Case Studies in Nephrology

SHM 2005
Patrick Murray, M.D.
Associate Professor of Medicine,
Anesthesia & Critical Care, and Clinical
Pharmacology
University of Chicago
[email protected]

Outline

Acute Renal Failure (ARF) Prevention

Renal Function Monitoring
Diagnostic Approach to ARF
Medical Management of ARF
Acute Renal Replacement Therapy (RRT)

Acute Renal/Kidney Failure

A rapid decrement in renal
function, occurring over days to
weeks, resulting in accumulation of
nitrogenous wastes (azotemia)

Case #1: Radiocontrast Nephropathy?

Case Presentation
66 yo AA female with 5 month history of low back pain,
admitted for tumor embolization
Nephrology consultation requested regarding increased
creatinine
HPI:
PMHx notable only for glaucoma. Meds: Vicodin, Elavil, occ. Advil
Developed LBP 5 months prior to admission, assoc. with weight loss and
fatigue
Infused CT of abdomen/pelvis 2 months PTA revealed a destructive soft
tissue mass with bone erosion at L-1, with extension through the right
foramen in dumbbell fashion
MRI, LSS plain films were confirmatory
CT-guided bx 2 months PTA: malignant hemangiopericytoma
Negative infused chest and head CT scans 1 month PTA
Admitted for preoperative tumor embolization and resection: received
100-150ml nonionic, low osmolar dye prior to admission

Malignant Hemangiopericytoma

Malignant Hemangiopericytoma

Examination

70kg woman
Temp 36.9
P 92 reg
BP 158/80
UOP ~30ml/hour
IVF D5.45 60ml/hour
HEENT: unremarkable, JVD 5-6 cm H2O
Cor- 2/6 pansystolic murmur LLSB, no gallop
Lungs- clear
Abdomen- soft, NT, ND, no masses or organomegaly. Foley
catheter
Extremities: warm, brisk capillary refill, minimal edema
Back- minimal lumbar tenderness
Neurologically intact

Laboratory Data

Na 137 / K 4.8 / Cl 97 / HCO3 24 / BUN 48 / Cr 4.5

Glucose 120 / AG 16 / Ca 9.6 / PO4 5 / Mg 1.9

WBC 6.1 / Hb 6.2 (NC, NC) / Hct 18.2 / Plts 120K

PTT 20 / INR 0.9 / Albumin 4.4 / LFTs wnl

Urinalysis:

Dipstick- SpG 1.016, 1+ protein, 1+ heme, o/w negative

Microscopy- occ. RBC, occ. granular casts, no crystals

U/S: normal kidney sizes (11.4cm), slight increased

echogenicity, no hydronephrosis

CXR: clear

Renal Function Trend

Date (Months Serum
BUN
Procedure
Prior To
Creatinine (mg/dl)
Admission)
(mg/dl)
8

0.9

21

N/A

Radiocontrast
volume
(nonionic,
ml)
N/A

1.2

27

CT scan

101-150

38

CT scan

101-150

4.5

48

Embolization 101-150

Estimated GFR = 13 ml/min/1.73m2

50

Hematocrit Levels Fall as

Kidney Function Declines
*

Mean Hct (vol %)

40

30

20

10

n=59

n=29

n=18

91

40-90

30-39

n=18
20-29

CCr (mL/min/1.73 m2)

Adapted from Radtke et al. Blood. 1979;54:877-884.
* 25%-40% of kidney function. 10%-15% of kidney function.

n=34

n=18

10-19

<10

Initial Hospital Course

Volume expansion: NS 150ml/hour
Serum creatinine trend: increased by maximum of 0.3mg/dl
within 72 hours
24 hour urine: 3.86 grams proteinuria, creatinine clearance
13ml/minute
Peripheral smear: numerous atypical plasma cells noted
SPEP: TP 7.1 g/dl, 0.1g/dl monoclonal kappa light chain spike
UIEP: 3.94 grams/24 hour proteinuria, with monoclonal free
kappa lights chains accounting for 44% of urine protein
Skeletal survey: lytic lesions in skull, vertebrae (T10, T12, L1),
right femur, bilateral tibias

Light Chain Immunostaining

KAPPA

LAMBDA

Subsequent Course
Tumor pathology:
Original stains for keratins, synaptophysins, and lymphoid
differentiation negative
Additional immunohistochemical stains positive for kappa
light chains, negative lambda = Plasmacytoma

BMBx:
Markedly hypercellular, 85% plasma cells, 10-20% immature

Rx with XRT, melphalan, and dexamethasone

Developed ESRD and initiated HD 1.5 years later
Expired 2.5 years after diagnosis

Renal Manifestations of Multiple Myeloma

Renal tubular acidosis
Proximal, with Fanconi syndrome

Myeloma kidney
Presents with ARF or CRI
Tubular injury and Cast Nephropathy (obstruction)

Amyloidosis (primary, AL) and Light Chain Deposition Disease

Whole light chains (LDDD) or Light chain fragments (amyloid)
deposited; typical presentation is nephrotic syndrome

Hypercalcemia
Uric acid nephropathy
Plasma cell renal infiltration
Drug-induced ARF: hypovolemia + radiocontrast, NSAIDs,
ACE inhibitors

Myeloma & Radiocontrast Nephropathy

Myeloma reportedly predisposes to radiocontrast
nephropathy
McCarthy CS, et al: Radiology 1992;183:519

Volume depletion promotes intratubular light chain

precipitation to form casts
Exacerbated by hypercalcemia
Smolens P, et al: J Lab Clin Med 1987;110:460

? Charge interaction between light chains and

radiocontrast promoting precipitation
Worse with ionic dyes, acid urine
Holland MD, et al: Kidney International 1985;27:46

Radiocontrast Nephropathy (RCN)

Definition: acute decrement in renal function following
radiocontrast administration
Usually defined as serum creatinine increase of 0.5mg/dl or
25% within 48 (-96) hours of dye

3rd commonest cause of hospital-acquired ARF

Usually acute-on-chronic renal failure, superimposed
on CKD (not normal renal function)
Typically, serum creatinine increases within 24-48
hours, reaches peak and plateau in 3-5 days, decreases
Increases morbidity, cost, and mortality
Adjusted odds ratio 5.5 for in-hospital mortality (vs no RCN)
Levy EM, et al: JAMA 1996;275:1489-94

Mortality Rates for Patients with

Radiocontrast Nephropathy

McCullough et.al Am. J. Med. 1997

Pathogenesis of RCN

Oxidant Injury
Hyperosmolar contrast triggers generation of
reactive oxygen species

Other Cytotoxic effects

Renal vasoconstriction
Aggravating in medullary hypoxia
Intratubular precipitation of dye crystals

Blood Flow and Interstitial O2 Content: Regional

Distribution in Cortex/Medulla
4.2 ml/
gm/min

1.9 ml/
gm/min

PaO2
+ 50

PaO2
10-20

Brezis M, Rosen S: N Engl J Med 1995;332:647-655

Mechanism

RCN Risk Factors

Confirmed

Suspected

Serum Cr > 1.5 mg/dl

Hypertension

Diabetic Nephropathy

Abnormal LFT

Class III/IV NYHC CHF

Age

Multiple Myeloma

Gender

Volume contrast media

Concomitant use
loop diuretics

Repeat dye < 48 hours

Porter G.A. Invest. Rad. 1993

RCN risk after Primary PCI in AMI

Variables (Odds Ratio):
Age 75 (5.28)
Anterior MI (2.17)
Time-to-reperfusion 6h (2.5)
Contrast 300ml (2.8)
IABP (15.51)

Marenzi G, et al: JACC 2004;44:1780-5

RCN Incidence
Study

No. Patients

Entry Cr

Incidence

Fenoldopam 1999
Multicenter trial

50

2.61

29.0%

P.R.I.N.C.E. 1999

98

2.46

36.7%

Endothelin Receptor
Antagonist Trial 1999

158

2.76

29.0%

ANP Multicenter Trial

1998

247

1.5-1.8

19.0%

1.5

11.6%

2.1

11.0%

Iohexol Cooperative
Study 1995
Solomon 1993
Harvard University

1196/509
78

Incidence Doubles In Patients With Diabetic

Nephropathy
Pre-Procedure
Creatinine Level

Incidence

<2

3.6 %

24

27 %

>4

81 %
Berns AS.Kidney Int. 1989

Radiocontrast Nephropathy Prevention:

General Measures
Estimate GFR
ARF: ? reversible
CRI: stratify risk, counselling, prophylaxis

Consider alternatives
Eg. MRA with gadolinium contrast

Adjust Medications
Stop NSAIDs
Hold diuretics
Consider holding ACE inhibitors or ARBs if for HTN, CKD, not CHF?
(opinion)
Hold metformin

Radiocontrast selection
Smallest volume of nonionic, isoosmolar dye preferred for high risk
patients

Clarifying the Nomenclature

Disease Severity

CKD Continuum

120180

ESRD

CRI

At
risk

75

55

25

15

GFR (mL/min/1.73 m2)

United States Renal Database System. 2000 Atlas of ESRD in the United States.

The Incidence of ESRD Is

Increasing
InIncidence of New Patients

100,000

Greatest Increase Seen in Diabetic ESRD

All ESRD

80,000

60,000
40,000

Diabetes

20,000

0
1989

Hypertension
Glomerulonephritis
1990

1991

1992

1993

1994

1995

1996

1997

1998

United States Renal Database System. 2000 Atlas of ESRD in the United States.

Estimates of CRI in the United States

Based on NHANES III Data
Millions of individuals

Unknown
SCr 1.4 mg/dL
SCr 1.5 mg/dL

6.2

SCr 1.7 mg/dL

2.5
0.8
0.26

SCr 2.0 mg/dL

RRT

Jones et al. Am J Kidney Dis. 1998;32:992-999 (published correction in Am J Kidney Dis.

2000;35:178). United States Renal Database System. 2000 Atlas of ESRD in the United States.

JNC VII: CKD is a Major CV Risk Factor

Major Risk Factors include:

Estimated GFR <60ml/min
Microalbuminuria
Target Organ Damage includes:
Chronic Kidney Disease

Chobanian AV, et al: Hypertension 2003;1206-52

Detection and Management Issues

in Patients at Risk
GFR

Kidney Damage

Metabolic Aspects

Serum creatinine

Microalbuminuria

Hemoglobin/hematocrit

BUN

Clinical proteinuria

Total cholesterol

Creatinine clearance
measured
calculated (CG)
GFR
measured
calculated (MDRD)

Triglycerides
Ca/PO4
iPTH
Serum bicarbonate
Serum electrolytes

BUN = blood urea nitrogen; CG = Cockcroft-Gault; GFR = glomerular filtration rate; MDRD = Modification of
Diet in Renal Disease Study; Ca/PO4 = calcium and phosphate; iPTH = intact parathyroid hormone.

Plasma Creatinine
Directly proportional to muscle mass (Kasiske & Keane, 1999)
Inversely proportional to GFR
Equations relating age, sex, race, size (muscle mass) to plasma
creatinine to estimate GFR all depend on steady-state conditions
If serum creatinine and GFR are unstable, these equations
(Cockroft-Gault, MDRD) are invalid
Serial plasma creatinine elevations of 0.5-1mg/dl/day signify the
absence of significant GFR (Moran SM, et al: Kidney Int 1985)
Creatinine clearance (24-hour collection) overestimates GFR
because of tubular secretion, increasingly inaccurate with
declining GFR in chronic glomerular disease (Shemesh O, et al:
Kidney International 1985;28:830-838)

24 hour Creatinine
Excretion (mg/day)

Creatinine Excretion (mg/d)

2000

1600

1200

800

400

Creatinine Excretion (mg/kg/d)

Excretion (mg/kg)

Relationship of
Age and
Sex to Creatinine
Excretion

Men (n=149)
0 |

24 hour Creatinine

Women (n=219)
|

25

20

15

10

Men (n=149)
0 | | | | | | | |
25 35 45 55 65 75 85 95

Age (y)

Women (n=219)

25 35 45 55 65 75 85 95

Age (y)

Kasiske &
Keane,
In: Brenner
& Rector,
1996

Non-Linear SCr-GFR relationship in CKD

20

16

8.0

4.0
2.0
1.0

NEPHRON LOSS
LOSS OF
62,500 125,000250,000 NEPHRONS

LOSS OF 1,000,000 NEPHRONS

25

12.5

LOSS OF 500,000 NEPHRONS

1.56
3.135
6.25

SERUM CREATININE (mg/dL)

Serum
Creatinine
(mg%)

50

100

Rudnick, et al, In: Brenner & Lazarus, 1988

Creatinine Clearance versus GFR (inulin CL)

in Chronic Glomerular Disease

Shemesh O, et al: Kidney International 1985;28:830-838

Creatinine CL (A) & Urea CL (B) vs. GFR

Creatinine CL (ml/min/1.73m2)
A

Urea CL (ml/min/1.73m2)
B

210

210

210

210

180

180

180

180

150

150

150

150

120

120

120

120

90

90

90

90

60

60

60

60

30

30

30

30

30

60

90

120 150 180 210

2m
GFR,mL/min per 1.73

30

60 90 120 150 180 210

2m
GFR,mL/min per 1.73

Levey, et al., Ann Int Med 1999;130:461-70

Mean of Creatinine CL & Urea CL vs GFR

210

Mean of Creatinine CL
& Urea CL (ml/min/1.73m2)

210

180

180

150

150

120

120

90

90

60

60

30

30

30

60

90

120

150

180

210

GFR, mL/min per 1.73 m2

Levey, et al., Ann Int Med 1999;130:461-70

R2=86.6%

180
150
120
90
60
30
0

30

60

90

120 150 180

GFR, mL/min/1.73 m2

GFR Predicted by Using Equation 7,

mL/min/1.73 m2

Creatinine Clearance, mL/min/1.73 m2

24-Hour Creatinine
Clearance
210

MDRD Study
Equation

180

R2=90.3%
No bias
150 Better precision
120
90
60
30
0

30 60
90 120 150
GFR, mL/min/1.73 m2

180

Levey, et al., Ann Int Med 1999;130:461-70

GFR Estimation
Abbreviated MDRD Study equation:
GFR (ml/min/1.73m2) =
186 x (SCr)-1.154 x (Age)-0.203 x (0.742 if
female) x (1.21if black)

Stage
1
2
3
4
5

Stages of
Chronic Kidney Disease
Description

GFR
2
(m L/m in/1.73 m )

Kidney Dam age with

Norm al or G FR
Kidney Dam age with Mild
GFR
Moderate G FR
Severe GFR
Kidney Failure

> 90
60-89
30-59
15-29
<15 or
Dialysis

Choice of Radiocontrast Agent

Na-Diatrizoate

Ionic Monomer

Iohexol

Nonionic Monomer

Iodixanol
Nonionic Dimer

Sandler NEJM 2003;348:551

C1

Types of Radiocontrast Agents

Osmolality
(mosm/kg)

Examples

First Generation
Ionic Monomers

High Osmolality
1500- 1800

Renografin, Hypaque

Second Generation
Non-Ionic Monomers

Low Osmolality
600-850

Iohexol,
Iopamidol

Iso-Osmolal
290

Iodixanol

Class

Newest Generation
Non-Ionic Dimers

Slide 42
C1

Carmella Blankstein, 10/10/2004

Nephrotoxicity in High-Risk Patients Study of Iso-Osmolar

and Low-Osmolar Non-Ionic Contrast Media
Background: Prior investigations comparing iodixanol and
low-osmolar contrast in low-risk, nondiabetic patients found
no difference in incidence of CIN.
Design: Prospective, randomized, double-blind, multi-center
study to compare nephrotoxic effects of iohexol vs. iodixanol
in patients with diabetes undergoing coronary or aortofemoral angiography.
9 Inclusion: DM (type 1 or 2) and Cr 1.5-3.5 (M) and 1.3-3.5 (F)
9 Exclusion: Severe concomitant disease, HD, Renal Transplant
Aspelin P, et al: NEJM 2003; 348:491-499

Aspelin P, et al: NEJM 2003; 348:491-499

Aspelin P, et al: NEJM 2003; 348:491-499

Aspelin P, et al: NEJM 2003; 348:491-499

Radiocontrast Nephropathy Prophylaxis

Fluids
Diuretics
Vasodilators
Antioxidants
Prophylactic renal replacement therapy

Comparative Efficacy of Saline, Mannitol and

Furosemide in RCN Prophylaxis

R. Solomon, et al: NEJM 1994

Mueller C, et al: Arch Int Med 162:329-36, 2002

Mueller C, et al: Arch Int Med 162:329-36, 2002

Mueller C, et al: Arch Int Med 162:329-36, 2002

Oral vs. Intravenous (0.45%) Pre-Hydration

36 patient RCT
Serum Creatinine 1.4mg/dl
(mean ~1.75mg/dl)
0.45% saline 75ml/hr for 12
hrs pre-and post-cath vs.
outpatient 1liter clear liquids
po over 10hr pre- & 0.45%
saline 300ml/hr for 6hrs
during/after cath.
Max. creatinine 0.210.38
(inpatient) vs. 0.120.23
(outpatient), p = NS
Taylor A, et al: Chest
1998;114:1570-74

Oral vs. Intravenous (0.9%) Pre-Hydration

53 patient RCT
Serum creatinine ~1.2mg/dl
(80ml/min)
Group 1 (0.9% saline 1ml/kg/hr
for 24hrs, beginning 12 hours
pre-cath) vs. Group 2
(unrestricted oral fluids)
RCN rate:
Grp 1: 1/27 (3.7%) vs. Grp 2: 9/26
(34.6%), p = 0.005
Trivedi H, et al: Nephron
2003;93:c29-c34

p = 0.02

p = 0.17

Prevention of Contrast - Induced Nephropathy

With Sodium Bicarbonate
Design:
A prospective, single-center, randomized trial in 119 patients
from 2002-2003.
Participants:
Patients with stable Cr 1.1mg/dl scheduled to
undergo either cardiac cath / IR procedure / CT
Intervention:
9154 mEq/L of either NaCl or Bicarbonate.
9 Bolus 3 mL/kg X 1 hr before iopamidol contrast then 1
mL/kg/hr during procedure and 6 hrs after.
Merten GJ, et al: JAMA 2004;291:2328-34

Prevention of Contrast - Induced Nephropathy

With Sodium Bicarbonate

Merten GJ, et al: JAMA 2004;291:2328-34

Prevention of Contrast - Induced Nephropathy

With Sodium Bicarbonate
Study Termination:
Midway through accumulation of patients, study
halted because of ethical concern about continuing
to expose the control group to the substantially
higher risk of contrast nephropathy.

Merten GJ, et al: JAMA 2004;291:2328-34

Prevention of Contrast - Induced Nephropathy

With Sodium Bicarbonate

Results:
(P = 0.02)

NaCl

Bicarbonate

Mean
Difference

Incidence of
nephropathy (No.

13.6 %

1.7 %

11.9 %

(8)

(1)

(CI = 2.9 21.2)

of pts)

Merten GJ, et al: JAMA 2004;291:2328-34

Prevention of Contrast - Induced Nephropathy

With Sodium Bicarbonate
Registry Phase:
191 patients with baseline Cr = 1.7mg/dl
Mean change in Cr = 0 %
CIN in 3 of 191 patients. (1.6%)

Merten GJ, et al: JAMA 2004;291:2328-34

Leon I. Goldberg, M.D., Ph.D.

(1927-1989)

(n = 15)
(n = 15)

Weisberg et.al., Renal Failure, 1993

Dopaminergic Agonists

Dopamine

Murphy MB et al: NEJM 2001; 345: 1548-56

Pilot Study of Fenoldopam Mesylate in Radiocontrast

Nephropathy: Incidence of RCN at 48 Hours

Tumlin J, et al: Am
Heart J 2002;143:894903

CONTRAST Trial: Algorithm

315 patients at 28 U.S. centers
cardiac procedures with calculated CrCl <60 ml/min

Hydrate
Randomize

Stratify by
diabetes

Fenoldopam
Fenoldopam

0.45 NS
1.5 cc/kg/hr
X 2-12 hrs

Matching
Matching placebo
placebo

0.05 ug/kg/min titrated to 0.10 ug/kg/min,

starting 1 before cath and continuing for 12 after

Primary endpoint: RCN (SCr increase 25%) within 24-96 hrs

Stone GW, et al: JAMA 2003;290:2284-91

CONTRAST Trial: Incidence of RCN

50%

P=0.54
40%

33.6%

P=0.42
30.1%

30%

28.5%
24.0%

P=0.27
0.32
0.26

20%
10%
0%
SCr increase
by > 25%

SCr increase
by > 50%

Mean Delta SCr

Stone GA, et al: JAMA 2003;290:2284-91

N-Acetylcysteine (NAC) Protocol

Tepel M, et al: NEJM 343:180-4, 2000

Randomized
All received 0.45% saline 1ml/kg/hr 12 hours preand post-contrast for CT
All received 75ml iopromide (Ultravist-300:
nonionic, low osmolality)
Placebo-controlled
N-acetylcysteine 600mg po bid for two days,
before & after contrast.

Effects on Renal Function

Tepel, NEJM 2000

Variable

Acetylcysteine Control
(n=41)
(n=42)

P Value

Baseline SCr
(mg/dl)

2.5 1.3

2.4 1.3

0.55

48hr SCr
(mg/dl)

-0.4 0.4

+0.2 0.6

< 0.001

ARF # (%)

1 (17)

9 (21)

0.01

Acetylcysteine for prevention of contrast

nephropathy: meta-analysis

(Birck et al., Lancet 2003)

GFR-independent effects of NAC on Serum

Creatinine Concentration
Are there effects of NAC on serum creatinine that are
independent of GFR ?
Protocol: 50 healthy volunteers with normal renal function
administered NAC 600mg po bid
Serum Cystatin C used as alternate marker of GFR
9 Cystatin C is a 13 kDa basic protein; a cysteine protease inhibitor,
produced at a constant rate by nucleated cells
9Completely cleared by unrestricted glomerular filtration, proximal
tubular reabsorption, and catabolism
9 Concentration independent of age, gender, and muscle mass.
Hoffman U, et al: J Am Soc Nephrol 2004;15:407-410

GFR-independent effects of NAC on Serum

Creatinine Concentration
eGFR

Serum Creatinine

Serum Cystatin C

Hoffman U, et al: J Am Soc Nephrol 2004;15:407-410

Effect of NAC on CPK Activity

Molecular and Cellular Biochemistry 2000;210:23-28

Prophylactic Hemodialysis
Post-contrast HD:

Simultaneous HD:

ARF 16 vs 24%; Week 1 HD 5 vs 15%

17 patients with SCr 3mg/dl

undergoing coronary angiography
RCT, 4 hours HD (+ saline) vs.
control (saline alone)
Radiocontrast clearance augmented
in HD grp (n = 7) vs control (n =
10)
No effect on creatinine clearance at
1 and 8 weeks, c/w baseline
2 patients per group started HD in
8 weeks
Frank H, et al: Clin Nephrol
2003;60:176

HD grp; n = 44

Non-HD grp; n = 50

HD grp; n = 24

Non-HD grp; n = 25

Vogt et al: Am J Med 2001;111:692

Hemofiltration

Access
Return
Replacement

CVVH
Continuous
Veno-Venous
Hemofiltration
Effluent

The Prevention of Radiocontrast-Agent-Induced

Nephropathy by Hemofiltration
Participants: 114 patients with CRI scheduled to
undergo coronary angiography or elective PCI.
9 Inclusion: Cr 2 or CrCl 50
9 Exclusion: ACS, Cardiogenic shock, Overt
CHF, Chronic Dialysis.
Marenzi G, et al: NEJM 2003;349:1333-40

The Prevention of Radiocontrast-Agent-Induced

Nephropathy by Hemofiltration
Study Desing:

Randomize

Hemofiltration
Hemofiltration
9Setting: ICU
9 CVVH via Femoral Vein
Start: 4-6 hrs pre procedure
Finish: 18-24 hrs post procedure
9 Used isotonic replacement
fluid at rate of 1000 ml / hour with an
equal ultrafiltrate rate
9 Heparin 5,000 U bolus

IV
IV Hydration
Hydration
9Setting: Step-down unit
9 IV Normal Saline @ 1mL/kg/hr
Start: 6-8 hrs pre procedure
Finish: 24 hrs post procedure

Marenzi G, et al: NEJM 2003;349:1333-40

The Prevention of Radiocontrast-Agent-Induced

Nephropathy by Hemofiltration

Marenzi G, et al: NEJM

2003;349:1333-40

The Prevention of Radiocontrast-Agent-Induced

Nephropathy by Hemofiltration

Results:
Hemofiltration

Hydration

CIN
(p<0.001

5%

50%

RRT

3%

25%

In-hospital
mortallity
(p=0.02)

2%

14%

10%

30%

One year
mortality
(p=0.01)

Marenzi G, et al: NEJM 2003;349:1333-40

The Prevention of Radiocontrast-Agent-Induced

Nephropathy by Hemofiltration
Limitations:
Flawed primary endpoint: HF lowers serum creatinine
independent of native renal function, radiocontrast effect
Different level of care for each group
ICU vs. floor
Heparin vs. No Heparin
Mechanism of benefit unclear: ? bicarbonate
High cost
Marenzi G, et al: NEJM 2003;349:1333-40

Radiocontrast Nephropathy Prevention

Estimate GFR
ARF: ? reversible
CRI: stratify risk, counselling, prophylaxis

Consider alternatives
Eg. MRA with gadolinium contrast

Adjust Medications

Stop NSAIDs
Hold diuretics
Consider holding ACE inhibitors or ARBs if for HTN, CKD, not CHF? (opinion)
Hold metformin

Radiocontrast selection
Smallest volume of nonionic, isoosmolar dye preferred for high risk patients

Volume expansion
Normal saline 1ml/kg/hour for 12 hours before and 12 hours after dye
Oral volume expansion prior if same-day/outpatient
Sodium bicarbonate 150mEq/l is preferred same-day therapy: 3ml/kg over 1 hour, then
1ml/kg/hr during and for 6 hours after procedure [CAVEAT: hypokalemia]

Consider N-acetyl cysteine (600mg po bid pre- and post-dye; IV option also)
No proven role for prophylactic renal replacement therapy, vasodilators

Case #2: Does this Patient Need Dialysis?

Case Presentation #2
43 yo white female, transferred from a community
hospital following 2 week hospitalization with
bacteremic pneumococcal pneumonia, progressing to
septic shock, ARDS, acute hypoxemic respiratory
failure
Previously healthy, no medications apart from oral
contraceptive, family history of fatal post-partum TTP
in sister
Right ventricular mass noted on echocardiogram,
systemic heparin initiated, transferred to UofC for
further evaluation and surgery
Helical CT and repeat echo obtained
Renal Consult for oliguric ARF

Examination

70kg woman
Temp 36.9
P 102 ST
BP 100/60, on NE infusion
CVP 22
ScvO2 70%
UOP 10ml/hour
IVF 40ml/hour Lasix 20mg/hour
Vent: A/C 60% O2, 10 PEEP, VT 400ml, RR 36, Ppeak 39,
Pplat 20
ABG 7.39 / 52 / 62 / 31, 91%
Extremities: warm, brisk capillary refill, minimal edema
Cor- loud P2; Lungs- bilateral rales; no other remarkable
findings
CXR: bilateral diffuse alveolar infiltrates
CT: multiple pulmonary emboli, diffuse consolidation

How bad is the renal dysfunction?

Urine output: what is adequate?......

..to maintain Fluid balance?
Oliguria may be appropriate in patients with hypovolemia
and prerenal azotemia
Adequate volume expansion reverses oliguria
Oliguria is maladaptive in patients with congestive heart
failure, cirrhosis, and acute tubular necrosis
Positive fluid balance causes volume overload
Diuretics dont increase renal blood flow, GFR, or nonelectrolyte solute excretion
Only electrolytes and associated water are excreted in the
extra urine output (UOP)
Diuretics can prevent volume overload in ARF, but not
nitrogenous waste accumulation (azotemia), and may be
associated with worse outcome (Mehta, JAMA Nov 2002)

Urine output: what is adequate?......

..to maintain Solute Excretion?
Traditional oliguria definition of 400ml/day assumes
maximal urine concentrating ability (1200mOsm/kg), and
solute production of 480mOsm/day (6mOsm/kg, in an 80kg
patient)
This corresponds to UOP of only 16ml/hour ( 0.2ml/kg/hour)
This UOP is clearly inadequate to maintain fluid balance in
the face of large obligate intakes in ICU patients
This UOP is also inadequate for solute clearance in those
with submaximal urinary concentrating ability (age, renal
disease), increased solute production/appearance
(hypercatabolism, parenteral nutrition), or both

RIFLE Criteria for Acute Renal Dysfunction

GFR Criteria*
Increase creat x1.5 or GFR
decrease > 25%

Risk

Increase creat x2
or GFR decrease
>50%

Injury

Increase creat x3
or GFR decrease
> 75%

Failure

Urine Output Criteria

UO < .5ml/kg/h
x 6 hr
UO < .5ml/kg/h
x 12 hr
UO < .3ml/kg/h
x 24 hr or
Anuria x 12 hrs

Persistent ARF = RRT > 4 weeks

Loss

High
Sensitivity

High
Specificity
* Abrupt (1-7 days)
Sustained (>24 hrs)

ESRD

End Stage Renal Disease * *

Kellum JA, et al: Curr Opin in Crit Care 2003;8:509-14

** RRT > 3months

www.ADQI.net

GFR assessment
Estimation by serum markers
Plasma creatinine
Plasma urea nitrogen
Plasma cystatin C

Estimation by clearance measurements

Endogenous markers
Creatinine clearance, Urea clearance, Combination techniques

Exogenous markers
Aminoglycoside clearance (clinical use)
Hot radionuclides
Cold radiocontrast agents

GFR, ml/min

120

Surgery, MI, Moran

sepsis
SM, Myers BD: Kidney International
1985;27:928-37

100

GFR
(ml/min) 80

Reversal of ischemia

60
40
20

Creatinine, mg%

Serum
Creatinine
(mg%)

0
7
6
5
4
3
2
1
0

14

21

28

Time, days

Abbreviated Creatinine Clearance

Good correlation (r = 0.95) between 2-hour and 22hour creatinine clearance in ICU patients
Sladen RN, et al: Anesthesiology 1987;67:1013-6

Good correlation between repeated 2-hour creatinine

clearances in ICU patients
Mean difference 0.8ml/min
Herget-Rosenthal S, et al: Clin Nephrol 1999;51:348-54

Acute GFR changes are detectable by 4-hour

creatinine clearances
Patel BM, et al: Anesthesiology 2002;96:576-82

Is the ARF Acutely Reversible?

Thadhani R, et al: NEJM 334:1448-60, 1996

Synergy & ATN Pathogenesis

Renal hypoperfusion/
ischemia

Fever

SEPSIS

Endotoxemia

Aminoglycosides
R. Zager, Am J Kid Dis 1992

Pharmacologic Approach to
Optimization of Renal Perfusion
1) MAP: fluids, inotropes, pressors targeting MAP 6080mmHg
2) CO: fluids, inotropes to achieve adequate cardiac
output
3) Renovascular resistance: renal vasodilators
4) Corticomedullary blood flow distribution: renal
vasodilators
5) Renal tubular oxygen consumption: diuretics
(furosemide, mannitol)

ARF DDX: Prenal Azotemia vs ATN

Param eter
B U N /C r ratio
U rine Sp. G rv.
U rine [N a]
U rine O sm
FEN a
U /P C reat
U /P O sm
Sedim ent

Prerenal
>20
>1.018
<20 m Eq/L
>500 m O sm /kg
<1%
>40
>1.5
H yaline, rare
gran casts

A TN
<10-15
<1.012
>40
<350
>1-3%
<20
1.0
R TC , m any
gran casts

ARF & Fractional Excretion of Urea (FEUN)

FEUrea (%) =

Uurea x Pcr x 100

Purea x Ucr
Normal, well-hydrated value: 50-65%
In ARF:
<35% suggests prerenal azotemia
>50% suggests ATN or other intrinsic renal disease
Valid even with diuretics (unlike high FENa)

Carvounis CP, et al: Kidney Int 2002;62:2223-29

PR

ATN

PR-D
ATN

PR-D
PR

ATN
PR

PR-D

PR
PR-D
ATN

Carvounis CP, et al: Kidney Int 2002;62:2223-29

Sensitivity: FENa (<1%) vs FEUN (<35%) vs U/PCr (>20)

Carvounis CP, et al: Kidney Int 2002;62:2223-29

Test performance: ROC curves

U/PCr

FEUN
FENa

FENa

Carvounis CP, et al: Kidney Int 2002;62:2223-29

Renal Tubular KIM-1: ATN vs Normal

NORMAL

ATN

Han WK, et al: Kidney International 2002; 62:237-44

Urinary KIM-1: ATN & other Renal Diseases

Han WK, et al: Kidney International

2002; 62:237-44

Assessing Renal Function in the Hospital

Real-time markers of renal blood flow, GFR, and injury are
not yet clinically available in the ICU
Monitoring of renal perfusion and function in ICU should
combine clinical assessment of several indices:
Urine output and fluid balance
GFR estimates
Blood markers (creatinine, urea, cystatin C, aminoglycosides)
Changes in plasma cystatin C are probably more sensitive than other
serum markers to detect acute renal dysfunction
Abbreviated urinary clearance measurements (creatinine, urea)
Tubular function indices (urine chemistries)
FEUN improves assessment of tubular function is diuretic-treated ARF
patients
Tubular injury indices (urine sediment microscopy, emerging markers)
Other plasma electrolytes which become dysregulated in the presence of renal
dysfunction (particularly potassium, phosphate, bicarbonate)

Dynamic changes in these parameters should be used to assess

effects of events or interventions on renal perfusion and function

Case #2: Laboratory Data

Transthoracic contrast echocardiogram:
Large multilobulated mass in the RV apex
Severely dilated RV, severely decreased performance, septal
flattening
Severe tricuspid regurgitation
No valvular vegetations or interatrial shunting. Severe tricuspid
regurgitation was also noted.
Na 134 / K 5 / Cl 101 / HCO3 13 / BUN 60 (52 prev. day) / Cr 3 (2.6
prev. day) / FENa 2% / FEUN 48% / U:P creatinine ratio 6:1
Glucose 104 / AG 20 / Ca 7.2 / PO4 5.9 / Mg 1.9
WBC 37.2 / Hct 31 / Plts 435K
PTT 70 / Albumin 2.3 / amylase 468 / lipase 398
TBili 0.7 / AlkP 107 / AST 919 / ALT 526 / CPK 79
U/S: normal kidneys, biliary tree, liver

ARF Interventions: Whats Available?

Phase: primary prevention (prophylaxis) vs secondary
prevention (therapy)
Etiology: ischemic vs. nephrotoxic vs. mixed
Setting: ICU vs. Perioperative vs. Radiocontrast vs.
Other (Renal transplant, Cirrhosis, Nephrotoxinsendogenous or exogenous)
Mechanism: perfusion vs. cytoprotection vs.
regeneration vs. other

Phases of Ischemic ARF

Molitoris BA: J Am Soc Nephrol 2003;14:265-267

Pharmacologic Approach to Optimization

of Renal Perfusion
1) MAP: fluids, inotropes, pressors targeting
MAP 60-80mmHg
2) CO: fluids, inotropes, vasodilators to achieve
adequate cardiac output
3) Renovascular resistance: renal vasodilators
4) Corticomedullary blood flow distribution: renal
vasodilators
5) Renal tubular oxygen consumption: diuretics
(other effects: loop diuretics, mannitol)

Acute Right Heart Syndromes

Acute pressure overload
PE (thrombus, air, fat, amniotic, tumor)
ARDS
Post-cardiac surgery

Acute-on-chronic pulmonary hypertension

Chronic pulmonary diseases

Chronic thromboembolism
Primary pulmonary hypertension
Sleep-disordered breathing

RV systolic dysfunction
RV infarction

Acute Right Heart Syndromes

Schmidt GA, Wood LDH, Principles of Critical Care 1998

Acute RV Failure Management

1. Preserve Systemic Blood Pressure
Vasopressors
Inotropes

2. Optimize RV Preload
CRRT > IHD

3. Reduce RV Afterload
High FIO2
Pulmonary Vasodilators

4. Specific Therapies
Thrombolysis for P.E.
Mechanical support (RVAD) for failing ventricle

ARF Prevention: Fluids

Effect of Fluids for ARF Prevention
Radiocontrast nephropathy: 0.45% saline
Solomon R, et al: NEJM 1994;331:1414-1416

Higher PAP improved early renal allograft function

Carlier M, et al: Transplantation 1982;34:201-204

Gelatin-based colloid not hetastarch prevents * septic ARF

Schortgen F, et al: Lancet 357:911-16, 2001

Albumin prevents ARF in cirrhotics with SBP

Sort P, et al: NEJM 341:403-9, 1999

No difference in RRT Days (0.52.3 vs 0.42), new organ

dysfunction, survival with saline vs albumin in 6997 pts
SAFE Study Investigators: NEJM 2004;350:2247-56

FACTT Trial
ARDSNetwork trial
Fluids and Catheters Treatment Trial
2 X 2 factorial design in Acute Lung Injury patients
CVC vs PAC
Fluid Conservative vs Fluid Liberal
CVP <4, PAOP <8 vs CVP 10-14, PAOP 14-18
Approx. 90% to 1,000 patient enrollment
Endpoints: 28 day survival, ventilator-free days, etc

ARF Prevention/Therapy: Inotropes

Late Goal-Directed Therapy
No difference in mortality or renal function (creatinine, urine output)
with either supranormal CO/DO2 or maintenance of SVO2 70% with
dobutamine versus control in 762 ICU patients
Gattinoni L, et al: NEJM 1995;333:1025-32

Increased mortality with supranormal oxygen delivery (dobutamine)

versus control in 100 ICU patients (54% vs 34% mortality)
Hayes MA, et al: NEJM 1994;330:1717-22

Early Goal-Directed Therapy

Improved survival in septic shock pts. randomized to E.R. resuscitation
titrated to normalize SCVO2 (70%, using dobutamine, transfusion) vs
standard care (CVP >8-12; MAP>65mmHg; UOP >0.5ml/kg/hr)
Rivers E, et al: NEJM 345:1368-77, 2001

Rivers E, et al:
NEJM 345:1368-77, 2001

Flow rate (L / min)

Normal Autoregulation
RBF
1.0

0.1

GFR
0

100
MAP (mm Hg)

200

Renal Effects of NE in Human Septic Shock

No adequate clinical trials
Increase UOP with BP increase after replacing
dopamine
[Martin C:Chest;1993;103:1826-31; Desjars
P:CCM:1987;15:134-7]

Increased UOP (23ml/hr to 66ml/hr) and CrCl

(29ml/min to 71ml/min) after 24 hours NE therapy
[Desjars P: CCM 1989;17:426-29]

Increased CrCl (75ml/min baseline, 89ml/min 24hrs,

102ml/min 48hrs)
[Redl-Wenzl, Int Care Med 1993;19:151-4]

Pressor effect of NE vs Dopamine

P aram eter N E
B aselin e

N E E ffect
a

MAP
(m m H g )

5410

8913

CI
2
(L /m /m )

5 .3 1 .3

5 .5 1 .2

SVRI
659221
(d y n .sec/
5
2
cm .m )
UOP
227
(m l/h o u r)
L actate
4 .8 1 .6
(m m o l/L )

1150350
15351
4 .4 1 .8

538

DOPA +
DOPA
2 5 g /k g / N E
m in
a
5910
888

5 .4 1 .1

5 .5 1 .0

647197

659217 1092337

246

8 .2 1 0

106100

4 .8 3 .2

4 .2 2 .0

3 .8 2 .0

DOPA
B aselin e

5 .9 1 .6

M a rtin et a l: C h e st 1 9 9 3 ;1 0 3 :1 8 2 6 -3 1

Patel BM, et al: Anesthesiology 2002;96:576-82

Patel BM, et al: Anesthesiology 2002;96:576-82

Patel, BM, et al: Anesthesiology 2002;96:576-82

ARF Prevention/Therapy: Vasodilators

Renal vasodilators have no proven benefit in ARF
Dopamine
Dopamine has not been proven to prevent or ameliorate ARF in any
setting
Kellum, JA & M. Decker J: Crit Care Med 29:1526-1531, 2001
ANZICS Group: Lancet 2000; 356: 2139-43

ANP
Large trials failed to demonstrate a benefit of ANP for..
RCN prophylaxis
Kurnik BR, et al: Am J Kid Dis 1998;31:674-80

ATN therapy
Allgren RL, et al: NEJM 1997;336:828-34
Lewis J, et al: Am J Kid Dis 2000;36:767-74

Kellum, JA & M. Decker J: Crit Care Med 2001;29:1526-1531

ANZICS Trial of Low-Dose Dopamine in ICU

Patients with Early Renal Dysfunction (Lancet, 12/00)
328 patient trial in 23 Australian and New Zealand
intensive care units
Randomized, double-blind, placebo-controlled trial
ICU patients with SIRS (systemic inflammatory
response syndrome) and acute renal dysfunction
Dopamine 2g/kg/min versus placebo infusion until:
1) RRT; 2) Death; 3) SAE judged related to trial
infusion; 4) SIRS and renal dysfunction resolved for
24 hrs; 5) ICU discharge

ANZICS Dopamine Trial Design

(ANZICS Trial, Lancet 2000)

Primary outcome: peak serum creatinine reached

during trial infusion
13 Secondary outcomes: to be discussed
Initial sample size of 115 per group for 80% power to
detect 20% decrease in peak SCr with dopamine
(=0.05)
Based on pretrial 6 center observational study

Two blinded interim analyses increased size to >300

patients for 90% power to detect a 25% difference in
peak SCr

Baseline Characteristics (ANZICS Trial, Lancet 2000)

Characteristic

Dopamine (n=161)

Placebo (n=163)

Age (yrs)

63 15

61 17

APACHE II

21 6

21 8

MAP (mmHg)

80 15

80 16

CVP (mmHg)

14 8

13 7

Shock

58 %

63 %

Mech. Ventilation

86 %

86 %

Oliguria

68 %

69 %

S.Cr (mg/dl)

2.07 0.96

2.06 0.92

S. Urea (mg/dl)

40 21

40.34 19.89

ANZICS Group, Lancet, Dec 2000

Urine Output (ml/hr)

250
200
150
100
50
0

DP

PL

B as elin e

DP

PL

>1hr

DP

PL

>24hr

DP

PL

>48hr

ANZICS Group: Lancet 2000; 356: 2139-43

ANZICS Group: Lancet 2000; 356: 2139-43

Blood Flow and Interstitial O2 Content: Regional

Distribution in Cortex/Medulla
4.2 ml/
gm/min

1.9 ml/
gm/min

PaO2
+ 50

PaO2
10-20

Brezis M, Rosen S: N Engl J Med 1995;332:647-655

ARF Prevention/Therapy: Vasodilators

Fenoldopam
DA-1-specific dopaminergic agonist
Small pilot trials suggested that fenoldopam improves RBF +/or GFR
during and after.
CABG: Halpenny M, et al: Anaesthesia 2001;56:953-60
AAA repair: Halpenny M, et al: Eur J Anaesthesiol 2002;19:32-9
Radiocontrast: Tumlin JA, et al: Am Heart J 2002;143:894-903

The CONTRAST trial in 315 patients found no effect of fenoldopam

vs placebo for RCN prevention
Stone GA, et al: JAMA 2003;290:2284-91

In another pilot study, Tumlin and colleagues found a 10% absolute

increase in dialysis-free survival (63% vs 73%, p=0.22) in 155
patients with early ARF in the ICU, treated with fenoldopam vs
placebo
ASN abstract, 2003; Am J Kidney Disease, in press 2005.

ANP for post-cardiac surgery ARF

Sward K, et al: Crit Care Med 2004 32:1310-5

ANP for post-cardiac surgery ARF

Sward K, et al: Crit Care Med 2004 32:1310-5

ARF Prevention/Therapy: Diuretics

Loop Diuretics
Prophylactic furosemide infusion increases rate of ARF after CABG
(Lassnigg, JASN), or radiocontrast (Solomon, NEJM; Weinstein,
Nephron)
Small trials have failed to demonstrate a benefit of loop diuretics for
ARF prevention or therapy

Mannitol
Mannitol does not prevent perioperative ARF, except before renal
transplant reperfusion
Van Valenberg PL, et al: Transplantation 1987;44:784-88
Weimar W, et al: Transplantation 1983;35:99-101

Increased RCN rate c/w 0.45% saline alone (Solomon)

Common use in myoglobinuria not based on RCT data

Comparative Efficacy of Saline, Mannitol and

Furosemide in RCN Prophylaxis

R. Solomon, et al: NEJM 1994

A Lassnigg, et al: JASN 11: 97-104, 2000

Diuretic Cocktail for post-cardiac surg. ARF

Sirivella, et al: Ann Thorac Surg 69:501-6

ICU/Perioperative ARF Prevention

Nephrotoxins/Insults
Endogenous
Rhabdomyolysis, Tumor lysis, Sepsis
Mechanical ventilation: lung-protective ventilation is also
renoprotective
ARDSNet: NEJM 2000;342:1301-08
Ranieri VM, et al: JAMA 2000;284:43-44

Glycemic control: decreased ARF and RRT with tight control

Van Den Berghe G, et al: NEJM 2001;345:1359-1367
Krinsley JS: Mayo Clinic Proc 2004;79:992-1000

Exogenous
Aminoglycosides: daily dosing
Amphotericin: liposomal
Chemotherapies, Radiocontrast, NSAIDs

Kidney-Lung Protective Ventilation?

ARDSNET Tidal Volume Trial
In addition to improved survival and ventilator-free days,
low VT group had more days without circulatory,
coagulation, and renal failure (renal: 2011 vs. 1811 days,
p=0.005)
ARDSNet: NEJM 2000;342:1301-08

Lung-Protective Mechanical Ventilation Strategy

Less inflammation in Lung Protective Strategy group
Ranieri VM, et al: JAMA 1999;282:54-61

Fewer pts. with organ system failure, and markedly fewer

with renal failure (p<0.04) at 72 hours in Lung Protective
Strategy group
Ranieri VM, et al: JAMA 2000;284:43-44

Kidney Protective Ventilation?

Ranieri VM, et al: JAMA 2000;284:43-44

IGF-1 Clinical Studies in ARF

54 patient double-blind RCT of IGF-1 SQ q12h X 72h,
beginning in ICU post-aortic surgery
Fewer patients had post-op decline in renal function within 72 hours
(22% IGF-1 vs 33% placebo, p<0.05)
Franklin S, et al: Am J Physiol 272:F257-259

72 patient multicenter DBRCT of IGF-1 (14 days) for ARF in

ICU patients
Baseline IGF-1 vs Placebo UOP (1.1L vs 1.4L) and GFR (6.4 ml/min
vs 8.7 ml/min) not different
No difference in subsequent UOP, GFR, dialysis (20% vs 17%), or
mortality (29% vs 30%)
Hirschberg R, et al: Kidney Int 55:2423-2432, 1999

64 patient DBRCT of IGF-1 SQ q12h X 6d vs placebo for

CRT recipients with delayed graft function: no difference in
day 7 inulin clearance, dialysis
Hladunewich MA, et al: Kidney Int 2003;593-602

ARF Interventions: Summary

Fluid administration is an accepted approach to prevention and
therapy of ARF, with supportive data in some patient subsets
It is unclear which systemic hemodynamic endpoints and
vasoactive drug strategies should be used to prevent or reverse
ARF
There are no definitive studies supporting the use of renal
vasodilators or diuretics for ARF prophylaxis or therapy
Several evolving aspects of ICU management apparently alter
the risk of ARF (ventilator management, glycemic control)
Cytoprotective, antiinflammatory, regenerative therapies have
not been adequately studied
Combination therapies (eg. vasodilator plus antiinflammatory)
or management protocols (eg. goal-directed therapy of ARF),
are also largely untested

Indications for RRT

Uremia
Encephalopathy
Pericarditis
Bleeding diathesis
Volume Overload
Hyperkalemia
Metabolic Acidosis
Severe
hyperphosphatemia
Intoxications

Prevention of uremic
complications
Prevention of
uncontrolled positive
fluid balance
Non-renal
indications

100% -

100% -

80%

80%

60%

60%

40%

40%

20%

20%

0%

0%

Simple ANP ICU

ARF trial setting

0 1

3 4

Number of failed organs

RA Star, Kidney Int, 1998

Diffusion

Diffusion: The movement of solutes from a higher to a

lower solute concentration area.

Hemodialysis
to waste

Dialysate Out

Dialysate In

Blood In
(from
patient)

Blood Out
(to
patient)

LOW PRESS
LOW CONC

HIGH PRESS
HIGH CONC

% Survival
100
80

HIGH Kt/V urea

60

CCF Score
Outcome

LOW Kt/V urea

40
20
0 |
0

1 2

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
CCF ICU ARF Score

Schiffl H, Lang S, Fischer R: NEJM 346:305-310, 2002

Schiffl H, Lang S, Fischer R: NEJM 346:305-310, 2002

Schiffl H, Lang S, Fischer R: NEJM 346:305-310, 2002

HD Hypotension
Hemodialysis-associated

Hemodialysis-independent

Osmolality
Rapid/excessive solute loss
Low sodium dialysis solution
Cardiovascular Reflexes
Bezold-Jarisch Reflex
Dialysate Temperature
Dialysate Calcium
Vasodilators
NO, Adenosine, Acetate
Membrane Reaction
Rare complications:
Hemolysis, Air Embolism

Hypovolemic: excessive
decreases in blood volume
Non-dialytic volume loss
Rapid or excessive UF
Cardiogenic: cardiac dysfunction
Arrhythmia
Systolic
Diastolic: including ischemia,
LVH, tamponade
Valvular: aortic stenosis
Impaired Vasoconstriction
Autonomic dysfunction,
Sepsis, Anaphylaxis, Meds

Standard Hemodialysis
Intracellular fluid

Extracellular fluid

Step 3
Water movement

Osmolality
320 mosmol/kg

Dialyzer

Step 1

Osmolality
320 mosmol/kg
falling to 290
mosmol/kg as
Step 2
diffusion occurs

Golper, TA 1999

Isosmotic
loss of
solutes
and water

Isolated Ultrafiltration
Intracellular fluid

Extracellular fluid

Step 3
Water movement

Osmolality
320 mosmol/kg

Dialyzer

Step 1

Osmolality
320 mosmol/kg
with rising plasma
oncotic pressure Step 2

Golper, TA 1999

Isosmotic
loss of
solutes
and water

Approach to HD Hypotension
Protocol for standard crystalloid, mannitol, albumin doses
(= empiric fluid challenge)
Vasopressor titration may be anticipated
Consider Hypovolemia
incorrect volume status assessment
consider hemorrhage (GI, retroperitoneal, hemothorax)

Consider Cardiac dysfunction

Arrhythmia / Systolic / Diastolic / Valvular

Consider Sepsis, Anaphylaxis, Addisons

RRT Rx: transfusion, sodium modeling, high calcium
bath, cool dialysate, IUF or sequential IUF-HD, CRRT

Ultrafiltration

Ultrafiltration: The movement of fluid through a membrane

caused by a pressure gradient.

Ultrafiltration
Blood In
(from patient)

Fluid Volume
Reduction
Blood Out
to waste
LOW PRESS

(to patient)
HIGH PRESS

Therapy Options

Access
Return

SCUF
Slow
Continuous
Ultrafiltration

Effluent

Solute Removal by Convection

Convection: The movement of solutes with a water-flow,

solvent-drag, e.g the movement of membrane-permeable
solutes with ultrafiltered water.

Hemofiltration

Blood In
(from patient)

Clearance

Blood Out
to waste
LOW PRESS

(to patient)
HIGH PRESS

Repl.
Solution

Therapy Options

Access
Return
Replacement

CVVH
Continuous
Veno-Venous
Hemofiltration
Effluent

CRRT (vs. IHD) Indications

Vasodilatory Shock
Cardiogenic Shock
Right heart syndromes

ARDS
Fluid balance, Buffering, ? Antiinflammatory therapy

Cerebral Edema
Severe Hyperphosphatemia
Prevention of Post-dialytic Rebound Intoxication
Lithium
Tumor Lysis, Rhabdomyolysis, Tissue Necrosis

Septic Shock ?

HD vs. CRRT: Hemodynamic Stability

HD

20

HD

10

C hange in D O

CAVH
PD

0
-10
-20
-30

D u r atio n o f tr eatm en t (h o u r s)

 M ean IC P %

CRRT: Intracranial Pressure

HD

HD
250

CAVH

200

PD

150
100

M ean C P P %

50
120

100
80
60

D u r a tio n o f tr e a tm e n t (h o u r s )

Phosphate Clearance
2.0
1.8

20

H i g h -fl u x H D (p o l y s u l fo n e )

C A V H D 4 L / h (p o l y a c r i l o n i tr i l e )

P r e -H D

1.4

16

4 h p o s t-H D

1.2
1.0
0.8

N a d i r E n d -H D
0.6

Serum Phosphorus (mg/dl)

Serum Phosphate (mM)

1.6

0.4

12

0.2

C h e m o th e r a p y

0.0

DeS oi & Um ans: AJKD, 1993

16

24

32

40

48

56

64

T i m e (H o u r s )
P i c h e tte e t a l : A J K D , 1 9 9 4

Post-dialysis Rebound
5

H D s ta r t

CAV HDF

Serum Lithium (mEq/L)

Serum Lithium (mEq/L)

H D r e s ta r t

E n d -H D
1

E n d -H D
0

12

18

24

T i m e (h o u r s )

30

36

42

16

24

32

40

T i m e (H o u r s )

48

56

64

Case #2: CRRT Initiation

Femoral dual-lumen 16.5cm catheter

Pre-filter CVVH mode, BFR 250ml/min
UFR 3000ml/hour (~ 42 ml/kg/hour)
No additional anticoagulation (on IV heparin)
Fluid balance: 100ml/hour net fluid removal
Pre-filter Replacement fluid: prepared by Pharmacy from base
NaCl 100mEq/L, KCl 2mEq/L, Na Bicarbonate 50mEq/l,
MgSO4 3mEq/L, dextrose 1g/L
Calcium drip via central vein
50ml of 10% CaCl2 in 100ml NS
Start at 20 ml/hour

Ronco et al, Lancet, July 2000

Ronco et al, Lancet, July 2000

Pulmonary edemagenesis
Alveolus
Pmv
Pisv

mv
is

Alveolus

Edema Flow =[(Pmv-Pis) - (

LVEDP
mv - is) ] Kf

CRRT Fluid Balance Management

CRRT was initiatied to control fluid
balance and azotemia..removing
fluid to achieve the lowest filling
pressures and PEEP compatible with
adequate systemic oxygenation and
perfusion on a non-toxic FIO2 .

2750

Routine
Protocol

EVLW (ml)

2250

*P <0.005 vs time 0

1750
1250
750
250 |
0

*
|

12

24

36

*
|

48

60

72

TIME (hours)
Mitchell, et al., Am Rev Respir Dis 1992

Probability of
Mechanical Ventilation

1.0

Routine (n=42)
Protocol (n=40)

0.8
0.6
0.4
0.2
0.0
|
0

10

20

30

40

Days of Mechanical Ventilation

Mitchell, et al., Am Rev Respir Dis 1992

Probability of being in ICU

1.0

Routine (n=49)
Protocol (n=52)

0.8
0.6
0.4
0.2
0.0
|
0

10

20
30
Days in ICU

40

Mitchell, et al., Am Rev Respir Dis 1992

HD vs. CRRT: Fluid Balance

65
HD
CAVH

B ody w eight (kg)

64
63
62
61
60

12
T im e (h o u r s )

16

20

24

Supportive Therapy Issues in Septic

CRRT Patients
High glucose PD solution
adversely effects glycemic
control
CRRT-induced hypothermia
has mixed effects
Increases SVR and BP
Possible cerebral protection
Masks fever

Van den Berghe G, et al. N Eng J Med 2001;345:1359-1367

Antibiotic clearance by CRRT

(>30ml/min CrCL, higher flux
membranes) differs from,
often exceeds intermittent HD

Calgary Sun Thu July 8, 2004

Alberta's chief adviser on health quality has released new recommendations for
the handling of potassium chloride in hospitals. Dr. John Cowell, CEO of the
Health Quality Council of Alberta released his findings after the deaths of two
patients at the Foothills Medical Centre earlier this year.
"The recommendations released today result from an ongoing review of the best
practices and safety guidelines for the handling of potassium chloride containing
products from five of the leading countries in terms of patient safety initiatives,"
Cowell said.
Among the recommendations, the health regions are being asked to immediately
implement system safeguards as outlined by the the Institute for Safe Medication
Practices' potassium chloride safety recommendations.
The recommendations also say the regions should use commercially premixed dialysis solutions wherever possible.
In instances where they aren't available commercially,the dialysis solutions
must be prepared only in the hospital pharmacy under rigorous quality
assurance conditions.

Calgary Sun Thu July 8, 2004

Calgary Health Region officials declined to comment yesterday, saying they had just
received the report and would comment on it later in the week.
An outside report into the deaths released last week cleared the Calgary Health
Region of any wrongdoing, citing unavoidable human error and listed 66
recommendations which the CHR has vowed to implement.
On March 25, 83-year-old Kathleen Prowse died after being inadvertently injected with
a dialysis mixture containing potassium chloride rather than sodium chloride.
It was later discovered 53-year-old Bart Wassing had died from the same error a
week earlier.
"More remains to be done, and the Council will be promoting the development of
overall guidelines for the reporting, disclosure and review of any medication incident in
Alberta's health system," Cowell said.
The HQCA will issue further recommendations on medication safety practices in the
fall.

Case #2: Subsequent Hospital Course

POD #1: Postoperative pulmonary hypertension and fluid

overload managed with nesiritide, 150-200ml/hour negative
balance, withdrawal of vasopressin
POD #2: Reexplored for Hb drop from 8g/dl to 6g/dl, no
bleeding source found, heparin held
POD #3:
UOP continued 10-15ml/hour
Citrate anticoagulation added on CRRT Day 8
PA catheter and dobutamine discontinued CRRT Day 9
CRRT stopped Day 10, with UOP 15-45/hour, BP 123/70, CVP
7
Next day: UOP 35ml/hour, BUN/Cr 26/1.1
Extubated, transferred to floor, and discharged home during
subsequent week
Last BUN / Creatinine 10 / 0.5

Summary: Approach to ARF

Incidence: at least 10% to 30% in ICU
Mortality: >50% in ICU
Etiology:
Prerenal azotemia > acute tubular necrosis (ATN) >> others in hospitalacquired cases
Acute glomerulonephritis and vasculitides are more common causes of
ARF developing outside the hospital, though still less common than
prerenal, ATN.
Differential diagnosis: based on site of lesion (pre-, intra-, or post-renal).
Prophylaxis and careful monitoring of high-risk patients is important
Care of ARF patients is supportive; the nondialytic measures include
maintenance of nutritional, volume, and electrolyte homeostasis
Emergent RRT: indicated when pulmonary edema, hyperkalemia, refractory
acidosis, or symptomatic uremia develops
Prophylactic RRT: considered with sustained anuria, persistent oliguria
with progressive azotemia and GFR <10ml/min, and to prevent
uncontrolled positive fluid balance