associate professor andrew bofinger mbbs fracp phd nephrology unit, greenslopes private hospital
TRANSCRIPT
Serum Creatinine, eGFR and Intravenous Contrast Agents
Associate Professor Andrew BofingerMBBS FRACP PhDNephrology Unit, Greenslopes Private Hospital
Functions of the Kidneys Participate in the maintenance of the constant extracellular
environment that is required for adequate functioning of the cells:- waste product excretion (such as urea, creatinine, and uric acid)- adjustment of urinary excretion of water and electrolytes to match net intake and endogenous production
Stimulation of erythrocyte production to maintain normal oxygen-carrying capacity of blood
Activation of Vitamin D, and contribution to Calcium & PO4 balance
Blood pressure and regulation of systemic renal hemodynamics (renin, prostaglandins, and bradykinin)
Anatomy of the Nephron
A normal kidney may contain between 500 thousand and 1.2 million glomeruli
GFR is the amount of filtrate produced by all of the glomeruli during a time period
The true measure of renal function Normal is around 125 ml/min/1.73m2
(120 for women and 130 for men) Direct measurement is laborious and not
suited to routine clinical use Estimates of GFR are usually used:
Creatinine clearance, eGFR
GFR (glomerular filtration rate)
Depends on the balance between:a) creatinine generation (metabolism of creatine in skeletal muscle and from dietary meat intake), andb) creatinine removal (filtration by the glomerulus and secretion by the proximal tubule) (some drugs may reduce tubular secretion)
Only reflects GFR in steady state (ie not in acutely deteriorating renal function) (Thought experiment: bilateral nephrectomy)
Rises as GFR falls. Increased tubular secretion may result in serum creatinine being lower than expected for the fall in GFR
During aging, both creatinine generation and removal fall, so serum creatinine often stable as GFR falls.
Serum Creatinine
Calculated from 24 hour urine creatinine excretion and serum creatinine:
Creatinine Clearance
Includes filtered and secreted creatinine,Therefore can OVERESTIMATE true GFR
Cockcroft and Gault Estimation of Creatinine clearance
This formula has been changed to account for the reporting of serum creatinine in umol/l.
This is the formula usually recommended for drug dosing.
An estimate of GFR derived from:- serum creatinine- gender- age
Therefore has all the limitations of serum creatinine Becomes less accurate as body build varies from the
“normal” (eg. Morbid obesity, amputees) However:
- is easier to visualise since linear rather than exponential- makes some allowance for changes in creatinine generation with age
eGFR (ESTIMATED GFR)
Stages of CKDStage GFR* Description
1 90+ Normal kidney function but urine findings or structural abnormalities or genetic trait point to kidney disease
2 60-89 Mildly reduced kidney function, and other findings (as for stage 1) point to kidney disease
3A3B
45-5930-44
Moderately reduced kidney function
4 15-29 Severely reduced kidney function
5 <15 or on dialysis Very severe, or endstage kidney failure
* All GFR values are normalized to an average surface area of 1.73m2
Increase in serum Creatinine > 25% or absolute increase of 44umol/L, usually within 72 hours
<5% patients at risk undergoing cardiac studies
BUT, high risk subsets, up to 50% CIN rates reported
Third leading cause of hospital acquired renal insufficiency
Associated with◦ systemic and cardiac in-hospital complications,◦ increased mortality, prolonged hospital stay
CONTRAST INDUCED NEPHROPATHY
PATIENT◦ eGFR <60 mL/min◦ Diabetic nephropathy◦ Low circulating volume◦ Nephrotoxic drugs◦ Older age◦ CCF
CONTRAST◦ High osmolar CM◦ Ionic CM◦ Increased volume of
CM, especially >100mL
CIN – RISK FACTORS
Periprocedural IV normal saline Avoid contrast if dehydrated Discontinue nephrotoxic drugs minimum 24
hours prior – ACEI, ARB, diuretics, NSAIDs, aminoglycosides
N-acetylcysteine and IV sodium bicarbonate- no proven benefit
Statin pretreatment still to be proven
CIN - PREVENTION
GADOLINIUM
Free gadolinium (Gd3+) highly toxic Bound to chelate for IV use Gd chelates renally excreted Half life significantly prolonged in renal
failure◦ Gadodiamide (Omniscan)
t½ normally 1.3 hours Renal impairment 34 hours
GADOLINIUM
GADOLINIUM
Nephrotoxicity
Nephrogenic systemic fibrosis
Types of toxicity of Gd-based IV contrast
Generally, Gd-based contrast agents are considered to be less nephrotoxic than iodinated contrast.
This may be due to:- lower viscosity- much lower volume used
Nevertheless, caution should be exercised with their use in patients with stages 4 and 5 CKD.
Nephrotoxicity
Systemic fibrosing disorder occuring in renal failure patients
Primarily affects the skin◦ ± lungs, skeletal muscle, heart, diaphragm and
oesophagus Usually begins with oedema and
erythematous or maculopapular rash involving the limbs
Skin becomes progressively thickened and indurated, plaque formation, peau d’orange
Nephrogenic Systemic Fibrosis - NSF
Symmetrical Affects limbs and trunk with facial
sparing Often knees to ankles Evolves over 2-12 months Initially may have severe burning pain and
itch Diffuse hair loss
NSF
First case recognised 1997 southern California
Cowper (US) first described NSF in the literature 2000◦ 15 renal dialysis patients seen over period of 3
years◦ Unique scleromyxoedema-like dermopathy◦ Initially named ‘nephrogenic fibrosing
dermopathy’
NEPHROGENIC SYSTEMIC FIBROSIS - HISTORY
In Copenhagen University Hospital, 2004-2006:
◦ 18 out of 190 patients with severe renal impairment who received Omniscan developed NSF all had GFR < 15mL/min 18% prevalence in stage 5 CKD
NSF - HISTORY
Grobner April 2006 proposed gadolinium as culprit
Danish Medicines Agency May 2006 issued warning; European Drug Committee banned Gadolinium use if GFR<30
US FDA issued public health advisory December 2006
NSF - HISTORY
eGFR < 30ml/min, most literature reports <15ml/min
Linear ionic compounds (Omniscan)◦ Incidence 3-7%
Linear non-ionic compounds (Magnevist)◦ Incidence 0.1-1%
Higher volume contrast Recurrent dosing (lifelong) Potential risk: neonates and foetus
(immature renal function)
RISK FACTORS
Transmetallation
Stage 5 (eGFR < 15 or dialysis) and AKI: highest risk
Stage 4 (eGFR 15 to 30): Some risk, but likely much lower than above
Stages 1 to 3 (eGFR > 30): appears to be little of no risk
CKD Stage and Risk of NSF after Gd-based Contrast
Danish Study
DO NOT USE GADOLINIUM IF eGFR< 15 mL/min or awaiting liver transplantation
Preferable to avoid if eGFR < 30 mL/min Use macrocyclic gadolinium eg MultiHance or Dotarem if
eGFR <30mL/min Give lowest dose required Avoid repeat dosing, especially within short time frame Pre-hydrate if renal impairment present Avoid in pregnancy, and age up to one year Consider performing hemodialysis after the exposure (and on
the next 2 days) in patients who are already maintained on hemodialysis.(There are no data that support prevention of NSF with this modality. The recommendation is based on the pharmacokinetics of GBC and the theoretical benefit of removing it with hemodialysis (95% plasma clearance). In contrast, peritoneal dialysis clears GBC poorly.)
RECOMMENDATIONS
Thankyou!
Questions?
History of exposure to gadolinium in setting of renal impairment
Clinical skin lesions, facial sparing
Skin biopsy: ◦ Haphazardly arranged dermal collagen bundles◦ Increased fibroblast-like cells and mucin
deposition Dermatologist and pathologist exclude
other causes
DIAGNOSIS
Exact aetiology unknown Clear association with Gadolinium exposure
in most cases◦ 2 weeks to 3 months prior◦ Cases more than 1 year post exposure
Usually middle aged, but seen in elderly and children
All have renal impairment – acute or chronic
NSF
Only proven improvement seen is with restoration of renal function (renal transplant)
Tried but no effect:◦ Prednisone◦ Plasma exchange◦ UV therapy
TREATMENT
Early signs – painful oedema and erythematous rash, especially limbs
Progressive induration, plaque formation and contractures
May affect skeletal muscle/organs, pulm fibrosis
High risk if ◦ eGFR <30◦ Linear gadolinium◦ Recurrent dosing
Only proven treatment renal transplantation
NSF - SUMMARY