Tuesday, November 22, 2011

Journal Club: Tolvaptan in ADPKD

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

No comments:

Post a Comment

All Posts

Search This Blog