Water, Water Everywhere: A New Cause and a New Treatment for Nephrogenic Diabetes Insipidus

Abstract

showed that the SHR-A3 rat has a novel truncating mutation in the gene encoding stromal interaction molecule 1 (STIM1), which is the endoplasmic reticulum Ca 21 sensor that triggers SOCE. Mamenko et al. 2 used whole-genome sequencing to uncover this novel mutation in the STIM1 gene. Mamenko et al. 2 made this discovery using a clever approach: they crossed SHR-A3 rats with a very closely related rat, the SHR-B2. The SHR-B2 rat shares 87% of its genome with the SHR-A3 rat but lacks the STIM1 mutation present in the SHR-A3 rat. Mamenko et al. 2 found a significant relationship between the inheritance of the STIM1 SHR-A3 mutant allele and the production of dilute urine.In addition to finding the mutation, Mamenko et al. 2 performed physiologic studies to show that the STIM1 mutation present in SHR-A3 rats resulted in increased urine volume, polydipsia, hypertonic plasma, and impaired urinary concentrating ability accompanied by elevated vasopressin levels (i.e., NDI). Mamenko et al. 2 used split-open collecting ducts from SHR-A3 rats and found decreased basal intracellular Ca 21 levels and a major defect in SOCE, which results in a failure of vasopressin to induce a sustained intracellular Ca 21 mobilization in SHR-A3 rat collecting ducts. This led to a reduction in AQP2 protein abundance and an increase in the intracellular retention of AQP2, thereby resulting in less AQP2 in the apical plasma membrane where it is needed to reabsorb water in collecting ducts from SHR-A3 rats. Mamenko et al. 2 used cultured cells to show that STIM1 knockdown reduces SOCE and basal intracellular Ca 21 levels and prevents vasopressinmediated translocation of AQP2 to the plasma membrane. Thus, Mamenko et al. 2 identified a novel genetic mutation and a novel physiologic mechanism for NDI through SOCE and STIM1 and elucidated an important role for Ca 21 signaling in the urinary concentrating mechanism. 2 The paper in JASN by de Groot et al. 3 addressed a different aspect of NDI: a new therapeutic approach to lithiuminduced NDI. Lithium is used to treat manic depressive illness (reviewed in ref. 4). Lithium enters cells by substituting for sodium on several transport proteins that normally transport sodium. However, the pathways for transporting lithium out of cells are more limited, resulting in intracellular lithium accumulation. Lithium inhibits adenylyl cyclase in the collecting duct. Vasopressin, through the V 2 R, activates adenylyl cyclase, stimulates cAMP production, and activates protein kinase A, which in turn, phosphorylates both AQP2 and the urea transporter-A1 and increases their apical plasma membrane accumulation (reviewed in ref. 5). Thus, by inhibiting the adenylyl cyclase-cAMP-protein kinase A signal transduction pathway, lithium disrupts the activation of vasopressinsensitive transport proteins in the collecting duct, which results in polyuria and NDI. In addition, chronic lithium therapy decreases both AQP2 and urea transporter-A1 protein abundance, further contributing to NDI. 6,7 Conventional therapy for lithium-ind...

Use of acetazolamide in lithium-induced nephrogenic diabetes insipidus: a case report

“…The acetazolamide-induced reduction in urine output in our patient can be a direct consequence of the severe polyuria. Furthermore, the GFR reduction could explain the small increase in urine osmolality (similar to Gordon’s report ( 17 ) and not verified in Groot’s report ( 18 ) where only mild polyuria was observed). In patients with a chronic Li-NDI, sudden water deprivation (such as deprivation after surgery) might result in significant clinical deterioration; the use of acetazolamide might be useful in reducing polyuria through a GFR reduction.…”

“…Based on the previous experience by Gordon et al . ( 17 ) and having in mind the data from Groot et al . ( 16 ), we decided to start acetazolamide.…”

“…This led to a rapid decrease in urine output and correction of natremia. Acetazolamide reduces the glomerular filtration rate by means of tubulo-glomerular feedback and reduces renal prostaglandin secretion contributing to attenuate polyuria ( 17 ). There was a consistent relationship between use of acetazolamide and polyuria stabilization with negative and positive controls as seen in Fig.…”

“…Following treatment with acetazolamide, daily urine output decreased, urinary osmolality increased and of serum sodium levels normalized. No major adverse effects were observed ( 17 ). Groot and coworkers recently published a series of mice and 6 human patients with Li-NDI.…”

Acetazolamide in Lithium-Induced Nephrogenic Diabetes Insipidus

“…Our experience documents the successful use of acetazolamide in a patient with lithium-induced nephrogenic diabetes insipidus and supports findings seen in animal models. 4 Craig E. Gordon, M.D. Swapna Vantzelfde, M.D.…”