Editorial Patiromer–an Oral Calcium-Loaded Potassium Binder: Kalirrhea with Calciuresis Michael Emmett and Ankit Mehta Clin J Am Soc Nephrol 11: 1723–1725, 2016. doi: 10.2215/CJN.08910816 In the absence of diarrhea, about 90% of ingested po- K, magnesium, calcium, and phosphate in healthy nor- Department of tassium (K) is absorbed and excreted into the urine. mal adults given varying doses of patiromer at vary- Internal Medicine, Renal K excretion is impaired by a marked reduction ing dosing intervals. As expected, urine K excretion Baylor University in kidney function, kidney disorders, or drugs which fell and urine calcium excretion increased moderately. Medical Center, sharply reduce the distal tubular delivery of sodium The urinary excretion of sodium, K, magnesium, and Dallas, Texas and/or reduce the renal tubular aldosterone action. phosphate all decreased, suggesting reduced intestinal These diseases and drugs increase the serum K concen- absorption, assuming the subjects were all in an equili- Correspondence: Dr. Michael Emmett, tration. Hyperkalemia has become more prevalent as brated steady state (see Figure 1). Department of a result of the increasing use of drugs which block the What is the potential clinical impact of these findings? Internal Medicine, renin-angiotensin-aldosterone system (RAAS). They The moderate increase in urine calcium excretion, com- Baylor University include drugs which reduce aldosterone generation bined with reduced urinary magnesium excretion, may Medical Center, 3500 Gaston Avenue, (direct renin inhibitors, angiotensin-converting enzyme increase the risk of calcium-containing kidney stones. Dallas, TX 75246. inhibitors and angiotensin II receptor blockers) and However, urine oxalate excretion was not measured, Email: m.emmett@ others that block aldosterone activity (spironolactone, and, therefore, calcium oxalate supersaturation could baylorhealth.edu eplerenone). These drugs are often indicated for pa- not be calculated. If some of the calcium is released from tients with already compromised renal function. There- patiromer, especially in the colon, then this may bind fore, effective and safe means of removing K from the oxalate and thereby reduce its absorption. Also, calcium body have been sought. released from patiromer in the small bowel probably Until recently, the major way to bind K in the gas- functions as a phosphate binder. This would be ad- trointestinal (GI) tract and thereby enhance excretion vantageous for many patients with CKD who require in the stool was the administration of sodium polysty- phosphate-binding drugs. However, there is some con- rene sulfonate, which is a poorly effective and poten- cern about the potential adverse peripheral vascular and tially dangerous medication (1,2). Recently, two new cardiovascular effects of increased oral calcium loads in K-binding agents have been developed (patiromer and this population. Some evidence suggests that patients zirconium cyclosilicate), and one (patiromer) has been using noncalcium-based phosphate binders have a lower approved for use by the Food and Drug Administra- mortality rate than patients using calcium-based phos- tion (FDA). A safe, oral, nonabsorbable K-binding phate binders (4,5). On the other hand, the amount of agent should mitigate the hyperkalemia risk of RAAS calcium released from patiromer and systemically ab- blockers and thereby be very beneficial to patients who sorbed is modest and may not be problematic. Clarifi- have been unable to tolerate optimal doses of these cation of these issues will require long-term studies in agents on that basis. However, while the GI K-binding CKD patients. Although parathyroid hormone levels agents which are currently available or in the develop- were not evaluated in this study it is likely they would mental pipeline are relatively selective for K, they also have fallen in response to the increased calcium absorp- bind other ions and substances. Also, these agents all tion from the GI tract. release other cations when K (or another cation) is Patiromer did not reduce serum K in these healthy bound; patiromer releases calcium whereas sodium individuals. Although initially surprising, this is to polystyrene sulfonate and zirconium cyclosilicate be expected. In normal patients, excretion of urine K each release sodium. will reduce sharply (to less than 1000 mg/L per day) in Whereas it is clear that patiromer releases calcium response to a major reduction of K intake (or ab- when it binds K (or another cation), the fate of the cal- sorption). In this study, the baseline K intake was cium ions released into the GI lumen is unclear. They about 4600–4700 mg/d and baseline urine K excre- may be systemically absorbed by the intestine (and ex- tion about 4400 mg/day. On the highest dose of pa- creted in the urine), bind to anions, such as phosphate tiromer the urine K excretion fell by about 1400 mg to or oxalate, in the bowel lumen, or rebind to patiromer. about3000mg/day.Onewouldnotexpectanormal In this issue of the Clinical Journal of American Society patient to measurably reduce their serum K concentra- of Nephrology, Bushinsky et al. (3) examined these tion in response to a change in dietary K intake from issues by studying the urinary excretion of sodium, 4600 mg/day to 3000 mg/day. Therefore, a fall in www.cjasn.org Vol 11 October, 2016 Copyright © 2016 by the American Society of Nephrology 1723 1724 Clinical Journal of the American Society of Nephrology Figure 1. | Patiromer administration and resultant changes in fecal and urine K, phosphate, and calcium. *Although the serum K did not fall in this study of normal individuals, patiromer has been shown to lower serum K in hyperkalemic patients with chronic kidney disease. Box colors: brown, GI tract; purple, fecal excretion; red, GI absorption changes; gray, hormonal effects; yellow, urinary excretion. Ca, calcium; CaPO4, calcium phosphate; K, potassium; Mg, magnesium; PTH, parathyroid hormone; PO4, phosphate. serum K should not be expected in normal subjects ingest- Patiromer may alsobindoral medications and reduce their ing this dose of patiromer. bioavailability. This issue has not yet been well studied. Differences between the dose-finding study and the Currently, the FDA warns that all other ingested medica- dosing-regimen study are interesting. It is known that tions be administered 6 hours before or after patiromer calcium-based phosphate binders are most effective when administration. ingested together with meals (6). Consistent with this finding RAAS inhibitors provide major benefits in many com- is the observation that patiromer reduces urine phosphate mon clinical disorders, including congestive heart failure, more effectively when ingested twice or three times a day diabetic nephropathy, and hypertension. Their optimal ap- rather than once daily. However, urine calcium excretion plication may be limited by one of their most common side was lowest with daily dosing. Furthermore, there was effects, especially in patients with CKD: hyperkalemia. It is no significant effect of dose timing intervals on reduction hoped that patiromer will allow clinicians to add/dose opti- of urine K. mize angiotensin-converting enzyme inhibitors/angiotensin Patiromer, when used in patients with diabetic kidney receptor blockers and aldosterone antagonists while miti- disease, has generated hypomagnesemia (7). In this study gating the hyperkalemia risk. of normal patients, urinary magnesium excretion fell, likely reflecting GI binding of magnesium; however, serum Disclosures magnesium levels did not fall. None. Clin J Am Soc Nephrol 11: 1723–1725, October, 2016 Editorial, Kalirrhea with Calciuresis, Emmett et al. 1725 References on mortality in patients with chronic kidney disease: an 1. Gruy-Kapral C, Emmett M, Santa Ana CA, Porter JL, Fordtran JS, updated systematic review and meta-analysis. Lancet 382: Fine KD: Effect of single dose resin-cathartic therapy on serum 1268–1277, 2013 potassium concentration in patients with end-stage renal disease. 6. Schiller LR, Santa Ana CA, Sheikh MS, Emmett M, Fordtran JS: J Am Soc Nephrol 9: 1924–1930, 1998 Effect of the time of administration of calcium acetate on phos- 2. Harel Z, Harel S, Shah PS, Wald R, Perl J, Bell CM: Gastrointestinal phorus binding. NEnglJMed320: 1110–1113, 1989 adverse events with sodium polystyrene sulfonate (Kayexalate) 7. Bakris GL, Pitt B, Weir MR, Freeman MW, Mayo MR, Garza D, use: a systematic review. Am J Med 126: 264.e9–264.e24, 2013 Stasiv Y, Zawadzki R, Berman L, Bushinsky DA; AMETHYST-DN 3. Bushinsky DA, Spiegel DM, Gross C, Benton WW, Fogli J, Hill Investigators: Effect of Patiromer on Serum Potassium Level in Gallant KM, Du Mond C, Block GA, Weir MR, Pitt B: Effect of Patients With Hyperkalemia and Diabetic Kidney Disease: The Patiromer on Urinary Ion Excretion in Healthy Adults. Clin J Am AMETHYST-DN Randomized Clinical Trial. JAMA 314: 151–161, Soc Nephrol 11: 1769–1776, 2016 2015 4. Patel L, Bernard LM, Elder GJ: Sevelamer Versus Calcium-Based Binders for Treatment of Hyperphosphatemia in CKD: A Meta- Analysis of Randomized Controlled Trials. Clin J Am Soc Nephrol Published online ahead of print. Publication date available at www. 11: 232–244, 2016 cjasn.org. 5. Jamal SA, Vandermeer B, Raggi P, Mendelssohn DC, Chatterley T, Dorgan M, Lok CE, Fitchett D, Tsuyuki RT: Effect of See related article, “Effect of Patiromer on Urinary Ion Excretion in calcium-based versus non-calcium-based phosphate binders Healthy Adults,” on pages 1769–1776..