Pharmacological Management of Acute Kidney Injury

Pharmacological Management
of Acute Kidney Injury
Dr.Sandhya Seneviratne
Consultant Nephrologist
National Institute of Nephrology, Dialysis &
Transplantation, NHSL, Colombo

Nephrology telephone referral
A 44 year old man was admitted with a 5
day history of abdominal pain and
vomiting. BP 67/43, pulse 132, Temp 39.1.
Urea 47mmol/l, sodium 132 mmol/l,
potassium 6.3 mmol/l, creatinine 675
umol/l.

RESUSCITATE

Be quick, do refer
• Treatment, investigation and assessment need
to happen simultaneously
• Investigations need to be carried out within a
matter of minutes
• One non-dialytic intervention has been shown
to be successful in improving the morbidity and
mortality of ARF
• Early referral is advisable in cases of pre-renal
failure not responding to fluids, intrinsic
• Mandatory in RPGN

It’s costly!
• Only modest improvements in mortality over the last 25
years or so
• Therefore pathophysiology and therapy are being
constantly reviewed.

Defined
• Defined as an abrupt sustained decline in
glomerular filtration rate causing retention of
nitrogenous waste products
• Usually accompanied by a rise in serum
creatinine and urea
• Usually associated with oliguria and loss of
normal water and solute homeostasis
• And is potentially reversible

Uraemia
• Is generally used to describe the ill-effects of
renal failure that we cannot yet explain
• ……..the ill-effects that would remain if the
extra-cellular volume and the inorganic ion
concentrations were kept normal and the
known renal synthetic products were replaced
in patients without kidneys

Diagnosis of ARF
• Clinically overt ARF poses no problem
• Typically diagnosed by observing a rising urea
and creatinine with a declining urine output
over a period of several days
• Unfortunately- creatinine and creatinine
clearance are sub-optimal indicators of renal
function, and often delay the diagnosis of ARF
• Need a marker of renal failure/quick method
of measuring function.

GFR and creatinine

Causes of ARF
• Pre-renal, renal and post-renal
• 50% - ischaemic
• 35% - nephrotoxic
• 15% - intrinsic
• 50% of hospital acquired ARF is multifactorial
• E.g.. Sepsis+aminoglycosides,
Radiocontrast + ACEI.

Principles of Management
1. Making the patient safe,
2. treating life-threatening metabolic disturbances,
irrespective of the cause
3. Non-dialytic treatment measures – drugs, nutrition,
fluid replacement
4. Initiating renal replacement therapy (RRT) when
appropriate
5. Investigating and treating the primary aetiology –
pre-renal, renal and post-renal

Clinical Definitions
Acute v Chronic Renal
Failure
Reversible Irreversible
v
Sudden Insidious onset
v

Acute Renal Failure
• Abrupt decline of previously normal renal
function causing retention of nitrogenous waste
products
• POTENTIALLY REVERSIBLE

Acute on Chronic Renal Failure
• Abrupt potentially reversible decline of renal
function in a patient with pre-existing renal impairment

Serum Creatinine = 150 umol/l
Weight 125 kg = 125 kg
Creatinine clearance = 118 ml/min
Serum Creatinine = 150 umol/l
Weight = 25 kg
Creatinine clearance = 20 ml/min

• What does he look like ?

Is he sick?

Or feeling well?

Treating Life-threatening Metabolic
Conditions
• Hyperkalaemia
• Fluid overload
• Acidosis
• Severe uraemia
• Bleeding diathesis.

Treatment of Hyperkalaemia
? Haemolysed
? Supplements
? drugs
Start low K +
diet
Hyperkalaemia
[K + ] > 6.5 mmol/L
±ECG changes
Dialyse
10% Ca gluconate 10ml IV
Any other indication
for dialysis?
10u s.insulin in 50ml
50% dextrose IV over
10mins
?NaHCO 3 if [HCO 3 ] < 20
mmol/L 300-600 ml
Persistent life-threatening
[K + ]
Recheck [K + ] 6 hrly
[K + ] but not lifethreatening
ion exchange resin +
lactulose + s.insulin/dextrose

A 63 year old lady presents with
prostration, one week after a change in
medication for CCF. BP is 70 systolic,
she has a bradycardia of 34 bpm and
moderate oedema.
Medication is frusemide 120 mg daily,
spironolactone 25 mg daily, ramipril 10
mg daily, carvedilol 3.125 mg bd,
hydralazine 50 mg bd, isosorbide
mononitrate SR 30 mg daily.

……and a serum potassium concentration of 9.6
mmol/l, pH 7.01, bicarbonate 7 mmol/l, creatinine 494
umol/l.

Treatment of Fluid Overload
• Avoid injudicious fluid replacement
• the fluid “challenge”, CVP lines especially in oedematous
patients with suspected intra-vascular fluid depletion, use
the correct fluid
• Nitrates
• Diuretics
• Oxygen
• Morphine
• Haemofiltration (in ICU)
• Venesection
• Dialysis.

Treatment of Pulmonary
Oedema in ARF
In oligo-anuric patient, nonresponsive
to diuretics
Emergency IHD if available on site
and normal or high BP
Otherwise CVVH in ITU/HDU

Treatment of Acidosis
• NaHCO 3 1.26% IV /oral of bicarbonate

Profound acidosis in the context of
oligo-anuria requires urgent
haemodialysis unless the patient is
dehydrated

Acetate vs. Bicarbonate
dialysis
Liver failure
Sepsis
Severly ill/critically ill
pregnancy

Correction of Hypovolaemia
• Type of replacement solution depends on
source of fluid loss
• Bleeding, haemodynamically unstable or HCt
very low → packed red cells
• Otherwise isotonic saline for plasma losses
• (use of starch, gelatin, colloids independent
risk factor for development of AKI)
• Urinary and GI losses are hypotonic therefore
initial replacement with 0.45% saline

Pre - renal
A Comparison of Albumin and Saline for Fluid
Resuscitation in the Intensive Care Unit (SAFE Study)
methods
Randomly assigned patients who had been admitted to the ICU to receive either 4 percent
albumin or normal saline for intravascular-fluid resuscitation during a period of 28 days. The
primary outcome measure was death from any cause during the 28-day period after
randomization.
conclusions
In patients in the ICU, use of either 4 percent albumin or normal saline for fluid resuscitation
results in similar outcomes at 28 days.

Treatment of Uraemia
• Look for the complications
• encephalopathy
• pericarditis
• pericardial effusion
• bleeding diathesis
• Pericardiocentesis
• Dialysis
• if HD initially short dialysis to prevent precipitating cerebral
oedema

Bleeding Diathesis
• Haematocrit to at least 30%
• Cryoprecipitate
• DDAVP
• Oestrogen
• Discontinue anti-platelet drugs
• H2-receptor blockers
• Dialysis

Non-dialytic supportive measures
• A brief review of the therapeutic options, and
a look at recent developments

Prevention of radiocontrast-induced nephropathy. Asif A,
Epstein M. Am J Kidney Dis. 2004 Jul;44(1):12-24
Radiocontrast is a common cause of hospitalacquired
ARF mainly in patients with preexisting
renal failure
Saline hydration is the sole proven effective
protection
The benefits of the antioxidant N-acetylcysteine, isoosmolar
contrast agents, fenoldopam (dopamine-1 [DA-
1] receptor agonist), hemodialysis, and hemofiltration,
are less certain.

Dopamine
Critical Care Medicine:
August 2001 - Volume 29 - Issue 8 - pp 1526-1531
Clinical Investigations
Use of dopamine in acute renal failure: A metaanalysis
(of 58 studies)
Conclusions: The use of low-dose dopamine for
the treatment or prevention of acute renal failure
cannot be justified on the basis of available
evidence and should be eliminated from routine
clinical use

Fenoldopam
Crit Care Med. 2005 Nov;33(11):2451-6.
Prophylactic fenoldopam for renal protection in sepsis: a
randomized, double-blind, placebo-controlled pilot trial.
Fenoldopam, a dopamine-1 receptor agonist, increases renal blood
flow and may, therefore, reduce the risk of acute renal failure in
such patients. 300 septic patients fenoldopam vs placebo
No significant difference in incidence of severe
ARF but smaller rises in creatinine in the
fenoldopam group

Efficacy of Fenoldopam in Reducing the Need for
Renal Replacement Therapy After Cardiac
Surgery. A Randomized Controlled Study.
On-going

Atrial Natriuretic Peptide for Management of Acute Kidney Injury:
A Systematic Review and Meta-analysis
Clin J Am Soc Nephrol 4: 261-272, 2009
© 2009 American Society of Nephrology
• Results: Nineteen RCTs (11 prevention, 8 treatment) involving 1861
participants were included. Pooled analysis of prevention trials
showed a trend toward reduction in renal replacement therapy in
the ANP group (OR = 0.45, 95% CI, 0.21 to 0.99) and good safety
profile, but no improvement in mortality. For the treatment of
established AKI, ANP, particularly in high doses, was associated with
a trend toward increased mortality and more adverse events.
Subgroup analysis of AKI after a major surgery (14 RCTs, 817
participants) showed a significant reduction in renal replacement
therapy requirement in the ANP group

Vasodilators (Other)
• Calcium Channel Blockers
• Useful post-transplant
• Given intrarenally may shorten course of ARF
(malaria, tropical diseases).

Diuretics
• Basis : wash away the dirt
• Conclusion : Diuretics can make oliguric renal
failure polyuric, and thereby easier to manage
• Frusemide
• Decreases work of TA
• May flush away obstructing casts, decreases
concentration of nephrotoxic substances
• Makes patient polyuric – prognosis better
• It’s ototoxic, therefore a trial only
• No solid evidence that it alters natural history.

Diuretics
• Mannitol
•No

Growth factors
• Basis : After sublethal injury the dysfunctional
kidney can restore normal function and structure
• Conclusion : renotrophic growth factors are a
promising area for future research
• Epidermal growth factor (EGF), Transforming
growth factor (TGF), Insulin-like growth factor-1
(IGF-1) and Hepatocyte growth factor (HGF)
• Found in the kidney
• High levels after injury
• IGF-1 two trials – benefits patients with less severe
renal injury.

Anti-inflammatory agents
• Basis : The ischaemic kidney produces a
number of inflammatory mediators;
tubular cells participate in immune and
inflammatory reactions
• Conclusion :Antibodies to ICAM-1, antineutrophil
agents are still at trial level

Nutrition in Acute Renal Failure
• Nutrition should not be compromised to minimize
azotaemia
• When ARF is isolated energy requirements are probably
not increased.
• >15%-20% in patients on IHD
• Recommendations
• Calories 30kcal/kg BW/day + adjustment factors
• 70% carbohydrates 30% lipids
• Proteins (on dialysis) 1.1-1.2g/kg BW/day (otherwise
0.8g/kg/day)
• Micronutrients? Se, vitamin E
• Enteral preferable
• TPN if necessary.

Renal Replacement Therapy in ARF
• When should dialysis be initiated?
• What mode of dialysis should be used?
• How much dialysis should be given?
No consensus
• Absolute indications
• uraemic pericarditis
• uraemic encephalopathy.

Renal Biopsy in ARF
• Generally not indicated
• Exclude pre- and post-renal by history,
examination, laboratory and radiological
investigation
• Intrinsic renal disease other than ischaemic or
toxin induced suspected
• Uncertainty of diagnosis, lack of spontaneous
recovery even with cessation of drug
• 15,720 – nephrectomy 0.06%
• Mortality – 0.1%
• Take the proper precautions.

Conclusion
• ARF is a medical emergency
• Priority is to make patient safe
• Early correct treatment of volume depletion is
important
• Obstruction should be excluded very early
• Newer non-dialytic therapies are being evaluated
• Nephrological referral improves mortality
• Dialysis is complicated – it is recommended that
nephrological opinion be obtained
• Nutrition should not be compromised
• Renal biopsy should be considered when in doubt.

Acknowledgements
• To Prof. Ken Farrington for some of the slides