Associate Professor Andrew Bofinger MBBS FRACP PhD Nephrology Unit, Greenslopes Private Hospital

 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 & PO 4 balance  Blood pressure and regulation of systemic renal hemodynamics (renin, prostaglandins, and bradykinin)

 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/1.73m 2 (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

 Depends on the balance between: a) creatinine generation (metabolism of creatine in skeletal muscle and from dietary meat intake), and b) 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.

Calculated from 24 hour urine creatinine excretion and serum creatinine: Includes filtered and secreted creatinine, Therefore can OVERESTIMATE true GFR

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

StageGFR*Description 190+ Normal kidney function but urine findings or structural abnormalities or genetic trait point to kidney disease Mildly reduced kidney function, and other findings (as for stage 1) point to kidney disease 3A 3B Moderately reduced kidney function Severely reduced kidney function 5<15 or on dialysisVery severe, or endstage kidney failure * All GFR values are normalized to an average surface area of 1.73m 2

 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

 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

 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

 Free gadolinium (Gd 3+ ) 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

 Nephrotoxicity  Nephrogenic systemic fibrosis

 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.

 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

 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

 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’

 In Copenhagen University Hospital, : ◦ 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

 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

 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)

 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

 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.)

 Thankyou!

 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

 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

 Only proven improvement seen is with restoration of renal function (renal transplant)  Tried but no effect: ◦ Prednisone ◦ Plasma exchange ◦ UV therapy

 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