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Title: Kallikreins and kinins in health and disease
Author: Cumming, Allan D.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1990
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Kinins are potent vasodilator peptides which increase capillary permeability, stimulate prostaglandin synthesis, and when infused intrarenally cause natriuresis and diuresis. Kinins are formed from kinogens by plasma or glandular kallikreins. Plasma kallikrein circulates as an inactive precursor, and interacts with coagulation, fibrinolytic and complement systems. Glandular kallikreins are found in salivary glands, pancreas and kidney. Previous studies found renal kallikrein only in distal tubular cells. Activity of the renal kallikrein-kinin system is inferred from urinary kallikrein excretion rate (UKall). Methods are described for measurement of plasma prekallikrein and urine kallikrein concentration, using specific synthetic tripeptide chromogenic substrates. In normal man, UKall increased promptly in response to saline infusion, correlating with increased sodium and water excretion. The ratio of plasma renin activity (PRA) to UKall was highly correlated with urinary sodium excretion (UNaV) (r-0.91). This correlation was also highly significant in normal man during a 9 hour clearance study under basal conditions (r-0.51). Histological and immunocytochemical studies were performed to characterise the granular glomerular peripolar cell. These cells were found to contain kallikrein in secretory granules, and to lie in close apposition to renin-containing cells. UKall, factored for glomerular filtration rate, was increased in patients with chronic renal failure. UKall fell in patients given captopril, in association with an increase in plasma creatinine. In patients with nephrotic syndrome (NS), UKall was raised, and there was increased glandular kallikrein activity in plasma. A role for kallikreins and kinins in the pathogenesis of NS is proposed. The PRA/UKall ratio correlated with UNaV (r-0.53). UKall, measured under clearance study conditions, was low in most patients with hepatic cirrhosis, particularly those with ascites. PRA/UKall was a strong correlate with UNaV (r-0.80). In an ovine model of acute renal failure (ARF) due to sepsis, reciprocal changes in PRA and UKall were observed, correlating with increased plasma catecholamines. PRA/UKall correlated with UNaV (r-0.82) and plasma albumin (r-0.82). This 'sodium-retaining' ARF may be due to neuro-endocrine mechanisms, including kallikrein and renin. Acute euvolaemic lowering of plasma protein concentration in sheep by plasmapheresis, did not affect UKall, PRA, or sodium excretion. The results support the concept that the renal kallikrein-kinin system is natriuretic and diuretic. Kallikrein released from PPCs may influence glomerular and tubular function. Relative activity of the renin-angiotensin and kallikrein-kinin systems appears to be an important determinant of renal function, and of sodium excretion in particular, in both health and disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available