Hyperoxic reperfusion exacerbates postischemic renal dysfunction

BACKGROUND: Hyperoxic reperfusion from global ischemia worsens functional outcome because of oxygen radical-mediated injury. This study tested the hypothesis that hyperoxic reperfusion would exacerbate postischemic renal dysfunction. METHODS: Twenty-nine healthy, uninephrectomized, male mongrel rabbits (Oryctolagus cuniculus) in 3 groups were subjected to 30 minutes of complete normothermic renal ischemia followed by reperfusion under hyperoxic or normoxic conditions. The groups were: hyperoxically reperfused (n = 8), normoxically reperfused (n = 8), hyperoxic sham (no ischemia, n = 5), and allopurinol-pretreated (50 mg/kg, intravenously), hyperoxically reperfused animals (n = 8). Plasma concentrations of creatinine, urea nitrogen and electrolytes were measured at 0, 24, 48, and 72 hours after ischemia and served as functional outcome markers. Histopathologic analysis of kidneys for injury was performed by an expert who was blinded to the procedures. RESULTS: Plasma creatinine in hyperoxically reperfused rabbits was significantly elevated above normoxic (P =.02) and sham (P =.003) animals by 48 hours and remained elevated to 72 hours. Plasma urea nitrogen in hyperoxically reperfused rabbits was significantly elevated above the normoxic group (P = .01), the sham group (P = .02), and the allopurinol group (P = .04) by 72 hours. These coincided with a significantly elevated histopathologic injury score in hyperoxically reperfused rabbits compared with sham (P = .019), normoxic (P = .035), and allopurinol-pretreated hyperoxically reperfused animals (P = .037). CONCLUSIONS: Hyperoxic reperfusion exacerbates renal dysfunction after 30 minutes of complete normothermic ischemia. This dysfunction may be mediated by oxygen radical-related injury.     

Defining the contribution of renal dysfunction to outcome after traumatic injury

Renal failure is frequently considered an ominous development after injury, but its impact on outcome is poorly understood. Renal dysfunction or failure can be defined in many ways, such as elevated serum creatinine or the need for dialysis. The best method to characterize renal dysfunction however, is not known. To determine which definition of renal dysfunction correlates best with outcome, we retrospectively analyzed all injured patients from 1994 to 2000 who had an Injury Severity Score > or =14 and a hospital length of stay >2 days for the development of renal impairment. One hundred sixty-seven patients (4%) developed a serum creatinine > or =2.0 mg/dL and 49 patients required dialysis. Patients with renal dysfunction were older, suffered from more comorbid medical problems, were more seriously injured, and were more likely to have been in shock. A serum creatinine > or =2.0 mg/dL, the maximum creatinine level, and need for dialysis, were highly correlated with death, and the total number of dialysis treatments was not. All measures of renal dysfunction correlated relatively poorly with length of stay. These data demonstrate that the simple measure of serum creatinine > or =2.0 mg/dL is associated with a significantly increased likelihood of death in injured patients and is a stronger predictor than other common indicators of renal impairment.     

Mechanisms of postischemic contractile dysfunction

Prolonged reversible postischemic contractile dysfunction that follows single or multiple brief periods of regional or global ischemia has been termed "stunned myocardium," and is thought to be the result of a decreased responsiveness of the cardiac myofilaments to calcium. A number of hypotheses have been proposed to explain the pathogenesis of stunned myocardium; however, the two major theories that are supported by the most experimental evidence suggest that the generation of oxygen-derived free radicals and a disturbance in calcium homeostasis are responsible for the postischemic contractile dysfunction observed. These mechanisms are not mutually exclusive, and data are available that support both theories. Evidence exists that indicates that one may pharmacologically enhance the recovery of stunned myocardium by use of oxygen radical scavengers, adenosine agonists, calcium channel blockers, and openers of the ATP-sensitive potassium channel, including the volatile anesthetic isoflurane. Ischemic preconditioning (IPC) has also been shown to produce delayed protection against myocardial stunning, and a novel pharmacological agent, monophosphoryl lipid A, has been shown to mimic the effect of IPC. Because stunning appears to occur in a number of clinical settings, it is important to understand the mechanisms involved and to develop pharmacological therapy that will result in an improved clinical outcome.     

The role of magnesium in postischemic cardiac dysfunction.

BACKGROUND. The biochemical basis for postischemic myocardial stunning is not fully elucidated. Magnesium is an important regulator of cellular energetic processes and excitation-contraction coupling. We hypothesized that the decrease in function in the postischemic period may be the result of an alteration in magnesium regulation. METHODS. In a Langendorf perfused rabbit heart model, we used 31P nuclear magnetic resonance spectroscopy to noninvasively determine intracellular Mg2+ and high-energy phosphate levels in the preischemic period and after a 30-minute period of normothermic ischemia. We measured adenosine triphosphate (ATP), phosphocreatine, and the phosphocreatine/inorganic phosphate ratio and calculated the free energy of ATP hydrolysis (delta GATP). On reperfusion, hearts were divided into three groups (n = 7 per group)--those receiving unmodified Krebs-Henseleit (control), 192 ng/ml dobutamine, or 5 mmol/L pyruvate. RESULTS. Function (expressed as the rate-pressure product) was approximately 77% of preischemic values in the control group, whereas in both dobutamine and pyruvate groups it returned to preischemic levels. ATP was decreased similarly in all groups in the postischemic period. Phosphocreatine/inorganic phosphate ratio and delta GATP were higher in the pyruvate group compared with the other groups. Intracellular Mg2+ was elevated significantly in the unmodified control postischemic group compared with preischemic, postischemic dobutamine, and pyruvate groups (1.0 +/- 0.12 vs 0.80 +/- 0.08, 0.64 +/- 0.08, and 0.70 +/- 0.05 mmol/L, respectively; p less than 0.05). CONCLUSIONS. We conclude that (1) postischemic "stunned" hearts have elevated Mg2+ levels in association with impaired contractile function, (2) inotropic agents improve contractile function in association with a decline in Mg2+ to preischemic levels despite differing effects on intracellular energetics, and (3) Mg2+ may play an important regulatory role in the heart after ischemia.     

The contribution of adult stem cells to renal repair

The kidney undergoes continuous, slow cellular turnover for tissue maintenance and rapid cell replacement after injury. The cellular origin of newly differentiated tubular epithelium remains controversial. In some non-renal organs, adult stem cells are recognized as the cell of origin for tissue replacement, such as the hematopoietic system, intestine and skin. These findings have prompted intense investigation for evidence of renal stem cells because of the great need for new therapeutic approaches to treat acute kidney injury and chronic kidney disease. Early excitement at reports that bone marrow-derived cells transdifferentiate into renal epithelial cells has been tempered by findings that show such events to be rare or potentially explained by cell fusion. More recent studies have focused on the possibility that renal progenitors exist within the kidney. In this review we compare data supporting the existence of adult renal stem cells with the body of evidence indicating that the kidney regenerates by self-duplication of differentiated cells. The identification of adult renal epithelial progenitor cells will ultimately determine the future direction of renal regenerative medicine.     

Reduction of renal edema by heparin in postischemic renal damage

Rats were subjected to unilateral renal artery clamping for 60 min and contralateral nephrectomy. 125I-labelled fibrinogen and 131I-labelled albumin were injected intravenously 24 h before the experiment. A significant increase in the fibrinogen and albumin content and weight was found already 5 and 15 min after reflow. Rats given heparin (2,000 IU/kg body weight) 5 min before clamping and killed 15 min after reflow showed significantly smaller increases in these values than rats given saline. Morphological studies showed fibrin deposition in Bowman's space, tubules and peritubular capillaries. The results indicate that fibrin deposition occurs and is of importance in the development of renal edema in this type of renal damage.     

The role of hypoxia in erectile dysfunction mechanisms

Chronic hypoxia is related to many pathological conditions: aging, heart and respiratory failure, sleep apneas, smoke, chronic obstructive pulmonary disease (COPD), diabetes, hypertension and arteriosclerosis, all characterized by reductions of sleep-related erections (SREs) and by erectile dysfunction (ED). Sleep-related erections occur naturally during rapid eye movement (REM) sleep in sexually potent men. Hypoxia is also a physiological condition at altitude. The level of inspired oxygen decreases progressively with the increase of altitude; for this reason, this study was performed to evaluate the relationship of SREs with hypoxic environment. SREs have been recorded by an erectometer (RigiScan) on three mountain climbers (mean age: 32.5) during a 26-day stay at an altitude ranging from 2000 to 5600 m above sea level. Twenty-four records have been made at progressively increasing altitudes. A data analysis was carried out on a statistical mean of the three values of each variable and an analysis of variance (ANOVA) and Newman-Keuls test were carried out for multiple comparison among groups. At altitudes over 4450 m, we found lack of rigidity at 80-100% and 60-79%. Mean % of rigidity and rigidity time of 80-100% (tip and base) decreased progressively with altitude. No significant reductions were shown in rigidity time at 0-19% and at 20-39% (tip and base), of total number, of total and mean duration of SREs. Pathological rigidometric records at high altitude in sexually potent men at sea level clarify the primary role of hypoxia in physiopathological ED pathway.     

Dietary protein prior to renal ischemia dramatically affects postischemic kidney function

Male Sprague-Dawley rats were maintained on high protein (60%), normal protein (20%), low protein (5%), or no protein (0%) diets for two or four weeks prior to 45 minutes of renal ischemia induced by renal pedicle clamping. Most (93%) of the rats on the high protein diet died within three days following renal ischemia. In addition, 69% of the rats on normal protein diets also died, most before the fourth day following ischemic insult. In contrast, 88% of the rats on the low protein diet lived, although some exhibited elevated serum creatinine levels for up to one to two weeks following ischemia. Finally, all of the rats on no protein diets lived, and most (75%) exhibited normal serum creatinine levels by the fourth day following ischemia. Shifting the diets of high protein and normal protein adapted rats to no protein diets immediately following ischemia did not improve postischemic survival. Also, changing the diets of no protein adapted rats to high protein diets immediately following ischemia did not significantly affect postischemic recovery. When rats were maintained on no protein diets for shorter periods of time prior to ischemia, it was found that approximately a week on this diet is necessary to provide maximum protection from postischemic acute renal failure. These findings demonstrate a dramatic effect of dietary protein prior to ischemic induced acute renal failure, and suggests that preoperative dietary protein intake should be an important consideration in those situations which are predisposed to postoperative acute renal failure.     

The contribution of urethrocystoscopy to evaluation of lower urinary tract dysfunction in women

The aim of this study was to determine whether the evaluation of lower urinary dysfunction with urodynamics and urethrocystoscopy provides unique information that is missed by urodynamics alone. Eighty-four women underwent multichannel urodynamics and urethrocystoscopy. Retrospective analysis included evaluation of the relationships between lower urinary tract lesions and risk factors using ² and Fisher's exact tests. Urethrocystoscopic findings changed the diagnosis and managment in 6 patients. New urethrocystoscopic findings included papillary transitional-cell carcinoma, cystitis glandularis, an intravesical suture and a urethral diverticulum. Clinical parameters were not predictive of these findings. Urethrocystoscopic findings also contributed to the final diagnosis in 10 patients with intrinsic sphincter deficiency. Considered alone, maximum urethral closure pressure 20 cm H₂O had a sensitivity of only 20% and a positive predictive value of 40% for this diagnosis. Urodynamics without urethrocystoscopy would have missed important diagnoses in 19% of women. Urethrocystoscopy and urodynamics complement one another, and both have a role in the evaluation of women with lower urinary tract dysfunction.EDITORIAL COMMENT: Urethrocystoscopy as an integral part of urinary incontinence evaluation was popularized by Dr Robertson in the early 1970s. With the appearance of the sensitive microtip pressure transducers and multichannel urodynamics, these modes of evaluation became the gold standard. The popularization of urodynamic studies has put a question mark against the role of cystourethrscopy in evaluating incontinence. This study provides important information on the role of urethrocystoscopy in addition to urodynamic studies. The change of managment based on endoscopic findings in 19% of women in this series, is the answer. One disturbing finding in this report is the very high incidence (5%) of cancer or precancer in women with urinary incontinence. Many urogynecologists do not find 1 in 20 of their patients having cancer or precancer of the lower urinary tract, except perhaps for referral centers for oncologists. Still we should keep these number in mind and look for bladder abnormalities when performing endoscopic studies in the evaluation of urinary incontinence.     

Alteration of postischemic renal pathology by prostaglandin infusion

Hepatic cholesterol synthesis, hepatic cyclic AMP, and portal and peripheral insulin and glucagon levels were investigated in nine dogs and three baboons after complete portacaval shunt. Cholesterol synthesis as measured with acetate incorporation was reduced in both species. Hepatic cyclic AMP increased in dogs. Changes in portal and systemic insulin were inconsistent, but hyperglucagonemia occurred regularly. Diminished hepatic cholesterol synthesis is apparently one factor, although probably not the only one, in the antilipidemic effect of portacaval shunt. This altered cholesterol metabolism may be due to a change in the hormonal environment of the liver caused by portal diversion.     

Free radical-mediated postischemic injury in renal transplantation.

Oxygen free radicals are generated during reperfusion of ischemic organs. Studies employing several species of laboratory animal (rat, dog, pig, rabbit, mouse) have documented protective effects of a variety of free-radical scavengers and antioxidants when administered before or immediately preceding reperfusion of ischemic kidneys. These protective agents include superoxide dismutase, dimethylthiorea, dimethyl sulfoxide, alpha-tocopherol, glutathione, the iron chelator deferoxamine, probucol, allopurinol and oxypurinol, and the spin-trapping agent PBN. Furthermore, deficiency of antioxidants (selenium, alpha-tocopherol, or catalase) exacerbates postischemic renal injury. These findings have been applied to renal transplantation in an attempt to decrease the incidence of posttransplantation acute renal failure. This is important because acute renal failure results in morbidity, increases hospital stay and the cost of transplantation, and complicates the use of cyclosporine. In porcine and in canine kidney transplantation, superoxide dismutase and allopurinol have provided renal protection. Transplantation is complicated because there may be prolonged hypoperfusion before harvesting plus a brief period of total ischemia during harvesting, followed by a prolonged period of cold ischemia and/or reperfusion, then followed by another brief period of ischemia and reperfusion during transplantation. Injury may occur at each of these phases by different mechanisms.     

The use of duplex Doppler ultrasonography to evaluate renal allograft dysfunction

This study evaluated the utility of duplex Doppler sonograms (DS) and the resistive index (RI) in the identification and differential diagnosis of various causes of renal allograft dysfunction. The efficacy of DS and RI was studied either during acute episodes of allograft dysfunction or during periodic posttransplantation longitudinal analyses. The unique features of each renal allograft results in poor correlative value for single isolated measurements of RI. We observed that the highest RIs were in ATN and that an RI of 0.9 was not specific for acute vascular rejection. Also, an RI of 0.9 was rare in acute cellular rejection. RI could not distinguish acute rejection, chronic rejection, CsA toxicity, or obstruction, although the mean RI was significantly different from normal in these groups. Serial studies of RI did document a change at the time of a clinical event compared to baseline. It is concluded that RI is not specific to any one clinical entity.     

Heparinoids with low anticoagulant potency attenuate postischemic endothelial cell dysfunction

Purpose: Although standard heparin has been demonstrated to reduce endothelial cell dysfunction in acute ischemia-reperfusion injury, its mechanism of action remains unknown. We hypothesized that heparin's salutary endothelial effects are independent of its conventional anticoagulant activity and are not caused by nonspecific polyanion effects.Methods: Isolated rat hindlimbs were perfused at constant pressure with an albumin-enriched crystalloid buffer. After 60 minutes of normothermic ischemia, endothelial function was assessed by measurement of endothelial-dependent vasodilation by log increment infusion of acetylcholine. Endothelial-independent vasodilation was measured by exposure to nitroprusside. Some groups were pretreated with heparinoids possessing minimal or intermediate anticoagulant activity.Results: Treatment with heparinoids with low anticoagulant activity significantly increased endothelial-dependent vasodilation when compared with the nontreated ischemic group and were statistically indistinguishable from the nonischemic control. Treatment with dextran sulfate, a randomly sulfated polymer with size and charge characteristics similar to heparin, did not change postischemic vasodilation. Endothelial-independent vasodilation was largely unaffected by ischemia-reperfusion or drug treatment.Conclusions: A heparinoid with negligible antithrombin-binding activity (Astenose) attenuated postischemic endothelial dysfunction, suggesting that its mechanism of action was independent of anticoagulant activity. Failure of dextran sulfate to be protective implied that the effect was not caused by nonspecific polyanion action. (J VASC SURG 1995;21:477-83.)