1. Acute Renal Failure James Paparello, MD
Division of Nephrology & Hypertension
Northwestern University

2. Goals: I. Briefly Review Acute Renal Failure
New Definitions
II. Interpret Data regarding the questions:
What is the work up for new acute renal failure in a hospitalized patient
What is appropriate follow up ?
Who is at risk for contrast induced nephropathy
Can it be prevented ?
What commonly used drugs in renal-impaired hospitalized patients need to be dose adjusted ?

3. I. Definitions and Physiology 101

4. Creatinine Released at steady rate from muscle, filtered by kidney
In steady state, allows tracking of kidney function in individual
Needs to be converted to GFR via formula (Cockcroft-Gault, MDRD)

5. Calculation of GFR
Direct measurement of 24 hour urine creatinine clearance (cumbersome, inaccurate)
Cockcroft-Gault Creatinine Clearance
Men: (140-age) * wt(kg) / 72 * SCr
Women: 0.85* [(140-age) * wt(kg) / 72 * SCr]
MDRD GFR Formula*:
170 x [SCr] x [Age] x [0.762 if female] x [1.180 if black] x [Alb]+0.318
*From Levey et al, 1999,Ann Intern Med 130:

6. Stages of Chronic Kidney Disease
Like heart failure
Stage 1: GFR >= 90 ml/min, proteinuria
Stage 2: GFR between 60 and 89 ml/min
Stage 3: GFR between 30 and 59 ml/min
Stage 4: GFR between 15 and 29 ml/min
Stage 5: GFR less than 15 ml/min

7. Why GFR ?
More accurate representation of renal function than serum creatinine, which can be misleading.
31 yo AA male in the office for life insurance physical:
BUN: 18 Cr: 1.1 Alb: 4.0 GFR: 95 cc/min
80 yo Caucasian woman in nursing home:
BUN: 18 Cr: 1.1 Alb: 4.0 GFR: 51 cc/min

8. Importance of the Steady State
Creatinine GFR= 0
Days
Total
Nephrectomy

9. Acute Renal Failure (ARF)
Definition may depend on whom you ask
Surgeon -- low urine output
Intensivist-- severe acidemia
Nephrologist-- rising serum creatinine
Frequency - depends on clinical setting
1% of all admissions to hospital
2-5% of all individuals during a hospitalization
4-15% during cardiopulmonary bypass
10-30% of all admissions to ICU
Large confusion in terminology and wide disparity in the definitions of terms
A review of 26 studies of post-op ARF found no 2 studies used the same definition

10. Definitions:
‘…a sudden and severe decrease in the glomerular filtration rate (GFR) sufficient to cause increases in BUN and Scr (azotemia), Na/H2O retention (edema), and development of acidemia and hyperkalemia…’
**review of 27 studies showed no 2 used the same defintion “chronic renal confusion”

11. New Definition: Mehta Crit Care 2007
An abrupt (within 48 h) reduction in kidney function currently defined as:
an absolute increase in serum creatinine of either >= 0.3 mg/dl, or
a percentage increase of >= 50 %
or a reduction in UOP (documented oliguria of < 0.5 ml/kg per h for > 6

12. RIFLE definition ADQI Group (Critical Care 2004, 8:R204-R212)
Proposed classification scheme for acute renal failure (ARF). The classification system includes separate criteria for creatinine and urine output (UO). A patient can fulfill the criteria through changes in serum creatinine (SCreat) or changes in UO, or both. The criteria that lead to the worst possible classification should be used. Note that the F component of RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function and End-stage kidney disease) is present even if the increase in SCreat is under threefold as long as the new SCreat is greater than 4.0 mg/dl (350 μmol/l) in the setting of an acute increase of at least 0.5 mg/dl (44 μmol/l). The designation RIFLE-FC should be used in this case to denote 'acute-on-chronic' disease. Similarly, when the RIFLE-F classification is achieved by UO criteria, a designation of RIFLE-FO should be used to denote oliguria. The shape of the figure denotes the fact that more patients (high sensitivity) will be included in the mild category, including some without actually having renal failure (less specificity). In contrast, at the bottom of the figure the criteria are strict and therefore specific, but some patients will be missed. *GFR = Glomerular Filtration Rate; ARF Acute Renal Failure

13. AKIN criteria for Acute Kidney Injury
Akin Stage
Serum Creatinine Criteria
Urine output criteria 1
Increase in S Cr of 1.5 to 2, or >= 0.3 mg/dl
< 0.5 ml/kg per h for 6 h 2
Increase in serum creatinine of 2-3 fold
< 0.5 ml/kg per h for 12 h 3
Increase in S Cr > 3 fold, or baseline Cr > 4 with an acute rise > 0.5 mg/dl
< 0.3 ml/kg per h for 24 h, or
Anuria for 12 h

14. Does this affect your practice ?
Slight changes in creatinine can represent renal failure (0.3 mg/dl)
UOP is an important parameter
More for research purposes

15. The New Creatinine:
You may notice creatinines being reported with an extra decimal (accurate to the hundredth):
BUN: 67
Cr: 2.42
GFR, Non-African American, estimated: L 27
GFR, African American, estimated L 33

16. Comments Section Chronic Kidney Disease: Less than 60 ml/min/1.73m2
Kidney failure: Less than 15 ml/min/1.73m2
Stable renal function is required for accurate estimation of creatinine clearance.
Efforts are underway to validate the equation in Hispanics, patients with diabetes, and individuals with normal renal function.

17. II. Evaluation of new Renal Failure
-Work up and Management

18. Categories of ARF

19. Urinary Indices Condition Prerenal ATN AGN Obs
U Osm > < *
U Na < > < > 40
FE Na < > < > 1

20. Prerenal ARF Decrease in GFR secondary to poor perfusion of kidney
GFR autoregulation impaired as MAP < mmHg
Clinically, may have
True hypovolemia
Decreased effective arterial blood volume (EABV)

21. Prerenal ARF Clinical Presentation Labs Diagnosis
Hemorrhage, diarrhea, vomiting, burns, fever
Heart failure, liver failure, nephrosis, sepsis
Meds: NSAIDs, ACE-I
Labs
Conc. urine (s.g. > 1.015), Uosm > 500 mmol/kg, low UNa (<10 mmol/l), FeNa < 1 %, BUN/Scr > 20 hyaline casts on microscopy
Diagnosis
Rapid recovery of GFR after improved renal perfusion

22. Prerenal Renal Failure
FeNa, U Na useful in setting of oliguria, and no diuretics
Fe Urea, FE Uric acid can be used if patient on diuretics

23. Postrenal ARF ~ Obstructive Uropathy
Acute renal failure occurring with obstruction of both urinary outflow tracts or the outflow tract of a single kidney
Etiologies:
Prostatic or cervical neoplasia
Neurogenic bladder
Intraluminal obstruction (crystals, stones, blood)

24. Obstructive Uropathy Pathogenesis (not well understood)
Transmission of pressure to glomerulus, decreasing GFR
Secondary renal vasoconstriction
Urine output not a good guide to obstruction
Normal Obstruction
GFR L/d 10 L/d
Tubular Resorp L/d 8 L/d
Urine Output L/d 2 L/d
Urine Na low over first hrs, then > 40
Prognosis depends on duration ( < 1 week favorable, > 12 weeks poor)
Ultrasound can miss early obstruction, retroperitoneal fibrosis, or dehydration and obstruction

25. Obstructive Uropathy Clinical: Treatment: May or may not be oliguric
Hyperkalemia
Diagnostic catheter placement or ultrasound
Treatment:
Relief of obstruction
Recovery of renal function may be inversely related to length of time obstruction persists
Recognize the possibility of a diuretic phase

26. Renal Imaging General
More helpful in evaluating patients with renal masses or urinary outflow disorders
Less useful in parenchymal disorders (except cystic disease)
May help direct further pathway of investigation or lead to specific diagnosis
Choice: proceeds from less invasive to more invasive and/or expensive studies

27. ULTRASONOGRAPHY Safe, non invasive, does not require contrast
Independent of renal function
Technically difficult in large patients
Most frequently used test
Easily detect hydronephrosis
Ultrasound can miss early obstruction, obstruction with retroperitoneal fibrosis, or dehydration
Aid in Renal Biopsy; Aspiration and percutaneous Nephrostomy

28. IVP Non-invasive, inexpensive, widely available
Excellent detail of entire urinary tract, especially the collecting system
Indications: hematuria, flank pain, papillary necrosis, urothelial malignancies and congenital abnormalities
Depends on renal function and contrast excretion: results poor if serum creatinine > mg/dl.
Uses contrast
Cumbersome

29. Plain Abdominal Radiograph (KUB)
Standard scout film in all IVP studies
Also useful for screening evaluation of patients with renal or ureteric stones
Limited by other calcific lesions in abdomen: gall stones, phleboliths, aorta, etc.

30. CT Scan
Offers much greater contrast resolution than conventional radiographs or tomograms
Unaffected by overlying bone or gas
Virtually entire urinary tract and retroperitoneum can be visualized
Main role in staging neoplasms and structural abnormalities (cystic disease, calculi, pyelonephritis)
Superseded IVP in trauma, biopsy and other interventions
Risks: contrast and radiation

31. MRI Delineating complex renal masses where CT is not definitive
Staging neoplasms, particularly evaluating renal vein and IVC invasion
Renovascular lesions: RAS and RVT
Beware Gadolinium with GFR < 30 cc/min

32. Isotope Renogram
Radionuclide agents administered and then patient imaged with a gamma camera
Records the number of counts emitted and their source
Both functional and structural study: renal perfusion, urinary outflow tract obstruction and parenchymal integrity
Useful in GFR and renal plasma flow estimation, renovascular disease, post-transplant, obstructive uropathy and in pts with contrast hypersensitivity

33. Categories of ARF

34. Intrinsic Renal Failure
Intrinsic ARF
Glomerular 5%
Tubular 85%
Interstitial 10%
Ischemic 60%
Toxic 40%

35. Intrinsic Renal Failure
Glomerular will usually be in setting of a systemic disease if the evaluation is taking place in the hospital
Dysmorphic RBC, RBC casts indicate glomerular hmaturia

36. Acute Interstitial Nephritis
“Many believe that AIN only occurs weeks after initiation of therapy with an offending drug, that it is invariably associated with fever, rash, and eosinophilia/uria, and that prior tolerance of a medication eliminates that drug as a potential cause of AIN.”
“All of these assumptions are false.”
Michel and Kelly, JASN 1998.

37. Acute Interstitial Nephritis
Clinical Presentation
Classic Triad of rash, fever, eosinophilia seen in under 30 %
Can occur within 2-3 days of exposure to agent, or after months (Classically, days)
U/A: hematuria (invariable), sterile pyuria, mild proteinuria, +/- eosinophils

38. Acute Interstitial Nephritis
Remove offending agent
Maintain adequate intravascular volume
Steroids are believed beneficial, but no prospective, randomized trials support them
Recommended: In appropriate histological or clinical presentation: 1 mg/kg x 2 weeks, rapid taper

39. Intrinsic Renal Failure
Intrinsic ARF
Glomerular 5%
Tubular 85%
Interstitial 10%
Ischemic 60%
Toxic 40%

40. NEJM 357:

43. Radiocontrast Nephropathy
Up to 11 % of hospital acquired acute renal failure
Definition:
“acute decline in kidney function after the administration of intravascular contrast material, in the absence of other causes”
An increase of > 25 % or > 0.5 mg/dL in S Cr between hours after administration of contrast

44. Risk Factors Pre-existing CKD (particularly GFR < 60)
Rise in cr of 0.5 more easily seen with lower GFRs
Diabetes Mellitus (increase risk 5 fold, endothelial dysfunction)
Heart Disease (MI, CHF)
Pre-existing CKD (particularly GFR < 60)
Diabetes Mellitus
Heart Disease
Hypotension
Age
Dehydration
Consider: Kidney transplant, proteinuria

45. Quantifying Risk JACC 2004 Risk Factor Score Hypotension 5 IABP CHF
Age > 75 4
Anemia 3
Diabetes
Contrast Media
1 point every 100 cc
Serum Creatinine > 1.5 or
GFR 40-60, 20-40, or < 20
2, 4, or 6 points
For Cardiac cath

46. Risk JACC 2004 Risk Score Risk of CIN Risk of dialysis 5 or less 7.5 %
0.04 %
6 to 10
14 %
0.12 %
11 to 16
26.1 %
1.09 %
16 or greater
57.3 %
12.6 %

47. Medications: Contrast Ace-Inhibitors Diuretics NSAIDs Volume
Type (High, Low, or Iso osmolar)
Ace-Inhibitors
Diuretics
NSAIDs

48. Contrast Agents Classification Name Osmolarity High Ioxathalamte 2150
Diatrozoate
2000
Low
Iobitridol
915
Iopamidol
796
Iohexol
780
Iopromide
770
Ioxaglate
600
Iso
Iodixanol
320
Viscosity

49. Guidelines: Consensus panel for CIN KI Suppl 100, 2006
13 member panel of nephrologists, cardiologists, and radiologists
Supported by Bracco Imaging and Schering, makers of low osmolarity contrast agents
Evaluate all patients for CIN risk
Optimize volume status
Prophylax high risk patients with evidence supported therapies
Use Low osmolarity media in all patients
Hold medication that adversely affects renal fuction
Follow up S Cr in 24 –72 hours (high risk patients)

50. Guidelines: CIN Consensus Working Panel Rev CV Med, 2006
3 radiologists, 2 cardiologists, and 2 neph
CIN is common, and can be serious
GFR < 60, DM are risk factors of particular note
History can identify high risk patients when labs not available
In an emergency, the procedure may need to be done before labs are back
The more risk factors present, the higher the risk of the procedure (up to 50 % CIN, 15 % ARF requiring dialysis)

51. Guidelines: CIN Consensus Working Panel Rev CV Med, 2006
2 nephrologists, 3 radiologists, and 2 cardiologists
Supported by GE healthcare, maker of iodixanol
Hydration: 1 – 1.5 ml/kg per hour isotonic crystalloid 3-12 hours before the procedure and 6-24 hours after
Insufficient data on oral versus IV
Dialysis not validated as an appropriate prophylactic measure.
High OSM contrast the greatest risk. Current evidence suggests in high risk patients, particularly with DM, non-ionic iso-osmolar contrast is associated with the lowest risk
Higher contrast volumes (> 100 cc) associated with higher risk. Even small volumes (30 cc) can cause CIN
Intra-arterial more risky than intravenous
Volume expansion may decrease the risk
No adjunctive treatment has been proved to be efficacious in reducing the risk.

52. Summary Recommendations
Assess risk
If high risk, avoid contrast if possible
If contrast needs to be given
Use lowest amount, low- or iso – osmolar
Insure adequate hydration
Stop potentially nephrotoxic meds. (NSAIDs, diuretics, metformin)
Avoid multiple repeat doses of nephrotoxins
Mucomyst does not appear to hurt, and may help

53. Algorithmic Approach McCullough PA et al, AM J Cardiol 98:2k-4k, 2006

54. Appropriate Follow up

59. Medications in Kidney Disease
Annals Int Med 12/07 – 3 drugs which account for 33 % of ER visits for adverse drug events
Insulin
Decreased dose required:
Kidneys metabolize up to 20 % of insulin
Uremia may contribute to insulin resistance
Anorexia with uremia may lower caloric intake
Digoxin
CrCl – dose is % q 36 hours
CrCl < 10 – dose is % q 48
Not removed with dialysis

60. Medications in Kidney Disease
DVT treatment: (inpatient or outpatient treatment in conjunction with warfarin)
STEMI: Initial: I.V.: 30 mg as a single dose in patients <75 years of age; omit I.V. bolus in patients 75 years of age. The first dose of the SubQ maintenance regimen is administered at the same time as the I.V. bolus. Maintenance: SubQ: 1 mg/kg every 24 hours in all patients
Unstable angina, NSTEMI: SubQ: 1 mg/kg once daily
Coumadin
No dosing adjustment necessary, but patients with renal failure at increased risk of bleeding
Lovenox
Cr Cl > 30 mL/minute: No specific adjustment recommended (per manufacturer)
Clcr <30 mL/minute:
  DVT prophylaxis: SubQ: 30 mg once daily
  DVT treatment: SubQ: 1 mg/kg once daily
Not recommended for patients on dialysis – if given requires careful follow up of anti-Factor Xa levels     

61. Medications in Kidney Disease
NSAIDs:
Decrease GFR and can push a patient with marginal GFR into acute renal failure. Associated with hyperkalemia.
In dialysis, main concern is bleeding risk
Antibiotics
Need to be dosed appropriately
If on dialysis, be sure levels are therapeutic (e.g. 1 gm of Vancomycin at HD Q week is often not enough)

62. Medications in Kidney Disease
Ace-I and ARBs may be beneficial
There is no great evidence that they should be held in acute renal failure:
They may contribute to hyperkalemia
They confound interpreting changes in GFR

63. Efficacy of ACE-I in CKD Hou et al NEJM, 354 p: 131-140, 2006

64. Dialysis Patients (GFR < 15)
Access is the bugbear of dialysis

65. Types of Access: Fistula.

66. Graft

67. Having a catheter increases your chance of having a blood infection
Marr, KI 1997

68. Tunneled Catheter

69. Take home points about access:
Avoid PIC lines if possible
Labs can be drawn at HD
Some antibiotics (vancomycin, aminoglycosides) can be dosed with HD
If changing a catheter (or pulling a catheter without exchange) check with renal team
Avoid subclavian lines
In predialysis patients, try to spare the veins of the non-dominant arm

70. Imaging in Dialysis patients
Dialysis must be done immediately after contrast studies (cath, CT) ?
No good evidence to support this (unless volume is an issue) but it is routinely requested

71. Imaging in Dialysis patients
Dialysis is necessary after MRI with gadolinium ?

72. Imaging in Dialysis patients
Dialysis is necessary after MRI with gadolinium ?
The FDA recommends dialysis in all patients with GFR < 30, who receive gadolinium, with 4 hours and another treatment the next day
To prevent Nephrogenic Systemic Fibrosis

73. Summary
Who is at risk for contrast nephropathy ?

74. Quantifying Risk JACC 2004 Risk Factor Score Hypotension 5 IABP CHF
Age > 75 4
Anemia 3
Diabetes
Contrast Media
1 point every 100 cc
Serum Creatinine > 1.5 or
GFR 40-60, 20-40, or < 20
2, 4, or 6 points
For Cardiac cath

75. Summary
How can contrast nephropathy be prevented ?

76. Recommendations Assess risk If contrast needs to be given
If high risk, avoid contrast if possible
If contrast needs to be given
Use lowest amount, low- or iso – osmolar
Insure adequate hydration
Stop potentially nephrotoxic meds. (NSAIDs, diuretics, metformin)
Avoid multiple repeat doses of nephrotoxins
Mucomyst does not appear to hurt, and may help

77. Summary
What is the work up for new acute renal failure ? What is the follow up ?

78. Summary Work up and follow up are individualized.
Use estimating equations for renal function
Remember to use them in the steady state
24 hour urine for protein and creatinine clearance is falling out of favor

79. Summary
What commonly used drugs need to be dose adjusted in renal patients ?

80. Summary “Start low, go slow”
Watch antibiotic dosing (both over and under) and anticoagulants
Nephrologists like ACE-I