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Evaluating factors that dictate struvite stone composition: A multi-institutional clinical experience from the EDGE Research Consortium.

Introduction

Struvite stones are thought to form in the presence of urease producing bacteria that create an environment favoring the formation of magnesium ammonium phosphate. They comprise 7 to 15% of all stone types (1,2), and 24% of staghorn calculi (3). They occur more frequently in women compared to men with a ratio of approximately 2:1. (4) Factors that predispose one to acquiring these stones include female sex, extremes of age, congenital urinary tract malformations, stasis from urinary obstruction, urinary diversion, neurogenic bladder, indwelling urethral catheters, distal renal tubular acidosis, medullary sponge kidney and those with diabetes mellitus (5). These stones may form in the kidney or bladder, and when in the kidney, they are bilateral in nearly 15% of cases (6). Presentation includes flank or abdominal pain in 70%, fever in 26%, gross hematuria in 18%, sepsis and recurrent urinary tract infections in 1%, though up to 8% are asymptomatic (6,7).

Struvite stones are one of the most common causes of staghorn calculi which are known to potentially form rapidly, in the order of 4 to 6 weeks (8). Composition is often heterogenous but typically has a component of magnesium ammonium phosphate (struvite), monoammonium urate, and/or carbonate apatite (8). For the sake of classification, "struvite" stones in this manuscript will also refer to carbonate apatite stones, since they are also considered "infection stones". Pathogenesis of struvite stones requires the presence of bacteria that express the enzyme urease, which breaks down urea to ammonia and carbon dioxide (C[O.sub.2]), creating a highly alkaline urine (pH 7.2 to 8.0). Alkaline conditions favor crystallization of magnesium ammonium phosphate. Bacteria that always produce urease include Proteus species, Providencia species, and Morganella morganii. However, other bacterial species heterogeneously produce urease. For example, 84% of Klebsiella, 55% of Staphylococcus, and 1.4% of E. coli species produce urease. (8) Collectively, this illustrates the wide array of bacterial species capable of causing struvite stone formation.

Interestingly, the presence of urease producing bacteria alone does not always result in struvite stone formation. A previous study has shown that out of the 39% of patients infected with a urease positive bacterial species, only 16% formed struvite stones. (9) Given these findings, a significant need exists to identify and better understand contributary factors that result in struvite stone formation, beyond the presence of a urease producing microorganism. The present study takes the first step and aims to evaluate stone, patient and microbiological factors involved with infection stones among 4 urological centers from the EDGE Research Consortium in North America and one affiliate-member from Europe.

Methods

The medical records of patients with struvite-containing calculi at the Vancouver General Hospital Stone Center, Mayo Clinic, Cleveland Clinic and University Hospital Grosshadern between October 2008 and April 2012 were retrospectively reviewed. Institutional research ethics board approval was obtained at each site. Patients were included in the study if they had a struvite calculus (or carbonate apatite) identified on stone analysis. Patients underwent various surgical techniques for stone removal and stones were obtained intra-operatively if possible. Stones were collected at the time of surgery if they underwent PCNL or SWL. Patients undergoing SWL strained their urine and collected stones for analysis. Analysis was performed by the respective hospital laboratories using Fourier-transform infrared (FTIR) spectroscopy and compared to a standardized library. Patients had urine collected prior to surgery as well as when symptoms arose. Patients were considered to have recurrent UTIs if they had 2 or more distinct infections within a 6-month time period.

Patients who underwent metabolic testing post-operatively including 24-hour urine tests were tested at least 90 days after being deemed stone free. Medical therapy to prevent stone disease was not instituted prior to obtaining the 24-hour urine test. Given that this study was multi-center and retrospective in design, not all stone entries had complete data; as such, denominators are declared in all domains of analysis. Statistical comparisons were made using Mann-Whitney, unpaired T-tests, and Fisher's exact test using Graph Pad, and Instat version 3.0 software.

Results

One hundred and twenty-one struvite stones were identified in this study: 65 from the VGH Stone Center, 5 from Mayo Clinic (Arizona), 19 from University Hospital Grosshadern, and 32 from Cleveland Clinic. Mean age was 53.4 (Range: 16 to 88) years. Female patients accounted for 63% and males for 37% of the study population. The mean BMI was 29.0 kg/[m.sup.2], with 34% of patients meeting the BMI definition of obesity (>30kg/[m.sup.2]). Of all struvite stones, 38% (25/65) were recurrent stones. The mean urinary pH was 6.53 +/- 0.86. Among 58 urinalyses performed, 54 (93.1%) were positive for leukocytes, 54 (93.1%) for red blood cells (RBC's), 23 (39.7%) for nitrites, 18 (31.0%) for protein, and 1 (1.7%) for glucose. Only 16/121 (13.2%) stones were homogenous in composition, while the remaining 105 (86.8%) contained one or more additional components. Specifically, 51 (42.1%) contained calcium phosphate, 41 (33.9%) contained calcium oxalate, 33 (27.3%) contained calcium carbonate, and 7 (5.8%) contained uric acid.

The most common location of stones was the kidney (100/121; 82.6%), followed by the ureter (13/121; 10.7%), and bladder (8/121; 6.6%). Of these, 31/121 (23.7%) were staghorn or partial staghorn stones in presentation. Many stones required a combination of treatment modalities. Most commonly, stones were treated with PCNL (38/117, 32.5%), followed by ureteroscopy (URS) (23/117, 19.7%), combination of percutaneous nephrolithotomy (PCNL) and Shockwave lithotripsy (SWL) (12/117, 10.3%), URS and SWL (12/117, 10.3%), URS and PCNL (10/117, 8.5%), PCNL and SWL and URS (10/117, 8.5%), PCNL and cystoscopic lithopaxy

(3/117, 2.6%), cystoscopic lithopaxy (3/117, 2.6%), SWL (3/117, 2.6%). One patient underwent a laparoscopic nephrectomy, 1 patient underwent a pyeloplasty and pyelolithotomy, 1 patient had URS, SWL, PCNL and cystoscopy with lithopaxy.

Urine cultures were collected from patients at the time of stone diagnosis and immediately prior to surgical treatment. Proteus species was cultured in 17 (11.3%) and E. coli in 23 (15.2%) isolates among all stone patients. Negative cultures were identified in 19 (12.6%) samples. Multiple species were often cultured per sample (Figure 1). Bacterial isolates were also compared based upon geographic location (Figure 2). Risk factors for stones and urinary infections are listed in Table 1.

Discussion

The present study was conducted to better understand clinical, bacterial and urinary factors implicated in the formation of pure or multi-compositional struvite stones.

Patients in our study with any component of struvite stone tended to have multiple comorbidities with risk factors for both urinary tract infections and stone disease. Notable comorbidities included neurogenic bladder, recurrent urinary tract infections, and diabetes mellitus, smoking history, dyslipidemia, hypertension and chronic kidney disease. This emphasizes the importance of effectively treating these individuals in a timely and definitive manner, as conservative treatment of patients suffering from multiple comorbidities has been shown to result in significantly higher morbidity (11). Patients with homogeneous struvite stones tended to have a greater history of smoking, bowel resection, and ileal conduit urinary diversions; however, this did not meet statistical significance when accounting for multiple statistical comparisons.

The majority of stones were located in the kidney. Multiple treatment modalities were necessary to achieve a stone free status, with PCNL most often being utilized along with perioperative antibiotics in all patients. Aggressive treatment removing all residual fragments is essential in managing struvite stones because they can serve as a nidus for post-operative infection and future stone growth (16).

Our results show that the diagnosis of infection stones based on urinalysis alone is not very reliable, as only 40% were nitrite positive and 93% were leukocytes or blood positive. Furthermore, classically described urease producing bacteria were isolated in only 30% of cases indicating that even urinary bacterial culture is not a reliable predictor for the presence of infection stones during preoperative evaluation. Similar to previous reports in the literature, we found significant heterogeneity among the bacterial isolates, (17-19) with the two most common being E. coli and Proteus. While this may suggest an increase in the number of urease-positive E. coli strains, it is more likely that patients are suffering from multi-species urinary tract infections, and E. coli is the most commonly isolated species due to the fact that its short replication rate results in it outcompeting and outgrowing other bacterial species. This is especially true in the high pH environment associated with the presence of urease-positive bacteria, which tends to be inhibitory for bacterial growth including P. mirabilis. Given that conventional urine culture techniques rely on the viability and growth of different bacterial species, only those that actually survive high urine pH conditions accompanying infection stones will be identified. This is verified by studies that have demonstrated that only ~25% of midstream urine cultures correlated to urease-positive isolates from stone cultures, raising the importance of both stone cultures and stone composition to verify the culprit and also the stone as struvite composition. (20) The reason that urease-positive bacterial species can still be isolated from stone cultures despite the unfavorably high pH of the urine, is that they are protected from a potentially unfavorable urinary environment by the surrounding stone, allowing them to survive. Further research, both clinical and laboratory based, are required to further evaluate coexistence and relationship among common urinary pathogens identified in this study and urease producing organisms in the setting of infections stones.

When assessing stone composition, nearly 87% of the stones identified as struvite were actually of mixed composition. Interestingly, no trends were identified among bacterial species and stone composition. This suggests that the formation of infection stones is not solely determined by the presence of urease positive bacterial species, but also requires additional urinary features. To explore this possibility, we compared 24-hour urine compositions between patients with pure struvite and mixed struvite stones. We did not find any significant differences in the most commonly tested parameters despite previous reports identifying hypercalciuria as a risk factor (21). Our lack of findings could be due to variation in 24-hr urinary values, a limited denominator in this data set, and the fact that the majority of our patients did not have urease producing bacterial species. Studying the role of specific urinary components in promoting struvite stone formation warrants further investigation, as the exact physico-chemical parameters that influence struvite crystallization kinetics in urine have not been established. Kinetic studies in response to struvite formation in wastewater treatment has shown that supersaturation and pH are the most influential parameters determining struvite formation, indicating that the concentration of individual parameters are important determinants for this process (22). In this setting, higher NaCl salt concentrations were also shown to result in higher struvite growth kinetics.

Homogeneous struvite stones tended to have a higher urinary pH of 7.04 compared to heterogeneous struvite stones (urinary pH of 6.55) but failed to reach statistical significance (p = 0.087). This may be due to these urine tests being performed in the absence of active infection and thus do not represent the urine during present infection with urease producing bacteria. Alternatively, it may suggest that homogeneous struvite stones tend to form when the normal urinary pH is closer to the [K.sub.sp] for struvite formation, while a more acidic starting pH means struvite formation may occur with a lower threshold in the presence of heterogenous nucleation with commonly identified calcium based stones. Here, calcium based stones may create a nidus, making subsequent struvite nucleation more likely in the setting of a urease producing bacteria. However, further research is required to test this hypothesis.

Limitations of the present study exist. Firstly, urine cultures are not always transparently reflective of stone cultures (9), and thus cultures demonstrating common urinary tract organisms may be over-represented in the present series. However, management decisions are guided by the urine culture as the stone culture is not available preoperatively. Having multiple centers increased the power of this data and generalizability, however, local practice patterns, bacterial profiles and laboratory techniques for culture, stone analysis and urinary profiles may differ. Thirdly, the exact stone sizes were not recorded; therefore, we were unable to discern differences in infected stones according to size. Lastly, the study was retrospective, and optimal timing of cultures in relation to time of stone diagnosis or treatment was not possible. Stone analysis was not available in all patients and may be routinely performed in future analyses to provide more complete information. Further prospective studies are required to most accurately characterize struvite stones, associated bacterial species and outcomes of definitive therapy. In addition, evidence to support duration of antibiotic use beyond definitive therapy or follow up regimens beyond definitive therapy is presently lacking and is important to define as nearly 40% of struvite stones in the present series represented a recurrent stone.

Conclusion

Patients with struvite stones often have multiple comorbidities. Many have risk factors for both stone formation, and urinary tract infections. The majority of struvite stones are heterogeneous in both composition and bacterial isolates. Few differences exist with respect to 24hr urinary studies, when comparing homogeneous struvite stones to those of mixed composition. Proteus mirabilis remains a common player in the pathogenesis of struvite stone formation, however, this study identified Enterococcus and E. coli as common bacterial isolates present in struvite stones and associated infections. This reinforces the importance of obtaining urine and stone cultures when managing struvite stones; bacteria beyond urease producing species may co-exist and contribute to urinary tract infection among these patients and the former may not be detectable in urine samples over-populated by non-urease producers. Thus, surgeons should remain suspicious of struvite stones preoperatively among patients fraught with recurrent UTI's, risk factors for UTIs or staghorn stones despite absence of a positive urine culture for a urease producing organism.

References

(1.) Hesse, A. & Bach, D. Harnsteine, Pathobiochemie and Klinisch-chemische Diagnostik., Vol

(2.) Lee, M. C. & Bariol, S. V. Changes in upper urinary tract stone composition in Australia over the pa. Band 5 (1982).st 30 years. BJU international 112 Suppl 2, 65-68, doi:10.1111/bju.l2383(2013).

(3.) Shafi, H. et al. Bacteriological study and structural composition of staghorn stones removed by the anatrophic nephrolithotomic procedure. Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia 24, 418-423 (2013).

(4.) Resnick, M. I. Evaluation and management of infection stones. Urol Clin North Am 8, 265-276 (1981).

(5.) Flannigan, R., Choy, W. H., Chew, B. & Lange, D. Renal struvite stones--pathogenesis, microbiology, and management strategies. Nat Rev Urol 11, 333-341, doi:10.1038/nrurol.2014.99 (2014).

(6.) Koga, S., Arakaki, Y., Matsuoka, M. & Ohyama, C. Staghorn calculi--long-term results of management. Br J Urol 68, 122-124 (1991).

(7.) Schwartz, B. F. & Stoller, M. L. Nonsurgical management of infection-related renal calculi. Urol Clin North Am 26, 765-778, viii (1999).

(8.) Bichler, K. H. et al. Urinary infection stones. Int J Antimicrob Agents 19, 488-498 (2002).

(9.) Margel, D. et al. Clinical implication of routine stone culture in percutaneous nephrolithotomy--a prospective study. Urology 67, 26-29, doi:10.1016/j.urology.2005.08.008 (2006).

(10.) Blandy, J. P. & Singh, M. The case for a more aggressive approach to staghorn stones. The Journal of urology 115, 505-506 (1976).

(11.) Teichman, J. M., Long, R. D. & Hulbert, J. C. Long-term renal fate and prognosis after staghorn calculus management. The Journal of urology 153, 1403-1407 (1995).

(12.) Marguet, C. G. et al. Simultaneous combined use of flexible ureteroscopy and percutaneous nephrolithotomy to reduce the number of access tracts in the management of complex renal calculi. BJU international 96, 1097-1100, doi:10.1111/j.l464-410X.2005.05808.x (2005).

(13.) Meretyk, S. et al. Complete staghorn calculi: random prospective comparison between extracorporeal shock wave lithotripsy monotherapy and combined with percutaneous nephrostolithotomy. The Journal of urology 157, 780-786 (1997).

(14.) Esen, A. A., Kirkali, Z. & Guler, C. Open stone surgery: is it still a preferable procedure in the management of staghorn calculi? Int Urol Nephrol 26, 247-253 (1994).

(15.) Lam, H. S. et al. Staghorn calculi: analysis of treatment results between initial percutaneous nephrostolithotomy and extracorporeal shock wave lithotripsy monotherapy with reference to surface area. The Journal of urology 147, 1219-1225 (1992).

(16.) Preminger, G. M. et al. Chapter 1: AUA guideline on management of staghorn calculi: diagnosis and treatment recommendations. The Journal of urology 173, 1991-2000 (2005).

(17.) Balk, N, Strohmaier, W., Schmid, M. & Bichler, K. in 2nd European Symposium on Stone Disease Vol. 18 (Urological Research, Basel, 1990).

(18.) Englert, K. M., McAteer, J. A., Lingeman, J. E. & Williams, J. C., Jr. High carbonate level of apatite in kidney stones implies infection, but is it predictive? Urolithiasis 41, 389-394, doi:10.1007/s00240-013-0591-6(2013).

(19.) Tavichakorntrakool, R. et al. Extensive characterizations of bacteria isolated from catheterized urine and stone matrices in patients with nephrolithiasis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 27, 4125-4130, doi:10.1093/ndt/gfs057 (2012).

(20.) Mariappan, P., Smith, G., Moussa, S. A. & Tolley, D. A. One week of ciprofloxacin before percutaneous nephrolithotomy significantly reduces upper tract infection and urosepsis: a prospective controlled study. BJU international 98, 1075-1079, doi:10.1111/j.l464-410X.2006.06450.x (2006).

(21.) Kristensen, C., Parks, J. H., Lindheimer, M. & Coe, F. L. Reduced glomerular filtration rate and hypercalciuria in primary struvite nephrolithiasis. Kidney Int 32, 749-753 (1987).

(22.) Ariyanto, E., Sen, T. & Ang, H. M. The influence of various physico-chemical process parameters on kinetics and growth mechanism of struvite crystallisation. Advanced Powder Technology 25, 682-694 (2014).

Figures and Table

Ryan Kendrick Flannigan (1); Andrew Battison (1); Shubha De (2); Mitchell R. Humphreys (3); Markus Bader (4); Ekaterina Lellig (5); Manoj Monga (2); Ben H. Chew (1); Dirk Lange (1)

(1) The Stone Centre at Vancouver General Hospital, Department of Urologic Sciences, University of British Columbia, Vancouver BC, Canada; (2) Stevan Streem Centre of Endourology & Stone Disease, The Cleveland Clinic, Cleveland, OH, United States; (3) Department of Urology, Mayo Clinic, Phoenix, Arizona, Mayo Clinic, Phoenix, AZ, United States; (4) UroClinic Munchen Giesig, Munich, Germany; (5) Klinikum Grosshadern der Universitat Munchen, Munich Germany

Cite as: Can Urol Assoc J 2017 Dec. 22; Epub ahead of print.

http://dx.doi.org/10.5489/cuaj.4804

Published online December 22, 2017

Caption: Fig. 1. Graph of bacterial species isolates from patient urine cultures presenting with A) homogeneous struvite stones; B) struvite and calcium oxalate; C) struvite and calcium phosphate; D) calcium carbonate; and E) calcium and other stone heterogeneities.

Caption: Fig. 2. Graph of the number of urinary bacterial isolates from patients with struvite stones based upon patient geographic location. MRSA: methicillin-resistant Staphylococcus; MSSA: methicillin-sensitive staphylococcus; VRE: vancomycin-resistant Enterococcus.
Table 1. Known risk factors for nephrolithiasis and urinary tract
infections based upon struvite stone composition.

Risk factors              All struvite  Heterogeneous  Homogenous
                          stones (%)    struvite (%)   struvite (%)

Recurrent UTIs            42 (34.7)     36 (34.2)      6 (37.5%)
Hypertension              29 (22.3)     27 (25.7)      2(12.5)
Smoking                   26 (21.5)     18 (17.1)      8 (50.0)
Diabetes mellitus         25 (20.7)     22 (21.0)      3 (18.8)
Wheelchair-dependent      15 (12.4)     10 (9.5)       5 (31.3)
Neurogenic bladder        14 (11.6%)    11 (10.5%)     3 (18.8)
Obesity                   13 (10.7)     11 (10.5)      2 (12.5)
Dyslipidemia              12 (9.9)      11 (10.5)      1 (6.3)
Pyelonephritis            11 (9.1)      10 (9.5)       1 (6.3)
Hyperparathyroid           9 (7.4)       9 (8.6)       0 (0.0)
Prior bowel resection      9 (7.4)       5 (4.8)       4 (25%)
Chronic kidney             8 (6.6)       6 (5.7)       2 (12.5)
disease
Retained ureteral stent    8 (6.6)       6 (5.7)       2 (12.5)
Indwelling catheter        8 (6.6)       7 (6.7)       1 (6.3)
UPJO/pyeloplasty           7 (5.8)       6 (5.7)       1 (6.3)
Calyceal diverticulum      6 (5.0)       6 (5.7)       0 (0.0)
Nephrocalcinosis           5 (4.1)       5 (4.8)       0 (0.0)
Ureteral obstruction       4 (3.3)       4 (3.8)       0 (0.0)
Medullary sponge           4 (3.3)       4 (3.8)       0 (0.0)
kidney
Bladder                    4 (3.3)       3 (2.9)       1 (6.3)
augment/Mitrofanoff
Ileal conduit              3 (2.5)       1 (1.0)       2 (12.5)
Self-catheter              3 (2.5)       2 (1.9)       1 (6.3)
Atrophic non-functioning   2 (1.7)       2 (1.9)       0 (0.0)
kidney
Stented                    1 (0.8)       1 (1.0)       0 (0.0)
HIV                        1 (0.8)       0 (0.0)       1 (6.3)
Extrophy                   1 (0.8)       1 (1.0)       0 (0.0)

Risk factors               p


Recurrent UTIs             0.785
Hypertension               0.353
Smoking                    0.006 (*)
Diabetes mellitus          1.000
Wheelchair-dependent       0.028 (*)
Neurogenic bladder         0.396
Obesity                    0.682
Dyslipidemia               1.000
Pyelonephritis             1.000
Hyperparathyroid           0.605
Prior bowel resection      0.018 (*)
Chronic kidney             0.285
disease
Retained ureteral stent    0.285
Indwelling catheter        1.000
UPJO/pyeloplasty           1.000
Calyceal diverticulum      1.000
Nephrocalcinosis           1.000
Ureteral obstruction       1.000
Medullary sponge           1.000
kidney
Bladder                    0.437
augment/Mitrofanoff
Ileal conduit              0.046 (*)
Self-catheter              0.349
Atrophic non-functioning   1.000
kidney
Stented                    1.000
HIV                        0.125
Extrophy                   1.000

(*) p<0.05; however, accounting for multiple comparisons, this does not
reach statistical significance.

Table 2. Comparison of 24-hour urinary values among patients with pure
struvite stones and those with heterogeneous (<100%) struvite stones

Urinary parameter     Homogeneous
                      struvite, mean [+ or -] SD

pH                      7.04[+ or -]1.05(n=13)
24-hour Na            139.33[+ or -]2.55 (n=15)
(mmol/day)
24-hour Ca              9.40[+ or -]0.39 (n=5)
(mmol/day)
24-hour K               3.91[+ or -]0.40(n=15)
(mmol/day)
24-hour Cl            104.62[+ or -]4.23 (n=13)
(mmol/day)
24-hour HC[O.sub.3]    25.69[+ or -]2.93 (n=13)
(mmol/day)

Urinary parameter     Heterogeneous struvite,
                      mean [+ or -] SD

pH                      6.55[+ or -]0.76 (n=69)
24-hour Na            139.05[+ or -]2.49 (n=87)
(mmol/day)
24-hour Ca              9.29[+ or -]0.62 (n=46)
(mmol/day)
24-hour K               4.02[+ or -]0.46 (n=96)
(mmol/day)
24-hour Cl            104.89[+ or -]3.73 (n=74)
(mmol/day)
24-hour HC[O.sub.3]    25.28[+ or -]3.15(n=81)
(mmol/day)

Urinary parameter     p

pH                    0.0871
24-hour Na            0.7477
(mmol/day)
24-hour Ca            0.5998
(mmol/day)
24-hour K             0.3713
(mmol/day)
24-hour Cl            0.6637
(mmol/day)
24-hour HC[O.sub.3]   0.9519
(mmol/day)


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Author:Flannigan, Ryan Kendrick; Battison, Andrew; De, Shubha; Humphreys, Mitchell R.; Bader, Markus; Lelli
Publication:Canadian Urological Association Journal (CUAJ)
Article Type:Report
Date:Apr 1, 2018
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