MANAGEMENT IN ACUTE KIDNEY INJURY. Wanniya Meenune,M.D. Renal unit, Department of Medicine Rajavithi Hospital, Rangsit University.

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1 MANAGEMENT IN ACUTE KIDNEY INJURY Wanniya Meenune,M.D. Renal unit, Department of Medicine Rajavithi Hospital, Rangsit University.

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4 KDIGO Clinical Practice Guideline for Acute Kidney Injury VOLUME 2 ISSUE 1 MARCH

5 SCOPE Pitfall in contrast induced AKI : in MRI aspect Common cause in Rhabdomyolysis in cardiac surgery : Drug-Drug interaction Dialysis intervention in AKI

6 MRI : SAFETY IN RENAL DISEASE?

7 Gadolinium toxicity

8 Gadolinium General Properties Lanthanide metal with paramagnetic Properties An ionic form to be soluble in water & injected as a contrast agent Form free ionic (Gd 3+ ) : highly toxic in human Type of Gadolinium By biochemical structure : linear chelate VS macro-cyclic chelate By charge : ionic VS nonionic Clin J Am Soc Nephrol 4: , 2009.

9 Structure of various GBC agents

10 Process of Transmetallation Non-ionic linear Clin J Am Soc Nephrol 4: , 2009.

11 FDA-approved GBC agents Agent GBC formulation Molecular Structure Charge Osmolality (mosm/l) Viscosity (mpa S) Stability Constant Excess Chelate (mg/ml) gadodiamide (Omniscan) gadopentetate (Magnevist) gadoversetamide (OptiMARK) gadobenate (MultiHance) gadoteridol (Prohance) gadobutrol (Gadovist) linear Nonionic linear Ionic 1, linear Nonionic 1, linear Ionic 1, Cyclic Nonionic Cyclic Nonionic NA NA NA NA

12 Pharmacokinetics of Gadolinium GBC agents : rapidly distribute into extracellular space (Plasma = interstitial compartments) GBC agents Limited protein binding Small volume distribution(0.3 L/kg) Elimination

13 Gadolinium Mean terminal half-life ( T1/2) hr 95% of injected dose is eliminated within 24 hr < 3% eliminated in feces In moderate renal insuffiency Mean terminal half-life = 5.6 hr In severe renal insuffiency Mean terminal half-life = 9.2 hr and up to 30 hr if GFR < 5 ml/min

14 GBC agents and Nephrotoxicity

15 GBC agents VS ioidated radiocontrast very similar in hyperosmolality very similar in renal clearance entire dependent on glomerular filtration GBC :potentially less nephrotoxic Due to lower viscosity used at lower volume ( 4-11 times less ) Example dose Typical body CT : 150 CC radiocontrast Typical MRI ( mmol/kg)= ml of GBC Clin J Am Soc Nephrol 4: , 2009.

16 GBC agents and Nephrotoxicity Experimental studies High dosages of GBC ( > 1.0 mmol/kg ) effect to Increase BUN&Cr Histopathology show vacuolization and necrosis of cortical tubular epithelial cell Invest Radiol 36: ,2001

17 GBC agents and Nephrotoxicity Studies support renal safety of GBC agents

18 Conclusion In year Average dosage about 0.26 mmol/kg( mmol/kg) Base line renal function average mean Cr about 2.36 mg/dl( mg/dl) Results show Contrast induce nephropathy From GBC agents = 0-5% From Radiocontrast = 17-40%

19 GBC agents and Nephrotoxicity Studies support nephrotoxicity of GBC agents

20 Conclusion In year Average dosage about 0.41mmol/kg( ) Base line renal function average mean Cr about 3.02 mg/dl( ) Results show Contrast induce nephropathy From GBC agents = % From Radiocontrast = % In addition,the majority of studies used arterial injection of GBC

21 GBC nephrotoxicity : What is the Bottom line?

22 Risk of Gadolinium-based Contrast (GBC) Nephrotoxicity vs. Radiocontrast Nephrotoxicity Advanced CKD ( 4&5) Higher doses Arterial injection Increased Nephrotoxicity of GBC agents Lower doses Lower viscosity Reduced Nephrotoxicity of GBC agents

23 GBC and Nephrogenic Systemic Fibrosis

24 N Engl J Med 361;22 nejm.org november 26, 2009

25 Clinical Photographs of the Patient at the Second Rheumatology Visit. Thickening and discoloration of the skin of the legs are seen, more on the left than on the right (Panel A). Irregular erythema of the skin of the left leg is evident (Panel B). There are yellow scleral plaques on both eyes and telangiectasias on the face (Panel C).

26 GBC and Nephrogenic Systemic Fibrosis(NSF) Nephrogenic Systemic Fibrosis : A New Disease Year 1997 found previous recognized fibrosing disorder of skin In 9 Pts with renal transplant recipient with allograft dysfunction 5 Pts with ESRD 1 Pt with AKI Histopathology : Similar to scleromyxedema Scleromyxedema-like disorder of renal dialysis pts nephrogenic fibrosing dermopathy

27 Nephrogenic Systemic Fibrosis Clinical manifestations Cutaneous manifestations Bone,Joint&Muscle Lung Myocardium Striated muscle Skin Tightening : usually limited to the extremities but sometimes involving trunk Skin Swelling Skin Hardening Skin Tightening Reddened or darkened patches on skin( Feel woody) Burning or itching Yellow raised spot on the white of eye

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29 Bone,Joint & Muscle problems Stiffness in joint Problems moving or straightening arms,hands,legs or feet Pain deep in hip bone or ribs Muscle weakness

30 NSF : Internal organs

31 NSF : Internal organs Paratrachea Lymph Node Lung

32 Diagnosis Nephrogenic Fibrosing Dermopathy(NFD) Skin Biopsy Histopathology : fibrosis or scarring of body organs

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34 Kidney International (2008) 73,

35 Demographics and clinical conditions that contributed to mortality in NSF patients Kidney International (2008) 73,

36 GBC Agents: The NSF Trigger?

37 GBC Agents: The NSF Trigger? Case-control studies with odd ratio for pts who had ESRD/CKD and were exposed to GBC agents Marckmann : Pts with ESRD developed symptoms of NSF within 2-75 day after gadodiamide exposure Clin J Am Soc Nephrol 4: , 2009.

38 Evidence to Incriminate GBC Agents in NSF

39 Evidence to Incriminate GBC Agents in NSF Evidence of importance of GBC agents as a trigger for NSF Documentation of Gd 3+ within tissue of pts with NSF using scanning electron microscopy, energy dispersive x-ray spectroscopy and energy filtered transmission electron microscopy (EFTEM technique) High et al : Pts with NSF found tissues contained fold higher amounts than normal healthy

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41 Are certain GBC Agents More Likely to caused NSF?

42 Relation GBC Agents and Risk of NSF Gadodiamide Gadopentetate Gadoversetamide 157 Unspecific GBC agents Confounded GBC agents No GBC agents Eur J Radiol 66: ,2008

43 Which Patients Are at Highest Risk to develop NSF after GBC Exposure?

44 Risk CKD to develop NSF The published literature clearly documents Advanced kidney disease : Highest risk ESRD on H/D : Nearly 80% to develop NSF CKD stage 5 and Acute kidney injury (AKI) : 20% CKD stage 4 : Small datas for conclusion CKD stage 1-3 : Now no Report to NSF

45 Treatment NSF

46 Case Report 1 Case Clin J Am Soc Nephrol 2: , 2007

47 After treatment Sodium thiosulfate(sts) 12.5 g X 3 session/week IV : months Improvement of Shiny,discolored,woody skin on inspection and palpation Improvement in pain and skin change

48 Current Status of GBC Agents in Kidney disease

49 Current Status of GBC Agents in kidney disease Due to no effective therapy for NSF,Avoidance of exposure by using alternative imaging modalities is the best option If Can not avoidance : Recommend Informed consent use a macrocyclic chelate,avoid linear chelate Use lowest dosage of GBC agents Avoid repeat exposure with GBC agents

50 Current Status of GBC Agents in kidney disease Options by some expert May consider performed H/D after exposure ( the next 2 day in Pts with on regular H/D ( But no data support ) But based on pharmacokinetic of GBC agent and theoretical benefit of removing it with H/D ( > 95% plasma clearance ) Peritoneal dialysis clears GBC poorly

51 Take Home Messages Severity of chronic kidney disease ( CKD ) ESRD on diaysis/ckd stage 5/Acute kidney injury : Highest risk to develop NSF CKD stage 4 : small Data shown prone to NSF CKD stage 1-3 : low risk to develop NSF Normal renal function : No risk to develop NSF

52 Gadodiamide ( linear non-ionic ) Risk to develop NSF Gadopentetate ( linear ionic ) Gadoteridol ( macro-cyclic ionic ) High dose of GBC : highest risk NSF

53 Rhabdomyolysis

54 Selected Drugs and toxins associated with Rhabdomyolysis (1) Excessive muscular hyperactivity,rigidity or seizure Amphetamines and derivatives Clozapine and olazapine Cocaine Lithium Monoamine oxidase inhibitors Seizure caused by a variety of agents Tetanus Tricyclic antidepressants

55 Selected Drugs and toxins associated with Rhabdomyolysis (2) Direct cellular toxicity Amatoxin-containing mushrooms Carbon monoxide Colchicine Ethylene glycol Other or unknown mechanism Barbiturates (prolonged immobility) Clofibrate Ethanol Hyperthermia caused by a variety of agents Sedative-hypnotic agents (prolonged immobility) trauma

56 FDA warning Interacting drugs เด อน ม นาคม พ.ศ. 2553,2554 กล ม strong CYP3A4 inhibitors เช น Itraconazole, Ketoconazole Posaconazole, HIV protease inhibitors, Erythromycin Clarithromycin Telithromycin, Nefazodone ให หล กเล ยงการใช Simvastatin

57 FDA warning Interacting drugs ป 2553 ป 2554 Gemfibrozil, Cyclosporine, Danazol ใช Simvastatin ได แต ต องไม เก น ขนาด 10 ม ลล กร มต อว น ให หล กเล ยง การใช Simvastatin

58 FDA warning Interacting drugs ป 2553 ป 2554 Amiodarone, Verapamil ใช Simvastatin ได แต ต องไม เก น ขนาด 10 ม ลล กร มต อว น ใช Simvastatin ได แต ต องไม เก นขนาด 10 ม ลล กร มต อว น

59 FDA warning Interacting drugs ป 2553 ป 2554 Ditiazem ใช Simvastatin ได แต ต องไม เก นขนาด 40 ม ลล กร มต อว น ใช Simvastatin ได แต ต องไม เก น ขนาด 10 ม ลล กร มต อว น Amlodipine, Ranolazine ไม ได กาหนด ใช Simvastatin ได แต ต องไม เก นขนาด 20 ม ลล กร มต อว น

60 Keys of Statin related rhabdomyolysis Type of statin Drug-Drug interaction

61 DIALYSIS INTERVENTION FOR TREATMENT OF AKI

62 SCOPE Timing of renal replacement therapy in AKI Criteria for stopping renal replacement therapy in AKI Modality of renal replacement therapy in AKI IHD( Intermitten hemodialysis) CRRT (continuous renal replacement therapy) SLED ( sustained low-effciency dialysis) PD (peritoneal dialysis) Dose of renal replacement therapy in AKI

63 TIMING OF RENAL REPLACEMENT THERAPY Provide RRT and when start RRT? In current practice : depend on clinical feature of volume overload,azotemia,hyperkalemia,severe acidosis Suspected AKI may recover on their own Well-known risks associated with RRT procedure;hypotension,arrhythmia,membrane bioincompatibility,complication of vascular accesss,anticoagulant adminstration

64 CHAPTER 5.1: TIMING OF RENAL REPLACEMENT THERAPY : Initiate RRT emergently when lifethreatening changes in fluid,electrolyte,and acid-base balance exist ( Not grade) 5.1.2: Consider the broader clinical context,the presence of conditions thay can be modified with RRT,and trends of laboratory tests-rather than single BUN and creatinine threshold alone-when making the decision to start RRT.(Not grade)

65 SOLUTE CONTROL BUN reflects factors not directly associated with kidney function, such as catabolic rate and volume status. o SCr is influenced by age, race, muscle mass, and catabolic rate, and by changes in its volume of distribution due to fluid administration or withdrawal.

66 VOLUME CONTROL Fluid overload is emerging as an important factor associated with, and possibly contributing to, adverse outcomes in AKI. Recent studies have shown potential benefits from extracorporeal fluid removal in CHF. Intraoperative fluid removal using modified ultrafiltration has been shown to improve outcomes in pediatric cardiac surgery patients.

67 CHAPTER 5.2 : CRITERIA FOR STOPPING RENAL REPLACEMENT THERAPY IN AKI 5.2.1: Discontinue RRT when it is no longer required,either because intrinsic kidney function has recovered to the point that it is adequate to meet patient needs, or because RRT is no longer consistent with the goals of care. (Not Graded)

68 CRITERIA FOR STOPPING RENAL REPLACEMENT THERAPY IN AKI Mean duration of RRT in 2 recent large RCTS was days More than 50% of patient with severe AKT will not improve,despite appropriated therapy Asssement of kidney function during RRT is not easy and depend on modality of RRT, In IHD,the fluctuation of solute level,post treatment rebound and from non-renal factor such as volume status and catabolic rate

69 CRITERIA FOR STOPPING RRT The process of stopping RRT may be consist of simple discontinuation of RRT May include change in the modality,frequency,duration of RRT Switching from CRRT to IHD,decreasing frequency of IHD from daily to every other day

70 CHAPTER 5.6 : MODALITY OF RRT IN PATIENTS WITH AKI

71 CHAPTER 5.6 : MODALITY OF RRT IN PATIENTS WITH AKI : Use continuous and intermittent RRT as complementary therapies in AKI patients. (Not Graded) : We suggest using CRRT, rather than standard intermittent RRT, for hemodynamically unstable patients. (2B) : We suggest using CRRT, rather than intermittent RRT, for AKI patients with acute brain injury or other causes of increased intracranial pressure or generalized brain edema. (2B)

72 TYPICAL SETTING OF DIFFERENT RRT MODALITY FOR AKI (FOR 70 KG PATIENT)

73 THEORETICAL ADVANTAGE AND DISADVANTAGES OF CRRT,IHD,SLED AND PD

74 ROLE OF PERITONEAL DIALYSIS IN AKI o Disdvantages : are the overall lower effectiveness especially in o Patients with splanic hypoperfusion or on vasopressors o The risk of protein loss o Unpredictable of solute and fluid removal Need for an intact peritoneal cavity Risk of peritonitis Diaphragmatic splinting leading to ventilatory compromise Fluctuating blood glucose levels

75 CHAPTER 5.8 : DOSE OF RRI IN AKI 5.8.1: The dose of RRT to be delivered should be prescribed before starting each session of RRT. (Not Graded) We recommend frequent assessment of the actual delivered dose in order to adjust the prescription. (1B) 5.8.2: Provide RRT to achieve the goals of electrolyte, acid-base, solute, and fluid balance that will meet the patient s needs. (Not Graded)

76 CHAPTER 5.8 : DOSE OF RRI IN AKI 5.8.3: We recommend delivering a Kt/V of 3.9 per week when using intermittent or extended RRT in AKI. (1A) 5.8.4: We recommend delivering an effluent volume of ml/kg/h for CRRT in AKI (1A). This will usually require a higher prescription of effluent volume. (Not Graded)

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78 ราคาในการทา CRRT ในแต ละส ทธ บ ตร ( ทา 3 day) ส ทธ บ ตร ประก น ส ขภาพ ต วกรอง + สายส งฟอก เล อด ( 1 set/day) = 5,500 bath/day * 3 day = 16,500 bath น ายาประมาณ 10 bag/ว น = 10,000 bath/da y * 3 day = 30,000 bath ค าทาการฟอก เล อดด วย เคร องไตเท ยม แบบไม รวม อ ปกรณ Bath/sessi on = 2,000 bath/da y*3day = 6,000 bath ราคาท งหมด 52,500 bath ราคาส วนเก น ท ผ ป วยต อง จ าย 46,500 bath

79 ราคาในการทา CRRT ในแต ละส ทธ บ ตร ( ทา 3 day) ส ทธ บ ตร ต วกรอง + สายส งฟอก เล อด ( 1 set/day) น ายาประมาณ 10 bag/ว น ค าทาการฟอก เล อดด วย เคร องไตเท ยม แบบไม รวม อ ปกรณ Bath/sessi on ราคาท งหมด ราคาส วนเก น ท ผ ป วยต อง จ าย ประก น ส งคม = 5,500 bath/day * 3 day = 16,500 bath = 10,000 bath/da y * 3 day = 30,000 bath = 3,000 bath/da y * 3 day = 9,000 bath 55,500 bath 46,500

80 ส ทธ บ ตร ต วกรอง + สายส ง ฟอกเล อด ( 1 set/day) น ายา ประมาณ 10 bag/ ว น ค าทาการ ฟอกเล อด ด วยเคร อง ไตเท ยม แบบไม รวม อ ปกรณ Bath/se ssion ราคา ท งหมด ราคา ส วนเก นท ผ ป วยต อง จ าย ต นส งก ด = 5,500 bath/day * 3 day = 16,500 bath = 10,000 bath/d ay * 3 day = 30,000 bath = 3,500 bath/d ay * 3 day = 10,500 bath 57,000 bath = ,000 = 30,900 bath

81 Thank you for attention

82 Cost of GBC agents(ร.พ. ราชว ถ ) Type Cost ( บาท) ปร มาณ ( cc ) Gadodiamide (Omniscan) 1, ml Gadopentetate (Magnevist) 1, ml Gadoversetamide (OptiMARK) NA Gadobenate (MultiHance) 1, ml Gadoteridol (Prohance) NA Gadobutrol (Gadovist) 1, ml Dotarem 1, ml