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

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
Direct Cytotoxicity
Rheologic Effects
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. 1997103368-375.
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. 20059513-19.
11
CIN and mortality
Adjusted OR 5.5 plt0.01
Levy et al. JAMA 1996 2751489-1494
12
Preventive strategies for CIN
Ineffective
Effective
Unclear benefit

• NAC
• Theophylline
• Aminophylline
• Ascorbic acid
• Statins
• Hemofiltration

• IVF
• Choice of contrast

• CCB
• Loop diuretics
• Mannitol
• Dopamine
• Fenoldopam
• ANP
• Hemodialysis

Possibly harmful
13
NAC for CIAKI (n83)
21
CIN (Scr ? ? 0.5 mg/dL _at_ 48h)
P0.01
2
Control
NAC
Tepel M, et al. N Engl J Med 2000 343180-184
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
Solomon R, Werner C, Mann D, DElia J, Silva P. N
Engl J Med. 19943311416-1420.
18
Isotonic v. hypotonic saline
P0.04
P0.93
P0.35
Mueller C, et al. Arch Int Med. 2002 162329-336
19
Saline vs. Bicarbonate IV fluid
(8/59)
P 0.02
(1/60)
Merten et al. JAMA 20042912328-2334
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
PNS
CIN
N76
N79
N77
N80
Dussol et al. Nephrology Dialysis
Transplantation. 2006212120-2126
22
Meta-analysis of IOCM v. LOCM
P0.003
IOCM
LOCM
NS
NS
pts
NS
McCullough et al. JACC 200648692-9
23
Meta-analysis of IOCM v. LOCM
Favors IOCM
Favors LOCM
Heinrich et al. Radiology 200925068-86
24
Summary of prevention

• NAC of unclear benefit
• I use 1200 mg po bid x 2 days
• IV fluids beneficial isotonic gtgt 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.
20072264-267.
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. 200869161-168
Mitka M. JAMA. 2007297252-253 Thomsen HS. Eur
Radiol. 2006162619-2621 Cowper SE.
http//www.icnfdr.org. Issa N et al. Cleve Clin J
Med. 20087595-111
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. 200869161-168
30
NSF Association With Renal Disease

• All reported NSF in pts with renal impairment
• Reported in stages 4-5 CKD
• eGFR lt30 mL/min/1.73 m2
• Most commonly dialysis pts

Most cases
NSF
Issa N et al. Cleve Clin J Med. 20087595-111.
31
(No Transcript)
32
NSF Incidence After GBCA in End-Stage Renal
Disease

• 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

Markmann P et al. J Am Soc Nephrol. 20062359-62
Deo A et al. Clin J Am Soc Nephrol. 2007264-7
Broome DR et al. AJR 2007586-92 Prince MR et
al. Radiology. 2008248807-816.
33
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 lt 30 developed NSF
• 0 of 485 pts with eGFR lt 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
29887-94
34
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.
20072200-202 Rofsky NM et al. Radiology.
2008608-12.
35
NSF Speculative Pathogenesis
1
4
5
2
3
cF, circulating fibrocyte Cyto,
cytokinesPerazella MA. Clin J Am Soc Nephrol.
20072200-202.
36
NSF and Specific GBCA

• Volunteer case reports to MedWatch (FDA) as of
  10/07

Penfield JG et al. Semin Dial. 200821129-134.
37
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
200772425-32
38
NSF and dose of GBCA

• Retrospective review - biopsy-confirmed NSF cases
  from 19972007 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. 2008248807-816.
39
NSF and pro-inflammatory state
Sadowski EA et al. Radiology. 2007243148-157.
40
NSF Associated Clinical Conditions

• Thrombotic events
• Idiopathic pulmonary fibrosis
• SLE
• Hypothyroidism
• ? serum Ca or PO4
• Hyperparathyroidism
• Metabolic acidosis

• Hypercoagulability states
• Surgical procedures
• Esp, reconstructive vascular components
• Hepatic disease
• Hepatorenal syndrome
• Liver transplantation
• Hepatitis B and C

• 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. 20087595-111.
41
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 - ? gt HD
• Reduced clearance of Gd with PD

Joffe P et al. Acad Radiol. 19985491-502
Prince MR et al. Radiology. 2008248807-816.
42
NSF attempted treatment strategies

• 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

- 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. 20087595-111.
43
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_2
00705.htm
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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 lt 0.1 in
  advanced CKD
• Treatment is limited
• Prevention is key in high risk pts

45

• 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
• _at_ 16 months of f/u
• 4 developed ESRD
• 17 had persistent CKD

JASN 163389-3396,2005
46
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

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Nephrocalcinosis
AJR136April 1981831
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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

49
Acute phosphate nephropathy Pathogenesis
50
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

51
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

52

• 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

53

• 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

54

• 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

55

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