Bianchi Am

C-Reactive Protein and Interleukin-6 Levels Are Related to Renal Function in Predialytic Chronic Renal Failure

Background: Several studies have provided convincing evidence that in apparently healthy subjects elevated serum levels of plasma C-reactive protein (CRP) are associated with an increased risk of experiencing myocardial infarction and sudden cardiac death. It has been claimed that, in dialytic patients, the hepatic synthesis of this ‘acute phase response’ plasma protein is primarily induced by the macrophage-derived interleukin 6 (IL-6). Little information is available, however, regarding CRP and IL-6 plasma levels in pre-dialytic renal failure. Methods: Plasma CRP by a modification of the laser nephelometry technique, IL-6 and serum albumin were determined in 103 chronic pre-dialytic patients (mean age 50 ± 6.3 years; creatinine clearance (Cr.cl.) 36.3 ± 23.1 ml/min). Results: CRP was >5 mg/l (normal upper range) in 42% of the global population. CRP and IL-6 were significantly related (r = 0.35, p < 0.0004). CRP and IL-6 were related to renal function (CRP vs. Cr.cl., r = –0.56, p < 0.0001; IL-6 vs. Cr.cl., r = –0.55, p < 0.0001, Spearman correlation coefficient). When patients were divided in tertiles according to renal function, CRP median value resulted 7.9 mg/l (interquartile interval: 5–12) in the first tertile (Cr.cl. <18.5 ml/min), 4.0 mg/l (3–6) in the second tertile (Cr.cl. 18.5–45 ml/min) and 3.2 mg/l (2.7–4.0) in the last tertile (Cr.cl. >45 ml/min) (p < 0.0001). A negative correlation between CRP and S-albumin was also found (r = –0.52, p < 0.0001, Spearman correlation coefficient). Conclusions: IL-6 and CRP were increased and were inversely related to creatinine clearance in our population of 103 chronic predialytic patients. The possibility of a decreased renal clearance of CRP and/or cytokines as a cause of an activated acute-phase response is discussed. A negative correlation between CRP and S-albumin was found confirming the link between chronic inflammation and malnutrition in chronic renal patients.

C REACTIVE PROTEIN IN PATIENTS WITH CHRONIC RENAL DISEASES

Base-line serum levels of plasma C-reactive protein (CRP) are predictive of future myocardial infarction and sudden cardiac death in apparently healthy subjects, suggesting the hypothesis that chronic inflammation might be important in the pathogenesis of atherothrombosis. CRP production is mediated by several inflammatory mediators: interleukin 6 (IL-6) is currently felt to be the major cytokine influencing the acute phase response. CRP and other acute phase proteins are elevated in dialysis patients and cardiovascular diseases represent the single largest cause of mortality in chronic renal failure patients. Little information is available, however regarding CRP and IL-6 plasma levels in pre-dialysis renal failure. Plasma CRP was determined by a modification of the laser nephelometry technique; IL-6 by immunoassay (RD System); and fibrinogen, serum albumin, cholesterol, triglycerides, hematocrit, white blood cell count, erythrocytic sedimentation rate (ESR) and urinary protein levels by standard laboratory techniques. Results were obtained in 102 chronic pre-dialysis patients whose mean age was 53 ± 5.8 years with a mean creatinine clearance (CCr) of 52 ± 37 mL/min). CRP was greater than 5 mg/L in 25% of the global population. CRP and IL-6 were 4.0 ± 4.6 mg/L and 5.8 ± 5.6 pg/mL, respectively and were not significantly correlated (r = 0.11, p = n.s.). CRP and IL-6 were however related with renal function (CRP versus CCr r = −0.40 p < 0.001; IL-6 versus CCr r = −0.45; p < 0.001). When patients were divided in two groups according to renal function, CRP resulted 7.4 ± 6.3 mg/L in the group of patients with a CCr lower than 20 mL/min (n = 32) and 2.76 ± 4.35 in the group of patients with a CCr higher than 20mL/min (n = 70) (p < 0.0001). CRP and IL-6 were positively related with ESR (r = 0.32 and 0.46 respectively). Serum albumin levels were not significantly different in the two groups of patients (3.2 ± 0.4 versus 3.0 ± 0.5 g/dL). CRP and serum albumin were not significantly related (r = 0.17). CRP and IL-6 correlated positively with ESR (r = 0.32 and 0.46 respectively). In pre-dialysis patients we have demonstrated an increase in both CRP and IL-6 that occurs as renal function decreases. These data provided evidence of the activation – even in the predialysis phase of renal failure – of mechanisms known to contribute to the enhanced cardiovascular morbidity and mortality of the uremic syndrome.

C-Reactive Protein as a Marker of Chronic Inflammation in Uremic Patients

Cardiovascular complications caused by an accelerated atherosclerotic disease represent the largest single cause of mortality in chronic renal failure patients. The rapidly developing atherosclerosis of the uremic syndrome appears to be caused by a synergism of different mechanisms, such as malnutrition, oxidative stress and genetic factors. Recent studies provide evidence that chronic inflammation plays an important role in the pathogenesis of cardiovascular diseases. Elevated serum levels of plasma C-reactive protein (CRP) are associated with an increased risk of experiencing myocardial infarction and sudden cardiac death in apparently healthy subjects. Several recently published papers have confirmed this strong association between CRP and the extent and severity of the atherosclerotic processes. In patients affected by predialytic renal failure, increased levels of CRP and interleukin (IL)-6 were recorded in 25% of our population; CRP and IL-6 were inversely related with renal function. These data suggest the activation – even in the predialytic phase of renal failure – of mechanisms known to contribute to the enhanced cardiovascular morbidity and mortality of the uremic syndrome. In recent years we have investigated the hypothesis that the chronic inflammatory state of the uremic patient could at least in part be due to the dialytic technique. We provide evidence suggesting that the increase of CRP in stable dialytic patients may be due to the stimulation of monocyte/macrophage by backfiltration of dialysate contaminants.

Mechanisms of acid-base homeostasis in acetate and bicarbonate dialysis, lactate hemofiltration and hemodiafiltration.

The different mechanisms of acidosis buffering were investigated in 15 RDT patients dialyzed in cross-over with four depurative techniques: acetate dialysis (AD), bicarbonate dialysis (BD), lactate hemofiltration (LHF) and hemodiafiltration (HDF) with acetate bath and lactate reinfusion fluid. Blood pH, bicarbonate, blood gases, intraerythrocytic pH — on red cell hemolisates — anion gap, L-lactate, pyruvate, adenosinmonophosphate (ADP) and 2-3 Diphosphoglycerate (2-3 DPG) levels were evaluated. During AD the intradialytic buffering is initially achieved by the CO2 fall and later by the acetate metabolism and an important bicarbonate shift from the intra to the extracellular space. A physiological compensation is obtained during BD with bicarbonate administration and a mild ventilatory response to the pCO2 increase. In LHF the massive lactate administration, with plasma levels of 7 mmol/l, strongly alters the Central Nervous System elettroneutrality inducing a hyperventilatory response with a purely pulmonary acidosis buffering. Furthermore the lactate/pyruvate ratio rose as high as 40:1 with ADP increase and cellular energy depletion. In HDF several different mechanisms are associated: the CO2 fixation, the acetate muscular metabolism, the intra-extracellular bicarbonate shift with the pulmonary response driven by lactate Central Nervous System penetration.

Protein layer on hemodialysis membranes: a new immunohistochemistry technique.

In order to investigate the nature of the protein layer deposited on hemodialysis membranes we developed a direct immunohistochemical technique using fluoresceinated antibodies to plasma proteins. Fifteen patients on regular dialytic treatment were dialyzed with CU, HE, PAN, PS and PMMA and the dialyzers analyzed at the end of a standard dialytic session. Snap frozen sections of hollow fiber devices were treated with flourescein-isothiocyanate conjugated antibodies for IgG, IgA, IgM, C3c, fibrinogen, factor VIII, factor Xllla-s, antithrombin III, fibrinogen degradation products (PDF) and plasminogen. Protein deposits were evaulated by a quantitative criteria, which evaluates the intensity of fluorescence and the area of the capillary wall occupied by this fluorescence by using an image analysis software. The coagulation cascade is activated by all membranes and similar deposits of these proteins were revealed, whereas important differences in C3c deposition were found.

BIOCOMPATIBILITY EVALUATION OF POLYAMIDE HEMOFILTRATION

Introduction Postdilution hemofiltration with a polyamide membrane is a renal replacement technique widely used, but very little information is available regarding the biocompatibility of this treatment. In this paper we report the results of an acute study of the biocompatibility of polyamide hemofiltration. Patients and methods Complement activation such as C3a and C5a Des Arg (RIA), granulocyte degranulation like alpha 1 elastase intradialytic increase (ELISA) and the expression of high affinity membrane receptors for IL-2 (anti-TAC) were determined. Beta 2-microglobulin (RIA) intradialytic decrease, as well as its convective removal, was evaluated. The nature of protein layer adsorbed onto the polyamide membrane, at the end of the dialytic session was investigated with a new immunohistochemical tecnique. Cell-associated cytokine concentration (like IL-1 beta and IL-1Ra - ELISA) was determined on mononuclear cell lysates. Results A low degree of complement activation was detected with the polyamide membrane when data were adjusted for hemoconcentration and for 1 m2 of membrane surface area. An important convective removal not only of Beta 2-microglobulin (258±20 mg/session), but also of the activated anaphylatoxins (225±76 ng/ml for C3a and 22.5±4 ng/ml for C5a) was revealed. A marked deposition of all coagulation factors with no detectable amount of immunoglobulins and complement factors was revealed on the polyamide membrane at the end of the dialytic session. No intradialytic (for IL-1beta) (from 14.1±3.0 to 13.5±2.9 pg/ 2.5 x 106 cell) and interdialytic (for IL-1Ra) (from 4572±1076 to 5408±615 pg/ 2.5 x 106 cell) cell-associated cytokine expression was induced by hemofiltration. Discussion and Conclusion Polyamide hemofiltration is a highly biocompatible technique due to the use of a synthetic membrane with a sterile reinfusion fluid and the convective removal of the activated anaphylatoxins and Beta 2-microglobulin.

Acute Suppression of Parathyroid Activity during Hemofiltration

Hemofiltration (HF) induces a significant reduction in parathormone (PTH). This effect is related not only to the convective removal of PTH molecules but also to the biological suppression of parathyroid glands by plasma-ionized calcium (iCa) increase. The acute inhibitory effect on parathyroid gland activity, ionized calcium mass balance, phosphate kinetics and intact PTH (PTHi) dialytic removal during post-dilution polyamide HF were studied in 31 chronic uremic patients. HF ensures good phosphate removal (from 2.54 +/- 1.19 to 1.27 +/- 0.35 mEq/l; p < 0.01), a positive iCa mass balance (8 +/- 4 mmol/session) with a iCa plasma increase and negligible convective PTHi removal (9 +/- 2 pg/ml). Study of the PTHi profile during HF characterized two different parathyroid responses: 26/31 patients showed a physiological parathyroid gland response to the iCa increase (from 1.17 +/- 0.09 to 1.42 +/- 0.07 mmol/l; p = 0.002) with a significant PTHi decrease (from 123 +/- 111 to 35 +/- 28 pg/ml; p = 0.01) and a maximal PTH inhibition of 88%. In 5 patients, with more severe hyperparathyroidism, in spite of a comparable increase in iCa (from 1.28 +/- 0.12 to 1.46 +/- 0.08 mmol/l; p = 0.02), this physiological calcium-PTHi feedback was lost, revealing an autonomization of the gland (maximal inhibition of 45%). In our experience, study of the PTHi profile during a single HF session may represent a clinical test for the functional exploration of parathyroid glands, suggesting future (medical or surgical) clinical strategy.

Role of ACE Inhibition in IgA Nephropathy

In ten patients with IgA nephropathy, GFR, RPF, FF, renal vascular resistance, FeNa and proteinuria were evaluated, baseline and after 16 weeks of Enalapril therapy. GFR did not change, RPF and FeNa increased, RVR and FF decreased. Daily urinary protein excretion reduced in five but two of 7 proteinuric pts. Enalapril may be effective in preventing the glomerular capillary hypertension and the development of the glomerular sclerotic lesions.

Paired Filtration Dialysis (PFD):Biocompatibility and Depurative Efficiency

Biocompatibility and depurative efficiency of Paired Filtration Dialysis was evaluated in a short-term (one month) follow up in 12 chronic uremic patients. Plasma granulocyte elastase slightly increased during the first hour of treatment, a transient but significative leukopenia was observed.Protein layer revealed a marked deposition of coagulation factors on polysulphone and trace amount of C3c and immunoglobulins on Hemophane. PFD allows an high depurative efficiency for small molecules (assessed by a Kt/V urea >1) and for Beta-2 MG even in a shorter dialytic time.

ACE Inhibition and Progression of Renal Injury in Man

Enalapril maleate, an angiotensin Converting Enzyme Inhibitor (CEI), is an effective antihypertensive agent. It lowers peripheral and Renal Vascular Resistances (RVR), increases Renal Plasma Flow (RPF) and Blood Flow (RBF), whereas Glomerular Filtration Rate (GFR) is usually unchanged. Since Angiotensin II (AII) alters renal hemodynamics by increasing efferent arteriolar resistance, reduces GFR by decreasing ultrafiltration coefficient (LpA), the product of the glomerular capillary wall hydraulic conductivity (Lp) and the effective capillary surface area available for filtration (A), and produces proteinuria, CEI may have the potentiality to correct intraglomerular hypertension, to normalize GFR and to decrease proteinuria.