Disturbances of prostacyclin metabolism in children with hemolytic-uremic syndrome and in first degree relatives

Plasma from 24 children with hemolytic uremic syndrome (HUS) (10 in acute, 14 in remission phase), 42 first degree relatives and 24 controls were studied for PGI2 supporting activity (PSA) from human umbilical arterial rings and the concentration of PGI2 metabolite (PGI2m). HUS patients in acute phase showed very low or absent level of plasma PSA, which remained depressed 3 months following presentation. Plasma from 2 out of 5 acute HUS patients showed inhibition against PGI2-like activity, and depressed preservation of PGI2 effect. The mean value of PGI2m in acute phase of HUS patients was elevated initially, but fell below control range by the day 14 and remained decreased at the end of 3rd month. Patients on long term remission showed a significantly lower concentration of plasma PGI2m. Eight of 14 HUS patients in remission and 18 of 42 family members had lower PSA levels than the controls. These studies confirmed a decreased PSA in HUS and suggest that persistently low PSA levels may reflect an inherited predisposition.     

Renal biopsy in patients with acute renal failure and prolonged bleeding time: a preliminary report

A significant percentage of acute renal failure patients may benefit from a diagnostic renal biopsy, but this procedure carries an unacceptable risk of hemorrhagic complications. We have previously shown that red cell transfusions and 1-deamino-8-D-arginine vasopressin (DDAVP) are effective in managing uremic bleeding. We now report the results of giving washed red cell transfusions or DDAVP to 9 patients with uremia due to acute renal failure to improve hemostasis and allow a diagnostic renal biopsy. All patients admitted to the study had prolonged bleeding time (BT), ie, more than 10 minutes, and our procedure shortened BT in all cases, though in two patients BT after the therapeutic procedure was still longer than normal. In these two, biopsy was not performed. The seven patients whose BT became normal underwent percutaneous biopsy. Only minor clinical complications were registered. Computerized tomography (CT) revealed an incidence of perirenal hematomas comparable to that usually reported in patients with normal or slightly depressed renal function who undergo renal biopsy. Our findings indicate that red cell transfusions or DDAVP can temporarily restore hemostasis, allowing a diagnostic percutaneous biopsy in patients with acute renal failure.     

Diamine oxidase in renal failure.

The enzyme, diamine oxidase, is present in many tissues and plays a role in the metabolism of certain amines, some of which may be toxic. In renal failure, plasma diamine oxidase activity was found to be increased in chronically uremic patients and before and after dialysis therapy in patients undergoing maintenance hemodialysis. Diamine oxidase activity was decreased in urine of the chronically uremic patients as compared to normal subjects. In chronically uremic rats, diamine oxidase activity was observed to be increased in plasma and reduced in urine as compared to sham-operated, pair-fed control rats. In the uremic rats diamine oxidase activity was also decreased in kidney and unchanged in liver and muscle. Total amine levels were elevated in plasma and reduced in urine of patients and rats with chronic renal failure. Although the clinical significance of abnormal diamine oxidase activity in renal failure is not clear, it is possible that this enzyme may have a pathophysiologic role in uremia.     

Acute renal failure with glomerular thrombosis in a patient with chronic scleroderma

A 48-year-old woman with a 20-year history of scleroderma presented with malignant hypertension, thrombocytopenia, and acute renal failure. Renal biopsy demonstrated vascular changes consistent with scleroderma and glomerular thrombi. Her clinical course was consistent with hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP)-like syndrome. Plasma exchange therapy was associated with an improvement in renal function and rise in platelet count. This case suggests that acute renal failure in patients with scleroderma can be associated with glomerular thrombi and may improve with plasma exchange therapy.     

Potentiation of uremic bleeding by hereditary storage pool disease.

This study demonstrates that specific bleeding tests can separate the thrombocytopathy of uremia alone from the bleeding disorders caused by uremia superimposed on preexisting platelet dysfunction. The case history of a uremic patient with exaggerated bleeding tendencies is presented. The findings in this patient are compared with the clinical characteristics and platelet function studies of nine other patients with chronic renal failure. The index and other uremic patients were similar except for the clinical bleeding and results of platelet function studies. The patient's nonocclusive bleeding time and measured blood loss during bleeding time tests were increased compared with the other uremic controls. In addition, her platelet aggregation in response to collagen was lower than that of the other uremic subjects. Repeat studies following renal transplantation were consistent with hereditary storage pool disease. An underlying platelet disorder may potentiate the hemostatic defects of uremia. The diagnosis should be suspected in patients with frequent and severe bleeding manifestations. Renal transplantation led to control of clinical bleeding.     

Anesthesia and ventilation for the uremic child

This article reviews the management of the uremic child from the perspective of an anesthesiologist and cardiopulmonary clinician. The acute stresses of anesthesia, surgery, and mechanical ventilation mandate a systematic, functional approach to addressing rapidly progressing complications that may occur in these patients. Chronic renal failure may be the result of many different renal diseases, but most share common implications during anesthesia [1, 2]. Furthermore, anesthesia can be associated with acutely decreased function of both normal and diseased kidneys [3].     

Effect of conjugated estrogens on platelet function and prostacyclin generation in CRF

In a double-blind, randomized, placebo-controlled cross-over study, we investigated in seven patients with chronic renal failure the effect of conjugated estrogens (0.6 mg/kg/day for 5 days) on template bleeding time and on thromboxane A2 (TxA2), beta-thromboglobulin (beta-TG) and prostacyclin (PGI2) concentrations in blood emerging from the template bleeding time incisions. Administration of conjugated estrogens resulted in a significant shortening of the bleeding time in six out of seven patients with a maximum effect 7 and/or 14 days following treatment. Both TxA2 (measured as thromboxane B2, TxB2) and beta-TG release in bleeding time blood were significantly higher following administration of conjugated estrogens as compared to placebo administration. No difference was seen in endothelial PGI2 (measured as 6-keto-prostaglandin F1 alpha) formation when patients were treated with conjugated estrogens as compared to placebo administration over the 28 day observation period. We conclude that in patients with chronic renal failure, infusion of conjugated estrogens results in a significant shortening of the bleeding time together with an increase in platelet reactivity, as indicated by an increase of TxA2 and beta-TG concentration in the microvasculature. No effect was seen on PGI2 production, thereby excluding a major effect on vascular prostaglandin metabolism.     

Treatment of Bleeding in Dialysis Patients

Bleeding is a common and potentially serious complication of acute and chronic renal failure. The pathogenesis of bleeding in uremia is multifactorial; however, the major role is played by abnormalities in platelet–platelet and platelet–vessel wall interaction. Platelet dysfunction is partially due to uremic toxins present in circulating blood. Despite decreased platelet function, abnormalities of blood coagulation and fibrinolysis predispose the uremic patients to a hypercoagulable state carrying the risk of cardiovascular and thrombotic complications. Dialysis improves platelet abnormalities and reduces, but does not eliminate, the risk of hemorrhage. Hemodialysis can even contribute to the bleeding through the continuous platelet activation induced by the interaction between blood and artificial surfaces and the use of anticoagulants. Correction of anemia improves hemostasis in uremic patients. Therapeutic management of bleeding in patients with uremia is discussed.     

Increased thromboxane biosynthesis in childhood hemolytic uremic syndrome

Vascular endothelial cell damage plays a central role in the pathogenesis of the hemolytic uremic syndrome (HUS), resulting in intravascular platelet activation and thrombotic microangiopathy. A deficiency of the antiaggregatory prostacyclin (PGI2) has been postulated by experiments under ex vivo conditions. However, this observation has not been confirmed in vivo. The pathophysiological contribution of thromboxane (Tx)A2, a potent vasoconstrictor and platelet-aggregating prostanoid which is predominantly produced by platelets, has not been elucidated so far. In order to quantitate endogenous formation of TxA2 in children with HUS, plasma concentrations of the enzymatic metabolite 11-dehydro-TxB2 of TxA2 and urinary excretion rates of three major TxA2 metabolites, TxB2, 11-dehydro-TxB2 and 2,3-dinor-TxB2 were analyzed using gas chromatography/mass spectrometry. PGI2 biosynthesis was assessed by measuring urinary excretion of an index metabolite of its systemic production, 2,3-dinor-6-keto-prostaglandin (PG) F1 alpha, and an index of its renal production, 6-keto-PGF1 alpha. TxA2 biosynthesis was markedly elevated in the acute phase of HUS. This activation could be detected for a longer period of time than the presence of thrombocytopenia. Concomitantly in the acute phase, renal PGI2 formation was significantly elevated and systemic PGI2 formation was elevated in 50% of the patients. These data indicate that TxA2 formation is increased in the acute phase in patients with HUS. This enhanced biosynthesis is consistent with increased platelet activation, whereas the increased PGI2 biosynthesis reflects predominantly renal endothelial cell damage.     

Increased production of prostacyclin after injury to the microvasculature in uraemic patients.

A recently described method to evaluate the primary haemostatic mechanism under in vivo conditions was utilised to investigate thromboxane A2 (TXA2) and prostacyclin (PGI2) production by platelets and vascular endothelial cells, respectively, in patients with severe chronic renal failure. Unlike some previous studies, a decrease in TXA2 production by uraemic platelets could not be demonstrated. PGI2--produced by microvascular endothelial cells after a standardised injury--was, however, 59% higher in patients than controls (P less than 0.05). An increased local level of this potent platelet inhibitory eicosanoid could play an important role in the bleeding tendency exhibited in chronic renal failure.     

Diamine oxidase activity in plasma and urine in uremia.

Diamine oxidase activity was measured in plasma or urine in 12 normal men, 4 men with chronic liver or heart disease, 13 men with chronic renal failure, and 12 men undergoing maintenance hemodialysis. Also in five studies in 4 patients, plasma diamine oxidase activity and total amine levels were measured at hourly intervals during a hemodialysis treatment. Plasma diamine oxidase activity was normal in patients with liver or heart disease and was at least three times normal in chronically uremic patients and in patients undergoing maintenance hemodialysis. Plasma diamine oxidase activities before and after a hemodialysis therapy were similar and did not change during dialysis until the 4th hour when they fell transiently; plasma total amine levels, which were elevated initially, tended to rise during the 4th hour of dialysis. Urinary diamine oxidase activity was reduced in the chronically uremic patients as compared to normal subjects. These observations are consistent with three alterations in diamine oxidase in patients with renal failure: activity (a) is increased in plasma of chronically uremic patients and those undergoing maintenance hemodialysis, (b) does not increase normally in response to heparin administration during dialysis therapy, and (c) is reduced in urine of chronically uremic patients.     

溶血性尿毒症性综合征14例临床分析

目的探讨溶血性尿毒症性综合征（HUS）的病因及临床诊疗。方法分析我院近10年来14例HUS患者的临床资料。结果13例患者具备HUS的典型临床表现，包括溶血性贫血、血小板减少和急性肾衰竭。1例患者虽不具有HUS的典型临床表现，但肾活检病理显示为典型的HUS肾脏微血管病变。经过包括血液净化在内的综合治疗，9例患者获得临床治愈，5例患者死亡。结论该病诊断主要依据病史、临床表现及病理检查进行综合分析，早期改善肾衰竭、纠正重度贫血并积极进行抗凝是治疗关键。     

Calpain is a mediator of myocardial injury in experimental uremia: is it activated by endogenous ouabain?

BACKGROUND: Incidence of cardiovascular disease is more than 20-fold higher in patients with chronic renal failure than in aged-matched individuals with normal renal function. Little is understood about the causes or the mechanism of uremia-induced cardiovascular injury, but the involvement of calpain as a possible mediator has recently been under investigation. Mean calpain activity was found to be 3.4-fold higher in the hearts of uremic rats than in control or spontaneously hypertensive (SHR) rats. In addition, calpain activity was found to be stimulated in myoblasts (Girardi) treated with media enriched with uremic serum compared with cells treated with serum from healthy volunteers. In this study, we assessed the impact of calpain activation in uremia and explored the possibility that calpain might be activated in uremia by endogenous ouabain. Ouabain is known to be elevated in uremia and is strongly associated with left ventricular hypertrophy in essential hypertension. METHODS: Calpain activity was measured in situ in human-derived myoblasts treated with low doses of ouabain similar to those concentrations found in uremic patients. RESULTS: Low concentrations of ouabain (10 nmol/L) caused a highly significant increase in calpain activity, which could be completely inhibited by the simultaneous chelation of intracellular and extracellular Ca2+, and by the chelation of extracellular Ca2+ alone. CONCLUSIONS: Calpain activity can be stimulated by nanomolar concentrations of ouabain due to an influx of extracellular Ca2+. As circulating ouabain is known to be elevated in uremia and strongly associated with LVH remodeling, we hypothesize that endogenous ouabain might be one of the factors that facilitates the remodeling of the left ventricle in patients with renal failure.     

Amino acid metabolism in the chronically uremic rat.

The chronically uremic rat has been used as a model to study amino acid metabolism in uremia. Uremic rats fed low protein diets (6% casein) survived longer than uremic rats receiving either higher levels of dietary protein or a low protein diet supplemented with a mixture of nonessential amino acids. Alterations in plasma amino acid levels were observed in the uremic rats and were similar to those found in patients with renal failure. Plasma concentrations of citrulline, free tryptophan, glycine and the methylhistidines were increased and levels of serine, ornithine, lysine, total tryptophan, tyrosine, and the tyrosine-phenylalanine ratio were reduced. The metabolic basis of the altered tyrosine-phenylalanine ratio in plasma was studied. Tyrosine aminotransferase (TAT) and phenylalanine hydroxylase (PHL) activity were normal in the liver, but renal PHL activity of was decreased as compared to control rats. Tissue concentrations of citrulline were also found to be raised in liver and muscle of uremic rats. The activity of ornithine transcarbamoylase, was reduced in the liver and arginine synthetase activity was decreased in the kidneys of uremic rats. Thus elevated citrulline levels in uremic tissue appear to be caused by a decrease conversion of citrulline to arginine in the kidney. Preliminary studies of tryptophan metabolism in uremic rats have shown elevated brain levels of 5-hydroxyindoleacetic acid and increased hepatic tryptophan oxygenase activity. Increased plasma amine levels were associated with altered activities of monoamine oxidase and diamine oxidase in kidney and other tissues.     

Thyroid Function in Renal Failure

Renal failure is often associated with abnormal thyroid function tests which may make the diagnosis of thyroid dysfunction difficult (Table 1). As many as one-half of patients with renal failure have low thyroid function indices. Although clinically the patients are usually euthroid, there is evidence from animal and human studies that there may be some degree of tissue hypothyroidism in patients with renal failure. Whether this tissue hypothyroidism reflects an adaptive reaction to the uremic state is not clear.
Contributory factors to the alteration in thyroid function tests in renal failure are multiple and include poor nutritional status, medications, metabolic disturbances, hemodialysis, and associated nonthyroidal illnesses. All of these are known to affect thyroid function tests, and it is difficult to dissociate their influence from that of the uremic state. In most instances, the changes in thyroid function tests are similar to those encountered during nonthyroidal illness and include low levels of T₃, with normal or low levels of T₄, a variable free thyroxine index, and a normal, suppressed, or elevated level of TSH. One feature distinguishing renal failure from other non-thyroidal illnesses is the often normal rT₃ and elevated free rT₃ levels seen in acute and chronic renal failure. This appears to be related to the increased binding of rT₃ to intracellular binding proteins.
During hemodialysis, the free T₄ level is elevated transiently but may be abnormally elevated or low in the presence of a coexistent nonthyroidal illness. TSH is normal or only slightly elevated.
Transplant patients, who often receive high doses of steroids, may have abnormal thyroid function tests, in particular hypothyroxinemia and suppressed levels of basal TSH.     

Apparent recurrence of hemolytic uremic syndrome in azathioprine-treated allograft recipients

The present study describes 3 adult patients with hemolytic uremic syndrome (HUS) leading to chronic renal failure. Following renal transplantation, the 3 patients developed microangiopathic hemolytic anemia associated with acute rejection crises and graft failure. In 2 patients the renal histology of the transplanted kidney was consistent with HUS. It is concluded that, in adult patients, HUS may recur after renal transplantation and contribute to renal graft failure.     

The effect of 10 percent human uremic serum upon human fibroblastic cell cultures

Cell culture experiments were undertaken to determine whether human uremic serum in 10% concentration has an inhibitory effect on the proliferation of human fibroblastic cells. Sera from patients with acute renal failure and elevated blood urea levels contains a labile toxic factor(s) which uniformly inhibits fetal fibroblastic cell proliferation. Enhancement of cell proliferation by uremic serum occurs when this toxicity is eliminated by storage at 4°C. for 2 weeks; the degree of enhancement is positively correlated with the level of blood urea of the donor. The toxic effect of uremic serum stored before investigation entirely at −30°C. may reflect the presence of factors responsible for inhibition of cell division during acute renal failure.     

beta blockade with pindolol: differential cardiac and renal effects despite similar plasma kinetics in normal and uremic man.

Cardiac and renal effects (measured as the reduction in exercise-induced tachycardia and PRA, respectively) and circulating drug concentrations after acute beta blockade with intravenous pindolol were compared between seven normal volunteers and six patients with terminal renal failure. Kinetic parameters were similar in both groups (total body clearance, 450 mg/min), indicating enhanced extrarenal elimination in patients. For any given drug concentration, however, the uremic patients responded to beta blockade with a greater decrease in pulse rate than did normal volunteers (P less than 0.001). Moreover, in the same group, the decrease of PRA was more marked (from 13.3 to 5.7 vs. 3.3 to 1.9 ng/ml/hr) and lasted longer (8 hours and more vs. 2 hours). Plasma aldosterone remained unchanged. These data reveal an increased dependency of both heart rate and renin release on beta adrenergic-mediated mechanisms in uremic man. They also show that kinetic findings in normal subjects cannot always be extrapolated to predict kinetic behavior in disease, and that similar kinetics do not imply similar effectiveness.     

A circulating inhibitor of the RBC membrane calcium pump in chronic renal failure.

A humoral inhibitor of the membrane calcium pump was studied in plasma from 28 normal controls, 33 patients receiving long-term hemodialysis, and 26 with chronic renal failure (CRF; creatinine clearance range was 6 to 97 ml/min). Calcium pump activity was measured as the rate of Sr2+ efflux in normal erythrocytes (RBCs) loaded with Sr2+ (a substitute of Ca2+ in the calcium pump). Plasma, and plasma ultrafiltrates from hemodialysis patients strongly inhibited calcium pump activity compared with controls without plasma (36 +/- 18 vs. 25 +/- 12, %INHIBITION/CONTROL, P < 0.05). Inhibition markedly decreased with acute hemodialysis (16 +/- 12 vs. 5 +/- 14, %INHIBITION/NORMAL PLASMA, N = 15, P < 0.001). In CRF, degree of inhibition correlated with the serum creatinine concentration (r = 0.75, P < 0.001). A kinetic study showed that plasma decreased the maximal rate of the Ca2+ pumps (Vmax) without affecting the apparent affinity for internal cations (KSr). Moreover, the plasma inhibitory factor had a low molecular weight, and was dialyzable and heat stable. In conclusion, we found evidence for an RBC membrane calcium pump inhibitor in uremic plasma, which correlates with the degree of renal insufficiency. Possibly, it may increase calcium content in RBCs and other cells and could thus be related to uremic toxicity and/or hypertension.     

肝硬变门脉高压症病人门体分流术后血浆前列环素含量变化的研究

用放射免疫分析方法观察了１５例肝炎后肝硬变门静脉高压症病人血中前列环素含量的变化。结果显示，门体分流术后，门静脉及周围静脉血中前列环素含量分别下降了４９．６３％（Ｐ＜０．０１）和２１．６４％（Ｐ＜０．０５）。门静脉血中前列环素含量的下降与门静脉压的下降呈正相关（ｒ＝０．７４，Ｐ＜０．０５）。表明肝硬变病人体内前列环素含量的增加主要是由于内脏血管内皮细胞合成增加所致，前列环素对门静脉高压症的形成以及维持其高压状态持续存在起一定作用。