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What's known on the subject? and What does the study add? There is a very limited literature on the syndrome described in this review. The largest series comes from Hong Kong and includes 59 patients – this was largely a description of the presenting problems and established the link between these symptoms and ketamine. Prior to this much smaller case series (including one from the same group) were all that exists. An increasing number of UK urologists are reporting seeing these patients and we have formed a collaboration interested in understanding the pathology and establishing an effective treatment pathway for these patients. This paper aims to consolidate this knowledge. Ketamine has become increasingly recognized as a drug of recreational use. Individuals using significant amounts have developed symptoms including a small painful bladder, ureteric obstruction, papillary necrosis and hepatic dysfunction. The present paper examines the current literature on the relationship between ketamine use and these symptoms. Our own clinical experience and the data available clarify the causal relationship, and further data help to elucidate the mechanism of damage. On the basis of continued work and development with patients who are ketamine users we suggest an assessment and treatment regime that includes cessation of ketamine use and adequate analgesia to overcome symptoms. In conclusion, it is important for medical practitioners who encounter patients with these symptoms to ask about recreational drug use. Ketamine remains a safe and effective drug to use under appropriate medical supervision. Patients identified as suffering from this syndrome will need to be referred to a urological unit with an interest in the treatment of the condition.

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BackgroundThere is an emerging association between ketamine abuse and the development of urological symptoms including dysuria, frequency and urgency, which have a neurological component. In addition, extreme cases are associated with severe unresolving bladder pain in conjunction with a thickened, contracted bladder and an ulcerated/absent urothelium. Here we report on unusual neuropathological features seen by immunohistology in ketamine cystitis.ResultsIn all cases, the lamina propria was replete with fine neurofilament protein (NFP+) nerve fibres and in most patients (20/21), there was prominent peripheral nerve fascicle hyperplasia that showed particular resemblance to Morton’s neuroma. The nerve fascicles, which were positive for NFP, S100 and the p75 low-affinity nerve growth factor receptor (NGFR), were generally associated with a well-developed and in places, prominent, epithelial membrane antigen+/NGFR+ perineurium. This peripheral nerve fascicle hyperplasia is likely to account for the extreme pain experienced by ketamine cystitis patients. Urothelial damage was a notable feature of all ketamine cystitis specimens and where urothelium remained, increased NGFR expression was observed, with expansion from a basal-restricted normal pattern of expression into the suprabasal urothelium.ConclusionsThe histological findings were distinguishing features of ketamine cystitis and were not present in other painful bladder conditions. Ketamine cystitis afflicts predominantly young patients, with unknown long-term consequences, and requires a strategy to control severe bladder pain in order to remove a dependency on the causative agent. Our study indicates that the development of pain in ketamine cystitis is mediated through a specific neurogenic mechanism that may also implicate the urothelium.

It is generally considered that the bladder is impervious and stores urine in unmodified form on account of the barrier imposed by the highly-specialised uro-epithelial lining. However, recent evidence, including demonstration of aquaporin (AQP) expression by human urothelium, suggests that urothelium may be able to modify urine content. Here we have we applied functional assays to an in vitro-differentiated normal human urothelial cell culture system and examined both whether AQP expression was responsive to changes in osmolality, and the effects of blocking AQP channels on water and urea transport. AQP3 expression was up-regulated by increased osmolality, but only in response to NaCl. A small but similar effect was seen with AQP9, but not AQP4 or AQP7. Differentiated urothelium revealed significant barrier function (mean TER 3862 Ω.cm2), with mean diffusive water and urea permeability coefficients of 6.33×10−5 and 2.45×10−5 cm/s, respectively. AQP blockade with mercuric chloride resulted in decreased water and urea flux. The diffusive permeability of urothelial cell sheets remained constant following conditioning in hyperosmotic NaCl, but there was a significant increase in water and urea flux across an osmotic gradient. Taken collectively with evidence emerging from studies in other species, our results support an active role for human urothelium in sensing and responding to hypertonic salt concentrations through alterations in AQP protein expression, with AQP channels providing a mechanism for modifying urine composition. These observations challenge the traditional concept of an impermeable bladder epithelium and suggest that the urothelium may play a modulatory role in water and salt homeostasis.

The bladder is an important tissue in which to evaluate xenobiotic drug interactions and toxicities due to the concentration of parent drug and hepatic/enteric-derived metabolites in the urine as a result of renal excretion. Breaching of the barrier provided by the bladder epithelial lining (the urothelium) can expose the underlying tissues to urine and cause harmful effects (e.g., cystitis or cancer). Human urothelium is most commonly represented in vitro as immortalized or established cancer-derived cell lines, but the compromised ability of such cells to undergo differentiation and barrier formation means that nonimmortalized, normal human urothelial (NHU) cells provide a more relevant cell culture system. The impressive capacity for urothelial self-renewal in vivo can be harnessed in vitro to generate experimentally-useful quantities of NHU cells, which can subsequently be differentiated to form a functional or "biomimetic" urothelium. When seeded onto permeable membranes, these barrier-forming human urothelial tissue models enable the modeling of serum and luminal (intravesical) exposure to drugs and metabolites, thus supporting efficacy/toxicity assessments. Biomimetic human urothelial constructs provide a potential step along the preclinical trail and may support the extrapolation from rodent in vivo data to determine human relevance. Early evidence is beginning to demonstrate that human urothelium in vitro can provide information that supersedes conventional rodent studies, but further validation is needed to support widespread adoption.

In vivo studies of implanted acellular biological scaffolds in experimental animals have shown constructive remodeling mediated by anti-inflammatory macrophages. Little is known about the human macrophage response to such biomaterials, or the nature of the signaling mechanisms that govern the macrophage phenotype in this environment. The cellular events at the interface of a tissue and implanted decellularized biomaterial were examined by establishing a novel ex vivo tissue culture model in which surgically excised human urinary tract tissue was combined with porcine acellular bladder matrix (PABM). Evaluation of the tissue-biomaterial interface showed a time-dependent infiltration of the biomaterial by CD68(+) CD80(-) macrophages. The migration of CD68(+) cells from the tissue to the interface was accompanied by maturation to a CD163(hi) phenotype, suggesting that factor(s) associated with the biomaterial or the wound edge was/were responsible for the active recruitment and polarization of local macrophages. Glucocorticoid receptor (GR) and peroxisome proliferator activated receptor gamma (PPARγ) signaling was investigated as candidate pathways for integrating inflammatory responses; both showed intense nuclear labeling in interface macrophages. GR and PPARγ activation polarized peripheral blood-derived macrophages from a default M1 (CD80(+)) toward an M2 (CD163(+)) phenotype, but PPARγ signaling predominated, as its antagonism blocked any GR-mediated effect. Seeding on PABM was effective at polarizing peripheral blood-derived macrophages from a default CD80(+) phenotype on glass to a CD80(-) phenotype, with intense nuclear localization of PPARγ. These results endorse in vivo observations that the infiltration of decellularized biological scaffolds, exemplified here by PABM, is pioneered by macrophages. Thus, it appears that natural factors present in PABM are involved in the active recruitment and polarization of macrophages to a CD163(+) phenotype, with activation of PPARγ identified as the candidate pathway. The harnessing of these natural matrix-associated factors may be useful in enhancing the integration of synthetic and other natural biomaterials by polarizing macrophage activation toward an M2 regulatory phenotype.