1. Aprotinin (Trasylol) is a cationic 6500 Da polypeptide that inhibits proteolytic enzymes, and when labelled with 99mTc it is a reproducible marker for the renal tubular turnover of small filtered proteins in man. Lysine potently inhibits tubular peptide uptake, and may thus depress the uptake and metabolism of aprotinin. This was investigated in 14 glomerulonephritic patients with normal renal function and variable proteinuria and in one healthy subject.
2. 99mTc-labelled aprotinin was given intravenously alone, and again 3 days later, immediately after the intravenous administration of 3–6 g of lysine, followed by an infusion over 1 h of 0.3–1.9 g of lysine/kg in individual patients. Activity over kidneys and in urine was measured over 24 h and chromatography was used to separate the undegraded peptide from free isotope.
3. At the low dosage of lysine (< 0.8 g/kg) given to six patients, kidney activity (representing tubular uptake) was unchanged, but early urine samples contained some undegraded aprotinin. Urinary excretion of free isotope, representing tubular metabolism, fell from 1.6 ± 0.2% of dose/h with no lysine to 0.9 ± 0.1% of dose/h in the 24 h after lysine, suggesting suppression of tubular aprotinin degradation. Corrected fractional degradation was calculated from the mean urinary excretion of free isotope over a given interval, determined by chromatography, divided by the mean cumulative kidney counts over this same interval, and this also fell after lysine from 0.06 ± 0.006 to 0.03 ± 0.006 h−1 (P<0.005) between 3.75 and 24 h.
4. By contrast, in nine subjects given more lysine (> 0.8 g/kg) tubular uptake fell and urine contained more undegraded aprotinin at all times. However, the corrected urinary excretion of free isotope (determined by chromatography) was unchanged and, paradoxically, fractional degradation rose from 0.06 + 0.01 to 0.10 ± 0.01% of dose/h (P<0.025) between 3.75 and 24 h.
5. Thus, lysine seemed to have a biphasic effect, inhibiting tubular peptide degradation at the low dosage, but depressing uptake into the tubular cell at the high dosage. This, in turn, might relieve intra cellular proteolytic enzymes from autoinhibition by aprotinin and result in a paradoxical restoration of tubular metabolism.