Update in Nephrology. Case: Question 1. Case presentation. Acute Kidney Injury. For her hypertension management, you decide to:

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1 Update in Nephrology Chronic Kidney Disease Renoprotection and Proteinuria, ACE and/or ARB Anemia management Update in Nephrology Renal artery stenosis Nephrogenic systemic fibrosis Division of Nephrology Advances in Internal Medicine June 18, 2008 Acute Kidney Injury Diuretics, dopamine, dialysis Radiocontrast nephropathy Kerry C. Cho, MD Assistant Clinical Professor Case presentation Case: Question 1 72 yo woman with HTN, chronic kidney disease, and subnephrotic proteinuria. Her urine protein:creatinine ratio is 0.8 and baseline creatinine is 3.1 mg/dl. Her home blood pressures are typically / Medications HCTZ 25 mg daily Metoprolol 25 mg twice daily Exam BP 140/90, pulse 60. Euvolemic, no bruits. For her hypertension management, you decide to: 1. Continue her current regimen and monitor BP. 2. Increase her HCTZ. 3. Increase her metoprolol. 4. Start an ACE inhibitor. Continue her current... 1% Increase her HCTZ. 1% 4% Increase her metoprolol. 93% Start an ACE inhibitor.

2 Benazepril in Advanced CKD Hou FF et al. NEJM 2006;354: Design 224 patients with creatinine mg/dl Benazepril 20 mg daily vs. placebo 1 end point: doubling of creatinine, ESRD, death Conclusions 43% reduction in primary end point 52% reduction in proteinuria 23% reduction in decline in kidney function Effects were independent of blood pressure Good safety profile Hou FF et al. NEJM 2006;354: ACE and ARB for CKD Conclusions ARBs decrease proteinuria independent of degree of proteinuria and underlying disease. Proteinuria reduction from ACE inhibitors and ARBs is similar Combination of ACE inhibitors and ARBs is more effective than either drug alone. Uncertainty about outcomes and adverse effects. Kunz R et al. Ann Intern Med 2008;148:30-48.

3 Case: Question 2 Abdominal ultrasound reveals a left kidney of 9.5 cm and right kidney of 11.2 cm. You decide to: 52% 1. Monitor her kidney function. 2. Refer for nephrology consultation. 34% 3. Refer for surgical revascularization. 4. Refer for percutaneous revascularization. 5% 8% Monitor her kidney fu... Refer for nephrology... Refer for surgical re... Refer for percutaneou... Balk E et al. Ann Intern Med 2006;145: Atherosclerotic Renal Artery Stenosis Case: Question 3 Medical Rx vs. revascularization No studies directly compare aggressive medical therapy with angioplasty and stent placement Quality of studies was poor. Limited applicability to current practice. Weak evidence to suggest large differences in mortality or CV events. Her hemoglobin is 10.2 g/dl with intact iron stores and negative stool occult blood tests. You decide to: 1. Start her on darbepoetin. 2. Start her on erythropoietin. 3. Monitor her for symptoms of anemia. 6% 28% 65% Bottom Line: Stop revascularization unless unequivocal clinical indications. Balk E et al. Ann Intern Med 2006;145: Start her on darbepoe... Start her on erythropo... Monitor her for symp...

4 CREATE Design Stage 3-4 CKD patients Epoetin beta Hemoglobin target vs g/dl Primary end point: Time to first CV event Conclusions No difference in time to first CV event No difference in echocardiography (LV mass index) Higher quality of life scores in high Hb group Drueke TB et al. NEJM 2006;355: Drueke TB et al. NEJM 2006;355: Singh AK et al. NEJM 2006;355: CHOIR Study of Epo Design 1432 patients with GFR ml/min Treated with Epoetin alfa Hemoglobin targets 11.3 vs g/dl Combined end point: Death, MI, CVA, CHF hospitalization Conclusions More events (primarily death and CHF) in high Hb group Similar quality of life in both groups

5 FDA Warning on ESA Avoid serious CV and thromboembolic events by using the lowest possible dose of ESA to gradually raise the Hb to the lowest level to avoid transfusion ESAs increased risk of death and serious CV events when dosed to achieve target Hb > 12 Tumor growth progression Advanced head and neck cancer patients receiving radiation therapy Increased risk of death in active malignancy patients not receiving therapy or metastatic breast cancer patients receiving chemotherapy Case: Question 4 She presents to the emergency department with chest pain and shortness of breath. She is diagnosed with an acute coronary syndrome. The cardiologist recommends cardiac catheterization. She is concerned about radiocontrast nephropathy. You decide to: 1. Tell the cardiologist that the catheterization is contraindicated. 2. Provide prophylaxis with N- acetylcysteine (NAC). 3. Provide prophylaxis with sodium bicarbonate. 4. Provide prophylaxis with normal saline. 5. Provide prophylaxis with NAC and IVF. Provide prophylaxis... Tell the cardiologist t... 0% 27% Provide prophylaxis... Provide prophylaxis... 13% 3% Provide prophylaxis... 58% Contrast Prophylaxis Prophylactic agents included: Acetylcysteine, theophylline, fenoldopam, dopamine, iloprost, statin, furosemide or mannitol. Conclusions Acetylcysteine 30 trials, low cost, widely available, few side effects More effective than hydration alone. Theophylline Possibly beneficial Kelly AM et al. Ann Intern Med 2008;148:

6 JAMA recommendations Pannu N et al. JAMA 2006;295: Alternative imaging modality Low-osmolar contrast or iso-osmolar contrast Minimize volume of contrast High-risk patients (CHOOSE ONE) Acetylcysteine mg PO twice daily day before and day of study Ascorbic acid 3 g PO before study, 2 g PO twice daily for one day after study Low to moderate risk patients (CHOOSE ONE) Normal saline Sodium bicarbonate Pannu N et al. JAMA 2006;295: NEJM Recommendations Alternative imaging modality Low-osmolar contrast or iso-osmolar contrast Minimize volume of contrast Hydration Pre/post hydration with IV normal saline 0.9% Acetylcysteine Cannot be recommended Publication bias, inconsistent results Sodium bicarbonate Barrett BJ, Parfrey PS. NEJM 2006;354: Methodological flaws in Merten study in JAMA Barrett BJ, Parfrey PS. NEJM 2006;354:

7 Case: Question 5 After her cardiac catheterization, she develops oliguric acute kidney injury from acute tubular necrosis. You decide to: 1. Start dopamine. 2. Start furosemide. 3. Consult nephrology for possible renal replacement therapy. 14% 14% 71% Start dopamine. Start furosemide. Consult nephrology f.. Ho KM and Sheridan DJ. BMJ 2006;333:420. Furosemide for ARF: Meta-analysis Furosemide for prevention or treatment of ARF. 9 randomized controlled studies, 849 patients. No difference in hospital mortality No difference in need for dialysis, duration of dialysis No difference in proportion of patients with oliguria. Increased risk of temporary deafness and tinnitus. Ho KM and Sheridan DJ. BMJ 2006;333:420. Friedrich JO et al. Ann Intern Med 2005;142:

8 Dopamine in ARF: Meta-analysis Dialysis Modality for ARF/AKI 61 trials, 3359 patients No effect on mortality or need for dialysis Increased urine output on day 1 by 24% Clinically insignificant improvements in serum creatinine and creatinine clearance Third negative meta-analysis of dopamine for ARF IHD = Intermittent hemodialysis CRRT = Continuous renal replacement therapy Conventional wisdom Continuous better than Intermittent Better solute, acid:base, and volume control Better hemodynamic stability Kellum JA et al. Crit Care Med 2001;29: Marik PE. Int Care Med 2002;28: Friedrich JO et al. Ann Intern Med 2005;142: IHD vs. CRRT: Conclusions No conclusive evidence of CRRT benefit ICU and hospital mortality ICU and hospital length of stay Kidney recovery Evidence Base 4 randomized trials with 731 patients Vinsonneau C et al. Lancet 2006;368: Uehlinger DE et al. Nephrol Dial Transplant 2005;20: Augustine JJ et al. Am J Kidney Dis 2004;44: Mehta RL et al. Kidney Int 2001;60: Retrospective analysis of PICARD data Cho KC et al. J Am Soc Nephrol 2006;17: Pannu N et al. JAMA 2008;299:

9 JAMA RRT for ARF/AKI Conclusions NOT IN SYLLABUS Recommendations Modality: IHD vs. CRRT No difference in mortality or kidney recovery Dialysis Dose Patients on CVVH should receive 35 ml/kg/hour of replacement fluid, improved survival compared to 20 ml/kg/hour Timing of initiation of renal replacement therapy (early vs. late) No conclusions. Pannu N et al. JAMA 2008;299: Epub ahead of print publication. ARF Trial Network (ATN) Study ARF Trial Network (ATN) Study Setting Multicenter VA-NIH trial of ICU ARF in US 1200 patient completed August 2007 Endpoints 1 = 60-day mortality 2 = Hospital and 1-year mortality, kidney recovery Intervention Conventional therapy: Every other day HD or low-dose CVVHDF/SLED Switch between modalities depending on stability Intensive therapy: Daily dialysis or high-dose CVVHDF/SLED Switch between modalities depending on stabilty Palevsky PM et al. Clinical Trials 2005;2: Palevsky PM et al. Clinical Trials 2005;2:

10 ATN Study Design ATN Study of Intensive vs. Conventional Renal Replacement Therapy: No Difference in Mortality Editorial about ATN Trial ATN Study Subgroup Analysis: No difference by Acuity, Oliguria, Gender, Sepsis

11 Case: Question 6 Risk Factors for GBCA NSF During her hospitalization, she develops abdominal pain and an increased anion gap with lactic acidosis. Her abdominal exam is benign. You are concerned about atherosclerosis of the abdominal aorta and ischemic bowel. 47% You decide to: 39% Acute or chronic kidney disease with GFR < 30 ml/min Hepatorenal syndrome Acute renal failure in peri-operative liver transplant period 1. Order an abdominal CT with contrast. 2. Order conventional angiography. 3. Order a gadolinium-enhanced MRI. 14% Order an abdominal... Order conventional... Order a gadolinium-... Nephrogenic Systemic Fibrosis (NSF) Nephrogenic Systemic Fibrosis (NSF) First described in 1997 Gadolinium-based contrast agents (GBCA) Associated with advanced kidney disease and dialysis patients Older, less accurate names nephrogenic fibrosing dermopathy dialysis-associated systemic fibrosis Multi-organ fibrosing syndrome 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 Heart Debilitating and potentially fatal

12 Nephrogenic Systemic Fibrosis (NSF) FDA Recommendations May 23, 2007 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. FDA Recommendations, continued Take Home Points on NSF For dialysis patients, consider prompt dialysis following GBCA exposure. Dialysis removes GBCA. However, it is unknown if hemodialysis prevents NSF. Rare syndrome Unknown incidence, risk, and pathogenesis Don t delay urgent MRI due to NSF risk. The risk, if any, for developing NSF among patients with mild to moderate renal insufficiency or normal renal function is unknown. Areas of Uncertainty Relative risk of iodinated contrast nephropathy vs. gadolinium-induced NSF? Dialysis to remove GBCA in chronic kidney disease patient not on dialysis?

13 Summary Chronic Kidney Disease Don t be afraid of ACE/ARB for renoprotection Consider using ACE and ARB Be careful using gadolinium Be careful using erythropoietin Carefully select patients for renal artery stenosis intervention Acute Renal Failure Avoid contrast, hydration, prophylaxis Don t use dopamine or diuretics More dialysis is better for ARF patients