[Myasthenia gravis. Opportunistic cytomegalovirus infection after long-term azathioprine therapy]. / Myasthenia gravis. Opportunistische Zytomegalievirus-Infektion nach langzeitiger Azathioprin-Therapie.

Opportunistic infections after long-term treatment with azathioprine (AZA) have not been noted in patients with myasthenia gravis (MG). We report on a 56-year-old woman with generalized MG who presented with cytomegalovirus infection after being treated with AZA for 17 years. The indication for immunosuppressive treatment in MG should be regularly reconfirmed, particularly since at least 50% of patients can discontinue AZA after two to four years without risk of exacerbation.

RenaGel (Geltex Pharmaceuticals Inc).

RenaGel, developed by GelTex, is a polymer that binds and removes dietary phosphate from the intestinal tract without being absorbed into the bloodstream. A US NDA for control of hyperphosphatemia in patients with chronic renal failure was filed in October 1997 and accepted for review in January 1998. Marketing approval was granted in November 1998. The compound has also achieved part B status in Europe. Merrill Lynch predict RenaGel will achieve worldwide sales of $220 million by 2001.

ABX-CBL (Abgenix Inc).

Abgenix has acquired rights to ABX-CBL, an antibody in phase II trials for the potential treatment of graft versus host disease (GvHD). The antibody, previously known as CBL-1 was discovered by the CV Cancer Center. Abgenix planned to continue phase II trials in GvHD in 1998 after completing a confirmatory clinical study required by a manufacturing process change. ABX-CBL will also be evaluated in kidney and other organ transplant rejection indications. In January 1998, Abgenix announced that it had commenced a phase II trial of the antibody at eight clinical centers to confirm the results of previous phase II trials. The study will involve 48 patients. Results of the trial were expected by the third quarter of 1998. However, by December 1998 they had not been reported. ABX-CBL could also potentially be used to treat inflammation and autoimmune diseases such as rheumatoid arthritis and psoriasis. In a clinical trial, ABX-CBL was administered to ten patients with acute steroid-resistant GvHD. The overall response rate was 90%, with GvHD completely resolved in five patients and improved by at least two grades in four others. The antibody was well-tolerated and did not exacerbate post-transplant immunodeficiency. In another study involving 43 patients who developed GvHD after kidney transplant, ABX-CBL was effective in reversing the first rejection and preventing recurrence of rejection. It was shown to be well tolerated with no serious adverse events reported.

[The differential diagnosis and therapy of hemolytic anemias after the transplantation of solid organs]. / Differentsial'naia diagnostika i terapiia gemoliticheskikh anemii posle transplantatsii solidnykh organov.

The clinical sign "anemia" is found in a majority of patients after solid organ transplantation. A variety of etiological factors cause reduced red blood counts--in different situations hemolysis is the culprit. Thrombotic microangiopathy (hemolytic uremic syndrome, transplant rejection or induced by immunosuppressive therapy), infections (bacterial, viral, fungal), and autoalloimmune reactions (differences in blood-group or Rhesus-antigens, drug induced RBC lysis) are most important pathologies to be considered in differential diagnostic steps. Methods applied in diagnostics, underlying pathologies and therapeutic consequences are described based on the clinical history of three transplant patients from a single university department. Therefore, hemolysis as a possible and important situation following organ transplantation should be considered, immediately traced back to the underlying disorder and effectively treated.

Early loss of renal transplants in patients with thrombophilia.

BACKGROUND: We considered the possibility that thrombophilia may propagate graft thrombosis and therefore we evaluated the protein C system, which is a natural anticoagulant. Potential alterations in this system include protein C or protein S deficiency, inhibition through a lupus anticoagulant (LA), or a resistance to activated protein C due to the factor V Leiden (FVL) mutation. METHODS: One hundred thirty-two consecutive renal transplant patients, not known to have abnormal thrombostasis, in whom 1-year graft survival could be assessed, underwent laboratory testing for protein C or S activity, LA, and FVL. Transplant survival and demographic data were extracted from the hospital record. RESULTS: We identified 18 patients with thrombophilia (FVL, 10; LA, 6; protein S, 2) who had received a total of 28 renal transplants. Of these 28 transplant recipients, 11 transplants were lost within the first year, compared with 21 of 155 transplants to 114 patients without thrombophilia (P=0.0003). Median graft survival for patients with thrombophilia was 30 months (range: 0 to 166), compared with 86 months (range: 0 to 212) for patients without thrombophilia (P<0.01). The presence of thrombophilia represented a 3.5-fold (95% confidence interval, 2.3-5.3-fold) risk for 1-year graft loss. CONCLUSION: In this retrospective study, patients with thrombophilia had a significantly higher risk of early transplant failure. These data point toward a potential contribution of thrombophilia to transplant loss, a hypothesis that needs further study.

[Chronic HIV- and chronic HBV infection with hematuria and proteinuria]. / Chronische HIV- und chronische HBV-Infektion mit Erythrozyturie und Proteinurie.

HISTORY AND CLINICAL FINDINGS: A medical examination, undertaken in an apparently healthy 30-year-old man because of his occupational exposure to chemicals, revealed haematuria and proteinuria. Physical examination was unremarkable except for oral hair-leukoplakia and swelling of the cervical, supraclavicular, axillary and inguinal lymph nodes. INVESTIGATIONS: Examination of the urine demonstrated selective glomerular proteins (1.5 g/24 h) and dysmorphic erythrocytes. SGOT and SGPT activities were raised (73 and 129 IU/l, respectively). Active hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) infections were demonstrated virologically. The CD4+ count in blood was reduced to 200 cells/microliter. Renal biopsy showed an IgA nephropathy. TREATMENT AND COURSE: Antiretroviral treatment with zidovudine and lamivudine were started. SGOT and SGPT activities and HIV load fell steadily, while CD4+ cell count rose markedly. Renal functions have remained stable during the past 6 months. CONCLUSION: Signs of glomerular damage are not unusual in systemic diseases, tumors or infections (Hepatitis B and HIV in this case) and they may be the first manifestations of the underlying disease.

Structure and binding properties of serum albumin in uremic patients at different periods of hemodialysis.

Few diagnostic methods are available that describe uremia related changes of the albumin molecule structure in hemodialysis patients. The impaired human serum albumin (HSA) function is an essential part of the uremic syndrome and probably influences the long-term outcome of patients on maintenance dialysis. The albumin binding capacity (characterized for different binding centers on the molecule) is one of the relevant clinical parameters. During the current study, marker substances were utilized to evaluate center-specific binding capacity. Patients were divided into 3 groups depending on the time on hemodialysis (HD) treatment (in years) with healthy blood donors as control. Compared to healthy persons, results demonstrate a considerable impairment of binding characteristics in HD patients. Only in patients on maintenance HD for more than 5 years did ligand binding properties improve significantly. A correlation between the time of chronic HD and the recovery in binding capacity was found for the majority of binding centers of the HSA molecule. Similar results were seen applying such analytical methods as thermography (melting points) and thermofluorescence. Binding capacity impairment found for specified binding centers on the HSA molecule as the main serum carrier protein may have a direct impact on different clinical situations and the HD long-term outcome.

[Continuous detoxication methods in acute kidney failure]. / Nepreryvnye metody detoksikatsii pri ostroi pochechnoi nedostatochnosti.

Recently, acute renal failure has often been managed with continuous extracorporeal detoxication of the blood. In this case detoxication unit worked for days or even weeks. The continuous detoxication (CD) has the advantages: no sharp homeostatic changes occur, blood detoxication covers the whole period of acute renal failure. Technical specifications of the equipment are provided, as well as the diseases most responding to CD and recommendations on anticoagulation and replacement of the lost amino acids and glucose. CD allows the physicians to adjust therapeutic scheme to current needs of the patient.

Microspheres based detoxification system: a new method in convective blood purification.

A variety of protein-bound or hydrophobic substances, accumulating as a result of pathologic conditions such as exogenous or endogenous intoxications, are removed poorly by conventional detoxification methods because of low accessibility (hemodialysis), insufficient adsorption capabilities (hemosorption), low efficiency (peritoneal dialysis), or economic limitations (high-volume plasmapheresis). Combining advantages of existing methods with microspheric technology, a module-based system was designed. Major operating parameters of the latter can be modified to allow for adjustment to individual clinical situations. An extracorporeal blood circuit including a plasmafilter is combined with a secondary high-velocity plasma circuit driven by a centrifugal pump. Different microspheric adsorbers can be combined in one circuit or applied in sequence. Thus, a prolonged treatment can be tailored using specially designed selective adsorber materials. Comparing this system with existing methods (high-flux hemodialysis, molecular adsorbent recycling system), results from our in vitro studies and animal experiments demonstrate the superior efficiency of substance removal.

Biophysical studies on the correction of uremic human serum albumin binding defects by in vitro charcoal adsorption treatment.

Spectrofluorimetry, flow microcalorimetry, and differential scanning microcalorimetry (DSMC) were used to study the conformation, binding function, and ligand loading of uremic albumin obtained from the blood plasma of 2 end-stage renal disease (ESRD) patients before and after charcoal plasma treatment at different pH values (3.0-9.0). The spectrofluorimetric patterns of conformational N-F transition at low pH (4.2-3.5) are practically identical for both samples of uremic human serum albumin (HSA) and control HSA from healthy donors. After the charcoal treatment at pH 3.0 and 4.0, the enthalpies of complexing on uremic HSA with bromsulfalein and sodium dodecylsulfate approach that of donor HSA. The binding affinity of uremic HSA for sodium octanoate, phenol red, and salicylic acid following low pH charcoal treatment even exceed those of donor HSA. At the same time the charcoal treatment of uremic plasma at neutral and alkaline pH does not notably improve the binding characteristics of isolated HSA. Adsorption at low pH values completely restores the tryptophan fluorescence spectrum position of uremic albumin and improves the thermodynamic characteristics of its melting process. Using DSMC data, it can nevertheless be concluded that some conformational changes or a certain amount of high-affinity bound endogenous ligands still remain after low pH uremic HSA purification. The latter conclusion requires additional improvements of adsorption treatment of uremic plasma.

[Changes in the picture of chronic diseases on long-term hemodialysis treatment]. / Izmeneniia v kartine khronicheskikh zabolevanii pri dlitel'nom lechenii gemodializom.

New data published in the literature provided evidence for appearance of an unknown variant of amyloidosis recorded in patients with a 5-15-year history of hemodialysis. Such amyloidosis may result from high blood levels of beta-2-microglobulin unremovable at standard hemodialysis. Even highly permeable membranes which permit beta-2-microglobulin penetration fail to produce negative balance of this metabolite as the procedure stimulates leukocyte activity and, consequently, beta-2-microglobulin production. In spite of the fact that contact of the blood with synthetic materials during hemodialysis is not longer than 3-5 hours, blood elements and endothelial cell metabolism, homeostasis undergo serious alterations. These effects of biocompatibility provoke the condition of enhanced activation similar to chronic inflammation. Thus, we deal with a new phenomenon in the field of hemodialysis. The efforts of investigators should be aimed at studying long-term adaptation of the body which rings atypical picture of chronic diseases.

Leukocyte adhesion molecules as biocompatibility markers for hemodialysis membranes.

Comparative flow cytometric measurement was used to evaluate the significance of leukocyte adhesion molecule (LAM) activity changes during hemodialysis (HD) with different cellulosic and non cellulosic membranes. Six hemodialysis patients (men) who were in a maintenance program for more than 6 months were treated consecutively with five different dialyzers (cuprophan, hemophan, 2 types of cellulose acetate, and polysulfone). During each study HD, blood was sampled from the arterial line at 0, 15, and 60 min and from the venous port at 3 min to harvest leukocytes immediately after the first cell-membrane contact. After whole blood lysis preparation, leukocytes were incubated with fluorescent antibodies to label LAM CD 11A/18 (LFA-1), CD 11B/18 (Mac-1), CD 11C/18 (p150/95), and CD 54 (ICAM-1) (Becton-Dickinson, San Jose, CA). Data were acquired for the granulocyte, monocyte, and lymphocyte population based on forward and 90 degrees scatter light measurements. Accuracy of gating was verified by CD 14/45 staining for all samples. Baseline integrin expression for the selected populations before biomaterial contact was found to be heterogeneous for different patients, but underwent changes for the same patient during HD treatment. The fluorescent intensity corresponding to specific integrins was characterized by different patterns of up/down regulation with maximal deviations occurring at 3 min. Fluorescent intensity of the granulocyte and monocyte populations sampled at 15 min was 40-50% lower as compared with those sampled immediately after the first biomaterial contact. Based on the basal fluorescence levels and values recorded after the first biomaterial contact and those at 15 min, two coefficients were generated to compare membrane properties.

Endothelium: the next frontier in biocompatibility.

Vascular endothelium plays a central role in two specific functional systems. It controls vascular tone, hemostasis, and substance transport. The endothelium is the "docking station" for trapping, deactivation, and regeneration of activated blood compounds and provides the principal clearance mechanism for biologically active mediators released by different cell types. The second function is a regenerational one. During the period between insults (or between dialysis sessions), the endothelium has to restore the "first line of defense," that is, to regenerate the injured athrombogenic surface of the vessel wall and its antioxidative potential, defoliate damaged endothelial cells, and interpolated new ones. These two important endothelial activities are required over and above its basic functions. Future research in artificial organs must take into account that continuous or intermittent blood-membrane contact creates an altered endothelial response. These altered responses may result in adaptional reactions that may differ substantially in the acutely ill patient on continuous venovenous hemofiltration (CVVH) or in a stable patient on maintenance hemodialysis. By a reduction in such factors as immediate or delayed cell-cell interactions (direct or indirect), it may be possible to influence the long-term outcome of chronic hemodialysis patients. Other research should strive to enhance those factors of endothelial function that are essential in the defensive and restorative properties of endothelial tissue. This is especially important in such continuous therapies as CVVH, long-term membrane oxygenation, and artificial heart and blood vessels. Currently, there are more unanswered questions than possible answers concerning endothelial functions in long-term hemodialysis patients, but it is clear that excluding endothelial cell behavior from investigation of extracorporeal therapy in the future would be a substantial omission.

[The results of using plasmapheresis in the acute rejection reaction after kidney transplants]. / Rezul'taty primeneniia plazmafereza pri reaktsii ostrogo ottorzheniia posle transplantatsii pochek.

We report about the results of plasmapheresis treatment of acute vascular rejection in patients after renal transplantation and compare this group of cadaveric-kidney recipients with another group of patients with acute vascular rejection that got only treatment with intensified immunosuppression (cyclophosphamide). The retrospective study was provided in a non-randomized form with 27 patients in the combined plasmapheresis-cyclophosphamide group and 31 patients in the cyclophosphamide group. The advantages and disadvantages of plasmapheresis treatment in acute rejection periods are discussed. Special attention is given to infectious complications in the early posttransplant period.