Statins in the prevention of lithium-associated diabetes insipidus: preliminary findings

Elie, Dominique; Segal, Marilyn; Low, Nancy; Mucsi, István; Holcroft, Christina; Shulman, Kenneth I.; Looper, Karl; Rej, Soham

doi:10.1038/ki.2014.409

Cited by 15 publications

(11 citation statements)

References 5 publications

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“…On repeated measures ANOVA, 60 study completers will allow us to observe an effect size of 0.34 at two-tailed alpha = 0.05 and Power (1-Beta) =0.8 [ 38 ]. In our previous cross-sectional findings in chronic lithium users, the effect size of statins on NDI was 0.33 [ 21 ], however that was not an intervention study. We acknowledge that there is relatively little data at the current time to justify the sample size.…”

Section: Methodsmentioning

confidence: 92%

“…In a recent cross-sectional study, we found that statins were associated with a lower risk of NDI amongst lithium users ( n = 71). In this study, lithium users who were also using statins were at lower risk (0%; 0/17) of developing NDI compared to lithium users who were not on statins (20.4%; 11/54) [ 21 ]. Two mice studies also demonstrated the effectiveness of statins in genetic forms of NDI, where statins increased the expression of membrane aquaporin 2 in renal tubules and doubled the urine osmolality [ 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

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Atorvastatin in the treatment of Lithium-induced nephrogenic diabetes insipidus: the protocol of a randomized controlled trial

et al. 2018

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BackgroundLithium is the gold-standard treatment for bipolar disorder, is highly effective in treating major depressive disorder, and has anti-suicidal properties. However, clinicians are increasingly avoiding lithium largely due to fears of renal toxicity. Nephrogenic Diabetes Insipidus (NDI) occurs in 15–20% of lithium users and predicts a 2–3 times increased risk of chronic kidney disease (CKD). We recently found that use of statins is associated with lower NDI risk in a cross-sectional study. In this current paper, we describe the methodology of a randomized controlled trial (RCT) to treat lithium-induced NDI using atorvastatin.MethodsWe will conduct a 12-week, double-blind placebo-controlled RCT of atorvastatin for lithium-induced NDI at McGill University, Montreal, Canada. We will recruit 60 current lithium users, aged 18–85, who have indicators of NDI, which we defined as urine osmolality (UOsm) < 600 mOsm/kg after 10-h fluid restriction. We will randomize patients to atorvastatin (20 mg/day) or placebo for 12 weeks. We will examine whether this improves measures of NDI: UOsm and aquaporin (AQP2) excretion at 12-week follow-up, adjusted for baseline.ResultsNot applicable.ConclusionThe aim of this clinical trial is to provide preliminary data about the efficacy of atorvastatin in treating NDI. If successful, lithium could theoretically be used more safely in patients with a reduced subsequent risk of CKD, hypernatremia, and acute kidney injury (AKI). If future definitive trials confirm this, this could potentially allow more patients to benefit from lithium, while minimizing renal risk.Trial registrationClinicalTrials.gov NCT02967653. Registered in February 2017.

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Section: Methodsmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Atorvastatin in the treatment of Lithium-induced nephrogenic diabetes insipidus: the protocol of a randomized controlled trial

et al. 2018

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“…Interestingly, a combination of two statins—fluvastatin and secretin—drastically reduced urine output by nearly 90% and doubled urine osmolality in mouse models of NDI in a mouse model 79 . Statin treatment was also found to be beneficial in NDI patients with inactivating mutation of the V2R 78 and in patients under lithium therapy 80 . Besides the effect in reducing urinary output in patients with NDI, the efficacy of the treatment with statins in increasing apical expression of AQP2 has been monitored by measuring the urinary excretion of AQP2 (u-AQP2), which was found to be increased in a time- and dose-dependent manner 81 .…”

Section: Vasopressin–aqp2 Pathway In Water Balance Disordersmentioning

confidence: 95%

Vasopressin–aquaporin-2 pathway: recent advances in understanding water balance disorders

et al. 2019

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The alteration of water balance and related disorders has emerged as being strictly linked to the state of activation of the vasopressin–aquaporin-2 (vasopressin–AQP2) pathway. The lack of responsiveness of the kidney to the vasopressin action impairs its ability to concentrate the urine, resulting in polyuria, polydipsia, and risk of severe dehydration for patients. Conversely, non-osmotic release of vasopressin is associated with an increase in water permeability in the renal collecting duct, producing water retention and increasing the circulatory blood volume. This review highlights some of the new insights and recent advances in therapeutic intervention targeting the dysfunctions in the vasopressin–AQP2 pathway causing diseases characterized by water balance disorders such as congenital nephrogenic diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion, nephrogenic syndrome of inappropriate antidiuresis, and autosomal dominant polycystic kidney disease. The recent clinical data suggest that targeting the vasopressin–AQP2 axis can provide therapeutic benefits in patients with water balance disorders.

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“…These effects were also maintained in patients chronically treated with statins for at least one year [ 167 ]. The preliminary findings showed that statins treatment (atorvastatin and rosuvastatin) was also beneficial in preventing lithium-induced NDI [ 168 ]. A randomized Phase 2 clinical study is ongoing to confirm the results ( ).…”

Section: Possible Therapeutic Strategies To Cure Congenital Ndimentioning

confidence: 99%

Hereditary Nephrogenic Diabetes Insipidus: Pathophysiology and Possible Treatment. An Update

Milano

Carmosino

Gerbino

et al. 2017

IJMS

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Under physiological conditions, excessive loss of water through the urine is prevented by the release of the antidiuretic hormone arginine-vasopressin (AVP) from the posterior pituitary. In the kidney, AVP elicits a number of cellular responses, which converge on increasing the osmotic reabsorption of water in the collecting duct. One of the key events triggered by the binding of AVP to its type-2 receptor (AVPR2) is the exocytosis of the water channel aquaporin 2 (AQP2) at the apical membrane the principal cells of the collecting duct. Mutations of either AVPR2 or AQP2 result in a genetic disease known as nephrogenic diabetes insipidus, which is characterized by the lack of responsiveness of the collecting duct to the antidiuretic action of AVP. The affected subject, being incapable of concentrating the urine, presents marked polyuria and compensatory polydipsia and is constantly at risk of severe dehydration. The molecular bases of the disease are fully uncovered, as well as the genetic or clinical tests for a prompt diagnosis of the disease in newborns. A real cure for nephrogenic diabetes insipidus (NDI) is still missing, and the main symptoms of the disease are handled with s continuous supply of water, a restrictive diet, and nonspecific drugs. Unfortunately, the current therapeutic options are limited and only partially beneficial. Further investigation in vitro or using the available animal models of the disease, combined with clinical trials, will eventually lead to the identification of one or more targeted strategies that will improve or replace the current conventional therapy and grant NDI patients a better quality of life. Here we provide an updated overview of the genetic defects causing NDI, the most recent strategies under investigation for rescuing the activity of mutated AVPR2 or AQP2, or for bypassing defective AVPR2 signaling and restoring AQP2 plasma membrane expression.

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Statins in the prevention of lithium-associated diabetes insipidus: preliminary findings

Cited by 15 publications

References 5 publications

Atorvastatin in the treatment of Lithium-induced nephrogenic diabetes insipidus: the protocol of a randomized controlled trial

Atorvastatin in the treatment of Lithium-induced nephrogenic diabetes insipidus: the protocol of a randomized controlled trial

Vasopressin–aquaporin-2 pathway: recent advances in understanding water balance disorders

Hereditary Nephrogenic Diabetes Insipidus: Pathophysiology and Possible Treatment. An Update

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