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The Use of Internal Stents in Chronic Ureteral Obstruction
Author's Accepted Manuscript The Use of Internal Stents in Chronic Ureteral Obstruction Julia Fiuk , Yige Bao , John G. Calleary , Bradley F. Schwartz , John D. Denstedt
PII: DOI: Reference:
S0022-5347(14)04935-0 10.1016/j.juro.2014.10.123 JURO 12022
To appear in: The Journal of Urology Accepted Date: 23 October 2014 Please cite this article as: Fiuk J, Bao Y, Calleary JG, Schwartz BF, Denstedt JD, The Use of Internal Stents in Chronic Ureteral Obstruction, The Journal of Urology® (2014), doi: 10.1016/j.juro.2014.10.123. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.
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The Use of Internal Stents in Chronic Ureteral Obstruction Julia Fiuk 1†, Yige Bao2,3,4†, John G. Calleary5#†, Bradley F. Schwartz1#† and John D. Denstedt1#*†
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Division of Urology, Southern Illinois University School of Medicine, Springfield, Illinois, USA 2 Division of Urology, Department of Surgery and 3 Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry Western University, London, Canada 4 Department of Urology, West China Hospital, Sichuan University, West China School of Clinical Medicine, Sichuan University, Chengdu, China 5 Department of Urology, North Manchester General Hospital, Manchester, United Kingdom † Contributed equally to the paper
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# This topic was presented by the authors at plenary session of American Urological Association meeting held in April 2012 at Atlanta.
*Corresponding author: Dr. John D. Denstedt Division of Urology, St. Joseph’s Hospital 268 Grosvenor Street London, Ontario Canada N6A 4V2 Phone: 519-646-6036 Fax: 519-646-6037 Email: [email protected]
ACCEPTED MANUSCRIPT Abstract Purpose
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Despite lack of a well-delineated definition, chronic ureteral obstruction (CUO) imposes significant quality of life loss, increased pathologic morbidity and risk of mortality as well as substantial economic burden. Ureteral stenting serves as an important therapeutic option to alleviate the obstruction. We thus assessed the recently-published literature on chronic ureteral obstruction; treatment options; types, benefits and shortcomings of current ureteral stents; as well as outcomes and complications of chronic ureteral stenting, with the goal of providing concise management guidelines.
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Material and Methods
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A systemic literature review was performed on Embase, Pubmed, Cochrane Controlled Trials Register and Google Scholar on ureteral obstruction and internal ureteral stents. Relevant reviews, original research articles and their cited references were examined, and a synopsis of original data was generated on a clinically oriented basis.
Results
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CUO can be classified into compression is either intrinsic (IUO) or extrinsic (EUO) to the ureteral wall, or obstruction that is of a benign (BUO) or malignant origin (MUO). Patients with MUO generally have a poor prognosis and are often difficult to manage. The aim of stenting is to adequately drain the upper urinary tracts while minimizing hospitalization and negative impact on quality of life. Facing the challenge of chronic ureteral obstruction, novel stents with new compositions, materials, coatings, and designs have been developed. Metallic stents are emerging as efficacious and financially viable alternatives. Early stent-related complications include iatrogenic injury, stent migration or patient discomfort, while late complications include infection, difficulties with stent exchange, hardware malfunction, infection, and stent encrustation.
Conclusions
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Stenting in CUO is a complex and challenging problem. Much work is being done in this area and many options are explored herein.
Key Words Ureteral obstruction, ureteral stents
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Abbreviations and Acronyms
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CUO, chronic ureteral obstruction; IUO, intrinsic ureteral obstruction; EUO, extrinsic ureteral obstruction; BUO, benign ureteral obstruction; MUO, malignant ureteral obstruction; MS, metal stents; PPS, Pentosan polysulfate; PC, Phosphorylchlorine copolymer; PVP, polyvinylpyrrolidone; PTFE, polyterafluoroethylene; mPEG, methoxy-terminated polyethylene glycol; DOPA, dihydroxyphenylalanine; DLC, diamond-like carbon; DES, drug-eluting stents; UTI, urinary tract infection; UPJ, ureteropelvic junction.
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ACCEPTED MANUSCRIPT Introduction
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Since its first description by Zimskind in 1967, the ureteral stent has undergone a plethora of evolutionary changes to become the ubiquitous tool urologists use today.1 Though the stenting algorithm for relief of acute obstruction is intuitive to most, management of chronic obstruction presents a far more complicated decision making process. The term “chronic ureteral obstruction” itself lacks a well-delineated definition, either depending on an arbitrarily assigned time period or referring to the need for repeated stenting procedures where definitive treatment is not possible. The nomenclature in chronic ureteral obstruction (CUO) is further muddled by opposing classification systems, dividing disease by either anatomic location (intrinsic vs extrinsic) or etiology (benign vs malignant).
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These patients, regardless of etiology, present with obstruction of their upper urinary tracts that both symptomatically decreases quality of life and pathologically adds morbidity and potentially increases mortality.2 The goal of treatment is to improve both parameters, if only from a genitourinary standpoint. The need for such treatment options will only become more pressing as treatments for life limiting diagnoses continue to improve.
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The practitioner must consider the various success rates and complications associated with each stent type in the currently available armamentarium. Though we have come a long way from the initial straight Zimskind silicone catheter, with advances in anchoring devices, composition, and coatings, we still strive to find the ideal stent. With each new iteration, we seek to decrease stent related symptoms, difficulty with replacement, and frank stent failure; however, potential improvements must be weighed against known limitations and patient-specific factors.
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In this update we address the broad divisions in types of chronic ureteral obstruction, as well as the disease and patient specific considerations for management options. We then present the various available types of stents and compare their benefits and shortcomings. We review techniques for placement for particular stents that may be novel for some urologists, and discuss the outcomes and complications seen in the setting of treating this heterogeneous disease state.
Methods
A systemic literature review was performed on Embase, Pubmed, Cochrane Controlled Trials Register and Google Scholar . Keywords included “ureteral obstruction” and “internal ureteral stents”. Relevant reviews, original research articles and their cited references were examined, and a synopsis of original data was generated on a clinically oriented basis.
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ACCEPTED MANUSCRIPT CUO: Cause, Prognosis and Management Options
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Two classification systems are generally used to describe the etiology of chronic ureteral obstruction (CUO). The first relates to the anatomic relationship of the obstruction to the ureteral wall - either intrinsic (IUO) or extrinsic (EUO). The second relates to whether the obstructing process is of a benign (BUO) or malignant origin (MUO).
Malignant Ureteral Obstruction (MUO)
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Intrinsic obstruction describes obstruction within the lumen of the urinary tract due to ureteropelvic junction (UPJ) stenosis, stone, ureteral stricture or secondary to genitourinary malignancies.3 Extrinsic obstruction is defined as that due to a benign or malignant process originating outside the urinary tract.
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The actual incidence of malignant ureteral obstruction is unknown.4 MUO can arise from intrinsic urologic malignancy, most commonly urothelial carcinoma, or extrinsically from another primary, most commonly gynecologic or colorectal. For non-urologic primary malignancies, the obstruction is due to direct invasion, nodal disease or involvement in an inflammatory process. Given that only approximately 21% of patients will have a urologic primary, a multidisciplinary approach to the patient is critical.
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Management of this population can be difficult as patients with MUO generally have a poor prognosis. The quoted overall survival rates range from approximately 2–15.3 months.5, 6. Early studies by Zadral et al showed the worst outcomes in patients with MUO secondary to metastatic breast cancer (3.74 mo., 0-11) compared to MUO secondary to other malignancies, such as cervical cancer (11.29 mo, 0-60). Disease stage or grade (other than metastases for breast cancer), age and degree of renal impairment had no effect on prognosis.7 The recommendation was that those with metastatic breast cancer, rapid disease progression or those in whom no further anti-cancer treatment was feasible should not be diverted. There is some evidence to suggest that those with MUO secondary to prostatic malignancy have better survival, and thus warrant more aggressive approaches to ureteral stenting.8 Further work by Skekarriz et al and Ganatra et al suggested that baseline creatinine may be a poor prognostic indicator.9, 10 Contemporary modern studies have proposed prognostic groups to more accurately predict overall survival and guide decision making.6, 8, 11 Izumi et al considered a series of gynecologic and colorectal cancer patients with an overall median survival of 228 days. Four prognostic factors: pre-diversion creatinine >1.2 ng/ml, availability of cancer therapy, location of primary malignancy and presence of bilateral obstruction allowed ranking into prognostic groups of Good (0-2), Intermediate (3-4) or Poor (5-7) outcomes with median survivals of 403, 252 or 51 days. Of note, this study Fiuk et al, Chronic Ureteral Obstruction Page 5
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contradicted earlier data regarding the importance of pre-diversion creatinine; to this day, baseline creatinine remains a controversial prognostic factor. Ishioka et al identified low serum albumin (<3 gm/dl), low-grade hydronephrosis and more than three indicators of widespread metastatic disease (metastatic deposits, nodal disease, ascites, pleural effusion) as poor prognostic indicators. Patient groups with good (0 risk factors), intermediate (1) and poor (2 or 3) risk factors had a six month survival of 69%, 24% and 2% respectively. Their model was validated by Lienert et al in a cohort with a larger proportion of urologic primaries with median survival (days) of 278, 173 and 63 for the good, intermediate or poor risk groups.8
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The aim in management of MUO ranges from definitive and potentially curative treatment across the spectrum to palliation only. The aim of stenting is to adequately drain the upper urinary tracts while minimizing hospitalization and negative impact on quality of life. In patients with a reasonable prognosis, there is evidence to suggest that stenting achieves this goal, both in terms of improved survival and improved quality of life (total 66% of study patients).2 Thus, though no ideal predictive model exists, the urologist should weigh overall prognosis versus symptomatic impact of obstruction when offering patients chronic stenting for MUO.
Benign Chronic Ureteral Obstruction (BUO)
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Though BUO is likely more common than MUO, its incidence is difficult to quantify. The etiology of BUO is varied and is generally due to intraluminal pathology, such as ureteropelvic junction obstruction, ureteral stones and stenosis. Extraluminal benign obstruction usually arises from localized mass effect of benign tumors (leiomyomas) or retroperitoneal fibrosis. Unlike MUO, benign obstruction tends to be unilateral and symptomatic12. In the majority of instances benign ureteral obstruction is primarily managed by definitive treatment of the underlying condition. However, in selected patient populations, such as those with advanced age, medical comorbidities, or diffuse or recurrent etiologies of extrinsic compression, chronic ureteral stenting may represent a reasonable alternative3.
Currently available and novel ureteral stents Ureteral stents are one of the most widely used urological devices for relieving ureteral obstruction. Though stent design has evolved in the past decades, none of the currently available models meets all requirements for an “ideal stent” (Table 1)13. Stent-associated symptoms are anticipated to varying degrees. In an attempt to overcome these challenges, innovations in stent design, coating and composition have been investigated.
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ACCEPTED MANUSCRIPT Currently, commonly-used ureteral stents are composed of polymeric compounds, including silicone, polyurethane, Silitek ®, C-flex®, Percuflex ® or Tecoflex®. The stents usually have a double pigtail design to prevent migration with side holes to improve drainage. These stents, however, tend to fail when significant radial compression is imposed, which is common in chronic ureteral obstruction. They also require periodic exchange, which adds to economic burden.
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Metal stents (MS), first applied in urology in 1988, have a longer dwell time and less stent change-associated morbidities. Four general types of MS are currently available: self-expandable, balloon-expandable, covered, and thermoexpandable shape-memory stents (Table 2). While self-expandable stents are among the most common MS, there is a growing interest in covered stents in attempt to reduce complications such as ingrowth and stent obstruction.
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Biodegradable stents are made with high molecular weight polymers such as polyglucolide, polylactide and UripreneTM, etc. These stents absorb over time, obviating the need for cystoscopic removal, and thus mitigate procedure-related complications, cost and patient discomfort. Their reliability of complete dissolution and controllability of degradation rate remains to be perfected.
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Application of anti-fouling coatings to ureteral stents reduces bacterial adhesion and encrustation. Common features of stent coatings include high biocompatibility, low friction, high bacteria and biofilm resistance and consequently, better long-term efficiency. Heparin-coated stents have been shown to be effective at reducing stent encrustation. In vivo studies showed no encrustation at 10-12 months dwell time, compared to the 76% encrustation rate of polymer stents at 12 months.14
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Hydrogel coating is able to absorb water, forming a thin liquid layer in the surface of the stent and thus preventing bacterial adhesion while providing improved lubrication. This feature also makes it possible to combine the hydrophilic matrix with hydrophobic drugs, thus increasing their antibacterial activity due to sustained release.15 Stents coated with polymers such as Pentosanpolysulfate (PPS), Phosphorylchlorine (PC) copolymer and polyvinylpyrollidone (PVP) provide excellent lubricant properties, enhanced biocompatibility and reduced encrustation. Polytetrafluoroethylene (PTFE) has been applied as coating for metallic stents in animal studies and is effective against urothelial hyperplasia.16 Methoxy-terminated polyethylene glycol (mPEG) conjugated with 3,4-dihydroxyphenylalanine (DOPA), inspired by compounds secreted by marine mussels, has demonstrated in vitro and in vivo resistance against urinary film formation and bacterial attachment.17 Silver coatings are another potentially effective strategy to reduce biofilm adherence, given silver’s wide-spectrum antimicrobial ability without the risk of inducing Fiuk et al, Chronic Ureteral Obstruction Page 7
ACCEPTED MANUSCRIPT resistance. Ironized silver, released from the metal after contact with bodily fluids, is able to inhibit bacterial genome replication. However, the actual effects of silver-coated stents are equivocal among published studies, possibly due to different techniques of silver particle manufacturing. Further in vitro and in vivo studies are needed.
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Diamond-like carbon (DLC) coatings have excellent biocompatibility. In a clinical trial of 10 patients prone to conventional stent encrustation, DLC-coated stents demonstrated remarkably less encrustation and improved patient comfort.18
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Drug-eluting stents (DES) aim to reduce urothelial hyperplasia and stent-related discomfort. Early attempts of manufacturing drug-eluting stents included dipping stents into antibiotic solutions such as ciprofloxacin, norfloxacin, gentamicin, and nitrofurantoin. However, these stents showed only short-term effects with little control of their drug releasing pharmacokinetics, leaving long term antibiotic concentrations at sub inhibitory levels and subsequently allowing for development of urinary tract infection (UTI).19 Newer DES incorporate the antibiotic into their biodegradable coating, thus modulating their pharmacokinetics to induce a stable and long-term release of the drug.20
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Triclosan-eluting stents (Triumph®) were designed to address stent related infection and discomfort. Triclosan is effective against both Gram-positive and Gram negative bacteria; animal studies have demonstrated significantly reduced P. mirabilis loads and pro-inflammatory cytokine release with Triclosan-eluting stents.21 In vitro attachment studies also showed decreased adhesion of E. coli, Klebsiella pneumoniae, and S. aureus.22 In two small clinical trials, patients receiving triclosan-eluting stents exhibited no difference in their biofilm formation, encrustation or infection development, but had significantly less stent-related symptoms.23, 24 However, triclosan-eluting stents are not approved by FDA due to concerns of development of triclosan resistance.
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DES impregnated with other agents, such as paclitaxel, ketorolac and chlorhexidine, have also demonstrated their safety and efficacy in vitro and animal studies.25 The clinical evidence for paclitaxel and cholorhexidine-eluting DES, however, is still pending. While a randomized clinical trial of 276 patients showed no significant general improvement in stent symptoms in the paclitaxel-eluting DES group, there was a demonstrated trend toward less narcotic usage in younger male patients.26 Novel modifications of stent design have been made to reduce stent symptoms, including stents with external helical grooves (e.g., Towers stent from Cook Urological and the Lithostent from ACMI), helical ridges (e.g., Spirastent®) and dual lumens. An antireflux-membrane valve can be applied and has been shown to produce significantly less vesicoureteral reflux-related symptoms.27 Stents with softer Fiuk et al, Chronic Ureteral Obstruction Page 8
ACCEPTED MANUSCRIPT tips (dual durometer stents) and stents with smaller intravesical portions (tail stents and Buoy stents) have demonstrated reduced bladder inflammation and irritative symptoms28.
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Combinations of currently available stent designs can enhance their efficacy. Ureteral stents with metal skeletons and polymeric coatings should achieve both surface inertness and compression resistance. A metal mesh stent with a paclitaxel drug-eluting coating was shown to generate less inflammation and hyperplasia, and a zotarolimus-eluting metal stent demonstrated significantly lower hyperplastic reaction at sustained anti-inflammatory levels.29 Alternatively, biodegradable metal alloy stents composed of a magnesium-yttrium alloy may bypass the issue of hyperplastic reactions by degrading before tissue overgrowth and encrustation even become an issue. 30
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Besides ureteral stenting, alternative options to urinary diversion include percutaneous drainage of the renal pelvis via nephrostomy tubes and novel techniques such as an extra-anatomic bypass linking the renal pelvis to the bladder via a subcutaneously tunneled synthetic conduit31. Patient factors, such as immunosuppressed states, and patient preference must weigh into decision making.
Stenting techniques
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Per manufacturer recommendations based on ex-vivo testing, most polymer stents require exchange every 3-6 months while metal stents have a purported dwell time of up to one year. While polymer stent placement - over a guidewire- is familiar to most practicing urologists, metal stent placement differs in technique and thus will be reviewed here. Unlike polymer double pigtail stents, metallic stents do not have lumens to permit placement via Seldinger technique. Instead, metallic stents are placed through an outer catheter or sheath. During retrograde placement, a guidewire is inserted into the ureteral orifice and advanced to the renal pelvis under fluoroscopy. A coaxial inner sheath and outer catheter included with the stent are then advanced over the guidewire.. The guidewire and inner catheter are then removed, allowing the metallic stent to be advanced through the outer sheath using the inner catheter as a pusher.32 The radio-opaque tip is placed at the desired location of the proximal curl. This can be confirmed by occasional fluoroscopy. The manufacturers utilize a clear sheath included in the packaging, and therefore it is the author’s recommendation to perform simultaneous cystoscopy to prevent passing the stent too far proximally in the ureter, as it is extremely difficult to retrieve these stents ureteroscopically. If passage of the wire next to the metal stent is not possible because of the degree of obstruction, ureteroscopy may be necessary to assist with wire placement. We find angled tip hydrophilic wires to be extremely helpful in performing this maneuver. Fiuk et al, Chronic Ureteral Obstruction Page 9
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Alternatively, metal stents can be placed using an antegrade technique for proximal obstruction or difficult to reach ureteral orifices. Standard percutaneous access is first obtained, followed by the routine antegrade nephrostogram. The area of obstruction is traversed with a wire and, if necessary to accommodate the coaxial sheath, dilated with a balloon dilator. The coaxial sheath system is passed over the wire and advanced anterograde under fluoroscopy to the bladder. The guidewire and inner catheter are removed, and the stent is placed as for retrograde placement. The introducer sheath is removed over the pusher, removing the pusher as the final step.33 It is paramount that the proximal loop curl is positioned in the collecting system and not in the parenchyma of the kidney.
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One of the major disadvantages of using metallic stents, which lack an inner lumen and thus cannot accommodate a guidewire, is the potential for total loss of access during stent exchange. Several authors have advocated for placing a guidewire alongside the metal stent before its removal in order to preserve access.33 Alternatively, Potretzke’s experience with four pediatric metallic stent exchanges suggests using the stent itself as an introducer for intra-ureteric sheath placement during stent replacement, thus preserving access while minimizing the need for additional equipment.34 Again, simultaneous cystoscopy is emphasized to prevent distal curl placement in the distal ureter.
Cost Considerations
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As with any chronic disease, the economic burden must be taken into account when evaluating therapeutic modalities. The cost of the two most common stents used in chronic obstruction, standard polymer and metal, has been well defined in the literature. Initial cost differences ($125 for polymer stents and $1040 for metal stents) are mitigated by the need for more frequent stent changes, yielding a counterintuitive lower annual cost for the more expensive product ($4211 for metal stents, 1 exchange per year vs $9648 for polymer stents, 4 exchanges per year).35 Additionally, one must take into account the burden of loss of productivity with each required procedure, which, in one study, was as high as a 40% self-reported decrease in work performance and a mean 6 day stent related loss of activity. 36 Outcomes of chronic ureteral stenting Outcomes in chronic ureteral stenting are divided into early technical success of stent placement and late success, measured by lack of stent failure. Success rates of 84.6 100% have been reported for stent placement in combined series with both MUO and BUO.33, 37 Rate of late failure varies by stent type, with a 16 - 44 % failure rate for polymer stents and a 0-44% failure rate for metal stents.3, 4, 6, 32, 33, 37-39 True incidence of both early and late failure are difficult to discern given the lack of randomized controlled trials comparing performance of both stent types in the face of various etiologies of chronic obstruction. Fiuk et al, Chronic Ureteral Obstruction Page 10
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Stent failure, the primary long term outcome measure in chronic stenting, has varying definitions in the literature. Broadly, it is defined as any ureteral unit that requires additional procedures after initial stent placement to manage symptoms or any patient whose chief complaint is not alleviated by stent placement.38 The majority of stent failure occurs within 6-12 months after initial placement. Patient reported symptoms such as urgency, frequency, dysuria, and flank pain serve as subjective evidence of failure, with flank pain being the most common chief complaint. Objective signs of stent failure include recurrent or persistent hydronephrosis, worsening creatinine, and stent encrustation, with elevated creatinine being most common.6, 39
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Inefficient drainage of the pelvicaliceal system, proven by progressive dilatation on subsequent imaging assessments, has been suggested as another marker of stent failure, but may overestimate stent failure in light of clinically insignificant yet radiographically evident dilatation.33 Other authors define stent failure as unanticipated or premature stent exchange, i.e., stent exchange prior to the manufacturer recommended stent dwell time (3 months for most polymer stents, 12 months for metal stents).32, 38, 39 Given that both metallic and polymer stents have a known and limited lifespan and that physicians rarely rely on radiographic evidence without clinical correlation, the most accurate measure of stent failure may be a persistence of the problem that prompted stenting in the first place.
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Proposed risk factors for stent failure include male gender, age, degree of hydronephrosis, serum creatinine level, type of malignancy, degree of local invasion of malignancy, laterality or level of obstruction, and stent diameter.3, 6, 32, 38 Though most series to date have been inadequately powered to draw meaningful conclusions, degree of hydronephrosis, serum creatinine level, gross invasion of the bladder and malignant extrinsic etiology of obstruction consistently appear in multiple retrospective studies as statistically significant predictors of stent failure.
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Complications:
As with failure rates, complications are divided by timing. Early complications in the immediate perioperative period include iatrogenic injury at the time of placement, stent migration or patient discomfort. Goldsmith et. al reported three cases of symptomatic subcapsular hematomas out of 25 metallic stent placements, all of which were managed conservatively. Stent migration occurs in 1-4% of all stent placements, with distal migration occurring more frequently than proximal migration (3-4% vs. 2 %) and being more dependent on stent design (double vs. single coil) and insertion technique.39-41 Up to 70% of patients undergoing chronic ureteral stenting report pain requiring some form of analgesia, with 15 % specifically reporting flank pain.42, 43
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Late complications, developing weeks to months after initial stent placement, include infection, difficulties with stent exchange, or hardware malfunction, such as stent fracture. Infection in chronic ureteral stenting ranges from asymptomatic bacteriuria to symptomatic UTI, with symptomatic infection being 2.3 times more likely than bacteriuria. Risk factors for infected stents include female gender, immunocompromised disease states, and stent dwell time, with dwell times greater than 1 month increasing the relative risk of infection by 4-9 times.15 Stent encrustation is responsible for the majority of difficult stent exchanges; bacterial colonization, subsequent biofilm formation, and calcium deposition are the likely causative factors leading to encrustation.44, 45 Dwell time again is a risk factor for encrustation, with a 9-27% versus 76% incidence of encrusted stents at 6 weeks and over 12 weeks.45, 46 In the author’s experience of over 100 metal stent exchanges, two stents required removal by PCNL secondary to significant encrustation. These included a benign prostatic hypertrophy patient with encrustation after 3 months dwell time and an ovarian cancer patient with encrustation after 13 months dwell time. Hardware malfunction, namely stent fracture, is relatively rare (0.3% - 10%), but has resulted in at least 3 cases of spontaneous passage of stent fragments in voided urine, or “stenturia”.46-48
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A rare but potentially devastating complication of chronic stenting is the development of arterial-ureteric fistula (AUF). One hundred and one patients with AUF have been identified in the literature; the majority have had preceeding vascular reconstruction of the affected vessel, though cases of AUF after ureteral stenting do exist. Hematuria is the only presenting symptom in the majority of cases, and multiple diagnostic studies are often required to make the diagnosis. Given the high mortality rate (7.1% - 23%) and its relation to diagnositic delay, a high degree of suspicion is necessary in the appropriate patient population.49
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The “lost” or “forgotten” stent represents an unfortunate late complication of stenting, as it is due to human factors and thus entirely preventable. As discussed above, increasing dwell times lead to increased risk of encrustation, often making removal more difficult and dangerous. In a retrospective series of 19 forgotten ureteric stents, Singh et al reported one death as a direct consequence of attempted removal.50 Numerous systems have been proposed to prevent forgotten stents, including bar coded wrist bands and the creation of a stent registry with automated appointment reminders. Regardless of the method used, urologists should play an active role in attempting to prevent this complication.
Conclusion Chronic ureteral obstruction can be caused by both benign and malignant conditions, with either intrinsic or extrinsic etiology. The therapeutic goal in malignant ureteral Fiuk et al, Chronic Ureteral Obstruction Page 12
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obstruction is to drain the upper urinary tract, minimize intervention and hospitalization and disruption to quality of life. Management goals of benign ureteral obstruction mirror this paradigm when definitive treatment of the primary cause is not plausible. For both conditions, in the appropriate patient populations, chronic ureteral stenting is a viable option. Complications of chronic stenting include patient discomfort, stent migration, infection, encrustation, hardware malfunction, and exchange difficulties. While there is no perfect stent that obviates all morbidity, major design advances have been made that may decrease these common problems.
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Cadieux, P. A., Chew, B. H., Knudsen, B. E. et al.: Triclosan loaded ureteral stents decrease proteus mirabilis 296 infection in a rabbit urinary tract infection model. J Urol, 175: 2331, 2006
22.
Lange, D., Elwood, C. N., Choi, K. et al.: Uropathogen interaction with the surface of urological stents using different surface properties. J Urol, 182: 1194, 2009
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12.
23.
Cadieux, P. A., Chew, B. H., Nott, L. et al.: Use of triclosan-eluting ureteral stents in patients with long-term stents. J Endourol, 23: 1187, 2009
24.
Mendez-Probst, C. E., Goneau, L. W., MacDonald, K. W. et al.: The use of triclosan eluting stents effectively reduces ureteral stent symptoms: a prospective randomized trial. BJU Int, 110: 749, 2012
25.
Chew, B. H., Davoudi, H., Li, J. et al.: An in vivo porcine evaluation of the safety, bioavailability, and tissue penetration of a ketorolac drug-eluting ureteral stent designed to improve comfort. J Endourol, 24: 1023, 2010 Fiuk et al, Chronic Ureteral Obstruction Page 14
ACCEPTED MANUSCRIPT Krambeck, A. E., Walsh, R. S., Denstedt, J. D. et al.: A novel drug eluting ureteral stent: a prospective, randomized, multicenter clinical trial to evaluate the safety and effectiveness of a ketorolac loaded ureteral stent. J Urol, 183: 1037, 2010
27.
Ecke, T. H., Bartel, P., Hallmann, S. et al.: Evaluation of symptoms and patients' comfort for JJ-ureteral stents with and without antireflux-membrane valve. Urology, 75: 212, 2010
28.
Krebs, A., Deane, L. A., Borin, J. F. et al.: The 'buoy' stent: evaluation of a prototype indwelling ureteric stent in a porcine model. BJU Int, 104: 88, 2009
29.
Kallidonis, P., Kitrou, P., Karnabatidis, D. et al.: Evaluation of zotarolimus-eluting metal stent in animal ureters. J Endourol, 25: 1661, 2011
30.
Lock, J. Y., Wyatt, E., Upadhyayula, S. et al.: Degradation and antibacterial properties of magnesium alloys in artificial urine for potential resorbable ureteral stent applications. J Biomed Mater Res A, 102: 781, 2014
31.
Lloyd, S. N., Tirukonda, P., Biyani, C. S. et al.: The detour extra-anatomic stent—a permanent solution for benign and malignant ureteric obstruction? Eur Urol, 52: 193, 2007
32.
Kadlec, A. O., Ellimoottil, C. S., Greco, K. A. et al.: Five-year experience with metallic stents for chronic ureteral obstruction. J Urol, 190: 937, 2013
33.
Liatsikos, E. N., Karnabatidis, D., Katsanos, K. et al.: Ureteral metal stents: 10-year experience with malignant ureteral obstruction treatment. J Urol, 182: 2613, 2009
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Potretzke, A. M., Chang, H., Kryger, J. V.: Technique for Resonance® stent exchange in patients with extrinsic obstruction: description of a novel approach and literature review. J Pediatr Urol, 8: 557, 2012
35.
Taylor, E. R., Benson, A. D., Schwartz, B. F.: Cost analysis of metallic ureteral stents with 12 months of follow-up. J Endourol, 26: 917, 2012
36.
Joshi, H. B., Stainthorpe, A., Keeley, F. X., Jr. et al.: Indwelling ureteral stents: evaluation of quality of life to aid outcome analysis. J Endourol, 15: 151, 2001
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Wang, H. J., Lee, T. Y., Luo, H. L. et al.: Application of resonance metallic stents for ureteral obstruction. BJU Int, 108: 428, 2011
38.
Rosevear, H. M., Kim, S. P., Wenzler, D. L. et al.: Retrograde ureteral stents for extrinsic ureteral obstruction: nine years' experience at University of Michigan. Urology, 70: 846, 2007
39.
Goldsmith, Z. G., Wang, A. J., Bañez, L. L. et al.: Outcomes of metallic stents for malignant ureteral obstruction. J Urol, 188: 851, 2012
40.
Calleary, J. G.: Chronic indwelling ureteral stents—what is the optimal approach? J Urol, 185: 2016, 2011 Fiuk et al, Chronic Ureteral Obstruction Page 15
ACCEPTED MANUSCRIPT Benson, A. D., Taylor, E. R., Schwartz, B. F.: Metal ureteral stent for benign and malignant ureteral obstruction. J Urol, 185: 2217, 2011
42.
Giannarini, G., Keeley, F. X., Jr., Valent, F. et al.: Predictors of morbidity in patients with indwelling ureteric stents: results of a prospective study using the validated Ureteric Stent Symptoms Questionnaire. BJU Int, 107: 648, 2011
43.
Richter, F., Irwin, R. J., Jr., Watson, R. A. et al.: Endourologic management of malignant ureteral strictures. J Endourol, 14: 583, 2000
44.
Kehinde, E. O., Rotimi, V. O., Al-Awadi, K. A. et al.: Factors predisposing to urinary tract infection after J ureteral stent insertion. J Urol, 167: 1334, 2002
45.
Kawahara, T., Ito, H., Terao, H. et al.: Ureteral stent encrustation, incrustation, and coloring: morbidity related to indwelling times. J Endourol, 26: 178, 2012
46.
el-Faqih, S. R., Shamsuddin, A. B., Chakrabarti, A. et al.: Polyurethane internal ureteral stents in treatment of stone patients: morbidity related to indwelling times. J Urol, 146: 1487, 1991
47.
Monga, M.: The dwell time of indwelling ureteral stents—the clock is ticking but when should we set the alarm? J Urol, 185: 387, 2011
48.
Singh, V., Gupta, A.: Stenturia: a rare complication of indwelling ureteral stent. Urol J, 6: 226, 2009
49.
van den Bergh, R. C., Moll, F. L., de Vries, J. P. et al.: Arterio-ureteral fistula: 11 new cases of a wolf in sheep's clothing. J Urol, 179: 578, 2008
50.
Singh, V., Srinivastava, A., Kapoor, R. et al.: Can the complicated forgotten indwelling ureteric stents be lethal? Int Urol Nephrol, 37: 541, 2005
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ACCEPTED MANUSCRIPT Table 1: Properties of the Ideal Ureteral Stent Description
Coefficient of friction Radiopacity Memory Durometery Elasticity Tensile strength Elongation capacity Biocompatibiltiy
Ease of insertion and removal from any access Able to be visualized during fluoroscopy Maintenance of its position within the ureter and minimal migration Strength of memory Easy manipulation of its shape Crystallization and cross-linking in the biomaterials Elongation at stent breakage Induce no tissue reaction and ingrowth
Biodurability Patient tolerability Affordable
Avoidance of degradation, corrosion and encrustation Minimal infection and stent-related symptom Cost-efficiency given the expenses of a single stent and its duration of efficacy
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Property
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Table 2: Types of metal urinary stents Material Structure
Type
Wallstent1
Self-expanding stent
Cobalt-based alloy
Monofilament wire woven into tubular mesh
Segmental
Accuflex2
Self-expanding stent
NiTinol11
Monofilament wire woven into tubular mesh
Segmental
Self-expanding, covered stent
NiTinol
Metal mesh externally coated with polyester fabric
Segmental
Balloon-expandable stent
Tantalum
Monofilament wire woven to tubular mesh
Segmental
Balloon-expandable stent
Stainless steel
Metal tube laser-etched into repeating, parallel loops
Segmental
Memokath 0516
Thermo-expandable, Shape-memory stent
NiTinol
Tight spiral coiled body with a bell-shaped anchoring structure at the proximal end
Segmental
Resonance7
Covered metal stent
Nickel-cobalt-chromium-molybdenum alloy
Allium stent8
Covered metal stent,
NiTinol
Uventa stent9
Self-expandable, Shape-memory stent
NiTinol
Silhouette stent10
Coil-reinforced stent
Nickel-cobalt-chromium-molybdenum alloy
1. Wallstent stent: Boston Scientific, Natick, MA, USA. 2. Accuflex stent: Boston Scientific, Natick, MA, USA. 3. Passager stent: Boston Scientific, Natick, MA, USA. 4. Strecker stent：Boston Scientific, Natick, MA, USA. 5. Palmaz-Schatz stent: Johnson and Johnson, Warren, PA, USA 6. Memokath™ 051 stent: Engineers & Doctors, A/S, Copenhagen, Denmark 7. Resonance® stent: Cook Urologic, Spencer, IN, USA 8. Allium Stent: Allium Ltd, Caesarea, Israel 9. Uventa stent: TaeWoong Medical Co., Ltd, Gveonggi-do, Korea 10. Silhouette stent: Applied Medical, Cleveland, OH, USA
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Tight metal spiral coil, double pigtail, without a lumen and end holes.
Full length
Triple layer, metal mesh placed between 2 polymer layers
Segmental
Triple layer, incorporates a PTFE membrane between two metal mesh layers
Segmental
Polyurethane double pigtail stent reinforced by a single piece of metal coil
Full length
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Strecker4
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Passager
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Length
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Metal Stent
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11. NiTinol: nickel titanium alloy.
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Figure 1. (a) Metal stent visible on bottom of screen as it is inserted into outer sheath. (b) Metal stent passed up into renal pelvis. (c) Coaxial inner catheter used to push metal stent out of sheath, forming a proximal curl in renal pelvis. (d) Distal curl seen on cystoscopy
ACCEPTED MANUSCRIPT IUO, intrinsic ureteral obstruction; EUO, extrinsic ureteral obstruction; BUO, benign ureteral obstruction;
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MUO, malignant ureteral obstruction; MS, metal stents; PPS, Pentosan polysulfate;
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PC, Phosphorylchlorine copolymer; PVP, polyvinylpyrrolidone;
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PTFE, polyterafluoroethylene; mPEG, methoxy-terminated polyethylene glycol; DOPA, dihydroxyphenylalanine; DLC, diamond-like carbon;
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DES, drug-eluting stents; UTI, urinary tract infection;
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UPJ, ureteropelvic junction.
PII: DOI: Reference:
S0022-5347(14)04935-0 10.1016/j.juro.2014.10.123 JURO 12022
To appear in: The Journal of Urology Accepted Date: 23 October 2014 Please cite this article as: Fiuk J, Bao Y, Calleary JG, Schwartz BF, Denstedt JD, The Use of Internal Stents in Chronic Ureteral Obstruction, The Journal of Urology® (2014), doi: 10.1016/j.juro.2014.10.123. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.
Embargo Policy All article content is under embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date. Questions regarding embargo should be directed to [email protected].
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The Use of Internal Stents in Chronic Ureteral Obstruction Julia Fiuk 1†, Yige Bao2,3,4†, John G. Calleary5#†, Bradley F. Schwartz1#† and John D. Denstedt1#*†
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Division of Urology, Southern Illinois University School of Medicine, Springfield, Illinois, USA 2 Division of Urology, Department of Surgery and 3 Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry Western University, London, Canada 4 Department of Urology, West China Hospital, Sichuan University, West China School of Clinical Medicine, Sichuan University, Chengdu, China 5 Department of Urology, North Manchester General Hospital, Manchester, United Kingdom † Contributed equally to the paper
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# This topic was presented by the authors at plenary session of American Urological Association meeting held in April 2012 at Atlanta.
*Corresponding author: Dr. John D. Denstedt Division of Urology, St. Joseph’s Hospital 268 Grosvenor Street London, Ontario Canada N6A 4V2 Phone: 519-646-6036 Fax: 519-646-6037 Email: [email protected]
ACCEPTED MANUSCRIPT Abstract Purpose
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Despite lack of a well-delineated definition, chronic ureteral obstruction (CUO) imposes significant quality of life loss, increased pathologic morbidity and risk of mortality as well as substantial economic burden. Ureteral stenting serves as an important therapeutic option to alleviate the obstruction. We thus assessed the recently-published literature on chronic ureteral obstruction; treatment options; types, benefits and shortcomings of current ureteral stents; as well as outcomes and complications of chronic ureteral stenting, with the goal of providing concise management guidelines.
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Material and Methods
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A systemic literature review was performed on Embase, Pubmed, Cochrane Controlled Trials Register and Google Scholar on ureteral obstruction and internal ureteral stents. Relevant reviews, original research articles and their cited references were examined, and a synopsis of original data was generated on a clinically oriented basis.
Results
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CUO can be classified into compression is either intrinsic (IUO) or extrinsic (EUO) to the ureteral wall, or obstruction that is of a benign (BUO) or malignant origin (MUO). Patients with MUO generally have a poor prognosis and are often difficult to manage. The aim of stenting is to adequately drain the upper urinary tracts while minimizing hospitalization and negative impact on quality of life. Facing the challenge of chronic ureteral obstruction, novel stents with new compositions, materials, coatings, and designs have been developed. Metallic stents are emerging as efficacious and financially viable alternatives. Early stent-related complications include iatrogenic injury, stent migration or patient discomfort, while late complications include infection, difficulties with stent exchange, hardware malfunction, infection, and stent encrustation.
Conclusions
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Stenting in CUO is a complex and challenging problem. Much work is being done in this area and many options are explored herein.
Key Words Ureteral obstruction, ureteral stents
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Abbreviations and Acronyms
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CUO, chronic ureteral obstruction; IUO, intrinsic ureteral obstruction; EUO, extrinsic ureteral obstruction; BUO, benign ureteral obstruction; MUO, malignant ureteral obstruction; MS, metal stents; PPS, Pentosan polysulfate; PC, Phosphorylchlorine copolymer; PVP, polyvinylpyrrolidone; PTFE, polyterafluoroethylene; mPEG, methoxy-terminated polyethylene glycol; DOPA, dihydroxyphenylalanine; DLC, diamond-like carbon; DES, drug-eluting stents; UTI, urinary tract infection; UPJ, ureteropelvic junction.
Fiuk et al, Chronic Ureteral Obstruction Page 3
ACCEPTED MANUSCRIPT Introduction
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Since its first description by Zimskind in 1967, the ureteral stent has undergone a plethora of evolutionary changes to become the ubiquitous tool urologists use today.1 Though the stenting algorithm for relief of acute obstruction is intuitive to most, management of chronic obstruction presents a far more complicated decision making process. The term “chronic ureteral obstruction” itself lacks a well-delineated definition, either depending on an arbitrarily assigned time period or referring to the need for repeated stenting procedures where definitive treatment is not possible. The nomenclature in chronic ureteral obstruction (CUO) is further muddled by opposing classification systems, dividing disease by either anatomic location (intrinsic vs extrinsic) or etiology (benign vs malignant).
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These patients, regardless of etiology, present with obstruction of their upper urinary tracts that both symptomatically decreases quality of life and pathologically adds morbidity and potentially increases mortality.2 The goal of treatment is to improve both parameters, if only from a genitourinary standpoint. The need for such treatment options will only become more pressing as treatments for life limiting diagnoses continue to improve.
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The practitioner must consider the various success rates and complications associated with each stent type in the currently available armamentarium. Though we have come a long way from the initial straight Zimskind silicone catheter, with advances in anchoring devices, composition, and coatings, we still strive to find the ideal stent. With each new iteration, we seek to decrease stent related symptoms, difficulty with replacement, and frank stent failure; however, potential improvements must be weighed against known limitations and patient-specific factors.
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In this update we address the broad divisions in types of chronic ureteral obstruction, as well as the disease and patient specific considerations for management options. We then present the various available types of stents and compare their benefits and shortcomings. We review techniques for placement for particular stents that may be novel for some urologists, and discuss the outcomes and complications seen in the setting of treating this heterogeneous disease state.
Methods
A systemic literature review was performed on Embase, Pubmed, Cochrane Controlled Trials Register and Google Scholar . Keywords included “ureteral obstruction” and “internal ureteral stents”. Relevant reviews, original research articles and their cited references were examined, and a synopsis of original data was generated on a clinically oriented basis.
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ACCEPTED MANUSCRIPT CUO: Cause, Prognosis and Management Options
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Two classification systems are generally used to describe the etiology of chronic ureteral obstruction (CUO). The first relates to the anatomic relationship of the obstruction to the ureteral wall - either intrinsic (IUO) or extrinsic (EUO). The second relates to whether the obstructing process is of a benign (BUO) or malignant origin (MUO).
Malignant Ureteral Obstruction (MUO)
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Intrinsic obstruction describes obstruction within the lumen of the urinary tract due to ureteropelvic junction (UPJ) stenosis, stone, ureteral stricture or secondary to genitourinary malignancies.3 Extrinsic obstruction is defined as that due to a benign or malignant process originating outside the urinary tract.
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The actual incidence of malignant ureteral obstruction is unknown.4 MUO can arise from intrinsic urologic malignancy, most commonly urothelial carcinoma, or extrinsically from another primary, most commonly gynecologic or colorectal. For non-urologic primary malignancies, the obstruction is due to direct invasion, nodal disease or involvement in an inflammatory process. Given that only approximately 21% of patients will have a urologic primary, a multidisciplinary approach to the patient is critical.
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Management of this population can be difficult as patients with MUO generally have a poor prognosis. The quoted overall survival rates range from approximately 2–15.3 months.5, 6. Early studies by Zadral et al showed the worst outcomes in patients with MUO secondary to metastatic breast cancer (3.74 mo., 0-11) compared to MUO secondary to other malignancies, such as cervical cancer (11.29 mo, 0-60). Disease stage or grade (other than metastases for breast cancer), age and degree of renal impairment had no effect on prognosis.7 The recommendation was that those with metastatic breast cancer, rapid disease progression or those in whom no further anti-cancer treatment was feasible should not be diverted. There is some evidence to suggest that those with MUO secondary to prostatic malignancy have better survival, and thus warrant more aggressive approaches to ureteral stenting.8 Further work by Skekarriz et al and Ganatra et al suggested that baseline creatinine may be a poor prognostic indicator.9, 10 Contemporary modern studies have proposed prognostic groups to more accurately predict overall survival and guide decision making.6, 8, 11 Izumi et al considered a series of gynecologic and colorectal cancer patients with an overall median survival of 228 days. Four prognostic factors: pre-diversion creatinine >1.2 ng/ml, availability of cancer therapy, location of primary malignancy and presence of bilateral obstruction allowed ranking into prognostic groups of Good (0-2), Intermediate (3-4) or Poor (5-7) outcomes with median survivals of 403, 252 or 51 days. Of note, this study Fiuk et al, Chronic Ureteral Obstruction Page 5
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contradicted earlier data regarding the importance of pre-diversion creatinine; to this day, baseline creatinine remains a controversial prognostic factor. Ishioka et al identified low serum albumin (<3 gm/dl), low-grade hydronephrosis and more than three indicators of widespread metastatic disease (metastatic deposits, nodal disease, ascites, pleural effusion) as poor prognostic indicators. Patient groups with good (0 risk factors), intermediate (1) and poor (2 or 3) risk factors had a six month survival of 69%, 24% and 2% respectively. Their model was validated by Lienert et al in a cohort with a larger proportion of urologic primaries with median survival (days) of 278, 173 and 63 for the good, intermediate or poor risk groups.8
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The aim in management of MUO ranges from definitive and potentially curative treatment across the spectrum to palliation only. The aim of stenting is to adequately drain the upper urinary tracts while minimizing hospitalization and negative impact on quality of life. In patients with a reasonable prognosis, there is evidence to suggest that stenting achieves this goal, both in terms of improved survival and improved quality of life (total 66% of study patients).2 Thus, though no ideal predictive model exists, the urologist should weigh overall prognosis versus symptomatic impact of obstruction when offering patients chronic stenting for MUO.
Benign Chronic Ureteral Obstruction (BUO)
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Though BUO is likely more common than MUO, its incidence is difficult to quantify. The etiology of BUO is varied and is generally due to intraluminal pathology, such as ureteropelvic junction obstruction, ureteral stones and stenosis. Extraluminal benign obstruction usually arises from localized mass effect of benign tumors (leiomyomas) or retroperitoneal fibrosis. Unlike MUO, benign obstruction tends to be unilateral and symptomatic12. In the majority of instances benign ureteral obstruction is primarily managed by definitive treatment of the underlying condition. However, in selected patient populations, such as those with advanced age, medical comorbidities, or diffuse or recurrent etiologies of extrinsic compression, chronic ureteral stenting may represent a reasonable alternative3.
Currently available and novel ureteral stents Ureteral stents are one of the most widely used urological devices for relieving ureteral obstruction. Though stent design has evolved in the past decades, none of the currently available models meets all requirements for an “ideal stent” (Table 1)13. Stent-associated symptoms are anticipated to varying degrees. In an attempt to overcome these challenges, innovations in stent design, coating and composition have been investigated.
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ACCEPTED MANUSCRIPT Currently, commonly-used ureteral stents are composed of polymeric compounds, including silicone, polyurethane, Silitek ®, C-flex®, Percuflex ® or Tecoflex®. The stents usually have a double pigtail design to prevent migration with side holes to improve drainage. These stents, however, tend to fail when significant radial compression is imposed, which is common in chronic ureteral obstruction. They also require periodic exchange, which adds to economic burden.
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Metal stents (MS), first applied in urology in 1988, have a longer dwell time and less stent change-associated morbidities. Four general types of MS are currently available: self-expandable, balloon-expandable, covered, and thermoexpandable shape-memory stents (Table 2). While self-expandable stents are among the most common MS, there is a growing interest in covered stents in attempt to reduce complications such as ingrowth and stent obstruction.
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Biodegradable stents are made with high molecular weight polymers such as polyglucolide, polylactide and UripreneTM, etc. These stents absorb over time, obviating the need for cystoscopic removal, and thus mitigate procedure-related complications, cost and patient discomfort. Their reliability of complete dissolution and controllability of degradation rate remains to be perfected.
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Application of anti-fouling coatings to ureteral stents reduces bacterial adhesion and encrustation. Common features of stent coatings include high biocompatibility, low friction, high bacteria and biofilm resistance and consequently, better long-term efficiency. Heparin-coated stents have been shown to be effective at reducing stent encrustation. In vivo studies showed no encrustation at 10-12 months dwell time, compared to the 76% encrustation rate of polymer stents at 12 months.14
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Hydrogel coating is able to absorb water, forming a thin liquid layer in the surface of the stent and thus preventing bacterial adhesion while providing improved lubrication. This feature also makes it possible to combine the hydrophilic matrix with hydrophobic drugs, thus increasing their antibacterial activity due to sustained release.15 Stents coated with polymers such as Pentosanpolysulfate (PPS), Phosphorylchlorine (PC) copolymer and polyvinylpyrollidone (PVP) provide excellent lubricant properties, enhanced biocompatibility and reduced encrustation. Polytetrafluoroethylene (PTFE) has been applied as coating for metallic stents in animal studies and is effective against urothelial hyperplasia.16 Methoxy-terminated polyethylene glycol (mPEG) conjugated with 3,4-dihydroxyphenylalanine (DOPA), inspired by compounds secreted by marine mussels, has demonstrated in vitro and in vivo resistance against urinary film formation and bacterial attachment.17 Silver coatings are another potentially effective strategy to reduce biofilm adherence, given silver’s wide-spectrum antimicrobial ability without the risk of inducing Fiuk et al, Chronic Ureteral Obstruction Page 7
ACCEPTED MANUSCRIPT resistance. Ironized silver, released from the metal after contact with bodily fluids, is able to inhibit bacterial genome replication. However, the actual effects of silver-coated stents are equivocal among published studies, possibly due to different techniques of silver particle manufacturing. Further in vitro and in vivo studies are needed.
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Diamond-like carbon (DLC) coatings have excellent biocompatibility. In a clinical trial of 10 patients prone to conventional stent encrustation, DLC-coated stents demonstrated remarkably less encrustation and improved patient comfort.18
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Drug-eluting stents (DES) aim to reduce urothelial hyperplasia and stent-related discomfort. Early attempts of manufacturing drug-eluting stents included dipping stents into antibiotic solutions such as ciprofloxacin, norfloxacin, gentamicin, and nitrofurantoin. However, these stents showed only short-term effects with little control of their drug releasing pharmacokinetics, leaving long term antibiotic concentrations at sub inhibitory levels and subsequently allowing for development of urinary tract infection (UTI).19 Newer DES incorporate the antibiotic into their biodegradable coating, thus modulating their pharmacokinetics to induce a stable and long-term release of the drug.20
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Triclosan-eluting stents (Triumph®) were designed to address stent related infection and discomfort. Triclosan is effective against both Gram-positive and Gram negative bacteria; animal studies have demonstrated significantly reduced P. mirabilis loads and pro-inflammatory cytokine release with Triclosan-eluting stents.21 In vitro attachment studies also showed decreased adhesion of E. coli, Klebsiella pneumoniae, and S. aureus.22 In two small clinical trials, patients receiving triclosan-eluting stents exhibited no difference in their biofilm formation, encrustation or infection development, but had significantly less stent-related symptoms.23, 24 However, triclosan-eluting stents are not approved by FDA due to concerns of development of triclosan resistance.
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DES impregnated with other agents, such as paclitaxel, ketorolac and chlorhexidine, have also demonstrated their safety and efficacy in vitro and animal studies.25 The clinical evidence for paclitaxel and cholorhexidine-eluting DES, however, is still pending. While a randomized clinical trial of 276 patients showed no significant general improvement in stent symptoms in the paclitaxel-eluting DES group, there was a demonstrated trend toward less narcotic usage in younger male patients.26 Novel modifications of stent design have been made to reduce stent symptoms, including stents with external helical grooves (e.g., Towers stent from Cook Urological and the Lithostent from ACMI), helical ridges (e.g., Spirastent®) and dual lumens. An antireflux-membrane valve can be applied and has been shown to produce significantly less vesicoureteral reflux-related symptoms.27 Stents with softer Fiuk et al, Chronic Ureteral Obstruction Page 8
ACCEPTED MANUSCRIPT tips (dual durometer stents) and stents with smaller intravesical portions (tail stents and Buoy stents) have demonstrated reduced bladder inflammation and irritative symptoms28.
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Combinations of currently available stent designs can enhance their efficacy. Ureteral stents with metal skeletons and polymeric coatings should achieve both surface inertness and compression resistance. A metal mesh stent with a paclitaxel drug-eluting coating was shown to generate less inflammation and hyperplasia, and a zotarolimus-eluting metal stent demonstrated significantly lower hyperplastic reaction at sustained anti-inflammatory levels.29 Alternatively, biodegradable metal alloy stents composed of a magnesium-yttrium alloy may bypass the issue of hyperplastic reactions by degrading before tissue overgrowth and encrustation even become an issue. 30
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Besides ureteral stenting, alternative options to urinary diversion include percutaneous drainage of the renal pelvis via nephrostomy tubes and novel techniques such as an extra-anatomic bypass linking the renal pelvis to the bladder via a subcutaneously tunneled synthetic conduit31. Patient factors, such as immunosuppressed states, and patient preference must weigh into decision making.
Stenting techniques
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Per manufacturer recommendations based on ex-vivo testing, most polymer stents require exchange every 3-6 months while metal stents have a purported dwell time of up to one year. While polymer stent placement - over a guidewire- is familiar to most practicing urologists, metal stent placement differs in technique and thus will be reviewed here. Unlike polymer double pigtail stents, metallic stents do not have lumens to permit placement via Seldinger technique. Instead, metallic stents are placed through an outer catheter or sheath. During retrograde placement, a guidewire is inserted into the ureteral orifice and advanced to the renal pelvis under fluoroscopy. A coaxial inner sheath and outer catheter included with the stent are then advanced over the guidewire.. The guidewire and inner catheter are then removed, allowing the metallic stent to be advanced through the outer sheath using the inner catheter as a pusher.32 The radio-opaque tip is placed at the desired location of the proximal curl. This can be confirmed by occasional fluoroscopy. The manufacturers utilize a clear sheath included in the packaging, and therefore it is the author’s recommendation to perform simultaneous cystoscopy to prevent passing the stent too far proximally in the ureter, as it is extremely difficult to retrieve these stents ureteroscopically. If passage of the wire next to the metal stent is not possible because of the degree of obstruction, ureteroscopy may be necessary to assist with wire placement. We find angled tip hydrophilic wires to be extremely helpful in performing this maneuver. Fiuk et al, Chronic Ureteral Obstruction Page 9
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Alternatively, metal stents can be placed using an antegrade technique for proximal obstruction or difficult to reach ureteral orifices. Standard percutaneous access is first obtained, followed by the routine antegrade nephrostogram. The area of obstruction is traversed with a wire and, if necessary to accommodate the coaxial sheath, dilated with a balloon dilator. The coaxial sheath system is passed over the wire and advanced anterograde under fluoroscopy to the bladder. The guidewire and inner catheter are removed, and the stent is placed as for retrograde placement. The introducer sheath is removed over the pusher, removing the pusher as the final step.33 It is paramount that the proximal loop curl is positioned in the collecting system and not in the parenchyma of the kidney.
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One of the major disadvantages of using metallic stents, which lack an inner lumen and thus cannot accommodate a guidewire, is the potential for total loss of access during stent exchange. Several authors have advocated for placing a guidewire alongside the metal stent before its removal in order to preserve access.33 Alternatively, Potretzke’s experience with four pediatric metallic stent exchanges suggests using the stent itself as an introducer for intra-ureteric sheath placement during stent replacement, thus preserving access while minimizing the need for additional equipment.34 Again, simultaneous cystoscopy is emphasized to prevent distal curl placement in the distal ureter.
Cost Considerations
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As with any chronic disease, the economic burden must be taken into account when evaluating therapeutic modalities. The cost of the two most common stents used in chronic obstruction, standard polymer and metal, has been well defined in the literature. Initial cost differences ($125 for polymer stents and $1040 for metal stents) are mitigated by the need for more frequent stent changes, yielding a counterintuitive lower annual cost for the more expensive product ($4211 for metal stents, 1 exchange per year vs $9648 for polymer stents, 4 exchanges per year).35 Additionally, one must take into account the burden of loss of productivity with each required procedure, which, in one study, was as high as a 40% self-reported decrease in work performance and a mean 6 day stent related loss of activity. 36 Outcomes of chronic ureteral stenting Outcomes in chronic ureteral stenting are divided into early technical success of stent placement and late success, measured by lack of stent failure. Success rates of 84.6 100% have been reported for stent placement in combined series with both MUO and BUO.33, 37 Rate of late failure varies by stent type, with a 16 - 44 % failure rate for polymer stents and a 0-44% failure rate for metal stents.3, 4, 6, 32, 33, 37-39 True incidence of both early and late failure are difficult to discern given the lack of randomized controlled trials comparing performance of both stent types in the face of various etiologies of chronic obstruction. Fiuk et al, Chronic Ureteral Obstruction Page 10
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Stent failure, the primary long term outcome measure in chronic stenting, has varying definitions in the literature. Broadly, it is defined as any ureteral unit that requires additional procedures after initial stent placement to manage symptoms or any patient whose chief complaint is not alleviated by stent placement.38 The majority of stent failure occurs within 6-12 months after initial placement. Patient reported symptoms such as urgency, frequency, dysuria, and flank pain serve as subjective evidence of failure, with flank pain being the most common chief complaint. Objective signs of stent failure include recurrent or persistent hydronephrosis, worsening creatinine, and stent encrustation, with elevated creatinine being most common.6, 39
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Inefficient drainage of the pelvicaliceal system, proven by progressive dilatation on subsequent imaging assessments, has been suggested as another marker of stent failure, but may overestimate stent failure in light of clinically insignificant yet radiographically evident dilatation.33 Other authors define stent failure as unanticipated or premature stent exchange, i.e., stent exchange prior to the manufacturer recommended stent dwell time (3 months for most polymer stents, 12 months for metal stents).32, 38, 39 Given that both metallic and polymer stents have a known and limited lifespan and that physicians rarely rely on radiographic evidence without clinical correlation, the most accurate measure of stent failure may be a persistence of the problem that prompted stenting in the first place.
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Proposed risk factors for stent failure include male gender, age, degree of hydronephrosis, serum creatinine level, type of malignancy, degree of local invasion of malignancy, laterality or level of obstruction, and stent diameter.3, 6, 32, 38 Though most series to date have been inadequately powered to draw meaningful conclusions, degree of hydronephrosis, serum creatinine level, gross invasion of the bladder and malignant extrinsic etiology of obstruction consistently appear in multiple retrospective studies as statistically significant predictors of stent failure.
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As with failure rates, complications are divided by timing. Early complications in the immediate perioperative period include iatrogenic injury at the time of placement, stent migration or patient discomfort. Goldsmith et. al reported three cases of symptomatic subcapsular hematomas out of 25 metallic stent placements, all of which were managed conservatively. Stent migration occurs in 1-4% of all stent placements, with distal migration occurring more frequently than proximal migration (3-4% vs. 2 %) and being more dependent on stent design (double vs. single coil) and insertion technique.39-41 Up to 70% of patients undergoing chronic ureteral stenting report pain requiring some form of analgesia, with 15 % specifically reporting flank pain.42, 43
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Late complications, developing weeks to months after initial stent placement, include infection, difficulties with stent exchange, or hardware malfunction, such as stent fracture. Infection in chronic ureteral stenting ranges from asymptomatic bacteriuria to symptomatic UTI, with symptomatic infection being 2.3 times more likely than bacteriuria. Risk factors for infected stents include female gender, immunocompromised disease states, and stent dwell time, with dwell times greater than 1 month increasing the relative risk of infection by 4-9 times.15 Stent encrustation is responsible for the majority of difficult stent exchanges; bacterial colonization, subsequent biofilm formation, and calcium deposition are the likely causative factors leading to encrustation.44, 45 Dwell time again is a risk factor for encrustation, with a 9-27% versus 76% incidence of encrusted stents at 6 weeks and over 12 weeks.45, 46 In the author’s experience of over 100 metal stent exchanges, two stents required removal by PCNL secondary to significant encrustation. These included a benign prostatic hypertrophy patient with encrustation after 3 months dwell time and an ovarian cancer patient with encrustation after 13 months dwell time. Hardware malfunction, namely stent fracture, is relatively rare (0.3% - 10%), but has resulted in at least 3 cases of spontaneous passage of stent fragments in voided urine, or “stenturia”.46-48
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A rare but potentially devastating complication of chronic stenting is the development of arterial-ureteric fistula (AUF). One hundred and one patients with AUF have been identified in the literature; the majority have had preceeding vascular reconstruction of the affected vessel, though cases of AUF after ureteral stenting do exist. Hematuria is the only presenting symptom in the majority of cases, and multiple diagnostic studies are often required to make the diagnosis. Given the high mortality rate (7.1% - 23%) and its relation to diagnositic delay, a high degree of suspicion is necessary in the appropriate patient population.49
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The “lost” or “forgotten” stent represents an unfortunate late complication of stenting, as it is due to human factors and thus entirely preventable. As discussed above, increasing dwell times lead to increased risk of encrustation, often making removal more difficult and dangerous. In a retrospective series of 19 forgotten ureteric stents, Singh et al reported one death as a direct consequence of attempted removal.50 Numerous systems have been proposed to prevent forgotten stents, including bar coded wrist bands and the creation of a stent registry with automated appointment reminders. Regardless of the method used, urologists should play an active role in attempting to prevent this complication.
Conclusion Chronic ureteral obstruction can be caused by both benign and malignant conditions, with either intrinsic or extrinsic etiology. The therapeutic goal in malignant ureteral Fiuk et al, Chronic Ureteral Obstruction Page 12
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obstruction is to drain the upper urinary tract, minimize intervention and hospitalization and disruption to quality of life. Management goals of benign ureteral obstruction mirror this paradigm when definitive treatment of the primary cause is not plausible. For both conditions, in the appropriate patient populations, chronic ureteral stenting is a viable option. Complications of chronic stenting include patient discomfort, stent migration, infection, encrustation, hardware malfunction, and exchange difficulties. While there is no perfect stent that obviates all morbidity, major design advances have been made that may decrease these common problems.
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ACCEPTED MANUSCRIPT Krambeck, A. E., Walsh, R. S., Denstedt, J. D. et al.: A novel drug eluting ureteral stent: a prospective, randomized, multicenter clinical trial to evaluate the safety and effectiveness of a ketorolac loaded ureteral stent. J Urol, 183: 1037, 2010
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ACCEPTED MANUSCRIPT Table 1: Properties of the Ideal Ureteral Stent Description
Coefficient of friction Radiopacity Memory Durometery Elasticity Tensile strength Elongation capacity Biocompatibiltiy
Ease of insertion and removal from any access Able to be visualized during fluoroscopy Maintenance of its position within the ureter and minimal migration Strength of memory Easy manipulation of its shape Crystallization and cross-linking in the biomaterials Elongation at stent breakage Induce no tissue reaction and ingrowth
Biodurability Patient tolerability Affordable
Avoidance of degradation, corrosion and encrustation Minimal infection and stent-related symptom Cost-efficiency given the expenses of a single stent and its duration of efficacy
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Table 2: Types of metal urinary stents Material Structure
Type
Wallstent1
Self-expanding stent
Cobalt-based alloy
Monofilament wire woven into tubular mesh
Segmental
Accuflex2
Self-expanding stent
NiTinol11
Monofilament wire woven into tubular mesh
Segmental
Self-expanding, covered stent
NiTinol
Metal mesh externally coated with polyester fabric
Segmental
Balloon-expandable stent
Tantalum
Monofilament wire woven to tubular mesh
Segmental
Balloon-expandable stent
Stainless steel
Metal tube laser-etched into repeating, parallel loops
Segmental
Memokath 0516
Thermo-expandable, Shape-memory stent
NiTinol
Tight spiral coiled body with a bell-shaped anchoring structure at the proximal end
Segmental
Resonance7
Covered metal stent
Nickel-cobalt-chromium-molybdenum alloy
Allium stent8
Covered metal stent,
NiTinol
Uventa stent9
Self-expandable, Shape-memory stent
NiTinol
Silhouette stent10
Coil-reinforced stent
Nickel-cobalt-chromium-molybdenum alloy
1. Wallstent stent: Boston Scientific, Natick, MA, USA. 2. Accuflex stent: Boston Scientific, Natick, MA, USA. 3. Passager stent: Boston Scientific, Natick, MA, USA. 4. Strecker stent：Boston Scientific, Natick, MA, USA. 5. Palmaz-Schatz stent: Johnson and Johnson, Warren, PA, USA 6. Memokath™ 051 stent: Engineers & Doctors, A/S, Copenhagen, Denmark 7. Resonance® stent: Cook Urologic, Spencer, IN, USA 8. Allium Stent: Allium Ltd, Caesarea, Israel 9. Uventa stent: TaeWoong Medical Co., Ltd, Gveonggi-do, Korea 10. Silhouette stent: Applied Medical, Cleveland, OH, USA
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Tight metal spiral coil, double pigtail, without a lumen and end holes.
Full length
Triple layer, metal mesh placed between 2 polymer layers
Segmental
Triple layer, incorporates a PTFE membrane between two metal mesh layers
Segmental
Polyurethane double pigtail stent reinforced by a single piece of metal coil
Full length
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Metal Stent
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11. NiTinol: nickel titanium alloy.
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Figure 1. (a) Metal stent visible on bottom of screen as it is inserted into outer sheath. (b) Metal stent passed up into renal pelvis. (c) Coaxial inner catheter used to push metal stent out of sheath, forming a proximal curl in renal pelvis. (d) Distal curl seen on cystoscopy
ACCEPTED MANUSCRIPT IUO, intrinsic ureteral obstruction; EUO, extrinsic ureteral obstruction; BUO, benign ureteral obstruction;
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MUO, malignant ureteral obstruction; MS, metal stents; PPS, Pentosan polysulfate;
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PC, Phosphorylchlorine copolymer; PVP, polyvinylpyrrolidone;
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PTFE, polyterafluoroethylene; mPEG, methoxy-terminated polyethylene glycol; DOPA, dihydroxyphenylalanine; DLC, diamond-like carbon;
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DES, drug-eluting stents; UTI, urinary tract infection;
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UPJ, ureteropelvic junction.