Clinical Investigation

Kidney International (1988) 34, 859–866; doi:10.1038/ki.1988.261

Progression of chronic renal failure is related to glucocorticoid production

Mackenzie Walser and Lynn Ward

Department of Pharmacology and Molecular Sciences and Department of Medicine, Johns Hopkins University, and Department of Nutrition, Johns Hopkins Hospital, Baltimore, Maryland, USA

Correspondence: Mackenzie Walser MD, Department of Pharmacology and Molecular Sciences, Johns Hopkins University, 725 N. Wolfe Street, Baltimore, Maryland 21205, USA.

Received 27 October 1987; Revised 18 April 1988.

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Abstract

Progression of chronic renal failure is related to glucocorticoid production. Progression of chronic renal failure during 35 treatment periods in 27 patients was measured as the rate of change of bimonthy radioisotope GFR for an average of 15 months. Treatments were comprised of: (1) mild protein restriction; (2) more severe protein and phosphorus restriction plus essential amino acids; or (3) the same diet plus ketoacids. Progression was significantly (P < 0.025) correlated with urinary 17-hydroxycorticosteroid excretion in all three treatment groups; overall r was 0.78 (P < 0.0001). Multiple regression analysis showed that the following factors were not additional significant determinants of progression: urea N excretion, phosphate excretion, protein excretion, serum calcium times phosphorus product, serum alkaline phosphatase, serum uric acid, serum triglycerides, serum cholesterol, etiology, mean arterial pressure, or ehalapril treatment. However, when urinary 17-hydroxycorticosteroid excretion was factored by GFR (with which it was correlated), additional significant regressors appeared: serum triglycerides and polycystic kidney disease, which tended to be associated with more rapid progression, and ketoacid treatment, which tended to be associated with slower progression. Mean 17-hydroxycorticosteroid excretion differed significantly between the three treatment groups, in the order (1) > (2) > (3)(though not when factored by GFR). Changing from essential amino acids to ketoacids (or vice versa) without change in diet was associated with lower 17-hydroxycorticosteroid excretion on ketoacids (but not when factored by GFR). Therefore, progression of chronic renal failure is related to glucocorticoid production (and to triglyceridemia, which is correlated with it). Ketoacids appear to slow progression in part by suppressing production of glucocorticoids.

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References

  1. Walser M: Ketoacids in the treatment of uremia. Clin Nephrol 3:180–187, 1975
  2. Nyberg G, Blohme G, Norden G: Constant glomerular filtration rate in diabetic nephropathy. Correlation to blood pressure and blood glucose control. Acta Med Scand 219:67–72, 1986
  3. Nath KA, Kren SM, Hostetter TH: Dietary protein restriction in established renal injury in the rat. Selective role of glomerular capillary pressure in progressive glomerular dysfunction. J Clin Invest 78:1199–1205, 1986 | PubMed | ISI | ChemPort |
  4. Anderson S, Meyer TW, Renke HG, Brenner BM: Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass. J Clin Invest 76:612–619, 1985 | PubMed | ISI | ChemPort |
  5. Walser M, Mitch WE, Collier VU: Effect of protein restriction plus ketoanalogues of essential amino acids on the course of chronic renal failure. Proc VII Int Congr Nephrol 483, 1978
  6. Ibels LS, Alfrey AC, Haut L, Huffer WE: Preservation of renal function in experimental renal disease by dietary restriction of phosphate. TV. N Engl J Med 298:112–126, 1978
  7. Barsotti G, Giannoni A, Morelli E, Lazzeri M, Vlamis I, Baldi R, Giovanetti S: The decline of renal function slowed by a very low phosphorus intake in chronic renal patients following a low nitrogen diet. Clin Nephrol 21:54–59, 1984 | PubMed |
  8. Acchiardo SR, Moore LW, Cockrell S: Does low protein diet halt the progression of renal insufficiency? Clin Nephrol 25:289–294, 1986
  9. Foley RJ, Weinman EJ: Urate nephropathy. Review. Am J Med Sci 288:208–211, 1984
  10. O'Donnell MP, Kasiske BL, Keane WF: Hyperlipidemia accompanies hypertension and precedes glomerular sclerosis in Dahl salt-sensitive rats. Clin Res 35:446A, 1987
  11. Diamond JR, Karnovsky MJ: Alimentary hypercholesterolemia selectively aggravates glomerular injury. Kidney Int 31:383, 1987
  12. Barsotti G, Cristofano C, Morelli E, Meola M, Lupetti S, Giovanetti S: Serum oxalic acid in uremia: Effect of a low-protein diet supplemented with essential amino acids and ketoanalogues. Nephron 38:54–57, 1984
  13. Mitch WE, Walser M, Steinman TI, Hill S, Zeger S, Tungsanga K: The impact on the progression of chronic renal failure of a ketoacid/amino acid supplement to a restricted diet. N Engl J Med 311:623–629, 1984 | PubMed | ISI | ChemPort |
  14. Gretz N, Korb E, Strauch M: Low-protein diet supplemented by keto acids in chronic renal failure: A prospective study. Kidney Int 24(Suppl 16):S263–S267, 1983
  15. Barsotti G, Guiducci F, Giovanetti S: Effects on renal function of a low-nitrogen diet supplemented with essential amino acids and ketoanalogues and of hemodialysis and free protein supply in patients with chronic renal failure. Nephron 27:113–117, 1981
  16. Burns J, Creswell E, Ell S, Flynn M, Jackson MA, Lee HA, Richards P, Rowlands A, Talbot S: Comparison of the effects of keto acid and essential amino acids on nitrogen homeostasis in uremic patients on moderately protein-restricted diets. Am J Clin Nutr 31:1767–1775, 1978
  17. Walser M, LaFrance ND, Ward L, Van Duyn MA: Progression of renal failure in patients given ketoacids following amino acids. Kidney Int 32:123–126, 1987
  18. Sapir DG, Walser M: Nitrogen-sparing induced early in starvation by infusion of branched-chain ketoacids. Metabolism 26:301–308, 1977
  19. Mitch WE, Walser M, Sapir DG: Nitrogen sparing induced by leucine compared to that induced by its keto analogue, alpha-ketoisocaproate, in fasting obese man. J Clin Invest 67:553–562, 1981
  20. Sapir DG, Stewart PM, Walser M, Moreadith C, Moyer ED, Imbembo AL, Rosenhein NB, Munoz S: Effects of alphaketo-isocaproate and of leucine on nitrogen metabolism in post-operative patients. Lancet 1:1010–1014, 1983
  21. Simmons PS, Miles JM, Gerich JE, Haymond MW: Increased proteolysis. An effect of increases in plasma Cortisol within the physiologic range. J Clin Invest 73:412–420, 1984
  22. Legaspi A, Albert JD, Calvano SE, Brennan MF, Lowry SF: Proteolysis of skeletal muscle in response to acute elevation of plasma Cortisol in man. Surg Forum 36:16–17, 1985
  23. Silber RH, Porter CC: The determination of 17,21-dihydroxy-20-ketosteroids in urine and plasma. J Biol Chem 210:923–932, 1954 | PubMed | ISI | ChemPort |
  24. Magil AB, Ballon HS: IgA nephropathy—evaluation of prognostic factors in patients with moderate disease. Nephron 47:246–252, 1987
  25. D'Amico G: The commonest glomerulonephritis in the world—IgA nephropathy. J Med 64:709–728, 1987
  26. LaFrance ND, Drew H, Walser M: Radioisotopic measurement of glomerular filtration rate in severe chronic renal failure. J Nucl Med (in press)
  27. SAS User's Guide: Statistics. Version 5 Edition, Cary, North Carolina, SAS Institute, 1985, p. 764
  28. Betts PR, Howse PM, Morris R, Rayner PHW: Serum Cortisol concentrations in children with chronic renal insufficiency. Arch Dis Child 50:245–247, 1975
  29. Wallace EZ, Rosman PM, Toshav N, Sacerdote A, Baltrhazar A: Pituitary-adrenocortical function in chronic renal failure: Studies of episodic secretion of Cortisol and dexamethasone sup-pressibility. J Clin Endocrinol Metab 50:46–51, 1980
  30. Manatus H, Sulon J, Von Frenckell R, Sepul A, Legros JJ: A study of psychological and endocrine variables on 14 patients treated by chronic hemodialysis. Neuropsychobiology 7:285–291, 1981
  31. Rosman PM, Benn R, Kay M, Tito J, Wallace EZ: Cortisol binding in uremic plasma. I. Absence of abnormal Cortisol binding to corticosteroid-bindiftg globulin. Nephron 37:160–165, 1984
  32. Rosman PM, Benn R, Kay M, Wallace EZ: Cortisol binding in uremic plasma. II. Decreased Cortisol binding to albumin. Nephron 37:229–231, 1984
  33. Henning HV, Ludwig-Kohn H: Neutral steroid metabolites in body fluids of patients with uremia and after renal transplantation, in Contributions to Nephrology, edited by GM Berlyne, S Giovannetti, S. Basel, Karger, 1986, pp. 153–166
  34. Bacon GE, Kenny FM, Murdaugh HV, Richards G: Prolonged serum half-life of Cortisol in renal failure. Johns Hopkins Med J 132:127–121, 1973
  35. Boer P, Thijssen JHH: The excretion of metabolites of Cortisol and aldosterone in male patients on haemodialysis treatment. Steroids 30:203–211, 1977
  36. Deck KA, Siemon G, Sieberth HG, vonBayer H: Cortisolver-lust und Plasrna-ll-hydroxy-corticosteroidprofil wahrend der Hae-modialyse. Verh Dt Ges inn Med 74:1195–1198, 1968
  37. Englert E, Brown H, Willardson DG, Wallach S, Simons EL: Metabolism of free and conjugated 17-hydroxycorticosteroids in subjects with uremia. J Clin Endocrinol Metab 18:36–48, 1958
  38. Billon-Rey S, Beylot M, Mathian B, Patricot MC, Berthezene R, Mornex K, Revol A: Comparison de la valeur du Cortisol libre urinaire et des 17-hydroxycorticosteroides urinaires pour le diagnostic du syndrome de Cushing. Presse Med 15:965–968, 1986
  39. Ellis D, Tran SD, Avner ED: Glucocorticoid-induced stimulation of Na-K ATPase activity in tubular epithelial cells is mediated by glucocorticoid receptors (GR). Kidney Int 31:165, 1987
  40. Avner ED, Sweeney WE, Young MC, Ellis D: Na-K ATPase activity modulates congenital murine polycystic kidney disease in vitro. (abstract) Clin Res 35:542A, 1987
  41. Grunfeld J-P, Eloy L, Araujo A, Russo-Marie F: Effects of gluco- and antiglucocorticoids on renal and aortic prostaglandin synthesis. Am J Physiol 251:F810–F816, 1986
  42. Erman A, Nasjletti A: Enhancement of renal medulla prostaglandin synthetase activity by dexamethasone treatment in the rat. Biochem Biophys Res Com 121:255–260, 1984
  43. Dunn M: The role of arachidonic acid metabolites in renal homeostasis. Non-steroidal anti-inflammatory drugs, renal function and biochemical, histological and clinical effects and drug interactions. Drugs 33(suppl 1):56–66, 1987 | PubMed | ISI | ChemPort |
  44. Garcia DL, Rennke HG, Brenner BM, Anderson S: Chronic glucocorticoid therapy amplifies glomerular injury in rats with renal ablation. J Clin Invest 80:867–874, 1987 | PubMed | ISI | ChemPort |
  45. Heymann W, Grupe WE: Increase in proteinuria due to steroid medication in chronic renal disease. Pediatrics 74:356–363, 1969
  46. Dowdle E, Saunders SJ: The acute effect of hydrocortisone sodium succinate on the proteinuria of the nephrotic syndrome. S Afr J Lab Clin Med 3:39–47, 1957
  47. Wetzels JFM, Gerlag PGG, Sluiter HE, Hoitsma AJ, Koene RAP: Prednisone-induced fluctuations of proteinuria in patients with a nephrotic syndrome. Nephron 44:344–350, 1986
  48. Clark I: The effect of cortisone on protein synthesis. J Biol Chem 200:69–76, 1953 | PubMed | ISI |
  49. Sellini M, Fierro A, Marchesi L, Manzo G, Giovannini C: Comportamento dei valori dei base e del ritmo circadiano dello ACTH, del cortisolo, della PRL e del GH nel corso di dieta iperproteica. Boll Soc It Biol Sper 57:963–969, 1981
  50. Slag MF, Ahmed M, Gannon MC, Nuttall FQ: Meal stimulation of Cortisol secretion: A protein induced effect. Metabolism 30:1104–1108, 1981
  51. Ishizuka B, Quigley ME, Yen SSC: Pituitary hormone release in response to food ingestion: Evidence for neuroendocrine signals from gut to brain. J Clin Endocrinol Metab 57:1111–1116, 1983
  52. Pende A, Musso NR, Montaldi ML, Pastorino G, Arzese M, Devilla L: Evaluation of the effects induced by four opiate drugs, with different affinities to opioid receptor subtypes, on anterior pituitary LH, TSH, PRL and GH secretion and on Cortisol secretion in normal men. Biomed Pharmacother 40:178–182, 1986
  53. Moguilewsky M, Philibert D: RU 38486: Potent antiglucocor-ticoid activity correlated with strong binding to the cytosolic glucocorticoid receptor followed by impaired activation. J Steroid Biochem 20:271–276, 1984 | Article | PubMed | ISI | ChemPort |
  54. Teutsch G, Costerousse G, Deraedt R, Benzoni J, Fortin M, Philibert D: 17-alpha-alkynyl-l 1, 17-dihydroxyandrostane derivaties: A new class of potent glucocorticoids. Steroids 38:651–665, 1981

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