2013 Essay Contest—Clinical
JOURNAL OF ENDOUROLOGY Volume 28, Number XX, XXXX 2013 ª Mary Ann Liebert, Inc. Pp. ---–--DOI: 10.1089/end.2013.0257
Contemporary Management of Struvite Stones Using Combined Endourologic and Medical Treatment: Predictors of Unfavorable Clinical Outcome Muhammad Waqas Iqbal, MD,1 Ramy F. Youssef, MD,1 Andreas Neisius, MD,1,2 Nicholas Kuntz, MD,1 Jonathan Hanna, BS,1 Michael N. Ferrandino, MD,1 Glenn M. Preminger, MD,1 Michael E. Lipkin, MD1
Abstract
Background and Purpose: Struvite stones have been associated with significant morbidity and mortality, yet there has not been a report on the medical management of struvite stones in almost 20 years. We report on the contemporary outcomes of the surgical and medical management of struvite stones in a contemporary series. Patients and Methods: A retrospective review of patients who were treated with percutaneous nephrolithotomy (PCNL) for struvite stones at Duke University Medical Center between January 2005 and September 2012 identified a total of 75 patients. Of these, 43 patients had adequate follow-up and were included in this analysis. Stone activity, defined as either stone recurrence or stone-related events, and predictors of activity were evaluated after combined surgical and medical treatment. Results: The study included 43 patients with either pure (35%) or mixed (65%) struvite stones with a median age of 55 – 15 years (range 21–89 years). The stone-free rate after PCNL was 42%. Stone recurrence occurred in 23% of patients. Postoperatively, 30% of patients had a stone-related event, while 60% of residual stones remained stable with no growth after a median follow-up of 22 months (range 6–67 mos). Kidney function remained stable during follow-up. Independent predictors of stone activity included the presence of residual stones > 0.4 cm2, preoperative large stone burden (> 10 cm2), and the presence of medical comorbidities (P < 0.05). Conclusions: Struvite stones can be managed safely with PCNL followed by medical therapy. The majority of patients with residual fragments demonstrated no evidence of stone growth on medical therapy. With careful follow-up and medical management, kidney function can be maintained and stone morbidity can be minimized. Initial large stone burden, residual stones after surgery, and associated medical comorbidities may have deleterious effect on stone recurrence or residual stone-related events. possible. In cases where complete stone removal is not possible or residual fragments remain, a detailed approach to prevent stone recurrence, stone-related hospital visits or procedures, and UTIs, and preservation of renal function is critical.9 The medical management of struvite stones includes antibiotic prophylaxis and the urease inhibitor acetohydroxamic acid (AHA). AHA has been shown to prevent stone recurrence in this population10,11 but has been associated with significant side effects, including nausea, vomiting, tremors, anxiety, headache, anemia, rash, hepatotoxicity, and deep venous thrombosis (DVT).12 The most recent report on the treatment of patients with struvite stones is from more than 18 years ago.8 Since that time, there have been significant advances in endourologic techniques as well as imaging and diagnostic modalities. We
Introduction truvite stones comprise 5% to 15% of all renal calculi1 and form as a result of infection with urease-splitting organisms.2 Once an ‘‘infection stone’’ is present, urinary tract infections (UTIs) tend to recur, leading to episodes of hematuria, flank pain, pyelonephritis, or sepsis. Over time, an untreated staghorn calculus can result in complications such as pyonephrosis, perinephric abscess formation, or xanthogranulomatous pyelonephritis with eventual loss of the kidney.3–5 Historically, nonsurgical management of infection stones was associated with a mortality of 28% compared with only 7.2% in patients who underwent surgical treatment.6 Despite advances in management, these calculi continued to cause significant morbidity.7,8 Effective management of struvite stones should begin with complete stone removal when
S
1
Division of Urologic Surgery, Duke University Medical Center, Durham, North Carolina. Department of Urology, Johannes Gutenberg University Mainz, Mainz, Germany.
2
1
2 report the outcomes of patients with infection stones treated with a combination of surgery and medical therapy from a contemporary surgical series. We evaluated various clinical parameters to determine predictors for stone recurrence or stone-related events in follow-up. Patients and Methods After obtaining Institutional Review Board approval, a retrospective chart review of all patients undergoing PCNL at our institution between January 2005 and September of 2012 was performed. A total of 610 patients were evaluated. Of these patients, 493 had data on stone analysis. A total of 75 patients whose stone analysis came back as struvite were identified. Pure struvite stones were defined as 100% magnesium ammonium phosphate – carbonate apatite, whereas mixed stones were defined as containing struvite as well as other stone components. Both pure and mixed struvite stone formers were included in the current review. Patients without adequate clinical (< 6 months) or radiologic follow-up data were excluded (32 patients). Patients had imaging studies 3 months after PCNL with either intravenous urography (IVU) (35%), noncontrast computed tomography (NCCT) of the abdomen/pelvis (44%), or plain radiography of the kidneys, ureters, and bladder (KUB) with tomography (21%) to establish stone-free status. Patients also had a serum complete metabolic profile and a baseline 24hour urinary metabolic evaluation at this time. Patients were regularly followed at the Stone Center at 3- and 6-month intervals initially and annually thereafter. Initial imaging was either IVU or NCCT, while follow-up imaging was typically performed annually with a KUB with tomography. Additional imaging studies were performed as clinically indicated. After PCNL, patients were treated with AHA and/or prophylactic antibiotics at the discretion of the treating physician. In addition, patients with specific metabolic abnormalities based on 24-hour urine results were treated with the appropriate medical therapy. Patients with specific metabolic defects based on 24-hour urine results were given additional dietary instructions. Demographic information from each patient was collected including age, sex, race, and body mass index (BMI). In addition, comorbidities related to struvite stones, urinary tract abnormalities, family history of stones, previous stone episodes, baseline and follow-up laboratory results, requirement of a staged procedure, baseline 24-hour urinary metabolic profiles, and UTI history were recorded. Radiologic imaging studies were evaluated to determine stone burden, stone-free status, and stone recurrence. Stone events, deterioration of renal function, type and duration of medical therapy, as well as complications associated with the therapy were also recorded. Stone burden was calculated by multiplying maximum length by the maximum width on KUB radiography or coronal CT image. These were added for patients with multiple stones. If coronal reformatted CT scans were not available, maximum length was calculated by noting the number of slices containing the stone and multiplying it by slice thickness. Struvite stone related comorbidities included spinal cord injury, spinal dysraphism, significant developmental delay, stroke, poor ambulation, neuropathic bladder, and diabetes mellitus. Stone-free status was evaluated after the primary PCNL or a staged procedure. Patients were considered stone free if they
IQBAL ET AL. had zero residual stone fragments on imaging. Stone growth/ recurrence was defined as an increase in size of a residual fragment or new stone formation on follow-up imaging. Stone-related events were defined as the following: (1) An acute emergency department visit secondary to pain, gross hematuria, or a febrile UTI that may necessitate placement of an emergent stent or percutaneous nephrostomy tube, or (2) a definitive endourologic procedure such as PCNL, ureteroscopy (URS), or shockwave lithotripsy (SWL) on follow-up. Stone activity was defined as having a stone recurrence or a stone event at follow-up. Remission was defined as having stable residual stones with no growth/recurrence, maintenance of stone-free status, or absence of stone-related events. Kidney function with serum creatinine level before surgery, 3 months postoperatively, and last follow-up was used to calculate the estimated glomerular filtration rate (eGFR) using Modification of Diet in Renal Disease eGFR equation.13 Patients were classified into the chronic kidney disease (CKD) stage ladder as per the recommendations from the National Kidney Foundation Kidney Disease Outcomes Quality Initiative.14 Change in eGFR and CKD stage during follow-up were calculated. The Pearson chi-square test was used to correlate different clinical variables to stone-related outcomes. Kaplan-Meier analyses were used to evaluate the differences in time to unfavorable clinical outcomes. Finally, multivariable Cox regression analysis was used to define independent predictors of unfavorable clinical outcome. All statistical analyses were performed using SPSS software version 19. Results Patient demographics, stone characteristics, and treatment The study included 43 patients with a median age of 55 – 15 years (range 21–89 years) with 15 (35%) pure and 28 (65%) mixed struvite stones. Patient demographics and stone characteristics are shown in Table 1. All patients were treated surgically with PCNL, including 11 (25%) staged procedures necessitating additional PCNL and/or URS; 40 (93%) were treated medically after PCNL. Median follow-up after PCNL or staged procedure was 22 months (range 6–67 mos). A total of 17 patients received AHA with antibiotic prophylaxis, 5 antibiotic prophylaxis alone and 24 received other metabolic stone preventive therapies (potassium citrate, sodium bicarbonate, calcium citrate, or chlorthalidone) alone or in combination with AHA or antibiotics. Clinical outcomes The stone-free rate after PCNL, including staged procedures, was 42%. Twenty-five (58%) patients had residual stones with median size of 0.56 cm2. Clinical outcomes including stone recurrence, stone-related events, and stone activity are shown in Table 2. Stone recurrence was absent in patients without residual stones (P = 0.002). In patients with residual fragments, stone recurrence/growth occurred in 40% of patients (10/25). Stone-related events developed in 13 (30%) patients overall. Patients with residual fragments were more likely to have a stone-related event than those who were rendered stone free (44% vs 11%) (P < 0.05). The median time to the first stone-related event or stone recurrence was 17
CONTEMPORARY MANAGEMENT OF STRUVITE STONES
3
Table 1. Patient Demographics and Stone Characteristics Patient characteristics
Number (%)
Age, median (range) Sex Male Female BMI, median (range) Race White Black All other Comorbidities Absent Present Family history of stones Absent Present Stone side Left Right Previous stone episodes Absent Present Number of stones Multiple Single Staghorn Stone burden (cm2), median (range) History of recurrent UTIs Absent Present
52 (21–89) 28 (65) 15 (35) 27.5 (14.5–45.5) 34 (79) 7 (16) 2 (5) 24 (56) 19 (44) 39 (91) 4 (9) 18 (42) 25 (58) 24 (56) 19 (44) 12 7 24 11.8
(28) (16) (56) (3–90)
22 (51) 21 (49)
UTI = urinary tract infection.
months. Remission of stone disease was seen in 63% (27/43) of patients. Patients who were stone free were more likely to be in remission than those who had residual stones (89% vs 44%), P = 0.003. Residual fragments > 0.4 cm2 had the strongest association with stone activity (P < 0.001), however. The median time to stone activity was significantly shorter in Table 2. Clinical Outcomes After Treatment of 43 Patients with Struvite Stones Patients (%) Stone-related events No Yes Stone recurrence No Yes Residual fragments No Stable residual fragments Growing residual fragments Stone activity No Yes
30 (70) 13 (30) 33 (77) 10 (23) 18 (42) 10 (23) 15 (35) 27 (63) 16 (37)
FIG. 1. Stone remission probabilities in 43 patients with struvite stones after percutaneous nephrolithotomy and effect of residual stones 0.4 cm2. patients with residual fragments > 0.4 cm2 compared with patients with no or small fragments (Fig. 1). Predictors of stone activity Association between various clinical factors with stone activity is shown in Table 3. Stone activity was noted in 16 (37%) patients and was associated with large stone burden (> 10 cm2) before PCNL, residual stones after PCNL, and residual stones > 0.4 cm2, (P < 0.05). The presence of existing comorbidities and staghorn stones demonstrated a trend toward stone activity (P = 0.063 and P = 0.051). Other clinical factors including age, sex, race, BMI, previous stone episodes, history of recurrent UTIs, stone composition, and use of various medical treatments were not associated with stone activity. On multivariable analysis, the presence of sizable residual stones > 0.4 cm2 was the most significant independent predictor of stone activity (P < 0.01). Other independent predictors of stone activity included preoperative large stone burden (> 10 cm2) and the presence of comorbidities (P < 0.05). Side effects of medical therapy Overall, medication side effects occurred in 17.5% (7/40) patients. Side effects including gastrointestinal irritation (1), anemia (2), headache (1), and DVT/pulmonary embolism (PE) (2) developed in 28% (5/18) patients receiving AHA. During medical treatment, nine patients had temporary interruptions (defined as at least 1 month) or discontinuation of AHA because of insurance-related issues, noncompliance, or side effects. Metabolic abnormalities Metabolic workup with 24-hour urine collection was performed in 27 patients. Sixty percent (3/5) of pure struvite stone formers and 77% (17/22) of our mixed stone formers
4
IQBAL ET AL. Table 3. Clinical Outcomes in 43 Patients with Struvite Stones and Correlation with Various Clinical Factors
Table 4. Metabolic Abnormalities in Struvite Stone Formers on 24-Hours Urine Collection
Total number Stone of patients (%) Remission activity P value 43 (100) Age Age < 55 24 (56) Age > 55 19 (44) Sex Female 28 (65) Male 15 (35) Race White 34 (79) Black 7 (16) Others 2 (5) Obesity BMI < 30 26 (60) BMI ‡ 30 17 (40) Comorbidities Absent 24 (56) Present 19 (44) Previous stone episodes Absent 24 (56) Present 19 (44) Family history of stones Absent 39 (91) Present 4 (9) Side Left 18 (42) Right 25 (58) History of recurrent UTIs Absent 22 (51) Present 21 (49) Staghorn stone Nonstaghorn 19 (44) Staghorn 24 (56) Stone burden < 10 cm2 20 (47) ‡ 10 cm2 23 (53) Residual stones Absent 18 (42) Present 25 (58) Residual stone > 0.4 cm2 Absent 20 (47) Present 23 (53) Stone composition Mixed struvite 28 (65) Pure struvite 15 (35) Acetohydroxamic acid No 25 (58) Yes 18 (42) Antibiotic prophylaxis No 17 (39) Yes 26 (61)
27 (63)
16 (37)
15 (56) 12 (44)
9 (56) 7 (44)
0.965
18 (67) 9 (33)
10 (63) 6 (37)
0.782
20 (74) 5 (19) 2 (7)
14 (88) 2 (12) 0 (0)
16 (59) 11 (41)
10 (63) 6 (37)
0.834
18 (67) 9 (33)
6 (37) 10 (63)
0.063
15 (56) 12 (44)
9 (56) 7 (44)
0.965
23 (85) 4 (15)
16 (100) 0 (0)
0.106
11 (41) 16 (59)
7 (44) 9 (56)
0.847
16 (59) 11 (41)
6 (37) 10 (63)
0.168
15 (56) 12 (44)
4 (25) 12 (75)
0.051
16 (59) 11 (41)
4 (25) 12 (75)
0.029
16 (59) 11 (41)
2 (12) 14 (88)
0.003
17 (63) 10 (37)
3 (19) 13 (81)
0.005
17(63) 10 (37)
11 (69) 5 (31)
0.7
16 (59) 11 (41)
9 (56) 7 (54)
0.847
12 (44) 15 (56)
5 (31) 11 (69)
0.392
BMI = body mass index; UTI = urinary tract infection.
0.441
Mixed struvite Pure struvite n = 22 (%) n = 5 (%) Hypocitraturia ( < 320 mg/24h) Hypercalciuria ( > 250 mg/24h) Gouty diathesis (pH £ 5.5) Hyperoxaluria ( > 50 mg/24h) Renal tubular acidosis
8 7 4 3 2
(36) (32) (18) (13) (9)
1 (20) 2 (40) 1 (20)
had metabolic abnormalities. Table 4 shows metabolic abnormalities in mixed struvite vs pure struvite stone formers. Overall 33% (9/27) struvite patients had hypocitraturia; 33% (9/27) hypercalciuria; 15% (4/27) gouty diathesis; 15% (4/27) hyperoxaluria; 7% (2/27) renal tubular acidosis (RTA). Kidney function outcomes Overall, the cohort maintained stable kidney function with median serum creatinine levels before surgery, 3 months postoperatively, and last follow-up, of 0.9 mg/dL (eGFR 70 mL/min/1.73 m2), 1.0 mg/dL (69 mL/min/1.73 m2), and 1.0 mg/dL (63 mL/min/1.73 m2), respectively. The median drop in eGFR at last follow-up was 6 mL/min/1.73 m2. Overall, 25 (58%) patients had stable kidney function, 4 (3%) improved, and 14 (33%) deteriorated by one CKD stage. UTIs Twenty-one (49%) patients had a history of UTI before PCNL. UTIs occurred in 23 (53%) patients during follow-up after PCNL, while frequent UTIs ( > 1 UTIs/year) occurred in 12 (28%) patients. UTI developed in 64% of patients (16/25) with residual stones during follow-up compared with 38% (7/18) who were stone free, P > 0.05. Among the patients in whom UTI developed after PCNL, 7(30%) had stone recurrence or stone-related events (P = 0.232) and 11 (48%) had stone activity. These factors did not correlate with clinical outcomes (P > 0.05), however. Discussion Studies on the management of struvite calculi lack definitive guidelines concerning postsurgical management. Previous studies are limited by inclusion of patients without well-documented struvite stones on stone analysis, high utilization of open surgery, SWL, or stone dissolving agents,15,16 or using KUB radiography as the sole imaging to work up and follow these patients.10,11,17 In addition, AHA has been rarely used outside the three randomized controlled trials for struvite stones performed in the early 1980s and 1990s. These factors make it difficult to compare the outcomes regarding the management of struvite stones from different studies. The current study is the first in almost two decades to evaluate the outcomes of patients with struvite stones. We used only PCNL and/or URS for primary stone removal with 79% of our patients having a noncontrast CT or IVU for initial follow-up with strict criteria to define stone-free status. Although the stone-free rate after PCNL in this series was only 42%, only 30% of the patients had a stone-related event postoperatively. In addition, of the patients with
CONTEMPORARY MANAGEMENT OF STRUVITE STONES residual fragments, only 40% of the patients had stone growth during the follow-up period. These findings emphasize the importance and efficacy of current medical management in patients with residual stones. It is ideal to render patients stone free during the initial surgery as demonstrated by the fact that none of the patients who were stone free had recurrence and only 11% of them had a stone-related event, compared with 44% of patients with residual fragments. Similarly, 89% of patients considered stone free were in remission, compared with 44% with residual stones, further supporting the significance of aggressive endourologic techniques to achieve a stone-free state. Of the three randomized controlled trials evaluating AHA use in struvite stone formers, none has reported stone-related events and used only KUB radiography alone to determine primary outcome measures.10,11,17 Previous studies have evaluated the effectiveness of AHA at preventing struvite stone growth or recurrence. Griffith and associates11 reported that 16.6% of their initial stone-free patients receiving acetohydroxamic acid had stone recurrence compared with 15.3% of stone-free patients in the placebo arm in a randomized double blind trial involving 210 spinal cord injury patients with chronic urease-splitting urinary infection and followed for 24 months. The active treatment arm had significantly longer intervals to stone recurrence (15 vs 9 months, P < 0.005); however, only 36% patients had struvite stone documented on stone analysis, and stone recurrence was defined as > 50% increase in stone area or appearance of a new stone on KUB radiography. Williams and colleagues17 reported that 36% of their patients in the placebo arm had recurrence as defined by > 100% increase in stone area detected by KUB radiography, compared with none in the AHA arm of a randomized controlled trial involving struvite stone formers receiving antibiotic prophylaxis. Stone volume did increase, however, in 22% of patients in the AHA arm. Another prospective, randomized trial involving struvite stones reported significantly less stone recurrence using AHA, compared with placebo (17% vs 46%). Recurrence was defined as > 25% increase in stone size on KUB radiography. None of the initial stone-free patients in the AHA group had recurrence, compared with 28% in the placebo group.10 Others have reported the risk of struvite stone recurrence after primary PCNL, followed by SWL, chemical dissolution, and antibiotic prophylaxis to be 27%, with mean interval to recurrence of 32.3 months.8 None of the above studies evaluated stone-related events in these patients or used more contemporary imaging such as NCCT. We observed stone growth in only 23.3% of patients, with 93% of patients continuing on medical preventive therapy (42% AHA, 60% antibiotic prophylaxis, 58% other metabolic stone preventive therapy). None of the patients who were stone free had stone recurrence, whereas 40% of patients with residual stones showed stone growth (P = 0.002) with median interval to stone growth of 18 months. Unfortunately, because of the small study size and retrospective nature, we were unable to analyze effects of any specific preventive medication on stone activity (ie, AHA + antibiotics vs AHA or antibiotics alone). While studies report occurrence of struvite stones more commonly in patients with anatomic abnormalities, neurogenic bladder, indwelling catheters, recurrent UTIs, or dia-
5 betes mellitus,4,5,17–20 the identification and role of factors predicting poor clinical outcomes after treatment has been lacking. We found the presence of comorbidities (such as spinal cord injury, spinal dysraphism, significant developmental delay, stroke, poor ambulation, neuropathic bladder, and diabetes mellitus), baseline stone burden > 10 cm2, and the presence of residual stone size more than 0.4 cm2 to be independent predictors of poor outcome on multivariable analysis. Streem and coworkers8 reported the presence of anatomic urinary tract abnormalities as the only significant factor associated with recurrence in a study involving 44 struvite patients who underwent an initial PCNL followed by SWL – chemical dissolution. Beck and Riehle21 reported that patients with 5-mm residual stones had a high likelihood of stone growth after SWL monotherapy for struvite stones, because stone growth developed in 78% of these patients after 3 months. We found residual stone size > 0.4 cm2 had the strongest association with stone activity. In addition, the time to stone recurrence or stone events was significantly shorter in these patients. For patients with residual stone burden greater than 0.4 cm2, a strong consideration needs to be made for further surgical management to remove the residual stone. Urease inhibitors have been advocated after stone removal to prevent recurrence20,22,23; however, administration may be associated with serious side effects.12,18,20 In our practice, AHA was prescribed at a dose of 250 mg orally bid. Overall, 42% of our patients received AHA. Of the patients who received AHA, side effects developed in 27.7% and 16.6% discontinued the medication because of side effects. This finding is less than the complications rates reported in the three randomized control trials using AHA where adverse events occurred in 45% to 78% and the discontinuation rate was 10% to 27%.10,11,17 The reductions in AHA-related complications may have been secondary to the reduced dose of medication used in our patient population. We transiently discontinued AHA in two patients secondary to anemia, while one of our patients permanently discontinued AHA because of nausea, vomiting, and headache. DVT developed in two patients, in one of whom PE developed. In comparison, previous reports have noted rates of anemia and headache between 2% and 25%10,11 and DVT in as high as 16%.17 Although antibiotic prophylaxis is advocated in struvite stone formers, there is a lack of definitive evidence for the role of antibiotics in preventing stone growth and recurrent UTIs; their impact on clinical outcomes; and the optimal duration of therapy.18,20,22–24 None of the randomized controlled trials examining AHA looked at the use of antibiotic prophylaxis.10,11,17 A UTI developed in 53% of our patients during follow-up; among these, 28% had frequent UTIs. A UTI developed in 64% of patients (16/25) with residual stones during follow-up compared with 38% (7/18) stone free, P > 0.05. We did not find any association between the occurrence of UTIs or antibiotic prophylaxis and stone growth or stone events. It has been suggested that patients with pure struvite stones do not need 24-hour urine metabolic evaluations.22 Lingeman and associates25 reported that only 14.2% of their pure struvite stone formers had a metabolic abnormality (hypercalciuria) whereas 100% of mixed struvite stones had abnormalities on 24-hour urine studies. In comparison, we found metabolic abnormalities (hypercalciuria, 2;
6 hypocitraturia, 1; hyperoxaluria, 1), in 60% of pure struvite stone formers and 77% of mixed stone formers (hypocitraturia, 8; hypercalciuria, 7; gouty diathesis, 4; hyperoxaluria, 3; RTA, 2). Our findings suggest that metabolic defects may play some role in pure struvite stone formation, and perhaps this finding needs further evaluation. Given the small number of patients with pure struvite stones who completed a metabolic evaluation, however, it is difficult to make a definitive statement. Struvite stone disease has been associated with significant renal injury.3–5 Preservation of renal function is one of the primary goals of management. Previously, Streem and Lammert26 reported stable or improved renal function in 93% of struvite stone formers who underwent PCNL followed by antibiotic prophylaxis. In our study, kidney function was maintained in 58% and improved in 3%. Unfortunately, onestep worsening of renal function as indicated by CKD stage developed in 33% of patients in our cohort. While this study is limited in the ability to control other confounders for renal deterioration, this finding validates the need for close follow-up in this at-risk population. Further studies are needed to better quantify the risk of renal deterioration in these patients. The stone-free rate of 42% achieved in the current study was relatively modest. This finding can be explained by the fact that 56% of our patients had staghorn calculi, with a mean overall stone burden of 1778 mm2, and postoperative imaging consisted of either CT scan or IVU. Secondly, stone free was strictly defined as absolutely no fragments on imaging. Comparably, Smith and colleagues27 reported stone-free rates of 82% in 2806 patients in the Clinical Research Office of the Endourological Society PCNL global study. This large multicenter study included a mean stone burden of only 463 mm2, used only plain film imaging, and defined stone free as residual stone fragments < 4 mm. More recently, Shahrour and coworkers28 reported stone-free rates of 51% after a single PCNL procedure in 351 patients, evaluated by a postoperative CT scan or intraoperative antegrade fluoroscopy. Lastly, the British Association of Urological Surgeons PCNL data registry of 1009 patients reported stone-free rates of 47% and 77% for staghorn and nonstaghorn calculi, respectively, using less stringent criteria.29 Our study has several limitations. It was a retrospective review with an inherent bias in treatment selection and follow-up. There was an absence of any uniform treatment protocol. Because of the small number of patients, we were unable to analyze effects of any specific preventive medication on stone activity. Although all the patients had NCCT or IVU, there was no uniformity to the imaging modalities used to diagnose and follow these patients, which affected the sensitivity and specificity of results. Conclusions Patients with struvite stones are a medically complex population of patients who need aggressive endourologic and medical treatement with continued clinical and radiologic surveillance. We validated that rendering patients stone free after PCNL followed by preventive medical therapy offers the best likelihood of avoiding stone recurrence or stone adverse events. Preoperative stone burden of greater than 10 cm2, residual stone size > 0.4 cm2, and the presence of patient-related comorbidities are independent risk factors for poor outcomes.
IQBAL ET AL. AHA can be associated with significant side effects in patients and should be used at a reduced dosage. With combined surgical and medical treatment as well as appropriate followup, stable renal function can be maintained in the majority of patients. Disclosure Statement Michael E. Lipkin is a consultant for Boston Scientific; Michael N. Ferrandino is a proctor for Intuitive Surgical. For the remaining authors, no competing financial interests exist. References 1. Levy FL, Adams-Huet B, Pak CY. Ambulatory evaluation of nephrolithiasis: An update of a 1980 protocol. Am J Med 1995;98:50–59. 2. Griffith DP, Musher DM. Prevention of infected urinary stones by urease inhibition. Invest Urol 1973;11:228–L33. 3. Koga S, Arakaki Y, Matsuoka M, Ohyama C. Staghorn calculi—long-term results of management. Br J Urol 1991;68: 122–124. 4. Cohen TD, Preminger GM. Struvite calculi. Semin Nephrol 1996;14:425–434. 5. Lerner SP, Gleeson MJ, Griffith DP. Infection stones. J Urol 1989;141:753–758. 6. Blandy JP, Singh M. The case for a more aggressive approach to staghorn stones. J Urol 1976;115:505–506. 7. Patterson DE, Segura JW, LeRoy AJ. Long-term follow-up of patients treated by percutaneous ultrasonic lithotripsy for struvite staghorn calculi. J Endourol 1987;1:177–180. 8. Streem SB. Long-term incidence and risk factors for recurrent stones following percutaneous nephrostolithotomy or percutaneous nephrostolithotomy/extracorporeal shock wave lithotripsy for infection related calculi. J Urol 1995;153: 584–587. 9. Michaels EK, Fowler JE Jr. Extracorporeal shock wave lithotripsy for struvite renal calculi: Prospective study with extended followup. J Urol 1991;146:728–732. 10. Griffith DP, Gleeson MJ, Lee H, et al. Randomized, doubleblind trial of Lithostat (acetohydroxamic acid) in the palliative treatment of infection-induced urinary calculi. Eur Urol 1991;20:243–247. 11. Griffith DP, Khonsari F, Skurnick JH, James KE. A randomized trial of acetohydroxamic acid for the treatment and prevention of infection-induced urinary stones in spinal cord injury patients. J Urol 1988;140:318–324. 12. Rodman JS, Williams JJ, Jones RL. Hypercoagulability produced by treatment with acetohydroxamic acid. Clin Pharmacol Ther 1987;42:346–350. 13. Levey AS, Greene T, Kusek JW, Beck GJ. A simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol 2000;11:155A. 14. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 2002;39(suppl 1):S1–S266. 15. Smith MJ, Boyce WH. Anatrophic nephrotomy and plastic calyrhaphy. J Urol 1968;99:521–527. 16. Stubbs AJ, Resnick MI, Boyce WH. Anatrophic nephrolithotomy in the solitary kidney. J Urol 1978;119: 457–460. 17. Williams JJ, Rodman JS, Peterson CM. A randomized double-blind study of acetohydroxamic acid in struvite nephrolithiasis. N Engl J Med 1984;311:760–764.
CONTEMPORARY MANAGEMENT OF STRUVITE STONES 18. Wang LP, Wong HY, Griffith DP. Treatment options in struvite stones. Urol Clin North Am 1997;24:149–162. 19. Segura JW. Staghorn calculi. Urol Clin North Am 1997; 24:71–80. 20. Rodman JS. Struvite stones. Nephron 1999;81(suppl l): 50–59. 21. Beck EM, Riehle RA. The fate of residual fragments after extracorporeal shock wave lithotripsy monotherapy for infection stones. J Urol 1991;145:6–10. 22. Preminger GM, Assimos DG, Lingeman JE, et al. Chapter 1: AUA guideline on management of staghorn calculi: Diagnosis and treatment recommendations. J Urol 2005;173:1991– 2000. 23. Streem SB, Yost A, Dolmatch B. Combination ‘‘sandwich’’ therapy for extensive renal calculi in 100 consecutive patients: Immediate, long-term and stratified results from a 10-year experience. J Urol 1997;158:342–345. 24. Griffith DP, Moskowitz PA, Carlton CE Jr. Adjunctive chemotherapy of infection-induced staghorn calculi. J Urol 1979;121:711–715. 25. Lingeman JE, Siegel YI, Steele B. Metabolic evaluation of infected renal lithiasis: Clinical relevance. J Endourol 1995;9:51–54. 26. Streem SB, Lammert G. Long-term efficacy of combination therapy for struvite staghorn calculi. J Urol 1992;147:563–566. 27. Smith A, Averch TD, Shahrour K, et al. CROES PCNL Study Group. A nephrolithometric nomogram for predicting treatment success of percutaneous nephrolithotomy. J Urol 2013;190:149–156. 28. Shahrour K, Tomaszewski J, Ortiz T, et al. Predictors of immediate postoperative outcome of single-tract percutaneous nephrolithotomy. Urology 2012;80:19–25.
7 29. Armitage JN, Irving SO, Burgess NA; British Association of Urological Surgeons Section of Endourology. Percutaneous nephrolithotomy in the United Kingdom: Results of a prospective data registry. Eur Urol 2012;61:1188–1193.
Address correspondence to: Michael E. Lipkin, MD Division of Urologic Surgery Duke University Medical Center DUMC 3167 Durham, NC 27710 E-mail: [email protected]
Abbreviations Used AHA ¼ acetohydroxamic acid BMI ¼ body mass index CKD ¼ chronic kidney disease DVT ¼ deep venous thrombosis eGFR ¼ estimated glomerular filtration rate IVU ¼ intravenous urography KUB ¼ kidneys, ureters, and bladder NCCT ¼ noncontrast computed tomography PCNL ¼ percutaneous nephrolithotomy PE ¼ pulmonary embolism RTA ¼ renal tubular acidosis SWL ¼ shockwave lithotripsy URS ¼ ureteroscopy UTI ¼ urinary tract infection
JOURNAL OF ENDOUROLOGY Volume 28, Number XX, XXXX 2013 ª Mary Ann Liebert, Inc. Pp. ---–--DOI: 10.1089/end.2013.0257
Contemporary Management of Struvite Stones Using Combined Endourologic and Medical Treatment: Predictors of Unfavorable Clinical Outcome Muhammad Waqas Iqbal, MD,1 Ramy F. Youssef, MD,1 Andreas Neisius, MD,1,2 Nicholas Kuntz, MD,1 Jonathan Hanna, BS,1 Michael N. Ferrandino, MD,1 Glenn M. Preminger, MD,1 Michael E. Lipkin, MD1
Abstract
Background and Purpose: Struvite stones have been associated with significant morbidity and mortality, yet there has not been a report on the medical management of struvite stones in almost 20 years. We report on the contemporary outcomes of the surgical and medical management of struvite stones in a contemporary series. Patients and Methods: A retrospective review of patients who were treated with percutaneous nephrolithotomy (PCNL) for struvite stones at Duke University Medical Center between January 2005 and September 2012 identified a total of 75 patients. Of these, 43 patients had adequate follow-up and were included in this analysis. Stone activity, defined as either stone recurrence or stone-related events, and predictors of activity were evaluated after combined surgical and medical treatment. Results: The study included 43 patients with either pure (35%) or mixed (65%) struvite stones with a median age of 55 – 15 years (range 21–89 years). The stone-free rate after PCNL was 42%. Stone recurrence occurred in 23% of patients. Postoperatively, 30% of patients had a stone-related event, while 60% of residual stones remained stable with no growth after a median follow-up of 22 months (range 6–67 mos). Kidney function remained stable during follow-up. Independent predictors of stone activity included the presence of residual stones > 0.4 cm2, preoperative large stone burden (> 10 cm2), and the presence of medical comorbidities (P < 0.05). Conclusions: Struvite stones can be managed safely with PCNL followed by medical therapy. The majority of patients with residual fragments demonstrated no evidence of stone growth on medical therapy. With careful follow-up and medical management, kidney function can be maintained and stone morbidity can be minimized. Initial large stone burden, residual stones after surgery, and associated medical comorbidities may have deleterious effect on stone recurrence or residual stone-related events. possible. In cases where complete stone removal is not possible or residual fragments remain, a detailed approach to prevent stone recurrence, stone-related hospital visits or procedures, and UTIs, and preservation of renal function is critical.9 The medical management of struvite stones includes antibiotic prophylaxis and the urease inhibitor acetohydroxamic acid (AHA). AHA has been shown to prevent stone recurrence in this population10,11 but has been associated with significant side effects, including nausea, vomiting, tremors, anxiety, headache, anemia, rash, hepatotoxicity, and deep venous thrombosis (DVT).12 The most recent report on the treatment of patients with struvite stones is from more than 18 years ago.8 Since that time, there have been significant advances in endourologic techniques as well as imaging and diagnostic modalities. We
Introduction truvite stones comprise 5% to 15% of all renal calculi1 and form as a result of infection with urease-splitting organisms.2 Once an ‘‘infection stone’’ is present, urinary tract infections (UTIs) tend to recur, leading to episodes of hematuria, flank pain, pyelonephritis, or sepsis. Over time, an untreated staghorn calculus can result in complications such as pyonephrosis, perinephric abscess formation, or xanthogranulomatous pyelonephritis with eventual loss of the kidney.3–5 Historically, nonsurgical management of infection stones was associated with a mortality of 28% compared with only 7.2% in patients who underwent surgical treatment.6 Despite advances in management, these calculi continued to cause significant morbidity.7,8 Effective management of struvite stones should begin with complete stone removal when
S
1
Division of Urologic Surgery, Duke University Medical Center, Durham, North Carolina. Department of Urology, Johannes Gutenberg University Mainz, Mainz, Germany.
2
1
2 report the outcomes of patients with infection stones treated with a combination of surgery and medical therapy from a contemporary surgical series. We evaluated various clinical parameters to determine predictors for stone recurrence or stone-related events in follow-up. Patients and Methods After obtaining Institutional Review Board approval, a retrospective chart review of all patients undergoing PCNL at our institution between January 2005 and September of 2012 was performed. A total of 610 patients were evaluated. Of these patients, 493 had data on stone analysis. A total of 75 patients whose stone analysis came back as struvite were identified. Pure struvite stones were defined as 100% magnesium ammonium phosphate – carbonate apatite, whereas mixed stones were defined as containing struvite as well as other stone components. Both pure and mixed struvite stone formers were included in the current review. Patients without adequate clinical (< 6 months) or radiologic follow-up data were excluded (32 patients). Patients had imaging studies 3 months after PCNL with either intravenous urography (IVU) (35%), noncontrast computed tomography (NCCT) of the abdomen/pelvis (44%), or plain radiography of the kidneys, ureters, and bladder (KUB) with tomography (21%) to establish stone-free status. Patients also had a serum complete metabolic profile and a baseline 24hour urinary metabolic evaluation at this time. Patients were regularly followed at the Stone Center at 3- and 6-month intervals initially and annually thereafter. Initial imaging was either IVU or NCCT, while follow-up imaging was typically performed annually with a KUB with tomography. Additional imaging studies were performed as clinically indicated. After PCNL, patients were treated with AHA and/or prophylactic antibiotics at the discretion of the treating physician. In addition, patients with specific metabolic abnormalities based on 24-hour urine results were treated with the appropriate medical therapy. Patients with specific metabolic defects based on 24-hour urine results were given additional dietary instructions. Demographic information from each patient was collected including age, sex, race, and body mass index (BMI). In addition, comorbidities related to struvite stones, urinary tract abnormalities, family history of stones, previous stone episodes, baseline and follow-up laboratory results, requirement of a staged procedure, baseline 24-hour urinary metabolic profiles, and UTI history were recorded. Radiologic imaging studies were evaluated to determine stone burden, stone-free status, and stone recurrence. Stone events, deterioration of renal function, type and duration of medical therapy, as well as complications associated with the therapy were also recorded. Stone burden was calculated by multiplying maximum length by the maximum width on KUB radiography or coronal CT image. These were added for patients with multiple stones. If coronal reformatted CT scans were not available, maximum length was calculated by noting the number of slices containing the stone and multiplying it by slice thickness. Struvite stone related comorbidities included spinal cord injury, spinal dysraphism, significant developmental delay, stroke, poor ambulation, neuropathic bladder, and diabetes mellitus. Stone-free status was evaluated after the primary PCNL or a staged procedure. Patients were considered stone free if they
IQBAL ET AL. had zero residual stone fragments on imaging. Stone growth/ recurrence was defined as an increase in size of a residual fragment or new stone formation on follow-up imaging. Stone-related events were defined as the following: (1) An acute emergency department visit secondary to pain, gross hematuria, or a febrile UTI that may necessitate placement of an emergent stent or percutaneous nephrostomy tube, or (2) a definitive endourologic procedure such as PCNL, ureteroscopy (URS), or shockwave lithotripsy (SWL) on follow-up. Stone activity was defined as having a stone recurrence or a stone event at follow-up. Remission was defined as having stable residual stones with no growth/recurrence, maintenance of stone-free status, or absence of stone-related events. Kidney function with serum creatinine level before surgery, 3 months postoperatively, and last follow-up was used to calculate the estimated glomerular filtration rate (eGFR) using Modification of Diet in Renal Disease eGFR equation.13 Patients were classified into the chronic kidney disease (CKD) stage ladder as per the recommendations from the National Kidney Foundation Kidney Disease Outcomes Quality Initiative.14 Change in eGFR and CKD stage during follow-up were calculated. The Pearson chi-square test was used to correlate different clinical variables to stone-related outcomes. Kaplan-Meier analyses were used to evaluate the differences in time to unfavorable clinical outcomes. Finally, multivariable Cox regression analysis was used to define independent predictors of unfavorable clinical outcome. All statistical analyses were performed using SPSS software version 19. Results Patient demographics, stone characteristics, and treatment The study included 43 patients with a median age of 55 – 15 years (range 21–89 years) with 15 (35%) pure and 28 (65%) mixed struvite stones. Patient demographics and stone characteristics are shown in Table 1. All patients were treated surgically with PCNL, including 11 (25%) staged procedures necessitating additional PCNL and/or URS; 40 (93%) were treated medically after PCNL. Median follow-up after PCNL or staged procedure was 22 months (range 6–67 mos). A total of 17 patients received AHA with antibiotic prophylaxis, 5 antibiotic prophylaxis alone and 24 received other metabolic stone preventive therapies (potassium citrate, sodium bicarbonate, calcium citrate, or chlorthalidone) alone or in combination with AHA or antibiotics. Clinical outcomes The stone-free rate after PCNL, including staged procedures, was 42%. Twenty-five (58%) patients had residual stones with median size of 0.56 cm2. Clinical outcomes including stone recurrence, stone-related events, and stone activity are shown in Table 2. Stone recurrence was absent in patients without residual stones (P = 0.002). In patients with residual fragments, stone recurrence/growth occurred in 40% of patients (10/25). Stone-related events developed in 13 (30%) patients overall. Patients with residual fragments were more likely to have a stone-related event than those who were rendered stone free (44% vs 11%) (P < 0.05). The median time to the first stone-related event or stone recurrence was 17
CONTEMPORARY MANAGEMENT OF STRUVITE STONES
3
Table 1. Patient Demographics and Stone Characteristics Patient characteristics
Number (%)
Age, median (range) Sex Male Female BMI, median (range) Race White Black All other Comorbidities Absent Present Family history of stones Absent Present Stone side Left Right Previous stone episodes Absent Present Number of stones Multiple Single Staghorn Stone burden (cm2), median (range) History of recurrent UTIs Absent Present
52 (21–89) 28 (65) 15 (35) 27.5 (14.5–45.5) 34 (79) 7 (16) 2 (5) 24 (56) 19 (44) 39 (91) 4 (9) 18 (42) 25 (58) 24 (56) 19 (44) 12 7 24 11.8
(28) (16) (56) (3–90)
22 (51) 21 (49)
UTI = urinary tract infection.
months. Remission of stone disease was seen in 63% (27/43) of patients. Patients who were stone free were more likely to be in remission than those who had residual stones (89% vs 44%), P = 0.003. Residual fragments > 0.4 cm2 had the strongest association with stone activity (P < 0.001), however. The median time to stone activity was significantly shorter in Table 2. Clinical Outcomes After Treatment of 43 Patients with Struvite Stones Patients (%) Stone-related events No Yes Stone recurrence No Yes Residual fragments No Stable residual fragments Growing residual fragments Stone activity No Yes
30 (70) 13 (30) 33 (77) 10 (23) 18 (42) 10 (23) 15 (35) 27 (63) 16 (37)
FIG. 1. Stone remission probabilities in 43 patients with struvite stones after percutaneous nephrolithotomy and effect of residual stones 0.4 cm2. patients with residual fragments > 0.4 cm2 compared with patients with no or small fragments (Fig. 1). Predictors of stone activity Association between various clinical factors with stone activity is shown in Table 3. Stone activity was noted in 16 (37%) patients and was associated with large stone burden (> 10 cm2) before PCNL, residual stones after PCNL, and residual stones > 0.4 cm2, (P < 0.05). The presence of existing comorbidities and staghorn stones demonstrated a trend toward stone activity (P = 0.063 and P = 0.051). Other clinical factors including age, sex, race, BMI, previous stone episodes, history of recurrent UTIs, stone composition, and use of various medical treatments were not associated with stone activity. On multivariable analysis, the presence of sizable residual stones > 0.4 cm2 was the most significant independent predictor of stone activity (P < 0.01). Other independent predictors of stone activity included preoperative large stone burden (> 10 cm2) and the presence of comorbidities (P < 0.05). Side effects of medical therapy Overall, medication side effects occurred in 17.5% (7/40) patients. Side effects including gastrointestinal irritation (1), anemia (2), headache (1), and DVT/pulmonary embolism (PE) (2) developed in 28% (5/18) patients receiving AHA. During medical treatment, nine patients had temporary interruptions (defined as at least 1 month) or discontinuation of AHA because of insurance-related issues, noncompliance, or side effects. Metabolic abnormalities Metabolic workup with 24-hour urine collection was performed in 27 patients. Sixty percent (3/5) of pure struvite stone formers and 77% (17/22) of our mixed stone formers
4
IQBAL ET AL. Table 3. Clinical Outcomes in 43 Patients with Struvite Stones and Correlation with Various Clinical Factors
Table 4. Metabolic Abnormalities in Struvite Stone Formers on 24-Hours Urine Collection
Total number Stone of patients (%) Remission activity P value 43 (100) Age Age < 55 24 (56) Age > 55 19 (44) Sex Female 28 (65) Male 15 (35) Race White 34 (79) Black 7 (16) Others 2 (5) Obesity BMI < 30 26 (60) BMI ‡ 30 17 (40) Comorbidities Absent 24 (56) Present 19 (44) Previous stone episodes Absent 24 (56) Present 19 (44) Family history of stones Absent 39 (91) Present 4 (9) Side Left 18 (42) Right 25 (58) History of recurrent UTIs Absent 22 (51) Present 21 (49) Staghorn stone Nonstaghorn 19 (44) Staghorn 24 (56) Stone burden < 10 cm2 20 (47) ‡ 10 cm2 23 (53) Residual stones Absent 18 (42) Present 25 (58) Residual stone > 0.4 cm2 Absent 20 (47) Present 23 (53) Stone composition Mixed struvite 28 (65) Pure struvite 15 (35) Acetohydroxamic acid No 25 (58) Yes 18 (42) Antibiotic prophylaxis No 17 (39) Yes 26 (61)
27 (63)
16 (37)
15 (56) 12 (44)
9 (56) 7 (44)
0.965
18 (67) 9 (33)
10 (63) 6 (37)
0.782
20 (74) 5 (19) 2 (7)
14 (88) 2 (12) 0 (0)
16 (59) 11 (41)
10 (63) 6 (37)
0.834
18 (67) 9 (33)
6 (37) 10 (63)
0.063
15 (56) 12 (44)
9 (56) 7 (44)
0.965
23 (85) 4 (15)
16 (100) 0 (0)
0.106
11 (41) 16 (59)
7 (44) 9 (56)
0.847
16 (59) 11 (41)
6 (37) 10 (63)
0.168
15 (56) 12 (44)
4 (25) 12 (75)
0.051
16 (59) 11 (41)
4 (25) 12 (75)
0.029
16 (59) 11 (41)
2 (12) 14 (88)
0.003
17 (63) 10 (37)
3 (19) 13 (81)
0.005
17(63) 10 (37)
11 (69) 5 (31)
0.7
16 (59) 11 (41)
9 (56) 7 (54)
0.847
12 (44) 15 (56)
5 (31) 11 (69)
0.392
BMI = body mass index; UTI = urinary tract infection.
0.441
Mixed struvite Pure struvite n = 22 (%) n = 5 (%) Hypocitraturia ( < 320 mg/24h) Hypercalciuria ( > 250 mg/24h) Gouty diathesis (pH £ 5.5) Hyperoxaluria ( > 50 mg/24h) Renal tubular acidosis
8 7 4 3 2
(36) (32) (18) (13) (9)
1 (20) 2 (40) 1 (20)
had metabolic abnormalities. Table 4 shows metabolic abnormalities in mixed struvite vs pure struvite stone formers. Overall 33% (9/27) struvite patients had hypocitraturia; 33% (9/27) hypercalciuria; 15% (4/27) gouty diathesis; 15% (4/27) hyperoxaluria; 7% (2/27) renal tubular acidosis (RTA). Kidney function outcomes Overall, the cohort maintained stable kidney function with median serum creatinine levels before surgery, 3 months postoperatively, and last follow-up, of 0.9 mg/dL (eGFR 70 mL/min/1.73 m2), 1.0 mg/dL (69 mL/min/1.73 m2), and 1.0 mg/dL (63 mL/min/1.73 m2), respectively. The median drop in eGFR at last follow-up was 6 mL/min/1.73 m2. Overall, 25 (58%) patients had stable kidney function, 4 (3%) improved, and 14 (33%) deteriorated by one CKD stage. UTIs Twenty-one (49%) patients had a history of UTI before PCNL. UTIs occurred in 23 (53%) patients during follow-up after PCNL, while frequent UTIs ( > 1 UTIs/year) occurred in 12 (28%) patients. UTI developed in 64% of patients (16/25) with residual stones during follow-up compared with 38% (7/18) who were stone free, P > 0.05. Among the patients in whom UTI developed after PCNL, 7(30%) had stone recurrence or stone-related events (P = 0.232) and 11 (48%) had stone activity. These factors did not correlate with clinical outcomes (P > 0.05), however. Discussion Studies on the management of struvite calculi lack definitive guidelines concerning postsurgical management. Previous studies are limited by inclusion of patients without well-documented struvite stones on stone analysis, high utilization of open surgery, SWL, or stone dissolving agents,15,16 or using KUB radiography as the sole imaging to work up and follow these patients.10,11,17 In addition, AHA has been rarely used outside the three randomized controlled trials for struvite stones performed in the early 1980s and 1990s. These factors make it difficult to compare the outcomes regarding the management of struvite stones from different studies. The current study is the first in almost two decades to evaluate the outcomes of patients with struvite stones. We used only PCNL and/or URS for primary stone removal with 79% of our patients having a noncontrast CT or IVU for initial follow-up with strict criteria to define stone-free status. Although the stone-free rate after PCNL in this series was only 42%, only 30% of the patients had a stone-related event postoperatively. In addition, of the patients with
CONTEMPORARY MANAGEMENT OF STRUVITE STONES residual fragments, only 40% of the patients had stone growth during the follow-up period. These findings emphasize the importance and efficacy of current medical management in patients with residual stones. It is ideal to render patients stone free during the initial surgery as demonstrated by the fact that none of the patients who were stone free had recurrence and only 11% of them had a stone-related event, compared with 44% of patients with residual fragments. Similarly, 89% of patients considered stone free were in remission, compared with 44% with residual stones, further supporting the significance of aggressive endourologic techniques to achieve a stone-free state. Of the three randomized controlled trials evaluating AHA use in struvite stone formers, none has reported stone-related events and used only KUB radiography alone to determine primary outcome measures.10,11,17 Previous studies have evaluated the effectiveness of AHA at preventing struvite stone growth or recurrence. Griffith and associates11 reported that 16.6% of their initial stone-free patients receiving acetohydroxamic acid had stone recurrence compared with 15.3% of stone-free patients in the placebo arm in a randomized double blind trial involving 210 spinal cord injury patients with chronic urease-splitting urinary infection and followed for 24 months. The active treatment arm had significantly longer intervals to stone recurrence (15 vs 9 months, P < 0.005); however, only 36% patients had struvite stone documented on stone analysis, and stone recurrence was defined as > 50% increase in stone area or appearance of a new stone on KUB radiography. Williams and colleagues17 reported that 36% of their patients in the placebo arm had recurrence as defined by > 100% increase in stone area detected by KUB radiography, compared with none in the AHA arm of a randomized controlled trial involving struvite stone formers receiving antibiotic prophylaxis. Stone volume did increase, however, in 22% of patients in the AHA arm. Another prospective, randomized trial involving struvite stones reported significantly less stone recurrence using AHA, compared with placebo (17% vs 46%). Recurrence was defined as > 25% increase in stone size on KUB radiography. None of the initial stone-free patients in the AHA group had recurrence, compared with 28% in the placebo group.10 Others have reported the risk of struvite stone recurrence after primary PCNL, followed by SWL, chemical dissolution, and antibiotic prophylaxis to be 27%, with mean interval to recurrence of 32.3 months.8 None of the above studies evaluated stone-related events in these patients or used more contemporary imaging such as NCCT. We observed stone growth in only 23.3% of patients, with 93% of patients continuing on medical preventive therapy (42% AHA, 60% antibiotic prophylaxis, 58% other metabolic stone preventive therapy). None of the patients who were stone free had stone recurrence, whereas 40% of patients with residual stones showed stone growth (P = 0.002) with median interval to stone growth of 18 months. Unfortunately, because of the small study size and retrospective nature, we were unable to analyze effects of any specific preventive medication on stone activity (ie, AHA + antibiotics vs AHA or antibiotics alone). While studies report occurrence of struvite stones more commonly in patients with anatomic abnormalities, neurogenic bladder, indwelling catheters, recurrent UTIs, or dia-
5 betes mellitus,4,5,17–20 the identification and role of factors predicting poor clinical outcomes after treatment has been lacking. We found the presence of comorbidities (such as spinal cord injury, spinal dysraphism, significant developmental delay, stroke, poor ambulation, neuropathic bladder, and diabetes mellitus), baseline stone burden > 10 cm2, and the presence of residual stone size more than 0.4 cm2 to be independent predictors of poor outcome on multivariable analysis. Streem and coworkers8 reported the presence of anatomic urinary tract abnormalities as the only significant factor associated with recurrence in a study involving 44 struvite patients who underwent an initial PCNL followed by SWL – chemical dissolution. Beck and Riehle21 reported that patients with 5-mm residual stones had a high likelihood of stone growth after SWL monotherapy for struvite stones, because stone growth developed in 78% of these patients after 3 months. We found residual stone size > 0.4 cm2 had the strongest association with stone activity. In addition, the time to stone recurrence or stone events was significantly shorter in these patients. For patients with residual stone burden greater than 0.4 cm2, a strong consideration needs to be made for further surgical management to remove the residual stone. Urease inhibitors have been advocated after stone removal to prevent recurrence20,22,23; however, administration may be associated with serious side effects.12,18,20 In our practice, AHA was prescribed at a dose of 250 mg orally bid. Overall, 42% of our patients received AHA. Of the patients who received AHA, side effects developed in 27.7% and 16.6% discontinued the medication because of side effects. This finding is less than the complications rates reported in the three randomized control trials using AHA where adverse events occurred in 45% to 78% and the discontinuation rate was 10% to 27%.10,11,17 The reductions in AHA-related complications may have been secondary to the reduced dose of medication used in our patient population. We transiently discontinued AHA in two patients secondary to anemia, while one of our patients permanently discontinued AHA because of nausea, vomiting, and headache. DVT developed in two patients, in one of whom PE developed. In comparison, previous reports have noted rates of anemia and headache between 2% and 25%10,11 and DVT in as high as 16%.17 Although antibiotic prophylaxis is advocated in struvite stone formers, there is a lack of definitive evidence for the role of antibiotics in preventing stone growth and recurrent UTIs; their impact on clinical outcomes; and the optimal duration of therapy.18,20,22–24 None of the randomized controlled trials examining AHA looked at the use of antibiotic prophylaxis.10,11,17 A UTI developed in 53% of our patients during follow-up; among these, 28% had frequent UTIs. A UTI developed in 64% of patients (16/25) with residual stones during follow-up compared with 38% (7/18) stone free, P > 0.05. We did not find any association between the occurrence of UTIs or antibiotic prophylaxis and stone growth or stone events. It has been suggested that patients with pure struvite stones do not need 24-hour urine metabolic evaluations.22 Lingeman and associates25 reported that only 14.2% of their pure struvite stone formers had a metabolic abnormality (hypercalciuria) whereas 100% of mixed struvite stones had abnormalities on 24-hour urine studies. In comparison, we found metabolic abnormalities (hypercalciuria, 2;
6 hypocitraturia, 1; hyperoxaluria, 1), in 60% of pure struvite stone formers and 77% of mixed stone formers (hypocitraturia, 8; hypercalciuria, 7; gouty diathesis, 4; hyperoxaluria, 3; RTA, 2). Our findings suggest that metabolic defects may play some role in pure struvite stone formation, and perhaps this finding needs further evaluation. Given the small number of patients with pure struvite stones who completed a metabolic evaluation, however, it is difficult to make a definitive statement. Struvite stone disease has been associated with significant renal injury.3–5 Preservation of renal function is one of the primary goals of management. Previously, Streem and Lammert26 reported stable or improved renal function in 93% of struvite stone formers who underwent PCNL followed by antibiotic prophylaxis. In our study, kidney function was maintained in 58% and improved in 3%. Unfortunately, onestep worsening of renal function as indicated by CKD stage developed in 33% of patients in our cohort. While this study is limited in the ability to control other confounders for renal deterioration, this finding validates the need for close follow-up in this at-risk population. Further studies are needed to better quantify the risk of renal deterioration in these patients. The stone-free rate of 42% achieved in the current study was relatively modest. This finding can be explained by the fact that 56% of our patients had staghorn calculi, with a mean overall stone burden of 1778 mm2, and postoperative imaging consisted of either CT scan or IVU. Secondly, stone free was strictly defined as absolutely no fragments on imaging. Comparably, Smith and colleagues27 reported stone-free rates of 82% in 2806 patients in the Clinical Research Office of the Endourological Society PCNL global study. This large multicenter study included a mean stone burden of only 463 mm2, used only plain film imaging, and defined stone free as residual stone fragments < 4 mm. More recently, Shahrour and coworkers28 reported stone-free rates of 51% after a single PCNL procedure in 351 patients, evaluated by a postoperative CT scan or intraoperative antegrade fluoroscopy. Lastly, the British Association of Urological Surgeons PCNL data registry of 1009 patients reported stone-free rates of 47% and 77% for staghorn and nonstaghorn calculi, respectively, using less stringent criteria.29 Our study has several limitations. It was a retrospective review with an inherent bias in treatment selection and follow-up. There was an absence of any uniform treatment protocol. Because of the small number of patients, we were unable to analyze effects of any specific preventive medication on stone activity. Although all the patients had NCCT or IVU, there was no uniformity to the imaging modalities used to diagnose and follow these patients, which affected the sensitivity and specificity of results. Conclusions Patients with struvite stones are a medically complex population of patients who need aggressive endourologic and medical treatement with continued clinical and radiologic surveillance. We validated that rendering patients stone free after PCNL followed by preventive medical therapy offers the best likelihood of avoiding stone recurrence or stone adverse events. Preoperative stone burden of greater than 10 cm2, residual stone size > 0.4 cm2, and the presence of patient-related comorbidities are independent risk factors for poor outcomes.
IQBAL ET AL. AHA can be associated with significant side effects in patients and should be used at a reduced dosage. With combined surgical and medical treatment as well as appropriate followup, stable renal function can be maintained in the majority of patients. Disclosure Statement Michael E. Lipkin is a consultant for Boston Scientific; Michael N. Ferrandino is a proctor for Intuitive Surgical. For the remaining authors, no competing financial interests exist. References 1. Levy FL, Adams-Huet B, Pak CY. Ambulatory evaluation of nephrolithiasis: An update of a 1980 protocol. Am J Med 1995;98:50–59. 2. Griffith DP, Musher DM. Prevention of infected urinary stones by urease inhibition. Invest Urol 1973;11:228–L33. 3. Koga S, Arakaki Y, Matsuoka M, Ohyama C. Staghorn calculi—long-term results of management. Br J Urol 1991;68: 122–124. 4. Cohen TD, Preminger GM. Struvite calculi. Semin Nephrol 1996;14:425–434. 5. Lerner SP, Gleeson MJ, Griffith DP. Infection stones. J Urol 1989;141:753–758. 6. Blandy JP, Singh M. The case for a more aggressive approach to staghorn stones. J Urol 1976;115:505–506. 7. Patterson DE, Segura JW, LeRoy AJ. Long-term follow-up of patients treated by percutaneous ultrasonic lithotripsy for struvite staghorn calculi. J Endourol 1987;1:177–180. 8. Streem SB. Long-term incidence and risk factors for recurrent stones following percutaneous nephrostolithotomy or percutaneous nephrostolithotomy/extracorporeal shock wave lithotripsy for infection related calculi. J Urol 1995;153: 584–587. 9. Michaels EK, Fowler JE Jr. Extracorporeal shock wave lithotripsy for struvite renal calculi: Prospective study with extended followup. J Urol 1991;146:728–732. 10. Griffith DP, Gleeson MJ, Lee H, et al. Randomized, doubleblind trial of Lithostat (acetohydroxamic acid) in the palliative treatment of infection-induced urinary calculi. Eur Urol 1991;20:243–247. 11. Griffith DP, Khonsari F, Skurnick JH, James KE. A randomized trial of acetohydroxamic acid for the treatment and prevention of infection-induced urinary stones in spinal cord injury patients. J Urol 1988;140:318–324. 12. Rodman JS, Williams JJ, Jones RL. Hypercoagulability produced by treatment with acetohydroxamic acid. Clin Pharmacol Ther 1987;42:346–350. 13. Levey AS, Greene T, Kusek JW, Beck GJ. A simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol 2000;11:155A. 14. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 2002;39(suppl 1):S1–S266. 15. Smith MJ, Boyce WH. Anatrophic nephrotomy and plastic calyrhaphy. J Urol 1968;99:521–527. 16. Stubbs AJ, Resnick MI, Boyce WH. Anatrophic nephrolithotomy in the solitary kidney. J Urol 1978;119: 457–460. 17. Williams JJ, Rodman JS, Peterson CM. A randomized double-blind study of acetohydroxamic acid in struvite nephrolithiasis. N Engl J Med 1984;311:760–764.
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Address correspondence to: Michael E. Lipkin, MD Division of Urologic Surgery Duke University Medical Center DUMC 3167 Durham, NC 27710 E-mail: [email protected]
Abbreviations Used AHA ¼ acetohydroxamic acid BMI ¼ body mass index CKD ¼ chronic kidney disease DVT ¼ deep venous thrombosis eGFR ¼ estimated glomerular filtration rate IVU ¼ intravenous urography KUB ¼ kidneys, ureters, and bladder NCCT ¼ noncontrast computed tomography PCNL ¼ percutaneous nephrolithotomy PE ¼ pulmonary embolism RTA ¼ renal tubular acidosis SWL ¼ shockwave lithotripsy URS ¼ ureteroscopy UTI ¼ urinary tract infection
