Pentoxifylline in renal disease, a tour through the literature

Tomorrow is another exciting edition of #NephJC. We will be discussing pentoxifylline in diabetic nephropathy. There is a summary of the article at NephJC.com.

In support of that article and to aid the discussion, Christos Argyropoulos has stepped up to the blogger plate to provide some color on pentoxifylline.

Joel

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In wild anticipation of next week’s #NephJC on Pentoxifylline (PTX)  let’s go over some of the known facts about the drug:

• It is a non-selective phosphodiesterase inhibitor.  PDEs are enzymes that inactivate cyclic nucleotides and have been organized in 11 families (Table 1 [1]) based on sequence, structural and pharmacological considerations. Inhibition of PDE4 by PTX (Figure 1) [1] increases cAMP & stimulates PKA activity. 
• Activation of PKA leads to phosphorylation of the cAMP response element binding protein (CREB) which in turn leads to suppression of the TNF-a[2,3] synthesis at the transcriptional level
• Inhibition of cAMP production by these phosphodiesterases has a broad range of immunomodulatory effects (Table 2[1])
• The drug also affects red cell deformability and favorably affects microcirculatory blood flow
• “Mainstream” indications: intermittent claudication, vascular dementia, sickling crises, acute alcoholic hepatitis



Figure 1: Pentoxifylline (white) complexed with PDE4 (ribbons). Also shown are the Mg2+ and Zn2+ cofactors of PDE4 (spheres)

• Pharmacokinetics: bioavailability (10-30%), elimination (mostly renal as 50-80% of the drug is recovered in the urine), half life (24-48 mins)

Is this the best review on treating hypertension in pregnancy? Updated

Note: this is a living post that is growing as I brush up on preeclampsia

From Hypertension:

Update on the Use of Antihypertensive Drugs in Pregnancy

Free PDF FTW!

Another great article:

New aspects of pre-eclampsia: lessons for the nephrologist

Also with a free PDF. Thanks NDT.

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Although these renal changes in general are believed to resolve completely after delivery, recent evidence suggests that pre-eclampsia may leave a permanent renal damage.

CKD is a risk factor for pre-eclampsia in advanced CKD 3-5, weak evidence

the risk for pre-eclampsia and other pregnancy complications is sub-stantially increased in women with chronic kidney disease (CKD) stages 3–5 

 CKD 1-3 is not a risk factor unless the woman also has hypertension, higher quality evidence.

but these women were not at increased risk for pre-eclampsia. However, there was a significant biological interaction between eGFR and hypertension making eGFR 60–89 ml/min per 1.73 m2 a risk factor for pre-eclampsia if the women were also hypertensive.

Pre-eclampsia increases the risk for subsequent kidney biopsy and subsequent ESRD:

In the first study, women with pre-eclampsia in their first pregnancy had a considerably increased risk of developing kidney disease that needed investigation with a kidney biopsy [Adverse Perinatal Outcome and Later Kidney Biopsy in the Mother in JASN]. 

women who previously had pre-eclampsia had a four to five times increased risk of later end-stage renal disease, independent of primary renal disease [Preeclampsia and the Risk of End-Stage Renal Disease in NEJM]. Women with recurrent pre-eclamptic preg- nancies and women who gave birth to offspring with low birth weight had an even higher risk. The increased risk remained significant throughout the follow-up period of nearly 40 years. 

 In regards to the natural history of pre-eclampsia:

It should also be kept in mind that although the extensive glomerular changes during pre-eclampsia are believed to completely resolve after pregnancy [The Glomerular Injury of Preeclampsia in JASN], no studies have routinely performed a kidney biopsy months after the pre-eclamptic pregnancy. The fact that as many as 20–40% have microalbuminuria after a pre-eclamptic pregnancy may argue for a permanent glomerular damage in a great proportion of these women [Microalbuminuria after pregnancy complicated by pre-eclampsia in NDT, Blood pressure and renal function seven years after pregnancy complicated by hypertension].

Warning about these conclusions regarding pre-eclampsia causing CKD:

When interpreting the studies of pre-eclampsia and later kidney disease, it should be remembered that pre-eclampsia might unmask asymptomatic or undiagnosed CKD, a disease that might have been present also before pregnancy. A pre-pregnancy eGFR >60 ml/min per 1.73 m2 measured at screening was in a population-based sample associated with future pre-eclampsia risk in hypertensive women [Kidney function and future risk for adverse pregnancy outcomes in NDT]

This article by Eiland, Nzerue, and Faulkner in PubMed Central does a nice job reviewing the pathogenesis of the preeclampsia.

Another good looking article

ACEi talk.

A pharmacist from Blue Cross, Kim Moon, sent me an e-mail and told me she was a fan of the PBFluids and my and twitter. That, of course, instantly made her my newest bestie. She then asked me to do a webinar addressing common issues that prevent primary care doctors from prescribing ACEi/ARB to patients with diabetes. I agreed, anything for a fan of the blog.

A couple of months ago and long before the lecture was written she needed a title, so I threw out, "ACE inhibitors, the good, the bad, and the ugly"

Then I saw this tweet:

'The good, the bad and the ugly' appears in the title of over 450 scientific papers. Just sayin' http://t.co/UvNkyXNLRN
— Dr John Weiner (@AllergyNet) June 9, 2014

How embarrassing. Well, here's the show:

ACE inhibitors: The Good, The Bad and The Ugly. from joel topf on Vimeo.

Link to video (740MB)

PDF (52.4MB) 

Keynote (132MB)

Streaming the video from google drive seems to be broken. Here is a forum describing the problem, and Google's lack of response to the issue. My work around has been to pony up the $60 and join Vimeo plus.

Imagine if the wards were really like the boards

1. You have a new patient with a drug you've never heard of before. Your next step is to:

1. Look it up on your phone.
2. Ask a colleague what the drug is.
3. Take a careful look at the patients medical history and try to figure out the purpose of the drug from the context. Hopefully it won't be relevant to the question you are asked.

2. The patient develops an infection and ID suggests adding clarithromycin. The patient is on a number of cardiac drugs and you are worried about QT prolongation. You should:

1. Look up the possible interactions on your phone.
2. Depend on your memory of potential drug-drug interactions. Because, though you hate to brag, you did pretty good in medical school and have a keen mind.
3. Give the clarithromycin, but also order telemetry for the patient, because you are a careful doctor.

3. A patient presents for confusion and is found to have hyponatremia. She has the following labs:

• Urine Na 80
• Urine K 40
• Serum Na 105
• Urine output 600 mL over the last 18 hours

Calculate the electrolyte free water clearance.

1. Don't worry that you are bad at math, this is probably SIADH so just prescribe tolvaptan.
2. I can't remember the equation, but this just smells like an experimental question. I'm sure I can take care of the patient without this calculation. Let's look at the possible choices and I'll take a logical guess.
3. Fire up MedCalc, put in the values. Out comes the answer.

4. The biopsy comes back for a patient with proteinruia. The Pathologist calls it dense deposit disease. You have never seen a patient with this before but you did do presentation on MPGN type two 11 years ago in fellowship.

1. Perfect, you've got this. This is nephrology, there's no way the standard of care has changed in the last decade.
2. Hit the computer and look it up on UpToDate and do a quick lit search focusing on the top nephrology journals. Consider eculizumab.
3. Review KDIGO GN clinical practice guidelines. Scream out loud when you find that it is not covered. Fall back on answer 2.