REVIEWS Ureteral stent-associated complications —where we are and where we are going Dirk Lange, Samir Bidnur, Nathan Hoag and Ben H. Chew Abstract | Ureteral stents are one of the most commonly used devices in the treatment of benign and malignant urological diseases. However, they are associated with common complications including encrustation, infection, pain and discomfort caused by ureteral tissue irritation and possibly irregular peristalsis. In addition, stent migration and failure due to external compression by malignancies or restenosis occur, albeit less frequently. As these complications restrict optimal stent function, including maintenance of adequate urine drainage and alleviation of hydronephrosis, novel stent materials and designs are required. In recent years, progress has been made in the development of drug-eluting expandable metal stents and biodegradable stents. New engineering technologies are being investigated to provide stents with increased biocompatibility, decreased susceptibility to encrustation and improved drug-elution characteristics. These novel stent characteristics might help eliminate some of the common complications associated with ureteral stenting and will be an important step towards understanding the behaviour of stents within the urinary tract. Lange, D. et al. Nat. Rev. Urol. advance online publication 23 December 2014; doi:10.1038/nrurol.2014.340

Introduction

Since the introduction of the modern-day double‑J u­reteral stent in 1978 by Finney et al.,1 ureteral stenting has become one of the most commonly performed procedures in urology. Stents are typically used to assist in the treatment of urolithiasis, to relieve benign or malignant obstruction, to promote ureteral healing, manage urinary leak, or are placed preoperatively to aid in intraoperative ureteral identification. However, despite their extensive use throughout urology, these indispensable urological tools are fraught with a wide array of complications, of which infection, encrustation and patient discomfort are the most common. A comprehensive understanding of common and uncommon complications is required to identify how stent design and clinical stent use can be improved. This Review provides an overview of stent-associated complications and discusses novel stent designs that are currently being developed in an attempt to overcome these complications and improve overall stent function and patient treatment.

Stent-associated complications

The Stone Centre at Vancouver General Hospital, Department of Urologic Sciences, University of British Columbia, Jack Bell Research Centre, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada (D.L., S.B., N.H., B.H.C.). Correspondence to: D.L. [email protected]

Stent discomfort The most common adverse effect of both acute and chronic stenting is stent-related discomfort. To better understand the scope of this problem, Joshi and colleagues developed and validated the Ureteral Stent Symptom Questionnaire (USSQ) to characterize and quantify stentrelated patient discomfort when using stents for the treatment of urolithiasis and nonmalignant obstruction.2 Their Competing interests D.L. and B.H.C. declare consulting associations with Bard Medical, Boston Scientific, Cook Medical, Olympus and PercSys. S.B. and N.H. declare no competing interests.

three-part study in 309 patients identified 38 items across six major health domains that were affected by stent use, including urinary symptoms, body pain, general health, work performance, sexual health and additional problems. This study was the first to gauge the scope of the problem and provide a standardized questionnaire, showing that >80% of patients who are stented for benign disease experi­ence irritative voiding symptoms, as well as pain and discomfort that is not restricted to the urinary tract but involves the whole body, addressing factors that can significantly impact daily functioning.2 In a later study, the USSQ also identified positioning of the distal stent loop within the bladder as a cause for stentassociated discomfort: patients in whom the distal loop crossed the bladder midline had the strongest association with five of six domains of the USSQ at both 7 days and 28 days after stent insertion.3 A subsequent randomized trial investigating location of the distal stent pigtail showed that excessive stent length in the bladder contributed to severe dysuria, urgency and more impaired quality of life than correct stent length.4 Pain often worsens during mictur­ition and can radiate to the ipsilateral flank secondary to ureteral pressure reflux and stent movement, both of which act via different mechanisms.5,6 Indwelling stents were previously shown to move as much as 2 cm within the urinary tract during normal daily activities, resulting in physical irritation and inflammation of the urothelium at the location of the stent curls in the bladder and kidney, likely resulting in additional pain and discomfort.4,5 Future research efforts should, therefore, focus on the development of stent designs and/or biomaterials that cause less irritation, especially since stent movement cannot be avoided.

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REVIEWS Key points ■■ Ureteral stents are associated with complications including infection, encrustation, haematuria and discomfort that can be caused by tissue irritation ■■ The role of bacterial adhesion and biofilm formation on stents in stent-associated UTIs is unclear and development of UTIs and their treatment might depend on patient immune status ■■ Encrustation and calcification are common problems that can lead to severe complications, which can be prevented by implementing electronic systems to monitor stent dwell times ■■ Metal stents are a good alternative to polymer stents in the treatment of extrinsically caused ureteral obstruction; flexible and drug-eluting metal designs could help ameliorate discomfort and stenosis, respectively ■■ Biodegradable ureteral stents could avoid complications, such as encrustation, but flaws in their biocompatibility still need to be addressed ■■ Future stent design will focus on biodegradable and metal stents that elute drugs to prevent complications and are engineered to treat specific urological conditions

Ureteral aperistalsis It has been widely accepted that indwelling stents affect ureteral peristalsis by triggering a period of hyperperistalsis, in which the ureter attempts to expel the stent (a partial obstruction), shortly after stent insertion and eventual cessation of peristaltic activity.7,8 Whether or not this aperistaltic state in itself might cause pain and discomfort is unknown and warrants additional investigation, especially given the fact that urine drainage from the kidneys in the absence of peristalsis is slow, likely explaining the mild ipsilateral hydronephrosis observed after stenting. Interestingly, however, the administration of selective α‑blockers such as tamsulosin, which inhibits ureteral contractility and decreases peak ureteral contraction pressures both in vitro and in vivo, effectively decreases patient pain and urinary symptoms.9–13 Similarly, alfuzosin was shown to improve urinary symptoms and body pain, with noted benefit on voiding and flank pain.14,15 It is unclear whether the symptom relief provided by α‑blockers is due to the prevention of ureteral peristalsis by inhibiting contraction or due to the restoration of peristalsis by relaxing the continuously contracted (cramped) state of the ureteral smooth muscle caused by the indwelling stent. If the latter is true, maintenance of ureteral peristalsis when a stent is in place might be beneficial and also alleviates residual h­ydronephrosis caused by the previous aperistalsis. Further research into this area is needed to better understand whether ureter-associated aperistalsis is a favourable consequence of stenting or whether maintaining peristalsis while a stent is in place would improve overall stent function. Stent migration Stent migration, especially of the distal end, and stent expulsion are not uncommon even with an appropriately positioned stent. Multiple factors have a role in facilitating stent movement within the urinary tract, including stent length and material, as well as stent diameter with 4.8 Fr silicone stents demonstrating increased distal migration compared with 6 Fr polyurethane stents.16–18 Patient-related factors include stent dwell time and renal movement with respiration, but further characterization

of these factors is needed. Although appropriate stent length is often determined based on the patient’s height, studies suggest that radiographic assessment of the distance between the ureteropelvic and ureterovesicular junction is more appropriate and associated with a lower frequency of distal migration.19 Distal stent migration can abrogate the benefits of stenting and worsen stent-related symptoms; however, it can be easily rectified using cystoscopy. A greater challenge is the less common proximal stent migration, with docu­mented incidences of 1–4.2%.20,21 Salvage of proximal migration requires retrograde stent retrieval via uretero­scopy and use of a stone basket or Fogarty catheter to enable stent capture with a success rate >90% when the distal stent end is below the pelvic brim. 22 Special cases of proximal migration include proximal displacement above the pelvic brim, migration above a stricture or a recent operative repair. In these instances, a percutaneous approach might be more successful than retrograde stent retrieval.23

Stent-induced UTIs Bacterial colonization of indwelling ureteral stents is an important problem—colonization rates of 42–90% have been reported.24,25 Although bacteria are capable of interacting and adhering to the bare stent surface, such direct interaction is unlikely to be the main mechanism driving bacterial adhesion and colonization. Deposition of a urinary conditioning film that changes the physical surface characteristics of indwelling urinary devices is well documented.26–28 Bacteria express proteins called adhesins that recognize and bind proteins that form a major part of the urinary conditioning film.29 It has long been hypothesized that the presence of this conditioning film increases bacterial adhesion and biofilm formation. In 2013, Elwood et al.28 tested this hypothesis and observed no difference in the adhesion and colonization of uropathogenic Escherichia coli and Staphylococcus aureus Newman between unconditioned stents and stents from patients containing a conditioning film. Although these findings refute the hypothesis that the conditioning film increases bacterial adhesion and colonization, they also indicate that preventing deposition of the film does not stop adhesion and colonization, as bacteria seem to interact just as well with a bare stent surface. Interestingly, despite the fact that the incidence of stent colonization can exceed 90%, only a subset of patients with positive stent cultures develop symptomatic UTIs, the incidence of which increases when indwelling time exceeds 90 days.30 In a large consecutive case series in 250 patients, urine cultures before and after stent insertion, as well as distal stent tip cultures, demonstrated that stent dwell time and systemic diseases, including diabetic nephropathy and chronic kidney disease (serum creatinine 200–500 μmol/l) without dialysis, were significantly associated with bacteriuria and stent colonization.31 Given the increased risk of UTIs, the authors recommend shortening of stent dwell times and antimicrobial prophylaxis for high-risk patients. However, in this context, it must be considered that patients with systemic

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REVIEWS disease have a high risk of carrying antibiotic-resistant bacterial strains, owing to prior antimicrobial therapy. Hence, the most effective antibiotic prophylaxis protocol has to be patient-specific and must be designed with careful consider­ation of the patient’s medical history and p­revious antibiotic use. Currently, urine culture is the most frequently used method to determine stent colonization and infection status while the stent is indwelling. However, a negative urine culture result does not necessarily rule out colonization of the stent, as the sensitivity of urine culture for detection of stent colonization is only 21–40%32 and increases with longer dwell times.30 The fact that the rate of positive urine cultures, despite positive stent cultures, is relatively low for short dwell times indicates that the source of stent colonization is not infected urine, but rather contamination of the stent during the insertion procedure. Furthermore, the bacterial species isolated from the urine is frequently not the same as that found on the stent. Species found on the stent can be highly variable, dependent on the section of the stent examined. This finding illustrates the fact that, similarly to biofilms found on Foley catheters, the films found on ureteral stents are often composed of multiple gram-positive and gram-negative species, rendering antibiotic therapy based on a single urinary isolate ineffective.

Stent encrustation Similarly to bacterial colonization, stent encrustation increases with dwell time. In patients with stents placed for urolithiasis, encrustation occurs in 9.2% of stents removed under 6 weeks, 47.5% of stents removed between 6 weeks and 12 weeks, and 76.3% of stents removed after 12 weeks. 20 Although the amount of encrustation tends to be worse on the proximal and distal pigtails, the section within the ureteral lumen is usually clear or the last to encrust, presumably because of the ‘wiping’ effect of ureteral peristalsis and the fact that the curls are constantly in contact with urine in the kidney and bladder.33 The complexity of the encrustation process is exemplified by the fact that, despite the use of a variety of materials with different physical characteristics, none of them are resistant to crystal deposition and eventual encrustation. Of all materials available, silicone is least prone to struvite and hydroxyapatite encrustation.29,34–36 It must be pointed out, however, that the degree to which a specific material encrusts is highly dependent on the experimental setup used. Often, companies assert antiencrustation characteristics of materials based on results from simple in vitro tests that do not recapitulate the conditions that materials are exposed to in patients. While simple in vitro experiments are certainly valid to identify promising materials and/or coatings that might resist encrustation, actual claims about their function in the clinical setting should only be based on results from relevant in vivo animal models or clinical trials. Although the exact mechanism of stent encrustation is not well understood, encrustation is believed to occur secondary to formation of a urinary conditioning film on the

stent surface. Conditioning film formation begins with the adsorption of urinary proteins onto the stent bio­material, generally via electrostatic interactions. Interestingly, as encrustation is not instantaneous, the hydrophilic surface coat of most stents that comes off shortly after stent insertion might be preventing the formation of a mature conditioning film during that time. Hence, continuously changing physical character­istics of the stent surface might be beneficial in the prevention of c­onditioning film d­eposition and resultant encrustation. One study showed that the encrusting material from stents has the same chemical composition as a concurrent stone.37 This stands to reason, as the stents are bathed in the same urine that is supersaturated with the same components that led to stone formation. Whether the crystals interact and adhere directly to the stent materi­al or whether they attach more firmly by interacting with components of the urinary conditioning film is unclear. Two studies have examined the conditioning film components found on the surface of encrusted and non­encrusted stents.38,39 Overall, the researchers identified over 300 unique proteins on the surface of these stents. Ig κ, IgH G1, α1 antitrypsin, as well as histones H2b and H3a were highly associated with stent encrustation, whereas uromodulin and histone H2a had a marginal association. The authors hypothesized that the net positive charge of these proteins might contribute to attracting negatively charged crystals and drive encrustation. Investigators of a second study proposed a different mechanism, after observing that stent condition­ing films contained calcium-binding proteins, including uro­modulin and S‑100 proteins. These proteins might enable calcium-­ containing crystals to attach to stent surfaces.28 In addition, the same study also found blood proteins, such as serum albumin, globulin and fibrinogen, which are known to interact with hydroxyapatite via electrostatic interactions, in stent conditioning films, r­epresenting another possible nidus for stent encrustation. Although the process of encrustation is highly prevalent even with modest dwell times (2 years, which usually only occur with forgotten stents. Grade IV and grade V encrustation often require multiple (1.94–2.70) procedures to remove the heavily encrusted stent.40

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REVIEWS a

Double-J stent

Guidewire

Ureteral lumen

Remove guidewire

c

Self-expandable Memokath® 051 stent Guidewire

Access sheath

Remove guidewire

Insertion system

Stent positioned in lumen of ureter Remove access sheath

b

Overcoming complications

Balloon-expandable stent

Expand balloon

The same authors note increased success in complete stent removal by freeing the stone burden associated with the distal aspect of the stent before the proximal section. Several authors have suggested a preoperative renogram to determine the function of the affected renal unit, as a severely encrusted stent within a poorly functioning renal unit might be best treated with n­ephroureterectomy and open cystolitholapaxy.33,42 Stents of grade IV and grade V in the FECal grading system are the almost inevitable consequence of prolonged dwell times—situations that typically arise when patients fail to attend follow-up visits for stent removal. Such circumstances cause considerable morbidity to the patient, especially in the long-term setting. To reduce the incidence of grade IV and grade V FECal stent encrustation, several groups have advocated the use of electronic stent registries (ESRs) that link stent information, including the date of insertion and proposed removal date, to the patient’s electronic medical record (EMR). The ESR should prompt the physician before scheduled removal and provide frequent reminders if no record of stent change or removal is logged in the EMR.43 One such system substantially decreased the incidence of forgotten stents from 12.5% to 1.5% over the course of 1 year making a strong case for the implementation of such systems into urological practice.43

Insert 20 ml sterile fluid at 65 ºC

Deflate and remove balloon

Expands to anchor in place

Reviews | Urology Figure 1 | Appearance and insertion of metal stents studiedNature for use in the ureter. a | Double-J stents can be made of metal or plastic and are most commonly inserted with the help of a pusher and a metal guidewire. They sit in the centre of the lumen. b | Balloon-expandable stents are placed with the help of an inflatable plastic balloon. After removal of the balloon, the stent is in direct contact with the lumen. c | Placement of the self-expandable Memokath®051 stent requires the use of a guidewire, access sheath and insertion system. Once in position, it is expanded to be in direct contact with the lumen by flushing with heated sterile fluid.

Metal stents to prevent external compression To overcome drawbacks of polymeric ureteral stents, including the need for periodic stent changes or stent obstruction and failure owing to external compression, metal-based stents have been developed (Figure 1). These stents can have various configurations including selfexpandable and conventional double‑J stents (Table 1). One of the double‑J metal stents is the Resonance® (Cook Medical, USA) stent, which is occluded at both ends and consists of tight coils of nickel–cobalt–­chromium–­ molybdenum alloy. 44 In 2013, one study reported the 5‑year experience with the Resonance® stent in a cohort of 47 patients involving 139 metallic stent placements for the treatment of chronic ureteral obstruction for both malignant and benign disease, which represents one of the most robust reports on the use of metal stents.45 The average dwell time was 8 months with a 28% failure rate owing to pain, progressive renal insufficiency, recurrent UTI, stent migration, progressive hydro­nephrosis, haema­turia, lower urinary tract symptoms and/or encrustation. Despite complications in both patient populations, adequate stent functioning was noted for the majority of patients, indicating that the use of metal stents is a­ppropriate for both benign and malignant disease. Apart from studies of double‑J stents, long-term follow-up studies of self-expandable metal stents have recently been published. In 2009, an 11-year follow-up study report of the use of a thermo-expandable metallic stent called Memokath®051 (Pnn Medical, Denmark) described data from 74 insertions in 55 patients.46 Despite complications including stent migration, encrustation and fungal infections, the authors concluded that

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REVIEWS Table 1 | Characteristics of selected metal ureteral stents Name

Material

Structure

Deployment

Resonance® (Cook Medical, USA)

Nickel–cobalt–chromium– molybdenum alloy

Tightly coiled metal wire with conventional kidney and bladder curls that are occluded

Through 8 Fr outer sheath

Silhouette® (Applied Medical, USA)

Polyurethane and metal

Polymer stent reinforced by metal wire coils

Guidewire and pusher

Passage™ (Prosurg, USA)

Metal Gold-plated metal (Snake stent)50

Spiral windings along a tubular coil structure configured with flexible, curved pigtails

Guidewire and pusher

Memokath®051 (Pnn Medical, Denmark)

Nickel–titanium alloy

Bare metal stent with a closed spiral shape and a fluted end for anchoring

Thermo-expandable, introduced inside an access sheath

Allium Ureteral Stent (Allium Medical, Israel)

Metal and polymer

Metal structure with self-radial-expanding design covered with a thin layer of polymeric material

10 Fr deployment device

Double‑J stents

Self-expandable stents

this novel self-expandable metal stent offered effective and durable long-term relief from ureteric obstruction and seemed to be a safe alternative to c­onventional double‑J stents. Similarly, in 2009, another study reported the 10-year experience of implantation of self-expandable metal mesh stents in 90 patients to treat malignant ureteral obstruction.47 The most common complications included stent migration, hyperplastic reaction and/or encrustation or tumour ingrowth. Interestingly, in several cases, secondary interventions did not ensure patency, resulting in the need for insertion of a double‑J or external-internal stent. The authors concluded that metal mesh stents provide long-term decompression of the upper urinary tract in the presence of extrinsic ureteral obstruction only in select cases. In contrast to self-expandable metal stents, studies using balloon-expandable metal stents are rare. One study in 12 patients with malignant ureteral obstruction found both balloon-expandable (n = 6) and self-­expandable (n = 6) stents to be safe and effective, with 11 out of a total of 14 ureters remaining patent over the follow-up period of 8–16 months (average 9 months).48 In another study in nine patients with malignant or benign u­reteral obstruction, a balloon-expandable stent (n = 1) was compared with self-expandable stents (n = 8).49 Overall, ureteric patency was maintained in all patients without complications. The authors concluded that the use of metal stents, such as those tested, is a safe and effective alternative to conventional double‑J stents. To date, longterm studies testing the effectiveness of these stents in the ureters of a large number of patients have not been performed and would be required before suggesting their potential use in the treatment of ureteral obstruction.

Novel metal stent designs Research into ureteral stent design is focused on the dev­ elopment of novel stents that overcome the most common complications associated with metal and polymer u­reteral stents discussed above. Receiving the most attention and showing the most promise are more flexible and drug-­eluting metal stents, as well as stents made of b­iodegradable material designed to dissolve over time.

Flexible metal stents One area of development focuses on improving the comfort of metal stents. Designs are changed to make stents more flexible, allowing them to adjust to the shape of the ureter as the patient moves. The recently developed Passage™ (Prosurg, USA) stent is a metallic coil stent with a spiral–coiling configuration that allows for both increased flexibility and durable radial compression.50 The Snake stent is a goldplated metallic version of the Passage™ stent. Unlike the Resonance®stent, which is tightly wound around a stainless steel guidewire, the Passage™ and Snake stents are less tightly wound and are open at both ends50— characteristics that might make them more flexible and possibly more comfortable for patients in comparison with the Resonance®stent. One study demonstrated that the Passage™ and Snake stents had much lower tensile strength and higher resistance to radial compression than the Resonance®and Silhouette®(Applied Medical, USA) stents.50 Low tensile strength is an important factor for patient comfort as well as prevention of stent migration.51 High resistance to extrinsic radial compression is important for preventing obstruction from tumour ingrowth or stent compression. Interestingly, polymer coating on the 7 Fr Snake stent increased its tensile strength above versions that lacked this coating but decreased the resistance to radial compression despite the presence of this polymer sheath.50 This finding suggests that stent thickness is a more determinant factor for high compressive strength than the configuration or design of the stent. The authors hypothesized that in situations when a metal stent is placed for alleviation of extrinsic ureteral obstruction a 6 Fr stent might be more effective than a larger 7 Fr stent. Whether novel, more-flexible metal stent designs improve overall patient comfort remains to be seen, as clinical trials are still outstanding. Drug-eluting metal stents
 In an effort to overcome complications associated with metal stents, such as restenosis, some progress has been made in the development of drug-eluting self-­ expandable metal ureteral stents. Similar stents are

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REVIEWS already used in other medical specialties, mainly in the management of coronary and vascular diseases, to prevent lumen resteno­sis.52,53 In preclinical and clinical tests, drug-eluting conventional double‑J ureteral stents have demonstrated limited effectiveness,54–56 possibly because of limited drug delivery to the ureteral tissues. Drug delivery via self-expandable stents similar to those used in cardiology might also be more effective than via ordinary metal stents in the ureter, as they expand to act as a mechanical scaffold enabling drug release in very close proximity to the tissue.53 The first study to test the efficacy of a paclitaxel-eluting metal mesh stent in the porcine ureter found that, 21 days after insertion, the majority of bare metal stents were occluded or stenosed by hyperplastic reaction, whereas the ureters containing a drug-eluting stent remained patent.57 In another study using porcine and rabbit models, a zotarolimuseluting metal stent prevented ureteral occlusion over an 8‑week dwell time compared with bare metal stents.58 Collectively, both studies make a convincing case for the use of expandable drug-eluting metal stents for the prevention of ureteral obstruction caused by stentinduced tissue hyperplasia. Considering that the majority of metal stents are placed to treat malignant obstruction of the ureter, future studies need to evaluate the efficacy of these stents in a similar setting, as malignant tissue might not respond in the same way as healthy tissue. Further­ more, the effect of expanding stents on ureteral physio­ logy and function should also be investigated, as expanding stents, unlike double‑J stents, push into the ureteral wall and interact directly with tissue, resulting in potential damage and/or ureteral dysfunction.

Biodegradable stent materials One of the most appealing stent designs with a high potential to overcome several stent-associated complications are biodegradable stents. In comparison with absorbable stents, which ameliorate patient morbidity associated with secondary procedures to remove polymer stents or forgotten stents, an added benefit of biodegradable stents is the fact that the physical character­istics of the biodegradable stent surface are constantly changing as the stent degrades, possibly decreasing bacterial interaction and adhesion, conditioning film deposition and encrustation. Furthermore, degradable stents might be beneficial for patient comfort as the material might be softer. Other possible advantages include an early degradation of the bladder coil, preventing bladder irritation and vesicoureteric reflux during voiding. Several materials have been used in the development of degradable ureteric stents, including polyglycolic acid, polylactic acid, poly(lactic-co-glycolic acid) and alginate-based materials.39,59–62 Early concepts of bio­ degradable stents involved the idea that degradation could be controlled by pharmacologically changing urine pH, triggering degradation following the desired dwell time.63,64 In vitro studies in artificial urine showed that at a pH 7.63,64 Although changing urinary pH might be an attractive way to control stent degradation, the

applicability of this method might be limited because variations in urinary pH could result in additional crystallization in an environment that might already be supersaturated. Preclinical studies Other stents based on polylactic acid and poly(lactic-coglycolic acid) have shown some promise in early-stage animal models, but have not been developed further to date.39 For example, in two studies, degradable polylactic acid stents had favourable drainage characteristics and antireflux properties, but degradation and biocompatibility were insufficient.65,66 By contrast, in a canine model such stents completely dissolved by 12 weeks and had good biocompatibility compared with a biostable plastic stent.67 In addition, a polylactic acid stent was effective in preventing hydronephrosis in a canine model of b­allistically induced ureteral injury.68 A poly(lactic-co-glycolic acid)-based stent tested in a porcine model following endopyelotomy demonstrated favourable radiographic and flow character­istics, but insufficient biocompatibility precluded further develop­ ment and use.39 Another study demonstrated no compli­ cations with the use of a poly(lactic-co-glycolic acid) horn stent after antegrade endopyelotomy.69 In a porcine model, a shortened helical spiral stent based on the same material demonstrated superior drainage and better antireflux properties than a standard double‑J stent, but biocompatibility was not specifically tested.70 Clinical studies and current developments One of the most extensive clinical evaluations of a bio­ degradable stent was performed on a proprietary alginate-­ polymer-based temporary ureteral drainage stent. In phase I and phase II clinical trials this stent facilitated urinary drainage, and demonstrated favourable tolerability and safety profiles.62,71 The stent was designed to last at least 48 h before degradation, but insufficient fragmentation and dissolution rates resulted in the need for secondary procedures to remove fragments in some patients. Median time to stent degradation was 15 days. Three patients retained fragments >3 months, requiring extra­corporeal shockwave lithotripsy and ureteroscopic manipulation for removal. Although these complications prevented further commercial development for fear that retained fragments might serve as nidi for further stone formation, much has been learned about the use of b­iodegradable materials in the urinary tract from this study. To date, the biodegradable ureteral stent showing most promise has been the Uriprene stent (Poly-Med, USA), which is constructed from a radiopaque, glycolic-lactic acid formula. One of the novelties of this stent is the fact that it has been designed to degrade in the distal (bladder coil) to proximal (renal coil) direction to prevent ureteral obstruction secondary to degrading stent fragments. Furthermore, the distal to proximal degradation should minimize the amount of time the renal coil is crossing the ureterovesical junction, potentially minimizing bladder symptoms and preventing vesicoureteric reflux and improving flank comfort during voiding.

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REVIEWS In vivo studies of the first generation Uriprene stent in a porcine model demonstrated its stability and bio­ compatibility before beginning to degrade at 4 weeks, with all stents having completely degraded in a predictable manner by 7–10 weeks.72 Further modification of the stent material resulted in favourable insertion and handling characteristics and predictable degradation by 2–4 weeks while maintaining excellent drainage and decreased incidence of hydronephrosis.61 Furthermore, the degree of inflammation was significantly lower in animals with Uriprene stents than in animals with biostable stents, suggesting that Uriprene stents are less irritative. Clinical studies testing the effectiveness and t­olerability of the final version of this stent are forthcoming. Although biodegradable stents have the potential to decrease patient morbidity, a stent that degrades within 3 weeks might not be suitable for situations that might require stenting for different durations, such as ureteric strictures or after shockwave lithotripsy. Hence, the decision to use a biodegradable stent must be made according to the clinical requirement and desired duration of stenting. Drug-eluting biodegradable designs Biodegradable stent technology is likely to have an important role in the future of ureteral stent design, as the degradable nature of these stents might be optimal to address specific clinical scenarios.59 For ureteric stents in general, several coating and eluting technologies aimed at improving biocompatibility and tolerability have been examined.54,73 Incorporating these new technologies into the design of stents made of biodegradable materials is an unexplored area. The most obvious feature to be easily incorporated is drug-eluting technology, which has been used extensively in cardiovascular applications;74 however, the use of drug-eluting biodegradable stents in urology has been limited. In 2009, a degradable prostatic urethral stent was engineered to elute a 5α-reductase inhibitor directly into the prostate in patients with BPH and urinary retention.75 Local release of the drug from the stent was thought to decrease the amount of dihydrotestosterone to help reduce prostatic volume. This study was the first to show the effectiveness of drug-eluting technology in combination with a degradable stent to provide mechanical relief from urinary obstruction secondary to prostatic enlargement.75 However, the effect was not as durable as anticipated, with approximately half of the patients requiring insertion of a suprapubic catheter before 1 month owing to acute urinary retention or comorbidities. Perhaps insertion of another stent of the same type or a higher drug dose in the stent material might avoid this complication. Tissue-engineered stents In addition to drug-elution technologies, there are multi­ ple other potential ways of engineering bio­degradable materials to address a specific clinical requirement. One study demonstrated that stents engineered using

chondro­c ytes are feasible both in vitro and in vivo, showing that autologous chondrocytes seeded onto tubular mesh composed of polyglycolic acid and poly(lactic-co-glycolic acid) might have future use as ureteric stents.76 Because the chondrocytes are autologous, such stents should have excellent biocompatibility. In vivo studies of tissue-engineered autologous-tissuecovered stents have been developed and could show promise in the treatment of cardiovascular diseases. Coating of stents with membranous autologous tissues should have a more favourable host response than conventional stents, as, after explantation, the stents contain mostly collagen and fibroblasts, indicating tissue r­emodelling rather than inflammation.77 Other considerations Some of the principles discovered through stent-­ engineering processes in other fields might find application in degradable ureteric stents in the future. For example, one study demonstrated some success with biodegradable metal stents based on magnesium for coronary artery stenting.78 Degradable materials in the blood must dissolve into inert materials that do not cause damage within the circulatory system or any organs. Fortunately, it seems that the requirements for degrad­ able materials in the urinary tract are not as stringent as for other parts of the body, as their debris will be excreted in the urine. Hence, materials can decompose into larger molecules because they should not come into contact with or cause harm to central physiological systems.

Conclusions

Although ureteral stents are associated with high morbidity, they are indispensable tools in urologic practice. Much progress has been made in designing stents that aim to overcome the most common complications, but none have been successful to date. Nevertheless, urologic stent design is an interesting and exciting field. The ideal stent will incorporate features from many of the stents engineered and tested so far. We, along with others, predict that the stent of the future might be in the form of a degradable stent engineered to be coated with and elute compounds to address not only stent-associated complications but also the specific urologic indication for its placement (that is, active stone dissolution therapy).60 Although much progress has been made with the design of materials that maintain patency and degrade in the desired time period, more research into how such designs can be modified to deliver adequate amounts of drugs to the ureteral tissue needs to be performed. Review criteria A search for original articles was performed in PubMed. No restrictions on date were used when selecting articles. The search terms used included “ureteral stents”, “stent complications”, “metal ureteral stents”, “drug-eluting ureteral stents” and “degradable ureteral stents”. The references of recent review articles were searched to identify key studies in their respective areas of ureteral‑stent-associated symptoms and biomaterial design.

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