Acute Renal Failure:

1. Acute Renal Failure: Only three possible causes: • Inadequate perfusion • Intrinsic renal damage • Obstruction to the outflow of urine

2. Is Renal Failure Acute or Chronic? • History: Get the old records • Take a history: • Longstanding or progressive symptoms? • Underlying illnesses? • Medications, including OTC meds? • Prior MD encounters or laboratory work? • Physical examination: • Does the patient appear chronically ill? • Volume status? • Diabetic retinopathy? • Ultrasound • Laboratory data: • Anemia • Creatinine level?

3. Acute Renal Failure: • Always rule out obstruction. • Pre-renal vs. intrinsic damage. • Urine sodium, FENa • U/P sodium / U/P creatinine • < 1 vs. > 1 • Urine sediment • Caveats: • Contrast nephropathyPigment nephropathy • Heart failure • Liver failure

4. Genesis of Acute Tubular Necrosis • Tubular obstruction by debris • Backleak across damaged epithelium • Proximal tubular damage leading to increased delivery to the macular densa with consequent reduction in GFR mediated by GT feedback.

5. Acute Renal Failure: Most Common Causes at PHD • Sepsis • Post-surgical (AAA, CABG) • Rhabdomyolysis • Drugs: • Contrast • NSAIDs • Illicit/suicidal • All of the above

6. Acute Tubular Necrosis: Reversing the Process or Speeding Recovery? • Diuretics • Atrial natriuretic peptide • Low dose dopamine • Recombinent insulin-like growth factor • Fenoldapam • Volume

7. Diuretics in ARF • Diuretics may increase urine output in a patient with ARF, and if volume overload is present be beneficial by converting an oliguric patient to one with polyuria, but there is not evidence that they hasten recovery. • They will, however, make physicians feel better and obscure the diagnosis by obviating the value of urine electrolytes. • If you feel compelled to give diuretics, please obtain urine electrolytes and creatinine first.

8. Anaritide in acute tubular necrosis. Auriculin Anaritide Acute Renal Failure Study Group The administration of anaritide did not improve the overall rate of dialysis-free survival in critically ill patients with acute tubular necrosis. However, anaritide may improve dialysis-free survival in patients with oliguria and may worsen it in patients without oliguria who have acute tubular necrosis. (Allgren RL; Marbury TC; Rahman SN; Weisberg LS; Fenves AZ; Lafayette RA; Sweet RM; Genter FC; Kurnik BR; Conger JD; Sayegh MH: N Engl J Med 1997 Mar 20;336(12):828-34)

9. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Socity (ANZICS) Clinical Trials Group Administration of low-dose dopamine by continuous intravenous infusion to critically ill patients at risk of renal failure does not confer clinically significant protection from renal dysfunction. (Bellomo R; Chapman M; Finfer S; Hickling K; Myburgh J; Lancet 2000 Dec 23-30;356(9248):2139-43)

10. Multicenter clinical trial of recombinant human insulin-like growth factor I in patients with acute renal failure. rhIGF-I does not accelerate the recovery of renal function in ARF patients with substantial comorbidity. (Hirschberg R; Kopple J; Lipsett P; Benjamin E; Minei J; Albertson T; Munger M; Metzler M; Zaloga G: Murray M; Lowry S; Conger J; McKeown W; O’shea M; Baughman R; Wood K; Haupt M; Kaiser R; Simms H; Warnock D; Summer W; Hintz R; Myers B; Haenftling K; Capra W; et al; Kidney Int 1999 Jun; 55(6):2423-32)

11. Fenoldopam mesylate for the prevention of contrast-induced nephropathy: a randomized controlled trial.CONTRAST Investigators. • Department of Cardiology, Cardiovascular Research Foundation and Lenox Hill Heart and Vascular Institute, New York, NY 10022, USA. gstone@crf.org • CONTEXT: The development of contrast-induced nephropathy in patients undergoing invasive cardiac procedures is associated with a marked increase in cardiovascular morbidity and mortality. Fenoldopam mesylate, a specific agonist of the dopamine-1 receptor, preserves renal blood flow after iodinated contrast administration and has shown promise in ameliorating contrast nephropathy in previous observational and small randomized trials. OBJECTIVE: To examine the efficacy of fenoldopam mesylate in preventing contrast nephropathy after invasive cardiovascular procedures. DESIGN: Prospective, placebo-controlled, double-blind, multicenter randomized trial with serial serum creatinine levels measured at a central biochemistry laboratory (at baseline and 1, 24, 48, and 72 to 96 hours after study drug administration) and 30-day clinical follow-up. PATIENTS AND SETTING: Between March 2001 and July 2002, 315 patients with creatinine clearance less than 60 mL/min (1.00 mL/s) at 28 centers in the United States were randomized to receive fenoldopam mesylate (n = 157) or placebo (n = 158). INTERVENTIONS: Patients were hydrated and randomized to receive intravenous fenoldopam (0.05 microg/kg/min titrated to 0.10 microg/kg/min) vs matching placebo, starting 1 hour prior to angiography and continuing for 12 hours. MAIN OUTCOME MEASURE: Contrast-induced nephropathy, defined as an increase of 25% or more in serum creatinine level within 96 hours postprocedure. RESULTS: Mean (SD) patient age was 70 (11) years, and 49% had diabetes mellitus. Mean (SD) baseline creatinine clearance was 29.0 (10.0) mL/min (0.48 [0.16] mL/s) (range, 7.5-56.8 mL/min [0.12-0.94 mL/s]), and 157 (108) mL of contrast was administered during the procedures. The primary end point of contrast-induced nephropathy occurred in 33.6% of patients assigned to receive fenoldopam vs 30.1% assigned to receive placebo (relative risk, 1.11; 95% confidence interval, 0.79-1.57; P =.61). There were no significant differences in the 30-day rates of death (2.0% vs 3.8%, P =.50), dialysis (2.6% vs 1.9%, P =.72), or rehospitalization (17.6% vs 19.9%, P =.66) in fenoldopam vs placebo randomized patients, respectively. CONCLUSION: The selectivedopamine-1 agonist fenoldopam mesylate does not prevent further renal function deterioration after contrast administration in patients with chronic renal insufficiency. • JAMA 290:2284-91,2003

12. Acute Tubular Necrosis: Reversing the Process or Speeding Recovery: • Once the insult has occurred, no pharmacologic intervention has been demonstrated to be of any benefit.

13. Acute Tubular Necrosis: Treatment • Optimize volume • Physical examination • Chest xray • Hemodynamic measurements? • Do not be over zealous with blood pressure control • Stop potential nephrotoxins; avoid repeated insults • Dye studies • Surgery • NSAIDs

14. Question: • Acute renal failure occurs on day 1 with a creatinine of 1.2. • On day 3, creatinine is 3.2. • On day 6, creatinine is 7.0 • Renal function is: • getting better? • unchanged? • getting worse?

15. Question: • Acute renal failure occurs on day one when a patient’s sole remaining kidney is removed for malignancy. Creatinine is 1.2. • On day 3, creatinine is 3.2. • On day 7, creatinine is 7.0. • Renal function is: • getting better? • staying the same? • getting worse?

16. Acute Tubular Necrosis: Treatment • Check the MAR daily for inappropriate drugs or wrong dosages. Do not depend on pharmacy alerts. • Avoid hypotension and overzealous short-term blood pressure management. • Watch potassium. • Meticulous general medical care. • nursing • line changes • Nutritional support? • Enteral if feasible • Little evidence supporting benefit of TPN in an illness of less than two weeks • If nutritional therapy is initiated, 1.5 gm/kg of protein

17. Acute Tubular Necrosis: Dialysis • When? • Volume status and electrolytes • Etiology and anticipated course • urine output • Risk • Biocompatible membranes • Hemodialysis vs. CVVHD • Is more better?

18. Timing of Initiation of Dialysis in Critically Ill Patients with Acute Kidney Injury. • “Among critically ill patients with AKI, initiation of dialysis at higher BUN concentrations was associated with an increased risk for death. Although the results could reflect residual confounding by severity of illness, they provide a rationale for prospective testing of alternative dialysis initiation strategies in critically ill patients with severe AKI.” • BUN <76 and >76 chosen. • Liu, et al. Clin.J.AM.Soc.Nephrol 1:915-919, 2006.

19. Acute Tubular Necrosis: Outcome • ICU mortality = 50%

20. Acute Tubular Necrosis: Prevention • Adequate volume status prior to an anticipated insult. • Bicarbonate? • Drugs: • NSAIDs • IV contrast • minimize dosage • avoid multiple sequential doses • avoid concomitant or recent NSAIDs • Stop ACEIs or ARBs in advance • mucomyst • Delay surgical procedures after a possible insult. • Avoid the second hit.

24. A Prevention of Contrast-Induced Nephropathy With Sodium Bicarbonate A Randomized Controlled Trial Gregory J. Merten, MD; W. Patrick Burgess, MD, PhD; Lee V. Gray, MD; Jeremiah H. Holleman, MD; Timothy S. Roush, MD; Glen J. Kowalchuk, MD; Robert M. Bersin, MD; Arl Van Moore, MD; Charles A. Simonton III, MD; Robert A. Rittase, PharmD; H. James Norton, PhD; Thomas P. Kennedy, MD, MPH JAMA. 2004;291:2328-2334. Objective  To examine the efficacy of sodium bicarbonate compared with sodium chloride for preventive hydration before and after radiographic contrast. Interventions  Patients received 154 mEq/L of either sodium chloride or sodium bicarbonate, as a bolus of 3 mL/kg per hour for 1 hour before iopamidol contrast, followed by an infusion of 1 mL/kg per hour for 6 hours after the procedure. Main Outcome Measure  Contrast-induced nephropathy, defined as an increase of 25% or more in serum creatinine within 2 days of contrast. Results  There were no significant group differences in age, sex, incidence of diabetes mellitus, ethnicity, orcontrastvolume. Baseline serum creatinine was slightly higher but not statistically different in patients receiving sodium bicarbonate treatment (mean [SD], 1.71 [0.42] mg/dL [151.2 {37.1} µmol/L] for sodium chloride and 1.89 [0.69] mg/dL [167.1 {61.0} µmol/L] for sodium bicarbonate; P = .09). The primary end point of contrast-induced nephropathy occurred in 8 patients (13.6%) infused with sodium chloride but in only 1 (1.7%) of those receiving sodium bicarbonate(mean difference, 11.9%; 95% confidence interval [CI], 2.6%-21.2%; P = .02). A follow-up registry of 191 consecutive patients receiving prophylactic sodium bicarbonate and meeting the same inclusion criteria as the study resulted in 3 cases of contrast-induced nephropathy (1.6%; 95% CI, 0%-3.4%). Conclusion  Hydration with sodium bicarbonate before contrast exposure is more effective than hydration with sodium chloride for prophylaxis of contrast-induced • renal failure.

25. MD Scientific,LLC announces issuance of U.S. Patent No.7,019,035 • Inventor: Burgess; W.Patrick • “U.S.patent describing he methodology of using bicarbonate (intravenous solution and oral preparations) fothe reduction or prevention of CIN was issued on March 28,2006….described in May 19,2004 article in the JAMA….” MD Scientific news release. • “Continued unauthorized use of the Method after March 28,2006 constitutes patent infringement.” letter to Mr. Hawthorne, 3/28/06.

27. N-Acetylcysteine and Contrast-Induced Nephropathy in Primary Angioplasty • Intravenous and oral N-acetylcysteine may prevent contrast-medium-induced nephropathy with a dose-dependent effect in patients treated with primary angioplasty and may improve hospital outcome (NEJM 354:2773, 2006)

28. Facts and fallacies concerning the prevention of contrast medium-inducednephropathy. Critical Care Medicine. 34(8):2060-2068, August 2006. Abstract: Objective: The aim of this article is to extract from recent medical literature and nephrologic practice the facts and fallacies concerning the possible prophylaxis of contrast medium-induced nephropathy. Data Synthesis: Considerable efforts have been made to develop pharmacologic therapy for the prevention of contrast medium-induced nephropathy, especially in patients at risk, such as elderly subjects and those with preexisting renal impairment, hypovolemia, or dehydration. There is general consensus that hydration protocols implemented before and after imaging with contrast medium may be effective in preventing contrast medium-induced nephropathy. However, definitive and convincing data related to amounts to be infused, infusion timing, and type of solutions (half-isotonic, isotonic saline solution, or bicarbonate) are lacking. Forced diuresis with furosemide or mannitol and use of dopamine, together with concomitant hydration, have been proved to be ineffective or even more risky in the event of inadequate maintenance of euvolemia. Various direct or indirect vasodilators have been investigated (atrial natriuretic peptide, calcium channel blockers, angiotensin-converting enzyme inhibitors, and endothelin receptor antagonists), yet results have been inconsistent and inconclusive. Recent large meta-analyses concerning the protective role of antioxidant action of N-acetylcysteine have led to the conclusion that the statistical significance of the results is borderline. Preventive hemodialysis has not proved to be useful; on the contrary, it might worsen the clinical conditions by inducing hypotension. Hemofiltration, despite some positive studies, is too complex and cannot be used extensively. Conclusions: It is believed that prevention is actually achieved by correcting hypovolemia, dehydration, or both. Normalization of body fluids is probably the true objective to be achieved by preventive measures in all patients, not only in those at risk. Because limited data have been collected in intensive care units, at present, no firm or specific recommendations can yet be provided for the critically ill.

29. Acute Tubular Necrosis: • ref: Diagnosis and Treatment of Acute Tubular Necrosis. Essen ML, and Schrier RW, Annals of Internal Medicine 137:744, 5Nov02.