Tolvaptan in Autosomal Dominant Polycystic Kidney
Disease: Three Years Experience
CJASN Oct 2011
ADPKD is an inherited disorder
resulting in renal cysts, urinary concentrating defects, hypertension, and ESRD.
The clinical manifestations include back pain from cyst hemorrage, stones, and
infection. Extrarenal manifestations include cerebral aneurysms and can be life
threatening .
A recent study evaluated the
potential use of Tolvaptan, a V2 receptor antagonist, for the purpose of
delaying progression of this disease. The
concept behind its use was based on animal studies that showed suppression of
vasopressin by forced hydration or V2 receptor blockade reduced cyst burden and
protected renal function.
Total Kidney Volume (TKV) is a
measurable end point that reflects outcomes in ADPKD including pain,
hypertension, renal insufficiency, and ESRD. The current study explored if the
use of V2 receptor antagonism in ADPKD pts could slow the rate of TKV expansion
and decline in GFR. There was one
treatment arm in which all patients carried the diagnosis of ADPKD and were
treated with tolvaptan. These patients were randomized in a 1:2 ratio to
historical controls obtained from the MDRD and CRISP trials. These controls had
ADPKD and were managed with blood pressure control. The treatment and control
arms were followed for three years and endpoints included rate of TKV growth
and rate of decline in eGFR. Results showed statistically significant
differences in TKV growth with the treatment arm showing slower progression.
Additionally rate of decline in eGFR was slower in the treatment arm in
comparison to controls. However the absolute mean differences in eGFR decline
were not significantly different suggesting that over a longer period of time,
perhaps that effect would be realized.
Over
the course of the study all treated patients experienced mild side effects
consistent with the mechanism of action of tolvaptan. Twelve patients in the
treatment arm withdrew and six of them withdrew secondary to side effects which
included renal impairment, acute renal failure, benign pituitary tumor, TIA, eye
swelling, and subarachnoid hemorrhage with a fatal outcome.
This
study seems to be a proof of concept that perhaps V2 receptor antagonism may be
an avenue for therapy in this disease population. A more rigorous and better
designed study is underway with over 1400 ADPKD patients concurrently
randomized into a treatment and control arm with long term follow up.
Post by Dr. Ezra Israel
Nephrology Fellow, Hofstra NSLIJ
Nephrology Fellow, Hofstra NSLIJ
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