Pathophysiology of Drug-Induced Hyponatremia

Abstract

Drug-induced hyponatremia caused by renal water retention is mainly due to syndrome of inappropriate antidiuresis (SIAD). SIAD can be grouped into syndrome of inappropriate antidiuretic hormone secretion (SIADH) and nephrogenic syndrome of inappropriate antidiuresis (NSIAD). The former is characterized by uncontrolled hypersecretion of arginine vasopressin (AVP), and the latter is produced by intrarenal activation for water reabsorption and characterized by suppressed plasma AVP levels. Desmopressin is useful for the treatment of diabetes insipidus because of its selective binding to vasopressin V2 receptor (V2R), but it can induce hyponatremia when prescribed for nocturnal polyuria in older patients. Oxytocin also acts as a V2R agonist and can produce hyponatremia when used to induce labor or abortion. In current clinical practice, psychotropic agents, anticancer chemotherapeutic agents, and thiazide diuretics are the major causes of drug-induced hyponatremia. Among these, vincristine and ifosfamide were associated with sustained plasma AVP levels and are thought to cause SIADH. However, others including antipsychotics, antidepressants, anticonvulsants, cyclophosphamide, and thiazide diuretics may induce hyponatremia by intrarenal mechanisms for aquaporin-2 (AQP2) upregulation, compatible with NSIAD. In these cases, plasma AVP levels are suppressed by negative feedback. In rat inner medullary collecting duct cells, haloperidol, sertraline, carbamazepine, and cyclophosphamide upregulated V2R mRNA and increased cAMP production in the absence of vasopressin. The resultant AQP2 upregulation was blocked by a V2R antagonist tolvaptan or protein kinase A (PKA) inhibitors, suggestive of the activation of V2R-cAMP-PKA signaling. Hydrochlorothiazide can also upregulate AQP2 in the collecting duct without vasopressin, either directly or via the prostaglandin E2 pathway. In brief, nephrogenic antidiuresis, or NSIAD, is the major mechanism for drug-induced hyponatremia. The associations between pharmacogenetic variants and drug-induced hyponatremia is an area of ongoing research.

Keywords: aquaporin-2; kidney; nephrogenic antidiuresis; vasopressin V2 receptor; water.

Figure 1

In vitro action of 4-hydroperoxycyclophosphamide (4-HC) for aquaporin-2 (AQP2) upregulation in inner medullary collecting duct (IMCD) cells. The effect of 4-HC, the active hepatic metabolite of cyclophosphamide, was tested in IMCD suspensions and primary cultured IMCD cells. (A) Intracellular cAMP levels were measured by ELISA in IMCD suspensions after treatment with vehicle, 10 nM dDAVP, 10 µM 4-HC, and 10 µM 4-HC + 100 nM tolvaptan at 37 °C for 30 min. (B) Immunoblot analysis of AQP2 was performed from primary cultured IMCD cells treated with 4-HC with and without tolvaptan. (C) Immunofluorescence microscopy for AQP2 in primary cultured IMCD cells shows that AQP2 targeting was induced to the plasma membrane (apical and lateral membrane) by 4-HC treatment (X-Z images). (D) Quantitative polymerase chain reaction data show that AQP2 and vasopressin-2 receptor (V2R) mRNA expression were increased by 4-HC treatment. Each bar represents mean ± SD. * p < 0.05 vs. control by the Mann–Whitney U-test. Adapted from Ref. [32] with permission.

Figure 2

In vitro action of haloperidolforaquaporin-2 (AQP2) upregulation in inner medullary collecting duct (IMCD) cells. (A) cAMP production was measured by ELISA in IMCD suspensions after treatment with vehicle (control), 100 nM tolvaptan (TV), 10 nM 1-desamino-8-D-arginine vasopressin (dDAVP), and 5 μM haloperidol (HP) at 37 °C for 30 min. (B) Immunoblot analyses of total AQP2, pSer256-AQP2, and pSer261-AQP2 in primary cultured IMCD cells treated with 5 μM HP with and without 100 nM TV for 30 min. (C) Immunoblot analyses of total AQP2, pSer256-AQP2, and pSer261-AQP2 in primary cultured IMCD cells treated with 5 μM HP with and without a PKA inhibitor H89 or Rp-cAMPS. (D) Immunoblot analyses of total AQP2, total CREB, and pCREB-1 in primary cultured IMCD cells treated with 10 nM dDAVP and 5 μM haloperidol (HP) with and without 100 nM TV. (E) Immunofluorescence microscopy for AQP2 in primary cultured IMCD cells shows that AQP2 trafficking was induced by dDAVP and haloperidol (HP) but attenuated by coadministration of TV or a PKA inhibitor. (F) Quantitative polymerase chain reaction data show that AQP2 and vasopressin-2 receptor (V2R) mRNA expression were increased by dDAVP and HP but reversed by TV cotreatment. Each bar represents mean ± SD. * p < 0.05 vs. control; ^# p < 0.05 vs. HP alone by the Mann–Whitney U-test. Adapted from Ref. [38] with permission.

Figure 3

In vitro action of sertraline foraquaporin-2 (AQP2) upregulation in inner medullary collecting duct (IMCD) cells. (A) cAMP production was measured by ELISA in IMCD suspensions after treatment with vehicle (control), 100 nM tolvaptan (TV), 10 nM 1-desamino-8-D-arginine vasopressin (dDAVP), and 1 μM sertraline (ST) at 37 °C for 30 min. (B) Immunoblot analyses of total AQP2, pSer256-AQP2, and pSer261-AQP2 were performed from primary cultured IMCD cells treated with 1 μM ST with and without 100 nM tolvaptan (TV) for 30 min. (C) Immunoblot analyses of total AQP2, pSer256-AQP2, and pSer261-AQP2 were performed from primary cultured IMCD cells treated with 1 μM ST with and without a PKA inhibitor H89 or Rp-cAMPS. (D) Immunoblot analyses of total AQP2, total CREB, and pCREB-1 in primary cultured IMCD cells treated with 10 nM dDAVP and 1 μM ST with and without 100 nM tolvaptan (TV). (E) Immunofluorescence microscopy for AQP2 in primary cultured IMCD cells shows that AQP2 trafficking was induced by dDAVP and ST but attenuated by coadministration of tolvaptan (TV) or a PKA inhibitor. (F) Quantitative polymerase chain reaction data show that AQP2 and vasopressin-2 receptor (V2R) mRNA expression were increased by dDAVP and sertraline (ST) but reversed by tolvaptan (TV) cotreatment. Each bar represents mean ± SD. * p < 0.05 vs. control; ^# p < 0.05 vs. ST alone by the Mann–Whitney U-test. Adapted from Ref. [38] with permission.

Figure 4

In vitro action of carbamazepine foraquaporin-2 (AQP2) upregulation in inner medullary collecting duct (IMCD) cells. (A) cAMP production was measured by ELISA in IMCD suspensions after treatment with vehicle (control), 100 nM tolvaptan (TV), 10 nM 1-desamino-8-D-arginine vasopressin (dDAVP), or 100 μM carbamazepine (CBZ) at 37 °C for 30 min. (B) Immunoblot analyses of total AQP2, pSer256-AQP2, and pSer261-AQP2 in primary cultured IMCD cells treated with 100 μM CBZ with and without 100 nM tolvaptan (TV) for 30 min. (C) Immunoblot analyses of total AQP2, pSer256-AQP2, and pSer261-AQP2 in primary cultured IMCD cells treated with 100 μM CBZ with and without a PKA inhibitor H89 or Rp-cAMPS. (D) Immunoblot analyses of total AQP2, total CREB, and pCREB-1 in primary cultured IMCD cells treated with 10 nM dDAVP and 100 μM CBZ with and without 100 nM TV. (E) Immunofluorescence microscopy for AQP2 in primary cultured IMCD cells shows that AQP2 trafficking was induced by dDAVP and CBZ but attenuated by coadministration of TV or a PKA inhibitor. (F) Quantitative polymerase chain reaction data show that AQP2 and vasopressin-2 receptor (V2R) mRNA expression were increased by dDAVP and CBZ but reversed by TV cotreatment. Each bar represents mean ± SD. * p < 0.05 vs. control; ^# p < 0.05 vs. CBZ alone by the Mann–Whitney U-test. Adapted from Ref. [38] with permission.

Figure 5

Different levels of action for drug-induced hyponatremia. Drugs that induce SIADH include vincristine and ifosfamide, and representative drugs for NSIAD are haloperidol, sertraline, carbamazepine, and cyclophosphamide. AQP2, aquaporin-2; cAMP, cyclic adenosine monophosphate; NSIAD, nephrogenic syndrome of inappropriate antidiuresis; PG, prostaglandin; PKA, protein kinase A; SIADH, syndrome of inappropriate antidiuretic hormone secretion.