Ketamine‐induced uropathy: A narrative systemic review of surgical outcomes of reconstructive surgery

Abstract Aims Refractory ketamine‐induced uropathy (KU) (RKU) has devastating effects on the lower urinary tract leading to ureteral obstruction and even renal failure. The only effective treatment for RKU is major surgical reconstruction or urinary diversion. Nevertheless, there is a paucity of awareness about this destructive condition; the aim of this study is to conduct a narrative systemic review of all surgical outcomes of RKU. Methods This is an English language literature review of surgical outcomes in KU patients who underwent reconstructive lower urinary tract surgery or urinary diversion through 5 August 2022. Two independent researchers assessed the relevance of each paper and disputes were settled by a third party. In‐vitro, animal studies, letters to the editor and papers that did not evaluate surgical outcomes were excluded. Results Of the 50 763 identified articles, 622 were relevant based on title, 150 based on abstract, but only 23 papers were relevant by content. In all, 875 patients were documented as having KU, of whom 193 (22%) underwent reconstructive surgery. The data were disconcerting, as the apparent rapid progression from the beginning of KU to end‐stage bladder was only a 1‐year difference of ketamine abuse between those patients who required surgery (4.4 years) and those that did not (3.4 years). Conclusions The data suggest that the time interval from the beginning of ketamine‐induced uropathy to the end‐stage bladder may be measured in months, confounding decision making. There is a dearth of literature about KU, and more research is needed to better understand this pathology.

generally occur during waking. 2 Known as 'K', 'Special K' or 'Dorothy' on the street, ketamine has become a popular recreational drug because of the powerful hallucinations and out-of-body experiences it affords. Furthermore, due to the misconception that ketamine is less addictive or potentially harmful than other black-market drugs, the use of street ketamine has increased over the years. 3 This, coupled with its availability (retailing at £20 per gram compared with £50 per gram for cocaine and £45 per gram for heroin, on the black market), 4 has led to cases of ketamine-associated pathology becoming more prevalent. In 2006, ketamine was made a Class C substance via the Misuse of Drugs Act, and in 2014, 1.8% of individuals aged 16-24 years reported using ketamine in the last year. 3 Recreational use of ketamine can cause very serious injury and dependence. Common side effects include memory loss, depression, thought dissociation, delusional thinking, abdominal cramps and cystitis-like symptoms. 5 Recently, there has been an emergence of data reporting a high prevalence of a symptom complex characterized by severe lower urinary tract symptoms (LUTS) including urinary frequency and urgency, small volume voids, painful haematuria and a biopsy revealing inflammation that resembled interstitial cystitis in those patients abusing ketamine. [6][7][8] In one study, approximately two thirds of ketamine abusers had at least one LUTS, while only 19% of control subjects had these symptoms. 9 This symptom complex has come to be termed 'ketamine-induced uropathy' (KU), 10 and its end stage is devastating usually requiring major surgical interventions.
However, given the destructive nature of end-stage KU, there is still a dearth of information about this symptom complex in the literature. In order to raise awareness of the disease amongst the public and medical communities, this systemic review and meta-analysis sought to compile all of the data available in the literature regarding outcomes of reconstructive surgery in those suffering from endstage KU.

| METHODS
This is an English language literature review of surgical outcomes in KU patients who underwent reconstructive lower urinary tract surgery (RLUTS) or urinary diversion through 5 August 2022. Two independent researchers read each paper's title and if both found the paper to be relevant, its abstract was read and then, after applying exclusion criteria, the full papers were read; all disagreements regarding relevance were settled by a vote amongst the researchers and a third party. The following search terms were employed to search PubMed, Medline and Scopus: ketamine abuse, ketamine abuse and surgery, ketamine and interstitial cystitis, ketamine abuse and interstitial cystitis, ketamine abuse and complications, ketamine and cystitis, ketamine abuse and cystitis, ketamine and cystoplasty, ketamine abuse and cystoplasty, ketamine abuse and ileocecocystoplasty, ketamine and ileocecocystoplasty, ketamine and enterocystoplasty, ketamine abuse and enterocystoplasty, ketamine abuse and augmentation enterocystoplasty, ketamine and augmentation enterocystoplasty, ketamine and augmentation cystoplasty, ketamine abuse and augmentation cystoplasty, ketamine abuse and bladder, ketamine and bladder, ketamine cystitis, ketamine-induced uropathy and surgery, ketamine and urinary diversion, ketamine abuse and urinary diversion, ketamine and cystectomy, and ketamine abuse and cystectomy. In vitro, animal studies, letters to the editor and papers that did not evaluate surgical outcomes were excluded.
We extracted the following data from each article: type of article (e.g., case report, case series, retrospective observational studies and literature review), time period over which study was conducted, number of patients (male and female), age, symptoms, symptom scores, For safety, we searched for reported general complications, methods for evaluating complications, prompted complications and description of loss to follow-up. For each category mentioned by a paper, they received one point. The point system ranges from 0 (worst quality) to 15 (best quality). By consensus, the authors agreed that a minimum threshold of eight categories was needed for a paper to be potentially scientifically valid enough. We bolded the categories that we deemed necessary to meet a threshold score in Table 4. The more categories a paper mentioned, the higher the score and the more scientific validity.
To aggregate the data, weighted averages were taken of all continuous variables, represented as mean ± standard deviation; categorical data are represented by number and percentage out of the whole (%). Based on the data present in the literature, we found it impossible to distinguish the outcomes of the various reconstructive surgeries as several papers reported on patient populations that had received different surgeries without linking outcomes to those procedures. Furthermore, demographic information on nonsurgical patients included in surgical publications were included as a means of assisting in the physicians in the decision-making process.

| RESULTS
The search criteria yielded a total of 49 825 for Scopus, 748 unique articles in PubMed and 190 unique articles in Medline. Of the 50 763 identified articles, 622 were relevant based on title, 150 based on abstract, but only 23 papers were relevant by content ( Figure 1). In all, 875 patients were documented as having ketamine cystitis, of whom 193 (22%) underwent reconstructive surgery (article descriptions can be found in Data S1). Demographic and the type of reconstructive surgery are depicted in Tables 1 and 2, respectively.
Overall, the quality of the studies reporting surgical outcomes was poor. Surgical success rates were available in only 110/193 patients (57%), and less than 50% of the patients had any outcome data with respect to pain, voids per day, bladder capacity and compliance or post-void residual urine (Table 4).
Surgical outcomes are summarized in Table 3. Mean follow-up was 20 ± 9.0 months, and ranged from 10 days to 35    Medical treatment may be helpful in stopping disease progression and relieving symptoms in the early stages of KU, as seen in our nonsurgical patient population. Such therapies include antimuscarinics and nonsteroid anti-inflammatory drugs, cystoscopic hydrodistension and intravesical instillation therapy with hyaluronic acid or heparin.
Intravesical treatment with surface protectants has been shown to reduce bladder pain; however, it is difficult to effectively treat the symptoms if patients continue using ketamine. 16 If surgical management is chosen, compliance with post-operative care and abstinence should be stressed to the patient before surgery. 17 In fact, all patients in this review who continued to experience pain post-operatively, or required a reoperation, had continued to abuse ketamine during or after treatment.
Surgical reconstruction is indicated for those with end-stage bladder disease characterized by refractory overactive bladder symptoms, bladder pain, low bladder capacity, and low bladder compliance. Of course, it is best accomplished before the onset of hydronephrosis  22 24 Reported loss to follow-up 22 Chiew, et al. 23   Chung et al. 18 and Lee et al. 19  There were significant limitations to this review because of the overall poor quality of the studies themselves, the most important of which were that a quantitative estimate of post-operative symptoms was available in less than a third of studies (mean = 22%, range = 0%-43%) And only 40% of studies even mentioned the length of follow-up, with a range of 10 days to 35 months. In addition, many of the studies were not explicit about which surgeries were done in patients requiring reoperations or even which patients needed reoperations.

| CONCLUSION
Ketamine-induced uropathy is a rapidly progressive, devastating condition that predominantly affects teenagers and young adults. It can T A B L E 4 (Continued) Reoperations 74 Average of surgical outcome data points 41 Threshold categories a 60 Overall categories a 53 Abbreviations: ABC, anaesthetic bladder capacity; CBC, cytometric bladder capacity; MBC, maximum bladder capacity; MVV, maximum voided volume; PVR, post-void residual volume; Q Max, maximum flow; UTI, urinary tract infection; VUR, vesicoureteral reflux. a Category refers to data deemed necessary to assess the scientific validity of each paper.
lead to end-stage bladder within a few years after its onset. Once refractory LUTS set in, the only effective treatment is major reconstructive surgery ranging from augmentation enterocystoplasty to cystoprostatectomy and urinary diversion.

AUTHOR CONTRIBUTIONS
All those that had contributed to the creation of this manuscript have been included in the author section.