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Biomedical subjects

D C Harris

Publications and source records attributed to D C Harris.

At least 55 records · Page 3Linked to original sources
PubMed1994

Dietary protein alters tubular iron accumulation after partial nephrectomy.

Reactive oxygen species (ROS) have been implicated in progression of disease in the rat remnant kidney (RK) model of chronic renal failure. Substantial amounts of iron accumulate in proximal tubular lysosomes of RK and could damage tubules by ROS generation. The effect of dietary protein intake on ROS, tubular damage and iron accumulation assessed by energy dispersive analysis was determined in RK (5/6 nephrectomy, N = 12) and sham-operated kidneys (SO, N = 10). In RK, mean lysosomal iron concentration, urinary iron and protein excretion and morphological damage were increased and GFR decreased. Dietary protein loading (40% vs. 12%) increased the number of iron-containing lysosomes (P < 0.05) and the mean lysosomal iron (P < 0.02) in proximal tubular cells after four weeks. In RK, high protein diet increased renal weight (P < 0.01), numerical density of iron-containing lysosomes and tubular damage (both P < 0.05). ROS generation, assessed by tissue and plasma malondialdehyde (MDA), was also increased (both P < 0.05). Plasma MDA correlated with tubular iron accumulation (r = 0.75). In RK fed a high protein diet (N = 18) treatment with the iron-chelator desferrioxamine reduced serum iron, urinary volume, and tubular iron accumulation and damage compared to controls (P < 0.01). In summary, in RK dietary protein manipulation altered urinary iron and protein excretion, proximal tubular iron accumulation, renal cortical ROS generation and ultrastructural damage. Desferrioxamine treatment reduced tubular lysosomal iron and ultrastructural damage. These results suggest a role for tubular iron as a determinant of tubular injury associated with dietary protein loading in rats with partial nephrectomy.

Animals↗
PubMed1994

Lysosomal iron accumulation and tubular damage in rat puromycin nephrosis and ageing.

1. Energy dispersive X-ray spectrometry was used to examine the relationship between proteinuria and increased urinary iron excretion, and structural and functional damage in puromycin nephrosis. 2. After 11-12 days rats treated with puromycin (10 mg/100 g, i.v.i.) had greater proteinuria (211.6 +/- 35.7 mg/day, mean +/- s.e.m.) and urinary iron excretion (15.4 +/- 2.2 micrograms/day) than saline-treated controls (14.5 +/- 1.4 mg/day and 1.1 +/- 0.2 micrograms/day, respectively, both P < 0.001). 3. On day 13, mean lysosomal iron concentration of proximal tubular cells (306.6 +/- 64.5 vs 11.9 +/- 8.6 mg%, P < 0.001), and proximal tubular cell damage assessed semi-quantitatively (1.17 +/- 0.10 vs 0.62 +/- 0.10, P < 0.001) were higher and creatinine clearance (0.15 +/- 0.01 vs 0.29 +/- 0.02 mL/min per g kidney weight, P < 0.001) lower than in control rats. 4. At days 35, 60 and 360 there were no differences in any of the measured parameters between rats treated with puromycin or saline, and in both groups proteinuria, tissue damage and lysosomal iron concentration increased with time. 5. Lysosomal iron accumulation was the only independent predictor of both functional and structural damage. 6. In conclusion, the apparent association between proteinuria and tubulo-interstitial damage in puromycin nephrosis, and with ageing, is best explained by factors associated with accumulation of iron within lysosomes of proximal tubule cells.

Aging↗
PubMed1994

The role of tubular iron accumulation in the remnant kidney.

Iron has been implicated in the pathophysiology of several models of acute and chronic renal disease. In this study, energy-dispersive x-ray spectrometry was used to quantify and localize iron in rat remnant kidneys (RK) and normal kidneys (NK) and to determine its pathophysiologic significance. Substantial iron accumulation occurred in proximal tubular cell secondary lysosomes of RK (P < 0.001 versus NK) and reached a plateau at 8 wk after partial nephrectomy. In NK, minor increases of iron also occurred with aging (P < 0.02). Proximal tubular iron accumulation correlated independently with protein excretion (r = 0.90) and impairment of GFR (r = 0.70) and was associated with tubular damage and phosphate accumulation (both P < 0.001). Iron nitrilotriacetate (1 mg/kg ip) increased tubular lysosomal iron accumulation and tubular damage (P < 0.001 versus nitrilotriacetate) in NK, comparable to levels seen in untreated RK, and increased cortical cytosolic malondialdehyde, consistent with reactive oxygen species generation. The iron chelator deferoxamine (30 mg/kg per day ip) significantly reduced iron accumulation and tubular damage in RK at 4 wk, compared with deferoxamine chelated to iron and untreated RK. These results suggest that filtered iron enters the remnant tubular lysosomes across the brush border membrane by endocytosis and may produce tubular damage in chronic renal disease by the generation of reactive oxygen species.

Animals↗
PubMed1994

Low-dosage epoetin in maintenance haemodialysis: costs and quality-of-life improvement.

Decisions about epoetin (recombinant human erythropoetin) dosage and target haematocrit in dialysis patients have been determined largely by the high acquisition cost of epoetin, but are made with incomplete knowledge about which target haematocrit gives the optimum clinical benefit. Haematopoietic response to epoetin may be determined by pharmacodynamic factors such as rate and frequency of administration, as well as by individual patient characteristics such as ethnicity. Resistance to epoetin may be due to iron or vitamin deficiency, natural or exogenous inhibitors of erythropoiesis and bone marrow fibrosis. The high acquisition cost of epoetin must be considered along with a number of other factors that can influence the true cost of epoetin treatment. Hidden costs of epoetin treatment include administration costs, changes in other treatments, extra laboratory tests and adverse events. Administration costs and extra laboratory surveillance add little to overall cost. Depletion of iron stores, hypertension, increased blood coagulability and reduced dialyser efficiency resulting from epoetin treatment may all add a small additional component to the true cost. Severe complications with significant cost implications are rare. Amongst the various components of true cost, only the acquisition cost can definitely be reduced by low dosage treatment. Balanced against the true and potential costs of epoetin are a number of benefits which can result in potential savings. The need for blood transfusion is all but abolished, avoiding the cost of transfusion and its complications. Sensitisation against histocompatibility antigens is reduced by avoiding transfusion, and so the waiting time for cadaveric transplantation may be reduced. Rates of hospitalisation for all causes, especially those associated with anaemia, may be reduced by epoetin treatment. By improving well-being, epoetin may allow patients to be transferred to minimal-care units or home where dialysis can be performed much more cheaply. Amongst the various potential benefits of epoetin, the one with the greatest potential to save money for society is improved productivity. To date, productivity improvements with epoetin have been demonstrated only in small studies. If the acquisition costs of epoetin are reduced by low dosage therapy, these potential benefits can cover a large proportion of the total cost of epoetin. Epoetin undoubtedly improves quality of life and activity, but it is not clear which level of haematocrit gives optimum improvement.(ABSTRACT TRUNCATED AT 400 WORDS)

Costs and Cost Analysis↗
PubMed1994

Lysosomal iron accumulation in diabetic nephropathy.

Iron accumulates within proximal tubular lysosomes in several models of renal disease and may play a role in the progression of proteinuric chronic renal disease by the generation of reactive oxygen species. In this study, tubular iron was examined at an ultrastructural level by energy dispersive x-ray spectrometry in streptozotocin (STZ) and BB diabetic rats, and in humans with diabetic nephropathy, and compared to their respective nondiabetic controls. Substantial amounts of iron accumulated in the secondary lysosomes of proximal tubules in STZ diabetic rats (4.16 +/- 0.47 iron-containing lysosomes/microns 2 x 10(-3) tubular area vs. 0.90 +/- 0.29 in controls, p < 0.001). Proximal tubular iron was related independently with urinary protein and transferrin excretion, suggesting increased cellular uptake of iron from the tubular fluid. Lysosomal iron accumulation was also associated with tubular damage (r = 0.55, p < 0.001). Minimal amounts of tubular iron were observed in BB diabetic and nondiabetic littermates. In humans with diabetic nephropathy, increased proximal tubular lysosomal iron concentration (35.6 +/- 13.0 mg% Fe vs. 9.5 +/- 2.7, p < 0.05) and numbers of iron-containing lysosomes were observed compared to nondiabetic controls, and the latter correlated with elevation of serum creatinine (r = 0.94, p = 0.016). These results suggest that filtered iron enters proximal tubular lysosomes across the brush-border membrane and are consistent with a role for iron in causing the tubular damage of diabetic nephropathy.

Animals↗
PubMed1993

Altered metabolism in the ex vivo remnant kidney. I. Effects of time, substrate and perfusion pressure.

Oxygen consumption is increased in the rat remnant kidney (RK), but the basis of this enhanced metabolic activity has not been defined fully. To characterize the hypermetabolism further, isolated RK and normal kidneys (NK) were perfused using a range of perfusion pressures and substrates, and at varying times after 5/6 nephrectomy. Altered and increased RK metabolism was found as early as 1 week after 5/6 nephrectomy. The rate of net glucose consumption was higher in RK than NK (e.g., 0-30 min, 2.42 +/- 0.28 vs. 1.21 +/- 0.33 mumol.min-1 x g-1), a difference not explained by changes in oxygen delivery or glycosuria. Ammonia production was significantly greater early in perfusion in RK than NK. Calculated nephron oxygen consumption (QO2) was greater in RK than NK for all substrates tested (e.g., pyruvate 5 mM: 552.3 +/- 43.1 vs. 173.3 +/- 25.6 pmol.min-1, p < 0.001). When considered together, site I mitochondrial substrates supported QO2 and net sodium reabsorption (TNa+) better than site II substrates. In RK, QO2 did not change with increasing perfusion pressure, and TNa+ rose only slightly for pressures > or = 120 mm Hg. In summary, RK hypermetabolism is characterized by increased oxygen consumption, glycolysis and ammoniagenesis, is not substrate-specific and does not appear to be an artefact of the altered physiology of remnant perfusion.

Ammonia↗
PubMed1993

Altered metabolism in the ex vivo remnant kidney. II. Effects of metabolic inhibitors and dietary protein.

To understand further the contribution of heightened net sodium reabsorption (TNa+) and other nontransport processes to increased and altered metabolic activity of the rat remnant kidney (RK), isolated RK and normal kidneys (NK) were perfused with and without metabolic inhibitors and following 4 weeks of low (12%)- or high (40%)-protein diet. 3-Mercaptopicolinate (200 microM) and 2-deoxyglucose (200 microM) reduced glucose production and consumption, respectively, without altering oxygen consumption (QO2). Ouabain reduced TNa+ and QO2 in NK but not RK, and increased glucose consumption in RK (by 67%, p < 0.02, n = 12) and NK (by 54%, p < 0.05, n = 12). Raising perfusate pH by 0.3 U to 7.65 increased glucose production in RK but not NK and reduced TNa+ in NK but not RK. Dietary protein restriction reduced QO2 (2.18 +/- 0.29 vs. 4.13 +/- 0.20 mumol-1 x min-1 x g-1, p < 0.001), TNa+ (8.74 +/- 4.39 vs. 38.83 +/- 8.32, p < 0.01) and ammoniagenesis (0-30 min, 0.16 +/- 0.05 vs. 0.32 +/- 0.10, p < 0.05) in RK, but not NK. In summary: (1) responses to ouabain and alkalosis, but not other metabolic inhibitors, were quite distinct in remnant versus normal kidneys, and (2) protein restriction limited sodium-transport-dependent and -independent hypermetabolism in RK.

Alkalosis↗
PubMed1993

Comparison of intermittent oral and intravenous calcitriol in hemodialysis patients with secondary hyperparathyroidism.

Both intermittent intravenous and intermittent oral calcitriol have been shown to be effective in the treatment of secondary hyperparathyroidism in hemodialysis patients and it has been claimed that intravenous calcitriol causes less hypercalcemia. However, there has been no published systematic comparison of the two routes of administration of intermittent calcitriol. Therefore in a prospective crossover study 11 (9 male) patients on maintenance hemodialysis were randomized to receive intravenous followed by oral calcitriol for 4 months each, or oral followed by intravenous calcitriol, commencing at 2 micrograms postdialysis three times per week. Initial serum immunoreactive parathyroid hormone (PTH) was 446 +/- 111 (normal < 65) pg/ml. Calcium-containing phosphate binders were not used. Calcitriol was ceased if hypercalcemia developed and restarted at 2 micrograms or 1 microgram when calcium returned to normal. Hypercalcemia was frequent (11 episodes in 8 patients on intravenous calcitriol and 10 episodes in 7 patients on oral calcitriol) and dose reduction to 1 microgram was necessary in 7 patients on intravenous and on 6 patients on oral. Serum PTH fell during both treatments. Parathyroid enlargement was seen in 10 glands from 4 patients, but no size reduction was demonstrated with treatment. There was no reduction in activity on quantitative metabolic bone scan. In summary, intermittent oral calcitriol and intermittent intravenous calcitriol were equally effective in reducing serum parathyroid hormone levels and at a dose of 2 micrograms postdialysis caused hypercalcemia with equal frequency.

Administration, Oral↗
PubMed1993

Interpatient variation in response to subcutaneous versus intravenous low dose erythropoietin.

Subcutaneous (SC) recombinant human erythropoietin (EPO) has been reported to correct anemia in hemodialysis patients at lower doses than intravenous (IV) EPO. Those trials involved relatively high doses of EPO or did not control adequately for time-related falls in dose requirements. Therefore, on open-label double-crossover study was performed to compare the hemoglobin (Hb) response to low dose SC versus IV EPO. Ten (4 male) maintenance hemodialysis patients previously stabilised on low dose EPO for 18 +/- 3 months (mean +/- SEM) were given EPO IV for 12 weeks (IV#1), then SC for 24 weeks and then IV for a further 20 weeks (IV#2). Iron status and other factors known to modify response to EPO were kept constant. EPO dose was not changed unless Hb rose above 100 g/l, when the dose was reduced to keep Hb between 90 and 100 g/l. Initial EPO dose was 64 +/- 10 u/kg/week. Mean Hb, measured monthly, was not different during the 3 treatment periods. There was wide interpatient variation in the relative response to IV versus SC EPO. Mean Hb was higher on IV EPO in 5 patients (by 6.1 +/- 2.0 g/l) and higher on SC EPO in 5 patients (by 12.1 +/- 4.1 g/l). The difference in mean Hb during IV versus SC administration was more than 5 g/l in 6 patients, being higher in 3 patients during IV administration (by 8.7 +/- 4.6 g/l) and in 3 during SC (by 17.4 +/- 4.6 g/l). In conclusion, the more efficient route of administration of EPO is not predictable for individual patients, and should be sought to allow possible dose reduction.

Anemia↗
PubMed1992

Iron accumulation in human chronic renal disease.

Iron, which has been shown to accumulate within proximal tubule lysosomes in proteinuric models of renal disease, may play a role in the progression of chronic renal disease by the generation of reactive oxygen species. Therefore, renal biopsies from humans with proteinuria and/or chronic renal failure were examined at an ultrastructural level for iron by energy dispersive analysis and compared with normal biopsies. Iron accumulated in proximal tubular lysosomes in renal disease (P < 0.05 v normals), accompanied in some cases by phosphorus and silicon. Both the number of iron-containing lysosomes per tubular cross-section (1.86 +/- 0.41 v 0.66 +/- 0.22, P < 0.05) and the mean concentration of lysosomal iron (254.5 +/- 73.4 mg/dL v 81.2 +/- 23.8, P < 0.001) was greater in patients with nephrotic syndrome (n = 12) than in those without (n = 8). Iron accumulation (number of iron-containing lysosomes/tubule) correlated with protein excretion (r = 0.68, P = 0.003, n = 20), but not with glomerular filtration rate. Damaged tubules contained greater amounts of iron than tubules with less damage (288.5 +/- 68.5 mg/dL v 80.4 +/- 13.9, P < 0.01). Further studies are needed to define the possible role of iron in causing tubular damage and progression of renal disease.

Chronic Disease↗
PubMed1991

Low dose erythropoietin in maintenance haemodialysis: improvement in quality of life and reduction in true cost of haemodialysis.

Human recombinant erythropoietin (r-HuEPO) improves quality of life in patients on maintenance haemodialysis, but the haemoglobin (Hb) level necessary to achieve this improvement is unknown. In this study, quality of life, functional capacity and symptoms of 28 haemodialysis patients with an initial Hb of 67 +/- 2 (mean +/- SEM) g/L were assessed after 0, 6 and 12 months of r-HuEPO, the dose of which was titrated to achieve a stable Hb of between 90 and 100 g/L. At six and 12 months Hb was 97 +/- 2 and 93 +/- 2 g/L, and mean r-HuEPO dose between three and six, and between nine and 12 months was 88 +/- 6 and 62 +/- 9 U/kg/week intravenously respectively. There was a significant improvement in level of activity and satisfaction with various aspects of life, and a reduction in fatigue, weakness, dyspnoea, angina and restless legs. Patients were able to walk 50% further in six minutes. The improvement in quality of life and function was similar to that reported from other centres whose target Hb was between 100 and 120 g/L, and where the r-HuEPO dose was 75% higher than in this study. Costs of r-HuEPO therapy were assessed. The drug itself costs +A3681/yr/patient, to which was added the estimated cost of additional dialyses and medications, bringing the total to +A5177/yr/patient. There was, however, a reduction in both hospitalisation by 8.3 days/yr/patient and medical consultation by 3.9 hours/yr/patient. Five patients commenced full-time work, one took up full-time study aimed at finding work, three transferred to home haemodialysis and six fewer patients drew social security benefits. The net cost saving from using low dose r-HuEPO was more than +A1,000/yr/patient.

Adult↗
PubMed1991

Hepatitis C virus infection in haemodialysis patients.

Antibody to hepatitis C has been variously detected in 1-20% of haemodialysis patients in recent studies from overseas. To determine the frequency of antibodies to the C100-3 protein of the hepatitis C virus (anti-HCV) a cross-sectional study was performed in 60 patients on maintenance haemodialysis in Western Sydney. Six patients (10%) were anti-HCV seropositive. Four of the six anti-HCV positive patients were also hepatitis B core antibody positive, compared with nine of 54 anti-HCV negative patients (p less than 0.05). All anti-HCV positive patients had received multiple blood transfusions. Serum alanine aminotransferase (ALT) was not useful as a screening test. Recent evidence suggests that anti-HCV seropositivity underestimates infectivity.

Antigens, Viral↗
PubMed1991

Desferrioxamine enhances the haemopoietic response to erythropoietin, but adverse events are common.

To determine whether the chelation of aluminium enhances the haemopoietic response to recombinant human erythropoietin (r-HuEPO), desferrioxamine (DFO) at a dose of 20-30 mg/kg was given to 7 of 17 transfusion-dependent haemodialysis patients treated with r-HuEPO (40 units/kg/dialysis i.v.). The two randomly allocated groups did not differ in age, initial haemoglobin, plasma aluminium, plasma aluminium after DFO challenge, and ferritin, but, by chance, dialysis time was longer in the DFO group (69 vs. 32 months; p = 0.02). DFO was administered for 16 +/- 4 (SE) dialyses. During this period, Hb rose faster in the DFO group, in relation to time (0.61 vs. 0.29 g/l day; p less than 0.05) and r-HuEPO dose (3.35 vs. 1.88 g/l/100 units r-HuEPO/kg; p less than 0.05). However, in the DFO group, there was a high incidence of side effects, especially visual toxicity. It is concluded that DFO enhances the effectiveness of r-HuEPO in correcting the anaemia of chronic renal failure, but the combination of DFO and r-HuEPO is unsafe under the conditions described.

Adult↗