Thursday, January 31, 2013

Issues & Developments with Kidney Safety

By Thomas Watson, MD
Nephrology Associates PC

As a nephrologist, I sometimes feel like the annoying little hall monitor who spends his 
days at school telling his colleagues what they can't do. Unfortunately, given that the kidneys are 
susceptible to so many different insults and that patients with chronic kidney disease are unique
in terms of their specific health needs, I am compelled to embrace that role as the so-called
"kidney safety police." I have decided to use this opportunity to participate in the Birmingham
Medical News Blog as a chance to update medical professionals on some of the most common
issues and recent developments in the world of "kidney safety." Many readers are already familiar 
with everything I am about to say, but hopefully, some of the following will lend some clarity:

With the ever-increasing incidence of MRSA seen in the ambulatory setting, we in the
nephrology community have noticed a much higher usage rate of oral sulfa antibiotics like
trimethoprim-sulfamethoxazole (i.e. Bactrim). These particular antibiotics, while they generally
have very good efficacy for MRSA, can wreak havoc in patients with chronic kidney disease.
In particular, they can cause both acute renal failure, and severe hyperkalemia. I encourage
outpatient basis. A much less common but present antibiotic side effect involves the use of
quinolones, which can cause interstitial nephritis -- prolonged courses of quinolones in
particular can uncommonly be a problem in this regard. Besides dosing adjustments that may
be required, other oral antibiotics are not generally nephrotoxic.

In the inpatient setting, there remain a number of pitfalls with regards to antibiotics and
kidney function. With newer antibiotics, and newer/safer formulations of some older antibiotics
(anti-fungals like amphotericin, for example), there has been, I believe, a decline in
antibiotic-induced acute renal failure on an inpatient basis. That being said, aminoglycosides
remain predictably nephrotoxic and should be used sparingly and carefully. The original
amphotericin B should be avoided in favor of the new liposomal formulations that have a
reduced incidence of acute renal failure. As always, any penicillin can cause allergic interstitial
nephritis. Daptomycin is a newer antibiotic that is tolerated well, but still has reports of up to
3% incidence of acute renal failure. The toxicity of vancomycin remains controversial.

Low Molecular Weight Heparins (LMWH):
There are two issues here. First, once daily dosing at a slightly reduced dose for DVT
prophylaxis is widely accepted in patients with ESRD and in patients with pre-dialysis CKD.
Not so with treatment doses. There have been no conclusions made regarding the use
of low molecular weight heparins at treatment doses for patients with CKD or ESRD. Studies
have demonstrated both an increase in bleeding events (i.e. overdose) and thrombotic events
(i.e. underdosed), even with the once daily dosing for treatment at 1mg/kg of enoxaparin for
example. Essentially, these findings demonstrate that we have no idea how best to dose
LMWH in patients with kidney disease. Some hospitals have made it possible to follow Factor
Xa levels and thus have a way of monitoring therapeutic efficacy -- in this case, I think the use
of LMWH is probably safe. The alternative is “the old-fashioned way--” i.e. unfractionated
heparin until the patient is therapeutic on warfarin.

Oral Diabetes Medicines:
Metformin: Most are aware of the problems with metformin in kidney disease, but I will
clarify: The problem with metformin is not that it is nephrotoxic (it isn’t). Metformin metabolism
in patients with CKD can lead to lactic acidosis; sometimes it can be severe and
life-threatening. There is some controversy in the literature about what threshold to use when
deciding when to stop metformin. Historically, it has been suggested that a creatinine of 1.5 is
the limit above which no one should take metformin. Using estimated GFR would provide a
more reliable means, and I would suggest using a GFR of 30 as the cutoff below which
patients should not take metformin. If someone has a higher GFR than 30, but has
progressive CKD, I would stop metformin earlier.

Sitagliptin: This is a newer diabetes medicine (DPP-IV inhibitor, trade name Januvia)
that should be given at lower doses for patients with CKD, and has had a few case reports of
actually causing some kidney damage. Dosing recommendations should be available on the
package insert, via Epocrates or UpToDate, or in the PDR.

Linagliptin: This is also a DPP-IV inhibitor (trade name Tradjenta), but it requires no
renal adjustment and has had no case reports of causing acute renal failure.

Pioglitazone: (trade name Actos) This medicine has its own non-renal problems,
although it does cause swelling in some patients. There are no renal issues with this
medicine, but again, its non-renal problems need to be considered as well.
Other oral diabetes medicines are well-tolerated in kidney disease (including
sulfonylureas, meglitinide derivatives, etc), but one should always keep in mind that patients
may require less drug as kidney disease progresses.

Although an uncommon complication of triglyceride-lowering therapy, fenofibrate has
been implicated in the development of kidney damage. I generally take my patients with CKD
off fenofibrate -- unfortunately, palatable triglyceride lowering therapy options are relatively
limited, so I generally don’t substitute anything. The longterm mortality risk associated with
CKD is higher than that associated with hypertriglyceridemia.

IV Contrast:
The risk for acute contrast nephropathy is present for anyone exposed to CT or
angiography-related contrast. The risk factors that increase the likelihood of nephropathy
include underlying CKD, age, diabetes, volume depletion, NSAID use, and type and amount of
contrast used. Many different agents have been studied as potential prophylactic agents, with
disappointing results in general. Limiting the volume of contrast appears to be the most
valuable measure available -- e.g. for cardiac catheterizations, avoiding the unnecessary left
ventriculogram and considering staged procedures. The only other prophylactic measure with
reliable positive data is volume expansion, probably with isotonic bicarbonate-based IV fluid
prior to the procedure. The data for N-acetylcysteine is equivocal at best, but since it is an
inexpensive therapy with no side effects, it is still widely used (the regimen I use is 1200 mg
twice daily on the day before and day of the procedure). Other prophylactic measures that
have been tried but are not effective (and, therefore, not recommended) include dialysis,
hemofiltration, vitamin C, theophylline, and statins.

Gadolinium has been associated with a condition called nephrogenic systemic fibrosis
in a small number of patients with CKD and ESRD. This disease is a diffuse sclerosing illness
that has no obvious treatment and can sometimes be fatal. Consequently, I do everything I
can to help my CKD and dialysis patients avoid exposure to gadolinium. There are some
reports that frequent dialysis immediately after exposure can limit the risk, but it is unclear.
Most of the time, an alternative to MRI with contrast can be found.

The use of Dabigatran (aka Pradaxa) is not recommended in patients with CKD/ESRD.

PICC Lines:
The increased use of peripherally inserted central catheters has been a boon to many
patients who have difficult venous access or need longterm home IV therapies. Unfortunately,
PICC lines should be avoided in patients with CKD/ESRD. PICC lines cause permanent
damage to the vein in which they are inserted, thus making that vein impossible to use for
dialysis access in the future. I know that considering dialysis “down the road” must not seem
very important when you have a patient in the hospital who needs access. On the other
hand, we, the nephrologists, see many patients every year who have limited options for
dialysis access (and thus, limited options for life), sometimes due to previous use of PICC
lines. So, we avoid PICC lines as much as possible in patients who have any chance of
needing dialysis in the future.

By no means is this an exhaustive list, but these are the most common issues that we
encounter in our patients. If there is ever a question, a nephrologist is but a phone call away.

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