Von Willebrand factor and autoantibodies against oxidized LDL in hemodialysis patients treated with vitamin E-modified dialyzers.

Oxidant stress is a well known cause of damage in the atherosclerotic process. Vitamin E is one of the most promising natural antioxidants. In this study we investigated if a vitamin E-coated dialyzer was able to reduce the plasma levels of auto-antibodies against oxidized-LDL, von Willebrand factor (vWf) and thrombomodulin (TM) as markers of endothelial damage. In this controlled 6-month prospective study, we investigated these markers in two matched groups (n=16 each) of patients on regular hemodialysis not yet diagnosed for atherosclerosis cardiovascular disease (ACVD) (mean age=58.3+/-7.0 yrs, mean dialysis age=30.1+/-10.0 months), in which cellulosic (CLS) and vitamin E-modified dialyzers (CLE) were compared. At inclusion all the patients were treated with CLS. Then, the study group was shifted to CLE for 6 months. At baseline the patients showed normal levels of vitamin E and high levels of oxLDL-Ab, vWf and TM compared to healthy subjects. In the CLE group oxLDL-Ab and vWf, but not TM levels, decreased progressively (from 472+/-287 to 264+/-199 mU/mL, p<0.0001 and from 101.1+/-7.5% to 76.7+/-18.5%; p<0.001, respectively), and vitamin E increased from 4.40+/-0.81 to 7.81+/-1.16 microg/mg of cholesterol. At the end of the study, 8 of the patients treated with CLE were randomly selected and went back to the membrane without Vitamin E for six months. They showed an significant increase in OxLDL-Ab and vWf levels and a significant reduction in tocoferol levels. In conclusion, CLE compared to cellulosic dialyzers can lower some indices of damage to LDL and endothelial cells.

[Clinical experience in HFR with a new resin-only sorbent cartridge]. / Sperimentazione clinica in HFR di una cartuccia rigenerante priva di carbone.

Adsorbent therapies have become increasingly popular over the last several years as they permit an additional method to selectively or non-selectively remove toxins. Adsorbents offer a unique removal strategy as they have an extremely high adsorption capacity due to their great surface area. This paper describes experiments that utilized a synthetic divinylbenzene styrenic resin cartridge to remove uremic toxins from chronic renal failure patients. The resin-only cartridge was tested as an alternative after a small number of patients (primarily taking ACE inhibitors) experienced gastrointestinal problems using hemodiafiltration with on-line regeneration (HFR). Subsequent laboratory evidence suggested that the particular carbon used in the cartridge was able to activate contact phase activation. This could potentially cause problems in patients taking ACE inhibitors, as they are unable to degrade bradykinin efficiently. The resin-only cartridge was tested in at 6 centers throughout Italy and included patients that had experienced previous reactions to the carbon-resin cartridge. At the conclusion of the study, no adverse reactions were reported and the cartridge exhibited excellent removal of b2 microglobulin and angiogenin.

Hyporeninemic hypoaldosteronism in patients with nephrotic syndrome.

Five nephrotic patients, who did not present sodium retention when on sodium balance, have been studied. All had membranous nephropathy, were normotensive and renal function was normal in 2 and slightly reduced in 3. The following parameters were measured: 24-hour excretion of aldosterone, the response of plasma renin activity (PRA) and of plasma aldosterone to upright posture, postural changes of the fractional excretion of sodium and lithium, and natriuretic response to spironolactone. The resting values of plasma aldosterone were low in all patients, and after stimulation by upright posture they increased hardly to the low-normal limit only in 1 patient. Resting PRA was normal in all patients and increased slightly, after stimulation. The 24-hour urinary excretion of aldosterone was low in 4 patients and borderline in 1. No natriuretic response to spironolactone was observed in any patients. After upright posture the fractional excretions of sodium and lithium decreased significantly and to the same extent in all patients. Four nephrotic patients with fluctuating, spontaneous episodes of sodium retention and of sodium excretion have been studied as controls. These patients had normal values of urinary aldosterone and of resting PRA and aldosterone. After upright posture the changes of PRA and of aldosterone were clearly evident in 2, and exaggerated in the other 2 patients. In these patients, a significant increase of sodium excretion occurred after treatment with spironolactone. These results suggest that a not negligible number of patients with nephrotic syndrome have hyporeninemic hypoaldosteronism. This diagnosis should be taken into account when investigating the role of aldosterone in sodium retention in nephrotic syndrome.

Familial membranous nephropathy.

Numerous HLA studies suggest that genetic factors play an important role in the development of membranous nephropathy (MN). We studied seven patients with idiopathic MN, from three unrelated families of Italian ancestry. Complement phenotype analysis and restriction fragment length polymorphism (RFLP) typing of HLA class II and of the switch region genes were done in family members. In the first family, the father, one son, and one daughter had MN; another daughter had clinical glomerulonephritis. The three members with MN shared one HLA haplotype carrying DR beta 11; in the two siblings with the disease, the second HLA haplotype carried the DR beta 3.2 allele. In families 2 and 3, two brothers had MN: in family 2, they differed in at least one haplotype; in family 3, they differed in both haplotypes. Only family 3 was informative with regard to the RFLP of the switch region genes: the two siblings were identical for both Ig heavy chain haplotypes. No clinical, laboratory or morphologic features consistent with a secondary form of the disease were found. Familial clustering of MN suggests a genetically transmitted mechanism.

Effect of exogenous reduced glutathione on the survival of red blood cells in hemodialyzed patients.

Reduced glutathione (GSH) is an important scavenger of free radicals in the red blood cell (RBC) membrane, and its deficiency may be a partial cause of increased hemolysis and shortened RBC survival in uremics. In this study we employed exogenous GSH (1200 mg i.v. at the end of each dialysis session for at least nine months) to treat anemia in a group of 28 hemodialyzed patients, 14 of whom were also receiving erythropoietin. RBC survival (51Cr T/2) was calculated before (26 patients) and at the end (15 pts) of GSH therapy. After the first three months anemia (RBC, hemoglobin, hematocrit, reticulocytes) improved significantly in 17 patients (60%), for as long as they were under therapy, but rapidly dropped to pre-treatment values when GSH was discontinued. The 51Cr T/2 increased significantly in responders, but not in those who did not respond. No significant differences were found between responders and non-responders as regards urea KT/V, PTH, serum iron, ferritin, dialysis membrane, dose of erythropoietin and basal 51Cr T/2. These results suggest that exogenous GSH may be a promising drug for the treatment of anemia in most hemodialyzed patients, particularly considering its low cost.

Considerations on the sodium retention in nephrotic syndrome.

Renin-angiotensin-aldosterone system, plasma atrial natriuretic peptide (PANP), and blood volume (BV) have been investigated in 20 nephrotic patients with normal renal function and with (group 1; n = 12) or without (group 2; n = 8) sodium retention. Patients of group 1 had a plasma albumin (PALB) concentration < 1.7 g/dl, low BV and PANP levels, a reduced fractional excretion of lithium (FELi), and high plasma angiotensin II levels. Patients of group 2 had PALB > 1.7 g/dl, and the other parameters were normal. The spontaneous intake of dietary sodium was lower in group 1 than in group 2. In all patients the BV was directly correlated with PALB, and the plasma renin activity (PRA) was inversely correlated with both BV and PALB. A nonlinear inverse relationship was present between plasma aldosterone (PALD) levels and fractional excretion of sodium (FENa). The acute expansion of the BV in patients of group 1 normalized PRA, PALD, PAII, FENa, and FELi and increased PANP. The administration of spironolactone to the patients of both groups had variable effects on FENa, did not modify PRA and PALD, and reduced body weight, PANP, and FELi, thus suggesting that the reduction of BV induced by the drug increased the proximal reabsorption of sodium. Three additional patients who had sodium retention, PALB of 2.3-2.4 g/dl, normal PRA and PALD, elevated urinary excretion of aldosterone, and a slightly low PANP showed a spontaneous normalization of urinary aldosterone and PANP associated with natriuresis and weight loss, but thereafter urinary aldosterone increased, PANP decreased, and the sodium retention began again. Our data suggest that in nephrotic patients with severe hypoalbuminemia, contraction of BV plays a major role in promoting the sodium retention through the activation of compensatory hormonal mechanisms. On the other hand, when PALB is not severely reduced, the patients have normal BV, but they are very sensitive to small changes of BV which are better evidenced by modifications of the urinary excretion of aldosterone and PANP rather than by the profiles of PRA and PALD.

Effect of angiotensin II on proximal tubular reabsorption in normal humans.

The effects of angiotensin II (AII) on proximal tubular reabsorption have been evaluated in 6 healthy volunteers under normal salt and water balance. One-hour clearance periods were performed before, during and after the infusion of pressor doses of AII; in 3 of the 6 subjects, the study was repeated with lower doses of AII. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were determined by the clearances of inulin and PAH, and the fractional excretion of lithium (FELi) was considered as an index of proximal sodium reabsorption. The effects of AII on the fractional excretion of beta 2 microglobulin (FE beta 2M) were also studied. Both doses of AII decreased GFR and RPF and increased the filtration fraction (FF); the modifications of these parameters, as well as the reduction of FELi and the fractional excretion of sodium (FENa) and the increase of plasma aldosterone and of plasma atrial natriuretic peptide (ANP), were more evident with pressor doses of AII, which increased the blood pressure from 129/83 to 142/95 mm Hg (p less than 0.01). AII did not modify FE beta 2M in either study. During AII, FELi decreased less than FENa and both were closely and inversely related to the variations of FF, whilst no relationship was present between FE beta 2M and FF. These results suggest that, in normal humans, the AII-induced rise of FF may be an important factor, even if not the only one, in enhancing the proximal reabsorption of lithium and thus of sodium, whilst it does not affect the absorption of beta 2M.

Two brothers with idiopathic membranous nephropathy and familial sensorineural deafness.

Genetic factors could play an important role in the pathogenesis of idiopathic membranous nephropathy, and a few cases of familial membranous nephropathy have been described: an increased incidence of some HLA antigens as DR3 and others has been reported. We present two brothers with idiopathic membranous nephropathy and sensorineural deafness. HLA typing was performed in the two patients and in the members of the family, and it showed the absence of linkage of an HLA antigen with the renal disease in the family.

Effect of exogenous prostaglandin E2 on plasma antidiuretic hormone in normal man. Role of angiotension II.

To verify if exogenous prostaglandin E2 (PGE2) is able to release antidiuretic hormone (ADH) and if endogenous angiotensin II plays a role in this eventual PGE2-induced stimulation of vasopressin, increasing doses of PGE2 were infused in 6 normal volunteers before (PGE2 study) and after the administration of 100 mg of captopril (captopril study). PGE2, even at an infusion rate of 40 and 60 ng/kg/min, did not modify blood pressure when it was infused alone; a significant fall of blood pressure was observed, in contrast, in the captopril study. PGE2 alone doubled the plasma levels of ADH. One hour after the subjects had been pre-treated with captopril, plasma levels of ADH fell by about 38%, then they increased by about 60% during the infusion of PGE2. These results suggest that in normal man endogenous angiotensin II is an important non-osmotic regulator of plasma ADH and that exogenous PGE2 can stimulate maximally the release of ADH only when the renin-angiotensin system is not impaired.

The causal role of salt depletion in acute renal failure due to captopril in hypertensive patients with a single functioning kidney and renal artery stenosis.

Captopril (C) causes ARF in hypertensive patients with renal artery stenosis (RAS) with a single functioning kidney (SK). Retrospective studies in two patients showed that episodes of C-induced ARF were preceded by a rise in urinary Na+ excretion and a rapid decrease in body weight. These observations prompted us to investigate whether extracellular fluid volume depletion secondary to C-induced natriuresis can be responsible for ARF. Prospective studies were performed in four patients with RAS-SK treated with C. These studies have shown that: ARF is associated with negative Na+ balance and is corrected by salt replacement, even without interrupting C; ARF is preceded by a rise in urinary prostaglandin (PG) E2 and 6-keto-F1 alpha; ARF is prevented by either saline infusion or aspirin administration; ARF does not occur when the dose of C is not sufficient to raise PGs and urinary N + excretion. We conclude therefore that C-induced ARF in patients with RAS-SK can be secondary to salt depletion dependent on a raised secretion of PGs.

Effects of PGE2 infusion on renal function in normal man before and after angiotensin II inhibition by captopril.

Increasing doses of prostaglandin E2 (PGE2) (5, 10, 20, 40, 60 ng/kg/min) were infused in 7 normal volunteers before and after angiotensin II synthesis inhibition by captopril (100 mg by mouth). PGE2 infusion alone did not alter blood pressure, while it increased the urinary excretion of both epinephrine and norepinephrine, enhanced p-aminohyppuric clearance (CPAH), inulin clearance (CIn), sodium and water excretion and decreased urinary osmolality. No changes of CIn, CPAH and catecholamines were observed after captopril alone, whilst there was a significant increase in urine output and sodium excretion and a decrease in urinary osmolality. In the presence of captopril, the infusion of PGE2 caused a significant fall in blood pressure and CIn, enhanced epinephrine excretion and sodium excretion, while it did not significantly reduce CPAH. Our findings suggest that an intact renin-angiotensin system is necessary to maintain GFR during PGE2 infusion.

Platelet dysfunction in uremia. II. Correction by arachidonic acid of the impaired exposure of fibrinogen receptors by adenosine diphosphate or collagen.

Previous studies showed that platelets from patients with uremia have a marked decrease in their aggregation response to adenosine diphosphate (ADP) and collagen as single agents or as a pair. It is known that small amounts of arachidonic acid can enhance the sensitivity of platelets to concentrations of ADP or collagen that do not cause aggregation when used singly. Stimulation of platelets by certain agonists induces the formation of fibrinogen receptors on the platelet surface. The binding of fibrinogen that follows is essential for platelet aggregation. The platelet membrane glycoprotein IIb-IIIa complex appears to be the site of the fibrinogen receptor. Therefore, we investigated the binding of iodine 125-labeled fibrinogen to uremic platelets exposed to ADP, collagen, or arachidonic acid as single agents and as pairs. When aggregation and binding were studied in response to ADP, collagen, or the combination of ADP with collagen, uremic platelets had reduced aggregation and bound abnormally low amounts of fibrinogen. In contrast, platelets from patients with uremia bound as much 125I-fibrinogen and aggregated as well as controls when ADP or collagen were used in combination with low concentrations of arachidonic acid. Studies with a monoclonal antibody (B 79.7) suggested that the number of glycoprotein IIb-IIa molecules is the same in uremic and normal platelets. We conclude that uremia impairs the exposure of fibrinogen receptors on platelets in response to ADP or collagen without affecting the glycoprotein IIb-IIa complex quantitatively. Correction by arachidonic acid of the impaired aggregation and exposure of fibrinogen receptors by ADP or collagen suggests that abnormal release of endogenous arachidonic acid plays a role in the dysfunction of platelets in uremia.

Angiotensin II inhibition with captopril on plasma ADH, PG synthesis, and renal function in humans.

Using captopril (C), an angiotensin (ANG) I converting-enzyme inhibitor, to increase endogenous prostaglandins (PGs) and to decrease endogenous ANG II synthesis, we studied the relationship between endogenous ANG II, PG, and antidiuretic hormone (ADH) release in seven normal volunteers before (control study) and after inhibition of PG synthesis by a single dose of aspirin (ASA study). In the control study, following the administration of 100 mg of C, there was a significant increase of plasma PGE2, plasma-renin activity (PRA), and urinary PGE2 and 6-keto-PGF1 alpha and a decrease of plasma ADH. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were unaffected by C; urine output, fractional sodium excretion (FENa), and osmolal clearance (Cosmol) increased; and urinary osmolality (Uosmol) decreased significantly after C. In the ASA study PG were undetectable in plasma and significantly reduced in urine 1 h after aspirin and did not increase when C was added. Plasma ADH decreased and PRA increased, as in the control study, after C, whereas GFR, RPF, urine output, FENa, Cosmol, and Uosmol were unchanged. These results suggest that the effect of C on ADH release may be mediated, to a large extent, by a fall in endogenous circulating ANG II, since ADH decreased in the presence of both high or undetectable levels of PGE2. The results also suggest that the increase in PGE2 induced by C may precipitate the diuretic and natriuretic effects of acute C administration.

Mechanism of action of indomethacin in tubular defects.

Indomethacin, a potent prostaglandin synthesis inhibitor, has been proven to be effective in a number of tubular defects characterized by enhanced prostaglandin (namely, prostaglandin E2 (PGE2) production, but its mechanism of action is poorly understood. To elucidate further the mechanism(s) by which indomethacin reverses the abnormal tubular functions, five children with different tubular defects (nephrogenic diabetes insipidus, three cases; Fanconi syndrome, one case; and pseudohypoaldosteronism, one case) were treated with indomethacin. Indomethacin, 1 mg/kg every eight hours, was given for 1 week to all children and then was given chronically to four of the children who responded to the drug. Its use was suspended in a 10 year-old-boy with nephrogenic diabetes insipidus because it proved ineffective. To assess the site along the nephron where indomethacin affects the solute and water excretion, an acute water load study was performed in three responsive children before and during the treatment. Indomethacin did not significantly alter the glomerular filtration rate but was effective in reducing diuresis and levels of urinary sodium and potassium excretion. In the child with Fanconi syndrome, indomethacin was also effective in controlling the urinary loss of phosphate, urate, glucose, and bicarbonate. Results of the water load studies show that indomethacin decreases the delivery of solute from the proximal tubule, reduces the fractional free water clearance, and increases the urine-plasma osmolar ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of angiotensin II on plasma ADH, prostaglandin synthesis, and water excretion in normal humans.

To verify whether angiotensin II (ANG II) stimulates ADH release in humans and to evaluate whether endogenous prostaglandins influence the resulting renal effect of ADH, nonpressor and low pressor doses of ANG II were infused in nine normal volunteers under normal conditions (control study) and after prostaglandin synthesis inhibition with aspirin (ASA study). During ANG II infusion plasma ADH increased in both conditions. Plasma PGE2, urinary PGE2, and urinary 6-keto-PGF1 alpha increased only in the control study, whereas they were undetectable in the plasma and significantly reduced in the urine in the ASA study. ANG II caused a significant fall of glomerular filtration rate, renal plasma flow (with an increase in filtration fraction), fractional sodium excretion, and urine output in both studies. Despite the reduced urine output, urine osmolality decreased significantly in the control study, whereas it increased after aspirin administration. These results suggest that intravenous ANG II stimulates ADH release in humans but that the renal effects of the resulting increase in plasma ADH are different depending on the presence or absence of endogenous prostaglandins.