Acute renal failure By :Chua Shiau Ying Moderator: Dr NikAzman
Learning objectives • Definition of acute renal failure • Aetiology • Management strategy • Biomarkers
Case 1 45 yrs old woman No known medical illness presented to ED with hx of fever and cough 3 days SOB worsening today O/E: • T:38.3 °C, • BP:80/40mmHg • HR: 120/min • RR: 28 • SPO2: 89%RA. • Lungs have bilateral rales
ABG : pH:7.26/Paco2:40/PaO2:120/Hco3-:15/lactate 6 • Initial labs: TWBC 2500 mm3, Hb 10 g/dl, Plt 103,000 mm3; • BUSE:Na 134 mEq/L, K 4.0,Cl 100 mEq/L,BUN 4.4mmol/l, Cr 85umol/l, Glucose 7.2mmol/l, • albumin 20 g/l. • CXR shows patchy infiltrate • admitted into ICU
Causes of ARF? prerenal renal Post renal
Acute azotemia/oliguria/anuric Non renal • High creatinine • Rhabdomyolysis • drugs: egcimetidine, trimethoprim, alpha methyldopa • High urea • Catabolism • GI Bleed • Drugs:tetracycline, • corticosteroid • Increased protein intake
Renal cause Post renal cause Pre-renal cause • Tubular injury • Interstitial nephritis • Glomerular and vascular causes • -glomerulonephritis • -TTP • -HUS • -IE • -thromboembolism • Nephrotoxic drugs • -aminoglycoside • -beta lactam • -amphotericin-B • -NSAID • -radiocontrast • -cytotoxic drugs • Obstructive uropathy • -blocked CBD • -prostatic disease • -intraabdominal/pelvic mass • -calculi • -blood clots • Hypovolemia • Peripheral vascular changes • -sepsis • -anaphylaxis • -liver failure • Reduced cardiac output -assess volume status Eg:lactate ,IVC diameter,BP, HR -cardiac output study • -USG • -KUB x-ray • -CT scan • IVU • Retrograde pyelogram -urine feme -drug hx, past medical hx -biopsy -CTD screening
Prerenalvs Renal??? Fractional excretion of Na = urine Na SrCreat ------------ x ------------- x 100 Sr Na urine Creat
Dilemma in Mx of AKI pt--Fluid… • Management of blood pressure and cardiac output require careful titration of fluid and vasopressor. • Studies have shown that positive fluid balance is an important factor associated with 60 days mortality.78,83,84 • “In the absence of hemorrhagic shock, we suggest using isotonic crystalloids rather than colloids (albumin or starches) as initial management for expansion of intravascular volume in patients at risk for AKI or with AKI. (2B)”
Albumin vscrytalloid • Results of the Saline vs. Albumin Fluid Evaluation (SAFE) study, a double blinded RCT comparing 4% human albumin in 0.9% saline with isotonic saline in ICU patients, seem to indicate that albumin is safe, albeit no more effective than isotonic saline (the standard of care choice of isotonic sodium chloride in most centers) for fluid resuscitation. • SAFE demonstrated further no difference in renal outcomes, at least based on the need for and duration of RRT
HES • The colloid osmotic pressure effect is strongly dependent upon the concentration of colloid in the solution; e.g., 6% HES is iso-oncotic, whereas 10% HES is hyperoncotic • In the Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP)study,93 patients with severe sepsis were randomly assigned to receive a hypertonic (10%) solution of low MW HES or an isotonic modified Ringer’s lactate solution
hypertonic HES group had a significantly higher rate of AKI (34.9% vs. 22.8%) and more days on which RRT was required
Vasopressors… • Persistent hypotension despite on going aggressive fluid resuscitation /after optimization of of intravascular volumerisk for AKI • Use of vasopressors in conjunction with fluids in pt with vasomotor shock with/at risk for AKI(1c) • Current clinical data insufficient to conclude which vasopressor is superior • Appropriate use of vasopressor in volume resuscitated pt can improve kidney perfusion.
Role of diuretic? • Loop diuretics—renoprotective? -may decrease o2 consumption in loop of Henle by inhibiting Na+ transportreducing ischemic injury -may hasten recovery AKI by washing out necrotic debri blocking tubules -inhibit PG dehydrogenasereducerenovascularresistanceincrease renal blood flow
Epidemiological data suggested that use of loop diuretic may increase mortality in pt with critical illness and AKI181 • There is no evidence that use of diuretic reduce the incidence or severity of AKI • Recommendations: • Not using diuretics to prevent AKI(1b) • Not using diuretics to treat AKI EXCEPT in the management of fluid overload.(2c)
When to dialyse? RECOMMENDATIONS: • Initiate RRT emergently when life threatening changes in fluid, electrolytes and acid base balance exists • Consider the broader clinical context
Potential application for RRT • Life threatening indications: • Hyperkalemia • Acidemia • Pulmonary oedema • Uremic complication:pericarditis,bleeding • Non emergent indications: • Solute control • Fluid overload • Correction of acid base balance
Renal support • Volume control • Nutrition
Case 2 • 25 yrs old gentleman, no known medical illness admitted into the ward following mva • He sustained crush injury left lower limb with fracture left femur • Ck:15000 • Creat: 120 • Urea : 12 • K+: 5.2 • Urine output : 40ml/hr
Diagnosis? • What other Ix to ask for ? • How would you manage this case? • What else to watch out?
1.Rhabdomyolysis • Clinical and biochemical syndrome characterized by muscle breakdown and necrosis resulting in leakage of intracellular muscle constituents into the interstitial space and plasma. • AKI OCCURS IN 30-50% PT WITH RHABDOMYOLYSIS
Classic triad • Muscle weakness • Muscle pain • Dark urine Occur in <10% of pt
2.What other Ix to ask for? • Red urine hematuria?myoglobinuria? • Creatininekinase(CK) -CK-MM -rise within 12 hrs of muscle injury, peak at 1-3 days, decline after 3-5 days • Sr electrolytes - hyperK - hypoCa - hyper phosphatemia • Urea,creatinine • hyperuricemia • coagulation profile
rhabdomyolysis 3rd space loss myoglobinemia hypovolemia Endotoxin & cytokine myoglobinuria Renin-angiotensin Direct cytotoxic effect Renal vasoconstriction Myoglobin cast Proximal tubular oxidative stress DCT obstruction Renal ischemia AKI
3.Management • Treat the underlying cause • Prevention of AKI • Correction of electrolytes disorder • Mx of complication
Prevention of AKI • Fluid replacement • Early, aggressive intravascular volume expansion by NS is the KEY to prevent AKI • Objective : to achieve minimum urine output goal of 2ml/kg/hr
2. Urine alkalinization with IV NaHCO3 • Increase the solubility of myoglobin and uric acid NaHCO3 limit formation of myoglobin casts and uric acid crystals. • Objective: to reach urine pH > 6.5 and serum pH 7.40-7.45 • No large randomised trial that shows alkalinisation of urine is better than early, aggressive hydration in the treatment of rhabdomyolysis
3. Diuretics • Use of diuretics controversial • Should ONLY be considered after adequate fluid resuscitation • Frusemide -increase urine outputflush toxic metabolites out of renal tubules • Mannitol -exerts antioxidative effects -act on PCT and contributes to excretion of myoglobin, heme reduce cast formation -1g/kg IV over 30mins or 25g IV followed by 5g/hr for total of 120g/day
4.Any role of RRT? • Used to treat complication of rhabdomyolysiseg: hyperkalemia, metabolic acidosis • Not effective in clearing myoglobin • Not shown to improve the outcome
4. What else to watch out ? • Electrolyte imbalance • AKI • Disseminated intravascular coagulopathy • Matabolic acidosis
Biomarkers of AKI • Serum creatinine were first used as biomarker of kidney function since 1917 • Breakdown product of creatine phosphate in muscle • Level affected by: • Age • Sex • Diet • Drugs eg: cimetidine, gemfibrozil, trimethoprim(competitive inhibition of creatinine secretion, GFR normal)
NGAL • member of the lipocalin family of proteins • expressed by immune cells, hepatocytes, and renal tubular epithelial cells • first identified as a potential marker for AKI in 2003 • In 2005,study of 71 children undergone cardiopulmonary bypass reported that20 patients who developed AKI by creatinine criteria. • Both serum and urine NGAL levels rose significantly within 2 hours of surgery (mean urine NGAL rose from 1.6 ug/L to 147 ug/L while serum NGAL rose from 3.2 ug/L to 61 ug/L). • creatinine elevations were not appreciated for at least 1 day following the surgery
its sensitivity for AKI was 1.00, and specificity was 0.98 . • 2-hour postoperative NGAL levels correlated with duration of AKI and length of hospital stay, while the 12-hour NGAL level correlated strongly with mortality .
A 2010 study evaluated 88 intensive care unit (ICU) adult patients and found that an NGAL level of ≥155 nmol/L predicted AKI with 82% sensitivity and 97% specificity  • “In a 2008 study, 635 adult patients admitted to a hospital each had a single urine NGALmeasurement made upon arrival to the emergency department, and NGAL levels were shown not only to correlate with the development of AKI but also predict a composite endpoint of nephrology consultation, dialysis, ICU admission, or mortality with an odds ratio of 24.71 .”
“For patients admitted to the ICU, NGAL can be a powerful predictor of AKI severity, as recently demonstrated in a study of 632 consecutive patients admitted to an ICU in whom both plasma and urine NGAL levels measured at admission were associated with AKI severity, and adding NGAL to a prediction model for development of AKI significantly improved the model’s accuracy .”
IL-18 • a widely expressed proinflammatory cytokine weighing 18 kDa • mediator of ischemic injury in the heart, brain, and kidney • IL-18 was found to be significantly elevated up to 48 hours before the creatinine-defined occurrence of AKI • “451 patients, 86 of whom developed AKI. Urinary IL-18 was used to construct a ROC curve, and while the AUC was only 0.62, it was found that elevated urinary IL-18 was independently predictive of a composite outcome of death or acute dialysis within 28 days (with an odds ratio of 1.86) .”
Translational Research Investigating Biomarker Endpoints for Acute Kidney Injury (TRIBE-AKI) study. The pediatric part of this study measured preoperative and postoperative urine IL-18 and NGAL as well as plasma NGAL in 311 children undergoing surgery for congenital heart disease. • 17% of the patients reached the primary outcome of severe AKI, defined as dialysis requirement or doubling of serum creatinine
1219 patients undergoing cardiac surgery had urine IL-18 and NGAL as well as plasma NGAL measured prior to surgery and for five postoperative days. • Multivariate analysis revealed that the highest quintiles of urine IL-18 and plasma NGAL at six hours were strongly associated with risk of AKI (adjusted odds ratios of 6.8 ) • Higher biomarker levels were also associated with longer hospitalization, longer length of ICU stay, higher risk of dialysis, and death .
Kidney injury molecule-1(KIM-1) • a type 1 transmembrane protein • Normal kidney tissuelow level • following ischemic injury, it is dramatically upregulated in regenerating proximal tubules • 2002 study, In 7 patients with ischemic ATN, mean KIM-1 levels were significantly higher than in 16 patients with other forms of AKI (2.92 ng/mLvs 0.63 ng/mL) 
Cystatin C • protease inhibitors produced by all nucleated cells . • cystatin C production is not influenced by muscle mass its level is not affected by age, race, or gender; and its urinary clearance does not involve tubular secretion • Cystatin C is freely filtered at the glomerulus and then nearly completely reabsorbed by the proximal tubules.