Acute Kidney Injury

1. Acute Kidney Injury • AKI - an abrupt increase in serum creatinine of at least 0.3 mg /dl or 1.5 over baseline over 48 hours (based on AKI Network Consensus 2007) • stage 1 increase in creatinine 1.5-2 fold • stage 2 increase in creatinine >2-3 fold • stage 3 increase in creatinine >3 fold (or need for dialysis or a peak Cr >4 mg/dl with at least a 0.5 mg/dl increase) • Increased morbidity and mortality with increasing stage

3. AKI - incidence and risks • Hospitalized patients – 5 to 7.5% • ICU – 10 to 30% • AKI – associated with increased cost or length of hospital stay, risk of end-stage renal disease • AKI -increased risk of death with AKI and sepsis, trauma, cardiopulmonary bypass, burn injuries (despite correction for comorbidities and severity of illness) Crit Care Med 2010:261 • Hyperglycemia in hospital increases risk AKI

4. Creatinine interpretation • Increased BUN/creatinine ratio – pre-renal, blood in gut, obstruction, steroids, tetracycline • Decreased BUN/creatinine ratio – rhabdomyolysis, reduced protein intake • False elevations in creatinine – ketones, trimethoprim, cimetidine • Rate of rise of creatinine – when daily creatinine elevation starts to go down a clue that renal function starting to improve • eGFR – can not be calculated if Cr not stable • Amputation - lower baseline creatinine • Indicator AKI – relatively late; need renal “troponin”

5. Non -ICU ICU

6. Diagnosis of prerenal azotemia Urine sediment (usually normal, without cellular elements or abnormal casts, unless chronic kidney disease is present) UNa< 15 meq/L (>20 in ATN) U/Pcreat> 20 (<15 in ATN) FeNa <1% (>1% in ATN) UNa/K <1/4 BUN/creat >20 Often remains a retrospective Dx made only after response to a fluid challenge

8. Replacement fluids • Ringers lactate - since contains K+ do not give to oliguric patient • ½ NS – avoid in hyponatremic patient • 0.9 NS resuscitation fluid of choice, but can worsen hyponatremia if SIADH • Hydroxyethyl starch – increased incidence of AKI (osmotic nephrosis) • ½ NS + 1 amp NaHCO3 if very acidotic

9. Colloid vs crystalloid • 7000 patients in medical and surgical ICUs in Saline vs Albumin Fluid Evaluation (SAFE) - randomized, double-blind trial comparing NS vs 4% human albumin. Results - no difference in 28 day survival, days spent in the ICU, days on mechanical ventilator. • Hypoalbuminemic patients - small randomized trial in which IV albumin improved sequential organ failure assessment (SOFA) compared with NS. • Spontaneous bacterial peritonitis - randomized trial comparing antibiotics alone vs antibiotics plus IV albumin (1.5 gm/kg immediately on diagnosis then 1 gm kg on day 3). Results - decreased renal failure and improved survival. Current standard of care in SBP.

10. Early Goal Directed Therapy • Definition - in patients with septic shock early intervention within the first 6 hours in the ED • Goals - in first 6 hours MAP> 65 mmHg, CVP 8-12, improvement in blood lactate, central venous 02 sat>70%, UO>0.5 ml/kg/hour • ED patients transferred to ICU with SIRS & mean creatinine 2.6 mg/dl: sBP<90 or lactate>4, central venous 02 sat <50. Compared with control group the EGDT group received more fluids, transfusions, and dobutamine, but physiologic goals reached quicker; hospital mortality reduced - 30% vs 45% • Above protocol is the basis for Surviving Sepsis Guidelines Clin J Am Soc Neph 2010:733

11. Fluid overload in AKI • 618 critically ill patients - Clin J Am Soc Neph 2010:733 • Prospective, multicenter, observational study • Examined the effect of fluid overload (>10% increase in body weight). • Those with fluid overload had more respiratory failure, mechanical ventilation, and sepsis. • Those with AKI and fluid overload had increased mortality at 30 and 60 days and at hospital discharge (corrected for severity of illness).

12. AKI fluid overload • 7000 patients with acute lung injury • Prospective randomized trial comparing conservative and liberal fluid management for 7 days. • The conservative group received more furosemide and fewer fluid boluses, gained 7 kg less. No difference in mortality but conservative group less days on vent, less time in the ICU, and trend for lower need for dialysis. • the CVP in the aggressive group was 12 at the start of the study and remained 12 despite the 7 kg weight gain whereas it went from 12 to 8 in the conservative group Clin J Am Soc Neph 2010:733

13. AKI - use of dopamine or diuretics • Low dose dopamine – does not reduce the incidence of AKI, the need for RRT or improve the outcome in AKI. Is associated with increased myocardial 02 demand and increased incidence of atrial fib • Diuretics - can sometimes convert oliguric to non oliguric but no data that shorten duration of AKI, reduce need for RRT, or improve overall outcomes. But can help control volume overload.

14. Abdominal compartment syndrome • World Congress on ACS defined a normal intra-abdominal pressure (IAP) to be between 5-7 mmHg in critically ill patients, elevated to be >8 mmHg, and intra-abdominal hypertension to be >12 • Abdominal compartment syndrome (ACS) – intra-abdominal pressure>20 mmHg associated with organ failure in one or more organs • The renal insufficiency results from decreased renal perfusion and correlates with the severity of the increased intra-abdominal pressure and a decreased abdominal perfusion pressure (Mean arterial pressure – intra-abdominal pressure)

15. Measurement of intra-abdominal pressure • Clamp drainage tube of Foley catheter • Instill 50 mL of sterile water into the bladder via the aspiration port • Measure pressure using a transducer attached to an 18 gauge needle inserted into the aspiration port (transducer should be zeroed at the level of the pubic symphysis)

16. Abdominal compartment syndrome systemic effects • Cardiac - decreased cardiac output, increased CVP, PCWP, SVR • Pulmonary – increased intra-thoracic and airway pressures, decreased pa02, increased paCO2 • GI – decreased splanchnic perfusion • Renal - reduced renal perfusion, GFR and urine output

17. ACS - causes and treatment Settings - trauma patient who requires massive volume resuscitation; mechanical limitations of the abdominal wall (tight surgical closures or scarring after burn injuries); intra-abdominal inflammation with fluid sequestration (eg. bowel obstruction, pancreatitis, and peritonitis). Treatment - Abdominal decompression: Paracentesis if massive ascites, surgical decompression may be required

18. Cardio-renal syndrome • As opposed to hepato-renal syndrome is not renal dysfunction due to cardiac disease but includes vice versa and also divides the responses into acute and chronic. • While creatinine is a better indicator of renal function the BUN in CHF correlates better with mortality. • The BUN also correlates much better with Na+ – high BUN and low Na+ suggest pre renal state and stimulation of the renin-angiotensin system and ADH. • Many patients admitted with CHF are not very edematous. Average weight loss in CHF hospitalization is only several kgs with many patients not losing any weight. So the notion of all CHF admissions being due to fluid overload is simplistic. In many patients it seems to be more related to preceding increase in systemic BP or pulmonary hypertension

19. Acute decompensated HF (ADHF) and intra-abdominal hypertension • 40 consecutive patients admitted to CHF unit for ADHF • Age 59 +/- 6 • LVEF 19 +/- 8 • Baseline Cr 2 +/- 0.8 • Baseline IAP 8 +/- 2 with 24 having high IAP • Elevated IAP associated with worsening renal function during that admission p=0.0009 • Intensive medical Rx improved hemodynamics and renal function in those with high IAP • Strong correlation between reduction in IAP and improved renal function seen in those with high IAP but neither changes in IAP or renal function correlated with hemodynamic changes JACC 2008:300

20. ADHF response to reduction IAP • 9 consecutive pts that were volume overloaded with ADHF and elevated IAP refractory to intensive medical therapy • All had progressive elevation in serum creatinine and worsening in IAP with IV loop diuretics • Within 12 hours after paracentesis 5.3 L or UF 1. 8 L there was a significant reduction in IAP from 13 to 7 and improvement in Cr from 3.4 to 2.4 but no change in hemodynamics J Card Failure 2008:508

21. ESCAPE • Evaluation Study of CHF And Pulmonary artery catheterization Effectiveness • In 433 patients compared hemodynamic monitoring with PAC vs CVP in ADHF • Renal dysfunction (eGFR <60) either baseline or worsening renal function (Cr increment >0.3) both shown to be associated with adverse outcomes during treatment of CHF. • No correlation between baseline hemodynamics or change in hemodynamics and worse renal function - so poor forward flow does not account for development of worse renal function

22. Rx of edema with ultrafiltration • Aggressive diuresis causes aldosterone and renin to increase in the CHF patient • Renin and aldosterone may have negative effects on cardiac and vascular function counteracting the benefit of volume removal. • Ultrafiltration can remove significant volume in CHF and may not stimulate the renin angiotensin system as much as diuretics • High dose diuretics – in retrospective studies in in acute Rx CHF associated with increased mortality JAMA 2002:2547

23. Ultrafiltration • Peripheral line - double lumen 6 or 7 French • Blood pump and filter (CHF solutions device) with a blood flow of 40-50 cc/min • Medical floor not ICU • Disposables - very expensive • Systemic heparin • Remove up to 4-8 kg per day. • No change in concentration of BUN, creatinine, K+, etc • UNLOAD - trial comparing UF vs IV diuretics in CHF: UF removed more volume than furosemide, patients discharged a little sooner and less likely to be readmitted within 30 days (because their renin-angiotensin system had not been activated?)

24. Diagnostic criteria for hepatorenal syndrome Chronic or acute hepatic disease with advanced hepatic failure and portal hypertension Creatinine > 1.5 mg/dL progressing over days/weeks. The absence of other apparent causes for the renal disease - shock, bacterial infection, nephrotoxic drugs, and the absence of US evidence of obstruction or parenchymal renal disease. Urine RBCs < 50 cells/HPF and protein excretion less than 500 mg/day. Lack of improvement in renal function after volume expansion with IV albumin (1 g/kg body weight per day up to 100 g/day) for at least 2 days, DC of diuretics. Urine Na<10

25. Hepatorenal syndrome • Type 1 - doubling of serum creatinine to a level greater than 2.5 mg/dL or reduction of the creatinine clearance by 50% or more to a value < 20 mL/min over a duration of 2 weeks, usually in hospitalized patients, no inciting agent. • Type 2 - moderate and stable reduction in GFR, insidious onset and slow progression of renal insufficiency in the setting of refractory ascites, better prognosis than type 1 • 5 randomized trials of splanchnic vasoconstricting agents (terlipressin or noradrenaline) plus albumin all demonstrated improved renal function and mortality benefit in responders. Crit Care Med 2010:261

26. ATN causes • Nephrotoxic contrast aminoglycosides myoglobin, hemoglobin • Ischemic cardiopulmonary arrest profound hypotension unwitnessed arrhythmia • Septic – often multifactorial

27. ATN - Recovery of renal function In contrast to the heart and brain, where ischemic injury results in permanent cell loss, the kidney is able to completely restore its structure and function after acute ischemic or toxic injury. The recovery from tubular necrosis involves the dedifferentiation and proliferation of remaining viable tubular epithelial cells followed by reestablishment of cellular polarity, normal histologic appearance, and physiologic function.

28. Diagnosis of ATN Urine sediment (in patient with high pre-test probability of ATN the presence of renal tubular epithelial cells or granular casts is confirmatory for ATN, but may be a relatively late sign) Clin J Am Soc Neph 2008:1615 UNa >20 in ATN U/Pcreat <15 in ATN FeNa >1% in ATN BUN/creat <20

29. Contrast media High-osmolal contrast media (osmolality 1500–1800 mOsm/kg) are first generation agents. Low-osmolal contrast media still have an increased osmolality compared with plasma (600–850 mOsm/kg), The newest nonionic radiocontrast agents have a lower osmolality, 290 mOsm/kg, iso-osmolal to plasma

30. Risk factors for contrast-induced nephropathy • Patient related – pre-existing renal insufficiency, diabetes mellitus, intravascular volume depletion, reduced cardiac output, common nephrotoxins(especially NSAIDs) • Procedure related – increased dose of radio-contrast, multiple procedures within 72 hours, intra-arterial administration, type of radio-contrast

31. Prevention of contrast nephropathy NS at a rate of 1 mL/kg per hour, begun at least 2 and preferably 6-12 hrs prior to the procedure, and continuing for 6-12 hrs after contrast administration. Isotonic sodium bicarbonate may be as or more effective (conflicting meta-analyses) Acetylcysteine – 600-1200 mg po BID, the day before and the day of the procedure, based upon its potential for benefit and low toxicity & cost. (conflicting meta-analyses)

32. Hemodialysis to prevent CIN • Routine hemofiltration or hemodialysis for the prevention of contrast nephropathy in patients with stage 3 and 4 CKD is not recommended. • More data are needed in stage 5 CKD (Prophylactic use of hemodialysis in patients with stage 5 CKD, can be considered, provided that a functioning access is already available) AJKD 2006:361 Extracorporeal blood purification therapies for prevention of radiocontrast-induced nephropathy: a systematic review. Am J Kidney Dis 2006; 48:361. Renal protection for coronary angiography in advanced renal failure patients by prophylactic hemodialysis. A randomized controlled trial. J Am Coll Cardiol 2007; 50:1015.

33. Treatment of rhabdomyolysis NS – early hydration may prevent severe AKI. Must monitor for fluid overload NaHCO3 – to raise urine pH >6.5; eg. I amp 1 L 1/2 NS; monitor serum pH Mannitol – eg. 50 cc of 20% to each L of IV fluid to increase UO; monitor osmolarity Initial rate of IV fluid about 500-1000 cc/hour; goal UO >300. All authorities agree with vigorous hydration but no consensus on the rate of IV fluids or the use of mannitol or NaHCO3

34. Indications for RRT Refractory fluid overload Hyperkalemia – eg, K+ >6.5 meq/L, rapidly rising levels, marked EKG changes espeically if patient oliguric or can not take kayexalate Marked metabolic acidosis in which are limited in giving NAaHCO3 due to volume constraints Signs of uremia, such as declining mental status, not eating, uremic pericarditis (rare)

35. CRRT vs intermittent hemodialysis • A number of meta-analyses have addressed this question. Current data do not support the superiority of either CRRT or IHD. • In Europe and Australia use of CRRT much higher than in US • Many patients during the course of AKI receive several modalities • Peritonal dialysis can be done also but may be difficult to give as much dialysis, no head to head trials showing that it is less effective

36. Timing of initiation of RRT Initiation of dialysis prior to the development of symptoms and signs of renal failure due to AKI is recommended. It is unproven whether initiation of earlier or prophylactic dialysis offers any clinical or survival benefit. If do start RRT before symptoms is no concensus on what level of BUN or creatinine to start

37. AKI - obstructive uropathy To cause AKI need bilateral obstruction or obstruction of sole kidney Always consider in the hospitalized patient that the Cr elevation could be bladder dysfunction from meds, reduced LOC, bedridden patient. Post-void residual by bladder scan Renal US - a very sensitive test, false negatives: retroperitoneal fibrosis, early obstruction, severe volume depletion

38. AKI - interstitial causes Suspect if WBC casts, marked pyuria, on a med that commonly causes intersitial nephritis, hypercalcemia Acute interstitial nephritis - most commonly due to drugs esp antibiotics, PPI Pyelonephritis Acute urate nephropathy Tumor lysis syndrome hypercalcemia

39. AKI - acute glomerulonephritis • Suspect if patient has marked proteinuria, RBC casts, marked hematuria • If is AKI and GN indicates possible RPGN • Relatively urgent need for a renal biopsy since creatinine can go up daily and may not be completely reversible • If seriously suspect may start steroids before the biopsy is back

40. AKI – vascular causes • Renal emboli – suspect in patient with AF other embolic phenomenona, high LDH • Cholesterol emboli – suspect if recent trauma or angio in elderly patient • TTP/HUS • Antiphospholipid syndrome • Renal vein thrombosis – suspect if nephrotic levels of proteinuria

41. Acute tubular necrosis • Ischemic – prolonged pre-renal azotemia, hypotension, hypovolemic shock, cardiac arrest, cardiopulmonary bypass • Nephrotoxic – drug-induced (radiocontrast agents, aminoglycosides, amphotericin B, cis-platinum, acetaminophen). Pigment nephropathy (hemoglobin, myoglobin) • Sepsis

42. AKI causes PRE RENAL - volume depletion, CHF, hepatorenal syndrome, abdominal compartment syndrome, drugs (ACEI, NSAIDs) POST RENAL RENAL acute tubular necrosis (ATN) nephrotoxic (eg, contrast, aminoglycosides, rhabdomyolysis), ischemic sepsis Interstitial - pyelonephritis, acute interstitial nephritis, myeloma, hypercalcemia, hyperuricemia, tumor lysis syndrome, intratubular obstuction - uric acid, myeloma Glomerular - primary GN vs. secondary to a systemic disease Vascular - renal emboli, cholesterol emboli, vasculitis, anti-phospholipid syndrome, renal vein thrombosis

44. Prediction of AKI after renal insult • Coronary intervention - risk factors: hypotension, IABP, CHF, age>75, anemia, diabetes, contrast volume, and serum creatinine. If patient has a very low score likelihood of CIN -7.5% versus 57% • Open heart surgery – risk factors: female, CHF, LVEF, preop IABP, COPD, IDDM, prior surgery, emergency surgery, prior creatinine elevation, valve surgery. Variation in need for dialysis 0.4-21 % • AKI after non cardiac surgery – risk factors: age>59, BMI>32, emergency surgery, high risk surgery, PVD, liver disease, COPD. Variation in risk of AKI 0.3 – 4.3

46. Acute kidney injury • PRERENAL - volume depletion, CHF, hepatorenal syndrome, abdominal compartment syndrome, drugs (ACEI, NSAIDs) • POST RENAL • RENAL acute tubular necrosis (ATN) nephrotoxic (especially contrast, aminoglycosides, rhabdomyolysis), ischemic sepsis • interstitial - pyelonephritis, acute interstitial nephritis, myeloma, hypercalcemia, hyperuricemia, tumor lysis syndrome, intratubular obstuction - uric acid, myeloma • glomerular - primary GN vs. secondary to a systemic disease • vascular - renal emboli, cholesterol emboli, vasculitis, anti-phospholipid syndrome, renal vein thrombosis

47. Treatment of hepato-renal syndrome • Management of underlying cause • Stop diuretics • Low salt diet and free water restriction if hyponatremia • Midodrine + Octreotide + Albumin • Terlipressin + Albumin • RRT • TIPS

48. Shortcomings The assignement of corresponding changes in serum creat and changes in urine output to the same strata is not based on evidence. The criteria that results in the least favorable rifle strata to be used. The patient would progress from "risk" on day one to "injury" on day two and "failure" on day three, even though the actual GFR has been <10 mL/min over the entire period. It is impossible to calculate the change in serum creatinine in patients who present with ARF but without a baseline measurement of the serum creat. The authors of the RIFLE criteria suggest back-calculating an estimated baseline creat using the four-variable MDRD equation, assuming a baseline GFR of 75 mL/min per 1.73 m2 .

49. Nephrotoxic ATN