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