Pediatric renal allograft transplantation does not normalize the increased cortisol/cortisone ratios of chronic renal failure

Schroth, Michael; Plank, Christian; Rauh, Manfred; Dörr, Helmuth-Günther; Rascher, Wolfgang; Dötsch, Jörg

doi:10.1530/eje.1.02121

Cited by 9 publications

(6 citation statements)

References 34 publications

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“…Each sample was measured in duplicate. Serum corticosterone was assessed by tandem mass spectrometry liquid chromatography as described previously [9].…”

Section: Methodsmentioning

confidence: 99%

Aldosterone-induced changes in the cardiac L-type Ca2+ current can be prevented by antioxidants in vitro and are absent in rats on low salt diet

Wagner

Рудакова

Volk

2008

Pflugers Arch - Eur J Physiol

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Mineralocorticoid receptor (MR) activation modulates cardiac L-type Ca(2+) current (I (CaL)) and transient outward K(+) current (I (to)). The exact circumstances of MR activation, however, remain elusive. Here, we investigate the influence of corticosteroids on MR-mediated changes in cellular electrophysiology. In vitro incubation of adult rat ventricular myocytes with the MR agonist aldosterone (100 nM, 24 h) increased I (CaL) density by 34% (n = 16; p < 0.01). This effect was abrogated by co-incubation with the MR antagonist spironolactone (10 muM). To investigate whether an increase in serum aldosterone concentration is sufficient for an increase in I (CaL) in vivo, rats were subjected to low Na(+) diet (LSD, 0.013% Na(+)) for 28 days. This increased serum aldosterone concentration from 0.19 +/- 0.04 nM (n = 6) in control animals (0.3% Na(+), CSD) to 16.1 +/- 2.1 nM (n = 6; p < 0.0001). Strikingly, I (CaL) density was similar in both CSD and LSD rats (-12.9 +/- 0.9 pA pF(-1), n = 18 and -13.7 +/- 1.1 pA pF(-1), n = 16, respectively), as was I (to) density. In vitro, the glucocorticoid corticosterone (1 microM) also increased I (CaL) and this effect was blocked by spironolactone (10 microM). Co-incubation with corticosterone (1 microM, the normal serum concentration) and aldosterone (100 nM, mimicking low Na(+) intake) did not further increase I (CaL) compared to corticosterone alone. Moreover, co-incubation of myocytes with N-acetylcysteine (10 mM) prevented the aldosterone (100 nM) or corticosterone (1 microM)-induced increase in I (CaL). In conclusion, an increase in serum aldosterone concentration in response to LSD is not sufficient for an increase in I (CaL) density in cardiomyocytes in vivo. This is supported in vitro by the absence of an effect of aldosterone on I (CaL) in the presence of a physiological concentration of corticosterone. Moreover, the cellular redox state may modulate MR activation.

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“…Each sample was measured in duplicate. Serum corticosterone was assessed by tandem mass spectrometry liquid chromatography as described previously [9].…”

Section: Methodsmentioning

confidence: 99%

Aldosterone-induced changes in the cardiac L-type Ca2+ current can be prevented by antioxidants in vitro and are absent in rats on low salt diet

Wagner

Рудакова

Volk

2008

Pflugers Arch - Eur J Physiol

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“…In line with this hypothesis, the urinary (THF+5aTHF)/THE ratioa surrogate marker of peripheral cortisol activationis independently correlated with the systemic inflammation marker C-reactive protein (CRP) in patients with CKD (79). Additionally, putative restoration of 11b-HSD type 2 activity through renal transplantation does not normalise the plasma cortisol/ cortisone ratio or urinary ratio of THF(s)/THE (81). It is therefore possible that upregulation of 11b-HSD1 activity may occur in CKD, but further proof is required to confirm this hypothesis.…”

Section: Hpa Axis Regulation Of Cortisol Secretion In Ckdmentioning

confidence: 99%

Cortisol excess in chronic kidney disease – A review of changes and impact on mortality

2023

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Chronic kidney disease (CKD) describes the long-term condition of impaired kidney function from any cause. CKD is common and associated with a wide array of complications including higher mortality, cardiovascular disease, hypertension, insulin resistance, dyslipidemia, sarcopenia, osteoporosis, aberrant immune function, cognitive impairment, mood disturbances and poor sleep quality. Glucocorticoids are endogenous pleiotropic steroid hormones and their excess produces a pattern of morbidity that possesses considerable overlap with CKD. Circulating levels of cortisol, the major active glucocorticoid in humans, are determined by a complex interplay between several processes. The hypothalamic-pituitary-adrenal axis (HPA) regulates cortisol synthesis and release, 11β-hydroxysteroid dehydrogenase enzymes mediate metabolic interconversion between active and inactive forms, and clearance from the circulation depends on irreversible metabolic inactivation in the liver followed by urinary excretion. Chronic stress, inflammatory states and other aspects of CKD can disturb these processes, enhancing cortisol secretion via the HPA axis and inducing tissue-resident amplification of glucocorticoid signals. Progressive renal impairment can further impact on cortisol metabolism and urinary clearance of cortisol metabolites. Consequently, significant interest exists to precisely understand the dysregulation of cortisol in CKD and its significance for adverse clinical outcomes. In this review, we summarize the latest literature on alterations in endogenous glucocorticoid regulation in adults with CKD and evaluate the available evidence on cortisol as a mechanistic driver of excess mortality and morbidity. The emerging picture is one of subclinical hypercortisolism with blunted diurnal decline of cortisol levels, impaired negative feedback regulation and reduced cortisol clearance. An association between cortisol and adjusted all-cause mortality has been reported in observational studies for patients with end-stage renal failure, but further research is required to assess links between cortisol and clinical outcomes in CKD. We propose recommendations for future research, including therapeutic strategies that aim to reduce complications of CKD by correcting or reversing dysregulation of cortisol.

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“…In chronic renal failure, 11beta-hydroxysteroid dehydrogenase type (11b-HSD2) activity is reduced, causing diminished cortisol inactivation which is thought to contribute to arterial hypertension in CKD [55]. Plasma and urinary cortisol/cortisone ratios are elevated, and it has been demonstrated they do not return to normal in children after renal allograft transplantation [56]. This suggests that renal transplantation does not normalize 11b-HSD2 activity.…”

Section: Hpa In Specific Systemic Diseasesmentioning

confidence: 99%

Systemic illness

et al. 2008

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Systemic illnesses are associated with alterations in the hypothalamic-pituitary-peripheral hormone axes, which represent part of the adaptive response to stressful events and may be influenced by type and severity of illness and/or pharmacological therapy. The pituitary gland responds to an acute stressful event with two secretory patterns: adrenocorticotropin (ACTH), prolactin (PRL) and growth hormone (GH) levels increase, while luteinizing hormone (LH), follicle-stimulating hormone (FSH) and thyrotropin (TSH) levels may either decrease or remain unchanged, associated with a decreased activity of their target organ. In protracted critical illness, there is a uniformly reduced pulsatile secretion of ACTH, TSH, LH, PRL and GH, causing a reduction in serum levels of the respective target-hormones. These adaptations are initially protective; however, if inadequate or excessive they may be dangerous and may contribute to the high morbidity and mortality risk of these patients. There is no consensus regarding the type of approach, as well as the criteria to use to define pituitary axis function in critically ill patients. We here provide a critical approach to pituitary axis evaluation during systemic illness.

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Pediatric renal allograft transplantation does not normalize the increased cortisol/cortisone ratios of chronic renal failure

Cited by 9 publications

References 34 publications

Aldosterone-induced changes in the cardiac L-type Ca2+ current can be prevented by antioxidants in vitro and are absent in rats on low salt diet

Aldosterone-induced changes in the cardiac L-type Ca2+ current can be prevented by antioxidants in vitro and are absent in rats on low salt diet

Cortisol excess in chronic kidney disease – A review of changes and impact on mortality

Systemic illness

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