Chromogranin A in uremia: Progressive retention of immunoreactive fragments

Abstract

Chromogranin A is a soluble protein that is stored and released with catecholamines from their secretory vesicles. Its measurement is a probe of exocytotic sympathoadrenal activity, and in plasma it may also be a useful tool in the diagnosis of peptide producing endocrine neoplasms. Because we have found that chromogranin A is elevated in secondary (uremic) hyperparathyroidism, we systematically investigated the influence of renal dysfunction and its attendant hyperparathyroidism on chromogranin A in several subject groups: normal controls (serum creatinine less than or equal to 1.2 mg/dl), nonazotemic renal transplant recipients, nonazotemic subjects with glomerular disease (serum creatinine between 1.2 and 2 mg/dl), mid-range renal disease subjects (serum creatinine between 2 and 7.5 mg/dl), and end-stage renal disease subjects (serum creatinine greater than 7.5 mg/dl). Plasma chromogranin A rose with deterioration of renal function, and the rise was independent of etiologic diagnosis, blood pressure, or indices of sympathoadrenal activity or hyperparathyroidism. Size fractionation of uremic plasma by gel filtration, and immunoextraction by region-specific anti-chromogranin A (anti-N-terminal, anti-C-terminal, and anti-mid-molecule) antibodies suggested that chromogranin A immunoreactivity circulates in uremia as lower molecular weight fragments of the parent chromogranin A molecule, with mid-molecule fragments the major constituent. This immunoreactivity is only minimally removed by peritoneal dialysis and is not at all hemodialyzable. The uremia-dose-dependent accumulation of chromogranin A immunoreactive fragments in renal failure suggests that the kidney is a major site of disposition or removal of the immunoreactivity. Furthermore, lack of detectable chromogranin A immunoreactivity in normal subjects' urine suggests that the immunoreactivity is destroyed as it is removed by the kidney. We conclude that plasma chromogranin A increases in proportion to degree of renal insufficiency and that renal function must therefore be controlled when using plasma chromogranin A in the investigation of amine or peptide hormone storage and release.