Tag: adpkd

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Crazy numbers: largest drop in hemoglobin without a transfusion

A drop in hemoglobin on 9 grams brings to mind the old surgical maxim “all bleeding stops” but I just had a case of a drop that big that includes three other confounding factors:

    1. He is a dialysis patient
    2. He didn’t died 
    3. He didn’t required a transfusion
He is a 58 year old patient with ADPKD, as part of this disease he had polycythemia and the day he was admitted with a chief complaint of dyspnea he had a hemoglobin of 19 g/dL. He had been advised that this was dangerous and he should go for phlebotomy. Sure enough he had a bilateral PE and multiple DVTs.


We started unfractionated heparin and ordered phlebotomy. So the next morning when we saw the decrease in the hemoglobin from 19 to 14 I was satisfied that he had a good response to phlebotomy. In reality, he never received the phlebotomy.

On that next hospital day he reported worsening flank pain. We ordered a CT to evaluate this and to help evaluate why his PD was failing. Turns out the pain and falling hemoglobin were due to a large bleeding renal cyst and renal hematoma. We stopped the heparin. The hemoglobin fell to 10 g/dL, a tidy 9 gram drop. We transferred him to the MICU. The initial plan was to embolise the bleeding kidney but the hemoglobin stabilized after stopping the heparin. After a few days of expectant testing and nervous observation we resumed the heparin and the hemoglobin held.
While we initially attributed the DVT solely to the erythrocytosis, he has a troubling family history (in addition to the ADPKD) that suggests thrombophilia.
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More ADPKD and sirolimus data: More definitive; less encouraging

Just a few weeks ago I was writing about the first patient data on the use of sirolimus in ADPKD. After years of being teased with promising animal data Perico et al. finally showed that sirolimus may help humans with ADPKD. That study was the first human data and so I forgave the fact that it was small, used a cross-over rather placebo design and was short in duration. And lastly it failed in its primary end point of total kidney volume but it showed less cyst volume (P=0.0558) and an increase in renal parenchymal volume (P=0.0089).

I had no idea that the next human data would be so quick in coming. Last week, the New England Journal of Medicine published two randomized, open label, controlled trials on the use of mTORs for ADPKD. Unfortunately, neither of them were encouraging.

The first article looked at everolimus, a newer mTOR inhibitor. It is by Walz et al. They looked at 392 patients and randomized to everolimus or placebo (double-blind) and maintained for 2 years. Patients had to have ADPKD and a GFR between 30 and 89 mL (Stage 2 and 3 CKD) or a GFR >89 and a kidney volume of 1,000 mL. Everolimus was titrated to keep trough levels between 3-8 ng/mL.

The primary end point was a change in kidney volume by MRI. The data showed decreased kidney volume with everolimus at 12 months but the advantage was no longer significant at 24 months.

Estimated GFR did not improve with everolimus:

Our linear regression model predicted a steep annual decline in the estimated GFR among patients receiving everolimus, owing to the significantly accelerated deterioration in renal function between months 6 and 18. However, the estimated GFR did not differ significantly between the everolimus group and the placebo group at 2 years.

The study also found a host of serious adverse events among the patients on everolimus. The ones found significantly more often with everolimus were:

  • Any
  • anemia
  • leukopenia
  • thrombocytopenia
  • stomatitis
  • diarrhea
  • folliculitis
  • hyperlipidemia
  • hypercholesterolemia
  • acne
  • angioedema
  • arthralgia
  • myalgia
  • ovarian cyst
  • epistaxis
  • peripheral edema

I was interested to see angioedema on the list as we had recently gone over a paper suggesting increased angioedema in transplant patients where sirolimus was implicated. During the discussion I had mentioned that this side effect would be important in the ADPKD trials. Walz et al. found a 5.6% rate of angioedema.

The second trial was by Serra et al. and was an 18 month, open-label, randomized controlled trial of 100 patients. They used sirolimus rather than everolimus. The study focused on patients with earlier disease, requiring a eGFR greater than 70 for enrollment. Patients had a 6 month run-in after enrollemnt where they needed to show 2% increase3 in kidney volume inorder to be randomized.

The results were not impressive:

And in their own words:

We found no significant difference in total kidney volume after 18 months of treatment with sirolimus, regardless of the patient’s age, sex, or albumin:creatinine ratio at randomization or whether they were receiving therapy with an ACE inhibitor or an ARB. Our estimate of the ratio of kidney volume in the sirolimus group to that in the control group rules out any clinically meaningful reduction in total kidney volume with the use of sirolimus.

I thought the accompanying editorial by Watnick and Germino was excellent. One of the primary points of the editorial was that this human, interventional data calls into question the use of change in kidney volume as being the ideal intermediate end-point.

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Nicest post about anything I’ve written on this blog

I got an e-mail from Lance Bukoff regarding the upcoming Boston Walk for PKD.

In my neighborhood the diseases that get the community involvement are breast cancer and special needs kids. Kidneys get almost no support though there is a great Zoo Kidney Walk by the NKF every Spring. Support the PKD walk.

Lance commented on my post about Sirolimus and ADPKD. I write this blog primarily for other medical professionals. I’m happy to have anyone read it, but the voice I use comes from my experience as a doctor and as a educator. Whenever a post gets picked up by patient groups I worry about how it will be perceived. I worry that I may have a glib when I mean to be funny or come across uncaring when I’m trying to be cooly scientific. I have had some close calls, but nothing has exploded, yet. This fear makes posts like Lance’s extra special.

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First patient data on sirolimus for ADPKD

UPDATE: please see this post with newer, more definitive data.

Initial patient visits for autosomal dominant polycystic kidney disease are different from just about any other patient visits. It is the only disease in which I spend a significant amount of time discussing the areas of bleeding edge research that have promise but are not yet available. I tell my patients about three current research thrusts:

  1. Combination ACEi-ARB
  2. ADH-antagonists
  3. mTOR inhibitors
I spend time doing this because the hardest thing for patients to accept with a new diagnosis of ADPKD is the twin truths of the disease: 1) the inevitability of the disease and 2) the lack of any effective intervention that can meaningfully make a difference. Most of the patients referred to me have a fair bit of knowledge about the disease. They have seen their siblings, a parent and a fair number of cousins, uncles and aunts go through dialysis, transplant and the other rigors of kidney failure. Everyone wants to know what they can do to reduce the progression, what can they do to avoid their genetic destiny. Tragically, I feel like a medical Cassandra because there is little I can do to intervene so I am left to weave tales of a happier tomorrow.
Well, tomorrow has gotten a little closer with the publishing of the first human study of mTOR inhibitors in ADPKD.

Polycystic kidney disease cells show abnormal activation of the Ser/Thr kinase target of of rapamycin. This enzyme coordinates cell growth and proliferation. In three animal models of PKD, there is evidence of inappropriate activation of mTOR in the renal cysts. Because of this, blocking mTOR with rapamycin (same thing as sirolimus) is one of the most promising research avenues in ADPKD. 

Up to now most of the data has depended on animal studies. Though there have been some retrospective analysis in humans with ADPKD who received a kidney transplant with sirolimus as part of their immunosupression. On average investigators found a 24% reduction in kidney volume with sirolimus compared to an 8% reduction with alternative agents (ref). Similar improvements in liver cysts were found, 12% reduction with sirolimus versus 14% increase without (ref).

In this latest study by Perica et al. they had 21 patients and they received either conventional therapy or sirolimus (initial dose: 3 mg daily) for six months and then each patient crossed over to the opposite arm, so every patient received both control and experimental therapy. Six patients dropped out for various reasons and the researchers ultimatly reduced their target sirolimus levels from 10-15 ng/ml to 5-10 ng/ml. The authors explained the adverse reactions in the discussion:

Three patients were prematurely withdrawn from the study because of the onset of an erythema nodosus in one case and thrombocytopenia in two cases after a few days of sirolimus therapy, when sirolimus dosage was titrated to target trough levels between 10 and 15 ng/ml (all events fully resolved with treatment withdrawal). The poor tolerability of this high-dosage regimen led us to reduce the target levels to 5 to 10 ng/ml. With this approach, no serious event requiring treatment interruption was observed.

The primary outcome was change in the kidney volume. The authors, additionally, looked at changes in cyst volume and renal parenchymal volume which was important as they found an increase in the renal parenchyma with stable cyst volume during sirolimus and a reduction in renal parenchyma and increase in cyst volume during usual care.

The primary outcome, a change in renal volume was not significant, P=0.45; however, cyst volume increased more on conventional therapy, P=0.013 and parenchymal volume increased more on sirolimus, P=0.005.

I know that the EBM snobs will turn their noses up at these secondary end-points but in a small pilot study I feel this shows real promise. It also indicates, to me, that total kidney volume might not be the best intermediate end point for ADPKD. It looks like sirolimus causes non-functioning cysts to be replaced with viable renal parenchyma, and it seems unfair to punished the drug for that but using total kidney volume as opposed to cyst volume does just that.
The authors then try to establish some dosing guidelines but this is probably a fool’s errand to run with only 15 people completing the protocol. Regardless of its validity they come to 0.049 mg/kg as the optimal dose (3.5 mg per day for a 70 kg male).
The authors had an interesting angle on some of the more common side effects associated with sirolimus:

Hypercholesterolemia is another widely known adverse effect of mTOR inhibitors. Our data, however, show that in patients without concomitant medications that may also ad- versely affect the lipid profile, such as steroids or calcineurin inhibitors, hypercholesterolemia is mild and can be easily managed just with dietary counseling. Thus, this adverse effect does not seem to be a major drawback of sirolimus therapy, even in the case of prolonged exposure.

The frustration of ADPKD comes from the inevitability paired with our medical impotence. Every year at our conferences we are shown western blots and animal models that hint at a new day. I believe the first rays of that new day are poking over the horizon.