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Update in nephrology Contrast induced nephropathy, nephrogenic systemic fibrosis and acute phosphate nephropathy

Update in nephrology Contrast induced nephropathy, nephrogenic systemic fibrosis and acute phosphate nephropathy. Steven D. Weisbord MD, MSc , FASN Renal-Electrolyte Division University of Pittsburgh School of Medicine.

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Update in nephrology Contrast induced nephropathy, nephrogenic systemic fibrosis and acute phosphate nephropathy

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  1. Update in nephrology Contrast induced nephropathy, nephrogenic systemic fibrosis and acute phosphate nephropathy Steven D. Weisbord MD, MSc, FASN Renal-Electrolyte Division University of Pittsburgh School of Medicine

  2. 1) A 45 year old WM with a serum creatinine of 1.0 mg/dL is undergoing a procedure. He is at risk for: • Contrast induced nephropathy • Acute phosphate nephropathy • Nephrogenic systemic fibrosis • Contrast nephropathy and acute phosphate nephropathy • Contrast nephropathy and nephrogenic systemic fibrosis • Acute phosphate nephropathy and nephrogenic systemic fibrosis • All of the above

  3. 2) A 45 year old WM with a serum creatinine of 1.8 mg/dL is undergoing a procedure. He is at risk for: • Contrast nephropathy • Acute phosphate nephropathy • Nephrogenic systemic fibrosis • Contrast nephropathy and acute phosphate nephropathy • Contrast nephropathy and nephrogenic systemic fibrosis • Acute phosphate nephropathy and nephrogenic systemic fibrosis • All of the above

  4. 3) A 45 year old WM on chronic hemodialysis is undergoing a procedure. He is at risk for: • Contrast nephropathy • Acute phosphate nephropathy • Nephrogenic systemic fibrosis • Contrast nephropathy and acute phosphate nephropathy • Contrast nephropathy and nephrogenic systemic fibrosis • Acute phosphate nephropathy and nephrogenic systemic fibrosis • All of the above

  5. Pathophysiology of CIN Radiocontrast Administration Intrarenal Vasoconstriction Rheologic Effects Direct Cytotoxicity Osmotic Load Generation of ROS Medullary Hypoxia CIN

  6. Risk factors for CIN • Patient-related • Renal insufficiency • Diabetes mellitus* • Intravascular volume depletion • Reduced cardiac output • Concomitant nephrotoxins • Procedure-related • ↑ volume of radiocontrast • Multiple procedures w/i 72 hours • Intra-arterial administration • Type of radiocontrast } additive risk * Diabetes alone not strong risk factor

  7. Renal Insufficiency and Diabetes Mellitus McCullough PA et al. Am J Med. 1997;103:368-375.

  8. Approach to screening with SCr • Known renal insufficiency • Diabetes mellitus • Proteinuria • Advanced age • Hypertension • Nephrotoxic drug use • History of kidney problem after radiocontrast • Advanced liver disease Consider screening SCr if pt has 1 or more of these: Weisbord SD, my approach

  9. Relationship Between Serum Creatinine and eGFR 59 ml/min/1.73m2 36 ml/min/1.73m2

  10. Implications of CIN • CIN may result in any or all of the following: • Delay in discharge of patient • Permanent kidney damage • Dialysis • Increased patient mortality Dangas G et al. Am J Cardiol. 2005;95:13-19.

  11. CIN and mortality Adjusted OR: 5.5; p<0.01 Levy et al. JAMA 1996; 275:1489-1494

  12. CCB Loop diuretics* Mannitol* Dopamine* Fenoldopam* ANP Hemodialysis* NAC Theophylline Aminophylline Ascorbic acid Statins Hemofiltration Preventive strategies for CIN Ineffective Unclear benefit Effective • IVF • Choice of contrast * Possibly harmful

  13. NAC for CIAKI (n=83) 21% % CIN (Scr ↑  0.5 mg/dL @ 48h) P=0.01 2% NAC Control Tepel M, et al. N Engl J Med 2000; 343:180-184

  14. Meta-Analyses of NAC ** Given degree of heterogeneity, calculation of summary estimate would be invalid

  15. NAC - summary • Protective effect unclear • Many studies to date have methodological flaws • Cheap and benign (in oral form) • Should not be used in lieu of other measures

  16. Clinical trials of volume expansion • 1994 → present • Provide clinical basis for: • Protective effect of IVF • Deleterious effect of furosemide • Superiority of isotonic IVF • Superiority of IVF to pt-directed oral fluids • Potential benefit of oral NaCl

  17. Rate of CIN: 11% 28% 40% Solomon R, Werner C, Mann D, D’Elia J, Silva P. N Engl J Med. 1994;331:1416-1420.

  18. Isotonic v. hypotonic saline P=0.04 P=0.93 P=0.35 Mueller C, et al. Arch Int Med. 2002; 162:329-336

  19. Saline vs. Bicarbonate IV fluid (8/59) P = 0.02 (1/60) Merten et al. JAMA 2004;291:2328-2334

  20. Meta-analysis of NaCl v. NaHCO3 OR 0.46 [0.26-0.82] Navaneethan SD et al. 617-627; 2009; American Journal of Kidney Diseases

  21. IV NaCl v. oral NaCl P=NS % CIN N=76 N=79 N=77 N=80 Dussol et al. Nephrology Dialysis Transplantation. 2006;21:2120-2126

  22. Meta-analysis of IOCM v. LOCM P=0.003 IOCM LOCM NS NS % pts NS McCullough et al. JACC 2006;48:692-9

  23. Meta-analysis of IOCM v. LOCM Favors IOCM Favors LOCM Heinrich et al. Radiology 2009;250:68-86

  24. Summary of prevention • NAC – of unclear benefit • I use 1200 mg po bid x 2 days • IV fluids beneficial – isotonic >> hypotonic • ? Superiority of NaHCO3 • Abbreviated regimen OK – 1 hr pre and 4-6 hr post • Low or iso-osmolal contrast • Mixed data on superiority of iso-osmolal

  25. Summary of CIN • Remains common due to high use of iodinated contrast • Risk factors well known – CKD • Adverse outcomes with CIN • Prevention: • Isotonic IV fluids • NAC - ? benefit • Choice of contrast

  26. NSF - History and Nomenclature • Disease initially identified in late 1990s as fibrosing skin condition • Named nephrogenic fibrosing dermopathy (NFD) • Subsequently found to also have systemic manifestations • skeletal muscle, lung, liver, testes, myocardium • most prominent findings are dermatologic • Re-named Nephrogenic Systemic Fibrosis (NSF) Cowper SE. Available at http://www.icnfdr.org; Deo A et al. Clin J Am Soc Nephrol. 2007;2:264-267.

  27. NSF: Skin manifestations • Distribution • Usually symmetrical • Extremities  trunk • Face/neck typically spared • Signs • Swelling and erythema of extremities • Induration: distal  proximal • Woody papules • Symptoms • Burning, itching, pain • Reduced flexibility  immobility • Muscle weakness } Can be very disabling Marckmann P et al. Clin Nephrol. 2008;69:161-168; Mitka M. JAMA. 2007;297:252-253; Thomsen HS. Eur Radiol. 2006:16:2619-2621;Cowper SE. http://www.icnfdr.org.Issa N et al. Cleve Clin J Med. 2008;75:95-111

  28. NSF: Epidemiology • No gender predilection • Affects patients of all ages; most commonly middle age • Affects various ethnic/racial groups • Seen in North America, Europe, and Asia • Only seen in pts with kidney disease Cowper SE. Available at http://www.icnfdr.org.

  29. NSF: Clinical appearance Occurs days to many months after exposure to GBCA Marckmann P et al. Clin Nephrol. 2008;69:161-168

  30. Stage I Stage II Stage III Stage IV Stage V 130 120 110 100 90 80 70 60 50 40 30 25 20 15 10 5 0 GFR NSF: Association With Renal Disease • All reported NSF in pts with renal impairment • Reported in stages 4-5 CKD • eGFR <30 mL/min/1.73 m2 • Most commonly dialysis pts Most cases NSF Issa N et al. Cleve Clin J Med. 2008;75:95-111.

  31. Markmann et al – 13 of 370 ESRD pts (3.5%) Deo et al – 3 of 87 ESRD pts – (3.4%) Broome et al – 12 of 301 HD-pt exposures (4%) Prince et al – 1 of 265 ESRD pt (0.4%) Incidence after GBCA in ESRD = 0.4-4% based on retrospective analyses NSF: Incidence After GBCA in End-Stage Renal Disease Markmann P et al. J Am Soc Nephrol. 2006:2359-62; Deo A et al. Clin J Am Soc Nephrol. 2007:264-7; Broome DR et al. AJR 2007:586-92; Prince MR et al. Radiology. 2008;248:807-816.

  32. Incidence of NSF in stages 4 and 5 CKD following MRA • 2 retrospective analyses of: • Large tertiary referral center in UK • Database of pts screened/enrolled in ASTRAL study • Results: • 0 of 252 pts with eGFR < 30 developed NSF • 0 of 485 pts with eGFR < 60 developed NSF • 1 of 1735 pts (0.06%) with CKD developed NSF (data extrapoloated and pt with NSF had stage 4-5 CKD) Chrysochou et al. Journal of Mag Reson Imag 29:887-94

  33. Gd is a lanthanide ion Free Gd is highly toxic Contrast agents for MR imaging – metal ion (Gd) bound to ligand (Gd-chelate complex) GBCA – excreted by the kidneys With impaired kidney function, T1/2 of GBCA increases ? displacement of Gd from chelate (transmetallation) Tissue exposure of Gd  ? Fibrosis leading to NSF NSF – Pathogenesis and GBCA Perazella MA. Clin J Am Soc Nephrol. 2007;2:200-202; Rofsky NM et al. Radiology. 2008:608-12.

  34. NSF: Speculative Pathogenesis 1 4 5 2 3 cF, circulating fibrocyte; Cyto, cytokinesPerazella MA. Clin J Am Soc Nephrol. 2007;2:200-202.

  35. NSF and Specific GBCA Volunteer case reports to MedWatch (FDA) as of 10/07 Penfield JG et al. Semin Dial. 2008;21:129-134.

  36. Risk factors for NSF - GBCA - GBCA strongly associated with NSF - Few case reports of NSF without known GBCA exposure Agarwal R et al. 2008 Nephrol Dial Transplant: 1-7; Wahba M. et al. Amer J. Transplant 2007;7:2425-32

  37. NSF and dose of GBCA • Retrospective review - biopsy-confirmed NSF cases from 1997–2007 in 2 large hospitals • 83,121 pts received GBCA • 15 cases of NSF confirmed after GBCA • 74,124 pts - low dose GBCA (0.1 mmol/kg) – NSF = 0% • 8,997 pts – high dose GBCA (0.2-0.4 mmol/kg) – NSF = 0.17% Prince MR et al. Radiology. 2008;248:807-816.

  38. NSF and pro-inflammatory state Sadowski EA et al. Radiology. 2007;243:148-157.

  39. Hypercoagulability states Surgical procedures Esp, reconstructive vascular components Hepatic disease Hepatorenal syndrome Liver transplantation Hepatitis B and C Thrombotic events Idiopathic pulmonary fibrosis SLE Hypothyroidism  serum Ca or PO4 Hyperparathyroidism Metabolic acidosis NSF: Associated Clinical Conditions • These conditions may be associated with increased use of MRI • Some conditions result from or cause renal disease Issa N et al. Cleve Clin J Med. 2008;75:95-111.

  40. NSF and other forms of renal disease • Acute kidney injury appears to be a risk factor for NSF • Acute kidney injury an “inpatient” disease • No need to routinely screen outpatients for acute kidney injury before MR • Peritoneal dialysis (PD) • Appears to be risk factor - ? > HD • Reduced clearance of Gd with PD Joffe P et al. Acad Radiol. 1998;5:491-502; Prince MR et al. Radiology. 2008;248:807-816.

  41. Oral steroids (eg, prednisone) Topical Dovonex (under occlusion) Extracorporeal photopheresis Plasmapheresis Cytoxan Thalidomide Ultraviolet therapy Physical therapy Pentoxifylline High-dose IV Ig therapy Renal transplantation IV sodium thiosulfate NSF: attempted treatment strategies - Most evidence anecdotal and/or unconfirmed. - Improving renal function may slow, arrest, and reverse NSF - PREVENTION IS KEY !!!! Cowper SE. Available at http://www.icnfdr.org; Issa N et al. Cleve Clin J Med. 2008;75:95-111.

  42. Prevention: FDA recommendations on use of GBCA • Screen all pts for renal dysfunction: history and/or lab tests • Avoid GBCA in pts with known risks for NSF unless diagnostic information cannot be obtained with non-contrast MR or other diagnostic procedures • When administering GBCA: • Do not exceed recommended GBCA dose in product labeling • Allow sufficient time for elimination of GBCA from the body prior to any re-administration • For pts on HD, consider prompt HD following GBCA http://www.fda.gov/cder/drug/InfoSheets/HCP/gcca_200705.htm

  43. Summary of NSF • Debilitating fibrosing condition - 10 skin findings • Associated with gadolinium contrast agents • Risk factors – high dose GBCA, inflammation • Incidence is 2-4% in dialysis and < 0.1% in advanced CKD • Treatment is limited • Prevention is key in high risk pts

  44. 7,349 native kidney bx • 31 cases of nephrocalcinosis • 21 of 31 pts had AKI and normal [Ca] + prior colonoscopy with oral sodium phosphate (OSP) • Mean baseline SCr 1.0 mg/dL • @ 16+ months of f/u: • 4 developed ESRD • 17 had persistent CKD JASN 16:3389-3396,2005

  45. Hyperphosphatemia and AKI • Acute tubular nephropathy and late radiologic vascular calcifications following treatment of a hypercalcemia with intravenous administration of phosphates – - Bernheim et al 1968 • Acute hyperphosphatemia and acute persistent renal insufficiency induced by oral phosphate therapy – Ayala et al. 1975 • Acute renal insufficiency caused by major hyperphosphatemia (normal blood uric acid) following treatment of acute lymphoblastic leukemia – Boudailliez et al 1986

  46. Nephrocalcinosis AJR:136;April 1981;831

  47. Acute phosphate nephropathy • Form of acute/subacute kidney injury: • Occurs following use of oral sodium phosphate solution for colonoscopy prep • Commonly leads to CKD • Can lead to ESRD

  48. Acute phosphate nephropathy: Pathogenesis

  49. Acute Phosphate nephropathy – risk factors • CKD – greater retention of po4 • Use of ACEi/ARB, diuretics, nsaids • Older age • Female gender • Higher doses of OPS and closer dosing interval

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