Wrestling Uremia in War and Peace

Having been draft deferred in World War II (WWII) and perceiving my inevitable service in a new conflict made probable by the nasty descent of the “iron curtain” in Europe, I volunteered in 1948 for training in internal medicine as a 1st Lieutenant and soon a Captain, Medical Corps, US Army. Married with one son, after a year of residency I reported to a research and development unit at the Walter Reed Army Medical Center in mid-1950 for my first assignment to evaluate treatments for Korean War casualties suffering from hepatitis B. However, three developments in the world became parameters of the sharp turn of events that fall by which my career as a nephrologist (a term not yet invented) and an expert in hemodialysis was launched by order of the Surgeon General, Department of the Army! One such parameter was Willem J. Kolff’s demonstration of a clinically effective “rotating drum” dialyzer that he built and used to treat patients in Kampen, The Netherlands, during the German occupation in WWII. After the war, he furnished the design to medical and engineering personnel at the Peter Bent Brigham Hospital in Boston, MA, USA where its effectiveness was again demonstrated in patients with ARF 1. A second parameter, also from WWII, was the report from the Board for the Study of the Severely Wounded from the Italian Theater that mortality rates of approximately 10% among the severely wounded who survived to enter the medical evacuation system were sharply revised upward to about 90% if they developed oliguric ARF. The third parameter took the form of confirming medical reports from medical officers in the Korean War, including that from a research survey team sent from Walter Reed Army Medical Center, that the WWII mortality experience of wounded ARF patients was being repeated. Recognizing these parameters, the leadership of the Army Medical Research and Development Command (notably Colonel William S. Stone) resolved to deploy a dialysis unit in Korea and arranged for training of its medical personnel. Accordingly, Major Marion E. McDowell and I received temporary duty orders to Dr. John Merrill’s service at the Brigham and began our training in the fall of 1950. We returned to establish dialysis units at the Walter Reed General Hospital (1951) and at the Brooke General Hospital, Fort Sam Houston in San Antonio, TX, USA (1952).

A more stable battlefront in 1952, but with ongoing human carnage, prompted the deployment from the Walter Reed Army Medical Center of a new field research effort: the US Army Surgical Research Team (USASRT-Korea) in support of the 8th US Army and Allied battle groups. Tasked with possibly improving the treatment of battle wounds, the team operated at a Mobile Army Surgical Hospital (MASH) that was minutes away by helicopter from the forward entry medical units (Battalion Aid Stations) 2. The team’s Renal Center was set up in early 1952 at the 11th Evacuation Hospital near Wonju in the mid-peninsula, within about 30 min of helicopter flying time from several MASH units across the front. The dialyzer and supplies were air shipped from our unit at Walter Reed and operated by the personnel who coauthored the definitive reports 3, 4. I became chief of the Renal Center in summer 1952 and continued the training of the medical officers as they were assigned to my team and recurrently traveled to the MASHs to alert the constantly arriving new physicians to the dangerous characteristics of posttraumatic ARF and the need to refer such patients promptly to our Center. The foregoing also illustrates the general role of Army research and development to detect potential health risks of troops wherever they may be deployed, and to explore and document measures for prevention and improved treatment.

Returning stateside and completing my training in internal medicine at Barnes Hospital with Drs. Barry Wood and Carl Moore, I joined the US Army Surgical Research Unit (USASRU; later the Institute of Surgical Research), the world-famous US Army Burn Center, as chief of its Renal Center (that I had helped establish 2 years earlier) in the Brooke General Hospital, Fort Sam Houston in 1954. In sharing both clinical and laboratory responsibilities with Dr. Arthur D. Mason, a surgeon also trained at Barnes Hospital, our work proceeded on two tracks, and both involved “paradigm shifts,” to us exciting new ways of thinking!

On the “clinical track,” while the dialysis unit was adjacent to the clinical service of the Burn Center, our burn patients did not develop ARF as a complication as predicted. Instead, our patients were referred, often flown to us, from military and civilian hospitals in the southwestern USA with ARF secondary to trauma, poisons, obstetrical accidents, or severe acute glomerular disease. We had expectations of low morbidity and mortality rates as we were expertly dialyzing in a shiny stateside hospital instead of in a prefab building in a rice paddy. Not so. In contrast to the optimistic tone of the contemporary literature, about 80% of our first patients died due to sepsis, poor wound healing, and wasting along with progressively worsening anorexia, nausea, vomiting, and mental alertness over successive dialyses. Were we unique or were other “dialyzers” having the same experience? With the Surgeon General’s support and with a year’s prior notice to the invited participants, we convened virtually all of the published authors on ARF in a Study Group on Acute Renal Failure for a 3-day, closed meeting in October 1957. Among the participants’ combined experiences, patient mortality averaged 49% in 1044 cases, 66% following trauma, that is, averages depending on the case mix, as we reported 5. Essentially, our experience was comprehensively confirmed by the study group as was our conviction that “there must be a better way,” that there was no reason to expect better than unacceptable results by continuing the concepts and methods in which we were trained. In retrospect, the ensuing paradigm shift seems so simple: instead of dialyzing with a big machine as infrequently as possible to reverse developed indications for dialysis (e.g., myocardial potassium intoxication and/or significant uremic symptoms), dialyze daily with a little machine to prevent those indications. Hence, we called this concept prophylactic (daily) hemodialysis 6, 7. As reported, the clinical transformation was amazing to us. Gone were the indications for dialysis, especially the emergent ones requiring dialysis in the wee hours. Wounds healed instead of dehiscing; patients ambulated when wounds permitted, and they ate unrestricted diets, sometimes even during dialysis. And a new formulation gradually dawned on us: that the dialysis-reversible toxicities that we noted might also impose more ubiquitous toxic effects on many cells, tissues, and organs, progressively augmented over time. One could then predict that daily dialysis should permit patients to traverse their inciting injury, and experience its risks for morbidity and mortality as if ARF did not exist. Most interesting to us is the accumulating evidence that “approximately daily dialysis” produces equally salubrious effects in end-stage CKD as it did for our ARF patients. It remains for the technology, logistics, and funding mechanisms, and requisite illumination to reach relevant officialdom, to catch up with the promise of more hopeful, better lives for these patients.

Our “other track” at the USASRU was to develop a clinically analogous model of ARF, in rats as it turned out, as a vehicle for studies of pathogenesis and prevention. For lack of convincing evidence (at that time) that ischemia (specifically and crucially in the sense of local oxygen debt) was a believable pathogenetic mechanism in the human disease as we knew it, we necessarily rejected clamping the renal arteries or infusing vasoconstrictors into them to produce ARF. Our argument, as I remember, was that arterial clamping produces infarction which we did not see in our autopsied combat casualties. Instead, we adopted the opposite approach (a paradigm shift). Dr. Mason found a “model that worked” in the literature in which we demonstrated its close similarity in multiple characteristics to spontaneously reversible human ARF 8–10 and how it might be prevented by effective diuretics 11. More portentous for me was Dr. Walter Essman’s demonstration that our rats’ behavior in a simple maze deteriorated and recovered in a time course that was superimposable on the blood urea nitrogen curve 12. That finding, together with findings by Drs. George Schreiner and John Kiley, led to the formulation (paradigm shift) that the dialysis-reversible symptoms of uremia (drowsiness, reduced mental acuity, anorexia, nausea, etc.) were generated by the central nervous system, that clinical uremia could be understood as a neurobehavioral syndrome. That formulation was verified in experiments in operant-conditioned monkeys when I returned to the Walter Reed Army Institute of Research in 1960¹ in collaboration with interested colleagues in neurophysiology (e.g., Drs. David Rioch and Joseph Sharp) and Dr. Gerald Murphy in surgical physiology 13. Meanwhile, colleagues further explicated the ARF model in rats by micropuncture techniques (Dr. William Cirksena) 14, and by electron and other micrographic methods (Drs. Seymour Rosen and Lionel Mailloux) 15, 16.²

Retiring from the Army in 1969 as a “bird” Colonel, I joined the Vanderbilt faculty as associate, then professor of medicine, with crucially important colleagues for next steps, that is, Dr. John Bourne, his graduate students and other colleagues in biomedical engineering, psychology, and neurology who coauthored the ensuing publications. Again, now in normal humans and in patients, the neurobehavioral measures quantitatively described responses to progressive renal failure, and the treatments by dialysis and successful renal transplantation 17.

However, nagged by the chronic question of the possible causal connection between the uremics’ clinical and chemical responses to dialysis and with Dr. Jonathan Lipman’s special expertise, we experimented with a “direct approach” to the question. We applied the clinically relevant quantified electroencephalogram as a neurobehavioral dependent-variable measure in bilaterally nephrectomized rats that could be peritoneally dialyzed, or not, in order to manipulate their body water composition (the chemical, independent variable). We measured the electroencephalographic responses to (undialyzed) progressive-to-terminal uremia, and in animals using standard human commercial dialysates or solutions made from distilled water to which chemical substances of interest were added or omitted. We published initial results of this “solute-specific dialysis”18 as the needed funds evaporated, and we are left, as before, with only the historical speculations.

Meanwhile, again, as a clinician, as in our initial experience with “rotating drum” dialysis, my in-center patients undergoing thrice-weekly hemodialysis with wonderful new machinery and membranes were often “unhappy campers,” occasionally becoming wasted, frequently feeling “drained” by the treatment, episodically noncompliant, generally depressed but putting a “good face on” for us caregivers, and seeming to hold me somewhat and somehow responsible for what happened to them. Things were better after we adjusted dialysis dose by patients’ weight (volume) using Kt/V calculations. And their situation was usually deemed preferable to the alternative.

Frustrated by these clinical intransigencies and after participating in the National Cooperative Dialysis Study (NCDS) 19, I retired after 10 years as co-medical director (with Dr. Keith Johnson) of the Dialysis Clinic, Inc. flagship unit in Nashville, and was attracted to the Modification of Diet in Renal Disease (MDRD) study and the possibility of retarding or halting progression of CKD to end stage by controlling patients’ blood pressure and their excretory load from excess dietary protein 20. I remained the principal investigator of the Vanderbilt center during all five phases of the study. In pilot phase 2, we documented progression by a negative slope of 1/serum creatinine in our quota of 12 patients. After beginning the study diet, the negative 1/Scr slopes became positive in three, zero in four, less negative in three, and more negative in two, indicating a favorable effect in 10 of the 12 patients. With those promising results, we sought reasons for the lack of general effect in the major phase 3 trial and found at least two: progression was assumed, not documented in randomized patients (although known to be uneven over time); and the case mix was “overloaded” by effective recruitment of patients with polycystic renal disease whose progression was faster and unaffected by the study treatments. My conclusion was/is that the mix of (undocumented) nonprogressors and fast progressors so widened the within-group and pooled variances that real differences between the randomized groups could not be statistically detected. However, several meta-analyses and subgroup analyses do affirm the value of the study controls, provided that patients are carefully monitored to avoid unhappy outcomes.

However, the MDRD’s prerandomization data showing deterioration of nutritional indices with declining glomerular filtration rate (GFR) below ∼50 mL/min (!) suggested: (i) that GFR or Scr levels required for admission to reimbursable dialysis effectively impose such wasting deterioration on our patients that even effective, daily dialysis may not entirely reverse it; and (ii) that patients’ pre-end-stage self-management of diet, blood pressure, and medications deserves more attention than it usually receives, especially if earlier intervention with (conventional, thrice weekly) dialysis turns out to be unhelpful or to damage some patients.

In fact, our patients over the 10-year MDRD study actually enacted the new paradigm for us that we named “health assurance coaching,” an approach to patient care that is applicable, I believe, to most if not all patients with any chronic medical disease 21. As in athletics, the players (the patients) do the scoring and the winning, not the coaches (the healthcare professionals)! Coaches make winning players in two fundamentally crucial ways: (i) they attractively describe and encourage winning skills; and (ii) they evoke in the players a vigorous sense of self-worth and an inspired will to win. Thus, we learned that our MDRD patients could be vested with and would accept responsibility for their own informed self-care for health. However, to accept this paradigm shift, we caregivers had to renounce the thrusts of our past training and of much current medical education: that effective caregivers are authoritative, prescriptive, and directive in dealing with their patients. We then often operate under the illusion that patients do what we tell them, and wonder why they so often don’t! Instead, we learned that “health assurance coaching” works, that patients in fact have ready access to care for themselves (in every waking hour!), that they can achieve high-quality care (if our gradual, staged, evidence-based coaching is top quality), and that they will reduce cost to themselves and to the community as their expert self-care reduces their use of healthcare resources. Thus, they achieve for themselves our national healthcare goals of ready access to high-quality care at reduced cost!

So, the career trajectory that began in 1950 has arrived in 2011 with the same focus: on better care of our patients, “that the next thousand should have a better time ‘wrestling uremia’ than the last thousand” because we asked: “must it be this way?,” and then accepted some exciting paradigm shifts to allow our patients to thrive.

BIOSKETCH

Dr. Paul E. Teschan was appointed by the Surgeon General to be a nephrologist as an Army medical officer, and to learn dialysis procedures with Dr. John Merrill’s team at the Brigham Hospital in order to apply that technology in wounded casualties with ARF in the Korean War. That experience led to his further clinical and laboratory research in uremia and dialysis in the military setting, and then as a civilian professor of medicine. Dr. Teschan is currently professor of medicine, emeritus, at Vanderbilt University in Nashville, TN, USA.