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OBJECTIVE: To determine if an innovative extracorporeal electrohydraulic shock wave device (sparker array) can effectively fracture artificial stones in vitro and in vivo, and if sparker array 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. METHODS: Utracal-30 artificial stones were placed in a holder at the focus of the sparker array and treated with 600 shock waves (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 shock waves and the fragments collected for analysis. Lesion analysis consisted of treating the left kidney of pigs with 1200 or 2400 shock waves 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 out of 7 kidneys showed evidence of hemorrhagic injury in the treated area. CONCLUSIONS: The sparker array consistently comminuted artificial stones demonstrating its ability to fracture stones like other lithotripters. Also, the sparker array 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.

Focused ultrasonic propulsion is a new noninvasive technique designed to move kidney stones and stone fragments out of the urinary collecting system. However, to our knowledge the extent of tissue injury associated with this technique is not known. We quantitated the amount of tissue injury produced by focused ultrasonic propulsion under simulated clinical treatment conditions and under conditions of higher power or continuous duty cycles. We compared those results to extracorporeal shock wave lithotripsy injury.A human calcium oxalate monohydrate stone and/or nickel beads were implanted by ureteroscopy in 3 kidneys of live pigs weighing 45 to 55 kg and repositioned using focused ultrasonic propulsion. Additional pig kidneys were exposed to extracorporeal shock wave lithotripsy level pulse intensity or continuous ultrasound exposure 10 minutes in duration using an ultrasound probe transcutaneously or on the kidney. These kidneys were compared to 6 treated with an unmodified Dornier HM3 lithotripter (Dornier Medical Systems, Kennesaw, Georgia) using 2,400 shocks at 120 shock waves per minute and 24 kV. Histological analysis was performed to assess the volume of hemorrhagic tissue injury created by each technique according to the percent of functional renal volume.Extracorporeal shock wave lithotripsy produced a mean ± SEM lesion of 1.56% ± 0.45% of functional renal volume. Ultrasonic propulsion produced no detectable lesion with simulated clinical treatment. A lesion of 0.46% ± 0.37% or 1.15% ± 0.49% of functional renal volume was produced when excessive treatment parameters were used with the ultrasound probe placed on the kidney.Focused ultrasonic propulsion produced no detectable morphological injury to the renal parenchyma when using clinical treatment parameters but produced injury comparable in size to that of extracorporeal shock wave lithotripsy when using excessive treatment parameters.

Focused ultrasound has the potential to expel small stones or residual stone fragments from the kidney, or move obstructing stones to a nonobstructing location. We evaluated the efficacy and safety of ultrasonic propulsion in a live porcine model.Calcium oxalate monohydrate kidney stones and laboratory model stones (2 to 8 mm) were ureteroscopically implanted in the renal pelvicalyceal system of 12 kidneys in a total of 8 domestic swine. Transcutaneous ultrasonic propulsion was performed using an HDI C5-2 imaging transducer (ATL/Philips, Bothell, Washington) and the Verasonics® diagnostic ultrasound platform. Successful stone relocation was defined as stone movement from the calyx to the renal pelvis, ureteropelvic junction or proximal ureter. Efficacy and procedure time was determined. Three blinded experts evaluated histological injury to the kidney in the control, sham treatment and treatment arms.All 26 stones were observed to move during treatment and 17 (65%) were relocated successfully to the renal pelvis (3), ureteropelvic junction (2) or ureter (12). Average ± SD successful procedure time was 14 ± 8 minutes and a mean of 23 ± 16 ultrasound bursts, each about 1 second in duration, were required. There was no evidence of gross or histological injury to the renal parenchyma in kidneys exposed to 20 bursts (1 second in duration at 33-second intervals) at the same output (2,400 W/cm(2)) used to push stones.Noninvasive transcutaneous ultrasonic propulsion is a safe, effective and time efficient means to relocate calyceal stones to the renal pelvis, ureteropelvic junction or ureter. This technology holds promise as a useful adjunct to surgical management for renal calculi.

Conduct a laboratory evaluation of a novel low-pressure, broad focal zone electrohydraulic lithotripter (TRT LG-380).Mapping of the acoustic field of the LG-380, along with a Dornier HM3, a Storz Modulith SLX, and a XiXin CS2012 (XX-ES) lithotripter was performed using a fiberoptic hydrophone. A pig model was used to assess renal response to 3000 shockwaves (SW) administered by a multistep power ramping protocol at 60 SW/min, and when animals were treated at the maximum power setting at 120 SW/min. Injury to the kidney was assessed by quantitation of lesion size and routine measures of renal function.SW amplitudes for the LG-380 ranged from (P(+)/P(-)) 7/-1.8 MPa at PL-1 to 21/-4 MPa at PL-11 while focal width measured ~20 mm, wider than the HM3 (8 mm), SLX (2.6 mm), or XX-ES (18 mm). For the LG-380, there was gradual narrowing of the focal width to ~10 mm after 5000 SWs, but this had negligible effect on breakage of model stones, because stones positioned at the periphery of the focal volume (10 mm off-axis) broke nearly as well as stones at the target point. Kidney injury measured less than 0.1% FRV (functional renal volume) for pigs treated using a gradual power ramping protocol at 60 SW/min and when SWs were delivered at maximum power at 120 SW/min.The LG-380 exhibits the acoustic characteristics of a low-pressure, wide focal zone lithotripter and has the broadest focal width of any lithotripter yet reported. Although there was a gradual narrowing of focal width as the electrode aged, the efficiency of stone breakage was not affected. Because injury to the kidney was minimal when treatment followed either the recommended slow SW-rate multistep ramping protocol or when all SWs were delivered at fast SW-rate using maximum power, this appears to be a relatively safe lithotripter.

Pretreating a pig kidney with 500 low-energy shock waves (SWs) before delivering a clinical dose of SWs (2000 SWs, 24 kV, 120 SWs/min) has been shown to significantly reduce the size of the hemorrhagic lesion produced in that treated kidney, compared with a protocol without pretreatment. However, since the time available for patient care is limited, we wanted to determine if fewer pretreatment SWs could be used in this protocol. As such, we tested if pretreating with 300 SWs can initiate the same reduction in renal lesion size as has been observed with 500 SWs.Fifteen female farm pigs were placed in an unmodified Dornier HM-3 lithotripter, where the left kidney of each animal was targeted for lithotripsy treatment. The kidneys received 300 SWs at 12 kV (120 SWs/min) followed immediately by 2000 SWs at 24 kV (120 SWs/min) focused on the lower pole. These kidneys were compared with kidneys given a clinical dose of SWs with 500 SW pretreatment, and without pretreatment. Renal function was measured both before and after SW exposure, and lesion size analysis was performed to assess the volume of hemorrhagic tissue injury (% functional renal volume, FRV) created by the 300 SW pretreatment regimen.Glomerular filtration rate fell significantly in the 300 SW pretreatment group by 1 hour after lithotripsy treatment. For most animals, low-energy pretreatment with 300 SWs significantly reduced the size of the hemorrhagic injury (to 0.8% ± 0.4%FRV) compared with the injury produced by a typical clinical dose of SWs.The results suggest that 300 pretreatment SWs in a voltage ramping treatment regimen can initiate a protective response in the majority of treated kidneys and significantly reduce tissue injury in our model of lithotripsy injury.

OBJECTIVE To test the idea that a pause (~3-min) in the delivery of shock waves (SW) soon after the initiation of treatment 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 Anesthetized female pigs were assigned to one of three SWL treatment protocols that did not involve a pause in SW delivery of more than 10 seconds (2000 SWs at 24 kV; 100 SWs at 12 kV + ~10-sec pause + 2000 SWs at 24 kV; 500 SWs at 12 kV + ~10-sec pause + 2000 SWs at 24 kV; all SWs 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 hemorrhagic 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 GFR and ERPF) 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% 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 to 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). Time between the initiation of the low- and high-amplitude SWs was ~4-min for these latter two groups compared to ~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 2-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 at hand. Keywords: kidney, lithotripsy, swine, tissue injury INTRODUCTION An undesirable side effect of SWL treatment is that SWs can injure renal and surrounding tissue [1]. The primary acute lesion is vascular trauma with breakage of blood vessels and pooling of blood within the parenchyma, which if extending to the kidney surface will result in subcapsular or perirenal hematomas [1]. Along with the vascular insult, there is damage to tubules and the production and release of proinflammatory cytokines and injurious agents (e.g. iron/reactive oxygen metabolites; vasoconstrictor peptides/ischemia; metabolic toxins) that can result in fibrosis and the loss of functional tissue [1,2]. Such SW-induced injury has been linked to adverse outcomes such as hypertension, diabetes and exacerbation of kidney stone disease [3–5]. This raises concern about the long-term safety of SWL, and developing SWL treatment strategies that reduce or prevent tissue injury would certainly help mitigate such concerns. One approach to reduce SWL-induced tissue injury has been to alter the manner in which SWs are delivered to the kidney [2,6], and in this regard we have reported that treatment of the pig kidney with low-amplitude SWs followed by a 3-min pause in treatment prior to applying high-amplitude SWs will reduce SWL-induced hemorrhagic lesion sizes by as much as 20-fold [7]. In fact, similar protocols in which low-amplitude SWs were substituted with a relatively small number of higher-amplitude SWs were also shown to reduce SW-induced tissue damage, implicating the 3-min pause in treatment to be a critical factor in the development of the renal protective response [8]. On the other hand, some clinical centers begin SWL treatment at a low power setting to condition the patient to treatment-related discomfort and then gradually ramp up to higher levels with continuous delivery of SWs. That is, there is typically no pause in treatment during the lithotripsy session [9–12]. It is unclear even with power ramping if continuous delivery of SWs can be used to protect the kidney from injury. Therefore, we sought to determine in our pig model, using a 2-step ramping protocol, whether a definitive pause in SW delivery is needed in order to protect the kidney from SWL-related tissue damage.

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. Keywords: shock wave lithotripsy, renal injury, narrow focal zone INTRODUCTION Renal injury is an unfortunate but expected consequence of shock wave lithotripsy (SWL). All patients experience at least mild haematuria, some develop subcapsular or perinephric haematomas, and in rare cases excessive bleeding can develop, requiring intervention [1–6]. SWL injury has not been well studied in patients but there is a wealth of information describing the renal response to SWs in experimental animals. The most thorough characterization has been conducted in the pig model where the severity of tissue damage and size of the haemorrhagic lesion are dependent on many factors, including treatment settings for power and shock wave (SW) rate, the sequence of SW delivery, the number of SWs and the size of the kidney [7–10]. This work in assessing treatment variables has helped to estimate the potential for injury in the clinical setting and has revealed treatment strategies that significantly reduce tissue damage [8,9,11–13]. Thus, there is a growing understanding of how treatment settings contribute to injury in SWL. However, little has been done in a systematic way to compare the injuries produced by different lithotriptors. Lithotriptors are not all the same. The SWs of all lithotriptors have similar features, but the acoustic output and dimensions of the focal zone produced by different machines can be very different [14]. Focal width is a critical feature of a lithotriptor and in working terms describes how tightly SW energy is focused in the patient. Focal width is important because it affects the mechanisms at play in stone breakage. Shear stress contributing to stone breakage is enhanced when the focal width is wider than the stone [15,16]. Also, since respiratory motion moves the stone in and out of the focal zone, a lithotriptor with larger focal width has an improved chance of hitting the target [17]. Indeed, patient studies have suggested that focal width can affect outcomes with lower stone-free rates for narrow focal width lithotriptors [18–22]. Focal width has also been implicated in SWL injury, with the suggestion of an increased occurrence of adverse effects with narrow focal width machines [23,24]. The focal widths of current lithotriptors cover a broad range, from ≈ 2.1 mm (Wolf Piezolith P3000) to ≈ 20 mm (LithoGold LG-380). Most machines are reported have a focal width of about 6–10 mm and it is not uncommon to find considerable variance for the values reported for a given machine. For example, reported values of focal width for the unmodified Dornier HM3 lithotriptor (Dornier Medical Systems, Kennesaw, GA, USA) run from ≈ 8 to ≈ 12 mm, the difference being due to how the measurements were conducted [14,25]. Accurate measures require rigorous mapping of the pressure field with a fibre-optic probe hydrophone and this is not an assessment often performed beyond the characterization required for the licensing and approval of a new lithotriptor [26]. The Storz Modulith SLX (Karl Storz Lithotripsy, Atlanta, GA, USA) is an electromagnetic lithotriptor that has gained considerable popularity within the urology community. This machine emerged during the wave of technical development spurred by interest in making SWL an anaesthesia-free procedure. Since discomfort during SWL is due largely to cutaneous sensation, the strategy used by many manufacturers was to widen the aperture of the shock source to spread the area of contact between the acoustic pulse and the body. This reduced pain at the skin but also narrowed the focal zone [14]. The SLX has a focal width of only ≈ 3 mm and produces higher acoustic pressures (P+≈ 90 MPa) than broader focal width machines (i.e. LG-380: FW ≈ 20 mm, P+≈ 20 MPa; XiXin CS2012: FW ≈ 18 mm, P+ ≈ 17 MPa; HM3: FW ≈ 8 mm, P+≈ 40 MPa) [26,27]. As kidney injury has not been adequately assessed for a narrow focal zone lithotriptor, we used the pig model to characterize the renal response to SWs for the SLX. SWs were administered under conditions that simulated clinical SWL at settings for SW number, power level and SW rate that have been reported for treating patients using this lithotriptor [28]. Data for morphology, lesion size and renal function were compared with similar, previously published data for pigs treated using the Dornier HM3 [10]. The study included assessment of the renal response to slow SW rate, a treatment strategy shown to protect against renal trauma in the pig model [9,10].

Introduction: An overlooked finding at the time of renal endoscopy for patients with nephrolithiasis is the appearance of the renal papillae. Recent work has demonstrated that it is possible to distinguish specific stone-forming phenotypes by endoscopic patterns of papillary appearance alone.(1–4) These variable expressions are likely to have clinical significance; yet, the ability to pursue such research efforts remains limited by the lack of a standardized system to describe these findings. Herein, we describe a novel grading system designed to standardize and simplify the description of renal papillary appearance in stone formers at the time of endoscopy. Materials and Methods: Since 1999, 342 patients have been prospectively enrolled and given consent to be part of an NIH funded project studying the pathogenesis of stone formation at a single institution (Methodist Hospital, Indiana University Health). Patients have been treated and studied using both percutaneous and retrograde ureteroscopic approaches. Digital scopes are utilized when feasible along with fluoroscopy to map the affected renal unit(s), and stones are removed and analyzed individually when possible.(5) Results: Four recurring abnormal papillary features were identified based upon the collective knowledge and expertise of the primary research team. Each variable was then quantitated based on the severity in appearance. Three features believed to be associated with papillary injury include ductal plugging, pitting, and loss of papillary contour. Ductal plugging is evident as either suburothelial deposits of yellow mineral or as dilated ducts of Bellini, presumably left behind after a plug has passed. These two subfeatures are considered the same for the purposes of grading. Pitting reflects crater-like erosion of the papillary surface. Loss of contour reflects global depression of the papilla relative to the surrounding tissue. Upon papillary inspection, each papilla receives a numerical grade from 0 to 2 for each of these measured domains. The three scores are then added together to create a sum total score regarding the degree of papillary injury ranging from 0 to 6. The fourth feature, the amount of Randall's plaque, is evident as white deposits along the papillary surface. It is not known to cause papillary injury(6) and, as such, is designated with an alphabetical subscore (a–c) rather than a number. Each papilla then receives a final unique score incorporating both the sum numerical and alphabetical grade. Reference examples are shown in the accompanying video. Conclusions: The creation of a standardized system to describe the papillary appearance in stone formers has considerable clinical and academic utility. On a clinical level, it could be applied as a tool to document intraoperative findings and determine changes in papillary appearance over time in recurrent stone formers. It also has the potential to distinguish high-risk patients with more pressing needs of metabolic evaluations, medical therapy, and surveillance imaging. As a research tool, it would help create a common language to describe papillary appearance and improve collaboration between researchers. It also might allow surgeons to better correlate endoscopic findings to pathological findings and clinical outcomes such as stone analysis, associated metabolic diseases, risk of progressive renal injury, and stone recurrence. No competing financial interests exist. Accompanying manuscript submitted to Journal of Endourology (END-2015-0298; in review). Runtime of video: 5 mins 37 secs

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

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

Nephrocalcinosis generally refers to the presence of calcium salts within renal tissue, but this term is also used radiologically in diagnostic imaging in disease states that also produce renal stones, so that it is not always clear whether it is tissue calcifications or urinary calculi that give rise to the characteristic appearance of the kidney on x-ray or computed tomography (CT). Recent advances in endoscopic imaging now allow the visual distinction between stones and papillary nephrocalcinosis, and intrarenal endoscopy can also verify the complete removal of urinary stones, so that subsequent radiographic appearance can be confidently attributed to nephrocalcinosis. This report shows exemplary cases of primary hyperparathyroidism, type I distal renal tubular acidosis, medullary sponge kidney, and common calcium oxalate stone formation. In the first three cases--all being conditions commonly associated with nephrocalcinosis--it is shown that the majority of calcifications seen by radiograph may actually be stones. In common calcium oxalate stones formers, it is shown that Randall's plaque can appear as a small calculus on CT scan, even when calyces are known to be completely clear of stones. In the current era with the use of non-contrast CT for the diagnosis of nephrolithiasis, the finding of calcifications in close association with the renal papillae is common. Distinguishing nephrolithiasis from nephrocalcinosis requires direct visual inspection of the papillae and so the diagnosis of nephrocalcinosis is essentially an endoscopic, not radiologic, diagnosis.

Data concerning nine forms of human stone disease, along with observations on normal people give new insights into formation of interstitial apatite plaque and intra-tubular crystal deposits. In general, across multiple disease states, one can reproduce the same relationships between plaque abundance as is seen among patients within individual disease states, so that the link between plaque and high urine calcium excretion, and low urine volume and pH seems increasingly secure. From this, one can propose a specific model of plaque formation, susceptible to experimental test. In many diseases, formation of inner medullary collecting duct and Bellini duct deposits is compatible with simple crystallization driven by urine supersaturations; this is expected in that these segments contain tubule fluid quite close in composition to final urine. But in ileostomy, small bowel disease and obesity bypass patients, crystals found in deposits are not those expected: apatite and urates in deposits, despite formation of highly acidic urine. Also, this discrepancy suggests the possibility of divergence between bulk urine pH and pH of focal collecting ducts, a new kind of possibility that is susceptible to experimental test.

No single theory of pathogenesis can properly account for human kidney stones, they are too various and their formation is too complex for simple understanding. Using human tissue biopsies, intraoperative imaging and such physiology data from ten different stone forming groups, we have identified at least three pathways that lead to stones. The first pathway is overgrowth on interstitial apatite plaque as seen in idiopathic calcium oxalate stone formers, as well as stone formers with primary hyperparathyroidism, ileostomy, and small bowel resection, and in brushite stone formers. In the second pathway, there are crystal deposits in renal tubules that were seen in all stone forming groups except the idiopathic calcium oxalate stone formers. The third pathway is free solution crystallization. Clear examples of this pathway are those patient groups with cystinuria or hyperoxaluria associated with bypass surgery for obesity. Although the final products may be very similar, the ways of creation are so different that in attempting to create animal and cell models of the processes one needs to be careful that the details of the human condition are included.

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 (≈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 ≈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 ≈30% and ≈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 ≈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.

The benefits of an attenuated total reflection Fourier transform infrared (ATR-FTIR) imaging approach for kidney biopsy analysis are described. Biopsy sections collected from kidney-stone formers are analyzed at the initial stages of stone development to provide insights into stone growth and formation. The majority of tissue analysis currently conducted with IR microspectroscopy is performed with a transflection method. The research presented in this manuscript demonstrates that ATR overcomes many of the disadvantages of transflection or transmission measurements for tissue analysis including an elimination of spectral artifacts. When kidney biopsies with small mineral inclusions are analyzed with a transflection approach, specular reflection and the Christiansen effect (anomalous dispersion) can occur, leading to spectral artifacts. Another effect specific to the analysis of mineral inclusions present in kidney biopsies is known as the reststrahlen effect whereby the inclusions become strong reflectors near an absorption band. ATR eliminates these effects by immersing the sample in a high index medium. Additionally, the focused beam size for ATR is decreased by a factor of four when a germanium internal reflection element is used, allowing the acquisition of spectra from small mineral inclusions several micrometers in diameter. If quantitative analysis of small mineral inclusions is ultimately desired, ATR provides the photometrically accurate spectra necessary for quantification.

Percutaneous nephrolithotomy (PCNL) can involve establishing more than one access into the urinary collecting system. The present study examined whether multiple percutaneous accesses results in a more severe reduction in renal function than that after single-percutaneous access.Adult female pigs were anesthetized, and percutaneous access to the left urinary collecting system was achieved by puncturing the lower pole calyx (single-tract access, n = 16) or serially puncturing the lower pole, interpolar region, and upper pole calyces [multiple (three)-tract access, n = 11]. Renal function measurements included glomerular filtration rate and effective renal plasma flow, and were taken immediately before and 1.5 and 4.5 hours after percutaneous access. We also examined glomerular function in a group of adult patients with normal preoperative serum creatinine (Cr) levels (or=1.4 mg/dL) who underwent either unilateral single-tract PCNL (23 patients) or unilateral multiple (two)-tract PCNL (10 patients). Access tracts were dilated to 30F with a NephroMax balloon dilator system in animal and human patients.Single- and multiple-tract percutaneous access procedures in pigs resulted in a similar renal functional response; both glomerular filtration rate and effective renal plasma flow significantly declined by approximately 60% immediately after access and remained depressed throughout the experimental observation period. A retrospective analysis of patients with normal serum Crs (or=1.4 mg/dL) who underwent single- or multiple-tract PCNL demonstrated that the procedures produced similar and significant increases in serum Cr on postoperative day 1 (0.33 +/- 0.09 [standard error of mean] mg/dL and 0.39 +/- 0.11 mg/dL, respectively) and day 2 (0.33 +/- 0.09 mg/dL and 0.25 +/- 0.09 mg/dL, respectively).Multiple-tract access does not lead to a more severe reduction in renal function than single-tract access; that is, the acute renal hemodynamic response to PCNL appears independent of the number of access tracts.

Patients with ileostomy typically have recurrent renal stones and produce scanty, acidic, sodium-poor urine because of abnormally large enteric losses of water and sodium bicarbonate. Here we used a combination of intra-operative digital photography and biopsy of the renal papilla and cortex to measure changes associated with stone formation in seven patients with ileostomy. Papillary deformity was present in four patients and was associated with decreased estimated glomerular filtration rates. All patients had interstitial apatite plaque, as predicted from their generally acid, low-volume urine. Two patients had stones attached to plaque; however, all patients had crystal deposits that plugged the ducts of Bellini and inner medullary collecting ducts (IMCDs). Despite acid urine, all crystal deposits contained apatite, and five patients had deposits of sodium and ammonium acid urates. Stones were either uric acid or calcium oxalate as predicted by supersaturation, however, there was a general lack of supersaturation for calcium phosphate as brushite, sodium, or ammonium acid urate because of the overall low urine pH. This suggests that local tubular pH exceeds that of bulk urine. Despite low urine pH, patients with an ileostomy resemble those with obesity bypass, in whom IMCD apatite crystal plugs are found. They are, however, unlike these bypass patients in having interstitial apatite plaque. IMCD plugging with sodium and ammonium acid urate has not been found previously and appears to correlate with formation of uric acid stones.

Cystinuria is the most common inherited cause of urinary tract stones in children. It can lead to obstructive uropathy, which is a major cause of renal failure. Genetic studies have identified two genes, SLC3A1 and SLC7A9, to be directly involved in cystine stone formation. Slc3a1 knockout male mice develop cystine stones in the bladder and, to a lesser extent, in the kidney. Slc3a1 knockout female mice also develop cystinuria, but they do not form stones. The specific aim of this study was to characterize bladder function in cystinuria mice.Eight control (4 male, 4 female) and 16 Slc3a1 knockout (9 male, 7 female) mice of mixed strain background (C57B/129, age 4-5 months) were evaluated. Each mouse was anesthetized and the bladder dome catheterized for cystometry. Immediately following cystometry, the bladder was excised, weighed, and separated into three full thickness strips for contractile studies.Bladders from cystinuria male mice had significantly increased weight, all of them had stones, decreased compliance, and decreased contractile responses to field stimulation, ATP, carbachol, and KCl. Compared with controls, female knockout mice showed normal bladder weight, decreased voiding pressure, slightly decreased compliance, and slightly decreased contractile responses.These studies clearly demonstrate that the bladder stones that developed in the male cystinuria mice resulted in a partial outlet obstruction. Although the female cystinuria mice did not have bladder stones, bladder function was mildly impaired; presumably by the presence of cystine crystals.

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 (≈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.

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.

A main mechanism of idiopathic hypercalciuria (IH) in calcium stone-forming patients (IHSF) is postprandial reduction of renal tubule calcium reabsorption that cannot be explained by selective reduction of serum parathyroid hormone levels; the nephron site(s) responsible are not as yet defined. Using fourteen 1-h measurements of the clearances of sodium, calcium, and endogenous lithium during a three-meal day in the University of Chicago General Clinical Research Center, we found reduced postprandial proximal tubule reabsorption of sodium and calcium in IHSF vs. normal subjects. The increased distal sodium delivery is matched by increased distal reabsorption so that urine sodium excretions do not differ, but distal calcium reabsorption does not increase enough to match increased calcium delivery, so hypercalciuria results. In fact, urine calcium excretion and overall renal fractional calcium reabsorption both are high in IHSF vs. normal when adjusted for distal calcium delivery, strongly suggesting a distal as well as proximal reduction of calcium reabsorption. The combination of reduced proximal tubule and distal nephron calcium reabsorption in IHSF is a new finding and indicates that IH involves a complex, presumably genetic, variation of nephron function. The increased calcium delivery into the later nephron may play a role in stone formation via deposition of papillary interstitial apatite plaque.

Shock wave lithotripsy (SWL) has proven to be a highly effective treatment for the removal of kidney stones. Shock waves (SW’s) can be used to break most stone types, and because lithotripsy is the only non-invasive treatment for urinary stones SWL is particularly attractive. On the downside SWL can cause vascular trauma to the kidney and surrounding organs. This acute SW damage can be severe, can lead to scarring with a permanent loss of functional renal volume, and has been linked to potentially serious long-term adverse effects. A recent retrospective study linking lithotripsy to the development of diabetes mellitus has further focused attention on the possibility that SWL may lead to life-altering chronic effects 1. Thus, it appears that what was once considered to be an entirely safe means to eliminate renal stones can elicit potentially severe unintended consequences. The purpose of this review is to put these findings in perspective. The goal is to explain the factors that influence the severity of SWL injury, update current understanding of the long-term consequences of SW damage, describe the physical mechanisms thought to cause SWL injury, and introduce treatment protocols to improve stone breakage and reduce tissue damage.

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 ( 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 ≈ 18 mm and that of the HM3 ≈ 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

Controversy exists over whether metabolic factors or urinary stasis predominate in the pathogenesis of calyceal diverticular calculi. We performed a study to better define the effects urinary stasis and metabolic abnormalities have in the pathogenesis of calyceal diverticular stones. Twenty-nine patients who underwent percutaneous treatment of calyceal diverticular calculi were studied. All patients underwent 24 h urine collection to evaluate metabolic risk factors. In three patients, urine was sampled directly from the diverticulum for metabolic studies. The urinary stone risk parameters of the patients with calyceal diverticular stones (Tic SF) were similar to those of a well-characterized cohort of calcium oxalate stone formers (CaOx SF). When compared to a group of normal people, the Tic SF and CaOx SF were significantly more hypercalciuric and their urine was significantly more supersaturated with calcium oxalate. Urine aspirated directly from the diverticulum had the lowest SSCaOx when compared to ipsilateral and contralateral renal pelves. The urinary risk profiles of patients with diverticular calculi are similar to those of CaOx SF, suggesting a metabolic etiology of diverticular stones. However, the SS CaOx of urine aspirated directly from the diverticula is significantly lower than that of the renal pelves; these data support the hypothesis that urinary stasis significantly contributes to the pathogenesis of calyceal diverticular calculi. Taken together, it seems likely that calyceal diverticular calculi arise from a combination of metabolic abnormalities and urinary stasis.

We describe the in vivo use of an optic-chemo microsensor to measure intraluminal papillary duct urine pH in a large mammal. Fiber-optic pH microsensors have a tip diameter of 140-µm that allows insertion into papillary Bellini ducts to measure tubule urine proton concentration. Anesthetized adult pigs underwent percutaneous nephrolithotomy to access the lower pole of the urinary collecting system. A flexible nephroscope was advanced towards an upper pole papilla with the fiber-optic microsensor contained within the working channel. The microsensor was then carefully inserted into Bellini ducts to measure tubule urine pH in real time. We successfully recorded tubule urine pH values in five papillary ducts from three pigs (1 farm pig and 2 metabolic syndrome Ossabaw pigs). Our results demonstrate that optical microsensor technology can be used to measure intraluminal urine pH in real time in a living large mammal. This opens the possibility for application of this optical pH sensing technology in nephrolithiasis.

Rats with small bowel resection fed a high-oxalate diet develop extensive deposition of calcium oxalate (CaOx) and calcium phosphate crystals in the kidney after 4 mo. To explore the earliest sites of renal crystal deposition, rats received either small bowel resection or transection and were then fed either standard chow or a high-oxalate diet; perfusion-fixed renal tissue from five rats in each group was examined by light microscopy at 2, 4, 8, and 12 wk. Rats fed the high-oxalate diet developed birefringent microcrystals at the brush border of proximal tubule cells, with or without cell damage; the lesion was most common in rats with both resection and a high-oxalate diet (10/19 with the lesion) and was significantly correlated with urine oxalate excretion ( P < 0.001). Rats with bowel resection fed normal chow had mild hyperoxaluria but high urine CaOx supersaturation; four of these rats developed birefringent crystal deposition with tubule plugging in inner medullary collecting ducts (IMCD). Two rats fed a high-oxalate diet also developed this lesion, which was correlated with CaOx supersaturation, but not oxalate excretion. Tissue was examined under oil immersion, and tiny birefringent crystals were noted on the apical surface of IMCD cells only in animals with IMCD crystal plugging. In one animal, IMCD crystals were both birefringent and nonbirefringent, suggesting a mix of CaOx and calcium phosphate. Overall, these animals demonstrate two distinct sites and mechanisms of renal crystal deposition and may help elucidate renal lesions seen in humans with enteric hyperoxaluria and stones.

Purpose: It has been proposed that calcium oxalate calculi begin as small stones attached to the renal papillae at sites of Randall’s plaque. However, no study has investigated the prevalence of attached stones in calcium oxalate stone formers or the relationship between stone attachment site and Randall’s plaque. In this study we used endoscopic examination of renal papillae in stone formers undergoing percutaneous nephrolithotomy to investigate both issues.Materials and Methods: Idiopathic calcium oxalate stone formers undergoing PNL for stone removal were enrolled in this study. Multiple papillae were examined and images were recorded by digital video. The presence or absence of papillary plaque and attached stones was noted, as was the site of stone attachment.Results: In 23 patients, 24 kidneys and 172 renal papillae were examined. All kidneys were found to have papillary plaque and 11 of the patients had attached stones. Most papillae (91%) contained plaque.Conclusions: The prevalence of attached st...

Urolithiasis is one of the most common urologic diseases in industrialized societies. Calcium oxalate is the predominant component in 70–80% of kidney stones1, and small changes in urinary oxalate concentration affect the risk of stone formation2. SLC26A6 is an anion exchanger expressed on the apical membrane in many epithelial tissues, including kidney and intestine3,4,5,6. Among its transport activities, SLC26A6 mediates Cl−-oxalate exchange5,6,7,8,9. Here we show that mutant mice lacking Slc26a6 develop a high incidence of calcium oxalate urolithiasis. Slc26a6-null mice have significant hyperoxaluria and elevation in plasma oxalate concentration that is greatly attenuated by dietary oxalate restriction. In vitro flux studies indicated that mice lacking Slc26a6 have a defect in intestinal oxalate secretion resulting in enhanced net absorption of oxalate. We conclude that the anion exchanger SLC26A6 has a major constitutive role in limiting net intestinal absorption of oxalate, thereby preventing hyperoxaluria and calcium oxalate urolithiasis.

The purpose of these studies was to test the hypothesis that Randall's plaque develops in unique anatomical sites of the kidney and that its formation is conditioned by specific stone-forming pathophysiologies. To test this hypothesis, we performed intraoperative mapping studies with biopsies of papilla from the kidneys of 15 idiopathic calcium oxalate (CaOx) stone formers, four intestinal bypass for obesity patients and ten brushite stone formers, and obtained papillary specimens from four non-stone formers after nephrectomy. Both light and electron microscopic examination of tissue changes along with infrared and electron diffraction analyses of mineral composition were performed. Distinct patterns of mineral deposition and papillary pathology were discovered in each of the three different stone forming groups. CaOx stone formers had predictable sites of interstitial apatite crystals beginning at the thin loops of Henle and spreading to the urothelium. These plaque areas are termed Randall's plaque and are thought to serve as sites for stone attachment. The papilla and medullary tubules appeared normal. The intestinal bypass patients only had intraluminal sites of crystalline material in the medullary collecting ducts. The brushite stone formers had the most severe form of cortical and medullary changes with sites of Randall's plaque, and yellowish intraluminal deposits in medullary collecting ducts. All deposits were determined to be apatite. The metabolic and surgical pathologic finding in three distinct groups of stone formers clearly shows that "the histology of the renal papilla from a stone former is particular to the clinical setting". It is observations like these that we believe will provide the insights to allow the stone community to generate better clinical treatments for kidney stone disease, as we understand the pathogenesis of stone formation for each type of stone former.

The mechanism(s) by which crystals are retained in the kidney resulting in stone disease remains unclear. Intratubular aggregation as well as crystal cell binding, or internalization and translocation, or alternatively nucleation and growth in the interstitial fluid are possible models. Our group is testing the hypothesis that calcium phosphate deposits in kidneys of patients with calcium renal stones arise in unique anatomical regions of the kidney. Furthermore, we believe that their formation is conditioned by specific stone forming pathophysiologies. To test this hypothesis, we performed intra-operative renal papillary biopsies during percutaneous nephrolithotomy of kidneys from 15 idiopathic calcium stone formers as well as kidney tissue from a patient who ingested ethylene glycol, and developed a new protocol to accurately identify the composition of the calcium deposits located in the renal tissue. We developed a new histological approach that incorporated a low-energy (low-E) reflective slide substrate that has similar characteristics to a common microscope slide and infrared absorption microspectroscopy. Infrared absorption microspectroscopy revealed the crystal deposits in the idiopathic calcium oxalate stone formers to be hydroxyapatite in composition with an occasional region of calcium carbonate, while calcium oxalate was the predominant mineral in the kidney of the patient who had ingested ethylene glycol. The results demonstrate that mixed sample types containing tissue and mineralized deposits are easily analyzed while mounted on a low-E slide using the attenuated total internal reflectance (ATR) method. Reflection/absorption (R/A) analysis allows one to quickly survey a tissue section and provides qualitative information about its components. Once interesting sites have been identified by R/A analysis, ATR analysis can then be used to collect the best data possible. ATR analysis provides spectra free from many of the artifacts associated with transmission and R/A analysis, and completes the full picture of the components contained in the crystal deposits and tissue. We present a method of analysis for mineralized materials embedded in kidney tissue that uses readily or easily obtainable materials and instrumentation. The sensitivity of this method allows tissue sections to remain unstained, alleviating the tedious and time-consuming constraints of earlier methods of visual analysis. The present method will save time and training, while simultaneously offering an unbiased analysis of mineralized components that is more accurate and conducive to patient treatments than previous methods.

Shockwave lithotripsy (SWL) predictably damages renal tissue and transiently reduces function in both kidneys. This study characterized the effects on renal function of a supraclinical dose of shockwaves (SWs) (8000) in porcine kidneys and tested the hypothesis that such excessive treatment would intensify and prolong the resulting renal impairment.Pigs aged 6 to 7 weeks were anesthetized and assigned to one of three groups. Groups 1 (N=8) and 2 (N=6) each received 8000 SWs at 24 kV (Dornier HM3) to the lower-pole calix of one kidney. Group 3 (7 pigs) received sham treatment. Renal function was monitored for the first 4 hours after SW treatment in Group 1 and for 24 hours in Group 2. Plasma renin activity was measured in Groups 2 and 3.The renal lesions produced by 8000 SWs comprised 13.8%+/-1.4% of the renal mass. In the 4-hour protocol, this injury was associated with marked reduction of the glomerular filtration rate (GFR), renal plasma flow (RPF), and urinary sodium excretion in both kidneys, although fractional sodium excretion was reduced only in the shocked kidneys. In the 24-hour protocol, GFR and RPF remained below baseline in shocked kidneys at 24 hours. Evidence of progressive ischemic injury was noted in shocked tissue at 24 hours after SW treatment.These findings support the hypothesis that the severity of the renal injury caused by SWL is related to the number of SWs administered and demonstrate the connection in this relation between renal structure and function.

Renal blood flow falls in both kidneys following delivery of a clinical dose of shockwaves (SW) (2000 SW, 24 kV, Dornier HM3) to only one kidney. The role of renal nerves in this response was examined in a porcine model of renal denervation. Six-week-old pigs underwent unilateral renal denervation. Nerves along the renal artery of one kidney were identified, sectioned and painted with 10% phenol. Two weeks later the pigs were anesthetized and baseline renal function was determined using inulin and PAH clearances. Animals then had either sham-shockwave lithotripsy (SWL) (group 1), SWL to the innervated kidney (group 2) or SWL to the denervated kidney (group 3). Bilateral renal function was again measured 1 and 4 h after SWL. Both kidneys were then removed for analysis of norepinephrine content to validate the denervation. Renal plasma (RPF) flow was significantly reduced in shocked innervated kidneys (group 2) and shocked denervated kidneys (group 3). RPF was not reduced in the unshocked denervated kidneys of group 2. These observations suggest that renal nerves play a pivotal role in modulating the vascular response of the contralateral unshocked kidney to SWL, but only a partial role, if any, in modulating that response in the shocked kidney.

While shock wave lithotripsy (SWL) is known to cause significant damage to the kidney, little is known about the initial injury to cells along the nephron. In this study, one kidney in each of six juvenile pigs (6-7 weeks old) was treated with 1,000 shock waves (at 24 kV) directed at a lower pole calyx with an unmodified HM-3 lithotripter. Three pigs were utilized as sham-controls. Kidneys were fixed by vascular perfusion immediately after SWL or sham-SWL. Three of the treated kidneys were used to quantitate lesion size. Cortical and medullary samples for light (LM) and transmission electron microscopy (TEM) were taken from the focal zone for the shock waves (F2), the contralateral kidney, and the kidneys of sham-SWL pigs. Because preservation of the tissue occurred within minutes of SWL, the initial injury caused by the shock waves could be separated from secondary changes. No tissue damage was observed in contralateral sham-SWL kidneys, but treated kidneys showed signs of injury, with a lesion of 0.2% +/- 0.1% of renal volume. Intraparenchymal hemorrhage and injury to tubules was found at F2 in both the cortex and medulla of SWL-treated kidneys. Tubular injury was always associated with intraparenchymal bleeding, and the range of tissue injury included total destruction of tubules, focal cellular fragmentation, necrosis, cell vacuolization, and membrane blebbing. The initial injury caused by SWL was cellular fragmentation and necrosis. Cellular vacuolization, membrane blebbing, and disorganization of apical brush borders appear to be secondary changes related to hypoxia.

The imprinted multimembrane-spanning polyspecific transporter-like gene 1 ( IMPT1) encodes a predicted protein with organic cation transport capabilities. As a first step in understanding the function of IMPT1, we identified the renal structures expressing this gene in knockout mice with adenine phosphoribosyltransferase (APRT) deficiency and 2,8-dihydroxyadenine (DHA) nephrolithiasis. IMPT1 mRNA was not detected using a standard in situ hybridization (ISH) protocol, but we observed intense staining in cortico-medullary tubules and glomeruli in wild-type mice using an improved reverse transcription-polymerase chain reaction (RT-PCR) ISH procedure. IMPT1 mRNA expression was significantly decreased in the cortical region in kidney sections from APRT-deficient male mice. APRT-deficient female mice are less severely affected by DHA-induced kidney stone disease, and we observed only a modest reduction in IMPT1 expression in kidneys from these mice. IMPT1 expression in APRT heterozygous mice was comparable to that in wild-type mice, suggesting imprinting of one of the parental alleles. These findings suggest that decreased IMPT1 mRNA expression may contribute to the impaired renal function in APRT-deficient male mice, and that RT-PCR ISH is a valuable tool for localizing the site of expression of transcripts that are not detectable using standard ISH procedures.

Purpose: In studies to understand better the role of cavitation in kidney trauma associated with shock wave lithotripsy we assessed structural and functional markers of kidney injury when animals were exposed to modified shock waves (pressure release reflector shock pulses) that suppress cavitation. Experiments were also performed in isolated red blood cells, an in vitro test system that is a sensitive indicator of cavitation mediated shock wave damage. Materials and Methods: We treated 6-week-old anesthetized pigs with shock wave lithotripsy using an unmodified HM3 lithotriptor (Dornier Medical Systems, Marietta, Georgia) fitted with its standard brass ellipsoidal reflector (rigid reflector) or with a pressure release reflector insert. The pressure release reflector transposes the compressive and tensile phases of the lithotriptor shock pulse without otherwise altering the positive pressure or negative pressure components of the shock wave. Thus, with the pressure release reflector the amplitude of the incident shock wave is not changed but cavitation in the acoustic field is stifled. The lower pole of the right kidney was treated with 2,000 shocks at 24 kV. Glomerular filtration rate, renal plasma flow and tubular extraction of para-aminohippurate were measured in the 2 kidneys 1 hour before and 1 and 4 hours after shock wave lithotripsy, followed by the removal of each kidney for morphological analysis. In vitro studies assessed shock wave induced lysis to red blood cells in response to rigid or pressure release reflector shock pulses. Results: Sham shock wave lithotripsy had no significant effect on kidney morphology, renal hemodynamics or para-aminohippurate extraction. Shock waves administered with the standard rigid reflector induced a characteristic morphological lesion and functional changes that included bilateral reduction in renal plasma flow, and unilateral reduction in the glomerular filtration rate and para-aminohippurate extraction. When the pressure release reflector was used, the morphological lesion was limited to hemorrhage of vasa recta vessels near the tips of renal papillae and the only change in kidney function was a decrease in the glomerular filtration rate at the 1 and 4-hour periods in shock wave treated kidneys. Red blood cell lysis in vitro was significantly lower with the pressure release reflector than with the rigid reflector. Conclusions: These data demonstrate that shock wave lithotripsy damage to the kidney is reduced when cavitation is suppressed. This finding supports the idea that cavitation has a prominent role in shock wave lithotripsy trauma.

To determine whether shock wave lithotripsy (SWL) may be a risk factor for renal functional impairment in a swine model of metabolic syndrome (MetS).Nine-month-old female Ossabaw pigs were fed an excess calorie atherogenic diet to induce MetS. At 15 months of age, the MetS pigs were treated with 2000 SWs or an overtreatment dose of 4000 SWs targeted at the upper pole calyx of the left kidney (24 kV at 120 SWs/min using the unmodified Dornier HM3 lithotripter; n=5-6 per treatment group). Serum creatinine (Cr) and blood urea nitrogen (BUN) levels were measured in conscious pigs before and ∼60 days after SWL to provide a qualitative assessment of how well both kidneys were filtering (glomerular filtration rate [GFR]). Bilateral renal function was assessed at ∼65 days post-SWL in anesthetized pigs with GFR and effective renal plasma flow (ERPF) quantified by the renal clearance of inulin and para-amino hippurate, respectively.Cr and BUN values were within normal limits before SWL and remained unchanged after lithotripsy in both the 2000 SW- and 4000 SW-treated pigs. GFR and ERPF of kidneys treated with SWL at either SW dose were similar to the contralateral nontreated kidney. Chronic histological changes in the SW-treated pole of the kidney included interstitial fibrosis, sclerotic glomeruli, and dilated and atrophic tubules.Our results are consistent with the view that a single SWL session does not result in renal impairment, even in the presence of MetS.

We performed a pilot study to assess whether renal shock wave lithotripsy influences metabolic syndrome onset and severity.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.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.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.

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.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.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 β 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.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.

Sequential analysis of kidney stone formation in the Aprt knockout mouse. Background We have previously shown that, as in human adenine phosphoribosyltransferase (APRT) deficiency, Aprt knockout mice form 2,8-dihydroxyadenine (DHA) renal stones. The disease develops earlier and is more severe in male than in female mice. To examine the biological bases for these differences, the area occupied by DHA crystals was quantified in kidney sections from male and female mice (strain 129) aged one day to eight months and this parameter was correlated with changes in renal histopathology. Aprt heterozygous and wild-type mice were used as controls. Methods Following anesthesia, the left kidney was removed and immediately frozen in dry ice. Unstained cryosections were examined by polarized light to determine total area of birefringent particles. The right kidney was perfused and embedded in plastic, and stained sections were viewed by light microscopy to examine the histopathology and to determine the location of the birefringent particles. A pathological score was assigned to the histological findings. The scores from the right kidney were compared with crystal/particle area in the left kidney, and the data were analyzed using two-way analysis of variance. The chemical composition of the particles was determined by x-ray diffraction analysis. Several stone fragments from the bladder were also examined by scanning electron microscopy (SEM). Results Crystals were detected in kidney sections from one- to two-day-old Aprt knockout mice. The crystal burden remained low in both sexes throughout the study except in males at the 120- to 240-day period. Furthermore, there was a substantial degree of renal pathology, primarily seen as interstitial fibrosis, in those males with a very high level of stone formation. The crystalline material was identified as 6-amino-2,8(3,9)-purine dione, a tautomeric form of DHA. SEM indicated that the crystals were spherical, with a diameter of 10 to 20 μm. Tissue staining and fixation procedures dramatically reduced the amount of birefringent material in kidney sections. Aprt heterozygotes of both sexes had low levels of crystalline material in the kidneys and no pathology. Birefringent material or pathological changes were not seen in kidneys from wild-type mice. Conclusions Both male and female Aprt knockout mice accumulate DHA. However, the area occupied by DHA crystals was significantly greater in 120- to 240-day-old males compared with the females of similar age. Also, substantial renal pathology was detected in kidneys of male mice that had very high levels of stone material.

The present study was designed to determine the effects of shock wave voltage (kV) on lesion size and renal function induced by shock wave lithotripsy (SWL) in the 6- to 8-wk-old pig. Each SWL-treated pig received 2000 shock waves at 12, 18, or 24 kV to the lower pole calyx of one kidney. A group of sham SWL pigs served as time controls. Bilateral GFR, renal plasma flow (RPF), and para-aminohippurate (PAH) extraction were measured 1 h before and 1 and 4 h after SWL in all treated and sham animals. The kidneys were removed at the end of each experiment for morphometric analysis. The SWL-induced lesion increased significantly in size as shock wave energy was increased from 12 to 24 kV. PAH extraction, a measure of tubular function, was not significantly affected at 12 kV, was transiently reduced at 18 kV, and was reduced for the duration of the experiment at 24 kV. GFR and RPF, however, were significantly and similarly reduced at the 1 h post-SWL period at all three kilovolt levels. At the 4-h post-SWL period, both GFR and RPF had returned to baseline levels. Lesion size and tubular injury were correlated with changes in kilovoltage, while changes in renal hemodynamics were already maximal at the lowest discharge voltage. These findings suggest that renal microvessels are highly sensitive to shock waves and that frank injury to tubules and vessels may be more closely related to discharge energy than is renal blood flow.

Studies of renal injury III: Lipid-induced nephropathy in type II diabetes Background Nephrotoxicity from elevated circulating lipids occurs in experimental and clinical situations. We tested the hypothesis that lipid-induced nephropathy causes advanced renal failure in rats with type II diabetes and dyslipidemia. Methods First generation (F1) hybrid rats derived from the spontaneous hypertensive heart failure rat (SHHF/Gmi-fa) and the LA/NIH-corpulent rat (LA/N-fa) were studied for 41 weeks while being on specific diets. Group 1 (14 rats) ingested 11.5% protein, 47.9% fat, and 40.6% carbohydrate. Group 2 (8 rats) ingested 26.9% protein, 16.7% animal fat, and 56.4% carbohydrate, and group 3 (20 rats) ingested 20.2% protein, 40.4% soy and coconut oil, and 39.4% carbohydrate. Results Hyperglycemia was more severe in rat groups 1 and 2 than in group 3. In contrast, circulating cholesterol and hydroperoxide levels were highest in group 3, intermediate in group 2, and lowest in group 1. Group 3 had severe renal failure secondary to glomerulosclerosis and tubulointerstitial disease, with striking deposition of the lipid peroxidation stress biomarker 4-hydroxynonenal in glomeruli and renal microvessels. Moreover, in group 3, increased arterial wall thickness also connoted vascular injury. In contrast, the glycoxidation stress biomarkers pentosidine and carboxymethyl-lysine were preferentially localized to renal tubules of hyperglycemic rats in groups 1 and 2 and did not segregate with the most severe renal injury. Glomerular and interstitial fibrosis was accompanied by proportional increases in renal transforming growth factor-β1 levels, which were threefold higher in the hypercholesterolemic rats of group 3 than in the hyperglycemic rats of group 1. Conclusions Acquisition of non-nodular glomerular sclerosis and tubulointerstitial disease is dependent on lipoxidation stress in rats with type II diabetes. On the other hand, in the absence of hypercholesterolemia, prolonged glycoxidation stress does not appear to be uniquely nephrotoxic.

The present study tested the hypothesis that renal disease potentiates the structural/functional changes induced by a clinical dose of shockwaves.Experimental pyelonephritis was induced in 6- to 8-week-old pigs before treatment with 2,000 shocks at 24 kV. These pigs were divided into two groups according to whether they were infected with a highly virulent (Group 1) or less virulent (Group 2) inoculation of E. coli. All animals were imaged by MR prior to SWL as a means of documenting the extent of pyelonephritis and immediately after SWL to examine the lesion produced by the shockwaves. The glomerular filtration rate (GFR), renal plasma flow (RPF) and para-aminohippurate (PAH) extraction were determined bilaterally on day 30 (Group 1) or day 80 (Group 2).In group 2, urine flow and sodium excretion were reduced by 50% from baseline in the shocked kidneys at both 1 and 4 hours post-SWL. A sustained reduction in RPF through 4 hours post-SWL was noted in the shocked kidneys in Group 1, but RPF was significantly reduced only at the 1-hour determination in Group 2. Large, consistent reductions in GFR were evident at 1 and 4 hours post-SWL in shocked and unshocked kidneys of Group 2 and in the shocked kidneys of Group 1. No significant changes were noted in PAH extraction.Acute pyelonephritis exaggerated the effect of a clinical dose of shockwaves on renal hemodynamics. This effect suggests that renal disease may be risk factor for SWL-induced injury.

The relationship between kidney size and impaired renal function induced by shock-wave lithotripsy (SWL) was examined in 6- and 10-wk-old anesthetized pigs. Each pig received 2000 shock waves, 24 kV, or sham SWL to the lower pole calyx of one kidney. Bilateral GFR, renal plasma flow (RPF), and para-aminohippurate extraction was measured 1 h before and 1 and 4 h after SWL. The kidneys were then removed for morphometric analysis. Mean kidney weights were 66.1 ± 2.7 g ( n = 9) and 103.1 ± 3.3 g ( n = 8) in the SWL groups, and 60.1 ± 2.6 g ( n = 9) and 82.3 ± 4.0 g ( n = 9) in the sham-SWL groups. SWL-induced lesions occupied a significantly greater volume of the small kidneys (6.1 ± 1.7 vol % versus 1.5 ± 0.2 vol % in the large kidneys). RPF was significantly reduced by SWL in small and large kidneys, but to a significantly greater extent in small kidneys. RPF was also significantly reduced in the contralateral kidneys of both groups, but only at 1 h after SWL. SWL significantly reduced GFR to similar degrees in both kidneys of both groups, regardless of kidney size. Para-aminohippurate extraction was likewise reduced to similar degrees in both groups, but this effect was evident only in the SWL-treated kidneys, and only in the pole to which the shock waves had been applied. The injury induced by SWL affected a larger fraction of small kidneys than large ones, and the renal vasoconstriction induced by SWL was greatest in small kidneys.

In studies of cells or stones in vitro, the material to be exposed to shock waves (SWs) is commonly contained in plastic vials. It is difficult to remove all air bubbles from such vials. Because SWs reflect at an air-fluid interface, and because existing gas bubbles can serve as nuclei for cavitation events, we sought to determine in our system whether the inclusion of small, visible bubbles in the specimen vial has an effect on SW-induced cell lysis. We found that even small bubbles led to increased lysis of red blood cells (1- to 3-mm diameter bubbles, 9.8+/-0.5% lysis, n = 7; no bubbles, 4.4+/-0.8%, n = 4), and that the degree of lysis increased with bubble size. Damage could not be reduced by centrifuging the cells to the opposite end of the vial, away from the bubble. B-scan ultrasound imaging of blood in polypropylene pipette bulbs showed that, with each SW, bubbles were recruited from the air interface, mixing throughout the fluid volume, and these appeared to serve as nuclei for increased echogenicity during impact by subsequent SWs; thus, bubble effects in vials could involve the proliferation of cavitation nuclei from existing bubbles. Whereas injury to red blood cells was greatly increased by the presence of bubbles in vials, lytic injury to cultured epithelial cells (LLC-PK1, which have a more complex cytoarchitecture than red blood cells) was not increased by the presence of small air bubbles. This suggests different susceptibility to SW damage for different types of cells. Thus, the presence of even a small air bubble can increase SW-induced cell damage, perhaps by increasing the number of cavitation nuclei throughout the vial, but this effect is variable with cell type.

The long-term effects of extracorporeal shockwave lithotripsy (SWL) on the kidneys of children treated for renal calculi are unclear. In order to determine if SWL has any negative effects on renal growth rates, we reviewed long-term (mean 9-year) follow-up data on 29 pediatric patients treated between 1984 and 1988 with an unmodified Dornier HM3 lithotripter. Changes in renal length, serum creatinine, and blood pressure were analyzed. Predicted renal growth was calculated using a formula for age-adjusted renal length. Treated kidneys were stratified into normal and abnormal groups based on a history of renal surgery, evidence of recurrent infection, and obvious anatomic abnormalities. Fifty-six upper urinary tract calculi were treated in 34 renal units. Twenty-two renal units (68%) were rendered stone free, and 65% of the patients continue to be stone free. At follow-up, one patient was classified as having new-onset hypertension, and the mean serum creatinine was 0.93 +/- 0.08 mg/dL. Both at treatment and at follow-up, no significant differences were found in the sizes of the treated and untreated kidneys. However, at treatment, the abnormal group of kidneys seemed to be smaller than expected (mean Z -1.30 +/- 1.10), whereas the group of normal kidneys was very close (mean Z 0.18 +/- 0.54) to the predicted length. At follow-up, the deviations between actual and predicted renal length were significantly more negative. Treated kidneys were an additional 1.26 +/- 0.49 SD units below their expected length (p = 0.02). Untreated kidneys were further below normal as well but possibly to a lesser degree (-0.82 +/- 0.36; p0.04). Although there was a trend for the abnormal group to have smaller kidneys than the normal group, both groups showed the same trend toward an age-adjusted reduction in renal growth at follow-up. The alterations in renal growth patterns observed in this population are unsettling and could be secondary to either treatment effect (SWL) or, more likely, to some underlying pathology intrinsic to pediatric kidneys with urolithiasis. Until further data are available, SWL in the pediatric population should be applied with caution and at the lowest dosage sufficient to achieve stone comminution.

Stone comminution and tissue damage in lithotripsy are sensitive to the acoustic field within the kidney, yet knowledge of shock waves in vivo is limited. We have made measurements of lithotripsy shock waves inside pigs with small hydrophones constructed of a 25-microm PVDF membrane stretched over a 21-mm diameter ring. A thin layer of silicone rubber was used to isolate the membrane electrically from pig fluid. A hydrophone was positioned around the pig kidney following a flank incision. Hydrophones were placed on either the anterior (shock wave entrance) or the posterior (shock wave exit) surface of the left kidney. Fluoroscopic imaging was used to orient the hydrophone perpendicular to the shock wave. For each pig, the voltage settings (12-24 kV) and the position of the shock wave focus within the kidney were varied. Waveforms measured within the pig had a shape very similar to those measured in water, but the peak pressure was about 70% of that in water. The focal region in vivo was 82 mm x 20 mm, larger than that measured in vitro (57 mm x 12 mm). It appeared that a combination of nonlinear effects and inhomogeneities in the tissue broadened the focus of the lithotripter. The shock rise time was on the order of 100 ns, substantially more than the rise time measured in water, and was attributed to higher absorption in tissue.

Open surgery for removal of upper urinary tract stones has long been associated with a high morbidity and mortality. So when shock wave (SW) lithotripsy (SWL) was introduced in the early 1980s, the climate was right for acceptance of a noninvasive method for stone comminution. The growth in popularity of SWL was extremely rapid, based in part on the perception that it was entirely safe [1]. Now, after a decade of clinical SWL, experience tells us differently. SWL may be very effective at breaking kidney stones, but it can also cause severe renal trauma that can lead to irreversible long-term complications [2, 3].

This study tested the hypothesis that the effects of SWL on hemodynamics in solitary kidneys differ from those in kidneys of binephric animals. Five female miniature pigs (Pitman-Moore, 6 months of age, 30-35 kg) were anesthetized for unilateral nephrectomy. Seven pigs served as binephric controls. Two weeks later, each pig was anesthetized, prepared for unilateral or bilateral urine collections, and subjected to SWL (Dornier HM3, 2000 shocks, 24 kV). Clearances of inulin (glomerular filtration rate; GFR) and para-aminohippurate (renal plasma flow; RPF) were measured 1 hour prior to and 1, 4, and 24 hours after SWL. The GFR and RPF were higher in uninephrectomized than in intact pigs at all time points. In both groups, SWL reduced GFR and RPF. In the binephric pigs, RPF was reduced at all times post-SWL, but in the uninephrectomized pigs, RPF was returning toward baseline by 4 hours post-SWL and was not different from baseline at 24 hours. A comparison of whole-animal GFR and RPF (righ plus left clearances in binephric pigs v solitary renal clearances in uninephrectomized pigs) showed that whole-animal GFR and RPF did not differ between the groups before or after SWL. Compensatory renal hypertrophy and improved hemodynamics in solitary kidneys may acutely attenuate the renal vasoconstrictive effect of SWL. The long-term consequences of the compensatory changes are unknown.

Two genes whose expression is likely to be altered during diabetes mellitus are aldose reductase (AD) and insulin-like growth factor-I (IGF-I). We proposed that gene expression of AD is increased in vascular smooth muscle during diabetes mellitus due to hyperglycemia, while IGF-I expression is decreased in insulin-deficient diabetes and elevated in insulin-resistant diabetes. The mRNA for both was measured in the renal glomerulus, in the vascular smooth muscle of large arterioles from the brain, kidney, and small intestine, and in the aorta of hypoinsulinemic streptozotocin (STZ)-treated rats and hyperinsulinemic Zucker diabetic fatty (ZDF) rats. Quantitative in situ hybridization was used to determine variations in expression. Expression of the AD gene was unchanged in STZ and ZDF rats, except for a decrease of about 50% in glomeruli and renal smooth muscle of STZ diabetic rats. Expression of IGF-I generally decreased in vascular smooth muscle of insulin-depleted STZ diabetic rats, but was normal in hyperinsulinemic ZDF rats. The data indicate that decreased expression of the AD gene is a specific problem in renal vascular smooth muscle and glomeruli in the insulin-depleted STZ model of diabetes. The expression of the IGF-I gene in vascular muscle was decreased in hypoinsulinemic diabetic animals, but did not increase in hyperinsulinemic diabetic rats.

Crystals are particles of endogenous inorganic or organic composition that can trigger kidney injury when deposited or formed inside the kidney. While decades of research have focused on the molecular mechanisms of solute supersaturation and crystal formation, the pathomechanisms of crystal-induced renal inflammation remain largely unknown. The recent discovery of the intracellular NLRP3 inflammasome as a pattern recognition platform that translates crystal uptake into innate immune activation via secretion of IL-1β and IL-18 revised the pathogenesis of gout, silicosis, asbestosis, atherosclerosis and other crystal-related disorders. As a proof of concept, the NLRP3 inflammasome was now shown to trigger inflammation and acute kidney injury (AKI) in oxalate nephropathy. It seems likely that this and potentially other innate immunity mechanisms drive crystalline nephropathies (CNs) that are associated with crystals of calcium phosphate, uric acid, cysteine, adenine, certain drugs or contrast media, and potentially of myoglobin during rhabdomyolysis and of light chains in myeloma. Here, we discuss the proven and potential mechanisms of renal inflammation and kidney injury in crystal-related kidney disorders. In addition, we list topics for further research in that field. This perspective may also provide novel therapeutic options that can help to avoid progressive tissue remodeling and chronic kidney disease in patients with kidney stone disease or other CNs.