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1 American Urological Association, Inc. Nephrolithiasis Clinical Guidelines Panel: Report on the Management of Staghorn Calculi Clinical Practice Guidelines

2 Nephrolithiasis Clinical Guidelines Panel Members and Consultants Joseph W. Segura, M.D., Chairman The Carl Rosen Professor of Urology Department of Urology The Mayo Clinic Rochester, Minnesota Dean G. Assimos, M.D. Assoc. Professor of Surgical Sciences Department of Urology The Bowman Gray School of Medicine Wake Forest University Winston-Salem, North Carolina Stephen P. Dretler, M.D. Director, Kidney Stone Center Massachusetts General Hospital Boston, Massachusetts Robert I. Kahn, M.D. Chief of Endourology California Pacific Medical Center San Francisco, California James E. Lingeman, M.D. Director of Research Methodist Hospital Institute for Kidney Stone Disease Associate Clinical Instructor in Urology Indiana University School of Medicine Indianapolis, Indiana Glenn M. Preminger, M.D., Facilitator Professor, Department of Urology Duke University Medical Center Durham, North Carolina Joseph N. Macaluso, Jr., M.D. Medical Dir.; Dir. of Grants & Research Urologic Institute of New Orleans Assoc. Professor & Dir. of Endourology, Lithotripsy & Stone Disease Louisiana State Univ. Medical Center School of Medicine New Orleans, Louisiana David L. McCullough, M.D. William H. Boyce Professor Chairman, Department of Urology The Bowman Gray School of Medicine Wake Forest University Winston-Salem, North Carolina Claus G. Roehrborn, M.D. Facilitator Coordinator Hanan Bell, Ph.D. Methodology and Statistical Consultant Curtis Colby Editor Patrick Florer Computer Database Design Consultant The Nephrolithiasis Clinical Guidelines Panel consists of board-certified urologists who are experts in stone disease. This Report on the Management of Staghorn Calculi was extensively reviewed by over 50 urologists throughout the country in the Fall of The Panel finalized its recommendations to AUA s Practice Parameters, Guidelines and Standards Committee, Chaired by Winston K. Mebust, MD, in December The AUA Board of Directors approved these practice guidelines at its meeting in January The Summary Report also underwent independent scrutiny by the Editorial Board of the Journal of Urology, was accepted for publication in March 1994, and appeared in its June issue. A guide to assist patients diagnosed with this condition has also been developed. The Technical Supplement to this Report is available upon request. The American Urological Association expresses its gratitude for the dedication and leadership demonstrated by the members of the Nephrolithiasis Clinical Guidelines Panel in producing the AUA s first explicit guideline using the Eddy methodology.

3 Introduction Urologists and patients can choose from many alternatives today for management of renal and ureteral calculi. The improvements in urologic equipment, radiologic technology, and interventional radiologic techniques have dramatically increased the means available for stone removal. As a consequence, however, questions have arisen regarding applications of particular modalities to treat the various types of stone disease. To help clarify treatment issues, the American Urological Association, Inc., convened the Nephrolithiasis Clinical Guidelines Panel in 1990 and charged it with the task of producing practice recommendations based on outcomes evidence from the treatment literature. The recommendations in this Report on the Management of Staghorn Calculi are to assist physicians in the treatment specifically of struvite staghorn calculi. Although relatively uncommon, these kidney stones present serious problems because they occur in the presence of urinary tract infections and because the stones themselves are infected. Treatment must remove stones completely to eradicate all infected stone material. The choice of treatment can be a source of controversy given the range of modalities and techniques now available, each with advantages and disadvantages. This makes struvite staghorn calculi an especially appropriate subject for evidence-based recommendations. A Patient s Guide and more detailed technical appendices are available upon request.

4 Contents Executive Summary: Treatment of staghorn calculi Methodology for development of treatment recommendations Background: Staghorn calculi Treatment outcomes and alternative modalities Treatment recommendations Limitations in the treatment literature Chapter 1: Methodology Literature search Article selection and data extraction Evidence combination Chapter 2: Staghorn calculi and their management Background Treatment Methods Chapter 3: Outcomes analysis for staghorn treatment alternatives Direct and indirect outcomes Combining outcome evidence The balance sheet Analysis of the balance sheet outcomes Chapter 4: Staghorn treatment recommendations Treatment outcomes and treatment recommendations The patient Recommendations: Standards For... Reference Only Recommendations: Guidelines Recommendations: Options Recommendation limitations Basic research needs References Appendix A: Data presentation a.1 Appendix B: Data abstraction worksheet b.1 Appendix C: Description of available techniques for management of renal and ureteral calculi c.1 Shock-wave lithotripsy c.1 Percutaneous nephrolithotomy c.3 Ureteroscopy C.4 Open lithotomy c.5 Index I.1 Production and layout by Lisa Emmons Tracy Kiely Betty Roberts Copyright 1994 American Urological Association, Inc.

5 Executive Summary: Treatment of staghorn calculi METHODOLOGY FOR DEVELOPMENT OF TREATMENT RECOMMENDATIONS In developing recommendations for managing staghorn calculi, the AUA Nephrolithiasis Clinical Guidelines Panel reviewed the available literature on treatment of struvite staghorn calculi. Relevant articles were selected for data extraction, and the panel devised a comprehensive data-extraction form to capture as much pertinent information as possible. Data analysis was conducted using the confidence profile method developed by Eddy and Hasselblad [Eddy, 1989; Eddy, Hasselblad, and Shachter, 1990]. Chapter 1, Methodology, provides a full description of the process. BACKGROUND: STAGHORN CALCULI Staghorn calculi are stones that fill the major part of the collecting system. Typically, such stones will occupy the renal pelvis, and branches of the stone will extend into the majority of the calices. The term partial staghorn is often used when a lesser portion of the collecting system is occupied by stone. There is, unfortunately, no agreement on how these terms should be defined, and the term staghorn is often used irrespective of the percentage of the collecting system occupied. There is also no widely accepted way to express the size of a staghorn calculus. As a result, stones of widely different volumes are all referred to as staghorns. Staghorn calculi are usually made of struvite (magnesium ammonium phosphate) with variable amounts of calcium, but stones made of cystine, calcium oxalate monohydrate, and uric acid can all fill the collecting system. Such stones are frequently found intermixed with struvite calculi in many series reported in the literature. The majority of staghorn stones are composed of struvite. These stones tend to be soft, and their radiologic appearance varies from relatively faint to moderately radiopaque. It is generally possible to predict on the basis of a plain x-ray film that a staghorn stone is composed of struvite. These stones are also called infected stones or infection stones because they occur only in the presence of urinary tract infection and only when the infection is secondary to organisms that elaborate the enzyme urease, which splits urea [Bruce and Griffith, 1981]. Cultures of pieces of struvite stones, taken both from the surface and from inside, have demonstrated that bacteria reside inside the stones and that the stones themselves are infected in contrast to stones made of cystine, calcium oxalate monohydrate, or other substances [Nemoy and Stamey, 1971]. An untreated struvite staghorn calculus will in time destroy the kidney, and the stone has a significant chance of causing the death of the affected patient [Rous and Turner, 1977; Koga, Arakai, Matsuoka, et al., 1991]. Moreover, struvite stones must be removed in their entirety to be certain of eradicating all of the infected stone material. If all of the infected material is not removed, the patient will continue to have recurrent urinary tract infections and the stone will eventually regrow. It may be possible to sterilize small amounts of struvite, but how much of the stone can be sterilized is uncertain and unpredictable [Pode, Lenkovsky, Shapiro, et al., 1988; Michaels and Fowler, 1991]. The panel found four modalities reported in the literature to be potential alternatives, on the strength of the evidence, for treating patients with struvite staghorn calculi: Open surgery referring to any method of open surgical exposure of the kidney and removal of stones from the collecting system; Percutaneous nephrolithotomy (PNL); Extracorporeal shock-wave lithotripsy (SWL); and Combinations of PNL and SWL. Because the panel was unable to conduct direct assessments of patient preferences, panel members themselves acted as patient surrogates judging treatment choices on the basis of probable outcomes. 1

6 TREATMENT OUTCOMES AND ALTERNATIVE MODALITIES After reviewing the literature and analyzing the data, the panel concluded that the following outcome probabilities are the most significant in setting forth recommendations for treatment of struvite staghorn calculi: The probability of being stone free following treatment; The probability of undergoing secondary, unplanned procedures; and The probability of having complications associated with the chosen primary treatment modality. The four modalities of open surgery, PNL, SWL, and combination PNL and SWL are all reasonable treatment alternatives for patients with struvite staghorn calculi. However, outcome probabilities differ markedly among the four. The following statements are based on both statistical analysis of abstracted data from the treatment literature and expert opinion. They form the basis of the panel s recommendations. The risk of having residual fragments following initial treatment is clearly higher after shock-wave lithotripsy monotherapy than after percutaneous nephrolithotomy, combination therapy, or open surgery. It is the expert opinion of the panel that residual fragments of infected calculi left in the renal collecting system may be associated with recurrent infections and eventual regrowth of these fragments into significant stones leading to additional morbidity, although literature to support this opinion is scarce. Shock-wave lithotripsy monotherapy carries a high probability of unplanned secondary procedures. Percutaneous nephrolithotomy, combination therapy, and open surgery are more likely to require general or regional anesthesia. The chance that a blood transfusion will be required is greater for percutaneous nephrolithotomy, combination therapy, and open surgery than for shock-wave lithotripsy monotherapy. Rates of complications following the four treatment modalities differ significantly for each modality. From the patient s viewpoint, a complication may have the same importance as a secondary, unplanned procedure, inasmuch as it may require a second anesthetic procedure or prolong the patient s hospital stay. Therefore, an analysis combining secondary, unplanned procedures and the complications associated with the primary treatment modalities chosen may accurately reflect the patient s viewpoint regarding desirability or undesirability of a given intervention. Of all four treatment modalities, shock-wave lithotripsy monotherapy has the highest combined complication and secondary, unplanned intervention rate. However, the complications associated with shock-wave lithotripsy tend to be less severe than those associated with percutaneous nephrolithotomy, combination therapy, or open surgery. The peer-reviewed literature does not stratify outcomes appropriately by either size or composition of staghorn calculi or the anatomy of the collecting system. Nevertheless, the panel believes that these factors impact the outcomes of alternative treatment procedures. Also, when choosing a treatment alternative, special circumstances such as the patient s overall health, body habitus, and other medical problems need to be taken into consideration by the treating physician. TREATMENT RECOMMENDATIONS The AUA Nephrolithiasis Clinical Guidelines Panel considered, in its recommendations, a total of five methods for managing struvite staghorn calculi including watchful waiting or observation, as well as the four active modalities: (1) open surgery, (2) percutaneous nephrolithotomy (PNL), (3) extracorporeal shock-wave lithotripsy (SWL), and (4) combinations of PNL and SWL. Levels of flexibility The panel graded recommendations for treatment by three levels of flexibility, based primarily on the strength of the scientific evidence for estimating outcomes of interventions. A standard is defined as the least flexible of the three; a guideline, more flexible; and an option, the most flexible. These three levels of flexibility [Eddy, 1992] for treatment recommendations are defined on page 5. The patient Panel recommendations for the treatment of staghorn calculi apply to standard and nonstandard patients whose stones are presumed to be composed of struvite (magnesium ammonium phosphate). 2

7 RECOMMENDATIONS Standards 1. As a standard, a newly diagnosed struvite staghorn calculus represents an indication for active treatment intervention. Although this recommendation was not formally subjected to data abstracting and statistical methods, the panel strongly believes based on expert opinion that a policy of watchful waiting and observation is not in the best interest of the standard patient with struvite staghorn calculi. 2. As a standard, a patient with a newly diagnosed struvite staghorn calculus must be informed about the four accepted active treatment modalities, including the relative benefits and risks associated with each of these treatments. Guidelines 1. As a guideline, percutaneous stone removal, followed by shock-wave lithotripsy and/or repeat percutaneous procedures as warranted, should be utilized for most standard patients with struvite staghorn calculi, with percutaneous lithotripsy being the first part of the combination therapy. 2. As a guideline, shock-wave lithotripsy monotherapy should not be used for most standard patients as a first-line treatment choice. 3. As a guideline, open surgery (nephrolithotomy by any method) should not be used for most standard patients as a first-line treatment choice. Options 1. As options, shock-wave lithotripsy monotherapy and percutaneous lithotripsy monotherapy are equally effective treatment choices for small-volume struvite staghorn calculi in collecting systems which are of normal or near normal anatomy. 2. As an option, open surgery is an appropriate treatment alternative in unusual situations where a staghorn calculus is not expected to be removable by a reasonable number of percutaneous lithotripsy and/or shock-wave lithotripsy procedures. 3. As an option for a patient with a poorly functioning, stone-bearing kidney, nephrectomy is a reasonable treatment alternative. 3

8 A standard patient is defined as an adult patient who has two functioning kidneys (function of both kidneys relatively equal) or a solitary kidney with substantially normal function, and whose overall medical condition, body habitus, and anatomy permit performance of any of the four accepted active treatment modalities including use of anesthesia. A nonstandard patient is defined as one with a struvite staghorn stone who does not fulfill the above criteria. For this patient, the choice of available treatment options may be limited to three or even fewer of the four accepted active treatment modalities, depending on individual circumstances. The recommended standards and guidelines on page 3 apply to the treatment of standard patients, followed by options for nonstandard patients. LIMITATIONS IN THE TREATMENT LITERATURE Limitations to the process of developing treatment recommendations became apparent during the panel s review of the literature. Most obviously, for the purpose of this document, there is no uniform system of categorizing staghorn calculi, no standard method of describing the collecting system, and no widely accepted system of reporting the size of staghorn calculi. Few prospective, randomized, controlled studies have been conducted concerning the treatment of struvite staghorn calculi. In addition, there is no uniform system in the literature for reporting outcomes following treatment for struvite staghorn calculi. Further uncertainty stems from differences in health care delivery systems in various countries as they impact the outcomes reported in the literature. Variability in the data leads to uncertainty in outcome estimates, which leads to flexibility in recommendations. This limitation applies to a variety of outcomes. Notwithstanding these limitations, the panel believes that the standards, guidelines, and options presented are well supported by the data reviewed. Recommendations are founded primarily on the data and partially on the expert opinion of panel members. Outcomes for which there is considerable uncertainty are clearly identified as such in the document. Whenever the panel s expert opinion prevailed over the limited amount of available data, this is specified in the document as well. 4

9 Chapter 1: Methodology The recommendations in this Report on the Management of Staghorn Calculi were developed following an explicit approach to the development of practice policies [Eddy, 1992], as opposed to an implicit approach relying solely on expert opinion without any open description of the evidence considered. The explicit approach attempts to provide mechanisms for arriving at recommendations that take into account the relevant factors for making selections between alternative interventions. Such factors include estimation of the outcomes from the interventions, consideration of patient preferences, and assessing when possible the relative priority of the interventions for a share of limited health care resources. Emphasis is placed on the use of scientific evidence in estimating the outcomes of the interventions. In developing the recommendations in this report, an extensive effort was made to review the literature on staghorn stones and to estimate the outcomes of the alternative treatment modalities as accurately as possible. The Nephrolithiasis Clinical Guidelines Panel members themselves served as proxies for patients in considering preferences with regard to health and economic outcomes. The review of the evidence began with a literature search and extraction of data as described below. The data available in the literature were displayed in evidence tables. From these tables, the panel developed estimates of the outcomes from the various interventions (shock-wave lithotripsy, percutaneous nephrolithotomy, combination shock-wave lithotripsy percutaneous stone removal and open removal). The panel used the FAST* PRO meta-analysis package as described below to combine the evidence from the various studies. These estimates of outcomes are arrayed on the balance sheet on page 13. The panel generated recommendations based on the outcomes shown in the balance sheet. These recommendations were graded according to three levels of flexibility, based on the strength of the evidence and on amount of variation in patient preferences. The three levels of flexibility for treatment recommendations [Eddy, 1992] are defined as follows: 1. Standard: A treatment policy is considered a standard if the health and economic outcomes of the alternative interventions are sufficiently well-known to permit meaningful decisions and there is virtual unanimity about which intervention is preferred. 2. Guideline: A policy is considered a guideline if the health and economic outcomes of the interventions are sufficiently well-known to permit meaningful decisions, and an appreciable but not unanimous majority agree on which intervention is preferred. 3. Option: A policy is considered an option if (1) the health and economic outcomes of the interventions are not sufficiently well-known to permit meaningful decisions, (2) preferences among the outcomes are not known, (3) patients preferences are divided among the alternative interventions, and/or (4) patients are indifferent about the alternative interventions. A standard has the least flexibility as a treatment policy. A guideline has significantly more flexibility, and options are even more flexible. As noted in the definitions, options can exist because of insufficient evidence or because patient preferences are divided. In the latter case particularly, the panel considered it important to take into account likely preferences of individual patients when selecting from among alternative interventions. LITERATURE SEARCH A literature search was performed utilizing MEDLINE. Articles retrieved from MEDLINE included all manuscripts related to renal calculi published from Articles prior to 1966 were identified by hand searching bibliographies and reference lists from other articles. Completeness of the search was confirmed by cross-checking indices of important journals. Journals deemed important, but not listed on MEDLINE (such as The Journal of Endourology), were also searched. The total yield was 1,250 articles. The specifics of the MEDLINE search criteria are included in the Technical Supplement. 5

10 All of the citations were imported into a Papyrus Bibliography System (Research Software Design, Portland, OR) and assigned specific keywords. Once keywords had been associated with each article, the articles could be sorted according to the mode of therapy (for example, medical or surgical), the stone location (renal or ureteral), and the primary mode of stone removal (for example, SWL vs. PNL vs. COMBO vs. OPEN). For reasons of practicality and validity, the panel decided that only articles from peer-reviewed journals in English-language literature would be utilized in the analysis. Prior to initiating abstraction of the articles, further searching of MEDLINE was performed with particular emphasis on the most recent articles on staghorn calculi. All pertinent stone articles as of January 1993 were included in the analysis. Search criteria from the Papyrus program to select appropriate articles for review were: keywords = CAL- CULI; KIDNEY; SURGICAL; RENAL; and STAGHORN. Further review by the entire panel of the 479 articles that met the initial search criteria yielded 110 articles with 136 differentiated groups of patients. These were articles containing viable data not duplicated in another manuscript. The articles are listed in Table A-1 and are the basis for the panel s analysis of staghorn calculi. ARTICLE SELECTION AND DATA EXTRACTION After identifying articles from the MEDLINE database and entering them into the Papyrus program, the panel reviewed the abstracts and selected the relevant citations for data extraction. A comprehensive data-extraction form was devised by the panel to capture as much pertinent information as possible from each article. A sample of the form is in Appendix B. The selected articles were divided among the panel members who then reviewed the articles and transcribed the data onto the form. Panel members reported that there is little consistency in the kidney stone literature in reporting outcomes data. All articles used to complete the report were reviewed by at least two panel members for accuracy. All articles excluded were by decision of the panel as a group. The forms from both reviews were forwarded to the panel facilitator, and any discrepancies in the data were resolved. All data were then entered into a PARADOX database. All computer entries were reviewed again by a subcommittee of the panel to ensure accuracy. Figure A-1, on page A.1 in Appendix A, represents the number of articles reviewed by the panel by year. Figure A-2 demonstrates the source of articles from the English-language literature. The majority of articles came from The Journal of Urology, Urology, The Journal of Endourology, and The British Journal of Urology. Figure A-3 on page A.2 shows the breakdown of articles selected for review and Figures A-4 and A-5, the breakdown of selected articles stratified by staghorn calculi and by treatment modalities, respectively. EVIDENCE COMBINATION In order to generate a balance sheet, estimates of the probabilities and/or magnitudes of the outcomes are required for each alternative intervention. Ideally, these come from a synthesis of the evidence. This synthesis or combination of the evidence can be performed in a variety of ways depending on the nature and quality of the evidence. For example, if there is one good randomized controlled trial, the results of that one trial alone may be used in the balance sheet. Other studies of significantly lesser quality would be ignored. If there are no studies of satisfactory quality for certain balance sheet cells or the studies found are not commensurable, then expert opinion is used to fill in those cells. If a number of studies have some degree of relevance to a particular cell or cells, then meta-analytic mathematical methods may be used. Different specific methods are available depending on the nature of the evidence. For this Report on the Management of Staghorn Calculi, the AUA elected to use the confidence profile method [Eddy, 1989; Eddy, Hasselblad, and Shachter, 1990], which provides methods for analyzing data from studies that are not randomized controlled trials. The FAST*PRO computer package [Eddy and Hasselblad, 1992] was used in the analysis. Because there are few randomized controlled trials for staghorn stones, the package was used to combine the single arms from various clinical series to estimate the outcome for each intervention. The series that were combined frequently showed very different results implying site-tosite variations that may be caused by differences in patient populations, in how the intervention was performed, or in the skill of those performing the intervention. Because of the differences, a ran- 6

11 dom-effects, or hierarchical, model was used to combine the studies. A random-effects model assumes that for each site there is an underlying true rate for the outcomes being assessed. It further assumes that this underlying rate varies from site to site. This siteto-site variation in the true rate is assumed to be normally distributed. The method of meta-analysis used in analyzing the staghorn data attempts to determine this underlying distribution. The results of the confidence-profile method are probability distributions. They can be described using a mean or median probability with a confidence interval. In this case, the 95-percent confidence interval is such that the probability (Bayesian) of the true value being outside the interval is 5 percent. The probability distribution can be displayed graphically (as a density function). This graph indicates the probability of any interval as the area under the graph on that interval. Thus, if a curve on a graph is very sharply peaked, the area under the curve is narrow indicating a narrow confidence interval. If a curve is relatively flat, this indicates a wide confidence interval. The total area under the graph is always equal to 1. The three graphs that follow illustrate a simple example of the use of the FAST*PRO software. Two studies looked at a certain outcome after a treatment for a given disease. In each study, 75 percent of the patients had the outcome. The first study had a total of 20 patients, and the second had a total of 1,000. If the software is used to update the probabilities for each site, the resultant (posterior) probability distributions of the true probability of the outcome can be graphed for each study. Note that both curves in the graph center on 75 percent, but the curve for the first study is much flatter. There is a much larger uncertainty about the true value with 20 patients studied than with a sample of 1,000. Figure 2 adds a third study of 600 patients with 400 (66.7 percent) having the outcome. This study centers over a different point and is intermediate in height between the first two studies. Probability Figure 2. Confidence profiles for studies 1 (15 of 20 pts.), 2 (750 of 1000 pts.), and 3 (400 of 600 pts.) If these studies are combined using the method described above, the result is a combined profile (Curve 4 in Figure 3). This profile is very narrow indicating that there is little difference among studies. Since two of the studies have the same result and the other is close, it is not surprising that there would be minimal site-to-site variation suggested by these studies. Probability Figure 3. Confidence profiles for studies 1, 2, and 3 and combined profile 4 (hierarchical Bayes ) Probability Figure 1. Confidence profiles for studies 1 (15 of 20 pts.) and 2 (750 of 1000 pts.) The method of computation is Bayesian in nature. This implies the assumption of a prior distribution that reflects knowledge about the probability of the outcome before the results of any experiments are known. The prior distributions 7

12 selected for this analysis are among a class of noninformative prior distributions, which means that they correspond to little or no preknowledge. The existence of such a prior can cause small changes in results, particularly for small studies. In the foregoing example, for instance, the mean of the distribution for the sample of size 20 is 0.74 rather than The effect of the prior distribution is to slightly discount the value of the experiment. This effect will not be pronounced except in very small studies, and the combination of multiple studies will reduce this tendency further. For the statistically sophisticated reader, the prior distribution for all probability parameters is Jefferey s prior (beta distribution with both parameters set to 0.5). The prior for the variance for the underlying normal distribution is gamma distributed with both parameters set to 0.5. In addition to graphical presentations, 95-percent confidence intervals are used to present results. The medians and 95-percent confidence intervals for the results of the three foregoing sample studies and the combination are as follows: Outcomes considered important to patients receiving treatment for nephrolithiasis were analyzed in such fashion. In some cases, surrogates for patient outcomes were analyzed for example, stone-free rate as a surrogate for symptom improvement. Evidence from all studies meeting inclusion criteria that reported a certain outcome were combined within each treatment modality. Graphs showing the combined results for each modality are also presented as an estimate of the difference between the modalities. With regard to certain outcomes, more data have been reported for one or another treatment modality. This results in a sharper and narrower peak in the graph reflecting the available data. However, the probability for certain outcomes can vary widely from study to study within one treatment modality. Such variability will result in a wide, flat combined distribution, which reflects considerable uncertainty about the outcome or considerable differences between sites and practitioners. Study Median 95% CI Combination As mentioned previously, there are few randomized controlled trials for staghorn stones. Thus, the differences seen by comparing studies as done here may be biased to some degree. For example, differences in patient selection may have had more weight in yielding the results shown than the differing effects of the treatment modalities. However, these results reflect the best outcome estimates known at the present time. 8

13 Chapter 2: Staghorn calculi and their management BACKGROUND Staghorn calculi are stones that fill the major part of the collecting system. Typically, such stones will occupy the renal pelvis, and branches of the stone will extend into the majority of the calices. The term partial staghorn is often used when a lesser portion of the collecting system is occupied by stone. There is, unfortunately, no agreement on how these terms should be defined, and the term staghorn is often used irrespective of the percentage of the collecting system occupied. There is also no widely accepted way to express the size of a staghorn calculus. As a result, stones of widely different volumes are all referred to as staghorns. Staghorn calculi are usually made of struvite (magnesium ammonium phosphate) with variable amounts of calcium, but stones made of cystine, calcium oxalate monohydrate, and uric acid can all fill the collecting system. Such stones are frequently found intermixed with struvite calculi in many series reported in the literature. The majority of staghorn stones are composed of struvite. These stones tend to be soft, and their radiologic appearance varies from relatively faint to moderately radiopaque. It is generally possible to predict on the basis of a plain x-ray film that a staghorn stone is composed of struvite. These stones are also called infected stones or infection stones because they occur only in the presence of urinary tract infection and only when the infection is secondary to organisms that elaborate the enzyme urease, which splits urea [Bruce and Griffith, 1981]. Cultures of pieces of struvite stones, taken both from the surface and from inside, have demonstrated that bacteria reside inside the stones and that the stones themselves are infected in contrast to stones made of cystine, calcium oxalate monohydrate, or other substances [Nemoy and Stamey, 1971]. An untreated struvite staghorn calculus will in time destroy the kidney, and the stone has a significant chance of causing the death of the affected patient [Rous and Turner, 1977; Koga, Arakai, Matsuoka, et al., 1991]. Moreover, struvite stones must be removed in their entirety to be certain of eradicating all of the infected stone material. If all of the infected material is not removed, the patient will continue to have recurrent urinary tract infections and the stone will eventually regrow. It may be possible to sterilize small amounts of struvite, but how much of the stone can be sterilized is uncertain and unpredictable [Pode, Lenkovsky, Shapiro, et al., 1988; Michaels and Fowler, 1991]. TREATMENT METHODS Four modalities reported in the literature are acceptable as potential alternatives for treating patients with struvite staghorn calculi: Open surgery referring to any method of open surgical exposure of the kidney and removal of stones from the collecting system; Percutaneous nephrolithotomy (PNL); Extracorporeal shock-wave lithotripsy (SWL); and Combinations of PNL and SWL. Open surgery Open surgical removal of the stone has been the so-called gold-standard, to which all other forms of stone removal have been compared. A variety of specific operations on the kidney may be performed in order to remove a staghorn calculus. Depending on anatomy, a pelviolithotomy, extended pyelotomy, nephrotomy, partial nephrectomy, or even nephrectomy may all play a role in specific cases. The most common operation performed today is anatrophic nephrolithotomy, and this is reflected in the literature over the past 20 years [Assimos, Boyce, Harrison, et al., 1989]. Anatrophic nephrolithotomy is usually performed with the patient in the flank position. A standard flank incision is made and frequently a rib is resected. After surgical exposure of the kidney, an incision is made lengthwise, bivalving the kidney and exposing the stone. Direct inspection and the use of intraoperative x-rays demonstrate that the kidney is stone free. The time allowed for removal of the stone is short, unless the kidney is cooled. The principles of the operation are well 9

14 established, with usual operating times of 3-7 hours. If the patient has had previous renal surgery, the operation may be more difficult [Stubbs, Resnick, and Boyce, 1978]. Hospitalizations of 7-14 days are the rule. In addition to the usual morbidity associated with any operation, flank incisions are painful and probably more painful than midline abdominal incisions. Many patients complain of numbness, paresthesia, and weakness of the abdominal wall resulting in bulging, which may be unsightly. The average postoperative disability is six weeks. This is based on the fact that a typical incision has regained about 80 percent of its preoperative strength by then, but recent work suggests that months may pass before many patients feel completely normal [Assimos, Wrenn, Harrison, et al., 1991]. Occasionally, the stone has caused enough damage to a kidney that nephrectomy is indicated. Such kidneys reveal the effects of years of chronic infection, episodes of acute pyelonephritis, and hydronephrosis [Assimos, Boyce, Harrison, et al., 1989]. The development of anatrophic nephrolithotomy and the demonstration that patients with infected stones could be stone free made an excellent case for this surgical approach, which became the standard throughout the 1960 s and 1970 s. In 1994, the incidence of open surgery for the treatment of all stones is about 1-2 percent. Staghorn calculi comprise most of the indications. The decision in favor of nephrectomy is usually made when the contralateral kidney is normal or nearly so, and when there is poor function in the affected kidney. Percutaneous stone removal Percutaneous nephrolithotomy (PNL), which became popular as a primary technique for stone removal in the early 1980s (Appendix C, page C.3), can theoretically be used for all stones. In practice, extracorporeal shock-wave lithotripsy (SWL) is used in the majority of situations where PNL was once employed. Struvite staghorn calculi, however, are often best managed by PNL either as a single technique or in combination with SWL. The procedure may be divided into two parts, access and stone removal. To achieve percutaneous access, the urologist or radiologist places a small flexible guide wire, under fluoroscopic control, through the patient s flank into the kidney and down the ureter. Care is taken to optimize the approach to the kidney so that the best approach to the stone is obtained. Once access is achieved, the tract is dilated to F. and the nephroscope introduced. Under direct vision, the stone is broken up (usually with an ultrasonic probe) and the pieces removed. One of the characteristics of struvite is that the stone is usually soft, and fragmentation with removal of the pieces is often quick. PNL has unquestioned advantages: (1) If the stone can be seen, it can almost always be destroyed. (2) The collecting system may be directly inspected so that small fragments may be identified and removed. (3) Because the tract can be kept open indefinitely, repeated inspections are possible. (4) The process is rapid, with success or lack of it being obvious immediately. Hospitalizations are usually from 4-10 days with most patients returning to light activity after 1-2 weeks. Transfusion rates for PNL in treating staghorn calculi vary from 5 to 50 percent. Retreatment rates that is, the rate at which the instrument must be reinserted through the tract to remove residual stones vary from 10 percent in simple situations to percent for more complicated problems. Stone-free rates of percent are regularly achievable using PNL. One disadvantage is that the expertise required for this operation is not as widely available as it once was, because a greater number of urology training programs are focusing less on PNL and more on shock-wave lithotripsy for stone management. Extracorporeal shock-wave lithotripsy Shock-wave lithotripsy (SWL) has become the standard method for management of many calculi in the urinary tract (Appendix C, page C.1). SWL is based on the principle that a high-pressure shock wave will release energy when passing through areas of different acoustic impedance. Shock waves generated outside the body can be focused 10

15 onto a stone using a variety of geometric techniques. The shock wave passes through the body without trauma and releases its energy as it passes into the stone. Hundreds, or sometimes thousands, of such shock waves are required to break up the average small stone, with the goal being to reduce the size of the stone to particles small enough to pass without significant pain. There are many different shock-wave machines available today. Although they are based on the same general principle, there are significant differences that relate to the use of these machines for treatment of large stones such as staghorn calculi. The original machine, the Dornier HM-3, probably the most common machine throughout the world, has the largest focal point and, in its unmodified version, the highest power of all current devices. In an effort to reduce the anesthesia requirement, newer machines often have less power and smaller focal points. This means that stones treated with such machines will often require more procedures to achieve the same result produced with fewer procedures by other devices. Obviously, for very large stones, multiple treatments may be required. Shock-wave lithotripsy has few short-term complications, its noninvasive nature has much appeal, and the technique is widely available. SWL has disadvantages, however, particularly in regard to the management of staghorns. The panel found, as stated on pages 14 and 19, a relatively higher risk of residual fragments following initial treatment and a high probability of unplanned secondary procedures. Because multiple treatments may be needed, use of SWL may not be practical to provide the required frequency of service if only mobile SWL is available and ancillary procedures directed toward the management of fragments are necessary. In addition, although many factors bear on the cost of any medical procedure, at the present time SWL is often more expensive than endourology or open surgery for the same condition [Hatziandreu, Carlson, Mulley, et al., 1990]. Combination PNL and SWL Some stones can be best managed by using both PNL and SWL on the same stone. This combines the main advantage of percutaneous ultrasonic lithotripsy, that of removing rapidly large volumes of easily accessible stone, with the advantage of SWL in easily treating small volumes of stone that are difficult or dangerous to access using PNL. The surgeon first utilizes PNL, making every effort to remove as much stone as possible, before using SWL. Experience has demonstrated that following SWL, the passage of fragments cannot be predicted. Therefore, depending upon the extent and location of residual stones, repeat SWL and/or repeat PNL may be necessary to remove residual fragments. Ancillary procedures Percutaneous nephrostomy tube placement (PNTP) may be necessary at any point in the management of staghorn stones. It is a routine part of PNL, of course, and is frequently used after SWL for drainage of an infected stone and for pain relief when obstruction is present. Preliminary stent insertion prior to SWL for staghorn calculi is so common as to be part of the procedure. Frequently a double-pigtail stent is placed and left indwelling for days or weeks to maintain drainage while fragments pass. Irrigations of the collecting system with solutions such as Renacidin to dissolve remaining fragments of infected stones, particularly after PNL, have been advocated by some. This is not a common procedure, probably because it often means added hospitalization. The panel did not find sufficient evidence in the literature to support the use of Renacidin as a primary procedure for treating infected stones. Ureteroscopy may be needed to remove fragments too large to pass spontaneously. General or regional anesthesia is necessary, but success rates are very high (95 percent or greater). Most often, ureteroscopy is an outpatient procedure. 11

16 Chapter 3: Outcomes analysis for staghorn treatment alternatives DIRECT AND INDIRECT OUTCOMES Any therapeutic medical intervention has a certain set of outcomes, some of which are desirable (benefits) and some of which are not (harms) [Eddy, 1990]. Direct health outcomes are those felt directly by the patient and have an impact on the quantity or quality of life. Indirect biologic outcomes are physiologic end points such as absence of infection or incidence of stone recurrence. These may be of great importance to the clinical researcher. Also, physicians, in general, believe that outcomes such as absence of residual stones, prevention of stone recurrence, and limitation of residual stone growth are of the greatest importance when assessing treatment options for staghorn calculi, although patients may not view these outcomes per se as important end points. An example of the difference between the two types of outcomes is illustrated by the patient with a recent myocardial infarction. Although the level of the CPK enzyme is an important parameter for the physician (indirect biologic outcome), it cannot be felt by the patient in any way. Meanwhile, the chest pain or death associated with the infarction has an immediate impact on the patient s quality or quantity of life (direct health outcome). Similarly, in treatment of staghorn calculi, the patient may not be interested in the stone-free rate, the chance of developing recurrent stones, or the incidence of growth of residual calculi following stone removal, despite the critical importance of these parameters to the physician unless the implications of the parameters are explained to the patient. However, the patient will very likely be interested in direct outcomes such as the degree of symptom improvement after treatment, the complications or side effects of treatment, mortality, and the cost and duration of hospital stay. For patients to participate in a shared decision-making process regarding treatment, they must be fully aware not only of the magnitude of the direct outcomes related to treatment alternatives, but also of the range of uncertainty associated with these outcomes. Indirect biologic outcomes can occasionally serve as proxies for direct health outcomes. The incidence of infection may serve as a proxy for the degree of symptom improvement after treatment, and stone-free rate is used as a proxy for stone recurrence and symptom recurrence because these data are not available in the current literature. COMBINING OUTCOME EVIDENCE The panel conducted a comprehensive review of the English-language literature and combined all outcome evidence for given treatment options, utilizing the confidence profile method as described on pages 6-8 of Chapter 1. The results of the combined review are presented in the balance sheet table on page 13. Outcomes with a wide confidence interval indicate considerable uncertainty in the medical knowledge base. This uncertainty is due either to a limited number of studies reported for a given intervention (as is the case for combination therapy) or to a wide variation in outcome probability reported in different studies (as is the case for shock-wave lithotripsy therapy). The short duration of many studies introduces uncertainty as well. The combined analysis is also weakened by the quality of the individual studies. As noted previously, there are currently few randomized, prospective controlled studies of staghorn calculi therapy in the literature. Therefore, most of the data analyzed by the panel come from clinical series. The limitations of including these types of studies are obvious. Nevertheless, if clinical series were not included, nothing could be said about the benefits and harms of various types of surgical removal of staghorn calculi. Further limitations arise from differences in study populations. In many cases, it is likely that patients who are entered into trials of alternative therapies have less severe disease states than those undergoing surgery. Moreover, the definition of staghorn calculi may differ significantly among various investigators, and some of the reports regarding the management of staghorn calculi do not specify the size of the stones or portion of the collecting system occupied. Thus, not all studies may be comparing treatment outcomes of stones of sim- 12