Clinical Investigation

Kidney International (1990) 37, 955–964; doi:10.1038/ki.1990.71

Chromogranin A in uremia: Progressive retention of immunoreactive fragments

Ray J Hsiao1, Matthew S Mezger1 and Daniel T O'Connor1

1Department of Medicine, University of California and Veterans Administration Medical Center, San Diego, California, USA

Correspondence: Daniel T O'Connor MD, Nephrology/Hypertension (V-111-H), V.A. Medical Center, San Diego, California 92161, USA.

Received 28 June 1989; Revised 16 October 1989; Accepted 19 October 1989.

Top

Abstract

Chromogranin A in uremia: Progressive retention of immunoreactive fragments. 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 creatinineless than or equal to1.2 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 <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-chromo-granin A (anti-N-terminal, anti-C-terminal, and antimid-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.

Top

References

  1. Smith AD, Winkler H: Purification and properties of an acidic protein from chromaffin granules of bovine adrenal medulla. Biochem J 103:483–492, 1967 | PubMed | ISI | ChemPort |
  2. Smith WJ, Kirshner N: A specific soluble protein from the catecholamine storage vesicles of bovine adrenal medulla. I. Purification and chemical characterization. Mol Pharmacol 3:52–62, 1967
  3. Blaschko H, Comline RS, Schneider FJ, Silver M, Smith AD: Secretion of a chromaffin granule protein, chromogranin, from the adrenal gland after splanchnic stimulation. Nature 215:58–59, 1967 | Article | PubMed | ISI | ChemPort |
  4. Sage JH, Smith WJ, Kirshner N: Mechanism of secretion from the adrenal medulla. I. A microquantitative immunologic assay for bovine adrenal catecholamine storage vesicle protein and its application to studies of the secretory process. Mol Pharmacol 3:81–89, 1967
  5. O'Connor DT, Deftos LJ: Secretion of chromagranin A by peptide-producing endocrine neoplasms. N Engl J Med 314:1145–1151, 1986
  6. Rabkin R, Kitaji J: Renal metabolism of peptide hormones. Miner Electrol Metab 9(4–6):212–216, 1983
  7. Cohn DV, Zangerle R, Fischer-Colbrie R, Chu LLH, Elting JJ, Hamilton JW, Winkler H: Similarity of secretory protein I from parathyroid gland to chromogranin A from the adrenal medulla. Proc Natl Acad Sci USA 79:6056–6059, 1982
  8. O'Connor DT: Chromogranin: Widespread immunoreactivity in polypeptide hormone producing tissues and in serum. Reg Peptide 6:263–280, 1983
  9. O'Connor DT, Pandian MR, Carlton E, Cervenka JH, Hsiao RJ: Rapid measurement of circulating human chromogranin A: In vitro stability, exploration of the neuroendocrine character of neoplasia, and assessment of the effects of organ failure. Clin Chem 35:1631–1637, 1989
  10. Doolittle RF: Of Urfs and Orfs: A Primer On How To Analyze Derived Aminoacid Sequences University Science Books, Mill Valley, California, 1986
  11. O'Connor DT, Takiyyuddin M: Synthetic peptide epitopes: Clues to the structure, conformation, distribution and processing of chromogranin A. (abstract) Clin Res 36:187A, 1988
  12. Harlow E, Lane D: Antibodies: A Laboratory Manual. Cold Spring Harbor Laboratory, New York, 1988
  13. Endres D, Brickman A, Goodman W, Maloney N, Sherrard D: N- and C-terminal PTH radioimmunoassays in assessment of renal osteodystrophy. Kidney Int 21:132, 1982
  14. Nussbaum SR, Zahradnik RJ, Lavigne JR, Brennan GL, Nozawa-Ung K, Kim LY, Keutmann HT, Wang C-A, Potts JT Jr, Segre GY: Highly sensitive two-site immunorediometric assay of parathyrin, and its clinical utility in evaluating patients with hypercalcemia. Clin Chem 33:1364–1367, 1987 | PubMed | ISI | ChemPort |
  15. Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein using the principle of protein dye binding. Anal Biochem 72:248–254, 1976 | Article | PubMed | ISI | ChemPort |
  16. Peuler JD, Johnson GA: Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine. Life Sci 21:625–636, 1977 | Article | PubMed | ISI | ChemPort |
  17. O'Connor DT, Bernstein KN: Radioimmunoassay of chromogranin A in plasma as a measure of exocytotic sympathoadrenal activity in normal subjects and patients with pheochromocytoma. N Engl J Med 311:764–770, 1984
  18. O'Connor DT, Burton DW, Deftos LJ: Chromogranin A: Immunohistology reveals its universal occurrence in normal polypeptide hormone producing endocrine glands. Life Sci 33:1657–1663, 1983 | Article | PubMed | ChemPort |
  19. O'Connor DT, Burton DW, Deftos LJ: Immunoreactive human chromogranin A in diverse polypeptide hormone producing human tumors and normal endocrine tissues. J Clin Endocrinol Metabol 57:1084–1086, 1983
  20. Lloyd RV, Wilson BS: Specific endocrine tissue marker defined by a monoclonal antibody. Science 222:628–630, 1983 | PubMed | ISI | ChemPort |
  21. Wilson BS, Lloyd RV: Detection of chromogranin in neuroendocrine cells with a monoclonal antibody. Am J Pathol 115:458–468, 1984 | PubMed | ISI | ChemPort |
  22. Cohn DV, Elting JJ, Frick M, Elde R: Selective localization of parathyroid secretory protein I/adrenal medulla chromogranin A in a wide variety of endocrine cells of the rat. Endocrinology 114:1963–1974, 1984 | PubMed | ISI | ChemPort |
  23. Kruggel W, O'Connor DT, Lewis RV: The amino terminal sequences of bovine and human chromogranin A and secretory protein I are identical. Biochem Biophys Res Com 127:380–383, 1985
  24. Wohlfarter T, Fischer-Colbrie R, Hogue-Angeletti R, Eiden LE, Winkler H: Processing of chromogranin A within chromaffin granules starts at C- and N-terminal cleavage sites. FEBS Lett 231:67–70, 1988
  25. Arnaud CD: Hyperparathyroidism and renal failure. Kidney Int 4:89–95, 1973 | PubMed | ISI | ChemPort |
  26. Freitag J, Martin KJ, Hruska KA, Anderson C, Conrades M, Ladenson J, Klahr S, Slatopolsky E: Impaired parathyroid hormone metabolism in patients with chronic renal failure. N Engl J Med 298:29–32, 1978 | PubMed | ISI | ChemPort |
  27. Hruska KA, Korkor A, Martin K: Peripheral metabolism of intact parathyroid hormone—role of liver and kidney and the effect of chronic renal failure. J Clin Invest 67:885–892, 1981 | PubMed | ISI | ChemPort |

Extra navigation

.
ADVERTISEMENT