Consequences of renal morphologic damage induced by inhibition of converting enzyme in rat renovascular hypertension

The consequences of morphologic changes in the kidney distal to a stenosis induced by chronic administration of a converting enzyme inhibitor were determined after induction of experimental renovascular hypertension in rats. The relationship between changes in morphology in the clipped kidney and diuresis, creatinine, and mortality was studied by converting a two-kidney, one-clip model into a one-kidney, one-clip model after 1 month of converting enzyme inhibition. The right renal artery was constricted with a clip of 0.2 mm diameter to increase blood pressure, the left kidney was left untouched. After 1 month, systolic blood pressure had increased to 173 +/- 27 mm Hg in the clipped animals (n = 47) compared with 139 +/- 8 mm Hg in sham-operated animals (n = 15; group 1). An inhibitor of angiotensin-converting enzyme, MK421 (2 mg/kg, po), or an equivalent volume of vehicle was then administered daily for 1 month. After treatment with the converting enzyme inhibitor, blood pressure (148 +/- 28 mm Hg) was virtually identical with that of a sham-operated, vehicle-treated control group (145 +/- 16 mm Hg, n = 15), and was significantly lower than that of untreated hypertensive rats (186 +/- 30 mm Hg, n = 17) (group 2). The weight of the left kidney was increased in the untreated hypertensive animals as compared with sham-operated controls (1260 +/- 168 mg for group 2 versus 1075 +/- 100 mg for group 1). After treatment with MK421, the weight of the contralateral kidney (1472 +/- 190 mg) was further increased. After 1 month of treatment with MK421 or vehicle, the unclipped left kidney was removed from all animals. The treated animals were then randomly divided into two groups: one in which treatment with MK421 was stopped (treated/untreated, n = 24; group 3) and a second in which the treatment was continued (treated/treated, n = 23; group 4). The ability of the rats to excrete a water load of 15 ml was then examined 12 hours after removal of the unclipped left kidney. In the two groups of treated rats, the urinary excretion of the water load was decreased and frequency of oliguria was increased as compared with controls and hypertensive untreated rats. Survival rates were affected by the treatment: 3 deaths occurred in the hypertensive untreated group 2, 10 in the treated/untreated group 3, and 12 in the treated/treated group 4. The majority of these deaths could be attributed to renal insufficiency.(ABSTRACT TRUNCATED AT 400 WORDS)     

Baroreceptor and somatic sensory regulation of kidney function in two-kidney, one-clip Goldblatt hypertensive rats.

The aim of this investigation was to characterize the renal haemodynamic and tubular responses to somatic afferent nerve stimulation following the removal of afferent nerve input from the atria or the carotid sinuses in chloralose-urethane-anaesthetized Sprague-Dawley rats and two-kidney, one-clip Goldblatt hypertensive rats. Bilateral stimulation of the brachial nerve plexi at 15 V, 1.3 Hz for 0.2 ms resulted in an increase in systemic blood pressure in each group of 10-40%, while renal perfusion pressure was maintained at a constant level. There were significantly larger falls in left renal blood flow and combined left and right glomerular filtration rate in all groups following selective denervation of either the cardiopulmonary or the carotid sinus baroreceptors, respectively. Brachial nerve stimulation decreased urine flow rate and absolute and fractional sodium excretion from both kidneys in Sprague-Dawley intact animals by 53, 65 and 59%; in vagotomized animals by 68, 77 and 63%; and in carotid sinus denervated animals by 86, 90 and 48%, respectively. The renal response in the Goldblatt group were similar to the normotensive group, but the main contribution of the total response was from the untouched left kidney. The inhibitory influence of the vagus and carotid sinuses on the renal sympathetic nerve-mediated sodium and water resorption appeared to be enhanced in the Goldblatt hypertensive rats when compared with the normotensive rats. The renal functional responses to somatic afferent nerve stimulation appeared to be well preserved in the renovascular hypertensive rats, although there were important differences in the contributions to the responses from the left and right kidneys. Furthermore, the baroreceptors exerted a greater influence on basal renal function in the hypertensive rats.     

Glomerular filtration in the isolated perfused kidney

Glomerular hemodynamics were studied of isolated perfused kidneys of 12-wk-old normotensive (NR) and spontaneously hypertensive (SHR) rats, using Pluronic F108 (BASF, Wyandotte, MI, USA) as a plasma expander. Glomerular filtration rate (GFR), proximal tubular hydrostatic pressure (PT) and glomerular capillary hydrostatic pressure (PGC) were approximately linearly related with renal perfusion pressure. PGC measured directly by micropuncture was comparable to PGC calculated from other parameters of glomerular dynamics using pore theory. We conclude that GFR in isolated kidneys perfused with Pluronic F108 is lower than in vivo, mainly as a result of an increase in PT. This rise in tubular pressure is due to an increased urine flow rate and an elevated tubular fluid viscosity. The difference in glomerular dynamics between NR and SHR kidneys is the result of an increased preglomerular vascular resistance in SHR, possibly due to an adaptive hypertrophic reaction to a sustained hypertension.     

“Structural autoregulation” of blood flow and GFR in the two renal vascular beds from two-kidney,one-clip renal hypertensive rats,as compared with kidneys from uni-nephrectomized and intact normotensive rats

Both kidneys from two-kidney, one-clip renal hypertensive rats (RHR) and the hypertrophied kidney of uni-nephrectomized rats (UNR) were investigated during artificial perfusion with 2% Dextran solution and kerosene at maximal vasodilatation, and studied with respect to organ weight, vascular resistance, preglomerular/postglomerular resistance ratio and glomerular filtration capacity. Paired perfusions were throughout used, isolated kidneys from age-matched normotensive rats serving as controls. The untouched, “high-pressure” RHR kidney had increased 40% in weight/100 g b. w. while its vascular resistance at maximal dilatation had increased almost 60%/g organ weight. Glomerular filtration capacity and preglomerular/postglomerular resistance ratio remained, however, largely unchanged.—The clipped “low-pressure”, RHR kidney was reduced 40% in weight and 45% in renal vascular resistance/g organ weight. It also showed a reduced pre/postglomerular resistance ratio and some reduction of filtration capacity.—The remaining hypertrophied kidney in UNR had increased 40% in weight, while its vascular resistance and filtration capacity/g organ weight, as well as its pre/postglomerular resistance ratio were unchanged. It is concluded that the kidney in renovascular hypertension rapidly adapts structurally not only in tissue mass, but also concerning total vascular resistance and pre/postglomerular resistance ratio, so as to chronically “autoregulate” GFR to match the altered pressure situation. Likewise, after unilateral nephrectomy the remaining, normotensive kidney increases in mass, with matched increases in blood flow and glomerular filtration capacity, while total resistance/g organ weight and the pre/postglomerular resistance ratio remain at normotensive levels.     

Structurally based changes of renal vascular reactivity in spontaneously hypertensive and two-kidney, one-clip renal hypertensive rats, as compared with kidneys from uninephrectomized and intact normotensive rats

Renal vascular beds from spontaneously hypertensive rats (SHR) at different stages of hypertension, from two-kidney, one-clip renal hypertensive rats (RHR) and from uninephrectomized rats (UNR) were in constant-flow, paired perfusions compared with kidneys from normotensive control rats (NCR) concerning vascular smooth muscle sensitivity to noradrenaline (NA) and resistance vessel reactivity, as reflected by the position, respectively the shape, of the dose-resistance response curves. None of these kidney variants differed significantly from controls concerning smooth muscle sensitivity to NA during in vitro perfusion. However, both the steepness and maximal pressor responses of the renal resistance curves increased progressively with age in SHR, to become ultimately much enhanced when related to age-matched controls. It suggests a well preserved smooth muscle contractility and a progressive elevation of the average wall/lumen ratio in the SHR renal resistance vessels. Also the untouched, "high-pressure" RHR kidneys showed increased vascular reactivity, while it was somewhat reduced in the clipped, "low-pressure" RHR kidneys and unchanged in the hypertrophied but normotensive UNR kidneys. These results, when combined with other findings concerning renal vascular design (G?thberg & Folkow 1982a), illustrate how the renal resistance vessels readily adapt structurally to hypertension, hypotension, kidney hypertrophy and also with age, and in directions which tend to chronically "autoregulate" glomerular blood supply and filtration.     

Induction of glomerulosclerosis by dietary lipids. A functional and morphologic study in the rat

Clinical and experimental data indicate that glomerular function and morphology may be influenced by plasma lipids. In familial lecithin-cholesterol-acyltransferase (LCAT) deficiency and in Fabry's disease, lipids accumulate in glomeruli and are assumed to induce sclerosis. The present study was undertaken to examine if dietary lipids could exert effects on the glomeruli of normal, unilaterally nephrectomized rats, and of rats with two-kidney, one clip (2-K,1C) hypertension. In rats with two kidneys on a diet rich in fat and cholesterol, cholesterol concentrations in very low density lipoproteins increased. In these rats the number of glomeruli with sclerotic foci was significantly higher than in rats on a low fat, cholesterol free diet. After 6 months on the diet the percentage of glomeruli with sclerosis (SC) was 13.2 +/- 4.1 (N = 9) in rats with a cholesterol diet and 1.8 +/- 0.6 (N = 11) in control rats (p less than 0.05). The fat and cholesterol diet exacerbated glomerular lesions in the remnant kidney model of uninephrectomized rats. The sclerosis in rats with only one kidney was 38.2 +/- 9.5 (N = 6) on a cholesterol diet compared with 8.7 +/- 3.0 (N = 6) in control rats after 6 months (p less than 0.05). After 3 to 4 months on a fat rich diet cholesterylester was increased in isolated glomeruli. The composition of the dietary lipids influenced the development of glomerular lesions. A linseed oil diet that is rich in unsaturated fatty acids, especially linolenic acid, did not cause major plasma lipid abnormalities and was accompanied by a low sclerosis (1.2 +/- 0.3; N = 9) for rats with two kidneys. In rats with chronic 2-K, 1C hypertension the percentage of glomeruli with partially sclerosed tufts in the unclipped kidney was significantly higher on a fat and cholesterol diet (F) than on a control diet (N) (SC: diet F 31.0 +/- 4.0, N = 13; diet N 12.2 +/- 2.6, N = 12; P less than 0.05). In the clipped kidney, protected against the arterial hypertension, only an increased number of glomeruli with mesangial expansion was noted in rats with the cholesterol diet. Glomerular hemodynamic factors seem to play an important pathogenetic role in the induction of glomerular sclerosis by a lipid rich diet. The fact that dietary lipids can aggravate glomerular lesions in states of arterial hypertension and nephron loss may have implications for the progression of renal disease in humans.     

Canine renal vascular response to hyperoncotic dextran in kidneys with or without glomerular filtration

The effect of intrarenal arterial infusion of hyperoncotic dextran on renal hemodynamics and excretion was studied in anesthetized dogs. To examine the role of glomerular filtration and tubular flow in the hemodynamic response, several kidney models were employed. Nonfiltering kidneys (NFK) were produced by combined ischemia and ureteral obstruction (UO). Additionally, kidneys with only UO and a lack of filtration as well as kidneys with only ischemia and glomerular filtration were studied. Renal blood flow in normal kidneys was increased by hyperoncotic dextran from 357 +/- 47 to 486 +/- 65 ml X min-1 X 100 g-1, with a corresponding decrease in renal vascular resistance. Ischemic kidneys responded likewise to the dextran infusion, increasing renal blood flow from 261 +/- 31 to 339 +/- 29 ml X min-1 X 100 g-1. Glomerular filtration rate was reduced by the dextran infusion from 80.1 +/- 7.9 to 60.7 +/- 6.6 in normal kidneys and from 31.8 +/- 9.6 to 20.2 +/- 5.8 ml X min-1 X 100 g-1 in ischemic kidneys. Urine flow and sodium excretion were also reduced in these kidneys. In contrast, both NFK and UO, which lacked filtration and tubular flow, did not vasodilate in response to dextran. Renal blood flow remained unchanged from control values (NFK: 146 +/- 6, UO: 111 +/- 22 ml X min-1 X 100 g-1) in these kidneys. These experiments show that the renal vascular response to hyperoncotic dextran is not due to a change in blood volume or viscosity nor to a direct pharmacologic action of dextran. The most likely explanation is that hyperoncotic dextran alters tubuloglomerular feedback control of renal vascular resistance by decreasing filtration and altering tubular flow and/or composition. However, the involvement of another intrarenal vasodilatory system cannot be discounted.     

Micropuncture studies after temporary ischemia of rat kidneys

Summary Micropuncture experiments were carried out on rat kidneys subjected to temporary ischemia (TI). Unilateral TI was performed by clamping the blood supply to the left kidney for 60 min. Time period between TI and investigating the kidney ranged from 1 h to 13 days. In another series of experiments blood supply to the left kidney was severely diminished for 24 h by a clip.-39% of animals developed anuria of the experimental kidney; in the other animals, urine flow rate was markedly decreased after TI (P<0.02). Employing the tracer microinjection technique considerable amounts (51%-oliguric kidneys; 17%-nonoliguric kidneys) of¹⁴C-labelled inulin injected into a proximal tubule of the damaged kidney were found in the urine of the contralateral kidney indicating backdiffusion of inulin through the damaged tubular epithelium. The amount of inulin recovered from both kidneys was decreased. Backdiffusion of inulin was detectable up to seven days after TI. Under control conditions 2% of inulin injected was found on the contralateral side, inulin recovered from both kidneys being approx. 100%. Dye intensity of Lissamine-green passing through the nephron was decreased noticeably after TI. Proximal tubular diameter and proximal free-flow pressure showed a large variability, the means being not significantly differnt from controls.—The results indicate that the concurrence of at least two factors are involved in the pathogenesis of acute renal damage induced by TI: Backdiffusion of tubular fluid through the damaged tubular epithelium and a decrease of glomerular filtration rate. The measurement of the clearance of inulin in kidneys damaged by ischemia does not represent the actual GFR, but underestimates this value proportionately to the degree of backdiffusion of inulin.Supported by the Deutsche Forschungsgemeinschaft, SFB 90, CARVAS.     

The effect of alloxan, and alloxan-induced diabetes on the kidney

Alloxan is known to induce diabetic renal changes as well as causing nephrotoxic alterations. However, no ultrastructural study has been performed to differentiate diabetic verses toxic affects of alloxan to the tubule and/or glomerulus. Therefore the present study used the "protected" kidney model to prevent one kidney from being exposed to the alloxan while allowing the other to receive the drug immediately. In all experimental animals the right renal hilum was gently occluded for 5 minutes and then released. This was performed prior to the injection of alloxan. Subsequently, the left renal hilum was occluded at the time of, and for 5 minutes after, alloxan administration (40 mg/kg i.v.). The experimental rats were divided into three groups: untreated diabetics, diabetics treated with protamine-zinc-insulin, and alloxan-treated rats that failed to become diabetic. Three groups of controls were included: one group received an equal volume of saline diluent as the experimental rats but no clamping of either renal hilum; another group received the saline and had the left renal hilum occluded for 5 minutes; and a third group had both the right and left renal hila occluded. All animals were followed and sacrificed after 9 weeks. Endogenous creatinine clearance did not change among groups. Alloxan-treated nondiabetic rats displayed marked interstitial nephritis in unprotected kidneys, while protected kidneys were normal. The diabetic state resulted in mesangial proliferation and focal glomerular basement membrane thickening as well as glomerular capillary endothelial abnormalities and visceral epithelial foot-process fusion. The endothelial changes consisted of focal areas showing a reduction in the size of endothelial fenestrae. All glomerular changes were ameliorated by insulin treatment. We conclude: 1) alloxan per se is distinctly nephrotoxic; and 2) the glomerular endothelium and epithelium are involved early in the course of experimental diabetes.     

Role of the glomerular–tubular imbalance with tubular predominance in the arterial hypertension pathophysiology

In previous investigations we caused renal tubular reabsorption preponderance relating to the glomerular filtration (Glomerular–tubular imbalance) and we observed that this fact conducted to volume expansion and development of arterial hypertension, in rats that previously were normotens. We based on this evidence and other which are reflected in the literature arrived at the following hypothesis: a greater proportion of tubular reabsorption relating to the filtered volume is the base of the establishment of the glomerular–tubular imbalance with tubular predominance (GTI-T), which favors to the Na⁺-fluid retention and volume expansion. All of which conduced to arterial hypertension. These facts explain a primary hypertensive role of the kidney, consistent with the results of renal transplants performed in different lines of hypertensive rats and their respective controls and in humans: hypertension can be transferred with the kidney. GTI-T aims to be, a common phenomenon involved in the hypertension development in the multiple ways which is manifested the hypertensive syndrome. In secondary hypertension, GTI-T is caused by significant disruptions of hormone secretions that control renal function, or obvious vascular or parenchymal damage of these organs. In primary hypertension the GTI-T has less obvious causes inherently developed in the kidney, including humoral, cellular and subcellular mechanisms, which may insidiously manifest under environmental factors influence, resulting in insidious development of hypertension. This would explain the state of prehypertension that these individuals suffer. So it has great importance to study GTI-T before the hypertension is established, because when hypertensive state is established, other mechanisms are installed and they contribute to maintain the hypertension. Our hypothesis may explaining the inability of the kidneys to excrete salt and water in hypertension, as Guyton and colleagues have expressed and constitutes a step forward in line with the hypothesis of this author.     

Regulation of glomerular angiotensin II receptor densities in renovascular hypertension: response to reduced sympathetic and vasopressin influence

The regulation of the density of angiotensin II receptors in renal glomeruli in response to changes in salt intake is altered in Sprague-Dawley rats with renovascular hypertension due to aortic constriction, and in hypertensive salt-sensitive Dahl rats (Sahlgren 1989, Sahlgren & Aperia 1989). This study examines the modulatory role of sympathetic activity and arginine-vasopressin on angiotensin II receptors in hypertensive Sprague-Dawley rats with aortic constriction as well as in normotensive control rats. Denervation of the left kidney caused a 50% increase in the glomerular angiotensin II receptor density in the denervated kidney in both hypertensive rats and normotensive controls. An even more marked increase in glomerular receptor density occurred in both hypertensive rats and controls after blocking the sympathetic nervous system with guanethidine. To block the effects of arginine-vasopressin we used a blocker of the V₁-receptors (predominant in vessels) and found an approximately 100% increase in the glomerular receptor density of angiotensin II in rats with aortic constriction. There was no reduction in blood pressure. Thus, on the receptor level the renin-angiotensin system is markedly influenced by the activity of other major pressor systems.     

Tubuloglomerular feedback in rat kidneys of different renin contents

Variations in flow rate through the loop of Henle in the range of 0--50 nl/min were induced using pressure controlled microperfusion. Simultaneously, with the aid of a second pressure-microperfusionsystem, the glomerular function of the same nephron was studied by continuous measurement of two parameters, early proximal flow rate (EPFR) and/or stop flow pressure (SFP). Elevation of loop perfusion above physiological values (40 nl/min) resulted in a drop of EPFR and SFP, whereas lowering perfusion rates had no effect. This feedback behaviour was studied in kidneys with different renin contents to test the role of the renin-angiotensin system in the mediation of the macula densa signal to the adjacent glomerular vessels. Renal renin content, measured after micropuncture experiments by incubation with substrate followed by radioimmunoassay of angiotensin I, was unaltered in control (Ia) and heminephrectomized rats (Ib), lowered in contralateral kidneys of 2 kidneys Goldblatt hypertensive rats (IIa), in DOCA- and salt-loaded rats (IIb), and in DOCA-, salt-loaded and heminephrectomized rats (IIc), and it was evaluated in clipped kidneys of Goldblatt hypertension rats (IIIa). Micropuncture evaluation of the tubuloglomerular feedback behaviour in these experimental groups revealed the following results: 1. a feedback response under all conditions independent of the widely varying renin contents (1000-fold), 2. an asymmetrical behaviour of the feedback response in all kidneys as demonstrated by suppression of EPFR and SFP at elevated loop flow rates, but no change of these parameters when loop flow was interrupted. 3. compared to controls the decrease of each GFR parameter between 0 and 40 nl/min loop perfusion was lower in DOCA- and salt-loaded rats (IIb, IIc). Additional heminephrectomy (IIc) had no further influence on the reduced feedback response in DOCA- and salt-loaded rats, whereas this maneuver reduced the renal renin content drastically. A somewhat higher response than in controls was found in heminephrectomized rats (IIb) and in clipped kidneys of Goldblatt hypertensive rats (IIIa). These different magnitudes of feedback responses do not correlate with the renal renin content. It has been concluded, therefore, that renal renin activity is not the sole determinant of the effectiveness of the tubuloglomerular feedback response.     

Regulation of glomerular angiotensin II receptor densities in renovascular hypertension: response to reduced sympathetic and vasopressin influence.

The regulation of the density of angiotensin II receptors in renal glomeruli in response to changes in salt intake is altered in Sprague-Dawley rats with renovascular hypertension due to aortic constriction, and in hypertensive salt-sensitive Dahl rats (Sahlgren 1989, Sahlgren & Aperia 1989). This study examines the modulatory role of sympathetic activity and arginine-vasopressin on angiotensin II receptors in hypertensive Sprague-Dawley rats with aortic constriction as well as in normotensive control rats. Denervation of the left kidney caused a 50% increase in the glomerular angiotensin II receptor density in the denervated kidney in both hypertensive rats and normotensive controls. An even more marked increase in glomerular receptor density occurred in both hypertensive rats and controls after blocking the sympathetic nervous system with guanethidine. To block the effects of arginine-vasopressin we used a blocker of the V1-receptors (predominant in vessels) and found an approximately 100% increase in the glomerular receptor density of angiotensin II in rats with aortic constriction. There was no reduction in blood pressure. Thus, on the receptor level the renin-angiotensin system is markedly influenced by the activity of other major pressor systems.     

Renal function and digoxin clearance during quinidine therapy

To investigate further the handling of digoxin by the kidneys during quinidine therapy, clearances of digoxin, 51Cr-EDTA, PAH and endogenous creatinine were measured together with beta 2-microglobulin in the urine before and during quinidine therapy in 10 patients on maintenance digoxin therapy. Renal clearance of digoxin (corrected for 30% plasma binding) decreased on the average by 55% (137 +/- 73 to 73 +/- 25 ml/min, mean +/- SD). The steady state plasma concentration of digoxin increased more than twofold (1 . 0 +/- 0 . 34 to 2 . 5 +/- 0 . 79 nmol/L, mean +/- SD). The clearances of 51Cr-EDTA and PAH were not altered during quinidine therapy, indicating that neither glomerular filtration nor total renal blood flow changed when quinidine was added. The ratio of the renal clearance of unbound digoxin to that of the glomerular filtration rate was above one for all 10 patients before quinidine, indicating the involvement of tubular secretion in the renal elimination of digoxin. After the administration of quinidine this ratio decreased in all patients (from 1 . 51 +/- 0 . 30 to 0 . 83 +/- 0 . 38, mean +/- SD). Some patients had ratios well below one suggesting re-absorption of digoxin. Beta 2-microglobulin excretion was unchanged during treatment with quinidine. It is concluded that a significant portion of the renal elimination of digoxin in man results from tubular secretion and that this excretory mechanism is inhibited by quinidine.     

Function in a transplanted reinnervated kidney

Summary In dogs, an autografted kidney was reinnervated by anastomosis of the central end of the vagus with the peripheral end of the renal nerve. Glomerular filtration and tubular water reabsorption determined by the inulin method showed no essential difference between the transplanted reinnervated and intact kidneys. There were no significant differences either between the transplanted reinnervated and intact kidneys with respect to phenol red excretion or glucose and sodium isotope tubular reabsorption. Reinnervation from the central end of the vagus improved renal function in the autografted kidney disturbed by transplantation.(Presented by Active Member AMN SSSR V. N. Chernigovskii) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 54, No. 7, pp. 18–22, July, 1962.     

“一肾一夹”高血压大鼠肾脏皮质钠泵α亚单位的基因表达

目的:探讨"一肾一夹(1k1c)"高血压大鼠肾脏皮质钠泵α亚单位各异构体基因表达的改变,为高血压发病机制的深入研究提供理论及实验依据。方法:分别应用RT-PCR及免疫组化技术,探讨1k1c高血压大鼠肾脏皮质钠泵α₁、α₂及α₃亚单位mRNA及蛋白水平基因表达的改变。结果: 正常大鼠肾脏皮质主要表达钠泵α₁亚单位,α₂与α₃亚单位表达较弱;在mRNA水平,1k1c高血压大鼠肾脏皮质钠泵α₁亚单位表达明显较强,α₂与α₃亚单位表达无改变,而在蛋白水平各亚单位基因表达与对照组比较均无明显差异。 结论: 1k1c高血压大鼠肾皮质钠泵α亚单位基因表达发生改变,这种改变可能参与该模型的血压升高机制。     

Clip-ablation. A model of experimental hypertension in the rat

A model of experimental hypertension has been developed in which the features of the two kidney-one clip and renal ablation models are combined in a single rat. It has been designated the clip-ablation model. It is produced by the placement of a silver clip with an opening of 0.13 mm on a branch of the left renal artery supplying one-third of that kidney, followed by right nephrectomy. In this way the effects of renin-dependent hypertension may be studied in glomeruli which are undergoing compensatory changes in response to reduction in renal mass. Clip-ablation rats were compared to rats with 1 1/3 reduction of renal mass at various intervals up to 28 days after operation. Systolic blood pressure rose with increasing time after operation in both groups with the increase being greater in the clip-ablation rats (177 +/- 10 mm Hg) as compared to the ablation rats (153 +/- 6 mm Hg) at 28 days. Plasma renin activity was increased slightly at 3 days in the ablation rats but had returned to normal levels by 28 days. By contrast, the plasma renin activity rose throughout the experimental period in the clip-ablation rats and attained a level of 32.3 +/- 8.0 ng/ml/hour by 28 days. Urine protein was significantly higher than normal only in the 28-day clip ablation rats (71.2 +/- 23.9 mg/24 hour). Glomerular damage index (GDI), a measure of glomerular injury, increased with longer intervals from operation in both experimental groups, paralleling the rise in systolic blood pressure. Beginning on day 14 and onward the GDI was always numerically higher in the clip-ablation rats than in the ablation rats. Stepwise multiple regression analysis indicated that the strongest predictor of GDI was the change in blood pressure. Plasma renin activity had an additional independent effect on GDI in the clip-ablation rats. The finding of more glomerular damage in the clip-ablation rats than in those with simple removal of comparable amounts of renal tissue is in contrast to the lesser amount of damage found in the two kidney-one clip model when compared with the model of removal of renal substance. It is likely that the compensatory hemodynamic changes in response to reduction in renal mass in the glomeruli of clip-ablation rats make them more vulnerable to injury when exposed to a renin-angiotensin induced hypertension.     

肝肾联合移植的适应证及时机

背景：肝肾联合移植以来,肾功能不全甚至肾功能衰竭已不再是肝脏移植的禁忌症。 目的：探寻肝肾联合移植适应证及移植时机,以利合理应用稀缺的实体器官供体。 方法：收集接受肝肾联合移植患者15例,回顾性分析其移植前状态与移植后移植肾及原肾恢复情况间的状态。 结果与结论：入组15例肝肾联合移植患者均手术顺利,至今存活,随访1.5-8(3.6±1.2)年。入组患者中出现移植肾功能延迟恢复1例,行床旁连续性肾脏替代治疗治疗2周后肾功能逐渐恢复;1例移植前行连续性肾脏替代治疗治疗 4周的肝肾综合征患者,移植后2个月行肾图检查提示原肾功能恢复正常;另2例移植前连续性肾脏替代治疗超过6周的肝肾综合征患者,移植后行肾图提示原肾功能未恢复;伴有原发肾病的终末期肝病患者移植前24 h尿蛋白> 500 mg、肾小球滤过率< 30 mL/min或经穿刺活检证实肾小球硬化率> 30%,肝肾联合移植后行肾图提示原肾逐渐失功。移植前行连续性肾脏替代治疗治疗超过6周的肝肾综合征患者,需施行肝肾联合移植;移植前伴有原发肾病的终末期肝病患者,如果24 h尿蛋白> 500 mg、肾小球滤过率< 30 mL/min或经活检证实肾小球硬化率> 30%,需施行肝肾联合移植。     

Intraglomerular thrombotic tendency and glomerular ADPase. Unilateral impairment of ADPase elicits a proaggregatory microenvironment in experimental glomerulonephritis

It has been proposed, predominantly from ex vivo studies, that glomerular ADPase may function as an antithrombotic principle within the rat kidney. Therefore, intraglomerular platelet aggregation was studied in vivo in rats after impairment of glomerular ADPase activity using local X-irradiation (20 Gy). Biochemical assays in suspensions of glomeruli obtained from rats 24 hours after local X-irradiation (group I) demonstrated a significant reduction in ADPase activity as compared to sham treated rats (group II; p less than 0.01). Cytochemical observations at the ultrastructural level showed that this reduction in glomerular enzyme activity represents in particular ADPase activity detectable in the basement membrane. Following X-irradiation, intraglomerular platelet aggregation was quantitatively studied in two groups of rats. Both groups received X-irradiation of the left kidney (20 Gy). Twenty-four hours after X-irradiation, animals received an intravenous injection of either 0.5 ml of saline (group III; N = 6) or 0.5 ml of heterologous nephrotoxic serum (NTS; group IV; N = 6). Subsequently, 24 hours after this injection, platelet aggregation in left kidneys was compared with aggregation in contralateral non-X-irradiated kidneys. The results showed that while X-irradiation per se did not induce intraglomerular platelet aggregation as compared with the contralateral kidney (0.20 +/- 0.08% versus 0.17 +/- 0.06% platelet aggregation/glomerulus), a significant increase in platelet aggregation could be demonstrated in X-irradiated kidneys in the early phase of nephrotoxic serum nephritis as compared with the contralateral nephritic kidney (2.45 +/- 0.66% versus 1.37 +/- 0.35% platelet aggregation per glomerulus; p less than 0.005). A potential effect of altered influx of inflammatory cells after X-irradiation could be excluded since no difference in H2O2 producing cells was observed between left and right kidneys. Thus, while ADPase impairment by X-irradiation does not induce platelet aggregation per se, it is clear that in proaggregatory conditions, like in NTS nephritis, the thrombotic tendency, due to decreased glomerular ADPase, is enhanced. These results demonstrate the functional significance of glomerular ADPase activity as an antithrombotic principle following platelet activation in vivo.     

Adenosine and kidney function

In this review we outline the unique effects of the autacoid adenosine in the kidney. Adenosine is present in the cytosol of renal cells and in the extracellular space of normoxic kidneys. Extracellular adenosine can derive from cellular adenosine release or extracellular breakdown of ATP, AMP, or cAMP. It is generated at enhanced rates when tubular NaCl reabsorption and thus transport work increase or when hypoxia is induced. Extracellular adenosine acts on adenosine receptor subtypes in the cell membranes to affect vascular and tubular functions. Adenosine lowers glomerular filtration rate (GFR) by constricting afferent arterioles, especially in superficial nephrons, and acts as a mediator of the tubuloglomerular feedback, i.e., a mechanism that coordinates GFR and tubular transport. In contrast, it leads to vasodilation in deep cortex and medulla. Moreover, adenosine tonically inhibits the renal release of renin and stimulates NaCl transport in the cortical proximal tubule but inhibits it in medullary segments including the medullary thick ascending limb. These differential effects of adenosine are subsequently analyzed in a more integrative way in the context of intrarenal metabolic regulation of kidney function, and potential pathophysiological consequences are outlined.