Duration of oliguria and anuria as predictors of chronic renal-related sequelae in post-diarrheal hemolytic uremic syndrome.

Prior long-term retrospective studies have described renal sequelae in 25-50% of postdiarrheal hemolytic uremic syndrome (HUS) survivors, but the ability to predict the likelihood of chronic renal-related sequelae at the time of hospital discharge is limited. We surveyed 357 children in our HUS registry who survived an acute episode of post diarrheal HUS (D+HUS) and were without end-stage renal disease (ESRD) at the time of hospital discharge. Of the 357 patients surveyed, 159 had at least 1 year (mean 8.75 years) of follow-up. Of these, 90 individuals were identified as having had at least 1 day of oliguria, with 69 individuals having had at least 1 day of anuria. The incidences of renal-related sequelae [proteinuria, low glomerular filtration rate (GFR), and hypertension] were determined among experimental groups based on oliguria and anuria duration. One or more sequelae (e.g. proteinuria, low GFR, hypertension) was seen in 25 (36.2%) of those who had no recorded oliguria and 34 (37.8%) of those with no recorded anuria. The prevalence of chronic sequelae increased markedly in those with more than 5 days of anuria or 10 days of oliguria, with anuria being a better predictor than oliguria of most related sequelae. A particularly high incidence of hypertension was seen in patients with > 10 days of anuria (55.6%) in comparison with those with no anuria (8.9%) [odds ratio (OR) 12.8; 95% confidence interval (CI) 2.9-57.5]. Patients with > 10 days of anuria were also at substantially increased risk for low GFR and proteinuria (OR 35.2; 95% CI 5.1-240.5). These findings may help identify children who need periodic and extended follow-up after hospital discharge.

Prognostic significance of microalbuminuria in postdiarrheal hemolytic uremic syndrome.

Patients who survive the acute phase of postdiarrheal hemolytic uremic syndrome (D+ HUS) may develop renal complications after years of apparent recovery. The optimal regimen for monitoring these children is unclear. We therefore determined if screening for microalbuminuria, in the absence of overt proteinuria at follow-up, increased the sensitivity for predicting long-term renal-related sequelae. We found that screening for microalbuminurea, within the first 6-18 months following an episode of HUS, increased the sensitivity for predicting later sequelae from 22 to 66.7%, compared to screening for overt proteinuria alone. These findings, if confirmed by a larger cohort with more years of follow-up, may facilitate early initiation of intervention strategies designed to reduce progressive renal damage.

Predictors of fatality in postdiarrheal hemolytic uremic syndrome.

OBJECTIVES: Describe the cause of deaths among patients with postdiarrheal hemolytic uremic syndrome (HUS) and identify predictors of death at the time of hospital admission. METHODS: Case-control study of 17 deaths among patients with HUS identified from the Intermountain HUS Patient Registry (1970-2003) compared against all nonfatal cases. RESULTS: Of the 17 total deaths, 15 died during the acute phase of disease. Two died because treatment was withdrawn based on their preexisting conditions, and 1 died because of iatrogenic cardiac tamponade; they were excluded from analysis. Brain involvement was the most common cause of death (8 of 12); congestive heart failure, pulmonary hemorrhage, and hyperkalemia were infrequent causes. Presence of prodromal lethargy, oligoanuria, or seizures and white blood cell count (WBC) >20 x 10(9)/L or hematocrit >23% on admission were predictive of death. In multivariate analysis, elevated WBC and elevated hematocrit were independent predictors. The combination of prodromal dehydration, oliguria, and lethargy and admission WBC values >20 x 10(9)/L and hematocrit >23% appeared in 7 of the 12 acute-phase deaths. CONCLUSIONS: Diarrheal HUS patients presenting with oligoanuria, dehydration, WBC >20 x 10(9)/L, and hematocrit >23% are at substantial risk for fatal hemolytic uremic syndrome. Such individuals should be referred to pediatric tertiary care centers.

Lipopolysaccharide upregulates renal shiga toxin receptors in a primate model of hemolytic uremic syndrome.

BACKGROUND: Although Shiga toxin (Stx) mediates classical hemolytic uremic syndrome (HUS), it is not fully understood why only some subjects exposed to Stx-expressing Escherichia coli develop HUS. We have previously shown in a baboon model of Stx-mediated HUS that coadministration of lipopolysaccharide (LPS) results in an augmented host response to otherwise subtoxic Stx1 doses. We used this model to test the hypothesis that LPS upregulates renal Stx receptor (Gb(3)) expression. METHODS: Juvenile baboons were treated with either Stx1 (100 ng/kg), LPS (1 mg/kg as two divided doses 24 h apart), or a sham injection of saline, and sacrificed and immediately autopsied at 72 h. Renal cortical tissue Gb(3) content was quantitated by lipid extraction and thin-layer chromatography, and Stx1 and Gb(3)/CD77 immunostaining was assessed by quantitative immunofluorescent microscopy. RESULTS: Compared to saline-injected controls, LPS administration resulted in a 2.2-fold increase in renal cortical Gb(3) by chromatography (p < 0.01), a 2.5-fold increase in Stx1 staining (p = 0.003) and a 1.7-fold increase in CD77 immunostaining (p = 0.004). Stx treatment did not significantly alter either Stx or CD77 immunostaining. CONCLUSION: These observations

Reduced nitric oxide bioavailability in a baboon model of Shiga toxin mediated hemolytic uremic syndrome (HUS).

BACKGROUND: Although there is agreement that post-diarrheal hemolytic uremic syndrome (D+ HUS) is caused by Shiga toxin (Stx)-producing E. coli, little is known about factors that mediate the host response to these toxins and potentially contribute to pathogenesis. Nitric oxide (NO) is a candidate mediator by virtue of its antiplatelet and renal vasodilatory properties. METHODS: We used a baboon model of HUS to measure plasma and urinary NO metabolites and expression of NO synthase (eNOS and iNOS) in renal tissue following the intravenous administration of Stx-1. RESULTS: Plasma concentrations through 60 hours of observation did not differ significantly from controls. Urinary values (indexed against urinary creatinine) tended, however, to rise during the initial 12 hours following administration of Stx-1. This was followed by a sustained reduction that coincided with the development of hemolytic anemia (schistocytosis) and other features of HUS. However, immunohistochemical staining for eNOS and iNOS in tissue obtained immediately after death at a median of 59 hours showed similar levels in control and Stx-treated animals, despite the presence of a florid thrombotic microangiopathy and tubular injury in the Stx-treated group. CONCLUSION: We propose that urinary NO metabolite reduction was due to NO inactivation subsequent to its avid binding to free hemoglobin released from lysed red blood cells, and that this contributed to the acute renal failure by facilitating vasoconstriction and platelet aggregation and adhesion within the renal microvasculature.

Hemolytic uremic syndrome; pathogenesis, treatment, and outcome.

PURPOSE OF REVIEW: The hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in infants and young children, and is a substantial cause of acute mortality and chronic morbidity. It is therefore relevant and appropriate that pediatricians remain familiar with the various subsets of the disease including its classification, management, and outcome. RECENT FINDINGS: This review will focus on recent information relative to epidemiology, pathogenesis, treatment, and outcome. It will include some of the newer associations between HUS and a variety of infections, including, but not limited to E. coli 0157:H7 (Shiga toxin-mediated) HUS, as well as the ever-increasing number of associations between HUS and a variety of drugs. It will review some of the newer therapies for the more common subsets, but will acknowledge that choosing evidence-based therapies is often limited by our incomplete understanding of the various pathogenic cascades, and that with the possible exception of Shiga toxin-mediated HUS(D+HUS), long-term outcome information is often limited by small numbers and limited follow-up. SUMMARY: This review should provide a framework for making the proper diagnosis, implementing appropriate treatment, and advising the family about anticipated outcome.

Osteoclast-type giant cell neoplasm of salivary gland. A microdissection-based comparative genotyping assay and literature review: extraskeletal "giant cell tumor of bone" or osteoclast-type giant cell "carcinoma"?

Primary salivary gland tumors resembling giant cell tumor of bone are very rare and have unsettled histogenesis. Both mesenchymal and epithelial origins have been suggested. We review 14 cases in the English-language literature and report another case, the first of which to be studied by microdissection-based microsatellite analysis. One-half of the tumors have been associated with a carcinoma, usually salivary duct carcinoma and carcinoma ex pleomorphic adenoma. Significant differences between this tumor and giant cell tumor of bone were observed. Unlike giant cell tumor of bone, in which the nuclei of the mononuclear and giant cells are similar, those of salivary gland show obvious differences between the nuclei of mononuclear cells and osteoclastic giant cells. In addition and in contrast to giant cell tumor of bone, the mononuclear cells of giant cell tumor of salivary gland express epithelial markers (epithelial membrane antigen, EMA; carcinoembryonic antigen, CEA) and androgen receptor. Genotypically, the microsatellite pattern of the giant cell component is more akin to the carcinomatous component and does not resemble giant cell tumor of bone. Biologically, giant cell tumor of salivary gland tends to be more aggressive than giant cell tumor of bone. We conclude that giant cell tumor of salivary gland is an unusual carcinoma that is not related to giant cell tumor of bone.

Response to Shiga toxin 1 and 2 in a baboon model of hemolytic uremic syndrome.

Post-diarrheal (D+) hemolytic uremic syndrome (HUS) is caused by Shiga-toxin (Stx)-producing Escherichia coli. There is epidemiological, cell culture, and mouse model evidence that Stx2-producing E. coli are more likely to cause HUS than strains that produce only Stx1, but this hypothesis has not been tested in a primate model of HUS. We have developed a baboon model of Stx-mediated HUS that was employed to compare the clinical, cytokine, and histological response to equal amounts of the two Shiga toxins. Animals given IV Stx2 developed progressive thrombocytopenia, hemolytic anemia, and azotemia, and urinary interleukin-6 levels rose significantly. Glomerular thrombotic microangiopathy was found at necropsy. Animals given Stx1 showed no cytokine response and no clinical, laboratory, or histological signs of HUS. Our findings from the primate model corroborate previous epidemiological, cell culture, and mouse model observations, and suggest that enteric infection with Stx2-producing E. coli is more likely to cause HUS than infection with organisms that produce only Stx1.

Recurrent hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) in children follows a diarrheal prodrome (D+) approximately 90% of the time, and recurrence due to enteric reinfection with Shiga toxin producing E. coli (e.g., O157:H7) can occur but is rare. It is not well recognized that nondiarrheal (D-) recurrences can also follow an episode of D+ HUS; we report 2 unrelated females who experienced multiple D- episodes following an initial episode of D+ HUS. We also present an HUS classification system that includes recurrence risk. It illustrates that recurrence is seen most frequently with familial HUS but can also occur in cases that are secondary to drugs, cancer, and pregnancy.

Prophylactic heparinization is ineffective in a primate model of hemolytic uremic syndrome.

The presence of abundant fibrin within the glomerular capillaries of patients with Shiga toxin (Stx)-mediated (post-diarrheal) hemolytic uremic syndrome (HUS) has suggested that heparin anticoagulation might be useful in the treatment of this disease. Although controlled studies have failed to show benefit, this lack of therapeutic efficacy could be due to administration of heparin after the thrombotic microangiopathy (TMA) had developed. If benefit could be demonstrated by giving heparin prior to the onset of the HUS, one could consider prophylactic heparinization of those at high risk of progressing from Stx colitis to HUS. We have developed a baboon model of Stx-mediated HUS, and have used this model to study the effect of prophylactic heparinization on the clinical expression and glomerular TMA of Stx-mediated HUS. A single intravenous infusion of Stx-1 at a dose that uniformly produces clinical and nephropathologic features of HUS was given with and without the prior administration of regular and low molecular weight heparin. Therapeutic levels of anticoagulation were achieved, but this did not reduce the clinical severity or lessen the TMA. Heparin anticoagulation may be ineffective because the rate of coagulation that occurs on the surfaces of dysfunctional endothelial surfaces exceeds the capacity of heparin/antithrombin-III inhibitor complexes to bind and block the factor Xa and thrombin that are generated on these surfaces. Our observations fail to support the use of heparin in preventing Stx-mediated HUS.

Renal prostacyclin biosynthesis in a baboon model of Shiga toxin mediated hemolytic uremic syndrome.

BACKGROUND/AIMS: Shiga toxin (Stx) and lipopolysaccharide (LPS) both participate in the pathogenesis of post-diarrheal (D+) hemolytic uremic syndrome (HUS), but little is known about factors that modulate the host response to these toxins. Prostacyclin (PGI(2)) is a potent renal vasodilator and inhibitor of platelet aggregation and adhesion. An inability to produce PGI(2) in response to endothelial cell injury could drive the pathogenic cascade. We therefore used a baboon model of HUS to measure PGI(2 )production following the administration of Stx and LPS. METHODS: Shiga toxin-1 (Stx-1), with and without LPS, was administered intravenously to baboons in various doses and schedules. 6-keto-PGF(1)alpha, the stable metabolite of PGI(2), was measured by ELISA in the plasma and urine. RESULTS: Plasma concentrations did not change significantly. Urine values increased significantly in some groups, but not in others, and HUS developed both in animals that did and did not exhibit a significant increase in urinary PGI(2) production. CONCLUSIONS: Renal PGI(2) biosynthesis appears to be affected by the dose and rate of Stx administration, and the timing of LPS infusion. PGI(2) does not protect our primate model from developing HUS.

von Willebrand Factor expression in a Shiga toxin-mediated primate model of hemolytic uremic syndrome.

von Willebrand Factor (vWF) is stored and released from activated or damaged endothelial cells and platelets, and its multimers have considerable prothrombotic properties. To investigate the role of vWF in the pathogenesis of post-diarrheal (D+) hemolytic uremic syndrome (HUS), we used a baboon model to study vWF expression following the intravenous administration of 100 ng/kg of Shiga toxin 1 (Stx 1), given either as a single dose, or as four divided doses, with and without lipopolysaccharide (LPS). vWF antigen was measured in plasma and urine obtained at 0, 12, 24, 36, 48, and 60 h by enzyme-linked immunosorbent assay (ELISA), and immunohistochemical expression of vWF in renal tissue obtained at autopsy was quantified by image analysis. Animals that received the single dose of Stx 1, or the four divided doses of Stx 1 plus LPS uniformly developed HUS, but those that received divided doses of Stx 1 without LPS, or LPS alone did not. Plasma vWF levels rose significantly in animals that received LPS, with or without Stx 1; but not in those that received Stx 1 alone. Urine vWF levels were generally undetectable. vWF expression was greater in renal tissue of animals that developed HUS than in those that did not, and was seen in both glomeruli, and, especially, peritubular capillaries. Since HUS developed in animals that did not experience a rise in plasma vWF levels, it does not appear that LPS-mediated systemic vWF release is essential to the pathogenesis of HUS in our model. The renal tissue findings, however, suggest a role for Stx-mediated intrarenal vWF release in the acute nephropathy of D+ HUS.

Response to single and divided doses of Shiga toxin-1 in a primate model of hemolytic uremic syndrome.

Postdiarrheal hemolytic uremic syndrome is caused by Shiga toxin (Stx)-producing Escherichia coli. It was shown previously that the baboon, like the human, has glycolipid receptors for Stx in the gut and the kidney and that a single 50- to 200-ng/kg intravenous dose of purified Stx-1 results in thrombocytopenia, hemolytic anemia, and renal thrombotic microangiopathy. For further characterization of factors that modulate disease expression, the baboon's response to the intravenous administration of 100 ng/kg Stx-1 given either rapidly as a single bolus or slowly as four 25-ng/kg doses at 12-h intervals was compared. Animals that received the Stx-1 as a single dose developed thrombocytopenia, schistocytosis, and acute renal failure. Urinary but not plasma tumor necrosis factor-alpha concentrations rose significantly by 6 h and then declined rapidly. Urinary and plasma interleukin-6 concentrations rose later. Glomeruli showed reduced patency of capillary loops, fragmented red blood cells, fibrin and platelet microthrombi, necrosis and detachment of endothelial cells, and accumulation of flocculent material in subendothelial spaces. Damage to tubular epithelium and peritubular capillary endothelium also was seen. Animals that received four divided doses of Stx-1 developed no clinical or histologic features of hemolytic uremic syndrome. It is concluded that in the primate model, disease expression is modulated by the rate of Stx administration, and it is speculated that in the human, the rate of Stx absorption from the gut is one determinant of disease severity.