EURURO-6264; No. of Pages 7 EUROPEAN UROLOGY XXX (2015) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Stone Disease Editorial by XXX on pp. x–y of this issue
Does Stepwise Voltage Ramping Protect the Kidney from Injury During Extracorporeal Shockwave Lithotripsy? Results of a Prospective Randomized Trial Veronika Skuginna y, Daniel P. Nguyen y, Roland Seiler, Bernhard Kiss, George N. Thalmann, Beat Roth * Department of Urology, University of Bern, Bern, Switzerland
Article info
Abstract
Article history: Accepted June 14, 2015
Background: Renal damage is more frequent with new-generation lithotripters. However, animal studies suggest that voltage ramping minimizes the risk of complications following extracorporeal shock wave lithotripsy (SWL). In the clinical setting, the optimal voltage strategy remains unclear. Objective: To evaluate whether stepwise voltage ramping can protect the kidney from damage during SWL. Design, setting, and participants: A total of 418 patients with solitary or multiple unilateral kidney stones were randomized to receive SWL using a Modulith SLX-F2 lithotripter with either stepwise voltage ramping (n = 213) or a fixed maximal voltage (n = 205). Intervention: SWL. Outcomes measurements and statistical analysis: The primary outcome was sonographic evidence of renal hematomas. Secondary outcomes included levels of urinary markers of renal damage, stone disintegration, stone-free rate, and rates of secondary interventions within 3 mo of SWL. Descriptive statistics were used to compare clinical outcomes between the two groups. A logistic regression model was generated to assess predictors of hematomas. Results and limitations: Significantly fewer hematomas occurred in the ramping group (12/213, 5.6%) than in the fixed group (27/205, 13%; p = 0.008). There was some evidence that the fixed group had higher urinary b2-microglobulin levels after SWL compared to the ramping group (p = 0.06). Urinary microalbumin levels, stone disintegration, stone-free rate, and rates of secondary interventions did not significantly differ between the groups. The logistic regression model showed a significantly higher risk of renal hematomas in older patients (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.00–1.05; p = 0.04). Stepwise voltage ramping was associated with a lower risk of hematomas (OR 0.39, 95% CI 0.19–0.80; p = 0.01). The study was limited by the use of ultrasound to detect hematomas. Conclusions: In this prospective randomized study, stepwise voltage ramping during SWL was associated with a lower risk of renal damage compared to a fixed maximal voltage without compromising treatment effectiveness. Patient summary: Lithotripsy is a noninvasive technique for urinary stone disintegration using ultrasonic energy. In this study, two voltage strategies are compared. The results show that a progressive increase in voltage during lithotripsy decreases the risk of renal hematomas while maintaining excellent outcomes. Trial registration: ISRCTN95762080 # 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: Christian Gratzke Keywords: Extracorporeal shockwave lithotripsy Randomized trial Renal damage Voltage ramping
y These authors contributed equally to this work. * Corresponding author. Department of Urology, University Hospital Bern, CH-3010 Bern, Switzerland. Tel. +41 31 6323621; Fax: +41 31 6322180. E-mail address: [email protected] (B. Roth).
http://dx.doi.org/10.1016/j.eururo.2015.06.017 0302-2838/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Skuginna V, et al. Does Stepwise Voltage Ramping Protect the Kidney from Injury During Extracorporeal Shockwave Lithotripsy? Results of a Prospective Randomized Trial. Eur Urol (2015), http://dx.doi.org/10.1016/ j.eururo.2015.06.017
EURURO-6264; No. of Pages 7 2
EUROPEAN UROLOGY XXX (2015) XXX–XXX
1.
Introduction
Introduction of the Dornier HM-3 lithotripter in the early 1980s for extracorporeal shockwave lithotripsy (SWL) revolutionized the treatment of urolithiasis [1]. Major urologic associations currently recommend SWL as firstline treatment for kidney stones 0.9 0.7 0.7 >0.9 0.6 0.5 0.2 – 0.7 – –
* * *
* *
*
CI = confidence interval. x2 test; all other p values were calculated using Fischer’s exact test. a Dindo-Clavien classification. *
disintegration, rates of secondary interventions, and complications other than hematomas did not significantly differ between the groups (Table 3). The logistic regression model showed a higher risk of renal hematoma in older patients (OR 1.03, 95% CI 1.00– 1.05; p = 0.04), and stepwise voltage ramping was associated with a lower risk (OR 0.39, 95% CI 0.19–0.80; p = 0.01, Table 4). There was some evidence that BMI is associated with a higher risk of hematomas, although this did not reach significance (OR 1.06, 95% CI 0.99–1.13; p = 0.09). Of note, total energy applied to patients with and without renal hematoma did not differ within the groups (40 995 vs 40 412 kV in the ramping group, p = 0.6; 42 036 vs 41 582 kV in the fixed group, p > 0.9).
Table 4 – Univariate logistic regression analysis of variables associated with renal hematomas 24 h after shockwave lithotripsy Variable
Age Female gender Body mass index Mode of energy application Number of shockwaves
Odds ratio (95% confidence interval) 1.03 1.09 1.06 0.39 1.00
(1.00–1.05) (0.53–2.22) (0.99–1.13) (0.19–0.80) (0.999–1.001)
p value
0.04 0.8 0.09 0.01 0.4
Stone analysis was available for 114/213 (54%) patients in the ramping group and 110/205 (54%) patients in the fixed group. There was no significant difference in stone composition between the groups (p = 0.4; Supplementary Fig. 1). 4.
Discussion
Since the advent of new-generation lithotripters, the increase in the frequency of renal hematomas associated with their use, most likely because of smaller focal zones and higher peak pressures, has raised concerns among the urologic community [19]. Although rarely symptomatic, renal hematomas may have devastating long-term effects [8]. Optimization of energy protocols is therefore an area of active research. The present study, representing the largest prospective randomized clinical trial investigating the effect of the mode of voltage application, demonstrates a beneficial effect of voltage ramping on renal damage without compromising clinical effectiveness. Lambert et al [11] reported on a randomized trial comparing voltage ramping and fixed energy during SWL. Although urinary markers for renal damage were routinely collected, the study design did not determine renal hematomas as an outcome and therefore the investigators did not systemically search for them. Moreover, the trial had
Please cite this article in press as: Skuginna V, et al. Does Stepwise Voltage Ramping Protect the Kidney from Injury During Extracorporeal Shockwave Lithotripsy? Results of a Prospective Randomized Trial. Eur Urol (2015), http://dx.doi.org/10.1016/ j.eururo.2015.06.017
EURURO-6264; No. of Pages 7 EUROPEAN UROLOGY XXX (2015) XXX–XXX
only 45 patients. Nevertheless, significant changes in microalbumin and b2-microglobulin levels documented 1 wk after SWL suggested less renal damage for voltage ramping. However, no changes were seen 24 h after SWL. These results contrast with our own, as we found evidence that b2-microglobulin levels (as a marker of tubular damage [13]), but not of microalbumin (as a marker of glomerular damage [13]), were higher in the fixed group 24 h after SWL, although the difference in b2-microglobulin not reach significance (p = 0.06). Under the hypothesis that 1 d may be too short for sufficient expression of urinary markers of renal damage in urine, we cannot exclude that higher levels of both urinary b2-microglobulin and microalbumin would have been detected at a later time point in the fixed group, as shown by Lambert et al [11]. However, others have demonstrated that microalbumin and b2-microglobulin were increased 24 h after SWL [13,19,20]. The kinetic energy of SWs cause stone fragmentation mainly via tear and shear forces and cavitation, but SWs also affect the surrounding renal parenchyma [21]. This may cause tearing of vessels, resulting in subcapsular or perirenal hematoma [21]. Renal hematomas may lead to parenchymal fibrosis and subsequent functional loss analogous to that produced by blunt renal trauma [8,22]. The mechanisms underlying the protective effect of stepwise voltage ramping are not fully understood. Willis et al [9] demonstrated that low-energy pretreatment of porcine kidneys significantly reduced the size of renal hemorrhagic lesions compared to no pretreatment. The authors hypothesized that lowenergy SWs induce some degree of renal vasoconstriction, rendering vessels stiffer and less susceptible to rupture during the application of higher voltages. This hypothesis was later corroborated in studies by the same group demonstrating that pretreatment with low-energy SWs induces early renal vasoconstriction during the application of high-energy SWs [23]. By contrast, vasoconstriction occurred only after SWL if pretreatment was absent. Nevertheless, effectors causing vasoconstriction during SWL are unknown and further research is needed to elucidate the full mechanism behind the renal protective response seen during voltage ramping. We found that age constitutes a risk factor for renal hematoma, in agreement with data reported by Dhar et al [15] showing a 1.67-fold increase in the risk of renal hematomas using a Modulith SLX (Storz) lithotripter for each 10-yr increment in age [15]. Possible reasons for their findings and ours could be increased capillary fragility associated with age and other uncontrolled factors such as intake of drugs affecting hemostasis (eg, selective serotonin reuptake inhibitors) or underlying medical comorbidity. Our study also demonstrated some evidence that patients with higher BMI suffered renal hematomas more frequently. This was also shown in a retrospective study of 10 887 SWL treatment sessions on 6177 patients [16]. Obesity is a state of chronic systemic inflammation and is characterized by oxidative stress that enhances the vulnerability of the vascular basement membrane, which in turn may increase the risk of bleeding during SWL [24,25]. In view of the above findings, we argue that in
5
patients with advanced age and/or high BMI, caution should be exercised during SWL, and concomitant treatment of both kidneys should be avoided. In terms of clinical effectiveness, stepwise voltage ramping performed as well as a fixed maximal voltage. However, it should be kept in mind that the upper bound of the 95% CI for the difference in stone-free rates (10%) did not exclude a clinically relevant difference in favor of the fixed group. In vitro and in vivo studies have suggested that a progressive increase in voltage during SWL produces greater stone comminution, mainly by maintaining favorable stress-wave and cavitation bubble dynamics that leads to constant fragmentation rates [26,27]. In the study by Lambert et al [11], the ramping group achieved a stone-free rate of 81% (18/22) compared to 48% (11/23) in the fixed group [11]. The definition of stone-free was less stringent than in the present study, as patients with fragments
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Stone Disease Editorial by XXX on pp. x–y of this issue
Does Stepwise Voltage Ramping Protect the Kidney from Injury During Extracorporeal Shockwave Lithotripsy? Results of a Prospective Randomized Trial Veronika Skuginna y, Daniel P. Nguyen y, Roland Seiler, Bernhard Kiss, George N. Thalmann, Beat Roth * Department of Urology, University of Bern, Bern, Switzerland
Article info
Abstract
Article history: Accepted June 14, 2015
Background: Renal damage is more frequent with new-generation lithotripters. However, animal studies suggest that voltage ramping minimizes the risk of complications following extracorporeal shock wave lithotripsy (SWL). In the clinical setting, the optimal voltage strategy remains unclear. Objective: To evaluate whether stepwise voltage ramping can protect the kidney from damage during SWL. Design, setting, and participants: A total of 418 patients with solitary or multiple unilateral kidney stones were randomized to receive SWL using a Modulith SLX-F2 lithotripter with either stepwise voltage ramping (n = 213) or a fixed maximal voltage (n = 205). Intervention: SWL. Outcomes measurements and statistical analysis: The primary outcome was sonographic evidence of renal hematomas. Secondary outcomes included levels of urinary markers of renal damage, stone disintegration, stone-free rate, and rates of secondary interventions within 3 mo of SWL. Descriptive statistics were used to compare clinical outcomes between the two groups. A logistic regression model was generated to assess predictors of hematomas. Results and limitations: Significantly fewer hematomas occurred in the ramping group (12/213, 5.6%) than in the fixed group (27/205, 13%; p = 0.008). There was some evidence that the fixed group had higher urinary b2-microglobulin levels after SWL compared to the ramping group (p = 0.06). Urinary microalbumin levels, stone disintegration, stone-free rate, and rates of secondary interventions did not significantly differ between the groups. The logistic regression model showed a significantly higher risk of renal hematomas in older patients (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.00–1.05; p = 0.04). Stepwise voltage ramping was associated with a lower risk of hematomas (OR 0.39, 95% CI 0.19–0.80; p = 0.01). The study was limited by the use of ultrasound to detect hematomas. Conclusions: In this prospective randomized study, stepwise voltage ramping during SWL was associated with a lower risk of renal damage compared to a fixed maximal voltage without compromising treatment effectiveness. Patient summary: Lithotripsy is a noninvasive technique for urinary stone disintegration using ultrasonic energy. In this study, two voltage strategies are compared. The results show that a progressive increase in voltage during lithotripsy decreases the risk of renal hematomas while maintaining excellent outcomes. Trial registration: ISRCTN95762080 # 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: Christian Gratzke Keywords: Extracorporeal shockwave lithotripsy Randomized trial Renal damage Voltage ramping
y These authors contributed equally to this work. * Corresponding author. Department of Urology, University Hospital Bern, CH-3010 Bern, Switzerland. Tel. +41 31 6323621; Fax: +41 31 6322180. E-mail address: [email protected] (B. Roth).
http://dx.doi.org/10.1016/j.eururo.2015.06.017 0302-2838/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Skuginna V, et al. Does Stepwise Voltage Ramping Protect the Kidney from Injury During Extracorporeal Shockwave Lithotripsy? Results of a Prospective Randomized Trial. Eur Urol (2015), http://dx.doi.org/10.1016/ j.eururo.2015.06.017
EURURO-6264; No. of Pages 7 2
EUROPEAN UROLOGY XXX (2015) XXX–XXX
1.
Introduction
Introduction of the Dornier HM-3 lithotripter in the early 1980s for extracorporeal shockwave lithotripsy (SWL) revolutionized the treatment of urolithiasis [1]. Major urologic associations currently recommend SWL as firstline treatment for kidney stones 0.9 0.7 0.7 >0.9 0.6 0.5 0.2 – 0.7 – –
* * *
* *
*
CI = confidence interval. x2 test; all other p values were calculated using Fischer’s exact test. a Dindo-Clavien classification. *
disintegration, rates of secondary interventions, and complications other than hematomas did not significantly differ between the groups (Table 3). The logistic regression model showed a higher risk of renal hematoma in older patients (OR 1.03, 95% CI 1.00– 1.05; p = 0.04), and stepwise voltage ramping was associated with a lower risk (OR 0.39, 95% CI 0.19–0.80; p = 0.01, Table 4). There was some evidence that BMI is associated with a higher risk of hematomas, although this did not reach significance (OR 1.06, 95% CI 0.99–1.13; p = 0.09). Of note, total energy applied to patients with and without renal hematoma did not differ within the groups (40 995 vs 40 412 kV in the ramping group, p = 0.6; 42 036 vs 41 582 kV in the fixed group, p > 0.9).
Table 4 – Univariate logistic regression analysis of variables associated with renal hematomas 24 h after shockwave lithotripsy Variable
Age Female gender Body mass index Mode of energy application Number of shockwaves
Odds ratio (95% confidence interval) 1.03 1.09 1.06 0.39 1.00
(1.00–1.05) (0.53–2.22) (0.99–1.13) (0.19–0.80) (0.999–1.001)
p value
0.04 0.8 0.09 0.01 0.4
Stone analysis was available for 114/213 (54%) patients in the ramping group and 110/205 (54%) patients in the fixed group. There was no significant difference in stone composition between the groups (p = 0.4; Supplementary Fig. 1). 4.
Discussion
Since the advent of new-generation lithotripters, the increase in the frequency of renal hematomas associated with their use, most likely because of smaller focal zones and higher peak pressures, has raised concerns among the urologic community [19]. Although rarely symptomatic, renal hematomas may have devastating long-term effects [8]. Optimization of energy protocols is therefore an area of active research. The present study, representing the largest prospective randomized clinical trial investigating the effect of the mode of voltage application, demonstrates a beneficial effect of voltage ramping on renal damage without compromising clinical effectiveness. Lambert et al [11] reported on a randomized trial comparing voltage ramping and fixed energy during SWL. Although urinary markers for renal damage were routinely collected, the study design did not determine renal hematomas as an outcome and therefore the investigators did not systemically search for them. Moreover, the trial had
Please cite this article in press as: Skuginna V, et al. Does Stepwise Voltage Ramping Protect the Kidney from Injury During Extracorporeal Shockwave Lithotripsy? Results of a Prospective Randomized Trial. Eur Urol (2015), http://dx.doi.org/10.1016/ j.eururo.2015.06.017
EURURO-6264; No. of Pages 7 EUROPEAN UROLOGY XXX (2015) XXX–XXX
only 45 patients. Nevertheless, significant changes in microalbumin and b2-microglobulin levels documented 1 wk after SWL suggested less renal damage for voltage ramping. However, no changes were seen 24 h after SWL. These results contrast with our own, as we found evidence that b2-microglobulin levels (as a marker of tubular damage [13]), but not of microalbumin (as a marker of glomerular damage [13]), were higher in the fixed group 24 h after SWL, although the difference in b2-microglobulin not reach significance (p = 0.06). Under the hypothesis that 1 d may be too short for sufficient expression of urinary markers of renal damage in urine, we cannot exclude that higher levels of both urinary b2-microglobulin and microalbumin would have been detected at a later time point in the fixed group, as shown by Lambert et al [11]. However, others have demonstrated that microalbumin and b2-microglobulin were increased 24 h after SWL [13,19,20]. The kinetic energy of SWs cause stone fragmentation mainly via tear and shear forces and cavitation, but SWs also affect the surrounding renal parenchyma [21]. This may cause tearing of vessels, resulting in subcapsular or perirenal hematoma [21]. Renal hematomas may lead to parenchymal fibrosis and subsequent functional loss analogous to that produced by blunt renal trauma [8,22]. The mechanisms underlying the protective effect of stepwise voltage ramping are not fully understood. Willis et al [9] demonstrated that low-energy pretreatment of porcine kidneys significantly reduced the size of renal hemorrhagic lesions compared to no pretreatment. The authors hypothesized that lowenergy SWs induce some degree of renal vasoconstriction, rendering vessels stiffer and less susceptible to rupture during the application of higher voltages. This hypothesis was later corroborated in studies by the same group demonstrating that pretreatment with low-energy SWs induces early renal vasoconstriction during the application of high-energy SWs [23]. By contrast, vasoconstriction occurred only after SWL if pretreatment was absent. Nevertheless, effectors causing vasoconstriction during SWL are unknown and further research is needed to elucidate the full mechanism behind the renal protective response seen during voltage ramping. We found that age constitutes a risk factor for renal hematoma, in agreement with data reported by Dhar et al [15] showing a 1.67-fold increase in the risk of renal hematomas using a Modulith SLX (Storz) lithotripter for each 10-yr increment in age [15]. Possible reasons for their findings and ours could be increased capillary fragility associated with age and other uncontrolled factors such as intake of drugs affecting hemostasis (eg, selective serotonin reuptake inhibitors) or underlying medical comorbidity. Our study also demonstrated some evidence that patients with higher BMI suffered renal hematomas more frequently. This was also shown in a retrospective study of 10 887 SWL treatment sessions on 6177 patients [16]. Obesity is a state of chronic systemic inflammation and is characterized by oxidative stress that enhances the vulnerability of the vascular basement membrane, which in turn may increase the risk of bleeding during SWL [24,25]. In view of the above findings, we argue that in
5
patients with advanced age and/or high BMI, caution should be exercised during SWL, and concomitant treatment of both kidneys should be avoided. In terms of clinical effectiveness, stepwise voltage ramping performed as well as a fixed maximal voltage. However, it should be kept in mind that the upper bound of the 95% CI for the difference in stone-free rates (10%) did not exclude a clinically relevant difference in favor of the fixed group. In vitro and in vivo studies have suggested that a progressive increase in voltage during SWL produces greater stone comminution, mainly by maintaining favorable stress-wave and cavitation bubble dynamics that leads to constant fragmentation rates [26,27]. In the study by Lambert et al [11], the ramping group achieved a stone-free rate of 81% (18/22) compared to 48% (11/23) in the fixed group [11]. The definition of stone-free was less stringent than in the present study, as patients with fragments
