Dermal angiopathy in hemodialysis patients: the effect of time.

We studied skin biopsies from 14 patients after 6 months to 18 years on hemodialysis (HD) to discern any effect of duration of treatment on skin and dermal capillaries. Patients selected for biopsy were without evidence of other diseases known to affect vasculature such as diabetes mellitus. Pathological changes compared with duration of HD were: capillary wall thickening, endothelial proliferation and new capillary formation, lipid content, and epidermal atrophy. Severity of morphologic changes were graded from 0 to 4+ by a pathologist who had no knowledge of HD duration. The earliest change observed was reduplication of the capillary basement membrane. Narrowing of capillary lumina due to endothelial cell proliferation and new capillary formation were noted after five years of HD; lipid droplets were noted in capillaries by five years; and epidermal atrophy by 10 years. Progressive severity of each finding was associated with length of time on HD. Neither amyloid nor Ca++ deposits were observed in any specimens. By clinical observation, easy bruisability and increased skin fragility were worse the longer the patient was on HD. Capillary occlusion inducing tissue ischemia could be a cause of the atrophic skin changes noted. However, no patient manifested dermal necrosis. While pathogenesis of the capillary changes in uremic skin is unknown, the changes have been shown to stabilize following successful kidney transplantation.

The effect of aluminum on the vanadium-mediated oxidation of NADH.

Aluminum catalyzes the oxidation of NADH by vanadate both in the presence and absence of a reducing sugar. The effect of aluminum is concentration dependent and inhibitable with superoxide dismutase but not catalase. The fructose-6-phosphate-free reaction is characterized by an initial lag phase which can be eliminated by preincubating aluminum with NADH, but is not altered by preincubating aluminum with vanadate, suggesting that the effect of aluminum is not directly on vanadate. Aluminum also catalyzes vanadyl-mediated oxidation of NADH, and this effect is similarly inhibitable by superoxide dismutase as well as catalase. It is suggested that aluminum catalyzes the oxidation of NADH by vanadium though enhancing the production of superoxide radicals and that this effect may account in part of the biological toxicity associated with aluminum, particularly when associated with the accumulation of other trace elements such as vanadium.

Carbamylated hemoglobin in prerenal azotemia.

UNLABELLED: Carbamylated hemoglobin (Carb Hb) levels were measured in 16 patients with a documented transient rise in BUN due to prerenal azotemia, in whom BUN levels before and after the episode were normal. They were compared with 13 controls. Carb Hb was expressed as carbamyl valine concentrations, which were significantly higher in the patients (166 micrograms/g Hb) than in controls (95.3 micrograms/g Hb, p < 0.01). The mean maximum BUN level in the patients was 51.8 +/- 23.9 mg/dl. There was a significant correlation between the product of mean BUN level times the number of days of BUN elevation, and the Carb Hb level (r = 0.5197; p < 0.05). There was no correlation between Carb Hb and either mean BUN level or maximum BUN level. Elevated Carb Hb was seen after a minimum of 4 days' BUN elevation. Four patients had no elevation of Carb Hb despite elevated BUN levels. CONCLUSION: Carb Hb may be elevated after a minimum of 4 days' transient BUN elevation; Carb Hb is not useful in differentiating between mild acute renal failure and prerenal azotemia.

Blood flow rate and access recirculation in hemodialysis.

We studied the effect of extracorporeal blood flow rate (BFR) on access recirculation (recirc) in 19 hemodialysis patients. BUN was determined in simultaneous peripheral (P), arterial (A), and venous (V) blood obtained at BFRs of 200, 400, and 600 ml/min. Percent recirc was calculated for each BFR using the formula (P-A)/(P-V) x 100. Venous drip-chamber (VP) and pre-blood-pump (AP) pressures were measured at each BFR. Fistulograms were performed in 10 patients, and stenoses were identified in 5, all at the proximal (arterial) end of the access. Recirc increased with increasing BFR from 200 to 400 ml/min but increased little from 400 to 600 ml/min. At all BFRs recirc in the stenotic patients was higher than that of non-stenotic or unstudied patients. Urea clearance, corrected for recirc, rose with blood flow both in stenotic and non-stenotic patients. There were no differences in AP or in VP between stenotic and non-stenotic patients. At BFR greater than or equal to 400 ml/min, a recirc threshold of 15% identified stenoses with sensitivity 100% and specificity 71%. We conclude (1) recirc increases with increasing BFR but not enough to outweight the concomitant increase in urea clearance; (2) significant access stenosis and recirc may be present even with low VP; (3) recirc was associated with arterial side stenoses; (4) at BFR greater than or equal to 400 ml/min, access stenosis is associated with recirc greater than 15%.

Effect of chromium on oxygen free radical metabolism, inhibition of superoxide dismutase and enhancement of 6-hydroxydopamine oxidation.

The effect of chromium on superoxide dismutase activity (SOD) as well as on the rate of hydroxydopamine oxidation was studied in vitro, since chromium is known as an environmental and occupational carcinogen and oxygen free radicals are implicated in carcinogenic processes. Chromium is a strong inhibitor of SOD activity in this system. The degree of inhibition is directly proportional to the chromium concentration (tested chromium range 0.166-0.33 mg/L in reaction mixture), to reaction time (tested range up to 10 minutes), and to substrate concentration. Autoxidation of 6-hydroxydopamine was increased by chromium concentration of 15 mg/L. The combination of excessive oxygen free radical production and inhibition of their elimination by inhibition of SOD activity may contribute to the toxic effects of chromium.

Effect of nickel on oxygen free radical metabolism. Inhibition of superoxide dismutase and enhancement of hydroxydopamine autoxidation.

The effect of nickel on superoxide dismutase activity (SOD), as well as on rate of hydroxydopamine oxidation, was studied in vitro since lipid peroxidation has been implicated in cell damage by nickel, whose toxicity and carcinogenicity are well established. Nickel strongly inhibits SOD activity. The degree of inhibition is directly proportion to the nickel concentration (tested range 0.066 to 0.33 microgram/mL in the reaction mixture); to the substrate concentration (tested range 0.4 x 10 4M to 1.1 x 10 4M 6-hydroxydopamine); and to reaction mixture. Autoxidation of 6-hydroxydopamine was increased by nickel concentrations higher than 15 micrograms/mL. The combination of excessive oxygen free radical production and inhibition of their elimination by inhibition of SOD activity may contribute to the nickel toxicity that has been reported in industrial accidents, as well as to the high incidence of cancer occurring in nickel workers. It may also contribute to many complications in uremic patients, in whom increased serum nickel levels were reported to be in a similar range to those inhibiting SOD.

Effect of aluminum on calcium binding to bovine intestinal calcium-binding protein.

Aluminum is known to inhibit vitamin D-dependent intestinal absorption of calcium. To investigate possible mechanisms of action, the effect of aluminum on the binding of calcium to bovine intestinal calcium-binding protein (CaBP) was studied by means of equilibrium dialysis. The results of these studies indicate that aluminum in concentrations up to 80 microM and up to 80 times the ambient calcium concentration did not significantly alter the affinity of CaBP for calcium (Kd = 0.17 microM) nor its molar capacity (2 mol/mol CaBP).

Inhibition of superoxide dismutase activity by silicon.

Elevated silicon levels have been found in the serum of uremic patients, in the brain of patients with senile dementia and in neuroglial tangles of Alzheimer patients. The effect of silicon on superoxide dismutase was studied in vitro, since excessive superoxide production occurs in renal failure, in inflammatory conditions and in the aging process. Silicon in concentrations similar to those found in serum of uremic patients inhibits superoxide dismutase activity. The degree of inhibition is directly proportional to silicon levels. Depression of superoxide dismutase by Si is likely to result in a decrease in oxygen free radical destruction and thus an increase in excessive local availability of oxygen free radicals. The increased silicon levels in brain, kidney, lung and RBC which are especially sensitive to oxygenation damage may contribute to a variety of important clinical complications, by means of excess oxygen free radicals.

Reduced superoxide dismutase activity in erythrocytes of dialysis patients: a possible factor in the etiology of uremic anemia.

Superoxide dismutase (SOD) plays a major part in the destruction of oxygen-free radicals in the body. SOD activity is impaired by several trace elements including aluminium and silicon which are found in increased levels in plasma and tissues of uremic man. SOD activity was investigated in the erythrocytes of normal controls and of dialysis patients to determine if lack of SOD-protective activity could be a contributory cause to the increased hemolysis of uremia. It was found that SOD levels in red cell hemolysate were significantly lower in dialysis patients (41.4 +/- 9.1 units/100 ml) compared to control (49.3 +/- 7.2 units/100 ml) (U = 7.3; p less than 0.005). When expressed per 100 ml of whole blood SOD levels were 3.25 +/- 0.93 units/100 ml in dialysis patients and 6.46 +/- 0.99 units/100 ml in controls (U = 96; p less than 0.001). It is concluded that inhibition of SOD activity in the erythrocytes of dialysis patients may contribute to their anemia.

Transcapillary oncotic pressure in the edema of congestive heart failure.

Tissue fluid and plasma oncotic pressure levels were measured in an unselected group of 13 patients presenting with congestive heart failure. Patients had a mean serum albumin of 3.6 g/dl +/- (SD) 0.35; serum oncotic pressure was 22.23 +/- 1.8 mm Hg; tissue fluid (lower leg) oncotic pressure was 0.985 +/- 0.34 mm Hg. The oncotic pressure gradient between plasma and tissue fluid was 21.25 Hg +/- 1.7. This is about 10 mm Hg greater than delta pi in normal man. The high value in congestive heart failure is a mechanism to protect against the formation of edema. The possible mechanisms responsible for the formation of edema in congestive heart failure are discussed.

Effect of aluminium on superoxide dismutase.

1. The effect of Al3+ on superoxide dismutase in vitro was studied, since in uraemia there is excessive superoxide production and frequently an elevated serum Al3+ level. Thus, the protective role of superoxide dismutase is particularly important. 2. Al3+ in concentrations similar to those found in the serum of uraemic patients inhibits superoxide dismutase activity. The degree of inhibition is directly proportional to the Al3+ level. 3. The combination of excessive oxygen free radical production with an increased Al3+ level may contribute to a variety of complications, including aluminium dementia or initiation and promotion of carcinogenic processes, which are known to be more common in uraemic patients.

Oedema protein concentrations for differentiation of cellulitis and deep vein thrombosis.

The differentiation between cellulitis and deep vein thrombosis was investigated in a series of patients with acutely swollen, painful, red legs. Oedema-fluid protein concentrations (as mean [SD]) were significantly higher in patients with cellulitis than in those with deep vein thrombosis (19.8 g/l [5.0] vs 5.85 g/l [1.6]), and the oncotic pressure of oedema-fluid was also significantly higher in cellulitis (6.3 mm Hg [1.3] vs 2.1 mm Hg [0.6]). In hospitals where phlebography, plethysmography, or doppler ultrasound are not available, measurement of oedema-fluid protein concentrations may be a rapid and inexpensive guide to the cause of a red, swollen leg.

Effect of aluminum on bidirectional calcium flux in rat everted intestinal sacs.

The effect of aluminum on intestinal calcium absorption was determined in male Sprague-Dawley rats using an everted intestinal sac technique. Bidirectional calcium flux in the duodena and ilea of normal rats was assessed by means of dual calcium isotopes. Two micromolar aluminum significantly inhibited net calcium absorption (J net) in the duodenum through suppression of mucosato-serosa flux (J m----s). Jm----s was reduced from 2.21 +/- 0.50 mumol Ca.h-1.g wet wt-1 in controls to 0.93 +/- 0.35 mumol Ca.h-1.g-1 in aluminum exposed sacs, and Jnet was reduced from 1.88 +/- 0.14 mumol Ca.h-1.g-1 to 0.55 +/- 0.41 mumol Ca.h-1.g-1 (P less than 0.001). Serosa-to-mucosa calcium flux (Js----m) was not similarly influenced by aluminum. Inhibition of Jm----s occurred whether aluminum was initially present on the mucosal or serosal side of the duodenal sac and inhibition of Jnet calcium by 2 muM A1 occurred at all ambient concentrations of calcium studied. In the ileum, aluminum had no effect on any component of calcium flux. Aluminum did not induce any suppression of glucose transport in either the duodenum or ileum, suggesting that the effect on calcium transport is relatively specific. These results suggest that aluminum inhibits calcium absorption in the duodenum through an effect on active mucosa-to-serosa transport, but has no effect on ileal calcium absorption, which in the rat is not mediated by an active process.

Heparin-free hemodialysis with a polyacrylonitrile membrane.

The low in vitro thrombogenicity of polyacrylonitrile (AN-69) membrane may offer the possibility of performing hemodialysis (HD) with little or no heparin. The authors sought to reduce heparin dosage using AN-69 dialyzers at blood flows of 400 to 600 ml/min. Over a 90 day period, 2228 HDs were performed: 1531 (69%) with AN-69, 528 (24%) with regenerated cellulose (RC), and 169 (8%) with cellulose acetate (CA) dialyzers. Two hundred and eighty-three HDs were performed without systemic heparin; blood compartments were prerinsed with 2,000 U heparin in 1,000 ml of 0.9% saline. Saline flushes were used in cases of rising venous drip chamber pressures or visible clotting. Incidence of clotting overall in AN-69 HDs was 0.52% (8/1531), 2.8% (15/528) with RC, and 11.2% (19/169) with CA. In heparin-free HDs, incidence with AN-69 was 1.3% (3/230), 28.6% with RC (4/14), and 25.6% with CA (10/39). AN-69 remained less thrombogenic when HDs were stratified by blood flow rate and vascular access was used. Urea clearance was no different in conventional and heparin-free treatments. Blood flow rates of 400 ml/min or higher had an independent antithrombogenic effect. It was concluded that the combination of high blood flow with AN-69 membrane allows marked reduction of HD heparin dose and safe routine use of heparin-free HD.