Ask the Experts – Rajiv Agarwal, MD, MS

Question 1. Hyperkalemia is among your research interests. What studies in this area presented at Kidney Week are particularly noteworthy?

Answer
The most exciting are the hyperkalemia studies of potassium binders that enable the use of spironolactone or RAAS [renin-angiotensin-aldosterone system] inhibitors in patients with CKD, a lot of whom have heart failure. Previously, patients on RAAS inhibitors who get hyperkalemia would perhaps stop the drug and lose the cardioprotective and renoprotective benefit of these medications. Now physicians have an option for controlling hyperkalemia in these patients and thus enabling patients to stay on a lifesaving drug long-term.

Question 2. What do you consider the most important take-home message from the findings of the AMBER study, which you led?

Answer
In a subgroup of about 60 patients with an estimated glomerular filtration rate of less than 30 [mL/min/1.73 m²] who were on spironolactone therapy, we showed that 43% of patients treated with placebo discontinued spironolactone within 12 weeks compared with only 16% of patients treated with patiromer. Treating 5 patients with stage 4 CKD with patiromer would enable 1 patient to continue on spironolactone. The number-needed-to-treat is fabulous. In fact, treating just 3 patients with stage 4 CKD with patiromer would avoid 1 patient having hyperkalemia.

Question 3. How do these binders — patiromer and zirconium cyclosilicate (ZS-9) — compare with sodium polystyrene sulfonate (Kayexalate)?

Answer
Both patiromer and zirconium cyclosilicate reduce potassium, and they are easier to take than sodium polystyrene sulfonate, which is like sand and patients have trouble taking it on a regular basis. Patiromer and zirconium cyclosilicate are better tolerated than sodium polystyrene sulfonate. Cost will be factor in the use of these agents, as it could limit access to them. If we can surmount the access issue, these drugs could improve management of hyperkalemia in CKD patients on spironolactone or RAAS inhibitor therapy.

Question 4. Will these new potassium binders have a role in the treatment of acute hyperkalemia?

Answer
The backbone of acute hyperkalemia treatment will likely remain drugs such as insulin, calcium gluconate, sodium bicarbonate, and sulbutanol inhalation. Patiromer, zirconium cyclosilicate, and sodium polystyrene sulfonate have little place in the treatment of acute hyperkalemia, but they could buy time, for example, to get patients on dialysis.

Question 5. Observational studies presented at the conference underscore the adverse effect of hyperkalemia on the clinical course of CKD. A study of CKD patients showed that hyperkalemia increases the risk of CKD progression, and another found that hyperkalemia excursions are associated with all-cause mortality in dialysis patients. What should be the take-home message for physicians?

Answer
These 2 observational studies are noteworthy. In the first one looking at CKD patients not on dialysis, compared with patients who experienced no hyperkalemia, those who had hyperkalemia had more than a 2-fold increased risk of a subsequent estimated glomerular filtration rate of less than 15 mL/min/1.73m². In the second study, which included patients on dialysis, the risk of mortality was 10% to 20% higher in the next 4 months when potassium was about 5 mEq/L at least once during the prior 4-month period. If potassium rose to more than 5.5 mEq/L, the mortality rate was 20% to 30% higher during the subsequent 4 months. One may be tempted to [presume] a cause-and-effect relationship, which is something I would not conclude short of doing clinical trials.

Question 6. Has your attendance at Kidney Week 2019 given you a sense of what might be the next big pharmacologic advance in hyperkalemia?

Answer
Mitigating the risk of hyperkalemia by using nonsteroidal selective mineralocorticoid receptor antagonists (MRAs). Some of these drugs are in development. The ARTS [MinerAlocorticoid Receptor Antagonist Tolerability Study] trial compared spironolactone with finerenone, a nonsteroidal MRA, in patients with CKD and heart failure. The trial showed a much higher incidence of hyperkalemia with spironolactone, yet the efficacies were similar. Two large trials comparing finerenone with placebo in patients with diabetic kidney disease are in progress: FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease]. In both trials combined, more than 13,000 patients have been randomized. These will be the largest trials of patients with diabetic nephropathy.

The primary end point of the FIDELIO-DKD trial is time to a 40% reduction in eGFR, time to an eGFR less than 15, time to dialysis initiation or transplantation, or death due to renal causes. The primary end point of the FIGARO-DKD trial is cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure.

These trials include patients who have been excluded from other diabetic nephropathy trials in that they include patients with a urinary albumin-to-creatinine ratio less than 300 mg/g. Most trials previously have included only patients with overt albuminuria. If the results of these trials are positive, they will result in a paradigm shift in the care of diabetic kidney disease. The FIDELIO trial should be completed in 2020 and the FIGARO in 2021. These are massive trials that will inform us whether nonsteroidal MRAs can protect the heart and the kidney in patients with DKD.