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Protein malnutrition, a condition associated with an albumin concentration less than 3.5 g/dL, has been shown to be a major risk factor for increased mortality in hemodialysis patients. The aim of this cross-over study was to evaluate the relationship between the type of membrane adopted and serum albumin changes by measuring peripheral blood mononuclear cells (PBMC) interleukin-6 (IL-6) release, serum albumin, and plasma concentrations of C-reactive protein (CRP) in 18 patients dialyzed with different membranes. During the study, all patients were dialyzed with cuprophan (CU), synthetically modified cellulosic (SMC) membrane (a new cellulosic membrane with lesser complement activation), and cellulose diacetate (CD) membrane, and have served as their own controls. IL-6 spontaneous release by PBMC resulted after 3 months of SMC (436.2 +/- 47.4 pg/mL) significantly (P < 0.05) reduced as compared with CU (569.3 +/- 24.5 pg/mL). This effect was more evident after 6 months of dialysis with SMC (220 +/- 35.3 pg/mL, P < 0.01 versus CU and versus 3 months of SMC). The passage to CD membrane was followed by a progressive new increase in the IL-6 PBMC release (332.3 +/- 30.7 after 3 months, and 351.2 +/- 35.8 pg/mL after 6 months, respectively) that, however, remained significantly (P < 0.05) lower than CU. The behavior of CRP plasma levels resembled that of IL-6 PBMC release (23.3 +/- 4.7 in CU, 11.0 +/- 2.1 after 3 months in SMC, and 7.9 +/- 1.5 after 6 months in SMC, respectively). IL-6 release values were positively correlated with circulating levels of CRP (r = 0.3264, P < 0.002). Serum albumin increased after 6 months of dialysis with SMC membranes (3.25 +/- 0.09 g/dL in CU and 3.64 +/- 0.07 g/dL in SMC, P < 0.05). When the patients were switched to CD, serum albumin showed a slight, though not statistically significant, decrease. Serum albumin concentrations negatively correlated with both IL-6 release values (r = -0.247, P < 0.05) and CRP plasma levels (r = -0.433, P < 0.001). In conclusion, our data clearly show that a significant relationship exists between biocompatibility of the membranes and serum albumin changes; serum albumin levels, in fact, are negatively correlated with the PBMC spontaneous IL-6 release values and CRP circulating levels.

Hemodiafiltration (HDF) is a very effective blood treatment resulting from the coupling of dialysis and hemofiltration and leading to reduction of dialysis time. The aim of this study was to evaluate the balance of bicarbonate and calcium through the filter during postdilutional HDF (with an ultrafiltration flow rate of 70 ml/min) and to verify the effect of ultrafiltration on the kinetics of these two solutes. The study was performed by simultaneously collecting three blood samples (at filter inlet and outlet and after reinfusion) at different ultrafiltration flow rates (12.5-90 ml/min), to measure blood pH, pCO2, plasma total CO2(TCO2), total calcium, ionized calcium and plasma protein concentration. Plasma bicarbonate concentration was calculated by measuring plasma TCO2. The results showed an inverse linear relationship between bicarbonate (r: -0.7938; p less than 0.001) and calcium (r: -0.8731; p less than 0.001) balance and ultrafiltration flow rate. In particular, in postdilutional HDF both bicarbonate and calcium balances through the filter were negative at ultrafiltration flow rates greater than 40 and 55 ml/min, respectively. The negative bicarbonate balance, however, was corrected by reinfusing a substituting solution containing bicarbonate (40 mmol/l). By contrast, the negative calcium balance cannot be corrected by reinfusion and requires a greater calcium concentration in the dialysate and oral calcium supplements.

Role of inhibition of atrial natriuretic factor release in the down-regulation of salt excretion. We investigated the role of atrial natriuretic factor (ANF) in the down-regulation of sodium excretion (U Na V). Seven subjects were sequentially studied while injesting a normal-salt diet (220mmol NaCl/day, NSD), a very low-salt diet (20mmol NaCl/day, VLSD) for six days, and again at NSD for nine days. After one day of VLSD, a negative salt balance of 85mmol was achieved and plasma ANF decreased from 19.1 (SE 2.5) to 7.2 (SE 2.1) pg/ml, whereas plasma renin activity (PRA) and plasma aldosterone (ALD) increased after the third and second day, respectively. During restoration of volemia (NSD), ANF increased after the third day; in contrast, PRA and ALD decreased earlier. Seven other subjects kept at low-salt diet (50mmol NaCl/day) were studied during ANF infusion (at 2, 4, 8 ng/min/kg body wt). Increases of ANF from 10.3 (SE 0.9) pg/ml (basal condition) to levels of 24.0 (SE 1.9) pg/ml (infusion study), occurring physiologically in the same subjects after NSD, evoked increases in U Na V that accounted for 62% of U Na V rise necessary to balance the NSD, whereas PRA or ALD did not change. Plasma ANF, unlike PRA or ALD, was directly correlated with U Na V. In conclusion: (a) ANF changes earlier than PRA and plasma aldosterone during VLSD; (b) PRA and ALD respond more promptly than ANF in the recovery from hypovolemia; (c) during ingestion of a low-salt diet, changes in plasma ANF by infusion account for more than half the increase in U Na V following the shift from low- to normal-salt diet independently of alterations in PRA and ALD.

Renal functional reserve: Its significance in normal and salt depletion conditions. The aim of this study was the evaluation, in healthy subjects, of the renal functional reserve (RFR), that is, the GFR increase induced by a combined infusion of amino acids (AA) and dopamine (D), in conditions of extracellular volume depletion caused by diuretic administration. In particular, this study was undertaken: a) to evaluate whether and to which extent, AA + D can reverse the functional GFR impairment induced by salt depletion, without volume restoration; b) to study whether any relationship may be found between the GFR in normal condition (the so-called “resting” GFR), and/or the renal functional reserve and the GFR impairment induced by salt depletion, in order to understand the role of both “resting” GFR and RFR in the degree of renal dysfunction induced by salt depletion. In control conditions the i.v. infusion of AA + D significantly increased RPF (+ 41% vs. baseline period) with a mean absolute increase of 211 ml/min. A similar pattern was observed in GFR behavior (+ 31.5% with 34 ml/min of mean absolute increase). A significant inverse exponential relationship was observed between GFR before A A + D i.v. infusion (“resting” GFR) and renal functional reserve (P < 0.05), suggesting that, in normal conditions, these inversely related parameters may widely vary according to the tone of the glomerular arterioles. Following salt depletion, we observed a variable degree of GFR impairment. Both GFR and RPF were significantly decreased (-25.9%, P < 0.05 and -29%, P < 0.05, respectively). The GFR impairment was mainly caused by a significant increase in tone of glomerular arterioles presumably induced by vasoactive substances (angiotensin, catecholamines) as mirrored by the increase of both plasma renin activity (PRA) and urinary norepinephrine (NE) excretion (+164% and +426%, respectively, vs. control period). AA + D infusion after salt depletion determined a striking rise of both GFR (+30 ml/min, corresponding to 37%) and RPF (+193 ml/min, corresponding to 31%) versus the baseline study of salt depleted condition. The GFR value obtained by AA + D i.v. infusion in the normal condition, however, was not reached presumably because of persistence of extracellular volume contraction, which was confirmed by the persistence of high values of PRA and NE urinary excretion and low values of urinary sodium excretion after AA + D i.v. infusion. GFR impairment due to salt depletion was directly related to the “resting” GFR (P < 0.05) and inversely related to the RFR (P < 0.01): the latter relationship suggests that the greater the “resting” tone of glomerular arterioles (and consequently the value of the RFR), the more minor the role of renal vasoconstriction in causing the fall of GFR following salt depletion. Finally, AA + D infusion in the salt depleted condition induced a GFR increase that is inversely related to the GFR value obtained after salt depletion (P < 0.05). This finding suggests that glomerular arteriolar tone influences, also in a salt depletion condition, the response to AA + D infusion: subjects with a lower GFR (with a greater vasoconstriction), in fact, show a greater increase in GFR after the infusion of these vasodilating substances. depletion condition, the response to AA + D infusion: subjects with a lower GFR (with a greater vasoconstriction), in fact, show a greater increase in GFR after the infusion of these vasodilating substances.

Extra-natriuretic effects of atrial peptide in humans. To evaluate extra-natriuretic effects of atrial natriuretic peptide (ANP), plasma ANP (pANP) levels were assessed in seven healthy men on low-sodium diet (80mEq NaCl/day), in basal conditions and during stepwise infusion of human ANP (2, 4, 8 and 16 ng/min/kg). To determine the individual physiological (PHY) pANP level, we measured pANP in the same subjects after a high-salt diet (400 mEq NaCl/day), that is, in a physiological stimulation of ANP. We then compared the effects of the PHY levels of ANP to the effects of pharmacological (PHA) pANP levels. Neither PHY nor PHA pANP levels modified creatinine clearance or blood pressure. The progressive rise in pANP levels was associated with increases in urinary excretion of Na + , K + and urea. ANP alone respectively accounted for 41%, 30% and 92% of the increase in natriuresis, kaliuresis and urea excretion that occurred after changing salt intake from 80 to 400 mEq/day. Pharmacological ANP levels raised C H 2 O and reduced U Osm . Interestingly, PHA levels were associated with significant decrease in serum K + (from 4.5 ± .1 to 4.0 ± .1 mEq/liter) and plasma urea (from 31.9 ± 5 to 24.2 ± 4 mg/dl). The mean cumulative urinary potassium and urea losses corresponded to the theoretical body losses of potassium and urea; moreover, the individual cumulative urinary losses of potassium and urea significantly correlated with the corresponding decrement in their plasma levels. In conclusion, ANP has both physiological and pharmacological significance in the control of potassium and urea metabolism by decreasing plasma levels of K + and urea through effects on the renal excretory function.

The body composition in overweight and obese hemodialyzed patients (HD) remains ill-defined. This study evaluates in HD patients the influence of body size, as indicated by body mass index (BMI, kg/m(2)), on body composition by measuring bioimpedance analysis (BIA)-derived variables (phase angle (PA), fat-free mass (FFM) and body cell mass (BCM).We studied 50 Caucasian patients (mean age 62.8+/-9.2 y) on standard bicarbonate hemodialysis for at least 12 months who regularly achieved dry weight in post-HD, received similar dialysis doses and were free from inflammation/infection. Thirty-eight gender- and age-matched healthy subjects were included as controls (CON). Both HD and CON were divided into three groups on the basis of their BMI(kg/m2) 18.5-24.9, normal-weight (NW); 25-29.9, overweight (OW); andor =30, obese (OB). In HD patients, BIA was performed 30 min after the end of dialysis.Seven patients were obese (12%) while 16 were overweight (32%); in CON, 12 were obese (31%) and 12 overweight (31%). BIA-measured extracellular water was comparable in all groups. PA, which was similar in normal-weight HD and CON (6.2+/-0.9 degrees and 6.3+/-0.8 degrees ), decreased in OW- and OB-HD patients (5.3+/-1.0 degrees and 5.2+/-0.6 degrees, respectively; P0.05 vs NW-HD) while it was unchanged in OW- and OB-CON (6.1+/-0.8 degrees and 5.9+/-0.5 degrees, P0.05 vs respective HD groups). In OW and OB patients, the lower PA values were coupled with a major reduction of BIA-derived percentage BCM and FFM (P0.05 vs NW-HD, and vs OW- and OB-CON). In patients, PA and BCM correlated with anthropometry-measured FFM. Of note, serum albumin and protein catabolic rate were significantly reduced in OB patients.In overweight and obese HD patients, BIA-derived FFM, BCM and PA are significantly lower with respect to normal-weight patients and BMI-matched controls. These abnormalities of body composition are coupled with reduction of anthropometric measures of lean mass and a decrease of protein intake that, however, becomes significant only in the obese. We therefore suggest that overweight and obese HD patients are at risk of protein malnutrition in spite of excessive energy intake. BIA may be considered as a useful diagnostic tool to detect such a condition early.

Role of different dialysis membranes in the release of interleukin-6-soluble receptor in uremic patients.BackgroundInterleukin-6 (IL-6) exerts its actions through a cell-surface receptor system that consists of two transmembrane subunits: the IL-6 binding glycoprotein gp 80 (IL-6R) and the signal-transducing component (gp 130). Soluble forms of the IL-6R (sIL-6R) are generated by shedding of the membrane-associated proteins. The sIL-6R binds the ligand IL-6 with comparable affinity as the membrane-associated IL-6R and enhances the actions of IL-6.MethodsOur aim was to evaluate the role of both uremia and different dialysis membranes on peripheral blood mononuclear cell (PBMC) release (either in absence or in presence of mitogen stimulation) and plasma levels of sIL-6R. Ten patients chronically dialyzed with cuprophan membranes (CU), eight patients on regular dialysis treatment with polymethylmethacrylate (PMMA) membranes, 11 uremic nondialyzed patients (UR), and 12 healthy subjects (CON) were included in the study.ResultsPBMCs harvested from CU spontaneously released significantly (P < 0.01) greater amounts of sIL-6R (881.8 ± 80.1 pg/mL), as compared with CON (267.5 ± 26.5 pg/mL), UR (258.4 ± 38.1 pg/mL), and PMMA (288.4 ± 24.6 pg/mL). Under mitogenic stimulation, the sIL-6R release was significantly (P < 0.01) increased in all groups. The greater PBMC production of sIL-6R in CU was followed by significantly (P < 0.01) higher levels of circulating soluble receptors (48.7 ± 2.5 ng/mL, 60%), as compared with CON (30.5 ± 1.9 ng/mL). UR also showed high circulating levels of sIL-6R (53.3 ± 5.9 ng/mL), probably secondary to an impaired urinary excretion. Circulating levels of sIL-6R in PMMA were comparable to CON (30.3 ± 3.3 ng/mL). Either the absence of monocyte activation or the adsorption of sIL-6R on the hydrophobic PMMA surface could explain this finding.ConclusionsThese results suggest an important role for poor dialysis biocompatibility of CU on the release of sIL-6R, which increases sIL-6R plasma levels, thereby enhancing the inflammatory effects of IL-6.

Background: Dry weight prescription is commonly based on symptoms induced by inappropriate fluid removal by hemodialysis (HD). Aim of this study was to compare the assessment of volume status by conventional bioelectrical impedance analysis (BIA) and the resistance-reactance (RXc) graph method in HD patients achieving their target dry weight determined on clinical criteria. Methods: We studied 39 HD patients (23 males and 16 females, mean age 52 ± 17 years, dialytic age 41.2 ± 37 months). Dry weight, prescribed according to the standard clinical criteria, was constantly achieved in the last 3 months. Patients symptom-free over the last 3 months were defined as asymptomatic. Patients with either muscular cramps or hypotensive episodes were defined as symptomatic. Thirty-three healthy volunteers (11 males, 22 females, mean age 50 ± 11 years) constituted the control group. Standard, single frequency (50 kHz), tetrapolar, BIA measurements were obtained in controls, and in patients before, every 60 min, and 30 min after one HD session. Total body water (TBW), and extracellular water (ECW) were calculated using conventional BIA regression equations. In both groups, tissue hydration was also assessed by the RXc graph method. Results: On the basis of 95% tolerance interval (mean ± 2 SD) for the ECW (%) calculated in healthy subjects (ECW = 35–44%), HD patients were divided into 3 groups according to their post-HD ECW: 72% normohydrated with ECW 35–44%, 10% overhydrated with ECW >44%, and 18% underhydrated with ECW 2 = 6.9, p = 0.03) where the majority (73%) were classified as underhydrated, while 0 and 27% were classified as over- and normohydrated, respectively. The frequency distribution of the 28 asymptomatic patients also significantly differed between conventional BIA and RXc graph hydration categories (χ2 = 10.8, p = 0.005), since 11, 71 and 18% vs. 0, 43 and 57% of patients were classified as over-, normo-, and underhydrated, respectively. Conclusions: The classification of volume status based on conventional BIA was insensitive to either clinical situation (presence or absence of symptoms). In contrast, the classification based on the RXc graph was consistent with the clinical course in symptomatic patients (73% dehydrated, and 27% normohydrated), while it did not reflect the clinical course in asymptomatic patients, 57% of whom were classified as (already) underhydrated. A longitudinal study will establish the clinical usefulness of RXc graph indications in asymptomatic patients.

A 68-year-old female treated by peritoneal dialysis (PD) for 4 years was hospitalized for cough and dyspnea without chest pain. Chest X-ray revealed massive right pleural effusion. High glucose content in pleural fluid in comparison with blood glucose level was suggestive of transdiaphragmatic leakage. To establish the communication between the peritoneal and pleural cavity, peritoneal scintigraphy was performed. Different 99mTc-labeled colloids have been used for peritoneal scintigraphy in the past years, such as sulfur colloid, macroaggregated albumin, and diethylenetriamine pentaacetic acid (DTPA), each with some important limitations. On the basis of the characteristics of icodextrin, an osmotic colloid agent routinely used in PD, such as its persistence in the peritoneal space, 99mTc-icodextrin scintigraphy was performed to confirm the diagnosis of peritoneopleural leakage (Fig. 1a, b). Therefore, 99mTc-icodextrin scintigraphy may represent a new, simple, noninvasive, cost-effective, well-tolerated, and safe radionuclide imaging method to clearly detect some causes of peritoneal dialysis failure.

p-Cresol is a by-product of the metabolism of aromatic aminoacid operated by resident intestinal bacteria. In patients with chronic kidney disease, the accumulation of p-cresol and of its metabolite p-cresyl-sulphate, that represents more than 95% of circulating p-cresol, causes endothelial dysfunction and ultimately increases the cardiovascular risk of these patients. Therapeutic strategies able to reduce plasma p-cresol levels are highly demanded but unfortunately not available yet. Because it has been reported that the phosphate binder sevelamer also sequesters p-cresol in vitro we hypothesized that it could do so also in peritoneal dialysis patients. To explore this hypothesis we measured total cresol plasma concentrations in 57 patients with end-stage renal disease on peritoneal dialysis patients, 29 receiving sevelamer for the treatment of hyperphosphatemia and 28 patients not assuming this drug. Among the patients not assuming sevelamer, 16 were treated with lanthanum whereas the remaining 12 received no drug because they were not hyperphosphatemic. When we compared total p-cresol plasma concentrations in these different groups of patients, we, we found that plasma p-cresol levels were significantly lower in patients receiving sevelamer than in subjects receiving lanthanum or no drug. Patients assuming sevelamer had also lower high sensitivity C-reactive protein serum concentrations compared to patients not assuming this drug. Multiple linear regression analysis showed that Conversely, no difference either in residual glomerular filtration rate, total weekly dialysis dose or serum phosphate levels were observed among the different groups. These results suggest that sevelamer could be an effective strategy to lower p-cresol circulating levels in peritoneal dialysis patients in which it could also favorably affect the cardiovascular risk because of its anti-inflammatory effect.

To evaluate the effects of hemodialysis treatment on the spontaneous cell release of interleukin-2 receptor (IL-2R), we studied 19 hemodialyzed patients (HD), 9 non hemodialyzed patients with chronic uremia (UR, glomerular filtration rate: 8.4 +/- 1.8 ml/min), and 8 healthy control subjects (C). We measured the release of IL-2R in the supernatant of peripheral blood mononuclear cells (PBMC) cultured for 24 hrs in Iscove's medium as well as the plasma levels of IL-2R. A significant increase of IL-2R release was detected in the supernatant of PBMC harvested from HD patients (32.4 +/- 2.4 and 34.2 +/- 5.6 U/3 x 10(6) PBMC daily before and after HD, respectively) as compared with UR (16.6 +/- 5.2 U/3 x 10(6) PBMC daily) and C (21.4 +/- 3.8 U/3 x 10(6) PBMC daily). Similarly, IL-2R plasma levels were significantly higher in HD (378.5 +/- 164.6 U/ml) than in UR (189.5 +/- 89.3 U/ml) and C (11.2 +/- 2.68 U/ml). To summarize, the current study demonstrates: a) an enhancement of spontaneous IL-2R cell release in HD patients; b) an increase of sIL-2R plasma levels in UR patients possibly related to reduced metabolism and/or urinary excretion, because it was not associated with high IL-2R cell release; and c) a further increment of IL-2R systemic levels in HD likely secondary to the high cell release of IL-2R. Therefore, a chronic T cell activation with increased release of IL-2R secondary to the dialysis procedure is suggested.

OBJECTIVE: Erythropoietin has been shown to have a protective effect in certain models of ischaemia-reperfusion, and in some cases the protection has been correlated with activation of signalling pathways known to play a role in cell survival and proliferation. We have studied whether erythropoietin would overcome direct toxic effects of hydrogen peroxide (H(2)O(2)) treatment to human renal proximal tubular (HK-2) cells. MATERIALS AND METHODS: HK-2 cells were incubated with H(2)O(2) (2 mm) for 2 h with or without erythropoietin at concentrations of 100 and 400 U/ml, and cell viability/proliferation was assessed by chemical reduction of MTT. Changes in phosphorylation state of the kinases Akt, glycogen synthase kinase-3beta (GSK-3beta), mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase 1 and 2 (ERK1/ERK2) were also analysed. RESULTS: Cells incubated with H(2)O(2) alone showed a significant decrease in viability, which did not significantly change by addition of erythropoietin at concentration of 100 U/ml, but was further reduced when concentration of erythropoietin was increased to 400 U/ml. Phosphorylation state of the kinases Akt, GSK-3beta, mTOR and ERK1/ERK2 of H(2)O(2)-treated HK-2 cells was slightly altered in the presence of erythropoietin at concentration of 100 U/ml, but was significantly less in the presence of erythropoietin at a concentration of 400 U/ml. Phosphorylation of forkhead transcription factor FKHRL1 was diminished in cells incubated with H(2)O(2) and erythropoietin at a concentration of 400 U/ml. CONCLUSIONS: Erythropoietin, at high concentrations, may significantly increase cellular damage in HK-2 cells subjected to oxidative stress, which may be due in part to decrease in activation of important signalling pathways involved in cell survival and/or cell proliferation.

Aim. To verify the rationale of a pelvic stop-flow technique for the perfusion of high-doses of mitomycin C and anthacyclines in patients with inoperable, recurrent pelvic cancer. Methods. The stop-flow technique was realized by using percutaneous double-balloon arterial–venous catheters that selectively isolate the pelvic vascular section and a perfusion provided by an extracorporeal pump for 20 min. Ten patients (pts) with unresectable pelvic recurrence from colon-rectal cancer were treated with a combination of Mitomycin C (MMC, 20 mg/sqm) plus doxorubicin (DOXO, 75 mg/sqm; 8 pts) or epirubicin (EPI, 75 mg/sqm; 2 pts) infused into the isolated pelvic compartment. Blood samples were collected from the extracorporeal vascular flow and from peripheral plasma, and analysed for drug quantitation. Results. During the procedure, there were no technical or hemodynamic complications, and no deaths occurred during surgery or in the postoperative period. MMC and DOXO peak levels measured in the extracorporeal system which irrotates the tumor area, were on average 21.6 (range: 4.3–44.3, MMC) and 17.2 (range: 1.8–48.4, DOXO) times higher than those observed in the peripheral blood. Similarly; the area under concentration (AUC) versus time curves measured in the pelvic compartment during stop-flow perfusion were 19.9 (range: 3.8–45.0, MMC) and 13.4 (range: 1.2–26.6, DOXO) times higher than the corresponding value in peripheral circulation. The drug percentage eliminated in the ultra filtrate was only 7.7% (MMC) and 0.9% (DOXO), and the plasmatic AUC0–24 were similar to those observed with iv bolus of equivalent drug doses. Minimal systemic and local toxicities were observed. One complete pathological and 2 partial responses were observed; pain remission in 8/10 patients. Median survival was 12 months (8–31). Conclusion. The endo-arterial administration into the local vasculature produces high pelvic-systemic concentration gradients during the stop-flow perfusion with limited local and systemic toxicity. The encouraging clinical results suggest further evaluation.

Pregnancy in dialysis patients is a rare occurrence. When pregnancy does occur, the risk of spontaneous abortion, stillbirth and neonatal complications, such as prematurity and growth retardation, are fairly high. The authors describe their experience in the follow-up of a patient with chronic renal failure who became pregnant during regular dialysis treatment and followed nutritional care. The outcomes were successful and she gave birth to a healthy baby. It is emphasized that special dedication to the nutritional control enabled a good outcome of the pregnancy. The importance of the nutritionist intervention in the follow-up of dialysis patients with the integration of a multidisciplinary staff is stressed.

We evaluated the levels of atrial natriuretic factor (ANF) in amniotic fluid and in maternal venous blood in pregnancies with fetal cardiac malformations and chromosomal abnormalities.Between the 16th and 18th week of pregnancy, 151 women were divided into three groups. Group A included patients at lowest risk, carrying a fetus with a normally developing heart and normal karyotype (control group). Group B included women with a fetus suffering from cardiac malformations, with or without associated chromosomal abnormalities. Group C included women carrying a fetus affected with chromosomal abnormalities without congenital cardiopathies. ANF was evaluated by radioimmunoassay.In maternal venous blood, the mean levels of ANF were 42.1, 53.1 and 38.7 pg/ml in groups A, B and C, respectively. In amniotic fluid, the mean levels of ANF were 34.2, 101.8 and 35.8 pg/ml in groups A, B and C, respectively. In group A (control group) there was no statistical difference in ANF levels across the gestational age range of 16-18 weeks, either in amniotic fluid or in maternal venous blood. A significant difference of ANF content in maternal venous blood was revealed in comparing group A with group B (p0.01), and group C with group B (p0.01). A statistically significant difference in ANF levels was also found in amniotic fluid between group A and group B (p0.01), and between group C and group B (p0.01). No statistically significant differences were found between group C and group A in comparing ANF levels in maternal venous blood and amniotic fluid.ANF levels in amniotic fluid and in maternal venous blood are increased early in the case of fetuses with cardiac malformations, with or without associated karyotype alteration. Chromosomally abnormal fetuses without heart malformations have normal ANF levels. These results could be useful for elucidating fetal pathophysiology mechanisms.

Renal hemodynamic response to maximal vasodilating stimulus in healthy older subjects.BackgroundIt is still unclear whether age per se is associated with preservation of renal functional reserve, that is, of the increase in glomerular filtration rate (GFR) induced by appropriate vasodilating stimulus.MethodsTo gain insights into this issue, we evaluated the renal response to a maximal vasodilating stimulus, represented by the combined infusion of mixed amino acid solution (AA) and dopamine at renal dose (D), in 10 young subjects (median age of 30 years, range of 19 to 32) and in 11 subjects of older age (median age of 67 years, range of 65 to 76). Two further age-matched groups of young (N = 15) and older (N = 11) living kidney donors underwent renal needle biopsy immediately before nephrectomy to perform semiquantitative scoring (0 to 3) of arteriosclerosis in intrarenal arteries. All of the study subjects were nonsmokers with healthy status proven by extensive diagnostic evaluation excluding any risk factor of renal dysfunction.ResultsBasal renal plasma flow (RPF) and GFR were proportionally lower in older subjects (RPF, 361 ± 29 vs. 618 ± 34mL/min/1.73m2, P < 0.001; GFR, 79 ± 4 vs. 127 ± 5.8mL/min/1.73m2, P < 0.001). After AA + D, a significant increase of RPF and GFR was observed in both groups, but the older subjects exhibited a smaller percentage increment (RPF, 25.5 ± 4.8 vs. 42.4 ± 5.8, P < 0.05; GFR, 19.6 ± 5.7 vs. + 33.8 ± 6.4, P < 0.05). Furthermore, the maximal vasodilating stimulus was not able to restore renal hemodynamics in older subjects to the level measured in young controls at baseline. Renal vascular resistances were higher (P < 0.05) in the older subjects both at baseline (0.19 ± 0.02 vs. 0.09 ± 0.004mm Hg/mL/min) and after AA + D (0.14 ± 0.01 vs. 0.06 ± 0.004). Light microscopy examination detected the presence of a greater degree of arteriosclerosis at the level of interlobular and arcuate arteries (0.89 ± 0.15 vs. 0.45 ± 0.08) and interstitial fibrosis/tubular atrophy (1.18 ± 0.13 vs. 0.53 ± 0.13) in older than in young subjects.ConclusionsTherefore, aging has adverse effects on renal function despite the absence of any risk factor for renal disease, including chronic smoking: (1) GFR and RPF are lower, and (2) the renal response to maximal vasodilating stimulus is impaired. These aging-related alterations of renal hemodynamics are possibly due to organic lesions in renal vasculature.

To evaluate the role of plasma tonicity in the postdialysis increment of plasma potassium (p[K(+)]), the outcome of two hemodiafiltration treatments that differed only in the Na(+) level in dialysate (Na(D))-143 mmol/L (high dialysate sodium concentration [H-Na(D)]) and 138 mmol/L (low dialysate sodium concentration [L-Na(D)])-were compared in the same group of uremic patients from the end of treatment (T0) to the subsequent 30 to 120 min and up to 68 h. Kt/V and intradialytic K(+) removal were comparable. At T0, plasma [Na(+)] was 145+/-1 and 137+/-1 mmol/L after H-Na(D) and L-Na(D), respectively (P

Background —The early/asymptomatic stages of heart failure (HF) are characterized by sodium retention secondary to derangement of sodium reabsorption at the proximal nephron level. Because this phenomenon is reversed by ACE inhibition, abnormalities of renal sodium handling may depend on intrarenal changes of angiotensin II (AII)/nitric oxide (NO) levels. Renal hemodynamic reserve (ie, the glomerular vasodilatory response to amino acid infusion) has been proposed as a reliable test to assess in vivo AII/NO balance. Methods and Results —In this study, the effects of 6 weeks of treatment with 5 mg/d of enalapril or with 50 mg/d of losartan on systemic hemodynamics and renal function were assessed, at baseline and after amino acid infusion (AA), in patients with mild HF (NYHA class I) and in healthy volunteers. Untreated HF patients showed a basal renal function comparable to that of healthy subjects. After AA, glomerular filtration rate and renal plasma flow significantly increased in healthy subjects (+29.0% and +30.4%, respectively), whereas no vasodilatory response was observed in HF. Although they did not affect basal renal hemodynamics, both enalapril and losartan restored a normal response to AA in HF patients. Blood pressure and heart rate were comparable in HF subjects and healthy subjects at baseline and were not modified by either treatment. Left ventricular ejection fraction was depressed in HF but did not change after either drug. Urinary excretions of cGMP and nitrate (indexes of NO activity in the kidney), comparable in healthy subjects and in HF patients, were unchanged by either enalapril or losartan and did not correlate with renal reserve. Conclusions —(1) Renal functional reserve is absent in patients with early/asymptomatic HF and normal renal function and (2) both enalapril and losartan restore a normal vasodilatory response to AA in these patients without affecting basal systemic and renal hemodynamics. These data suggest a major role of AII in the development of early abnormalities in patients with HF.

Inflammatory effects of peritoneal dialysis: Evidence of systemic monocyte activation. We evaluated in peritonitis-free patients undergoing continuous ambulatory peritoneal dialysis (CAPD) the release of both interleukin-6 (IL-6) and β-2-microglobulin (β2m) by cultured peripheral blood mononuclear cells (PBMC), as well as the levels of serum amyloid A (SAA), that is, the main hepatic acute phase protein during inflammation. The same measurements were obtained in hemodialysis (HD) patients, uremic non-dialyzed patients (ESRD) and healthy controls (CON). In CAPD, IL-6 production from PBMC was markedly increased in comparison to the control value (600.7 ± 104.3 vs. 14.2 ± 3.6 pg/3 × 106 PBMC/24 hr, P < 0.005). Similarly, a striking enhancement of the PBMC release of β2m was detected in CAPD with respect to CON (10.1 ± 2.6 vs. 0.063 ± 0.013 µg/3 × 106 PBMC/24 hr, P < 0.001). Also, the SAA levels were significantly greater in CAPD patients (21.3 ± 8.7 µg/dl) than in controls (3.14 ± 0.17 µg/dl, P < 0.05). Analogous increases of both IL-6 and β2m cell releases, as well as of SAA levels, were observed in HD patients. No difference concerning the three parameters was detected between CON and ESRD. In conclusion, CAPD induces per se PBMC activation with an enhanced release of both IL-6 and β2m; this is associated to higher levels of SAA. These systemic inflammatory effects are comparable to those observed in HD patients indicating that CAPD is similar to HD in terms of biocompatibility of the treatment.

Recombinant interleukin-2 (rIL-2) is widely used in patients with advanced cancer to enhance killer cell functions. However, the main drawback of rIL-2 therapy is the frequent development of oliguric acute renal failure (ARF), presumably due to a vascular leak syndrome. The aim of this study was to evaluate the effect of low-dose dopamine infusion on this form of ARF. Nine patients with metastatic renal cancer and previous unilateral nephrectomy were treated with a continuous intravenous infusion of rIL-2 (3 × 10 6 Cetus units/m 2 /d) for 5 days (study A). After 1 week, all the patients repeated the same cycle, but with the addition of a continuous intravenous infusion of dopamine (2 μg/min/kg body weight) that was started at the third day of treatment (study B). During study A, all patients showed a progressive (up to 34%) decrease of creatinine clearance. After rIL-2 withdrawal, these alterations persisted and were associated with a reduction in urinary output, sodium urinary excretion, and plasma protein. In study B, dopamine administration after renal function impairment (‡glomerular filtration rate=−44%) led to a prompt improvement of creatinine clearance. Creatinine clearance showed a further significant enhancement after the withdrawal of both drugs, reaching a value within the baseline range on the third day of follow-up. Similarly, the decline in urinary output and sodium excretion during rIL-2 was promptly counteracted by dopamine; in addition, after withdrawal of rIL-2 and dopamine, plasma protein levels were normalized. In conclusion, our data suggest that rIL-2-induced ARF in cancer patients is due to renal hypoperfusion mainly caused by a reduction in oncotic pressure. Importantly, intravenous infusion of dopamine at low dosage is effective in reversing this form of renal impairment; such a therapeutic approach, while reducing recovery time, avoids dose reduction or discontinuation of rIL-2 treatment.

Background. In recent years a reduction of oral cyclosporin A (CsA) dose has been adopted to minimize its adverse renal effects. To date, however, little is known about the intrinsic renal and immunological effects of low-dose CsA. Methods. Four oral doses of the drug (2, 3, 4 and 5 mg/kg body wt) and placebo (P) were randomly administered in two half-doses to seven healthy subjects. Studies were performed during water diuresis 4 h after administration of the 2nd half-dose, i.e. when the biological activity of the drug is considered maximal. Renal function was evaluated after all doses. In the same subjects, the levels of interleukin-2 (IL-2) and IL-2 receptor (IL-2R), that are the main immunological targets of CsA, were measured in the supernatant of peripheral blood mononuclear cells cultured with phytohaemagglutinin (PHA) after P, 3 and 5 mg/kg of the drug. Results. CsA induced a dose-dependent and proportional decrease of GFR and RPF associated with increasing renal vascular resistances (RVR) in presence of unmodified blood pressure. Similarly, Na + urinary excretion decreased in a dose-dependent manner due to both GFR reduction and to an higher tubular reabsorption mainly localized at the level of the proximal nephron. All these changes were significant only after 4 and 5 mg/kg. A significant suppression of PHA-stimulated IL-2 and IL-2R cell release was observed following 5 mg/kg only. Conclusions. This study suggests that nephrotoxic and immunosuppressive effects of low-dose CsA are strictly linked.

Hemodialysis related induction of interleukin-6 production by peripheral blood mononuclear cells. Interleukin-6 (IL-6) has a complex spectrum of biological activities, for example, growth and differentiation of B cells and synthesis of acute-phase proteins by the liver. To evaluate the role of this cytokine in the inflammatory response induced by blood interaction with hemodialysis membranes, we have investigated the IL-6 synthesis and release in supernatant of 24-hour cultured peripheral blood mononuclear cells (PBMC) isolated from: (a) 10 hemodialyzed patients, (b) seven patients with advanced chronic renal failure (GFR ≤10 ml/min), and (c) eight healthy control subjects. In the same groups of subjects we evaluated the relationship between IL-6 synthesis and release and beta-2-microglobulin (β2m) production. Before and after dialytic treatment hemodialysis patient blood samples were drawn using the following criteria: (1) after two months of dialysis with cuprophan membranes, (2) after one and two months of dialysis with polymethylmethacrylate (PMMA) membranes, and finally, (3) after one further month of dialysis with cuprophan membranes. IL-6 was determined after 72 hours of incubation of PBMC supernatant serial dilutions with IL-6-dependent hybridoma cell line, 7TD1. Compared to IL-6 synthesis in control subjects (6.0 ± 5.6 U/3 × 106 PBMC/24 hr), hemodialyzed patients, when treated with cuprophan membranes, showed significantly higher value of IL-6 production both before (23 ± 13 U/3 × 106 PBMC/24 hr) and after (26.2 ± 11.3 U/3 × 106 PBMC/24 hr) the dialytic session. When patients were hemodialyzed with PMMA membranes, at the start of dialysis IL-6 levels were not significantly different from values observed in healthy controls (10.6 ± 4 U/3 × 106 PBMC/24 hr, after 1 month of dialysis and 7.8 U/3 × 106 PBMC/24 hr, after 2 months, respectively). When the patients were switched back to cuprophan membranes, IL-6 production was greatly increased after one month of dialysis (CU2, 44.6 ± 9.4 U/3 × 106 PBMC/24 hr, at the start of dialysis) reaching values significantly higher than those obtained in the first period with cuprophan membranes. No difference was observed between the values of IL-6 production obtained pre- and post-dialysis with cuprophan or PMMA membranes. IL-6 production values in uremic non-dialyzed patients were similar to values found in control subjects (8.6 ± 6.4 U/3 × 106 PBMC/24 hr). β2m release showed a behavior quite similar to IL-6 throughout the study. In fact, a statistically significant linear relationship was obtained between β2m and IL-6 values of production (r = 0.8296, P < 0.001). In conclusion, our results show higher levels of IL-6 production in hemodialyzed patients treated with cuprophan membranes, thereby suggesting a chronic stimulation. β2m production is highly related to IL-6 production; this relationship suggests a possible implication for this cytokine in the pathogenesis of dialysis amyloidosis.

This study was designed to evaluate beta-adrenergic responsiveness as assessed by the generation of cyclic AMP after the subcutaneous administration of epinephrine in 31 subjects: normal controls, patients with chronic renal insufficiency, hemodynamically stable patients on chronic acetate dialysis and hemodynamically unstable patients with acetate intolerance on chronic bicarbonate dialysis. As compared with controls, only unstable patients on bicarbonate dialysis presented impaired beta-responsiveness, which, in turn, was acutely reduced only after acetate but not bicarbonate dialysis. Our results show that acetate dialysis impairs the beta-adrenergic responsiveness and that the observed beta-hyporesponsiveness in unstable patients with acetate intolerance may represent part of a broader spectrum of autonomic dysfunction which may develop in some patients on chronic hemodialysis.

Abstract The onset and the mechanisms leading to Na + retention in incipient congestive heart failure (CHF) have not been systematically investigated. To investigate renal Na + handling in the early or mild stages of CHF, Na + balance and renal clearances were assessed in 10 asymptomatic patients with idiopathic or ischemic dilated cardiomyopathy and mild heart failure (HF) off treatment (left ventricular ejection fraction, 29.7±2%) and in 10 matched normal subjects during a diet containing 100 mmol/d of NaCl and after 8 days of high salt intake (250 mmol/d). Six patients were studied again after 6 weeks of treatment with enalapril (5 mg/d PO). At the end of the high salt diet, in patients with mild HF the cumulative Na + balance exceeded by 110 mmol that of normal subjects (F=3.86, P + in the two groups, fractional excretion of Na + , fractional clearance of free water, and fractional excretion of K + (indexes of distal delivery of Na + ) increased in normal subjects and were reduced in patients with mild HF. During enalapril treatment, in the mild HF patients the cumulative Na + balance was restored to normal; furthermore, enalapril significantly attenuated the abnormalities in the distal delivery of Na + . Our results indicate that a defective adaptation of Na + reabsorption in the proximal nephron is associated with Na + retention in response to increased salt intake in the early or mild stages of HF. These abnormalities of renal Na + handling are largely reversed by enalapril.

Acute increase in plasma osmolality as a cause of hyperkalemia in patients with renal failure. These studies were performed in patients with chronic renal failure to understand the mechanism(s) of hyperkalemia secondary to hypertonic NaCl infusion. In 10 patients, after intravenous infusion of either 5% or 2.5% NaCl (6mEq per kg body wt for 120 minutes in both solutions), the maximum increase in plasma potassium averaged 0.6 (range 0.3 to 1.3) mmol/liter (P < 0.01) or 0.3 (range 0.2 to 0.6) mmol/liter (P < 0.01), respectively. The rise of both plasma potassium and osmolality was significantly higher during 5% NaCl than during 2.5% NaCl infusion (P < 0.01). A significant linear correlation (P < 0.01) between plasma potassium and osmolality was observed. Urinary potassium excretion was increased to a similar extent by 5% NaCl and 2.5% NaCl infusion. The observed hyperkalemia, secondary to NaCl infusion, was independent of venous pH, plasma bicarbonate, anion gap, insulin levels, and urinary norepinephrine and epinephrine excretion, and was associated with a fall in plasma aldosterone concentration. In separate studies, nine patients were treated with desoxycorticosterone acetate (DOCA; 20mg i.m. for three days) before receiving saline (5%) infusion. DOCA did not prevent the level increase in plasma potassium that remained significantly correlated with plasma osmolality (P < 0.01). In conclusion, hypertonic NaCl infusion in patients with renal failure causes a clinically relevant hyperkalemia despite increased renal excretion of potassium. This hyperkalemia is independent of acid-base or hormonal mechanisms known to regulate extrarenal homeostasis of potassium, and is strictly correlated with a rise in plasma osmolality.

The pathophysiology and prevention of contrast media (CM)-induced nephropathy in chronic renal failure (CRF) are still ill defined. GFR, RPF, endothelin-1 (ET-1) levels, urinary sodium concentration, and fractional excretion of sodium were measured in CRF patients undergoing water diuresis in basal conditions and 20 to 120 min after an iv bolus of either the high-osmolar CM diatrizoate (D) or the low-osmolar CM iopamidol (I). The two CM induced an immediate and progressive decline of both GFR and RPF in the absence of hypovolemia, more pronounced in D (-36% at 120 min) than after I (-19% at 120 min; P < 0.05 versus D). Both CM determined a marked and steady increase of the fractional excretion of sodium. The natriuresis could not be totally ascribed to a CM-induced osmotic diuresis as because the urinary sodium concentration markedly increased. In two further groups of patients receiving D, we studied the effects of pretreatment with a single dose of either captopril or nifedipine. Both drugs, although not preventing the increase of natriuresis, partially antagonized D-induced renal hypoperfusion: GFR and RPF were equally reduced by 20% in D/captopril and D/nifedipine (P < 0.05 versus D). In unpretreated patients receiving either D or I, plasma ET-1 did not change but urinary levels increased; these changes were, however, dissociated from those observed in renal hemodynamics. Both plasma and urinary levels of ET-1 did not vary in pretreated groups. The 72-h follow-up evidenced a significant reduction of renal function only in the unpretreated D group. Therefore, the main findings after CM administration in CRF patients are: (1) an immediate GFR decline proportional to the osmolarity of CM and secondary to the renal hypoperfusion that is neither caused by hypovolemia nor mediated by ET-1, (2) an early tubular dysfunction at the level of the proximal nephron, and (3) a protective effect of single-dose pretreatment with either captopril or nifedipine on D-induced acute and short-term GFR changes.