Background

2. Background • Acute Kidney Injury (AKI) is an abrupt loss of renal function that results in the retention of nitrogenous and other waste products.  This can lead to metabolic and organ dysfunction.   • Renal function is most easily monitored by measuring the serum creatinine level and estimating the glomerular filtration rate (GFR)

3. What is GFR? How is it Calculated? • The Glomerular Filtration Rate (GFR) is the volume of fluid filtered from glomerularcapillaries into the Bowman’s capsule per unit time

4. Risk Factors for AKI • Age > 75 yrs • Chronic kidney disease (CKD, eGFR < 60 mls/min/1.73m2) • Cardiac failure  • Diabetes mellitus • Hypovolemia • Nephrotoxic medication • Atherosclerotic peripheral vascular disease • Liver disease • Sepsis

5. Definitionof AKI As per the Acute Kidney Injury Network: •  An abrupt (within 48hrs) reduction in kidney function defined as an increase in serum creatinine level of 0.3mg/dl                                             OR •  An increase in serum creatinine ≥ 50%                                             OR • Urine output is < 0.5ml/kg/hr for >6 consecutive hours 

6. Etiologies of AKI • Prerenal- causes that decrease effective blood flow to the kidneys • Volume loss (dehydration, bleeding, renal loss, GI loss, burns, 3rd spacing),  decreased cardiac output, systemic vasodilation, renal artery disease, etc.

7. Etiologies of AKI • Intrinsic (Renal)- causes due to damage to the kidney itself • Acute tubular necrosis, glomerulonephritis, acute interstitial nephritis, vasculitides, autoimmunity, drugs, infection, etc.

8. Etiologies of AKI • Postrenal- causes as a result of urinary tract obstruction, can occur anywhere from the renal pelvis to the urethra. • Stone, stricture, tumor, clot, prostate etiology, bladder neck obstruction, extraluminal compression, etc.

9. Baseline Set of Laboratories to Consider • Biochemistry • urea and electrolytes • Hematology • CBC • Urinalysis (+/- microscopy, eosinophils) • Urinary Biochemistry • electrolytes, urea, osmolality • Microbiology • urine/blood culture when/if infection suspected • Imaging • renal ultrasound • CXR, abdominal x-ray • ECG

10. Urine Patterns in Renal Disease

11. Management Importantly, manangement of AKI is varied and depends on the cause.  Given no effective pharmaceutical options, management of AKI is primarily supportive. However, some general principles can be applied. • Prerenal azotemia is usually responsive to isotonic fluid repletion • Managament of ATN includes discontinuation of nephrotoxic agents, optimization of hemodynamics, continued monitoring of renal function (acid/base status, electrolyte abnormalities). • Postrenal causes warrant removal of the obstruction.

12. Management Cont. • Things to do for patients with AKI • Renally dose medications • Avoid nephrotoxins • Monitor I/Os • Serial assessment of serum creatinine • Renal Replacement Therapy (i.e dialysis) is the central component of care for patients with severe AKI   • The generally accepted indications for renal replacement therapy in the setting of AKI include: • Acidosis • Electrolyte disturbance • Ingestion/Intoxication • Volume Overload • Overt Uremia

13. 5 Key Steps in Evaluating Acute Renal Failure • Obtain a thorough history and physical; review the chart in detail • Do everything you can to accurately assess volume status • Always order a renal ultrasound • Look at the urine • Review urinary indices

14. Acute Renal Failure Muddy Brown Casts: Highly suggestive of ATN. Pigmented granular casts as seen in hyperbilirubinemia can be confused for these. UpToDate Images.

15. Acute Renal Failure White Blood Cell Casts: Raises concern for interstitial nephritis. Can be seen in other inflammatory disorders. Also seen in pyelonephritis. UpToDate Images.

16. Acute Renal Failure • Hematuria Nonglomerular hematuria: Urologic causes. Bladder/Foley trauma. Nephrolithiasis. Urologic malignancy. May be “crenated” based upon age of urine, osmolality – NOT dysmorphic.

17. Acute Renal Failure Dysmorphic Red Cells: Suggestive of glomerular bleeding as seen with glomerulonephritis. Blebs, buds, membrane loss. Rarely reported in other conditions – DM, ATN. Red Blood Cell Casts: Essentially diagnostic of vasculitis or glomerulonephritis.

18. Acute Renal Failure Crystals – Pretty and important. Uric acid crystals: Seen in any setting of elevated uric acid and an acidic urine. Seen with tumor lysis syndrome. Calcium oxalate crystals: Monohydrate – dumbell shaped, may be needle-like. Dihydrate – envelope shaped. Form independent of urine pH. Seen acutely in ethylene glycol ingestion. UpToDate Images.

19. Diagnostic Evaluation of Renal Failure 100- 80- 60- 40- 20- 0- 15% 25% Cumulative % Correct Diagnosis 60% Hx, PE, Labs Therapeutic Trials Renal Biopsy

20. Renal Biopsy-When? • Exclude pre- and post-renal failure, and clinical findings are not typical for ATN • Extra-renal manifestations that suggest a systemic disorder • Heavy proteinuria • RBC casts

21. Case 1 A 42 year male is admitted to the SICU after sustaining multiple trauma. His course is complicated by Enterobacter sepsis with profound hypotension requiring support with intravenous dopamine. The urine output has gradually decreased to only 300 ml per day. The urine sodium is 78.

23. Ischemic Acute Renal Failure • A form of ATN often following a prerenal insult • Severity of renal failure correlates with duration of insult • Treatment is to optimize renal perfusion, avoid additional nephrotoxic insults and other supportive measures

24. Conditions that Lead to Pre-renal Acute Renal Failure Intravascular Volume Depletion Decreased Effective Circulating Volume CHF Cirrhosis Nephrosis Generalized or Localized Reduction in Renal Blood Flow Sepsis Hepatorenal Syndrome Ischemic Acute Renal Failure

25. Phases of Ischemic Epithelial Tubular Injury Pre-renal Initiation GFR Extension Maintenance Recovery Time

27. Risk Factors for Ischemic Tubular Injury • Volume depletion • Aminoglycosides • Radiocontrast • NSAIDs, Cox-2 inhibitors • Sepsis • Rhabdomyolysis • Preexisting renal disease • HTN • Diabetes mellitus • Age > 50 • Cirrhosis

30. Case 2 A 56 y.o. male presents with complaints of persistent fever, chills, sore throat, and myalgias for the past 14 days. Ten days ago he started taking amoxicillin he had on hand for dental prophylaxis. His physical exam is remarkable for fever to 38.6oC, an exudative pharyngitis and a diffuse maculopapular rash.

31. Case 2 Laboratory Data Result Normal Range Serum Na 134 mEq/L 135-145 K 5.7 mEq/L 3.5-5 Cl 106 mEq/L 100-111 Total CO2 14 mEq/L 24 BUN 46 mg/dL 4-15 Creatinine 3.8 mg/dL 0.6-1.0 Glucose 96 mg/dL 60-100 Whole blood WBC 12 x109/L 4.5-11.0 Hgb 11 gm/dL 13.5-17.5 Hct 33 % 41.0-53.0 Platelets 216 x109/L 150-440 Urine Specific gravity 1.010 1.002-1.036 Protein 2+ Negative Blood Trace Negative Glucose Negative Negative The urine sediment shows 3-5 RBC’s/h.p.f., 20-25 WBC’s/h.p.f., coarse granular and white cell casts, and rare red cell casts.

32. Case 2

33. Acute Interstitial Nephritis-Etiology • Allergic/Drug induced • Autoimmune • Sarcoid -SLE • Sjogren’s • Toxins • Chinese herb nephropathy -Heavy metals • Light chain cast nephropathy • Infiltrative • Leukemia • Lymphoma • Infections (Legionella, CMV, HIV, Toxoplasma)

34. Acute Interstitial NephritisClinical Presentation • Non-oliguric ARF • Fever in allergic and infectious types (except NSAID type) • Rash in allergic type (except NSAID induced) • Eosinophilia • UA: WBC casts Eosinophiluria (allergic) Hematuria (NSAID related)

35. Common Causes of Drug Induced AIN • NSAIDS • Antibiotics • Penicillins • methacillin • Ampicillin, amoxacillin, carbenacillin, oxacillin • Cephalosporins • Quinolones (ciprofloxacin) • Anti-tuberculous medications (rifampin, INH, ethambutol) • Sulfonamides (TMP-SMX, furosemide, thiazides) • Miscellaneous • Allopurinol, cimetidine, dilantin

36. Acute Kidney Injury: AIN causes DRUGS • ACEI • Allopurinol • Cephalosporins • Cimetidine • Fluoroquinolones • Loop diuetics • NSAIDS • PCN • Phenytoin • Rifampin • Sulfonamides • Tegretol • Thiazides INFECTION • Bacterial • Agents causing pyelonephritis • Legionella • Brucella • Yersinia • Viral • Hantavirus • HIV • CMV,EBV,HSV

37. Acute Interstitial NephritisTreatment • Withdrawal of offending agent • Treatment of underlying process if infectious/autoimmune etiology • Trial of corticosteroids, especially in allergic presentations 1 mg/kg/day or 2 mg/kg every other day • No randomized trials proving efficacy • Reversal of renal failure usually seen in < 6 weeks

38. Rhabdomyolysis • Often develops in the setting of crush injury, especially if superimposed circulatory shock • Hallmarks of diagnosis • CK > 10,000 • (+) dipstick for blood but no RBCs • Treatment • Volume expansion (judiciously if severe oliguria or azotemia) • Fasciotomy when indicated for compartment syndrome (“second wave phenomenon”) • Avoid calcium repletion unless neuromuscular manifestations present • Rebound hypercalcemia in recovery phase

39. Aminoglycoside Nephrotoxicity • Generally presents 1 week after exposure • Non-oliguric • Low trough levels do not guard against nephrotoxicity • Incidence of ATN • 10% after 1 week • 40% after 2 weeks • Risk factors for ATN • Advanced age - Superimposed sepsis • Liver disease - Hypotension

40. Radiocontrast-Induced Acute Renal Failure • Induces renal vasoconstriction and direct cytotoxicity via oxygen free radical formation • Risk factors: • Renal insufficiency - Diabetes • Advanced age - > 125 ml contrast • Hypotension • Usually non-oliguric ARF; irreversible ARF rare

41. Contrast Induced Nephropathy • Assess CIN risk • eGFR <30 – Hospital admission, Nephrology consult, Dialysis planning, renal protection • eGFR 30-59 – Discontinue NSAIDs, IV volume expansion, Intra-arterial: isoosmolar, Intra-venous: iso-osmolar or low osmolar contrast; limit contrast volume • eGFR >60, Discontinue metformin • Optimal Volume Status • Low-osmolality contrast media • F/U Creatinine 24 – 72hr after contrast exposure • Adequate IV volume expansion with isotonic crystalloid for 3 – 12hr before the procedure and continue for 6 – 24hr afterward. Oral fluid data is insufficient • No adjunctive medical or mechanical treatment has been proved to be efficacious • Prophylactic hemodialysis and hemofiltration not validated

42. Acute Renal Failure due toIntratubular Obstruction • Crystalluria • Ethylene glycol: Calcium oxalate • Tumor lysis: Urate and Calcium phosphate • Medications • Acyclovir • Methotrexate • Sulfonamides • Anti-retroviral agents • Myeloma cast nephropathy

45. Case 3 A 35-year-old Hispanic female presents with a one month history of periorbital and lower extremity edema. Over two days prior to presentation she has experienced arthralgias in her wrists and elbows. On physical examination she is in no acute distress. Blood pressure is 162/94, temperature 37.4 . Her skin exam is significant for a malar erythematous rash. The heart and lungs are normal. There is 3+ edema to the thighs bilaterally.

46. Case 3 Laboratory Data Result Normal Range Serum Na 138 mEq/L 135-145 K 4.2 mEq/L 3.5-5 Cl 108 mEq/L 100-111 Total CO2 17 mEq/L 24 BUN 75 mg/dL 4-15 Creatinine 3.5 mg/dL 0.6-1.0 Glucose 83 mg/dL 60-100 Anti-neutrophil antibody 1:160 Negative Whole blood WBC 5.9 x109/L 4.5-11.0 Hgb 11.9 gm/dL 13.5-17.5 Hct 34 % 41.0-53.0 Platelets 153 x109/L 150-440 Urine Specific gravity 1.015 1.002-1.036 Protein 3+ Negative Blood 3+ Negative RBC >50/h.p.f. 0-4 Sodium 10 mEq/L Variable Creatinine 35 mg/dL Variable

47. Case 3

48. AKI: Glomerulonephritis (RPGN)/Systemic Vasculitis • Immune-Complex Mediated • SLE • Cryoglobulinemic vasculitis • Henoch-Schönlein purpura • Post-strep GN • Direct Ab attack • Anti-GBM disease • Goodpasture’s syndrome • Pauci-immune vasculitis • Microscopic polyangiitis • Wegener’s granulomatosis • Churg-Strauss syndrome • Thrombotic Microangiopathy • TTP • HUS • Scleroderma renal crisis • Preeclampsia • Malignant hypertension

49. AKI: Summary Small changes in creatinine can have grave clinical consequences ABCDE assessment and careful management of fluid status is mainstay of treatment Get help early

50. Future fixes… • Neutrophil Gelatinase-Assoc. Lipocalin (NGAL) • Levels in blood and urine rise within a few hours after injury • Cystatin C • Absorbed by kidney, but not secreted • Rises one day before Cr • Interleukin 18 • Produced by caspase-I which is implicted in pathogenesis of ARF Have been shown to predict AKI severity in post-op hearts