CBP: Nephrology - UBC Critical Care Medicine, Vancouver BC

Case Presentation  43 year old gentleman with Crytogenic Cirrhosis is admitted to the ICU after massive GI bleed secondary to bleeding esophageal varices. His varices have been successfully banded and he is admitted post-procedure. He received multiple units of blood, as well as platelets to correct his thrombocytopenia and FFP to correct his coaglulopathy (INR 4.3). He also received 6 L of crystalloid. He is now hemodynamically stable, however, his respiratory requirements have increased, in keeping with his CXR findings of acute pulmonary edema.

 PSV, 12/5, FiO2 .45  He is kept intubated over night and given multiple boluses of Lasix (total of 200mg) to help encourage diuresis.  When assessed in the morning, it is noted that he has been anuric over night. His admission BUN/Cr were 11/87, and are now 23/192. He is now on PSV 16/8 and FiO2 is .65.  His electrolytes reveal: Na – 128, K – 5.3, Cl- 97, tCO2 – 18.  ABG: 7.31/39/84/19/-2

Question 1  Briefly describe Hepatorenal syndrome and it’s pathophysiology. What are some predisposing factors? (Federico)

DEFINITION Hepatorenal syndrome is a clinical condition that usually occurs in patients

with advanced liver disease and portal hypertension that is characterized by : -Renal failure, with creatinine level more than 1.5mg/dl

-Marked decrease in GFR and renal plasma flow (RPF) in the absence of other identifiable cause of renal failure. -Marked abnormality in systemic hemodynamics

-Activation of endogenous vasoactive systems. HRS occurs predominantly in the setting of cirrhosis, but it may also develop in other types of severe chronic liver diseases, such as alcoholic hepatitis, or in acute liver failure .

The theory that best fits with the observed alterations in the renal and circulatory function in HRS is the vasodilation theory, which proposes that HRS is the result of the effect of vasoconstrictor systems acting on the renal circulation and activated as a homeostatic mechanisms to improve the extreme underfilling of the arterial circulation .That leads to decreased renal perfusion and glomerular filtration rate (GFR )but tubular function is preserved .

There are two well-differentiated clinical patterns of HRS Type 1 HRS

•Characterized by rapid and progressive impairment of renal function defined as a doubling of the initial serum creatinine to a level greater than 2.5 mg/dl or a 50% reduction of the initial 24-hour creatinine clearance to a level lower than 20 ml/min in less than 2 weeks . •Usually occur in severe liver failure (Jaundice, encephalopathy, and coagulopathy) •Occur frequently after precipitating factor (e.g. GI bleeding) •Median survival time is only 2 weeks

Type 2 HRS •Characterized by a less severe and non-progressive reduction of GFR . •Associated with relatively preserved liver function. •The main clinical consequence of this type of HRS is refractory ascites, due to a lack of response to diuretics . •Median survival time is about 6 months.

The International Ascites Club has defined criteria for the diagnosis of HRS. Major criteria, necessary only for the diagnosis, are as follows: 1.

Low GFR, defined by a serum creatinine greater than 1.5 mg/dL or 24hour clearance lower than 40 mL/min

2.

Absence of shock, ongoing bacterial infection, fluid losses and current treatment with nephrotoxic drugs

3.

No sustained improvement in renal function (decrease in serum creatinine to 40 mL/min) following diuretic withdrawal and plasma volume expansion with albumin (or 1.5 L of isotonic saline).

4.

Proteinuria less than 500 mg/d

5.

Absence of any evidence of obstructive uropathy or parenchymal disease as shown by ultrasonography

Precipitating factors 1.

Bacterial infections

2.

Bleeding

3.

Large volume paracentesis without plasma expansion

 Patient remains anuric and is given a further bolus of 100mg of Lasix.  Patient remains anuric despite most recent dose of Lasix.

Question 2  Any role for increasing doses of Lasix in an anuric patient? Any harm? Any benefit? (Federico)

Diuretics in AKI Regarding

an increased appreciation for the potential detrimental downstream effects of volume overload, it may be reasonable to try diuretics for control of volume overload. The clinician should, however, be careful not to delay initiation of RRT for volume overload in the critically ill patient with AKI (Crit.Care 2010, vol 38, n1)

Question 3  Define Acute Kidney Injury (Federico)

RIFLE Criteria  The Acute Dialysis Quality Initiative Group proposed the RIFLE system classifying ARF into 3 severity groups and 2 clinical outcome categories

Incidence of AKI in the ICU  AKI occurs in ~ 7% of all hospitalized patients, whereas it occurs in 36% – 67% of critically ill patients.

 On average, 5 % of ICU patients with AKI require renal replacement therapy.

Dennen P, Douglas IS, Anderson R. Acute kidney injury in the intensive care unit: an update and primer for the intensivist. Crit Care Med. 2010 Jan;38(1):261-75

AKI and mortality  In most studies, mortality rates rise proportionally with severity of AKI.

 Even small increases in serum creatinine have been associated with increasing mortality in various ICU populations despite adjusting for severity of illness and comorbidities.

 In patients with AKI requiring RRT, mortality rates reach 50% to 70%.

Dennen P, Douglas IS, Anderson R. Acute kidney injury in the intensive care unit: an update and primer for the intensivist. Crit Care Med. 2010 Jan;38(1):261-75

AKI and other outcomes  AKI is also associated with:  Increased length of stay  Increased incidence of CKD and end-stage kidney disease  Increased cost

 For example, an increase in SCr of 0.5 mg/dl (38 mmol/L)was associated with a:  6.5-fold increase in the odds of death  3.5 day increase in LOS  nearly $7500 in excess hospital costs

Dennen P, Douglas IS, Anderson R. Acute kidney injury in the intensive care unit: an update and primer for the intensivist. Crit Care Med. 2010 Jan;38(1):261-75 Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. 2005 Nov;16(11):3365-70

Traditional methods for detecting AKI  Currently available measures do not detect actual kidney injury the way troponin detects myocardial injury:  Creatinine  Urea  Urine output

 Rather they are markers of abnormal renal function, that can be used to presume kidney inury has occurred.

Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care. 2007 Dec;13(6):638-44.

Serum creatinine  Used to estimate GFR

 Pros  Produced at a relatively constant rate  Freely filtered by glomerulus  Not reabsorbed or metabolized by the kidney.

Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care. 2007 Dec;13(6):638-44.

Serum creatinine  Used to estimate GFR  Cons  10-40% is secreted by the tubules  Relatively insensitive (may need a 50% reduction in function before a detectable rise in SCr is seen)  Creatinine production varies based on age/sex/muscle mass/diet  Certain disease states can increase production (rhabdo)  Certain drugs can decrease secretion (cimetidine, trimethoprim)  Certain factorsmay affect assay (ketoacidosis, cefoxitin, flucytosine)  Does not reflect real-time changes in GFR

Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care. 2007 Dec;13(6):638-44.

Delay in SCr rise

Waikar SS, Bonventre JV. Creatinine kinetics and the definition of acute kidney injury. J Am Soc Nephrol. 2009 Mar;20(3):672-9

Urea  Rate of production is not constant    

Increases with protein intake Increases in critical illness (burns/sepsis/trauma) GI Bleed Steroids

 40% - 50 % of urea is reabsorbed by the kidney (even more when dry)

Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care. 2007 Dec;13(6):638-44.

Urine output  Pros  A dynamic gauge of kidney function.  May be a barometer for change in kidney perfusion

 Cons  Poor sensitivity and specificity  Can have severe AKI with normal or increased urine output

Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care. 2007 Dec;13(6):638-44.

Novel methods for detecting AKI  Serum Cystatin C

 Kidney injury molecule-1

 Neutrophil gelatinase-associated lipocalin (NGAL)

 Urinary IL-18

Serum cystatin c  An endogenous cysteine proteinase inhibitor

 Synthesized at a relatively constant rate

 Released into plasma by all nucleated cells in the body

Knight EL, Verhave JC, Spiegelman D, et al. Factors influencing serum cystatin C levels other than renal function and the impact on renal function measure- ment. Kidney Int 2004; 65:1416–1421

Serum cystatin c  Reportedly not affected by patient age, sex, muscle mass or diet

 However, one large study showed that age, sex, height, weight, smoking status, and CRP levels were all associated with cystatin c levels.

 Also found to be affected by abnormal thyroid function, immunosuppression (steroids), and systemic inflammation Knight EL, Verhave JC, Spiegelman D, et al. Factors influencing serum cystatin C levels other than renal function and the impact on renal function measure- ment. Kidney Int 2004; 65:1416–1421

Serum cystatin c  Almost 99% is filtered by the glomerulus

 Not secreted or reabsorbed by the tubules

 Therefore a rise in cystatin c is a good indication of a decrease in GFR

Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care 13:638–644.

Serum cystatin c  Cystatin C-based estimates of GFR may perform better in those with lower SCr concentrations such as:     

Elderly patients Children Renal transplant recipients Cirrhotics Those that are malnourished

 May be more sensitive to early and mild changes of kidney function compared with creatinine

Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care 13:638–644.

Kidney injury molecule-1  A transmembrane glycoprotein that is normally minimally expressed in kidney tissue.

 Shows marked upregulation in proximal renal tubular cells in response to ischemic or nephrotoxic AKI

 Shed from proximal cells and detected in the urine by immunoassay

Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care 13:638–644.

Kidney injury molecule-1  Urinary levels of KIM-1 are significantly higher in established AKI compared with other causes of AKI (i.e. PRA, contrast-induced nephropathy) or CKD.

 Thus, KIM-1 may represent an early, noninvasive biomarker for proximal tubular AKI.

 More studies needed to define its role

Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care 13:638–644.

Neutrophil gelatinase-associated lipocalin (NGAL) 

Belongs to the lipocalin superfamily



Markedly upregulated in response to kidney ischemic or nephrotoxic injury



May be an early and sensitive urinary biomarker of ischemic and nephrotoxic AKI.



Early elevations in urinary NGAL after kidney transplan- tation have been shown to be predictive of:  

delayed graft failure Need for RRT during the first week following transplantation

Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care 13:638–644.

Interleukin-18  IL-18 can be induced in the proximal tubule and detected in the urine in ischemic AKI  Is increased in the urine of patients with established AKI when compared to those with prerenal failure, urinary tract infection, CKD or healthy controls.  Elevated urinary IL-18 values have been shown to preceded clinical evidence of overt AKI (50% increase in SCr) by 24 – 48 h in critically ill patients with ARDS.

 Urinary IL-18 values of at least 100pg/ml were associated with an estimated 6.5 increased odds of developing AKI within 24 h. Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care 13:638–644.

Summary of novel markers

Bagshaw SM, Bellomo R. Early diagnosis of acute kidney injury. Curr Opin Crit Care 13:638–644.

Question 5  What are some traditional and novel methods for early detection of kidney injury? (Marios)

 Patient continues to have increasing ventilation support requirments and is now on .85 FiO2. His K+ is now 5.6. He is given routine hyperK+ therapy. He has been started on vasopressors because of declining MAP

Question 6, 7  What are the indications for CRRT vs IHD. Is one better? What are their associated advantages and disadvantages? (Neil)  When should RRT be initiated?

A,E,I,O,U

CRRT review Chest 2007

Acute Renal Failure Lancet review.pdf

Bouman et al.TimingofCRRT-CurrOpCritCare2007.pdf

CRRT review Chest 2007

Lameire et al. Lancet 2005

CRRTvsIHDCochrane2007.pdf

Question 8  Define the different modes of CRRT. Use a diagram to highlight the differences? (Noemie)

 It is decided to start the patient on CRRT therapy. What kind of anticoagulation should he receive?

Question 9  Compare the different modes of anticoagulation.  Explain the use of citrate and how to dose it. Please explain the calcium gap. (Noemie)

Anticoagulation  Heparin  Can be given systemically or through circuit  Aim for PTT 35-45 sec

 Regional citrate

Intensive Care Med 2004;30:260-265

Kidney International 2005;67:2361-2367

Intensive Care Med 2004;30:260-265

Kidney International 2005;67:2361-2367

Anticoagulation  Citrate    

Citrate infusion pre-filter Leads to calcium chelation and  clotting time Aiming for post filter iCa btw 0.25-0.35 Post-filter calcium infusion to restore systemic Ca and clotting function

Citrate  Concerns:    

Pricy Operator training + time consuming Repeat labs q6h: Post filter iCa, Systemic iCa and total Ca Risk of hypocalcemia

Calcium  Total plasma Calcium:  40% bound to albumin  45% circulates as ionized calcium  15% bound to organic/inorganic anions

Citrate and Calcium Gap  50% of citrate cleared through dialyser  Remaining citrate metabolized in the liver to Bicarbonate  If citrate systemic delivery >> pt’s ability to metabolize citrate  Systemic accumulation of Calcium Citrate hypocalcemia

Calcium gap  Calcium gap: Total calcium - ionized Ca

 Citrate accumulation causes Total calcium and  iCa

 Pt with acute renal failure and liver failure are at increased risk of citrate accumulation

Tidbits from Dodek  Citrate toxicity, only clinically relevant if:  Leads to hypernatremia  Leads to metabolic acidosis (when citrate is not metabolized, b/c it is an acid)  +/- Metabolic acidosis (because it is converted to HCO3)  Hypocalcemia (but just turn up your Ca infusion)  In relation to above, calcium gap not all that relevant

Question 10  What is an ideal dialysis dose? (Todd)

What is the ideal dialysis dose?  I don’t know.  And I’m not the only one.

Speaking of flashbacks…  2 recent studies addressing the issue of “dose” of renal replacement therapy  The first included multiple RRT modalities…

 IHD, SLED, CVVHDF  Patients enrolled had ATN requiring dialysis and either sepsis or one additional nonrenal organ failure  Excluded patients with chronic kidney disease

 CVVHDF dose was 20 cc/kg/hr in the less intensive group and 35 cc/kg/hr in the intensive group  In the IHD/SLED patients, dosing was 3 times per week or 6 times per week, respectively

Essentially no difference  Mortality, recovery of renal function, ICU-free days, organ failure scores, or discharge home without dialysis.

The second rule of (city wide) Journal Club…

 Critically ill patients with AKI requiring dialysis  Excluded if on dialysis pre-admission

 CVVHDF, with post-filter replacement fluid  25 cc/kg/hr vs 40 cc/kg/hr  Dialysate: replacement fluid (Hmosol B0) 1:1

 What does this mean…?

 That the dose is unimportant? That the dose beyond a (not quite determined) value is not important? Are we looking for the wrong outcomes?

What box should I check?  At RCH: 35 cc/kg hr (as opposed to 45)  Saves a few bucks on dialysis/replacement fluid.

Question 11  It turns out the patient has been feeling very suicidal lately  What are the indications for RRT in acute intoxications (Todd)

What are the indications for RRT in acute intoxications?  If there is indication of severe toxicity

 If elimination can be improved by an extracorporeal technique.  HD, HF, hemoperfusion, MARS

Current Opinion in Critical Care 2007, 13:668– 673

 Dialysis techniques: Discussed already.  Hemoperfusion: adsorption of toxins  MARS: hemoperfusion technique using albumin exchanger.

Or hemofiltration And possibly: Carbamazapine, diltiazem, phenytoin and mushrooms

 Patient stabilized on CRRT therapy and slowly his renal function has shown some improvements with production of small amounts of urine. His hemoglobin has remained stable and HD he is off pressors. However, you are called to his bed side stat as his BP has suddenly dropped. His repeat HgB shows a drop of 35. You are entertaining a retroperitoneal bleed and want to do a CT contrast of his abdo/pelvis.

Question 12  Does RRT decrease the incidence of Contrast induced nephropathy? (Todd)

decrease the incidence of contast-induced nephropathy?  It should. But there’s no evidence that it does.  One trial randomized patients to low-dose hemofiltration in ICU vs ward care with NS at 1cc/kg/hr, prior to PCI and found no difference in CIN or mortality. Duration was approx. 6 hours pre- and 20 hours post- contrast load.  58 pts per group, average Cr 270.  Other strategies, i.e. iso-osmolar contrast, NAC, were included

PRISMA geeks rejoice…  Femoral HD line  Pump speed 100 cc/min  Replacement fluid at 1000 cc/hr

 No net fluid off  Heparin anticoagulation

The fine print  Control group needed more renal replacement therapy (25% vs 3% in intervention group)

The end!  You now know all about the kidneys!!!