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Hyperkalemia, an update

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a short talk about mild hyperkalemia. Wat do you do with the potassium of 5.7 mmol/L?

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Hyperkalemia, an update

  1. 1. Conflicts of interest • ZS Pharma honorarium* • Relypsa bought me breakfast* • Astute speaker bureau • Alexis honorarium • Astellas travel honorarium • Davita partner in multiple dialysis units and a vascular access center
  2. 2. 66 year old white male CC: cough and fever Started on TMP-SMX 3 days ago PMHx: CKD 3, DM2, Hypertension 140 5.7 110 21 1.4 18 124
  3. 3. 66 year old white male CC: cough and fever Started on TMP-SMX 3 days ago PMHx: CKD 3, DM2, Hypertension 140 5.7 110 21 1.4 18 124 How would you manage the potassium a. You call that hyperkalemia? Do nothing b. Stop the ACEi/ARB and TMP-SMX c. Some combination of IV calcium, 
 nebulized albuterol, insulin and glucose d. 30 grams oral kayexalate e. answers b, c and d http://bit.ly/HyperK
  4. 4. 66 year old white male CC: cough and fever Started on TMP-SMX 3 days ago PMHx: CKD 3, DM2, Hypertension 140 5.7 110 21 1.4 18 124 How would you manage the potassium a. You call that hyperka-
 lemia? Do nothing. b. Stop the ACEi/ARB and TMP-SMX c. Some combination of IV calcium, 
 nebulized albuterol, insulin and glucose d. 30 grams oral kayexalate e. answers b, c and d http://bit.ly/HyperK
  5. 5. Fralick M, Macdonald EM, Gomes T, et al. Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study. BMJ. 2014;349:g6196.
  6. 6. Ontario residents Age ≥ 66 On an ACE or ARB Over 17 years 39,000 cases of sudden death 1,110 within 7 days of being prescribed an antibiotic
  7. 7. Amoxicillin TMP-SMX Cipro Norfloxacin Nitrofurantoin 1.0 1.0 1.8 (1.5-2.2) 1.7 (1.4-2.0) 0.8 (0.6-1.1) 0.9 (0.7-1.3) 1.4 (1.1-1.8) 1.3 (1.0-1.6) 0.7 (0.5-1.0) 0.6 (0.5-0.9) 7 Day unadjusted adjusted 1.0 1.0 1.8 (1.5-2.1) 1.5 (1.3-1.7) 0.9 (0.7-1.1) 1.1 (0.9-1.3) 1.5 (1.3-1.8) 1.2 (1.0-1.4) 0.8 (0.7-1.1) 1.0 (0.8-1.3) 14 Day unadjusted adjusted
  8. 8. Amoxicillin TMP-SMX Cipro Norfloxacin Nitrofurantoin 1.0 1.0 1.8 (1.5-2.2) 1.7 (1.4-2.0) 0.8 (0.6-1.1) 0.9 (0.7-1.3) 1.4 (1.1-1.8) 1.3 (1.0-1.6) 0.7 (0.5-1.0) 0.6 (0.5-0.9) 7 Day unadjusted adjusted 1.0 1.0 1.8 (1.5-2.1) 1.5 (1.3-1.7) 0.9 (0.7-1.1) 1.1 (0.9-1.3) 1.5 (1.3-1.8) 1.2 (1.0-1.4) 0.8 (0.7-1.1) 1.0 (0.8-1.3) 14 Day unadjusted adjusted
  9. 9. Amoxicillin TMP-SMX Cipro Norfloxacin Nitrofurantoin 1.0 1.0 1.8 (1.5-2.2) 1.7 (1.4-2.0) 0.8 (0.6-1.1) 0.9 (0.7-1.3) 1.4 (1.1-1.8) 1.3 (1.0-1.6) 0.7 (0.5-1.0) 0.6 (0.5-0.9) 7 Day unadjusted adjusted 1.0 1.0 1.8 (1.5-2.1) 1.5 (1.3-1.7) 0.9 (0.7-1.1) 1.1 (0.9-1.3) 1.5 (1.3-1.8) 1.2 (1.0-1.4) 0.8 (0.7-1.1) 1.0 (0.8-1.3) 14 Day unadjusted adjusted
  10. 10. 3 deaths per 1,000 prescriptions TMP-SMX, over age 65, on an ACEi or ARB
  11. 11. Antoniou T, Gomes T, Juurlink DN. Arch Intern Med. 2010;170:1045-9. Risk of admission for hyperkalemia rises 7-fold for people* prescribed TMP-SMX *Age ≥66, ACEi/ARB
  12. 12. dct ccd K + 3 Na+ 2 K+ ATPase + Principal cell
  13. 13. dct ccd K + 3 Na+ 2 K+ ATPase + Principal cell S o d i u m f l o w s d o w n a c h e m i c a l g r a d i e n t
  14. 14. dct ccd K + 3 Na+ 2 K+ ATPase + +– +– +– Principal cell S o d i u m f l o w s d o w n a c h e m i c a l g r a d i e n t G e n e r a t e s a n e g a t i v e c h a rg e i n t h e t u b u l e
  15. 15. dct ccd K + 3 Na+ 2 K+ ATPase + +– +– +– Principal cell S o d i u m f l o w s d o w n a c h e m i c a l g r a d i e n t G e n e r a t e s a n e g a t i v e c h a rg e i n t h e t u b u l e P o t a s s i u m s e c re t i o n
  16. 16. dct ccd K + 3 Na+ 2 K+ ATPase + +– +– +– Principal cell A n y p ro c e s s t h a t b l o c k s t h e e N a C c h a n n e l c a n c a u s e h y p e r k a l e m i a D r u g s • Tr i a m t e re n e • A m i l o r i d e • Tr i m e t h o p r i m ( a b x ) D i s e a s e s • Ty p e 1 RTA ( e l e c t ro g e n i c ) • P s e u d o h y p o a l d o - s t e ro n i s m t y p e 1 STOP
  17. 17. dct ccd K + 3 Na+ 2 K+ ATPase + +– +– +– Principal cell A n y p ro c e s s t h a t b l o c k s t h e e N a C c h a n n e l c a n c a u s e h y p e r k a l e m i a D r u g s • Tr i a m t e re n e • A m i l o r i d e • Tr i m e t h o p r i m ( a b x ) D i s e a s e s • Ty p e 1 RTA ( e l e c t ro g e n i c ) • P s e u d o h y p o a l d o - s t e ro n i s m t y p e 1 STOP
  18. 18. But what if we ignore TMP/SMX…how dangerous is a potassium of 5.5 to 6.5?
  19. 19. Veterans N=245,808 2,103,422 measurements of potassium Einhorn LM. Arch Intern Med. 2009;169(12):1156-62.
  20. 20. Veterans N=245,808 2,103,422 measurements of potassium 0 20,000 40,000 60,000 80,000 Hyperkalemia 21,352 44,907 5.5-6.0 ≥6.0 Einhorn LM. Arch Intern Med. 2009;169(12):1156-62.
  21. 21. Veterans N=245,808 2,103,422 measurements of potassium 0 20,000 40,000 60,000 80,000 Hyperkalemia 21,352 44,907 5.5-6.0 ≥6.0 Incidenceper1,000patientmonths 0.0 2.5 5.0 7.5 10.0 RAAS No RAAS 1.772.3 8.227.67 CKD No CKD Einhorn LM. Arch Intern Med. 2009;169(12):1156-62.
  22. 22. 5,945 patients died within 1 day of a potassium measurement, odds ratio of death based on potassium OddsRatioofdeathin1day 0 10 20 30 40 No CKD CKD 3 CKD 4 CKD 5 8.0 11.6 19.5 31.6 2.3 5.75.4 10.3 1.31.01.11.0 K < 5.5 K 5.5-6.0 K ≥ 6.0 Einhorn LM, Zhan M, Hsu VD, et al. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med. 2009;169(12):1156-62.
  23. 23. 5,945 patients died within 1 day of a potassium measurement, odds ratio of death based on potassium OddsRatioofdeathin1day 0 10 20 30 40 No CKD CKD 3 CKD 4 CKD 5 8.0 11.6 19.5 31.6 2.3 5.75.4 10.3 1.31.01.11.0 K < 5.5 K 5.5-6.0 K ≥ 6.0 Einhorn LM, Zhan M, Hsu VD, et al. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med. 2009;169(12):1156-62.
  24. 24. 5,945 patients died within 1 day of a potassium measurement, % deaths for K and CKD status%ofpotassiumwithadeathin24hours 0 10 K < 5.5 K 5.5-6.0 K ≥ 6.0 4.8% 1.8% 0.4% 8.6% 3.2% 0.3% No CKD CKD Einhorn LM, Zhan M, Hsu VD, et al. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med. 2009;169(12):1156-62.
  25. 25. 5,945 patients died within 1 day of a potassium measurement, % deaths for K and CKD status%ofpotassiumwithadeathin24hours 0 10 K < 5.5 K 5.5-6.0 K ≥ 6.0 4.8% 1.8% 0.4% 8.6% 3.2% 0.3% No CKD CKD Einhorn LM, Zhan M, Hsu VD, et al. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med. 2009;169(12):1156-62. The odds of death increased with severity of hyperkalemia; however, the risk of death was greater in the absence of CKD than in the presence of CKD.
  26. 26. How about some prospective data?
  27. 27. How about some prospective data?
  28. 28. 64.3±12.1 Age female male Asian Black/African American WhiteWeight potassium <5.5 5.5-6.0 ≥6.0 5.6 50% 35% 14% eGFR openlabeltreat 4.6 85.1±18.6 46.3±30.5 Kosiborod M, Rasmussen HS, Lavin P, et al. HARMONIZE randomized clinical trial. JAMA. 2014;312(21):2223-33.
  29. 29. p l a c e b o 1 . 2 5 & 2 . 5 g 5 & 1 0 g AT R I A L F I B 0 0 1 AT R I A L F L U T T E R 0 1 0 B R A D Y C A R D I A 0 0 1 PA L P I TAT I O N S 0 0 1 S I N U S TA C H Y C A R D I A 0 0 1 V E N T R I C U L A R E X T R A S Y S T O L E 0 0 1
  30. 30. p l a c e b o 1 . 2 5 & 2 . 5 g 5 & 1 0 g AT R I A L F I B 1 0 1 L E F T B B B 0 1 0 B R A D Y C A R D I A 0 0 1 C H F 1 0 0 C V D I S O R D E R 1 0 0 D I A S T O L I C D Y S F U N C T I O N 0 0 1 L O N G Q T 0 0 1
  31. 31. 65.0±9.1 Age female male White Weight potassium 4.455.9 eGFR 4.6 85.1±18.6 35.4±16.2 5.17 K ≥ 5.5 openlabeltreat blindedplacebo Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer. N Engl J Med. 2015;372(3):211-21.
  32. 32. 2 patients during the initial treatment phase and 1 in the patiromer group during the randomized withdrawal phase had ECG changes consistent with hyperkalemia
  33. 33. How about some prospective data? Disagreement between the retrospective view from 30,000 feet and carefully collected prospective data.
  34. 34. P o t a s s i u m 8 . 5 m m o l / L d u e t o r h a b d o m y o l y s i s
  35. 35. P o t a s s i u m o f 9 . 9 , h e m o l y z e d s p e c i m e n
  36. 36. 66 year old white male CC: cough and fever Started on TMP-SMX 3 days ago PMHx: CKD 3, DM2, Hypertension 140 5.7 110 21 1.4 18 124 How would you manage the potassium a. You call that hyperkalemia? Do nothing b. Stop the ACEi/ARB and TMP-SMX c. Some combination of IV calcium, 
 nebulized albuterol, insulin and glucose d. 30 grams oral 
 kayexalate http://bit.ly/HyperK
  37. 37. 1938 Food, Drug, and Cosmetic Act
  38. 38. 1962 Kefauver, Harris Amendment
  39. 39. 10 oliguric patients Treated with Sorbitol, SPS, or both.
  40. 40. Sorbitol aloneSPS in blue
  41. 41. Sorbitol aloneSPS in blue Potassium(mmol/L) 3 4 5 6 7 8 Day 0 Day 5
  42. 42. Sorbitol aloneSPS in blue Potassium(mmol/L) 3 4 5 6 7 8 Day 0 Day 5
  43. 43. Sorbitol aloneSPS in blue Potassium(mmol/L) 3 4 5 6 7 8 Day 0 Day 5
  44. 44. 32 patients SPS 20-60 grams a day 23 oliguric AKI 9 CKD everyone was treated, no controls 30 patients treated between 1 and 6 days 2 treated for 35 and 280 days respectively
  45. 45. Numberofpatients 0 1 2 3 4 5 Change in Potassium (mmol/L) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2+ potassium change in the first 24 hours
  46. 46. Numberofpatients 0 1 2 3 4 5 Change in Potassium (mmol/L) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2+ potassium change in the first 24 hours
  47. 47. that was enough for approval
  48. 48. Potassium(mmol/L) 4.00 4.25 4.50 4.75 5.00 Time (hours) 0 4 8 12 Placebo Phenol SPS Phenol SPS Sorbitol SPS Serum potassium after single dose
  49. 49. Potassium(mmol/L) 4.00 4.25 4.50 4.75 5.00 Time (hours) 0 4 8 12 Placebo Phenol SPS Phenol SPS Sorbitol SPS Serum potassium after single dose patients are not hyperkalemic | N=6
  50. 50. Potassium 5.0-5.9 mmol/L GFR < 40 mL/min PlaceboSPS 30 g qD Primary outcome: mean difference in potassium from baseline to the day after the last dose of study drug 7 days 7 days
  51. 51. 16 randomized 
 to SPS 15 analyzed K+ fell 1.25 4 11 17 randomized 
 to placebo 16 analyzed K+ fell 0.21 10 6 P=0.07 P<0.001 eukalemia
  52. 52. 16 randomized 
 to SPS 15 analyzed K+ fell 1.25 1 14 17 randomized 
 to placebo 16 analyzed K+ fell 0.21 10 6 P=0.002 P<0.001
  53. 53. “increase in constipation, nausea, and vomiting in patients receiving SPS and an increased prevalence of diarrhea in the placebo group.”
  54. 54. 1938 Food, Drug, and Cosmetic Act
  55. 55. Five patients received kayexalate and sorbitol enemas for hyperkalemia Lillemoe KD, Romolo JL, Hamilton SR, Pennington LR, Burdick JF, Williams GM. Intestinal necrosis due to sodium polystyrene (Kayexalate) in sorbitol enemas: clinical and experimental support for the hypothesis. Surgery. 1987;101(3):267-72.
  56. 56. Five patients received kayexalate and sorbitol enemas for hyperkalemia Lillemoe KD, Romolo JL, Hamilton SR, Pennington LR, Burdick JF, Williams GM. Intestinal necrosis due to sodium polystyrene (Kayexalate) in sorbitol enemas: clinical and experimental support for the hypothesis. Surgery. 1987;101(3):267-72.
  57. 57. Five patients received kayexalate and sorbitol enemas for hyperkalemia all five of them developed colonic necrosis and four died Lillemoe KD, Romolo JL, Hamilton SR, Pennington LR, Burdick JF, Williams GM. Intestinal necrosis due to sodium polystyrene (Kayexalate) in sorbitol enemas: clinical and experimental support for the hypothesis. Surgery. 1987;101(3):267-72.
  58. 58. Harel Z, Harel S, Shah PS, Wald R, Perl J, Bell CM. Gastrointestinal adverse events with sodium polystyrene sulfonate (Kayexalate) use: a systematic review. Am J Med. 2013;126(3):264.e9-24.
  59. 59. 23 case reports 30 articles 7 case series 58 cases
  60. 60. 23 case reports 30 articles 7 case series 58 cases 0 10 20 30 40 Before 1990 1990-2000 After 2000 31 24 3
  61. 61. 23 case reports 30 articles 7 case series 58 cases 0 10 20 30 40 Before 1990 1990-2000 After 2000 31 24 3 mean age 58 years
  62. 62. 23 case reports 30 articles 7 case series 58 cases 0 10 20 30 40 Before 1990 1990-2000 After 2000 31 24 3 women men mean age 58 years
  63. 63. 23 case reports 30 articles 7 case series 58 cases 0 10 20 30 40 Before 1990 1990-2000 After 2000 31 24 3 women men mean age 58 years No CKD ESRD CKD
  64. 64. 23 case reports 30 articles 7 case series 58 cases 0 10 20 30 40 Before 1990 1990-2000 After 2000 31 24 3 women men mean age 58 years No CKD ESRD CKD Chronic Acute
  65. 65. 23 case reports 30 articles 7 case series 58 cases 0 10 20 30 40 Before 1990 1990-2000 After 2000 31 24 3 women men mean age 58 years No CKD ESRD CKD Chronic Acute SPS SPS+Sorbitol
  66. 66. 23 case reports 30 articles 7 case series 58 cases 0 10 20 30 40 Before 1990 1990-2000 After 2000 31 24 3 women men mean age 58 years No CKD ESRD CKD Chronic Acute 20% Sorbitol 70% Sorbitol SPS SPS+Sorbitol
  67. 67. 45 with colon
  68. 68. 1 with esophagus 2 with stomach 12 with small bowel 45 with colon
  69. 69. 58 cases of gastrointestinal ischemia from 1973 to 2013 is 9 kg of kayexalate (guessing 5 doses per episode) 58 cases is that a lot
  70. 70. 5 million doses of kayexalate used per year 58 cases of gastrointestinal ischemia from 1973 to 2013 is 9 kg of kayexalate (guessing 5 doses per episode) 58 cases is that a lot
  71. 71. 5 million doses of kayexalate used per year 150,000 kg of kayexalate 58 cases of gastrointestinal ischemia from 1973 to 2013 is 9 kg of kayexalate (guessing 5 doses per episode) 58 cases is that a lot
  72. 72. 5 million doses of kayexalate used per year 150,000 kg of kayexalate 58 cases of gastrointestinal ischemia from 1973 to 2013 is 9 kg of kayexalate (guessing 5 doses per episode) 58 cases is that a lot
  73. 73. 5 million doses of kayexalate used per year 150,000 kg of kayexalate 58 cases of gastrointestinal ischemia from 1973 to 2013 is 9 kg of kayexalate (guessing 5 doses per episode) 58 cases is that a lot
  74. 74. avoid kayexalate in patients with sick bowels (infection, constipation, ischemic disease, GI bleed) avoid kayexalate in post transplant patients avoid kayexalate enemas
  75. 75. 66 year old white male CC: cough and fever Started on TMP-SMX 3 days ago PMHx: CKD 3, DM2, Hypertension 140 5.7 110 21 1.4 18 124 How would you manage the potassium a. You call that hyperkalemia? Do nothing b. Stop the ACEi/ARB and TMP-SMX c. Some combination of IV
 calcium, nebulized albu-
 terol, insulin and glucose d. 30 grams oral kayexalate
  76. 76. Allon Et al. Annals of Int Med; 1989: 110, 426-429 inhaled beta-agonists are effective
  77. 77. • 8 studies show this works • 20 mg works better than 10 mg • IV administration is no better than nebulized • additive to insulin • may be repeated after 2 hours Allon Et al. Annals of Int Med; 1989: 110, 426-429 inhaled beta-agonists are effective
  78. 78. Allon Et al. Annals of Int Med; 1989: 110, 426-429 inhaled beta-agonists are effective
  79. 79. • give regular insulin intravenously rather than subcutaneously Blumberg Et al. Amer J Med; 1988: 85, 507-512. as is intravenous insulin
  80. 80. Blumberg Et al. Amer J Med; 1988: 85, 507-512. but sodium bicarbonate is not
  81. 81. Blumberg Et al. Amer J Med; 1988: 85, 507-512. but sodium bicarbonate is not
  82. 82. Blumberg Et al. Amer J Med; 1988: 85, 507-512. but sodium bicarbonate is not
  83. 83. Blumberg Et al. Amer J Med; 1988: 85, 507-512. Blumberg Et al. Kidney International; 1992: 41, 369-374.
  84. 84. • 4 mmol/min for 1 hour • 240 mmol of NaHCO3 • 0.5 mmol/min for 5 hours • 150 mmol of NaHCO3 • Total 390 mmol NaHCO3 
 (8 amps) in 1140 mL Blumberg Et al. Amer J Med; 1988: 85, 507-512. Blumberg Et al. Kidney International; 1992: 41, 369-374.
  85. 85. insulin and glucose Theoretical maximum 
 134 mmol/min 14 liters x 4 mmol/liter 
 = 56 mmol
  86. 86. insulin and glucose Theoretical maximum 
 134 mmol/min 14 liters x 4 mmol/liter 
 = 56 mmol
  87. 87. insulin and glucose Maximum hypoglycemic effect at 100microUnits/mL Maximum hypokalemic effect at 500 microUnits/mL Theoretical maximum transport of 134 mmol/min
  88. 88. insulin and glucose Maximum hypoglycemic effect at 100microUnits/mL Maximum hypokalemic effect at 500 microUnits/mL Theoretical maximum transport of 134 mmol/min
  89. 89. insulin and glucose Maximum hypoglycemic effect at 100microUnits/mL Maximum hypokalemic effect at 500 microUnits/mL Theoretical maximum transport of 134 mmol/min
  90. 90. 600 400 200 0 Maximum kalemic effect Maximum glycemic effect 60 80 100 12040200 10 units of IV insulin
  91. 91. 600 400 200 0 Maximum kalemic effect Maximum glycemic effect 60 80 100 12040200 10 units of IV insulin
  92. 92. 600 400 200 0 Maximum kalemic effect Maximum glycemic effect 60 80 100 12040200 10 units of IV insulin
  93. 93. 600 400 200 0 Maximum kalemic effect Maximum glycemic effect 60 80 100 12040200 10 units of IV insulin
  94. 94. 29 of the 221 (13%) episodes resulted in hypoglycemia. Glucose 51–60 mg/dL in 16 episodes Glucose ≤ 50 mg/dL in 13 episodes All patients with hypoglycemic episodes received 25 g of dextrose with insulin. Hypoglycemia occurred at a median of 2 h and persisted for a median of 2 h
  95. 95. Albuterol lowers the potassium independent and additively with insulin glucose Guhan AR, Cooper S, Oborne J, Lewis S, Bennett J, Tattersfield AE. Systemic effects of formoterol and salmeterol: a dose-response comparison in healthy subjects. Thorax. 2000;55(8):650-6. Albuterol stimulates glucosegenesis
  96. 96. 66 year old white male CC: cough and fever Started on TMP-SMX 3 days ago PMHx: CKD 3, DM2, Hypertension 140 5.7 110 21 1.4 18 124 How would you manage the potassium a. You call that hyperkalemia? Do nothing b. Stop the ACEi/ARB and TMP-SMX c. Some combination of IV calcium, 
 nebulized albuterol, insulin and glucose d. 30 grams oral kayexalate e. answers b, c and d http://bit.ly/HyperK
  97. 97. potassium calcium exchanger Patiromer
  98. 98. Patiromer for Oral Suspension (FOS) is a high capacity, non- absorbed, oral potassium binder. Patiromer is a dry, odorless powder for suspension in small amounts of water. Patiromer is insoluble in typical solvents and passes through the GI tract without being metabolized or broken down.
  99. 99. CKD stage 3 or 4 Potassium 5.1–6.5 RAAS inhibitor 4 week single group phase 8 week single blind placebo controlled withdrawal phase • 52 on placebo • 55 on patiromer K 5.1-5.5 4.2 g bid n=92 K 5.5-6.5 8.4 g bid n=151 K 3.8-5.0
  100. 100. How would you manage the potassium a. You call that hyperkalemia? Do nothing b. Stop the ACEi/ARB and TMP-SMX c. Some combination of IV calcium, 
 nebulized albuterol, insulin and glucose d. 30 grams oral kayexalate e. Patiromer (Veltassa) e. answers b, c and d

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