ACTH revisited—potential implications for patients with renal disease

Anna-Lena Berg1 and Margret Arnadottir2,

1 Department of Nephrology, University Hospital, Lund, Sweden and 2 Department of Internal Medicine, National University Hospital, Reykjavik, Iceland

Introduction

Adrenocorticotrophic hormone (ACTH) facilitates the synthesis of adrenal glucocorticoids by maintaining the enzymes that control the side-chain cleavage of cholesterol, the rate-limiting step in the biosynthesis of steroids 1]. Thus, ACTH is involved in the control of adrenal lipid metabolism. Recent studies have revealed that treatment with ACTH in pharmacological dosage also influences plasma lipoprotein metabolism. This applies to both healthy individuals [24] and patients with different types of renal disease [57]. Moreover, the results of one of these recent studies suggest that treatment with ACTH has beneficial effects on the glomerular function of patients with idiopathic membranous nephropathy [7].

Effects of ACTH on plasma lipoprotein metabolism in healthy individuals

Short-term administration of ACTH to healthy individuals resulted in a rapid and pronounced reduction in the plasma cholesterol concentration [2,3]. The concentrations of low-density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B decreased by roughly 25%, and those of lipoprotein(a) by about 40% [24]. The effects on the concentrations of triglycerides and high-density lipoprotein (HDL) cholesterol were inconsistent, i.e. either a reduction in triglycerides and an increase in HDL cholesterol [2,3] or no change in these variables (Arnadottir et al., unpublished data). In short, treatment with ACTH led to changes in the lipoprotein profile that are associated with reduced cardiovascular risk.

The lipid-lowering mechanisms of ACTH have not yet been established. However, important pieces of information are available. First, the reduction in LDL cholesterol seems to be a direct effect of ACTH since this was not observed during high-dose steroid treatment [3]. In contrast, lipoprotein(a) fell during the steroid challenge indicating that the lipoprotein(a)-lowering effect of ACTH may be secondary to increased steroid load 3]. Second, the addition of ACTH to the culture medium of HepG2 cells (human hepatoma cell line) led to increased cellular uptake of labelled LDL suggesting that ACTH facilitates the uptake of LDL by hepatocytes 3,8]. Third, it was recently shown that ACTH induces a marked increase in the plasma concentration of apo E, both the fraction associated with apo B and that which is not associated with apo B (Arnadottir et al., unpublished data). Possibly, the improved hepatic uptake of LDL is mediated by apo E-enrichment of these lipoproteins rather than increased number of LDL receptors.

Effects of ACTH on plasma lipoprotein pattern in patients with renal disease

Short-term treatment with ACTH has been given to several categories of patients with renal disease representing different abnormalities of lipoprotein metabolism, i.e. moderately hyperlipoproteinaemic patients on chronic steroid treatment (renal transplant recipients and patients with glomerulonephritis) 5], haemodialysis patients manifesting full-blown uraemic dyslipoproteinaemia [6], and severely hyperlipoproteinaemic nephrotic patients [7]. In general, the results were similar to those observed in healthy individuals. As expected, the steroid-treated patients had rather low initial levels of ACTH whereas the dialysis patients had increased ACTH levels due to ACTH resistance. These findings may be reflected by the more rapid and somewhat more marked lipid-lowering response in the steroid-treated patients than in the dialysis patients. Pronounced changes were observed in the plasma lipoprotein pattern of nephrotic patients during ACTH treatment (Figure 1AGo) [7]. However, as depicted in Figure 1BGo, the simultaneous decrease in urinary protein excretion was quite as dramatic and the cause-effect relationship is therefore unclear.



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Fig. 1. ACTH was given to fourteen nephrotic patients with idiopathic membranous nephropathy for 56 days (each intramuscularinjection of Synacthen Depot 1 mg is indicated by an arrow). Theupper part of the figure (A) shows the median changes in the serumconcentrations of cholesterol (open circles), triglycerides (closedcircles) and lipoprotein(a) (open squares). The lower part of thefigure (B) shows the median changes in the serum concentrations ofalbumin (dark rectangles) and the urinary excretion of albumin(open circles), IgG (closed circles) as well as alpha-1-microglobulin(open squares) (reproduced with permission from reference 7).

 
Interestingly, in haemodialysis patients, but not in healthy individuals, ACTH induced an increase in the fraction of apo CIII not associated with apo B without an obvious influence on triglyceride/HDL metabolism [6]. In uraemic patients, there appears to be a basic disturbance in the control of the hepatic synthesis of apo CIII [9] that may be enhanced by ACTH.

Potential benefits of ACTH treatment in nephrology

ACTH has previously been used in the treatment of several inflammatory diseases. Obviously, such therapy had the advantage of preventing suppression of adrenocortical function. However, questionable clinical benefits when compared to steroid treatment in combination with the disadvantage of parenteral administration led to the abandonment of ACTH treatment. Given the increased knowledge of the risks associated with hyperlipoproteinaemia, future comparison between steroids and ACTH must take into consideration the different influences of these agents on the plasma lipoprotein pattern i.e. the beneficial effects of ACTH [3] versus the adverse effects of steroids [10]. Since hyperlipoproteinaemia is one of the main risk factors for the development of atherosclerosis, long-term treatment with ACTH instead of steroids might be associated with cardiovascular benefit. If that proves to be the case, ACTH treatment would be of particular value in nephrology in view of the greatly increased cardiovascular mortality observed in patients with chronic renal failure [11], many of whom are subjected to long-term steroid treatment. In particular, this applies to renal transplant recipients but may also be relevant to patients with steroid-responsive glomerulonephritides.

The nephrotic subjects in the study referred to above [7] suffered from idiopathic membranous nephropathy. Within 8 weeks of treatment, all 14 patients displayed a marked decrease in the urinary albumin excretion (a median of 80%) and a moderate improvement of the glomerular filtration rate (a median of 28%). However, all the patients relapsed after discontinuance of ACTH treatment. The five most severely affected patients, who had all previously been resistant to high-dose steroid treatment (the Ponticelli regimen in four cases) were allowed to resume treatment with Synacthen Depot (ACTH1–24) in the estimated optimal dose of 1 mg i.m. twice a week. All five patients responded again to this therapy and were successfully treated for a total of 12 months. They were subsequently followed for another 18 months without any signs of relapse [7]. While arranging for a controlled trial we have continued to treat nephrotic patients with idiopathic membranous nephropathy with ACTH. Seven out of eight patients responded whereas one patient with grade III glomerular changes and severe interstitial fibrosis did not (Berg et al., unpublished data). Neither the findings from the published study [7] nor the unpublished data are controlled but the pattern and consistency of the response suggest that ACTH has beneficial effects on the glomerular function of patients with idiopathic membranous nephropathy. The mechanisms behind these effects are not known. Experimental studies clearly show that hyperlipoproteinaemia aggravates proteinuric renal disease but there is controversy about the effect of lipid-lowering treatment on urinary protein excretion in humans [12]. Moreover, there is a consensus by now that steroids, in the absence of alkylating agents, are ineffective in the treatment of idiopathic membranous nephropathy [13] rendering the increased steroid load an unlikely explanation. Perhaps ACTH possesses a specific immunomodulating activity or an antiproteinuric effect. An increase in the glomerular filtration rate in this setting may, at least partly, be secondary to remission of the nephrotic syndrome.

Future work

The efficacy of ACTH treatment in reducing circulating apo B-containing lipoproteins in healthy individuals as well as in several categories of patients with renal disease has been proven beyond doubt. However, the mechanisms behind the lipid-lowering effects are still elusive and the novel hypotheses regarding clinical benefits of ACTH need confirmation. Controlled, long-term studies are needed to investigate the potential benefit of reduced cardiovascular risk associated with exchanging ACTH for steroids in renal transplant recipients and to confirm the antiproteinuric effect observed in patients with idiopathic membranous nephropathy.

Notes

Correspondence and offprint requests to: Margret Arnadottir, Department of Internal Medicine, National University Hospital, IS-101 Reykjavik, Iceland. Back

References

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