Mechanism by which shock wave lithotripsy can promote formation of human calcium phosphate stones.

Human stone calcium phosphate (CaP) content correlates with higher urine CaP supersaturation (SS) and urine pH as well as with the number of shock wave lithotripsy (SWL) treatments. SWL does damage medullary collecting ducts and vasa recta, sites for urine pH regulation. We tested the hypothesis that SWL raises urine pH and therefore Cap SS, resulting in CaP nucleation and tubular plugging. The left kidney (T) of nine farm pigs was treated with SWL, and metabolic studies were performed using bilateral ureteral catheters for up to 70 days post-SWL. Some animals were given an NH4Cl load to sort out effects on urine pH of CD injury vs. increased HCO3 (-) delivery. Histopathological studies were performed at the end of the functional studies. The mean pH of the T kidneys exceeded that of the control (C) kidneys by 0.18 units in 14 experiments on 9 pigs. Increased HCO3 (-) delivery to CD is at least partly responsible for the pH difference because NH4Cl acidosis abolished it. The T kidneys excreted more Na, K, HCO3 (-), water, Ca, Mg, and Cl than C kidneys. A single nephron site that could produce losses of all of these is the thick ascending limb. Extensive injury was noted in medullary thick ascending limbs and collecting ducts. Linear bands showing nephron loss and fibrosis were found in the cortex and extended into the medulla. Thus SWL produces tubule cell injury easily observed histopathologically that leads to functional disturbances across a wide range of electrolyte metabolism including higher than control urine pH.

Effect of renal shock wave lithotripsy on the development of metabolic syndrome in a juvenile swine model: a pilot study.

PURPOSE: We performed a pilot study to assess whether renal shock wave lithotripsy influences metabolic syndrome onset and severity. MATERIALS AND METHODS: Three-month-old juvenile female Ossabaw miniature pigs were treated with shock wave lithotripsy (2,000 shock waves at 24 kV with 120 shock waves per minute in 2) or sham shock wave lithotripsy (no shock waves in 2). Shock waves were targeted to the upper pole of the left kidney to model treatment that would also expose the pancreatic tail to shock waves. Pigs were then instrumented to directly measure arterial blood pressure via an implanted radiotelemetry device. They later received a hypercaloric atherogenic diet for about 7 months. Metabolic syndrome development was assessed by the intravenous glucose tolerance test. RESULTS: Metabolic syndrome progression and severity were similar in the sham treated and lithotripsy groups. The only exception arterial blood pressure, which remained relatively constant in sham treated pigs but began to increase at about 2 months towards hypertensive levels in lithotripsy treated pigs. Metabolic data on the 2 groups were pooled to provide a more complete assessment of metabolic syndrome development and progression in this juvenile pig model. The intravenous glucose tolerance test revealed substantial insulin resistance with impaired glucose tolerance within 2 months on the hypercaloric atherogenic diet with signs of further metabolic impairment at 7 months. CONCLUSIONS: These preliminary results suggest that renal shock wave lithotripsy is not a risk factor for worsening glucose tolerance or diabetes mellitus onset. However, it appears to be a risk factor for early onset hypertension in metabolic syndrome.

Shock wave lithotripsy targeting of the kidney and pancreas does not increase the severity of metabolic syndrome in a porcine model.

PURPOSE: We determined whether shock wave lithotripsy of the kidney of pigs with metabolic syndrome would worsen glucose tolerance or increase the risk of diabetes mellitus. MATERIALS AND METHODS: Nine-month-old female Ossabaw miniature pigs were fed a hypercaloric atherogenic diet to induce metabolic syndrome. At age 15 months the pigs were treated with 2,000 or 4,000 shock waves (24 kV at 120 shock waves per minute) using an unmodified HM3 lithotripter (Dornier MedTech, Kennesaw, Georgia). Shock waves were targeted to the left kidney upper pole calyx to model treatment that would also expose the pancreatic tail to shock waves. The intravenous glucose tolerance test was done in conscious fasting pigs before lithotripsy, and 1 and 2 months after lithotripsy with blood samples taken for glucose and insulin measurement. RESULTS: Pigs fed the hypercaloric atherogenic diet were obese, dyslipidemic, insulin resistant and glucose intolerant, consistent with metabolic syndrome. Assessments of insulin resistance, glucose tolerance and pancreatic ß cell function from fasting plasma glucose and insulin levels, and the glucose and insulin response profile to the intravenous glucose tolerance test were similar before and after lithotripsy. CONCLUSIONS: The metabolic syndrome status of pigs treated with shock wave lithotripsy was unchanged 2 months after kidney treatment with 2,000 high amplitude shock waves or overtreatment with 4,000 high amplitude shock waves. These findings do not support a single shock wave lithotripsy treatment of the kidney as a risk factor for the onset of diabetes mellitus.

Optimising an escalating shockwave amplitude treatment strategy to protect the kidney from injury during shockwave lithotripsy.

UNLABELLED: Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Animal studies have shown that one approach to reduce SWL-induced renal injury is to pause treatment for 3-4 min early in the SWL-treatment protocol. However, there is typically no pause in treatment during clinical lithotripsy. We show in a porcine model that a pause in SWL treatment is unnecessary to achieve a reduction in renal injury if treatment is begun at a low power setting that generates low-amplitude SWs, and given continuously for ≈ 4 min before applying higher-amplitude SWs. OBJECTIVE: • To test the idea that a pause (≈ 3 min) in the delivery of shockwaves (SWs) soon after the initiation of SW lithotripsy (SWL) is unnecessary for achieving a reduction in renal injury, if treatment is begun at a low power setting that generates low-amplitude SWs. MATERIALS AND METHODS: • Anaesthetised female pigs were assigned to one of three SWL treatment protocols that did not involve a pause in SW delivery of >10 s (2000 SWs at 24 kV; 100 SWs at 12 kV + ≈ 10-s pause + 2000 SWs at 24 kV; 500 SWs at 12 kV + ≈ 10-s pause + 2000 SWs at 24 kV). • All SWs were delivered at 120 SWs/min using an unmodified Dornier HM3 lithotripter. • Renal function was measured before and after SWL. • The kidneys were then processed for quantification of the SWL-induced haemorrhagic lesion. Values for lesion size were compared to previous data collected from pigs in which treatment included a 3-min pause in SW delivery. RESULTS: • All SWL treatment protocols produced a similar degree of vasoconstriction (23-41% reduction in glomerular filtration rate and effective renal plasma flow) in the SW-treated kidney. • The mean renal lesion in pigs treated with 100 low-amplitude SWs delivered before the main dose of 2000 high-amplitude SWs (2.27% functional renal volume [FRV]) was statistically similar to that measured for pigs treated with 2000 SWs all at high-amplitude (3.29% FRV). • However, pigs treated with 500 low-amplitude SWs before the main SW dose had a significantly smaller lesion (0.44% FRV) that was comparable with the lesion in pigs from a previous study in which there was a 3-min pause in treatment separating a smaller initial dose of 100 low-amplitude SWs from the main dose of 2000 high-amplitude SWs (0.46% FRV). The time between the initiation of the low - and high-amplitude SWs was ≈ 4 min for these latter two groups compared with ≈ 1 min when there was negligible pause after the initial 100 low-amplitude SWs in the protocol. CONCLUSIONS: • Pig kidneys treated by SWL using a two-step low-to-high power ramping protocol were protected from injury with negligible pause between steps, provided the time between the initiation of low-amplitude SWs and switching to high-amplitude SWs was ≈ 4 min. • Comparison with results from previous studies shows that protection can be achieved using various step-wise treatment scenarios in which either the initial dose of SWs is delivered at low-amplitude for ≈ 4 min, or there is a definitive pause before resuming SW treatment at higher amplitude. • Thus, we conclude that renal protection can be achieved without instituting a pause in SWL treatment. It remains prudent to consider that renal protection depends on the acoustic and temporal properties of SWs administered at the beginning stages of a SWL ramping protocol, and that this may differ according to the lithotripter being used.

Evaluation of shock wave lithotripsy injury in the pig using a narrow focal zone lithotriptor.

UNLABELLED: What's known on the subject? and What does the study add? Of all the SW lithotriptors manufactured to date, more research studies have been conducted on and more is known about the injury (both description of injury and how to manipulate injury size) produced by the Dornier HM-3 than any other machine. From this information have come suggestions for treatment protocols to reduce shock wave (SW)-induced injury for use in stone clinics. By contrast, much less is known about the injury produced by narrow-focus and high-pressure lithotriptors like the Storz Modulith SLX. In fact, a careful study looking at the morphology of the injury produced by the SLX itself is lacking, as is any study exploring ways to reduce renal injury by manipulating SW delivery variables of this lithotriptor. The present study quantitates the lesion size and describes the morphology of the injury produced by the SLX. In addition, we report that reducing the SW delivery rate, a manoeuvre known to lower injury in the HM-3, does not reduce lesion size in the SLX. OBJECTIVE: • To assess renal injury in a pig model after treatment with a clinical dose of shock waves using a narrow focal zone (≈3 mm) lithotriptor (Modulith SLX, Karl Storz Lithotripsy). MATERIALS AND METHODS: • The left kidney of anaesthetized female pigs were treated with 2000 or 4000 shock waves (SWs) at 120 SWs/min, or 2000 SWs at 60 SWs/min using the Storz SLX. • Measures of renal function (glomerular filtration rate and renal plasma flow) were collected before and 1 h after shock wave lithotripsy (SWL) and the kidneys were harvested for histological analysis and morphometric quantitation of haemorrhage in the renal parenchyma with lesion size expressed as a percentage of functional renal volume (FRV). • A fibre-optic probe hydrophone was used to determine acoustic output and map the focal width of the lithotriptor. • Data for the SLX were compared with data from a previously published study in which pigs of the same age (7-8 weeks) were treated (2000 SWs at 120 or 60 SWs/min) using an unmodified Dornier HM3 lithotriptor. RESULTS: • Treatment with the SLX produced a highly focused lesion running from cortex to medulla and often spanning the full thickness of the kidney. Unlike the diffuse interstitial haemorrhage observed with the HM3, the SLX lesion bore a blood-filled core of near-complete tissue disruption devoid of histologically recognizable kidney structure. • Despite the intensity of tissue destruction at the core of the lesion, measures of lesion size based on macroscopic determination of haemorrhage in the parenchyma were not significantly different from kidneys treated using the HM3 (2000 SWs, 120 SWs/min: SLX, 1.86 ± 0.52% FRV; HM3, 3.93 ± 1.29% FRV). • Doubling the SW dose of the SLX from 2000 to 4000 SWs did not significantly increase lesion size. In addition, slowing the firing rate of the SLX to 60 SWs/min did not reduce the size of the lesion (2.16 ± 0.96% FRV) compared with treatment at 120 SWs/min, as was the case with the HM3 (0.42 ± 0.23% FRV vs 3.93 ± 1.29% FRV). • Renal function fell significantly below baseline in all treated groups but was similar for both lithotriptors. • Focal width of the SLX (≈2.6 mm) was about one-third that of the HM3 (≈8 mm) while peak pressures were higher (SLX at power level 9: P+≈90 MPa, P-≈-12 MPa; HM3 at 24 kV: P+≈46 MPa, P-≈-8 MPa). CONCLUSIONS: • The lesion produced by the SLX (narrow focal width, high acoustic pressure) was a more focused, more intense form of tissue damage than occurs with the HM3. • Slowing the SW rate to 60 SWs/min, a strategy shown to be effective in reducing injury with the HM3, was not protective with the SLX. • These findings suggest that the focal width and acoustic output of a lithotriptor affect the renal response to SWL.

Effect of shock wave number on renal oxidative stress and inflammation.

OBJECTIVE To determine if the magnitude of the acute injury response to shock-wave lithotripsy (SWL) depends on the number of SWs delivered to the kidney, as SWL causes acute renal oxidative stress and inflammation which are most severe in the portion of the kidney within the focal zone of the lithotripter. MATERIALS AND METHODS Pigs (7-8 weeks old) received 500, 1000 or 2000 SWs at 24 kV from a lithotripter to the lower pole calyx of one kidney. At 4 h after treatment the kidneys were removed, and samples of cortex and medulla were frozen for analysis of the cytokine, interleukin-6, and for the stress response protein, heme oxygenase-1 (HO-1). Urine samples taken before and after treatment were analysed for the inflammatory cytokine, tumour necrosis factor-α. For comparison, we included previously published cytokine data from pigs exposed to sham treatment. RESULTS Treatment with either 1000 or 2000 SWs caused a significant induction of HO-1 in the renal medulla within the focal zone of the lithotripter (F2, 1000 SWs, P < 0.05; 2000 SWs, P < 0.001). Interleukin-6 was also significantly elevated in the renal medulla of the pigs that received either 1000 or 2000 SWs (P < 0.05 and <0.001, respectively). Linear dose-response modelling showed a significant correlation between the HO-1 and interleukin-6 responses with SW dose (P < 0.001). Urinary excretion of tumour necrosis factor-α from the lithotripsy-treated kidney increased only for pigs that received 2000 SWs (P < 0.05). CONCLUSION The magnitude of renal oxidative stress and inflammatory response in the medulla increased with the number of SWs. However, it is not known if the HO-1 response is beneficial or deleterious; determining that will inform us whether SWL-induced renal injury can be assessed by quantifying markers of oxidative stress and inflammation.

Pretreatment with low-energy shock waves reduces the renal oxidative stress and inflammation caused by high-energy shock wave lithotripsy.

The purpose of this study was to determine if pretreatment of porcine kidneys with low-energy shock waves (SWs) prior to delivery of a clinical dose of 2,000 SWs reduces or prevents shock wave lithotripsy (SWL)-induced acute oxidative stress and inflammation in the treated kidney. Pigs (7-8 weeks old) received 2,000 SWs at 24 kV (120 SW/min) with or without pretreatment with 100 SWs at 12 kV/2 Hz to the lower pole calyx of one kidney using the HM3. Four hours post-treatment, selected samples of renal tissue were frozen for analysis of cytokine, interleukin-6 (IL-6), and stress response protein, heme oxygenase-1 (HO-1). Urine samples were taken before and after treatment for analysis of tumor necrosis factor-α (TNF-α). Treatment with 2,000 SWs with or without pretreatment caused a statistically significant elevation of HO-1 and IL-6 in the renal medulla localized to the focal zone of the lithotripter. However, the increase in HO-1 and IL-6 was significantly reduced using the pretreatment protocol compared to no pretreatment. Urinary excretion of TNF-α increased significantly (p < 0.05) from baseline for pigs receiving 2,000 SWs alone; however, this effect was completely abolished with the pretreatment protocol. We conclude that pretreatment of the kidney with a low dose of low-energy SWs prior to delivery of a clinical dose of SWs reduces, but does not completely prevent, SWL-induced acute renal oxidative stress and inflammation.

Renal functional effects of simultaneous bilateral single-tract percutaneous access in pigs.

OBJECTIVE: To present our findings of simultaneous bilateral percutaneous nephrolithotomy (sbPCNL) on bilateral renal haemodynamic and excretory function in an in vivo pig model, as despite sbPCNL being a treatment strategy for patients with bilateral renal stones, the functional response of both kidneys to such a procedure is unknown. MATERIALS AND METHODS: Nine anaesthetized female pigs ( approximately 70 kg) had a single-tract PCNL procedure in the left kidney and then the right kidney in one session (sbPCNL). Percutaneous access was achieved by a 30 F balloon dilator system. Bilateral renal function was measured before, 1.5 and 4.5 h after sbPCNL and included glomerular filtration rate (GFR), effective renal plasma flow (RPF), renal extraction of para-aminohippurate (EPAH, a measure of the efficiency of tubular organic anion transport), urine flow (UV), absolute sodium excretion (UNaV) and fractional sodium excretion (FENa). RESULTS: Both kidneys had similar baseline haemodynamic and excretory function, and showed comparable changes after sbPCNL. Bilateral GFR and RPF decreased by approximately 35% at 1.5 and 4.5 h after sbPCNL; EPAH was reduced to a similar degree in both kidneys at 1.5 h after sbPCNL and remained depressed throughout the observation period; bilateral UV and UNaV progressively decreased by approximately 30% and approximately 60% at 1.5 and 4.5 h after sbPCNL, respectively; bilateral FENa did not significantly change at 1.5 h after sbPCNL but decreased significantly by approximately 50% at 4.5 h. CONCLUSIONS: Both kidneys responded in a similar fashion after sbPCNL, with declines in haemodynamic and excretory function. These bilateral functional responses were comparable to those previously reported after unilateral PCNL, and help to reduce concerns that PCNL of both kidneys in one session could lead to greater functional complications, at least acutely.

A chronic outcome of shock wave lithotripsy is parenchymal fibrosis.

Shock wave lithotripsy (SWL) is widely viewed as an effective noninvasive method to break stones within the kidney and ureter. However, it is a technology that is not without trauma to the kidney--acute vascular, tubular and interstitial damage is often reported that if severe enough can lead to renal fibrosis (scarring) and permanent loss of functional parenchyma. These chronic changes can potentially lead to serious long-term adverse effects. The risk of developing chronic fibrotic lesions after lithotripsy is influenced by the number of shock waves (SWs) administered, SW power, rate of SW delivery and the number of SWL treatment sessions. The interplay between these risk factors is largely unknown, but progress has been made in identifying SWL protocols and pharmacologic therapies that can ameliorate the acute and chronic tissue damage that is an unintended consequence of SWL treatment.

In Vivo Renal Tubule pH in Stone-Forming Human Kidneys.

Introduction: There is evidence that patients with a history of ileostomies, who produce acidic urine and form uric acid or calcium oxalate stones, may plug some collecting ducts with calcium phosphate (CaP) and urate crystals. This is a paradoxical finding as such minerals should not form at an acid pH. One possible explanation is the presence of acidification defects due to focal damage to inner medullary collecting duct and Bellini duct (BD) cells. We sought to further investigate this hypothesis through direct measurement of ductal pH in dilated BDs in patients with ileostomies undergoing percutaneous nephrolithotomy (PCNL) for stone removal. Methods: After obtaining institutional review board approval, we used a fiber-optic pH microsensor with a 140-µm-diameter tip to measure intraluminal pH from the bladder, saline irrigant, and dilated BDs of patients undergoing PCNL. Results: Measurements were taken from three patients meeting inclusion criteria. Measured pH of bladder urine ranged from 4.97 to 5.58 and pH of saline irrigant used during surgery ranged from 5.17 to 5.75. BD measurements were achieved in 11 different BDs. Mean intraductal BD pH was more than 1 unit higher than bulk urine (6.43 ± 0.22 vs 5.31 ± 0.22, p < 0.01). Conclusions: This is the first evidence for focal acidification defects within injured/dilated BDs of human kidneys producing highly acidic bulk phase urine. These results may help explain the paradoxical finding of CaP and urate plugs in dilated ducts of patients with stone-forming diseases characterized by highly acidic urine.

Assessment of renal injury with a clinical dual head lithotriptor delivering 240 shock waves per minute.

PURPOSE: Lithotriptors with 2 treatment heads deliver shock waves along separate paths. Firing 1 head and then the other in alternating mode has been suggested as a strategy to treat stones twice as rapidly as with conventional shock wave lithotripsy. Because the shock wave rate is known to have a role in shock wave lithotripsy induced injury, and given that treatment using 2 separate shock wave sources exposes more renal tissue to shock wave energy than treatment with a conventional lithotriptor, we assessed renal trauma in pigs following treatment at rapid rate (240 shock waves per minute and 120 shock waves per minute per head) using a Duet lithotriptor (Direx Medical Systems, Petach Tikva, Israel) fired in alternating mode. MATERIALS AND METHODS: Eight adult female pigs (Hardin Farms, Danville, Indiana) each were treated with sham shock wave lithotripsy or 2,400 shock waves delivered in alternating mode (1,200 shock waves per head, 120 shock waves per minute per head and 240 shock waves per minute overall at a power level of 10) to the lower renal pole. Renal functional parameters, including glomerular filtration rate and effective renal plasma flow, were determined before and 1 hour after shock wave lithotripsy. The kidneys were perfusion fixed in situ and the hemorrhagic lesion was quantified as a percent of functional renal volume. RESULTS: Shock wave treatment resulted in no significant change in renal function and the response was similar to the functional response seen in sham shock wave treated animals. In 6 pigs treated with alternating mode the renal lesion was small at a mean +/- SEM of 0.22% +/- 0.09% of functional renal volume. CONCLUSIONS: Kidney tissue and function were minimally affected by a clinical dose of shock waves delivered in alternating mode (120 shock waves per minute per head and 240 shock waves per minute overall) with a Duet lithotriptor. These observations decrease concern that dual head lithotripsy at a rapid rate is inherently dangerous.

Effect of initial shock wave voltage on shock wave lithotripsy-induced lesion size during step-wise voltage ramping.

OBJECTIVE: To determine if the starting voltage in a step-wise ramping protocol for extracorporeal shock wave lithotripsy (SWL) alters the size of the renal lesion caused by the SWs. MATERIALS AND METHODS: To address this question, one kidney from 19 juvenile pigs (aged 7-8 weeks) was treated in an unmodified Dornier HM-3 lithotripter (Dornier Medical Systems, Kennesaw, GA, USA) with either 2000 SWs at 24 kV (standard clinical treatment, 120 SWs/min), 100 SWs at 18 kV followed by 2000 SWs at 24 kV or 100 SWs at 24 kV followed by 2000 SWs at 24 kV. The latter protocols included a 3-4 min interval, between the 100 SWs and the 2000 SWs, used to check the targeting of the focal zone. The kidneys were removed at the end of the experiment so that lesion size could be determined by sectioning the entire kidney and quantifying the amount of haemorrhage in each slice. The average parenchymal lesion for each pig was then determined and a group mean was calculated. RESULTS: Kidneys that received the standard clinical treatment had a mean (sem) lesion size of 3.93 (1.29)% functional renal volume (FRV). The mean lesion size for the 18 kV ramping group was 0.09 (0.01)% FRV, while lesion size for the 24 kV ramping group was 0.51 (0.14)% FRV. The lesion size for both of these groups was significantly smaller than the lesion size in the standard clinical treatment group. CONCLUSIONS: The data suggest that initial voltage in a voltage-ramping protocol does not correlate with renal damage. While voltage ramping does reduce injury when compared with SWL with no voltage ramping, starting at low or high voltage produces lesions of the same approximate size. Our findings also suggest that the interval between the initial shocks and the clinical dose of SWs, in our one-step ramping protocol, is important for protecting the kidney against injury.

Pretreatment with low-energy shock waves induces renal vasoconstriction during standard shock wave lithotripsy (SWL): a treatment protocol known to reduce SWL-induced renal injury.

OBJECTIVE: To test the hypothesis that the pretreatment of the kidney with low-energy shock waves (SWs) will induce renal vasoconstriction sooner than a standard clinical dose of high-energy SWs, thus providing a potential mechanism by which the pretreatment SW lithotripsy (SWL) protocol reduces tissue injury. MATERIALS AND METHODS: Female farm pigs (6-weeks-old) were anaesthetized with isoflurane and the lower pole of the right kidney treated with SWs using a conventional electrohydraulic lithotripter (HM3, Dornier GmbH, Germany). Pulsed Doppler ultrasonography was used to measure renal resistive index (RI) in blood vessels as a measure of resistance/impedance to blood flow. RI was recorded from one intralobar artery located in the targeted pole of the kidney, and measurements taken from pigs given sham SW treatment (Group 1; no SWs, four pigs), a standard clinical dose of high-energy SWs (Group 2; 2000 SWs, 24 kV, 120 SWs/min, seven pigs), low-energy SW pretreatment followed by high-energy SWL (Group 3; 500 SWs, 12 kV, 120 SWs/min + 2000 SWs, 24 kV, 120 SWs/min, eight pigs) and low-energy SW pretreatment alone (Group 4; 500 SWs, 12 kV, 120 SWs/min, six pigs). RESULTS: Baseline RI (approximately 0.61) was similar for all groups. Pigs receiving sham SW treatment (Group 1) had no significant change in RI. A standard clinical dose of high-energy SWs (Group 2) did not significantly alter RI during treatment, but did increase RI at 45 min after SWL. Low-energy SWs did not alter RI in Group 3 pigs, but subsequent treatment with a standard clinical dose of high-energy SWs resulted in a significantly earlier (at 1000 SWs) and greater (two-fold) rise in RI than that in Group 2 pigs. This rise in RI during the low/high-energy SWL protocol was not due to a delayed vasoconstrictor response of pretreatment, as low-energy SW treatment alone (Group 4) did not increase RI until 65 min after SWL. CONCLUSIONS: The pretreatment protocol induces renal vasoconstriction during the period of SW application whereas the standard protocol shows vasoconstriction occurring after SWL. Thus, the earlier and greater rise in RI during the pretreatment protocol may be causally associated with a reduction in tissue injury.

Localization of renal oxidative stress and inflammatory response after lithotripsy.

OBJECTIVE To determine if the acute renal oxidative stress and inflammation after extracorporeal shock wave lithotripsy (ESWL), thought to be mediated by ischaemia, is most severe in the portion of the kidney within the focal zone of the lithotripter, and if these effects result primarily from ischaemic injury. MATERIALS AND METHODS Pigs (7-8-weeks old) received either 2000 shock waves at 24 kV to the lower-pole calyx of one kidney or unilateral renal ischaemia for 1 h. A third group (sham) received no treatment. Timed urine and blood samples were taken for analysis of lipid peroxidation and the inflammatory cytokines, tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). At 4 h after treatment, kidneys were removed and samples of cortex and medulla were frozen for analysis of cytokines and heme oxygenase-1 (HO-1). RESULTS ESWL did not affect urinary excretion of malondialdehyde, but did elicit an eight-fold induction of HO-1 in the portion of the renal medulla within the focal zone of the lithotripter (F2), while remaining unchanged elsewhere in the treated kidney. There was no induction of HO-1 in renal tissue after ischaemia-reperfusion. Urinary excretion of TNF-alpha increased from the lithotripsy-treated kidney by 1 h after treatment, but was unaffected by ischaemia-reperfusion. As with the HO-1 response after lithotripsy, IL-6 increased only in the renal medulla at F2. By contrast, ischaemia-reperfusion increased IL-6 in all samples from the treated kidney. CONCLUSION These findings show that the acute oxidative stress and inflammatory responses to ESWL are localized to the renal medulla at F2. Furthermore, the differing patterns of markers of injury for ESWL and ischaemia-reperfusion suggest that ischaemia is not the principal cause of the injury response after ESWL.

Extracorporeal shock wave lithotripsy at 60 shock waves/min reduces renal injury in a porcine model.

OBJECTIVE: To determine if extracorporeal shock wave lithotripsy (ESWL) at 60 shock waves (SWs)/min reduces renal damage and haemodynamic impairment compared to treatment at 120 SWs/min. MATERIALS AND METHODS: One kidney in each of 19 juvenile pigs (7-8 weeks old) was treated at 120 or at 60 SWs/min (2000 SWs, 24 kV) with an unmodified HM-3 lithotripter (Dornier Medical Systems, Kennesaw, GA, USA). Renal function was determined before and after ESWL treatment by inulin clearance, extraction and clearance of para-aminohippuric acid. Both kidneys were then removed to measure parenchymal lesion size by sectioning the entire kidney and quantifying the size of the haemorrhagic lesion in each slice. RESULTS: ESWL at 60 SWs/min significantly reduced the size of the acute morphological lesion compared to 120 SWs/min (0.42% vs 3.93% of functional renal volume, P = 0.011) and blunted the decrease in glomerular filtration rate and renal plasma flow normally seen after treatment at 120 SWs/min. CONCLUSIONS: Treatment at a firing rate of 60 SWs/min produces less morphological injury and causes less alteration in renal haemodynamics than treatment at 120 SWs/min in the pig model of ESWL-induced renal injury.

Independent assessment of a wide-focus, low-pressure electromagnetic lithotripter: absence of renal bioeffects in the pig.

OBJECTIVE: To assess the renal injury response in a pig model treated with a clinical dose of shock waves (SWs) delivered at a slow rate (27 SW/min) using a novel wide focal zone (18 mm), low acoustic pressure (<20 MPa) electromagnetic lithotripter (Xi Xin-Eisenmenger, XX-ES; Xi Xin Medical Instruments Co. Ltd., Suzhou, PRC). MATERIALS AND METHODS: The left kidneys of anaesthetized female pigs were treated with 1500 SWs from either an unmodified electrohydraulic lithotripter (HM3, Dornier MedTech America, Inc., Kennesaw, GA, USA; 18 kV, 30 SW/min) or the XX-ES (9.3 kV, 27 SW/min). Measures of renal function (glomerular filtration rate, GFR, and renal plasma flow) were collected before and after SW lithotripsy, and kidneys were harvested for histological quantification of vascular haemorrhage, expressed as a percentage of the functional renal volume (FRV). A fibre-optic probe hydrophone was used to characterize the acoustic field, and the breakage of gypsum model stones was used to compare the function of the two lithotripters. RESULTS: Kidneys treated with the XX-ES showed no significant change in renal haemodynamic function and no detectable tissue injury. Pigs treated with the HM3 had a modest decline from baseline ( approximately 20%) in both GFR (P > 0.05) and renal plasma flow (P = 0.064) in the treated kidney, but that was not significantly different from the control group. Although most HM3-treated pigs showed no evidence of renal tissue injury, two had focal injury measuring 0.1% FRV, localized to the renal papillae. The width of the focal zone for the XX-ES was approximately 18 mm and that of the HM3 approximately 8 mm. Peak positive pressures at settings used to treat pigs and break model stones were considerably lower for the XX-ES (17 MPa at 9.3 kV) than for the HM3 (37 MPa at 18 kV). The XX-ES required fewer SWs to break stones to completion than did the HM3, with a mean (sd) of 634 (42) and 831 (43) SWs, respectively (P < 0.01). However, conditions were different for these tests because of differences in physical configuration of the two machines. CONCLUSION: The absence of renal injury with the wide focal zone XX-ES lithotripter operated at low shock pressure and a slow SW rate suggests that this lithotripter would be safe when used at the settings recommended for patient treatment. That the injury was also minimal using the Dornier HM3 lithotripter at a slow SW rate implies that the reduced tissue injury seen with these two machines was because they were operated at a slow SW rate. As recent studies have shown stone breakage to be improved when the focal zone is wider than the stone, a wide focal zone lithotripter operated at low pressure and slow rate has the features necessary to provide better stone breakage with less tissue injury.

Potential for cavitation-mediated tissue damage in shockwave lithotripsy.

PURPOSE: Shockwave lithotripsy (SWL) injures renal tissue, and cavitation has been reported to mediate some of these effects. Much of the work characterizing the cavitation injury of SWL has been performed in small animals or in vitro. We describe experiments that promote cavitation during SWL and estimate the spatial distribution of the resulting hemorrhagic lesion in a large-animal (porcine) model of clinical lithotripsy. MATERIALS AND METHODS: The lower pole calix of the left kidney in female farm pigs was targeted for SWL with a Dornier HM3 lithotripter. Intraventricular injections of polystyrene microspheres were made before and at intervals during lithotripsy to blanket systemic circulation with cavitation nuclei. Following SWL, the abdominal viscera were inspected and the kidneys were processed for morphologic analysis. RESULTS: Extensive surface hemorrhage occurred over both the targeted and contralateral kidneys, along with widespread petechial hemorrhage over the spleen, intestines, and peritoneum. The targeted kidneys developed subcapsular hematomas. Histology revealed focal and diffuse damage to the targeted kidneys and vascular rupture in both kidneys with complete necrosis of the walls of intralobular arteries and veins. CONCLUSIONS: These results demonstrate the potential for unfocused shockwaves to damage blood vessels outside the focal zone of the lithotripter when the vasculature is seeded with cavitation nuclei. The wide distribution of damage suggests that the acoustic field of a lithotripter delivers negative pressures that exceed the cavitation threshold far off the acoustic axis. The findings underscore that conditions permissive for cavitation can lead to dramatic sequelae during SWL.

Preliminary Report on Stone Breakage and Lesion Size Produced by a New Extracorporeal Electrohydraulic (Sparker Array) Discharge Device.

OBJECTIVE: To determine if an innovative extracorporeal electrohydraulic shock wave (SW) device (sparker array [SPA]) can effectively fracture artificial stones in vitro and in vivo, and if SPA treatment produces a renal lesion in our pig model of lithotripsy injury. Results of these experiments will be used to help evaluate the suitability of this device as a clinical lithotripter. MATERIALS AND METHODS: Ultracal-30 artificial stones were placed in a holder at the focus of the SPA and treated with 600 SWs (21.6 kV, 60 shocks/min). Stone fragments were collected, dried, and weighed to determine stone breakage. In vivo stone breakage entailed implanting stones into pigs. These stones were treated with 600 or 1200 SWs and the fragments were collected for analysis. Lesion analysis consisted of treating the left kidney of pigs with 1200 or 2400 SWs and quantitating the hemorrhagic lesion. RESULTS: In vitro, 71% ± 2% of each artificial stone was fractured to <2 mm in size. In vivo stone breakage averaged 63%. Renal injury analysis revealed that only 1 of 7 kidneys showed evidence of hemorrhagic injury in the treated area. CONCLUSION: The SPA consistently comminuted artificial stones demonstrating its ability to fracture stones like other lithotripters. Also, the SPA caused little to no renal injury at the settings used in this study. These findings suggest further research is warranted to determine the potential of this device as a clinical lithotripter.

Assessment of Cu-ETS as a PET radiopharmaceutical for evaluation of regional renal perfusion.

UNLABELLED: The copper(II) complex of ethylglyoxal bis(thiosemicarbazone) (Cu-ETS) was evaluated as a positron emission tomography (PET) radiopharmaceutical for assessment of regional renal perfusion. METHODS: The concordance of renal flow estimates obtained with 11- and 15-microm microspheres was confirmed in four immature farm pigs using co-injected (46)Sc- and (57)Co-microspheres administered into the left ventricle. With the use of both immature farm pigs (n=3) and mature Göttingen minipigs (n=6), regional renal radiocopper uptake following intravenous [(64)Cu]Cu-ETS administration was compared to microsphere measurements of renal perfusion. The distribution and kinetics of [(64)Cu]Cu-ETS were further studied by PET imaging of the kidneys. The rate of [(64)Cu]Cu-ETS decomposition by blood was evaluated in vitro, employing octanol extraction to recover intact [(64)Cu]Cu-ETS. RESULTS: The co-injected 11- and 15-microm microspheres provided similar estimates of renal flow. A linear relationship was observed between the renal uptake of intravenous [(64)Cu]Cu-ETS and regional renal perfusion measured using microspheres. [(64)Cu]Cu-ETS provided high-quality PET kidney images demonstrating the expected count gradient from high-flow outer cortex to low-flow medulla. When incubated with pig blood in vitro at 37 degrees C, the [(64)Cu]Cu-ETS radiopharmaceutical was observed to decompose with a half-time of 2.8 min. CONCLUSION: Cu-ETS appears suitable for use as a PET radiopharmaceutical for evaluation of regional renal perfusion, affording renal uptake of radiocopper that varies linearly with microsphere perfusion measurements. Quantification of renal perfusion (in ml min(-1) g(-1)) with [(60,61,62,64)Cu]Cu-ETS will require correcting the arterial input function for the fraction of blood radiocopper remaining present as the intact Cu-ETS radiopharmaceutical, since the Cu-ETS chelate has limited chemical stability in blood. Rapid octanol extraction of blood samples appears suitable as an approach to capturing the actual blood concentration of [(60/61/62/64)Cu]Cu-ETS.

Development of a novel magnetic resonance imaging acquisition and analysis workflow for the quantification of shock wave lithotripsy-induced renal hemorrhagic injury.

The current accepted standard for quantifying shock wave lithotripsy (SWL)-induced tissue damage is based on morphometric detection of renal hemorrhage in serial tissue sections from fixed kidneys. This methodology is time and labor intensive and is tissue destructive. We have developed a non-destructive magnetic resonance imaging (MRI) method that permits rapid assessment of SWL-induced hemorrhagic lesion volumes in post-mortem kidneys using native tissue contrast to reduce cycle time. Kidneys of anesthetized pigs were targeted with shock waves using the Dornier Compact S lithotripter. Harvested kidneys were then prepared for tissue injury quantification. T1 weighted (T1W) and T2 weighted (T2W) images were acquired on a Siemens 3T Tim Trio MRI scanner. Images were co-registered, normalized, difference (T1W - T2W) images generated, and volumes classified and segmented using a Multi-Spectral Neural Network (MSNN) classifier. Kidneys were then subjected to standard morphometric analysis for the measurement of lesion volumes. Classifications of T1W, T2W and difference image volumes were correlated with morphometric measurements of whole kidney and parenchymal lesion volumes. From these relationships, a mathematical model was developed that allowed predictions of the morphological parenchymal lesion volume from MRI whole kidney lesion volumes. Predictions and morphology were highly correlated (R = 0.9691, n = 20) and described by the relationship y = 0.84x + 0.09, and highly accurate with a sum of squares difference error of 0.79%. MRI and the MSNN classifier provide a semi-automated segmentation approach, which provide a rapid and reliable means to quantify renal injury lesion volumes due to SWL.