Atherosclerosis in uremia: a longitudinal study.

The ways by which uremia may lead to atherosclerosis are still unknown. Furthermore, whether atherosclerosis is accelerated with prolonged hemodialysis is still under debate. The results of a longitudinal study carried out in 47 selected patients who were treated first with dietary regimen followed by dialysis and then transplantation indicate: 1) The longer the duration of uremia on low protein diet, the worse are the clinical and metabolic problems of atherosclerosis. 2) In subsequent regular dialysis treatment 2 distinct clinical and metabolic pictures may emerge, slowly progressive or comparatively accelerated, according to whether dialysis is initiated early or late. 3) In subsequent transplantation the avoidance of risk factors largely depends on the time at which regular dialysis begins. 4) Early direct transplantation without dialysis proves similar to transplantation in patients treated with early dialysis as far as prevention of accelerated atherosclerosis is concerned.

The presence of posttransplant HLA-specific IgG antibodies detected by enzyme-linked immunosorbent assay correlates with specific rejection pathologies.

Posttransplant monitoring of anti-HLA antibodies with routine techniques gives unsatisfactory results due to a variety of technical limitations. We investigated how a new alternative technique correlates with posttransplant clinical events. A total of 313 nonselected serum samples from 136 patients were screened by an ELISA utilizing captured soluble HLA class I antigens. We observed the absence of anti-HLA antibody production in acute rejection cases responding to standard antirejection therapy. On the other hand, we showed a clear presence of these antibodies in acute rejection episodes not responding to standard therapy (P<0.0001) and in chronic rejection (P<0.001). We conclude that routine posttransplant monitoring by ELISA offers early risk assessment that is crucial for proper immunosuppression and for antirejection therapy choice.

Effects of renal substitutive programs on amino acid patterns in chronic uremia.

Abnormalities in the amino acid patterns are a constant finding in chronic renal failure and can be regarded as one of the typical biochemical alterations of uremia. This paper evaluates the long-term effects of various artificial substitutive treatments and renal transplantation on plasma and tissue amino acid patterns in chronically uremic patients. Fifty-three patients were included in the study: 35 on artificial treatments (9 on hemodialysis, 9 on hemofiltration, 4 on hemoperfusion, 6 on continuous ambulatory peritoneal dialysis, and 7 on intermittent peritoneal dialysis) and 18 with well-functioning renal transplants. Complete plasma aminograms were performed in all patients before starting the treatment, and repeated every 3 months up to 1 year (artificial therapies) and 3 years (renal transplantation). The amino acid composition of the bone was also determined in 8 dialysis patients and 9 transplant patients. None of the artificial therapies was associated with normal plasma patterns either in the short- or in the long-term, whereas successful renal transplantation led to normalization of the plasma profile within 2 to 4 months in all patients. However, bone amino acid composition remained altered both in artificially treated and in transplanted patients.

Cytomegaloviru; antibody in the urine of renal transplant patients.

Small amounts of cytomegalovirus (CMV) antibody were detected in the urine of renal transplant patients excreting the virus. The antibody was probably produced locally, as a result of active CMV infection of the urinary tract.

Parameters for indication of plasmapheresis and the interpretation of results.

Plasmapheresis has been employed in the treatment of various immunological disorders, and its efficacy has mainly been attributed to the removal of humoral factors. Besides these effects, plasmapheresis may induce some modifications to the cellular immunological status, contributing to the restoration of altered immunological function. In immunological renal diseases various parameters may be followed to decide the use of plasmapheresis, and to judge the effect of treatment. They include clinical, functional, and morphological investigations. In patients with lupus nephritis the main indications for plasmapheresis are the presence of impaired renal function and histological signs of activity in renal biopsy. In these patients plasmapheresis is able to modify humoral and cellular immunological abnormalities. Renal function and clinical course may improve in most cases. In patients with arteritis and acute renal failure the response to plasmapheresis combined with immunosuppressive drugs is better than the response to drug therapy alone. In acute renal transplant rejection plasmapheresis may be of value in improving the graft prognosis, when humoral factors are demonstrable in the pathogenesis of graft damage and vascular lesions are present in the kidney.

Short-term thoracic duct drainage in drug resistant immunologically mediated glomerulonephritis. Evaluation of lymph and blood lymphocyte characteristics during drainage.

Thoracic duct drainage has so far been employed in clinical nephrology mainly in renal transplantation and in immunologically mediated glomerulonephritis. The effectiveness of duct drainage in producing immunosuppression has been widely demonstrated, and several authors have used long-term, and others short-term drainage. 12 patients suffering from drug resistant immunologically mediated glomerulonephritis were treated with short-term (mean 10 days) thoracic duct drainage. In order to define the time, type and evolution of changes in immunological status, humoral and cellular immunity were studied daily in all patients. Marked changes (mainly in the number of lymphocytes drained and in their nucleic acid content and E-rosette forming capacity) take place in the first (4-5) days of drainage. These findings, together with positive clinical and laboratory results obtained in our patients, suggest that satisfactory immunosuppression may be achieved by short-term drainage, which is simpler and safer than long-term drainage. The procedure might thus be extended to a wider number of immunological diseases where drug therapy fails to take effect.

Effect of plasmapheresis on cellular immunity abnormalities in patients with systemic lupus erythematosus.

The effect of plasmapheresis on cellular immunity was studied in 10 patients with active lupus erythematosus (SLE) by evaluating before and after treatment the percentage of E-rosette forming cells (E-RFC), the inhibitory effect of patients' sera on rosette formation by normal lymphocytes, the Con A-induced suppressor activity and T-cell subsets studied by means of monoclonal antibodies. After plasmapheresis a significant improvement was observed in E-rosette formation and in Con A-induced suppressor activity, along with a marked reduction in the inhibitory effect of patients' sera on rosette formation. No change was observed in the number and percentage of T-cell subsets. These findings suggest that plasmapheresis may remove some circulating factors responsible for the immunoregulatory T-cell dysfunction observed in patients with active SLE.

Priorities in renal replacement programs.

The various alternative programs in renal replacement therapy have precise meritocratic ranking which unfortunately is still largely ideal today. New directions and scientific plans (bioartificial kidney, new immunomodulators, gene therapy) have to be followed to make today's ideal ranking become reality.

Progression rate of residual renal function in conservative treatment and early dialysis.

A retrospective comparative study was carried out in patients with chronic renal failure on conservative treatment (26 cases) and early dialysis (23 cases). The two groups were well matched for age, sex, etiology of renal disease and residual Ccr. In contrast with other papers, patients on dialysis showed a gentler deterioration rate of residual renal function than those on conventional low protein diet regimen. Between the two groups statistically significant differences concerned the control of blood pressure, serum phosphate and uric acid.

Evaluation of a new coated charcoal for hemoperfusion in uremia.

A new coated charcoal for hemoperfusion in uremia was investigated in 14 patients with end stage renal disease who underwent hemoperfusion or combined hemodialysis-hemoperfusion (39 seances). Investigations concerned removal of small molecules, coagulation and hematological status and amino acids and some hormones equilibrium. Clinical observations were also made in all patients. The methacrylate-coated charcoal enabled the removal of "toxins" up to 5000 daltons and the total solute removal did not significantly differ from previous hemoperfusion systems. However, the new coating membrane showed improved biocompatibility, in terms of clinical side effects and/or platelet and fibrinogen alterations.

Prevention of chronic glomerular uremia in steroid resistant glomerulonephritis. A clinical trial with a new antithrombotic agent.

To investigate the possibility of slowing down disease progression 27 patients with primary glomerular diseases unresponsive to steroids and cytotoxic drugs were treated with Defibrotide. This drug is a single stranded DNA fraction which has profibrinolytic and deaggregating properties and can promote the generation and release of prostacyclin from vascular tissue. Before treatment all patients showed proteinuria in excess of 1 g/day and 16 had a nephrotic syndrome (59%); 10 patients had serum creatinine above 1.6 mg/dl (37%) and 6 were hypertensive. After therapy a significant decrease in daily proteinuria was observed, although the reduction exceeded 50% of pre-treatment values in only 16 patients (59%). A progressive decrease in serum creatinine occurred in patients with abnormal renal function; serial measurement of renal plasma flow showed a progressive improvement with an average increase of 6 and 12%, after 1 and 3 months of treatment, respectively. These observations confirm the view that drugs improving endothelial function and renal hemodynamics can be of value in the treatment of chronic glomerular diseases and can contribute to the maintenance of renal function.

Hemoperfusion in reduced-time programmes for chronic uremia. Long-term results.

This paper reports the Authors' 8 year experience in the clinical use of charcoal hemoperfusion as a means to reduce the weekly time of treatment in chronic uremic patients. Two different programmes were applied. Programme A (34 patients) which involved substituting the 3 procedures per week of standard dialysis (4 hours duration each) by 2 procedures of combined hemodialysis and hemoperfusion, again of 4 hours duration each. Programme B (18 patients) which involved substituting the 3 procedures per week of 4 hours duration by 3 procedures of 3 hours each, 2 of combined hemodialysis and hemoperfusion, 1 of conventional dialysis. The net weekly reduction was 33% for Programme A and 25% for Programme B. The efficacy of the two Programmes was evaluated by clinical, hematochemical, nutritional and instrumental parameters.

Ten years experience with plasma exchange in renal transplantation.

Plasma exchange has been used in our renal transplantation programme for over ten years to treat 86 patients divided into four groups. Five patients had preformed cytotoxic antibodies before transplantation (group A); 13 sensitized patients (greater than 60% PRA) underwent prophylactic plasma exchange in the immediate post-operative period (group B); 62 patients were treated for acute vascular rejection (group C); six patients had chronic graft rejection (group D). Plasma exchange is a valid tool for the treatment of acute vascular rejection, provided that it is started before irreversible graft damage occurs: 75% rejection crises were reversed by plasma exchange and the actuarial graft survival from the rejection episode was 75% at one year, 66% at two and 50% at five years. Serum creatinine before treatment and glomerular thrombosis at graft biopsy correlated with the response to plasma exchange. In sensitized patients and in those with chronic rejection the results were disappointing and suggest that in these clinical conditions plasma exchange should be used only in selected cases.

Plasma exchange in renal allograft rejection.

Circulating anti-HLA antibodies against mismatched donor antigen have been found in 7 patients during acute rejection episodes, where renal biopsy showed severe vascular lesions. 4 patients were submitted to combined therapy with plasmapheresis and cyclophosphamide, while the other 3 were treated by cyclophosphamide alone. In the 4 patients treated plasmapheresis induced a rapid disappearance of circulating cytotoxic antibodies, which remained negative in 3 cases where cyclophosphamide was continued after plasmapheresis. No change in antibody occurred in the three cases treated by cyclophosphamide alone. Renal function showed an improvement in 3 of the 4 patients treated by plasma exchange; all patients on drug therapy alone showed a rapid and progressive impairment of renal function and returned to RDT within 2 months.

Combined hemodialysis-hemoperfusion treatment reduces the time of substitutive therapy in chronic uremia.

Charcoal hemoperfusion has long been used in chronic uremia as an adjunct or substitute for conventional hemodialysis. In this study a regular combination of hemoperfusion and hemodialysis was used to cut down the weekly substitutive sessions from 3 to 2. Ten RDT patients were treated with the reduced-time schedule for 5-56 weeks. Clinical and metabolic conditions remained stable in all patients and no sign of inadequate treatment appeared. Long-term charcoal hemoperfusion was confirmed to be a safe and risk-free procedure. No change in platelets, white cells, red cells, fibrinogen and other hematochemical parameters were detected.

Regular hemoperfusion in regular dialysis treatment. A long-term study.

The capacity of activated charcoal to remove toxins from the blood is well established. Its poor biocompatibility, inability to remove urea, electrolytes and water, and high cost have so far been the major objection to a wider use of charcoal with chronic uremic patients. The availability of a charcoal coated by a new highly hydrophilic methacrylate based on membrane enabled us to keep 18 uremic patients on a combined hemodialysis-hemoperfusion schedule for 4-52 weeks. Investigations concerned patients in whom relapsing signs of uremia occurred despite technically adequate dialysis, and other cases where dialysis was both technically and clinically adequate. In the first group of patients, the combined programme led to an improvement of the dialysis resistant clinical signs, while certain positive metabolic effects were also observed. In the second group, the hemodialysis-hemoperfusion treatment allowed a reduction of about 30% in time of treatment per week. Tolerance of the new coated charcoal was good throughout treatment in terms both of biocompatibility and of side effects.

Strategies in renal failure and the impact of lipids.

The main points to note in terms of strategies in renal failure and the impact of lipids are: 1) Timing and typing of dyslipidemia; 2) Occurrence of dyslipidemia in the course of strategies (conservative, dialysis and transplantation); 3) How the strategies can handle the impact of lipids. Analysis of point 1 confirms what a complex profile uremic dyslipidemia presents, involving the type, class, composition and enzyme systems involved in lipid metabolism. In conservative and dialysis, type IV (triglycerides) predominates; in transplantation, type II (cholesterol). Examination of point 2 shows the non obligatory relationship between dyslipidemia and the various strategies of treatment. Lipid abnormalities, type IV or II, occur in 50-60% of patients. Uremic factors for dyslipidemia include: 1) enhanced hepatic stimulation or altered removal in conservative strategies; 2) the same causes plus "specific" promotors in dialysis (dialysis fluid, plasticizer leaching; bioincompatibility, etc.); 3) steroid therapy and other "accessories" in transplantation. A genetic predisposition is very likely present in all patients. Point 3, finally, analyzes the various "supplements" that each strategy requires to cope with the lipid impact. Generic rules (ranging from doing nothing, to diet, drugs, etc.) are of value in all strategies when dyslipidemia occurs. More specific rules include: a) Conservative strategies: appropriate dietetic optimization and modulation (protein-lipid-carbohydrate ratio in terms of calories); b) Dialysis: timing treatment and improving biocompatibility; c) Transplantation: reducing steroids as much as possible.

Long-term comparative evaluation of synthetic and cellulosic membranes in dialysis.

A long-term retrospective evaluation (5 years) compares two groups of RDT patients (group 1 on continuous treatment with cellulosic membranes and group 2 with synthetic membranes) regarding survival, general clinical morbidity, and beta 2M-related morbidity. The results showed no significant long-term differences between the groups either for survival or general morbidity despite some differences in biocompatibility. The higher intradialytic removal of beta 2M by synthetic membranes did not lead to a reduction in either pre-dialysis beta 2M values or beta 2M related morbidity. The higher cost of synthetic over cellulosic membranes and the disappointing of many clinical expectations suggest that the use of such membranes, in association with alternative techniques, should take place only according to certain "elective" indications such as old age, diabetes, vascular instability or intradialytic disequilibrium syndrome.

Biocompatibility of charcoal hemoperfusion. Effects of long-term treatment on lymphocyte characteristics and function.

Biocompatibility of charcoal hemoperfusion was studied in a group of 15 uremic patients, evaluating the effects of long-term treatment on some structural and functional parameters of circulating lymphocytes: in vivo distribution of T-cell subsets; surface T3, T4 and T8 antigen expression, in vivo and in vitro DNA synthesis. A comparative analysis was performed with patients on conventional dialysis using cuprophan membranes.

Plasma exchange treatment in rapidly progressive glomerulonephritis associated with anti-neutrophil cytoplasmic autoantibodies.

This study reports on 12 patients with acute renal failure due to biopsy-proven rapidly progressive glomerulonephritis and signs of systemic disease in whom antineutrophil cytoplasmic autoantibodies (ANCA) were detected by indirect immunofluorescence (IIF) on alcohol-fixed neutrophils and assessed in serial determinations by ELISA. The diagnosis was: Wegener's granulomatosis in nine patients who showed a diffuse cytoplasmic pattern at IIF (c-ANCA), and microscopic polyarteritis in three where a perinuclear pattern (p-ANCA) was seen. All patients underwent a course of plasma exchange - PE - (3-10 sessions per patient) associated with steroids and cyclophosphamide. The ANCA titer dropped steeply during PE in all cases and was followed by disappearance of systemic symptoms and renal function improvement within four weeks. After a follow-up period of 50 +/- 31.2 months all patients were alive without signs of disease activity; ten had stable renal function, with serum creatinine 1.8 +/- 0.7 mg/dl; two had entered regular dialysis treatment after 44 and 82 months. Our results suggest that the rapid removal of ANCA by means of PE can help control disease activity and reduce the risk of death or end-stage renal disease.