[Prophylactic prescription of low-molecular-weight heparin in the non-surgical setting: impact of recommendations]. / Prescription préventive des héparines de bas poids moléculaire en milieu non chirurgical: l'impact de recommandations.

OBJECTIVE: Low-molecular-weight heparins (LMWH) had official approval for use for venous thromboembolism prophylaxis only for surgery patients when this survey was conducted, but were nevertheless often used in non-surgery patients. We conducted this "before and after" survey from May 1998 to April 1999 to assess the impact of the recommendations implemented in the beginning of 1999. METHODS: Data on the use of LMWH were collected on three different days within a three week interval in all non-surgery departments at the Tenon hospital before distribution of expert recommendations early in 1999. Published in La Presse Médicale in January 2000, these recommendations issued from an external panel of 43 experts who were contacted to establish a consensus opinion using the Delphi method. Data were again collected on three different days after implementation of the recommendations. Implementation was based on a patient-specific prescription order form requested by the hospital pharmacy for delivery to the department. RESULTS: Data were collected for 121 prescriptions prior to the recommendations and for 158 after. Sex-ratio, mean age and percentage of LMWH prescriptions did not differ significantly between the two periods. There was a lower number of non-appropriate prescriptions after implementation of the recommendations from 54.5% to 35.4% (p = 0.01) with better conformity for recommendation A (high-risk patients) (36% versus 43%, NS) and for recommendation B (= 2 risk situations or = 1 risk situation and = 2 aggravating factors) (10% versus 22%, p = 0.01). Better conformity of LMWH prescriptions in oncology and radiotherapy departments partially explained this general improvement, but the difference remained significant when excluding these two departments (p = 0.04). CONCLUSION: This study shows that physician compliance with recognized expert recommendations can improve their implementation. This procedure is now in general use in the Tenon hospital.

[Prevention of venous thromboembolism in a non-surgical medical ward. Proposed indications for low molecular weight heparin]. / Prévention de la maladie thromboembolique veineuse en milieu hospitalier non chirurgical. Propositions d'indications des héparines de bas poids moléculaire.

OBJECTIVE: The efficiency of venous thromboembolism prophylaxis with low molecular weight heparins (LMWH) has not been established in non surgical patients, so their official preventive use has been limited in France since 1995 to surgery. However, a survey conducted in 5 university hospitals in non surgical patients showed that 21-29% of patients still received a LMWH prescription. It seemed necessary to define the medical conditions for which the practical use of these heparins would be justified. We contacted external experts to obtain a consensus by using the Delphi method. METHODS: The Delphi method, created by the "Rand Corporation" in the USA and used in medicine since the nineteen seventies, is based on a light logistic, with questionnaires been sent by mail with a feed-back report A total of 48 experts were chosen by local staff teams in the 5 hospitals. For the 3 rounds, from March to October 1998, questions were devised by a multicentred staff team. RESULTS: Among the 48 experts contacted, 32 completed the 3 questionnaires, 7 of them did for 2, and 43 did for at least one questionnaire. The experts first defined a list of 12 risk or high risk situations and 11 aggravating factors. For any high risk situation, prescription is justified. For other cases, 2 risk situations are required, or one risk situation with at least 2 aggravating factors, to justify a prescription. If no risk situation is present, prescription is, according to experts, usually not justified. CONCLUSION: The maximal agreement defines the situations in which one use of low molecular weight heparins is proposed to prevent deep venous thrombosis in non surgical inpatients, in most current hospital situations and for more than 24 hours of hospitalization. Clinical trials are needed, to validate their effectiveness and define the optimal dose in these indications. To date, epidemiological studies should be conducted to evaluate the experts proposals by estimating risk factors for deep venous thrombosis.

Impact of guidelines implemented in a paris university hospital: application to the use of antiemetics by cancer patients.

AIMS: To assess the impact with time of guidelines on antiemetic use in an 850-bed Paris university hospital with a high proportion of cancer patients. METHODS: Guidelines on the use of antiemetics available in cancer chemotherapy were drafted according to the Delphi technique. Their implementation was based upon a patient-specific antiemetic prescription form. To assess the impact of guideline implementation over time, discrepancies between current practice and the guidelines were compared before guideline implementation (between March and August 1995) and after implementation (between March and August 1997, and March and August 1998). RESULTS: Before the Delphi panel's guidelines were implemented, 5-HT3 antagonists were inappropriately administered in 70% of cases. After guideline implementation, this proportion dropped significantly (P<0.0001, Fisher's exact test) to 22% between March and August 1997 and 28% between March and August 1998. CONCLUSIONS: Implementation of guidelines seems to have resulted in significant changes with time, although a causal relationship has not been demonstrated. The development of guidelines by our hospital's multidisciplinary working group helped the various consultants to adjust medical practices to take account of these changes.

Reduction of tumour necrosis factor alpha expression and signalling in peripheral blood mononuclear cells from patients with thalassaemia or sickle cell anaemia upon treatment with desferrioxamine.

Recent evidence indicates that the rate of progression of the HIV-1 disease is significantly reduced in thalassaemia major patients upon treatment with high doses of desferrioxamine (DFX). The authors have previously demonstrated that in vitro exposure of mononuclear cells to DFX decreases the bioavailability of tumour necrosis factor alpha (TNF-alpha) which has a stimulatory effect on HIV-1 replication. In this study, therefore, TNF-alpha bioavailability from mononuclear cells isolated from 10 patients with thalassaemia or sickle cell anaemia given DFX as compared to 10 untreated subjects has been evaluated. Evidence is presented showing that DFX treatment reduces TNF-alpha bioavailability (P<0.05) by inhibiting its steady state (P<0.05) and by enhancing its inactivation through binding to soluble TNF-alpha receptor type II (P<0.05). We also show that DFX treatment limits the in vivo activation of NF-kappaB, a transcription factor involved in both TNF-alpha gene transcription and TNF-alpha signalling (P<0.005). We conclude that TNF-alpha bioavailability and signalling are impaired in patients upon DFX treatment. This mechanism may contribute to delayed progression of the HIV-1 infection in vivo.

[Hemolytic-uremic syndrome with renal thrombotic microangiopathy]. / Syndrome hémolytique et urémique avec microangiopathie thrombotique rnale.

Hemolytic-uremic syndrome (HUS) is characterized by intravascular hemolytic anemia with fragmented erythrocytes and thrombocytopenia, acute renal failure, and glomerular/arteriolar fibrin deposition. Most childhood HUS are postdiarrheal (enterocolitic) while adult HUS have various causes, such as shigellosis, pregnancy, malignant hypertension, AIDS, antineoplastic chemotherapy and organ transplantation. Disorders of endothelial hemostatic functions, induced in some cases by bacterial toxins, may have a role in the onset of microthromboses. HUS treatments are both supportive, including antihypertensive drugs and dialysis, and antithrombotic, including plasma infusions or plasma exchanges and antiplatelet agents.

Methylprednisolone and cyclophosphamide pulse therapy in crescentic glomerulonephritis: safety and effectiveness.

In a previous study, we found that aggressive immunosuppressive therapy with continuous high-dose oral steroid and cyclophosphamide combined with plasma exchanges for extracapillary crescentic glomerulonephritis gave controversial results since, although disease activity was controlled, iatrogenic complications had led to death in some aged patients. We then modified our therapeutic regimen, and we analyze here the evolution of 30 consecutive patients who were admitted for biopsy-proven crescentic glomerulonephritis between 1989 and 1991. The mean plasma creatinine level at admission was 393 +/- 59 mumol/L (range 70 to 1100), and 15 patients had crescent formation in more than 50% of glomeruli on initial renal biopsy. Ten patients did not receive any immunosuppressive treatment since they either had a normal renal function or they had terminal renal failure and no severe extrarenal manifestation. The 20 other patients received initial steroid pulses 500 mg x3 (n = 17), low oral steroid treatment (n = 20), cyclophosphamide pulses (n = 13), or oral cyclophosphamide (n = 3). In 4 cases plasma exchanges were also used. As a whole, 10 patients (33%) were discharged with a normal renal function, and 18 patients (60%) had chronic renal failure, 7 of them requiring dialysis or transplantation; only 2 patients died of pulmonary hemorrhage. No severe iatrogenic complication was observed. These results indicate that reduction in oral steroid dosage, cyclophosphamide pulse therapy rather than continuous oral treatment, and plasma exchanges do not induce overimmunosuppression and iatrogenic complication. It can be safe, well tolerated, and as effective as a more intensive immunosuppressive regimen for the treatment of crescentic extracapillary glomerulonephritis.

[Reduction of TNF-alpha release and clinical effects of the first injection of OKT3]. / Réduction de la libération de TNF-alpha et des effets cliniques de la première injection d'OKT3.

In order to prevent the adverse effects of a first OKT3 injection in renal transplant recipients, we administered polyclonal antilymphocyte globulins (ATG Fresenius, 4 mg/kg/j) for 3 days before OKT3 injection. Compared with a historical group of 5 patients who did not receive ATG pretreatment before OKT3 injection, the patients who were pretreated by ATG had a significantly lower absolute number of circulating lymphocytes before the first OKT3 injection (363 +/- 107 vs 1,230 +/- 80/mm3, P < 0.001), a lower raise in plasma TNF-alpha level 2 hours after OKT3 injection (178 +/- 42 vs 735 +/- 127 pg/ml, P < 0.005) and a significant decrease in frequency and intensity of clinical symptoms, mainly chills, dyspnea, and headaches. However, fever and peak creatinine level were similar in both groups. A 80 percent success rate of crisis treatment was achieved in both groups and there was no increase in infectious complications. In conclusion, pretreatment with ATG induces a lymphocyte depletion, and decreases the amounts of TNF-alpha released as well as the side-effects of a first OKT3 injection.

Quantification and modulation of thrombomodulin activity in isolated rat and human glomeruli.

Thrombomodulin (TM), the endothelial cell surface receptor for thrombin-mediated activation of protein C and of its anticoagulant system, is involved in maintaining vascular nonthrombogenicity, and depressed TM activity may induce intravascular fibrin formation. TM antigen was previously found by immunohistochemical methods in rabbit glomeruli. We therefore attempted to identify the corresponding TM activity in isolated detergent-solubilized rat and human glomeruli. Like purified lung TM, rat glomeruli extracts accelerated the hydrolysis by activated protein C of the chromogenic substrate S-2238 in the presence of 10 nM thrombin, as determined by spectrophotometry. One mg glomerular protein promoted the formation of 681 +/- 115 nmol activated protein C, the equivalent of the amount generated by 845 ng of purified rabbit TM. TM activity correlated with the protein content of the glomerular extracts (r = 0.94). These extracts prolonged rat plasma activated partial thromboplastin time. Incubation of glomeruli with tumor necrosis factor-alpha (TNF) or E. coli lipopolysaccharide depressed their TM-like activity in a dose and time dependent manner. Incubation with TNF suppressed their anticoagulant activity. In human glomeruli, TM activity was also found at a level which corresponded to their TM antigen content, and was determined by ELISA with mouse monoclonal antibody. These results indicate that measurement of glomerular TM activity might help to clarify the mechanisms of intraglomerular fibrin deposition in renal diseases.

Glomerular coagulation system in renal diseases.

Glomeruli possess a complex hemostasis system with prothrombotic (procoagulant, antifibrinolytic) and antithrombotic (anticoagulant, fibrinolytic) properties that can act locally on platelet adhesion or aggregation, on plasmatic coagulation pathways, and on fibrinolysis. In vitro, inflammatory mediators, such as TNF, favor glomerular thrombogenic properties through enhancement of thromboplastin synthesis and of plasminogen activator inhibitor PAI-1, and through decrease in thrombomodulin activity. In some diseases, intraglomerular fibrin formation appears to be favored by increased glomerular prothrombotic properties, for example: augmented thromboplastin activity in immune glomerulonephritides and in Shwartzman phenomenon, excessive thromboxane A2 synthesis, and decreased fibrinolytic activity in severe renal allograft rejection. In other diseases glomerular hemostasis appears to function homeostatically, for example, in thrombin-induced disseminated intravascular coagulation with enhancement of fibrinolytic activity favoring fibrin dissolution. Novel methods allowing the study of glomerular hemostatic activities in renal biopsy fragments should help to understand the mechanisms of fibrin deposition in human diseases and to treat it on a logical basis.

Aseptic necrosis of bone following renal transplantation: relation with hyperparathyroidism.

Bone status, calcium and phosphate metabolism were prospectively evaluated in 98 renal transplant recipients with stable renal function. Aseptic necrosis of bone was found in 30 patients, leading to arthroplasty in 12 patients. Plasma parathyroid hormone and nephrogenic cyclic adenosine monophosphate (cAMP) values were greater and the duration of pre-transplant chronic renal failure longer in patients with aseptic necrosis of bone than in those who were not affected. Cumulative oral corticosteroid doses and the number of acute rejection episodes treated by intravenous methylprednisolone pulses were similar in patients with or without aseptic necrosis of bone. Hyperparathyroidism was confirmed histologically in 14 patients, comprising 4 cases of adenoma and 10 of diffuse hyperplasia. Serum parathyroid hormone correlated positively with serum creatinine (r = 0.47; P less than 0.001) and with cumulative corticosteroid dose (r = 0.30; P less than 0.003). This study suggests that hyperparathyroidism is a factor in the pathogenesis of aseptic bone necrosis. The frequency and severity of bone necrosis may be decreased by early detection and treatment of post-transplant hyperparathyroidism.

Tamm-Horsfall protein accumulation in glomeruli during acetazolamide-induced acute renal failure.

A patient with ocular hypertension was treated with acetazolamide. Acute renal failure developed rapidly and renal biopsy showed mild tubular lesions and crystal formation in a tubular lumen. By immunofluorescence studies with a monoclonal antibody, Tamm-Horsfall protein, normally absent from the proximal segments of the nephron, was detected in most glomeruli. This strongly suggests that tubular obstruction plays a major part in some cases of acetazolamide-induced acute renal failure.

Enhanced glomerular procoagulant activity and fibrin deposition in rats with mercuric chloride-induced autoimmune nephritis.

The mechanism involved in glomerular fibrin deposition was investigated during mercuric chloride (HgCl2)-induced autoimmune glomerulonephritis in the Brown Norway rat. To ascertain whether the local hemostatic system was activated secondarily to the immunological conflict, the ability of glomerular lysates to induce coagulation in vitro was assessed in treated and control rats. Glomerular procoagulant activity (PCA) of HgCl2-injected rats was measured on day 12 (latent phase of the disease), day 20 (acme), and days 32 and 42 (recovery phase) after the first mercury injection. PCA rose 3-fold (p less than 0.02) at day 20 and then almost returned to control values. Proteinuria, PCA, and the incidence of glomerular fibrin deposits peaked concomitantly at day 20. Glomerular PCA was characterized as thromboplastin. The number of Ia positive cells detected by monoclonal OX-6 antibody was not different from the control number at any phase of the disease; the number of macrophages per glomerular section detected by electron microscopy at day 20 in HgCl2-injected rats was 1.80 +/- 0.60, versus 0.30 +/- 0.11 in the controls. No correlation was found between glomerular PCA and either the number of monocytes/macrophages or of Ia-positive cells present in the glomeruli. Since glomerular PCA was maximal at the onset of fibrin formation in the glomeruli and then decreased toward its basal level, and since the fibrin disappeared, it is concluded that increased production of thromboplastin by glomeruli, with activation of the extrinsic coagulation pathway, may contribute to intraglomerular fibrin deposition in HgCl2-induced glomerulonephritis.

Relative contribution of intrinsic lung dysfunction and hypoventilation to hypoxemia during hemodialysis.

Two mechanisms have been proposed to explain hemodialysis (HD)-induced hypoxemia: reversible lung damage due to intrapulmonary leukostasis as a consequence of the contact of blood with the dialyzer membrane, or alveolar hypoventilation due to the loss of carbon dioxide through the dialyzer. To assess the role of these factors, seven chronically uremic patients were studied before and during 4-hr HD sessions using a cuprophane membrane and either acetate (AHD) or bicarbonate (BHD) dialysate. In AHD only we observed, by comparison with predialysis values, a significant hypoxemia, and a decrease of alveolar ventilation (VA), lung carbon dioxide output, and respiratory exchange ratio. In both the AHD hypoxemic group and BHD nonhypoxemic group, there was a similar decrease in lung carbon dioxide diffusing capacity (DLCO) and of white blood cells (WBC), and a positive correlation between arterial oxygen pressure and VA without modification of alveolo arterial PO2 difference, an argument against the existence of ventilation-perfusion or ventilation-diffusion mismatching. We conclude that, although WBC sequestration induced a lung damage evidenced by DLCO impairment, the key factor of hypoxemia observed in AHD was the hypoventilation.

Acute interstitial nephritis due to drug hypersensitivity. An up-to-date review with a report of 19 cases.

The clinical, biologic, and pathologic features and the course and treatment of acute interstitial nephritis (AIN) due to drug hypersensitivity are reviewed. The authors report 19 additional cases of AIN, outlining some particular and unusual features. The drugs most often responsible now are penicillins and cephalosporins, cotrimoxazole, thiazide diuretics, glafenin and its derivatives, and nonsteroid anti-inflammatory agents. Diagnosis of AIN should be considered in any case of rapidly progressive renal failure occurring during drug therapy, especially when fever, skin rash, arthralgias, macroscopic hematuria, and blood or urinary eosinophilia are present. In the absence of the preceding symptoms, systematic early renal biopsy may be helpful to detect intersitial infiltrates containing lymphocytes, plasma cells, and eosinophils and/or granulomas with epithelioid cells. Immunologic tests are inconstantly positive. Their sensitivity and specificity often are doubtful in the absence of precise knowledge of the pathogenetic factors involved. Recovery may be hastened in some cases by corticoid therapy. Recurrence of the disease will be avoided by definitive suppression of offending and related drug(s).

Drug-induced granulomatous interstitial nephritis.

Among 22 cases of drug-induced acute interstitial nephritis (AIN), noncaseating interstitial granulomas were found in eight cases (36%). Acute renal failure (ARF), oliguric in three patients, appeared within 1-20 days after the beginning of therapy. Clinical symptoms suggesting a hypersensitivity reaction were unusual, marked blood eosinophilia was absent, and immunologic tests were inconstantly positive. The discovery of interstitial granulomas may be a clue to the diagnosis of drug-induced AIN, especially when the inflammatory infiltrates do not contain eosinophils. Since significant residual renal impairment may be observed the benefit of early steroid therapy must be debated.

A new form of familial glomerulonephritis.

An unusual familial glomerular disease, characterized by the presence of diffuse round mesangial deposits of C3, is described in 2 siblings (1 male and 1 female) and their mother. The clinical picture in the 3 patients was a long-lasting proteinuria. An acute hemolytic uremic syndrome with malignant hypertension developed in the male at the age of 24 years, requiring bilateral nephrectomy. The glomerulonephritis recurred on a renal allograft. This disease is not HLA-linked and no characteristic abnormality of complement profile was seen in the 3 patients.

Prognostic importance of vascular lesions in acute renal failure with microangiopathic hemolytic anemia (hemolytic-uremic syndrome): clinicopathologic study in 20 adults.

Renal biopsies obtained from 20 adult patients within 30 days after onset of acute renal failure with microangiopathic hemolytic anemia ("the hemolytic-uremic syndrome") were studied. Lesions were graded independently by two observers without knowledge of the clinical history. All patients who did not have refractory hypertension were treated with heparin. Ten of the patients died, and four developed end-stage renal failure requiring chronic dialysis. Six patients, however, had a relatively good outcome: two recovered completely and four developed mild-to-moderate chronic renal failure not requiring dialysis. The six patients with a good outcome had significantly less severe arterial intimal thickening on biopsy compared with the remaining patients with a poor outcome. The patients with a good outcome and those with a poor outcome did not differ in the severity of glomerular lesions. The clinical features did not allow a prediction of late outcome. These results suggest that early renal biopsies may be helpful in predicting prognosis in the "hemolytic-uremic syndrome." This clinical syndrome may occur either in apparently healthy people, or may complicate the course of a chronic essential hypertension.