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1 Test Your Skills in Difficult Cases 1:30 3:30pm Test Your Skills in Difficult Cases: Nephrology, Hypertension, and Atrial Fibrillation Presenter Disclosure Information The following relationships exist related to this presentation: LaTonya J. Hickson, MD, has no financial relationships to disclose SPEAKER LaTonya J. Hickson, MD Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Case 1: Kidney Stones Prevention of Recurrent Stones 40-year-old male History of migraines and inflammatory bowel disease (2 loose stools per day) Presents for follow up after an ED visit for flank pain CT imaging revealed a few 2-3 mm stones bilaterally His pain has subsided although no stones were passed 2013 meta-analysis: Single stone (calcium) episode history: Increased fluid intake Multiple stone episodes: Thiazide diuretics Allopurinol (in those with uric acid) Citrate Fink, HA et al. Ann Intern Med. 2013;158: Dietary Modifications to Prevent Recurrent Kidney Stones Fluid Intake/ Urine Output 2-3 liters/day Standard Calcium Intake Dietary calcium preferred over supplements to bind oxalate in intestinal tract Case 2: Hyponatremia 69-year-old female Presents for follow up of right shoulder pain from a supraspinatus tear Sodium Intake Less than 5 g of salt or 2 g of sodium Minimize the following: Meat/Protein Intake Leads to high urine acid excretion (uric acid) Ferraro PM, et al. Clin J Am Soc Nephrol Jul;8(8): Sugar-Sweetened Soda and Punch Avoid fructose, but beer, wine, O.J. may be good Oxalate Intake Avoid high oxalate foods (spinach, soy, almonds) Medical History: Hypertension moderate left renal artery stenosis Hyperlipidemia COPD alcohol abuse Medications: Pravastatin Metoprolol Ibuprofen prn Aspirin HCTZ Tiotropium bromide HCTZ=hydrochlorothiazide Vitals: BP: 120/70 mmhg HR: 72 bpm Weight: 62 kg BMI: 21 kg/m 2 Exam: No edema Normal mentation 1

2 Case 2: Hyponatremia Drug-Induced Hyponatremia Treatment Changes: HCTZ held Another antihypertensive agent prescribed Patient advised to monitor free water intake and eat high-sodium diet One Week Later: She returns feeling lightheaded She has orthostatic hypotension Serum Na is down to 117 mmol/l No mental status changes Your colleague repeats advice and schedules repeat labs 2 days later Repeat Labs: Serum Na: 120 mmol/l Serum osmolality: 257 mosm/kg Uric acid: 3 mg/dl Urine osmolality: 182 mosm/kg Urine Na: 12 mmol/l Thiazides >> loop diuretics, indapamide, amiloride Antidepressants (SSRI s) Antipsychotics Antiepileptics NSAIDs Amlodipine Angiotensin-converting enzyme inhibitors Liamis G, et al. Am J Kidney Dis. 2008;52: Common Drugs Trimethoprimsulfamethoxazole Anticancer agents (cisplatin, cyclophosphamide, vincristine) Antiarrhythmia (amiodarone) Immune globulin Diuretic-Induced Hyponatremia High risk individuals: Elderly Females High alcohol consumption Low body mass index Concomitant agents associated with SIADH SIADH=syndrome of inappropriate antidiuretic hormone secretion Diuretic-Induced Hyponatremia Diagnostic Algorithm Obtain serum uric acid level Uric acid <4 SIADH mechanism Infuse hypertonic saline vs. administer oral sodium chloride and furosemide Liamis, G. J Investig Med. 2007;55: Liamis G, et al. Am J Kidney Dis. 2008;52: Uric acid >4 Volume depletion mechanism Infuse 0.9% normal saline vs. encourage high-salt diet Case 3: Kidney Disease Progression and Hypertension Annual evaluation of 55-year-old African American man with diabetes, hypertension, and chronic kidney disease (CKD) stage 3 BP: 150/90 mmhg on amlodipine 5 mg and furosemide 20 mg daily Labs Serum creatinine (egfr) 1.6 mg/dl (45 ml/min/1.73m 2 ) Serum potassium 3.6 mmol/l Serum bicarbonate 22 mmol/l Serum uric acid 7 mg/dl Urine albumin:creatinine ratio 20 mg/g Drugs & CKD Progression Spironolactone Effective in resistant hypertension management and may minimize renal injury due to ischemia 1 Sodium bicarbonate Some benefit in slowing CKD progression 2 Calcitriol May aid in lowering proteinuria which may also slow CKD progression 3 Allopurinol* Some benefit in slowing CKD progression. Target of uric acid level to be determined 4 1.Barrera-Chimal J, et al. Kidney Int Jan;83(1): Chen W, Ambramowitz, MK. Am J Kidney Dis Aug 7. [Epub ahead of print] 3. De Borst, MH, et al. J Am Soc Nephrol Aug 8. [Epub ahead of print] 4. Jalal DI, et al. Am J Kidney Dis Jan;61(1): * Dose adjustment required with low egfr 2

3 2012 KDIGO Clinical Practice Guideline for Management of Blood Pressure in CKD Target BP 140/90 mmhg 130/80 mmhg KDIGO. Kidney Int. 2012;2 (5): Population CKD patients with normal urine albumin excretion (<30 mg/24 hrs) in diabetic and nondiabetic patients CKD patients with moderately or severely increased albuminuria (urine albumin excretion >30 mg/24 hrs) All renal transplant patients First line drugs: ACE-I and ARB Note: New HTN guidelines pending ACE-I=angiotensinconverting enzyme inhibitors ARB=angiotensin receptor blockers JNC 8=Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Clinical Pearls The ARB losartan has a uricosuric effect 1 Allopurinol has been associated with lowering blood pressure in clinical trials 2 African-Americans have a 4-fold increased risk of developing end-stage renal failure compared to Caucasians 3 1. Miao Y, et al. Hypertension. 2011;58(1): Shi Y, et al. Kidney Blood, Press Res. 2011;35(3): Tareen N, et al. Kidney Int. 2005;68:S137 S140. Case 4: Edema 57-year-old woman with hypertension Presents with a 2-month history of lower extremity edema Labs Serum creatinine: 0.9 mg/dl Serum albumin: 3.3 g/dl Serum total cholesterol: 270 mg/dl Serum total AST: 35 U/L Urine dipstick blood: negative Urine dipstick protein: 3+ AST= aspartate aminotransferase When Is it Most Appropriate to Do a 24- Hour Urine Collection? When formal documentation of actual protein excretion rate (not a predicted rate) is needed Common scenario: Nephrotic range proteinuria (>3,500 mg/day) The random urine studies correlate less accurately with measured protein excretion rates beyond the nephrotic range. Comparison of Urine Protein Studies in the Setting of Nephrotic Range Proteinuria Protein/Osmolality ratio: Predicted protein: 41,950 mg/24 hr Albumin/creatine ratio: >4,384 mg/g 24 hr total protein: 12,168 mg/24 hr Case 4 (Edema): Further Testing Labs Serum creatinine: 0.9 mg/dl Serum liver enzymes: Normal Serum albumin: 3.3 g/dl 24 hour urine protein: 4,000 mg Serum total cholesterol: 270 mg/dl Chest radiograph: Pulmonary vascular congestion Echocardiogram: Ejection fraction 55% 3

4 Nephrotic Syndrome Protein in Urine HIGH; >3.5 gm/day Protein in Blood LOW; hypoalbuminemia Lipids in Urine Fat in casts, fatty casts Lipids in Blood Dyslipidemia (exacerbated) Risk Factors for Bleeding Post Kidney Biopsy Inpatient status Thrombocytopenia Prior use of anti-platelet therapy Younger patients Females Edema Sethi I, et al. Semin Dial Mar 12. [Epub ahead of print] Manno C, et al. Kidney Int Oct;66(4): Nephrology Referral Progressive renal dysfunction Example: egfr decline >4 ml/min/year Progressive proteinuria or nephrotic range proteinuria Persistent hematuria Uncontrolled hypertension egfr 45 ml/min/1.73m2 (egfr 30) Abnormal urine sediment Expectant renal replacement therapy Diagnostic Laboratory Tests for Glomerular Diseases Serologic studies (for systemic disease) C-reactive protein Erythrocyte sedimentation rate Anti nuclear antibody Complement levels (total, C3, C4) Streptococcal antibodies profile -- (if infection suspected) HIV Syphilis (RPR) Hepatitis B and C serologies Serum and Urine monoclonal protein studies Serum free light chains Cryoglobulins/ Cryofibrinogen Rheumatoid factor Creatinine kinase ANCA panel for Vasculitis Anti-Glomerular Basement membrane Glomerular Diseases Commonly Associated with Nephrotic Syndrome Primary Diseases Minimal change disease Focal segmental glomerulosclerosis Membranous nephropathy Amyloidosis Light chain deposition disease Diabetic glomerulosclerosis A Simplified Guide to Analyzing Urinary Sediment Urine microscopy findings Potential disease processes Granular casts, muddy brown Acute tubular necrosis casts, renal epithelial cells WBCs, WBC casts +/- Infection: urinary tract, eosinophils pyelonephritis; interstitial nephritis (allergic) RBCs Nonspecific urologic or renal process (workup microscopic hematuria) RBCs, RBC casts, dysmorphic Glomerulonephritis RBCs Bland sediment (few cells, hyaline casts) All of the above, diuretic use, prerenal states, obstructive and renovascular disease 4

5 Case 5: Gross Hematuria 22-year-old woman Presents with complaints of gross hematuria and intermittent urinary tract infections Occasionally has had strep pharyngitis Creatinine 1.5 mg/dl Urine protein: 1,500 mg/day Her urine is pictured above You order a urinalysis and review her urine sample under the microscope IgA Nephropathy Most common cause of glomerulonephritis in developed countries Presentation Gross hematuria (generally after upper respiratory infection) Microscopic hematuria Progression to end-stage renal disease Proteinuria, elevated creatinine, hypertension Henoch Schönlein Purpura: vasculitis involving multiple organs (skin, GI tract, kidneys) Case 6 New patient: 55-year-old man with hypertension Presents with chronic back pain and increased abdominal girth Discloses that several family members have renal failure BP: 160/85 mmhg despite HCTZ 12.5 mg daily, metoprolol 50 mg twice daily, amlodipine 5 mg daily Labs Blood urea 20 nitrogen: Serum creatinine: Urinalysis: 1.8 (egfr 39) bland sediment with few hyaline casts Evaluation of Newly Elevated Creatinine Obtain Urinalysis/Urine Dipstick in Office Address risk factors and reversible causes (e.g. volume depletion, newly added ACEI/ARB or other medications) Repeat creatinine and urinalysis Persistently abnormal No Observe Normal Yes TO fix -Renal Imaging and arrows at the bottom should disappear when the left hand side disappears. Renal Imaging Abnormal (Proteinuria, hematuria) Renal Imaging Proceed to next slide Evaluation of Newly Elevated Creatinine (cont d) Renal Imaging Normal Repeat Creatinine Persistently abnormal or stable Refer to Nephrology for assessment and/or CKD management Refer to Urology for obstruction management Abnormal: cystic, mass, obstruction, CKD Case 7: Newly Elevated Creatinine You recently treated a 68-year-old man for possible sinusitis with amoxicillin and ibuprofen Several days later He returned with persistent symptoms and was transitioned to levofloxacin Serum creatinine 1.8 mg/dl (159 μmol/l) 3 weeks later He presents with headache, knee pain, nausea/vomiting, and fatigue Serum creatinine 6.9 mg/dl (610 μmol/l) 5

6 Case 7: Laboratory Tests Pulmonary-Renal Syndromes C3 Normal C4 Normal C-reactive protein 130 mg/dl Sedimentation rate 90 c-antineutrophil cytoplasmic antibody Positive Myeloperoxidase titer Negative Proteinase : 1 Urine 24 hr proteinuria predicted 1,560 mg Urine renal epithelial cells & granular Present casts Urine red blood cells per high power field Patient now complains of new onset bloody sputum ANCA vasculitis Granulomatosis with polyangiitis (GPA), formerly known as Wegener s granulomatosis Microscopic polyangiitis (MPA) Eosinophilic granulomatosis with polyangiitis (EGPA) formerly known as Churg-Strauss Anti-glomerular basement membrane disease (Goodpasture s syndrome) Lupus Cryoglobulinemia Urgent immunosuppressive treatment is indicated in this group Summary AF and Stroke Nephrology cases can be challenging A general understanding of how best to manage complex cases with (or sometimes without) a nephrologist is critical Primary care doctors and providers serve on the front line Early recognition of kidney disease and subsequent referral may make a great difference in long term patient and renal outcomes Stroke is the most common complication of AF Approximately 15% of all strokes in the US are caused by AF Ischemic stroke associated with AF is often more severe than stroke of other etiologies Stroke risk persists: Asymptomatic vs symptomatic Paroxysmal vs permanent Fuster V, et al. Circulation. 2006;114:e257-e354.; Benjamin EJ, et al. Circulation. 1998;98: ; Lloyd-Jones D, et al. Circulation. 2009;119:e Clinic Patient: Jean 69-year-old female with paroxysmal AF History of HTN; taking hydrochlorothiazide Peripheral vascular disease Normal LV function No diabetes, no TIA/CVA Mild to moderate SOB when she goes into Afib, HR 125 beats/min CHADS 2 Congestive heart failure Hypertension Age 75 years Diabetes mellitus Stroke or TIA (*2 points) For nonvalvular Afib Gage BF, et al. JAMA. 2001;285:

7 Stroke Risk in AF ACP/AAFP Guidelines CHADS 2 Score Adjusted Stroke Rate * (95% CI) CHADS 2 Risk Level ( ) Low ( ) Low ( ) Moderate ( ) Moderate ( ) High ( ) High ( ) High Aspirin Aspirin/ Warfarin Warfarin CHA 2 DS 2 -VASc Clinical Feature Points CHF 1 HTN 1 Age 75 2 Diabetes mellitus 1 Stroke, TIA, or embolism 2 Vascular disease (prior MI, PVD, aortic 1 plaque) Age 65 to 74 1 Female gender 1 * Expected rate of stroke per 100 patient years Adapted from Snow V, et al. Ann Intern Med. 2003;139: Adapted from Coppens M, et al. Eur Heart J. 2013;34(3): European Society of Cardiology Guidelines for Antithrombotic Therapy CHA 2 DS 2 -VAS c score Adjusted stroke rate (%/year) Recommended antithrombotic therapy 0 0 ASA mg or no therapy. No therapy preferred Either oral anticoagulation or ASA mg daily, anticoagulation preferred Oral anticoagulation Oral anticoagulation Oral anticoagulation Oral anticoagulation Oral anticoagulation Oral anticoagulation Oral anticoagulation Oral anticoagulation Adapted from EHRA, et al. Europace. 2010;12: Warfarin and Antiplatelet Therapy Warfarin: Risk Benefit Profile Odds Ratio Adapted from Fuster V, et al. Circulation. 2006;114:e Ischemic Stroke Intracranial Bleeding International normalization ratio (INR) 2011 Focused Update Recommendation ACCF/AHA/HRS Class IIb (New Recommendation) The addition of clopidogrel to aspirin (ASA) to reduce the risk of major vascular events, including stroke, might be considered in patients with AF in whom oral anticoagulation with warfarin is considered unsuitable due to patient preference or the physician s assessment of the patient s ability to safely sustain anticoagulation. (Level of Evidence: B) Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Wann LS, et al. Circulation. 2011;123:

8 RE-LY: Randomized Evaluation of Longterm Anticoagulation Therapy 18,113 patients with atrial fibrillation randomized to dabigatran (110 mg or 150 mg twice daily) versus warfarin (INR target 2.0 to 3.0) Novel Anticoagulants High risk AF patients, mean CHADS 2 score = 2.1 At least one Prior CVA or TIA LVEF <40% NYHA Class I or greater CHF Age >75 yrs Age 65 to 74 and one of DM HTN CAD Connolly SJ, et al. N Engl J Med. 2009;361: RE-LY: Safety Outcomes with Dabigatran Dabigatran 110 mg vs. Warfarin Dabigatran 150 mg vs. Warfarin Event RR (95% CI) P value RR (95% CI) P value Major bleeding 0.80 ( ) ( ) 0.31 Life threatening 0.68 ( ) < ( ) 0.04 ROCKET-AF: Rivaroxaban for the Prevention of Stroke and Non-CNS Embolism 14,264 patients with atrial fibrillation randomized to rivaroxaban (20 mg once daily) versus warfarin (INR target 2.5) Major or minor bleeding 0.78 ( ) < ( ) Intracranial bleeding 0.31 ( ) < ( ) <0.001 Gastrointestinal bleeding 1.10 ( ) ( ) <0.001 Adapted from Connolly SJ, et al. N Engl J Med. 2009;361: Patel et al. NEJM : Rate of Bleeding Events Variable Principal safety end point: major and nonmajor clinically relevant bleeding Rivaroxaban (N=7111) Events (%) Event Rate No/100 pt yr Events (%) Warfarin (N=7125) Event Rate No/100 pt yr P Value Major Bleeding Any Decrease in hemoglobin 2 g/dl Transfusion Critical bleeding Fatal bleeding Intracranial hemorrhage Nonmajor clinically relevant bleeding Adapted from Patel, et al. NEJM. 2011;365: ARISTOTLE (Apixiban vs. Warfarin INR ) Characteristic Apixaban (n=9120) Warfarin (n=9081) Age, years, median (25 th, 75 th PCTL) 70 (63, 76) 70 (63, 76) Women, % Qualifying risk factors, % Age 75 yrs Prior stroke, TIA, or SE Heart failure or reduced LV EF Diabetes Hypertension CHADS score, mean (+/- SD) 2.1 (+/- 1.1) 2.1 (+/- 1.1) 1, % , % , % Granger CB, et al. N Engl J Med. 2011;365:

9 ARISTOTLE: Bleeding Outcomes New Anticoagulants vs Warfarin: Summary Outcome Apixaban (N=9088) Event Rate (%/yr) Warfarin (N=9052) Event Rate (%/yr) HR (95% CI) P Value Primary safety outcome: ISTH major bleeding (0.60, 0.80) <0.001 Intracranial (0.30, 0.58) <0.001 Gastrointestinal (0.70, 1.15) 0.37 Major or clinically relevant nonmajor bleeding (0.61, 0.75) <0.001 GUSTO severe bleeding (0.35, 0.60) <0.001 TIMI major bleeding (0.46, 0.70) <0.001 Any bleeding (0.68, 0.75) <0.001 Warfarin Dabigatran Rivaroxaban Apixaban Monitoring Yes No No No Frequency Once daily BID Once daily BID Stroke Decreased No difference Decreased Ischemic Stroke Decreased No difference No difference Intracranial bleed Decreased Decreased Decreased Major Bleeding No difference No difference Decreased GI Bleeding Increased Increased No difference MI Increased No difference No difference Moderate Renal Disease Okay CrCl reduce dose CrCl reduce dose Okay HD or CrCl <15 Okay No No No Reversal Agent Yes No Maybe Maybe Mortality No difference (p=0.051) No difference Decreased (p=0.047) Adapted from Granger CB, et al. N Engl J Med. 2011;365: RACE II Rate vs. Rhythm Control Goal heart rate <80 beats/min vs <110 beats/min Permanent AF <80 years Resting AF rate >80 beats/min Primary outcome composite Death from cardiovascular causes Hospitalization for heart failure Stroke or systemic embolism Major bleeding Arrhythmic events including syncope or VT Implantation of pacemaker or ICD Van Gelder et al. NEJM 2010;362: ACCF/AHA/HRS Updates Treatment to a goal resting heart rate <80 beats/min is not beneficial compared to <110 beats/min in patients with atrial fibrillation who have LVEF >40% and no or minimal symptoms (Class III) Treatment Options First line Calcium channel blockers verapamil or diltiazem Beta blockers Digoxin as adjunct only May use if heart failure also Amiodarone: rarely for rate control AV node ablation and pacing Do NOT use dronedarone for rate control Wann LS, et al. Circulation. 2011;123: ; Wann LS, et al. Circulation. 2011;123: Wann LS, et al. Circulation. 2011;123:

10 Jean Paroxysmal AF Rhythm Control Added metoprolol XL 50 mg daily Two week follow up HR in sinus is 65 beats/min, in AF is 70 beats/min Still symptomatic AFFIRM In whom do I use rhythm control? No difference in death, disabling stroke, major bleed, or cardiac arrest Rhythm control associated with more adverse drug effects Rhythm control group had less warfarin use Symptomatic patients even with good HR Likely undertreated population HF patients precipitated by AF Younger patients? Reversible causes (thyrotoxic?) Short duration of antiarrhythmic use AFFIRM Investigators, et al. NEJM. 2002;347(23); Back to Jean Paroxysmal AF Metoprolol discontinued and started on sotalol 120 mg BID 8 week follow up Still having symptomatic episodes Atrial Fibrillation Ablation 10

11 AF Ablation Complication Rates Type of Complication # of patients Rate, % Death Tamponade Pneumothorax Hemothorax Sepsis, abscesses, or endocarditits Permanent diaphragmatic paralysis Total femoral pseudoaneurysm Total arterovenous fistulas Valve damage/ requiring surgery 11/ Atrium esophageal fistulae Stroke TIA PV stenoses requiring intervention Cappato, et al. Circulation. 2010;3: Heart Rhythm Consensus AF Ablation Indications Symptomatic AF refractory or intolerant to at least one Class I or III antiarrhythmic Paroxysmal (I) Persistent (IIa) Longstanding Persistent (IIb) Symptomatic AF as first line Paroxysmal (lia) Persistent (IIb) Long standing persistent (IIb) Calkins, et al. I. 2012;9: Back to Jean Post ablation follow-up Oral anticoagulation after for at least 2 months Use CHADS 2 or CHA 2 DS 2 -VASc to determine whether to stop oral anticoagulation after 2 months Consider antiarrhythmic for 2-3 months ECG every 3-6 months for 2 years 24 Holter every 6-12 months for 2 years Event monitor if return of symptoms not picked up on ECG or Holter Conclusions Warfarin alternatives are becoming available, with pluses and minuses Rate control: <110 beats/min (if asymptomatic) Rhythm control if symptomatic Catheter ablation for those who have failed at least one antiarrhythmic or do not want to take an antiarrhythmic Questions? 11

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