The Role of Cell Swelling in Ischemic Renal Damage and the Protective Effect of Hypertonic Solute

The failure of blood flow to return to the kidney following a transient period of ischemia has long been recognized. The cause of this "no-reflow" has been investigated in the rat after a transient period of total obstruction of the renal arteries. The vascular pattern of the kidneys as visualized with silicone rubber injection shows a diffuse patchy ischemia throughout the kidney, which persists after release of the obstructed renal artery. Electron microscopic studies of ischemic kidneys showed that all cellular elements were swollen and limiting the available vascular space. Functional studies revealed an increase in plasma urea nitrogen and creatinine after 1 hr or longer ischemic periods. The ischemia, cell swelling, "no-reflow," and subsequent renal dysfunction occurring after obstruction to the renal arteries were corrected by the administration of hypertonic mannitol, but were unaffected by an equivalent expansion of the extracellular fluid volume either with isotonic saline or isotonic mannitol, showing that the osmotic effect was primary. The hypothesis is presented that ischemic swelling of cells may occlude small blood vessels so that recirculation does not resume even after the initial cause of the ischemia is no longer present; solutes which do not penetrate cell membranes are able to shrink swollen cells, increase the available vascular space and thus permit reflow of blood to the ischemic organ.     

Pre- or post-ischemic treatment with a novel Na+/Ca2+ exchange inhibitor, KB-R7943, shows renal protective effects in rats with ischemic acute renal failure

We investigated the effects of pre- or post-ischemic treatment with KB-R7943, a new Na+/Ca2+ exchange inhibitor, on ischemic acute renal failure (ARF) in rats, and these were compared with the effects of verapamil. Ischemic ARF was induced by clamping the left renal pedicle for 45-min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function markedly decreased 24 h after reperfusion. Pre-ischemic treatment with KB-R7943 or verapamil attenuated the ARF-induced renal dysfunction. The ischemia/reperfusion-induced renal dysfunction was overcome by post-ischemic treatment with KB-R7943 but not with verapamil. Histopathological examination of the kidney of ARF rats revealed severe renal damage, and suppression of the damage was seen with post-ischemic treatment with KB-R7943. KB-R7943 markedly suppressed the increment of endothelin-1 (ET-1) content in the kidney at 2, 6, and 24 h after reperfusion. No significant changes in Na+/Ca2+ exchanger protein expression in renal tissue were observed with 45-min ischemia, 6 h after reperfusion and KB-R7943 treatment. These results suggest that Ca2+ overload via the reverse mode of Na+/Ca2+ exchange, followed by ET-1 overproduction, seems to play an important role in the pathogenesis of the ischemia/reperfusion-induced ARF. KB-R7943, which is effective in both cases of pre- and post-ischemic treatments, may prove to be an effective therapeutic agent for cases of ischemic ARF.     

Atrial natriuretic polypeptide (ANP) as protective agent of renal ischemia

The effect of atrial natriuretic polypeptide (ANP) on hemodynamics and renal function was evaluated after the reconstructive surgery of the left renal artery in a patient with renovascular hypertension secondary to Takayasu's arteritis. The reconstructive surgery was done using the femoral artery, since we were unable to obtain adequate vein segments to fit the renal artery. The femoral artery was reconstructed by her saphenous vein segments. After 30 min of the aortorenal bypass operation, alpha-human ANP (alpha-hANP) was infused intravenously for 10 min at a rate of 0.1 microgram/kg/min. Although total peripheral resistance was decreased by alpha-hANP infusion, blood pressure was not changed because of the increased cardiac output. Glomerular filtration rate was increased markedly with concomitant increase in urine volume and urinary excretions of sodium, potassium and phosphate. Fractional excretions of water and sodium were not changed, but fractional excretion of phosphate and potassium clearance were increased. Thus, the infusion of alpha-hANP markedly improved the renal function of the ischemic kidney by the reconstructive surgery of the renal artery, suggesting that alpha-hANP seems clinically applicable as a protective agent in renal ischemia at renovascular surgery as well as the renal transplantation.     

RENAL INSUFFICIENCY FOLLOWING TRYPSIN INJECTION INTO THE RENAL ARTERIES

1. The injection of trypsin into both renal arteries of the dog was found to cause an acute necrosis of large sections of the kidney, an immediate excretory insufficiency, and a transient hypertension. 2. Dogs surviving the acute phase of the trypsin injection, developed a chronic renal excretory insufficiency with no hypertension, despite the severity and duration of the renal excretory insufficiency. 3. The application of a Goldblatt clamp to the renal artery of one of the two kidneys, previously injected with trypsin, led to a rise in blood pressure which returned at once to normal when the ischemic kidney was removed, even though the pre-existing renal excretory insufficiency was augmented. This experience demonstrated unequivocally that chronic renal excretory insufficiency and hypertension are not directly related. 4. The application of a Goldblatt clamp to the renal artery of one kidney and the simultaneous injection of trypsin into the other led to a hypertension. The later removal of the ischemic kidney led to a severe renal excretory insufficiency, at the same time the pre-existing hypertension disappeared. This indicated again that renal excretory insufficiency and renal ischemia produced different phenomena and that the former had no direct relation to hypertension.     

THE ETIOLOGY OF HYPERTENSION DUE TO COMPLETE RENAL ISCHEMIA

1. Perfusates of totally ischemic kidneys of cats contain a pressor substance which is not present in the perfusates of normal kidneys, ischemic hind limbs, or ischemic gravid uteri. 2. The pressor material in ischemic renal perfusates originates directly in the kidney as a result of complete ischemia. 3. The pressor principle contained in ischemic renal perfusates is the cause of the hypertension which follows the reestablishment of circulation in completely ischemic kidneys, since perfusates of unreleased completely ischemic kidneys contain more pressor material than perfusates of released ischemic kidneys of the same animal. 4. The pressor principle in ischemic renal perfusates is presumed to be renin for the following reasons, (a) Both substances are destroyed by boiling, (b) Both substances induce tachyphylaxis. (c) The configuration of both pressor curves is identical, (d) The pressor action of both is not reversed by 933F, proving they are not epinephrine-like substances. (e) When incubated with plasma, both form a heat-stable pressor substance. (f) The pressor effect of both is uninfluenced by a previous injection of cocaine, (g) Unreleased, completely ischemic kidneys yield more pressor material on extraction than do released ischemic kidneys of the same animal. 5. The perfusates of blood-free ischemic kidneys contain more renin than those of blood-filled ischemic kidneys. 6. A method is described by which the power of various substances to inhibit or enhance the production of renin in the ischemic kidney may be tested. 7. A small amount of the heat-stable pressor substance, presumably angiotonin or hypertensin, is formed by the reaction of the pressor material (renin) and plasma in the vessels of the kidney during the period of complete ischemia.     

Electroporation-mediated HGF gene transfection protected the kidney against graft injury

The annual rate of kidney graft loss caused by chronic allograft nephropathy (CAN) has not improved over the past decade. Recent reports suggest that acute renal ischemia results in development of CAN. The goal of the present study was to assess the renoprotective potential and safety of hepatocyte growth factor (HGF) gene transfer using a porcine kidney transplant warm ischemia injury model. Following left porcine kidney removal, 10 min of warm ischemic injury was intentionally induced. Next, the HGF expression vector or vehicle was infused into the renal artery with the renal vein clamped ex vivo, and electric pulses were discharged using bathtub-type electrodes. Kidney grafts were then transplanted after removing the right kidney. Histopathological examination of vehicle-transfected kidney transplant revealed initial tubular injury followed by tubulointerstitial fibrosis. In contrast, HGF-transfected kidneys showed no initial tubular damage and no interstitial fibrosis at 6 months post-transplant. We conclude that electroporation-mediated ex vivo HGF gene transfection protects the kidney against graft injury in a porcine model.     

Unilateral renal ischaemia in the rat: effect of method of occlusion of the blood supply on function of ipsilateral and contralateral kidneys

The functions of right and left kidneys were measured immediately preceding, during and for 4 h after 45 min occlusion of the blood supply to the left kidney. The blood supply was occluded by placing a clamp around the renal artery near to the aorta (group 1), near to the renal hilus (group 2) or by clamping the renal pedicle after prior separation of the kidney from perirenal tissue (group 3). During ischaemia right kidneys had increased urine flow rates and excretion of sodium and water, but inulin clearances (CIn) remained unchanged. After ischaemia left kidneys were isosthenuric with depressed CIn. Occlusion of the renal artery alone resulted in nonoliguric kidneys in which CIn was reduced to 10% and 1% respectively for groups 1 and 2. The most severe damage to function was seen in the kidneys of group 3 which were oliguric and in which CIn was depressed to 0.1% of the pre-ischaemic value. It is concluded that the pedicle clamp method produced complete renal ischaemia and the most severe damage to function. Occlusion of the renal artery produced incomplete ischaemia and a less severe fall in function which depended upon the site of occlusion.     

Biochemical and antiarrhythmic effects of three calcium channel antagonists in ischemic canine hearts

The cardioprotective and antiarrhythmic effects of diltiazem, nilvadipine, and verapamil were evaluated in 33 dogs. The left anterior descending coronary artery (LAD) was occluded for two hours, 25 minutes after saline administration (controls); ten minutes after diltiazem (0.25 mg/kg); 15 minutes after nilvadipine (1 micrograms/kg/min); or ten minutes after verapamil (0.4 mg/kg). Changes in blood pressure and heart rate were monitored throughout the experiment. Two hours after LAD occlusion, mitochondria were prepared from ischemic and nonischemic areas and their function was measured polarographically. Fractionation of myocardial tissue from the ischemic and nonischemic areas was performed and activities of lysosomal enzymes were measured. LAD occlusion induced mitochondrial dysfunction and leakage of lysosomal enzymes in the ischemic area. Administration of the calcium antagonists preserved mitochondrial function and prevented leakage of lysosomal enzymes. All three calcium antagonists reduced the incidence of ventricular arrhythmias during ischemia. The results indicate that calcium may play an important role in the development of biochemical and electrical disturbances during ischemia.     

异丙酚对大鼠肾缺血再灌注损伤后肾组织ICAM-1表达的影响

目的探讨异丙酚不同给药时机对大鼠肾缺血再灌注损伤后肾组织ICAM-1表达的影响。方法50只SD大鼠随机分为5组,每组10只:假手术对照组(C)、缺血再灌注组(I)、及异丙酚预先给药组(P1),异丙酚即时给药组(P2),异丙酚延迟给药组(P3)。缺血前1h,C、I组经鼠尾静脉以2mL/h速度输注生理盐水,P1组阻断前1h经鼠尾静脉缓注异丙酚30mg/kg/h,继以持续输注30mg/kg/h至松开后3h,P2组阻断肾动脉同时静脉缓注异丙酚30mg/kg/h至松开后4h,P3组在松开阻断同时静脉缓注异丙酚30mg/kg/h至松开后4h 45min。阻断肾动脉后关闭腹腔,缺血45min后,再次打开腹腔,显露肾脏,松开动脉夹,逐层缝合腹部正中切口,再灌注24h处死大鼠。观察血肌酐(Cr)、尿素氮(BUN),肾组织ICAM-1mRNA表达及ICAM-1蛋白的变化。结果I组血Cr、BUN与C组比明显增高(P<0.05),P1和P2组较I组明显下降(P<0.05),P3组与I组相比无统计学意义(P>0.05)。肾缺血再灌注后,肾组织ICAM-1 mRNA和蛋白表达明显增加(P<0.01),P1和P2组与I组相比可明显减少ICAM-1 mRNA及其蛋白表达(P<0.01或<0.05),P3组的变化不明显,无统计学意义(P>0.05)。结论异丙酚预先和即时给药对大鼠肾缺血再灌注损伤有明显的保护作用,此保护部分是通过减少ICAM-1 mRNA及其蛋白表达来实现的,而延迟给药无此保护作用。     

急性心力衰竭绵羊搏动性导管泵辅助肾缺血-再灌注后的形态学改变

背景:有关心力衰竭辅助循环后出现急性肾功能衰竭的报道较多,但在该背景下对肾脏组织的形态学分析却鲜有文献涉及.目的:建立绵羊急性心力衰竭模型,在此背景下于国内首次观察搏动性导管泵短期辅助后缺血一再灌注肾脏的形态学改变.设计、时间及地点:自身对照动物实验,于2003-07/2004-04在上海第二医科大学附属仁济医院心血管外科研究室完成.材料:搏动性导管泵由欧洲人工脏器协会主席、荷兰Groningen大学生物医学工程教授、搏动性导管泵发明者GerhardRakhorst提供.方法:取10只绵羊进行左心衰竭诱导,建立肾缺血一再灌注模型,建模成功后开始搏动性导管泵辅助,辅助持续3 h.主要观察指标:分别于心力衰竭前、心力衰竭时及辅助后每隔45 min监测并记录血流动力学参数:辅助3h后取肾脏行光镜和电镜观察.结果:10只绵羊中7只成功支持达到规定的时间.成功的7只绵羊在支持期间血流动力学逐步恢复并趋向稳定,血压接近正常的基线值.光镜和电镜检查发现肾脏缺血一再灌注后轻度的急性改变,主要表现为肾小球细胞数量增多,血管扩张充血,肾曲管上皮水肿变性;肾髓质血管扩张充血,间质水肿.结论:急性心力衰竭绵羊经短期辅助后虽恢复了血流动力学指标,但肾脏病理改变依然存在,提示在辅助循环期间,仅凭血流动力学的稳定来判断肾功能的预后是不可靠的.     

异搏定和环孢素A对急性缺血性肾损伤后内皮素的影响

目的：观察内皮素（ＥＴ）在急性缺血性肾损伤后的变化及异搏定对肾的保护作用和环孢素Ａ（ＣｓＡ）肾毒性与ＥＴ之间的关系。方法：通过阻断大鼠肾动脉６０分钟造成急性缺血性肾功能衰竭（ＩＡＲＦ）模型，用放射免疫方法测定肾脏缺血再灌注１小时、６小时和２４小时血浆及肾组织中ＥＴ的变化；同时观察异搏定和ＣｓＡ对ＥＴ肾功能的影响。结果：ＩＡＲＦ时，血浆及肾组织中ＥＴ在３个时间点均有不同程度的升高；异搏定可降低ＩＡＲＦ大鼠血浆和肾组织中的ＥＴ含量；ＣｓＡ引起ＥＴ活性进一步升高，并加重肾损伤。结论：ＥＴ可能是导致ＩＡＲＦ的一个重要因子；异搏定能抑制ＩＡＲＦ时ＥＴ的分泌和释放而保护肾脏；ＣｓＡ的肾毒性可能与其诱导ＥＴ的分泌和释放有关。     

Preventive effect of lactacystin, a selective proteasome inhibitor, on ischemic acute renal failure in rats.

To elucidate the role of a proteasome-dependent proteolytic pathway in the pathogenesis of acute renal failure (ARF), we examined the effect of a selective proteasome inhibitor, lactacystin, on ARF induced by ischemia/reperfusion. Ischemic ARF was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in untreated ARF rats markedly decreased at 24 h after reperfusion. Intraperitoneal injection of lactacystin at a dose of 0.1 mg/kg before the occlusion tended to attenuate the deterioration of renal function. The higher dose of lactacystin (1 mg/kg) markedly attenuated the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of untreated ARF rats revealed severe lesions, such as tubular necrosis, proteinaceous casts in tubuli, and medullary congestion, all of which were markedly suppressed by the higher dose of lactacystin. In addition, endothelin (ET)-1 content in the kidney after the ischemia/reperfusion was significantly increased, being the maximum level at 6 h after the reperfusion, and this elevation was abolished by the higher dose of lactacystin. These results indicate that lactacystin prevents the development of ischemia/reperfusion-induced ARF, and the effect is accompanied by suppression of the enhanced ET-1 production in the kidney, thereby suggesting that a proteasome-dependent proteolytic pathway has a crucial role in the pathogenesis of ischemic ARF, possibly through the enhancement of ET-1 production in postischemic kidneys.     

骨髓间充质干细胞治疗肾缺血再灌注损伤的旁分泌机制

背景：骨髓间充质干细胞已用于肾缺血再灌注损伤修复的实验动物研究。目的：探讨骨髓间充质干细胞治疗肾缺血再灌注损伤的旁分泌机制。方法：体外培养、纯化并体外DAPI标记大鼠骨髓间充质干细胞,经下腔静脉移植入肾缺血再灌注损伤模型大鼠体内,观察骨髓间充质干细胞对肾缺血再灌注损伤肾功能的保护作用以及在受体鼠体内的迁移情况,并应用免疫组织化学法检测骨髓间充质干细胞治疗后第2天缺血肾脏组织中血管内皮生长因子、肿瘤坏死因子α细胞因子的表达。结果与结论：与注射生理盐水的对照组比较,细胞移植组大鼠血清肌酐和尿素氮水平在移植后第1、2天明显降低（P〈0.05）,但细胞移植组移植后第1、2天肾组织中均未见DAPI阳性细胞;第3、4天则逐渐可见DAPI阳性细胞。免疫组织化学染色结果显示,与对照组相比,移植后第2天肾组织中可见较多血管内皮生长因子阳性细胞,而肾组织中肿瘤坏死因子α阳性细胞明显减少。结果显示旁分泌机制参与了骨髓间充质干细胞治疗肾缺血再灌注损伤。     

急性胎盘缺血时脐血流改变的实验研究

目的 研究在不同胎盘缺血情况下胎羊脐带动静脉血流信号的变化。方法 双胎妊娠母羊2只，分别对其胎羊进行结扎脐动脉，结扎胎盘小叶及螺旋脐带等处理，观察脐血流的改变。结果 结扎—根脐动脉使脐血流阻力增高，胎盘小叶被结扎60％时，脐动静脉血流均有改变。结论 胎盘代偿功能正常下出现胎盘缺血情况，胎羊通过一系列生理调节将脐血流维持在正常范围，胎盘功能失代偿时，先出现脐动脉血流变化，继而出现不可逆脐静脉血流变化。在胎盘缺血情况下，脐带螺旋易引起脐血流改变。     

Effects of verapamil and converting enzyme inhibition on bilateral renal function of two-kidney, one-clip hypertensive rats

Experiments were conducted in two-kidney, one-clip renal vascular hypertensive rats (GHR) to assess the responses of each kidney to acute treatment with the antihypertensive calcium channel blocking agent verapamil in the presence and in the absence of converting enzyme inhibitor (CEI). One group of GHR (0.2 mm inner diam. clip 3 weeks before study) were examined during a control period, and during a second period of infusion of verapamil (600 micrograms h-1 kg-1). A second group of GHR were examined during a control period, during CEI (teprotide, 3 mg h-1 kg-1) infusion and during a third period of verapamil (600 micrograms h-1 kg-1) infusion superimposed on CEI infusion. Although systemic blood pressure (BP) decreased from 175 +/- 4 to 149 +/- 5 mmHg (mean +/- SEM) in response to verapamil alone, renal blood flow for non-clipped kidneys increased from 5.9 +/- 0.4 to 6.5 +/- 0.3 ml/min, indicating a 30% reduction of renal vascular resistance (P values less than or equal to 0.01; n = 9). Glomerular filtration rate (GFR) for non-clipped kidneys (n = 24) increased from 0.91 +/- 0.09 to 1.47 +/- 0.14 ml/min and filtration fraction increased from 0.32 +/- 0.04 to 0.47 +/- 0.03 (P values less than or equal to 0.05). Urine flow rate and absolute and fractional sodium excretion for non-clipped kidneys increased. GFR for clipped kidneys decreased during verapamil. Treatment with CEI alone resulted in nearly identical responses of BP and function of the non-clipped kidney, except filtration fraction was unchanged. The addition of verapamil to ongoing converting enzyme blockade tended to augment the increased GFR of the non-clipped kidney. Plasma renin activity (PRA) increased from 30 +/- 3 to 59 +/- 7 ng of angiotensin (ANG) I h-1 ml-1 with verapamil alone, a significantly larger increment than the increase of PRA from 27 +/- 5 to 39 +/- 9 ng of ANG I h-1 ml-1 in GHR subjected to comparable blood pressure reduction by mechanical aortic constriction. Verapamil resulted in many similar effects on renal function to those observed during blockade of converting enzyme. The increased filtration fraction observed in response to verapamil may be the result of vasodilatation of the afferent arteriole or of an increase in the glomerular ultrafiltration coefficient.     

Contrasting effects of verapamil and nifedipine on pH of ischemic myocardium in the dog

It remains unknown whether the actions of verapamil to depress and nifedipine to enhance contractile function of ischemic myocardium influence the degree of myocardial ischemic injury. Thus, we measured intramyocardial pH using fiberoptic pH probes in 43 anesthetized open-chest dogs pretreated for 30 min with verapamil, or nifedipine in doses that decreased aortic pressure 10 to 15 mm Hg before ligation of the left anterior descending coronary artery for 15 min. Drugs were continued during the 15-min ischemic period until the animals were euthanized without reperfusion: verapamil, 10-20 micrograms/kg/min and nifedipine, 2 to 4 micrograms/kg/min i.v. Verapamil-treated dogs showed higher pH of ischemic subendocardium after 15 min ischemia (6.75 +/- 0.07) than did the nifedipine (6.48 +/- 0.04) or placebo (6.43 +/- 0.05) groups, even if the animals were paced (6.71 +/- 0.11) to prevent the negative chronotropic effect of verapamil (P less than 0.01). Neither verapamil nor nifedipine changed collateral myocardial blood flow from 0.10 +/- 0.02 in the subendocardium and 0.17 +/- 0.03 ml/min/g in the subepicardium. Left ventricular function estimated by left ventricular dp/dt was depressed 15% by verapamil and enhanced 26% by nifedipine. Thus, verapamil, but not nifedipine, relieves acidosis of ischemic myocardium after acute coronary occlusion in doses that sustain a 10 to 15 mm Hg decrease in aortic pressure. Nifedipine, in doses that produced the same 10 to 15 mm Hg decrease in mean aortic pressure, did not increase intramyocardial pH, as it enhanced contractile function, estimated by left ventricular dp/dt.(ABSTRACT TRUNCATED AT 250 WORDS)     

迟发缺血预处理低温保存肾移植供体中血红素加氧酶1的表达

背景：缺血预适应延迟反应通过诱导保护性蛋白增强组织对缺血再灌注损伤的耐受能力;血红素加氧酶1参与缺血预适应延迟保护作用。迟发缺血预处理对低温保存肾脏的作用及血红素加氧酶1是否参与其中尚不清楚。目的：观察缺血预处理诱导血红素加氧酶1的迟发缺血预处理反应对低温保存肾脏移植供体的作用。方法：雄性SD大鼠随机分入5组：空白对照组、低温保存组、缺血预处理组、缺血＋低温组（n=12）;缺血＋给药＋低温组。各组大鼠均行右肾切除,预处理或假手术操作处理后24h采用大鼠肾脏非循环离体灌注模型获取肾脏,分别于保存24,48,72h取样。缺血＋给药＋低温组除上述处理外,还于原位低温灌注术前1h接受1次血红素加氧化酶1抑制剂锡原卟啉腹腔注射。低温保存肾脏于各保存终点留取保存液,测定pH值和乳酸脱氢酶含量;切取1/2肾脏按照光镜要求制备标本送检;剩余1/2肾脏用于免疫印迹法测定血红素加氧酶1表达,比色法测定皮质Na-K-ATP酶活性、丙二醛和还原型谷胱甘肽含量;未保存肾脏仅通过免疫印迹法测定血红素加氧酶1的基础表达情况。结果与结论：迟发缺血预处理诱导了肾组织血红素加氧酶1的表达,与单纯低温保存组相比保存24,48h后,缺血＋低温组保存液pH值、乳酸脱氢酶活性降低;肾脏组织Na-K-ATP酶活性、谷胱甘肽含量增加,丙二醛含量降低;同时点预处理组肾组织光镜形态学改变稍好于单纯低温保存组。给予血红素加氧酶1抑制剂后,这种保护作用消失。提示,迟发缺血预处理延长了肾脏低温保存时限,这可能与诱导血红素加氧酶1,增加组织抗氧化能力,减轻低温保存氧应激有关。     

Progressive renal insufficiency induces increasing protection against ischemic acute renal failure

The purpose of this study was to determine whether progressive renal insufficiency alters the resistance of residual nephrons to ischemic acute renal failure. Normal rats were subjected to either sham nephrectomy (2K rats; n = 7); right nephrectomy (1K rats; n = 7); or right nephrectomy plus variable degrees of ablation (one third to three fourths) of the left kidney (less than 1K rats; n = 10). Nine additional 1K rats received varying doses of nephrotoxic antiserum (NTX rats). One week later, glomerular filtration rate was determined and then ischemic acute renal failure was induced in all remaining renal tissues (25-minute renal artery occlusion). After ischemia, glomerular filtration rate was measured for 160 minutes, renal blood flow was determined, and the kidneys were fixed by in vivo perfusion. The 2K and non-NTX 1K rats had comparable percent recoveries of glomerular filtration rate (22% +/- 5%; 23% +/- 5%) despite a 64% higher renal blood flow for the 1K group. The less than 1K rats had a significantly higher percent recovery of glomerular filtration rate (53% +/- 11%; p less than 0.01), their absolute postischemic glomerular filtration rates were comparable to those of the 2K rats, and they showed significantly less morphologic evidence of ischemic renal injury (p less than 0.01). Both NTX and non-NTX rats with renal ablation showed a strong inverse correlation between baseline glomerular filtration rate and log percent filtration rate recovery (r = -0.75, p less than 0.02; r = -0.83, p less than 0.001, respectively). The less than 1K rats (n = 6) subjected to ischemia 1 day (rather than 1 week) after renal ablation were not protected against acute renal failure (18 +/- 5%) filtration rate recovery) despite renal blood flow comparable with that in other less than 1K rats. In conclusion, progressive renal insufficiency can confer increasing protection on residual nephrons against ischemic acute renal failure once a threshold reduction in functioning renal mass is achieved (greater than 1K). The present data suggest that this protection is not a result of compensatory renal hypertrophy, increased blood flow, or increased solute excretion per nephron, but probably arises as a delayed consequence of renal insufficiency-induced alterations of the internal milieu.     

Effect of theophylline on the initiation phase of postischemic acute renal failure in rats

These experiments were designed to test, pharmacologically, the hypothesis that adenosine mediates the reduction in glomerular filtration rate (GFR) observed during the initiation phase of postischemic acute renal failure (ARF). Six groups of pentobarbital-anesthetized rats were studied; in all groups, the left renal arteries were completely occluded for either 30 or 45 minutes, and 30 minutes after relieving the occlusion, two consecutive 40-minute clearances were begun. Two control groups received no pretreatment; two experimental groups were pretreated with intravenous theophylline (24 mumol/kg prime followed by 0.28 mumol/min/kg infusion); two further experimental groups were pretreated with a higher dose of theophylline (111 mumol/kg prime followed by 1.1 mumol/min/kg infusion). As assessed by reduction in inulin clearance, the impairment of GFR was directly related to the duration of ischemia. The lower dose of theophylline had no significant effects on inulin clearances of right or left kidneys in either group (previously ischemic for 30 or 45 minutes). The higher dose of theophylline also had no significant effects on right kidney inulin clearances, but it significantly increased the inulin clearances of left kidneys previously ischemic for 30 to 45 minutes. This theophylline-induced increase in inulin clearance after 30 minutes of ischemia was accompanied by an increase in renal plasma flow. Because theophylline is a competitive antagonist at adenosine receptors, these results are consistent with the hypothesis that endogenous adenosine mediates, at least in part, the hemodynamic changes in postischemic ARF in rats.