Partialfunktionen der Niere bei Cirrhosis hepatis

Zusammenfassung Wir untersuchten 23 Patienten mit laparoskopisch oder bioptisch gesichterter Lebercirrhose (10 Patienten ohne Ascites und 13 Patienten mit Ascites). Es wurde die Inulin- und PAH-Clearance und das tubuläre Transportmaximum für PAH bestimmt.Bei Lebercirrhosen ohne Ascites fand sich sowohl eine Verminderung mäßigen Grades der Inulin- und PAH-Clearance als auch eine Einschränkung der Nierendurchblutung. Das tubuläre Transportmaximum für PAH war normal. Bei Ascites fand sich eine deutliche Herabsetzung der Inulin-Clearance und der PAH-Clearance, eine Verminderung der Nierendurchblutung und eine signifikant erhöhte Wasserrückresorption. Das tubuläre Transportmaximum für PAH war im Bereich der Norm. Die Ursachen der Funktionseinschränkung werden diskutiert.

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Summary 1. Inulin clearance and PAH clearance was studied in 23 patients withLaennec's cirrhosis, in 13 Patients ascites was demonstrable.2. In patients withLaennec's cirrhosis without ascites, inulin clearance and PAH clearance as well as renal blood flow was lower than normal controls. The maximal rate of tubulär transport for PAH was normal.3. In patients withLaennec's cirrhosis with ascites, inulin clearance, PAH clearance and renal blood flow was very low. Water reabsorption was significant higher than in normal controls. The maximal rate of tubular transport for PAH was normal.4. The results are discussed.

     

Increased urinary kallikrein excretion during prostaglandin E1 infusion in anaesthetized dogs and its relation to natriuresis and diuresis.

. The effect of intra-arterial prostaglandin E1 (PGE1) infusion on urinary kallikrein, sodium, potassium and water excretion was studied in normal anaesthetized dogs. 2. Infusion of PGE1 caused a dose-related increase in urinary excretion of kallikrein, sodium, potassium and water as well as an increase in renal blood flow (R.B.F.) and a fall in urinary osmolality and renal vascular resistance. 3. The changes occurred in the absence of appreciable changes in inulin clearance (Cin), arterial blood pressure, haematocrit, and plasma sodium and potassium concentrations. 4. The increased urinary kallikrein excretion correlated positively with the natriuresis, diuresis and kaliuresis and the increase in renal blood flow, but negatively with the urinary osmolality and renal vascular resistance. 5. It is concluded that renal kallikrein is involved in the renal response to arterial infusion of PGE1.     

Structural aspects of the liver in patients with biliary disease and portal hypertension.

Structural changes were examined in liver tissue from 28 patients with chronic bile duct obstruction in whom portal hypertension was diagnosed. Extrahepatic portal occlusion was found in three patients and cirrhosis of the liver in two. In the remaining 23 patients diffuse hepatocyte hyperplasia and portal fibrosis were observed, but a normal spatial relation between portal tracts and hepatic venous radicles was, for the most part, retained. Liver tissue was also examined from a group of 76 patients with chronic bile duct obstruction in whom there was no indication of portal hypertension but some evidence of hepatocyte hyperplasia and fibrosis. Both these features were much less extensive than the changes seen in the group of patients ostensibly suffering from portal hypertension. The findings suggest that the combination of portal hypertension and chronic bile duct obstruction may not imply the unremitting, progressive, and irreversible changes that accompany cirrhosis because the normal vascular relations are retained. In the light of increasing experimental and clinical evidence of the resorption of collagen and the remodelling of hepatic plates it seems that the structural abnormalities in duct obstruction may substantially regress.     

Renal response to four hours of biliary obstruction in the dog

Clearance studies were performed in anesthetized dogs before and 4 h after the acute obstruction of the common bile duct (ABDL). ABDL was not associated with any change in systemic hemodynamics or plasma volume. Glomerular filtration rate (GFR) rose by 15.3%, PAH clearance by 13.3%, and renal blood flow by 13% (all values significant at P less than 0.05). Fractional excretion rates of water and sodium rose from 0.29 to 1.1 and from 0.21 to 0.76%, respectively (P less than 0.05). These changes in renal function were associated with a failure of bile excretion rather than distension of the biliary tree or failure of bile to enter the duodenum. They did not depend on intact hepatic nerves, alteration of hepatic perfusion, or the release of gastrointestinal vasoactive peptides. The increment in renal perfusion was maintained for 2-3 days before returning to baseline levels. Several lines of evidence suggested that factors influencing the renal tubule and the renal microcirculation might be separate in nature: e.g., urinary sodium excretion (UNaV) could increase without a change in GFR; if ABDL was relieved, delta UNaV and delta GFR returned to base line with different time courses; and controlling perfusion to the left kidney during ABDL reduced but did not abolish the increase in UNaV. Both effects could be transferred to recipient dogs by cross-perfusion. We have demonstrated, therefore, that 4 h of ABDL may significantly influence renal function through the appearance of humoral factors in the circulation.     

FLORID DUCT LESIONS AND EXTENSIVE BILE DUCT LOSS OF THE INTRAHEPATIC BILIARY TREE IN CHRONIC LIVER DISEASES OTHER THAN PRIMARY BILIARY CIRRHOSIS

Intrahepatic biliary tree with either florid duct lesions or a moderate to severe degree of the duct loss in four livers with chronic hepatic diseases other than primary biliary cirrhosis were studied with histometric and serial section observations. Florid duct lesions, distributed segmentally in the liver, were found in one case with incomplete septal cirrhosis and one case with idiopathic portal hypertension. The florid duct lesions including marked plasma cell infiltration and occasional periductal granulomas, were not associated with any bile duct loss in the two cases. The duct lesions were reversible in one case during a long clinical course. On the other hand, a moderate to severe bile duct loss with biliary epithelial degeneration and necrosis was associated with no or little periductal inflammatory cell infiltration in one other case with chronic intrahepatic cholestasis, probably drug-induced, and in one case with idiopathic portal hypertension. Although florid duct lesions and bile duct loss were important diagnostic features of primary biliary cirrhosis, one of them was observed to develop independently in severely diseased livers, not consistent with a diagnosis of primary biliary cirrhosis, sclerosing cholangitis or intrahepatic bile duct paucity syndrome.     

The effects of ureteral occlusion and renal venous constriction on kidney kallikrein-kinin and prostaglandin systems in dogs

Olsen , U. B. The effects of ureteral occlusion and venal cenous constriction on kidney kallikrein-kinin and prostaglandin systems in dogs. Acta physiol. scand. 1978. 104. 443–452. The intrarenal pressure was raised to 40–50 mmHg by ureteral occlusion or by renal venous constriction in anesthetized dogs loaded with 10% mannitol in saline and with a urine flow of approximately I ml/min/ kidney. Both manoeuvres produced vasodilation and decreased urine creatinine excretion (GFR). Ureteral occlusion was associated with a marked antinatriuresis, which contrasted the variable decrements in sodium excretion during renal venous constriction. Ureteral occlusion did not affect urine excretion of kallikrein or kinins, whilst renal venous constriction decreased urinary kallikrein excretion, yet markedly increased urinary kinin excretion. Ureteral occlusion and renal venous constriction comparably increased urine prostaglandin (E-like) excretion by a presumably pressure dependent mechanism. Inhibition of prostaglandin synthesis by indomethacin abolished the vasodilation during renal venous constriction and this was accompanied by marked reductions of urinary creatinine (GFR) and kallikrein excretions. whilst the kinin excretion was enhanced as observed before the administration of indomethacin.     

Development of renal lesions in dogs after 11/12 reduction of renal mass. Influences of dietary protein intake

Renal failure was induced in 15 normal Beagle dogs by ligation of approximately 5/6 of the renal arteries of the left kidney and contralateral nephrectomy in order to determine how: (a) 11/12 reduction in total renal mass influences urine protein excretion and renal morphology in dogs, and (b) dietary protein intake influences renal function, urine protein excretion, and renal morphology in canine renal failure. Dogs were fed a reduced protein diet for 12 weeks after induction of renal failure, while compensatory renal hypertrophy developed. Renal function was then evaluated and dogs were distributed into 2 groups with approximately equal degrees of renal dysfunction. One group was fed a high protein diet (42% protein) and a second group was fed moderately restricted protein diets (18% protein). After 8 weeks, renal function, magnitude of proteinuria, and renal morphology were re-evaluated. Inulin clearance increased in all dogs fed the 42% protein diet and 3 of 10 dogs fed the 18% protein diets. Proteinuria was significantly greater in dogs fed the high protein diet than dogs fed the reduced protein diets. Compared with previously nephrectomized contralateral control kidneys, glomerular sclerosis and renal interstitial lesions had developed in all dogs, regardless of severity of renal dysfunction or diet fed. Although reduced dietary protein intake did not prevent development of renal lesions, renal lesions were significantly more severe in the 5 dogs fed the 42% protein diet and 3 dogs fed the 18% protein diets in which inulin clearance increased, than in 7 dogs fed the reduced protein diets in which inulin clearance did not increase.     

Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat.

Hepatic morphological abnormalities were examined in rats whose bile ducts had been either cannulated and then obstructed or irreversibly ligated for 5, 10, 15 and 28 days or longer. Throughout the experiment most of the morphological changes observed in the cannulated group were comparable to those in the ligated group. Portal inflammation and marginal bile duct proliferation were noted with the same frequency in both groups. Biliary obstruction for 15 days or more led to cirrhosis. After 28 days obstruction, five out of six cannulated rats and four out of six ligated animals respectively developed cirrhosis. The development of cirrhosis was progressive and associated with ascites. It is concluded that in the rat the morphological sequelae of long term cholestasis induced by either cannulation and obstruction or ligation of bile ducts are similar and are accompanied by cirrhosis. The advantages of this experimental model for the study of human cirrhosis are discussed.     

Role of apoptosis in the remodeling of cholestatic liver injury following release of the mechanical stress

It has been known for a long time that portal fibrosis consecutive to experimental common bile duct ligation is reversible following obstacle removal, but the mechanisms involved remain unknown. We have studied the effect of bilioduodenal anastomosis and of simple biliary decompression on the remodeling of the lesion in bile duct-ligated rats. Rats were subjected to common bile duct ligation for 7 days or 14 days. Bilioduodenal anastomosis was performed after 14 days of bile duct ligation and animals sacrificed at intervals. In other animals, after 7 days or 14 days of ligation, the common bile duct was merely decompressed by bile aspiration and animals sacrificed 24 h later. Collagen deposition, alpha-smooth muscle actin expression and apoptosis were evaluated. Bile was collected and the bile acid profile assessed. After anastomosis, collagen deposition and alpha-smooth muscle actin expression decreased and were back to control values after 7 days. These parameters remained practically unchanged 24 h after biliary decompression. Bile duct ligation by itself induced apoptosis of some fibroblastic and bile ductular cells after 7 days; this was back to normal after 14 days. After anastomosis or decompression, apoptosis of both fibroblastic and bile ductular cells increased greatly and was accompanied by ultrastructural features of extracellular matrix degradation. Total bile acid content decreased after common bile duct ligation, the proportion of dihydroxylated bile acids decreasing and that of trihydroxylated bile acids increasing. Biliary decompression and anastomosis did not modify total concentration and composition of the biliary bile acid pool. In summary, we show that mere biliary decompression, by relieving the mechanical stress, is as effective as bilioduodenal anastomosis to induce apoptosis of portal cells that likely triggers portal fibrosis regression.     

The Effect of Indomethacin on Renal Blood Flow Distribution during Hemorrhagic Hypotension in Dog

The effect of indomethacin in hemorrhagic hypotension (HH) on total renal blood flow (RBF) and cortical flow distribution was studied in 9 pentobarbital anesthesized dogs. Local blood flow was measured as hydrogen clearance by 6 platinum electrodes in outer and inner cortex. RBF was recorded by electromagnetic flowmeter. Injection of indomethacin (3–5 mg/kg b.wt.) to inhibit prostaglandin synthesis, reduced renal blood flow only a few percent in control period. After the pretreatment with indomethacin, bleeding to mean arterial pressure 50 mmHg decreased RBF abruptly to 25% of control flow. Thus a renal vasoconstriction is observed both in early and late periods of bleeding in contrast to the initial vasodilation observed during the first half an hour of HH when prostaglandin formation was not blocked. Local blood flow in outer cortex decreased proportionally to flow in inner cortex during bleeding in both the indomethacin treated as in the untreated group, indicating an equal vasodilatory effect of prostaglandin in all parts of renal cortex during early periods of HH.     

Gadolinium chloride suppresses hepatic oval cell proliferation in rats with biliary obstruction.

Liver injury due to bile duct ligation (BDL) is histologically characterized by cholestasis, bile ductular proliferation, hepatocellular damage, portal fibrosis, and ultimately biliary cirrhosis. Stem cells within the liver may act as progenitor cells for small epithelial cells termed oval cells that can differentiate into bile duct cells or hepatocytes, whereas myofibroblasts are the principal source of collagen production in fibrosis. The aims of this study were to determine 1) whether BDL induces oval cell proliferation and 2) whether blockade of Kupffer cells affects oval cell proliferation, bile duct proliferation, and myofibroblast transformation in experimental biliary obstruction. Male Sprague-Dawley rats were divided into two groups to receive either a single dose of gadolinium chloride (a selective Kupffer cell blocking agent) or vehicle. One day later, the gadolinium- and vehicle-treated groups were further subdivided to receive either BDL or sham operation. The rats were sacrificed on day 7 postoperatively. Serum was collected for measurement of aspartate aminotransferase, gamma-glutamyl transpeptidase, and bilirubin levels. Liver tissue was taken for evaluation of fibrosis, bile ductular cells, oval cells, and myofibroblasts. BDL resulted in elevated aspartate aminotransferase, gamma-glutamyl transpeptidase, and bilirubin in serum, and gadolinium pretreatment did not modify these effects. BDL induced marked oval cell proliferation, which was completely prevented by gadolinium pretreatment. Gadolinium did not affect the induction of bile duct expansion or myofibroblasts after BDL. We conclude that experimental biliary obstruction induces oval cell proliferation, which can be prevented by gadolinium pretreatment. This suggests that bile ductular proliferation and myofibroblast transformation are not mediated by Kupffer cells and that ductular proliferation can proceed in the absence of oval cells. Alternatively, gadolinium may directly affect oval cell proliferation after BDL.     

Ascites als Komplikation hepatischer Speicherung von Hydroxyethylstärke (HES) bei Langzeitdialyse

Summary Three adult dialysis patients developed ascites after having received repeatedly the plasma substitue hydroxyethyl starch (HES 40/0.5). In two cases (total dose 180, and 330 g HES, respectively) the ascites was reversible after discontinuation of the HES administration. In the third case (total dose 915 g HES) the ascites could be controlled only by implantation of a Denver shunt. In this latter case it was shown by histological, electron microscopical, and biochemical findings that the ascites was caused by hepatic sinusoidal obstruction due to an extreme storage of HES in the sinusoidal lining cells. Additional storage was detected in hepatocytes, bile duct epithelia, endothelial cells, and fibroblasts in the portal tracts. Biochemically HES was found in liver tissue at a concentration of 4% (w/w). Although in renal impairment plasma clearance of HES is not significantly different from normal individuals, long-term administration of HES must be regarded inadvisable because of tissue storage which apparently is especially significant in this condition.

     

Infection by gram-negative organisms via the biliary route results in greater mortality than portal venous infection

Cholangitis requires bile duct obstruction and infection. Patients with cholangitis are often more affected than those with infections that reach the liver through the portal vein. We will attempt to study the influences of (i) route of entry and (ii) presence of bile duct obstruction on hepatic infection. C57BL/6 mice received injections of Escherichia coli or lipopolysaccharide into the obstructed bile duct or portal vein and were monitored for survival. Livers were assayed for bacteria, and cytokine mRNA was measured. In order to examine the effect of biliary obstruction on hepatic infection, animals were subjected to bile duct ligation 1 day prior to portal vein injection and were monitored for survival. The 50% lethal dose (LD(50)) for E. coli injected into the bile duct was 50 CFU/animal; the LD(50) for E. coli injected into the portal vein was 5 x 10(7) CFU/animal. Initial hepatic delivery of bacteria was equivalent 1 h after injection into the bile duct or portal vein. However, by 24 h, a significantly greater amount of bacteria was recovered from the livers of the bile duct-injected group. Interleukin 10 (IL-10) and IL-1RA mRNA was expressed at greater levels in the bile duct-injected group. Prior bile duct ligation followed by portal vein injection resulted in a higher incidence of death than when sham operation was performed prior to portal vein injection. Our data suggest that the increased mortality from cholangitis, compared with that from other hepatic infections, is related to the different route of delivery of pathogen and the maladaptive response (possibly involving IL-10 and IL-1RA) to biliary obstruction itself.     

Infection by Gram-Negative Organisms via the Biliary Route Results in Greater Mortality than Portal Venous Infection

Cholangitis requires bile duct obstruction and infection. Patients with cholangitis are often more affected than those with infections that reach the liver through the portal vein. We will attempt to study the influences of (i) route of entry and (ii) presence of bile duct obstruction on hepatic infection. C57BL/6 mice received injections of Escherichia coli or lipopolysaccharide into the obstructed bile duct or portal vein and were monitored for survival. Livers were assayed for bacteria, and cytokine mRNA was measured. In order to examine the effect of biliary obstruction on hepatic infection, animals were subjected to bile duct ligation 1 day prior to portal vein injection and were monitored for survival. The 50% lethal dose (LD₅₀) for E. coli injected into the bile duct was 50 CFU/animal; the LD₅₀ for E. coli injected into the portal vein was 5 × 10⁷ CFU/animal. Initial hepatic delivery of bacteria was equivalent 1 h after injection into the bile duct or portal vein. However, by 24 h, a significantly greater amount of bacteria was recovered from the livers of the bile duct-injected group. Interleukin 10 (IL-10) and IL-1RA mRNA was expressed at greater levels in the bile duct-injected group. Prior bile duct ligation followed by portal vein injection resulted in a higher incidence of death than when sham operation was performed prior to portal vein injection. Our data suggest that the increased mortality from cholangitis, compared with that from other hepatic infections, is related to the different route of delivery of pathogen and the maladaptive response (possibly involving IL-10 and IL-1RA) to biliary obstruction itself.     

Morphological and functional phases in the development of experimental cirrhosis of the liver induced by carbon tetrachloride

Summary A toxic hepatitis leading to cirrhosis of the liver was induced in 36 dogs by prolonged administration of carbon tetrachloride. Biopsy specimens were taken periodically during the whole period of a long-term experiment; portal pressure, splenic and blood changes, and weight were observed. Observations were made not only on the developmental stages of the cirrhosis, but also on such complications as hypersplenism, portal hypertension, ascites, etc.(Presented by Active Member AMN SSSR V. V. Parin) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 54, No. 9, pp. 110–114, September, 1962     

PSA-NCAM expression in the rat medial prefrontal cortex

Modulation of soluble guanylate cyclase (sGC) by nitric oxide (NO) is altered in brain from cirrhotic patients. The aim of this work was to assess whether an animal model of cirrhosis, bile duct ligation, alone or combined with diet-induced hyperammonemia for 7-10 days reproduces the alterations in NO modulation of sGC found in brains from cirrhotic patients. sGC activity was measured under basal conditions and in the presence of NO in cerebellum and cerebral cortex of the following groups of rats: controls, bile duct ligation without or with hyperammonemia and hyperammonemia without bile duct ligation. In cerebellum activation of sGC by NO was significantly lower in bile duct ligated rats with (12 +/- five-fold) or without (14 +/- six-fold) hyperammonemia than in control rats (23 +/- seven-fold). In cerebral cortex activation of sGC by NO was higher in rats with bile duct ligation with hyperammonemia (124 +/- 30-fold) but not without hyperammonemia (59 +/- 15-fold) than in control rats (66 +/- 11-fold). The combination of bile duct ligation and hyperammonemia reproduces the alterations in the modulation of soluble guanylate cyclase by NO found in cerebral cortex and cerebellum of cirrhotic patients while bile duct ligation or hyperammonemia alone reproduces the effects in cerebellum but not in cerebral cortex.     

Haemodynamic conditions for renal PGE2 and renin release during alpha- and beta-adrenergic stimulation in dogs

Constriction of the renal artery and infusion of an alpha-adrenergic agonist induce autoregulated vasodilation and increase prostaglandin E2 (PGE2) and renin release. The enhancement of renin release during autoregulated vasodilation might be mediated by prostaglandins. To examine this hypothesis, experiments were performed in three groups of anaesthetized dogs. In six dogs constriction of the renal artery to a perfusion pressure below the range of autoregulation raised renin release from 2 +/- 1 to 27 +/- 6 micrograms AI X min-1 and PGE2 release from 1 +/- 1 to 10 +/- 2 pmol X min-1. After administration of indomethacin (10 mg X kg-1 b.wt), PGE2 release was effectively blocked and constriction of the renal artery raised renin release only from 0.1 +/- 0.1 to 6 +/- 1 micrograms AI X min-1. During subsequent continuous infusion of a beta-adrenergic agonist, isoproterenol (0.2 micrograms X kg-1 X min-1), constriction of the renal artery raised renin release from 0.1 +/- 0.1 to 52 +/- 11 micrograms AI X min-1, although there was no rise in PGE2 release. In six dogs, intrarenal infusion of phenylephrine, an alpha- adrenergic agonist, increased PGE2 and renin release before, but not after, indomethacin administration. In six other dogs, phenylephrine infused during isoproterenol infusion increased renin release equally before and after indomethacin administration. Thus the enhancing effect of constricting the renal artery or infusing an alpha-adrenergic agonist is not dependent upon prostaglandins. We propose that autoregulated dilation enhances renin release whether the stimulatory agent is a prostaglandin or a beta-adrenergic agonist.     

Prostaglandins,a Link between Renal Hydro- and Hemodynamic in Dogs

An increase of the intrarenal pressure to 40 mmHg induced by ureteral constriction or by kidney compression is shown to be followed by increased renal blood flow in anesthetized dogs. This hyperemia is probably the result of enhanced intrarenal prostaglandin activity since it is followed by increased urinary prostaglandin E excretion and is abolished by indomethacin pretreatment. The increase of renal blood flow seems to be due to dilation of the afferent arteriole in order to maintain the filtration pressure. The glomerular filtration rate is thus severely depressed in indomethacin pretreated dogs. Urine and electrolyte excretion is comparably reduced during elevated intrarenal pressure in non-pretreated and in indomethacin pretreated dogs, which suggests that factors other than glomerular filtration rate are involved. Urine osmolarity is positively correlated with renal blood flow, and urine osmolarity increases during elevated intrarenal pressure in non pretreated dogs, whilst urine osmolarity remains unchanged in dogs pretreated with indomethacin.