Evaluation of urinary concentrating defects in lithium treated patients with a dDAVP test

Lithium is a common therapeutic agent used to treat patients with various mood
disorders. In Western countries about 0.1% of humans are being treated with
lithium. However, its use has been associated with several forms of renal
injury. The most common presentation of lithium-induced nephrotoxicity is
nephrogenic diabetes insipidus (NDI), characterized by resistance to
vasopressin, polyuria, and polydipsia. Slightly impaired renal concentrating
ability is found in about 50% of patients. Initially, the decreased urinary
concentrating ability is largely reversible after cessation of lithium.
However, continued treatment ultimately results in polyuria due to nephrogenic
diabetes insipidus (NDI) in about 20% of patients. Nephrogenic diabetes
insipidus induced by lithium may even persist despite the cessation of
treatment, indicating irreversible renal damage. This functional lesion is
associated with chronic focal interstitial fibrosis predominantly in the
medullary region of the kidney which may be progressive, leading to end-stage
renal failure.

Lithium-induced nephrogenic diabetes insipidus results from accumulation of
lithium in the collecting tubular cells after entry into these cells through
the epithelial sodium channels (ENaC) in the luminal membrane. Lithium blocks
vasopressin-induced reabsorption by inhibiting adenylate cyclase activity, and
hence cyclic adenosine monophosphate production, and also by decreasing the
apical membrane expression of aquaporin 2, the collecting tubule water channel.

Besides polyuria due to nephrogenic diabetes insipidus, however, both central
diabetes insipidus (CDI) and primary polydipsia have also been described in
patients treated with lithium. Therefore, a dDAVP test should be performed to
establish the correct diagnosis.

Lithium induced defects in urinary concentration can frequently be ameliorated
by treatment with diuretics (thiazide, amiloride). In addition, early treatment
with amiloride is thought to prevent the development of renal insufficiency.
However, most patients with lithium induced nephrogenic diabetes insidipus only
present with complaints in an advanced stage of the disease. The exact
prevalence of urinary concentration defects in lithium treated patients is
unknown. Early recognition of an impaired urinary concentration may be helpful
in selecting lithium treated patients at risk of severe nephrogenic diabetes
insipidus and allow increased surveillance and an earlier start of treatment.
In the current study we aim to explore the prevalence of urinary concentration
defects and nephrogenic diabetes insipidus in a Dutch population of lithium
treated patients.

Primary Objective: to explore the prevalence of urinary concentration defects
(NDI) in a Dutch population of lithium treated patients.

Secondary Objectives: to determine the relation of the dDAVP test results with
complaints (micturition history) and clinical parameters (duration of lithium
therapy, plasma lithium concentration, baseline plasma creatinine, sodium and
potassium concentration and baseline urinary osmolality) of lithium treated
patients.

This is a cross-sectional study with an estimated duration of one year.

Patients will be recruited from the populations of the participating hospitals.
Patients willing to participate will be fully informed about the nature of the
study. After having obtained written informed consent, an initial screening
will be performed in order to assess the eligibility of these patients.

This screening includes evaluation of the exclusion criteria:
general contra-indications for participation in a trial:
o inability to give informed consent
o pregnancy
o unstable psychiatric condition

alternative causes of (nephrogenic) diabetes insipidus:
o hypo/hyperkalemia (plasma potassium < 3.0 or > 5.5 mmol/l)
o severe hypercalcemia (albumin-corrected plasma calcium > 2.80 mmol/l)
o hyperglycemia (plasma glucose > 10.0 mmol/l)
o history of amyloidosis, Sjögren*s syndrome or Sickle cell anemia
o previous treatment with ifosfamide
o established primary polydipsia or central diabetes insipidus

contra-indications for dDAVP administration:
o inability to comply with water restriction
o renal insufficiency (GFR < 45 ml/min/1.73 m2)
o hyponatremia (plasma sodium < 130 mmol/l)

other:
o concomitant treatment with desmopressin or democlocycline

Eligible patient will be evaluated during an additional visit (approximately 6
hours) at the outpatient clinic. At baseline, subjective symptoms (micturition
history) and vital signs (body height and weight, blood pressure and heart
rate) will be recorded. In addition, baseline blood levels of creatinine,
sodium, potassium, calcium, osmolality and lithium and baseline urine levels of
osmolality and glucose will be determined. Water intake will be restricted to
500 ml over the next 6 hours. After voiding, 40 µg 1-desamino-8-D-arginine
vasopressin (dDAVP) will be administered intranasally. Throughout the day,
urine volume and maximal renal concentrating ability will be determined by
measuring osmolality in urine collected every 60-120 minutes for a total
duration of 6 hours. In addition, water intake, body weight, blood pressure and
heart rate will be determined at two hour intervals. Patients with a clearly
decreased maximal urinary osmolality (urine osmolality < 600 mosmol/kg) after
dDAVP administration will be diagnosed as lithium induced nephrogenic diabetes
insipidus. Finally, patients will be observed for possible adverse events of
dDAVP.

Patients may be exposed to the risk of adverse effects as a consequence of
their participation in this study. Adverse reactions occurring most often (but
still infrequently) include transient headache, nausea, nasal congestion,
rhinitis nosebleed, sore throat, cough, upper respiratory infections and
flushing occasionally along with mild abdominal cramps. In addition, intranasal
DDAVP at high dosage infrequently produce a slight elevation of blood pressure.
Since dDAVP is administered only once, there is no prolonged action and
development of severe adverse reactions is thus unlikely. Furthermore, many of
these risks are substantially minimized by increased subject monitoring before,
during, and after treatment. Although no treatment benefits can be guaranteed
to the study participants, patients may be rewarded for participation in this
study since the thorough evaluation may be more than the standard of care. In
addition, early recognition of an impaired urinary concentration may be helpful
in selecting lithium treated patients at risk of severe nephrogenic diabetes
insipidus and allow increased surveillance and an earlier start of treatment.
Finally, information obtained from this study may improve the evaluation and
care for patients with lithium induced NDI in the future.