To the Editor:
Systemic sclerosis (SSc) is characterized by the widespread involvement of the microvasculature and by severe damage to the endothelium as well as by the modification of vascular tone control. The endothelium-dependent control of vascular tone is one of the main functions that is jeopardized during endothelial injury.
The work of Cailes et al is a precious report showing the impairment of the endothelium-dependent control of the vascular tone in the lungs of SSc patients. Actually, our group was the first to report in 1990 such a result in the acral circulation of patients with SSc. We demonstrated that during the evolution of the disease, the endothelium-dependent vasodilation was impaired either when the level of von Willebrand factor, the marker of endothelial injury, was normal in the early phase of the disease or when it was greatly raised in the advanced phase of the disease. The failure of endothelial-dependent regulation of vasodilation then was confirmed in the acral circulation by Bedarida et al and in the skin circulation by La Civita et al.
Recent data indirectly also demonstrate a defective vasodilating ability in the renal vasculature of SSc patients who have no sign of kidney involvement during standard clinical evaluations. In fact, we have found that the renal functional reserve, or the ability of the kidney to increase its glomerular filtration rate (GFR) and effective plasma flow (ERPF) when challenged with a protein or an amino acid load is blunted in patients with SSc. During the amino acid load test, GFR, ERPF, and total renal vascular resistance (TRVR) remained substantially unchanged in 20 SSc patients ([mean [+ or -] SD] GFR, -2 [+ or -] 13.1 mL/min; ERPF, -4.1 [+ or -] 62.5 mL/min; and TRVR, 662 [+ or -] 2,215 dyne [multiplied by] [s.sup.-1] [cm.sup.-5]), whereas 10 healthy control subjects showed the expected significant changes in these parameters (GFR, 30.0 [+ or -] 13.3 mL/min [p [is less than] 0.001]; ERPF, 111.6 [+ or -] 39.6 mL/min [p [is less than] 0.001]; TRVR, -1,659 [+ or -] 559 dyne [multiplied by] [s.sup.-1] [multiplied by] [cm.sup.-5]5 [p [is less than] 0.004]). Only five of 20 SSc patients had a GFR increase comparable to that of the control subjects ([is greater than or equal to] 10%). The defective response was not dependent on the duration or the clinical subset of the disease, and it could be observed early in the course of the illness (median time interval from diagnosis, 18 months).
There is general agreement that the activation of the renal functional reserve depends on preglomerular vasodilation, and nitric oxide has been indicated as a major mediator of the phenomenon. Thus, the defective renal functional response to the protein load reflects an impaired endothelial-dependent vasodilation in the renal vasculature.
In conclusion, the analysis of the literature of the last decade shows that in SSc, the endothelium-dependent control of the vascular tone is profoundly deranged in different organs. This evidence strongly suggests that the pivotal aim of the physician, in particular in the early phase of the disease, is the protection of the endothelium in order to keep its function at a steady level. This might allow an adequate tissular blood flow, thus avoiding the damage due to ischemia and reperfusion, as well as the further breakdown of vessel patency.
Correspondence to: Riccardo Livi, MD, PhD, Department of Internal Medicine, Section of Rheumatology and Nephrology, Viale Pieraccini, 18-50139 Firenze, Italy; e-mail: firstname.lastname@example.org
 Matucci Cerinic M, Kahaleh BM, LeRoy EC. The vascular involvement in systemic sclerosis. In: Furst D, Clements P, eds. Systemic sclerosis. Philadelphia, PA: Lea and Febiger, 1995; 153-174
 Matucci Cerinic M, Generini S, Pignone A. New approaches to Raynaud's phenomenon. Curr Opin Rheumatol 1997; 544:9-14
 Cailes J, Winter S, Du Bois RM, et al. Defective endothelially mediated pulmonary vasodilation in systemic sclerosis. Chest 1998; 114:178-184
 Matucci Cerinic M, Pietrini U, Marabini S. Local venomotor response to intravenous infusion of substance P and glyceryl trinitrate in systemic sclerosis. Clin Exp Rheumatol 1990; 8:561-564
 Bedarida G, Kim D, Blaschke TF, et al. Venodilation in Raynaud's disease. Lancet 1993; 342:1451-1454
 La Civita L, Rossi M, Vagheggini G, et al. Microvascular involvement in systemic sclerosis: laser Doppler evaluation of reactivity to acetylcholine and sodium nitroprusside by iontophoresis. Ann Rheum Dis 1998; 57:52-55
 Livi R, Teghini L, Pignone A, et al. Renal functional reserve is impaired in patients with systemic sclerosis without clinical signs of kidney involvement. 2000 Ann Rheum Dis (in press)
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