Advances in Internal Medicine: Acute and Chronic Kidney Disease
Objectives Radiocontrast Issues – Contrast nephropathy – Prophylaxis – Gadolinium MRI
Chronic Kidney Disease Kerry C. Cho, MD Glenn M. Chertow, MD MPH Nephrology UCSF 25 May 2007
Case 1 78 year old woman with hypercholesterolemia, HTN, DM, and chronic kidney disease (baseline creatinine 1.4 mg/dL) presents for routine cardiac catheterization. Medications include atorvastatin, metformin, HCTZ, metoprolol, benazepril, and ibuprofen. The interventional cardiologist asks you about prophylaxis for contrast nephropathy .
Case 1: Risk Factors Which factors increase her risk of contrast nephropathy? A. Diabetes mellitus B. Chronic kidney disease C. Female gender D. Age > 75 years E. Hypertension F. Hyperlipidemia
– HTN, ACE/ARBs – Dyslipidemia – Anemia and Erythropoietin
Bone Metabolism – Hyperparathyroidism – Vitamin D deficiency – Hyperphosphatemia
Case 1: Risk Factors Which factors increase her risk of contrast nephropathy? A. Diabetes mellitus B. Chronic kidney disease C. Female gender D. Age > 75 years E. Hypertension F. Hyperlipidemia
Case 1: Medications The following medications should be stopped prior to her cardiac catheterization: A. Metformin B. HCTZ C. Benazepril D. Ibuprofen E. All of the above.
Case 1: Medications The following medications should be stopped prior to her cardiac catheterization: A. Metformin – Stop for 48 hrs post-contrast and check kidney function before resuming B. HCTZ – Stop C. Benazepril – Evidence lacking, but often recommended D. Ibuprofen – Stop
Case 1: Prophylaxis For contrast nephropathy prophylaxis, you propose: B. Isotonic sodium bicarbonate D. High dose acetylcysteine
Case 1: Prophylaxis For contrast nephropathy prophylaxis, you propose: A. Normal saline B. Isotonic sodium bicarbonate C. Regular dose acetylcysteine D. High dose acetylcysteine E. Hemodialysis
Isotonic Sodium Bicarbonate Protocol – Liter of D5W with 150 mEq/L NaHCO3 – 3 mL/kg/hour for 1 hour pre-contrast – 1 mL/kg/hour for 6 hours post-contrast
Results – Nephropathy = 25% increase in creatinine – 13.6% with NaCl vs. 1.7% with NaHCO3
Merten GJ et al. JAMA 2004;291: 2328-34.
Confirmatory studies for NaHCO3 RENO – Emergency cardiac catheterization – 111 patients ± kidney disease – NaHCO3/NAC (pre/post) vs. saline/NAC (post) – Cr increase ≥ 0.5 mg/dL: 1.8% vs. 21.8% REMEDIAL – Coronary and peripheral angiograms – 326 patients with creatinine ≥ 2.0 mg/dL – NaHCO3/NAC vs. NaCl/NAC vs. NaCl/ascorbic acid – Cr increase ≥ 25%: 1.9% vs. 9.9% vs 10.3% Recio-Mayoral A et al. JACC 2007. Briguori C et al. Circulation 2007.
Acetylcysteine Prophylaxis Original protocol Acetylcysteine (NAC) 600 mg PO twice daily Day before and day of contrast exposure 0.45% NaCl at mL/kg/hour x 12 hrs pre/post Nephropathy: ≥0.5 mg/dL increase in Cr 2% NAC/NaCl vs. 21% placebo/NaCl What’s the latest with NAC prophylaxis? Tepel M. NEJM 2000;343:180-4.
> 20 NAC Randomized Trials High-dose N-Acetylcysteine – – – – –
354 patients with MI and 1° angioplasty 1200 mg IV pre, 1200 mg PO bid x 48 hrs 600 mg IV pre, 600 mg PO bid x 48 hrs Nephropathy = ≥ 25% increase in creatinine 8% high dose vs. 15% low dose vs 33% placebo
NAC: Conclusions? Meta-analyses – More than a dozen, 3 new since 2005 – Neutral – Benefit – Benefit
Zagler A et al. Am Heart J 2006;151:140-5. Liu R et al. J Gen Int Med 2005;20:193-200. Duong MH et al. Cath Card Interv 2005;64:471-9.
2 meta-meta-analyses – Inconclusive – Bagshaw SM et al. Arch Intern Med 2006;166:161-6. – Biondi-Zoccai GG et al. BMJ 2006;332:202-9.
Marenzi G et al. NEJM 2006;354:2773-82.
Contrast Nephropathy Reviews New England Journal of Medicine – – – –
Hydration, possibly with 0.9% NS 12 hrs pre/post NaHCO3 not recommended pending confirmation NAC not recommended pending confirmation Barrett BJ, Parfrey PS. NEJM 2006;354:379-86.
JAMA – Saline or sodium bicarbonate – NAC, inconclusive • 600-1200 mg PO twice daily
Contrast Nephropathy Summary
Alternative imaging modalities if possible Hold diuretics, NSAIDs if possible Minimize volume of contrast Low-osmolar or iso-osmolar contrast Prophylaxis for high-risk patients – IV hydration: NaHCO3 > NaCl – Acetylcysteine: cheap and safe, but effective?
Do not delay urgent contrast for prophylaxis.
– Pannu N et al. JAMA 2006;295:2765-79.
Case 1: FollowFollow-up Post-cath, she has atheroembolic disease with low complements and eosinophilia. Her kidney function deteriorates, but stabilizes at creatinine 3.2 mg/dL. Estimated GFR 15 mL/min. She does not require dialysis. Three years later, she develops hemiparesis and altered mental status. The neurologist asks about MRI to evaluate a lesion seen on non-contrast head CT.
Case 1: Clinical crossroads You recommend: A. Contrast-enhanced CT scan B. Gadolinium-enhanced MRI
Nephrogenic Systemic Fibrosis (NSF) Gadolinium-based contrast agents (GBCA) Seen in patients on dialysis or with advanced kidney disease Older, less accurate names – nephrogenic fibrosing dermopathy – dialysis-associated systemic fibrosis
First described in 1997 Rare, debilitating, and potentially fatal
NSF: MultiMulti-organ involvement Skin—burning or itching, reddened or darkened patches; skin swelling, hardening and/or tightening Eyes—yellow scleral plaques Bones, joints and muscles—joint stiffness, limited range of motion, pain deep in the hips or ribs, muscle weakness Lungs, diaphragm, pericardium, myocardium
http://www.fda.gov/cder/drug/InfoSheets/HCP/gcca_200705.htm
NSF: An Emerging Syndrome Patients: ARF, CKD, or ESRD Onset: days to weeks after exposure to gadolinium Pathogenesis: Unknown, related to acidosis? Diagnosis: Skin biopsy Treatment: Unknown Natural history: Unknown Prevention: Avoidance of gadolinium
Risk Factors for GBCA NSF Acute or chronic kidney disease with GFR < 30 mL/min Hepatorenal syndrome Acute renal failure in peri-operative liver transplant period
http://www.fda.gov/cder/drug/InfoSheets/HCP/gcca_200705.htm
FDA Recommendations May 23, 2007
FDA Recommendations Continued
Screen all patients for kidney disease. Avoid use of GBCA unless other imaging modalities are not available or diagnostic information essential. Do not exceed recommended dose GBCA. Allow sufficient time for GBCA elimination before another gadolinium MRI. Repeated doses and/or high-dose GBCA are risk factors for NSF.
For dialysis patients, consider prompt dialysis following GBCA exposure. Dialysis removes GBCA. “However, it is unknown if hemodialysis prevents NSF.” “The risk, if any, for developing NSF among patients with mild to moderate renal insufficiency or normal renal function is unknown.”
http://www.fda.gov/cder/drug/InfoSheets/HCP/gcca_200705.htm
http://www.fda.gov/cder/drug/InfoSheets/HCP/gcca_200705.htm
NSF: Unanswered Questions Rare syndrome (200+ patients) Unknown incidence, risk, and pathogenesis Relative risk of iodinated contrast nephropathy vs. gadolinium-induced NSF? Treatment of NSF? Don’t delay urgent MRI due to NSF risk.
Case 2: Lipid Management What are your targets for LDL and triglyceride? A. < 130 mg/dL and 150 mg/dL B. < 100 mg/dL and 150 mg/dL C. < 70 mg/dL and 150 mg/dL
Case 2 56 year old man with type 2 DM and chronic kidney disease. He takes metformin. Blood pressure is 144/87 mmHg. HbA1c LDL Creatinine Urine albumin
8.2%. 125 mg/dL. 1.5 mg/dL, eGFR 62 mL/min 700 mg/gram creatinine
Case 2: Lipid Management What are your targets for LDL and triglyceride? B.< 100 mg/dL and 150 mg/dL ADA 2007 and ATP III Guidelines 2001 NKF KDOQI 2003 Guidelines CKD is CHD equivalent, Goal LDL < 100 mg/dL
Case 2 What is his blood pressure target? A. 140/90 B. 130/80 C. 125/75
Case 2 What is his blood pressure target? A. 140/90 B. 130/80 C. 125/75 American Diabetes Association, 2007 National Kidney Foundation, KDOQI 2004 Joint National Committee 7, 2003
Case 2 What anti-hypertensive agent do you choose? A. ACE inhibitor B. Angiotensin-receptor blocker C. HCTZ D. Metoprolol E. Amlodipine
ACE inhibitors/ARB in Diabetes Preferred agents in DM patients – HTN – Diabetic nephropathy +/- HTN – Prevention of microalbuminuria in HTN DM pts • Ruggenenti P et al. NEJM 2004;351:1941-1951.
– Regression of microalbuminuria in DM1
Case 2 What anti-hypertensive agent do you choose? A. ACE inhibitor B. Angiotensin-receptor blocker
ACE or ARB in Type 2 DM? DETAIL Trial: Telmisartan vs. Enalapril in DM2 – Early nephropathy with mild-moderate HTN – Telmisartan 80 mg vs. enalapril 20 mg – Equivalent effect on GFR at 5 years follow-up
• Perkins BA et al. NEJM 2003;348:2285-2293.
Type 1 DM pts Æ ACE
Clinical equivalence of ACE and ARB
– Lewis EJ et al. NEJM 1993;329:977-986.
Type 2 DM pts Æ ARB – NEJM 2001;345. IDNT, RENAAL, IRMA 2.
Barnett AH et al. NEJM 2004;351:1952-1961.
ACE and ARB in Diabetic CKD Steno Diabetes Center1 – 24 patients with type 1 DM, macroalbuminuria – Enalapril vs. enalapril/irbesartan – Combination reduced albuminuria and BP after 8 wks
CALM Group2 – 199 patients with type 2 DM, microalbuminuria, HTN – Candesartan, lisinopril, or combination for 24 weeks – Combination improved DBP, possibly proteinuria 1 Jacobsen
P et al. Kidney Intl 2003;63:1874-80. CE et al. BMJ 2000;321:1440-44.
2 Morgensen
Case 2 His insurance company will not approve losartan 25 mg twice daily. You start benazepril 5 mg daily. One week later his K is 5.1 mEq/L and his creatinine has increased to 1.8 mg/dL. You decide to: A. Stop benazepril and ask the insurance company for losartan. B. Continue benazepril and follow his K and creatinine.
ACE inhibitors: Effective and safe in advanced CKD 422 non-diabetic patients with Cr 1.5-5.0 mg/dL – 104 patients with Cr 1.5-3.0 mg/dL – 224 patients with Cr 3.1-5.0 mg/dL
Hyperkalemia with ACE Inhibitors Hyperkalemia (potassium > 6 mEq/L) in 5% of patients with creatinine 3.1-5.0 mg/dL – No difference between benazepril and placebo groups
Benazepril 20 mg daily vs. placebo 1° endpoint = doubling of Cr, ESRD, or death – 43% reduction in primary endpoint – 52% reduction in proteinuria – 23% reduction in decline of kidney function Hou FF et al. NEJM 2006;354:131-140.
Can these study results be generalized to real world conditions? Less frequent lab draws and physician visits Less available dietary review and training
Hou FF et al. NEJM 2006;354:131-140.
Managing Hyperkalemia with ACE and ARB Tolerate mild hyperkalemia (K < 5.5 mEq/L) Strategies to lower potassium – – – – –
Consider diuretics (thiazide or loop) Low-potassium diet, dietary review Avoid salt substitutes Sodium polystyrene Review meds that increase K • NSAIDs, trimethoprim, spironolactone, amiloride, pentamidine, beta blockers
Palmer BF. NEJM 2004;351-585-592.
Anemia in CKD You continue benazepril and instruct him on avoiding high-potassium foods. His blood pressure improves to 124/72 mm Hg. Follow-up labs show creatinine 1.8 mg/dL, potassium 4.7 mg/dL, and Hb 9.8 g/dL. Colonoscopy last year was negative. Iron stores are intact (ferritin > 100, saturation > 20%). You start him on erythropoietin. Natl Kidney Foundation, KDOQI 2006 Anemia Guidelines
Anemia in CKD: Erythropoietin Safety? What’s your target Hb? A. 10-11 g/dL B. 11-12 g/dL C. 12-13 g/dL D. Normal Hb
CHOIR Trial Correction of Hemoglobin and Outcomes In Renal Insufficiency
1432 patients with GFR 15-50 mL/min Epoetin alfa, 10,000-20,000 units weekly SQ Hb target 11.3 vs. 13.5 g/dL 1° endpoint = composite death + CV outcomes Hazard ratio 1.34 for high Hb target – Primarily death and hospitalization for CHF
No improvement in quality-of-life indices
Singh AK et al. NEJM 2006;355:2085-98.
CREATE Trial Cardiovascular Risk Reduction by Early Anemia Treatment
603 patients with GFR 15-35 mL/min and mild anemia Epoetin beta (not available in US) Target Hb = High (13-15) or Low (10.5-11.5) No difference in 1° endpoint, time to first CV event Improvement in quality-of-life indices
Drueke TB et al. NEJM 2006;355:2071-84.
FDA Warnings and Guidelines March 9, 2007 Not approved for pre-operative use to reduce post-operative blood cell transfusions Æ increased DVT Decreased survival in metastatic breast cancer patients receiving chemotherapy Increased death in patients with active malignancy not undergoing chemotherapy or radiation therapy
FDA Warnings and Guidelines March 9, 2007 Target Hb < 12 g/dL Check Hb twice weekly until Hb stabilizes Increased mortality and CV events – chronic kidney disease – cancer patients on chemotherapy – surgical patients
Potential for tumor growth progression Hypertension http://www.fda.gov/cder/drug/InfoSheets/HCP/RHE2007HCP.htm
Epo in CKD and ESRD: Summary Before starting Epo therapy Anemia of CKD seen early, GFR 50-60 mL/min Rule out other causes of anemia Check iron stores, do not check Epo levels Consider risk factors: malignancy, CV risk, DVT risk After starting Epo therapy Target Hb < 12 g/dL Frequent monitoring of Hb and blood pressure Questionable benefit in quality of life
http://www.fda.gov/cder/drug/InfoSheets/HCP/RHE2007HCP.htm
Case 3
Case 3
72 year old man with a history of coronary artery disease, atrial fibrillation, aortic aneurysm repair and chronic kidney disease, with a SCr of 5.6 mg/dL He has limited exercise tolerance, lower extremity edema and claudication and early morning nausea He presents to your office with left leg pain
There is jugular venous distension and an S3 gallop, centripetal obesity, multiple excoriations on the skin of the thorax and back, and a faint uremic fetor Other laboratory studies are notable for K 5.8 mmol/L, HCO3 17 mmol/L, BUN 105 mg/dL, albumin 2.8 g/dL, C-reactive protein 14.5 g/L, Ca 9.8 mg/dL, PO4 6.4 mg/dL, PTH 98 pg/mL, 25OH vitamin D 9 ng/mL
Case 3 Medications include Coumadin, Coreg, Vasotec, Lasix, Phoslo, Hectoral and Nephrovite The patient had received a two week course of cephalexin for cellulitis from an urgent care center with some improvement in pain and erythema
Case 3 Appropriate interventions include: a. Intravenous piperacillin/tazobactam b. Vascular surgery consultation c. Dermatology consultation d. Initiation of hemodialysis e. Amputation
Case 3 Appropriate interventions include: a. Continue hemodialysis b. Stop warfarin c. Stop oral calcium d. Stop doxercalciferol e. Amputation
Case 3 The following lesion was present on the medial aspect of the left leg Dorsalis pedis pulses were palpable bilaterally
Case 3 The patient started hemodialysis with no untoward complications Punch biopsy of the skin showed calcific uremic arteriolopathy (calciphylaxis) with calcium deposition within the blood vessel wall
Case 3 Unproven therapies for CUA include: a. Parathyroidectomy b. Cinacalcet c. Hyperbaric oxygen d. Sodium thiosulfate e. Amputation
Screening for 2° 2° Hyperparathyroidism
Vitamin D Deficiency
CKD Stage
Serum PTH
Ca and PO4
25-OH Vit D (ng/mL) [nmol/L]
Definition
Ergocalciferol (Vitamin D2)
Follow-up
30-59
3
Annual
Annual
