16 replies to this topic

[scuba]

http://www.cancernetwork.com/...long-term-cml-treatment

 

"Treatment of chronic myeloid leukemia (CML) with various tyrosine kinase inhibitors (TKIs) can induce changes in glomerular filtration rate (GFR) over time and have other kidney-related effects, according to a new study. Imatinib and dasatinib were associated with a decrease in GFR, while nilotinib was associated with an increase."

 

This is why less TKI (especially Sprycel) are a better apporach if less works. TKI's affect other organs in our body in addition to attacking CML. It's a balance between response and not doing other damage elsewhere.

 

Our goal should be to stop taking any TKI. They are toxic and likely do long term damage. They also keep us alive when CML would certainly kill us sooner without them. So - be prudent. Keep monitoring PCR and if possible lower dose. You'll help your kidneys.

 

Disclaimer: This is my opinion.

[kat73]

This certainly happened to me.  I had life-long normals on BUN, creatinine, and therefore, GFR.  I started 400 mg imatinib in September 2009 and in December had my first abnormal levels.  This went unnoticed by my then-onc for several months!  And what did I know?  I was a brand-new CML patient and there was nothing about this in the LLS literature I was given.  When I asked about it, finally he woke up and sent me to a nephrologist for a workup.  Yes, the article is right, there is no real underlying bad thing going on - conclusion was Gleevec was causing some sort of measureable impact, but there was no threat as long as it stabilized, which it did.  Nobody back then suggested lowering dosage.  Instead, I am followed by the nephrologist twice a year, and because it HAD caused secondary hyperthyroidism I had to add Calcitriol and Vitamin D to my pill regimen.  Forever.  The numbers never went back to normal, even when I switched to Sprycel later on.  But, they haven't advanced either.  My GFR went from over 90 to 50 where I am (regularly) now.  Creatinine stays stable at 1.1 (at its worst, in 2009, it was 1.5 and GFR in the 30's).  The BUN is stuck in the 20's no matter how much water I drink.

[M.A.]

I did a lot of research into the effect of TKIs on kidney function after starting Dasatinib. I was freaked out when my eGFR decreased, blood creatinine level increased and urine protein levels increased. This was particularly distressing to me because I have had type one diabetes for almost 38 years which puts me at risk for renal failure but I had been extremely lucky with my kidney function up until CML diagnosis.

 

So far, for me, it looks like Dasatinib's effect on my eGFR and blood creatinine level has continued but stabilised, and the urine protein seems to have stabilised at a low level which is good news. I just did a new set of tests yesterday, so if this board is still up and running next week (!!!!) I can report on the results if anyone's interested.

 

I found several in-depth research papers outlining the probable mechanisms for effects of TKIs on kidney function and a couple of scary individual case studies (in those patients, kidney function was restored once the TKI was stopped) but here is one that looks a little more positive...

 

It seems to confirm (as Trey has indicated previously) that the TKI increases the concentration of creatinine in the blood by inhibiting its secretion by the tubules of the kidneys. It's this creatinine that is measured in our regular blood tests and is used to estimate eGFR. The paper suggests creatinine is not a good measure of kidney function in patients on TKIs and suggests using cystatin c instead of creatinine as a measure of kidney function. It also says apparent decreases in kidney function should be reversed on cessation of TKI (as Buzz has found and I hope you find too one day Kat).

 

Fingers crossed!

 

Here's the paper:

https://www.scienced...152265015014147

 

Imatinib Increases Serum Creatinine by Inhibiting Its Tubular Secretion in a Reversible Fashion in Chronic Myeloid Leukemia (2016)

 

Background

 

Monitoring renal function is important in imatinib-treated patients with chronic myeloid leukemia because serum creatinine may increase during the course of therapy. The mechanism of this increase and its reversibility on treatment cessation have never been investigated.

 

Results

In 4 imatinib-treated patients who underwent thorough renal exploration, the part of creatinine clearance due to tubular secretion was negligible (2.4, 3.1, −1.3, and 2.8 mL/min) and significantly lower than that measured in their respective controls (17.7 ± 5.6, 43.0 ± 18.0, 23.1 ± 6.7, and 18.6 ± 5.6 mL/min, P < .001). In 1 patient, exploration was repeated after imatinib discontinuation and evidenced a recovery of creatinine tubular secretion (20.3 vs. 17.9 ± 5.2 mL/min in the control population, P = .2). In 15 patients of imatinib discontinuation studies, a median decrease in serum creatinine of 17.9% was observed after imatinib cessation. Resumption of treatment in 6 patients led to a median increase in serum creatinine of 18.8%.

 

Conclusions

Imatinib completely blunts tubular secretion of creatinine, a previously unreported pharmacologic property. This inhibition increases serum creatinine independently of any glomerular dysfunction and is fully reversible on imatinib cessation.

[Buzzm1]

During the time that I was taking Gleevec, my GFR degraded to a low of 50 and my Creatinine reached a high of 1.38.  After I stopped Gleevec, my GFR returned to normal and my Creatinine decreased to 1.16 according to a lab test one year later.

[kat73]

M.A.- Thanks for that article; I hadn't seen that one.  As a result, I will take it to my nephrologist next visit and ask him what he thinks about the cystatin-c test for me.  See, this is what is so great about this forum!  I never would have seen that article, since I've stopped looking into the kidney thing.  And, although it probably doesn't change anything about what's being done for me, it really helps to understand more about what's going on.  It also validates that I wasn't crazy all those years ago, back when I was the only one it had happened to amongst my onc's CML patients.  He didn't believe the Gleevec had done it.  Felt pretty lonely and scared.

[M.A.]

No you weren't crazy Kat and you are not alone. Kidney effects weren't specifically studied in the early TKI trials unfortunately.

 

All of my doctors shrugged off my concerns and said the changes in my kidney function were probably due to the type one diabetes and not the TKIs. I had to resort to entering ten years worth of blood and urine test results into an excel spreadsheet (four complete blood panels per year) and graphing them to 'prove' that the change occurred at precisely the time I started Dasatinib. Still, all I got was a bit of a nod and a shrug, but I think it's stopped my doctor from pushing me (so far) to increase my dose.

[kat73]

M.A.  Gosh, all that work.  They should hire you and pay you for your research!  I admire your determination and thank you for it.

 

BTW, my husband and I are thoroughly enthralled with Rake on Acorn.  Before that, East of Everything, and before that, A Place to Call Home.  Y'all are the best!

[M.A.]

:-)

[M.A.]

I mentioned in my above post that my kidney issues seemed to have stabilised, with only a small amount of change due to Sprycel over the past two years, hoping this would be reassuring for others with mild chronic kidney disease who end up with CML, and to add to the data we have on the effects of Sprycel on kidney function.

 

Unfortunately I just got a new set of test results today and it seems one of my markers for kidney damage (urine protein) has skyrocketed. I am going to repeat the test in case it's erroneous, but just thought I'd add this now before this forum is shuts down.

 

Also, does anyone have an email address for one of the CML experts in the US who might be open to communicating with me or my doctor on this? I feel I might be at a point where I need to make a difficult decision and I would love to speak to a specialist who has seen so many CML patients that they might actually have encountered someone in my situation before and know what to do. My doctors here definitely have not.

[M.A.]

New proteinuria test results have just come in. 

 

Big long rant warning...

 

Protein/creatinine ratio now a third of what it was in the test done last Thursday. Massive relief!!! It's still high for me and three times the upper limit of normal but it's a heck of a lot better than I thought it was. Will retest in a week.

 

The difficult thing for me to navigate is that for over twenty years I have taken enalapril (an ACE inhibitor that lowers blood pressure) to protect my kidneys and slow down diabetic kidney damage. It's worked really well and for the three years prior to CML diagnosis my very stable and mild diabetic kidney disease seemed to have reversed, with proteinuria in the normal range and no evidence of diabetic kidney disease, but the protein started showing up once I started Sprycel.

 

My haematologist took me off enalapril for the first three months of Sprycel which didn't help. I went back on it at that point but it's now hard to work out what's the Sprycel and what's due to the decrease in enalapril.

 

The conundrum: Sprycel lowers blood pressure for me so I am unable to take the normal dose of the kidney-protective drug enalapril. I take only half of what I used to take. So I have proteinuria and low amounts of protection for my kidneys on the low dose. 

 

I was thinking of increasing my Sprycel for three months to see if I could knock the BCR ABL down a log, and this is probably what my haematologist will advise me to do on Thursday, but now I'm not sure...

[Red Cross Kirk]

I'm not smart enough right now to understand all of the interactions you're discussing.  If you think more S will be bad for your kidneys due to a low dose of your other med, then I wouldn't worry about taking more S, trying to reduce your PCR.  You're in a good place with your PCR trend so far.

[M.A.]

Thanks for replying Kirk, I appreciate your input!

 

Sorry my rant was so technical... after all these years dealing with the terminology it's easy to forget how indecipherable it can be!

[kat73]

M.A. - I do understand your predicament, since it's of concern to me, too, as you know.  I haven't had the protein show up in the urine . . . yet!  So I'm in the "so far so good" box.  But I still don't know what to tell you to do.  According to the studies (thanks to you) kidney effects are supposed to reverse off Gleevec.  That didn't happen for me, and I've still got 'em on Sprycel.  I get the conundrum of the high blood pressure med.  In this Scylla and Charybdis navigation, I would choose to protect my kidneys over pushing the CML down further.  You are in a safe place with your PCR number.  So, my feeling is, leave that alone as a focus for awhile.  Concentrate on doing whatever the nephrologist advises to get that proteinuria outta there and find a really good blood pressure level (between the effect of the Sprycel and some other? bp med) you can maintain.  My thinking is, that what with the longterm diabetes, the kidney status is much more important for the future than pushing for MR 4.5.  Does this make sense?

[zdyurek]

* i m writing on behalf of my mother 

* english is not my native language , sorry in advance

 

As research points , TKIs effect kidneys on some of patients . Sadly my mother is one of them . 

 

Also according to Gleevec FDA approval revised 09/2016

 

https://www.accessda...1588s047lbl.pdf

 

2.12 Dose Modification Guidelines

 

Renal Impairment: Patients with moderate renal impairment (CrCL=20-39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL=40-59 mL/min). For patients with moderate renal impairment doses greater than 400 mg are not recommended. Imatinib should be used with caution in patients with severe renal impairment. A dose of 100 mg/day was tolerated in two patients with severe renal impairment.

 

If it didnt effect , i guess they didnt write these .

 

About my mother history , we dont have much blood works before her diagnosis . 

 

but before the start of her treatment her creatine value was about 0.6 - 0.7. ( AUGUST - OCT 2015 )

At march 2016 her value jumped to 0.93 and three months later it was 1.31 . then last 18 month her values keep about 1.3 - 1.55 . stabilized some way.

 

Also she has proteinuria but i m not sure it is about usage of gleevec . we werent keeping attention to her blood pressure . her values were 160/90 . ( using just one drug ) 

 

As soon as we keep her bp at range of 120-150 ( with two drugs ) her microalbumin value in 24h urine dropped from 764 to 421 . ( 0 -300 normal range)

and microprotein value raised a little . ( 573 to 637 ) ( 0 - 150 normal range )

 

her kidney chart

 

 

 

 

* urikoliz is a brand for allopurinol , i forgot to edit it .

[M.A.]

Thank you so much for your input kat and zdyurek.

 

Zdyurek, your English is very good. I really appreciate you posting those new guidelines for Gleevec in patients with renal impairment and also all your mother's detailed results. I have copied all your data and will take a detailed look at it in the morning. Very useful. 

 

Kat, yes, I think of my two conditions as opposite sides of a set of scales. There is risk on both sides, but the heaviest side of the scales for me at this stage feels like the potential for kidney damage. Fortunately things are still at the 'mild' stage but I do need to keep an eye on the kidney results and make changes if a more serious trend begins. The kidney issue is why I decided to reduce my own dose without doctors' approval initially although this was a very difficult decision.

 

It would be so useful to be able to talk to one of the US guys who specialises in CML right now as there will be someone, I bet, who has seen enough patients on Sprycel, with my response, to be able to advise me what to do.

 

It will be interesting to hear what my haematologist says tomorrow night when he makes the decision about what to write on my next six month batch of Sprycel scripts.

 

Thanks everyone!

[kat73]

M.A. - Your kidney issues are followed by an endocrinologist, you say (in PM - thanks!) What about, in addition to bringing in some fresh thoughts from CML experts, a second opinion by a nephrologist?

[M.A.]

Thanks kat

 

I have seen a nephrologist a few times but they had no or little knowledge of CML unfortunately and were of no real help. They just said to keep taking the full dose of TKI and keep monitoring the kidneys.

 

My endocrinologist at least looked up "kidneys and CML" and gave me a few papers to read, but his comment was, "it's ok, it looks like once you stop the Sprycel it should reverse." He hadn't realised Sprycel was generally a  life-long treatment.

 

I think I will try to find a new nephrologist to go to again though, someone who will be interested enough to do some research.