1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57
The Natural History of Nonobstructing Asymptomatic Renal Stones Managed with Active Surveillance Benjamin M. Dropkin,* Rachel A. Moses, Devang Sharma and Vernon M. Pais, Jr. From the Geisel School of Medicine at Dartmouth, Hanover (BMD, DS, VMP), and Section of Urology, Dartmouth Hitchcock Medical Center, Lebanon (RAM, VMP), New Hampshire
Purpose: We documented the natural history of asymptomatic nonobstructing renal calculi managed with active surveillance and explored factors predicting stone related events to better inform shared decision making. Materials and Methods: Patients with asymptomatic nonobstructing renal calculi electing active surveillance of their stone(s) were retrospectively reviewed. Stone characteristics, patient characteristics, and stone related events were collected. We evaluated the effects of stone size and location on development of symptoms, spontaneous passage, requirement for surgical intervention, and stone growth. Results: We identified 160 stones with an average size of 7.0 4.2 mm among 110 patients with average followup of 41 19 months. Forty-five (28% of total) stones caused symptoms during followup. Notably 3 stones (3% of asymptomatic subgroup, 2% of total stones) caused painless silent obstruction necessitating intervention after an average of 37 17 months. The only significant predictor of spontaneous passage or symptom development was location. Upper pole/mid renal stones were more likely than lower pole stones to become symptomatic (40.6% vs 24.3%, p ¼ 0.047) and to pass spontaneously (14.5% vs 2.9%, p ¼ 0.016). Conclusions: Among asymptomatic nonobstructing renal calculi managed with active surveillance, most remained asymptomatic through an average followup of more than 3 years. Less than 30% caused renal colic, less than 20% were operated on for pain and 7% spontaneously passed. Lower poles stones were significantly less likely to cause symptoms or pass spontaneously. Despite 3 stones causing silent hydronephrosis suggestive of obstruction, regular followup imaging facilitated interventions that prevented renal loss.
Abbreviations and Acronyms ARC ¼ asymptomatic nonobstructing renal calculi AS ¼ active surveillance BMI ¼ body mass index CT ¼ computerized tomography KUB ¼ plain x-ray of the kidneys, ureters and bladder Accepted for publication November 10, 2014. Nothing to disclose. * Correspondence: 14 Sachem Circle, Apt. 8, West Lebanon, New Hampshire 03784 (FAX: 518-489-1768; e-mail: Benjamin.m.dropkin. [email protected]).
See Editorial on page . Editor’s Note: This article is the of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages and .
Key Words: kidney calculi, asymptomatic diseases, watchful waiting
THE age controlled prevalence of kidney stones in the United States has increased markedly from 5.2% in 1994 to 8.4% in 2010.1 Associated health care costs are estimated at well over $2 billion annually.2 The proportion of kidney stones that are
asymptomatic nonobstructing renal calculi found incidentally on unrelated imaging is unknown but is presumably increasing as the use of radiologic services continues to increase.3,4 Therefore, optimizing management of ARC is paramount to
0022-5347/15/1934-0001/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Dochead: Adult Urology
http://dx.doi.org/10.1016/j.juro.2014.11.056 Vol. 193, 1-5, April 2015 Printed in U.S.A.
www.jurology.com
FLA 5.2.0 DTD JURO11999_proof 19 January 2015 7:48 pm EO: JU-14-1566
j
1
58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114
2
115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171
NATURAL HISTORY OF ASYMPTOMATIC RENAL STONES
maximizing patient outcomes and minimizing unnecessary stone related spending. Available literature on active surveillance as a management strategy for ARC is limited to a small number of retrospective5e7 and prospective8e10 studies that have reported spontaneous passage rates of 3% to 20% and intervention rates of 7% to 26%. Keeley et al compared AS to prophylactic extracorporeal shock wave lithotripsy in patients with small ARC and found no significant differences in stone-free rate, quality of life, renal function, symptoms or hospital admissions between the 2 groups during an average of followup of 2 years.10 However, a policy of observation may ultimately necessitate the use of more invasive therapies when compared with prophylactic interventions. Prior studies have also suggested that lower pole location and smaller stone size may be protective against adverse outcomes.5e7 In 2013 the European Association of Urology issued a grade C recommendation that asymptomatic calyceal stones can be followed with AS including annual followup imaging for 2 to 3 years while intervention should be considered after this period.11 The American Urological Association has not yet released a guideline statement on this issue. We documented the natural history of ARC managed with AS, and explored predictive factors for stone related events to add to the existing literature and better inform shared decision making.
MATERIALS AND METHODS We retrospectively identified all patients with documented ARC seen by a single surgeon between June 25, 2008 and December 28, 2010 who elected AS of their stone(s) with routine followup imaging. All patients with ARC were counseled regarding management options including AS and possible surgical interventions as dictated by stone size and location. Our AS protocol consisted of recommended renal ultrasound 6 months after initial presentation with continued followup renal ultrasound every 6 months in cases of increasing stone size or burden or every 12 months in cases of stone stability with the intention to treat if the patient experienced severe pain attributable to obstruction or silent hydronephrosis. Patients with at least 6 months of documented followup were eligible for study inclusion. When possible, we reviewed documented medical encounters from before June 25, 2008 to identify the first radiologic observation of the ARC(s). Patients were not excluded from study based on a history of stone related intervention(s). However, asymptomatic stones that were believed to be fragments from prior stone related intervention were excluded. CT, ultrasound and KUB images from our institution and from outside institutions were used as methods of diagnostic and followup imaging. We collected data on stone characteristics (size, location, and date and modality of first radiographic visualization for the largest Dochead: Adult Urology
172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 RESULTS 191 Baseline Patient and Stone Demographics 192 Table 1 presents baseline characteristics of the ½T1 193 entire cohort. We identified 160 stones (84 left and 194 76 right) with an average size of 7.0 4.2 mm 195 among 110 patients (60 male and 50 female). 196 Average patient age was 56 14 years and average 197 BMI was 30 9 kg/m2. Stones were initially iden198 tified using CT (79, 49.4%), ultrasound (78, 48.8%) 199 or KUB (3, 1.8%). No renal units were lost during 200 followup. 201 202 Natural History of ARC 203 The supplementary table (http://jurology.com/) 204 presents the clinical outcomes of our stone cohort. 205 Overall 115 stones (72% of total) did not cause renal 206 colic. Eighteen stones (11% of total) were followed 207 and then treated electively. Notably 3 stones (2% of 208 total) caused painless silent hydronephrosis neces209 sitating intervention and 45 stones (28% of total) did 210 cause symptoms. There were 27 stones (17% of 211 total) that required surgery for renal colic or 212 symptomatic obstruction, and 33 stones (21% of 213 total) grew to greater than 50% of their initially 214 documented size. The majority of these high growth 215 216 217 Table 1. Baseline patient demographics and stone characteristics 218 219 Mean SD mos followup (range) 40.6 18.6 (7e86) 220 Mean SD pt age (range) 55.8 13.8 (19e82) Mean SD mm initial stone diameter (range) 7.0 4.2 (1e25) 221 30.0 9.3 (17e85) Mean SD kg/m2 BMI (range) 222 No. male (%) 60 (55) 223 No. stone history (%) 140 (87) No. multiple stones (%) 122 (76) 224 No. stone location (%): 225 Lower pole 41 (25) 226 Mid calyx 35 (22) Upper calyx 81 (51) 227 Renal pelvis 3 (2) 228 nonobstructing stone present in each kidney), patient characteristics (age, BMI at inclusion, gender, and history of prior stones) and stone related events (elective stone removal, stone growth, spontaneous passage, development of renal colic defined as ipsilateral abdominal or flank pain that a medical provider thought was most likely attributable to nephrolithiasis, development of silent obstruction, emergency department visits and surgical intervention for pain). We then compared the effects of stone size (less than 1 cm, or 1 cm or greater) and location (upper/mid renal and lower pole) on development of symptoms, spontaneous passage, requirement for surgical intervention and stone growth greater than 50% of initial size using chi-square and bivariate logistic regression analysis. Patients who electively underwent intervention without symptoms or in whom silent hydronephrosis developed were included in the natural history analysis and excluded from the predictive analyses.
FLA 5.2.0 DTD JURO11999_proof 19 January 2015 7:48 pm EO: JU-14-1566
NATURAL HISTORY OF ASYMPTOMATIC RENAL STONES
229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285
Table 2. Effect of ARC location on clinical outcome No./Total No. Lower Pole (%) EQ1
Became symptomatic Spontaneous passage Required surgical intervention Growth greater than 50% of size on first visualization
17/70 2/70 13/70 13/70
(24.3) (2.9) (18.6) (18.6)
No./Total No. Nonlower Pole (%) 28/69 10/69 14/69 13/69
(40.6) (14.5) (20.3) (18.8)
Table 4. Logistic regression of predictors of symptom development p Value 0.047* 0.016* 0.830 1.000
stones (66% of high growth subgroup) remained asymptomatic through the end of followup while 2 (6% of high growth subgroup) caused symptoms requiring surgical management. Twelve stones (8% of total) passed spontaneously during followup and 22 stones (14% of total) led to hydronephrosis.
½T2
½T3
½T4
½F1
Effect of ARC Location and Size on Clinical Outcome Table 2 summarizes the effect of ARC location on clinical outcome. Lower pole stones were significantly less likely than nonlower pole stones to cause symptoms (24.3% vs 40.6%, p¼0.047) or to pass spontaneously (2.9% vs 14.5%, p¼0.016). We did not find a significant difference in rates of surgical intervention or growth to greater than 50% of initial size between the lower pole and nonlower pole stone groups. Table 3 summarizes the effect of ARC size on clinical outcome. We did not find ARC size to be a predictor of any of our documented clinical outcomes. Table 4 presents our multivariate analysis. Controlling for age, stone size, stone location, history of stones, multiple stones on first imaging and stone growth, the only factor independently predictive of symptom development was stone location in the lower pole. Kaplan-Meier analysis revealed that lower pole stones were significantly less likely to require surgical intervention or pass spontaneously during followup (log rank p ¼ 0.04, see figure).
DISCUSSION In one of the largest retrospective studies to date, we evaluated the natural history of ARC as well as the effects of ARC location and size on clinical outcome. We found that among our cohort of 160 stones with a mean size of 7.0 mm followed for an average of 41 19 months, 28% of the stones Table 3. Effect of ARC size on clinical outcome No./Total No. No./Total No. Less than 10 mm 10 mm or Greater (%) (%) p Value Became symptomatic Spontaneous passage Required surgical intervention Growth greater than 50% of size on first visualization
Dochead: Adult Urology
36/116 11/116 19/116 23/116
(31.0) (9.5) (16.4) (19.8)
9/23 1/23 8/23 3/23
(39.1) (4.3) (34.8) (1.3)
3
0.471 0.690 0.079 0.568
Age: 20e35 35e50 50e65 65e85 Female Stones larger than 1 cm Lower pole stone History of stones Multiple stones Stone growth greater than 50%
OR
CI: Lower
CI: Upper
1.00 0.34 0.35 0.92 1.26 1.35 0.34 0.51 1.19 0.46
0.06 0.08 0.35 0.51 0.36 0.14 0.19 0.32 0.12
2.00 1.52 2.40 3.12 5.02 0.81 1.36 4.34 1.73
p Value 0.38
0.61 0.66 0.02 0.18 0.80 0.25
became symptomatic with 17% requiring surgical intervention. The only significant predictor of spontaneous passage or symptom development was stone location. In one of the first retrospective reviews of ARC Glowacki et al examined 107 ARC with an average followup of 31.6 months, and found that ARC were more likely to remain asymptomatic than to cause symptoms (68% vs 34%), with 17% of the total cohort requiring surgery.6 While there was a trend for higher stone related events in patients with previous stone events, multiple stones at study initiation and larger stones, none of these associations were statistically significant. Similarly, these characteristics were not predictive of stone migration in our cohort (table 4). In contrast to our study Glowacki et al did not evaluate stone location as a predictor of stone events.6 More recently Koh et al examined a cohort of 85 stones with a mean size of 5.7 mm followed for an average of 46 months, and found that 20% passed spontaneously and 7% required surgical intervention.7 Similarly we found that 28% of our cohort exhibited symptomatic stone migration with 8% passing spontaneously and 17% requiring surgical intervention for symptomatic obstruction. Koh et al also examined the effect of stone size on clinical outcome, and found that rates of spontaneous passage for stones less than 5 mm were higher than for stones 5 to 10 mm and stones greater than 10 mm (28%, 5% and 0%, p not reported).7 They also found a trend for larger stones to necessitate surgical intervention more frequently (rates for stones less than 5 mm, 5 to 10 mm and greater than 10 mm were 5%, 10% and 14%, respectively, p¼0.477) and to progress clinically (rates of progression for stones less than 5 mm, 5 to 10 mm and greater than 10 mm were 40%, 52% and 71%, respectively, p¼0.282). While neither the study by Koh et al nor our study revealed statistically significant relationships between stone size and the need for surgical intervention, both studies suggest that larger stones are more likely to require surgical intervention, and
FLA 5.2.0 DTD JURO11999_proof 19 January 2015 7:48 pm EO: JU-14-1566
286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342
NATURAL HISTORY OF ASYMPTOMATIC RENAL STONES
Time to Event
0.2
0.4
Survival 0.6
0.8
Non−Lower Pole Lower Pole
0.0
343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399
1.0
4
0
20
40
60
80
Time (Months)
Kaplan-Meier survival analysis of stone location in predicting probability of not having intervention or spontaneous passage of initially asymptomatic stones.
both may have reached this conclusion with larger stone cohorts. In contrast to our study Koh et al found no statistically significant relationship between stone location and migration.7 However, lower pole stones in their series were less likely than middle or upper pole stones to pass spontaneously (11.5% vs 16.2% vs 36.4%, p¼0.092). While an important study, their series included only 85 stones, which likely impacted their ability to demonstrate significant differences between groups. Burgher et al studied a cohort of 300 patients with a mean stone size of 10.8 mm followed for an average of 39 months.5 In contrast to our study, they found that the majority of ARC (77%) progressed clinically (stone growth, pain or need for surgical intervention). Burgher et al did not look at stone location as a predictor of stone migration.5 They did find that lower pole stones were significantly more likely than mid and upper pole stones to grow during followup (61% vs 47%, p ¼ 0.002). Conversely we found no association between stone location and growth rate. Burgher et al also found initial ARC size to be predictive of progression with stones 4 mm or greater on presentation being 26% more likely to fail observation than smaller stones (p ¼ 0.012).5 Although not significant, we also found that larger stones were more likely to fail active surveillance and require surgical intervention (34.8% vs 16.4%, p¼0.079) with our AS protocol. In contrast to the studies by Koh7 and Burgher5 et al, previous studies have singularly evaluated Dochead: Adult Urology
management strategies for lower pole ARC. Yuruk et al randomized 94 patients with asymptomatic lower pole stones to observation or shock wave lithotripsy and followed them for an average of 19 5 months.9 Of the 34 stones managed with observation 22% had symptoms due to spontaneous passage (3.1%) or required surgical intervention (19%). Similar to our cohort, the majority of the observed lower pole stones (greater than 80%) in their study remained asymptomatic through the end of followup. Inci et al evaluated 27 lower pole ARC with a mean size of 8.8 mm followed for an average of 52 months.8 They found that 33% progressed (stone growth, pain or need for surgical intervention) and 11% required surgical intervention. The findings of these prior asymptomatic stone cohorts are echoed in our survival analysis which shows that lower pole stones were less likely to have an event during our comparable followup period (see figure). Additionally, Raman and Pearle conducted a meta-analysis seeking optimum management of lower pole calculi.12 Their study revealed that lower pole stones larger than 2 cm treated with percutaneous nephrolithotomy had less morbidity. However, consistent with our study, they also concluded that lower pole stones less than 1 cm may be observed with equivalent morbidity outcomes as shock wave lithotripsy and ureteroscopy with laser lithotripsy. They also found observation to have the least cost and surgical risk among available management stratgeies.12
FLA 5.2.0 DTD JURO11999_proof 19 January 2015 7:48 pm EO: JU-14-1566
400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456
NATURAL HISTORY OF ASYMPTOMATIC RENAL STONES
457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505
Importantly we also found that 2% of our stone cohort caused asymptomatic hydronephrosis detected on routine imaging and was subsequently treated surgically. The decision was made to exclude these individuals from the statistical analysis as we wanted to specifically identify which patients may use health care resources for symptomatic stones. However, the possibility of the development of silent hydronephrosis supports the role of continued followup for patients with ARC. This retrospective study had several important limitations. Almost half of the stones in our cohort had size initially evaluated on renal ultrasound, which is less reliable than CT or KUB for estimating stone size. Patients who were excluded from study due to a lack of 6 months of followup may have sought treatment elsewhere or remained asymptomatic. Some patients chose to treat asymptomatic stones after initially electing active surveillance so we cannot know how these stones would have fared if left untreated. Finally, some patients may have been considered symptomatic
5
from a renal stone when in fact the symptoms were due to another cause of pain such as gastrointestinal or other genitourinary or musculoskeletal pathology.
CONCLUSIONS Among our cohort of 160 ARC managed with active surveillance about 60% remained asymptomatic through an average followup of more than 3 years, while less than 30% caused renal colic, less than 20% were operated on for pain and 7% spontaneously passed. Lower poles stones were significantly less likely than stones outside of the lower pole to cause symptoms or pass spontaneously. Our results were generally consistent with the findings of prior studies. Despite 3 stones causing silent obstruction, regular followup imaging facilitated interventions that prevented renal loss. These data can help patients and providers make informed decisions regarding the management of asymptomatic nonobstructing renal stones.
REFERENCES 1. Scales CD Jr, Smith AC, Hanley JM et al: Prevalence of kidney stones in the United States. Eur Urol 2012; 62: 160.
with observant on of asymptomatic calculi. J Endourol 2004; 18: 534.
2. Pearle MS, Calhoun EA, Curhan GC et al: Urologic diseases in America project: urolithiasis. J Urol 2005; 173: 848.
6. Glowacki LS, Beecroft ML, Cook RJ et al: The natural history of asymptomatic urolithiasis. J Urol 1992; 147: 319.
3. Bansal AD, Hui J and Goldfarb DS: Asymptomatic nephrolithiasis detected by ultrasound. Clin J Am Soc Nephrol 2009; 4: 680. 4. Bhargavan M and Sunshine JH: Utilization of radiology services in the United States: levels and trends in modalities, regions, and populations. Radiology 2005; 234: 824. 5. Burgher A, Beman M, Holtzman JL et al: Progression of nephrolithiasis: long-term outcomes
Dochead: Adult Urology
7. Koh LT, Ng FC and Ng KK: Outcomes of long-term follow-up of patients with conservative management of asymptomatic renal calculi. BJU Int 2012; 109: 622. 8. Inci K, Sahin A, Islamoglu E et al: Prospective long-term followup of patients with asymptomatic lower pole caliceal stones. J Urol 2007; 177: 2189.
9. Yuruk E, Binbay M, Sari E et al: A prospective, randomized trial of management for asymptomatic lower pole calculi. J Urol 2010; 183: 1424. 10. Keeley FX Jr, Tilling K, Elves A et al: Preliminary results of a randomized controlled trial of prophylactic shock wave lithotripsy for small asymptomatic renal calyceal stones. BJU Int 2001; 87: 1. 11. T€urk C, Knoll T and Petrik A: Guidelines on urolithiasis. Arnhem (The Netherlands): European Association of Urology 2013. 12. Raman JD and Pearle MS: Management options for lower pole renal calculi. Curr Opin Urol 2008; 18: 214.
FLA 5.2.0 DTD JURO11999_proof 19 January 2015 7:48 pm EO: JU-14-1566
506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554
The Natural History of Nonobstructing Asymptomatic Renal Stones Managed with Active Surveillance Benjamin M. Dropkin,* Rachel A. Moses, Devang Sharma and Vernon M. Pais, Jr. From the Geisel School of Medicine at Dartmouth, Hanover (BMD, DS, VMP), and Section of Urology, Dartmouth Hitchcock Medical Center, Lebanon (RAM, VMP), New Hampshire
Purpose: We documented the natural history of asymptomatic nonobstructing renal calculi managed with active surveillance and explored factors predicting stone related events to better inform shared decision making. Materials and Methods: Patients with asymptomatic nonobstructing renal calculi electing active surveillance of their stone(s) were retrospectively reviewed. Stone characteristics, patient characteristics, and stone related events were collected. We evaluated the effects of stone size and location on development of symptoms, spontaneous passage, requirement for surgical intervention, and stone growth. Results: We identified 160 stones with an average size of 7.0 4.2 mm among 110 patients with average followup of 41 19 months. Forty-five (28% of total) stones caused symptoms during followup. Notably 3 stones (3% of asymptomatic subgroup, 2% of total stones) caused painless silent obstruction necessitating intervention after an average of 37 17 months. The only significant predictor of spontaneous passage or symptom development was location. Upper pole/mid renal stones were more likely than lower pole stones to become symptomatic (40.6% vs 24.3%, p ¼ 0.047) and to pass spontaneously (14.5% vs 2.9%, p ¼ 0.016). Conclusions: Among asymptomatic nonobstructing renal calculi managed with active surveillance, most remained asymptomatic through an average followup of more than 3 years. Less than 30% caused renal colic, less than 20% were operated on for pain and 7% spontaneously passed. Lower poles stones were significantly less likely to cause symptoms or pass spontaneously. Despite 3 stones causing silent hydronephrosis suggestive of obstruction, regular followup imaging facilitated interventions that prevented renal loss.
Abbreviations and Acronyms ARC ¼ asymptomatic nonobstructing renal calculi AS ¼ active surveillance BMI ¼ body mass index CT ¼ computerized tomography KUB ¼ plain x-ray of the kidneys, ureters and bladder Accepted for publication November 10, 2014. Nothing to disclose. * Correspondence: 14 Sachem Circle, Apt. 8, West Lebanon, New Hampshire 03784 (FAX: 518-489-1768; e-mail: Benjamin.m.dropkin. [email protected]).
See Editorial on page . Editor’s Note: This article is the of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages and .
Key Words: kidney calculi, asymptomatic diseases, watchful waiting
THE age controlled prevalence of kidney stones in the United States has increased markedly from 5.2% in 1994 to 8.4% in 2010.1 Associated health care costs are estimated at well over $2 billion annually.2 The proportion of kidney stones that are
asymptomatic nonobstructing renal calculi found incidentally on unrelated imaging is unknown but is presumably increasing as the use of radiologic services continues to increase.3,4 Therefore, optimizing management of ARC is paramount to
0022-5347/15/1934-0001/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Dochead: Adult Urology
http://dx.doi.org/10.1016/j.juro.2014.11.056 Vol. 193, 1-5, April 2015 Printed in U.S.A.
www.jurology.com
FLA 5.2.0 DTD JURO11999_proof 19 January 2015 7:48 pm EO: JU-14-1566
j
1
58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114
2
115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171
NATURAL HISTORY OF ASYMPTOMATIC RENAL STONES
maximizing patient outcomes and minimizing unnecessary stone related spending. Available literature on active surveillance as a management strategy for ARC is limited to a small number of retrospective5e7 and prospective8e10 studies that have reported spontaneous passage rates of 3% to 20% and intervention rates of 7% to 26%. Keeley et al compared AS to prophylactic extracorporeal shock wave lithotripsy in patients with small ARC and found no significant differences in stone-free rate, quality of life, renal function, symptoms or hospital admissions between the 2 groups during an average of followup of 2 years.10 However, a policy of observation may ultimately necessitate the use of more invasive therapies when compared with prophylactic interventions. Prior studies have also suggested that lower pole location and smaller stone size may be protective against adverse outcomes.5e7 In 2013 the European Association of Urology issued a grade C recommendation that asymptomatic calyceal stones can be followed with AS including annual followup imaging for 2 to 3 years while intervention should be considered after this period.11 The American Urological Association has not yet released a guideline statement on this issue. We documented the natural history of ARC managed with AS, and explored predictive factors for stone related events to add to the existing literature and better inform shared decision making.
MATERIALS AND METHODS We retrospectively identified all patients with documented ARC seen by a single surgeon between June 25, 2008 and December 28, 2010 who elected AS of their stone(s) with routine followup imaging. All patients with ARC were counseled regarding management options including AS and possible surgical interventions as dictated by stone size and location. Our AS protocol consisted of recommended renal ultrasound 6 months after initial presentation with continued followup renal ultrasound every 6 months in cases of increasing stone size or burden or every 12 months in cases of stone stability with the intention to treat if the patient experienced severe pain attributable to obstruction or silent hydronephrosis. Patients with at least 6 months of documented followup were eligible for study inclusion. When possible, we reviewed documented medical encounters from before June 25, 2008 to identify the first radiologic observation of the ARC(s). Patients were not excluded from study based on a history of stone related intervention(s). However, asymptomatic stones that were believed to be fragments from prior stone related intervention were excluded. CT, ultrasound and KUB images from our institution and from outside institutions were used as methods of diagnostic and followup imaging. We collected data on stone characteristics (size, location, and date and modality of first radiographic visualization for the largest Dochead: Adult Urology
172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 RESULTS 191 Baseline Patient and Stone Demographics 192 Table 1 presents baseline characteristics of the ½T1 193 entire cohort. We identified 160 stones (84 left and 194 76 right) with an average size of 7.0 4.2 mm 195 among 110 patients (60 male and 50 female). 196 Average patient age was 56 14 years and average 197 BMI was 30 9 kg/m2. Stones were initially iden198 tified using CT (79, 49.4%), ultrasound (78, 48.8%) 199 or KUB (3, 1.8%). No renal units were lost during 200 followup. 201 202 Natural History of ARC 203 The supplementary table (http://jurology.com/) 204 presents the clinical outcomes of our stone cohort. 205 Overall 115 stones (72% of total) did not cause renal 206 colic. Eighteen stones (11% of total) were followed 207 and then treated electively. Notably 3 stones (2% of 208 total) caused painless silent hydronephrosis neces209 sitating intervention and 45 stones (28% of total) did 210 cause symptoms. There were 27 stones (17% of 211 total) that required surgery for renal colic or 212 symptomatic obstruction, and 33 stones (21% of 213 total) grew to greater than 50% of their initially 214 documented size. The majority of these high growth 215 216 217 Table 1. Baseline patient demographics and stone characteristics 218 219 Mean SD mos followup (range) 40.6 18.6 (7e86) 220 Mean SD pt age (range) 55.8 13.8 (19e82) Mean SD mm initial stone diameter (range) 7.0 4.2 (1e25) 221 30.0 9.3 (17e85) Mean SD kg/m2 BMI (range) 222 No. male (%) 60 (55) 223 No. stone history (%) 140 (87) No. multiple stones (%) 122 (76) 224 No. stone location (%): 225 Lower pole 41 (25) 226 Mid calyx 35 (22) Upper calyx 81 (51) 227 Renal pelvis 3 (2) 228 nonobstructing stone present in each kidney), patient characteristics (age, BMI at inclusion, gender, and history of prior stones) and stone related events (elective stone removal, stone growth, spontaneous passage, development of renal colic defined as ipsilateral abdominal or flank pain that a medical provider thought was most likely attributable to nephrolithiasis, development of silent obstruction, emergency department visits and surgical intervention for pain). We then compared the effects of stone size (less than 1 cm, or 1 cm or greater) and location (upper/mid renal and lower pole) on development of symptoms, spontaneous passage, requirement for surgical intervention and stone growth greater than 50% of initial size using chi-square and bivariate logistic regression analysis. Patients who electively underwent intervention without symptoms or in whom silent hydronephrosis developed were included in the natural history analysis and excluded from the predictive analyses.
FLA 5.2.0 DTD JURO11999_proof 19 January 2015 7:48 pm EO: JU-14-1566
NATURAL HISTORY OF ASYMPTOMATIC RENAL STONES
229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285
Table 2. Effect of ARC location on clinical outcome No./Total No. Lower Pole (%) EQ1
Became symptomatic Spontaneous passage Required surgical intervention Growth greater than 50% of size on first visualization
17/70 2/70 13/70 13/70
(24.3) (2.9) (18.6) (18.6)
No./Total No. Nonlower Pole (%) 28/69 10/69 14/69 13/69
(40.6) (14.5) (20.3) (18.8)
Table 4. Logistic regression of predictors of symptom development p Value 0.047* 0.016* 0.830 1.000
stones (66% of high growth subgroup) remained asymptomatic through the end of followup while 2 (6% of high growth subgroup) caused symptoms requiring surgical management. Twelve stones (8% of total) passed spontaneously during followup and 22 stones (14% of total) led to hydronephrosis.
½T2
½T3
½T4
½F1
Effect of ARC Location and Size on Clinical Outcome Table 2 summarizes the effect of ARC location on clinical outcome. Lower pole stones were significantly less likely than nonlower pole stones to cause symptoms (24.3% vs 40.6%, p¼0.047) or to pass spontaneously (2.9% vs 14.5%, p¼0.016). We did not find a significant difference in rates of surgical intervention or growth to greater than 50% of initial size between the lower pole and nonlower pole stone groups. Table 3 summarizes the effect of ARC size on clinical outcome. We did not find ARC size to be a predictor of any of our documented clinical outcomes. Table 4 presents our multivariate analysis. Controlling for age, stone size, stone location, history of stones, multiple stones on first imaging and stone growth, the only factor independently predictive of symptom development was stone location in the lower pole. Kaplan-Meier analysis revealed that lower pole stones were significantly less likely to require surgical intervention or pass spontaneously during followup (log rank p ¼ 0.04, see figure).
DISCUSSION In one of the largest retrospective studies to date, we evaluated the natural history of ARC as well as the effects of ARC location and size on clinical outcome. We found that among our cohort of 160 stones with a mean size of 7.0 mm followed for an average of 41 19 months, 28% of the stones Table 3. Effect of ARC size on clinical outcome No./Total No. No./Total No. Less than 10 mm 10 mm or Greater (%) (%) p Value Became symptomatic Spontaneous passage Required surgical intervention Growth greater than 50% of size on first visualization
Dochead: Adult Urology
36/116 11/116 19/116 23/116
(31.0) (9.5) (16.4) (19.8)
9/23 1/23 8/23 3/23
(39.1) (4.3) (34.8) (1.3)
3
0.471 0.690 0.079 0.568
Age: 20e35 35e50 50e65 65e85 Female Stones larger than 1 cm Lower pole stone History of stones Multiple stones Stone growth greater than 50%
OR
CI: Lower
CI: Upper
1.00 0.34 0.35 0.92 1.26 1.35 0.34 0.51 1.19 0.46
0.06 0.08 0.35 0.51 0.36 0.14 0.19 0.32 0.12
2.00 1.52 2.40 3.12 5.02 0.81 1.36 4.34 1.73
p Value 0.38
0.61 0.66 0.02 0.18 0.80 0.25
became symptomatic with 17% requiring surgical intervention. The only significant predictor of spontaneous passage or symptom development was stone location. In one of the first retrospective reviews of ARC Glowacki et al examined 107 ARC with an average followup of 31.6 months, and found that ARC were more likely to remain asymptomatic than to cause symptoms (68% vs 34%), with 17% of the total cohort requiring surgery.6 While there was a trend for higher stone related events in patients with previous stone events, multiple stones at study initiation and larger stones, none of these associations were statistically significant. Similarly, these characteristics were not predictive of stone migration in our cohort (table 4). In contrast to our study Glowacki et al did not evaluate stone location as a predictor of stone events.6 More recently Koh et al examined a cohort of 85 stones with a mean size of 5.7 mm followed for an average of 46 months, and found that 20% passed spontaneously and 7% required surgical intervention.7 Similarly we found that 28% of our cohort exhibited symptomatic stone migration with 8% passing spontaneously and 17% requiring surgical intervention for symptomatic obstruction. Koh et al also examined the effect of stone size on clinical outcome, and found that rates of spontaneous passage for stones less than 5 mm were higher than for stones 5 to 10 mm and stones greater than 10 mm (28%, 5% and 0%, p not reported).7 They also found a trend for larger stones to necessitate surgical intervention more frequently (rates for stones less than 5 mm, 5 to 10 mm and greater than 10 mm were 5%, 10% and 14%, respectively, p¼0.477) and to progress clinically (rates of progression for stones less than 5 mm, 5 to 10 mm and greater than 10 mm were 40%, 52% and 71%, respectively, p¼0.282). While neither the study by Koh et al nor our study revealed statistically significant relationships between stone size and the need for surgical intervention, both studies suggest that larger stones are more likely to require surgical intervention, and
FLA 5.2.0 DTD JURO11999_proof 19 January 2015 7:48 pm EO: JU-14-1566
286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342
NATURAL HISTORY OF ASYMPTOMATIC RENAL STONES
Time to Event
0.2
0.4
Survival 0.6
0.8
Non−Lower Pole Lower Pole
0.0
343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399
1.0
4
0
20
40
60
80
Time (Months)
Kaplan-Meier survival analysis of stone location in predicting probability of not having intervention or spontaneous passage of initially asymptomatic stones.
both may have reached this conclusion with larger stone cohorts. In contrast to our study Koh et al found no statistically significant relationship between stone location and migration.7 However, lower pole stones in their series were less likely than middle or upper pole stones to pass spontaneously (11.5% vs 16.2% vs 36.4%, p¼0.092). While an important study, their series included only 85 stones, which likely impacted their ability to demonstrate significant differences between groups. Burgher et al studied a cohort of 300 patients with a mean stone size of 10.8 mm followed for an average of 39 months.5 In contrast to our study, they found that the majority of ARC (77%) progressed clinically (stone growth, pain or need for surgical intervention). Burgher et al did not look at stone location as a predictor of stone migration.5 They did find that lower pole stones were significantly more likely than mid and upper pole stones to grow during followup (61% vs 47%, p ¼ 0.002). Conversely we found no association between stone location and growth rate. Burgher et al also found initial ARC size to be predictive of progression with stones 4 mm or greater on presentation being 26% more likely to fail observation than smaller stones (p ¼ 0.012).5 Although not significant, we also found that larger stones were more likely to fail active surveillance and require surgical intervention (34.8% vs 16.4%, p¼0.079) with our AS protocol. In contrast to the studies by Koh7 and Burgher5 et al, previous studies have singularly evaluated Dochead: Adult Urology
management strategies for lower pole ARC. Yuruk et al randomized 94 patients with asymptomatic lower pole stones to observation or shock wave lithotripsy and followed them for an average of 19 5 months.9 Of the 34 stones managed with observation 22% had symptoms due to spontaneous passage (3.1%) or required surgical intervention (19%). Similar to our cohort, the majority of the observed lower pole stones (greater than 80%) in their study remained asymptomatic through the end of followup. Inci et al evaluated 27 lower pole ARC with a mean size of 8.8 mm followed for an average of 52 months.8 They found that 33% progressed (stone growth, pain or need for surgical intervention) and 11% required surgical intervention. The findings of these prior asymptomatic stone cohorts are echoed in our survival analysis which shows that lower pole stones were less likely to have an event during our comparable followup period (see figure). Additionally, Raman and Pearle conducted a meta-analysis seeking optimum management of lower pole calculi.12 Their study revealed that lower pole stones larger than 2 cm treated with percutaneous nephrolithotomy had less morbidity. However, consistent with our study, they also concluded that lower pole stones less than 1 cm may be observed with equivalent morbidity outcomes as shock wave lithotripsy and ureteroscopy with laser lithotripsy. They also found observation to have the least cost and surgical risk among available management stratgeies.12
FLA 5.2.0 DTD JURO11999_proof 19 January 2015 7:48 pm EO: JU-14-1566
400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456
NATURAL HISTORY OF ASYMPTOMATIC RENAL STONES
457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505
Importantly we also found that 2% of our stone cohort caused asymptomatic hydronephrosis detected on routine imaging and was subsequently treated surgically. The decision was made to exclude these individuals from the statistical analysis as we wanted to specifically identify which patients may use health care resources for symptomatic stones. However, the possibility of the development of silent hydronephrosis supports the role of continued followup for patients with ARC. This retrospective study had several important limitations. Almost half of the stones in our cohort had size initially evaluated on renal ultrasound, which is less reliable than CT or KUB for estimating stone size. Patients who were excluded from study due to a lack of 6 months of followup may have sought treatment elsewhere or remained asymptomatic. Some patients chose to treat asymptomatic stones after initially electing active surveillance so we cannot know how these stones would have fared if left untreated. Finally, some patients may have been considered symptomatic
5
from a renal stone when in fact the symptoms were due to another cause of pain such as gastrointestinal or other genitourinary or musculoskeletal pathology.
CONCLUSIONS Among our cohort of 160 ARC managed with active surveillance about 60% remained asymptomatic through an average followup of more than 3 years, while less than 30% caused renal colic, less than 20% were operated on for pain and 7% spontaneously passed. Lower poles stones were significantly less likely than stones outside of the lower pole to cause symptoms or pass spontaneously. Our results were generally consistent with the findings of prior studies. Despite 3 stones causing silent obstruction, regular followup imaging facilitated interventions that prevented renal loss. These data can help patients and providers make informed decisions regarding the management of asymptomatic nonobstructing renal stones.
REFERENCES 1. Scales CD Jr, Smith AC, Hanley JM et al: Prevalence of kidney stones in the United States. Eur Urol 2012; 62: 160.
with observant on of asymptomatic calculi. J Endourol 2004; 18: 534.
2. Pearle MS, Calhoun EA, Curhan GC et al: Urologic diseases in America project: urolithiasis. J Urol 2005; 173: 848.
6. Glowacki LS, Beecroft ML, Cook RJ et al: The natural history of asymptomatic urolithiasis. J Urol 1992; 147: 319.
3. Bansal AD, Hui J and Goldfarb DS: Asymptomatic nephrolithiasis detected by ultrasound. Clin J Am Soc Nephrol 2009; 4: 680. 4. Bhargavan M and Sunshine JH: Utilization of radiology services in the United States: levels and trends in modalities, regions, and populations. Radiology 2005; 234: 824. 5. Burgher A, Beman M, Holtzman JL et al: Progression of nephrolithiasis: long-term outcomes
Dochead: Adult Urology
7. Koh LT, Ng FC and Ng KK: Outcomes of long-term follow-up of patients with conservative management of asymptomatic renal calculi. BJU Int 2012; 109: 622. 8. Inci K, Sahin A, Islamoglu E et al: Prospective long-term followup of patients with asymptomatic lower pole caliceal stones. J Urol 2007; 177: 2189.
9. Yuruk E, Binbay M, Sari E et al: A prospective, randomized trial of management for asymptomatic lower pole calculi. J Urol 2010; 183: 1424. 10. Keeley FX Jr, Tilling K, Elves A et al: Preliminary results of a randomized controlled trial of prophylactic shock wave lithotripsy for small asymptomatic renal calyceal stones. BJU Int 2001; 87: 1. 11. T€urk C, Knoll T and Petrik A: Guidelines on urolithiasis. Arnhem (The Netherlands): European Association of Urology 2013. 12. Raman JD and Pearle MS: Management options for lower pole renal calculi. Curr Opin Urol 2008; 18: 214.
FLA 5.2.0 DTD JURO11999_proof 19 January 2015 7:48 pm EO: JU-14-1566
506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554
