November 3, 2012 N Engl J Med DOI: /NEJMoa

ADPKD - m/c monogenic kidney disease - 4 th leading cause of ESRD -Progressive development of kidney cysts, Kidney pain, HTN, kidney failure. But, effective treatment has been lacking…. Studies of animal models vasopressin and second messenger cAMP -kidney-cyst cell proliferation -luminal fluid secretion. Suppression of vasopressin release -vasopressin V2-receptor blockade - Reduce the cyst burden and protect kidney function Tolvaptan (vasopressin V2-receptor antagonist) - Tx of dilutional hyponatremia or volume overload in heart failure BACKGROUND

Phase 3, multicenter, double-blind, placebo-controlled, 3-year trial Randomly assigned 1445 patients 18 to 50 years of age, who had ADPKD Total kidney volume of 750 ml or more Estimated creatinine clearance of 60 ml per minute or more Tolvaptan (v2-receptor antagonist): placebo.= 2:1 Primary outcome -Annual rate of change in the total kidney volume. Secondary end points -Composite of time to clinical progression (worsening kidney function, kidney pain, hypertension, albuminuria) - Rate of kidney-function decline METHODS

Patient Enrollment and Outcomes. primary efficacy analysis :1307(90.4%) secondary efficacy analysis :1445 (100%) secondary safety analysis:1444 (99.9%) 23.0% 13.8% 1157 patients (80.1%)

RESULTS

Effect of Tolvaptan on the Annual Slopes of Total Kidney Volume PRIMARY END POINT Over the 3-year period, total kidney volume increased by 2.8% per year (95% CI, 2.5 to 3.1) with tolvaptan versus 5.5% per year (95% CI, 5.1 to 6.0) with placebo. 2.8% 5.5% Tolvaptan changed the rate of growth by −2.7 percentage

Annual Treatment Effects of Tolvaptan on Total Kidney Volume. within 14-day since last dose windowhaving their MRI while taking drug Differences in least-squares (LS) = TKV changes for tolvaptan vs placebo groups by year Intetn to treat placebo. tolvaptan −9.2 % points (95% CI, −11.1 to −7.3; P<0.001)  treatment effect of 49.2%0

Tolvaptan had a beneficial effect on total kidney volume in all subgroups

Secondary end point kidney function (Reciprocal of sCr level) Tolvaptan, −2.61 (mg per milliliter) -1 per year vs placebo,−3.81 (mg per milliliter) −1 per year −2.61 −3.81 Treatmenteffect was an increase of 1.20 (mg per milliliter) −1 per year (95% CI, 0.62 to 1.78; p<0.001)

Effect of Tolvaptan on Annual Slope of Estimated Glomerular Filtration Rate (eGFR). −2.72 −3.70 Treatment effect, an increase of 0.98 ml per minute per 1.73 m 2 per year; 95% CI, 0.60 to 1.36; p<0.001

Tolvaptan had a beneficial effect on renal function in all stratification subgroups..

Effect of Tolvaptan on the Time to Multiple Events Associated with Autosomal Dominant Polycystic Kidney Disease (ADPKD) secondary composite end point Clinical Progression

Cumulative hazard of multiple events of ADPKD progression Clinical Progression

Cumulative hazard of worsening kidney function Composite end point by effects on kidneyfunction decline 2 events per 100 person-years of follow-up 5 events per 100 person-years of follow-up

Cumulative hazard of clinically significant kidney pain. 5 events per 100 person-years of follow-up Composite end point by effects on kidney pain 7 events per 100 person-years of follow-up

Effect of Tolvaptan on Time Albuminuria Outcomes Worsening Hypertension

2 MI and 1 SAH occurred in the placebo group

CONCLUSIONS Tolvaptan, as compared with placebo, - Slowed the increase in total kidney volume - Slowed the decline in kidney function over a 3-year period in patients with ADPKD But … Associated with a higher discontinuation rate, Owing to adverse events.