Hervé Favre

Anticoagulation in patients treated by continuous venovenous hemofiltration: a retrospective study.

The most adequate anticoagulation regimen during extracorporeal renal replacement therapy can be difficult to define. Two hundred fifty-five critically ill patients with a mean age (+/- SD) of 58.2 +/- 16.3 years were treated by continuous venovenous hemofiltration (CVVH) between 1986 and 1992 in our intensive care units. Blood was circulated through hemofilters, either polyacrylonitrile (AN 69; Hospal, Lyon, France) or polyamide (FH 66; Gambro, Lund, Sweden), using a roller pump and an air safety system. The patients were classified into three subgroups according to the amount of heparin needed to achieve an adequate anticoagulation (ie, prevention of extracorporeal circuit clotting without inducing a patients bleeding tendency): group 1, 37 patients who received no heparin (14.5%); group 2, 189 patients who received 100 to 700 IU/hr of heparin (74.1%); and group 3: 29 patients who received more than 700 IU/hr of heparin (11.4%). We analyzed the filter survival, the routine coagulation parameters, and the evolution of the patients for each group. Median duration of treatment was 144 hours (range, 4 to 1,152 hours). There were no differences in requirement of heparin among the two types of membrane: AN 69 (mean +/- SD), 393 +/- 106 IU/hr v FH 66, 374 +/- 35.3 IU/hr (range, 0 to 2,000 IU/hr). There were no relationships between the amount of heparin the patients received and the mean survival of the filters (group 1, 22.1 +/- 14.8 hr; group 2, 24.7 +/- 13.2 hr; group 3, 23 +/- 9.6 hr).(ABSTRACT TRUNCATED AT 250 WORDS)

Cell shrinkage triggers the activation of mitogen-activated protein kinases by hypertonicity in the rat kidney medullary thick ascending limb of the Henle's loop. Requirement of p38 kinase for the regulatory volume increase response.

The kidney medulla is exposed to very high interstitial osmolarity leading to the activation of mitogen-activated protein kinases (MAPK). However, the respective roles of increased intracellular osmolality and of cell shrinkage in MAPK activation are not known. Similarly, the participation of MAPK in the regulatory volume increase (RVI) following cell shrinkage remains to be investigated. In the rat medullary thick ascending limb of Henle (MTAL), extracellular hypertonicity produced by addition of NaCl or sucrose increased the phosphorylation level of extracellular signal-regulated kinase (ERK) and p38 kinase and to a lesser extent c-Jun NH2-terminal kinase with sucrose only. Both hypertonic solutions decreased the MTAL cellular volume in a dose- and time-dependent manner. In contrast, hypertonic urea had no effect. The extent of MAPK activation was correlated with the extent of MTAL cellular volume decrease. Increasing intracellular osmolality without modifying cellular volume did not activate MAPK, whereas cell shrinkage without variation in osmolality activated both ERK and p38. In the presence of 600 mosmol/liter NaCl, the maximal cell shrinkage was observed after 10 min at 37 °C and the MTAL cellular volume was reduced to 70% of its initial value. Then, RVI occurred and the cellular volume progressively recovered to reach about 90% of its initial value after 30 min. SB203580, a specific inhibitor of p38, almost completely inhibited the cellular volume recovery, whereas inhibition of ERK did not alter RVI. In conclusion, in rat MTAL: 1) cell shrinkage, but not intracellular hyperosmolality, triggers the activation of both ERK and p38 kinase in response to extracellular hypertonicity; and 2) RVI is dependent on p38 kinase activation.

Anticoagulation in Continuous Extracorporeal Renal Replacement Therapy

In recent years, continuous renal replacement therapies (CRRT) have gained much favor in the treatment of acute renal failure (14). At our center, the majority of ARF patients (80%) receive one or another mode of CRRT (5) . Such a therapeutic approach allows management of fluid balance without quantitative limitations, even in hemodynamically unstable patients ( 1 , 6). A potential drawback of CRRT is the need for ongoing anticoagulation to prevent clotting of the extracorporeal circuit (7). At present, the dialysis components (filter and tubing) do not have the antithrombogenic characteristics of the endothelium. In about 80% of the severely ill patients treated in intensive care units in whom CRRT is performed, prevention of clotting in the extracorporeal circuit is achieved by low dose heparin (500-700 U/h.) given into the arterial blood line before the filter (8, 9). These doses of heparin are similar to the doses used to prevent thromboembolic complications (10) and are therefore well tolerated. Among the remaining 20% of the patients who are at high risk of bleeding, anticoagulation for CRRT may cause severe hemorrhages accompanied by a high morbidity and mortality rate (11-13). In this category of patients, 3.5 to 10% of deaths (9) and about 25% of new hemorrhagic episodes (13) have been directly attributed to the anticoagulation. The purpose of this paper is to review the different methods available to prevent clotting in the extracorporeal circuit and to maintain the functional capacity of the filters during CRRT.

Drug combination therapy of systemic lupus erythematosus

ConclusionsThis long-term study on 73 patients with severe SLE has shown that drug combination therapy with steroids, CsA, MTX and Cy permits a control of disease activity and maintenance of kidney function with very few side effects and, to a large extent, allows patients a good quality of life in both professional and personal terms. In particular, it has been possible to drastically reduce steroid medication (Table 5). The mortality rate is now well under 1% per year, but is still three to four times higher than in an ageand sex-matched control population. Further efforts are necessary to improve the management of SLE. The investigation of the cytokine network might lead to the introduction of new agents [6]. There is also hope that CsA analogues, devoid of or with less toxicity, will be developed.

Autoimmune hematologic diseases associated with infraclinical systemic lupus erythematosus in four patients: A human equivalent of the NZB mice

In four patients with a diagnosis of autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura antinuclear antibodies and circulating immune complexes (Clq-BA test) have developed at some time in their history. Renal biopsy material was assayed with different methods. Immunofluorescence studies revealed granular deposits of immunoglobulin G (IgG), immunoglobulin M (IgM) and third component of complement (C3). Upon optic microscopy, three patients had mild mesangial proliferation, one a focal glomerulonephritis. Upon electron microscopy, all patients exhibited mesangial and/or subendothelial deposits. The patients have been followed for 18 to 37 years since the beginning of their disease. There has been no clinical evidence of systemic lupus erythematosus (SLE), although they present in their glomeruli immunologic and anatomic features compatible with this disease. These patients seem to be a human equivalent of the black NZB mouse which presents immunohematologic disorders and some biologic markers of SLE without having a full clinical picture of SLE.

Drug-combination therapy of rheumatoid arthritis

With the acceptance of the autoimmune pathogenesis of rheumatoid arthritis (RA), resistance to immune suppressive therapy of this disabling disease is gradually disappearing. Like all chronic autoimmune diseases, there is a wide spectrum of disease expression from very mild to very severe forms. Pincus [28] stressed this point by differentiating between patients in the general population with a mild form, usually self limiting, and most patients identified in clinical rheumatology. Patients in the former group are unlikely to have residual disease 3-5 years later, while patients in the latter group will probably have evidence of disease 3-5 years later, generally with progression of the disease process. This paper deals with treatment of the severe, self-perpetuating form of RA. With the increasing evidence of the predominant role of T lymphocytes in the pathogenesis of RA, it seemed logical to try cyclosporine A (CsA) for the control of disease activity in view of its selective immune suppressive action via T lymphocytes. Experience thus far has shown that no currently available drug is capable of controlling disease activity if used as monotherapy. This is certainly the case with CsA. In 1983 we first tried CsA in association with small doses of steroids, given on 4 days per week, in 4 patients. Three of the patients noted a certain improvement, but not sufficient to justify this combination therapy for severe forms of RA [21]. Subsequently, we added weekly injections of methotrexate (MTX), 15 mg i.v. or i.m., for 4 out of 6 weeks. Far better results were obtained with this drug combination [20]. Upon kidney biopsy, no relevant signs of CsA toxicity were found and this drug combination therapy was applied to an additional 25 patients [21]. To assess treatment efficacy, a standard score of clinical and laboratory parameters was used [20]. To assess disease activity in terms of normalisation of lectin-induced IL-2 production as well as spontaneous Ig production in tissue culture, a lymphocyte activity score [14] was used. It was essentially the lymphocyte activity score which implied the need for rather prolonged