This document discusses acute kidney injury (AKI), including: 1) Definitions and diagnostic criteria for AKI based on increases in serum creatinine and decreases in urine output. 2) New biomarkers for detecting AKI such as NGAL, IL-18, and KIM-1. 3) Causes of AKI including prerenal, intrinsic renal, and postrenal etiologies. Prerenal and acute tubular necrosis are most common. 4) Supportive treatment is typically used while research investigates potential pharmacologic therapies like dopamine, ANP, and fenoldopam.

1. Acute Renal Failure aka Acute Kidney Injury Pouneh Nouri MD Georgetown University Hospital Division of Nephrology

2. Definition of Acute Kidney Injury (AKI) based on “Acute Kidney Injury Network” Stage Increase in Serum Creatinine Urine Output 1 1.5-2 times baseline OR 0.3 mg/dl increase from baseline <0.5 ml/kg/h for >6 h 2 2-3 times baseline <0.5 ml/kg/h for >12 h 3 3 times baseline OR 0.5 mg/dl increase if baseline>4mg/dl OR Any RRT given <0.3 ml/kg/h for >24 h OR Anuria for >12 h

3. RIFLE criteria for diagnosis of AKI based on The “Acute Dialysis Quality Initiative” Am J Kidney Dis. 2005 Dec;46(6):1038-48 Increase in S Cr Urine output R isk of renal injury I njury to the kidney F ailure of kidney function 0.3 mg/dl increase 2 X baseline 3 X baseline OR > 0.5 mg/dl increase if S Cr >=4 mg/dl < 0.5 ml/kg/hr for > 6 h < 0.5 ml/kg/hr for >12h Anuria for >12 h L oss of kidney function E nd-stage disease Persistent renal failure for > 4 weeks Persistent renal failure for > 3 months

4. Increase in Creatinine without AKI Inhibition of tubular creatinine secretion Trimethoprim, Cimetidine, Probenecid Interference with creatinine assays in the lab (false elevation) glucose, acetoacetate, ascorbic acid, cefoxitin flucytosine

5. Increase in BUN without AKI Increased production GI Bleeding Catabolic states (Prolonged ICU stay) Corticosteroids Protein loads (TPN-Albumin infusion)

6. New Biomarkers in AKI Alternatives to Serum Creatinine Urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL) Ann Intern Med 2008;148:810-819 Urinary Interleukin 18 Am J Kidney Dis 2004;43:405-414 Urinary Kidney Injury Molecule 1 (KIM-1) J Am Soc Nephrol 2007;18:904-912

7. AKI and Mortality(Brigham and Womens, 9210 adults) Multivariable Odds Ratio for Death Chertow et al, JASN 16:3365-70; 2005 AKI ( Δ in S Cr >0.5) Age (per 10 yr) CKD CV dis. Respiratory dis GI dis. Cancer Infection 6.5 1.7 2.5 1.5 3 2.4 2.9 7.5 <0.0001 <0.0001 <0.0001 <0.04 <0.0001 <0.001 <0.0001 <0.0001

8. Major Disease Categories Causing AKI Disease Category Incidence Prerenal azotemia caused by acute renal hypoperfusion 55-60% Intrinsic renal azotemia caused by acute diseases of renal parenchyma: -Large renal vessels dis. -Small renal vessels and glomerular dis. -ATN (ischemic and toxic) -Tubulo-interestitial dis. -Intratubular obstruccttion 35-40% *>90%* Postrenal azotemia caused by acute obstruction of the urinary tract <5%

9. Prerenal Azotemia Intravascular volume depletion bleeding, GI loss, Renal loss, Skin loss, Third space loss Decreased cardiac output CHF Renal vasoconstriction Liver Disease, Sepsis, Hypercalcemia Pharmacologic impairment of autoregulation and GFR in specific settings ACEi in bilateral RAS, NSAIDS in any renal hypoperfusion setting

10. Intrinsic Renal Azotemia Large Renal Vessel Disease Thrombo-embolic disease Renal Microvasculature and Glomerular Disease Inflammatory: glomerulonephritis, allograft rejection Vasospastic : malignant hypertension, scleroderma crisis, pre-eclampsia, contrast Hematologic : HUS-TTP, DIC Acute Tubular Necrosis (ATN) Ischemic Toxic Tubulo-interestitial Disease Acute Interestitial Nephritis (AIN), Acute cellular allograft rejection, viral (HIV, BK virus), infiltration (sarcoid) Intratubular Obstruction myoglobin, hemoglobin, myeloma light chains, uric acid, tumor lysis, drugs (indinavir, acyclovir, foscarnet, oxalate in ethylene glycol toxicity)

11. Postrenal azotemia Stones Blood clots Papillary necrotic tissue Urethral disease anatomic: posterior valve functional: anticholinergics, L-DOPA Prostate disease Bladder disease anatomic: cancer, schistosomiasis functional: neurogenic bladder

12. Initial diagnostic tools in AKI History and Physical exam Detailed review of the chart, drugs administered, procedures done, hemodynamics during the procedures. Urinalysis SG, PH, protein, blood, crystals, infection Urine microscopy casts, cells (eosinophils) Urine lytes Renal imaging US, Mag-3 scan, Retrograde Pyelogram Markers of CKD iPTH, size<9cm, anemia, high phosphate, low bicarb Renal biopsy

13. Likelihood ratio (LR) of ATN vs pre-renal azotemia on the basis of the number of granular casts in urinary sediment Clin J Am Soc Nephrol 4:691-693, 2009 Granular casts/hpf LR for ATN LR for pre-renal 0 0.23 4.35 1-5 2.97 0.34 6-10 9.68 0.1

14. RBC cast Hyaline cast Granular cast Granular cast Granular cast WBC cast WBC cast Oval fat body and Hyaline cast

15. Treatment of AKI Treatment is largely supportive in nature! Pharmacologic treatments under study: Dopamine: no benefit Atrial Natriuretic Peptide (ANP) or ANP-analogue (Anaritide): promising Human Insulin like growth factor 1: no benefit Renal Replacement therapy remains the cornerstone of management of minority of patients with severe AKI Nephron Clin Pract 2009;112:c222-c229

16. Is there a role for Dopamine in prevention or treatment of AKI in ICU setting? Clinical Outcomes: No effect on mortality No effect on the need for or incidence of Renal Replacement Therapy (RRT) Renal Physiologic Outcomes: Diuretic effect and increased creatinine clearance on the first day which was not significant on the following days. Adverse effect: on the immune, respiratory, and endocrine system. Ann Intern Med. 2005;142:510-524 ANZICS Clinical Trial Group. Lancet 2000;356:2139-2143

17. Role of ANP analogues in AKI? 61 patients in 2 cardiothoracic ICU with post-op AKI assigned to receive recombinent ANP (50ng/kg/min) or placebo The need for RRT before day 21 after development of AKI was significantly lower in ANP group (21% vs 47%) The need for RRT or death after day 21 was significantly lower in ANP group (28% vs 57%) Crit Care Med . 2004 Jun;32(6):1310-5

18. Is there a role for Fenoldepam in prevention or treatment of AKI in ICU setting? Dopamine-1 receptor agonist, lack of Dopamine-2, and alpha-1 receptor effect, make it a potentially safer drug than Dopamine! Reduces in hospital mortality and the need for RRT in AKI Reverses renal hypoperfusion more effectively than renal dose Dopamine So far so good specially in cardiothoracic ICU patients, awaiting more powered trials in other groups! J Cardiothorac Vasc Anesth . 2008 Feb;22(1):23-6. J Cardiothorac Vasc Anesth. 2007 Dec;21(6):847-50 Am J Kidney Dis. 2007 Jan;40(1):56-68 Crit Care Med. 2006 Mar;34(3):707-14

19. Is there a role for diuretics in the treatment of AKI in ICU setting? PICARD Study: Cohort study of 552 pts in 4 UC hospitals: Odds Ratio In-hospital Mortality 1.77 Non-recovery of renal function 1.68 Improved urine output and shorter duration of RRT (none has clinical relevance in ICU pts) But diuretics continue to be used for volume control in AKI in ICU setting! JAMA. 2002 Nov 27;288(20):2547-53 Crit Care Resusc. 2007 Mar;9(1):60-8

20. Results of individual RCTs comparing CRRT to IHD in AKI in ICU Study n n Primary endpoint Mortality Mortality Persistent RRT requirement CRRT IHD CRRT IHD CRRT IHD Mehta et al KI 2001 84 82 ICU mortality 59.5 41.5 14 7 Augustine et al AJKD 2004 40 40 In-hospital mortality 67.5 70 61.5 66.7 Uehlinger et al NDT 2005 70 55 In-hospital mortality 47 51 2.7 3.7 Vinsonneau et al Lancet 2006 175 184 60-day mortality 67.4 68.5 1.8 0 Lins et al NDT 2009 172 144 In-hospital mortality 58.1 62.5 16.9 25.5

21. CRRT vs SLED (Sustained low efficiency dialysis) SLED became popular because of CRRT disadvantages: Expensive, continuous pt immobilization, need for specialized machines and pre-mixed commercial solutions, and anticoagulation Only 2 small studies compared these 2 in hemodynamically unstable pts with AKI They did not see significant differences in hemodynamic parameters and solute clearance They did not look at any patient-relevant outcomes, so the jury is still out there Am J Kidney Dis 2004;43:342-349 J Artif Organs 2007;30:1083-1089 Am J Kidney Dis 2008;51:804-810

22. Results of RCTs comparing benefits of the intensity of RRT (high vs low dose dialysis) * Veterans Administration/National Institute of Health Acute Renal Failure Trial Network Study Study n Low dose modality High dose modality Endpoint Results for low dose Results for high dose P Schiffl et al NEJM 2002 146 Thrice-weekly IHD Daily IHD 1-Mortality 2-Time to renal recovery 46% 16 days 28% 9 days Sig Ronco et al Lancet 2000 425 CVVH dose of 20 ml/kg/h CVVHDF dose of 35 or 45 ml/kg/h 90-day survival 34% 59% Sig Palvesky et al NEJM 2008* 1100 High dose : CRRT 35 ml/kg/h or SLED X 6/wk or IHD X 6/wk Low dose: CRRT 20 ml/kg/h or SLED X 3/wk or IHD X 3/wk 60-day mortality 51.8% 53.6% NS RENAL Clinical Trial (not published) 1500 CVVHDF 25 ml/kg/h CVVHDF 40 ml/kg/h 90-day Survival NS

23. Overall conclusion on RRT modality benefit in AKI CRRT does not confer a survival advantage as compared to IHD SLED may replace CRRT although there is no outcome benefit study up to this date There is limited data regarding the ideal timing of RRT initiation and the preferred mode of solute clearance No evidence to support a more intensive strategy of RRT in the setting of AKI

24. Case 1 26 yo F is involved in a MVA, with multiple fractures, blunt chest and abdominal trauma. She was briefly hypotensive on arrival to ED, received 6L NS and normalized BP. Non contrast CT showed small retroperitoneal hematoma. On day#2 her S Cr is 0.9 mg/dl, lipase is elevated and tense abdominal distension is noted. US showed massive ascites . UOP drops to <20 cc/hr despite of 10 L total IV intake. On day#3, S Cr is 2.1mg/dl, CVP is 17 , U Na is 10 meq/L , with a bland sediment. What is the cause of her AKI? What bedside diagnostic test and therapeutic intervention is indicated?

25. Bladder pressure was 29 mmHg UOP and S Cr improved with emergent paracenthesis. Dx: Abdominal Compartment Syndrome causing decreased renal perfusion from increased renal vein pressure.

26. Case 2 59 yo M, s/p liver transplant in 2001 and acute on chronic rejection, now decompensated ESLD , is admitted with worsening ascites, hepatic encephalopathy and GI bleed (which is now controlled). The only medications he has been receiving are Lactulose and prilosec. He has been hemodynamically stable with average BP~100/70 mmHg.He had a 3.5 L paracenthesis on day 2. His S Cr has been slowly rising from 1.2 to 4.7 mg/dl within the 2 nd to 4 th day of admission and his UOP has dropped to 150 cc/day. His daily FeNa is <1% despite of 2 L fluid challenge . His Urine sediment is blend . His renal US is normal. What is the cause of his AKI?

27. Patient required HD. He had a second liver transplant and came off HD after the surgery with stable S Cr of 1.4 mg/dl. Dx: Hepatorenal Syndrome (HRS )

28. Hepatorenal Syndrome Major diagnostic criteria: No improvement with at least 1.5 L fluid challenge S Cr >1.5 mg/dl or GFR< 40 cc/min Absence of proteinuria (<500 mg/d) Other causes are rouled out (obstruction, ATN, etc.) Minor diagnostic criteria: Urine volume < 400 cc/day U Na < 10 meq/L S Na < 130 meq/L Urine RBC < 50/hpf

29. Case 3 52 yo F underwent matched allo-Hematopoietic Stem cell transplant (HSTC) for AML. Between days 3-7 she gradually gained 8 Kg and edema developed . Since day#7 her Bili rose daily and peaked at 8 with jaundice, RUQ tenderness, and ascites. Liver US showed reversal of flow in the portal vein . Since day#8 S Cr rose slowly from baseline of 1.0 to 3.5 mg/dl, with 400 cc/day UOP on day#10. Her FeNa was 0.05% despite of 1.5L fluid challenge. Her urine sediment was blend. What is the most likely cause of her AKI?

30. She required HD for volume control, and remained HD dependent. Dx: Portal/Hepatic Veno-Occlusive Disease (VOD) VOD is responsible for 90% of hepatorenal syndromes in HSCT

31. Case 4 45 yo M with CHF and Bipolar Disorder on Lithium for 10 years, admitted for abdominal pain after a heavy meal, which turned out to be due to acute cholecyctitis. He was kept NPO on D5 1/2NS 50 cc/hr. Next morning he felt well but thirsty and hungry, BP=120/80, I/O=1200/4500 . His S Cr rose from 1.2 to 1.9 mg/dl. S Na 149 meq/L. U Na 10 meq/L. U Osm 190 mOsm/Kg . What is the cause of his AKI?

32. Patients IVF was changed to ½ NS, replacing 80% of UOP per hour. S Cr and S Na improved to baseline in 2 days. Dx: Prerenal azotemia secondary to renal free water loss in DI.

33. Case 5 68 yo F with CAD, DM, HTN, PVD, CKD with baseline S Cr of 1.4 mg/dl underwent elective cardiac angio and stent placement. No new meds. She has been hemodynamically stable throughout the procedure and afterward. Since day#2 post procedure, her S Cr has been gradually rising to 2.5 mg/dl with 500-600 cc/day UOP. UA showed SG 1.025, 1+ protein. Urine eosinophils (+). Serology tests showed low complements . She was discharged and in her f/u visit in 3 weeks she had S Cr of 2.7. What could be the cause of her AKI?

34. She never required RRT, but her S Cr continued to rise slowly to 3.1 mg/dl. She died 7 months later. Dx: Cholesterol emboli

35. Case 6 18 yo F with no PMH admitted with projectile vomitting, fatigue, and low PO intake. Her BP=200/110 , normal UOP with dry mucosa, trace edema , and otherwise normal exam. BUN=120 mg/dl, Creat=10 mg/dl which continued to rise on the following days, Hct=25% without schistocytes on PBS, UA: 3+ protein, 3+ blood, >50 RBC, many RBC casts . FeNa 1%. US showed normal sized kidneys. What other tests do you order? What may be the cause of her AKI?

36. ANA (-), normal complements, cryo (-), serology for hepatitis B, and C (-), P-ANCA (+), C-ANCA (-), anti-GBM (-), ASO (-), UPEP and SPEP without M spike, ESR 80. Her renal Bx showed crescentic glomerulonephritis, minimal non-specific immune complex deposits, without chronic changes. She remained dialysis dependent despite of steroid, cytoxan, and 10 plasmapheresis treatments. Dx: Pauci-immune Crescentic Glomerulonephritis due to Wegner’s granulomatosis

37. Case 7 54 yo F with CAD, on statin , started a new exercise program with intense weight training . She was brought to ED with neck pain, and LE weakness . VS stable, normal UOP, with dry mucosa. LE muscle strength 2/5 bilaterally. BUN 40 mg/dl, creatinine=8 mg/dl. FeNa 1.5%. Renal US normal. UA: 1.010, 3+ blood, few RBCs , few granular casts. What would be the next test to order? What may be the cause of her AKI?

38. Her CPK=57,700 She was treated with IV NaHCO 3 gtt to alkalinize urine to PH>6.5 . Her UOP remained normal but she required HD for uremia. Dx: ATN due to Rhabdomyolysis

39. Case 8 47 yo M with CAD, and CHF, admitted with LE cellulitis, started on Zosyn . On day#4 of admission BP=90/60, HR=68, normal UOP. LE edema(+), few pruritic purpuric rash on the shins. S Cr rose from 1.1 to 3.5 mg/dl. BUN=96 mg/dl. UA: trace protein, small blood, few RBCs, moderate WBC, with few WBC casts . FeNa>1%, Urine eosinophil (+). Renal US showed 13 cm kidneys . What may be the cause of his AKI? What would be your next step?

40. Zosyn was stopped. Patient required two HD treatment for uremia. Renal biopsy showed Acute Interestitial Nephritis. Subsequently he was started on Prednisone for one month and remained HD independent with stable S Cr of 1.8-2 mg/dl. Dx: AIN secondary to Zosyn

41. Case 9 72 yo M with DM, and prostate cancer metastatic to the bone, s/p XRT, on hormonal therapy. He is admitted with weakness, progressive weight loss, and persistent nausea. His med list also includes Diclofenac sodium daily for hip pain. BP=150/90, 350cc of urine collection immediately after foley placement, and normal exam. BUN=107 mg/dl, creatinine=9.8 mg/dl (2.0 almost 6 months PTA), which remained unchanged with hydration. Uric acid=8.2 mg/dl. UA: 1.010, 1+ protein, 1+ blood, few RBCs, no cast, no WBC. US showed 10-11 cm kidneys, no hydronephrosis. What seems to be the cause for his AKI?

42. Patient was initiated on HD for uremia and remained HD dependent for his symptomatic uremia. Patient and his family were concerned about his renal recovery (outcome), so a renal Bx was done showing severe chronic interstitial nephritis, with fibrosis and glomerulosclerosis. Dx: ESRD due to chronic tubulo-interstitial disease secondary to NSAIDs

43. Case 10 32 yo M s/p Cadaveric Renal Transplant (CRT) in 2006 for adult PCKD, on prograf, prednisone, and cellcept, and history of BK viruria is admitted for increased Creatinine=1.9 mg/dl, Hct=27%, WBC 2,500, Plt 90,000. He seems well hydrated, with stable VS, and normal exam. UA: 1.015, no protein, no blood, few granular casts. FeNa 1%. (-) BK virus PCR in the blood. What would be your next step? What seems to be the cause for his allograft failure?

44. Renal Bx showed acute cellular rejection BANFF IIb. No BK viral inclusions were identified. He received IV Solumedrol and Thymoglobulin and his creatinine dropped to a stable level of 1.3-1.4 mg/dl. Dx: Acute cellular rejection

45. Case 11 59 yo F with prolonged HTN, s/p OLT in 2000, on norvasc, prograf and prednisone was brought in for AMS . T=39 , BP=95/60, HR=104, UOP=20 cc/hr, intubated for airway protection, otherwise normal exam. BUN=80 mg/dl, creatinine=6 mg/dl (normal baseline), K=6.5 meq/L, Hct=20%, Plt=20000 , FeNa 1%, urine eosinophil (-), UA: 2+ blood , no protein, RBC > 50/hpf , no WBC, no cast. What would be your next step? What could be the reason for her AKI?

46. Her PBS showed many schistocytes and fragmented RBCs. Her Prograf was replaced with Sirolimus She underwent plasmapheresis, and required HD for anuria, and persistent hyperkalemia. She came off HD after 2.5 months with stable creatinine=1.2 mg/dl. Dx: TTP secondary to Prograf

47. Case 12 72 yo F with depression and hypothyroidism, was found by neighbors on the floor, unconscious, in respiratory distress. Intubated for airway protection. VS stable, anuric, Lungs CTA. BUN 50 mg/dl, Creatinine=4 mg/dl, with high anion gap metabolic acidosis , and an osmolar gap of > 10 . Lactic acid=1.8, FeNa 1%, urine eosinophil (-), UA: 1.020, 1+ blood, no protein, few RBCs, many oxalate crystals , few granular casts. US showed normal sized kidneys with no hydronephrosis. What is your next step? What seems to be the cause for her AKI?

48. Her ethylene Glycol level came back after 2 days to be 40 mg/dl. Pt was given Fomepizole and initiated on HD for persistent acidemia. She remained HD dependent, eventually extubated, started therapy for depression and discharged to NH. Dx: Ethylene Glycol toxicity

49. Case 13 38 yo M with post ERCP pancreatitis, is admitted to ICU, intubated for hypoxic respiratory distress, is anuric , febrile, and hypotensive , requiring massive volume resuscitation, on two vasopressors. He has received 11 L of NS and other IV meds within the last 8 hours and currently his CVP~12, has coarse crackles, and 2+ edema. His Creatinine rose from 1.2 to 3.5 the morning after the above event, FeNa > 1%, U Na 45 meq/L , UA: 1.010, no protein, no blood, moderate epithelial cells, many muddy brown granular cell casts, moderate epithelial cell casts . US showed normal sized kidneys with no hydronephrosis. What is the cause of his AKI?

50. He was started on CVVH for volume control. Has had a long hospital stay complicated with polymicrobial bacteremia and VAP. Dx: ATN secondary to renal ischemia and sepsis

51. Natural Clinical Course of ATN Initiation Phase (hours to days) Continuous ischemic or toxic insult Evolving renal injury ATN is potentially preventable at this time Maintenance Phase (typically 1-2 wks) Maybe prolonged to 1-12 months Established renal injury GFR < 10 cc/min, The lowest UOP Recovery Phase Gradual increase in UOP toward post-ATN diuresis Gradual fall in S Cr (may lag behind the onset of diuresis by several days)

52. When to do renal biopsy in AKI ? Any evidence of glomerular disease - nephrotic range proteinuria -sub-nephrotic range proteinuria with hematuria -RBC cast AKI in renal allograft Determine the prognosis and chance of recovery of renal function in dialysis dependent AKI. Whenever potential Bx result can change the management or prognosis.

53. When to initiate RRT in a patient with AKI ? 1) Renal Replacement Therapy: Electrolytes imbalances Acid-base disturbances Uremic complications -Encephalopathy -Pericarditis -Persistant nausea, and food intolerance

54. 2) Renal/Multiorgan Support Therapy -Protects other organs by improving overall body milieu (balance of inflammatory mediators) -Allowing therapies for other organs that pt could not otherwise tolerate -volume resuscitation -aggressive nutrition

55. 3) Removal of toxic agents in overdose -Ethylene Glycol -Methanol -Salicylates -Lithium -Theophylline -Isopropanol

56. Thank you!