Biomedical subjects
Publications and source records attributed to A L Linton.
If current limitations on health care funding continue, medical practitioners will face increasing pressure to conserve scarce resources and to participate in the allocation of funds. This article discusses the ethical and economic aspects of the physician's role and briefly reviews some efficiency measures that might mitigate the effects of rationing of health care services.
We describe an animal model of generalized sepsis, induced in the sheep by cecal perforation, which reproduces the high systemic flow and peripheral vasodilation seen in early human sepsis. Despite volume loading, animals demonstrate a fall in glomerular filtration rate, oliguria, low fractional sodium excretion, maintained urine osmolarity, and increased plasma renin activity. Histologically, kidneys show no consistent abnormality; overall the findings suggest volume contraction or hypoperfusion. This is contradicted, however, by maintained blood pressure and pulmonary capillary wedge pressure, increased cardiac output, and reduced peripheral resistance. Increased Fc lysozyme and low molecular weight proteinuria suggest tubular damage. These paradoxical observations are currently unexplained.
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67Ga scintigraphy was performed in 44 patients with various biopsy proven forms of renal disease and in a further 64 patients, some with clinically diagnosed renal disease and some with non-renal disorders. Renal uptake of gallium at 48 hours was graded by two blinded observers and by tissue ratios determined by computer. All 11 patients with biopsy proven acute drug-induced interstitial nephritis demonstrated intense, diffuse, bilateral renal 67Ga uptake, a phenomenon observed in only five of the other 30 patients with biopsy proven renal disease and in four of the 64 patients with clinical diagnoses only. No patient with acute tubular necrosis demonstrated significant renal gallium uptake. It is suggested that 67Ga scintigraphy is an excellent screening test for the presence of acute interstitial nephritis and helps to identify which patients with unexplained acute renal failure require renal biopsy.
We studied the functional effects of intraperitoneal sepsis on systemic hemodynamics in general, and on renal function in particular, in sheep in whom bacterial peritonitis was induced by cecal perforation. In the first group of seven sheep (group 1) fluid was administered throughout the period of sepsis to maintain pulmonary capillary wedge pressure as close to presepsis values as possible. These sheep exhibited hemodynamic changes known to be associated with sepsis in man: increased cardiac output and decreased systemic vascular resistance. In a second group of seven sheep (group 2) fluid intake was restricted; compared with group 1, these sheep demonstrated a smaller increase in cardiac output that did not persist and that was associated with an increase in the systemic vascular resistance during the septic period. Plasma renin levels increased fivefold in group 2 but were unchanged in group 1. Serial renal biopsies during the septic period revealed that all sheep had evidence of tubular cell damage on electron microscopy: cell swelling, loss of the microvillous brush border, and cell necrosis. Both groups of sheep also demonstrated marked tubular proteinuria similar to that found in humans with generalized sepsis. Despite this, sheep in group 1 exhibited no functional renal changes: creatinine clearance levels rose slightly from control values, urine concentrating ability was unimpaired, and fractional excretion of sodium increased appropriately in response to a sodium load. In contrast, group 2 sheep exhibited a fall in creatinine clearance levels but fractional sodium excretion did not fall as would have been expected were renal function entirely normal. The results suggest that generalized "hyperdynamic" sepsis induces tubular cell damage and tubular proteinuria by an unknown mechanism. However, this does not necessarily produce renal impairment since the glomerular filtration rate does not fall unless volume contraction is also allowed to occur.
A sheep model is described which produces acute pulmonary hypertension, leucopenia and hypoxia after blood, previously placed in contact with a Cuprophan hollow fibre artificial kidney, re-enters the circulation. Relationships between these manifestations (acute pulmonary hypertension, leucopenia and hypoxia) were examined in normal leucopenic and Indomethacin pre-treated sheep. The degree of pulmonary vascular response, and severity of leucopenia and hypoxia were all directly interrelated and were dependent upon the volume of blood injected. The induction of leucopenia did not affect the pulmonary hypertension or hypoxia. Pre-treating the animals with the cyclo-oxygenase inhibitor, Indomethacin, abolished both the pulmonary hypertension and the hypoxia without any effect on the development of neutropenia. These results suggest that leucocytes do not play a role in the haemodynamic response nor in the hypoxia; activation of the cyclo-oxygenase system is necessary for the development of acute pulmonary hypertension which causes hypoxia subsequent to alterations in ventilation perfusion relationships.
Generalised sepsis was induced in sheep by caecal perforation. Serial measurement of haemodynamic parameters revealed that the subsequent generalised sepsis induced increased cardiac output and decreased systemic resistance comparable to that known to occur in man. Glomerular filtration rate in these animals fell significantly 48 hours after induction of sepsis and there was evidence of tubular damage in the finding of low molecular weight proteinuria and increased clearance of lysozyme. Pathological examination of the kidney revealed normal glomeruli, no consistent changes in tubular cells on light microscopy, negative immunofluorescence, but structural changes in proximal tubular cells on EM. In this model, non-hypotensive sepsis predictably produces damage to proximal tubular cells accompanied by reduction in GFR.
Three patients were recently treated for thrombotic thrombocytopenic purpura (TTP). One presented with toxic shock syndrome; TTP developed but promptly responded to a regimen of antiplatelet agents, steroids and plasma exchange. In another the manifestations of TTP developed after presentation with hypertension and abdominal pain. This patient responded to a similar regimen but required extended treatment before remission could be maintained with medications alone. In the third patient the full TTP syndrome appeared after several days of plasma exchange treatment for hemolyticuremic syndrome. He did not respond. It is suggested that TTP may present in many forms initially, that microangiopathic hemolysis may be a late manifestation and that the optimal therapy is not known.
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A sheep model is described that reliably produces acute pulmonary hypertension after blood, previously in contact with a number of different dialysis membranes including Cuprophan, enters the animal's circulation. This hemodynamic manifestation is associated with myocardial ischemia and arrhythmias and coincides in time with neutropenia but precedes maximal hypoxemia. The resulting pulmonary vascular response occurs following both exposure of flowing blood to a dialyzer in an extracorporeal circuit and reinjection of blood previously in static contact with a number of different devices for varying periods of time. Increasing volumes (1-15 ml) previously in static contact (10 min) with regenerated cellulose, saponified cellulose ester, and Cuprophan (hollow fiber and sheet form) caused varying increments in mean pulmonary artery pressure. Contact with either polyacrylonitrile or cellulose acetate resulted in little response. This effect was magnified with all the surfaces, even polyacrylonitrile and cellulose acetate, by prolonging the duration of contact up to 30 min. The hemodynamic events that occurred with this model are similar to those reported in the clinical entity of "dialyzer hypersensitivity." This model may be of value in the quest for elucidation of the mechanisms involved in this syndrome.
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Thirty-nine patients with systemic lupus erythematosus (SLE) and diffuse proliferative glomerulonephritis have been enrolled in a multi-centre randomised controlled prospective study of chronic 4L plasma exchange therapy performed every three to four weeks. In the patients randomised to the pheresis (P) group and who received either albumin or plasma as replacement, there was a difference of 33 per cent better renal function at this time in the study. This difference did not achieve a significance with a p value of less than 0.05. However, the 30 patients randomised into the P group to receive albumin replacement did demonstrate a 50 per cent difference from the C group which was significant at a p value of less than 0.045. This also correlated with a statistically significant reduction in immune complex titres in the P versus the C groups. Chronic 4L plasma exchange with albumin replacement may be a useful therapeutic adjunct in patients with SLE and diffuse proliferative glomerulonephritis.
Attempts at the identification of specific uremic toxins have, to date, been unrewarding and yet there is vogue for the measurement of, and the control by devices of hypothetical levels of, "middle molecular weight" toxins. In an attempt to elucidate whether small or middle molecular weight retention products are responsible for uremic platelet and peripheral nerve conduction defects, 14 patients with end-stage renal disease established on hemodialysis were studied using a conventional hemodialyzer and an experimental device which combined hemodialysis and hemoperfusion and which has enhanced in vitro vitamin B12 clearances. With the latter device reduced BUN and creatinine clearances were encountered and over a 2-month treatment period patient's serum BUN rose. In spite of this, there was improvement in the velocity of platelet aggregation to 10 microM adenosine diphosphate and to a standard collagen preparation associated with treatment by the experimental device. There was not, however, any demonstrable influence made on nerve conduction studies. The study suggests that different uremic retention products influence platelet and peripheral nerve function and that further efforts into studying the function of living cells or systems, in uremia might have better yield in the future guidance of the adequacy of dialysis than will the biochemical measurements of various waste products.
Urine protein excretion patterns have been studied in 42 patients with sepsis and compared with that in 21 healthy controls. Patients with sepsis were shown to have highly significant increases in fractional clearances for beta 2-microglobulin, albumin, amylase and immunoglobulin G as compared with the controls. Analysis of the pattern of protein excretion demonstrates that the proteinuria is of the tubular rather than the glomerular type. There was no evidence that administration of aminoglycoside antibiotics contributed to the production of tubular proteinuria, and in particular these drugs did not appear to affect the excretion of beta 2-microglobulin.
Twelve patients with systemic lupus erythematosus and biopsy-proved diffuse proliferative glomerulonephritis were randomly allocated to a control group (to continue receiving conventional therapy only) or to a plasmapheresis group (to receive conventional therapy along with one 4-I plasma exchange a month). The six patients treated with plasmapheresis had better preservation of renal function, reduced disease activity, fewer admissions to hospital and less need for steroid and immunosuppressive therapy than the six control patients. The patients treated with plasmapheresis also showed evidence of reduced immunologic activity and had no side effects attributable to the plasma exchange. These results suggest that monthly plasma exchange should be assessed in a controlled randomized trial as a possible therapeutic adjunct in patients with systemic lupus erythematosus and diffuse proliferative glomerulonephritis.
Eight patients who met the clinical, immunological and renal morphologic criteria for systemic lupus erythematosus with diffuse proliferative nephritis were plasma exchanged on a monthly basis for a total of 119 months. Renal function, episodes of disease activity, hospitalizations, frequency of immunological abnormalities, and monthly quantity of steroid and azathioprine therapy were compared with their course up to one year prior to the onset of the plasma exchange program. The changes noted in these parameters indicate that chronic plasma exchange therapy is safe, may be beneficial and requires controlled prospective study to determine the role in the treatment of patients with systemic lupus erythematosus and diffuse proliferative glomerulonephritis.
1. Renal localization of autologous 111In-labelled platelets was studied in patients with chronic glomerulonephritis. External imaging was performed with a gamma-camera fitted with a medium energy collimator and the images were collected by a computer. 2. Images of 111In-labelled platelet distribution showed that there was a marked contribution to the radioactivity within each renal silhouette from adjacent spleen or liver. It was not possible to demonstrate renal accumulation of 111In-labelled platelets. 3. The application of 111In-labelled platelets to the study of intrarenal platelet consumption in chronic glomerulonephritis is limited by the sensitivity of current techniques and the scatter from adjacent splenic and hepatic radioactivity.