Impairment of platelet aggregation in hemolytic uremic syndrome: evidence for platelet "exhaustion"

Thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure are the hallmarks of hemolytic-uremic syndrome (HUS). This report presents the results on platelet studies from 10 consecutive HUS patients in childhood. During their acute illness, they all displayed a characteristic pattern of impaired platelet function: no aggregating responses to epinephrine, some to ADP, and moderate to collagen. In addition, platelet contents of beta-thromboglobulin (beta TG) were markedly reduced. As these patients improved clinically, their platelet- aggregating responses also normalized despite their uremic state. Incubation of platelets with uremic plasma or guanidino-succinic acid, a uremic toxin, had minor effects on platelet-aggregating activity. Since low levels of platelet beta TG suggest that these platelets were in an exhausted state, in vitro experiments were performed to exhaust normal platelets by incubation at 37 degrees C. A proportional impairment of platelet-aggregating responses and decreasing levels of platelet beta TG were noted. Furthermore, the pattern of impairment was similar to that found in the platelet-aggregating activities of HUS patients. Thus, "exhaustion," in addition to azotemia and thrombocytopenia, are factors that contribute to the functional impairment of platelets in these patients. Further studies to reveal mechanisms that lead to platelet exhaustion in HUS are of fundamental importance in the understanding of this illness.     

New glucose-6-phosphate dehydrogenase mutations associated with chronic anemia

We have identified the glucose-6-phosphate dehydrogenase mutations responsible for enzyme deficiency in nine individuals with chronic nonspherocytic hemolytic anemia. We found the variants Tokyo, Iowa, Shinshu, and Guadalajara in British subjects and Kobe in an Italian. In addition we have determined the variant Corum has the mutation 820 G-- >A and have found in British subjects the mis-sense mutations 224 T-- >C, 488 G-->A and 833 C-->T which have not been described before. Some, but not all, of the mutations involve amino acids located near putative substrate binding sites.     

Plasma cell leukemia (PCL): A report on 15 patients

Fifteen patients presenting with plasma cell leukemia (PCL) are reported in detail. The clinicopathologic features of PCL differ from typical myeloma and resemble those of acute leukemia: patients with PCL have less bone disease but a much higher incidence of organomegaly and tissue infiltration as well as diffuse marrow involvement and more pronounced pancytopenia. One of the reported patients developed meningeal plasma cell leukemia and is reported in detail. Cytomorphologic assessment of PCL cells showed nuclear immaturity and obvious nuclear/cytoplasmic asynchrony. Despite the use of cytotoxic agents known to be effective in myeloma, the prognosis in PCL is poor, and the median survival of the reported patients was only 2 mo.     

Interleukin 4 in inflammatory bowel disease and mucosal immune reactivity

BACKGROUND & AIMS: Interleukin (IL) 4 has immunoregulatory and anti- inflammatory activities, but little is known about IL-4 in the human gut. We investigated production of IL-4 by isolated lamina propria mononuclear cells (LPMCs) from normal and inflamed intestine and its capacity to modulate local immune responses. METHODS: IL-4 levels were measured by enzyme-linked immunosorbent assay in cultures of control and inflammatory bowel disease LPMCs, and the effect of IL-4 on LPMC proliferation and interaction with IL-2, IL-1 beta, lipopolysaccharide, bacterial antigens, superantigen, and antibodies to various T-cell receptors was investigated. RESULTS: Various stimuli induced LPMCs to produce IL-4, but inflammatory bowel disease cells expressed IL-4 messenger RNA and secreted protein in significantly lower amounts than control cells. IL-4 failed to stimulate proliferation by fresh LPMCs, but a vigorous dose-dependent response was observed after preactivation by phytohemagglutinin, IL-2, or IL-4. When added to fresh LPMCs, IL-4 inhibited IL-2-induced proliferation. IL-4 amplified proliferation to IL-1 beta, lipopolysaccharide, peptidoglycan-polysaccharide complexes, staphylococcus enterotoxin A, and antibodies to the CD3 and CD28 receptors but not to tetanus toxoid. CONCLUSIONS: Decreased production of IL-4 in inflammatory bowel disease may cause defective immunosuppressive and anti-inflammatory mechanisms and may contribute to disease pathogenesis. The ability of IL-4 to differentially modulate LPMC reactivity probably influences mucosal immune homeostasis. (Gastroenterology 1996 Jun;110(6):1683-95)     

Human granulocytes generated in continuous bone marrow culture are physiologically normal

A long-term bone marrow culture system has been derived for maintenance and proliferation of human hemopoietic stem cells and granulocytes in vitro for up to 20 wk. The granulocytes generated in these cultures at 8 wk were comparable to fresh human peripheral blood granulocytes in physiologic properties, including phagocytosis, degranulation, respiratory burst, and bacterial killing: individual granulocytes generated up to 20 wk in several cultures demonstrated normal superoxide-generating capacity by NBT dye reduction slide test. Thus, human granulocytes generated in continuous marrow culture retain many biologic functions associated with bacterocidal capacity in vivo and indicate that this system should be of value in studies of disorders of granulocyte differentiation.     

Predictors of Health Utility among 60-Day Survivors of Acute Kidney Injury in the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study

Background and objectives: Health-related quality of life (HRQOL) after acute kidney injury (AKI) is an area of great importance to patients. It was hypothesized that HRQOL after AKI would relate to intensity of dialysis during AKI and dialysis dependence at follow-up.Design, setting, participants, & measurements: The Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study was a multicenter, prospective, randomized trial of intensive versus less intensive renal replacement therapy in critically ill patients with AKI. Of 1124 participants, 415 survived at least 60 days and completed the Health Utilities Index (HUI), which measures 8 health attributes and calculates an overall HRQOL score, also called a utility score. How strongly pre–intensive care unit (ICU) health, severity of illness, hospital course, intensity of dialysis, and outcome were associated with 60-day HUI scores was assessed, after adjustment for demographics.Results: The overall HUI score was 0.40 ± 0.37, indicating severely compromised health utility and was associated with only admission from home and hospital and ICU length of stay (LOS). Ambulation was better among those with a shorter hospital and ICU LOS. Better cognition was associated with dialysis independence and with fewer comorbid chronic illnesses. Emotion was associated with only hospital LOS. Pain was associated with ICU LOS.Conclusions: Health utility was low in this cohort of patients after AKI, and intensity of dialysis did not affect subsequent health utility. The effects of a lengthy hospitalization generally outweighed the effects of delayed recovery of kidney function on HRQOL after AKI.A cute kidney injury (AKI) is common among hospitalized patients and is particularly prevalent among patients cared for in the intensive care unit (ICU) setting (1–3). AKI has been associated with increased morbidity, mortality, and costs (1–4). It remains unclear to what extent treatment of or recovery from AKI influences health-related quality of life in survivors of AKI. There have been several reports of health-related quality of life (HRQOL) among survivors of AKI in the ICU (5–10). However, many of these studies are limited by small sample size and low response rate. In addition, follow-up times are variable among and sometimes within studies, ranging from 3 months to several years. Several measures of HRQOL have been used, including the Medical Outcomes Study Short Form 36-item health survey (SF-36) (9), EuroQol (EQ-5D) (5), and Nottingham Health Profile (6,8,10), and also health utilities by time trade-off (7) or visual analog scale (5) and Activities of Daily Living (7,8). Perhaps because of this variability, results are mixed. On balance, limitations in mobility were fairly common, ranging from 29 to 60% (6,8). However, patients generally reported a favorable health status, with 62 to 77% of patients reporting “good” or “excellent” health status (7,10). Health utility on the EQ-5D index was 0.68 compared with an age- and sex-matched norm of 0.86 (5), but in the same study utility by visual analog scale was not different from the general population. Health utility by the time trade-off method was reported by Hamel et al. to be 0.84, but no normative data were presented (7).The availability of HRQOL data in a large cohort of survivors of AKI requiring renal replacement therapy (RRT) provides a unique opportunity to study HRQOL and its potential determinants in this population. The Veterans Affairs/National Institutes of Health (VA/NIH) Acute Renal Failure Trial Network (ATN) study (ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT00076219","term_id":"NCT00076219"}}NCT00076219) was a multicenter randomized trial of intensive versus less intensive renal replacement therapy in critically ill patients with acute kidney injury conducted between November 2003 and July 2007 at 27 VA and university-affiliated medical centers (11,12). Although the major goals of the ATN study were to assess the effects of treatment assignment on 60-day mortality, in-hospital mortality, and recovery of renal function, HRQOL was also assessed at 60 days among survivors with the intention of establishing the effect of dialysis intensity on HRQOL and of assigning health utilities to facilitate performance of cost-effectiveness analysis.We hypothesized that study treatment assignment and ongoing dialysis dependence at 60 days would be potential determinants of HRQOL. Although intensive dialysis did not lead to shorter hospital stays or more rapid recovery of renal function (12), both of which might have contributed to improved HRQOL at 60 days, we postulated that better control of uremia could have direct effects on HRQOL. In addition, given that patients receiving maintenance dialysis routinely report impaired HRQOL (13–15), we also hypothesized that ongoing need for dialysis would be an important determinant of HRQOL at 60 days.     

Depressed Mood,Usual Activity Level,and Continued Employment after Starting Dialysis

Background and objectives: When patients start dialysis, their employment rate declines and disability benefits are an option. With patient sociodemographic and clinical characteristics including disability income status controlled, we investigated the significance of depressed mood and usual activity level as predictors of patients'' continued employment after dialysis start.Design, setting, participants, & measurements: Incident patients from 296 randomly selected dialysis clinics were surveyed in the Comprehensive Dialysis Study (CDS). Participants provided information about employment status, disability income status, education, depressive symptoms measured by the Patient Health Questionnaire-2 (PHQ-2), and usual activity level/energy expenditure measured by the Human Activity Profile. Age, gender, race, insurance, diabetes, inability to ambulate or transfer, chronic obstructive pulmonary disease, cardiovascular conditions, and hemoglobin and serum albumin values at treatment start were obtained from US Renal Data System files. Dialysis modality was defined at time of interview.Results: Among 585 CDS participants who worked in the previous year, 191 (32.6%) continued working after dialysis start. On the basis of the PHQ-2 cutoff score ≥3, 12.1% of patients who remained employed had possible or probable depression, compared with 32.8% of patients who were no longer employed. In adjusted analyses, higher Human Activity Profile scores were associated with increased likelihood of continued employment, and there was a borderline association between lower PHQ-2 scores and continued employment.Conclusions: Screening and management of depressive symptoms and support for increased activity level may facilitate patients'' opportunity for continued employment after dialysis start, along with generally improving their overall quality of life.Employment can foster personal self-esteem and responsibility and represents an important value in American society. Individuals'' ability to engage in productive activity provides a marker of the effectiveness of care. Many patients with ESRD leave the labor market after starting dialysis, however (1–3). Renal failure that requires dialysis conveys entitlement to disability benefits, which is a recognized disincentive to patients'' maintenance of employment (4), but symptoms of depression (5–7) and reduced capacity to engage in physical activity (8) may also be important contributors. No previous studies have investigated the associations among these variables (9).Most employed dialysis patients are individuals who continue the jobs that they held before starting dialysis treatment (1). The Comprehensive Dialysis Study (CDS) surveyed a national cohort of patients soon after dialysis start (10). We hypothesized that, after adjusting for current disability income status, other sociodemographic characteristics, and clinical variables, CDS participants'' depressed mood and their energy expenditure reflected in usual activity level would be independently associated with employment maintenance after dialysis start.