Aldosterone resistance in kidney transplantation is in part induced by a down‐regulation of mineralocorticoid receptor expression<sup>1</sup>

Heering, P.; Kurschat, Christine; Vo, DT; Klein-Vehne, N.; Fehsel, Karin; Ivens, Katrin

doi:10.1046/j.1399-0012.2003.00154.x

Cited by 44 publications

(40 citation statements)

References 21 publications

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“…Although some studies found CNIs to increase plasma renin activity (31, 32), others observed suppressed levels (13, 33, 34). Some studies showed that CNIs inhibit the mineralocorticoid receptor, and this effect was held to be responsible for signs of hypoaldosteronism such as hyperkalemia and acidosis (35, 36). Indeed, treatment with fludrocortisone alleviated these symptoms in kidney transplant patients (36).…”

Section: Vascular Effects Of Calcineurin Inhibitorsmentioning

confidence: 99%

“…Some studies showed that CNIs inhibit the mineralocorticoid receptor, and this effect was held to be responsible for signs of hypoaldosteronism such as hyperkalemia and acidosis (35, 36). Indeed, treatment with fludrocortisone alleviated these symptoms in kidney transplant patients (36). On the other hand, in rats, treatment with the mineralocorticoid receptor antagonist eplerenone also prevented some of the adverse effects of CNIs, including hypertension and reductions in glomerular filtration rate and renal blood flow (37).…”

Section: Vascular Effects Of Calcineurin Inhibitorsmentioning

confidence: 99%

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Pathogenesis of calcineurin inhibitor–induced hypertension

et al. 2012

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This article reviews the current understanding of the mechanisms of calcineurin inhibitor–induced hypertension. Already early after the introduction of cyclosporine in the 1980s, vasoconstriction, sympathetic excitation and sodium retention by the kidney had been shown to play a role in this form of hypertension. The vasoconstrictive effects of calcineurin inhibitors are related to interference with the balance of vasoactive substances, including endothelin and nitric oxide. Until recently, the renal site of the sodium-retaining effect of calcineurin inhibitors was unknown. We and others have shown that calcineurin inhibitors increase the activity of the thiazide-sensitive sodium chloride cotransporter through an effect on the kinases WNK and SPAK. Here, we review the pertinent literature on the hypertensinogenic effects of calcineurin inhibitors, including neural, vascular and renal effects, and we propose an integrated model of calcineurin inhibitor–induced hypertension.

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Section: Vascular Effects Of Calcineurin Inhibitorsmentioning

confidence: 99%

Section: Vascular Effects Of Calcineurin Inhibitorsmentioning

confidence: 99%

Pathogenesis of calcineurin inhibitor–induced hypertension

et al. 2012

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“…According to recent studies, aldosterone resistance may also be associated with a reduction in MR expression, probably mediated by transcriptional mechanisms. [16][17][18][19] G protein-coupled receptor 48 (GPR48/ LGR4) belongs to the G protein-coupled receptor superfamily. It has recently been reported to bind R-spondin and mediate its signaling in intestinal crypt cells, 20,21 yet its function has not been well investigated.…”

Section: Introductionmentioning

confidence: 99%

GPR48 Increases Mineralocorticoid Receptor Gene Expression

Wang

et al. 2012

Journal of the American Society of Nephrology

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Aldosterone and the mineralocorticoid receptor (MR) are critical to the maintenance of electrolyte and BP homeostasis. Mutations in the MR cause aldosterone resistance known as pseudohypoaldosteronism type 1 (PHA1); however, some cases consistent with PHA1 do not exhibit known gene mutations, suggesting the possibility of alternative genetic variants. We observed that G protein-coupled receptor 48 (Gpr48/ Lgr4) hypomorphic mutant (Gpr48 m/m ) mice had hyperkalemia and increased water loss and salt excretion despite elevated plasma aldosterone levels, suggesting aldosterone resistance. When we challenged the mice with a low-sodium diet, these features became more obvious; the mice also developed hyponatremia and increased renin expression and activity, resembling a mild state of PHA1. There was marked renal downregulation of MR and its downstream targets (e.g., the a-subunit of the amiloride-sensitive epithelial sodium channel), which could provide a mechanism for the aldosterone resistance. We identified a noncanonical cAMP-responsive element located in the MR promoter and demonstrated that GPR48 upregulates MR expression via the cAMP/protein kinase A pathway in vitro. Taken together, our data demonstrate that GPR48 enhances aldosterone responsiveness by activating MR expression, suggesting that GPR48 contributes to homeostasis of electrolytes and BP and may be a candidate gene for PHA1.

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“…It is noteworthy that not all studies demonstrated lower renin levels in CNItreated patients and, in fact, some studies demonstrated increases in renin levels, perhaps associated with CNI-induced renal vasoconstriction (7). Further work by Heering et al demonstrated that although mean aldosterone levels do not differ between CNI-treated transplant patients and normal controls, there was an almost four-fold decrease in the expression of the mineralocorticoid receptor in the peripheral leukocytes in CNI-treated patients (8). Despite this decrease in mineralocorticoid receptor expression, patients with hyperkalemia treated with fludrocortisone had improvement in both serum potassium levels and their metabolic acidosis.…”

Section: Case Discussionmentioning

confidence: 99%

“…Corticosteroid use suppresses production of adrenal corticosteroids and has a minor effect on aldosterone synthesis and thus would be unlikely to have a major effect on potassium homeostasis unless at high doses and associated with a marked catabolic effect. Heering et al demonstrated that aldosterone levels did not substantially differ between renal transplant patients and normal controls (8,22). Finally, upregulation of the aldosterone receptor in the distal tubule leads to increased sodium reabsorption as well as increased potassium excretion resulting in either normal or low serum potassium levels.…”

Section: Case Discussionmentioning

confidence: 99%

American Society of Nephrology Quiz and Questionnaire 2015

Rosner

Perazella

Choi

2016

Clinical Journal of the American Society of Nephrology

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The Nephrology Quiz and Questionnaire remains an extremely popular session for attendees of the annual Kidney Week meeting of the American Society of Nephrology. During the 2015 meeting the conference hall was once again overflowing with eager quiz participants. Topics covered by the experts included electrolyte and acid-base disorders, glomerular disease, end-stage renal disease and dialysis, and kidney transplantation. Complex cases representing each of these categories together with single-best-answer questions were prepared and submitted by the panel of experts. Before the meeting, training program directors of nephrology fellowship programs and nephrology fellows in the United States answered the questions through an internet-based questionnaire. During the live session members of the audience tested their knowledge and judgment on the same series of case-oriented questions in a quiz. The audience compared their answers in real time using a cell-phone app containing the answers of the nephrology fellows and training program directors. The results of the online questionnaire were displayed, and then the quiz answers were discussed. As always, the audience, lecturers, and moderators enjoyed this highly educational session. This article recapitulates the session and reproduces selected content of educational value for the Clinical Journal of the American Society of Nephrology readers. Enjoy the clinical cases and expert discussions.

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Aldosterone resistance in kidney transplantation is in part induced by a down‐regulation of mineralocorticoid receptor expression¹

Cited by 44 publications

References 21 publications

Pathogenesis of calcineurin inhibitor–induced hypertension

Pathogenesis of calcineurin inhibitor–induced hypertension

GPR48 Increases Mineralocorticoid Receptor Gene Expression

American Society of Nephrology Quiz and Questionnaire 2015

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Aldosterone resistance in kidney transplantation is in part induced by a down‐regulation of mineralocorticoid receptor expression1

Cited by 44 publications

References 21 publications

Pathogenesis of calcineurin inhibitor–induced hypertension

Pathogenesis of calcineurin inhibitor–induced hypertension

GPR48 Increases Mineralocorticoid Receptor Gene Expression

American Society of Nephrology Quiz and Questionnaire 2015

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Product

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Aldosterone resistance in kidney transplantation is in part induced by a down‐regulation of mineralocorticoid receptor expression¹