Bevacizumab and acute renal failure


July first. The ultimate deer in the headlights day.

I spent much of my day pointing out where the bathrooms were and telling the new residents that, “Yes. You do need to do the admission on the patient that you were called about at 3 pm.”

I am attending on the Nephrology consult service and we have a neat case. Bevacizumab induced thrombotic microangiopathy with acute renal failure. The patient is recovering renal function and the only thing I am going to add to the case at this point is removing the Quinton, but its interesting seeing a rare(?) complication on the bleeding edge of medicine.

In March of 2008 this case series was published in the NEJM.

Vascular endothelial growth factor or VEGF is a critical factor in the growth of blood vessels. I once saw Dr. Judah Folkman, the father of anti-angiogenesis treatment speak at IUPUI. Bevacizumab is a humanized mouse antibody targeted against VEGF. It was the first anti-angiogenesis drug licensed in the U.S. (I guess thalidomide doesn’t count).


Funny thing is, the kidney is pretty vascular and this drug causes proteinuria in 21 to 64% and hypertension in 3 to 36%.

Eremina Et al. published a 6 patient series inwhich patients developed proteinuria and renal failure following exposure to bevacizumab. All 6 patients had a renal biopsies consistant with thrombotic microangiopathy (TMA). TMA is most commonly associated with TTP but these patients did not have systemic signs of this: no fever, no mental status changes. Hematologically only one patient had schistocytes, only one patient had thrombocytopenia and anemia was found in only 2 of the 6 cases. TMA is also seen in pregnancy related renal failure, hypertensive emergency, and scleroderma renal crisis. Pre-eclampsia, one form of pregnancy related renal failure that causes TMA is also associated with decreased VGEF. Patients with pre-eclampsia have decreased due to metabolism by increased sFlt (soluble fms-like tyrosine kinase) produced in the placenta.

In addition to the case series, the authors performed an animal study where they created a mouse inwhich they could turn off the VEGF gene by feeding it tetracycline. When they did this they were able to produce an identical renal lesion.

Lastly they took the mice who were tetracycline to shut down the VEGF gene, and supplemented them with human VEGF. This failed to ameliorate the renal pathology.

In addition to demonstrating a new, and severe side effect of a powerful new anti-cancer weapon, Eremina Et al have demonstrated a previously unknown aspect of renal physiology. The importance of VEGF to capillary endothelial cell health. A remaining puzzle is how a protein made in the renal podocytes (epithelial cells) traverses across the basement membrane (against the primary flow from capillary to the urinary space) to protect the glomerular capillary endothelium.

Interestingly, in the NEJM series, none of the patients required dialysis. Additionally there was no consensus on how to treat this condition. One patient received plasmapheresis, as is required with TTP. One received cyclophosphamide and prednisone as is done with all glomerular lesions that look scary. Our patient received both dialysis for a few days and two plasmapheresis sessions. The dialysis was needed for her renal failure and the plasmapheresis seems right as the half life of monoclonal antibodies is long (Bevacizumab has a half-life of 20 days).

The authors finish their discussion talking about how their animal model in does not match the human condition: 100% of the mice were affected versus a small minority of humans; the human lesion is reversible while it is not in mice.

July first lecture on IVF, Diuretics and dysnatremia


Today I gave the first lecture of the ’08-’09 Academic Year. This was morning report for internal medicine. I did a lecture on IVF, diuretics, total body water and dysnatremia. It was a good lecture but Powerpoint only. I am about half-way done with the killer handout I am working on and am disapointed that I didn’t finish it. Hopefully will have it done for the next lecture in two weeks.

Fluids And Electrolytes July1

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My fellow just answered a question I have had for years.

Part of the dogma of evaluating iron deficiency in patients with anemia is that after a transfusion the iron indices are altered. Over and over the question comes up…

How long after a transfusion do you have to wait before checking to see if the patient is iron deficient?

Well Jabri, my current fellow went to the literature and found this reference. It looks like the answer is you should be safe 48 hours after the transfusion. This surprised me, I expected the acute effects of the transfusion to persist longer than that.

Abstract from the paper:

The effect of transfusion of packed red blood cells on serum iron level, total iron-binding capacity, and transferrin saturation was studied. Samples of blood from 37 hemodynamically stable patients were obtained for analysis at various intervals following the transfusion of packed red blood cells. In 10 patients with possible iron deficiency, a significant rise in serum iron level and transferrin saturation occurred during the 24 hours following transfusion, which persisted at a marginally significant level up to 36 hours. In the remaining 27 patients, a significant rise was also noted in serum iron level and transferrin saturation results, but the rise did not persist beyond the 24 hours after transfusion. No change in total iron-binding capacity was noted in either group. These data show that the diagnosis of iron deficiency (based on a transferrin saturation of < 0.16) might be missed if iron studies are performed on patients within 24 hours following packed red blood cell transfusion. Therefore, if serum iron studies are obtained for patients suspected of having iron deficiency anemia, these studies are best done on blood samples obtained before blood transfusion.

Getting ready for a Fluids and Electrolytes lecture


Only a nephrologist ever capitalizes Fluids and Electrolytes.

I am so excites. I get to give the first lecture on July 1. I love the nervous energy that comes with fresh second years and new interns still getting used to the length of their newly lengthened coats.

I am working over my standard F&E Emergencies. I am putting together a new handout designed to be kept in the pocket. While working on the talk I re-found this classic review of diuretic therapy by Craig Brater. Dr. Brater was elevated to Dean of Indiana University Medical School right before I got married at the end of my residency. We had our rehearsal dinner at this Columbia Club on the Circle. I bumped into Dr. Brater right before dinner and congratulated him on becoming the dean.

Data Capture Form

We are going to study renal and patient survival in our CKD clinic. One of our team members who is charged with creating the data capture form wanted to look at prior form. So here it is.

Journal Club: Albuminuria

Today’s journal club was on Aliskiren (Tekturna)combined with Losartan versus Losartan alone from the NEJM and Benazepril + Amlodipine (Lotrel) versus ACEi + HCTZ (Lotensin HCT) from KI. Both studies use change in albuminuria for the primary endpoint.

The Aliskiren study had an expected outcome. The shocker would have been if it had gone the other way. The surprising thing was how close they came to showing an actual decrease in progression (p=0.07) in only 6 months and with only 600 patients. Looks like aliskiren + ARB is a lock to slow the progression to doubling of creatinine and prevention of dialysis.

The Guard study was a surprise because the old generic lowered albuminuria more than the new hotness Lotrel. A lot of spin in the discussion on why that may have occurred.

Teaching on Two Ell: Acute Renal Failure and GFR

Yesterday we discussed the problem with the curvilinear relationship between gfr and creatinine and how the MDRD equation dispenses with this problem. Today we will go over a handout introducing GFR, MDRD and how to manage them, including referral to a nephrologist.

Additionally I want to do my canned acute renal failure lecture. This lecture has been made obsolete by the recent ATN data and data from Vanderbilt so it will need to be revised.

ARF No ATN Data

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