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.     

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.     

Effects of erythropoietin-gene electrotransfer in rats with adenine-induced renal failure

BACKGROUND: We previously demonstrated that erythropoietin (Epo) expression increases in five-sixths nephrectomized rats, after muscle-targeted gene transfer by in vivo electroporation, using plasmid DNA expressing rat Epo (pCAGGS-Epo). Here, we apply this method to a rat model with severe anemia associated with chronic renal failure; these rats have hematocrit levels in the 30-35% range, similar to those in humans with end-stage renal disease. METHODS: Wistar rats were treated to produce adenine-induced uremia. The uremic rats were then treated with muscle-targeted gene transfer using pCAGGS-Epo. Some uremic rats died from chronic renal failure; one of these was dissected, and the kidneys were histologically examined. For the remaining rats, we measured body weight and blood pressure, and obtained blood samples regularly. RESULTS: The uremic rats showed severe anemia, with hematocrit levels at 32.6 +/- 3.3%. Epo-gene transfer increased Epo expression and serum Epo levels, and also increased the hematocrit levels to 64.5 +/- 4.8%. The dose of pCAGGS-Epo used in this study did not induce severe hypertension. CONCLUSIONS: Continuous Epo-gene expression improves the anemia associated with chronic renal failure, and without severe side effects. Our results support the potential use of gene electrotransfer for human gene therapy applications.     

Ribonuclease inhibition of erythropoiesis in anemia of uremia

The anemia of chronic renal failure was studied by assessing the effect of uremic serum on proliferation of human marrow erythroid stem cells into colonies in vitro. Of 50 sera tested, 46 inhibited "CFU-E" colony formation by a mean of 72%, and 42 inhibited "BFU-E" colonies by a mean of 53.5%, compared to normal sera. Analysis of the uremic sera revealed a striking increase of ribonuclease activity in every patient. Mean activity in the study group was 17,346 U/ml serum (range 6,700-36,250) compared to control mean of 1,047 +/- 247 U/ml. Purified ribonuclease added to marrow cultures in concentrations simulating uremic serum produced a dose-dependent decrease in CFU-E colonies suggesting that the substance has a role in the production of anemia of renal failure.     

Sexual dysfunction in uremia.

In summary, sexual dysfunction is a common finding in both men and women with chronic renal failure. Common disturbances include erectile dysfunction in men, menstrual abnormalities in women, and decreased libido and fertility in both sexes. These abnormalities are primarily organic in nature and are related to uremia as well as the other comorbid conditions that frequently accompany the chronic renal failure patient. Fatigue and psychosocial factors related to the presence of a chronic disease are also contributory factors. Disturbances in the hypothalamic-pituitary-gonadal axis can be detected before the need for dialysis but continue to worsen once dialytic therapy is initiated. Impaired gonadal function is prominent in uremic men, whereas the disturbances in the hypothalamicpituitary axis are more subtle. By contrast, central disturbances are more prominent in uremic women. Therapy is initially directed toward optimizing the delivery of dialysis, correcting anemia with recombinant erythropoietin, and controlling the degree of secondary hyperparathyroidism with vitamin D. For many practicing nephrologists, sildenafil has become the first-line therapy in the treatment of impotence. In the hypogonadal man whose only complaint is decreased libido, testosterone may be of benefit. Regular gynecologic follow-up is required in uremic women to guard against potential complications of unopposed estrogen effect. Uremic women should be advised against pregnancy while on dialysis. Successful transplantation is the most effective means of restoring normal sexual function in both men and women with chronic renal failure.     

The role of erythrocytes phosphatidylserine exposure in anemia in peritoneal dialysis patients

BACKGROUND: An increased red blood cell (RBC) phosphatidylserine (PS) exposure in uremic patients was found that could promote macrophage recognition and decrease RBC survival time. Furthermore, a reduced red cell life span was found to contribute anemia in patients with renal failure. It is therefore possible to hypothesize that increased PS externalization of RBC may influence renal anemia. The present study preliminarily explored the role of erythrocytes' PS exposure in anemia in uremic patients. METHOD: Erythrocyte PS exposure was measured in 67 stable patients on continuous ambulatory peritoneal dialysis (CAPD). An investigation was conducted in the relationship between the level of erythrocyte PS exposure and hemoglobin concentration. A flow-cytometric assay based on FITC-Annexin V was used to measure the PS exposure of erythrocytes. RESULTS: An inverse correlation was found between the percentage of PS-positive RBCs and hemoglobin concentration (r = -0.2601, p < 0.05). Logistic regression analysis revealed that the percentage of PS-positive RBCs was identified as a risk factor for anemia (Hazards ratio = -0.421, p < 0.05). CONCLUSION: This study found that elevated PS exposure in erythrocytes might be a risk factor for anemia and contribute to the development of anemia in peritoneal dialysis 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。     

Tacrolimus-induced hemolytic uremic syndrome and end-stage renal failure after liver transplantation

BACKGROUND: Hemolytic uremic syndrome (HUS) is a rare complication in solid organ transplantation. It can be associated with severe hypertension. Several risk factors have been identified including immunosuppressive drugs such as cyclosporin A and, more recently, tacrolimus. METHODS: Here we report a case of tacrolimus-induced HUS in a 61-yr-old woman after liver transplantation. Hypertension, microangiopathic anemia and end-stage renal failure occurred 2 yr after liver transplantation. RESULTS: At admission, she had malignant hypertension with a severe hypertensive retinopathy, renal failure (creatininemia: 800 micromol/L) and microangiopathic anemia (Hb: 7.3 g/dL, a low platelet count and elevated lactate dehydrogenase). At renal biopsy, histologic findings were ischemic and sclerotic glomeruli with hyaline thrombi, severe mesangiolysis and interstitial fibrosis. CONCLUSION: Despite steroid treatment, antihypertensive agents and fresh frozen plasma therapy, end-stage renal failure was observed and chronic hemodialysis treatment was required.     

Cardiovascular hemodynamic effects of correction of anemia of chronic renal failure with recombinant-human erythropoietin

The results of 8 to 12 weeks of treatment of the anemia of uremia with rHuEPO in patients with chronic renal failure and uremia are: a sustained increased hematocrit; increased RBC mass, and subsequent increased MAP; and increased TPRI. The observed trends of decreased LVEF, and echo Doppler evidence of a trend toward LV systolic and diastolic dysfunction, although not individually statistically significant, represent 3 separate evaluation techniques coupled with hypertension and TPRI increase during administration of rHuEPO to increase the hematocrit and packed red blood cell volume in patients with chronic renal failure and anemia. Increased TPRI and hypertension associated with correction of uremic anemia vasodilation and the increased blood viscosity have been noted in earlier investigations with transfusions. The hypertension and elevated TPRI demonstrated during rHuEPO therapy in patients with progressive chronic renal failure associated with increased hematocrit, and the trends toward systolic and diastolic cardiac dysfunction are noted herein. These changes were associated with the combined increase of packed RBC mass and plasma volume in this study. The natural progressive course of worsening of renal function exhibited by these patients could have limited their ability to regulate plasma volume, making them vulnerable to volume-dependent hypertension and a significant preload adding to potential cardiac dysfunction in addition to the increased TPRI.     

Decreased bilirubin-binding capacity in uremic serum caused by an accumulation of furan dicarboxylic acid

In chronic renal failure, substances that are effectively excreted in healthy subjects accumulate in serum. These substances, uremic toxins, include a variety of organic acids. It has been reported that a decrease in the bilirubin (BR) binding capacity occurs in the serum of renal failure patients. 3-Carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) has a high affinity for human serum albumin (HSA) and is a potent inhibitor of the serum protein binding of many drugs. We recently reported that CMPF and BR share the binding site for dicarboxylate molecules on the HSA molecule [Pharm Res 1999;16:916-923]. In this study, in order to confirm whether CMPF is involved in the decrease of BR serum binding capacity in chronic renal failure patients, the total concentrations of uremic toxins, CMPF, and indoxyl sulfate (IS) and the free BR concentration in serum from healthy volunteers and renal failure patients were determined. Both total CMPF and IS concentrations correlate with the free BR concentration. However, results from the peroxidase method reveal that IS cannot displace BR under the physiological condition [IS]/[HSA] <1. We, therefore, conclude that CMPF is one of the substances which contribute to the decreased binding capacity of BR in uremic serum.     

The Role of Erythrocytes Phosphatidylserine Exposure in Anemia in Peritoneal Dialysis Patients

Background. An increased red blood cell (RBC) phosphatidylserine (PS) exposure in uremic patients was found that could promote macrophage recognition and decrease RBC survival time. Furthermore, a reduced red cell life span was found to contribute anemia in patients with renal failure. It is therefore possible to hypothesize that increased PS externalization of RBC may influence renal anemia. The present study preliminarily explored the role of erythrocytes' PS exposure in anemia in uremic patients. Method. Erythrocyte PS exposure was measured in 67 stable patients on continuous ambulatory peritoneal dialysis (CAPD). An investigation was conducted in the relationship between the level of erythrocyte PS exposure and hemoglobin concentration. A flow-cytometric assay based on FITC-Annexin V was used to measure the PS exposure of erythrocytes. Results. An inverse correlation was found between the percentage of PS‐positive RBCs and hemoglobin concentration (r?=??0.2601, p < 0.05). Logistic regression analysis revealed that the percentage of PS‐positive RBCs was identified as a risk factor for anemia (Hazards ratio?=??0.421, p < 0.05). Conclusion. This study found that elevated PS exposure in erythrocytes might be a risk factor for anemia and contribute to the development of anemia in peritoneal dialysis patients.     

The Evidence of Occult Hypervolemia; Improvement of Cardiac Functions After Kidney Transplantation

The term cardiorenal syndrome (CRS) has been used to define interactions between acute or chronic dysfunction of the heart or kidney. When primary chronic kidney disease contribute to cardiac dysfunction, it is classified as type 4 CRS. Cardiac dilatation, valve regurgitations, and left ventricular dysfunction are observed in end-stage renal failure patients with uremic cardiomyopathy. Because of perioperative risks in these patients, they may not be considered a candidate for kidney transplantation. However, uremic cardiomyopathy can be corrected when volume control is achieved by appropriate dose and duration of ultrafiltration. By presenting two cases with occult hypervolemia in uremic cardiomyopathy whose cardiac functions improved early after kidney transplantation, attention is drawn to the importance of kidney transplantation on cardiac function in such patients primarily and the importance of strict volume control on cardiac function in dialysis patients waiting for kidney transplantation.     

Oxidative stress in hemodialysis patients: is NADPH oxidase complex the culprit?

Oxidative stress results from an imbalance between oxidant production, including reactive oxygen species (ROS), reactive nitrogen species (RNS), chlorinated compounds, and antioxidant defense mechanisms. Most reports prove that oxidative stress is present in ESRD patients. Several studies tend to accreditate the hypothesis by which oxidative stress is a strong co-factor for the development of complications related to long-term HD such as atherosclerosis, amyloidosis, malnutrition, anemia, and infection. In order to evaluate the rationale for curative action against oxidative damage in chronic renal failure patients, we reviewed the putative factors involved in this process. Antioxidant systems are severely impaired in uremic patients and gradually altered with the degree of renal failure. Moreover, the inflammatory state caused by the hemoincompatibility of the dialysis system plays a critical role in the activation of NADPH oxidase, aggravating the pro-oxidant status of uremic patients. Prevention of ROS overproduction by improvement of dialysis biocompatibility, an important component of adequate dialysis, might be completed by antioxidant supplementation.     

Hemolytic uremic syndrome in a patient with gastric adenocarcinoma: partial recovery of renal function after gastrectomy

We report on a patient with gastric adenocarcinoma and severe renal failure caused by hemolytic uremic syndrome with predominantly vascular involvement. Evolution was favorable with partial recovery of renal function after tumor excision and administration of fresh plasma. Although microangiopathic hemolytic anemia is frequently associated with solid tumors, the appearance of a typical hemolytic uremic syndrome with carcinoma is exceptional.     

Anemia of chronic renal failure: inhibition of erythropoiesis by uremic serum

The pathogenesis of anemia in patients with end-stage renal disease was studied by assessing the effect of uremic serum on the proliferation and maturation of erythroid progenitor cells, BFU-E and CFU-E, into colonies in vitro. Nucleated peripheral blood cells from 10 anemic patients produced normal or increased numbers of BFU-E colonies in response to added erythropoietin when cultured in control serum, but declined a mean of 63% when autologous uremic serum was substituted. Uremic sera from 90 patients cultured with normal human marrow produced a mean decrease in BFU-E colony growth of 72%, and of CFU-E colony growth of 82%, compared to control serum. Neither hemodialysis nor peritoneal dialysis was effective in removing the inhibitor. We conclude that patients with uremia have adequate circulating erythroid progenitors that respond to erythropoietin normally when removed from the uremic environment, and that uremic serum is toxic and inhibitory to erythropoiesis. This may be an important mechanism in the anemia of chronic renal failure.     

A 12-year-old girl with hemolytic uremic syndrome as initial symptom of systemic lupus erythematosus and a literature review

We describe a 12-year-old girl with systemic lupus erythematosus (SLE) who first presented with an atypical hemolytic uremic syndrome (HUS) associated with hypocomplementemia, and compare the clinical manifestations and prognosis between SLE patients with HUS and thrombotic thrombocytopenic purpura in the reported literature. Diagnoses were based on renal failure, hemolytic anemia, and thrombocytonemia, including the observation of fragmented red blood cells, hypocomplementemia and on the American College of Rheumatology criteria for SLE. Cocktail therapy may have been effective against the pathological condition of SLE. In 4 patients with SLE and HUS, prednisolone and immunosuppressive drugs were administered, and none of the patients suffered from chronic renal insufficiency. The prognosis for SLE patients with HUS is good. These findings suggest that SLE should be suspected in any HUS patient presenting with hemolytic anemia, thrombocytopenia, acute renal failure and hypocomplementemia, and the therapeutic response and prognosis for SLE with HUS are good.     

Reversibility of adenine-induced renal failure in rats

Background. A renal failure model prepared from rats fed on an adenine diet provides valuable information about the pathomechanism of various complications associated with a persistent uremic state. To establish an animal experimental model in which the animals survive in a persistent uremic state, it is essential to settle a point of no return, i.e., an irreversible point. We investigated an irreversible point using the rat renal failure model induced by adenine treatment. Methods. Rats were fed on a diet containing 0.75% adenine for 2, 4, or 6 weeks, and they were then fed an adenine-free diet for an additional 4 weeks to evaluate the degree of recovery from renal dysfunction. Results. The rats fed on the adenine diet for 2 weeks showed a decrease in mean serum creatinine(s-Cr) from 1.8 mg/dl before to 0.7 mg/dl after the observation period, with mild anemia. The rats fed on the adenine diet for 4 weeks showed persistent renal dysfunction. Although the mean s-Cr decreased from 2.7 to 2.0 mg/dl, it continued to be higher than the normal range, and the anemia worsened. In the rats fed on the adenine diet for 6 weeks, the mean s-Cr increased from 3.4 to 3.6 mg/dl. Hypoproteinemia was also observed and some animals died. Conclusion. Based on the above results, it was concluded that to prepare a model of chronic renal failure in rats compatible to chronic renal failure seen clinically, the administration of a 0.75% adenine diet for 4 weeks is most appropriate. Received: April 24, 1998 / Accepted: October 12, 1998     

The association between congestive heart failure and chronic renal disease

PURPOSE OF REVIEW: Recent findings on the relationship between congestive heart failure and renal failure are summarized in this review. RECENT FINDINGS: Congestive heart failure is found in about one-quarter of cases of chronic kidney disease. The most common cause of congestive heart failure is ischemic heart disease. The prevalence of congestive heart failure increases greatly as the patient's renal function deteriorates, and, at end-stage renal disease, can reach 65-70%. There is mounting evidence that chronic kidney disease itself is a major contributor to severe cardiac damage and, conversely, that congestive heart failure is a major cause of progressive chronic kidney disease. Uncontrolled congestive heart failure is often associated with a rapid fall in renal function and adequate control of congestive heart failure can prevent this. The opposite is also true: treatment of chronic kidney disease can prevent congestive heart failure. There is new evidence showing the cardioprotective effect of carvedilol in patients on dialysis, and of simvastatin and eplerenone in patients with congestive heart failure. Use of non-steroidal anti-inflammatory drugs doubles the rate of hospitalization in patients with congestive heart failure. Anemia has been found in one-third to half the cases of congestive heart failure, and may be caused not only by chronic kidney disease but by the congestive heart failure itself. The anemia is associated with worsening cardiac and renal status and often with signs of malnutrition. Control of the anemia and aggressive use of the recommended medication for congestive heart failure may improve the cardiac function, patient function and exercise capacity, stabilize the renal function, reduce hospitalization and improve quality of life. Congestive heart failure, chronic kidney disease and anemia therefore appear to act together in a vicious circle in which each condition causes or exacerbates the other. Both congestive heart failure and anemia are often undertreated. Cooperation between nephrologists and other physicians in the treatment of patients with anemic congestive heart failure may improve the quality of care and the subsequent prognosis for both congestive heart failure and chronic kidney disease. SUMMARY: Adequate and early detection and aggressive treatment of congestive heart failure and chronic kidney disease and the associated anemia may markedly slow the progression of both diseases.     

Morphology of the heart and arteries in renal failure

In patients with renal failure, cardiovascular complications are a major clinical problem; cardiac death is the main cause of death in these patients. Cardiac risk is increased by a factor of 20 in uremic patients, compared with matched segments of the general population. It has been known for a long time that atherosclerosis, particularly plaque in the epicardiac coronary conduit arteries, are more frequent in patients with chronic renal failure. Recently, however, clinical studies showed that myocardial infarction is responsible for only 30% to 50% of all cardiac deaths. In contrast, 30% to 40% of patients with renal failure and ischemic heart disease show patent coronary arteries on coronary angiogram. Thus, it is very likely that in uremic patients myocardial ischemia tolerance is markedly reduced even in the absence of classical atherosclerosis (i.e., relevant stenosis of coronary arteries). This finding in uremic patients can be at least partially explained by structural and metabolic abnormalities of the myocardium, and in part by alterations of the extracardiac vasculature. The present paper focuses on structural changes of the heart and the vasculature, in particular on atherosclerosis of cardiac and extracardiac arteries, and its potential repercussions for cardiovascular function. In 1827 Richard Bright already pointed to the common presence of left ventricular hypertrophy (LVH) and thickening of the aorta in patients with end-stage renal failure (ESRF). At present, cardiovascular complications account for 45% of all deaths in uremic patients [1]. The recent report of Herzog, Ma, and Colins [2] documented a 59.3% 1-year mortality rate in dialyzed patients who survived myocardial infarction (i.e., mortality was significantly higher than in the general population). It is widely acknowledged that several specific structural and nonstructural alterations of the heart and the extracardiac vasculature are present in patients with renal failure, which presumably contribute to the markedly increased cardiovascular risk in these patients [3].