Prevention of Lithotripsy-Induced Renal Injury by Pretreating Kidneys with Low-Energy Shock Waves
Lynn R. Willis*,
Andrew P. Evan,
Bret A. Connors,
Rajash K. Handa*,
Philip M. Blomgren and
James E. Lingeman
* Pharmacology and Toxicology; Anatomy and Cell Biology, Indiana University School of Medicine; and Methodist Hospital Institute for Kidney Stone Disease, Indianapolis, Indiana
Address correspondence to: Dr. Lynn R. Willis, Department of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202. Phone: 317-274-1562; Fax: 317-274-7714; willisl{at}iupui.edu
Received for publication June 17, 2004.
Accepted for publication December 10, 2005.
Lithotripsy shock waves (SW) to one renal pole damage that polebut protect the opposite pole from the damage inflicted by another,immediate application of SW. This study investigated whetherthe protection (1) occurs when the first treatment causes noinjury, (2) is caused by SW or injury, (3) exhibits a threshold,and (4) occurs when the same pole receives both treatments.Six- to 7-wk-old anesthetized female pigs were studied. Thefollowing groups were studied: group 1 (n = 4), 2000 SW at 12kV to one pole and 2000 SW at 24 kV (standard) to the oppositepole; group 2 (n = 6), same as group 1 except 500 12-kV SW pretreatment;group 3 (n = 8), 500 12-kV, 2000 standard SW, all to the samepole; and group 4 (n = 8), same as group 3 except 100 12-kVSW pretreatment. Mean ± SD lesion size in group 1, firstpole treated, was 0.66 ± 0.82% of functional renal volume(FRV; P < 0.05 versus 5.22 ± 3.6% FRV with no pretreatment[NP]; 95% confidence interval [CI] –7.0 to –2.1)and 0.50 ± 0.68% FRV in the opposite pole after 2000standard SW (P < 0.05 versus NP; 95% CI –9.4 to –0.08).Mean lesion size (first pole) in group 2 was 0.020 ±0.028% FRV (P < 0.01 versus NP; 95% CI –9.2 to –1.2)and 0.43 ± 0.54% FRV in the opposite pole after 2000standard SW (P < 0.05 versus NP; 95% CI –8.8 to –0.82).Same-pole SW (groups 3 and 4) also protected. Mean lesion sizeswere 0.28 ± 0.33% (P < 0.01 versus NP; 95% CI –8.0to –1.9) in group 3 and 0.39 ± 0.48% FRV (P <0.01 versus NP; 95% CI –8.2 to –1.7) in group 4.It is concluded that the pretreatment protocol substantiallylimits the renal injury that normally is caused by SWL and occurswhen the pretreatment and standard SW are applied to the samepole. The threshold for the protection may be <100 SW.
Shock wave lithotripsy (SWL) remains the principal treatmentfor symptomatic renal calculi despite increasing awareness thatSW damage the renal parenchyma (1–5). Clinical interestin treatment strategies aimed at minimizing the renal damageis high, and manufacturers of second- and third-generation lithotriptershave produced machines with higher power and smaller focal zones,ostensibly to enhance stone comminution and diminish injuryto renal tissue. Ironically, this combination seems actuallyto have exacerbated the problem of renal injury caused by SW.The incidence of perirenal hematomas in patients who were treatedwith the first-generation unmodified Dornier HM3 lithotripter,for example, has been reported consistently as <1% (6,7),whereas that for such second-generation lithotripters as theStorz Modulith and Dornier Doli-S have been reported as 4.1(8) and 12% (9), respectively.
This article reports a treatment strategy, devised in a porcinemodel, in which the renal damage that is caused by a clinicaldose of SW that is applied with the unmodified Dornier HM3 lithotriptercan be minimized or, possibly, prevented. The strategy derivesfrom our initial observation (10) that the application of 2000SW at 24 kV to one renal pole (upper or lower), which normallyproduces a hemorrhagic lesion amounting to nearly 7% of thefunctional renal volume (FRV) (5), caused substantially lessinjury in the opposite pole (lesion size was 0.1% FRV) when2000 SW (also at 24 kV) were applied immediately to that pole(Figure 1).
Figure 1. Digitized serial-section images (coronal plane) of a kidney that had been treated first with 2000 shock waves (SW) at 24 kV to the lower pole (shock wave lithotripsy [SWL] 1) and immediately thereafter with the same "dose" (2000 SW at 24 kV) to the opposite pole (SWL 2). The circles denote the focal zone (F2) of the SW. Hemorrhagic lesions that were identified in the parenchyma are shown in red. The lesion in the lower pole composed 6.8% of the functional renal volume (FRV), whereas that in the upper pole was barely detectable (0.1% FRV).
The studies described in this article aimed at confirming andcharacterizing this protective response and asked whether (1)the response occurred after pretreatment with low-energy SW,which cause minimal detectable damage to the renal parenchyma;(2) the response was initiated by tissue injury or by the SWindependent of injury; (3) a minimum, or threshold, exists forthe number of SW needed to initiate the protective response;and (4) the protection occurs when the pretreatment and standardSW are applied to the same renal pole.
The experimental protocol used in this study was carried outin accordance with the National Institutes of Health Guide forthe Care and Use of Laboratory Animals and was approved by theInstitutional Animal Care and Use Committees of the IndianaUniversity School of Medicine and Methodist Hospital. Femalefarm pigs, 6 to 7 wk of age (Hardin Farms, Danville, IN), wererandomly assigned to one of the following treatment groups.Group 1 (n = 4) received 2000 SW at 12 kV to one renal pole(upper or lower) and 2000 SW at 24 kV to the opposite pole ofthe same kidney. The rationale for this treatment strategy stemsfrom our earlier observation (11) that renal tissue that wastreated with 2000 SW at low activation energy (12 kV) sustainedlittle to no injury. The pigs of group 2 (n = 6) were treatedin the identical manner as those of group 1 except that theinitial treatment consisted of 500 SW at 12 kV. Group 3 (n =8) received 500 SW at 12 kV to one renal pole (upper or lower)and 2000 SW at 24 kV to the same pole of the same kidney. Group4 (n = 8) was treated in the identical manner as group 3 exceptthat the pretreatment consisted of 100 SW at 12 kV. SW wereapplied only to one kidney in each animal, albeit twice in eachexperiment.
On the day of the experiment, each pig was anesthetized (15to 20 mg/kg ketamine and 2 mg/kg xylazine for induction andintubation and 1 to 3% isoflurane and 100% oxygen for maintenance)and prepared for renal clearance experiments. Respiration wasspontaneous. Surgical procedures for placement of arterial,renal venous, and bilateral ureteral catheters have been describedpreviously (5). Isotonic saline was infused intravenously at1 to 3% of body weight during the 90 min preceding the startof sample collection to maintain adequate hydration and urineflow.
Polyfructosan, 5% (Inutest; Henstettler, Linz, Austria), andsodium para-aminohippurate (PAH), 10%, were infused intravenouslyin isotonic saline at 1 ml/min to attain steady-state concentrations.At 45 min into the infusion, three consecutive 15-min baselinecollections of urine were obtained from each kidney. Femoralarterial and bilateral renal venous blood samples were drawnat the midpoint of each collection period. At the conclusionof the third collection, the pigs were disconnected from theanesthesia machine and transferred (unconscious) to the lithotripsysuite (a trip of approximately 5 min), where administrationof isoflurane anesthesia was resumed and preparations for SWL(unmodified Dornier HM3) were made. F2 was targeted on the lowerpole calyx of the right or left kidney with the aid of fluoroscopy,and a small amount of contrast medium was injected through theureteral catheter. SW then were delivered to that calyx at arate of 2 impulses per second according to one of the protocolsdescribed above (only one kidney in each animal received SWL).An interval of 3 min duration elapsed after the applicationof the 12-kV SW, during which F2 was retargeted and 2000 SWwere applied at 24 kV to the opposite pole of that kidney (groups1 and 2) or to the same site that had received the low-energySW (groups 3 and 4). The electrode was changed during the 3-mininterval. At the end of the lithotripsy treatment, the pigswere removed immediately from the water bath and returned tothe surgical suite for three 15-min urine collections with midpointblood samples at 1 and 4 h after SWL. The kidneys then wereperfusion-fixed in situ (5) and removed for routine or quantitativemorphologic analysis (12).
Lesion sizes were determined in the shocked kidneys from threeof four kidneys in group 1, four of six kidneys in group 2,six of eight kidneys in group 3, and five of eight kidneys ingroup 4 (kidneys not used for determination of lesion size wereused for routine histology). Lesion size was determined as afraction of functional renal volume (FRV) for each whole kidneyafter serial sections (120 µm) that were digitally photographedfor computer-assisted segmentation were obtained. The hemorrhagicregions were identified and colorized (13). Kidneys that wereused for quantifying lesion size could not be used also forroutine histology because different tissue preparation methodsare required for each process. Consequently, the kidneys thatwere used for routine histology were embedded in paraffin, sectionedat 7 µm, and stained with hematoxylin and eosin.
Urine and plasma samples were analyzed by standard colorimetricmethods (14,15). Clearances of polyfructosan and PAH were calculatedas estimates, respectively, of GFR and renal plasma flow (RPF).The concentration of PAH in renal venous blood was used to calculatethe renal extraction of PAH, which provides an index of renaltubular secretory function. The clearance data were analyzedby one-way repeated-measures ANOVA. When the F test was statisticallysignificant, the Newman-Keuls test and group t test were usedwhere appropriate. Mean data are presented ± SD and 95%confidence intervals (CI) for differences. P < 0.05 was thecriterion for statistical significance.
Figure 2 shows digitized and colorized cross-sections of thethree kidneys from group 1. The first dose of 2000 SW was administeredto the pigs of this group at an activation energy (12 kV) thatnormally causes minimal injury to renal tissue (11). Accordingly,the mean size of the lesions that were produced after the pretreatmentin these pigs was 0.66 ± 0.82% of FRV (individual lesionsizes are provided in Figure 2). Had the second dose of 2000SW at 24 kV been applied to kidneys without any pretreatment,hemorrhagic lesions that are similar in size to what we normallyobserve after application of a single dose of 2000 SW at 24kV to one renal pole would have been expected. The mean sizeof such lesions (i.e., those in unprotected kidneys) that havebeen measured to date in our laboratory is 5.22 ± 3.61%of FRV (n = 12 kidneys). By comparison, the second applicationof SW to the pretreated kidney of group 1 produced lesions thatwere, on average, only approximately 10% as large as lesionsthat were produced in the absence of the low-energy treatment(0.50 ± 0.68% of FRV; P < 0.05; 95% CI –0.94to –0.08).
Figure 2. Digitized images (mid-coronal plane) of three kidneys from group 1. One pole of each kidney was pretreated with 2000 SW at 12 kV (SWL 1). The opposite pole then was treated immediately with a standard clinical "dose" of SW (2000 at 24 kV). The circles denote F2 for each treatment. Hemorrhagic lesions are shown in red; cumulative lesion sizes that were measured in each pole are shown as % FRV.
Figure 3 shows digitized and colorized cross-sections of thefour kidneys from group 2. This experiment asked whether theprotective response could be initiated by a smaller number oflow-energy SW (500) applied to the pole opposite that to whichthe higher energy SW were applied. The initial treatment with500 low-energy SW produced small lesions that composed, on average,0.020 ± 0.028% of FRV. The subsequent application of2000 SW at 24 kV to the opposite poles of these kidneys producedminimally detectable lesions in three of them and a small lesion(1.24% of FRV) in the other (mean lesion size 0.41 ±0.53% of FRV). The total mean lesion size (both poles combined)in these kidneys was 0.43 ± 0.54% of FRV, which is significantlyless than the mean reported above for treatment of only onepole with 2000 SW at 24 kV with no pretreatment (P < 0.02;95% CI –8.8 to –0.82).
Figure 3. Digitized images (mid-coronal plane) of four kidneys from group 2. One pole of each kidney was pretreated with 500 SW at 12 kV (SWL 1). The opposite pole then was treated immediately with a standard clinical "dose" of SW (2000 at 24 kV). The circles denote F2 for each treatment. Hemorrhagic lesions are shown in red; cumulative lesion sizes that were measured in each pole are shown as % FRV.
The treated kidneys of groups 1 and 2 sustained similar meanreductions of GFR and RPF at 1 and 4 h after the applicationof both doses of SW (Figure 4). The reductions that were observedin both variables were similar in magnitude to those that wereobserved after the single application of 2000 SW at 24 kV toone renal pole (5), but because the number of animals in eachgroup was small, statistical analysis was not definitive forall time points (Table 1). Accordingly, the data from both groupswere pooled for analysis (Table 1), which confirmed the agreementbetween the hemodynamic responses in pretreated and nonpretreatedkidneys (5).
Figure 4. Renal hemodynamics measured in groups 1 (dashed lines) and 2 (light solid lines) before and at 1 and 4 h after the protection protocol (low-energy SW to one renal pole; standard clinical SW to the opposite pole) had been applied (see Materials and Methods for details). The dashed and light solid lines show data from individual pigs; the heavy solid lines denote mean data for the combined groups. *P < 0.01 versus baseline for post hoc comparisons. See Results and Table 1 for details of analysis.
Table 1. Renal hemodynamic data for groups 1 and 2a
The experiments that were conducted in group 3 tested the hypothesisthat application of the low-energy SW to the same renal poleto which the higher energy SW were applied likewise protectedthe tissue from the usual injury. Figure 5a shows digitizedand colorized cross-sectional views from three of the six kidneysthat were quantified in this group. Four kidneys had lesionsat our limit of resolution (0.1% of FRV); the other two lesionscomposed 0.34 and 0.91% of FRV. Mean lesion size for the groupwas 0.28 ± 0.33% of FRV, which is significantly less(P < 0.01; 95% CI –8.9 to –1.9) than the lesionthat normally is produced by 2000 SW applied at 24 kV withoutany pretreatment (Figure 6).
Figure 5. Digitized images (mid-coronal plane) of three kidneys each from groups 3 (a) and 4 (b). The same pole of each kidney received the pretreatment (a, 500 SW; b, 100 SW) and the standard "dose" of SW. The circles denote F2. Hemorrhagic lesions are shown in red; cumulative lesion sizes that were measured in each pole are shown as % FRV.
Figure 6. Mean size of lesions that were measured in groups 3 and 4 () and in kidneys that were treated with a single standard "dose" of SW to a single pole without pretreatment with low-energy SW (5). *P < 0.01 for post hoc comparisons.
Figure 7 shows a stained section (hematoxylin and eosin) fromone of the group 3 kidneys that had a minimally detectable lesion(<0.1% FRV). A single damaged blood vessel is evident inFigure 7a (shocked pole) amid a large expanse of tissue withno discernible indication of damage. Very few damaged vesselswere seen in the cortex, whereas tubular and vascular injurywas always evident in at least one papilla. Figure 7b showsa histologic section taken from the opposite, nonshocked anduninjured pole of the same kidney for comparison.
Figure 7. Light microscopic hematoxylin- and eosin-stained sections comparing tissue injury in lower and upper poles of a kidney from group 3. (a) The level of vascular damage seen in the shocked pole of a kidney that was treated with 500 SW at 12 kV followed by 2000 SW at 24 kV applied to the same location on the kidney. Note the single damaged artery and vein (arrows) in the center of the field. A ring of hemorrhage surrounds both vascular structures. The nearby nephrons and blood vessels are normal. (b) A section through the upper pole of the same kidney. No evidence of vascular or tubular injury can be seen. Note the normal profiles of several arteries and veins in the center of the panel (arrows). Magnification, x150.
Figure 5b shows digitized and colorized views of three kidneysfrom group 4 in which the low-energy treatment was limited to100 SW at 12 kV. This experiment asked whether a threshold numberof SW must be administered to elicit the protective response.Lesion sizes were quantified in five of the eight kidneys inthis group. Two of the lesions were at the limit of resolution(0.1% of FRV). The other three lesions composed 0.12, <0.1,and 0.94% of FRV (the mean lesion size was 0.39 ± 0.48%of FRV). The mean lesion size for group 4 did not differ significantlyfrom that for group 3 but was significantly less (P < 0.01;95% CI –8.2 to –1.7) than that for kidneys thathad not received the initial low-energy treatment (Figure 6).
Figure 5 demonstrates the variability of lesion sizes that wereobserved between kidneys in groups 3 and 4. Figure 8, whichshows three sections from one kidney in each group, presentsa glimpse of the lesion as viewed within the kidneys. Each kidneyshown in Figure 8 had lesions that were at or near the limitof resolution.
Figure 8. Digitized serial-section images (coronal plane) of one kidney each from groups 3 (a) and 4 (b). The figure illustrates the distribution of lesions through the thickness of the parenchyma in each kidney (compare with Figure 1). Red indicates hemorrhage.
Figure 9 and Table 2 summarize the renal hemodynamic data thatwere obtained from groups 3 and 4 and compares them with ourpreviously published data (5) that were obtained from kidneysthat received no low-energy treatment before receiving 2000SW at 24 kV. Baseline GFR in groups 3 and 4 did not differ significantlyfrom each other or from animals that had received no pretreatment(5). SWL produced similar, statistically significant reductionsof GFR in both groups at the 4-h determination. However, whereasthe reduction was gradual in group 3 (no significant changein GFR was seen at 1 h after SWL), the reduction was precipitousin group 4 (in which GFR was reduced by 52.4 ± 8.1% at1 h after SWL) and differed significantly from the corresponding1-h value in group 3 (P < 0.01; 95% CI –63.6 to –8.3).
Figure 9. Renal hemodynamics measured before and at 1 and 4 h after SWL in groups 3 (dashed line) and 4 (dotted line). The data are displayed in comparison with previously published data (5) for kidneys that received only a single treatment of 2000 SW at 24 kV. See Results and Table 2 for details of statistical analysis of these data.
Table 2. Renal hemodynamic data for groups 3 and 4 and for unprotected kidneysa
Baseline values for RPF, likewise, were not significantly differentbetween groups 3 and 4 and the group that received no low-energytreatment (Figure 9, Table 2). As was the case with GFR, SWLproduced a relatively small reduction of RPF at 1 h after SWLin group 3 compared with the reduction that was observed at1 h after SWL in group 4. Indeed, that reduction in group 4was more than twice as large as and significantly differentfrom what occurred in group 3 (P < 0.02; 95% CI –58.2to –7.7). RPF had returned to values that were not significantlydifferent from baseline in all three groups at 4 h after SWL.
These studies confirm and at least partially characterize theprotection that is provided by pretreatment of a kidney withlow-energy SW against the renal injury and bleeding that ordinarilyare caused by a typical dose of SW used in clinical lithotripsy.We first observed the protective response in kidneys in whichopposite renal poles had been treated in succession with standard-energySW (24 kV), which caused substantial damage to the first poleto be treated and minimal damage to the second pole (Figure 1)(10). Accordingly, the first series of experiments describedin this report (group 1) asked whether the initial tissue injuryor the SW, per se, invoked the response; i.e., the first setof SW was applied at an input energy (12 kV) that caused minimalto no detectable tissue damage in the kidney (11). Because theprotection occurred in this setting, too (Figure 2), we concludedthat the SW, not the tissue injury that was caused by the SW,mediated the protection.
The extent of the renal injury that was caused by the SW inthese studies was delineated and quantified only by morphometricanalysis. Such analysis provides accurate quantitative estimatesof lesion size by direct examination of the lesion (13). Inretrospect, our experimental design can be criticized for failingto include an indirect assessment of renal injury, such as thatprovided by the assay of urinary enzymes that are released bytissue injury (16), because confirmation of the protection phenomenonin humans will necessarily require indirect methods for assessinglesion size.
Similarly, the strength of the conclusions that we have drawnfrom each experiment could be criticized as merely tentativegiven our relatively small group sizes. The effective counterargumentto this criticism, however, derives from examination of theresults that were obtained in each series, in which, in comparisonwith lesions that were measured in nonprotected kidneys (5),differences in lesion size were large, better than marginallystatistically significant, and consistent across all four experimentalgroups.
Such criticisms notwithstanding, the potential utility of thisprotective protocol in clinical lithotripsy is obvious giventhat the literature reports numerous instances of renal injuryand impairment occurring after SWL (4). Although some practitionersmay believe that the modifications made in second-generationlithotripters, e.g., smaller focal zones and higher peak pressures,should reduce the incidence of renal injury and impairment—inparticular, the incidence of subcapsular hematomas—theopposite seems to be the case (8,9). Indeed, Gerber et al. (17)recently reported lower stone-free rates and higher complicationand retreatment rates for the Lithostar Plus and Modulith SLXlithotripters compared with the Dornier HM3 lithotripter. Thesefindings are particularly relevant given that lithotripsy retreatmentsfor incompletely comminuted stones commonly occur and undoubtedlymultiply the potential for renal injury and functional impairment.Moreover, Evan et al. (18) recently proposed that SWL-inducedrenal injury, particularly to the papilla, may actually promotethe growth of brushite stones, which resist breakage by lithotripsy.If this proposal holds true, then it should draw even more attentionto the potential clinical usefulness of the protective phenomenondescribed in this report.
Given the potential clinical applicability of the protectionprotocol and the time required to administer the low-energySW, during which little stone breakage would be expected, itis important to know whether fewer than 2000 low-energy SW willevoke the response. The experiments in group 2, in which 500low-energy SW were applied as pretreatment, answered this questionin the affirmative and set the stage for the experiments ofgroups 3 and 4, in which both sets of SW were applied to thesame renal pole. The experiments of group 3 aimed at defining—andsubsequently affirmed—the potential relevance of the protectionprotocol for human lithotripsy because ethical considerationspreclude applying even low-energy SW to a portion of the kidneyin which there is no stone. The SW had been applied to oppositerenal poles in groups 1 and 2 to isolate and characterize theindividual effects of each set of SW.
The experiments of group 4 did not identify a threshold foractivation of the protective response; i.e., nearly identicalprotective responses occurred in groups 3 and 4 after pretreatmentwith either 500 or 100 low-energy SW. Although it certainlywould be of scientific interest to identify a threshold forthe response, if one exists, the clinical point is made by theseresults in any case. That is, the protective response was evokedby what amounts to a minimum number of low-energy SW, and ifthose SW do not contribute directly to stone breakage, thenthey consume only a small fraction of the total treatment timewhile contributing substantially to minimizing the tissue injurythat would otherwise be caused by the higher energy SW thatare needed to break stones.
Limitations of current imaging technology make it difficultfor practitioners to know when SWL has broken a kidney stonesufficiently for complete elimination of the fragments froma patient’s urinary tract. Accordingly, it is not uncommonclinical practice to administer the near-maximum or maximumallowable number of SW for a given machine to provide the highestprobability of optimum stone breakage. This practice, althoughensuring the best fragmentation, undoubtedly increases the riskfor unnecessary renal injury and impairment because the severityof the injury that is induced by SWL is related to the numberof SW administered (19,20). Accordingly, any SW that are administeredin excess of the number needed to convert the stone to passablefragments increase the risk for tissue injury and complicationsfor the patient, without therapeutic gain. On the basis of theseresults, the low-energy pretreatment protocol should permitthe application of maximal numbers of SW to promote completestone breakage while minimizing or at least reducing the severityof the renal injury that is caused by the SW.
The experiments described herein were not designed to identifythe mechanism of the protective response. Nevertheless, thedata provide some basis for speculation and future planning.The lesion that is caused by SWL is hemorrhagic (21,22); thebleeding presumably derives from blood vessels that are brokenwithin the path of the SW (see Figure 7). Vessels of the renalpapilla seem to be the most susceptible to breakage by SW (11).Accordingly, the reduced incidence of bleeding in the protectedkidneys invites the hypothesis that the low-energy SW initiatedsome degree of renal vasoconstriction, which persisted duringapplication of the higher energy SW. Our subsequent observationthat these kidneys were vasoconstricted 1 h after SWL (Figure 9)supports (but does not prove) this hypothesis. Alternatively,the low-energy SW may have reduced the clotting time of bloodissuing from vessels that were damaged by the SW. We have nodata for or against the latter possibility, but the hemodynamicdata in Figures 4 and 9 and earlier studies from this laboratory(5,11,23,24) and others (3,25–31) demonstrate the occurrenceof renal vasoconstriction after SWL and support the former hypothesis.Even so, because all of our measurements of renal hemodynamicswere made at least 1 h after the SW had been applied, they donot answer directly the question of whether renal vasoconstrictionoccurred during SWL or whether vasoconstriction occurred intime to reduce the subsequent bleeding. The test of this hypothesiswill require measurement of renal blood flow during the applicationof the low- and higher energy SW.
One interesting aspect of the hemodynamic data that were obtainedfrom the pigs in groups 3 and 4 was that the reduction of RPFthat was recorded 1 h after SWL in group 3 (500-SW pretreatment)was significantly diminished in comparison with the reductionsthat were noted at the same time point in group 4 (Figure 9,Table 2). Although these experiments were not designed to addressthe reasons behind such a difference in hemodynamic responsesbetween groups and the difference may be merely coincidental,the observation suggests that the dynamics of the renal vasoconstrictorresponses to the 100- and 500-SW pretreatments differed. Onepossibility is that the shocked kidneys of both groups werevasoconstricted to similar degrees by the pretreatments, i.e.,before measurement 1 h after SWL, and that the kidneys of group3 (500 low-energy SW pretreatment) recovered more quickly thandid the kidneys of group 4. Alternatively, it may be that thekidneys of group 3 were less severely vasoconstricted by theirpretreatment regimen than were the kidneys of group 4 by theirs;i.e., perhaps renal plasma flow in the kidneys of group 3 neverfell to the levels reached in the shocked kidneys of group 4.If the latter hypothesis were true and if the post-SWL vasoconstrictionis caused largely by the higher energy SW, then perhaps thehigher dosage of low-energy SW that was given to group 3 conditionedthe vasculature or the renal nerves so as to ameliorate thevasoconstriction that was initiated thereafter by the higherenergy SW. Other explanations of this response clearly are possible,but full elucidation of the mechanism awaits further study.
The studies reported here were conducted with a first-generationlithotripter, in pigs, and with no kidney stones present. Althoughwe find our data convincing, given that the protective responseuniformly occurred in four independent experiments involvinga total of 26 pigs, the response nonetheless should be confirmedin other laboratories, with other lithotripters, and with stonespresent. The inference from our studies, at least for the unmodifiedDornier HM3 lithotripter, is that the protective response thatwas so evident here in porcine kidneys likewise will be evidentin human patients with stones. Although direct morphologic analysisof human kidneys for lesions is not possible to the extent possiblein porcine kidneys, sophisticated imaging studies and measurementof indirect indicators of renal injury (e.g., urinary enzymes)should reveal whether the protective response also occurs inhuman kidneys.
Acknowledgments
This project was supported in part by Public Health Servicegrant P01-DK43881.
We are indebted to Jeremy Doherty, William Fat-Anthony, KelliWind, and Anne McCurdy for expert assistance.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Abstract
Introduction
) and in kidneys that were treated with a single standard "dose" of SW to a single pole without pretreatment with low-energy SW (
