Renal transplantation and immunological abnormalities in thrombotic microangiopathy of adults: report of 5 cases.

Renal transplantation was performed in five adult patients with thrombotic microangiopathy, three of whom had had a bilateral nephrectomy prior to transplantation. The graft remained functional in three patients 72, 18, and 12 months after transplantation. One patient developed a thrombosis of the renal artery and one patient died from infection. There was no clinical or histological evidence of recurrence of thrombotic microangiopathy in the five patients after transplantation. Immunological investigations were performed in four of five patients before transplantation: C3 and C1q levels were low in two patients; serum C3-splitting activity and circulating immune complexes were present in all four patients and remained unchanged on haemodialysis and/or after bilateral nephrectomy. Complement abnormalities and immune complexes were not detected in the three patients with successful renal transplantation.

Role of coagulation in glomerular injury.

A role for coagulation in renal diseases is suggested by the presence of glomerular fibrin deposits in numerous experimental and human renal diseases, some of which are of toxic origin. Fibrin may exert detrimental effects by occluding glomerular capillaries, by attracting macrophages or by direct cytotoxicity to mesangial cells. Intraglomerular fibrin deposition or formation may result in part from changes in the normal multiple haemostatic properties of glomeruli. In glomerular clotting of systemic origin, e.g., glycerol-induced acute renal failure with intravascular coagulation, inhibition by drugs of glomerular fibrinolytic activity leads to persistent thrombi and permanent renal damage. In immune glomerulonephritis, fibrin formation may depend on activation of glomerular prothrombotic properties: for example, glomerular procoagulant (tissue factor-like) activity is enhanced at the peak of mercuric chloride-induced autoimmune glomerulonephritis, characterized by massive fibrin deposits. Finally, fibrin deposits probably contribute to the progressive renal lesions and chronic renal failure seen in rats with kidney damage, in which anticoagulant therapy has a beneficial effect.

Changes in erythromycin pharmacokinetics induced by renal failure.

As erythromycin ototoxicity appears to be favored by renal insufficiency, its pharmacokinetics were assessed in chronic uremic patients treated by maintenance hemodialysis in comparison with normal subjects. Two groups of 8 patients each were studied, the first one on an interdialytic day, the second immediately after the end of an hemodialysis session. All subjects ingested a single dose of 1 gram of erythromycin ethylsuccinate. Times of peak serum concentration and biological half-lifes were similar in patients and in controls. Maximum serum concentrations and areas under the serum concentration time-curve were higher in patients than in controls whereas apparent oral clearances were lower in the former. The differences between the two groups of patients were not significant. These pharmacokinetic changes are suggestive of an enhanced bioavailability of erythromycin in chronic renal failure which might predispose uremics to the ototoxicity of the drug.

Physiological significance of increased levels of endogenous atrial natriuretic factor in human acute renal failure.

In twelve patients with acute renal failure, mean plasma levels of atrial natriuretic factor (ANF) and of its second messenger cGMP were found elevated at the early phase of the disease, but tended to return towards normal values at recovery. Variations of plasma ANF and cGMP were correlated significantly (p less than 0.05) with those of total blood volume. At the early phase of the disease, plasma ANF was also correlated with the excreted fraction of filtered sodium (FENa) (r = 0.95). Moreover, plasma ANF and FENa peaked concomitantly at the onset of the diuretic phase in the five patients who were not treated by diuretics or dialysis and were studied sequentially during the course of the disease. It is suggested that enhanced plasma ANF levels might reflect one of the mechanisms of adaptation controlling body fluid balance in acute renal failure.

Persistent intravascular C3 activation after bilateral nephrectomy in patients with thrombotic microangiopathy.

Four patients with thrombotic microangiopathy had evidence of intravascular C3 activation on presentation which persisted after bilateral nephrectomy. In several serum samples, C3-splitting activity was not associated with the presence of circulating immune complexes, which were detected in all four patients before nephrectomy and in three after nephrectomy.

[Spinal cord compression secondary to extramedullary hematopoiesis in a patient with thalassemia]. / Compression médullaire par hématopoïèse ectopique chez un patient atteint de bêta-thalassémie.

A 19-year-old man with homozygous beta thalassemia presented with signs of thoracic spinal cord compression secondary to extramedullary hematopoiesis. The patient was treated with hypertransfusion and hydroxyurea. After two months, clinical signs had resolved and magnetic resonance imaging showed significant regression of the extradural mass. Pathophysiology and therapeutic options in this condition are briefly discussed.

[Prevention of sickle cell crises with multiple phlebotomies]. / Prévention des crises douloureuses drépanocytaires par saignées itératives.

OBJECTIVES: Sickle cell disease patients suffering from frequent painful crises were submitted to phlebotomies in order to reduce hospitalization days due to pain, through hemoglobin (Hb) level reduction and iron deficiency in patients with an hemoglobin level equal to or above 9.5 g/dL. PATIENTS: Seven sickle cell disease patients (four SC, three SS), aged four to 24 years, were submitted to sequential phlebotomies during periods from 18 months to four years. METHODS: The number of hospitalization days for crises was considered. The volumes and frequencies of phlebotomies were adjusted according to the patients ages, the hemoglobin concentrations and the serum ferritin levels. RESULTS: One hundred and forty-four hospitalization days were recorded in the seven patients in the year preceding the treatment. During the study period, the annual numbers of hospitalization days were respectively 20, five, six and one. Mean hemoglobin concentration was 10.7 g/dL before phlebotomies and 8.8 to 9.2 g/dL during the four years of treatment. Mean corpuscular volume, mean corpuscular hemoglobin concentration and serum ferritin were also reduced. The volume of phlebotomies was 116 to 39 mL/kg/year according to the patients. COMMENTS AND CONCLUSION: The striking decrease of the number of hospitalization days for all the patients suggests a closed relationship between therapy and clinical improvement. The mechanism of this effect is probably multifactorial: a) the concentration of Hb level is known to influence the blood viscosity and its decrease always improved rheology in sickle cell disease patients; b) the mean corpuscular hemoglobin concentration is a critical factor concerning the HbS molecule polymerization in sickle cell disease, and its slight reduction may have an important biological effect. We observed these two biological modifications in our patients and suggest that they mediate the clinical effects. The iron deficiency induced by phlebotomies has no evident deleterious consequence either on height and weight in the children or on intellectual performance in any patients.

[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.

[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.

[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.

[Vasculorenal risks of oral contraceptives]. / Risque vasculo-rénal des contraceptifs oraux

PIP: A few cases of acute vascular nephropathology with severe hypertension attributed to oral contraceptives have been published. Various brands of pill had been used; the duration of the contraceptive treatment varied from 3 months to 10 years. The renal histological studies revealed the existence of thrombotic microangiopathic lesions or nephroangiosclerosis with fibrin deposits. The existence of such lesions made necessary the administration of heparin, the discontinuation of the contraception and the prescription of antihypertensive agents. Renal failure was irreversible in most cases. It is likely that oral contraceptives are connected with these accidents as they have been proved to often increase the blood pressure and provoke changes in the hemostasis through their estrogen content. Therefore it is necessary to regularly check the blood pressure of oral contraceptive users. The contraceptive treatment must be discontinued if hypertension appears, and another method of contraception must be recommended. This almost inevitably allows the blood pressure to drop back to normal. The disorders caused by oral contraceptives being related to their estrogen content, one may hope that the new "mini-pills" will make hypertensive and vasculorenal accidents disappear.^ieng