Arginine Metabolism, Pulmonary Hypertension, and Sickle Cell Disease—ReplyArginine Metabolism, Pulmonary Hypertension, and Sickle Cell Disease—Reply

In Reply: Dr Waugh raises the potential role of citrulline supplementation as a mechanism to increase arginine levels. A carefully designed trial to compare the efficacy of oral arginine vs citrulline may be worthwhile, particularly in children. However, citrulline levels are generally higher in adult patients with pulmonary hypertension and correlate with rising creatinine levels,¹ suggesting impaired ability of kidneys to convert citrulline to arginine. Although we found that the ratio of arginine to ornithine was an excellent biomarker of arginase activity in this patient population and correlated with severity of pulmonary hypertension and mortality, including citrulline in the denominator of this ratio (arginine/[ornithine + citrulline]) identified a group of patients at even greater risk of early death. Therefore, patients with renal dysfunction and secondary accumulation of citrulline may require special consideration, as chronic end-organ damage to the kidney is common in patients with SCD and pulmonary hypertension and is associated with increased risk of death.²

Drs Kielstein and Cooke call attention to an important factor that we did not characterize in our study. A recent small study indicated that levels of ADMA, a competitive inhibitor of endogenous NO synthase, are elevated in patients with SCD.³ We believe this represents a broader common pathway linking hemolysis, arginase, competitive endogenous NO synthase inhibitors, and plasma hemoglobin-mediated NO scavenging directly to endothelial dysfunction. Since elevated ADMA is associated with high triglyceride levels, hypercholesterolemia, and increased cardiovascular risk,⁴ the association between increased triglyceride levels and increased plasma arginase activity that we found in patients with SCD¹ may indicate a yet undefined link between arginase and other aspects of vascular disease.

We have proposed that hemolysis-associated endothelial dysfunction may represent a novel mechanism for human disease in hereditary and acquired hemolytic anemias.^{1 ,5} Novel therapies aimed at maximizing arginine and NO bioavailability through arginine (or citrulline) supplementation,⁶ arginase inhibition, enhanced clearance of ADMA, and treatments that lower hemolytic rate will likely benefit patients with SCD.