Hypovolemic models of acute tubular necrosis in the rat kidney.

Studies were undertaken to determine whether a hypotensive episode under variable conditions is capable of inducing experimental acute renal failure in rats. Animals were subjected to hypovolemic shock by withdrawing volumes of blood necessary to maintain a systolic pressure of 30-40 mm Hg for 105-110 min. The blood was then reinfused and the animal was allowed to recover for 48 h prior to sacrifice. In an attempt to increase the injury, a second group of animals was salt-depleted prior to injury, a third group was volume-depleted by being deprived of H2O for 72 h prior of injury, a fourth group received 7.5 mg/kg indomethacin 30 min prior to injury, and a fifth group had 30% of the blood which was removed to produce shock hemolyzed and returned following the injury. In all groups examined, light microscopy revealed a moderate to severe acute tubular necrosis localized mainly in the outer stripe of the outer zone as defined by Peter (1909). Tubular damage was confined to the medullary pars recta of the proximal tubule and only in the most severe cases did injury involve the cortical pars recta and pars convoluta. Casts were present in the distal tubules and collecting ducts. Despite these significant histologic alterations, BUN values from all experimental groups remained within control levels. These studies clearly show that extensive necrosis of the medullary pars recta can be dissociated from the development of acute renal failure.     

重症急性肾损伤患者经连续性肾脏替代治疗后肾功能恢复的影响因素

目的：通过研究重症急性肾损伤患者经连续性’肾脏替代治疗后肾功能恢复的影响因素,为重症急性肾损伤患者的诊治及预后提供科学依据。方法：选取2009年7月至2013年10月本院住院且采用CRRT治疗的284例重症急性肾损伤患者,记录患者的一般资料、APACHEII评分、血液生化指标、伴随症状及肾功能预后情况,将预后情况和各影响因素进行Logistic回归分析得出影响。肾功能恢复的影响因素。结果：284例重症急性肾损伤患者中,肾功能恢复有89例（31．33％）;肾功能恢复组的年龄、衰竭器官数、APACHEⅡ评分、动脉血二氧化碳分压、合并慢性肾脏病率及合并严重基础疾病率均低于肾功能未恢复组,而平均动脉压和血小板计数高于肾功能未恢复组（P〈0．05）,两组间合并机械通气率和合并少／无尿率无统计学差异（P〉0．05）;衰竭器官数、APAC—HEⅡ评分、合并严重基础疾病及AKl分期为CRRT治疗重症急性肾损伤患者肾功能恢复的危险因素。结论：CRRT治疗重症急性肾损伤的主要危险因素为衰竭器官数、APACHEⅡ评分、合并严重基础疾病及AKl分期。在临床治疗中,应正确评估病情,早期及时采取CRRT治疗,以提高生存率,促进肾脏功能恢复。     

Loxosceles gaucho venom-induced acute kidney injury--in vivo and in vitro studies

Background

Accidents caused by Loxosceles spider may cause severe systemic reactions, including acute kidney injury (AKI). There are few experimental studies assessing Loxosceles venom effects on kidney function in vivo.

Methodology/Principal Findings

In order to test Loxosceles gaucho venom (LV) nephrotoxicity and to assess some of the possible mechanisms of renal injury, rats were studied up to 60 minutes after LV 0.24 mg/kg or saline IV injection (control). LV caused a sharp and significant drop in glomerular filtration rate, renal blood flow and urinary output and increased renal vascular resistance, without changing blood pressure. Venom infusion increased significantly serum creatine kinase and aspartate aminotransferase. In the LV group renal histology analysis found acute epithelial tubular cells degenerative changes, presence of cell debris and detached epithelial cells in tubular lumen without glomerular or vascular changes. Immunohistochemistry disclosed renal deposition of myoglobin and hemoglobin. LV did not cause injury to a suspension of fresh proximal tubules isolated from rats.

Conclusions/Significance

Loxosceles gaucho venom injection caused early AKI, which occurred without blood pressure variation. Changes in glomerular function occurred likely due to renal vasoconstriction and rhabdomyolysis. Direct nephrotoxicity could not be demonstrated in vitro. The development of a consistent model of Loxosceles venom-induced AKI and a better understanding of the mechanisms involved in the renal injury may allow more efficient ways to prevent or attenuate the systemic injury after Loxosceles bite.     

Ischemic Acute Kidney Injury Perturbs Homeostasis of Serine Enantiomers in the Body Fluid in Mice: Early Detection of Renal Dysfunction Using the Ratio of Serine Enantiomers

The imbalance of blood and urine amino acids in renal failure has been studied mostly without chiral separation. Although a few reports have shown the presence of D-serine, an enantiomer of L-serine, in the serum of patients with severe renal failure, it has remained uncertain how serine enantiomers are deranged in the development of renal failure. In the present study, we have monitored serine enantiomers using a two-dimensional HPLC system in the serum and urine of mice after renal ischemia-reperfusion injury (IRI), known as a mouse model of acute kidney injury. In the serum, the level of D-serine gradually increased after renal IRI in parallel with that of creatinine, whereas the L-serine level decreased sharply in the early phase after IRI. The increase of D-serine was suppressed in part by genetic inactivation of a D-serine-degrading enzyme, D-amino acid oxidase (DAO), but not by disruption of its synthetic enzyme, serine racemase, in mice. Renal DAO activity was detected exclusively in proximal tubules, and IRI reduced the number of DAO-positive tubules. On the other hand, in the urine, D-serine was excreted at a rate nearly triple that of L-serine in mice with sham operations, indicating that little D-serine was reabsorbed while most L-serine was reabsorbed in physiological conditions. IRI significantly reduced the ratio of urinary D−/L-serine from 2.82±0.18 to 1.10±0.26 in the early phase and kept the ratio lower than 0.5 thereafter. The urinary D−/L-serine ratio can detect renal ischemia earlier than kidney injury molecule-1 (KIM-1) or neutrophil gelatinase-associated lipocalin (NGAL) in the urine, and more sensitively than creatinine, cystatin C, or the ratio of D−/L-serine in the serum. Our findings provide a novel understanding of the imbalance of amino acids in renal failure and offer a potential new biomarker for an early detection of acute kidney injury.     

Intrarenal haemodynamics in uranyl nitrate-induced acute renal failure

Intrarenal haemodynamics were investigated in the dog at various intervals after the iv. injection of 10 mg/kg uranyl nitrate (UN). Renal blood flow (RBF), as determined by measuring the renal venous effluent and by radioactive microspheres, decreased by about 23% at 6 hr after UN administration, as compared to normal controls, then rose and reached controls at 24 to 48 hr; subsequently, RBF increased and surpassed controls by about 36% at 96 hr. Thus, the early phase (6 hr) and the late phase (96 hr) of uranyl nitrate-induced acute renal failure (UNARF) were characterized by an increase and by a decrease, respectively, in overall renal vascular resistance. Glomerular filtration rate (GFR) diminished to about 37% of controls at 6 hr, with no change in urinary output (V). In the following hours, however, GFR and V fell quickly and reached practically zero at 12 to 24 hr. Approximate calculations revealed a predominantly preglomerular vasoconstriction in the early phase and post-glomerular vasodilatation in the late phase. Radioactive microspheres showed a nearly proportionate decrease in perfusion of all cortical layers in the early phase (6 hr); in the late phase (96 hr), however, blood flow to the outermost layer remained unaltered, while perfusion of the inner cortical and juxtamedullary layers increased significantly.     

Renal actions of atrial natriuretic peptide on the postischemic kidney

The objective of this study was to evaluate the renal actions of atrial natriuretic peptide (ANP) in the unilateral postischemic kidney of anesthetized dogs with a severe reduction in glomerular filtration rate. The dose of atrial natriuretic peptide (50 ng.kg-1.min-1) we gave did not alter the mean systemic arterial pressure, renal blood flow, and glomerular filtration rate in the normal kidney, as determined in foregoing studies. ANP was infused into the intrarenal artery continuously for 60 min after the release from 45 min of complete renal artery occlusion. In the vehicle-infused group, the glomerular filtration rate fell dramatically (6% of control), the renal blood flow decreased (60% of control), and the mean systemic arterial pressure tended to increase (136% of control). The urine flow rate and urinary excretion of sodium decreased significantly (25 and 25%, respectively) at 30 min after reflow in the postischemic period. Continuous renal artery infusion of ANP resulted in a marked increase in urine flow rate (246% of control) and the urinary excretion of sodium (286% of control). The administration of ANP led to an improvement in renal blood flow (99% of control) and glomerular filtration rate (40% of control), and attenuated the rise in mean systemic arterial pressure (109% of control), compared with findings in the vehicle-infused group. Plasma renin activity and prostaglandin E2 concentration in the renal venous blood were elevated after the release from complete renal artery occlusion in both groups. These results indicate that the vascular effects of ANP on the postischemic kidney were enhanced and that the peptide maintained the natriuretic effect.     

Reversal of anemia with allogenic RBC transfusion prevents post-cardiopulmonary bypass acute kidney injury in swine

Anemia during cardiopulmonary bypass (CPB) is strongly associated with acute kidney injury in clinical studies; however, reversal of anemia with red blood cell (RBC) transfusions is associated with further renal injury. To understand this paradox, we evaluated the effects of reversal of anemia during CPB with allogenic RBC transfusion in a novel large-animal model of post-cardiac surgery acute kidney injury with significant homology to that observed in cardiac surgery patients. Adult pigs undergoing general anesthesia were allocated to a Sham procedure, CPB alone, Sham+RBC transfusion, or CPB+RBC transfusion, with recovery and reassessment at 24 h. CPB was associated with dilutional anemia and caused acute kidney injury in swine characterized by renal endothelial dysfunction, loss of nitric oxide (NO) bioavailability, vasoconstriction, medullary hypoxia, cortical ATP depletion, glomerular sequestration of activated platelets and inflammatory cells, and proximal tubule epithelial cell stress. RBC transfusion in the absence of CPB also resulted in renal injury. This was characterized by endothelial injury, microvascular endothelial dysfunction, platelet activation, and equivalent cortical tubular epithelial phenotypic changes to those observed in CPB pigs, but occurred in the absence of severe intrarenal vasoconstriction, ATP depletion, or reductions in creatinine clearance. In contrast, reversal of anemia during CPB with RBC transfusion prevented the reductions in creatinine clearance, loss of NO bioavailability, platelet activation, inflammation, and epithelial cell injury attributable to CPB although it did not prevent the development of significant intrarenal vasoconstriction and endothelial dysfunction. In conclusion, contrary to the findings of observational studies in cardiac surgery, RBC transfusion during CPB protects pigs against acute kidney injury. Our study underlines the need for translational research into indications for transfusion and prevention strategies for acute kidney injury.     

Renal Cortical Lactate Dehydrogenase: A Useful,Accurate, Quantitative Marker of In Vivo Tubular Injury and Acute Renal Failure

Studies of experimental acute kidney injury (AKI) are critically dependent on having precise methods for assessing the extent of tubular cell death. However, the most widely used techniques either provide indirect assessments (e.g., BUN, creatinine), suffer from the need for semi-quantitative grading (renal histology), or reflect the status of residual viable, not the number of lost, renal tubular cells (e.g., NGAL content). Lactate dehydrogenase (LDH) release is a highly reliable test for assessing degrees of in vitro cell death. However, its utility as an in vivo AKI marker has not been defined. Towards this end, CD-1 mice were subjected to graded renal ischemia (0, 15, 22, 30, 40, or 60 min) or to nephrotoxic (glycerol; maleate) AKI. Sham operated mice, or mice with AKI in the absence of acute tubular necrosis (ureteral obstruction; endotoxemia), served as negative controls. Renal cortical LDH or NGAL levels were assayed 2 or 24 hrs later. Ischemic, glycerol, and maleate-induced AKI were each associated with striking, steep, inverse correlations (r, −0.89) between renal injury severity and renal LDH content. With severe AKI, >65% LDH declines were observed. Corresponding prompt plasma and urinary LDH increases were observed. These observations, coupled with the maintenance of normal cortical LDH mRNA levels, indicated the renal LDH efflux, not decreased LDH synthesis, caused the falling cortical LDH levels. Renal LDH content was well maintained with sham surgery, ureteral obstruction or endotoxemic AKI. In contrast to LDH, renal cortical NGAL levels did not correlate with AKI severity. In sum, the above results indicate that renal cortical LDH assay is a highly accurate quantitative technique for gauging the extent of experimental acute ischemic and toxic renal injury. That it avoids the limitations of more traditional AKI markers implies great potential utility in experimental studies that require precise quantitation of tubule cell death.     

Novel finding of caveolin-2 in apical membranes of proximal tubule and first detection of caveolin-2 in urine: A promising biomarker of renal disease

Caveolin-2 (Cav-2) is expressed in a variety of cell tissue, and it has also been found in renal tissue. The expression of Cav-2 in proximal tubules is still unclear. The aim of this study was to carry out a complete evaluation of the expression pattern of Cav-2 in rat renal cortex to clarify and deepen the knowledge about the localization of Cav-2 in the proximal tubules and also to evaluate its presence in urine. Male Wistar rats were used to assess Cav-2 expression by Western blot analysis in homogenates, apical, and basolateral membranes from kidney cortex, in lysates and total plasma membranes from renal cortical cell suspensions, in urine, and in urinary exosomes. Cav-2 was clearly expressed in renal cortex homogenates and in both apical and basolateral membranes isolated from kidney cortex, with a greater expression on the former membranes. It was also observed in lysates and in plasma membranes from cortical cell suspensions. Moreover, Cav-2 was found in urine and in its exosomal fraction. These results confirmed the presence of Cav-2 in proximal tubule cells in the kidney of healthy rats, and showed for the first time its expression at the apical membrane of these cells and in urine. Besides, urinary exosomal pathway could be involved in Cav-2 urinary excretion under normal conditions. We observed an increase in the urinary abundance of Cav-2 in two models of acute kidney injury, and thus we proposed the urinary excretion of Cav-2 as a potential biomarker of kidney injury.     

Modulation of renal hemodynamics by renal eicosanoids during vasopressor infusions in man

Pressor doses of norepinephrine (NE) (n = 8) and angiotensin II (A II) (n = 5) were infused in normal volunteers to determine whether the systemic administration of vasopressor hormones influence renal eicosanoid production and whether, in turn, the eicosanoids produced could modulate renal hemodynamics and electrolyte excretion. At the doses administered, both pressor substances induced the expected rise in blood pressure, a significant decrease (P less than 0.05) in renal blood flow and a proportionally smaller fall in glomerular filtration rate, resulting in a consistent augmentation in filtration fraction. Fractional sodium excretion was concomitantly reduced. NE infusion produced only slight modifications in urinary prostaglandin (PG)E2, 2,3-dinor-6-keto-PGF1 alpha and thromboxane (TX)B2, while urinary 6-keto-PGF1 alpha and PGF2 alpha were increased by 38% and 176% respectively. The increase in urinary 6-keto-PGF1 alpha (the non-enzymatic degradation product of PGI2, predominantly of cortical origin) was proportional to the level of circulating NE (r = 0.78, P less than 0.05) and to the renal vascular resistance (r = 0.85, P less than 0.01), suggesting an immediate compensatory role for PGI2 in response to the NE-induced pressor stimulus. The renal production of PGE2 and PGF2 alpha (predominantly medullary) was inversely correlated with the filtration fraction: the greater the increase in PGE2 and PGF2 alpha the lower the elevation in filtration fraction or the decline in renal blood flow upon NE administration. All infusion variably stimulated the renal eicosanoid production: PGE2, 41%; PGF2 alpha, 102%; 6-keto-PGF1 alpha, 38%; 2,3-dinor-6-keto-PGF1 alpha, 38%; and TXB2, 25%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Incidence of severe acute renal failure in adults: results of a community based study.

OBJECTIVE--To determine the age related incidence of severe acute renal failure in adults in two health districts in England. DESIGN--Prospective study of patients identified as having severe acute renal failure within a two year period; subsequent monitoring of outcome for a further two years. SETTING--Two health districts in Devon. SUBJECTS--Those adults in a population of 444,971 who developed severe acute renal failure (serum creatinine concentration > 500 mumol/l) for the first time during two years, with subsequent fall of the serum creatinine concentration below the index value. MAIN OUTCOME MEASURES AND RESULTS--125 adults (140 per million total population yearly, 172 per million adults) developed severe acute renal failure, of whom 90 (72%) were over 70. Age related incidence rose from 17 per million yearly in adults under 50 to 949 per million yearly in the 80-89 age groups. In 31 patients (25%) the cause was prostatic disease, which was related to a good prognosis (84% (26) alive at three months). Overall survival was 54% (67) at three months and 34% (42) at two years and was not significantly age related. 18 per million total population yearly (22 per million adult population) received acute dialysis. Referral rate for specialised opinion was 51 per million total population yearly with an estimated appropriate referral rate of 70 per million per year. CONCLUSIONS--The incidence of severe acute renal failure in the community is at least twice as high as the incidence reported from renal unit based studies. Prostatic disease, a preventable and treatable problem, is the most common cause. Survival figures indicate that age alone should not be a bar to specialist referral or treatment.     

Role of prostaglandins in the cortical distribution of renal blood flow following reductions in renal perfusion pressure

The purpose of this study was to examine the role of prostaglandins in the redistribution of renal cortical blood flow that occurs following reductions in renal perfusion pressure. The distribution of blood flow to the renal cortex was examined using radio-labeled microspheres (15 +/- 1 micron). It was found that in animals not treated with a prostaglandin synthesis inhibitor a decrease in renal perfusion pressure to the limit of renal blood flow autoregulation was associated with a decrease in fractional flow to the outer cortex (Zone I) and an increase in fractional flow to the inner cortex (Zones III and IV). A further decrease in renal perfusion pressure below the limit of autoregulation produced a further decrease in the fractional flow to Zone I and a further increase in fractional flow to Zones III and IV. In contrast, in animals treated with the prostaglandin synthesis inhibitor meclofenamate (5 mg/kg, i.v. bolus) a reduction in renal perfusion pressure to the limit of renal blood flow autoregulation produced no change in fractional blood flow to any of the 4 cortical zones. A further decrease in renal perfusion pressure, however, did produce a fall in fractional blood flow to Zone I and an increase in fractional flow to Zones III and IV. In conclusion, the results of this study indicate that within, but not below, the limit of renal blood flow autoregulation prostaglandin synthesis is an important factor in the regulation of renal cortical blood flow distribution.     

Early effect of Crotalus durissus terrificus venom on kidney circulation

Local blood flow was measured in renal cortex (1 mm below cortical surface) by means of the hydrogen clearance method in urethanized rats. Recording of blood pressure from femoral artery was performed. Crotalus durissus terrificus venom injection (one mg/kg i.v.) significantly decreased cortical blood flow at 10 min, without a significant arterial pressure modification. Posterior injection of mannitol 200 mg induced a significant increase in cortical blood flow, although initial values were not reached. Electron microscopy showed thromboses in the glomerular capillaries 35 minutes after venom injection. It is suggested that the precocious effect of this venom on renal cortical blood flow may be instrumental in the development of the renal acute insufficiency induced by Crotalus durissus terrificus venom.     

Role of prostagalandins in the cortical distribution of renal blood flow following reductions in renal perfusion pressure

The purpose of this study was to examine the role of prostaglandins in the redistribution of renal cortical blood flow that occurs following reductions in renal perfusion pressure. The distribution of blood flow to the renal cortex was examined using radio-labeled microspheres (15 ± 1 μm). It was found that in animals not treated with a prostaglandin synthesis inhibition a decrease in renal perfusion pressure to the limit of renal blood flow autoregulation was associated with a decrease in fractional flow to the outer cortex (Zone I) and an increase in fractional flow to the inner cortex (Zones III and IV). A further decrease in renal perfusion pressure below the limit of autoregulation produced a further decrease in the fractional flow to Zone I and a further increase in fractional flow to Zones III and IV. In contrast, in animals treated with the prostaglandin synthesis inhibitor meclofenamate (5 mg/kg, i.v. bolus) a reduction in renal perfusion pressure to the limit of renal blood flow autoregulation produced no change in fractional blood flow to any of the 4 cortical zones. A further decrease in renal perfusion pressure, however, did produce a fall in fractional blood flow to Zone I and an increase in fractional flow to Zones III and IV. In conclusion, the results of this study indicate that within, but not below, the limit of renal blood flow autoregulation prostaglandin synthesis is an important factor in the regulation of renal cortical blood flow distribution.     

N-acetyl-L-cysteine improves renal medullary hypoperfusion in acute renal failure

This study evaluated the effects of N-acetyl-L-cysteine (NAC), a free radical scavenger, and N(omega)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthesis inhibitor, on the changes in renal function, intrarenal blood flow distribution (laser-Doppler flowmetry), and plasma peroxynitrite levels during the acute renal failure (ARF) produced by inferior vena cava occlusion (IVCO; 45 min) in anesthetized rats. Renal blood flow fell on reperfusion (whole kidney by -45.7%; cortex -58.7%, outer medulla -62.8%, and papilla -47.7%); glomerular filtration rate (GRF) also decreased (-68.6%), whereas fractional sodium excretion (FE(Na%)) and peroxynitrite and NO/NO plasma levels increased (189.5, 46.5, and 390%, respectively) after ischemia. Pretreatment with L-NAME (10 microg. kg(-1). min(-1)) aggravated the fall in renal blood flow seen during reperfusion (-60%). Pretreatment with NAC (150 mg/kg bolus + 715 microg. kg(-1). min(-1) iv) partially prevented those changes in renal function (GFR only fell by -29.2%, and FE(Na%) increased 119.4%) and laser-Doppler blood flow, especially in the outer medulla, where blood flow recovered to near control levels during reperfusion. These beneficial effects seen in rats given NAC seem to be dependent on the presence of NO, because they were abolished in rats pretreated with L-NAME. Also, the antioxidant effects of NAC prevented the increase in plasma peroxynitrite after ischemia. In conclusion, NAC ameliorates the renal failure and the outer medullary vasoconstriction induced by ICVO, effects that seem to be dependent on the presence of NO and the scavenging of peroxynitrite.     

The effect of prostaglandin synthetase inhibitors on renal function: studies in normal rats during sodium or water diuresis and in rats with chronic renal insufficiency

The effect of acute infusion of the prostaglandin synthetase inhibitors - meclofenamate or indomethacin - was examined in awake rats. Studies were performed in normal rats undergoing either sodium or water diuresis and in salt-replete rats with chronic renal insufficiency. Prostaglandin synthetase inhibitors had no effect on renal plasma flow, glomerular filtration rate or fractional excretion of sodium in any of the groups. Absolute urinary excretion rates for sodium and potassium decreased only in the normal, salt-replete rats. In contrast, prostaglandin synthetase inhibitors consistently decreased urinary flow and osmolar clearance under all experimental conditions studied. In the normal, salt-replete rats the fall in urine flow was preceded by an increase in urinary excretion of cyclic AMP. These results show that inhibitors of prostaglandin synthesis enhance the ability of the kidney to reabsorb water. This effect may be secondary to increased cyclic AMP generation and to increased urea recirculation resulting in higher urea accumulation in the renal medulla.     

Role of angiotensin II in renal hemodynamic functions during the initial stages of acute ureteral obstruction

This investigation examines the role of Angiotensin II in renal hemodynamic functions during acute unilateral ureteral obstruction (UUO) in a dog model. An electro magnetic flow probe was utilized to assess renal blood flow while the arteriovenous extraction technique of technetium 99m DTPA was utilized for the assessment of changes in filtration fraction and glomerular filtration rate. The effects of Angiotensin II receptor blockade on renal hemodynamic functions during acute UUO was evaluated in six dogs and compared to acute ureteral obstruction without receptor blockade in seven dogs. Angiotensin II blockade with (Sar1, Thr8)-Angiotensin II during UUO led to a striking increase in renal blood flow that was significantly different in comparison to normalized values from UUO alone (+delta 63 +/- 17 vs. +delta 22 +/- 6% at 30 min; p less than 0.05). There were, however, no significant differences in the magnitude of the decrease in filtration fraction and glomerular filtration rate in comparison to UUO alone. This investigation demonstrates that Angiotensin II has an inhibitory effect on the initial increase in renal blood flow with acute UUO. The possibility of successful pharmacologic intervention in the setting of UUO can be examined using animal models similar to the one described here. Pharmacologic treatment in the setting of acute UUO in patients might permit better preservation of renal function.     

Involvement of Rho kinase pathway in the mechanism of renal vasoconstriction and cardiac hypertrophy in rats with experimental heart failure

Rho-dependent kinases serve as downstream effectors of several vasoconstrictor systems, the activities of which are upregulated in congestive heart failure (CHF). We evaluated renal and cardiac effects of Y-27632, a highly selective Rho kinase inhibitor, in an experimental model of volume-overload CHF. Effects of acute administration of Y-27632 (0.3 mg/kg) on renal hemodynamic and clearance parameters and effects of chronic treatment (10.0 mg.kg(-1).day(-1) for 7 days via osmotic minipumps) on cardiac hypertrophy and cumulative Na+ excretion were studied in male Wistar rats with aortocaval fistula and control rats. The Y-27632-induced decrease in renal vascular resistance (from 40.4 +/- 4.6 to 26.0 +/- 3.1 resistance units, P < 0.01) in CHF rats was associated with a significant increase in total renal blood flow (+34%) and cortical and medullary blood flow (approx +37 and +27%, respectively). These values were significantly higher than those in control rats and occurred despite a decrease in mean arterial pressure (-15 mmHg). Despite the marked renal vasodilatory effect, Y-27632 did not alter glomerular filtration rate and renal Na+ excretion. Chronic administration of Y-27632 did not alter daily or cumulative renal Na+ excretion in CHF rats but was associated with a significant decrease in heart-to-body weight ratio, an index of cardiac hypertrophy: 0.32 +/- 0.007, 0.46 +/- 0.017, and 0.37 +/- 0.006% in control, CHF, and CHF + Y-27632 rats, respectively. The findings suggest that Rho kinase-dependent pathways are involved in the mechanisms of renal vasoconstriction and cardiac hypertrophy in rats with volume-overload heart failure. Selective blockade of these signaling pathways may be considered an additional tool to improve renal perfusion and attenuate cardiac hypertrophy in heart failure.     

Hemodynamic changes in the kidney in a pediatric rat model of sepsis-induced acute kidney injury

Sepsis is a leading cause of acute kidney injury (AKI) and mortality in children. Understanding the development of pediatric sepsis and its effects on the kidney are critical in uncovering new therapies. The goal of this study was to characterize the development of sepsis-induced AKI in the clinically relevant cecal ligation and puncture (CLP) model of peritonitis in rat pups 17-18 days old. CLP produced severe sepsis demonstrated by time-dependent increase in serum cytokines, NO, markers of multiorgan injury, and renal microcirculatory hypoperfusion. Although blood pressure and heart rate remained unchanged after CLP, renal blood flow (RBF) was decreased 61% by 6 h. Renal microcirculatory analysis showed the number of continuously flowing cortical capillaries decreased significantly from 69 to 48% by 6 h with a 66% decrease in red blood cell velocity and a 57% decline in volumetric flow. The progression of renal microcirculatory hypoperfusion was associated with peritubular capillary leakage and reactive nitrogen species generation. Sham adults had higher mean arterial pressure (118 vs. 69 mmHg), RBF (4.2 vs. 1.1 ml·min(-1)·g(-1)), and peritubular capillary velocity (78% continuous flowing capillaries vs. 69%) compared with pups. CLP produced a greater decrease in renal microcirculation in pups, supporting the notion that adult models may not be the most appropriate for studying pediatric sepsis-induced AKI. Lower RBF and reduced peritubular capillary perfusion in the pup suggest the pediatric kidney may be more susceptible to AKI than would be predicted using adults models.