Introduction
Many kidney disorders are treated with corticosteroids, and immunosuppressive treatment following renal transplantation typically involves prednisolone. Secondary adrenal insufficiency (AI) due to long-term glucocorticoid prescription in patients on hemodialysis (HD) is a diagnostic diffculty. This is exacerbated further by the fact that AI and renal replacement therapy may both cause unspecific symptoms including weariness and orthostatic hypotonia. Adrenal insufficiency that goes unnoticed can be fatal.
As a result, evaluating adrenal function in HD patients is a standard practice, especially following glucocorticoid medication or in persistent hypotensive patients. There are concerns concerning adrenocorticotropic hormone (ACTH) and cortisol metabolism and clearance, as well as hemoconcentration, as complicating variables during hemodialysis (HD). As a result, ACTH testing is now done either before or between HD sessions. The goal of this review is to assess the existing evidence on the validity of adrenal insufficiency tests in patients on chronic renal replacement therapy.
Methods
A literature search of PubMed database for interventional and observational clinical trials was performed. Of 218 potentially eligible articles, 16 studies involving 381 participants were included. Seven studies performed an ACTH test before HD or in between HD sessions. Study Flow Chart in Fig. 1.
Results
Pharmacokinetic aspects of serum cortisol, ACTH and CRH
Only Deck et al. investigated the change in cortisol with respect to HD. Plasma clearance rate was 30–63% higher during HD in five out of seven cases, resulting in decreased plasma cortisol during and increased plasma cortisol after HD. Akmal et al. also pointed out that the cortisol levels increased after the end of HD. They assessed changes in cortisol pre- and post-HD in 21 HD patients and found that values post-HD about doubled as compared to pre-HD values.
Furthermore, they compared serum cortisol and serum ACTH (both pre- and post-HD) in five patients without steroids and two patients who received large doses of steroids for about 6 weeks. After HD, there was an increase in cortisol and ACTH in all five non-steroid patients. The other two steroid patients had reduced values of ACTH and cortisol and were diagnosed with steroid-induced AI.
In patients without HD, CRH values were in upper normal range. They postulated that accumulated uremic toxins could inhibit the enzymes which degrade CRH. Therefore, clearance rate would be lower and CRH levels would increase. On the other hand, HD could benefit the degradation of CRH by eliminating these inhibiting toxins. CRH in HD patients was still in a normal, but lower range.
ACTH testing
The study from Valentin et al. was the only case-control study which allegedly detected adrenal insufficiency in HD patients based on lab value . In their cohort of patients on HD not treated with prednisolone, only 3% of cases had hypoadrenalism. In the other Thve studies which performed an ACTH test, there were no HD patients diagnosed with AI. In the cases, cortisol increased significantly after ACTH stimulation, and there was no significant difference to controls.
Clodi et al. described the time of the peak of serum cortisol after stimulation with different doses of exogenous ACTH. The test was performed in seven HD patients , seven CAPD patients, and seven healthy controls. On one hand, there was a significant increase in serum cortisol after stimulation in all three groups but with different peak times (30 min after 1 μg, 60 min after 5 μg and 120 min after 250 μg). On the other hand, they also described a trend towards blunted and delayed cortisol release following 1 μg ACTH in HD patients.
CRH stimulation test
Grant et al. and Vigna et al. both performed a stimulation test using 100 μg synthesized corticotropin releasing hormone (CRH). They investigated the time of the peak of ACTH and cortisol after injection. The control groups in both studies reached the ACTH peak 30 min after CRH administration. There was no difference in time of cortisol peak between the case and control groups in each study, as well as between the two studies. Four other studies also conducted a CRH stimulation test with different results.
Siamopoulos et al. all reported increased stimulated plasma cortisol in controls and cases. In the case series of Sakao et al., peak levels of ACTH and cortisol were both lower than two-fold of their basal values in four out of five cases. Zager et al. showed that the reaction of cortisol and other adrenal hormones after infusion of ACTH in CAPD patients was comparable to healthy subjects.
Quantitative analysis
The risk of bias was considered in all 16 studies using the SIGN checklists. The overall quality of two out of three observational studies and one out of three case series was assessed as unacceptable.
Conclusion
This is the first attempt to generate a systematic review and meta-analysis on the validity of adrenal function testing in patients undergoing renal replacement therapy. The meta-analysis of baseline serum cortisol levels revealed no significant difference between cases and controls regarding basal serum cortisol, showing that basal cortisol values are comparable to reference values in patients undergoing HD.
Due to the pharmacokinetic evidence and lack of clinical studies, ACTH testing should be performed either before HD or on a day without HD. Theoretically, postponing the test from before HD to during HD would benefit the patient in terms of comfort.
References:
1. Bancos I, Hahner S, Tomlinson J, Arlt W. Diagnosis and management of adrenal insufficiency. Lancet Diab Endocrinol. 2015;3(3):216–26.
2. Chadban SJ, Atkins RC. Glomerulonephritis. Lancet. 2005;365(9473):1797–806.
3. Oelkers W. Adrenal insufficiency. N Engl J Med. 1996;335(16):1206–12.
4. Tomino Y. How to treat patients with chronic kidney disease: with special focus on IgA nephropathy. Nephrology (Carlton). 2018;23(Suppl 4):76–9.
5. Webster AC, Nagler EV, Morton RL, Masson P. Chronic kidney disease. Lancet. 2017;389(10075):1238–52.
6. Valentin A, Borresen SW, Rix M, Elung-Jensen T, Sorensen SS, Feldt-Rasmussen U. Adrenal insufficiency in kidney transplant patients during low-dose prednisolone
7. Almutary H, Bonner A, Douglas C. Symptom burden in chronic kidney disease: a review of recent literature. J Ren Care. 2013;39(3):140–50.
8. Murtagh FE, Addington-Hall J, Higginson IJ. The prevalence of symptoms in end-stage renal disease: a systematic review. Adv Chronic Kidney Dis. 2007;14(1):82–99.
9. Arregger AL, Cardoso EM, Zucchini A, Aguirre EC, Elbert A, Contreras LN. Adrenocortical function in hypotensive patients with end stage renal disease. Steroids.
10. Bleicken B, Hahner S, Ventz M, Quinkler M. Delayed diagnosis of adrenal insufficiency is common: a cross-sectional study in 216 patients. Am J Med Sci. 2010;339(6):525–31.
11. Dineen R, Thompson CJ, Sherlock M. Adrenal crisis: prevention and management in adult patients. Ther Adv Endocrinol Metab. 2019;10:2042018819848218.
12. Abdu TA, Elhadd TA, Neary R, Clayton RN. Comparison of the low dose short synacthen test (1 microg), the conventional dose short synacthen test (250
microg), and the insulin tolerance test for assessment of the hypothalamo-pituitary-adrenal axis in patients with pituitary disease. J Clin Endocrinol Metab. 1999;84(3):838–43.
13. Weitzman ED, Fukushima D, Nogeire C, Roftwarg H, Gallagher TF, Hellman L. Twenty-four hour pattern of the episodic secretion of cortisol in normal subjects. J Clin Endocrinol Metab. 1971;33(1):14–22.
14. Bay WH, Van Cleef S, Owens M. The hemodialysis access: preferences and concerns of patients, dialysis nurses and technicians, and physicians. Am J Nephrol. 1998;18(5):379–83.
15. Hagren B, Pettersen IM, Severinsson E, Lützén K, Clyne N. Maintenance haemodialysis: patients’ experiences of their life situation. J Clin Nurs. 2005;14(3):294–300.
16.Deck T, Siemon G, Sieberth HG, von Bayer H. Cortisol loss and plasma 11-hydroxy-corticosteroid profile during hemodialysis. Verh Dtsch Ges Inn Med. 1968;74:1195–8.
17. Knapp E, Staudinger E, Difirich P. Behavior of free plasma cortisol during extracorporeal hemodialysis. Klin Wochenschr. 1970;48(20):1243–4.
18. Wallace EZ, Rosman P, Toshav N, Sacerdote A, Balthazar A. Pituitary-adrenocortical function in chronic renal failure: studies of episodic secretion of cortisol and dexamethasone suppressibility. J Clin Endocrinol Metab. 1980;50(1):46–51.
19. Shimamoto K, Ando T, Nakao T, Watarai I, Miyahara M. Permeability of antidiuretic hormone and other hormones through the dialysis membrane in patients undergoing chronic hemodialysis. J Clin Endocrinol Metab. 1977;45(4):818–20.
