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Update in nephrology Contrast nephropathy acute phosphate

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Update in nephrology Contrast nephropathy acute phosphate Powered By Docstoc
					        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
1) A 45 year old WM with a serum creatinine of
   1.0 mg/dL is undergoing a procedure. He is at
   risk for:
  a) Contrast induced nephropathy
  b) Acute phosphate nephropathy
  c) Nephrogenic systemic fibrosis
  d) Contrast nephropathy and acute phosphate
     nephropathy
  e) Contrast nephropathy and nephrogenic systemic
     fibrosis
  f) Acute phosphate nephropathy and nephrogenic
     systemic fibrosis
  g) All of the above
2) A 45 year old WM with a serum creatinine of
  1.8 mg/dL is undergoing a procedure. He is at
  risk for:
  a) Contrast nephropathy
  b) Acute phosphate nephropathy
  c) Nephrogenic systemic fibrosis
  d) Contrast nephropathy and acute phosphate
     nephropathy
  e) Contrast nephropathy and nephrogenic systemic
     fibrosis
  f) Acute phosphate nephropathy and nephrogenic
     systemic fibrosis
  g) All of the above
3) A 45 year old WM on chronic hemodialysis is
  undergoing a procedure. He is at risk for:
  a) Contrast nephropathy
  b) Acute phosphate nephropathy
  c) Nephrogenic systemic fibrosis
  d) Contrast nephropathy and acute phosphate
     nephropathy
  e) Contrast nephropathy and nephrogenic systemic
     fibrosis
  f) Acute phosphate nephropathy and nephrogenic
     systemic fibrosis
  g) All of the above
            Pathophysiology of CIN

                Radiocontrast Administration



   Intrarenal    Rheologic Osmotic Generation     Direct
Vasoconstriction Effects    Load    of ROS      Cytotoxicity



         Medullary Hypoxia



                             CIN
                    Risk factors for CIN
• Patient-related
   –   Renal insufficiency
   –   Diabetes mellitus*        }
                              additive risk

   –   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

   * Diabetes alone not strong risk factor
  Renal Insufficiency and Diabetes Mellitus

   Creatinine Clearance                            CIN Requiring Dialysis
         (mL/min)                         Non-Diabetic            Diabetic
                 50                            0.04%               0.2%
                 40                                0.3%             2%
                 30                                2%               10%
                 20                                12%              43%
                 10                                48%              84%

McCullough PA et al. Am J Med. 1997;103:368-375.
      Approach to screening with SCr

 Consider screening SCr if pt has 1 or more of these:
  •   Known renal insufficiency
  •   Diabetes mellitus
  •   Proteinuria
  •   Advanced age
  •   Hypertension
  •   Nephrotoxic drug use
  •   History of kidney problem after radiocontrast
  •   Advanced liver disease

Weisbord SD, my approach
                                    Relationship Between Serum
                                        Creatinine and eGFR
                                                         75yo AAM      75yo WF
                        120
eGFR (mL/min/1.73 m )
2




                        100
                                                           59 ml/min/1.73m2
                        80

                        60
                                                           36 ml/min/1.73m2
                        40

                        20

                         0
                              0.5    1.0   1.5   2.0     2.5   3.0   3.5      4.0   4.5   5.0   5.5   6.0

                                                       Serum creatinine (mg/dL)
                              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.
                                   CIN and mortality

                                                                Mortality
                50%

                40%                              Apache II   No AKI     AKI
    Mortality




                30%                                0-3        4%       17%

                20%                                4-7        5%       40%
                10%
                                                   8-11       28%      52%
                0%
                        No AKI         AKI
                                                   >12        33%      62%
                      Adjusted OR: 5.5; p<0.01


Levy et al. JAMA 1996; 275:1489-1494
              Preventive strategies for CIN

      Ineffective        Unclear benefit       Effective
•    CCB                 •   NAC              • IVF
•    Loop diuretics*     •   Theophylline     • Choice of
•    Mannitol*           •   Aminophylline      contrast
•    Dopamine*           •   Ascorbic acid
•    Fenoldopam*         •   Statins
•    ANP                 •   Hemofiltration
•    Hemodialysis*
    * Possibly harmful
                                                NAC for CIAKI (n=83)
                                          25%
                                                                  21%
        % CIN (Scr ↑  0.5 mg/dL @ 48h)




                                          20%

                                          15%
                                                   P=0.01
                                          10%

                                          5%
                                                            2%
                                          0%
                                                            NAC    Control

Tepel M, et al. N Engl J Med 2000; 343:180-184
                         Meta-Analyses of NAC
                                                                    RR
                              Studies        Subjects            (95% CI)            Heterogeneity

 Pannu, et al                     15            1776         0.65 (0.43-1.00)            Yes
 Kshirsagar, et al                16            1538                  **                 Yes
 Nallamothu, et al                20            2195         0.73 (0.52-1.03)            Yes
 Duong, et al                     14            1584         0.57 (0.37-0.88)            Yes
 Kelly, et al                     26            3393         0.62 (0.44-0.88)            Yes
 Gonzalez et al                   22            2746                  **                 Yes
    Subgroup 1                    18            2445         0.87 (0.68-1.12)             No
    Subgroup 2                    4             301          0.15 (0.07-0.33)             No

** Given degree of heterogeneity, calculation of summary estimate would be invalid
             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
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
  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.
                Isotonic v. hypotonic saline


                            P=0.04


                                                             P=0.93


                                                    P=0.35




Mueller C, et al. Arch Int Med. 2002; 162:329-336
           Saline vs. Bicarbonate IV fluid
                                        (8/59)
       14%                     13.6%
       12%                                                     P = 0.02
       10%
        8%
        6%                                       (1/60)   rate of CIN
        4%                                1.7%
        2%
        0%
                NaCl (n=59)             NaHCO3
                                        (n=60)

Merten et al. JAMA 2004;291:2328-2334
            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
                      IV NaCl v. oral NaCl
            16
                                                              15.2%
            14
            12          P=NS
% CIN       10
                                                      7.5%
             8
                     6.6%
                                     5.2%
             6
             4
             2
             0
                    Oral                IV           IV/Theo         IV/Fur
                   N=76            N=77            N=80            N=79


 Dussol et al. Nephrology Dialysis Transplantation. 2006;21:2120-2126
              Meta-analysis of IOCM v. LOCM
                P=0.003

         16        15.5%
                                                      IOCM     LOCM
         14
         12                            NS
         10
                                                 NS             NS
 % pts




         8
         6                             5.1%
               3.5%
         4
                                2.4%                 1.9%    1% 1.6%
         2                                    0.6%
         0
               +CKD/+DM        +CKD/-DM       -CKD/+DM       -CKD/-DM


McCullough et al. JACC 2006;48:692-9
         Meta-analysis of IOCM v. LOCM




                       Favors IOCM         Favors LOCM




Heinrich et al. Radiology 2009;250:68-86
        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
               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
              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.   26
                     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. 27
 2006:16:2619-2621; Cowper SE. http://www.icnfdr.org. Issa N et al. Cleve Clin J Med. 2008;75:95-111
                             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.
              NSF: Clinical appearance




     Occurs days to many months after exposure to GBCA

Marckmann P et al. Clin Nephrol. 2008;69:161-168
 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



               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




Issa N et al. Cleve Clin J Med. 2008;75:95-111.
                                                                                                       30
31
NSF: Incidence After GBCA in End-Stage
            Renal Disease
   1.     Markmann et al – 13 of 370 ESRD pts (3.5%)
   2.     Deo et al – 3 of 87 ESRD pts – (3.4%)
   3.     Broome et al – 12 of 301 HD-pt exposures (4%)
   4.     Prince et al – 1 of 265 ESRD pt (0.4%)

              Incidence after GBCA in ESRD = 0.4-4% based on
                           retrospective analyses


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
  NSF – Pathogenesis and GBCA

• 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

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, cytokines
Perazella 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

                                                  FDA-reported Published case
 Agent                                              cases, n     reports, n
 Gadodiamide                                          283            93
 Gadopentetate dimeglumine                            125            18
 Gadoversetamide                                       20            0
 Gadobenate dimeglumine                               10*            1‡
 Gadoteridol                                           9†            0
 *Only 2 received that GBCA alone; †Only 1 received that GBCA alone;
 ‡Patient also received Omniscan



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
                                                                                                        37
Agarwal R et al. 2008 Nephrol Dial Transplant: 1-7; Wahba M. et al. Amer J. Transplant 2007;7:2425-32
                           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%




                                                                 38
Prince MR et al. Radiology. 2008;248:807-816.
       NSF and pro-inflammatory state




                                                  39
Sadowski EA et al. Radiology. 2007;243:148-157.
       NSF: Associated Clinical Conditions
    • Hypercoagulability states                   • Thrombotic events
    • Surgical procedures                         • Idiopathic pulmonary
       – Esp, reconstructive                        fibrosis
         vascular components                      • SLE
    • Hepatic disease                             • Hypothyroidism
       – Hepatorenal syndrome                     •  serum Ca or PO4
       – Liver transplantation                    • Hyperparathyroidism
       – Hepatitis B and C                        • Metabolic acidosis

    - 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.
    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
NSF: attempted treatment strategies
• Oral steroids (eg,                                  • Thalidomide
  prednisone)                                         • Ultraviolet therapy
• Topical Dovonex (under                              • Physical therapy
  occlusion)
                                                      • Pentoxifylline
• Extracorporeal
  photopheresis                                       • High-dose IV Ig therapy
• Plasmapheresis                                      • Renal transplantation
• Cytoxan                                             • IV sodium thiosulfate

- 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

                                                                   43
 http://www.fda.gov/cder/drug/InfoSheets/HCP/gcca_200705.htm
            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
• 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
       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
                         Nephrocalcinosis




AJR:136;April 1981;831
    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
Acute phosphate nephropathy: Pathogenesis
    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
    Acute phosphate nephropathy -
             prevention
• Boxed warning for OSP preparations
• Oral preps no longer available OTC
• Recognize risk factors
• Work closely with gastroenterologists to avoid
  OSP preparations in pts at risk
• Some recommendations are to avoid OSP
  completely
1) A 45 year old WM with a serum creatinine of
   1.0 mg/dL is undergoing a procedure. He is at
   risk for:
  a) Contrast induced nephropathy
  b) Acute phosphate nephropathy
  c) Nephrogenic systemic fibrosis
  d) Contrast nephropathy and acute phosphate
     nephropathy
  e) Contrast nephropathy and nephrogenic systemic
     fibrosis
  f) Acute phosphate nephropathy and nephrogenic
     systemic fibrosis
  g) All of the above
2) A 45 year old WM with a serum creatinine of
  1.8 mg/dL is undergoing a procedure. He is at
  risk for:
  a) Contrast nephropathy
  b) Acute phosphate nephropathy
  c) Nephrogenic systemic fibrosis
  d) Contrast nephropathy and acute phosphate
     nephropathy
  e) Contrast nephropathy and nephrogenic systemic
     fibrosis
  f) Acute phosphate nephropathy and nephrogenic
     systemic fibrosis
  g) All of the above
3) A 45 year old WM on chronic hemodialysis is
  undergoing a procedure. He is at risk for:
  a) Contrast nephropathy
  b) Acute phosphate nephropathy
  c) Nephrogenic systemic fibrosis
  d) Contrast nephropathy and acute phosphate
     nephropathy
  e) Contrast nephropathy and nephrogenic systemic
     fibrosis
  f) Acute phosphate nephropathy and nephrogenic
     systemic fibrosis
  g) All of the above
???

				
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