Japan
Japan (日本)
Japan enters their seventh (7th) consecutive World Cup and second (2nd) NephroWorldCup with a stronger team than ever before (Video 1). The Samurai Burū field a squad that is likely to be familiar to many NephroWorldCup players: a study to assess diuresis in heart failure patients with advanced chronic kidney disease. Cardiologists and Nephrologists are well aware of the limitations when escalating doses of loop diuretic, especially in the context of advanced kidney dysfunction. Some have tried intravenous formulations (instead of oral or intermittent dosing). Others have synergized the effects of the loop diuretic with a thiazide diuretic. Recent data from the AVANTI trial show that a new synergy is being investigated: loop diuretic + vaptan therapy (Carousel 1). Enter The Samurai Burū.
Carousel 1: AVANTI trial results: using a vaptan as an adjunct with or replacement to furosemide | Presented at the 2021 European Society of Cardiology annual meeting | Courtesy of Dr. Sarah Hudson (enter full screen for further details)
The AVANTI trial suggested no benefit in adding a vaptan to loop diuretic therapy in patients with heart failure (Carousel 1). That data may have stopped an ordinary NephroWorldCup team, but not Japan. Japanese researchers have known (as we all have) that patients with both heart and kidney failure are a unique population requiring dedicated trial data to determine optimal treatment strategies. Extrapolating data from one trial and 'making it fit' this unique population minimizes the significant effect that kidney dysfunction imparts on overall care. Thus The Samurai Burū field an ambitious NephroWorldCup team: a randomized trial of heart and kidney failure patients to compare vaptan versus high-dose loop diuretic therapy.
Figure 1: Selected baseline criteria for Vaptan and Furosemide groups, respectively
The Japan team is an open-label randomized multi-center (single nation) trial of thirty-three (33) heart and kidney failure patients. Baseline ejection fraction was 60-64% and eGFR approximately 13.8 mL/min/1.73 square-meter (Figure 1). Patients were receiving furosemide at baseline. If randomized to the furosemide arm, these patients would receive an additional 100 mg/d increase. If randomized to the tolvaptan group, patients would continue their entry furosemide dose + 15 mg/d of tolvaptan.
The primary endpoint was the change in urine volume over the seven (7) day study period. A key secondary endpoint was worsening of creatinine.
Using tolvaptan in this unique patient population resulted in a higher urine volume than an escalated dose of furosemide (Figure 2). On average, there was a 5-fold increase in urine output when combining tolvaptan with furosemide (standard dose) versus the higher dose of furosemide (between 120-200 mg/d). The diuretic effect of the combination was sustained over the seven (7) day study period (Figure 3). In the furosemide arm, the diuretic effect is lost at day 4 (Figure 3).
Figure 2: Average change in urine volume during study →
← Figure 3: Daily change in urine volume
Figure 4: Average change in urine volume based on baseline urine osmolality
To add to the impact of these results, The Samurai Burū sub-categorized urinary response based on the baseline urine osmolality. Tolvaptan + furosemide resulted in a far greater diuretic effect in those with higher osmolality (UOsm > 313.5 mOsm/kg). Lastly, and even though the philosophy of 'permissive hypercreatinemia' is rapidly percolating through the CVRM space, using tolvaptan resulted in a smaller increase in creatinine than high-dose loop diuretics (18.8% in the tolvaptan arm versus 58.8% in the high-dose furosemide arm).
How will Japan fair in the 2022 NephroWorldCup? Are these results impressive given that they focus specifically on patients with concurrent heart and kidney failure (Video 2)? Is an ejection fraction of 60% sufficient to diagnose patients with heart 'failure'? Do the results of AVANTI cloud these results? One thing is known: vaptan adjuvant therapy with loop diuretics will continue to be studied until the right patient population is discovered.
Video 2: Tolvaptan and heart failure by Dr. Frederik Verbrugge