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)

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.

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.

Long-term follow-up of minoxidil therapy in refractory hypertension. A prospective trial in patients with various degrees of renal insufficiency.

Thirty patients with various degrees of renal insufficiency (4 on dialysis treatment) and severe hypertension refractory to conventional agents were treated with minoxidil and followed for up to 182 weeks. BP averaging 203 +/- 8.8/125 +/- 4.1 mm Hg supine and 194 +/- 7.8/125 +/- 3.9 upright before treatment, fell to 155 +/- 6.2/92 +/- 3.4 and 146 +/- 6.3/92 +/- 3.2 respectively within 1 week with 5 to 30 mg daily of minoxidil and remained stabilized around these normal values for three years or more. However, increasing doses of the drug became necessary after 52 weeks of therapy. Serum creatinine increased slightly during long-term treatment in most patients suggesting that the fall in renal function with time should be attributed to the natural progression of normotensive chronic renal failure. Adequate dialysis (in the 4 dialyzed patients) and high-ceiling diuretics prevented fluid imbalance during minoxidil therapy, while beta-blocking agents allowed complete control of reflex tachycardia.

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.

[Membranoproliferative glomerulonephritis as an unusual initial manifestation in a case of plasmacytoma]. / Glomerulonefrite membranoproliferativa quale insolita manifestazione d'esordio in un caso di plasmocitoma.

The Authors describe a case of membranoproliferative glomerulonephritis associated with nephrotic syndrome in a 50-year-old man with plasmocytoma. The bone marrow and the immunoelectrophoresis of the serum and urine showed a Bence-Jones positive multiple myeloma with plasma cells secreting only k light chain. The patient responded immediately to monthly courses of cyclophosphamide, melphalan, vincristine and prednisone. He showed still, 27 months after the diagnosis, complete remission of the disease.

[Treatment of arterial hypertension with minoxidil in renal insufficiency]. / Trattamento dell'ipertensione arteriosa con minoxidil nell'insufficienza renale.

Minoxidil was administered to 13 patients with arterial hypertension resistant to ordinary antihypertensive drugs and with various degrees of renal failure. Four patients were followed in this way for 50 weeks. Blood pressure values fell from 208 +/- 9.8/124 +/- 4.8 to 153.1 +/- 7.8/86.9 +/- 2.6 at the end of the treatment period. Propanolol and furosemide were used to offset sodium retention and reflex tachycardia. There was no decrease in renal function. In patients examined for the longest period, the minoxidyl dose, after an intermediate reduction stage, reached the 8th week value. Hypertrichosis was the most disturbing side-effect, especially for the female patients. The question of pericarditis is discussed.

[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.

Relationship of glomerular filtration rate and hypoalbuminaemia to renal glucose reabsorption.

Ten glucose titration studies were performed on 10 patients with chronic renal disease without renal failure. Six of them had nephrotic syndrome. The results show that patients with marked hypoalbuminaemia (i.e. patients with nephrotic syndrome) have a marked splay in the glucose titration curve. This observation is consistent with the hypothesis that physical factors play a main role in tubular reabsorption and indicate that proximal tubular reabsorption is decreased in nephrotic syndrome.

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.

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.

Blood pressure control in end-stage renal disease in man: indirect evidence of a complex pathogenic mechanism besides renin or blood volume.

1. In twenty-three uraemic patients on regular dialysis, plasma renin activity and blood volume were measured before and after a single dialysis. Three groups were identified; the first had a low or normal plasma renin activity and a high or normal blood volume, the second had a high plasma renin activity and a low blood volume and the third had both variables above normal. 2. In spite of these differences, diastolic blood pressure before and after dialysis was the same in the three groups and multiple regression analyses failed to demonstrate any dependence of blood pressure on plasma renin activity, blood volume or body weight taken separately or together. 3. We conclude that other factors besides plasma renin activity and blood volume are important in maintaining arterial hypertension in terminal renal failure.

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.

Relationship between serum albumin concentration and tubular reabsorption of glucose in renal disease.

Micropuncture studies in rats and dogs have provided evidence for a cause-and-effect relationship between peritubular protein concentration and proximal tubular reabsorption (PTR). If this effect is obtained in man, hypoalbuminemia in nephrotic syndrome should lead to a fall in PTR. Sodium excretion, however, is very low in nephrotic patients; but this sodium retention may be due to distal over-reabsorption. Glucose may be used as a marker of PTR. Because of the linkage between glucose and sodium, glucose reabsorption is expected to be suppressed when PTR of sodium is suppressed. Glucose titration studies were performed in 21 patients with chronic glomerulonephritis without renal failure divided in three groups: I (six patients) with serum albumin greater than 3 g/100 ml; II (five patients) with serum albumin of 2 to 3 g/100 ml; and III (10 patients with edema and nephrotic syndrome) with serum albumin less than 2 g/100 ml. The minimum threshold for glucose decreased in nephrotic patients (group III), and its fall was related directly to hypoalbuminemia. The splay of titration curve was markedly increased in group III when compared to the titration curves of patients without nephrotic syndrome (groups I and II). The splay point was 0.78 in group I, 0.52 in group II, and 0.37 in group III. These data provide evidence that glucose reabsorption is decreased in nephrotic syndrome and are consistent with a fall in PTR in nephrotic syndrome.

Water excretion in nephrotic syndrome. Relationship between blood volume and plasma vasopressin.

In order to verify whether or not an increased secretion of ADH may cause the water retention commonly observed in nephrotic syndrome, 12 nephrotic patients and 11 normal subjects were studied in basal conditions and following a water load or iso-osmotic blood volume expansion. A significant direct correlation was observed between plasma ADH and Posm in controls but not in nephrotics. Plasma ADH was inversely correlated with BV in nephrotics but not in controls. Blood volume expansion in nephrotic patients was effective in reducing plasma ADH and promoting a water diuresis. These results demonstrate a sustained volume mediated secretion of ADH in nephrotic syndrome, which is responsible for the impairment in water excretion.

Short time personalised dialysis: good results in spite of high levels of small and middle molecules.

After almost two years of experience with 43 patients we believe that a short (3 X 4, 3 X 3 hr/week) personalised dialysis is a safe treatment that allows a high survival rate and a good rehabilitation of patients. Pre-dialysis levels of small and middle molecules, the latter only calculated, did not correlate with 5 typical uraemic parameters. Some patients, who formerly experienced standard dialysis, are now equally well or better, without evidence of increasing toxicity, in spite of their higher pre-dialysis levels of small and especially of middle molecules.