Complications of Acute and Chronic Kidney Disease: A Focus on Hyperkalemia. Mitchell H. Rosner, MD James Tumlin, MD Peter A. McCullough, MD, MPH

Transcription

1 Complications of Acute and Chronic Kidney Disease: A Focus on Hyperkalemia Mitchell H. Rosner, MD James Tumlin, MD Peter A. McCullough, MD, MPH

2 Case #1 A 29 year-old male with ESRD secondary to focal segmental glomerulosclerosis is noted to have persistent hyperkalemia on his monthly labs. For instance, for the past 4 months his routine labs have shown potassium levels of 5.9 meq/l, 6.7 meq/l, 6.2 meq/l and 6.5 meq/l. Of note, labs are routinely drawn on the mid-week dialysis (Wednesday or Thursday) session He has met with the dietician on repeated occasions and states that he cannot handle a low potassium diet and maintain his caloric and protein needs.

3 Case #1 Continued You have prescribed several pharmacological agents to try and keep the serum potassium level within a normal range including: high-dose loop diuretics, sodium polystyrene sulfonate and sodium bicarbonate. None have led to any change in the serum potassium levels There is no evidence of AV access problems nor of hemolysis

4 Case #1 Continued His other notable history includes: Hypertension Recent episodes of atrial fibrillation which have occurred on dialysis within the first 30 minutes and resolved spontaneously within a few hours. He has started apixaban given the frequency of these episodes Secondary hyperparathyroidism Anemia of ESRD treated with erythropoietin

5 Case #1 Question-What risk factors that contribute to hyperkalemia among ESRD patients can be controlled by the clinician? Dietary K+ Intake: Average dietary intake 1.0 meq/kg/day Sandle et.al. Clin Sci, 73: , 1987 Dialysis Access: Reduced total clearance Recirculation: of K+; correction with restored circulation Pharmacologic: High Dose Combination Management: Diuretics Gut K+ Binders

6 Case #1 Question-What risk factors that contribute to hyperkalemia among ESRD patients can be controlled by the clinician? Dietary K+ Intake: What Foods do we need to remind our patients to avoid? White Beans: One cup (179 gms) cooked White Beans 1004 mg K+ Leafy Green Vegetables One cup uncooked (salad) (167 mg K+) One cup cooked (spinach) (839 mg K+)

7 Case #1 Question-What risk factors that contribute to hyperkalemia among ESRD patients can be controlled by the clinician? Dietary K+ Intake: What Foods do we need to remind our patients to avoid? Yogurt (Plain, Non-Fat) One cup (245 gms) no added fruit 625 mg K+ Guacamole Dip One cup pureed (Super Bowel Dip) (1216 mg K+) Super Bowl-34 Super Bowl ,000,000 lbs. Avocados ,000,000 lbs. Avocados

8 Case #1 Question-What risk factors that contribute to hyperkalemia among ESRD patients can be controlled by the clinician? Dietary K+ Intake: What Foods do we need to remind our patients to avoid? McDonald s Super Size Fries One serving (117 gms) K mg Na+-266 mg Calories-370 cal Guacamole Dip One Burger (Super Secrete Sauce) K mg Na mg Calories-563 cal

9 Can we really control dietary intake?

10 Corporate Opposition to the Proper Care and Management of the ESRD Patient Erlanger Medical Center UT College of Medicine Thriving McDonald s Franchise 1 Block from Hospital Campus

11 Case #1 Question-What risk factors that contribute to hyperkalemia among ESRD patients can be controlled by the clinician? Dietary K+ Intake: Average dietary intake 1.0 meq/kg/day Sandle et.al. Clin Sci, 73: , 1987 Reduction Dialysate K+: J curve Mortality rates with reduction in dialysate bath Dialysis Access: Reduced total clearance Recirculation: of K+; correction with restored circulation Pharmacologic: Management: High Dose Combination Diuretics Gut K+ Binders

12 Common Sites of Venous Occlusion and Recirculation

13 Case #1 Question-What risk factors that contribute to hyperkalemia among ESRD patients can be controlled by the clinician? Dietary K+ Intake: Average dietary intake 1.0 meq/kg/day Sandle et.al. Clin Sci, 73: , 1987 Reduction Dialysate K+: J curve Mortality rates with reduction in dialysate bath Dialysis Access: Reduced total clearance Recirculation: of K+; correction with restored circulation Pharmacologic: Management: High Dose Combination Diuretics Gut K+ Binders

14 Can we safely lower Dialysate K+ Concentrations to treat Refractory Hyperkalemia?

15 Hyperkalemia and Cardiovascular Risk Across Clinical Demographics Kovesdy et.al. Clin J. Am. Soc. Nephrol. 2: , 2007

16 J Curve Cardiovascular Survival: Function of High and Low K+ Dialysate Kovesdy et.al. Clin J. Am. Soc. Nephrol. 2: , 2007

17 Effect of Ultralow Dialysate K+ and Cardiovascular Survival 0-1 K+ 25 CV Death 2.0 K+ 18 CV Death 3.0 K+ 22 CV Death 4.0 K+ 26 CV Death 0-1 K+ 25 CV Death 2.0 K+ 17 CV Death 3.0 K+ 20 CV Death 4.0 K+ 24 CV Death Ghassan et.al. Journal Nephrol. 23:33-40, 2010

18 Case #1 Question-What risk factors that contribute to hyperkalemia among ESRD patients can be controlled by the clinician? Dietary K+ Intake: Average dietary intake 1.0 meq/kg/day Sandle et.al. Clin Sci, 73: , 1987 Reduction Dialysate K+: J curve Mortality rates with reduction in dialysate bath Dialysis Access: Reduced total clearance Recirculation: of K+; correction with restored circulation Pharmacologic: Management: High Dose Combination Diuretics Gut K+ Binders

19 What about using Fludrocortisone?

20 A Randomized Controlled Trial of Fludrocortisone for the Treatment of Hyperkalemia in Hemodialysis Patients Kaisar et.al. Am. J. Kid. Dis. 47(5): , 2006

21 A Randomized Controlled Trial of Fludrocortisone for the Treatment of Hyperkalemia in Hemodialysis Patients No benefit to Fludrocortisone therapy in ESRD Hyperkalemia Kaisar et.al. Am. J. Kid. Dis. 47(5): , 2006

22 Sodium Zirconium Cyclosilicate: Selective K+ Binding Matrix Stavros et.al. Plos One, December 22, 2014 Page 1-12

23 Sodium Zirconium Cyclosilicate: Selective K+ Binding Matrix Stavros et.al. Plos One, December 22, 2014 Page 1-12

24 Sodium Zirconium Cyclosilicate In the Treatment of Hyperkalemia It is hypothesized that ZS-9 uses a selectivity filter analogous to that of physiologic K+ channels to achieve its selectivity for capturing K+ ions. Hydrated cations, such as Na+ and Ca2+, have larger ionic diameters and require more energy to shed their hydration shell than K+. The selectivity of ZS-9 for K+ is confirmed by the ion exchange characterization data, which showed that in mixed cation solutions, ZS-9 had 9.3 times more capacity for K+ than SPS and, at all concentration ratios tested, it was more than 125 times more selective for K+ compared with SPS. Stavros et.al. Plos One, December 22, 2014 Page 1-12

25 Sodium Zirconium Cyclosilicate: Selective K+ Binding Matrix Tumlin et.al. Presented ASN San Diego November 2015 provided to study investigator for personal use only

26 Long-Term Safety & Efficacy of ZS-9 in the Treatment of CKD Associated Hyperkalemia Tumlin et.al. Presented ASN San Diego November 2015 provided to study investigator for personal use only

27 ZS-9 Dosing Distribution over 52-Weeks Tumlin et.al. Presented ASN San Diego November 2015 provided to study investigator for personal use only

28 Percentage of Patients Achieving K+-< 5.1 meq/l Tumlin et.al. Presented ASN San Diego November 2015 provided to study investigator for personal use only

29 Sustained Control of Hyperkalemia: Absence of Tachyphylaxis Serum Potassium (meq/l) * * * * * * * * * * * * * * * * n= Baseline Time (Weeks) * Change from AP baseline Paired t-test P-value < u Baseline mean serum K+ = 5.6 meq/l Tumlin u 99% et.al. of patients Presented achieved ASN normokalemia San Diego November in the Acute 2015 Phase provided to study investigator for personal use only CONFIDENTIAL AND PROPRIETARY

30 ZS-9 Side Effect Profile: Incidence of Hypokalemia Tumlin et.al. Presented ASN San Diego November 2015 provided to study investigator for personal use only

31 Case #1 Questions What are the potential risks of hyperkalemia in the ESRD patient? How do these risks differ from patients with acute forms of hyperkalemia? What is the best treatment option for a patient such as this one? What are the potential risks of such treatments? Are there potential drug-drug interactions to worry about with the newer potassium lowering drugs?

32 Case #2 A 62 year-old male with a history of systolic heart failure, coronary artery disease, type 2 diabetes mellitus hypertension, hyperlipidemia and stage 3B CKD is seen for management of his recurrent hyperkalemia as well as for optimization of his medical regimen to slow CKD progression and manage his heart failure

33 Case #2 Relevant Labs Lab Value July 2015 September 2015 January 2016 Potassium (meq/l) Bicarbonate (meq/l) Creatinine (mg/dl) Glucose (mg/dl) Kayexalate given Lisinopril dose decreased Kayexalate given Chlorthalidone started Lisinopril stopped Kayexalate given Patient referred

34 Case #2 Past Treatment In response to the hyperkalemia, the following measures were attempted: The patient was prescribed sodium polystyrene sulfonate without effect The patient was prescribed chlorthalidone 25 mg daily The patient s lisinopril was initially decreased and then stopped altogether Despite these changes, the hyperkalemia persists and has prompted several ED visits

35 Case #2: Key Questions What newer options for the treatment of hyperkalemia exist? How would you manage the need for optimum therapy of heart failure and slowing progression of CKD with the risks of hyperkalemia? What do you think the benefits of these new potassium lowering medications will be in the management of patients with heart failure and CKD?

36 Novel Potassium Binders McCullough PA, et al. Rev Cardiovasc Med. 2014;15(1): (Data from ASH SR. ASN Kidney Week 2013.)

37 Time to First Serum Potassium Level 5.5 mmol/l The recommended starting dose of Veltassa (Patiromer) is 8.4 grams administered orally once daily with food. Doses: 8.4, 16.8 and 25.2 grams patiromer packets Weir MR et al. N Engl J Med. Published online November 21, 2014 at NEJM.org.

38 Primary Efficacy End Point in the Randomized Withdrawal Phase, According to Subgroup Weir MR et al. N Engl J Med. Published online November 21, 2014 at NEJM.org.

39 Effect of Sodium Zirconium Cyclosilicate on Potassium Lowering for 28 Days Among Outpatients With Hyperkalemia: The HARMONIZE Randomized Clinical Trial Kosiborod M et al. JAMA. 2014;312(21):

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41 Case #3 A 59 year-old male with type 2 diabetes mellitus and stage 4 CKD recently enrolls in an intensive exercise program. He exercises intensely for about 60 minutes including some aggressive weight lifting. Several hours later, he notes severe leg and arm pain and he notices that his urine is red. In the emergency room, his vital signs are stable and examination is notable for severe lower and upper extremity tenderness Labs return with a potassium of 6.5 meq/l, CPK is 125,000 U/L His current medications are: Ramipril 10 mg daily Carvedilol 25 mg bid Insulin lantus and lispro Atorvastatin Furosemide 40 mg bid

42 Hyperkalemic Source: Leakage of Intracellular K+ From Myocyte Stores Total K+ content of an average 70 kg person-3500 mmol. 98% K+ is intracellular 2% is extracellular Due to asymmetric distribution, small shifts between intracellular and extracellular compartments can result in major changes in serum-potassium concentration Triphasic Ca++ release; initial Release of intracellular stores Followed by deposition within Necrotic muscle; late release

43 Clinical Objective in the Treatment of Rhabdomyolysis Prophylaxis of potentially exacerbating complications: ETOH induced rhabdomyolysis Hypomagnesemia Hypophosphatemia ETOH withdrawal seizures Unrecognized trauma-e.g. retroperitoneal bleed Compartment Syndrome: Progressive myonecrosis Distal limb ischemia Lactic acidosis-k+ transcellular shifts Control of Hyperkalemia Acute Management: CaCl 2 Insulin-Glucose Oral binders- Kayexelate Patiromer ZS-9 Renal Replacement Therapy: CRRT

44 What about Bicarbonate and/or Mannitol?

45 Efficacy of Bicarbonate-Mannitol Therapy in the Preventing Dialysis Dependent Acute Kidney Injury Study Objective: To determine the safety and efficacy of Mannitol-HCO3 infusion in prevention of dialysis dependent AKI Study Methods: Retrospective review of 2083 admissions to UCLA ICU for trauma associated rhabdomyolysis between & Definitions: Abnormal CPK: > 520 IU/KL AKI: Serum Cr 2.0 or > Treatment: Bicarbonate-Mannitol infusions: Mannitol 0.5 g/kg infused at 100mg/kg/hr Bicarbonate: Bolus with 100 meq NaHCO3 100 meq diluted in 1,000 ml ½ NS Infusion 2-10 mls/kg/hr Primary Endpoints: All cause mortality Rate of renal replacement therapy Brown et.al. Journal Trauma. 56: , 2004

46 Rate of Renal Failure as Function of Serum CPK Brown et.al. Journal Trauma. 56: , 2004

47 Rate of Renal Failure as Function of Serum CPK Brown et.al. Journal Trauma. 56: , 2004

48 Case #3 How would you manage the acute hyperkalemia in this patient with the newer potassium lowering medications? How rapidly do these new medications work? What advantages to these medications have over sodium polystyrene sulfonate? After acute lowering of this patient s serum potassium, how would you manage the patient s medications?

49 Case #4 A 62 year-old male with a history of type 2 diabetes mellitus, hypertension, hyperlipidemia and stage 3B CKD is admitted to the CCU with an acute STelevation myocardial infarction. Initial labs reveal: Potassium 5.9 meq/l Bicarbonate 17 meq/l Creatinine 2.5 mg/dl (baseline was 2.0 mg/dl) Glucose 201 mg/dl Troponin 15 ng/ml ECG with ST-elevation in leads V4-6

50 Case #4 The patient s home medications included: Amlodipine 10 mg daily Metoprolol 50 mg bid Simvastatin 20 mg daily Insulin Omeprazole 20 mg daily

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54 Serum K + >= 5.5 meq/l During Hospitalization was Associated with Death in >60% of Patients (Greater than 12x risk versus K + between ) Serum K + During Hospitalization and Mortality in Patients with AMI Source: Goyal et al. JAMA 2012

55 Case #4 Caveats with conventional approaches Risk of hypokalemia with overcorrection Albuterol 10 mg neb may induce tachycardia Contrast-AKI could worsen hyperkalemia Strong mandate for RAS inhibitors if LV dysfunction How would you manage hyperkalemia in this patient? What are reasonable options to manage acute hyperkalemia in this situation? Neither patiromer nor ZS9 have acute use data

56 Case #4 Continued The patient undergoes cardiac catheterization with successful placement of a drug-eluting stent in the left anterior descending artery Post-catheterization, the patient s ejection fraction is 35%. His labs over the next few days reveal the following: Serum potassium ranges from 4.9 to 5.7 meq/l Creatinine returns to prior baseline How would you manage his discharge medications balancing the treatment of his heart failure, recent MI, CKD and risks of hyperkalemia? 2 indications for RASi: AMI with LV dysfunction and DM- CKD Compelling data for benefit with additional eplerenone in this case

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58 Synthesis Renal Function Stable Compelling Indication for RAASi Post-MI low LVEF or HF Progressive HF Progressive CKD with proteinuria Renal Function Unstable Risk AKI, Risk K Less compelling Indication for RAASi HTN ASCVD Stage 5 CKD Full Court Press Monitor carefully Look forward to new agents for potassium control Select Away from RAASi Still have to monitor carefully Use fall back drugs with less efficacy Expect poor outcomes 58

59 Summary 4 cases with a spectrum of etiologies and therapies for hyperkalemia Discussion of the role and limitations of historically used therapies Role of novel oral medications ZS-9 Patiromer