ZS-9 LEADS TO A RAPID AND PREDICTABLE ON-DRUG RATE OF DECLINE IN SERUM K+ IN CKD PATIENTS WITH HYPERKALEMIA ON RAAS INHIBITORS (RAASi)

NKF 2014 Spring Clinical Meetings Abstracts

337 ZS-9, A NOVEL SELECTIVE CATION TRAP, DOES NOT SIGNIFICANTLY INCREASE SODIUM EXCRETION WHEN USED FOR THE TREATMENT OF HYPERKALEMIA IN PATIENTS WITH CKD: Bhupinder Singh1, Stephen R. Ash2, Philip Lavin3, Alex Yang4, Henrik S. Rasmussen5. 1Southwest Clin. Research Inst., Tempe, AZ; 2Indiana Univ. Health Arnett, Lafayette, IN; 3Boston Biostats. Research Fdn., Framingham, MA; 4Xelay Acumen, Belmont, CA; 5ZS Pharma, Coppell, TX, USA. Hyperkalemia is associated with significant mortality and limits use of life-saving RAAS inhibitors, yet prevalent treatments are poorly tolerated and not always effective. The nonselective organic resin Kayexalate® is the only approved hyperkalemia therapy in the U.S. However, its use has been associated with Na+ loading, potentially worsening fluid retention and hypertension. ZS-9 is an inorganic, nonsystemic cation exchanger designed to entrap excess K+. In a Phase 2 trial in 90 patients with CKD and hyperkalemia, ZS-9 led to a rapid and sustained decrease in serum K+ vs placebo, with acceptable safety (Ash et al. ASN 2013). Here we present results for serum and 24-hr urine Na+. Patients (eGFR: 30-60 mL/min/1.73 m2; serum K+: 5-6 mEq/L) received ZS-9 10g (N=24) or placebo (N=30) orally TID for 2-4 days, depending on serum K+ (only 2 days needed for ZS-9 10g), with regular meals as in-patients. Serum and 24-hour urine samples were collected during treatment and serum was collected through Day 7. RAAS inhibitors were continued during the study. At baseline, serum Na+ was 140 mmol/L for placebo and 138 mmol/L for ZS-9 10g (p=NS); 24-hour urine Na+ was 145 mmol for placebo and 115 mmol for ZS-9 10g (p=NS). Serum Na+ remained within normal limits, with no significant differences between groups through Day 7; 24-hour urine Na+ increased slightly by Day 2 (+37 and +25 mmol, respectively; p=NS). Results were consistent in the subsets on RAAS inhibitors (ZS-9 10g, n=20; placebo, n=18). There were no cases of significant hypocalcemia (≤8 mg/dL), hypomagnesemia (≤1.2 mmol/L), or hypokalemia (≤3.0 mmol/L) with ZS-9. ZS-9 10g had no clinically relevant effect on 24-hour urine Na+ excretion, including in patients on RAAS inhibitors.

338 ZS-9 LEADS TO A RAPID AND PREDICTABLE ON-DRUG RATE OF DECLINE IN SERUM K+ IN CKD PATIENTS WITH HYPERKALEMIA ON RAAS INHIBITORS (RAASi): Bhupinder Singh1, Stephen R. Ash2, Philip Lavin3, Alex Yang4, Henrik S. Rasmussen5. 1Southwest Clin. Research Inst., Tempe, AZ; 2IU Health Arnett, Lafayette, IN; 3Boston Biostats. Research Fdn., Framingham, MA; 4Xelay Acumen, Belmont, CA; 5ZS Pharma, Coppell, TX, USA. ZS-9, a novel cation exchanger designed to entrap excess K+, reduced serum K+ vs placebo, with favorable safety, in a Phase 2 study (N=90; Ash et al. ASN 2013). As the time to onset of serum K+ decline is clinically important, we assessed mean serum K+ rate of change. Patients (eGFR: 30-60 mL/min/1.73 m2; serum K+: 5-6 mEq/L) received ZS-9 10g (N=24) or placebo (N=30) orally TID for 2-4 days with regular meals (8am, 12pm, 6pm), depending on serum K+ (only 2 days needed for ZS-9 10g). Serum K+ was measured 0.5 hr, 1 hr, and 2 hr after 1st dose and 4 hr after all doses. Mean serum K+ over 2 initial treatment evaluation periods (Hr 0-14 and 24-38) and off-drug nighttime rebound periods (Hr 14-24 and 38-48) were assessed, including in the RAASi subsets (ZS-9 [n=20]; placebo [n=18]). Mean baseline serum K+ was 5.1 mEq/L for ZS-9 10g and placebo (RAASi subsets: 5.1, ZS-9 10g; 5.2, placebo). There was a greater mean daytime rate of decline in serum K+ for ZS-9 10g vs placebo, overall and in the RAASi subset (p=0.001 and 0.005, respectively; Table). No significant difference was seen in mean nighttime rebound rate. ZS-9 may allow for rapid and predictable treatment of hyperkalemia in CKD patients on RAAS inhibitors. Serum K+ rate of Placebo ZS-9 10g p-value change (mEq/L/hr) Average Over Two Treatment Periods (Hr 0-14 and Hr 24-38) –0.011 –0.038 0.001 Overall population –0.012 –0.040 0.005 RAASi subset Average Over Two Rebound Periods (Hr 14-24 and Hr 38-48) 0.010 0.024 0.166 Overall population 0.005 0.022 0.192 RAASi subset

Am J Kidney Dis. 2014;63(5):A1-A121

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340 EVERYTHING THAT LOOKS AND BEHAVES LIKE AMYLOID MIGHT NOT BE AMYLOID Manisha Singh, Neriman Gokden, Shree Sharma, University of Arkansas for Medical Sciences, Little Rock, Arkansas Light chain cast nephropathy or Myeloma cast nephropathy or myeloma kidney refers to acute or chronic kidney injury secondary to presence of monoclonal immunoglobulin light chains in the urine and is one of the defining criteria’s of multiple myeloma. It may precede the diagnosis of multiple myeloma. We report a 55-year-old male patient who presented with acute kidney injury. Laboratory evaluation revealed creatinine 6.3 mg/dl, uric acid 8.7, positive SPEP, lytic lesions in pelvis, femur and skull. Bone marrow biopsy revealed involvement by plasma cell myeloma. Renal biopsy revealed myeloma cast nephropathy with associated acute tubular injury, mild tubular atrophy and interstitial fibrosis and vascular disease. The casts on immunofluorescence were showing 3+ positivity for lambda but were negative for kappa. These casts were unusual because they were positive for congo red (amyloidogenic). Notably no overt evidence of amyloid deposits was identified within the glomeruli, blood vessels or tubular basement membranes on light microscopy, immunofluorescence or electron microscopy. Amyloidogenic light chain cast nephropathy is a variant of myeloma cast nephropathy and in most patients is not associated with systemic amyloidosis. Our patient is currently undergoing treatment for IgG lambda type multiple myeloma and has no evidence of systemic amyloidosis.

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