Highlights from the 17th Annual International CRRT Meetings from San Diego, CA.
February 14 – 17, 2012


Contents

  1. Thinking Outside of the Box: A Novel Strategy to Prevent Shock-induced AKI

  2. Use of NGAL in Management of Cardio-renal Syndromes

  3. Saline is really bad for you

  4. How to start an Ultrafiltration Program





Acute Kidney Injury: Controversies, Challenges and Solutions
Thinking Outside of the Box: A Novel Strategy to Prevent Shock-induced AKI
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Presenter: Todd W. Costantini, MD — University of California San Diego
Blogger: MJ Barchman, MD — East Carolina University

This was absolutely one of the most intriguing talks I heard at this year’s meeting. Dr. Costantini reviewed the notion that the intestine plays a key role in generating the systemic inflammatory response (SIRS) to injury. This gut barrier breakdown causes an intestinal inflammatory response with cytokine production and recruitment of inflammatory cells all of which leads to SIRS which may be a contributor to local inflammation in the kidney and result in AKI (Deitch, et al. Crit Care Med 2004;32:533-38). The tight junction proteins, occludin, ZO-1 and the actin cytoskeleton, attach adjacent cells and provide an epithelial barrier in the gut. A model of severe burn injury alters expression of occludin and decreases the barrier function (Costantini, et al. Shock 2009;31:416-22) and results in increased intestinal permeability (Costantini, et al. J Surg Res. 2009;156:64-9). This same phenomenon has been seen in traumatic brain injury leading to efforts to uncover the “neuro-enteric axis” (Bansal V, et al. J Neurotrauma. 2009;26:1353-59), thus the finding that vagal nerve stimulation can provide anti-inflammatory effects. The vagus nerve carries parasympathetic fibers to the heart, lungs and branches into enteric nervous system supplying parasympathetic fibers to the abdominal organs. The acetyl choline mediated nerve stimulation of the intestine leads to production of TNFα and IL-1 among other things. Stimulation of the vagus nerve has been found to attenuate the systemic inflammatory response to endotoxin (Borovikova LV, et al. Nature 2000;405:458-462) and vagotomy in the same model lead to increased levels of TNF. This finding led to further studies showing that vagal nerve stimulation decreased burn-induced intestinal permeability by decreasing loss of occludin and that the effect could be reproduced up to 90 minutes after the injury. Furthermore, this same architecture preserving effect was observed in lung tissue with vagal stimulation by preventing pulmonary NF-KB activation (Krzyzaniak, et al. Surgery. 2011;150:379-389). Vagal nerve stimulation also prevented histologic kidney injury, decreases renal myeloperoxidase cell count by immunohistochemistry and prevented the shock-induced altered localization of renal epithelial ZO-1. His conclusions were that vagal nerve stimulation exerts potent local and systemic anti-inflammatory effects, modulates epithelial barrier function and that therapeutics aimed at increasing efferent vagal nerve signaling may represent a strategy to limit shock induced AKI.


Acute Kidney Injury: Controversies, Challenges and Solutions

Use of NGAL in Management of Cardio-renal Syndromes
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Presenter: Dinna Cruz, MD, MPH — San Bartolo Hospital, Vicenza, Italy
Blogger: MJ Barchman, MD — East Carolina University


Dr. Cruz focused primarily on Cardio-Renal Syndrome (CRS) Type I and use of NGAL as a marker for evolving AKI when attempting to treat with aggressive diuresis. The idea here is to monitor for a bump in NGAL which preceeds the increase in creatinine to know when to back off on or stop diuretics altogether to avoid AKI which will further complicate management of these patients. She pointed out that there are 3 forms of NGAL: a monomeric 25 kD form or “free” NGAL which is secreted by distal renal tubular epithelial cells and is more specific for ATN; a dimeric 45 kD form which is primarily secreted by PMNs and when found in the urine is more likely to be an indicator of UTI or pyelonephritis than AKI; and a heterodimeric 135 kD form which is an NGAL-MMP complex. There are 2 assays to measure NGAL at this point one of which is the ‘Competitive Assay’ which is not as good at detecting NGAL at low levels typically seen in CRS and the ‘Sandwich Assay’ which is much better for detecting “free” NGAL with a coefficient of variation that is much less, ie, the results are more reliable at the lower levels seen in CRS patients. The need for this assay is obvious when comparing mean NGAL levels across patient types, ie, mean NGAL levels for ICU pts is 220 ng/ml, mean levels for CRS pts is 79 ng/ml and when contrast is an additional variable the NGAL levels are ~ 100ng/ml. She stressed that when we begin to use the NGAL Sandwich Assay in monitoring our CRS pts that following trends will be much more important than a single value. For example, as you diurese a decompensated heart failure patient, checking BNP and NGAL levels along with our usual markers of urine output, JVP, lung exam and creatinine on a daily basis may allow us to stop or decrease diuretic therapy once the pt is clinically improving but NGAL levels have bumped up suggesting impending AKI before increase in creatinine levels are seen, thus avoiding AKI. This was one of several talks that have led me to believe that NGAL is almost ready for regular clinical use when employed in conjunction with our other clinical markers.


Acute Kidney Injury: Controversies, Challenges and Solutions

Saline is really bad for you
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Presenter: John Kellum, MD — University of Pittsburgh
Blogger: MJ Barchman, MD — East Carolina University

At last year’s meeting, I heard an intriguing talk by Can Ince, PhD, a physiologist from the University of Amsterdam, lambasting the use of normal saline as our primary volume expander. He said the acidity of the solution had detrimental effects on flow through the capillary beds and showed amazing video of flow through capillary beds before and during saline infusion ~ during saline infusion, the capillary beds clamped down and flow in the microcirculation was markedly reduced ~ so, although BP was improved, perfusion to the tissues was paradoxically decreased.

This year, Dr. Kellum, a critical care guy, again presented data supporting this notion. He presented a convincing argument that infusion of even 1 liter of normal saline reliably produces a hyperchloremic metabolic acidosis due to changes in the strong ion difference (SID) ~ normally, this is about 40 ([Na+] of 140 – [Cl-] of 100 = 40) but after NS infusion, this SID falls to ~32. If high volume resuscitation with NS is undertaken (eg, 6 liters in a 100 kg man), mortality increases from 29% to 35% if hyperchloremic metabolic acidosis develops. Furthermore, in this setting, it is likely that MORE volume will be required for adequate resuscitation since acidosis aggravates hemodynamic stability, ie, BP is lower and this too has adverse effects on outcomes (PICARD study, Bouchard, et al, Kidney International (2009) 76, 422–427). When looking at biomarkers of renal injury, urine NGAL and cystatin C both increase in subjects resuscitated with saline compared to more physiologic solutions such as ‘plasmalyte’. Plasmalyte is a solution developed by Baxter to mitigate some of these problems seen with saline as a volume expander ~ I frankly had never heard of this solution ~ and Dr. Kellum was not trying to sell the solution, just the idea that we may want to rethink the fluids we use to optimize intravascular volume, blood pressure and tissue perfusion. He also pointed out that cytokine production, inflammation and free radical formation all increase in the setting of hyperchloremic metabolic acidosis. This is a hard pill to swallow for someone who has always believed that NS was the best choice for resuscitating the patient in shock but I must say that I am much more likely to use lactated Ringer’s solution or 0.5%NS with added bicarb after hearing these compelling talks. It may even be worth looking into the cost of plasmalyte to see if we can demonstrate improved survival in the critically ill patient in need of volume resuscitation.


Acute Kidney Injury: Controversies, Challenges and Solutions

How to start an Ultrafiltration Program
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Presenter: Emil Paganini, MD — Cleveland Clinic
Blogger: MJ Barchman, MD — East Carolina University

This was one of the key topics I wanted to learn about at this year’s meeting. With the impending changes in reimbursement for patients readmitted within thirty days and concerns about length of stay (LOS), especially for the heart failure population, I wanted to hear about the pros and cons of a UF program, indications for instituting UF therapy, reimbursement for this procedure and effects on prognosis for this population. Our cardiologists have been pushing for this and if UF is going to become an accepted therapeutic option for the decompensated heart failure patient, I feel strongly that it should remain under the control of the experts in the procedure, the nephrologists.

Dr. Paganini gave a very nice overview outlining several options that could be implemented within the confines of individual institutions. The first decision needs to be “where will the program be housed?” Possibilities include nephrology, cardiology, gastroenterology (because this therapy could be applied to the cirrhotic patient as well, especially those being bridged to transplant), or a multidisciplinary user group. The goals of the program need to be outlined ~ is it to be an acute care procedure for immediate treatment or a long term therapy for chronic application. Should the program be inpatient or outpatient? Reimbursement currently dictates this to a large extent as Dr. Paganini said that Pennsylvania is the only state reimbursing outpatient UF at this time.

There are potentially three general groups of patients who might be considered candidates for UF therapy:
1) new patients with NYHA class III-IV heart failure in the ED,
2) previously known heart failure patients who have decompensated and
3) heart failure patients who fail therapy within the thirty day time frame.

He suggested an algorithm for choosing patients who might benefit from UF by applying a “renal stress test”. CHF patients with eGFR less than 15 ml/min should be considered for immediate UF or CRRT since their likelihood to fail diuretic therapy is high and these folks are also more likely to be pushed to ESRD requiring chronic dialytic therapy.

For all other patients a “renal stress test” with 2 different levels is applied: for patients with eGFR > 60 ml/min, a level 1 test is done with 1 mg/kg IV furosemide q 12 hrs and for patients with eGFR 500 ml in 6 hrs, IV diuretic therapy is continued but if the U/O is < 500 ml in 6 hours, UF would likely be more effective. He highlighted that diuretics do have the disadvantage of electrolyte disturbances which can be more readily controlled with CRRT/UF techniques and also that less salt is ‘removed’, ie, urine make up approximates 0.5% NS with loop diuretic where about 140 meq/liter can be removed with UF. He also suggested use of a crit line to help control volume removal so that UF can be done appropriately slowly so as not to compromise renal perfusion during the process.

Access for the procedure poses special problems because AVF/AVG placement may aggravate CHF due to the additional shunt (high output failure) but temporary catheters every 2-3 weeks for the chronic patient may cause attrition of potential available vascular access sites over time. He raised the intriguing idea of reconsidering the subcutaneous “Life Site” access that has not really shown good longevity in chronic hemodialysis patients requiring 3x/week cannulation but might be useful in a patient who only needs therapy every 2-4 weeks. He pointed out that the pulmonary hypertension patient requires special consideration since they are dependent on filling pressures and that rate of UF must be even slower.

The ultimate goals of an Ultrafiltration Program as stated by Dr. Paganini should be:
1) Restoration of diuretic responsiveness once organ edema is ameliorated,
2) Decreased LOS for the decompensated CHF patient,
3) Decreased hospital costs (pts admitted to MIU, MICU, HDU ?) and
4) Decreased readmission rates.

I’ll add one of my own which is suggested by #1 above, that is preservation of existing renal function so that we do not turn these folks into chronic dialysis patients unnecessarily.


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