- Email: [email protected]
Profile of the Ammonium Acid Urate Stone Former Based on a Large Contemporary Cohort
Accepted Manuscript Title: Profile of the Ammonium Acid Urate Stone Former Based on a Large Contemporary Cohort Author: Derek J. Lomas, Christopher D Jaeger, Amy E. Krambeck PII: DOI: Reference:
S0090-4295(16)30745-2 http://dx.doi.org/doi: 10.1016/j.urology.2016.10.027 URL 20097
To appear in:
Urology
Received date: Accepted date:
8-6-2016 14-10-2016
Please cite this article as: Derek J. Lomas, Christopher D Jaeger, Amy E. Krambeck, Profile of the Ammonium Acid Urate Stone Former Based on a Large Contemporary Cohort, Urology (2016), http://dx.doi.org/doi: 10.1016/j.urology.2016.10.027. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof 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.
Profile of the Ammonium Acid Urate Stone Former Based On A Large Contemporary Cohort
Derek J. Lomas, Christopher D Jaeger, Amy E. Krambeck
Department of Urology Mayo Clinic, Rochester, Minnesota
Word Count of Abstract: 224 Word Count of Manuscript Text: 2569 Figures: 1 Tables: 2 Key Words: Ammonium acid urate; urolithiasis; urinary calculi; risk factors; demography
Corresponding Author:
Amy E. Krambeck, M.D. Department of Urology Mayo Clinic 200 First Street SW Rochester, MN 55905 Phone # 507-266-4446 Fax # 507-284-4951 Email: [email protected]
Conflicts of Interest: None 1 Page 1 of 15
Funding disclosure: None
Abstract Objective: To evaluate and profile Ammonium acid urate (AAU) stone formers utilizing a large contemporary cohort. Materials and Methods: A retrospective review of all patients with documented AAU urolithiasis on stone analysis was performed from 1995-2013. A stone was considered AAU if it contained at least 10% of the total composition on stone analysis. Results: Of 12,421 stones, a total of 111 AAU stones were identified in 89 patients. Seventy-two patients (81%) had mixed composition stones. Of the 89 AAU patients, 10 (11%) had chronic kidney disease, 12 (13%) had recurrent urinary tract infections, 8 (9%) had diabetes mellitus, 25 (28%) had a history of ileostomy or bowel resection, and 11 (12%) had significant diarrhea or inflammatory bowel disease. Additionally, 20 (22%) had prior prostate surgery with bladder neck contracture and 8 (9%) were managed with a chronic indwelling catheter. Surgical intervention was required in 74 patients (83%). At median follow−up of 4.9 years, 19 patients (21%) had stone recurrence with a median time to recurrence of 22 months (IQR 10.5, 42). Conclusions: AAU stones are rare. In addition to previously-described risk factors for AAU stone formation, patients with prior prostate surgery and bladder neck contracture or a surgically-altered bladder may be at increased risk for formation. Furthermore, the long-term follow-up provided by this large AAU cohort demonstrates a significant risk for stone recurrence.
2 Page 2 of 15
INTRODUCTION Urolithiasis remains a common condition with a prevalence of 8.8% in the United States.1 Despite the prevalence of urolithiasis, ammonium acid urate (AAU) stones remain rare in industrialized countries with reported prevalence among stone formers ranging from 0.2 to 3.1%.2-4 Previously identified risk factors for AAU stone formation include inflammatory bowel disease, ileostomy diversion, laxative abuse, morbid obesity, recurrent urinary tract infection (UTI), and recurrent uric acid calculi.3-6 While these risk factors have been suggested, validation is lacking due to small cohort sizes. We sought to evaluate and profile AAU stone formers at our institution utilizing a large contemporary cohort. MATERIALS AND METHODS After institutional review board approval, a retrospective review of all patients with documented AAU calculi on stone analysis from 1995 to 2013 was performed. Stone analysis was performed using Fourier Transform Infrared (FTIR) spectrometry. A stone was considered to be AAU if it contained at least 10% ammonium urate.
The stones
were classified according to the percentage of ammonium urate in each stone as well as by any secondary components and location. The charts of all patients identified as AAU stone formers were reviewed. Demographic data including age at stone formation and sex was collected. Stone history including previous stone episodes, interventions, and recurrent stone episodes following initial AAU stone episode was also assessed. Patients were classified by 3 Page 3 of 15
potential risk factors for stone formation including recurrent UTIs, chronic kidney disease, diabetes mellitus, hypertension, ileostomy and/or extensive bowel resection, chronic diarrhea, alternative diets, previous prostate surgery, chronic urinary catheterization, and family history of urolithiasis. Stone burden was determined by the sum of maximal stone diameters of CT scan as well operative reports. When available, 24 hour urine studies and urinalysis pH were included. RESULTS Of the 12,421 stones analyzed, a total of 111 AAU stones were identified in 89 patients for a prevalence of 0.9%.
Median age at AAU stone event was 55 (IQR 39.5-70.5) and
69% of the patients were male. Previous stone passage or surgery was noted in 34 (38%) patients. For the AAU stone, 74 (83%) required surgical intervention. Figure 1 shows the distribution of the AAU stone content. In 42 (47.2%) patients, AAU represented 50% or greater of the total stone composition. Pure AAU stones were noted in 17 (19%) patients. Seventy-two (80.9%) patients in total had mixed composition stones. In those patients, the other component of the stone was struvite (52.8%), CaPO4-Apatite (27.8%), uric acid (6.9%), calcium oxalate dihydrate (6.9%), Brushite (2.8%), and calcium oxalate monohydrate (2.8%). Median stone burden was 0.8 cm in the upper tract, 2.5 cm in the bladder, 2.1 cm in pouches/conduits, 2.5 cm in augmented bladders, and 4.0 cm in neobladders. Of the 89 AAU patients, 10 (11%) had a history of chronic kidney disease, 12 (13%) had recurrent urinary tract infections, 8 (9%) had diabetes mellitus, 25 (28%) had a history of ileostomy or extensive bowel resection, and 11 (12%) had significant diarrhea or 4 Page 4 of 15
inflammatory bowel disease. Additionally, 20 (22%) had prior prostate surgery with bladder neck contracture (BNC) and 8 (9%) were managed with a chronic indwelling catheter, and no patients had documented laxative abuse. Thirty-two (36%) patients had multiple risk factors while 21(24%) had no identifiable risk factors. Stone location included 38 (42.7%) within the upper urinary tract, 35 (39.3%) within a native bladder, 7 (7.9%) within an augmented bladder, 6 (6.7%) within a continent catheterizable pouch or conduit, and 3 (3.4%) in an ileal neobladder. AAU was the primary stone component in 55.2%, 45.7%, 42.9%, and 33.3% of upper tract, bladder, augmented bladder, and continent catheterizable pouches respectively.
Table 1
shows AAU containing stones stratified by primary component and location. AAU stone location varied based on comorbidities. Table 2 shows AAU stone location based on comorbidity. Patients with CKD or significant diarrhea/inflammatory bowel disease had predominately upper tract AAU stones, 71.4% and 100% respectively. Patients with diabetes mellitus had equal distribution between the upper tract and native bladder with 50% of AAU stones in each. Patients with recurrent UTI, Ileostomy/bowel resection, prior prostate surgery with bladder neck contracture (BNC), and chronic urinary catheter formed more stones in the lower urinary system (native bladder, augmented bladders/ ileal neobladders , conduits, continent catheterizable pouches) compared to the upper tracts, 53.8, 60.0%, 95.0%, and 75.0% respectively. It is worth noting that when looking at patients with ileostomy and bowel resection with native bladders and absence of other risk factors, 5 of 7 (71.4%) patients had upper tract stones.
5 Page 5 of 15
Median urine pH was obtained from urinalysis specimens. Amongst mixed composition AAU stone formers was 6.3 (range: 5.2-8.7) while pure AAU stones occurred at median pH of 5.8 (range: 5.2-6.7). Metabolic testing consisting of 24 hour urine collection with supersaturation was available in 7 patients. Five patients had low urine volume (< 2L/day) (mean: 1550 mL, range: 464-2905 mL), 3 had hypomagnesuria (mean: 80 mg, range: 3-231 mg), 4 had hypocitraturia (mean: 242 mg, range: 23-738 mg), 1 had hyperoxaluria (mean: 0.29 mmol, range 0.12-0.5 mmol), and 3 had hyperuricosuria (mean: 567 mg, range: 158-868mg). At median follow-up of 4.9 years (IQR 1.8-8.5), 19 patients (21%) had stone recurrence with a median time to recurrence of 22 months (IQR 10.5-42). DISCUSSION This study again demonstrates the rarity of AAU stones in a North American cohort with an observed incidence on 0.9%. Incidence of AAU stones in industrialized areas has varied throughout studies over time and has ranged from 0.2 to 3.1%.2-4 We found our cohort to be primarily males (69%). Previous studies have been mixed on the gender predominance of AAU stone formers with males representing 44-66% of the cohorts.3, 4, 7, 8
AAU stones have been described as either endemic or sporadic. Endemic AAU stones are found in developing countries where a purine rich, phosphorus poor diet, combined with decreased fluid intake and diarrheal states , results in urine with high concentrations of AAU and uric acid leading to stone formation.6 In our study, we sought to characterize sporadic AAU stone formers. Previously identified conditions 6 Page 6 of 15
found to be associated with AAU stone formation include inflammatory bowel disease, ileostomy diversion, laxative abuse, morbid obesity, recurrent urinary tract infection, and recurrent uric acid calculi.3-5, 7, 9 In sporadic stones, several mechanisms have been proposed.
In those with conditions that promote dehydration such as laxative abuse
and chronic diarrheal states the mechanism is similar to endemic stones.5 Dehydration results from gastrointestinal fluid losses which then leads to volume depleted state and intracellular acidosis. Increased ammonium in the urine for buffering together with low levels of sodium in the urine results in urate combining with the ammonium to form AAU. In our cohort, 25 (28%) patients had a history of ileostomy or extensive bowel resection and 11 (12%) patients had significant diarrhea or inflammatory bowel disease.
Chou
et al retrospectively reviewed 25 patients with urinary stones containing AAU crystals. 7 They found an incidence of 0.7% over a 5 year period. This group was compared to all other patients with non-AAU urolithiasis during the same period. The authors found that 36% of AUU stone patients had irritable bowel syndrome (IBS) while only 13% in the non-AAU group had IBS, a significant difference. Soble et al evaluated 44 North American AAU stone formers of which 11 (25%) had a history of inflammatory bowel disease with 10 (22.7%) had undergone ileostomy diversion.4 Contrary to previous studies, we did not identify any patients in our cohort with suspected laxative abuse.
Nevertheless, the association between laxative abuse and
AAU urolithiasis has been reported in many studies.
Dick et al, first described 9
patients with AAU urolithiasis and documented laxative abuse with phenolphthalein.5 All patients in the study had sterile urine and were without a history of recurrent UTIs. 7 Page 7 of 15
The patients underwent 24 hour urine studies which demonstrated low urine volume, low urinary sodium, low urinary citrate, and low urinary potassium. The authors postulated that gastrointestinal water losses as well intracellular acidosis stimulated an increase in urinary ammonia. Due to the low amount of urinary sodium, urate in the urine combines with ammonium ions to form AAU. The authors also found that once the patients had discontinued laxatives, urinary volume, sodium, potassium, magnesium, and citrate levels returned to within the normal range. Since the initial study by Dick et al, several authors have reported on laxative abuse in this stone population with prevalences of 13.6 to 70%.4, 7, 8 Kuruma et al found that laxative abuse was more common amongst those producing pure AAU stones (70%) compared to those with mixed AAU stones (26.3%).8 Despite our cohort not having any patients with documented laxative abuse, it appears to be risk factor unique to AAU lithiasis and laxative use should be part of the history obtained from AAU stone formers as discontinuation of the laxative will reverse the urinary conditions leading to AAU stone formation. Recurrent UTIs have also been described as a risk factor for AAU urolithiasis. 3-5, 7
In
patients with urinary infections with urease producing organisms, the urine becomes alkalized and rich in ammonium. If the urine is simultaneously saturated with uric acid, AAU crystallization can occur.3, 4 In the study by Chou et al, urinary tract infection with a positive culture was present in more than half (52%) of patients with AAU stones. 7 The most common organisms isolated were Proteus and Klebsiella species, both urease producing. Soble et al found that 16 patients (36.4%) in their AAU cohort had a history of recurrent UTIs. Pichette et al found that 35% of the stones containing AAU crystals 8 Page 8 of 15
were predominantly infectious (struvite or Apatite). In our cohort we found only 8 (9%) patients had recurrent urinary tract infections. However, when evaluating patient’s with mixed composition stones, 80.6% had infection associated stones (struvite or carbonated apatite). This would suggest that the rate of UTI is underreported in our study and that our patients had asymptomatic bacteruria at some point. We also found that 20(22%) patients in our cohort had a prior prostate surgery with development of BNC. Of these 20 patients, 18 (90%) had lower tract stones, 16 (80%) had infectious stones, and 15 (75%) had no other identifiable risk factors for AAU stones.
While prostate surgery with BNC has not been previously reporting as a risk
factor for AAU stones, bladder dysfunction with urinary stasis was identified in 8 (57%) of the patients with lower tract AAU stones in the study by Pichette et al.3 The authors proposed that urinary stasis may be a potential risk factor that allows AAU crystallization for occur as AAU precipitation is time-dependent process.
We would add that the
likely chronically infected urine, as evidenced by the infectious stone composition of the patients in our cohort with BNC is theoretically the main driving factor predisposing these patients to AAU stone formation. In our cohort we also had 16 patients with surgically altered lower tracts.
These
patients had neobladders, bladder augmentations, urinary conduits, or pouches. All stones in the altered bladder patients had an infectious component. Again in these patients, infection with urealytic organisms due to chronic colonization of the lower tract is likely predisposing them AAU stone formation. In addition, use of the bowel to create the urinary augmentation or diversion alters both intestinal and urinary absorption of fluid and electrolytes in these patients further complicating the matter. 9 Page 9 of 15
CKD has also been associated with AAU stones. Chou et al found that 60% of their patients with AAU stones had CKD, as opposed to 26% of other stone formers (p=0.001).7 In our cohort, 11% of the patients had documented CKD. The relationship between AAU stones and CKD remains unclear and whether CKD is the cause or effect of the AAU urolithiasis. It could be that alterations in the kidney’s ability to acidify the urine lead to an alkaline environment conducive to AAU stone formation. We also had almost a quarter of our cohort with no identifiable risk factors for AUU stones. These idiopathic stone AAU stone formers more frequency formed upper tract stones when compared to those patients with any of the other risk factors, 66% vs 35% respectively. In our study, we also reported on the percent content of AUU in each stone. AAU stone composition has previously been reported and has varied across studies. We report that almost half (47.2%) of patients had predominantly AAU stones with 19% having pure AAU stones.
Soble et al found that predominantly AAU stone
stones were less common, representing 25% of patients in their study and no patients had pure AAU stone.4 Pichette et found that 41 (3.1%) AAU containing stones in 37 patients.3 Of those stones, 3 (7%) were predominately AAU and no stone was pure AAU.
They concluded that predominately or pure AAU stones were exceptionally rare.
Kuruma et al evaluated AAU stone formers in a Japanese cohort.
8
They found a
prevalence of 0.38% in 8664 evaluated stones. Contrary to Pichette et al’s study, pure AAU was common, representing 13 of the 33 AAU stones (39.4%). The patients in the study were stratified as either being mixed type AAU stone former or pure stone formers. They found the characteristics of each stone former to be different. Pure AAU stone former were more commonly young females (median age of 24) while mixed 10 Page 10 of 15
stone formers were predominately older males. We did not appreciate these trends in our cohort. Both males and females had predominantly mixed composition stones (82% and 79% respectively). We did note that none of the pure AAU stones formed in patients with urinary diversion or augmentations, the majority (72.2%) of patients had upper tract stones, and the almost half (47.1%) had ileostomy, extensive bowel resection, diarrhea, or inflammatory bowel disease. Finally, we also found our cohort to have significant risk for stone recurrence when followed up to 4.9 years, with 21% of them having a stone recurrence at a median time of 22 months. Indeed other authors have found recurrent stones to be common in this patient population with reported recurrence ranging from 24.3-58.6%.3, 8 While no specific guidelines for the metabolic management of AAU stones exist, general stone prevention principles can be applied.10 Patients with identified AAU stones should undergo 24 hour urine collections and any correctable abnormalities should be addressed. In addition, AAU stone formation is more common is states of dehydration so fluid intake that will achieve a urine volume of at least 2.5 liters daily can be recommended. Many AAU stones also contain infectious stone components including struvite. In this population, monitoring for infection with urease-producing organisms and treatment of these may help to reduce AAU mixed stone formation. There are several limitations to our study. First is its retrospective nature. It is possible the some potential risk factors were not documented in the record and thus underreported.
In addition, metabolic analyses were performed on only a few patients
and thus the small sample size limits the results. Since the study spanned several
11 Page 11 of 15
decades treatment surgically and metabolically was not standardized. Despite these limitations the study is one of the largest contemporary studies of AAU stone sin North America and offers insight into other risk factors for formation and high risk of recurrence. CONCLUSION AAU stones are rare. In addition to previously-known risk factors for AAU stone formation, patients with prior prostate surgery and bladder neck contracture or surgically-altered bladder may be at increased risk for formation. Furthermore, the longterm follow-up provided by this large AAU cohort demonstrates a significant risk for stone recurrence.
12 Page 12 of 15
References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Scales CD, Smith AC, Hanley JM, Saigal CS, Project UDiA. Prevalence of kidney stones in the United States. European urology. 2012;62:160-165. Herring L. Observations on the analysis of ten thousand urinary calculi. The Journal of urology. 1962;88:545-562. Pichette V, Bonnardeaux A, Cardinal J, et al. Ammonium acid urate crystal formation in adult North American stone-formers. American journal of kidney diseases. 1997;30:237-242. Soble JJ, HAMILTON BD, STREEM SB. Ammonium acid urate calculi: a reevaluation of risk factors. The Journal of urology. 1999;161:869-873. Dick W, Lingeman J, Preminger G, Smith L, Wilson D, Shirrell W. Laxative Abuse as a Cause for Ammonium-Urate Renal Calculi. Urolithiasis: Springer; 1989:303-305. Klohn M, Bolle J, Reverdin N, Susini A, Baud C-A, Graber P. Ammonium urate urinary stones. Urological research. 1986;14:315-318. Chou Y-H, Huang C-N, Li W-M, et al. Clinical study of ammonium acid urate urolithiasis. The Kaohsiung journal of medical sciences. 2012;28:259-264. Kuruma H, Arakawa T, Kubo S, et al. Ammonium acid urate urolithiasis in Japan. International journal of urology. 2006;13:498-501. Pak CY, Poindexter JR, Adams-Huet B, Pearle MS. Predictive value of kidney stone composition in the detection of metabolic abnormalities. The American journal of medicine. 2003;115:26-32. Pearle MS, Goldfarb DS, Assimos DG, et al. Medical management of kidney stones: AUA guideline. The Journal of urology. 2014;192:316-324.
13 Page 13 of 15
Figure 1. Frequency distribution of ammonium acid urate (AAU) percent content in stones 25
Fraquency (N)
20
15
10
5
0 10
20
30
40
50
60
70
80
90
100
Percent AAU Content
14 Page 14 of 15
Table 1. AAU Containing Stones Stratified By Primary Component and Location Primary Stone Component Total AAU Calcium oxalate dihydrate Calcium oxalate monohydrate CaPO4 (apatite) CaPO4 (brushrite) Struvite Uric Acid
All Upper Locations Tract 89 38 42 21 2 2
Bladder Augment/ Pouch/Conduit Neobladder 35 10 6 16 3 2 0 0 0
1
1
0
0
0
16 1 25 2
6 1 6 1
6
2
2
12 1
5 0
2 0
Table 2. AAU Stone Location Based On Comorbidity
CKD Recurrent UTI Diabetes Ileostomy/Resection Diarrhea/IBD BNC Chronic Catheter Surgically Altered Lower Tract Multiple Risk Factors No Identified Risk Factors
All Upper Locations Tract 7 5 12 5 8 4 25 10 11 11 20 1 8 2 16 0 32 21
11 14
Bladder Augment/ Pouch/Conduit Neobladder 1 0 1 6 0 1 4 0 0 2 7 6 0 0 0 18 0 1 5 1 0 0 10 6 7 7
8 0
6 0
15 Page 15 of 15
S0090-4295(16)30745-2 http://dx.doi.org/doi: 10.1016/j.urology.2016.10.027 URL 20097
To appear in:
Urology
Received date: Accepted date:
8-6-2016 14-10-2016
Please cite this article as: Derek J. Lomas, Christopher D Jaeger, Amy E. Krambeck, Profile of the Ammonium Acid Urate Stone Former Based on a Large Contemporary Cohort, Urology (2016), http://dx.doi.org/doi: 10.1016/j.urology.2016.10.027. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof 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.
Profile of the Ammonium Acid Urate Stone Former Based On A Large Contemporary Cohort
Derek J. Lomas, Christopher D Jaeger, Amy E. Krambeck
Department of Urology Mayo Clinic, Rochester, Minnesota
Word Count of Abstract: 224 Word Count of Manuscript Text: 2569 Figures: 1 Tables: 2 Key Words: Ammonium acid urate; urolithiasis; urinary calculi; risk factors; demography
Corresponding Author:
Amy E. Krambeck, M.D. Department of Urology Mayo Clinic 200 First Street SW Rochester, MN 55905 Phone # 507-266-4446 Fax # 507-284-4951 Email: [email protected]
Conflicts of Interest: None 1 Page 1 of 15
Funding disclosure: None
Abstract Objective: To evaluate and profile Ammonium acid urate (AAU) stone formers utilizing a large contemporary cohort. Materials and Methods: A retrospective review of all patients with documented AAU urolithiasis on stone analysis was performed from 1995-2013. A stone was considered AAU if it contained at least 10% of the total composition on stone analysis. Results: Of 12,421 stones, a total of 111 AAU stones were identified in 89 patients. Seventy-two patients (81%) had mixed composition stones. Of the 89 AAU patients, 10 (11%) had chronic kidney disease, 12 (13%) had recurrent urinary tract infections, 8 (9%) had diabetes mellitus, 25 (28%) had a history of ileostomy or bowel resection, and 11 (12%) had significant diarrhea or inflammatory bowel disease. Additionally, 20 (22%) had prior prostate surgery with bladder neck contracture and 8 (9%) were managed with a chronic indwelling catheter. Surgical intervention was required in 74 patients (83%). At median follow−up of 4.9 years, 19 patients (21%) had stone recurrence with a median time to recurrence of 22 months (IQR 10.5, 42). Conclusions: AAU stones are rare. In addition to previously-described risk factors for AAU stone formation, patients with prior prostate surgery and bladder neck contracture or a surgically-altered bladder may be at increased risk for formation. Furthermore, the long-term follow-up provided by this large AAU cohort demonstrates a significant risk for stone recurrence.
2 Page 2 of 15
INTRODUCTION Urolithiasis remains a common condition with a prevalence of 8.8% in the United States.1 Despite the prevalence of urolithiasis, ammonium acid urate (AAU) stones remain rare in industrialized countries with reported prevalence among stone formers ranging from 0.2 to 3.1%.2-4 Previously identified risk factors for AAU stone formation include inflammatory bowel disease, ileostomy diversion, laxative abuse, morbid obesity, recurrent urinary tract infection (UTI), and recurrent uric acid calculi.3-6 While these risk factors have been suggested, validation is lacking due to small cohort sizes. We sought to evaluate and profile AAU stone formers at our institution utilizing a large contemporary cohort. MATERIALS AND METHODS After institutional review board approval, a retrospective review of all patients with documented AAU calculi on stone analysis from 1995 to 2013 was performed. Stone analysis was performed using Fourier Transform Infrared (FTIR) spectrometry. A stone was considered to be AAU if it contained at least 10% ammonium urate.
The stones
were classified according to the percentage of ammonium urate in each stone as well as by any secondary components and location. The charts of all patients identified as AAU stone formers were reviewed. Demographic data including age at stone formation and sex was collected. Stone history including previous stone episodes, interventions, and recurrent stone episodes following initial AAU stone episode was also assessed. Patients were classified by 3 Page 3 of 15
potential risk factors for stone formation including recurrent UTIs, chronic kidney disease, diabetes mellitus, hypertension, ileostomy and/or extensive bowel resection, chronic diarrhea, alternative diets, previous prostate surgery, chronic urinary catheterization, and family history of urolithiasis. Stone burden was determined by the sum of maximal stone diameters of CT scan as well operative reports. When available, 24 hour urine studies and urinalysis pH were included. RESULTS Of the 12,421 stones analyzed, a total of 111 AAU stones were identified in 89 patients for a prevalence of 0.9%.
Median age at AAU stone event was 55 (IQR 39.5-70.5) and
69% of the patients were male. Previous stone passage or surgery was noted in 34 (38%) patients. For the AAU stone, 74 (83%) required surgical intervention. Figure 1 shows the distribution of the AAU stone content. In 42 (47.2%) patients, AAU represented 50% or greater of the total stone composition. Pure AAU stones were noted in 17 (19%) patients. Seventy-two (80.9%) patients in total had mixed composition stones. In those patients, the other component of the stone was struvite (52.8%), CaPO4-Apatite (27.8%), uric acid (6.9%), calcium oxalate dihydrate (6.9%), Brushite (2.8%), and calcium oxalate monohydrate (2.8%). Median stone burden was 0.8 cm in the upper tract, 2.5 cm in the bladder, 2.1 cm in pouches/conduits, 2.5 cm in augmented bladders, and 4.0 cm in neobladders. Of the 89 AAU patients, 10 (11%) had a history of chronic kidney disease, 12 (13%) had recurrent urinary tract infections, 8 (9%) had diabetes mellitus, 25 (28%) had a history of ileostomy or extensive bowel resection, and 11 (12%) had significant diarrhea or 4 Page 4 of 15
inflammatory bowel disease. Additionally, 20 (22%) had prior prostate surgery with bladder neck contracture (BNC) and 8 (9%) were managed with a chronic indwelling catheter, and no patients had documented laxative abuse. Thirty-two (36%) patients had multiple risk factors while 21(24%) had no identifiable risk factors. Stone location included 38 (42.7%) within the upper urinary tract, 35 (39.3%) within a native bladder, 7 (7.9%) within an augmented bladder, 6 (6.7%) within a continent catheterizable pouch or conduit, and 3 (3.4%) in an ileal neobladder. AAU was the primary stone component in 55.2%, 45.7%, 42.9%, and 33.3% of upper tract, bladder, augmented bladder, and continent catheterizable pouches respectively.
Table 1
shows AAU containing stones stratified by primary component and location. AAU stone location varied based on comorbidities. Table 2 shows AAU stone location based on comorbidity. Patients with CKD or significant diarrhea/inflammatory bowel disease had predominately upper tract AAU stones, 71.4% and 100% respectively. Patients with diabetes mellitus had equal distribution between the upper tract and native bladder with 50% of AAU stones in each. Patients with recurrent UTI, Ileostomy/bowel resection, prior prostate surgery with bladder neck contracture (BNC), and chronic urinary catheter formed more stones in the lower urinary system (native bladder, augmented bladders/ ileal neobladders , conduits, continent catheterizable pouches) compared to the upper tracts, 53.8, 60.0%, 95.0%, and 75.0% respectively. It is worth noting that when looking at patients with ileostomy and bowel resection with native bladders and absence of other risk factors, 5 of 7 (71.4%) patients had upper tract stones.
5 Page 5 of 15
Median urine pH was obtained from urinalysis specimens. Amongst mixed composition AAU stone formers was 6.3 (range: 5.2-8.7) while pure AAU stones occurred at median pH of 5.8 (range: 5.2-6.7). Metabolic testing consisting of 24 hour urine collection with supersaturation was available in 7 patients. Five patients had low urine volume (< 2L/day) (mean: 1550 mL, range: 464-2905 mL), 3 had hypomagnesuria (mean: 80 mg, range: 3-231 mg), 4 had hypocitraturia (mean: 242 mg, range: 23-738 mg), 1 had hyperoxaluria (mean: 0.29 mmol, range 0.12-0.5 mmol), and 3 had hyperuricosuria (mean: 567 mg, range: 158-868mg). At median follow-up of 4.9 years (IQR 1.8-8.5), 19 patients (21%) had stone recurrence with a median time to recurrence of 22 months (IQR 10.5-42). DISCUSSION This study again demonstrates the rarity of AAU stones in a North American cohort with an observed incidence on 0.9%. Incidence of AAU stones in industrialized areas has varied throughout studies over time and has ranged from 0.2 to 3.1%.2-4 We found our cohort to be primarily males (69%). Previous studies have been mixed on the gender predominance of AAU stone formers with males representing 44-66% of the cohorts.3, 4, 7, 8
AAU stones have been described as either endemic or sporadic. Endemic AAU stones are found in developing countries where a purine rich, phosphorus poor diet, combined with decreased fluid intake and diarrheal states , results in urine with high concentrations of AAU and uric acid leading to stone formation.6 In our study, we sought to characterize sporadic AAU stone formers. Previously identified conditions 6 Page 6 of 15
found to be associated with AAU stone formation include inflammatory bowel disease, ileostomy diversion, laxative abuse, morbid obesity, recurrent urinary tract infection, and recurrent uric acid calculi.3-5, 7, 9 In sporadic stones, several mechanisms have been proposed.
In those with conditions that promote dehydration such as laxative abuse
and chronic diarrheal states the mechanism is similar to endemic stones.5 Dehydration results from gastrointestinal fluid losses which then leads to volume depleted state and intracellular acidosis. Increased ammonium in the urine for buffering together with low levels of sodium in the urine results in urate combining with the ammonium to form AAU. In our cohort, 25 (28%) patients had a history of ileostomy or extensive bowel resection and 11 (12%) patients had significant diarrhea or inflammatory bowel disease.
Chou
et al retrospectively reviewed 25 patients with urinary stones containing AAU crystals. 7 They found an incidence of 0.7% over a 5 year period. This group was compared to all other patients with non-AAU urolithiasis during the same period. The authors found that 36% of AUU stone patients had irritable bowel syndrome (IBS) while only 13% in the non-AAU group had IBS, a significant difference. Soble et al evaluated 44 North American AAU stone formers of which 11 (25%) had a history of inflammatory bowel disease with 10 (22.7%) had undergone ileostomy diversion.4 Contrary to previous studies, we did not identify any patients in our cohort with suspected laxative abuse.
Nevertheless, the association between laxative abuse and
AAU urolithiasis has been reported in many studies.
Dick et al, first described 9
patients with AAU urolithiasis and documented laxative abuse with phenolphthalein.5 All patients in the study had sterile urine and were without a history of recurrent UTIs. 7 Page 7 of 15
The patients underwent 24 hour urine studies which demonstrated low urine volume, low urinary sodium, low urinary citrate, and low urinary potassium. The authors postulated that gastrointestinal water losses as well intracellular acidosis stimulated an increase in urinary ammonia. Due to the low amount of urinary sodium, urate in the urine combines with ammonium ions to form AAU. The authors also found that once the patients had discontinued laxatives, urinary volume, sodium, potassium, magnesium, and citrate levels returned to within the normal range. Since the initial study by Dick et al, several authors have reported on laxative abuse in this stone population with prevalences of 13.6 to 70%.4, 7, 8 Kuruma et al found that laxative abuse was more common amongst those producing pure AAU stones (70%) compared to those with mixed AAU stones (26.3%).8 Despite our cohort not having any patients with documented laxative abuse, it appears to be risk factor unique to AAU lithiasis and laxative use should be part of the history obtained from AAU stone formers as discontinuation of the laxative will reverse the urinary conditions leading to AAU stone formation. Recurrent UTIs have also been described as a risk factor for AAU urolithiasis. 3-5, 7
In
patients with urinary infections with urease producing organisms, the urine becomes alkalized and rich in ammonium. If the urine is simultaneously saturated with uric acid, AAU crystallization can occur.3, 4 In the study by Chou et al, urinary tract infection with a positive culture was present in more than half (52%) of patients with AAU stones. 7 The most common organisms isolated were Proteus and Klebsiella species, both urease producing. Soble et al found that 16 patients (36.4%) in their AAU cohort had a history of recurrent UTIs. Pichette et al found that 35% of the stones containing AAU crystals 8 Page 8 of 15
were predominantly infectious (struvite or Apatite). In our cohort we found only 8 (9%) patients had recurrent urinary tract infections. However, when evaluating patient’s with mixed composition stones, 80.6% had infection associated stones (struvite or carbonated apatite). This would suggest that the rate of UTI is underreported in our study and that our patients had asymptomatic bacteruria at some point. We also found that 20(22%) patients in our cohort had a prior prostate surgery with development of BNC. Of these 20 patients, 18 (90%) had lower tract stones, 16 (80%) had infectious stones, and 15 (75%) had no other identifiable risk factors for AAU stones.
While prostate surgery with BNC has not been previously reporting as a risk
factor for AAU stones, bladder dysfunction with urinary stasis was identified in 8 (57%) of the patients with lower tract AAU stones in the study by Pichette et al.3 The authors proposed that urinary stasis may be a potential risk factor that allows AAU crystallization for occur as AAU precipitation is time-dependent process.
We would add that the
likely chronically infected urine, as evidenced by the infectious stone composition of the patients in our cohort with BNC is theoretically the main driving factor predisposing these patients to AAU stone formation. In our cohort we also had 16 patients with surgically altered lower tracts.
These
patients had neobladders, bladder augmentations, urinary conduits, or pouches. All stones in the altered bladder patients had an infectious component. Again in these patients, infection with urealytic organisms due to chronic colonization of the lower tract is likely predisposing them AAU stone formation. In addition, use of the bowel to create the urinary augmentation or diversion alters both intestinal and urinary absorption of fluid and electrolytes in these patients further complicating the matter. 9 Page 9 of 15
CKD has also been associated with AAU stones. Chou et al found that 60% of their patients with AAU stones had CKD, as opposed to 26% of other stone formers (p=0.001).7 In our cohort, 11% of the patients had documented CKD. The relationship between AAU stones and CKD remains unclear and whether CKD is the cause or effect of the AAU urolithiasis. It could be that alterations in the kidney’s ability to acidify the urine lead to an alkaline environment conducive to AAU stone formation. We also had almost a quarter of our cohort with no identifiable risk factors for AUU stones. These idiopathic stone AAU stone formers more frequency formed upper tract stones when compared to those patients with any of the other risk factors, 66% vs 35% respectively. In our study, we also reported on the percent content of AUU in each stone. AAU stone composition has previously been reported and has varied across studies. We report that almost half (47.2%) of patients had predominantly AAU stones with 19% having pure AAU stones.
Soble et al found that predominantly AAU stone
stones were less common, representing 25% of patients in their study and no patients had pure AAU stone.4 Pichette et found that 41 (3.1%) AAU containing stones in 37 patients.3 Of those stones, 3 (7%) were predominately AAU and no stone was pure AAU.
They concluded that predominately or pure AAU stones were exceptionally rare.
Kuruma et al evaluated AAU stone formers in a Japanese cohort.
8
They found a
prevalence of 0.38% in 8664 evaluated stones. Contrary to Pichette et al’s study, pure AAU was common, representing 13 of the 33 AAU stones (39.4%). The patients in the study were stratified as either being mixed type AAU stone former or pure stone formers. They found the characteristics of each stone former to be different. Pure AAU stone former were more commonly young females (median age of 24) while mixed 10 Page 10 of 15
stone formers were predominately older males. We did not appreciate these trends in our cohort. Both males and females had predominantly mixed composition stones (82% and 79% respectively). We did note that none of the pure AAU stones formed in patients with urinary diversion or augmentations, the majority (72.2%) of patients had upper tract stones, and the almost half (47.1%) had ileostomy, extensive bowel resection, diarrhea, or inflammatory bowel disease. Finally, we also found our cohort to have significant risk for stone recurrence when followed up to 4.9 years, with 21% of them having a stone recurrence at a median time of 22 months. Indeed other authors have found recurrent stones to be common in this patient population with reported recurrence ranging from 24.3-58.6%.3, 8 While no specific guidelines for the metabolic management of AAU stones exist, general stone prevention principles can be applied.10 Patients with identified AAU stones should undergo 24 hour urine collections and any correctable abnormalities should be addressed. In addition, AAU stone formation is more common is states of dehydration so fluid intake that will achieve a urine volume of at least 2.5 liters daily can be recommended. Many AAU stones also contain infectious stone components including struvite. In this population, monitoring for infection with urease-producing organisms and treatment of these may help to reduce AAU mixed stone formation. There are several limitations to our study. First is its retrospective nature. It is possible the some potential risk factors were not documented in the record and thus underreported.
In addition, metabolic analyses were performed on only a few patients
and thus the small sample size limits the results. Since the study spanned several
11 Page 11 of 15
decades treatment surgically and metabolically was not standardized. Despite these limitations the study is one of the largest contemporary studies of AAU stone sin North America and offers insight into other risk factors for formation and high risk of recurrence. CONCLUSION AAU stones are rare. In addition to previously-known risk factors for AAU stone formation, patients with prior prostate surgery and bladder neck contracture or surgically-altered bladder may be at increased risk for formation. Furthermore, the longterm follow-up provided by this large AAU cohort demonstrates a significant risk for stone recurrence.
12 Page 12 of 15
References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Scales CD, Smith AC, Hanley JM, Saigal CS, Project UDiA. Prevalence of kidney stones in the United States. European urology. 2012;62:160-165. Herring L. Observations on the analysis of ten thousand urinary calculi. The Journal of urology. 1962;88:545-562. Pichette V, Bonnardeaux A, Cardinal J, et al. Ammonium acid urate crystal formation in adult North American stone-formers. American journal of kidney diseases. 1997;30:237-242. Soble JJ, HAMILTON BD, STREEM SB. Ammonium acid urate calculi: a reevaluation of risk factors. The Journal of urology. 1999;161:869-873. Dick W, Lingeman J, Preminger G, Smith L, Wilson D, Shirrell W. Laxative Abuse as a Cause for Ammonium-Urate Renal Calculi. Urolithiasis: Springer; 1989:303-305. Klohn M, Bolle J, Reverdin N, Susini A, Baud C-A, Graber P. Ammonium urate urinary stones. Urological research. 1986;14:315-318. Chou Y-H, Huang C-N, Li W-M, et al. Clinical study of ammonium acid urate urolithiasis. The Kaohsiung journal of medical sciences. 2012;28:259-264. Kuruma H, Arakawa T, Kubo S, et al. Ammonium acid urate urolithiasis in Japan. International journal of urology. 2006;13:498-501. Pak CY, Poindexter JR, Adams-Huet B, Pearle MS. Predictive value of kidney stone composition in the detection of metabolic abnormalities. The American journal of medicine. 2003;115:26-32. Pearle MS, Goldfarb DS, Assimos DG, et al. Medical management of kidney stones: AUA guideline. The Journal of urology. 2014;192:316-324.
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Figure 1. Frequency distribution of ammonium acid urate (AAU) percent content in stones 25
Fraquency (N)
20
15
10
5
0 10
20
30
40
50
60
70
80
90
100
Percent AAU Content
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Table 1. AAU Containing Stones Stratified By Primary Component and Location Primary Stone Component Total AAU Calcium oxalate dihydrate Calcium oxalate monohydrate CaPO4 (apatite) CaPO4 (brushrite) Struvite Uric Acid
All Upper Locations Tract 89 38 42 21 2 2
Bladder Augment/ Pouch/Conduit Neobladder 35 10 6 16 3 2 0 0 0
1
1
0
0
0
16 1 25 2
6 1 6 1
6
2
2
12 1
5 0
2 0
Table 2. AAU Stone Location Based On Comorbidity
CKD Recurrent UTI Diabetes Ileostomy/Resection Diarrhea/IBD BNC Chronic Catheter Surgically Altered Lower Tract Multiple Risk Factors No Identified Risk Factors
All Upper Locations Tract 7 5 12 5 8 4 25 10 11 11 20 1 8 2 16 0 32 21
11 14
Bladder Augment/ Pouch/Conduit Neobladder 1 0 1 6 0 1 4 0 0 2 7 6 0 0 0 18 0 1 5 1 0 0 10 6 7 7
8 0
6 0
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