Laboratory Studies
A chemistry panel may help identify electrolyte abnormalities that may be causing the patient's concentrating defect and natriuresis (ie, hypernatremia, hypokalemia, hypercalcemia, elevated BUN and creatinine). Uncontrolled diabetes mellitus may cause similar findings from osmotic diuresis; however, in that disorder, the serum glucose level will be elevated.
Urine and serum osmolality may help determine if the patient has a concentrating defect. Urine osmolality will be less than 100 mOsm/kg despite normal or higher-than-normal serum osmolality.
The prevalence of decreased urine osmolality was similar in adult and geriatric lithium users in a cross-sectional study of 100 patients (12.5% in geriatric patients and 17.9% in adult patients), but affected geriatric patients were significantly less likely to report urinary and thirst symptoms. Urine specific gravity less than 1.010 was correlated with urine osmolality of less than 300 mOsm/kg. Age, duration of lithium treatment, and serum lithium level were each independently associated with urine osmolality level. [27]
High urine output accompanied by elevated blood urea nitrogen (BUN) and serum creatinine levels [28] can be due to volume depletion with any polyuric syndrome, such as nephrogenic diabetes insipidus, central diabetes insipidus, or osmotic diuresis; the polyuric phase of acute renal failure; or chronic renal failure.
Assess the patient's lithium level: Check the plasma vasopressin level to rule out central diabetes insipidus.
Perform full toxicology screen to exclude the possibility of multiple toxin ingestion, particularly in the case of suicide attempts.
Imaging Studies
A magnetic resonance imaging (MRI) study of the sella can be ordered for patients who have abnormal hormonal findings (ie, elevated prolactin level) and if multiple endocrine disorders or masses that may be causing central diabetes insipidus are suggested.
MRI examination of the kidneys, while not necessary for diagnosis, has demonstrated the presence of renal cysts in many patients. These are described as microcysts and can be quite numerous. [29, 30]
Renal ultrasound can be used to assess for suggested obstructive causes.
Other Tests
Other tests that can be used in the diagnosis of lithium toxicity include the following:
-
Water deprivation test
-
Vasopressin challenge [31]
-
Electrocardiogram: Look for evidence of cardiac conduction abnormalities, such as T wave flattening
-
Thyroid function studies
Water deprivation test
This test documents whether the patient has a concentrating defect. First, baseline measurements of urine and serum osmolality and electrolytes are obtained. Strict water deprivation is then imposed for 4-18 hours (usually 8 h).
Urine output and weight are carefully monitored before and after fluid deprivation. Serum and urine osmolality and electrolyte levels are measured hourly after initiation of fluid deprivation. A patient without a concentrating defect should have a 2- to 4-fold increase in urine osmolality.
Vasopressin challenge
This test differentiates central and nephrogenic diabetes insipidus. Following the water deprivation test, 5 U of vasopressin is administered subcutaneously (ie, vasopressin as 5 U of aqueous arginine vasopressin or 1 mcg of desmopressin SC or 10 mcg of desmopressin by nasal spray). Serum and urine osmolality are measured 1-2 hours later.
Patients with complete central diabetes insipidus fail to increase their urine osmolality after water deprivation (ie, concentrating defect), but they have more than a 50% increase in urine osmolality from baseline after vasopressin administration. Patients with nephrogenic diabetes insipidus also fail to show an increase in urine osmolality after deprivation (ie, concentrating defect) but have less than a 10% increase in urine osmolality from baseline after vasopressin administration. Reports have described patients with combined central and nephrogenic defects who show a 10-50% increase in urine osmolality.
Histologic Findings
In reports of small groups of patients, lithium use has been associated with many nonspecific renal lesions.
The histology of acute renal lesions associated with lithium intoxication tends to involve the distal nephron and includes acute tubular necrosis with nonspecific changes such as distal tubular flattening, proximal tubular necrosis, and cytoplasmic vacuolation and cellular and nuclear polymorphism of the distal tubular epithelial cells. In 1978, Kincaid-Smith described a more specific acute lesion consisting of glycogen deposition in the swollen and vacuolated cytoplasm of the distal tubular epithelial cells. These lesions can reverse when lithium administration is stopped.
The development of chronic renal lesions with prolonged lithium use is controversial. Earlier studies have cited interstitial fibrosis, tubular atrophy, and glomerulosclerosis among the chronic changes attributed to lithium. Furthermore, studies suggested that these lesions correlated clinically with the duration of lithium use and concomitant neuroleptic treatments. The data, however, had several limiting factors. The biopsy samples were obtained from a subgroup that had a history of acute lithium toxicity, and many of the histological changes were also identified in the control group. Other more specific chronic lesions include distal tubular dilation and microcyst formation. No evidence indicates that chronic glomerular lesions persist after discontinuing lithium.
Animal studies that used toxic doses of lithium demonstrated epithelial degeneration and dilatation of the distal part of the nephron in dogs, and rats had degenerative changes in the proximal tubules. Rats exposed to levels corresponding to the therapeutic range in humans had ultrastructural lesions, including mitochondrial changes with bulging cytoplasm in tubular cells, liquefaction, karyolysis, and karyorrhexis of the distal tubule and collecting duct.
