How Best to Prevent & Manage Acute Renal Failure ?

Dr. T.R.ChandrashekarDirector Critical Care,

K.R. HospitalBangalore

Some facts about ARF

• Incidence=1-25%. • Mortality =28-90%• High Attributable risk• 35 different definitions have been used in the literature,

creating confusion and making comparisons among the studies difficult.

• This situation has impaired the study of ARF as well as the development of possible treatments.

• Recent data indicates that a small change in SC influences outcome.(>0.3 increase in SC ).

• A change from 1.5 mg/ml—1.8mg/dl is significant

Definition of ARF

• Acute renal failure (ARF) is defined as an abrupt and sustained decline in the glomerular filtration rate (GFR), which leads to accumulation of nitrogenous waste products and uremic toxins.

• Few caveats• No consensus on • Assessment of renal function tests• The exact cutoffs values for the diagnosis • The degrees to which the process is “abrupt” or

“sustained” are variable.

• The term Acute kidney injury (AKI) has been put forth as the preferred nomenclature to replace acute renal failure with the understanding that the spectrum of AKI is broad and includes different degrees of severity

• Because the most powerful tool to improve outcome of AKI is prevention,

• The definition should have a high sensitivity, be multifaceted, and allow detection of patients who are at risk to develop kidney injury, as well as those with already established AKI and those with established ARF

Diagnostic criteria for acute kidney injury

• An abrupt (within 48 hrs) reduction in kidney function currently defined as

• An absolute increase in serum creatinine of more than or equal to 0.3 mg/dl or A % increase in serum creatinine of more than or equal to 50%

or • A reduction in urine output ( documented oliguria

of less than 0.5ml/kg per hour for more than 6 hrs).

AKIN march 2007

To rule out Foley’s catheter blockTo correlate with clinical pictureDoes nor require baseline SC valuesCorrect volume status Look for easily correctable causes for reduced UO

Acute Dialysis Quality Initiative (ADQI) -RIFLE classification of AKI.

Three stages of increasing severity

Two outcome variables

Modified RIFLE criteria for AKI

Stage Serum Creatinine criteria U.O criteria

1 Increase in SC of >= to 0.3 mg/dl or increase to >= to150-200% from baseline

< 0.5ml/kg/hr for more than 6 hrs

2 Increase to >= to 200%-300 % from baseline

< 0.5ml/kg/hr for more than 12 hrs

3 Increase to >= to 300% from baseline

SC >= 4.0mg/dl with an acute increase of at least 0.5mg/dl

<0.3ml/kg/hr for 24 hrs or Anuria for 12 hrs

Classification/Staging system for AKI

Modified RIFLE criteria for AKI

• The staging system proposed is highly sensitive and is based on recent data indicating that a small change in SC influences outcome.

• One criteria either SC or UO has to be fulfilled to qualify for staging.

• Patients receiving RRT are considered stage -3 irrespective of the stage they are in at the time of RRT.

Causes of AKI CASE-I• A 20yr old boy with H/o RTA with

Hemoperitonium, Thready pulse 150/mt , sweating, restless, BP 70/40mm Hg, UO in last four hrs 30ml

• PRE-RENAL- Low volume/ Hypoperfusion

CASE-II• A 40 yr old male with small bowel

perfusion 2 days back comes with thready pulse 160/mt, cold extremities, restless, BP 80/ 50 mmHg,, Spo2 90% on 4l of O2. with anuria

• ATN-ischemic/ toxic

CASE-III• A 40 yr old male with small bowel

perfusion 2 days back comes with thready pulse 160/mt, cold extremities, restless, BP 80/ 50 mmHg, distended of abdomen which is very tense, spo2 90% on 4l of O2. with Anuria

• Decreased renal perfusion –ACS

CASE-IV

• A 70 yr old man with no urine output since 2 days, ultrasound shows BPH with distended bladder hydronephrosis and SC of 2.5 mg/dl

• Post- Renal

Pre renal causes

Low volume states

NSAIDS,ACEI

Renal artery stenosis

Post renal causes

Renal stones, ureteric stones

Ca Cervix

Prostate hypertrophy, tumors

Renal papillary necrosis

Renal causes

Glomerular –Glomerularnephritis

ATN

Hypoperfusion and toxins

Tubulointerstitial

Drugs, Myeloma

Causes of AKI

Etiology of ARF

0

10

20

30

40

50

60

70

80

Prerenal Intrarenal Obstruct Idiopath

Outpatient

Inpatient

ATN is the cause in more than 90%

Sepsis is the leading cause of ATN

DD of type of AKI

• Perform careful history, physical exam and urinalysis (sediment and chemistry)

• If a patient has been hospitalized for some time prior to developing ARF, you must prepare a flow sheet of vital signs, weights, I/Os, labs, fluids and medications

• Imaging- Ultrasound examination, C.T scan, IVP etc…

Laboratory Findings in Acute Renal Failure Index Prerenal

Azotemia Oliguric Acute

Renal Failure (ATN)

BUN/PCr Ratio >20:1 10-15:1

Urine sodium (UNa), meq/L

<20 >40

Urine osmolality, mosmol/L H2O

>500 <350

Fractional excretion of sodium

<1% >2%

Response to volume Cr won’t improve much Cr improves with IVF

Urinary Sediment Bland ATN: muddy brown granular casts, cellular debris, tubular epithelial cells

• Let us look at an Ex.

40 year old DM in ketosis due to vomiting

• Urea 200, SC 5mg/dl• Ratio BUN/SC=40• Urine Spot

Na=15meq/l• Prerenal

• Let us look at an EX. 40 year old DM in ketosis due to vomiting

• Urea 200, SC 5mg/dl• Ratio BUN/SC=40• Urine Spot

Na=50meq/l• Prerenal + ATN

DD of type of AKIGot a diureticProlonged hypoperfusion and ATN

Prerenal azotemia and ischemic tubular necrosis represent a continuum. Azotemia progresses to necrosis when blood flow

is sufficiently compromised to result in the death of tubular cells.

Urine chemistries cannot be not relied on to rule out active renal injury

Mechanism of ATN

Hypo-perfusion

GFR

Renal blood flow

Cortical vasoconstriction

AnuriaOliguric Renal failure

Septic shock Volume depletion

Drugs Low cardiac output

Toxins Tubular

malfunction

Non-oliguric renal failure

Cell sheddingDeath

Tubular obstruction

Medullary hypoxia Endothelial damage

Backleak

MECHANISM OF ATN

End stage renal failure

10%

Chronic Renal

impairment30%

Full functional recovery

60%

Prognosis in ATN

How best to prevent AKI ?

1. No drugs are currently available to enhance or hasten renal recovery once ARF occurs

2. There is now clear evidence that ARF is associated with excess mortality, irrespective of whether the patient requires renal replacement therapy.

3. Hence prevention is the only powerful tool to improve outcome of AKI.

24 – 48 hrs

For AnaesthesiologistThis is when and where prediction and prevention strategies must be applied

Window of Opportunity

How best to prevent AKI ?

Non pharmacological Rx

• Ensuring adequate hydration (reversing dehydration),

• Maintenance of adequate mean arterial pressure,

• Minimizing exposure to nephrotoxins

Pharmacological Rx

• Loop diuretics

• Mannitol

• Dopamine & Fenoldopam

• Natriuretic Peptides

Identification of patients at high risk to develop AKI-Elderly, DM, HT, Sepsis etc..

Renal replacement therapy

Hydration • NS or RL• CVP = 8-12 cm H2O, MAP> 65mmHg• Optimal rate of infusion remain unclear and

should be individualized.

• Peripheral edema is of cosmetic concern in sepsis

• The available experimental data are not supportive of a beneficial effect of additional fluid therapy on renal function, in the context where cardiac output is normal or increased and mean

arterial pressure is re-established.

Hydroxyethyl starch (HES)

• A recent multicenter German study, the Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis study, indicates that HES administration in patients with severe sepsis may be associated with an increased risk of acute renal failure.

• ( 27th International Symposium of Intensive Care and Emergency Medicine, Brussels, March 2006.)

• Effects of hydroxyethyl starch administration on renal function in critically ill patients

• The administration of HES had no influence on renal function or the need for RRT in the ICU.

Br J Anaesth 2007; 98: 216–24

Maintain renal perfusion pressure

• Target MAP >=65 mmHg

• Which vasopressors to be used ?

• Role of low dose dopamine

Vasopressors • Noradrenaline is the drug of choice in AKI

in sepsis

• Norepinephrine has been demonstrated to preserve splanchnic blood flow better than dopamine

• Optimise fluid before starting vasopressors• Low dose dopamine should not be used for

renal protection in severe sepsis

• Conclusion: Low-dose dopamine offers transient improvements in renal physiology, but no good evidence shows that it offers important clinical benefits to patients with or at risk for acute renal failure

Meta-Analysis: Low-Dose Dopamine Increases Urine Output but Does Not Prevent Renal Dysfunction or Death

Ann Intern Med. 2005;142:510-524.

CASE-III• A 40 yr old male with small bowel

perfusion 2 days back comes with thready pulse 160/mt, cold extremities, restless, BP 80/ 50 mmHg, distended abdomen which is very tense, Spo2 89% on 6l of O2 with Anuria.

ACS

• Oliguria is one of the first visible signs of elevated IAP

• “Normal IAP is approximately 5-7 mmHg in critically ill adults.”

• “IAH is defined by a sustained or repeated pathological elevation in IAP ≥ 12mmHg.”

• “ACS is defined as a sustained IAP > 20mmHg (with or without an APP < 60mmHg) that is associated with new organ dysfunction/ failure.”

Monitoring & Management - ACS

Surgical decompression or if the pt is sick put flank drains

Nephrotoxic drug exposure

• Minimizing nephrotoxin exposure is an important strategy to prevent ARF in the ICU setting

• Aminoglycosides, • Amphotericin,-lipid forms of amphotericin B be

used preferentially in patients with renal insufficiency or evidence of renal tubular dysfunction.

• Radiocontrast • are the most commonly encountered

nephrotoxins in the ICU

Aminoglycoside

• Once-daily dosing is postulated to decrease tubular cell toxicity by reducing the fraction of the cumulative dose of drug taken up by proximal tubular cells.

• Once-daily aminoglycoside dosing schedules demonstrated that there were no differences in the efficacy of aminoglycosides & there was a trend toward lower nephrotoxicity

Radiocontrast agents

• Reduce renal function by altering renal hemodynamics

• Exert direct toxic effects on tubular epithelium. • Renal free-radical production increases after

contrast agent administration and may in part be responsible for the renal injury.

• Lowest volume necessary of nonionic,• Iso-osmolar, contrast medium be used in

conjunction with IV isotonic fluids in all high-risk patients.

Radiocontrast agents

• NS 1ml/kg/hr/24hrs• N-acetyl cysteine (NAC) 1200mg BD a day before and

on the day of contrast administration• Administration of 200mg theophylline 30 min before the

procedure in a high risk pt Bicarbonate- Alkalinizing urine should reduce renal

medullary damage D5W with 3 amps HCO3; bolus 3.5 mL/kg 1 hour pre-procedure, Then 1mL/kg/hour for 6 hours post-procedure• Insufficient evidence to support the use of prophylactic

hemofiltration to prevent contrast nephropathy

Diuretics

• Belief – Converts oliguric renal failure into non oliguric which carries lower risk

• Clearing tubular debris in ATN• One retrospective study showed diuretic use

was associated with significantly increased risk of death or nonrecovery of renal function.

• Diuretics are never a treatment for oliguria but

are sometimes required for management of volume overload.

• Mannitol should not be used to prevent or treat ARF from any cause.

Mehta JAMA 2002

Treatment: DiureticsTreatment: Diuretics

Diuretics: Effects on outcome (large observational studies)• 4-center, retrospective analysis of patients referred for nephrology

consults (1989 - 1995; n = 552)

• With adjustments for co-variates and propensity score, diuretic use was associated with:

– Significantly increased risk of death or non-recovery of renal function (odds ratio 1.77; 95% CI 1.14 - 2.76)

Mehta et al. JAMA. 2002;288:2547-53.

• 52-center, prospective inception cohort of ICU patients (n = 1743)

• No differences in mortality, or renal recovery, even after adjustment for the same co-variates and propensity score

– Odds ratio 1.22 (p = 0.15)

• However, no benefit associated with diuretics either!

Uchino et al. Crit Care Med. 2004;32:1669 –77.

Prevention of AKI summary

Strategies that are likely to be effective

Isotonic hydration (IV route)Once-daily dosing of aminoglycosidesUse of lipid formulations of amphotericin BUse of iso-osmolar nonionic contrast media

Strategies of unknown efficacy

NACTheophyllineLow-dose recombinant ANP (in cardiac surgical patients)

Strategies that are not effective

Loop diureticsDopamine and dopamine receptor agonistsANPsProphylactic hemofiltration

Indications for RRT in AKI

• Volume overload• Hyperkalemia• Metabolic acidosis• Uremia signs or Symptoms • Progressive azotemia in the absence of uremia• Uremic encephalopathy• Uremic neuropathy/myopathy• Uremic pericarditis• Drug overdose with dialyzable toxin

Goals of RRT

• To maintain fluid and electrolyte, acid-base, and solute homeostasis

• To prevent further insults to the kidney

• To promote healing and renal recovery

• To permit other support measures such as nutrition to proceed without limitation.

RRT

• IHD=CRRT• Daily dialysis in sepsis improves outcome• Most of the conventional assessment of

dose of dialysis –underdosing• IHD- can be done without anticoagulants• More solute removal- severe hyperkalemia• CRRT-in hemodynamically unstable pts• Septic mediators removal ?

Renal Replacement therapy

=

What do you think is the problem ?

• 70 yr old gentleman with HT, DM IHD, has BPH posted for TURP, well preserved baseline BP 160/90 mm Hg on ACE-I, insulin, Asprin which was stopped 7 days back

• Under epidural• During the procedure has increased bleeding,

BP 130/90 mmHg post operatively on Inj Inac 50 mg tid/ 20mics fentanyl tid

• Baseline SC 1.6 mg/dl increases to 2.5, next day what went wrong ?

Normotensive Ischemic Acute Renal Failure

• Normotensive ischemic acute renal failure may develop in pts with hypertension, chronic kidney disease, and old age, on some drugs like ACE-I, ARB, COX2 inhibitors all of which are associated with narrowing and blunted vasodilatory capacity of renal vessels

• Treated quickly by replacing volume, treating infection, or stopping medications such as NSAIDs, diuretics, and antihypertensive agents, especially ACE inhibitors or angiotensin-receptor blockers. Normotensive Ischemic Acute Renal Failure, NEJM Volume 357(8), 23 August 2007, pp 797-805

Do not overlook a drop in systolic blood pressure to the low normal range in patients with

increased risk of normotensive AKI

Take home thoughts

• Even a small rise in SC to the tune 0.3mg/dl can influence the outcome

• Prevention is the only powerful tool available for managing AKI

• Use standard definitions like AKI and Modified RIFILE classification in all studies.

• AKI=ATN

Take home thoughts

• Time is important-EGDT Energy failure may be due to primitive

hemodynamic inadequacy and/or mitochondrial dysfunction

• Prolonged energy failure leads to irreversible mitochondrial dysfunction (necrosis – apoptosis)

• Once MMDS starts shock becomes irreversible• Source control, appropriate antibiotics,

hemodynamic stabilisation, APC etc…

“Back to basics": Optimise Volume and Defend Pressure.There are no magic bullets just high quality intensive care