Kolff’s Credo: New Ways of Thinking!

Paul E. Teschan, M.D.

Vanderbilt University, Nashville, Tennessee, U.S.A.

Abstract: Dr. Willem J. Kolff’s imaginative venturesome-ness in adopting ‘‘new ways of thinking’’ has served as anencouraging model for this author’s research career. Inappreciation of his leadership and beginning with the fa-vorable results that attended the initial use of theBrigham-Kolff artificial kidney at a renal center in theKorean war, this presentation summarizes four experi-ences to illustrate how ‘‘new ways of thinking’’ producednew results and new research, namely, the concept and useof prophylactic daily hemodialysis; the use of a model ofacute renal failure in rats to examine mechanisms ofpathogenesis and means of prevention; the recognition of

patients’ uremic illness as an encephalopathy that can bequantified by appropriate measures; and the use of dailyperitoneal dialysis and quantified EEGs in rats to explorerelationships between dialysis-induced concentrations ofpotentially toxic solutes, quantified indices of symptomaticuremic encephalopathy, and concurrent, localized meta-bolic abnormalities in the brain. The results of these ‘‘newways of thinking’’ suggest that we may ultimately come tounderstand the clinical uremic illness and its response todialysis. Key Words: Kolff—Innovation—Renal fail-ure—Dialysis—Uremia—Encephalopathy.

It is alleged, but it is inconceivable, that Dr. Wil-lem J. Kolff’s retirement is at hand. It would notoccur to those of us who have known him over theyears to apply the word ‘‘retire,’’ in any of its forms,to Pim Kolff. However, if the inconceivable turns outto be true, then we should grasp this opportunity tosurvey at least some of the revolution that Pim’swork began in the world and that impelled the ca-reers of many, including my own.

It is hard to imagine and for some of us to remem-ber how it was for patients and doctors before therewere artificial kidneys. The evident adversaries werethe disease in the kidney and the progressive, usuallyfatal clinical illness imposed by (prolonged) acute orchronic renal failure. A less evident, but highly in-fluential adversary was the professional consensusthat a downhill course was inevitable and that doc-toring was not likely to help very much. This defeat-ism is not unheard of today.

Subsequent history illustrates the consequences ofDr. Kolff’s daring to try ‘‘new ways of thinking,’’ forexample, to imagine that the patient’s abnormalblood chemistry might contribute to clinical illness,

to imagine how continuous flow dialysis might nor-malize the chemistry and so make the patient better;and to imagine the design of an apparatus to makethe dialysis process clinically possible and then tobuild it, use it, and prove that it worked. Pim’s de-scriptions of all this treat the concurrent World WarII and the occupation of his country by Germantroops as relatively minor impediments (1,2).

After the war Dr. Kolff’s experiences and the de-sign of the rotating drum dialyzer were favorablyreceived by Drs. George Thorn, John Merrill, andCarl Walter and their associates at the Brigham Hos-pital in Boston, primarily for use in patients withacute renal failure. Collaborating with the Brighamgroup, the dialyzer was redesigned and built in stain-less steel and plastic by Mr. Edward A. Olson inAshland, Massachusetts. Dr. Merrill began trainingphysician teams in the comprehensive care of thesepatients and in the operation of the dialyzer safelyon appropriate indications.

The onset of the Korean War again directed theattention of the U.S. Army Medical Service to thefindings in World War II of higher (90%) mortalityrates in wounded soldiers who developed acute renalfailure in contrast to the 10% estimated rate amongthose who did not. Col. William S. Stone as Chief ofArmy Medical R & D was mainly responsible for thenew venture, establishing renal units with Brigham-

Received June 1998.Address correspondence and reprint requests to Dr. Paul E.

Teschan, 2710 Hemingway Drive, Nashville, Tennessee 37215-4014, U.S.A.

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Kolff dialyzers at Walter Reed and Brooke GeneralHospitals and staffing them with Merrill trained phy-sicians. Thus, Major Marion E. McDowell and Cap-tain Paul E. Teschan were so trained in 1950, thestart of my career in nephrology. Meanwhile, anArmy R & D survey team in Korea had again docu-mented the high mortality among wounded soldierswith posttraumatic acute renal failure. Accordingly,a renal center initially led by Captains Lloyd H.Smith and Robert S. Post and associates was estab-lished, with a dialyzer and supporting laboratory, atthe 11th Evacuation Hospital, within about 30 min-utes’ helicopter flying time of the mobile Army sur-gical hospital (MASH) installations. The reports de-scribed the clinical care and dialyses that proceededaccording to our training, the interesting logisticaladaptations, patients’ unique metabolic behaviors,and an apparent reduction in overall mortality (3,4).

Subsequently, at our stateside renal center, how-ever, too many of our patients with acute renal fail-ure continued to die, with infections, wasting, andwound dehiscences, in contrast to the optimistic as-sertions in the contemporary literature. AccordinglyI proposed, and the Surgeon General authorized, aclosed 3 day conference in October 1957, a StudyGroup on Acute Renal Failure to include everyonewho had published experience with acute renal fail-ure by that date (Fig. 1). In the initial session, theparticipants pooled their case records of 1,044 pa-tients, revealing an overall mortality of 49% and a66% rate following traumatic injury. Thus, our ex-perience was confirmed together with our convictionthat the conventional practice of awaiting clinically

significant uremic symptoms and/or blood chemicalabnormalities before using the dialyzer was some-how inadequate. To continue the same methodswould certainly guarantee the same unacceptable re-sults. This was the turning point, the requirement for‘‘new ways of thinking.’’

FOUR NEW WAYS OF THINKING ABOUTRENAL FAILURE

Dr. Kolff’s venturesome spirit contributed encour-agement to a path forward through more than 30years of research, of which the following summary isoffered in appreciation.

Prophylactic daily dialysisIn a major departure from our training and con-

temporary practice, we reasoned that if infrequentuse of a big dialyzer could reverse uremic symptomsand normalize blood chemistry, then daily use of asmall dialyzer might prevent both the symptoms andthe chemical abnormalities. Moreover, if the symp-toms signaled an intoxication that might impairmany functions of cells and tissues, then preventingthe symptoms might imply relief from that ubiqui-tous intoxication, and patients might then convalescefrom the initiating event, eat, ambulate, control theirinfections, and heal their wounds as if their renalfunction were normal.

Again with the Surgeon General’s authorization,our team of enlisted clinical technicians assembledthe MacNeill-Collins 1 m2 dialyzers, cared for thepatients during the dialysis procedure, and main-tained the data flow sheets. Chronic cannulation ofarteries and veins, portable equipment for militaryfield use, and a method for regional heparinizationwere developed.

The new methods worked dramatically. As re-ported in detail, the predicted value of this ‘‘new wayof thinking’’ was confirmed by the patients’ clinicaland chemical stability (5,6). The new findings con-trasted strikingly with our prior clinical experienceusing the conventional methods of that era. How-ever, the anticipated favorable effect on mortalityhas not been subsequently demonstrated among pa-tients with acute renal failure (7,8). The concept hasfound its major application, instead, among patientswith end-stage chronic renal disease.

Acute renal failure in rats: Pathogenesisand prevention

Our objective was to develop an experimentalmodel with documented similarities to human acuterenal failure (ARF). Because autopsies of woundedcasualties with ARF in World War II and in Korea

FIG. 1. The photograph is of the Study Group on Acute RenalFailure at the U.S. Army Surgical Research Unit, Brooke ArmyMedical Center, Fort Sam Houston, Texas, October 13–16, 1957.Seated left to right are Drs. George Schreiner, Hadley Conn,Garland Herndon, Paul Doolan, Bill Bluemle, Graham Bull (Bel-fast), and Willem Kolff. Standing left to right are Drs. Paul Te-schan, John Kiley, Arthur Mason, John Merrill, Gabriel Richet(Paris), and Milton Rubini.

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had failed to show evidence of renal infarction, werejected as irrelevant the models involving renal ar-tery clamping or intraarterial norepinephrine infu-sions that unreliably produced a reversible lesionand that derived from a prior assumption that renalischemia, as that resulting from clamped renal arter-ies, causes ARF. Instead, the ‘‘new way of thinking’’was the opposite: to find a method in the literaturethat actually produced reversible ARF, document itssequential clinical, chemical, and histological charac-teristics, and then investigate its pathogenesis.

A remarkable analogy to reversible ARF in hu-mans was demonstrated (9–11). The renal lesion ap-peared to represent intratubular obstruction andcould usually be prevented, along with the abnormalblood chemistry, by diuretics that were effective inthe model (12). Later studies by means of micro-puncture suggested that reduced glomerular filtra-tion was the more probable primary mechanism (13).However, the observable, abnormal behavior of therats with ARF led to another research focus, quan-tified neurobehavior.

Quantified neurobehavior in animals and humansOur clinical observations confirmed estimates in

the literature that renal failure (somehow) producedsymptoms referable to impaired cognitive functionsof the brain, i.e., an encephalopathy. The observed,changed behavior of our rats with ARF led to ex-perimental documentation of their impaired cogni-tive (not motor) T-maze performance that paralleledthe rise and fall of the blood urea nitrogen (14). Thisfinding prompted the next ‘‘new way of thinking.’’We predicted that if the disabling, dialysis reversibleand dialysis preventable symptoms in patients withacute or chronic renal failure were generated mainlyby the brain, then measures of brain function shouldobjectively quantify the effects both of the diseaseand of dialysis on the encephalic generator of theclinical illness of renal failure. Such quantified ob-jectivity should then contrast favorably with clini-cians’ subjective approximations in written clinicalprogress notes.

Consistent with the findings by Kiley (15), ourstudies in monkeys (16) and in patients with progres-sive and end-stage chronic renal failure (17) con-firmed that prediction and further demonstrated thatthese quantified electroencephalographic and cogni-tive functions could be used to address the vexingquestion, ‘‘How much dialysis is enough?’’ (18,19).

Symptoms versus solutes: Pathogenesis of uremicillness and the effect of dialysis

In the initial descriptions, ‘‘uremic’’ symptoms inpatients with renal failure are thought to represent

an intoxication. The reversal or prevention of thesesymptoms by dialysis procedures led to the obvioussupposition that toxic substances are inadequatelyexcreted by failing kidneys but are removed by di-alysis. This effect using the early cellophane mem-branes led to a molecular characterization of suchtoxins (20).

Our quantified outcome measures related to di-alysis permitted another ‘‘new way of thinking,’’namely, to revisit Kolff’s earlier perceptions and, atlast, to test the hypothesis, derived from clinical ob-servations, that none of the conventionally measuredblood solutes in their usual concentrations in ourpatients’ plasma, contributed to the encephalopathicsymptoms, the clinical illness of renal failure. Themethods included daily peritoneal dialyses in bilat-erally nephrectomized rats with controlled variationsin dialysate composition as the independent variableand repeated, quantified electroencephalograms asthe dependent variable. Measurements of glucosemetabolism in selected areas of the brain in severalcircumstances embodied a first attempt to localizemetabolic sites of the functional impairment that wasdiscerned in the intact animal.

The findings suggested that some, but not all, ofthe encephalopathic effects were associated withconventionally measured moieties and that glucosemetabolism was impaired in some cerebral loci, al-though not where abnormalities might intuitivelyhave been expected (21). Further work awaits thehappy combination of interest, skills, and reasonablefunding; but the methods may yet provide a rationalmeans to sort the enormous accumulation in the lit-erature, if not in the patients, of proposed, symptom-related uremic toxins (22,23).

REFERENCES

1. Kolff WJ. New ways of treating uremia: The artificial kidney,peritoneal lavage, intestinal lavage. London: Churchill, 1947.

2. Kolff WJ. First clinical experience with the artificial kidney.Ann Intern Med 1965;62:608–19.

3. Teschan PE, Post RS, Smith LH Jr, Abernathy RS, Davis JH,Gray DM, Howard JM, Johnson KE, Klopp E, Mundy RL,O’Meara MP, Rush BF. Post-traumatic renal insufficiency inmilitary casualties I. Clinical characteristics. Am J Med 1955;18:172–86.

4. Smith LH Jr, Post RS, Teschan PE, Abernathy RS, Davis JH,Gray DM, Howard JM, Johnson KE, Klopp E, Mundy RL,O’Meara MP, Rush BF. Post-traumatic renal insufficiency inmilitary casualties II. Management, use of an artificial kidney,prognosis. Am J Med 1955;18:187–98.

5. O’Brien TF, Baxter CR, Teschan PE. Prophylactic daily he-modialysis. Trans Am Soc Artif Intern Organs 1959;5:77–80.

6. Teschan PE, Baxter CR, O’Brien TF, Freyhof JM, Hall WH.Prophylactic hemodialysis in the treatment of acute renal fail-ure. Ann Intern Med 1960;53:992–1016.

7. Conger JD. A controlled evaluation of prophylactic dialysis inpost-traumatic acute renal failure. J Trauma 1975;15:1056–63.

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8. Gillum DM, Dixon BS, Yanover MJ, Kelleher SP, ShapiroMD, Benedetti RG, Dillingham MA, Paller MS, Goldberg JP,Tomford RC, Gordon JA, Conger JD. The role of intensivedialysis in acute renal failure. Clin Nephrol 1986;25:249–55.

9. Mason AD Jr, Teschan PE. Studies in acute renal failure I.Development of a reproducible lesion in experimental ani-mals. J Surg Res 1963;3:430–41.

10. Teschan PE, Mason AD Jr. Studies in acute renal failure II.Incidence, mortality, urinary and plasma chemical alterationsand clinical characteristics of reversible acute renal failure inthe rat. J Surg Res 1963;3:442–9.

11. Mason AD Jr, Teschan PE, Muirhead EE. Studies in acuterenal failure III. Renal histologic alterations in acute renalfailure in the rat. J Surg Res 1963;3:450–6.

12. Teschan PE, Lawson NL. Studies in acute renal failure. Pre-vention by osmotic diuresis and observations on the effect ofplasma and extracellular volume expansion. Nephron 1966;3:1–16.

13. Cirksena WJ, Keller HI, Bernier G, Teschan PE. Pathoge-netic studies in a model of pigment nephropathy in the rat. In:Gessler U, Schroder K, Weidinger H, eds. Pathogenesis andclinical findings with renal failure. Symposium of the 4th medi-cal clinic, Nurnberg, December 12–13, 1969. Stuttgart: GeorgThieme Verlag, 1971:105–17.

14. Essman WB. Effects of an experimentally induced acute renalfailure on a learned maze response in rats. J Gen Psych 1962;67:51–6.

15. Kiley JE, Woodruff MW, Pratt KL. Evaluation of encepha-lopathy by EEG frequency analysis in chronic dialysis pa-tients. Clin Nephrol 1976;5:245–50.

16. Teschan PE, Murphy GP, Sharp JC. Investigation of behav-ioral performance during urine reinfusion in the male pri-mate. Am J Physiol 1964;206:510–4.

17. Teschan PE, Ginn HE, Bourne JR, Ward JW, Hamel B, Nun-nally JC, Musso M, Vaughn WK. Quantitative indices of clini-cal uremia. Kidney Int 1979;15:676–97.

18. Teschan PE, Ginn HE, Bourne JR, Ward JW, Schaffer JD. Aprospective study of reduced dialysis. ASAIO J 1983;6:108–22.

19. Singh S, Yium J, Macon E, Clark E, Schaffer JD, Teschan PE.Multicenter study of change in dialysis therapy: Maintenancedialysis to continuous ambulatory peritoneal dialysis. Am JKidney Dis 1992;20:18–33.

20. Schreiner GE, Maher JF, eds. Uremia: Biochemistry, patho-genesis and treatment. Springfield, Massachusetts; C.C. Thom-as, 1961:50–1.

21. Lipman JJ, Lawrence PL, DeBoer DK, Shoemaker MO,Sulser D, Tolchard S, Teschan PE. Role of dialyzable solutesin the mediation of uremic encephalopathy in the rat. KidneyInt 1990;37:892–900.

22. Teschan PE. On the pathogenesis of uremia. Am J Med 1970;48:671–7.

23. Bergstrom J, Furst P. Uremic toxins. In: Drukker W, ParsonsFM, Maher JF, eds. Replacement of renal function by dialysis.Boston: Martinus Nijhoff Publishers, 1983:354–90.

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