Calcineurin Inhibitors Downregulate HNF-1β and May Affect the Outcome of HNF1B Patients After Renal Transplantation

Faguer, Stanislas; Esposito, Laure; Casemayou, Audrey; Pirson, Yves; Decramer, Stéphane; Cartery, C.; Hazzan, Marc; Garrigue, Valérie; Roussey, G.; Cointault, Olivier; Ho, Thien Anh; Merville, Pierre; Devuyst, Olivier; Gourdy, Pierre; Chassaing, Nicolas; Bascands, Jean-Loup; Kamar, Nassim; Schanstra, Joost P.; Rostaing, Lionel; Chauveau, Dominique

doi:10.1097/tp.0000000000000993

Cited by 6 publications

(7 citation statements)

References 26 publications

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“…We also added an exploratory analysis on the role of genetic variation in the HNF1b gene on the risk of PTDM. This HNF1b hypothesis was based on reports that (i) patients with HNF1b mutations develop hypomagnesaemia and diabetes mellitus [32,49,50], (ii) patients with HNF1b mutations are more prone to develop PTDM [37], (iii) CNIs down-regulate HNF1b [37] and (iv) SNPs in HNF1b are associated with diabetes mellitus in the general population [33-36, 51, 52]. Although the univariate analysis showed an association between the HNF1b SNP rs752010 G > A and PTDM, significance was lost when adjusting for age and sex ( Table 5).…”

Section: Discussionmentioning

confidence: 99%

“…Patients with mutations in the HNF1b gene develop diabetes mellitus and hypomagnesaemia [31,32], and single nucleotide polymorphisms (SNPs) in HNF1b are associated with diabetes mellitus in the general population [33][34][35][36]. Interestingly, a recent study showed that CNIs down-regulate HNF1b, increasing the risk of PTDM 2-to 3-fold in patients with HNF1b mutations [37]. This provided a rationale to explore the role of HNF1b in KTRs receiving tacrolimus.…”

Section: Introductionmentioning

confidence: 99%

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Serum magnesium, hepatocyte nuclear factor 1β genotype and post-transplant diabetes mellitus: a prospective study

Burgh

Moes

Kieboom

et al. 2019

Nephrology Dialysis Transplantation

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Background Retrospective studies suggest that tacrolimus-induced hypomagnesaemia is a risk factor for post-transplant diabetes mellitus (PTDM), but prospective studies are lacking. Methods This was a prospective study with measurements of serum magnesium and tacrolimus at pre-specified time points in the first year after living donor kidney transplantation (KT). The role of single nucleotide polymorphisms (SNPs) in hepatocyte nuclear factor 1β (HNF1β) was also explored because HNF1β regulates insulin secretion and renal magnesium handling. Repeated measurement and regression analyses were used to analyse associations with PTDM. Results In our cohort, 29 out of 167 kidney transplant recipients developed PTDM after 1 year (17%). Higher tacrolimus concentrations were significantly associated with lower serum magnesium and increased risk of hypomagnesaemia. Patients who developed PTDM had a significantly lower serum magnesium trajectory than patients who did not develop PTDM. In multivariate analysis, lower serum magnesium, age and body mass index were independent risk factors for PTDM. In recipients, the HNF1β SNP rs752010 G > A significantly increased the risk of PTDM [odds ratio (OR) = 2.56, 95% confidence interval (CI) 1.05–6.23] but not of hypomagnesaemia. This association lost significance after correction for age and sex (OR = 2.24, 95% CI 0.90–5.57). No association between HNF1β SNPs and PTDM was found in corresponding donors. Conclusions A lower serum magnesium in the first year after KT is an independent risk factor for PTDM. The HNF1β SNP rs752010 G > A may add to this risk through an effect on insulin secretion rather than hypomagnesaemia, but its role requires further confirmation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Serum magnesium, hepatocyte nuclear factor 1β genotype and post-transplant diabetes mellitus: a prospective study

Burgh

Moes

Kieboom

et al. 2019

Nephrology Dialysis Transplantation

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“…6 and 13) were known to have had cholestatic episodes, but in both cases, cholestasis developed after renal transplantation and during immunosuppressive treatment with calcineurin inhibitors. In vitro, calcineurin inhibitors downregulate HNF1B gene transcription and translation, and the downregulation of the nonmutated allele has been associated with posttransplantation cholestasis (28). Thus, a pretransplantation diagnosis of HNF1B disease warrants careful follow-up of hepatic and biliary laboratory parameters, which is crucial for an early diagnosis of more severe forms of cholestasis.…”

Section: Discussionmentioning

confidence: 99%

“…Bile duct imaging is rare in patients with HNF1B disease. In endoscopic retrograde cholangiopancreatography (ERCP), one patient had extrahepatic biliary atresia that was confirmed by surgery, and on magnetic resonance imaging (MRI), one patient had slightly dilated intra-and extrahepatic bile ducts (25,28). A few studies provide a limited number of patients who have undergone abdominal MRI (11,28).…”

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confidence: 99%

Biliary Anomalies in Patients With HNF1B Diabetes

Kettunen

Parviainen

Miettinen

et al. 2017

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…L'inibitore delle calcineurine (CNI) potrebbe giocare un ruolo particolare nello slatentizzare questa forma di diabete attraverso un'inibizione dose-dipendente della trascrizione dell'allele sano di HNF1β. Questi dati, se confermati, potrebbero fornire un'indicazione ad adottare protocolli di minimizzazione del CNI in questi pazienti (13).…”

Section: Tabella I -Principali Caratteristiche Delle Adtkdunclassified

Autosomal dominant tubulointerstitial kidney disease (ADTKD)

Quaglia

Battista

Merlotti

et al. 2017

Giornale di Tecniche Nefrologiche e Dialitiche

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Autosomal Dominant Tubulointerstitial Kidney Diseases (ADTKD) are a group of autosomal dominant hereditary nephropathies which share a rather aspecific pathological picture of interstitial fibrosis and tubular atrophy (IFTA) and a slowly progressing tubulointerstitial clinical profile: end-stage renal disease (ESRD) generally occurs between 30 and 50 years. Four types of ADTKD have been described so far, each showing some peculiarities: hepatocyte nuclear factor-1 β (HNF1β) ADTKD, in which ADTKD can be associated with renal cysts and a wide spectrum of congenital abnormalities of kidney and urinary tract (CAKUT) and extra-renal manifestations (diabetes, liver enzyme alterations, genital malformations), uromodulin (UMOD) ADTKD, characterised by early onset of hyperuricemia and gout, mucin-1 (MUC-1) ADTKD, a recently discovered form which appears to be an isolated tubulointerstitial nephropathy, and renin (REN) ADTKD, which appears in childhood and is characterised by anemia and mild signs of hyporeninism. A better awareness is needed in order to perform genetic analysis whenever clinical setting is compatible with this nephropathy. A timely diagnosis can have an important impact on both the patient and his family members in terms of therapy and prognosis, also at the prospect of renal transplant.

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Calcineurin Inhibitors Downregulate HNF-1β and May Affect the Outcome of HNF1B Patients After Renal Transplantation

Cited by 6 publications

References 26 publications

Serum magnesium, hepatocyte nuclear factor 1β genotype and post-transplant diabetes mellitus: a prospective study

Serum magnesium, hepatocyte nuclear factor 1β genotype and post-transplant diabetes mellitus: a prospective study

Biliary Anomalies in Patients With HNF1B Diabetes

Autosomal dominant tubulointerstitial kidney disease (ADTKD)

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