First synthesised in the 1960s as an antagonist of the N-methyl-D-aspartate receptor, ketamine is a short-acting anaesthetic agent which can also serve as an analgesic for chronic pain management.1 Ketamine was used recreationally beginning in the 1970s and subsequently became popular among young people.2 In Hong Kong, ketamine was the most commonly abused psychotropic substance from 2009 to 2014; for example, 5280 individuals reportedly abused ketamine in 2009.3 Data from the Central Registry of Drug Abuse indicate that ketamine abuse persists in Hong Kong, although its rate of abuse has decreased in the past several years. For example, 405 individuals reportedly abused ketamine in 2019, which comprised 7.3% of all drug users in Hong Kong that year.3

Ketamine abuse is known to affect the urinary system, and lower urinary tract symptoms (LUTS) are the most common manifestations. In 2007, the clinical feature of ketamine-associated cystitis was proposed by Shahani et al4 in their report of nine patients with a history of ketamine abuse who had LUTS; those patients also presented with bladder wall thickening, reduced bladder capacity, and cystoscopic findings indicative of cystitis. In 2008, Chu et al5 described 59 patients with a history of ketamine abuse who had LUTS. Their findings indicated that although ketamine abuse consistently affected the lower urinary tract, it also affected the upper urinary tract in some patients, as indicated by the presence of hydronephrosis, renal papillary necrosis, and an elevated level of creatinine. Because ketamine-associated uropathy (KAU) is a relatively new clinical entity, and its incidence is influenced by the time- and location-dependent popularity of ketamine, relevant literature remains limited. Thus, it is challenging to optimise management for young patients who present with uropathy and a history of ketamine abuse.

Here, we performed a systematic review and meta-analysis of KAU to summarise its key clinical manifestations, the results of urological assessments, and current management approaches. This review is expected to provide insights concerning the optimal management of KAU.

This systematic review and meta-analysis of published literature regarding KAU was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement.6

A literature search was conducted using combinations of keywords and Medical Subject Headings (MeSH) terms related to ‘ketamine use’, ‘ketamine addict’, ‘urinary tracts’, ‘urinary organs’, and ‘urological examinations’. Databases included in the search were Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials. The search was limited to human studies published in English up to 26 June 2020, excluding conference abstracts. The reference lists of the included articles were searched to identify additional relevant literature. The search strategy is shown in the online Appendix 1.

All articles retrieved from the literature search were independently screened by at least two independent reviewers. Case series, case-cohort studies, non-randomised studies, and randomised controlled trials related to ketamine abuse and uropathy were included. Articles were excluded if they met any of the following criteria: they were editorials, commentaries, reviews, or case reports; they described non-human studies; the full text was not available in English; no full text was available; and/or they described the use of ketamine for anaesthesia. Disagreements during the screening process were resolved by a third senior reviewer.

The following data were extracted from eligible studies using a standardised form: patient demographics, clinical features, examination results (eg, urodynamics, radiological workup, and endoscopic workup), and the treatment administered. Patient demographics included age, sex, and cumulative exposure to ketamine. Clinical features included presenting symptoms and the results of urinalysis and renal function tests. Urodynamic results included the voided volume, maximum urine flow rate (Qmax), and detrusor overactivity. Radiological features included hydronephrosis, ureteral stricture, and descriptive findings (eg, bladder wall thickening). Endoscopic workup included cystoscopic findings and bladder biopsy results. Questionnaire scores were also recorded. Finally, treatments and the corresponding responses were recorded.

Quantitative and qualitative assessments were conducted in this systematic review and meta-analysis. Quantitative assessments included prevalences of urological symptoms, scores of questionnaires that reflected urological symptoms, and results of urodynamics workups. Pooled data were analysed by OpenMeta[Analyst] when results were available for more than two studies with >100 patients. The studies included in each pooled analysis were individually reviewed to ensure that there was no patient overlap among the studies. Random effects models and double arcsine transformation were used to pool the results. Cochran’s Q test was used to identify heterogeneity, and P<0.10 was considered indicative of significant heterogeneity. I2 statistics were used to measure variations across studies, and I²>50% was considered indicative of significant heterogeneity. Qualitative assessments included narrative descriptions of cystoscopic findings, bladder biopsy results, and treatments administered.

In total, 1365 articles were identified by database searches, whereas no articles were identified by manual searches. After the removal of duplicates, 913 articles remained; 730 articles were removed during the initial screening, and 138 articles were removed during full-text screening. Forty-five articles were included in the qualitative analysis, and 37 articles were included in the quantitative analysis. The PRISMA flow diagram is shown in the Figure.

Our analysis included 4890 patients (3518 men and 1372 women) with a mean age of 25.46 ± 6.03 years and mean ketamine exposure duration of 54.99 ± 43.54 months.

Our meta-analysis concerning clinical manifestations of KAU included 37 studies with 4314 patients. All reported manifestations are summarised in Table 1 and online Appendix 2. Frequency was the most common manifestation (pooled prevalence 77.1%, 95% confidence interval [CI]=56.9%-92.2%), followed by urgency (69.9%, 95% CI=48.8%-87.3%), bladder or suprapubic pain (60.4%, 95% CI=35.3%-82.9%), and nocturia (58.0%, 95% CI=38.5%-76.2%). Additionally, substantial numbers of patients presented with dysuria, haematuria, and/or incontinence. Upper urinary tract involvement was less common. The pooled prevalence of hydronephrosis was 30.2% (95% CI=22.0%-39.2%), whereas approximately 20% of patients presented with ureteral strictures and 10% of patients presented with impaired renal function.

Various questionnaires and scoring systems were used among studies to assess the severities of patient symptoms. The International Prostate Symptom Score (IPSS), Interstitial Cystitis Symptom Index (ICSI), Interstitial Cystitis Problem Index (ICPI), Pelvic Pain and Urgency/Frequency (PUF) total score, and Visual Analogue Scale (VAS) were most commonly used. Our meta-analysis of symptom scores included 13 studies (2135 patients); the results are summarised in Table 2 and online Appendix 3. Five studies with 1366 patients were focused on IPSS; the pooled score was 11.61 (95% CI=6.37-16.84). Five studies (1263 patients) were focused on ICSI and ICPI; the pooled ICSI score was 11.11 (95% CI=4.12-18.09) and the pooled ICPI score was 10.24 (95% CI=3.84-16.64). The pooled PUF score was 21.66 (95% CI=20.12-23.20), and the pooled VAS score was 6.46 (95% CI=4.62-8.30).

Bladder assessments in the reviewed articles included cystoscopy, urodynamic studies, videocystometry, bladder imaging, and bladder biopsy. The results are shown in Table 2 and online Appendix 4. Fifteen studies (1221 patients) included data regarding bladder capacity, including functional bladder capacity, cystometric capacity, or maximum cystometric capacity. The pooled functional bladder capacity was 95.23 mL (95% CI=63.57-126.88 mL). The pooled and maximum cystometric capacities were 97.37 mL (95% CI=58.23-136.51 mL) and 202.09 mL (95% CI=169.06-235.13 mL), respectively.

Urodynamic studies revealed a pooled mean voided volume of 113.31 mL (95% CI=59.44-167.19 mL) and a pooled mean Qmax of 8.69 mL/s (95% CI=5.54-11.83 mL/s). The pooled prevalence of detrusor overactivity was 63.9% (95% CI=45.6%-80.3%). Videocystometry or bladder imaging (eg, ultrasound or computed tomography) showed vesicoureteral reflux with a pooled prevalence of 22.0% (95% CI=12.4%-33.5%).

In total, 14 studies included cystoscopy results and bladder biopsy findings. Common findings on cystoscopy included epithelial inflammation in the bladder mucosa, erythematous patches, neovascularisation, and ulcerations. Petechial haemorrhage was observed in patients with severe disease. Bladder biopsy results were consistent with the above inflammatory changes. Urothelial denudation and focal reactive changes were evident. The lamina propria exhibited granulation tissue, vascular congestion, and oedema, along with infiltrating inflammatory cells including lymphocytes, eosinophils, and mast cells. Perivesical fibrosis was present in some patients. Chu et al5 found such inflammatory changes in 71% of their patients.

Treatments for KAU considerably varied among studies, and there were no trends consistent among all studies. In total, 19 articles described the treatment of KAU, which included oral, intravesical, and surgical treatments. Yee et al7 and Wu et al8 adopted a tiered treatment approach, which began with the least invasive oral treatment and was escalated to the most invasive surgical treatment if other treatments failed. However, ketamine abstinence was regarded as a key aspect of patient management in 11 of the 19 articles. Various treatments with their potential indications and efficacies are summarised in Table 3.7 8 9 10 11 12 13 14 15 16 17 18

Oral treatment approaches involved non-steroidal anti-inflammatory drugs, opioid or non-opioid analgesics, anticholinergics, pregabalin, steroids, antibiotics, antihistamines, antioxidants, and/or pentosane polysulphate sodium. Yee et al7 and Wu et al18 reported that oral treatments led to positive outcomes; most patients showed improvements in symptoms, functional bladder capacity, voided volume, PUF scores, and EuroQol VAS scores. In a case series of nine patients, Shahani et al4 observed that oral pentosane polysulphate sodium produced symptomatic relief when combined with ketamine abstinence. However, 11 patients in another study exhibited poor responses to treatment involving non-steroidal anti-inflammatory drugs, anticholinergics, and antibiotics.14

In total, seven studies reviewed intravesical instillation of hyaluronan solutions (eg, sodium hyaluronate and hyaluronic acid). In six of these studies (34 patients), 30 patients showed improvements in symptoms, including suprapubic pain (2 patients) and bladder capacity (4 patients).7 13 14 15 16 19 In the remaining study (2 patients), intravesical treatment did not lead to symptomatic improvement.12

Surgical treatments for patients with KAU included hydrodistension and bladder reconstruction. In most studies, surgical treatments were performed after patients had not responded to oral treatment. Three studies described the efficacy of hydrodistension, which involves the use of fluid to stretch the bladder in an anaesthetised patient. Wu et al8 reported that hydrodistension led to improvements in voided volume, PUF score, frequency, and nocturia in 35 of 47 patients (74.5%). Chang et al12 and Li et al13 reported that 70.0% (14/20) and 71.4% (10/14) of patients, respectively, exhibited symptomatic relief after hydrodistension. In a few studies, botulinum toxin type A injection was conducted along with hydrodistension. Whereas Zeng et al20 reported that symptoms were generally improved with such treatment, Sihra et al21 found that only four of 29 patients experienced subjective symptomatic relief.

Another surgical approach comprises bladder reconstruction, which can be achieved by augmentation cystoplasty or by cystectomy and subsequent construction of a neobladder or an ileal conduit.21 Augmentation cystoplasty increases the bladder capacity by anastomosing a segment of elastic gastrointestinal tract to the diseased fibrotic bladder wall. In the cystectomy method, retention of the bladder neck is combined with the construction of a neobladder to store urine or an ileal conduit to divert urine. Among five studies concerning these reconstruction methods, all demonstrated efficacy in the treatment of advanced ketamine cystitis (KC; a key feature of KAU).9 10 11 17 22 Lee et al10 reported that 26 of 26 patients showed postoperative improvements in bladder capacity, voided volume, and residual volume; similarly, Hung et al9 reported that all eight patients showed postoperative improvements in bladder capacity, renal function, and pain perception. Furthermore, concomitant ureteral reimplantation can be performed in patients with vesicoureteral reflux severity of grade ≥3.10 Importantly, surgical treatments were only effective when patients avoided further ketamine abuse.10 11 17 22

Ketamine-associated uropathy is a clinical entity that has emerged with the increasing popularity of ketamine as an illicit drug among young people. In 37 studies with >4000 patients, the most common manifestations—observed in approximately 60% of patients diagnosed with KAU—were frequency, nocturia, urgency, and bladder pain. Other common urinary symptoms, with prevalences of 40% to 50%, included dysuria, haematuria, and incontinence. Upper urinary tract involvement (eg, hydronephrosis and/or ureteral stricture) was observed in fewer than one-third of patients; renal function was impaired in <10% of patients. Further examinations revealed functional and cystometric bladder capacities of <100 mL, as well as voiding dysfunction. The bladder assessment findings were consistent with the clinical manifestations among affected patients. Symptom severity may be associated with the chronicity and dose of ketamine abuse.23 In the United Kingdom, a survey of 3806 individuals—51.1% with a long-term history of ketamine abuse and 33.8% with a history of ketamine abuse in the previous 1 year—revealed that the dose and frequency of ketamine abuse were associated with the extent of urinary symptoms.23 In Taiwan, Tsai et al14 observed that urinary symptoms began 1 month after the initiation of ketamine abuse and were considerably worse after 1 year of abuse.

Despite the establishment of an association between ketamine abuse and urinary tract damage, the underlying pathophysiology remains unclear. Multiple hypotheses have been proposed to explain the mechanisms that underlie the onset of urinary tract damage. Chu et al5 described four potential mechanisms: direct toxin damage to the urinary tract interstitium, microvascular injury to the urinary tract, autoimmune reaction to ketamine exposure in the urothelial epithelium and submucosa, and (less likely) unrecognised bacteriuria. The initial mechanism ultimately induces chronic inflammatory changes in the bladder, which lead to fibrosis, poor compliance, and contracture. The extent of bladder fibrosis may serve as an indicator of disease severity.24 The occurrence of fibrotic changes is consistent with the common manifestations of frequency, nocturia, and pain associated with reduced bladder capacity; the occurrence of such changes is also consistent with the reduced bladder capacity observed during further urological workup. Wu et al8 attributed the onset of LUTS and reduced bladder capacity among individuals abusing ketamine to a dysfunctional bladder epithelium and a defective glycosaminoglycan layer. The results of our review indicated that glomerulation, erythematous congestion, neovascularisation, and ulceration were common findings in cystoscopic examination of the urothelial epithelium. Bladder biopsy examinations revealed that urothelial denudation was common; infiltrating eosinophils and mast cells were observed in the lamina propria. Accordingly, KAU may involve hypersensitivity or an allergic reaction; this hypothesis is supported by the work of Jhang et al,25 who found that the level of serum immunoglobulin E was higher in patients with KAU than in the control group. Although the exact pathophysiological mechanism remains unclear, the urothelial changes induced by ketamine and its metabolites suggest the onset of an inflammatory process that results in cystitis.8

Ketamine cystitis, a key feature of KAU, is closely associated with LUTS. Notably, KC is similar to interstitial cystitis (IC) in terms of clinical and histological findings. Despite these similarities, it is not difficult to distinguish KC and IC. The presence of cystitis in a patient with a history of ketamine abuse is strongly suggestive of KC. However, it is challenging to determine whether a patient is engaged in ketamine abuse because many patients do not voluntarily provide such information. The onset of cystitis in a patient aged ≤30 years is a potential clue because IC / bladder pain syndrome usually occurs in patients aged ≥40 years. Because of differences in pathophysiology, Yek et al26 suggested that the course of disease progression differed between KC and IC. For example, KC causes bladder contraction that leads to progressive obstructive uropathy and the onset of hydronephrosis / hydroureter. This process explains the potential for upper urinary tract involvement in patients with KAU. In contrast, IC is a chronic bladder condition; its severity generally is not equivalent to the severity of KC.24 In a comparison of clinical characteristics between 16 patients with IC and 13 patients with KC, Wu et al18 found that patients with KC had more severe bladder dysfunction, along with reduced bladder capacity, greater bladder wall thickness, and increased bladder mass volume. Patients with KC also reported greater subjective discomfort (ie, a lower VAS score), compared with patients who had IC.

The similarities between KC and IC should be considered during the workup of suspected KAU. The main consideration involves the use of questionnaires in assessing symptoms and disease severity. Among the articles included in this review, the IPSS, ICSI, ICPI, and PUF were commonly used to assess IC; they generally helped to identify patients who required further examination.27 Clemons et al28 suggested that the ICSI and ICPI were suitable for the assessment of LUTS in patients with IC, but these questionnaires may not be appropriate for use during initial diagnosis. Accordingly, Clemons et al28 proposed that 7 of 15 and 5 of 14 should be regarded as the respective scores for the ICSI and ICPI. In our review, the pooled ICSI and ICPI scores were 11.11 and 10.24, respectively. In 2012, the PUF score was validated by Ng et al29 for the assessment of LUTS associated with the use of street ketamine—the score was correlated with disease severity, as indicated by patient symptoms and the results of other examinations. In that study, Ng et al29 proposed using a PUF score of 17 as a threshold to indicate serious urological consequences. In our review, the pooled PUF score was 21.66. The use of questionnaires during the workup of suspected KAU is a subjective assessment of patient symptoms that may provide insights concerning disease severity and quality of life. Although there is no consensus or standardised questionnaire specific to KAU, these non-invasive questionnaires are useful for initial patient assessment and can help guide subsequent management.

In addition to the use of subjective questionnaires, the workup of suspected KAU commonly consists of radiological, urodynamic, and endoscopic assessments. Despite the absence of standard diagnostic criteria, suspicion of KAU may be based on the presence of urinary tract symptoms combined with a history of ketamine abuse. Multiple aspects should be considered during the workup of suspected KAU. The main goal is the exclusion of other causes that explain the symptoms, including urinary tract infections and urolithiasis. Therefore, standard initial examinations comprise urinalysis, urine culture, and X-ray imaging. Anatomical involvement can be assessed by computed tomography urography to identify upper urinary tract involvement (eg, ureteral stricture, vesicoureteral reflux, and hydronephrosis) and confirm lower urinary tract involvement (eg, diffuse bladder wall thickening, mucosal enhancement, and inflammatory changes in perivesical tissue).30 Urinary system functionality can be evaluated by urodynamics studies that investigate voided volume, Qmax, detrusor compliance, and detrusor overactivity. Cystoscopy and biopsy enable detailed bladder assessments that clarify cystitis severity and should be considered during a later stage of workup if indicated. However, caution is needed when considering the use of cystoscopy. Routine cystoscopy is not recommended17 because it may discourage young patients from undergoing further medical examinations, with long-term impacts on their health.

Although there is no specific regimen or algorithm for the treatment of KAU, ketamine abstinence is consistently effective, regardless of KAU severity. The effects of ketamine abstinence on alleviating and controlling symptoms of KAU are well known.31 32 In a study of 66 individuals with a history of ketamine abuse, Mak et al33 observed significantly improved maximal voided volume after ≥1 year of abstinence (387 mL), compared with patients who had <3 months of abstinence (243 mL). Yee et al24 found that hydronephrosis spontaneously resolved in patients who abstained from ketamine abuse. At initial presentation, medications such as analgesics, anti-inflammatory drugs, and antihistamines were commonly used for symptomatic control.26 Further management options involve intravesical instillation of pentosan polysulphate and hyaluronic acid to protect the bladder lining and repair the damaged glycosaminoglycan layer in the urothelium.19 There is considerable variation in patient responses to the above oral and intravesical treatments. Surgery is indicated when conservative treatments fail. Bladder reconstruction surgery generally leads to improvements in symptoms and bladder functionality,32 but it carries more risks than other treatment options. The available treatment options comprise a spectrum of effectiveness and invasiveness. The most invasive bladder reconstruction surgery is associated with greater effectiveness. Yee et al7 proposed a standardised treatment protocol that comprised the following four-tier approach, where patients receive increasingly invasive treatment if less invasive treatments are ineffective: (1) anti-inflammatory or anticholinergic drugs, (2) opioid or pregabalin, (3) intravesical hyaluronic acid, and (4) hydrodistension and bladder reconstruction surgery (including augmentation cystoplasty and cystectomy with an ileal conduit or neobladder). Wu et al8 adopted a similar tiered approach that involved assigning patients to three clinical staging groups according to their radiological and urodynamic findings. Stage I patients received lifestyle modification guidance and appropriate medications, stage II patients underwent hydrodistension, and stage III patients underwent bladder reconstruction surgery if other treatments were ineffective for 3 months. This tiered approach favourably balances the invasiveness and effectiveness among the available treatment modalities.

There were some limitations in this systematic review and meta-analysis. First, all included studies were retrospective; there is a need for prospective studies of patients with KAU. Second, there was heterogeneity among the included studies, primarily because of variations in workup and treatment; standardisation would be beneficial for future management of patients with KAU. Third, treatment efficacy could not be fully assessed because baseline characteristics were not described in a consistent manner in the included studies. Fourth, because the incidence of KAU depends on the locality-dependent popularity of ketamine, most studies were from Asian countries/regions (eg, Taiwan and Hong Kong). Nevertheless, this comprehensive review provides an important summary concerning the limited available information about KAU.

Patients with KAU most commonly present with frequency, urgency, suprapubic pain, and nocturia; the upper urinary tract is occasionally involved. The occurrence of urinary symptoms in young patients with a history of ketamine abuse should lead to suspicion of KAU. Validated symptom scores are useful in patient-based subjective assessment of symptom severity and treatment progress, whereas radiological and urodynamic examinations objectively define the extent of urinary tract involvement and the functional impairment that results from KAU. In terms of management, ketamine abstinence is essential and a tiered treatment approach is preferred, beginning with the least invasive medications and progressing to surgery if conservative treatments are ineffective.

Concept or design: EOT Chan, VWS Chan, MCS Wong, JYC Teoh.
Acquisition of data: EOT Chan, VWS Chan, TST Tang, V Cheung.
Analysis or interpretation of data: EOT Chan, VWS Chan, JYC Teoh.
Drafting of the manuscript: EOT Chan.
Critical revision of the manuscript for important intellectual content: MCS Wong, CH Yee, CF Ng, JYC Teoh.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

As editors of the journal, MCS Wong, CF Ng, and JYC Teoh were not involved in the peer review process. Other authors have disclosed no conflicts of interest.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethics approval is not required for this study which is a review on published research and not involving patient data collection and retrieval of patient data.

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