- The Silent Problem in ESRD
F. Parker III, MD
ESRD patients far exceeds anything acceptable. Vast improvements
in the delivery of care in ESRD (end-stage renal disease) have only
translated to modest improvements in mortality outcomes. Consider
enhancements in membranes, quantity of dialysis, anemia and iron
control, social services, intradialytic symptom control, and many,
many others. Why has there not been a commensurate improvement?
is a fundamental underlying cause of morbid and mortal events which
the nephrology community now understands more lucidly.
simplistically, presents an overview of the problem.
The story starts
long before patients develop ESRD.
with chronic renal insufficiency begin to develop anemia that
is more than just erythropoeitin deficiency. It seems to be an
anemia, in part, like ones seen in chronic inflammatory states,
such as rheumatoid arthritis.
begin to eat less protein. And the albumin drops. But experts
tell us that one almost has to starve in order to decrease protein
synthesis just from a dietary protein intake. Why do pre-ESRD
patients begin to eat less and why does albumin decrease, disproportionately,
along with other visceral protein markers.
- Then creatinine
excretion begins to decrease, suggesting that somatic protein
stores are decreasing. And this when dietary protein intake should
be sufficient to maintain somatic stores.
- Iron metabolism
changes, again like that of other chronic disease states.
- And cardiovascular
disease becomes more prevalent, with increased atherosclerosis
and left ventricular disease, disproportionate to what one would
expect from the associated lipid disorders, hypertension, and
volume control - though these are often poorly controlled.
trend and possible binding pattern begins to emerge and we are provoked
to pause and query: Is there an underlying common process
which is the provocateur?
Then ESRD, with
associated renal replacement therapy follows, and all of the above
entities and others seem to accelerate. Patients begin to die of
an assortment of cardiovascular diseases, infections, access thromboses,
rapidly deteriorating residual renal function, bone disease associated
with "amyloid" deposits, visceral protein depletion uncorrected
by dietary intervention, lessening muscle mass, vastly abnormal
iron metabolism, and the list goes on.
it may indeed be possible to put this into a common pattern, a common
inciting process. I believe that underlying all of these clinically
observed problems is the indolent process of CHRONIC INFLAMMATION.
Patients become increasingly "inflamed" as preESRD worsens, and
then the inflammatory process is probably augmented by components
of renal replacement therapy.
We know that
they are inflamed because there are markers of inflammation: high
levels of cytokines, markers of positive and negative and acute
phase reactions, and disease patterns which are characteristic of
inflammation emerge, just for starters.
Allow the following
result in the Systemic Inflammatory Response (SIR).
note: TNF is tumor necrosis factor.
and tumor necrosis factor are three pro-inflammatory cytokines,
mainly produced by monocytes.
Definitions are from mondofacto.)
And there is
a certain common pattern that results. Once the SIR has begun, it
can manifest itself in a positive or negative manner:
note: Definitions for : hemostasis,
and antithromboticfrom mondofacto.)
Note that the
manifestations of this SIR are many of the clinical phenomenon of
ESRD patients: changes in albumin, transferrin, hemostasis, accumulation
of macroglobulins, etc.
ESRD is associated
with SIR. But, perhaps, so is renal replacement therapy. The very
therapy that is necessary for removal of solute and water, though
highly successful in accomplishing this, may be provoking the inflammatory
process more so. Possibilities would include:
to "contaminants" and bioincompatible materials in
and other materials of the dialyzer
solution (water and concentrate)
access punctures and manipulations
infections and antibiotics
- And on and
All of these
could be and/or have been demonstrated to be associated with cytokine
release with resulting cascade of inflammatory processes.
So the overall
picture looks something like this:
The pre ESRD
patient has an ongoing inflammatory process, which may or may not
be aggravated by diabetes or congestive heart failure or infection.
Then renal replacement therapy is imposed which is pro-inflammatory.
The cascade of events results in all of the disease entities we
see each day in the dialysis setting, ending in death.
that emerges is an ESRD patient who has an underlying permeating
inflammatory disease that ultimately results in an unrelenting decline
in health. I have omitted the evidence that confirms that the ESRD
has markers of inflammation. I have further omitted those data showing
the relationship of inflammation to the progression of cardiovascular
disease and other clinical conditions seen in the ESRD population.
And, I have omitted showing the relationship of inflammatory markers
to morbidity and mortality.
therapy prolongs life for a modest duration. At the same time, though,
we may be aggravating the inflammatory response and accelerating
the ultimate outcome. We clearly must move beyond thinking of treating
solute and water removal and correction of obvious manifestations
of renal failure such as anemia, bone disease, and other metabolic
changes. We must begin to search out and correct the permeating
and pervasive inflammatory process.