Chronic lithium ingestion in patients with bipolar (manic-depressive) illness has been associated with several different forms of renal injury. Nephrogenic diabetes insipidus (NDI) is the most common renal side effect of lithium therapy [1,2].
The predominant form of chronic renal disease associated with lithium therapy is a chronic tubulointerstitial nephropathy . Although the majority of studies show infrequent and relatively mild renal insufficiency attributable to lithium therapy, end-stage renal disease (ESRD) secondary to lithium-associated chronic tubulointerstitial nephropathy does occur in a small percentage of patients [2,4-7]. Relatively less is known about potential glomerular toxicity of lithium, particularly the nephrotic syndrome. Additional kidney manifestations of lithium exposure include renal tubular acidosis and hypercalcemia. (See "Lithium poisoning".)
NEPHROGENIC DIABETES INSIPIDUS
Normally, water permeability of principal cells in the collecting tubule is regulated by antidiuretic hormone (ADH). Aquaporin-2 water channels (AQP2), which normally reside in the endosomes of principal cells, move to and fuse with the luminal membrane under the influence of ADH, thereby allowing water to be reabsorbed down the favorable concentration gradient. (See "Chapter 6B: Antidiuretic hormone and water balance", section on 'Actions'.)
Chronic lithium ingestion can lead to resistance to ADH, resulting in polyuria and polydipsia in up to 20 to 40 percent of patients [3,8]. Lithium enters the principal cells of the collecting duct through epithelial sodium channels in the luminal membrane [8,9]. It then accumulates in these cells and interferes with the ability of ADH to increase water permeability. Several possible mechanisms may be involved [1,8,10-13]:
Lithium may increase expression of cyclooxegenase-2 and therefore increase urinary prostaglandin E2 excretion by medullary interstitial cells . These prostaglandins then act on principal cells to induce lysosomal degradation of AQP2 water channels and a decline in urine concentrating ability.