Acute Renal Failure in the ICU

1. Acute Renal Failurein the ICU

2. Review of Anatomy and Physiology Glomerulus -forms ultrafiltrate of plasma

3. Review of Anatomy and Physiology Proximal Tubule -reabsorbs isosmotically 65-70% of -reclaims all the glucose, amino acids, and bicarbonate Secretes protein bound drugs

4. Review of Anatomy and Physiology Loop -reabsorbs 15-25% of filtered NaCl -Creates the gradient for the countercurrent multiplier

5. Distal Tubule -reabsorbs few percent -fine tunes- volume, osmolarity (ADH), K (aldosterone), acid-base Review of Anatomy and Physiology

6. Background • ARF- an abrupt reduction in renal function sufficient to result in azotemia.

7. Case Presentation • 88 yo wf with MMP including: CHF, NIDDM, HTN, COPD, and CAD, presents with 3 day h/o subjective fevers, chills, headache, night sweats, flank pain, dysuria, and mild confusion. • Vitals t 103 p120 rr13 pox 98% RA • Exam – Right flank tenderness • 140/100/50 --------------- 3.0/30/1.1

8. Presentation (cont) • ER course • CXR negative • As patient appeared “ill”, arrangements made for ICU admission for treatment of presumed urosepsis • Prior to admission- given Toradol 40mg IM for her headache. Narcotics avoiding 2nd to concern of clouding the picture regarding her mental status changes

9. Glomerular Filtration Rate • Direct measure of renal function • reduced prior to the onset of symptoms of renal failure • impairment of GFR correlates with structural abnormalities seen on biopsy • Normal GFR is approximately 120cc/min • Decreases with age- by age 80, GFR 80 • Asymptomatic metabolic abnormalities (hyperphosphatemia, hypocalcemia, anemia, hyperparathyroidism, osteoporosis) begin at a GFR of < 50 cc/min • Dialysis usually initiated at GFR < 10 cc/min

10. Glomerular Filtration Rate • Difficult to directly measure • as a result in clinical practice we usually estimate from serum creatinine or creatinine clearance.

11. - For early disease, serum creatinine is a poor marker of GFR -lose of 50% of function without a change in Cr - example- transplant donor -For late disease, serum creatinine is a poor marker of GFR -large change in creatinine is a minimal change in GFR - example- Cr change from 3 to 4 is a change in GFR of only a few cc/min (3cc/min in this pt) -Serum creatinine only valid in steady-state -ie immediately after a bilateral nephrectomy– serum creatinine initially normal

12. Creatinine Clearance • Effort to improve on the poor results obtained by using serum creatinine • Creatinine is generated from muscle metabolism of creatine • Therefore proportional to muscle mass • Age • Sex • Weight

13. Creatinine Clearance • Most commonly used equation is the Cockcroft Gault Equation • Attempt to account for variable muscle mass • ((140-age) * weight (kg) ) / (72 *serum creatinine) • *.85 for females • Derived from approximately 100 white Canadian males without renal disease • Yet we extrapolate to everyone • As a result– average error 15% • can be >50% off in 10% of cases • Not uncommon to have a normal serum creatinine with a GFR as low as 20 cc/min

14. Our little old lady • Her baseline serum creatinine = 1.1 • “Normal” per the computer values– therefore ER didn’t think twice about administering NSAID • Cockcroft-Gault • Calculated CrCl of 27cc/min– or consistent with moderate to severe renal failure • 24hr post Toradol, Scr increased to 1.5 • CrCl decreased by 25% to 20 cc/min

15. Afferent Efferent Glomerulus NSAID associated ARF • Primarily hemodynamically mediated • Renal physiology

16. Afferent Efferent Glomerulus NSAID associated ARF A diseased kidney or a patient with effective volume depletion (CHF, cirrhosis, dehydration, etc) relies upon prostaglandins to dilate the afferent arteriole to maintain adequate perfusion/GFR Prostaglandins

17. Prostaglandins Prostaglandins Afferent Afferent Efferent Efferent Glomerulus Glomerulus NSAID associated ARF NSAIDS block prostaglandins -In musculoskeletal injury this limits vasodiliation and resultant swelling around sites of injury -but unfortunately also blocks PGs in the kidney NSAIDS

18. NSAID associated ARFNormal baseline renal function Afferent Efferent Afferent NSAIDS Glomerulus Efferent Glomerulus Prostaglandins Because there is no baseline PG production, NSAIDS have no effect on renal function in patients with normal volume and renal function

19. NSAID associated ARFBaseline abnormal renal function or baseline PG dependent Prostaglandins Afferent NSAIDS Efferent Glomerulus Cirrhosis, CHF, renal disease or volume depleted Prostaglandins Afferent Efferent Glomerulus Because there is baseline PG production which is blocked by NSAIDS, the effect is a resultant increased creatinine

20. NSAID associated ARFBaseline abnormal renal function or baseline PG dependent • In this case the creatinine bump is analogous to angina • It is a manifestation of decreased renal blood flow • If addressed in the early stages, it is associated with no permanent damage • Discontinuation of NSAIDS will usually lead to a complete reversal of an increased serum creatinine • If allowed to persist, can result in irreversible renal damage • Unfortunately, the only way to know the damage is irreversible it to wait until it occurs • Impact of ASA qd?

21. Little old Lady • ARF noted and no further NSAIDS given • On admission, she was noted to be have hypertension. Given her history of CHF, addition of an ACE-I was felt indicated. Lisinopril 20mg po qd added to her regimen. • The following day, her serum creatinine was back to 1.5. Why?

22. Afferent Efferent Glomerulus ACE-I and renal function • Like NSAIDS, the bump in serum creatinine is primarily hemodynamically mediated =Ace-I effect- analogous to removing the end cap from the hose

23. Afferent Efferent Glomerulus ACE-I and renal function • Unlike NSAIDS which bump the creatinine by starving the kidney for blood, ACE-Is bump the creatinine, but in the process actually increases renal blood flow. =Ace-I effect- analogous to removing the end cap from the hose

24. Little old Lady • As patient trending toward hypotension, ACE-I d/cd. Creatinine decreased back to 1.3. • Urine culture positive for GNR sensitive to cipro or bactrim. To minimize the development of flouroquinolone resistance, ICU avoids levaquin and prescribes Bactrim for presumed urosepsis • The next day the patient’s serum creatinine has again increased to 1.5 • What happened?

25. Bactrim and Serum creatinine • Creatinine is removed from the body by glomerular filtration and by active transport in the proximal tubule • In patients with normal renal function, approximately 10% of the daily load is secreted • As renal failure progresses, the proportion can increase to up to 50%

26. Bactrim and Serum creatinine • Bactrim competes with creatinine for the limited number of active transporters • Once saturated- every molecule of bactrim transported is one less molecule of creatinine secreted– resulting in increased serum creatinine WITHOUT A CHANGE IN RENAL FUNCTION • Minimal bump if low serum creatinine (recall you can lose 50% of function without a change in serum creatinine). But a large bump is serum creatinine already elevated (because depend on transporter to remove up to 50% of creatinine and on steep part of curve) Blood creatinine bactrim creatinine creatinine bactrim bactrim creatinine creatinine creatinine bactrim Tubule creatinine bactrim creatinine creatinine bactrim bactrim creatinine bactrim bactrim Urine Space bactrim

27. Little old Lady • Remains febrile so switched to levaquin and gentamicin. Forty-hours later, Scr now elevated to 2.2 and associated with oliguria. • Was it gentamicin nephrotoxicity?

28. Aminoglycoside Nephrotoxicity • Aminoglycosides are non-protein bound and freely filtered at the level of the glomerulus. Renal excretion is the major route of elimination. • Accumulate in the tubules where they cause toxicity • Injury visible by EM and light microscopy

29. Gentamicin Nephrotoxicity • No hard and fast rule regarding toxicity • Dependent upon duration and total dose • Risk factors- old age, volume depleted, hypomagnesemia • Extremely rare before 72hours. Earliest onset typically at 5-7 days. • Presents with rising BUN/creatinine associated with POLYURIA and other signs of tubular dysfunction • Proteinuria, bicarb wasting, hypomagnesemia

30. Afferent Efferent Glomerulus Gentamicin Nephrotoxicity • Why polyuria? GFR of 120cc/min equals 173 liters of ultrafiltrate per day If nl urine output 1 liter per day, tubules reabsorb 172/173 liters or 99.4% of the UF If tubule damaged (by gentamicin or other nephrotoxin), even a 2% decrease in reabsorption results in an extra two liters of urine per day Proximal Tubule -reabsorbs 70-80% of total volume -reabsorbs all glucose, protein, and bicarb

31. Gentamicin Nephrotoxicity • No specific therapy beyond stopping the medication • Consider non-nephrotoxic replacement. If must have an aminoglycoside– tobramycin is less nephrotoxic • Will take days to weeks to resolve as the gentamicin is gradually released from the tubules • Used to therapeutic advantage in treating UTIs

32. Gentamicin Nephrotoxicity • Peaks and Troughs • “Peaks kill bugs, troughs kill kidneys” • Not that simple • Mix of peaks, troughs, and overall duration • Peak studies derived using troughs of 6-7 • Trough studies derived using very high peaks • My practice– if life threatening infection– aim for high troughs (doesn’t do any good to preserve the kidneys and have the patient die). Nephrotoxicity, if it occurs won’t be for many days, by then you have either controlled the infection or lost the patient. • Experimental nephrotoxicity- canine studies

33. Gentamicin Nephrotoxicity • QD dosing Traditional therapeutic range Post-antibiotic effect (concentration independent killing)

34. Gentamicin Nephrotoxicity Traditional therapeutic range Post-antibiotic effect (concentration independent killing) No antibiotic coverage

35. Little old lady • Continues to spike temperatures despite multiple days of broad spectrum antibiotics. What gets ordered next?

36. Little old lady • Contrast CT scan to r/o peri-nephritic abscess or other intra-abdominal process • Serum creatinine 48 hours later 3.0

37. Contrast Nephropathy -Reported incidence of acute renal failure is highly variable (up to 50% depending upon the study) -but renal failure in studies is typically defined as a bump in Scr of 50% or 0.5 mg/dl -clinically don’t care unless unless requires dialysis- incidence of dialysis is much less -Risk factors- diabetes, baseline renal dysfunction, chronic renal insufficiency, relative volume depletion (CHF, cirrhosis, ascites, nephrosis, diarrhea) -Risk is OVERRATED -Practically- unless serum creatinine >5.0-6.0 or diabetic with serum creatinine >4.0, highly unlikely to experience irreversible renal dysfunction or dialysis

38. Contrast Nephropathy - Traditional teaching is that multiple myeloma is at higher risk for contrast nephropathy– this is not true • Prevention of contrast nephropathy • HYDRATION, HYDRATION, HYDRATION- NS vs. ½ NS- doesn’t matter • Non-ionic better than ionic • Minimize volume of contrast and use non-ionic contrast • Mucomyst protocol--- Jury still out. Probably doesn’t help.

39. Little old Lady • No abscess noted • Continues to spike temperatures s/p a week on broad spectrum antibiotics • What gets added next?

40. Little old Lady • Amphotericin • Polyene antibiotic that is the treatment of choice for the majority of serious fungal infections. • Works by attacking ergosterol in fungal membranes • Acts like a MAC of human complement- literally “punches” holes in the cell walls leading to osmotic cell death • Cholesterol in mammalian cell walls is very similar • Minor cross reactivity, increases with increased levels • Where tissue is typically exposed to the highest drug levels in the human body??

41. Amphotericin toxicity • What tissue is typically exposed to the highest drug concentrations? • Kidney- especially the distal tubules where urine concentration occurs. • Therefore the cross-reactivity of amphotericin for cholesterol is most severe in the distal tubules of the kidney.

42. Amphotericin toxicity • What are the manifestations? • All the distal tubule functions- acid-base, volume, potassium, Mg • What can you do to minimize? Distal Tubule -reabsorbs few percent -fine tunes- volume, osmolarity (ADH), K (aldosterone), acid-base

43. Amphotericin toxicity • Minimize toxicity • NS loading • Liposomal Amphotericin • Decreased solubilizing agent- which causes direct nephrotoxicity • Uptake primarily by the RES cells- lower dose with less net renal exposure Distal Tubule -reabsorbs few percent -fine tunes- volume, osmolarity (ADH), K (aldosterone), acid-base

44. Little old Lady Continues to spike through amphotericin and progresses to frank hypotension with pressures 60-80s for several hours • Within 24hrs serum creatinine increased to 5.5, and continues to elevate 1 point per day

45. ATN • Acute tubular necrosis • Number one etiology of renal failure in the unit setting • Usually 2nd to hypotension • Manifest by isosthenuric urine, course and fine granular casts in the urine sediment • No effective therapy. Supportive treatment only • Given no additional insults- usually reversible over a 4-6 week period

46. ARF in ICU • Mortality severe • MICU- 30-50% • SICU- 50-75% • Unchanged for 30 years- despite tremendous advances in acute dialysis and patient management. • Why? • Patients die with renal failure, not from it.

47. ARF in ICUManagement • Conversion of non-oliguric to oliguric renal failure • Not a therapeutic maneuver– prognostic only • Useful for assisting in volume management and hyperkalemia, but no impact on ATN • Nephrectomy analogy

48. ARF in ICUManagement • Avoidance of dialysis – renal recovery will be faster and more complete if dialysis is not initiated • Don’t exacerbate the situation • No NSAIDS, contrast, avoid hypotension etc

49. ARF in ICUManagement • Renal purpose is to maintain homeostasis- volume, acid-base, and electrolyte • Volume • Insensible losses 500-1000cc/day– if inputs less than that– no volume issues • KVO- even 10cc/hr (1 liter every four days—if HD only removes one liter– that means an extra treatment each week just for the KVO) • Obviously maximally concentrate all IVs • Sedation– use longer acting agent – volume of MSO4 is much less than Fentanyl, BZ less volume than propofol

50. ARF in ICUManagement • Renal purpose is to maintain homeostasis- volume, acid-base, and electrolyte • Electrolytes (primarily K) • Obviously don’t give exogenous K– hidden sources include antibiotics, Lactated ringers, unnecessary K in TPN • Goal is < 60 meq/day for dialysis patient, none for a ARF patient