Relationship of endoscopic lesions of the renal papilla with type of renal stone and 24 h urine analysis.

BACKGROUND: Our purpose was to study the relationship of the 3 different types of endoscopic calcifications of the renal papilla (Randall's plaque, intratubular calcification, papillary crater) with the type of stone and urine analysis. METHODS: This prospective study examined 41 patients (age range: 18 to 80 years) who received retrograde intrarenal surgery (RIRS) for renal lithiasis (mean stone size: 15.3 ± 7.2 mm). The renal papilla injuries were endoscopically classified as Randall's plaque, intratubular calcification, or papillary crater. Calculi were classified as uric acid, calcium oxalate monohydrate (COM; papillary and cavity), calcium oxalate dihydrate (COD), or calcium phosphate (CP). A 24 h urine analysis of calcium, oxalate, citrate, phosphate, and pH was performed in all patients. The relationship of each type of papillary injury with type of stone and urine chemistry was determined. Fisher's exact test and Student's t-test were used to determine the significance of relationships, and a p value below 0.05 was considered significant. RESULTS: The most common injury was tubular calcification (78%), followed by Randall's plaque (58%), and papillary crater (39%). There was no significant relationship of Randall's plaque with type of stone. However, endoscopic intratubular calcification (p = 0.025) and papillary crater (p = 0.041) were more common in patients with COD and CP stones. There were also significant relationships of papillary crater with hypercalciuria (p = 0.036) and hyperoxaluria (p = 0.024), and of Randall's plaque with hypocitraturia (p = 0.005). CONCLUSIONS: There are certain specific relationships between the different types of papillary calcifications that were endoscopically detected with stone chemistry and urine analysis. COD and CP stones were associated with endoscopic tubular calcifications and papillary craters. Hypercalciuria was associated with tubular calcification, and hypocitraturia was associated with Randall's plaque.

The Effect of Cortex/Medulla Proportions on Molecular Diagnoses in Kidney Transplant Biopsies: Rejection and Injury Can Be Assessed in Medulla.

Histologic assessment of kidney transplant biopsies relies on cortex rather than medulla, but for microarray studies, the proportion cortex in a biopsy is typically unknown and could affect the molecular readings. The present study aimed to develop a molecular estimate of proportion cortex in biopsies and examine its effect on molecular diagnoses. Microarrays from 26 kidney transplant biopsies divided into cortex and medulla components and processed separately showed that many of the most significant differences were in glomerular genes (e.g. NPHS2, NPHS1, CLIC5, PTPRO, PLA2R1, PLCE1, PODXL, and REN). Using NPHS2 (podocin) to estimate proportion cortex, we examined whether proportion cortex influenced molecular assessment in the molecular microscope diagnostic system. In 1190 unselected kidney transplant indication biopsies (Clinicaltrials.govNCT01299168), only 11% had <50% cortex. Molecular scores for antibody-mediated rejection, T cell-mediated rejection, and injury were independent of proportion cortex. Rejection was diagnosed in many biopsies that were mostly or all medulla. Agreement in molecular diagnoses in paired cortex/medulla samples (23/26) was similar to biological replicates (32/37). We conclude that NPHS2 expression can estimate proportion cortex; that proportion cortex has little influence on molecular diagnosis of rejection; and that, although histology cannot assess medulla, rejection does occur in medulla as well as cortex.

Renal medullary and urinary oxygen tension during cardiopulmonary bypass in the rat.

Renal hypoxia could result from a mismatch in renal oxygen supply and demand, particularly in the renal medulla. Medullary hypoxic damage is believed to give rise to acute kidney injury, which is a prevalent complication of cardiac surgery performed on cardiopulmonary bypass (CPB). To determine the mechanisms that could lead to medullary hypoxia during CPB in the rat kidney, we developed a mathematical model which incorporates (i) autoregulation of renal blood flow and glomerular filtration rate, (ii) detailed oxygen transport and utilization in the renal medulla and (iii) oxygen transport along the ureter. Within the outer medulla, the lowest interstitial tissue P$_{\rm O2}$, which is an indicator of renal hypoxia, is predicted near the thick ascending limbs. Interstitial tissue P$_{\rm O2}$ exhibits a general decrease along the inner medullary axis, but urine P$_{\rm O2}$ increases significantly along the ureter. Thus, bladder urinary P$_{\rm O2}$ is predicted to be substantially higher than medullary P$_{\rm O2}$. The model is used to identify the phase of cardiac surgery performed on CPB that is associated with the highest risk for hypoxic kidney injury. Simulation results indicate that the outer medulla's vulnerability to hypoxic injury depends, in part, on the extent to which medullary blood flow is autoregulated. With imperfect medullary blood flow autoregulation, the model predicts that the rewarming phase of CPB, in which medullary blood flow is low but medullary oxygen consumption remains high, is the phase in which the kidney is most likely to suffer hypoxic injury.

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

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

Analysis of microcracks caused by drop shatter testing of porcine kidneys.

Although kidney trauma is a relatively common injury, its microscopic biomechanics are poorly understood. Experimental low-grade trauma in pig kidneys was studied using optical microscopy. We observed ruptures in the cortex as well as in the medulla. Both parts of the renal parenchyma were damaged, even in areas of the kidneys that were free of macroscopic cracks on the surface. To determine which constituents of the renal cortex and medulla, i.e. tubular parts of the nephron or the interstitial connective tissue, were less resistant to injury during the drop shatter test, we applied a simple stereological method to discriminate between random and tissue-specific rupture propagation. The ruptures propagated predominantly through the interstitial connective tissue of the renal cortex and medulla. The volume fraction of the tubules assessed by the Cavalieri principle was 90.4% within the renal cortex and 52.4% within the medulla. The most frequently affected blood vessels were the arcuate and interlobular veins, followed by the arcuate and interlobular arteries. No disruptions of the renal calyces were found.

Postnatal adrenalectomy impairs urinary concentrating ability by increased COX-2 and leads to renal medullary injury.

We hypothesized that aldosterone promotes development of the renal medulla in the postnatal period and that cyclooxygenase-2 (COX-2) activity contributes to renal dysfunction after impaired aldosterone signaling. To test these hypotheses, rat pups underwent either sham operation or adrenalectomy at postnatal day 10. Adrenalectomized rats were divided into no steroid substitution (ADX), corticosterone replacement (ADX-C), and corticosterone and DOCA substitution (ADX-CD) groups that received subcutaneous pellets with steroids. Without replacement, pups failed to thrive and exhibited impaired urinary-concentrating ability. The renal medulla was significantly smaller, and the medullary interstitial osmolality was lower in the ADX group, whereas COX-2 and PGE2 tissue levels were significantly elevated compared with levels shown in sham animals. Substitution with DOCA and corticosterone corrected these changes, whereas corticosterone replacement alone improved survival but not weight gain and urinary-concentrating ability. Administration of a COX-2 inhibitor to ADX rats (parecoxib, 5 mg.kg(-1).day(-1), days 17-20) increased weight gain, urinary-concentrating ability, and papillary osmolality. After fluid deprivation, parecoxib attenuated weight loss and the increase in plasma Na+ concentration and osmolality. It is concluded that mineralocorticoid is required for normal postnatal development of the renal medulla. COX-2 contributes to impaired urine-concentrating ability, NaCl loss, and extracellular volume depletion in postnatal mineralocorticoid deficiency.

A cumulative shear mechanism for tissue damage initiation in shock-wave lithotripsy.

Evidence suggests that inertial cavitation plays an important role in the renal injury incurred during shock-wave lithotripsy. However, it is unclear how tissue damage is initiated, and significant injury typically occurs only after a sufficient dose of shock waves. Although it has been suggested that shock-induced shearing might initiate injury, estimates indicate that individual shocks do not produce sufficient shear to do so. In this paper, we hypothesize that the cumulative shear of the many shocks is damaging. This mechanism depends on whether there is sufficient time between shocks for tissue to relax to its unstrained state. We investigate the mechanism with a physics-based simulation model, wherein the basement membranes that define the tubules and vessels in the inner medulla are represented as elastic shells surrounded by viscous fluid. Material properties are estimated from in-vitro tests of renal basement membranes and documented mechanical properties of cells and extracellular gels. Estimates for the net shear deformation from a typical lithotripter shock (approximately 0.1%) are found from a separate dynamic shock simulation. The results suggest that the larger interstitial volume (approximately 40%) near the papilla tip gives the tissue there a relaxation time comparable to clinical shock delivery rates (approximately 1 Hz), thus allowing shear to accumulate. Away from the papilla tip, where the interstitial volume is smaller (approximately 20%), the model tissue relaxes completely before the next shock would be delivered. Implications of the model are that slower delivery rates and broader focal zones should both decrease injury, consistent with some recent observations.

Effect of renal medullary H2O2 on salt-induced hypertension and renal injury.

Dahl salt-sensitive (SS) and consomic, salt-resistant SS-13(BN) rats possess substantial differences in blood pressure salt-sensitivity even with highly similar genetic backgrounds. The present study examined whether increased oxidative stress, particularly H2O2, in the renal medulla of SS rats contributes to these differences. Blood pressure was measured using femoral arterial catheters in three groups of rats: 1) 12-wk-old SS and consomic SS-13(BN) rats fed a 0.4% NaCl diet, 2) SS rats fed a 4% NaCl diet and chronically infused with saline or catalase (6.9 microg x kg(-1) x min(-1)) directly into the renal medulla, and 3) SS-13(BN) fed high salt (4%) and infused with saline or H2O2 (347 nmol x kg(-1) x min(-1)) into the renal medullary interstitium. After chronic blood pressure measurements, renal medullary interstitial H2O2 concentration ([H2O2]) was collected by microdialysis and analyzed with Amplex red. Blood pressure and [H2O2] were both significantly higher in SS (126 +/- 3 mmHg and 145 +/- 17 nM, respectively) vs. SS-13(BN) rats (116 +/- 2 mmHg and 56 +/- 14 nM) fed a 0.4% diet. Renal interstitial catalase infusion significantly decreased [H2O2] (96 +/- 41 vs. 297 +/- 52 nM) and attenuated the hypertension (146 +/- 2 mmHg catalase vs. 163 +/- 4 mmHg saline) in SS rats after 5 days of high salt (4%). H2O2 infused into the renal medulla of consomic SS-13(BN) fed high salt (4%) for 7 days accentuated the salt sensitivity (145 +/- 2 mmHg H2O2 vs. 134 +/- 1 mmHg saline). [H2O2] was also increased in the treated group (83 +/- 1 nM H2O2 vs. 44 +/- 9 nM saline). These data show that medullary production of H2O2 may contribute to salt-induced hypertension in SS rats and that chromosome 13 of the Brown Norway contains gene(s) that protect against renal medullary oxidant stress.

Influence of colloid, preservation medium and trimetazidine on renal medulla injury.

In organ transplantation, preservation injury is an important factor which could influence short-term and long-term graft outcome. The renal medulla is particularly sensitive to oxidant stress and ischemia-reperfusion injury (IRI). Using an autotransplant pig kidney model, we investigated renal function and medullary damage determined between day 1 and week 2 after 24- or 48-h cold storage in different preservation solutions: University of Wisconsin solution (UW), Hopital Edouard Herriot solution (a high Na+ version of UW), ECPEG (high Na+ preservation solution with PEG) and ICPEG (a high K+ version of ECPEG) with or without trimetazidine (TMZ). TMZ improved renal preservation and increased renal function when added in each preservation solution (particularly HEH and ECPEG). Medullary damage led to the early appearance of trimethylamine-N-oxide (TMAO) followed by 1H-NMR in urine and plasma. TMZ and ECPEG is the most efficient association to reduce medullary damage. This study clarifies the role of colloid and polarity solution and the role of mitochondrial protection by TMZ.

Morphological changes induced in the pig kidney by extracorporeal shock wave lithotripsy: nephron injury.

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.

Repetitive brief ischemia: intermittent reperfusion during ischemia ameliorates the extent of injury in the perfused kidney.

Acute renal failure commonly follows reduced renal perfusion or ischemia. Reperfusion is essential for recovery but can itself cause functional and structural injury to the kidney. The separate contributions of ischemia and of reperfusion were examined in the isolated perfused rat kidney. Three groups were studied: brief (5 min) ischemia, 20 min ischemia, and repetitive brief ischemia (4 periods of 5 min) with repetitive intervening reperfusion of 5 min. A control group had no intervention, the three ischemia groups were given a baseline perfusion of 30 min before intervention and all groups were perfused for a total of 80 min. In addition, the effects of exogenous *NO from sodium nitroprusside and xanthine oxidase inhibition by allopurinol were assessed in the repetitive brief ischemia-reperfusion model. Brief ischemia produced minimal morphological injury with near normal functional recovery. Repetitive brief ischemia-reperfusion caused less functional and morphological injury than an equivalent single period of ischemia (20 min) suggesting that intermittent reperfusion is less injurious than ischemia alone over the time course of study. Pretreatment with allopurinol improved renal function after repetitive brief ischemia-reperfusion compared with the allopurinol-untreated repetitive brief ischemia-reperfusion group. Similarly, sodium nitroprusside reduced renal vascular resistance but did not improve the glomerular filtration rate or sodium reabsorption in the repetitive brief ischemia-reperfusion model. Thus, these studies show that the duration of uninterrupted ischemia is more critical than reperfusion in determining the extent of renal ischemia-reperfusion injury and that allopurinol, in particular, counteracts the oxidative stress of reperfusion.

Conservative management with percutaneous intervention of major blunt renal injuries.

This retrospective study assessed the results of treatment of patients with renal trauma to determine the optimal management (conservative or surgical) for patients with grade III renal injuries. During the past 12 years 108 patients (including 43 children) with renal injuries were managed: 43 had grade I injuries (renal contusion), 33 had grade II (minor laceration), 31 had grade III (major laceration), and 1 had grade IV (pedicle injury). All patients with grades I and II injuries were successfully managed conservatively. The patient with renal pedicle injury underwent uneventful nephrectomy. Nineteen patients with grade III injuries (including 5 patients with shattered kidneys and 3 patients with polar avulsion) were managed conservatively, and 2 developed progressively enlarging urinomas that required percutaneous drainage with complete resolution. No patient in this group developed perinephric abscess or urinary fistulae, and no delayed nephrectomy was necessary. Long-term follow-up of 7 patients in this group, including 3 with shattered kidneys and 2 with polar avulsion, showed that none have developed hypertension. Twelve patients with grade III injuries were managed surgically. Six (50%) patients underwent total (4 patients) or partial (2 patients) nephrectomy. In 6 patients, the surgical intervention was only open drainage of the perinephric collection and/or parenchymal suturing. It was concluded that conservative management with timely percutaneous or endoscopic intervention in patients with major renal injuries results in minimal loss of renal tissue without significant late complications.

Early renal medullary hypoxic injury from radiocontrast and indomethacin.

We evaluated the acute changes in cortical and outer medullary oxygen tension and the alterations in renal function and morphology within the first 90 minutes after the administration of indomethacin and iothalamate to anesthetized Sprague-Dawley rats. Both agents were found to produce marked and protracted outer medullary hypoxia averaging 12 +/- 4 and 9 +/- 2 mm Hg, respectively (mean +/- SE). Given together to salt depleted uninephrectomized rats they produced an early hypoxic injury localized selectively in the outer medulla. This lesion progressed from 3 +/- 1% of medullary thick ascending limbs (mTALs) at 15 minutes to 22 +/- 7% at 24 hours. Condensed "dark" cells were observed at 15 minutes, probably representing a type of early injury. Residual red cell mass, quantified in the outer medullary vasculature of perfusion-fixed kidneys and presumably reflecting stasis, was substantially increased in iothalamate treated rats. Red cell mass in the interbundle zone correlated with mTAL necrosis. Taken together, these results show an early period of medullary hypoxia, accompanied by a selective injury to mTALs in the central interbundle zone with apparent stasis. These findings contrast sharply with the ischemia-reflow pattern of renal damage and emphasize the important role of medullary hypoxia in the genesis of acute renal failure in this model.

Effect of glycine on medullary thick ascending limb injury in perfused kidneys.

The addition of 2 mM glycine to the recirculating perfusate of isolated perfused rat kidneys almost completely prevented the severe morphological injury to tubular cells lining the medullary thick ascending limb (mTAL) that normally develops in this preparation. Glycine was similarly effective in reducing mTAL injury associated with hypoxic perfusion, indomethacin and amphotericin. Fractional reabsorption of sodium was increased with glycine, without any change in perfusate flow to the whole kidney and without consistent improvement in GFR. L-alanine demonstrated a similar though less pronounced cytoprotective action, but glutamine, cysteine, glutamate, cysteine plus glutamate, 1-serine and 4-aminoisobutyric acid all had little or no effect in preventing severe mTAL injury. The protective effect of glycine was unimpaired by the arginine analogue NG-monomethyl-l-arginine (L-NMMA), suggesting that the endothelial-derived relaxing factor, NO, was not involved. The action of glycine was not reduced by the addition of a substrate (benzoate) or a product (hippurate) of the glycine N-acyltransferase reaction. Glycine did not depress the respiration of dispersed mTALs prepared from rat kidneys. The cytoprotective effect of glycine in the mTAL of perfused kidneys, shared with l-alanine, appears to be relatively specific for these amino acids and probably unrelated to a diminution in cell work.

Attempted nonoperative management of blunt renal lacerations extending through the corticomedullary junction: the short-term and long-term sequelae.

A total of 50 patients who sustained a renal laceration extending through the corticomedullary junction following blunt trauma underwent an attempt at nonoperative (expectant) management of the urological injury. Of the patients 18% could not be stabilized and they subsequently underwent emergency laparotomy. Among our stabilized patients 2 major categories existed: 1) 30 patients with vascularized renal fragments and 2) 11 in whom a fragment of the kidney was devascularized. A statistically significant difference in the length of hospital stay (p equals 0.01) and the need for delayed surgical intervention (p less than 0.001) was noted between the 2 groups. We recommend that the physician must have a heightened awareness of probable complications in patients with major renal lacerations associated with devitalized fragments and suggest that early surgical management should be considered.

Comparative studies of cellular reactions to injuries between the inner medulla and the cortex of rat kidneys.

The inner medulla and the cortex of the rat kidney were surgically traumatized or threaded with a silk suture, and the sequence of morphologic events occurring in these two topographic locations were studied by light microscopy on Days 7, 14, and 28. On Days 7, 14, and 28 following the infliction of the surgical trauma, such cellular reactions as mononuclear cell infiltration and fibroblastic proliferation were less intense in the injured site of the inner medulla than in the cortex. Numerous foreign body type giant cells appeared about the suture material in the cortex as early as Day 7 and were persistently present on Days 14 and 28. A similar type of foreign body giant cells did not appear about the suture material within the inner medulla throughout the experiment. Our results suggest that there is a difference in cellular reaction to injury or to a foreign body between the inner medulla and the cortex of rat kidneys.