To the Editor:-Subtle proximal renal tubular injury causes impaired reuptake of filtered [small alpha, Greek]1and [small beta, Greek]2microglobulins; therefore, urine measurement of these low-molecular-weight (LMW) proteins has become popular as a sensitive marker of renal insult. Elevated urine [small alpha, Greek]1-or [small beta, Greek]2-microglobulinlevels have been cited as evidence to assess renal injury and the use of antifibrinolytic agents during cardiac surgery in several recent reports and reviews. [2-7]Other studies have measured [small beta, Greek]2microglobulinuria during the perioperative period to evaluate renal protection strategies for cardiac surgical patients. However, none of these articles have acknowledged important interactions between antifibrinolytic agents and the proximal renal tubular transport mechanism that is responsible for reuptake of filtered microglobulins and other LMW proteins. [9,10]When lysine analogue antifibrinolytic agents (ie., [small epsilon, Greek]-aminocaproic acid, tranexamic acid) are used during cardiac surgery [small alpha, Greek](1) and [small beta, Greek]2-microglobulinuriashould be expected, unrelated to renal tubular injury. Lysine and its analogues have been shown to specifically block renal binding sites, causing a profound but reversible inhibition of LMW protein reuptake and so-called “tubular proteinuria”(including [small alpha, Greek]1and [small beta, Greek]2microglobulinuria). This effect is so potent that urine LMW protein measurement after a small dose of intravenous lysine has been proposed as a tool for estimating glomerular filtration rate. Aprotinin has not been reported to inhibit tubular reuptake of microglobulins. However, aprotinin is metabolized by the same renal transport system as LMW proteins. Although the influence of aprotinin on renal processing of LMW proteins has not been evaluated, [small alpha, Greek](1) microglobulinuria without change in serum creatinine has been reported in cardiac surgical patients after the use of this agent. A possible mechanism to explain these observations without implicating renal injury is that high levels of aprotinin in glomerular filtrate may temporarily exceed tubular reserve for LMW protein reuptake, causing microglobulinuria.
In light of the interactions between renal LMW protein metabolism and available antifibrinolytic drugs, [small alpha, Greek]1and [small beta, Greek]2microglobulinuria should be considered unreliable markers of renal injury during cardiac surgery whenever these agents are used. In addition, the conclusions of cardiac surgical studies in which microglobulinuria is used to assess renal insult should be carefully evaluated for the use of antifibrinolytics. The renal metabolism of albumin and other LMW proteins (e.g., lysozyme, ribonuclease, retinol binding protein) is also influenced by antifibrinolytic therapy, and similar concerns about their use as markers of proximal tubular insult apply. A second interesting ramification of the interactions of antifibrinolytic agents with renal transport mechanisms is that effects that confound the use of microglobulin markers for tubular injury may also constitute a renal insult. Evidence unrelated to LMW protein metabolism implicates antifibrinolytic agents as harmful to the kidney during cardiac surgery. [4,7]It is possible that tubular proteinuria from antifibrinolytic agents and increased proximal tubular metabolism caused by active transport and catabolism of aprotinin may represent significant additional perioperative renal stresses for the cardiac surgical patient. These issues have yet to be studied.
Mark Stafford Smith, M.D., C.M., F.R.C.P.C.
Assistant Professor; Division of Cardiothoracic Anesthesia; Department of Anesthesiology; Duke University Medical Center; Durham, North Carolina 27710;firstname.lastname@example.org
(Accepted for publication November 5, 1998.)