lower efficacy of medical expulsion therapy for stones < 10 mm vs stones > 10 mm. Zheng, S. et al.[40] 2010 Systematic review and meta-analysis SWL + Tamsulosin
- - Tamsulosin facilitated the clearance of fragments and decreased stone passage time post SWL and was effective at reducing pain.
Hassan Ismail Mohamed[41] 2013 Prospective randomised, controlled study SWL + Tamsulosin 130 5-15mm Ureter
Table 6: Characteristics of articles on predictors of success Author Date Type of Study Factor Number of patients Conclusion and notes
Salem, S. et al.[18]
2010 Prospective study
Size and location of stone
3241 SWL was most effective at treating <10mm (SFR 90.4%) and stones in the renal pelvis (SFR 77.5%) and distal ureter (SFR 84%) and least effective at treating stones >20mm (SFR 66.02% and 43.66% for stones 20-29mm and >30mm respectively) and stones located in the renal calyx (SFR 47.4%) and proximal ureter (SFR 78.3%)
Knoll, T. et al.[19]
2012 Review Size of stone - Effectiveness decreased as stone size increased.
(SFR: 100%, 93% and 86% for calculi of <1 cm, 1–2 cm and >2cm, respectively.)
Khalifa, B.B. et al.[20]
2016 Retrospective study
Density of stone 68 For every 100HU increase, there is significantly less odds of being successfully treated with SWL (OR 0.75, 95% CI 0.854–0.923, p = 0.01). SWL is least effective at treating stones of harder composition (higher density) e.g. calcium oxalate monohydrate. (SFR: 100%, 83% and 38% for stones <500HU, 500-1000HU and >1000HU respectively.)
Kang, D.H. et al.[21] 2016 Metanalysis of randomised control trials Frequency of shock waves used
36 12. CONCLUSION
1. SWL is the most commonly used method in the treatment of symptomatic ureteral and renal stones with a SFR of 64-100%. It is most effective for smaller stones (<10mm) in the renal pelvis and distal ureter and is least effective for larger stones (>10mm), stones of higher density (calcium oxalate monohydrate) and stones in complex ureteral or renal areas such as inferior pole calyx or middle and proximal ureter, these situations are more effectively treated by RIRS or PNL.
2. While SWL is highly effective for accurately selected patients (such as patients with small (<10mm) and less dense (<1000HU) stones located in the distal ureter or renal pelvis), it does result in short and long term complications, although these complications for the majority are benign and occur less than alternative treatment modalities. The most common complications that occur are colicky pain,
macroscopic haematuria and obstruction due to steinstrasse.
3. SWL is less effective than RIRS (SFR 86.1-100%) and PNL (SFR 91.4%-98%) at treating renal and ureteric stones and it requires more sessions (up to three sessions) to reach the same SFR as one session of RIRS or PNL and requires more auxiliary treatments (in 19.1-25% of cases vs 5.9-8.8% for RIRS and 4.7-6.6% for PNL). RIRS yields a slightly higher complication rate than SWL (4.3-11.1% vs 5.7-7.6%), however, the rates are comparable. The complication rates of PNL however, are significantly higher than SWL (13-22.1%).
13. LIMITATIONS OF STUDY
38 14. REFERENCES
1. Srisubat A, Potisat S, Lojanapiwat B, Setthawong V, Laopaiboon M. Extracorporeal shock wave lithotripsy (ESWL) versus percutaneous
nephrolithotomy (PCNL) or retrograde intrarenal surgery (RIRS) for kidney stones. Cochrane Database of Systematic Reviews [Internet]. 2014. Available from:
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007044.pub3/full
2. Curhan G. Kidney stones in adults: Epidemiology and risk factors [Internet]. Uptodate.com. 2020 [cited 18 March 2021]. Available from:
https://www.uptodate.com/contents/kidney-stones-in-adults-epidemiology-and-
risk-factors?search=urolithiasis%20incidence&source=search_result&selectedTitle=1 ~150&usage_type=default&display_rank=1#H926160909
3. Izamin I, Aniza I, Rizal AM, Aljunid SM. Comparing extracorporeal shock wave lithotripsy and ureteroscopy for treatment of proximal ureteric calculi: a cost-effectiveness study. Med J Malaysia. 2009 Mar;64(1):12-21. PMID: 19852314. Available from: http://www.e-mjm.org/2009/v64n1/Proximal_Ureteric_Calculi.pdf
4. Awad Y, Idris S, Ramadan N. EFFECTIVENESS OF ESWL IN UPPER URINARY TRACT CALCULI. Journal of Surgical Arts [Internet]. 2014;. Available from:
https://www.researchgate.net/publication/274780081_EFFECTIVENESS_OF_ES WL_IN_UPPER_URINARY_TRACT_CALCULI_Ust_uriner_sistem_taslarinda_E SWL'nin_etkinligi
5. Urolithiasis | ISUD [Internet]. Imop.gr. Available from: http://www.imop.gr/en/uroinfo-urolithiasis%23
6. C. Türk (Chair), A. Neisius, A. Petrik, C. Seitz, A. Skolarikos (Vice-chair), K. Thomas. Guidelines Associates: N.F. Davis, J.F. Donaldson, R. Lombardo, N. Grivas, Y. Ruhayel (2020). Guidelines on Urolithiasis. [Access date 18th March
7. Daudon M, Frochot V, Bazin D, Jungers P. Drug-Induced Kidney Stones and Crystalline Nephropathy: Pathophysiology, Prevention and Treatment. Drugs [Internet]. 2017. 78(2):163-201. Available from: https://doi.org/10.1007/s40265-017-0853-7
8. Kidney stones - Diagnosis and treatment - Mayo Clinic [Internet]. Mayoclinic.org. 2020. Available from: https://www.mayoclinic.org/diseases-conditions/kidney-stones/diagnosis-treatment/drc-20355759
9. Grasso M, Paik L, Green D, Alexander B, DeBeatham W. Extracorporeal Shockwave Lithotripsy: Practice Essentials, History of the Procedure,
Pathophysiology [Internet]. Emedicine.medscape.com. 2018. Available from: https://emedicine.medscape.com/article/444554-overview#a1
10. D’Addessi A, Vittori M, Racioppi M, Pinto F, Sacco E, Bassi P. Complications of Extracorporeal Shock Wave Lithotripsy for Urinary Stones: To Know and to Manage Them—A Review. The Scientific World Journal [Internet]. 2012. 2012:1-6. Available from: https://www.hindawi.com/journals/tswj/2012/619820/
12. Kang D, Cho K, Ham W, Chung D, Kwon J, Choi Y et al. Ureteral stenting can be a negative predictor for successful outcome following shock wave lithotripsy in patients with ureteral stones. Investigative and Clinical Urology [Internet]. 2016; 57(6):408. Available from: https://doi.org/10.4111/icu.2016.57.6.408
11. Kim C, Chung D, Rha K, Lee J, Lee S. Effectiveness of Percutaneous Nephrolithotomy, Retrograde Intrarenal Surgery, and Extracorporeal Shock Wave Lithotripsy for
40 13. Chang K, Lee J, Park S, Kang D, Lee H, Cho K. Impact of Pretreatment
Hydronephrosis on the Success Rate of Shock Wave Lithotripsy in Patients with Ureteral Stone. Yonsei Medical Journal [Internet]. 2017 ;58(5):1000. Available from: http://10.3349/ymj.2017.58.5.1000
14. Curhan G, Aronson M, Preminger G. UpToDate [Internet]. Uptodate.com. 2019. Available from:
https://www.uptodate.com/contents/diagnosis-and-acute-
management-of-suspected-nephrolithiasis-in-adults?search=urolithiasis%20medical%20treatment&topicRef=7376&source=se e_link#H17
15. Torricelli F, Danilovic A, Vicentini F, Marchini G, Srougi M, Mazzucchi E. Extracorporeal shock wave lithotripsy in the treatment of renal and ureteral stones. Revista da Associação Médica Brasileira [Internet]. 2015. 61(1):65-71. Available from: http://dx.doi.org/10.1590/1806-9282.61.01.065
16. Burr J, Ishii H, Simmonds N, Somani BK. Is flexible ureterorenoscopy and laser lithotripsy the new gold standard for lower pole renal stones when compared to shock wave lithotripsy: Comparative outcomes from a University hospital over similar time period. Cent European J Urol. 2015; 68: 183-186. Available from:
http://ceju.online/journal/2015/calculi-laser-lithotripsy-lower-pole-stone-ureteroscopy-509.php
18. Salem S, Mehrsai A, Zartab H, Shahdadi N, Pourmand G. Complications and outcomes following extracorporeal shock wave lithotripsy: a prospective study of 3,241 patients. Urological Research [Internet]. 2010; 38(2):135-142. Available from: https://doi.org/10.1007/s00240-009-0247-8
19. Knoll T, Buchholz N, Wendt-Nordahl G. Extracorporeal shockwave lithotripsy vs. percutaneous nephrolithotomy vs. flexible ureterorenoscopy for lower-pole stones. Arab Journal of Urology [Internet]. 2012;10(3):336-341. Available from: https://doi.org/10.1016/j.aju.2012.06.004
20. Ben Khalifa B, Naouar S, Gazzah W, Salem B, El Kamel R. Predictive factors of extracorporeal shock wave lithotripsy success for urinary stones. Tunis Med. 2016 May;94(5):397-400. PMID: 27801492. Available from:
https://pubmed.ncbi.nlm.nih.gov/27801492/
21. Kang D, Cho K, Ham W, Lee H, Kwon J, Choi Y et al. Comparison of High,
Intermediate, and Low Frequency Shock Wave Lithotripsy for Urinary Tract Stone Disease: Systematic Review and Network Meta-Analysis. PLOS ONE [Internet]. 2016; 11(7):e0158661. Available from:
https://doi.org/10.1371/journal.pone.0158661
22. Resorlu B, Unsal A, Ziypak T, Diri A, Atis G, Guven S et al. Comparison of retrograde intrarenal surgery, shockwave lithotripsy, and percutaneous
nephrolithotomy for treatment of medium-sized radiolucent renal stones. World Journal of Urology [Internet]. 2012; 31(6):1581-1586. Available from:
https://doi.org/10.1007/s00345-012-0991-1
23. Bas O, Bakirtas H, Sener N, Ozturk U, Tuygun C, Goktug H et al. Comparison of shock wave lithotripsy, flexible ureterorenoscopy and percutaneous
42 24. Kumar A, Kumar N, Vasudeva P, Kumar Jha S, Kumar R, Singh H. A
Prospective, Randomized Comparison of Shock Wave Lithotripsy, Retrograde Intrarenal Surgery and Miniperc for Treatment of 1 to 2 cm Radiolucent Lower Calyceal Renal Calculi: A Single Center Experience. Journal of Urology [Internet]. 2015; 193(1):160-164. Available from: https://doi.org/10.1016/j.juro.2014.07.088
25. Sener N, Abdurrahim Imamoglu M, Bas O, Ozturk U, Goksel Goktug H, Tuygun C et al. Prospective randomized trial comparing shock wave lithotripsy and flexible ureterorenoscopy for lower pole stones smaller than 1 cm. Urolithiasis [Internet]. 2013; 42(2):127-131. Available from: https://doi.org/10.1007/s00240-013-0618-z
26. Hassan M, El-Nahas A, Sheir K, El-Tabey N, El-Assmy A, Elshal A et al. Percutaneous nephrolithotomy vs. extracorporeal shockwave lithotripsy for treating a 20–30 mm single renal pelvic stone. Arab Journal of Urology [Internet]. 2015; 13(3):212-216. Available from: https://doi.org/10.1016/j.aju.2015.04.002
27. Demirbas, M., Samli, M., Karalar, M., & Kose, A. C. Extracorporeal Shockwave Lithotripsy for Ureteral Stones: Twelve years of Experience with 2836 Patients at a Single Center. Urology Journal, 2012; 9(3), 557-561. Available from:
https://doi.org/10.22037/uj.v9i3.1592
28. Choi J, Song P, Kim H. Predictive Factors of the Outcome of Extracorporeal Shockwave Lithotripsy for Ureteral Stones. Korean Journal of Urology [Internet]. 2012; 53(6):424. Available from: https://doi.org/10.4111/kju.2012.53.6.424
29. Ur Rehman M, Adnan M, Hassan A, Humayun Akhtar F, Javed N, Ali F.
Comparison of Ureteroscopic Pneumatic Lithotripsy and Extracorporeal Shock Wave Lithotripsy for Proximal Ureteral Calculi. Cureus [Internet]. 2020;. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250525/
30. Islam M, Malik A, Ureteroscopic Pneumatic versus Extracorporeal Shock Wave Lithotripsy for Lower Ureteral Stones. Journal of the College of Physicians and Surgeons Pakistan. 2012; 22 (7): 444-447. Available from:
31. Mira Moreno A, Montoya Lirola M, García Tabar P, Galiano Baena J, Tenza Tenza J, Lobato Encinas J. Incidence of Infectious Complications after Extracorporeal Shock Wave Lithotripsy in Patients Without Associated Risk Factors. Journal of Urology [Internet]. 2014;192(5):1446-1449. Available from: http://10.1016/j.juro.2014.05.091
32. Kumar A, Vasudeva P, Nanda B, Kumar N, Das M, Jha S. A Prospective Randomized Comparison Between Shock Wave Lithotripsy and Flexible
Ureterorenoscopy for Lower Caliceal Stones ≤2 cm: A Single-Center Experience. Journal of Endourology [Internet]. 2015; 29(5):575-579. Available from:
https://doi.org/10.1089/end.2013.0473
33. Lawler A, Ghiraldi E, Tong C, Friedlander J. Extracorporeal Shock Wave Therapy: Current Perspectives and Future Directions. Current Urology Reports [Internet]. 2017; 18(4). Available from: https://doi.org/10.1007/s11934-017-0672-0
34. Denburg M, Jemielita T, Tasian G, Haynes K, Mucksavage P, Shults J et al. Assessing the risk of incident hypertension and chronic kidney disease after exposure to shock wave lithotripsy and ureteroscopy. Kidney International [Internet]. 2016; 89(1):185-192. Available from:
https://doi.org/10.1038/ki.2015.321
35. Krambeck A, Rule A, Li X, Bergstralh E, Gettman M, Lieske J. Shock Wave Lithotripsy is Not Predictive of Hypertension Among Community Stone Formers at Long-Term Followup. Journal of Urology [Internet]. 2011; 185(1):164-169. Available from: https://doi.org/10.1016/j.juro.2010.09.033
44 37. Chen K, Mi H, Xu G, Liu L, Sun X, Wang S et al. The Efficacy and Safety of
Tamsulosin Combined with Extracorporeal Shockwave Lithotripsy for Urolithiasis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Journal of Endourology [Internet]. 2015; 29(10):1166-1176. Available from: https://pubmed.ncbi.nlm.nih.gov/25915454/
38. Li M, Wang Z, Yang J, Guo X, Wang T, Wang S et al. Adjunctive Medical
Therapy with α-Blocker after Extracorporeal Shock Wave Lithotripsy of Renal and Ureteral Stones: A Meta-Analysis. PLOS ONE [Internet]. 2015; 10(4):e0122497. Available from: https://pubmed.ncbi.nlm.nih.gov/25860144/
39. Skolarikos A, Grivas N, Kallidonis P, Mourmouris P, Rountos T, Fiamegos A et al. 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 [Internet]. 2015; 86(6):1057-1064. Available from:
https://pubmed.ncbi.nlm.nih.gov/26383613/
40. Zheng S, Liu L, Yuan H, Wei Q. Tamsulosin as adjunctive treatment after shockwave lithotripsy in patients with upper urinary tract stones: A systematic review and meta-analysis. Scandinavian Journal of Urology and Nephrology [Internet]. 2010; 44(6):425-432. Available from:
https://pubmed.ncbi.nlm.nih.gov/21080841/
41. Mohamed H. The efficacy of tamsulosin therapy after extracorporeal shock-wave lithotripsy for ureteric calculi: A prospective randomised, controlled study. Arab Journal of Urology [Internet]. 2013; 11(4):398-404. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4443006/
42. Meltzer A, Burrows P, Wolfson A, Hollander J, Kurz M, Kirkali Z et al. Effect of Tamsulosin on Passage of Symptomatic Ureteral Stones. JAMA Internal Medicine [Internet]. 2018;178(8):1051. Available from:
43. Silberstein J, Lakin CM, Kellogg Parsons J. Shock wave lithotripsy and renal haemorrhage. Rev Urol. 2008;10(3):236-241. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2556492/
44. Kidney stone manipulation: ESWL [Internet]. Helderberg Urology | Dr. Ferdi Marias Urologist. 2018 [cited 1 April 2021]. Available from:
