Biomedical subjects
Publications and source records attributed to J E Scoble.
A 42-year-old man suffered a head injury in a road traffic accident and subsequently developed anosmia and isolated adrenocorticotropic hormone (ACTH) deficiency. There was no other evidence of pituitary dysfunction. No previous case of isolated ACTH deficiency following head injury has been reported.
In order to investigate the pathogenesis of medullary nephrocalcinosis, rabbit inner medullary collecting duct cells were grown in media containing different Ca++, PTH and pH levels. It was found that high Ca++ (7.8mM) only reduced growth slightly and that crystalline deposits were found under the cells. This suggests that high Ca++ is not severely toxic to the cells but can lead to deposition of calcium beneath the basement membrane. PTH did not effect cell growth even in the presence of high Ca++ implying that it has an indirect effect on tubular cells in medullary nephrocalcinosis associated with hyperparathyroidism. In renal tubular acidosis these cells are subjected to a persistently high urinary pH and low interstitial pH. Raising the pH reduced the cell growth in normal Ca++ medium whereas lowering the pH increased cell growth in vitro. Our results show that nephrocalcinosis is not due to the direct effect of raised pericellular Ca++ or PTH alone and that persistently alkaline tubular fluid may play a role.
Three mg/kg bodyweight per day of intravenous methylprednisolone for 3 consecutive days is as effective as 15 mg/kg bodyweight per day of methylprednisolone in reversing acute renal allograft rejection (80% vs 68%; 95% confidence intervals of the difference are -8% to 32%). This dose was not associated with an increased incidence of further rejection episodes. It may not be necessary to continue with the common practice of administering high-dose intravenous methylprednisolone for acute renal graft rejection.
The epithelial cell line LLC-PK1, which expresses many proximal tubular characteristics, was used to investigate the relationship between calcium, the calcium channel blocker verapamil, and cyclosporine toxicity. The LLC-PK1 cells took up cyclosporine when this was added in a concentration of 2 micrograms/ml, and this uptake was maximal at 30 min (112 +/- 3 ng cyclosporine/mg cell protein). At 12 micrograms/ml it inhibited the sodium glucose cotransporter, as assessed by phlorizin-inhibitable 14C-alpha-methyl glucopyranoside (alpha-MG) uptake (control 37.2 +/- 6.3, 12 micrograms/ml 21.2 +/- 1.1 mumol/hr/mg protein). Cyclosporine at 2 micrograms/ml did not affect cell growth after 5 days (control 945 +/- 60 micrograms cell protein per 25 cm2 flask, 2 micrograms/ml cyclosporine/ml 1046 +/- 32 micrograms protein/flask), even in the presence of 7.6 mM ionized calcium (862 +/- 37 micrograms protein/flask). Cyclosporine at 12 micrograms/ml inhibited cell growth (286 +/- 27 micrograms protein/flask), and raising the ambient ionized calcium concentration to 7.6 mM reduced cell growth further (91 +/- 6 micrograms protein/flask). Cyclosporine at concentrations of 2 and 12 micrograms/ml produced increasing cell vacuolation, as seen in vivo. Short-term uptake of 2 micrograms/ml cyclosporine could be inhibited by 1.0 mM and 0.5 mM verapamil (49 +/- 9.5 and 71 +/- 6.4 ng cyclosporine/mg cell protein, respectively, at 30 min). However, in the presence of 2 micrograms/ml cyclosporine 0.1 mM verapamil was toxic to the cells grown over five days (44 +/- 5 micrograms protein/flask). At 0.01 mM verapamil was not toxic to cell growth (921 +/- 29 micrograms protein/flask), but raising the medium calcium to 7.6 mM reduced cell growth (652 +/- 96 micrograms/ml). Inhibition of cyclosporine uptake did not occur with 0.01 mm verapamil (control 145.6 +/- 12.3 vs. 0.01 mM verapamil 150.4 +/- 3.8 ng cyclosporine/mg cell protein). The LLC-PK1 cell line represents a good in vitro model for cyclosporine renal tubular toxicity, as the in vivo observation of glycosuria and proximal tubular cell vacuolation in cyclosporine nephrotoxicity can be reproduced. In vitro this is shown to be associated with inhibition of sodium-dependent glucose cotransport. Verapamil inhibited cyclosporine uptake, but only at concentrations that were toxic to the cells. Verapamil potentiated rather than reduced the increased cyclosporine toxicity produced by increasing the medium calcium concentration. The suggested protective effect of verapamil against cyclosporine nephrotoxicity is therefore unlikely to be due to inhibition of cyclosporine uptake or of calcium entry into proximal tubular cells.
Renovascular disease is a potentially curable cause of renal failure. In a prospective survey over an eighteen month period atherosclerotic renal artery disease was the cause of renal failure in 14% of patients over the age of fifty years accepted for renal replacement therapy at this hospital. Ten patients were found to be suffering from atherosclerotic renovascular disease causing renal failure but in only one was treatment able to reverse renal failure. The major problem with this group of patients is the widespread nature of their disease affecting many other organs. Significant morbidity is associated with their investigation. Although potentially curable, atherosclerotic renovascular disease is a frequent cause of renal failure in patients over the age of fifty years but is also difficult to treat.
The survival from acute renal failure requiring renal replacement therapy was studied in 90 critically-ill patients admitted to an intensive care unit. Mean age (+/- SD) was 51 +/- 14.6 (range 17 to 81) years. Mechanical ventilation was required in 88 patients and 71 patients received total parenteral nutrition. Thirty-three per cent of patients left the intensive care unit alive and 24 per cent survived to leave hospital. Final survival was 20 per cent in medical patients (n = 49), 29 per cent in surgical patients (n = 38) and 100 per cent in obstetric patients (n = 3). Hypotension, requirement for inotropic support, oliguria and sepsis were all associated with a poorer prognosis. The mode of renal replacement therapy did not affect survival, but additional haemodialysis was required in 33 of 65 patients treated by continuous arteriovenous haemofiltration but none of 22 treated with continuous arteriovenous haemodialysis (p less than 0.001). APACHE II score was calculated for 87 patients. Mean APACHE II score was 26.1 +/- 6.9 (range 14 to 44). APACHE II score on admission predicted the likelihood of survival well. No patients with a score of more than 40 survived, compared to 40 per cent of those with scores of 10 to 19. Pre-existing organ insufficiency or immunosuppression meriting a CHE score of 5 was associated with a very poor survival (1 of 30 patients). APACHE II score is a reliable indicator of severity of illness and likelihood of survival in critically-ill patients with acute renal failure. The widespread adoption of APACHE II scoring for patients with acute renal failure requiring intensive care would facilitate medical audit and comparison of studies from various centres.
Disordered renal acid-base handling can be associated with a wide variety of diseases. Although early diagnosis is important to avoid complications, renal tubular acidosis is frequently not recognized. The pathophysiology, clinical features, diagnosis and treatment of this group of disorders are described in the light of recent advances in our knowledge of renal tubular transport mechanisms.
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The role of dibutyryl 3',5'-cyclic adenosine monophosphate (dibutyryl cAMP) as putative second messenger for parathyroid hormone (PTH) in regulating canine proximal tubular basolateral membrane Na+-Ca2+ exchange and passive calcium permeability was assessed, as was the nature of this passive calcium permeability. Dibutyryl cAMP (50 mg) infused in vivo over 30 min increased fractional phosphate excretion from 4.9 +/- 1.8% to 20.5 +/- 4.6%, P less than 0.05, n = 6, but had no effect on either passive Ca2+ efflux or sodium-stimulated Ca2+ efflux from Ca2+-preloaded basolateral membrane vesicles (BLMV). Both of these mechanisms have been previously shown to be stimulated by PTH. Further studies were performed to investigate the mechanism of the passive calcium flux. Calcium uptake by BLMV was blocked by lanthanum (La3+) but not by the calcium-channel blocker verapamil. La3+ blocked efflux of Ca2+ from preloaded vesicles when it was placed in the external solution. This La3+-blockable efflux was larger in potassium equivalent BLMV prepared from normal dogs than in BLMV prepared from thyroparathyroidectomized dogs. Benzamil produced 50% inhibition of sodium-stimulated Ca2+ uptake at 250 microM whereas neither amiloride nor diltiazem achieved 50% inhibition at the maximal doses studied. Benzamil, 1 mM, had no effect on passive calcium efflux and neither did the substitution of sucrose for potassium, which has been shown to affect Ca2+-Ca2+ exchange by the Na+-Ca2+ exchanger. This suggests that the calcium flux under potassium equivalent conditions was not mediated by Ca2+-Ca2+ exchange by the Na+-Ca2+ exchanger. These results demonstrate that the basolateral membrane of proximal tubular cells possesses both a Na+-Ca2+ exchanger inhibitable by benzamil and a passive calcium permeability not inhibited by benzamil nor by verapamil but by La3+. Neither of these two mechanisms of calcium flux was affected by dibutyryl cAMP whereas both have been shown to be stimulated by PTH.
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A women with a history of urethral stenosis, not causing significant urinary tract obstruction but requiring dilation, presented at the age of 49 with renal failure (creatinine clearance of 16-20 ml/min). Investigations (including pyelography) directed to finding the cause of her renal failure were negative with the exception of renal biopsy which revealed granulomata, one of which showed caseation. Treatment with antituberculous drugs arrested the decline in glomerular filtration rate and was later associated with sustained improvement in renal function. Tuberculosis should always be considered as a possible cause of unexplained renal failure even if the classical pyelographic features of tuberculosis, i.e. calyceal distortion and calcification, are absent. Appropriate treatment may improve renal function and avert the need for renal replacement therapy.
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