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Upper urinary tract damage caused by ketamine snorting—A report of nine cases
Urological Science 26 (2015) 182e185
Contents lists available at ScienceDirect
Urological Science journal homepage: www.urol-sci.com
Original article
Upper urinary tract damage caused by ketamine snortingdA report of nine cases Hsiang-Ying Lee a, b, Yu-Chao Hsu c, Chao-Yu Hsu d, Eric Chieh-Lung Chou e, f, Ching-Chia Li a, b, Yung-Shun Juan b, g, *, Mei-Yu Jang g, * a
Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan, ROC Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, ROC Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC d Division of Urology, Department of Surgery, Tungs' Taichung Metro Harbor Hospital, Taichung, Taiwan, ROC e Department of Urology, China Medical University Hospital, Taichung, Taiwan, ROC f School of Medicine, China Medical University, Taichung, Taiwan, ROC g Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan, ROC b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 March 2015 Received in revised form 15 July 2015 Accepted 16 July 2015 Available online 16 September 2015
Objective: The toxicity of ketamine to genitourinary system not only involved in lower urinary tract, which include urinary frequency, urgency, suprapubic pain, dysuria and hematuria, but also upper urinary tracts. However, the reports of ketmaine-induced upper urinary tract damage were rare. Materials and methods: Herein, we reported nine ketamine abusers presented with moderate flank pain with hydronephrosis and lower urinary tract symptoms from three medical centers located around Taiwan. Results: All patients were diagnosed of hydronephrosis by sonography or abdominal computed tomography scans and 7 cases combined with acute kidney injury. They all receive ureteroscopy exam and double-J stenting. All of their flank pain and renal function impairment improved during follow up. Conclusion: To the best of our knowledge, currently there is no standard therapy for ketamine-induced nephropathy, we therefore supplied a therapeutic choice for those ketamine abuser combined with hydronephrosis and/or acute kidney injury. Copyright © 2015, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: hydronephrosis ketamine urinary tract damage
1. Introduction Ketamine, an N-methyl-D-aspartate receptor antagonist, was used to induce anesthesia due to its acute-onset and short-acting characteristics. Ketamine is known to be a potent dissociative, making the user feel that their mind has somehow become detached from their body. In the meantime, ketamine is cheaper than other drugs and easy to obtain1; therefore, ketamine has become a popular recreational drug in nightclubs in recent years. However, the impact of ketamine on the general system arouses society's attention and imposes a great burden to health care resources. Toxicity of ketamine in the genitourinary system was first reported in 2007 by Shahani et al.2 Since then, some researchers have shared
* Corresponding authors. Kaohsiung Municipal Hsiaokang Hospital, Number 482, Shanming Road, Siaogang District, Kaohsiung City 812, Taiwan, ROC. E-mail addresses: [email protected] (Y.-S. Juan), [email protected] (M.-Y. Jang).
their experiences of dealing with ketamine-induced uropathy patients in several reports. Around 20e30% of ketamine abusers complain about lower urinary tract symptoms (LUTS), which include urinary frequency, urgency, suprapubic pain, dysuria, and hematuria.3 In addition to injury to the lower urinary tract, ketamine and its metabolites also devastate the upper urinary tract, leading to varying degrees of hydronephrosis and renal function impairment. Herein, we describe nine ketamine abusers with a history of drug abuse for over 5 years, who suffered from bilateral hydronephrosis; these nine patients came from three different medical centers in Taiwan. 2. Case reports A total of four male and five female ketamine abusers, aged 25e42 years (mean, 31 years), who underwent double-J stenting due to hydronephrosis at three institutions (Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan; Tungs' Taichung
http://dx.doi.org/10.1016/j.urols.2015.07.008 1879-5226/Copyright © 2015, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
H.-Y. Lee et al. / Urological Science 26 (2015) 182e185
183
Table 1 Drug-using history and characteristics of patients.a Patient no.
Sex
Age (y)
Route of administration
Duration of taking ketamine (y)
Amount of ketamine taken (g/d)
Preoperative serum creatinine (mg/dL)
Postoperative serum creatinine (mg/dL)
Hydronephrosis
1 2 3 4 5 6 7 8 9
F M M F F M F F M
34 29 42 31 25 27 30 28 31
Snort Snort Snort Snort Snort Snort þ smoking Snort Snort Snort
8 12 15 11 6 5 5 4e5 2
5e10 1e5 10 4 5 5 2.5 1 5
2.01 1.51 2.64 1.73 2.7 1.5 0.75 2.15 0.7
1.66 1.0 1.09 0.92 0.6 1.04 0.45 1.08 0.58
Bilateral / Leftb Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral
Patient no.
Severity of hydronephrosisa
Level of obstruction
Follow-up period (mo)
Estimated GFR (mL/min/1.73 m2)
Receive URSdbiopsy or not
Biopsy pathology result
Persistent DJ stent currently
DJ stent indwelling duration (mo)
1
1
M/3
8
34.91
Y
Cystitis cystica and glandularis
Y (left)
2 3
2 2
L/3 L/3
12 48
54.17 71.96
N Y
4 5 6
2 2 Left: 2 Right: 1 3 3 Left: 4 Right: 3
L/3 L/3 M/3
4 6 34
34 23.4 25
N Y N
L/3 L/3 L/3
27 49 18
7 8 9
42 43 >60
Inflammation with eosinophilic infiltration Fibroepithelial polyps
N N N
Y (bilateral) Y (bilateral) Y (bilateral) Y (bilateral) N
18
Y (bilateral) Y (bilateral) N
12
F ¼ female; M ¼ male. a Severity of hydronephrosis with renosonography: Grade 1 is anterioreposterior distance >5 mm, Grade 2 means calyx can be seen, Grade 3 is blunting calyces, and Grade 4 is cortical thinning. b Bilateral hydronephrosis initially, then only the left side after months of follow-up.
Metro Harbor Hospital Kaohsiung, Taiwan; and Chang Gung Memorial Hospital, Taoyuan, Taiwan), were included in this study. Characteristics of these patients are listed in Table 1. They all came to hospitals with moderate flank pain and severe LUTS, including dysuria, frequency, urgency, and voiding pain. Three of the patients also suffered from acute pyelonephritis with fever. These three patients received antibiotic treatment initially. The other patients had neither pyuria nor bacterial growth in urine culture. All patients had ultrasonographic evidence of hydronephrosis at the time of diagnosis. Seven of these patients also had impaired renal function (Table 1). The first case revealed bilateral hydronephrosis, with the creatinine level going up to 2.01 mg/dL at the first visit. During 1-month follow-up and cessation of ketamine abuse, right hydronephrosis was subsided. As hydronephrosis with persistent flank pain continued, ureterorenoscopy was performed to examine the cause of hydronephrosis. Inflammatory polyps over the middle-third ureteral wall were noted during ureteroscopy (Fig. 1) and were biopsied. A double-J stent was inserted at the end of surgery. The pathology result of polyps was characterized by cystical dilated luminal spaces and cuboidal to columnar appearance of the umbrella cell layer representing a picture of chronic inflammation. Scattered eosinophils were also seen focally (Fig. 2). The other patients with bilateral hydronephrosis, acute kidney injury, and ureter stenosis were examined by noncontrast abdominal computed tomography (CT; Fig. 3). Ureteral polyps and ulcerative ureteritis with mucosa erosion were discovered in all nine patients while receiving bilateral ureterorenoscopy, and three patients received polyp biopsy concurrently. These patients were noted to have partial or complete recovery of renal function with improvement in hydronephrosis after inserting a double-J stent. Seven patients retained the indwelling double-J stent until now, and in the other two patients the double-J stent was removed after
18 months and 12 months, respectively, of follow-up. All these patients were encouraged to discontinue ketamine abuse to prevent further urinary function deterioration. 3. Discussion Severe LUTS with chronic cystitis among ketamine abusers were discussed in the literature; about 20e30% of patients may suffer from LUTS.4 However, the adverse effect of ketamine on the upper urinary tract is less investigated. In Chu et al's study,4 51% of
Fig. 1. Ureterorenoscopic findings of Patient 1: anesthetized ureterorenoscope reveals ureter polyps.
184
H.-Y. Lee et al. / Urological Science 26 (2015) 182e185
Fig. 2. (A) Cystitis cystica (arrow) and cystitis glandularis (arrowhead) (magnification 100). (B) Eosinophil infiltration (magnification 400).
ketamine cystitis patients had ketamine-induced unilateral or bilateral hydronephrosis found by sonography. Owing to its high incidence and the fact that it may cause irreversible renal damage with concomitant infection, determining the involvement of the upper urinary tract is important. The actual mechanism of urinary tract destruction is still not clear, but there are some hypotheses.
Fig. 3. Noncontrast abdominal computed tomography of Patient 4 shows bilateral hydronephrosis.
Chu et al4 proposed that ketamine and its metabolites, such as norketamine and dehydronorketamine, cause direct toxicity to bladder epithelial cell, microvasculature toxicity, neural and neurotransmitter toxic effects, or immunological reaction.5 We supposed that the toxic effect of ketamine to ureteral urothelial cell presents similar mechanism with lower urinary tract mucosa due to the same structure. Although it is unclear whether the severity of abuse is related to the severity of upper urinary tract damage, in most of our patients, prolonged drug abuse and intake of a large dosage of ketamine seem to have possibly caused ureteral inflammation with hydronephrosis and renal function impairment. Therefore, a close follow-up of renal function and imaging studies are necessary for these high-risk patients. The level of damage of the upper urinary tract in our patients is concordant with the findings of Huang et al,6 who discovered ureteral wall thickening with hydronephrosis, which is related to chronic inflammation. In Huang et al's7 study, retrograde pyelography also showed ureteral strictures with segmental beading, which were characterized as “walking-stick ureters.” Abdominal CT is a useful imaging tool to evaluate the cause of hydronephrosis and the extent of obstruction. As we know, no previous studies have presented the ureterorenoscopic picture of the ureteral wall. Among our patients, ureteral wall thickening and inflammatory polyps occurred not just at the vesicoureteric junction, these affected the entire ureter and/or a part of the ureter away from the distal ureter, although most of the literatures described that stenosis occurs at the vesicoureteric junction.1,4,8 This finding is also different from previous studies, which suggested that most cases of hydronephrosis were the result of impaired bladder compliance and vesicoureteral reflux.4,9 Ketamine is metabolized by liver microsomal enzymes and excreted from the kidney by conjugating to water-soluble glucuronide derivatives.10 From the pathological features of the ureteral wall, it presented with inflammatory cell infiltration and fibrosis, which may be caused by the continuous contact with a high concentration of ketamine and its metabolites in urine. From our experience, LUTS are more frequent and appear earlier than upper urinary tract symptoms. We suppose that the longer contact duration of toxic urine with the urothelium might be a contributing factor. There are several treatment choices for relief of hydronephrosis with acute kidney injury, including percutaneous nephrostomy insertion and double-J stenting for urinary diversion. Some physicians may have a concern that the double-J stent will aggravate LUTS due to contact with the bladder wall. However, in these patients, not only their flank pain, impaired renal function, and hydronephrosis were improved, but also LUTS did not get worse. In fact, the crucial key to decrease the severity of LUTS is cessation of ketamine use. Compared with percutaneous nephrostomy, the double-J stent implantation is a less invasive procedure. In addition, we can directly view the condition of the ureteral wall by ureterorenoscope and perform biopsy at the same time. It remained unclear for how long the double-J stent should be indwelled or when it should be removed. Some of these ketamine abusers even tried to remove the double-J stent, but hydronephrosis and deterioration of renal function were noted thereafter; therefore, a double-J stent was inserted again. It is still unknown when hydronephrosis and acute kidney injury develop after ketamine abuse. Based on the experience of our patients here, we can state that it may appear several years later. Winstock et al11 emphasized that the harmful effects of ketamine on the urinary tract are dose related, and it is compatible with the findings in most of our patients who presented with large-dosage dependency. Some of our cases achieved hydronephrosis improvement after abstinence from ketamine abuse; by contrast, when they continued to snort ketamine, the symptoms progressed and the double-J stent had to be kept indwelled. In
H.-Y. Lee et al. / Urological Science 26 (2015) 182e185
some cases, we performed biopsy of both the ureter and the bladder wall. With respect to sequential LUTS and similar urothelial structure, if a patient discontinued ketamine abuse when LUTS occurred, it was postulated that the upper urinary tract injury might decline. In conclusion, LUTS are the principal presenting symptoms in patients with ketamine abuse; however, ketamine-related upper urinary tract injuries, including ureteral inflammation, ureteral stricture, hydronephrosis, and impaired renal function, have drawn physicians' attention in recent years. In our opinion, abdominal CT and ureterorenoscopy are important diagnostic tools for evaluation of the extent of upper urinary tract damage. If ureteral stenosis with inflammation, which leads to hydronephrosis and renal function impairment, was found, preserving renal function and relieving symptoms by urinary diversion are crucial. Nevertheless, the underlying mechanism and pathogenesis are not clear now. Longer time is required to observe the disease progression, and also further animal or basic experimental research has to be conducted. We put forward our experiences of treatment plan and propose our point of view regarding treatment of patients with ketamine-induced uropathy. Conflicts of interest The authors declare that they have no financial or non-financial conflicts of interest related to the subject matter or materials discussed in the manuscript.
185
Sources of funding No funding was received for the work described in the article.
References 1. Chu PS, Kwok SC, Lam KM, Chu TY, Chan SW, Man CW, et al. ‘Street ketamine’associated bladder dysfunction: a report of ten cases. Hong Kong Med J 2007;13: 311e3. 2. Shahani R, Streutker C, Dickson B, Stewart RJ. Ketamine-associated ulcerative cystitis: a new clinical entity. Urology 2007;69:810e2. 3. Middela S, Pearce I. Ketamine-induced vesicopathy: a literature review. Int J Clin Pract 2011;65:27e30. 4. 4. Chu PS, Ma WK, Wong SC, Chu RW, Cheng CH, Wong S, et al. The destruction of the lower urinary tract by ketamine abuse: a new syndrome? BJU Int 2008;102: 1616e22. 5. Wei YB, Yang JR, Yin Z, Guo Q, Liang BL, Zhou KQ. Genitourinary toxicity of ketamine. Hong Kong Med J 2013;19:341e8. 6. Huang LK, Wang JH, Shen SH, Lin AT, Chang CY. Evaluation of the extent of ketamine-induced uropathy: the role of CT urography. Postgrad Med J 2014;90: 185e90. 7. Huang PW, Meng E, Cha TL, Sun GH, Yu DS, Chang SY. ‘Walking-stick ureters’ in ketamine abuse. Kidney Int 2011;80:895. 8. Chiew YW, Yang CS. Disabling frequent urination in a young adult. Ketamineassociated ulcerative cystitis. Kidney Int 2009;76:123e4. 9. Chen CH, Lee MH, Chen YC, Lin MF. Ketamine-snorting associated cystitis. J Formos Med Assoc 2011;110:787e91. 10. Moore KA, Sklerov J, Levine B, Jacobs AJ. Urine concentrations of ketamine and norketamine following illegal consumption. J Anal Toxicol 2001;25:583e8. 11. Winstock AR, Mitcheson L, Gillatt DA, Cottrell AM. The prevalence and natural history of urinary symptoms among recreational ketamine users. BJU Int 2012;110:1762e6.
Contents lists available at ScienceDirect
Urological Science journal homepage: www.urol-sci.com
Original article
Upper urinary tract damage caused by ketamine snortingdA report of nine cases Hsiang-Ying Lee a, b, Yu-Chao Hsu c, Chao-Yu Hsu d, Eric Chieh-Lung Chou e, f, Ching-Chia Li a, b, Yung-Shun Juan b, g, *, Mei-Yu Jang g, * a
Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan, ROC Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, ROC Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, ROC d Division of Urology, Department of Surgery, Tungs' Taichung Metro Harbor Hospital, Taichung, Taiwan, ROC e Department of Urology, China Medical University Hospital, Taichung, Taiwan, ROC f School of Medicine, China Medical University, Taichung, Taiwan, ROC g Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan, ROC b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 March 2015 Received in revised form 15 July 2015 Accepted 16 July 2015 Available online 16 September 2015
Objective: The toxicity of ketamine to genitourinary system not only involved in lower urinary tract, which include urinary frequency, urgency, suprapubic pain, dysuria and hematuria, but also upper urinary tracts. However, the reports of ketmaine-induced upper urinary tract damage were rare. Materials and methods: Herein, we reported nine ketamine abusers presented with moderate flank pain with hydronephrosis and lower urinary tract symptoms from three medical centers located around Taiwan. Results: All patients were diagnosed of hydronephrosis by sonography or abdominal computed tomography scans and 7 cases combined with acute kidney injury. They all receive ureteroscopy exam and double-J stenting. All of their flank pain and renal function impairment improved during follow up. Conclusion: To the best of our knowledge, currently there is no standard therapy for ketamine-induced nephropathy, we therefore supplied a therapeutic choice for those ketamine abuser combined with hydronephrosis and/or acute kidney injury. Copyright © 2015, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: hydronephrosis ketamine urinary tract damage
1. Introduction Ketamine, an N-methyl-D-aspartate receptor antagonist, was used to induce anesthesia due to its acute-onset and short-acting characteristics. Ketamine is known to be a potent dissociative, making the user feel that their mind has somehow become detached from their body. In the meantime, ketamine is cheaper than other drugs and easy to obtain1; therefore, ketamine has become a popular recreational drug in nightclubs in recent years. However, the impact of ketamine on the general system arouses society's attention and imposes a great burden to health care resources. Toxicity of ketamine in the genitourinary system was first reported in 2007 by Shahani et al.2 Since then, some researchers have shared
* Corresponding authors. Kaohsiung Municipal Hsiaokang Hospital, Number 482, Shanming Road, Siaogang District, Kaohsiung City 812, Taiwan, ROC. E-mail addresses: [email protected] (Y.-S. Juan), [email protected] (M.-Y. Jang).
their experiences of dealing with ketamine-induced uropathy patients in several reports. Around 20e30% of ketamine abusers complain about lower urinary tract symptoms (LUTS), which include urinary frequency, urgency, suprapubic pain, dysuria, and hematuria.3 In addition to injury to the lower urinary tract, ketamine and its metabolites also devastate the upper urinary tract, leading to varying degrees of hydronephrosis and renal function impairment. Herein, we describe nine ketamine abusers with a history of drug abuse for over 5 years, who suffered from bilateral hydronephrosis; these nine patients came from three different medical centers in Taiwan. 2. Case reports A total of four male and five female ketamine abusers, aged 25e42 years (mean, 31 years), who underwent double-J stenting due to hydronephrosis at three institutions (Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan; Tungs' Taichung
http://dx.doi.org/10.1016/j.urols.2015.07.008 1879-5226/Copyright © 2015, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
H.-Y. Lee et al. / Urological Science 26 (2015) 182e185
183
Table 1 Drug-using history and characteristics of patients.a Patient no.
Sex
Age (y)
Route of administration
Duration of taking ketamine (y)
Amount of ketamine taken (g/d)
Preoperative serum creatinine (mg/dL)
Postoperative serum creatinine (mg/dL)
Hydronephrosis
1 2 3 4 5 6 7 8 9
F M M F F M F F M
34 29 42 31 25 27 30 28 31
Snort Snort Snort Snort Snort Snort þ smoking Snort Snort Snort
8 12 15 11 6 5 5 4e5 2
5e10 1e5 10 4 5 5 2.5 1 5
2.01 1.51 2.64 1.73 2.7 1.5 0.75 2.15 0.7
1.66 1.0 1.09 0.92 0.6 1.04 0.45 1.08 0.58
Bilateral / Leftb Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral
Patient no.
Severity of hydronephrosisa
Level of obstruction
Follow-up period (mo)
Estimated GFR (mL/min/1.73 m2)
Receive URSdbiopsy or not
Biopsy pathology result
Persistent DJ stent currently
DJ stent indwelling duration (mo)
1
1
M/3
8
34.91
Y
Cystitis cystica and glandularis
Y (left)
2 3
2 2
L/3 L/3
12 48
54.17 71.96
N Y
4 5 6
2 2 Left: 2 Right: 1 3 3 Left: 4 Right: 3
L/3 L/3 M/3
4 6 34
34 23.4 25
N Y N
L/3 L/3 L/3
27 49 18
7 8 9
42 43 >60
Inflammation with eosinophilic infiltration Fibroepithelial polyps
N N N
Y (bilateral) Y (bilateral) Y (bilateral) Y (bilateral) N
18
Y (bilateral) Y (bilateral) N
12
F ¼ female; M ¼ male. a Severity of hydronephrosis with renosonography: Grade 1 is anterioreposterior distance >5 mm, Grade 2 means calyx can be seen, Grade 3 is blunting calyces, and Grade 4 is cortical thinning. b Bilateral hydronephrosis initially, then only the left side after months of follow-up.
Metro Harbor Hospital Kaohsiung, Taiwan; and Chang Gung Memorial Hospital, Taoyuan, Taiwan), were included in this study. Characteristics of these patients are listed in Table 1. They all came to hospitals with moderate flank pain and severe LUTS, including dysuria, frequency, urgency, and voiding pain. Three of the patients also suffered from acute pyelonephritis with fever. These three patients received antibiotic treatment initially. The other patients had neither pyuria nor bacterial growth in urine culture. All patients had ultrasonographic evidence of hydronephrosis at the time of diagnosis. Seven of these patients also had impaired renal function (Table 1). The first case revealed bilateral hydronephrosis, with the creatinine level going up to 2.01 mg/dL at the first visit. During 1-month follow-up and cessation of ketamine abuse, right hydronephrosis was subsided. As hydronephrosis with persistent flank pain continued, ureterorenoscopy was performed to examine the cause of hydronephrosis. Inflammatory polyps over the middle-third ureteral wall were noted during ureteroscopy (Fig. 1) and were biopsied. A double-J stent was inserted at the end of surgery. The pathology result of polyps was characterized by cystical dilated luminal spaces and cuboidal to columnar appearance of the umbrella cell layer representing a picture of chronic inflammation. Scattered eosinophils were also seen focally (Fig. 2). The other patients with bilateral hydronephrosis, acute kidney injury, and ureter stenosis were examined by noncontrast abdominal computed tomography (CT; Fig. 3). Ureteral polyps and ulcerative ureteritis with mucosa erosion were discovered in all nine patients while receiving bilateral ureterorenoscopy, and three patients received polyp biopsy concurrently. These patients were noted to have partial or complete recovery of renal function with improvement in hydronephrosis after inserting a double-J stent. Seven patients retained the indwelling double-J stent until now, and in the other two patients the double-J stent was removed after
18 months and 12 months, respectively, of follow-up. All these patients were encouraged to discontinue ketamine abuse to prevent further urinary function deterioration. 3. Discussion Severe LUTS with chronic cystitis among ketamine abusers were discussed in the literature; about 20e30% of patients may suffer from LUTS.4 However, the adverse effect of ketamine on the upper urinary tract is less investigated. In Chu et al's study,4 51% of
Fig. 1. Ureterorenoscopic findings of Patient 1: anesthetized ureterorenoscope reveals ureter polyps.
184
H.-Y. Lee et al. / Urological Science 26 (2015) 182e185
Fig. 2. (A) Cystitis cystica (arrow) and cystitis glandularis (arrowhead) (magnification 100). (B) Eosinophil infiltration (magnification 400).
ketamine cystitis patients had ketamine-induced unilateral or bilateral hydronephrosis found by sonography. Owing to its high incidence and the fact that it may cause irreversible renal damage with concomitant infection, determining the involvement of the upper urinary tract is important. The actual mechanism of urinary tract destruction is still not clear, but there are some hypotheses.
Fig. 3. Noncontrast abdominal computed tomography of Patient 4 shows bilateral hydronephrosis.
Chu et al4 proposed that ketamine and its metabolites, such as norketamine and dehydronorketamine, cause direct toxicity to bladder epithelial cell, microvasculature toxicity, neural and neurotransmitter toxic effects, or immunological reaction.5 We supposed that the toxic effect of ketamine to ureteral urothelial cell presents similar mechanism with lower urinary tract mucosa due to the same structure. Although it is unclear whether the severity of abuse is related to the severity of upper urinary tract damage, in most of our patients, prolonged drug abuse and intake of a large dosage of ketamine seem to have possibly caused ureteral inflammation with hydronephrosis and renal function impairment. Therefore, a close follow-up of renal function and imaging studies are necessary for these high-risk patients. The level of damage of the upper urinary tract in our patients is concordant with the findings of Huang et al,6 who discovered ureteral wall thickening with hydronephrosis, which is related to chronic inflammation. In Huang et al's7 study, retrograde pyelography also showed ureteral strictures with segmental beading, which were characterized as “walking-stick ureters.” Abdominal CT is a useful imaging tool to evaluate the cause of hydronephrosis and the extent of obstruction. As we know, no previous studies have presented the ureterorenoscopic picture of the ureteral wall. Among our patients, ureteral wall thickening and inflammatory polyps occurred not just at the vesicoureteric junction, these affected the entire ureter and/or a part of the ureter away from the distal ureter, although most of the literatures described that stenosis occurs at the vesicoureteric junction.1,4,8 This finding is also different from previous studies, which suggested that most cases of hydronephrosis were the result of impaired bladder compliance and vesicoureteral reflux.4,9 Ketamine is metabolized by liver microsomal enzymes and excreted from the kidney by conjugating to water-soluble glucuronide derivatives.10 From the pathological features of the ureteral wall, it presented with inflammatory cell infiltration and fibrosis, which may be caused by the continuous contact with a high concentration of ketamine and its metabolites in urine. From our experience, LUTS are more frequent and appear earlier than upper urinary tract symptoms. We suppose that the longer contact duration of toxic urine with the urothelium might be a contributing factor. There are several treatment choices for relief of hydronephrosis with acute kidney injury, including percutaneous nephrostomy insertion and double-J stenting for urinary diversion. Some physicians may have a concern that the double-J stent will aggravate LUTS due to contact with the bladder wall. However, in these patients, not only their flank pain, impaired renal function, and hydronephrosis were improved, but also LUTS did not get worse. In fact, the crucial key to decrease the severity of LUTS is cessation of ketamine use. Compared with percutaneous nephrostomy, the double-J stent implantation is a less invasive procedure. In addition, we can directly view the condition of the ureteral wall by ureterorenoscope and perform biopsy at the same time. It remained unclear for how long the double-J stent should be indwelled or when it should be removed. Some of these ketamine abusers even tried to remove the double-J stent, but hydronephrosis and deterioration of renal function were noted thereafter; therefore, a double-J stent was inserted again. It is still unknown when hydronephrosis and acute kidney injury develop after ketamine abuse. Based on the experience of our patients here, we can state that it may appear several years later. Winstock et al11 emphasized that the harmful effects of ketamine on the urinary tract are dose related, and it is compatible with the findings in most of our patients who presented with large-dosage dependency. Some of our cases achieved hydronephrosis improvement after abstinence from ketamine abuse; by contrast, when they continued to snort ketamine, the symptoms progressed and the double-J stent had to be kept indwelled. In
H.-Y. Lee et al. / Urological Science 26 (2015) 182e185
some cases, we performed biopsy of both the ureter and the bladder wall. With respect to sequential LUTS and similar urothelial structure, if a patient discontinued ketamine abuse when LUTS occurred, it was postulated that the upper urinary tract injury might decline. In conclusion, LUTS are the principal presenting symptoms in patients with ketamine abuse; however, ketamine-related upper urinary tract injuries, including ureteral inflammation, ureteral stricture, hydronephrosis, and impaired renal function, have drawn physicians' attention in recent years. In our opinion, abdominal CT and ureterorenoscopy are important diagnostic tools for evaluation of the extent of upper urinary tract damage. If ureteral stenosis with inflammation, which leads to hydronephrosis and renal function impairment, was found, preserving renal function and relieving symptoms by urinary diversion are crucial. Nevertheless, the underlying mechanism and pathogenesis are not clear now. Longer time is required to observe the disease progression, and also further animal or basic experimental research has to be conducted. We put forward our experiences of treatment plan and propose our point of view regarding treatment of patients with ketamine-induced uropathy. Conflicts of interest The authors declare that they have no financial or non-financial conflicts of interest related to the subject matter or materials discussed in the manuscript.
185
Sources of funding No funding was received for the work described in the article.
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