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Mortality in 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?

Perhaps there is a fundamental underlying cause of morbid and mortal events which the nephrology community now understands more lucidly.

The following, simplistically, presents an overview of the problem.

The story starts long before patients develop ESRD.

• Patients 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.
• Patients 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.

An underlying 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.

Broadly speaking, 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 pictorial concept:

Many diseases result in the Systemic Inflammatory Response (SIR).

(Ed. note: TNF is tumor necrosis factor. Interleukin-1, interleukin-6 and tumor necrosis factor are three pro-inflammatory cytokines, mainly produced by monocytes. Definitions are from the © On-line Medical Dictionary.)

And there is a certain common pattern that results. Once the SIR has begun, it can manifest itself in a positive or negative manner:

Positive manner:

(Ed. note: Definitions for : hemostasis, phagocytosis, proteolytic, antimicrobial, antioxidant, and antithrombotic from the © On-line Medical Dictionary.)

Negative manner:

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:

• Exposure to "contaminants" and bioincompatible materials in
  • membranes and other materials of the dialyzer
  • dialysis solution (water and concentrate)
  • tubing
• Recurrent access punctures and manipulations
• Recurrent hypotensive episodes
• Hypervolemia
• Recurrent infections and antibiotics
• And on and on….

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.

The picture 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.

Renal replacement 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.

February 2000