Lithium salts, particularly lithium carbonate, are frequently used to treat bipolar disorder and mania. Lithium poisoning, which can occur as a result of reduced renal elimination, prescribing error, drug-drug interactions, or deliberate overdosage, produces neurologic injury that can be permanent. Hemodialysis is often recommended to treat lithium poisoning. This presentation describes what nephrologist needs to know about lithium intoxication treatment.

1. What a Nephrologist needs to know
about Lithium Intoxication
Dr. Aris Tsalouchos
Azienda Usl Toscana centro
S.O.S Nefrologia Pescia

2. Lithium Pharmacology/Pharmacokinetics

3. Lithium Handling in the Kidney
Lithium is not metabolized and is eliminated by:
 urine: almost all (90–98%)
other : minimal elimination in sweat and feces
GFR: all lithium is filtered
80% is absorbed in proximal convoluted tubules similar to sodium.
20% is cleared (20–40 mL/min or 1/5 GFR).
Reabsorption in the distal parts of the nephron by the epithelium
sodium channel (ENaC) IS BLOCKED BY AMILORIDE

4. J Intensive Care Med. 2017 May;32(4):249-263.
Multicompartmental kinetics of lithium and
the effect of duration of therapy

6. Overview of Lithium Poisoning
 The therapeutic steady-state [Li+] is 0.6–1.2 mEq/L
 Mild toxicity: 1.5–2.5 mEq/L
 Moderate toxicity: 2.5–3.5 mEq/L
 Severe toxicity: > 3.5 mEq/L
What About Lithium Levels? Standard teaching about serum lithium
blood levels is this:
However………….

7. Overview of Lithium Poisoning
 Lithium plasma concentrations greater than 1.2 mmol/L are potentially
toxic and concentrations greater than 2.0 mmol/L can be fatal.
Toxicity has been observed with levels as low as 1 mmol/L.
Clinicians should maintain a high level of suspicion and a low threshold to treat patients
with suspected lithium toxicity and signs of lithium intoxication, noting that serum lithium
levels do not accurately predict toxicity and should not dictate treatment.

8. Medical considerations when administering lithium

9. Three clinically recognized patterns of lithium poisoning:
Overview of Lithium Poisoning
I. ACUTE POISONING: Patients usually do not have a tissue body
burden.
SIGNS AND SYMPTOMS
 Predominantly gastrointestinal (GI): nausea, vomiting, cramping, and
sometimes diarrhea.
 Progression of acute toxicity can involve Neuromuscular signs such
as: tremulousness, dystonia, hyperreflexia, and ataxia.
 Cardiac dysrhythmias have been reported but rarely occur. The most
common electrocardiographic finding is T-wave flattening.
Medscape.Updated: Aug 21, 2018

12. Overview of Lithium Poisoning
Three clinically recognized patterns of lithium poisoning:
II. ACUTE-ON-CHRONIC POISONING: These patients take lithium
regularly and have taken a larger dose recently
SIGNS AND SYMPTOMS
 Both GI and neurologic symptoms + ECG findings
Serum levels can be difficult to interpret. Patients should be
treated according to their clinical manifestations
Medscape.Updated: Aug 21, 2018

13. Overview of Lithium Poisoning
Three clinically recognized patterns of lithium poisoning:
III. CHRONIC: These patients typically have a large body burden of
lithium and may be difficult to treat.
Chronic lithium toxicity is usually precipitated by introduction
of a new medication that may impair renal function/excretion or
cause a hypovolemic state
SIGNS AND SYMPTOMS
 Primarily neurologic. Mental status is often altered and can progress
to coma and seizures. Many severely poisoned patients can develop a
syndrome of irreversible lithium-effectuated neurotoxicity (SILENT)
such as cognitive impairment, sensorimotor peripheral neuropathy, and
cerebellar dysfunction. Medscape.Updated: Aug 21, 2018

14. SYSTEMIC EFFECTS…
Renal toxicity is common with chronic lithium therapy, and may
take any of the following forms:
 Nephrogenic diabetes insipidus (NDI): The most common
presentation of lithium-induced nephrotoxicity occurs in up to 40%
of patients
 Distal Renal tubular acidosis (RTA)
 Chronic tubulointerstitial nephritis
 Nephrotic syndrome (Minimal Change Disease).
Medscape.Updated: Aug 21, 2018

15.  The most common endocrine disorder secondary to chronic toxicity
is hypothyroidism. Lithium is taken up avidly by thyroid cells and blocks
thyroid hormone release from thyroglobulin, which inhibits adenylate
cyclase and prevents thyroid-stimulating hormone (TSH) from
activating thyroid cells via the TSH receptor. It may also affect thyroid
hormone synthesis. Myxedema coma has been reported as a
complication of toxicity.
 Acute exposure to lithium can cause leukocytosis, whereas chronic
exposure can produce aplastic anemia.
 Patients who are on long-term lithium therapy can develop localized
edema, dermatitis, and skin ulcers.
SYSTEMIC EFFECTS…
Medscape.Updated: Aug 21, 2018

16. J Am Soc Nephrol 10: 666–674, 1999

17. J Am Soc Nephrol 10: 666–674, 1999

18. Treatment of lithium intoxication
General recommendations…….

19. Treatment of lithium intoxication
Indication for extracorporeal methods……….

22. Lithium Rebound
Lithium rebound is defined as an increase in [Li+] observed
after ECTR cessation. This phenomenon may be caused by:
 Redistribution of lithium from deeper compartments/red blood
cells to the plasma
Ongoing absorption from the gastrointestinal tract
 The rise in [Li+] is maximal after 6–12 hours (reaching 0.5–1.0
mEq/L) and not associated with recurrent symptoms as lithium moves
away from the toxic compartment.
In every reported patient with lithium rebound associated with
clinical deterioration, the rise was attributed to ongoing absorption of
extended-release formulations

23. LITHIUM –ASSOCIATED DIABETES INSIPIDUS
Pathophysiology
The lack of response to ADH is due to the inhibition of adenylate cyclase and resultant
decreased formation of cyclic cAMP
Therapy (2005) 2(4), 669–675

24.  Even when the drug can be discontinued, lithium-induced DI may
take several weeks to correct and may not ever completely resolve
 Over 25% of patients who develop polyuria while taking lithium
will have a diminished ability to concentrate their urine 1 year after
stopping lithium
LITHIUM –ASSOCIATED DIABETES INSIPIDUS

25. LITHIUM –ASSOCIATED DIABETES INSIPIDUS
Diagnosis
Therapy (2005) 2(4), 669–675

26. LITHIUM –ASSOCIATED DIABETES INSIPIDUS
Diagnosis
Water deprivation test

27. Water deprivation test………….
 Contraindications: Hypovolaemia or hypernatraemia
 N.B: Stop the test if the patient's weight decreases by more than 3%
of body weight (or by 4kg) or the serum osmolality rises >300mOsm/kg.
 Interpretation :
 Urine osmolality > 600mOsm/kg excludes diabetes insipidus. The
test can then be stopped if this is achieved.
 Urine osmolality < 400mOsm/kg and raised serum osmolality
indicates an inability to concentrate urine and in the absence of renal
tubular disease this indicates diabetes insipidus.
If urine osmolality at 4 pm < 600mOsm/kg, give 20 μg of
desmopressin (DDAVP) intranasally

29. Therapy (2005) 2(4), 669–675

30. LITHIUM –ASSOCIATED DIABETES INSIPIDUS
Treatment