1.INTRODUCTION

1.1.Aims and scope

The European Association of Urology (EAU) Urolithiasis Guidelines Panel has prepared these guidelines to help urologists assess evidence-based management of stones/calculi in the urinary tract and incorporate recommendations into clinical practice. This document covers most aspects of the disease, which is still a cause of significant morbidity despite technological and scientific advances. The Panel is aware of the geographical variations in healthcare provision. Management of bladder stones are dealt with in a separate guideline authored by the same guideline group.

It must be emphasised that clinical guidelines present the best evidence available to the experts but following guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions - also taking personal values and preferences/individual circumstances of patients into account. Guidelines are not mandates and do not purport to be a legal standard of care.

1.2.Panel composition

The EAU Urolithiasis Guidelines Panel consists of an international group of clinicians with particular expertise in this area. All experts involved in the production of this document have submitted potential conflict of interest statements, which can be viewed on the EAU, website Uroweb: http://uroweb.org/guideline/urolithiasis/.

1.3.Available publications

A quick reference document (Pocket guidelines) is available, both in print and as an app for iOS and Android devices. These are abridged versions, which may require consultation together with the full text versions. Also a number of scientific publications are available [1-3]. All documents can be accessed through the EAU website: http://uroweb.org/guideline/urolithiasis/.

1.4.Publication history and summary of changes

1.4.1.Publication history

The EAU Urolithiasis Guidelines were first published in 2000. This 2020 document presents a limited update of the 2019 version.

1.4.2.Summary of changes

The literature for the entire document has been checked and, wherever relevant, updated (see Methods section 2.1).

For 2020, conclusions and recommendations have been rephrased and strength ratings reassessed across a number of sections. Updated recommendations include the following:

3.3.2.3 Guidelines for laboratory examinations and stone analysis

3.4.10.5 Summary of evidence and guidelines for the management of renal stones

2.METHODS

2.1.Data identification

For the 2020 Urolithiasis Guidelines, new and relevant evidence has been identified, collated and appraised through a structured assessment of the literature.

A broad and comprehensive scoping exercise covering all areas of the guideline was performed. The search was limited to studies representing high levels of evidence only (i.e. systematic reviews with meta-analysis (MA), randomised controlled trials (RCTs), and prospective non-randomised comparative studies) published in the English language. The search was restricted to articles published between 1st May 2018 and 2nd May 2019. Databases covered by the search included Medline, EMBASE, Ovid and the Cochrane Libraries. A total of 887 unique records were identified, and screened for relevance. The search strategy is published online: http://uroweb.org/guideline/urolithiasis/?type=appendices-publications.

A total of 30 new papers have been added, and 28 outdated references removed from the Urolithiasis 2020 Guidelines publication.

For each recommendation within the guidelines there is an accompanying online strength rating form, the basis of which is a modified GRADE methodology [4,5]. Each strength-rating form addresses a number of key elements, namely:

1. the overall quality of the evidence which exists for the recommendation, references used in this text are graded according to a classification system modified from the Oxford Centre for Evidence-Based Medicine Levels of Evidence [6];
2. the magnitude of the effect (individual or combined effects);
3. the certainty of the results (precision, consistency, heterogeneity and other statistical or study related factors);
4. the balance between desirable and undesirable outcomes;
5. the impact of patient values and preferences on the intervention;
6. the certainty of those patient values and preferences.

These key elements are the basis which panels use to define the strength rating of each recommendation. The strength of each recommendation is represented by the words ‘strong’ or ‘weak’ [7]. The strength of each recommendation is determined by the balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including certainty of estimates), and nature and variability of patient values and preferences. The strength rating forms will be available online.

Additional information can be found in the general Methodology section of this print, and online at the EAU website: http://www.uroweb.org/guideline/.

A list of associations endorsing the EAU Guidelines can also be viewed online at the above address.

2.2.Review

The 2015 Urolithiasis Guidelines were subjected to peer-review prior to publication.

2.3.Future goals

For the 2021 text update the Urolithiasis Guidelines Panel aim to perform extended literature searches and systematic reviews on how best to conduct follow-up in stones patients, where current evidence is poor.

3.GUIDELINES

3.1.Prevalence, aetiology, risk of recurrence

3.1.1.Introduction

Stone incidence depends on geographical, climatic, ethnic, dietary and genetic factors. The recurrence risk is basically determined by the disease or disorder causing the stone formation. Accordingly, the prevalence rates for urinary stones vary from 1% to 20% [8]. In countries with a high standard of life such as Sweden, Canada or the USA, renal stone prevalence is notably high (> 10%). For some areas an increase of more than 37% over the last 20 years has been reported [9-11]. There is emerging evidence linking nephrolithiasis to the risk of chronic kidney disease [12].

Stones can be stratified into those caused by: infection, or non-infectious causes, genetic defects [13]; or adverse drug effects (drug stones) (Table 3.1). See also section 3.2.

Table 3.1: Stones classified by aetiology*

*See Section 4.4.2

3.1.2.Stone composition

Stone composition is the basis for further diagnostic and management decisions. Stones are often formed from a mixture of substances. Table 3.2 lists the most clinically relevant substances and their mineral components.

Table 3.2: Stone composition

3.1.3.Risk groups for stone formation

The risk status of stone formers is of particular interest because it defines the probability of recurrence or regrowth, and is imperative for pharmacological treatment.

About 50% of recurrent stone formers have just one lifetime recurrence [10,14]. Highly recurrent disease is observed in slightly more than 10% of patients. Stone type and disease severity determine low- or high risk of recurrence (Table 3.3) [15,16].

Table 3.3: High-risk stone formers [15-31]

3.2.Classification of stones

Urinary stones can be classified according to size, location, X-ray characteristics, aetiology of formation, composition, and risk of recurrence [10,32-34].

3.2.1.Stone size

Stone size is usually given in one or two dimensions, and stratified into those measuring up to 5, 5-10, 10-20, and > 20 mm in largest diameter.

3.2.2.Stone location

Stones can be classified according to anatomical position: upper, middle or lower calyx; renal pelvis; upper, middle or distal ureter; and urinary bladder. Treatment of bladder stones is not discussed in these guidelines.

3.2.3.X-ray characteristics

Stones can be classified according to plain X-ray appearance [kidney-ureter-bladder (KUB) radiography] (Table 3.4), which varies according to mineral composition [34]. Non-contrast-enhanced computed tomography (NCCT) can be used to classify stones according to density, inner structure and composition, which can affect treatment decisions (Section 3.3) [32,34].

Table 3.4: X-ray characteristics

3.3.Diagnostic evaluation

3.3.1.Diagnostic imaging

The most appropriate imaging modality will be determined by the clinical situation, which will differ depending on if a ureteral or a renal stone is suspected.

Standard evaluation includes a detailed medical history and physical examination. Patients with ureteral stones usually present with loin pain, vomiting, and sometimes fever, but may also be asymptomatic [35]. Immediate evaluation is indicated in patients with solitary kidney, fever or when there is doubt regarding a diagnosis of renal colic. Ultrasound (US) should be used as the primary diagnostic imaging tool, although pain relief, or any other emergency measures, should not be delayed by imaging assessments. Ultrasound is safe (no risk of radiation), reproducible and inexpensive. It can identify stones located in the calyces, pelvis, and pyeloureteric and vesico-ureteral junctions (US with filled bladder), as well as in patients with upper urinary tract (UUT) dilatation. Ultrasound has a sensitivity of 45% and specificity of 94% for ureteral stones and a sensitivity of 45% and specificity of 88% for renal stones [36,37].

The sensitivity and specificity of KUB is 44-77% [38]. Kidney-ureter-bladder radiography should not be performed if NCCT is being considered [39]; however, it is helpful in differentiating between radiolucent and radiopaque stones and should be used for comparison during follow-up.

3.3.1.1.Evaluation of patients with acute flank pain/suspected ureteral stones

Non-contrast-enhanced computed tomography has become the standard for diagnosing acute flank pain, and has replaced intravenous urography (IVU). Non-contrast-enhanced CT can determine stone diameter and density. When stones are absent, the cause of abdominal pain should be identified. In evaluating patients with suspected acute urolithiasis, NCCT is significantly more accurate than IVU [40].

Non-contrast-enhanced CT can detect uric acid and xanthine stones, which are radiolucent on plain films, but not indinavir stones [41]. Non-contrast-enhanced CT can determine stone density, inner structure of the stone, skin-to-stone distance and surrounding anatomy; all of which affect selection of treatment modality [34,42-44]. The advantage of non-contrast imaging must be balanced against loss of information on renal function and urinary collecting system anatomy, as well as higher radiation dose [45-48].

Radiation risk can be reduced by low-dose CT, which may, however, be difficult to introduce in standard clinical practice [49-51]. In patients with a body mass index (BMI) < 30, low-dose CT has been shown to have a sensitivity of 86% for detecting ureteral stones < 3 mm and 100% for calculi > 3 mm [52]. A MA of prospective studies [51] has shown that low-dose CT diagnosed urolithiasis with a pooled sensitivity of 93.1% (95% CI: 91.5-94.4), and a specificity of 96.6% (95% CI: 95.1-97.7%). Dual-energy CT can differentiate uric acid containing stones from calcium-containing stones [53].

3.3.1.2.Radiological evaluation of patients with renal stones

Intravenous urography (IVU) can provide information about renal function, the anatomy of the collecting system and the level of an obstruction, while CT allows for rapid 3D data acquisition including information on stone size and density, skin-to-stone distance and surrounding anatomy, but at the cost of increased radiation exposure. Low-dose and ultra-low-dose protocols seem to yield comparable results to standard-dose protocols with the exception of detection of very small stones or stones in obese patients [51,52,54,55].

A small randomised study showed that in supine percutaneous antegrade ureteroscopy (PNL), pre-operative planning using CT, compared to IVU, resulted in easier access and shorter operating times [56].

In case stone removal is planned and the renal collecting system needs to be assessed, a contrast study should be performed [57].

3.3.1.3.Summary of evidence and guidelines for diagnostic imaging

3.3.2.Diagnostics - metabolism-related

Besides imaging, each emergency patient with urolithiasis needs a succinct biochemical work-up of urine and blood besides imaging. At this point, no distinction is made between high- and low-risk patients for stone formation.

3.3.2.1.Basic laboratory analysis - non-emergency urolithiasis patients

Biochemical work-up is similar for all stone patients. However, if no intervention is planned, examination of sodium, potassium, C-reactive protein (CRP), and blood coagulation time can be omitted.

Only patients at high risk for stone recurrence should undergo a more specific analytical programme [16]. Stone-specific metabolic evaluation is described in Chapter 4.

The easiest method for diagnosing stones is by analysis of a passed stone using a validated method as listed in section 3.3.2.3. Once the mineral composition is known, a potential metabolic disorder can be identified.

3.3.2.2.Analysis of stone composition

Stone analysis should be performed in all first-time stone formers.

In clinical practice, repeat stone analysis is needed in the case of:

• recurrence under pharmacological prevention;
• early recurrence after interventional therapy with complete stone clearance;
• late recurrence after a prolonged stone-free period [58,59].

Patients should be instructed to filter their urine to retrieve a concrement for analysis. Stone passage and restoration of normal renal function should be confirmed.

The preferred analytical procedures are infrared spectroscopy (IRS) or X-ray diffraction (XRD) [60-62]. Equivalent results can be obtained by polarisation microscopy. Chemical analysis (wet chemistry) is generally deemed to be obsolete [60,63].

3.3.2.3.Guidelines for laboratory examinations and stone analysis [16,22,57,64]

3.3.3.Diagnosis in special groups and conditions

3.3.3.1.Diagnostic imaging during pregnancy

In pregnant women radiation exposure may cause non-stohastic (teratogenesis) or stohastic (carcinogenesis, mutagenesis) effects. Teratogenic effects are cumulative with increasing dose, and require a threshold dose (< 50 mGy are considered as safe) and depend on the gestation age (minimum risk prior to 8th week and after the 23rd week). Carcinogenesis (dose even < 10 mGy present a risk) and mutagenesis (500-1000 mGy doses are required, far in excess of the doses in common radiographic studies) get worse with increasing dose but they do not require a dose threshold and are not dependent on the gestational age [65].

There is no imaging modality that should be routinely repeated in pregnant women. Scientific societies and organisations agree on the safety of the diagnostic evaluation when US [66], X-ray imaging [67,68], and MRI [69,70] are used as and when indicated [71-77]. A radiographic procedure should not be withheld from a pregnant woman if the procedure is clearly indicated and doing so will affect her medical care.

It is generally recommended that an investigation resulting in an absorbed dose to the foetus of greater than 0.5 mGy requires justification.

Ultrasound (when necessary, using changes in renal resistive index and transvaginal/transabdominal US with a full bladder) has become the primary radiological diagnostic tool when evaluating pregnant patients suspected of renal colic. However, normal physiological changes in pregnancy can mimic ureteral obstruction [73-75].

Magnetic resonance imaging can be used, as a second-line procedure [71], to define the level of urinary tract obstruction, and to visualise stones as a filling defect [69]. As 3 Tesla (T) MRI has not been evaluated in pregnancy, the use of 1.5T is currently recommended [72,77]. The use of gadolinium is not routinely recommended in pregnancy to avoid toxic effects to the embryo [73].

For the detection of urolithiasis during pregnancy, low-dose CT is associated with a higher positive predictive value (95.8%), compared to MRI (80%) and US (77%). As per White et al. low-dose CT offers improved diagnostic accuracy that can avoid negative interventions such as ureteroscopy [78]. Although low-dose CT protocols reduce the radiation exposure, judicious use is currently recommended in pregnant women as a last-line option [73].

3.3.3.1.1.Summary of evidence and guidelines for diagnostic imaging during pregnancy

3.3.3.2.Diagnostic imaging in children

Children with urinary stones have a high risk of recurrence; therefore, standard diagnostic procedures for high-risk patients apply, including a valid stone analysis (Section 3.1.3 and Chapter 4). The most common non-metabolic disorders facilitating stone formation are vesico-ureteral reflux (VUR), UPJ obstruction, neurogenic bladder, and other voiding difficulties [79].

When selecting diagnostic procedures to identify urolithiasis in children, it should be remembered that these patients might be uncooperative, require anaesthesia, and may be sensitive to ionising radiation. Again, the principle of ALARA (As Low As Reasonably Achievable) should be observed [80-82].

Ultrasound

Ultrasound is the primary imaging technique [83] in children. Its advantages are absence of radiation and no need for anaesthesia. Imaging should include both the fluid-filled bladder with adjoining portion of the ureters, as well as the upper ureter [84-88]. Colour Doppler US shows differences in the ureteral jet [85] and resistive index of the arciform arteries of both kidneys, which are indicative of the grade of obstruction [86]. Nevertheless, US fails to identify stones in > 40% of children [87-90] and provides limited information on renal function.

Plain films (KUB radiography)

Kidney-ureter-bladder radiography can help to identify stones and their radiopacity, and facilitate follow-up.

Intravenous urography

The radiation dose for IVU is comparable to that for voiding cysto-urethrography (0.33 mSV) [91]. However, the need for contrast medium injection is a major drawback.

Helical computed tomography

Recent low-dose CT protocols have been shown to significantly reduce radiation exposure [48,55,92]. In children, only 5% of stones escape detection by NCCT [85,92,93]. Sedation or anaesthesia is rarely needed with modern high-speed CT equipment.

Magnetic resonance urography

Magnetic resonance urography (MRU) cannot be used to detect urinary stones. However, it might provide detailed anatomical information about the urinary collecting system, the location of an obstruction or stenosis in the ureter, and renal parenchymal morphology [94].

3.3.3.2.1.Summary of evidence and guidelines for diagnostic imaging in children

3.4.Disease Management

3.4.1.Renal colic

Pain relief

Non-steroidal anti-inflammatory drugs (NSAIDs) (including metamizoledipyrone), and paracetamol are effective in patients with acute stone colic [95-97], and have better analgesic efficacy than opioids [98]. The addition of antispasmodics to NSAIDs does not result in better pain control. Patients receiving NSAIDs are less likely to require further analgesia in the short term. It should be taken into consideration that the use of diclofenac and ibuprofen increased major coronary events [99,100]. Diclofenac is contraindicated in patients with congestive heart failure (New York Heart Association class II-IV), ischaemic heart disease and peripheral arterial- and cerebrovascular disease. Patients with significant risk factors for cardiovascular events should be treated with diclofenac only after careful consideration. As risks increase with dose and duration, the lowest effective dose should be used for the shortest duration [99,100].

Opioids, particularly pethidine, are associated with a high rate of vomiting compared to NSAIDs, and carry a greater likelihood of further analgesia being needed [97,101] (see below). If an opioid is used, it is recommended that it is not pethidine. Data on other types of non-opioid and non-NSAID medication is increasing. Ketamine in combination with morphine, compared to morphine alone, leads to morphine consumption reduction, less pain, nausea and vomiting [102,103]. Patients receiving ketamine and NSAIDs attained greater reduction in pain scores with less side effects, and better functional state, as well as less further analgesia requirement than those administered pethidine [104]. However, when comparing ketamine vs. NSAID (ketolorac) alone, equal efficacy but higher rates of dizziness, agitation and hypertension with ketamine were observed [105]. Conflicting results have been reported regarding the utility of intravenous lidocaine. Acupuncture seems to be effective in renal colic alone or in combination, but there is limited data [106,107].

Prevention of recurrent renal colic

Facilitation of passage of ureteral stones is discussed in Section 3.4.9. For patients with ureteral stones that are expected to pass spontaneously, NSAID tablets or suppositories (e.g., diclofenac sodium, 100-150 mg/day, 3-10 days) may help reduce inflammation and the risk of recurrent pain [108,109]. Although diclofenac can affect renal function in patients with already reduced function, it has no functional effect in patients with normal renal function [110].

The systematic review and MA by Hollingsworth et al. [111] addressed pain reduction as a secondary outcome and concluded that medical expulsive therapy (MET) seems efficacious in reducing pain episodes of patients with ureteral stones.

If analgesia cannot be achieved medically, drainage, using stenting, percutaneous nephrostomy or stone removal, is indicated [112].

3.4.1.1.Summary of evidence and guidelines for the management of renal colic

* Affects glomerular filtration rate (GFR) in patients with reduced renal function.

** Recommended to counteract recurrent pain after ureteral colic.

*** Maximum single oral dose recommended 1000 mg, total daily dose up to 5000 mg, not recommended in the last three months of pregnancy [113].

3.4.2.Management of sepsis and/or anuria in obstructed kidney

The obstructed kidney with all signs of urinary tract infection (UTI) and/or anuria is a urological emergency. Urgent decompression is often necessary to prevent further complications in infected hydronephrosis secondary to stone-induced, unilateral or bilateral, renal obstruction.

Decompression

Currently, there are two options for urgent decompression of obstructed collecting systems:

• placement of an indwelling ureteral stent;
• percutaneous placement of a nephrostomy tube.

There is little evidence to support the superiority of percutaneous nephrostomy over retrograde stenting for primary treatment of infected hydronephrosis. There is no good quality evidence to suggest that ureteral stenting has more complications than percutaneous nephrostomy [114,115].

Only one RCT [116] compared different modalities of decompression of acute infected hydronephrosis. The complications of percutaneous nephrostomy insertion have been reported consistently, but those of ureteral stent insertion are less well described [114]. Definitive stone removal should be delayed until the infection is cleared following a complete course of antimicrobial therapy. A small RCT showed the feasibility of immediate ureteroscopic stone removal combined with an appropriate antibiotic regimen; however, at the cost of longer hospital stay and higher analgesic requirements [117].

Further measures

Following urgent decompression of the obstructed and infected urinary collecting system, both urine- and blood samples should be sent for culture-antibiogram sensitivity testing and antibiotics should be initiated immediately thereafter or continued, if initiated prior to testing. The regimen should be re-evaluated in the light of the culture-antibiogram results. Although clinically well accepted, the impact of a second antibiogram test on treatment outcome has not yet been evaluated. Intensive care might become necessary [118].

3.4.2.1.Summary of evidence and guidelines for the management of sepsis and anuria

3.4.3.Medical expulsive therapy

Medical expulsive therapy should only be used in informed patients if active stone removal is not indicated. Treatment should be discontinued if complications develop (infection, refractory pain, deterioration of renal function). Several drug classes are used for MET [119-122]. When using α-blockers for MET, possible side effects include retrograde ejaculation and hypotension [109].

Patients treated with α-blockers, calcium-channel inhibitors (nifedipine) and phosphodiesterase type 5 inhibitors (PDEI-5) (tadalafil) are more likely to pass stones with fewer colic episodes than those not receiving such therapy [109,123,124]. Based on studies with a limited number of patients [122,124-126], no recommendation for the use of PDEI-5 or corticosteroids in combination with α-blockers in MET can be made.

Tamsulosin showed an overall superiority to nifedipine for distal ureteral calculi [127]. A class effect of α-blockers has been demonstrated in MAs [126,128,129]. However, there is contradictory evidence between these studies and several well-designed, multicentre, placebo-controlled, double-blinded randomised studies showing limited, or no, benefit using α-blockers, besides some advantage for distal ureteral stones > 5 mm [130-132]. A published MA, including 55 trials with a data search cut-off of July 1st 2015, including the publications addressed above, assessed stone passage as primary outcome [111]. Based on the well-designed sensitivity analyses of this MA, α-blockers promote spontaneous stone expulsion of large stones located in any part of the ureter. There are small trials of uncertain quality suggesting tadalafil alone or in combination with tamsulosin may be beneficial for ureteric stone passage [124]. A large double-blind, placebo-controlled study of 3,296 patients with distal ureteral stones, across 30 centres, evaluated the efficacy and safety of tamsulosin. Participants were randomly assigned (1:1) to tamsulosin (0.4 mg) or placebo groups for 4 weeks. Tamsulosin benefits from a higher stone expulsion rate than the placebo (86% vs. 79%; p < 0.001) for distal ureteral stones. Subgroup analysis identified a significant benefit of tamsulosin for the treatment of large distal ureteral stones (> 5 mm) but no benefit for smaller stones (≤ 5 mm). Considering the secondary end points, tamsulosin-treated patients reported a shorter time to expulsion (p < 0.001), required lower use of analgesics compared with placebo (p < 0.001), and significantly relieved renal colic (p < 0.001). No differences in the incidence of adverse events were identified between the two groups [133].

The primary outcome of most trials assessing MET was stone passage, or follow up, up to four weeks. No data are currently available to support other time-intervals.

The Panel concludes that MET seems efficacious in the treatment of patients with ureteral stones who are amenable to conservative management. The greatest benefit might be among those with > 5 mm distal stones [134].

Medical expulsive therapy in special situations is addressed in the relevant chapters.

3.4.3.1.Summary of evidence and guideline for MET

3.4.4.Chemolysis

Percutaneous irrigation chemolysis

Percutaneous chemolysis is rarely used nowadays, for practical reasons. Percutaneous irrigation chemolysis may be an option for infection-stones and theoretically also for uric acid stones. For dissolution of struvite stones, Suby’s G solution (10% hemiacidrin; pH 3.5-4) can be used. The method has been described in case series and literature reviews [135-137].

Oral chemolysis

Stones composed of uric acid, but not sodium or ammonium urate stones, can be dissolved by oral chemolysis. Prior stone analysis may provide information on stone composition. Urinary pH measurement and X-ray characteristics can provide information on the type of stone.

Oral chemolitholysis is based on alkalinisation of urine by application of alkaline citrate or sodium bicarbonate. The pH should be adjusted to 7.0-7.2. Chemolysis is more effective at a higher pH, which might, however, promote calcium phosphate stone formation. Patients will need to adjust the dosage of alkalising medication by self-monitoring the pH of their urine. No RCTs are available for this therapy, which has been in use for decades. Rodman, et al. [138] reviewed the principles and provided guidance to its clinical use, which was supported by Becker, et al. in 2007 [139]. Monitoring of radiolucent stones during therapy is the domain of US; however, repeat-NCCT might be necessary [138,139].

In the case of uric acid obstruction of the collecting system, oral chemolysis in combination with urinary drainage is indicated [140]. A combination of alkalinisation with tamsulosin can increase the frequency of spontaneous passage of distal ureteral uric acid stones as shown in one RCT for stones > 5 mm [140].

3.4.4.1.Summary of evidence and guidelines for chemolysis

3.4.5.Extracorporeal shock wave lithotripsy (SWL)

The success of SWL depends on the efficacy of the lithotripter and the following factors:

• size, location (ureteral, pelvic or calyceal), and composition (hardness) of the stones (Section 3.4.9.3);
• patient’s habitus (Section 3.4.10.3);
• performance of SWL (best practice, see below).

Each of these factors significantly influences the retreatment rate and final outcome of SWL.

Best clinical practice

Stenting

Routine use of internal stents before SWL does not improve stone free rates (SFRs), nor lowers the number of auxiliary treatments. It may, however, reduce formation of steinstrasse [141-144].

Pacemaker

Patients with a pacemaker can be treated with SWL, provided that appropriate technical precautions are taken. Patients with implanted cardioverter defibrillators must be managed with special care (firing mode temporarily reprogrammed during SWL treatment). However, this might not be necessary with new-generation lithotripters [145].

Shock wave rate

Lowering shock wave frequency from 120 to 60-90 shock waves/min improves SFRs [146-154]. Tissue damage increases with shock wave frequency [155-157].

Number of shock waves, energy setting and repeat treatment sessions

The number of shock waves that can be delivered at each session depends on the type of lithotripter and shock wave power. There is no consensus on the maximum number of shock waves [158]. Starting SWL on a lower energy setting with stepwise power (and SWL sequence) ramping can achieve vasoconstriction during treatment [155], which prevents renal injury [159-161]. Animal studies [162] and a prospective randomised study [163] have shown better SFRs (96% vs. 72%) using stepwise power ramping, but no difference has been found for fragmentation or evidence of complications after SWL, irrespective of whether ramping was used [164].

There are no conclusive data on the intervals required between repeated SWL sessions. However, clinical experience indicates that repeat sessions are feasible (within 1 day for ureteral stones).

Improvement of acoustic coupling

Proper acoustic coupling between the cushion of the treatment head and the patient’s skin is important. Defects (air pockets) in the coupling gel deflect 99% of shock waves [165]. Ultrasound gel is probably the most widely-used agent available as a lithotripsy coupling agent [166].

Procedural control

Results of treatment are operator dependent, and experienced clinicians obtain better results. During the procedure, careful imaging control of localisation contributes to outcome quality [167].

Pain control

Careful control of pain during treatment is necessary to limit pain-induced movements and excessive respiratory excursions [168-171].

Antibiotic prophylaxis

No standard antibiotic prophylaxis before SWL is recommended. However, prophylaxis is recommended in the case of internal stent placement ahead of anticipated treatments and in the presence of increased bacterial burden (e.g., indwelling catheter, nephrostomy tube, or infectious stones) [64,172,173].

Medical therapy after extracorporeal shock wave lithotripsy

In spite of conflicting results, most RCTs and several MAs support MET after SWL for ureteral or renal stones as adjunct to expedite expulsion and to increase SFRs. Medical expulsion therapy might also reduce analgesic requirements [174-182].

Post treatment management

Mechanical percussion and diuretic therapy can significantly improve SFRs and accelerate stone passage after SWL [183-185].

Complications of extracorporeal shock wave lithotripsy

Compared to PNL and ureteroscopy (URS), there are fewer overall complications with SWL [186,187] (Table 3.5).

Table 3.5: Shock wave lithotripsy-related complications [188-202]

The relationship between SWL and hypertension or diabetes is unclear. Published data are contradictory; however, no evidence exists supporting the hypothesis that SWL may cause long-term adverse effects [203-209].

3.4.5.1.Summary of evidence and guidelines for SWL

3.4.6.Ureteroscopy (URS) (retrograde and antegrade, RIRS)

The current standard for rigid ureteroscopes is a tip diameter of < 8 French (F). Rigid URS can be used for the whole ureter [203]. However, technical improvements, as well as the availability of digital scopes, also favour the use of flexible ureteroscopes in the ureter [210].

Percutaneous antegrade removal of ureteral stones is a consideration in selected cases, i.e. large (> 15 mm), impacted proximal ureteral calculi in a dilated renal collecting system [211-213], or when the ureter is not amenable to retrograde manipulation [213-217].

Ureteroscopy for renal stones (RIRS)

Technical improvements including endoscope miniaturisation, improved deflection mechanism, enhanced optical quality and tools, and introduction of disposables have led to an increased use of URS for both renal and ureteral stones. Major technological progress has been achieved for RIRS. A recent systematic review addressing renal stones > 2 cm showed a cumulative SFR of 91% with 1.45 procedures/patient; 4.5% of the complications were > Clavien 3 [210,218,219]. Digital scopes demonstrate shorter operation times due to the improvement in image quality [218].

Stones that cannot be extracted directly must be disintegrated. If it is difficult to access stones within the lower renal pole that need disintegration; it may help to displace them into a more accessible calyx [220].

Best clinical practice in ureteroscopy

Access to the upper urinary tract

Most interventions are performed under general anaesthesia, although local or spinal anaesthesia is possible. Intravenous sedation is suitable for female patients with distal ureteral stones [221]. Antegrade URS is an option for large, impacted, proximal ureteral calculi [211-213,222].

Safety aspects

Fluoroscopic equipment must be available in the odds ratio (OR). We recommend placement of a safety wire, even though some groups have demonstrated that URS can be performed without it [223-225]. Balloon and plastic dilators should be available, if necessary.

Prior rigid URS can be helpful for optical dilatation followed by flexible URS, if necessary. If ureteral access is not possible, insertion of a JJ stent followed by URS after seven to fourteen days offers an alternative [226]. Bilateral URS during the same session is feasible resulting in equivalent-to-lower SFRs, but slightly higher overall complication rates (mostly minor, Clavien I and II) [227,228].

Ureteral access sheaths

Hydrophilic-coated ureteral access sheaths, which are available in different calibres (inner diameter from 9 F upwards), can be inserted (via a guide wire) with the tip placed in the proximal ureter.

Ureteral access sheaths allow easy, multiple, access to the UUT and therefore significantly facilitate URS. The use of ureteral access sheaths improves vision by establishing a continuous outflow, decreases intra-renal pressure, and potentially reduces operating time [229,230].

The insertion of ureteral access sheaths may lead to ureteral damage, the risk is lowest in pre-stented systems [231]. No data on long-term side effects are available [231,232]. Whilst larger cohort series showed no difference in SFRs and ureteral damage, they did show lower post-operative infectious complications [233]. Use of ureteral access sheaths depends on the surgeon’s preference.

Stone extraction

The aim of URS is complete stone removal. “Dust and go” strategies should be limited to the treatment of large (renal) stones [234]. Stones can be extracted by endoscopic forceps or baskets. Only baskets made of nitinol can be used for flexible URS [235].

Intracorporeal lithotripsy

The most effective lithotripsy system is the holmium:yttrium-aluminium-garnet (Ho:YAG) laser, which is currently the optimum standard for URS and flexible nephroscopy (Section 3.4.6), because it is effective in all stone types [236,237]. Pneumatic and US systems can be used with high disintegration efficacy in rigid URS [238,239]. However, stone migration into the kidney is a common problem, which can be prevented by placement of special anti-migration tools proximal of the stone [240]. Medical expulsion therapy following Ho:YAG laser lithotripsy increases SFRs and reduces colic episodes [241].

Stenting before and after URS

Routine stenting is not necessary before URS. However, pre-stenting facilitates ureteroscopic management of stones, improves the SFR, and reduces intra-operative complications [242,243].

Randomised prospective trials have found that routine stenting after uncomplicated URS (complete stone removal) is not necessary; stenting might be associated with higher post-operative morbidity and costs [244-247]. A ureteral catheter with a shorter indwelling time (one day) may also be used, with similar results [248].

Stents should be inserted in patients who are at increased risk of complications (e.g., ureteral trauma, residual fragments, bleeding, perforation, UTIs, or pregnancy), and in all doubtful cases, to avoid stressful emergencies. The ideal duration of stenting is not known. Most urologists favour 1-2 weeks after URS. Alpha-blockers reduce the morbidity of ureteral stents and increase tolerability [249,250].

Medical expulsive therapy after ureteroscopy

Medical expulsion therapy following Ho:YAG laser lithotripsy accelerates the spontaneous passage of fragments and reduces episodes of colic [241].

Complications of ureteroscopy

The overall complication rate after URS is 9-25% [203,251,252]. Most complications are minor and do not require intervention. Ureteral avulsion and strictures are rare (< 1%). Previous perforations are the most important risk factor for complications.

3.4.6.1.Summary of evidence and guidelines for retrograde URS, RIRS and antegrade ureteroscopy

3.4.7.Percutaneous nephrolithotomy

Percutaneous nephrolithotomy remains the standard procedure for large renal calculi. Different rigid and flexible endoscopes are available and the selection is mainly based on the surgeon’s own preference. Standard access tracts are 24-30 F. Smaller access sheaths, < 18 F, were initially introduced for paediatric use, but are now increasingly utilised in the adult population [253].

Contraindications

Patients receiving anti-coagulant therapy must be monitored carefully pre- and post-operatively. Anti-coagulant therapy must be discontinued before PNL [254].

Other important contraindications include:

• untreated UTI;
• tumour in the presumptive access tract area;
• potential malignant kidney tumour;
• pregnancy (Section 3.4.14.1).

Best clinical practice

Intracorporeal lithotripsy

Several methods for intracorporeal lithotripsy during PNL are available. Ultrasonic and pneumatic systems are most commonly used for rigid nephroscopy, whilst laser is increasingly used for miniaturised instruments [255]. Flexible endoscopes also require laser lithotripsy to maintain tip deflection, with the Ho:YAG laser having become the standard.

Pre-operative imaging

Pre-procedural imaging evaluations are summarised in Section 3.3.1. In particular, US or CT of the kidney and the surrounding structures can provide information regarding interpositioned organs within the planned percutaneous path (e.g., spleen, liver, large bowel, pleura, and lung).

Positioning of the patient

Both prone and supine positions are equally safe, although the supine position confers some advantages, it depends on appropriate equipment being available to position the patient correctly, for example, X-ray devices and an operating table. Most studies cannot demonstrate an advantage of supine PNL in terms of OR time. Prone position offers more options for puncture and is therefore preferred for upper pole or multiple accesses [256,257]. On the other hand, supine position allows simultaneous retrograde access to the collecting system, using flexible ureteroscope [258,259].

Puncture

Although fluoroscopy is the most common intra-operative imaging method, the (additional) use of US reduces radiation exposure [260,261].

Pre-operative CT or intra-operative US allows identification of the tissue between the skin and kidney and lowers the incidence of visceral injury. The calyceal puncture may be done under direct visualisation using simultaneous flexible URS [259,261,262].

Dilatation

Dilatation of the percutaneous access tract can be achieved using a metallic telescope, single (serial) dilators, or a balloon dilatator. Although there are papers demonstrating that single step dilation is equally effective as other methods, the difference in outcomes is most likely related to surgeon experience rather than to the technology used [263].

Choice of instruments

The Urolithiasis Panel performed a systematic review assessing the outcomes of PNL using smaller tract sizes (< 22 F, mini-PNL) for removing renal calculi [253]. Stone-free rates were comparable in miniaturised and standard PNL procedures. Procedures performed with small instruments tend to be associated with significantly lower blood loss, but the duration of procedure tends to be significantly longer. There were no significant differences in any other complications. However, the quality of the evidence was poor with only two RCTs and the majority of the remaining studies were single-arm case series only. Furthermore, the tract sizes used, and types of stones treated, were heterogeneous; therefore, the risk of bias and confounding were high.

Nephrostomy and stents

The decision on whether, or not, to place a nephrostomy tube at the conclusion of the PNL procedure depends on several factors, including:

• presence of residual stones;
• likelihood of a second-look procedure;
• significant intra-operative blood loss;
• urine extravasation;
• ureteral obstruction;
• potential persistent bacteriuria due to infected stones;
• solitary kidney;
• bleeding diathesis;
• planned percutaneous chemolitholysis.

Small-bore nephrostomies seem to have advantages in terms of post-operative pain [253,264,265]. Tubeless PNL is performed without a nephrostomy tube. When neither a nephrostomy tube nor a ureteral stent is introduced, the procedure is known as totally tubeless PNL [266]. In uncomplicated cases, the latter procedure results in a shorter hospital stay, with no disadvantages reported [267].

Complications of percutaneous nephrolithotomy

A systematic review of almost 12,000 patients shows the incidence of complications associated with PNL; fever 10.8%, transfusion 7%, thoracic complication 1.5%, sepsis 0.5%, organ injury 0.4%, embolisation 0.4%, urinoma 0.2%, and death 0.05% [268].

Peri-operative fever can occur, even with a sterile pre-operative urinary culture and peri-operative antibiotic prophylaxis, because the renal stones themselves may be a source of infection. Intra-operative renal stone culture may therefore help to select post-operative antibiotics [269]. Intra-operative irrigation pressure < 30 mmHg and unobstructed post-operative urinary drainage may be important factors in preventing post-operative sepsis [270]. Bleeding after PNL may be treated by briefly clamping of the nephrostomy tube. Super-selective embolic occlusion of the arterial branch may become necessary in the case of severe bleeding.

3.4.7.1.Summary of evidence and guidelines for endourology techniques for renal stone removal

3.4.8.General recommendations and precautions for stone removal

3.4.8.1.Antibiotic therapy

Urinary tract infections should always be treated if stone removal is planned. In patients with clinically significant infection and obstruction, drainage should be performed for several days before starting stone removal. A urine culture or urinary microscopy should be performed before treatment [271].

Peri-operative antibiotic prophylaxis

For prevention of infection following URS and percutaneous stone removal, no clear-cut evidence exists [272]. In a review of a large database of patients undergoing PNL, it was found that in patients with negative baseline urine culture, antibiotic prophylaxis significantly reduced the rate of post-operative fever and other complications [273]. Single dose administration was found to be sufficient [274].

3.4.8.2.Antithrombotic therapy and stone treatment

Patients with a bleeding diathesis, or receiving antithrombotic therapy, should be referred to an internist for appropriate therapeutic measures before deciding on stone management [275-279]. In patients with an uncorrected bleeding diathesis, the following are at elevated risk of haemorrhage or perinephric haematoma (PNH) (high-risk procedures):

• SWL (hazard ratio of PNH up to 4.2 during anti-coagulant/anti-platelet medication [280-282]);
• PNL;
• percutaneous nephrostomy;
• laparoscopic surgery;
• open surgery [275].

Shock wave lithotripsy is feasible and safe after correction of the underlying coagulopathy [283-287]. In the case of an uncorrected bleeding disorder or continued antithrombotic therapy, URS, in contrast to SWL and PNL, might offer an alternative approach since it is associated with less morbidity [288-290]. Despite appropriate cessation of anti-platelet agents, following standardised protocols, prolonged haematuria in tube drainage after PNL has been reported [291]. Only data on flexible URS are available which support the superiority of URS in the treatment of proximal ureteral stones [292,293].

Table 3.6: Risk stratification for bleeding [277-279,294]

Table 3.7: Suggested strategy for antithrombotic therapy in stone removal [277-279]

(In collaboration with a cardiologist/internist weigh the risks and benefits of discontinuation of therapy, vs. delaying elective surgical procedures).

3.4.8.2.1.Summary of evidence and guidelines for antithrombotic therapy and stone treatment

3.4.8.3.Obesity

A high BMI can pose a higher anaesthetic risk and a lower success rate after SWL [295] and PNL, and may influence the choice of treatment.

3.4.8.4.Stone composition

Stones composed of brushite, calcium oxalate monohydrate, or cystine are particularly hard, as well as homogeneous stones with a high density on NCCT [42,296]. Percutaneous nephrolithotomy or RIRS and URS are alternatives for removal of large SWL-resistant stones.

3.4.8.4.1.Guidelines for stone composition

3.4.8.5.Contraindications of procedures

Contraindications of extracorporeal SWL

There are several contraindications to the use of extracorporeal SWL, including:

• pregnancy, due to the potential effects on the foetus [297];
• bleeding diatheses, which should be compensated for at least 24 hours before and 48 hours after treatment [298];
• uncontrolled UTIs;
• severe skeletal malformations and severe obesity, which prevent targeting of the stone;
• arterial aneurysm in the vicinity of the stone [299];
• anatomical obstruction distal to the stone.

Contraindications of URS

Apart from general problems, for example with general anaesthesia or untreated UTIs, URS can be performed in all patients without any specific contraindications.

Contraindications of PNL

Patients receiving anti-coagulant therapy must be monitored carefully pre- and post-operatively. Anti-coagulant therapy must be discontinued before PNL [290]. Other important contraindications include:

• untreated UTI;
• tumour in the presumptive access tract area;
• potential malignant kidney tumour;
• pregnancy (Section 3.4.14.1).

3.4.9.Specific stone management of ureteral stones

3.4.9.1.Conservative treatment/observation

There are only limited data regarding spontaneous stone passage according to stone size [300]. It is estimated that 95% of stones up to 4 mm pass within 40 days [203].

Based on an analysis of available evidence, an exact cut-off size for stones that are likely to pass spontaneously cannot be provided; < 10 mm may be considered a best estimate [203]. Therefore, the Panel decided not to include stone size but rather recommend “small”, suggesting < 6 mm. The Panel is aware of the fact that spontaneous stone expulsion decreases with increasing stone size and that there are differences between individual patients.

Sexual intercourse has been reported to be beneficial in facilitating stone expulsion in men with ureteral stones, in one meta-analysis consisting of three RCTs [301].

3.4.9.2.Pharmacological treatment, medical expulsive therapy

Medical expulsive therapy should only be used in informed patients if active stone removal is not indicated. Treatment should be discontinued if complications develop (infection, refractory pain, deterioration of renal function). In case of known uric acid stones in the distal ureter, a combination of alkalinisation with tamsulosin can increase the frequency of spontaneous passage. For details see Sections 3.4.3 and 3.4.4.

3.4.9.3.Indications for active removal of ureteral stones

Indications for active removal of ureteral stones are [203,300,302]:

• stones with a low likelihood of spontaneous passage;
• persistent pain despite adequate analgesic medication;
• persistent obstruction;
• renal insufficiency (renal failure, bilateral obstruction, or single kidney).

3.4.9.4.Selection of procedure for active removal of ureteral stones

Overall, SFRs after URS or SWL for ureteral stones are comparable. However, larger stones achieve earlier stone-free status with URS. Although URS is effective for ureteral calculi, it has greater potential for complications. However, in the current endourological era, the complication rate and morbidity of URS has been significantly reduced [303]. It has been demonstrated that URS is a safe option in obese patients (BMI > 30 kg/m2) with comparable SFRs and complication rates. However, in morbidly obese patients (BMI > 35 kg/m2) the overall complication rates double [304].

The Panel performed a systematic review to assess the benefits and harms of URS compared to SWL [305]. Compared with SWL, URS was associated with a significantly greater SFR of up to four weeks, but the difference was not significant at three months in the included studies. Ureteroscopy was associated with fewer retreatments and need for secondary procedures, but with a higher need for adjunctive procedures, greater complication rates and longer hospital stay. Counterbalancing for URS’s higher SFRs, SWL is associated with lower morbidity. Clavien-Dindo grade complications were, if reported, less frequent in patients treated with SWL.

Bleeding disorder

Ureteroscopy can be performed in patients with bleeding disorders, with a moderate increase in complications (see also Section 3.4.8.2) [290].

3.4.9.4.1.Summary of evidence and guidelines for selection of procedure for active removal of ureteral stones

*See stratification data [203].

Figure 3.1: Treatment algorithm for ureteral stones (if active stone removal is indicated)

SWL = shock wave lithotripsy; URS = Ureteroscopy.

3.4.10.Specific stone management of renal stones

The natural history of small, non-obstructing asymptomatic calculi is not well defined, and the risk of progression is unclear. There is still no consensus on the follow-up duration, timing and type of intervention. Treatment options are chemolysis or active stone removal.

3.4.10.1.Conservative treatment (observation)

Observation of renal stones, especially in calyces, depends on their natural history (Section 3.4.10.3). The recommendations provided are not supported by high-level literature. There is a prospective trial supporting annual observation for asymptomatic inferior calyceal stones, < 10 mm. In case stone growth is detected, the follow-up interval should be lowered. Intervention is advised for growing stones > 5 mm [306].

3.4.10.2.Pharmacological treatment of renal stones

Dissolution of stones through pharmacological treatment is an option for uric acid stones only, but information on the composition of the stone will need to guide the type of treatment selected. See sections 3.4.4. and 3.4.8.4.

3.4.10.3.Indications for active stone removal of renal stones

Indications for the removal of renal stones, include:

• stone growth;
• stones in high-risk patients for stone formation;
• obstruction caused by stones;
• infection;
• symptomatic stones (e.g., pain or haematuria) [307];
• stones > 15 mm;
• stones < 15 mm if observation is not the option of choice;
• patient preference;
• comorbidity;
• social situation of the patient (e.g., profession or travelling);
• choice of treatment.

The risk of a symptomatic episode, or need for intervention in patients with asymptomatic renal stones seems to be ~10-25% per year, with a cumulative five-year event probability of 48.5% [306,308,309]. A prospective RCT with more than 2 years clinical follow-up reported no significant difference between SWL and observation when comparing asymptomatic calyceal stones < 15 mm in terms of SFR, symptoms, requirement for additional treatment, quality of life (QoL), renal function, or hospital admission [310]. Although some have recommended prophylaxis for these stones to prevent renal colic, haematuria, infection, or stone growth, conflicting data have been reported [309,311,312]. In a follow-up period of almost five years after SWL, two series have demonstrated that up to 25% of patients with small residual fragments needed treatment [190,313]. Although the question of whether calyceal stones should be treated is still unanswered, stone growth, de novo obstruction, associated infection, and acute and/or chronic pain are indications for treatment [307,314,315].

3.4.10.4.Selection of procedure for active removal of renal stones

For general recommendations and precautions see Section 3.4.8.

3.4.10.4.1.Stones in renal pelvis or upper/middle calyces

Shock wave lithotripsy, PNL and RIRS are available treatment modalities for renal calculi. While PNL efficacy is hardly affected by stone size, the SFRs after SWL or URS are inversely proportional to stone size [316-319]. Shock wave lithotripsy achieves good SFRs for stones up to 20 mm, except for those at the lower pole [318,320,321]. Endourology is considered an alternative because of the reduced need for repeated procedures and consequently a shorter time until stone-free status is achieved. Stones > 20 mm should be treated primarily by PNL, because SWL often requires multiple treatments, and is associated with an increased risk of ureteral obstruction (colic or steinstrasse) with a need for adjunctive procedures (Figure 3.2) [186]. Retrograde renal surgery cannot be recommended as first-line treatment for stones > 20 mm in uncomplicated cases as SFRs decrease, and staged procedures will be required [322-324]. However, it may be a first-line option in patients where PNL is not an option or contraindicated.

3.4.10.4.2.Stones in the lower renal pole

The stone clearance rate after SWL seems to be lower for stones in the inferior calyx than for other intra-renal locations. Although the disintegration efficacy of SWL is not limited compared to other locations, the fragments often remain in the calyx and cause recurrent stone formation. The reported SFR of SWL for lower pole calculi is 25-95%. The preferential use of endoscopic procedures is supported by some current reports, even for stones < 1 cm [186,316,317,319,320,324-332].

The following can impair successful stone treatment by SWL [327,333-337]:

• steep infundibular-pelvic angle;
• long calyx;
• long skin-to-stone distance;
• narrow infundibulum;
• Shock wave-resistant stones (calcium oxalate monohydrate, brushite, or cystine).

Further anatomical parameters cannot yet be established. Supportive measures such as inversion, vibration or hydration may facilitate stone clearance (See 3.4.5 Extracorporeal shock wave lithotripsy (SWL)) [184,338].

If there are negative predictors for SWL, PNL and RIRS might be reasonable alternatives, even for smaller calculi [325]. Retrograde renal surgery seems to have comparable efficacy to SWL [186,317,320,339]. Recent clinical experience has suggested a higher SFR of RIRS compared to SWL, but at the expense of greater invasiveness. Depending on operator skills, stones up to 3 cm can be treated by RIRS [219,340-342]. However, staged procedures are frequently required.

In complex stone cases, open or laparoscopic approaches are possible alternatives.

3.4.10.5.Summary of evidence and guidelines for the management of renal stones

Figure 3.2: Treatment algorithm for renal stones (if/when active treatment is indicated)

*The term ‘Endourology’ encompasses all PNL and URS interventions.

PNL = percutaneous nephrolithotomy; RIRS = retrograde renal surgery; SWL = shock wave lithotripsy;
URS = ureteroscopy.

3.4.11.Laparoscopy and open surgery

Advances in SWL and endourological surgery (URS and PNL) have significantly decreased the indications for open or laparoscopic stone surgery [343-348]. There is a consensus that most complex stones, including partial and complete staghorn stones, should be approached primarily with PNL. Additionally, a combined approach with PNL and RIRS may also be an appropriate alternative. However, if percutaneous approaches are not likely to be successful, or if multiple endourological approaches have been performed unsuccessfully; open or laparoscopic surgery may be a valid treatment option [349-355].

Few studies have reported laparoscopic stone removal. These procedures are usually reserved for special cases. When expertise is available, laparoscopic ureterolithotomy can be performed for large proximal ureteral stones as an alternative to URS or SWL [356,357]. These more invasive procedures have yielded high SFRs and lower auxiliary procedure rates [211,212,222,358]. A recent systematic review showed no difference in the post-operative phase for stented or unstented laparoscopic ureterolithotomy [358]. A few studies with limited numbers of patients have reported using robotic surgery in the treatment of urinary stones [359]. Open surgery should be considered as the last treatment option, after all other possibilities have been explored.

3.4.11.1.Summary of evidence and guideline for laparoscopy and open surgery

3.4.12.Steinstrasse

Steinstrasse is an accumulation of stone fragments or stone gravel in the ureter and may interfere with the passage of urine [360]. Steinstrasse occurs in 4-7% cases of SWL [200], and the major factor in the development of steinstrasse formation is stone size [361].

A major problem of steinstrasse is ureteral obstruction, which may be silent in up to 23% of cases. A MA including eight RCTs (n = 876) suggests a benefit of stenting before SWL in terms of steinstrasse formation, but does not result in a benefit on SFRs or less auxiliary treatments [142].

When steinstrasse is asymptomatic, conservative treatment is an initial option. Medical expulsion therapy increases stone expulsion and reduces the need for endoscopic intervention [362,363]. Ureteroscopy and SWL are effective in treatment of steinstrasse [202,364]. In the event of UTI or fever, the urinary system should be decompressed, preferably by percutaneous nephrostomy [115,117].

3.4.12.1.Summary of evidence and guidelines for steinstrasse

3.4.13.Management of patients with residual stones

Following initial treatment with SWL, URS or PNL residual fragments may remain and require additional intervention [313,365,366]. Most of the studies indicate that initial imaging is performed on the first day or the first week after treatment. However, false positive results from dust or residual fragments, that will pass spontaneously without causing any stone-related event, might lead to over-treatment. As a consequence, imaging at four weeks seems most appropriate [367-369]. Compared to US, KUB and IVU, NCCT scan has a higher sensitivity to detect small residual fragments after definitive treatment of ureteral or kidney stones [370,371]. However, more than half of the patients with a residual fragment on NCCT images may not experience a stone-related event [372].

It is clear that NCCT has the highest sensitivity to detect residual fragments; however, this must be balanced against the increased detection of clinically insignificant fragments and the exposure to ionising radiation when compared with KUB and US. In the absence of high level supporting evidence, the timing of follow-up imaging studies and need for secondary intervention is left to the discretion of the treating physician. Recurrence risk in patients with residual fragments after treatment of infection stones is higher than for other stones [373]. For all stone compositions, 21-59% of patients with residual stones required treatment within five years. Fragments > 5 mm are more likely than smaller ones to require intervention [190,374,375]. There is evidence that fragments > 2 mm are more likely to grow, although this is not associated with increased re-intervention rates at one year follow up [365].

3.4.13.1.Summary of evidence and guideline for management of patients with residual stones

3.4.14.Management of specific patient groups

3.4.14.1.Management of urinary stones and related problems during pregnancy

Clinical management of a pregnant urolithiasis patient is complex and demands close collaboration between patient, radiologist, obstetrician and urologist. For diagnostic imaging see Section 3.3.1.

If spontaneous passage does not occur, or if complications develop (e.g., intractable symptoms, severe hydronephrosis or induction of premature labour), placement of a ureteral stent or a percutaneous nephrostomy tube is necessary as it is more effective than conservative treatment for symptom relief [376,377].

Unfortunately, these temporising therapies are often associated with poor tolerance, and they require multiple exchanges during pregnancy, due to the potential for rapid encrustation [378].

Ureteroscopy has become a reasonable alternative in these situations [369,379]. When compared to temporary ureteral JJ stenting until after delivery, ureteroscopy resulted in fewer needs for stent exchanges, less irritative LUTS and better patient satisfaction [380].

Non-urgent ureteroscopy in pregnant women is best performed during the second trimester, by an experienced urologist. Counselling of the patient should include access to neonatal and obstetric services [73].

Although feasible, percutaneous removal of renal stones during pregnancy remains an individual decision and should be performed only in experienced centres. Pregnancy remains an absolute contraindication for SWL.

3.4.14.1.1.Summary of evidence and guideline for the management of urinary stones and related problems during pregnancy

3.4.14.2.Management of stones in patients with urinary diversion

Aetiology

Patients with urinary diversion are at high risk for stone formation in the renal collecting system and ureter or in the conduit or continent reservoir [381,382]. Metabolic factors (hypercalciuria, hyperoxaluria and hypocitraturia), infection with urease-producing bacteria, foreign bodies, mucus secretion, and urinary stasis are responsible for stone formation [383] (section 3.1.3). One study has shown that the risk for recurrent upper tract stones in patients with urinary diversion subjected to PNL was 63% at five years [384].

Management

Smaller upper-tract stones can be treated effectively with SWL [217,385]. In the majority of cases, endourological techniques are necessary to achieve stone-free status [214]. In individuals with long, tortuous conduits or with invisible ureter orifices, a retrograde endoscopic approach might be difficult or impossible.

For stones in the conduit, a trans-stomal approach can be used to remove all stone material (along with the foreign body) using standard techniques, including intracorporeal lithotripsy and flexible endoscopes. Trans-stomal manipulations in continent urinary diversion must be performed carefully to avoid disturbance of the continence mechanism [386].

Before considering any percutaneous approach in these cases, CT should be undertaken to assess the presence of overlying bowel, which could make this approach unsafe [387], and if present, an open surgical approach should be considered.

Prevention

Recurrence risk is high in these patients [384]. Metabolic evaluation and close follow-up are necessary to obtain the risk parameters for effective long-term prevention. Preventive measures include medical management of metabolic abnormalities, appropriate therapy of urinary infections, and hyperdiuresis or regular irrigation of continent reservoirs [388].

3.4.14.2.1.Summary of evidence and guideline for the management of stones in patients with urinary diversion

3.4.14.3.Management of stones in patients with neurogenic bladder

Aetiology, clinical presentation and diagnosis

Patients with neurogenic bladder develop urinary calculi because of additional risk factors such as bacteriuria, hydronephrosis, VUR, renal scarring, lower urinary tract reconstruction, and thoracic spinal defect [389]. The most common causes are urinary stasis and infection (Section 3.1.3). Indwelling catheters and surgical interposition of bowel segments for treatment of bladder dysfunction both facilitate UTI. Although calculi can form at any level of the urinary tract, they occur more frequently in the bladder; especially if bladder augmentation has been performed [390,391].

Diagnosis of stones may be difficult and delayed in the absence of clinical symptoms due to sensory impairment and vesico-urethral dysfunction. Difficulties in self-catheterisation should lead to suspicion of bladder calculi. Imaging studies are needed (US, CT) to confirm the clinical diagnosis prior to surgical intervention.

Management

Management of calculi in patients with neurogenic bladder is similar to that described in Section 3.3.3. In myelomeningocele patients, latex allergy is common; therefore, appropriate measures need to be taken regardless of the treatment [392]. Any surgery in these patients must be performed under general anaesthesia because of the impossibility of using spinal anaesthesia. Bone deformities often complicate positioning on the operating table [393]. The risk of stone formation after augmentation cystoplasty in immobile patients with sensory impairment can be significantly reduced by irrigation protocols [388].

For efficient long-term stone prevention in patients with neurogenic bladder, correction of the metabolic disorder, appropriate infection control, and restoration of normal storing/voiding function of the bladder are needed.

3.4.14.3.1.Summary of evidence and guideline for the management of stones in patients with neurogenic bladder

3.4.14.4.Management of stones in patients with transplanted kidneys

Stones in transplanted kidneys can either be transplanted or present de novo allograft stones. Usually they are detected by routine US examination, followed by NCCT in cases of unclear diagnosis [394].

Aetiology

Transplant patients depend on their solitary kidney for renal function. Impairment causing urinary stasis/obstruction therefore requires immediate intervention or drainage of the transplanted kidney. Risk factors for de novo stone formation in these patients are multi-fold:

• Immunosuppression increases the infection risk, resulting in recurrent UTIs.
• Hyper-filtration, excessively alkaline urine, renal tubular acidosis (RTA), and increased serum calcium caused by persistent tertiary hyperparathyroidism [395] are biochemical risk factors.

Stones in kidney allografts have an incidence of 1% [396].

Management

Selecting the appropriate technique for stone removal in a transplanted kidney is difficult, although management principles are similar to those applied in other single renal units [397-399]. Additional factors such as transplant function, coagulative status, and anatomical obstacles due to the iliacal position of the organ, directly influence the surgical strategy.

For large or ureteral stones, careful percutaneous access and subsequent antegrade endoscopy are more favourable. The introduction of small flexible ureteroscopes and the holmium laser has made URS a valid treatment option for transplant calculi; however, one must be aware of potential injury to adjacent organs [399-401]. Retrograde access to transplanted kidneys is difficult due to the anterior location of the ureteral anastomosis, and ureteral tortuosity [402-404]. Treatment of donor stones may be needed pre-transplant and increases the pool available for renal transplants. Post-transplant stone disease may also need treatment to maintain the allograft function. A systematic review evaluating the outcomes of pre- vs. post-transplant URS demonstrated a 100% SFR with an overall 7.5% complication rate, compared to SFR of 60-100% with an overall complication rate of 12.9% for post-transplant URS; most complications were Clavien 1 [405].

3.4.14.4.1.Summary of evidence and guideline for the management of stones in patients with transplanted kidneys

3.4.14.5.Special problems in stone removal

Table 3.8: Special problems in stone removal

3.4.15.Management of stones in children

The true incidence of nephrolithiasis in children remains unclear due to the global lack of large epidemiological studies. Data derived from nation-wide epidemiological studies, studies performed in different counties worldwide [416,417], and large-scale databases [418,419] indicate that the incidence and prevalence of paediatric urinary stone disease has increased over the last few decades. Although boys are most commonly affected in the first decade of life [420] the greatest increase in incidence has been seen in older female adolescences [416,417,421].

Stone composition is similar in children as in adults, with a predominance of calcium oxalate stones. Compared to historical data, metabolic abnormalities responsible for stone formation are less commonly identified in children nowadays [422-424]. Hypocitraturia, low urine volume and hypercalciuria predominate [82,422-424]. Age may affect the predominant metabolic abnormality with hypercalciuria and hypocitraturia being the most common disorder present in children < 10 and > 10 years old, respectively [424]. Genetic or systemic diseases (e.g. cystinuria or nephrocalcinosis) contributing to stone formation are rare in children accounting for less than 17% of the identifying causes [422,425]. The role of diet remains unclear in children, although there is some evidence that children are drinking less water and taking greater daily amounts of sodium than is recommended [426-428].

For diagnostic procedures see Section 3.3.3.2, for acute decompression see Section 3.4.2. and for metabolic evaluation see Chapter 4.

3.4.15.1.Clinical presentation

Children with urinary stones can be asymptomatic or present with non-specific symptoms that necessitate a high index of suspicion for proper diagnosis. Symptoms are age-dependent with infants presenting with crying, irritability and vomiting in 40% of cases [429] while in older children flank pain, micro or gross haematuria and recurrent UTIs are more common [430].

3.4.15.2.Conservative management

There is a lack of evidence on conservative management of paediatric stones with evidence for ureteric calculi coming from the placebo arms of medical expulsive trials, while evidence for renal stones comes from small cohort studies, either on primary stones [431,432] or residual fragments remained after SWL, RIRS or PNL [433]. Expectant management for single, asymptomatic lower-pole renal stones could be the initial approach with increased odds of stone passage, especially in patients with non-struvite, non-cystine stones < 7 mm, with no anatomic abnormalities [431]. Intervention may be needed for stones located elsewhere independently of their size [431-433].

3.4.15.3.Medical expulsive therapy in children

There are limited studies on MET as off-label expulsive therapy for children with stones which show conflicting outcomes. A recent MA of five trials showed that adrenergic α-antagonists (tamsulosin 0.2-0.4 mg/day and doxazosin 0.03 mg/kg/day) are effective for MET increasing SFR compared to control (OR = 2.7, p = 0.001) without significantly increasing the treatment-emergent adverse events (OR = 2.01, p = 0.17) [434]. Similarly, an updated systematic review of six placebo-controlled studies showed that α-blockers might increase SFR of distal ureteric stones (RR: 1.34, 95% CI: 1.16 - 1.54) [435]. Due to study limitations and very serious imprecision, no conclusion could be drawn regarding the effect of MET on hospital stay, pain episodes or secondary procedures for residual fragments after definitive stone treatment [435].

3.4.15.4.Extracorporeal shock wave lithotripsy

Shock wave lithotripsy is still the first-line treatment for most ureteral stones in children. However, it is less likely to be successful for stones > 10 mm in diameter, impacted stones, calcium oxalate monohydrate or cystine stones, or for stones in children with unfavourable anatomy and in whom localisation is difficult [436].

Studies on extracorporeal SWL in children suggest an overall SFR of 70-90%, retreatment rate of 4-50% and need for auxiliary procedures in 4-12.5% of cases [437-441]. A MA of 14 studies reporting on 1,842 paediatric patients treated with SWL found significantly higher SFR for stones < 10 mm than for stones > 10 mm and higher retreatment rates as the stone size increased [436]. For best clinical practice see Section 3.4.5. A recent MA on slow SWL vs. rapid SWL for renal stones revealed very low-quality evidence about the effects of SWL on SFRs, serious adverse events or complications of treatment and secondary procedures for residual fragments [435]. Shock wave lithotripsy is well tolerated; however, good treatment outcomes are more likely to require the administration of general anaesthesia to children. With improvements in modern (second and third generation) lithotripters, successful treatment using intravenous sedation, patient-controlled analgesia or no medication at all has been increasingly performed in a select population of older, co-operative children [442].

Based on the results of a recent MA which compared SWL to dissolution therapy for intra-renal stones, and SWL to ureteroscopy with holmium laser or pneumatic lithotripsy for renal and distal ureteric stones, no firm conclusions can be drawn about the effects of SWL on SFR, serious adverse events or complications of treatment and secondary procedures for residual fragments [435].

When SWL was compared to mini-percutaneous nephrolithotomy for lower pole renal stones 1-2 cm in size SWL resulted in lower SFRs (RR: 0.88, 95% CI: 0.80 - 0.97; moderate quality evidence) and higher rates of secondary procedures (RR: 2.50, 95% CI: 1.01 - 6.20; low-quality evidence); however, SWL showed less severe adverse events (RR: 0.13, 95% CI: 0.02 - 0.98; low quality evidence) [443].

3.4.15.5.Endourological procedures

Rigid/semi-rigid ureteroscopy

In recent years ureteroscopy is increasingly used in children with ureteral stones [444]. Ureteroscopy proved to be effective with SFR of 81-98% [445-447], retreatment rates of 6.3%-10% [448] and complication rates of 1.9-23% [445-447,449]. Similar to adults, routine stenting is not necessary before URS. However, pre-stenting may facilitate URS, increase SFR and decrease complication rates [450]. Stenting after URS is a strong indicator for retreatment requiring anaesthesia in children [451].

Flexible ureteroscopy/retrograde intrarenal surgery

Retrograde intra-renal surgery with flexible ureteroscopes (FURS) has become an efficacious treatment modality for paediatric renal stones. Recent studies report SFRs of 76-100%, retreatment rates of 0-19% and complication rates of 0-28% [452-455]. Younger age, cystine composition [456], large stone diameter [455] and lack of pre-stenting predispose to FURS failure in children [450].

Although high-level evidence is lacking to support a strong recommendation [435], FURS may be a particularly effective treatment option for lower calceal stones in the presence of unfavourable factors for SWL [447,453,457].

For large and complex kidney stones RIRS has a significantly lower SFR compared to PNL (71% vs. 95%), but is associated with less radiation exposure, lower complication rates and a shorter hospital stay [458]. Similarly, retrospectively data indicate that RIRS may achieve lower SFRs compared to minor micro-percutaneous surgery in favour of shorter operative time, shorter fluoroscopy time, and less hospitalisation time [459,460]. A recently published MA confirmed the aforementioned results [461].

Percutaneous nephrolithotomy

Indications for PNL in children are similar to those in adults, and include renal stones > 2 cm, or smaller stones resistant to SWL and ureteroscopic treatment. Reported SFRs with paediatric PNL are 71.4-95% after a single session [458-460,462,463] with an overall complication rate of 20% [464]. High degree of hydronephrosis, increased number of tracts and operative time [465] and large tract size [463,466-468] are associated with increased blood loss. Child age [467] and stone burden [463] predispose to the use of larger instruments during PNL in children. Miniaturisation of equipment increases the opportunity to perform tubeless PNL in appropriately selected children, which can reduce the length of hospital stay and post-operative pain [469,470].

Concerns have been raised regarding possible adverse effects of PNL on the renal parenchyma of the developing child. However, focal damage is only reported in 5% of cases [471]. Using pre- and post-PNL dimercaptosuccinic acid (DMSA) scans, Cicekbilek et al. demonstrated that PNL tracts between 12-24 Charrière in size did not cause significant harm to paediatric kidneys [462].

3.4.15.6.Open and laparoscopic/robot-assisted stone surgery

With the advances in ESWL, PNL and RIRS, very few cases of paediatric urolithiasis require open surgery. Data extracted from the National Inpatient Sample (NIS) databases for 2001-2014 showed that in the USA incisional procedures (mainly nephrolithotomy, pyelolithotomy and ureterotomy) were performed in 2.6% of hospitalised patients (52% aged 15-17 years) who required surgical intervention for urinary stones [472]. Laparoscopy for the management of paediatric renal and ureteric stones is a safe and effective procedure when specific indications are followed. Stone free rates of 100% were reported when laparoscopic pyelolithotomy was applied for a ≥1cm single stone located in an extra-renal pelvis [473], or when laparoscopic ureterolithotomy was applied to impacted ureteric stones ≥1.5 cm, or to ureteric stones that were refractory to SWL or URS [474]. There are extremely limited data available on efficacy and complications of robot-assisted laparoscopic management of paediatric urolithiasis [475].

3.4.15.7.Special considerations on recurrence prevention

All paediatric stone formers need metabolic evaluation and recurrence prevention with respect to the detected stone type. Children are in the high-risk group for stone recurrence (See Chapter 4).

3.4.15.8.Summary of evidence and guidelines for the management of stones in children

4.FOLLOW UP: METABOLIC EVALUATION AND RECURRENCE PREVENTION

4.1.General metabolic considerations for patient work-up

4.1.1.Evaluation of patient risk

After stone passage, every patient should be assigned to a low- or high-risk group for stone formation (Figure 4.1). For correct classification, two items are mandatory:

• reliable stone analysis by infrared spectroscopy or X-ray diffraction;
• basic analysis (Section 3.3.2).

Only high-risk stone formers require specific metabolic evaluation. Stone type is the deciding factor for further diagnostic tests. The different stone types include:

• calcium oxalate;
• calcium phosphate;
• uric acid;
• ammonium urate;
• struvite (and infection stones);
• cystine;
• xanthine;
• 2,8-Dihydroxyadenine;
• drug stones;
• stones of unknown composition.

Figure 4.1: Assignment of patients to low- or high-risk groups for stone formation

4.1.2.Urine sampling

Specific metabolic evaluation requires collection of two consecutive 24-hour urine samples [476,477]. The collecting bottles should be prepared with 5% thymol in isopropanol or stored at < 8°C during collection to prevent the risk of spontaneous crystallisation in the urine. Pre-analytical errors can be minimised by carrying out urinalysis immediately after collection. Alternatively, boric acid (10 g powder per urine container) can also be used. The collecting method should be chosen in close cooperation with the particular laboratory. Urine pH should be assessed during collection of freshly voided urine four times daily using sensitive pH-dipsticks or a pH-meter [22,478].

Spot urine samples are an alternative method of sampling, particularly when 24-hour’s urine collection is difficult, for example, in non-toilet trained children [479]. Spot urine studies normally link the excretion rates to creatinine [480], but these are of limited use because the results may vary with collection time and patients’ sex, body weight and age.

4.1.3.Timing of specific metabolic work-up

For the initial specific metabolic work-up, the patient should stay on a self-determined diet under normal daily conditions and should ideally be stone free for at least twenty days [481]. Follow-up studies are necessary in patients taking medication for recurrence prevention [482]. The first follow-up 24-hour urine measurement is suggested eight to twelve weeks after starting pharmacological prevention of stone recurrence. This enables drug dosage to be adjusted if urinary risk factors have not normalised, with further 24-hour urine measurements, if necessary. Once urinary parameters have been normalised, it is sufficient to perform 24-hour urine evaluation every twelve months. The Panel realise that on this issue there is only very limited published evidence, and aim to set up a systematic review on the ideal timing of the 24-hour urine collection.

4.1.4.Reference ranges of laboratory values

Tables 4.1-4.4 provide the internationally accepted reference ranges for the different laboratory values in serum and urine.

Table 4.1: Normal laboratory values for blood parameters in adults [482,483]

BE = base excess (loss of buffer base to neutralise acid); HCO = bicarbonate; PCO = partial pressure of carbon dioxide; PO = partial pressure of oxygen.

4.1.5.Risk indices and additional diagnostic tools

Several risk indices have been developed to describe the crystallisation risk for calcium oxalate or calcium phosphate in urine [484-487]. However, clinical validation of these risk indices for recurrence prediction or therapy improvement is ongoing.

Table 4.2: Normal laboratory values for urinary parameters in adults

Table 4.3: Normal values for spot urine samples: creatinine ratios (solute/creatinine) in children [488]

Table 4.4: Solute excretion in 24-hour urine samples in children [490,491]*

*24 h urine parameters are diet and gender dependent and may vary geographically.

4.2.General considerations for recurrence prevention

All stone formers, independent of their individual risk, should follow the preventive measures in Table 4.5. The main focus is normalisation of dietary habits and lifestyle risks. Stone formers at high risk need specific prophylaxis for recurrence, which is usually pharmacological treatment based on stone analysis.

Table 4.5: General preventive measures

Caution: Protein requirements are age dependent; therefore, protein restriction in childhood should be handled carefully. * Avoid excessive consumption of vitamin supplements.

4.2.1.Fluid intake

An inverse relationship between high fluid intake and stone formation has been repeatedly demonstrated [489-492]. The effect of fruit juices is mainly determined by the presence of citrate or bicarbonate [493]. If hydrogen ions are present, the net result is neutralisation. However, if potassium is present, both pH and citrate are increased [494,495]. One large moderate quality RCT randomly assigned men with more than one past renal stone of any type and soft drink consumption of at least 160 mL/day to reduced soft drink intake or no treatment. Although the intervention significantly reduced the risk for symptomatic recurrent stones (RR: 0.83; CI: 0.71-0.98), the level of evidence for this outcome is low because results were from only one trial [496].

4.2.2.Diet

A common sense approach to diet should be taken, that is, a mixed, balanced diet with contributions from all food groups, without any excesses [497-499].

Fruits, vegetables and fibre: Fruit and vegetable intake should be encouraged because of the beneficial effects of fibre, although the role of the latter in preventing stone recurrences is debatable [500-503]. The alkaline content of a vegetarian diet also increases urinary pH.

Oxalate: Excessive intake of oxalate-rich products should be limited or avoided to prevent high oxalate load [504], particularly in patients who have high oxalate excretion.

Vitamin C: Although vitamin C is a precursor of oxalate, its role as a risk factor in calcium oxalate stone formation remains controversial [505]. However, it seems wise to advise calcium oxalate stone formers to avoid excessive intake.

Animal protein: Animal protein should not be consumed in excess [491,506] and limited to 0.8-1.0 g/kg body weight. Excessive consumption of animal protein has several effects that favour stone formation, including hypocitraturia, low urine pH, hyperoxaluria and hyperuricosuria.

Calcium intake: Calcium should not be restricted, unless there are strong reasons for doing so, due to the inverse relationship between dietary calcium and stone formation [501,507]. The daily requirement for calcium is 1,000 to 1,200 mg [22]. Calcium supplements are not recommended except in enteric hyperoxaluria, when additional calcium should be taken with meals to bind intestinal oxalate [491,497,504,508]. Older adults who do not have a history of renal stones but who take calcium supplements should ensure adequate fluid intake since it may prevent increases in urine calcium concentration, and thereby reduce or eliminate any increased risk of renal stones formation associated with calcium supplement use [509].

Sodium: Daily sodium (NaCl) intake should not exceed 3-5 g [22]. High intake adversely affects urine composition:

• calcium excretion is increased by reduced tubular reabsorption;
• urinary citrate is reduced due to loss of bicarbonate;
• increased risk of sodium urate crystal formation.

Calcium stone formation can be reduced by restricting sodium and animal protein [491,506]. A positive correlation between sodium consumption and risk of first-time stone formation has been confirmed only in women [507]. There have been no prospective clinical trials on the role of sodium restriction as an independent variable in reducing the risk of stone formation.

Urate: Intake of purine-rich food should be restricted in patients with hyperuricosuric calcium oxalate [510,511] and uric acid stones. Intake should not exceed 500 mg/day [22].

4.2.3.Lifestyle

Lifestyle factors may influence the risk of stone formation, for example, obesity [512] and arterial hypertension [513,514].

4.2.4.Summary of evidence and guideline for recurrence prevention

4.3.Stone-specific metabolic evaluation and pharmacological recurrence prevention

4.3.1.Introduction

Pharmacological treatment is necessary in patients at high risk for recurrent stone formation. The ideal drug should halt stone formation, have no side effects, and be easy to administer. Each of these aspects is important to achieve good compliance. Table 4.6 highlights the most important characteristics of commonly used medication.

Table 4.6: Pharmacological substances used for stone prevention - characteristics, specifics and dosage

4.4.Calcium oxalate stones

The criteria for identification of calcium oxalate stone formers with high recurrence risk are listed in Chapter 3.1.2.

4.4.1.Diagnosis

Blood analysis requires measurement of creatinine, sodium, potassium, chloride, ionised calcium (or total calcium + albumin), uric acid, and parathyroid hormone (PTH) (and vitamin D) in the case of increased calcium levels. Urinalysis requires measurement of urine volume, urine pH profile, specific weight, calcium, oxalate, uric acid, citrate, sodium and magnesium.

4.4.2.Interpretation of results and aetiology

The most common metabolic abnormalities associated with calcium stone formation are hypercalciuria, which affects 30-60% of adult stone formers, and hyperoxaluria (26-67%), followed by hyperuricosuria (15-46%), hypomagnesiuria (7-23%), and hypocitraturia (5-29%). However, ranges tend to differ based on ethnicity [546].

• Elevated levels of ionised calcium in serum (or total calcium and albumin) require assessment of intact PTH to confirm or exclude suspected hyperparathyroidism (HPT).
• “Acidic arrest” (urine pH constantly < 5.8) may promote co-crystallisation of uric acid and calcium oxalate.
• Similarly, increased uric acid excretion (> 4 mmol/day in adults or > 12 mg/kg/day in children) can act as a promoter.
• Urine pH levels constantly > 5.8 in the day profile indicate RTA, provided UTI has been excluded. An ammonium chloride loading test confirms RTA and identifies RTA subtype (Section 4.6.5).
• Hypercalciuria may be associated with normocalcemia (idiopathic hypercalciuria, or granulomatous diseases) or hypercalcaemia (hyperparathyroidism, granulomatous diseases, vitamin D excess, or malignancy).
• Hypocitraturia (male < 1.7 mmol/d, female < 1.9 mmol/d) may be idiopathic or secondary to metabolic acidosis or hypokalaemia.
• Oxalate excretion > 0.5 mmol/day in adults (> 0.37 mmol/1.73 m2/day in children) confirms hyperoxaluria.

  primary hyperoxaluria (oxalate excretion mostly > 1 mmol/day), appears in three genetically determined forms;

  secondary hyperoxaluria (oxalate excretion > 0.5 mmol/day, usually < 1 mmol/day), occurs due to intestinal hyperabsorption of oxalate or extreme dietary oxalate intake;

  mild hyperoxaluria (oxalate excretion 0.45-0.85 mmol/day), commonly found in idiopathic calcium oxalate stone formers.

• Hypomagnesiuria (< 3.0 mmol/day) may be related to poor dietary intake or to reduced intestinal absorption (chronic diarrhoea).

Figure 4.2: Diagnostic and therapeutic algorithm for calcium oxalate stones

1 Be aware of excess calcium excretion.
2 tid = three times/day (24h).
3 No magnesium therapy for patients with renal insufficiency.
4 There is no evidence that combination therapy (thiazide + citrate) or (thiazide + allopurinol) is superior to thiazide therapy alone [516,550].
5 Febuxostat 80 mg/d.

4.4.3.Specific treatment

General preventive measures are recommended for fluid intake and diet. Hyperoxaluric stone formers should consume foods with low oxalate content, whereas hyperuricosuric stone formers benefit from daily dietary reduction of purine. Figure 4.2 summarises the diagnostic algorithm and the pharmacological treatment of calcium oxalate stones [495,497,515-518,521,522,524,527,530-532,534-541,546-549]. There is only low level evidence on the efficacy of preventing stone recurrence through pre-treatment stone composition examination and biochemistry measures, or on-treatment biochemistry measures [497].

4.4.4.Summary of evidence and guidelines for pharmacological treatments for patients with specific abnormalities in urine composition (based on 24-hour urine samples)

4.5.Calcium phosphate stones [497,515,524,534,535,539,551]

Some calcium phosphate stone formers are at high risk of recurrence. Further information on identifying high-risk patients is provided in Section 3.1.2.

Calcium phosphate mainly appears in two completely different minerals: carbonate apatite and brushite. Carbonate apatite crystallisation occurs at a pH > 6.8 and may be associated with infection. Brushite crystallises at an optimum pH of 6.5-6.8 at high urinary concentrations of calcium (> 8 mmol/day) and phosphate (> 35 mmol/day). Its occurrence is not related to UTI. Possible causes of calcium phosphate stones include HPT, RTA and UTI; each of which requires different therapy.

4.5.1.Diagnosis

Diagnosis requires blood analysis for: creatinine, sodium, potassium, chloride, ionised calcium (or total calcium + albumin), and PTH (in the case of increased calcium levels). Urinalysis includes measurement of: volume, urine pH profile, specific weight, calcium, phosphate and citrate.

4.5.2.Interpretation of results and aetiology

General preventative measures are recommended for fluid intake and diet. The diagnostic and therapeutic algorithm for calcium phosphate stones is shown in Figure 4.3.

Figure 4.3: Diagnostic and therapeutic algorithm for calcium phosphate stones

HPT = hyperparathyroidism; RTA = renal tubular acidosis; UTI = urinary tract infection.

4.5.3.Pharmacological therapy [497,515,524,534,535,539,551]

Hyperparathyroidism and RTA are common causes of calcium phosphate stone formation. Although most patients with primary HPT require surgery, RTA can be corrected pharmacologically. If primary HPT and RTA have been excluded, pharmacotherapy for calcium phosphate calculi depends on effective reduction of urinary calcium levels using thiazides. If urine pH remains constantly > 6.2, urinary acidification with L-methionine may be beneficial; however, it is not commonly used and needs monitoring for systemic acidosis development. For infection-associated calcium phosphate stones, it is important to consider the guidance given for infection stones.

4.5.4.Summary of evidence and guidelines for the management of calcium phosphate stones

4.6.Disorders and diseases related to calcium stones

4.6.1.Hyperparathyroidism [552-554]

Primary HPT is responsible for an estimated 5% of all calcium stone formation. Renal stones occur in approximately 20% of patients with primary HPT. Elevated levels of PTH significantly increase calcium turnover, leading to hypercalcaemia and hypercalciuria. Serum calcium may be mildly elevated and serum PTH may be within the upper normal limits and, therefore, repeated measurements may be needed; preferably with the patient fasting. Stones of HPT patients may contain both calcium oxalate and calcium phosphate.

If HPT is suspected, neck exploration should be performed to confirm the diagnosis. Primary HPT can only be cured by surgery.

4.6.2.Granulomatous diseases [555]

Granulomatous diseases, such as sarcoidosis, may be complicated by hypercalcaemia and hypercalciuria secondary to increased calcitriol production. The latter is independent of PTH control, leading to increased calcium absorption in the gastrointestinal tract and suppression of PTH. Treatment focuses on the activity of the granulomatous diseases and may require steroids, hydroxychloroquine or ketoconazole. Treatment should be reserved for a specialist.

4.6.3.Primary hyperoxaluria [533]

Patients with primary hyperoxaluria (PH) should be referred to specialised centres, as successful management requires an experienced interdisciplinary team. The main therapeutic aim is to reduce endogenous oxalate production, which is increased in patients with PH. In approximately one-third of patients with PH type I, pyridoxine therapy normalises or significantly reduces urinary oxalate excretion. The goal of adequate urine dilution is achieved by adjusting fluid intake to 3.5-4.0 L/day in adults (children 1.5 L/m2 body surface area) and following a circadian drinking regimen.

Therapeutic options for preventing calcium oxalate crystallisation include hyperdiuresis, alkaline citrates and magnesium. However, in end-stage renal failure, PH requires simultaneous liver-kidney transplantation.

Treatment regimens are:

• pyridoxine in PH type I: 5-20 mg/kg/day according to urinary oxalate excretion and patient tolerance;
• alkaline citrate: 9-12 g/day in adults, 0.1-0.15 mq/kg/day in children;
• magnesium: 200-400 mg/day (no magnesium in the case of renal insufficiency).

4.6.3.1.Summary of evidence and guideline for the management of primary hyperoxaluria

4.6.4.Enteric hyperoxaluria [504,508,556-558]

Enteric hyperoxaluria is a particularly problematic condition in patients with intestinal malabsorption of fat. This abnormality is associated with a high risk of stone formation, and is seen after intestinal resection and malabsorptive bariatric surgery, as well as in Crohn’s disease and pancreas insufficiency. In addition to hyperoxaluria, these patients usually present with hypocitraturia due to loss of alkali. Urine pH is usually low, as are urinary calcium and urine volume. All these abnormalities contribute to high levels of supersaturation with calcium oxalate, crystalluria, and stone formation. Specific preventive measures are:

• restricted intake of oxalate-rich foods [504];
• restricted fat intake [504];
• calcium supplementation at meal times to enable calcium oxalate complex formation in the intestine [508,556-558];
• sufficient fluid intake to balance intestinal loss of water caused by diarrhoea;
• alkaline citrates to raise urinary pH and citrate.

4.6.4.1.Summary of evidence and guidelines for the management of enteric hyperoxaluria

4.6.5.Renal tubular acidosis [497,524,559,560]

Renal tubular acidosis is caused by severe impairment of proton or bicarbonate handling along the nephron. Kidney stone formation most probably occurs in patients with distal RTA type I. Figure 4.4 outlines the diagnosis of RTA. Table 4.7 shows acquired and inherited causes of RTA.

Figure 4.4: Diagnosis of renal tubular acidosis

BGA = blood gas analysis; RTA = renal tubular acidosis.

** An alternative ammonium chloride loading test using NH4Cl load with 0.05 g/kg body weight over three days might provide similar results and may be better tolerated by the patient. A second alternative in these cases could be the furosemide acidification test.

Renal tubular acidosis can be acquired or inherited. Reasons for acquired RTA can be obstructive uropathy, recurrent pyelonephritis, acute tubular necrosis, renal transplantation, analgesic nephropathy, sarcoidosis, idiopathic hypercalciuria, and primary parathyroidism; it may also be drug-induced (e.g. zonisamide).

Table 4.7: Inherited causes of renal tubular acidosis

The main therapeutic aim of RTA treatment is restoring a normal acid-base equilibrium. Despite the alkaline pH of urine in RTA, alkalinisation using alkaline citrates or sodium bicarbonate is important for normalising the metabolic changes (intracellular acidosis) responsible for stone formation (Table 4.8). The alkali load reduces tubular reabsorption of citrate, which in turn normalises citrate excretion and simultaneously reduces calcium turnover. Therapeutic success can be monitored by venous blood gas analysis (base excess: ± 2.0 mmol/L) in complete RTA. If excessive calcium excretion (> 8 mmol/day) persists after re-establishing acid-base equilibrium, thiazides may lower urinary calcium excretion.

Table 4.8: Pharmacological treatment of renal tubular acidosis

4.6.5.1.Summary of evidence and guidelines for the management of tubular acidosis

4.6.6.Nephrocalcinosis [561]

Nephrocalcinosis (NC) refers to increased crystal deposition within the renal cortex or medulla, and occurs alone or in combination with renal stones. There are various metabolic causes. The main risk factors are: HPT, PH, RTA, vitamin D metabolic disorders, idiopathic hypercalciuria and hypocitraturia, and genetic disorders, including Dent’s disease, Bartter’s syndrome and medullary sponge kidney. The many causes of NC means there is no single standard therapy. Therapeutic attention must focus on the underlying metabolic or genetic disease, while minimising the biochemical risk factors.

4.6.6.1.Diagnosis

Diagnosis requires the following blood analysis: PTH (in the case of increased calcium levels), vitamin D and metabolites, vitamin A, sodium, potassium, magnesium, chloride, and blood gas analysis. Urinalysis should investigate urine pH profile (minimum four times daily), daily urine volume, specific weight of urine, and levels of calcium, oxalate, phosphate, uric acid, magnesium and citrate.

4.7.Uric acid and ammonium urate stones

All uric acid and ammonium urate stone formers are considered to be at high risk of recurrence [22]. Uric acid nephrolithiasis is responsible for approximately 10% of renal stones [562] and associated with hyperuricosuria or low urinary pH. Hyperuricosuria may be a result of dietary excess, endogenous overproduction (enzyme defects), myeloproliferative disorders, tumour lysis syndrome, drugs, gout or catabolism [563]. Low urinary pH may be caused by decreased urinary ammonium excretion (insulin resistance or gout), increased endogenous acid production (insulin resistance, metabolic syndrome, or exercise-induced lactic acidosis), increased acid intake (high animal protein intake), or increased base loss (diarrhoea) [563].

Ammonium urate stones are extremely rare, comprising < 1% of all types of urinary stones. They are associated with UTI, malabsorption (inflammatory bowel disease and ileostomy diversion or laxative abuse), potassium deficiency, hypokalaemia and malnutrition. Suggestions on uric acid and ammonium urate nephrolithiasis are based on level 3 and 4 evidence.

4.7.1.Diagnosis

Figure 4.5 shows the diagnostic and therapeutic algorithm for uric acid and ammonium urate stones. Blood analysis requires measurement of creatinine, potassium and uric acid levels. Urinalysis requires measurement of urine volume, urine pH profile, specific weight of urine, and uric acid level. Urine culture is needed in the case of ammonium urate stones.

4.7.2.Interpretation of results

Uric acid and ammonium urate stones form under completely different biochemical conditions. Acidic arrest (urine pH constantly < 5.8) promotes uric acid crystallisation.

Hyperuricosuria is defined as uric acid excretion > 4 mmol/day in adults or > 0.12 mmol/kg/day in children. Hyperuricaemia may be present, but there is only weak evidence for its association with stone formation [564].

Hyperuricosuric calcium oxalate stone formation can be distinguished from uric acid stone formation by urinary pH, which is usually > 5.5 in calcium oxalate stone formation and < 5.5 in uric acid stone formation and occasional absence of hyperuricosuria in patients with pure uric acid stones [565,566]. Ammonium urate crystals form in urine at pH > 6.5, high uric acid concentration when ammonium is present serves as a cation [567-569].

4.7.3.Specific treatment

General preventive measures are recommended for fluid intake and diet. Hyperuricosuric stone formers benefit from purine reduction in their daily diet. Figure 4.5 describes pharmacological treatment [22,480,562,563,565-574]. For uric acid stones, allopurinol may change the stone composition distribution in patients with gout to a pattern similar to that in stone formers without gout [575].

Figure 4.5: Diagnostic and therapeutic algorithm for uric acid- and ammonium urate stones

1 d: day.
2 tid: three times a day.
3 A higher pH may lead to calcium phosphate stone formation.
4 In patients with high uric acid excretion, allopurinol may be helpful.

4.7.4.Summary of evidence and guidelines for the management of uric acid- and ammonium urate stones

4.8.Struvite and infection stones

All infection-stone formers are deemed at high risk of recurrence. Struvite stones represent 2-15% of the stones sent for analysis. Stones that contain struvite may originate de novo or grow on pre-existing stones, which are infected with urea-splitting bacteria [576]. There are several factors predisposing patients to struvite stone formation (Table 4.9) [577].

4.8.1.Diagnosis

Blood analysis requires measurement of creatinine, and urinalysis requires repeat urine pH measurements and urine culture.

4.8.2.Interpretation

Infection stones contain the following minerals: struvite and/or carbonate apatite and/or ammonium urate. Urine culture typically provides evidence for urease-producing bacteria, which increase ammonia ions and develop alkaline urine (Table 4.10). Carbonate apatite starts to crystallise at a urine pH level of 6.8. Struvite only precipitates at pH > 7.2 [578,579]. Proteus mirabilis accounts for more than half of all urease-positive UTIs [580,581].

4.8.3.Specific treatment

General preventive measures are recommended for fluid intake and diet. Specific measures include complete surgical stone removal [577], short- or long-term antibiotic treatment [582], urinary acidification using methionine [529] or ammonium chloride [583], and advice to restrict intake of urease [584,585]. For severe infections, acetohydroxamic acid may be an option [584,585] (Figure 4.6); however, it is not licensed/available in all European countries.

Eradication of infection after complete stone removal is desirable. The evidence regarding the duration of post-operative antibiotic administration is inconclusive.

4.8.4.Summary of evidence and guidelines for the management of infection stones

Table 4.9: Factors predisposing to struvite stone formation

Table 4.10: Most important species of urease-producing bacteria

Figure 4.6: Diagnostic and therapeutic algorithm for infection stones

1 Discussed with uric acid stones.
^* When nationally available.
bid = twice a day; tid = three times a day; AHA = acetohydroxamic acid.

4.9.Cystine stones

Cystine stones account for 1-2% of all urinary stones in adults and 6-8% of the stones reported in paediatric studies [32,586]. All cystine stone formers are deemed at high risk of recurrence.

4.9.1.Diagnosis

Blood analysis includes measurement of creatinine, and urinalysis includes measurement of urine volume, pH profile, specific weight, and cystine.

Interpretation

• Cystine is poorly soluble in urine and crystallises spontaneously within the physiological urinary pH range.
• Cystine solubility depends strongly on urine pH: at pH 6.0, the limit of solubility is 1.33 mmol/L.
• Routine analysis of cystine is not suitable for therapeutic monitoring.
• Regardless of phenotype or genotype of the cystinuric patient, the clinical manifestations are the same [587].
• There is no role for genotyping patients in the routine management of cystinuria [588,589].
• Reductive therapy targets the disulphide binding in the cysteine molecule. For therapy monitoring, it is essential to differentiate between cystine, cysteine and drug-cysteine complexes. Only high-performance liquid chromatography (HPLC)-based analysis differentiates between the different complexes formed by therapy.
• Diagnosis is established by stone analysis. The typical hexagonal crystals are detectable in only 20-25% of urine specimens from patients with cystinuria [590].
• The cyanide nitroprusside colorimetric qualitative test detects the presence of cystine at a threshold concentration of 75 mg/L, with a sensitivity of 72% and specificity of 95%. False-positive results in patients with Fanconi’s syndrome, homocystinuria, or those taking various drugs, including infection stones [591].
• Quantitative 24-hour urinary cystine excretion confirms the diagnosis in the absence of stone analysis.
• Levels above 30 mg/day are considered abnormal [592,593].

4.9.2.Specific treatment

General preventative measures for fluid intake and diet are recommended. A diet low in methionine may theoretically reduce urinary excretion of cystine; however, patients are unlikely to comply sufficiently with such a diet. A restricted intake of sodium is more easily achieved and is more effective in reducing urinary cystine. Patients are usually advised to avoid sodium consumption > 2 g/day [594]. A high level of diuresis is of fundamental importance, aiming for a 24-hour urine volume of > 3 L [587,590,594,595]. A considerable fluid intake evenly distributed throughout the day is necessary.

4.9.2.1.Pharmacological treatment of cystine stones

The main therapeutic option for avoiding cystine crystallisation is to maintain urine pH > 7.5, to improve cysteine solubility and ensure appropriate hydration with a minimum of 3.5 L/day in adults, or 1.5 L/m2 body surface area in children [587,590,594,595].

Free cystine concentration can be decreased by reductive substances, which act by splitting the disulphide binding of cysteine.

Tiopronin is currently the best choice for cystine reduction. However, side effects often lead to treatment termination, for example when nephrotic syndrome develops or when there is poor compliance, especially with long-term use. After carefully considering the risk of early tachyphylaxis, put into place a dose-escape phenomenon for long-term use, and recurrence risk, tiopronin is recommended at cystine levels > 3.0 mmol/day or in the case of recurring stone formation, notwithstanding other preventive measures [587,590,594,595].

Figure 4.7: Metabolic management of cystine stones

4.9.3.Summary of evidence and guidelines for the management of cystine stones

4.10.2,8-Dihydroxyandenine stones and xanthine stones [22]

All 2,8-Dihydroxyadenine and xanthine stone formers are considered to be at high risk of recurrence. Both stone types are rare. Diagnosis and specific prevention are similar to those for uric acid stones.

4.10.1.2,8-Dihydroxyadenine stones

A genetically determined defect of adenine phosphoribosyl transferase causes high urinary excretion of poorly soluble 2,8-Dihydroxyadenine. High-dose allopurinol or febuxostat are important options, but should be given with regular monitoring [596].

4.10.2.Xanthine stones

Patients who form xanthine stones usually show decreased levels of serum uric acid. There is no available pharmacological intervention.

4.10.3.Fluid intake and diet

Recommendations for general preventive measures apply. Pharmacological intervention is difficult; therefore, high fluid intake ensures optimal specific weight levels of urine < 1.01. A purine-reduced diet decreases the risk of spontaneous crystallisation in urine.

4.11.Drug stones [515]

Drug stones are induced by pharmacological treatment [597] (Table 4.10). Two types exist:

• stones formed by crystallised compounds of the drug;
• stones formed due to unfavourable changes in urine composition under drug therapy.

Table 4.11: Compounds that cause drug stones

4.12.Matrix Stones

Pure matrix stones are extremely rare with less than 70 cases described in the literature. They are more prevalent in females. The main risk factors are recurrent UTIs, especially due to P. mirabilis or E. coli, previous surgery for stone disease, chronic renal failure and haemodialysis. Complete endourological removal, frequently via the percutaneous approach, is critical. Given the rarity of matrix calculi a specific prophylactic regimen to minimise recurrence cannot be recommended. Eliminating infections and prophylactic use of antibiotics are most commonly proposed [598].

4.13.Unknown stone composition [16]

An accurate medical history is the first step towards identifying risk factors as summarised below (see Chapter 4.13.1).

Diagnostic imaging begins with US examination of both kidneys to establish whether the patient is stone free. Stone detection by US should be followed by KUB and unenhanced multislice CT in adults to differentiate between calcium-containing and non-calcium stones.

Blood analysis demonstrates severe metabolic and organic disorders, such as renal insufficiency, HPT or other hypercalcaemic states and hyperuricaemia. In children, hyperoxalaemia should additionally be screened for.

Urinalysis is performed routinely with a dipstick test as described above. Urine culture is required if there are signs of infection. Constant urine pH < 5.8 in the daily profile indicates acidic arrest, which may promote uric acid crystallisation. Persistent urine pH > 5.8 in the daily profile indicates RTA, if UTI is excluded [559,560].

Microscopy of urinary sediment can help to discover rare stone types, because crystals of 2,8-Dihydroxyadenine, cystine and xanthine are pathognomonic for the corresponding disease. In cases in which the presence of cystine is doubtful, a cyanide nitroprusside colorimetric qualitative test can be used to detect the presence of cystine in urine, with a sensitivity of 72% and specificity of 95%. False-positive results are possible in patients with Fanconi’s syndrome or homocystinuria, or in those taking various drugs, including ampicillin or sulfa-containing medication [591,599].

Following this programme, the most probable stone type can be assumed and specific patient evaluation can follow. However, if any expulsed stone material is available, it should be analysed by diagnostic confirmation or correction.

4.13.1.Recommendations for investigations for the assessment of patients with stones of unknown composition [16,22,64,515]

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6.CONFLICT OF INTEREST

All members of the Urolithiasis Guidelines Panel have provided disclosure statements of all relationships that they have that might be perceived as a potential source of a conflict of interest. This information is publicly accessible through the European Association of Urology website: http://www.uroweb.org/guidelines/. This guidelines document was developed with the financial support of the European Association of Urology. No external sources of funding and support have been involved. The EAU is a non-profit organisation and funding is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements have been provided.

7.CITATION INFORMATION

The format in which to cite the EAU Guidelines will vary depending on the style guide of the journal in which the citation appears. Accordingly, the number of authors or whether, for instance, to include the publisher, location, or an ISBN number may vary.

The compilation of the complete Guidelines should be referenced as:

EAU Guidelines. Edn. presented at the EAU Annual Congress Amsterdam 2020. ISBN 978-94-92671-07-3.

If a publisher and/or location are required, include:

EAU Guidelines Office, Arnhem, The Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/.

References to individual guidelines should be structured in the following way:

Contributors’ names. Title of resource. Publication type. ISBN. Publisher and publisher location, year.