Induction of Microalbuminuria by L-Arginine Infusion in Healthy Individuals: An Insight Into the Mechanisms of Proteinuria Elena Bello, MD, Carlos Caramelo, MD, Marı ´a D. Lo ´ pez, RN, Marı ´a J. Soldevilla, PhD, Francisco R. Gonzalez-Pacheco, PhD, Adela Rovira, MD, Rosa Garcı ´a Delgado, PhD, Jose ´ M. Alcazar, MD, Nieves Martell, MD, Javier Gonza ´ lez, MD, Luis M. Ruilope, MD, and Santos Casado, MD ● Despite evidence from individuals with diabetes mellitus or reduced renal mass, the actual relationship between protein- or amino acid–induced changes in renal function and urinary albumin excretion (UAE) is largely unknown in subjects without renal disease. In humans, infusions of L-arginine have been used recently in vascular and renal pathophysiological studies. The present study was undertaken to analyze the mechanisms involved in a particular effect; namely, the behavior of UAE during amino acid loading. A prospective interventional protocol was performed on 10 healthy adults by means of an intravenous infusion of L-arginine. The main results show that L-arginine induced a significant increase in UAE from 13.1  3.8 before to 53.3  11.1 g/min after the infusion (P F 0.005). This increment was simultaneous to an increase in glomerular filtration rate (GFR) and renal plasma flow (RPF). Furthermore, L-arginine markedly increased the urinary excretion of  2 -microglobulin. UAE correlated significantly with GFR (r  0.738; P  0.014) and RPF (r  0.942; P F 0.0001), but not with urinary  2 -microglobulin (r  0.05; P  not significant). Furthermore, marked differences (P  0.001) were found between the percentage of increase in UAE (306.8%  163.2%) with respect to either albumin filtered load (FLAlb; 57.9%  16.3%) and  2 -microglobulin excretion (1,088.5%  424.6%). No changes were found in vehicle-infused individuals. In conclusion, the present study shows, in controlled conditions, that L-arginine infusion induces a relevant increase in UAE in healthy individuals that significantly exceeds that expected from the increase in GFR alone. The intense and simultaneous increment in  2 -microglobulin excretion strongly suggests that the effect of L-arginine on UAE is, in a relevant part, mediated through a blockade in the tubular protein reabsorption pathways. However, the profound differences observed in the changes induced by L-arginine on UAE and  2 -microglobulin excretion and the differences in the correlation of UAE and  2 -microglobulin with respect to GFR suggest that substantial diversity exists in the mechanisms by which L-arginine affects the renal management of albumin and  2 -microglobulin. These findings are relevant for understanding the renal response to L-arginine and protein/amino acid loads.  1999 by the National Kidney Foundation, Inc. INDEX WORDS: Microalbuminuria; L-arginine; healthy humans; renal hemodynamics; tubular protein reabsorption. A T THE PRESENT TIME, microalbuminuria is the only practical biochemical marker for the diagnosis of several diseases affecting the glomerulus at an early subclinical stage. 1,2 Fur- thermore, microalbuminuria of possible hemody- namic origin has been found in subjects without anatomic evidence of glomerular injury, as oc- curs after physical exercise or during febrile illnesses. 3 The normal rate of albumin excretion is less than 20 mg/d (15 mg/min); persistent values between 30 and 300 mg/d (20 to 200 mg/min) in a patient with diabetes are usually indicative of diabetic nephropathy. 1 Microalbuminuria is also a useful marker in the detection of renal injury in hypertensive and atherosclerotic patients. 1,4 The current explana- tion for the pathogenesis of microalbuminuria lies mainly in a theory based on the development of glomerular hyperfiltration and, most probably, an increase in intraglomerular flow and/or pres- sure. 5-7 Basically, the tenets of this theory sustain that renal injury leads to a reduction in the number of nephron units, therefore leading the remaining nephrons to increase their individual contribution to the total renal function. This excessive filtration by each glomerulotubular unit would provoke the saturation of the capacity of the proximal tubule cells to reabsorb all the filtered albumin and, subsequently, the appear- From the Instituto de Investigaciones Me ´dicas, Funda- cio ´n Jime ´nez Dı ´az; Hypertension Units, Hospital Doce de Octubre; and the Hospital Clı ´nico de San Carlos, Universi- dad Auto ´noma and Universidad Complutense, Madrid, Spain. Received July 28, 1998; accepted in revised form Decem- ber 1, 1999. Supported in part by grant no. 96/0022 of the Fondo de Investigaciones Sanitarias de la Seguridad Social, Spain; Bristol Myers Squibb, Madrid Spain; Caramelo SA, La Corunta, Spain; and the Instituto Reina Sofı ´a de Investiga- cio ´n Renal, Spain. E.B. is the recipient of a fellowship from the Ministerio de Sanidad. Address reprint requests to Carlos Caramelo, MD, Labo- ratorio de Nefrologı ´a, Fundacio ´n Jime ´nez Dı ´az, Universi- dad Auto ´noma de Madrid, Avda Reyes Cato ´licos, 2, 28040 Madrid, Spain. E-mail: ccaramelo@uni.fjd.es  1999 by the National Kidney Foundation, Inc. 0272-6386/99/3306-0003$3.00/0 1018 American Journal of Kidney Diseases, Vol 33, No 6 (June), 1999: pp 1018-1025