Lithium and the Kidney

The reported incidence of polyuria varies between 4% in the United Kingdom and 50% in some Scandinavian countries (187). This may reflect local variations in the advice given to patients concerning fluid intake when receiving lithium therapy. Polyuria may, of course, be secondary to polydipsia and may not be related to any renal damage at all. Thirst has been reported as a common complaint in lithium-treated patients, affecting approximately 70% of patients in one recent study 

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Gitlin M. Lithium and the kidney an updated review. Drug Sal 1999 20 231-243. 

Batlle D, Dorhout-Mees EJ. Lithium and the kidney. In De Broe ME, Porter GA, Bennett WM, Verpooten GA, editors. Clinical Nephrotoxins Renal Injury from Drugs and Chemicals. Dordrecht, The Netherlands, Boston Kluwer Academic Publishers, 1998 383-95. 

Lithium reduces the kidney s ability to concentrate urine and may cause a nephrogenic diabetes insipidus with low urine specific gravity and low osmolality polyuria (urine volume greater than 3 L/day). This may be treated with loop diuretics, thiazide diuretics, or triamterene. If a thiazide diuretic is used, lithium doses should be decreased by 50% and lithium and potassium levels monitored. 

Sheehan M, de Belleroche J Facilitation of GABA release by cholecystokinin and caerulein in rat cerebral cortex. Neuropeptides 3 429-434, 1983 Sherman AD, Petty F Additivity of neurochemical changes in learned helplessness and imipramine. Behav Neural Biol 35 344-353, 1982 Sherman WR Lithium and the phosphoinositide signaling system, in Lithium and the Cell. Edited by Birch NJ. London, Academic Press, 1991, pp 121-157 Sherman WR, Munsell LY, Gish BG, et al Effects of systemically administered lithium on phosphoinositide metabolism in rat brain, kidney, and testis. J Neurochem 44 798-807, 1985... 

Lithium NSAIDs delay the excretion of lithium by the kidney and may cause lithium toxicity. 

Grof P, MacCrimmon DJ, Smith EKM, Daigle L, Saxena B, Varma R, Grof E, Keitner G, Kenny J. Long-term lithium treatment and the kidney. Can J Psychiatry 1980 25 535-544. 

The benign effects of lithium on the kidney will be experienced by the majority of patients as increased thirst (polydipsia) and increased urination (polyuria). To ensure adequate lithium excretion, patients must be advised to maintain fluid intake, even in the presence of polyuria. 

Not fully understood. It eould be that, as with the ACE inhibitors, angiotensin n reeeptor antagonists inhibit aldosterone secretion, resulting in increased sodium loss by the kidney tubules. This causes lithium retention and thus an increase in lithium levels. However, angiotensin II receptor antagonists have less effect on aldosterone than the ACE inhibitors, making a clinically significant interaction less likely. Animal studies show that ramipril, but not losartan, decreases the excretion of lithium by the kidney, which would support this idea. 

In nephrogenic diabetes insipidus the kidney s ability to respond to AVP is impaired by different causes, such as drugs (e.g. lithium), chronic disorders (e.g. sickle cell disease, kidney failure) or inherited genetic disorders (X-linked or autosomal NDI). This type of diabetes insipidus can not be treated by exogenous administration of AVP or AVP analogues. Instead, diuretics (hydrochlorothiazide combined or not with amiloride) and NSAI (indomethacin) are administrated to ameliorate polyuria. 

The answer is c. (Katzung, p 493.) Lithium treatment frequently causes polyuria and polydipsia. The collecting tubule of the kidney loses the capacity to conserve water via anti diuretic hormone. This results in significant free-water clearance, which is referred to as nephrogenic diabetes insipidus. 

Many of the adverse effects of lithium can be ascribed to the action of lithium on adenylate cyclase, the key enz)nne that links many hormones and neurotransmitters with their intracellular actions. Thus antidiuretic hormone and thyroid-stimulating-hormone-sensitive adenylate cyclases are inhibited by therapeutic concentrations of the drug, which frequently leads to enhanced diuresis, h)rpoth)n oidism and even goitre. Aldosterone synthesis is increased following chronic lithium treatment and is probably a secondary consequence of the enhanced diuresis caused by the inhibition of antidiuretic-hormone-sensitive adenylate cyclase in the kidney. There is also evidence that chronic lithium treatment causes an increase in serum parathyroid hormone levels and, with this, a rise in calcium and magnesium concentrations. A decrease in plasma phosphate and in bone mineralization can also be attributed to the effects of the drug on parathyroid activity. Whether these changes are of any clinical consequence is unclear. 

Menaker There is a similar effect in rodents. You can get effects on mice and rats with lithium in the drinking water, but you cannot get effects in hamsters. The reason for this is that because hamsters are desert animals they have an incredibly powerful kidney, and they simply don t allow the hthium concentration in the blood to rise to a level where it will do anything. 

A related issue is the patient s ability to metabolize and eliminate drugs adequately. For example, lithium is excreted entirely by the kidneys, and if a patient suffers from significantly impaired renal function, high, potentially toxic levels could develop on standard doses. Although the dose could be adjusted to compensate for the decrease in drug clearance, it might be more appropriate to choose another mood stabilizer such as valproate or carbamazepine, because they are primarily metabolized through the liver. 

Certain antibiotics (e.g., oral tetracyclines) may diminish lithium s clearance through the kidneys, leading to increases in plasma levels and possible intoxication (344, 345) (Table 10-20). 

Lithium is rapidly absorbed, reaching peak serum concentrations in 2-3 hours. It is not protein-bound and is excreted unchanged by the kidney at a rate proportional to the glomerular filtration rate. It is best given as a single daily dose around 22.00 hours and steady state serum levels are reached after 5-7 days of dosing, with the elimination half-life being around 10-24 hours for most people. Most proprietary formulations of lithium in current use are in the form of a slow-release preparation. There can be variations in kinetics between different proprietary brands and it is therefore best for individual patients to remain on the same brand. 

Lithium is often used in the treatment of mania in the aged. Because it is cleared by the kidneys, dosages must be adjusted appropriately and blood levels monitored. Concurrent use of thiazide diuretics reduces the clearance of lithium and should be accompanied by further reduction in dosage and more frequent measurement of lithium blood levels. 

Because lithium is not bound to any plasma or tissue proteins, it is widely distributed throughout the body. Lithium ions are eliminated mainly by the kidneys. There is a direct relationship between the amount of sodium chloride ingested and the fraction of filtered lithium resorbed, in that, the lower the sodium intake, the greater is the lithium retention. The contraindications are significant cardiovascular or renal diseases that would compromise its excretion. 

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