Diuretic Resistance and Toxicity in the setting of ADHF

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Recurrence of Kidney Disease in 118,465 Admissions1. eCrCl >90 60

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Diuretic Resistance and Toxicity in the setting of ADHF John Wigneswaran MD Chief Medical Officer CHF Solutions Inc. June 2009

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Frequency of Kidney Disease in 118,465 Admissions 1 eCrCl >90 60 – 89 30 – 59 15–29 <15 mL/min Heywood et al.  J Am Coll Cardiol . 2005;173A:843-848.

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The Cardiorenal Syndrome of HF Diuretic Therapy Increased Morbidity and Mortality Neurohormonal Activation Development of Diuretic and Natriuretic Resistance Diminished Blood Flow Impaired Renal Function Decreased Renal Perfusion??

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Mechanisms of Renal Failure: 1. Expanded Renal Vein Pressures, lessened sodium discharge, diminished GFR 2. Expanded Interstitial edema-prompting to hypoxia 3. Interruption of renal autoregulation by incitement of vascular reflexes Mc

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Mechanisms of Sodium and Water Retention in ADHF Heart Failure Catecholamines ↑ Vasopressin ↑ Atrial Natriuretic Peptide ↑ Renin ↑ Aldo ↑ ANP Resistance AII ↑ Passive Na and H 2 O Reabsorption Proximal Tubule ↑ Via Efferent Constriction (roundabout impact ) Na Reabsorption Collecting Duct ↓ Excretion of Free Water Collecting Tubule ↓ Thirst Na Reabsorption Proximal & Distal Tubule ↑ Na Reabsorption Proximal Tubule ↑ (Direct Effect) Inhibition of Renin and Aldosterone Secretion Na Reabsorption Collecting Duct ↑ Courtesy of Robert Schrier, MD, University of Colorado School of Medicine.

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Most Common Intravenous Medications All Enrolled Discharges (n=105,388) October 2001 – January 2004 100 88% 90 80 70 60 Patients (%) 50 40 30 10% 20 6% 3% 1% 10 0 IV Diuretic Dobutamine Dopamine Milrinone Nesiritide Nitroglycerin Nitroprusside IV Vasoactive Meds ADHERE ® Registry. Benchmark Report. 2004.

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Diuretics and ADHF No long haul investigations of diuretics for the treatment of ADHF 1 Despite far reaching use in ADHF, their impact on dismalness and mortality is not known 2 1. Ravnan et al. Stuff Heart Fail . 2002;8:80. 2. Kramer et al. Nephrol Dial Transplant . 1999:14(suppl 4):39-42.

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Diuretic Resistance Can be depicted as a clinical state in which the diuretic reaction is reduced or lost before the helpful objective of alleviation from edema has been achieved 1 Affects 20%–30% of patients with HF 2 1. Kramer et al. Nephrol Dial Transplant . 1999;14(suppl 4):39-42. 2. Ellison. Cardiology . 2001;96:132-143.

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Diuretic Resistance: Two Types "Braking" marvel A diminishing in light of a diuretic after the main measurement has been regulated Long-term resilience Tubular hypertrophy to make up for salt misfortune Brater. N Engl J Med . 1998;339:387.

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Diuretics Activate Neurohormonal Systems in HF 50 1000 Mean, 95% Confidence Interval 600 10 Plasma Renin Activity (ng/mL/h) Plasma Aldosterone (pmol/L) 2.5 200 0.5 P =.0007 100 P =.0002 After Diuretic (n=11) After Diuretic (n=11) Before (n=12) Before (n=12) Bayliss et al. Br Heart J. 1987;57:17

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Furosemide Monotherapy Causes Significant Decline in Renal Function (GFR) Change in GFR after IV furosemide 80 mg in CHF 15 Placebo 10 5 0 - 5 GFR (% Change) IV furosemide - 10 - 15 - 20 - 25 0 500 1000 1500 2000 2500 Urine Output (mL) 0 – 8 h Gottlieb et al. Dissemination . 2002;105:1348.

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Reaccumulation of Na + Despite Ongoing Furosemide Treatment 1 300 250 200 150 100 50 0 Na + Excretion Net Diuresis After 4 Days of Rx = 0 mL U Na V, mEq/6 h Na + Intake Before F 1 F 2 F 3 F 4 Time, Days F = Furosemide Na + Reaccumulation Between Furosemide Doses 1. Wilcox et al. Kidney Int. 1987;31:135 .

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Dose Response Curves for Loop Diuretics in ADHF Are Altered Fractional Na Excretion 20 18 16 14 12 10 8 6 4 2 0 Normal CRF CHF Decreased Maximal Response Secretory Defect FE Na ,% 0.01 0.1 1 10 100 [Furosemide], µg/mL Ellison. Cardiology . 2001;96:132-143.

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Brater. N Engl J Med . 1998;339:387-395.

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Diuretic Toxicity Peacock et. al. concentrates 82,540 patients from the ADHERE Registry Eshaghian et. al. concentrated 1,354 patients with HF Patients were isolated into gatherings by diuretic dosage The ≥80 mg bunches… Had fundamentally higher mortality Were 3x times more inclined to get dialysis (≥160 mg) There is an autonomous, measurement subordinate relationship between circle diuretic utilize and debilitated survival HF patients on measurements ≥ 80 mg would profit by Aquapheresis Eshaghian S. et al. Am J Cardiol 2006;97:1759 –1764. Peacock WF Cardiology 2009;113:12-19.

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Outcomes with Standard Care Change in Weight During Hospitalization January 2001 to April 2006 (n=96,094) Evidence of Incomplete Relief From Congestion Nearly half of ADHF patients released with weight pick up or losing under 5 lbs 27% 30 26% 25 20 Enrolled Discharges (%) 13% 15 16% 7% 6% 10 3% 2% 5 0 (<- 20) (–20 to –15 ) (- 15 to –10) (–10 to –5) (–5 to 0) (0 to 5) (5 to 10) (>10) Change in Weight (lbs) Adhere National Benchmark Report Data, January 2001 to April 2006. Note: n speaks to the quantity of patients who have both gauge and release weight, and the rate is figured in view of the aggregate patients in the relating populace. Patients without pattern or release weight are precluded from the histogram computations.

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ULTRAFILTRATION takes into account the generation of plasma water from entire blood over a semipermeable film in light of a transmembrane weight angle The resulting liquid or ultrafiltrate is isotonic to plasma Ronco et al. Cardiology . 2001;96:155-168.

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1940 1950 1960 1970 1980 A History of Ultrafiltration 1979: Paganini and others revealed the viable use of ultrafiltration in a volume-over-burden quiet 4 1974: Silverstein portrayed single ultrafiltration on 5 ESRD patients by means of an adjusted dialysis circuit 3 1949: Schneierson proposed irregular peritoneal dialysis for refractive ADHF 1 1954: Kolff noticed that ultrafiltration could be utilized for a "diminishment of unmanageable edema" 2 1. Schneierson SJ . Am J Med Soc. 1949;298. 2. Kolff et al. Cleve Clin Q. 1954;21 . 3. Silverstein et al. N Engl J Med. 1974;291:747-751. 4. Paganini et al. Adv Ren Replace Ther. 1996;3:166-173.

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Hemodynamic Effects of UF in CHF CO (L/m) SV (mL) 5.0 – 4.0 – 3.0 – 2.0 – 70 – 60 – 50 – 40 – 30 – Before UF 1 liter 2 liter 3 liter 4 liter After UF 24h after UF Before UF 1 liter 2 liter 3 liter 4 liter After UF 24h after UF RAP (mmHg) PWP (mmHg) 30 – 25 – 20 – 15 – 10 - 25 – 20 – 15 – 10 – 5 – 0 - Before UF 1 liter 2 liter 3 liter 4 liter After UF 24h after UF Before UF 1 liter 2 liter 3 liter 4 liter After UF 24h after UF Marenzi et al. J Am Coll Cardiol . 2001;38:963-968.

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+ 170 – + 80 – + 40 – % 0 – - 40 - Effects of Ultrafiltration versus IV Furosemide Neurohormones NE PRA ALD + 80 – + 40 – % 0 – 140 – + 80 – + 40 – % 0 – 140 – d 0 1d 2d 3d 4d 3m d 0 1d 2d 3d 4d 3m d 0 1d 2d 3d 4d 3m Triangles = Ultrafiltration Squares = Furosemide Agostoni et al. Am J Med. 1994;96:191-199.

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Ultrafiltration and Severe Chronic Kidney Disease High rates of ultrafiltration might be related with exacerbating renal capacity in certain patient subsets 4/11 patients with ADHF, late Stage 4/Stage 5 CKD (CrCl <30 mL/min), experienced ARF * with high rates and volumes of UF (up to 485 mL/h for 8 h, numerous medicines) 1 High ultrafiltration rates and concurrent serious endless kidney infection are essential variables to consider while endorsing ultrafiltration *>0.3 mg/dL creatinine increment Liang et al. J Card Fail . 2006;12:707-714.

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Fluid Removal by Ultrafiltration Interstitial Space (edema) Ultrafiltration can expel liquid from the blood at a similar rate that liquid can be actually enlisted from the tissue The transient evacuation of blood illicits compensatory systems, named plasma or intravascular refill (PR), went for limiting this diminishment 1,2 Na P H 2 O Na K UF K PR P Vascular Space Na Vascular Space Na 1. Lauer et al. Curve Intern Med . 1983;99:455-460. 2. Marenzi et al. J Am Coll Cardiol . 2001;38:4.

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Conclusions Diuretic Resistance might be found in 1/3 of confirmations for ADHF Loop Diuretic PK/PD properties may assume a part in choosing treatment conventions High Doses of diuretics might be related with poor results

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