Mechanism of Lithium-Induced Polyuria in the Rat
| Title: | Mechanism of Lithium-Induced Polyuria in the Rat |
|---|---|
| Authors: | Carney, Shane L.; Ray, Cheryl; Gillies, Alastair H.B. |
| Publisher: | Kidney International |
| Date Published: | August 01, 1996 |
| Reference Number: | 17 |
While many studies have demonstrated a nephrogenic diabetes insipidus syndrome (NDI) with prolonged lithium (Li) treatment, experiments in the isolated rat papillary collecting duct have suggested that the defect may be due to a circulating factor that inhibits the action of arginine vasopressin (AVP). Since Li-treatment can produce a form of hyperparathyroidism and parathyroid hormone (PTH) can act as a partial agonist to AVP, in vivo and in vitro studies were performed on rats made polyuric by daily intraperitoneal (i.p.) Li (4 mmol/kg) treatment. Li-treatment for three weeks produced an increase in PTH (194 +/- 20 compared with 118 +/- 18 pg/ml in control rats; P < 0.01) as well as an increase in the plasma calcium concentration (2.38 +/- 0.05 compared with 2.25 +/- 0.04 mmol/liter; P < 0.05). Clearance studies were performed on water loaded Li-treated and control rats, and the defect in urine concentration was only observed with a low physiological concentration of AVP (10 mU/kg body wt over 5 min). Maximal urine osmolality was 328 +/- 31 compared with 613 +/- 81 mOsm/kg (P < 0.05) in controls. There was no detectable difference with a prolonged maximal physiological AVP concentration (10 mU bolus and 50 mU/kg body wt per hr) and papillary solute concentrations were unchanged. When Li-treated rats had been parathyroidectomized (PTX), a significant difference in urine concentration with the low AVP concentration could not be demonstrated when compared to non-PTX control rats. In the isolated papillary collecting duct preparation a medium was used that contained fresh plasma from Li-treated or control rats, both intact and PTX. Experiments using plasma from Li-treated intact rats produced only a 25.4 +/- 5.1% increase in diffusional water permeability with the addition of AVP (200 microU/ml) compared to 52.6 +/- 9.0% in control rats (P < 0.01). However, when plasma from Li-treated PTX rats was used, the AVP induced increase in water permeability (54.7 +/- 11.2%) was not significantly different from that observed in PTX control rats. These studies show that the NDI-like defect in Li-treatment is small and easily overcome by higher concentrations of AVP and suggest that the concentration defect is at least in part due to increased circulating levels of PTH acting as a partial agonist to AVP and thereby inhibiting its hydroosmotic action.
This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
It has been shown that the nephrogenic diabetes insipidus (NDI)-like syndrome induced by prolonged lithium use occurs because the collecting duct cells in the kidney do not respond to arginine vasopressin (AVP). (AVP tells the kidneys to channel water into the blood stream rather than passing it into the urine.) A series of experiments with rats, however, challenges this hypothesis. In several studies lithium neither decreased water permeability in cells nor inhibited the water reabsorption action of AVP. Clearly there are significant contradictions in available experimental data. The authors' studies were aimed at resolving these contradictions.
There is a possibility that lithium treatment produces a circulating factor that inhibits the response of the collecting duct to AVP or inhibits the release of a facilitatory factor to AVP. In addition, it has been shown that lithium treatment produces a form of primary hyperparathyroidism. (In hyperparathyroidism, the parathyroid gland produces too much parathyroid hormone (PTH). PTH regulates the amount of calcium in the blood. Too much of the hormone raises the blood's calcium level; this can lead to osteoporosis and other disorders.) This knowledge of lithium treatment combined with evidence that PTH can partially inhibit the action of AVP suggests that PTH could be a cause of the NDI syndrome. Therefore, the authors studied how high and low AVP levels affected urine concentration in chronic lithium-treated animals and compared that to non-chronic lithium-treated control animals, both groups with and without their parathyroid glands.
Results
- Lithium treated rats had a significantly elevated PTH concentration when compared to non-treated animals.
- High levels of AVP produced a prompt and significant increase in urine osmolality in both the control and lithium-treated rats. But the inhibitory effect of lithium was again observed with the administration of a low concentration of AVP.
- The removal of the parathyroid glands abolished the inhibitory effect of lithium; AVP was again able to do its job.
Discussion
Lithium treatment seems to produce a modest form of NDI. This defect is partially due to a state of hyperparathyroidism, itself produced by lithium, whereby excessive circulating levels of PTH inhibit the action of low levels of AVP infused over a short time period. This inhibitory effect is overcome by higher doses of AVP. There is good evidence that lithium increases water intake in rats with hereditary diabetes insipidus. This could be the main cause of observed polyuria. Excessive water drinking combined with mild hyperparathyroidism could be the major basis for the NDI defect induced by lithium treatment in rats and probably humans.