MEDICAL CONSIDERATIONS IN THE ELI A ... - Europe PMC

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MEDICAL CONSIDERATIONS IN THE TREATMENT OF RENAL DISEASE* ELI A. FRIEDMAN, M.D. Professor, Department of Medicine State University of New York Downstate Medical Center Brooklyn, N.Y.

THE legendary practitioner who advised patients suffering from colds to contract treatable pneumonia foreshadowed today's nephrologist who has little to offer most kidney patients until uremia supervenes. Tabulations of renal diseases which lead to irreversible uremia illustrate this assertion. Glomerulonephritis, a poorly understood disease, untreatable nowadays, accounts for more than half of the diagnosed cases of uremia.1 Equally enigmatic, chronic pyelonephritis is second in prevalence; it causes approximately zo% of end-stage renal disease. Both chronic pyelonephritis and chronic glomerulonephritis elude precise definition and probably represent groups of diseases which are unrelated except for common pathologic changes.2 Genetic diseases, such as polycystic disease and hereditary interstitial nephritis, and degenerative renal vascular disorders are additional examples of untreatable progressive renal disease. Only one in IO of the patients who develop uremia can be expected to benefit from today's medical regimens (Table I). A more optimistic appraisal of the medical treatment of kidney disease is derivable from the assessment of symptomatic improvement in nonuremic patients. For example, increased comfort and reduction in edema occurs in most nephrotic patients given diuretics. Similarly, corticosteroids diminish proteinuria in most patients with lipoid nephrosis. Whether steroid therapy is beneficial in the long run is debatable. Black, in a controlled, prospective study of steroids in adult nephrotics, found higher mortality (2 i of 6i patients) in prednisone-treated pa*Presented as part of a Symposium on Uremia: Current Concepts and Management held by the Section on Medicine of the New York Academy of Medicine January 14, 1975. This research was supported in part by the Kidney Foundation of New York, Inc., New York, N.Y., and the New York State Kidney Disease Institute, Albany, N.Y.

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TABLE I. RENAL DISEASES IN WHICH MEDICAL MANAGEMENT IS OF NO PROVEN VALUE

Chronic glomerulonephritis Membranoproliferative glomerulonephritis Focal sclerosis Membranous glomerulonephritis Diabetic glomerulosclerosis Genetic renal disease (medullary cystic disease, polycystic disease, and Alport's syndrome) Amyloidosis

TABLE II. RENAL DISEASES IN WHICH MEDICAL MANAGEMENT IS EFFICACIOUS

Lipoid nephrosis Lupus nephritis (focal) Pyelonephritis Polyarteritis (some cases) Hypertensive fibrinoid necrosis (some cases) Urate nephropathy (early stages) Nephrocalcinosis

Wegener's granulomatosis Tuberculosis Cystinuria

tients than in controls (I 5 of 64 patients). Weighing the potential for adverse diseases of medical progress against reduction in proteinuria and diuresis induced by steroids3 offers a difficult choice in the management of the nephrotic. Complications chargeable to steroids are highest in hypertensive and elderly patients who might best be treated at first with diuretics alone. Treatment is worthwhile in symptomatic infection of the urinary tract. Prompt, usually dramatic alleviation of fever and discomfort is predictable with antimicrobial drugs. Whether asymptomatic bacteriuria should be treated is unclear. The prevalence of bacteriuria has ranged from 2% to i6% in various groups of women. Without controlled evidence that sustained bacteriuria leads to loss of renal function, the value of treatment must be weighed against the risk of renal disease resulting from sensitivity to or overdosage with antibiotics. Vol. 51, No. 11, December 1975

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There are some renal diseases, albeit too few, in which current therapy is specific and strikingly beneficial (Table II). Some "medical" causes of renal calculi respond to management with drugs. Cystinuric patients maintained on oral d-penicillamine may cease to produce additional calculi; large staghorn calculi may dissolve. Perhaps the best example of effective medical management of renal disease is Wegener's granulomatosis. This disease, when untreated, leads to fatal uremia in a mean of five months. Cytotoxic drug regimens, including cyclophosphamide, induced complete remission in i6 of i8 patients for as long as 61/2 years. Focal and -diffuse glomerulonephritis in Wegener's granulomatosis is reversible.4 Thiazide diuretics may stop the formation of stones in hypercalcuric patients. Despite these and other examples (Table II), present management for the majority of patients with progressive renal disease consists of periodic measurements of the declining glomerular filtration rate. Renal impairment caused by hypertension is a problem shared by the cardiologist, endocrinologist, and nephrologist. Each specialist searches for surgically curable forms of hypertension. The potential for preserving renal function by effective drug therapy underscores the importance of identifying the huge population at risk (30% of black and io% of white adults). Control of hypertension in established renal disease may retard further renal damage but only rarely results in substantial improvement in renal function. It is reasonable to expect that the list of diseases responsive to treatment will grow as diagnostic precision increases. Newer techniques, especially percutaneous renal biopsy, have facilitated understanding of the natural history of renal diseases previously viewed only at the autopsy table. Many forms of glomerulonephritis with varied prognosis and varied clinical course are known to exist. Glomerulonephritis with varied prognosis and varied clinical course are known to exist. Glomerulonephritis is now a generic term for a family of diseases probably differing markedly in pathogenesis.5 A key to the unraveling of glomerulonephritis has been the fluorescent antibody-labeling technique applied to unfixed sections of kidney obtained at biopsy. Damage resulting from immunological processes is inferable in most cases of glomerulonephritis. Immunoglobulins or complement were detected in 66% of I,956 renal biopsies studied by Wilson and Dixon.6 Classification of glomerulonephritis according to the type and location of immuBull. N. Y. Acad. Med.


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nologic deposits has yielded new entities, such as Berger's nephropathy.7 Unfortunately, use of our rapidly growing knowledge of pathogenesis and morphologic patterns of damage has not as yet been translated into improved therapy. Trials of immunosuppressive drug therapy have been for the most part unconvincing and disappointing. At present, although differentiation of diseases such as rapidly progressive glomerulonephritis, membranoproliferative glomerulonephritis, and focal sclerosis -which are probably distinct entities-is accomplished easily with available diagnostic techniques, therapeutic intervention in the usually inevitable downhill course is haphazard and ineffective. By contrast to the limited effectiveness of attempts to alter the course of parenchymatous renal disease, the rapid advances in the medical management of end-stage uremia have been startling. Prior to i960 Addis described the physician's conduct in the finale of uremia as follows: "It is our job to do our best to keep them on the firing line to the very last gasp. Since our best endeavor amounts to almost nothing, we need not take ourselves too seriously. The situation is now more clearly than ever not in our hands and can no longer be influenced appreciably by us. More and more we cease to play even a minor role in the drama. We retreat to the wings to watch the last act of the tragedy."8 Scribner's introduction of the external arteriovenous plastic shunt for repetitive hemodialysis changed the prognosis of uremia as surely as insulin affected the management of diabetes mellitus. "I believe that the consequences of this little ingenious cannula will be very% great," predicted W. J. Kolff in i96o.9 During the 15 years that maintenance hemodialysis has been in use, the mortality from uremia has fallen from ioo% to less than 2% in some series.'0 Great social and economic consequences are attributable to the procedure. At least so new uremic patients per million of population per year between the ages of 13 and 65 years of age can now be "saved."" Planning for the orderly screening and allocation of treatment for all potentially treatable kidney patients is now a concern of governments and professional committees. Each new patient who has a kidney problem should be subjected to a systematic study. One schema for assessment is proposed in Table III. At the start the establishment of a specific diagnosis assumes high priority. The identification of correctable factors, including obstruction, Vol. 51, No. 11, December 1975

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TABLE III. RATIONAL MANAGEMENT OF PROGRESSIVE RENAL DISEASE

A) Establish the diagnosis 1) Determine any reversible component of the disease 2) Provide genetic counseling 3) Project the course of the disease B) Quantify the patient's present status 1) Creatinine clearance 2) Urine culture 3) Nerve-conduction time 4) Metabolic bone survey 5) Inventory of potential kidney donors C) Initiate surveillance and treatment 1) Control blood pressure 2) Restrict phosphorus 3) As creatinine clearance falls below 15 ml./min.: a) Check for fistula b) Type donors c) Restrict protein d) Prescribe correct quantity of salt D) As uremia supervenes, effect a life plan 1) Dialysis: hospitalization, outpatient, or home 2) Transplantation: live or cadaveric donor

urinary infection, and hypertension, is important. When the diagnosis has been made, it is often possible to ascertain at what rate future losses of renal function will occur. Azotemia in scleroderma or diabetic glomerulosclerosis signifies rapid deterioration and usually indicates that uremia will supervene in less than a year. A prolonged course lasting five or more years is probable in urate nephropathy and polycystic disease. Decisions relating to employment, marriage, and housing may depend on sound prognostication. Patients with inherited diseases such as cystinuria, medullary cystic disease, or Alport's syndrome frequently desire estimates of the risk that the disease will be transmitted to their children. Once the diagnosis of progressive renal disease is made, it is necessary to measure residual renal function. For all clinical purposes, endogenous creatinine clearance is an excellent indicator of glomerular filtration rate. In renal failure, increased tubular secretion of creatinine causes a high estimate as compared with insulin clearance but this is unimportant in serial measurement. Baseline x-ray examinations of the bones, measurements of motor nerve conduction and of proteinuria, and cultures of the urine are obtained repeatedly. At this juncture, advice to the patient should include a description of Bull. N. Y. Acad. Med.


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hemodialysis and renal transplantation. Membership in the Kidney Foundation and in the National Association of Patients on Hemodialysis and Transplantation also can be suggested. Most patients derive comfort and information from association with other patients in similar straits. Potential kidney donors may be identified and the possibility of transplantation may be discussed with the family. After the initial studies have been completed, surveillance visits are scheduled at a frequency determined by the course of the disease. No therapeutic maneuvers are of value when the creatinine clearance is above 25 ml./min. Intestinal binding of phosphate by oral administration of aluminum hydroxide may reduce the severity of renal osteodystrophy; unfortunately, few patients accept over the long term the nauseating and constipating side effects of phosphate binders. When endogenous creatinine clearance falls to Is ml./min. a myriad of uremic symptoms and signs begin to invade the patient's life. Anemia, loss of weight, a reversed sleep pattern, easy bruising, restless legs, urochrome pigmentation of the skin, and nausea cause progressive debilitation. In patients with creatinine clearances of 5 to 15 ml./min. improvement can be expected from a protein-restricted (40 gm.), salt-adjusted (2 to 6 gm.) diet. During this preterminal phase, the problem of vascular access for dialysis must be addressed. Unless contraindicated by extensive vascular disease, as in heroin addicts and some diabetics, the surgically preferable procedure is the creation of an internal arteriovenous fistula.12 Autologous saphenous veins or heterologous grafts of the carotid artery may be utilized for patients whose own extremity vessels are not suitable. The timing for commencement of dialysis is not definable precisely. There is no generally applicable clearance value or complex of signs and symptoms. It is useless to sustain a uremic patient without dialysis when to do so permits only marginal existence between clinic visits. The decision to start maintenance hemodialysis may be made when creatinine clearance values fall to about 5 ml./min. or when the quality of life permitted by nondialytic conservative treatment is unsatisfactory. Dialysis is not indicated in patients whose creatinine clearance is higher than IO ml./min. The prompt commencement of dialysis is mandated if the patient develops paralytic peripheral motor neuropathy, hemorrhagic pericardial tamponade, or a bleeding diathesis. Once the patient can no longer be sustained by conservative means, Vol. 51, No. 11, December 1975

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therapeutic options should be reviewed in consultation with a surgeon specializing in transplantation. The aims of maintenance hemodialysis are twofold: to remove excess water and to extract toxic nitrogenous wastes from the circulanon. Commonly used dialyzers of the coil (Kolff), flat-plate (Kiil), and hollow-fiber variety expose the patient's blood to a thin cellulosederived membrane, usually Cuprophan, approximately one square meter in surface area. In the future, the introduction of membranes more permeable to compounds of molecular weight 200 to 2,000 (Socalled "middle molecules") may permit shorter dialyses with equal efficacy. Simplification of hardware and the development of disposable inserts and tubing have greatly reduced the technical difficulty of dialysis. Nowadays, after a physician has supervised the early dialyses, subsequent hemodialyses are performed by nurses, technicians, relatives, or by the patient himself. The frequency and duration of dialysis treatment depend on the patient's size and dietary habits, the dialyzer utilized, and the residual renal function. For example, excellent rehabilitation of a small woman whose creatinine clearance is 3 ml./min. may be effected with threehour hollow-fiber dialyses given twice a week. At the other extreme, a large muscular laborer unable to adhere to his low-protein, low-salt diet may require three or four seven-hour coil dialyses weekly. Variation up or down from the first estimate of the number of hours of dialyses which are needed is empiric. A catabolic course, progressive neuropathy, inability to sustain obligations of work, school, or home are all indications for increased dialysis time. No single laboratory test or clinical measurement (such as motor-nerve conducting velocity) is a reliable guide to the adequacy of dialysis. Periodic hemodialyses, even thrice weekly, correct uremia only incompletely. Patients who have received dialysis regularly remain azotemic, acidotic, and anemic, and evince chemical abnormalities approximating those of moderately severe renal failure (creatinine clearance of 5 to i0 ml./min.). In consequence, such patients are given proteinrestricted, salt-limited diets; the principal factor modulating the dietary regimen is the amount of residual renal function. A comparison of creatinine clearances shows the limited extent to which the usual regimen of dialysis compensates for the absence of renal function. For examBull. N. Y. Acad. Med.


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TABLE IV. REASONS FOR FAILURE IN REHABILITATION BY MAINTENANCE HEMODIALYSIS 1) Complications of inadequately treated uremia a) Progressive neuropathy b) Osteodystrophy and pathological fractures c) Pericardial tamponade d) Pulmonary edema from intravascular overload 2) Progression of systemic disease a) Intracerebral hemorrhage and heart failure in malignant hypertension b) Myocardial infarction, heart failure c) Necrosis of extremity d) Amyloid cardiomyopathy e) Polyserositis of systemic lupus erythematosus or other collagen disease f) Malignancy g) Oxalosis h) Sickle-cell disease 3) Exhaustion of vascular access sites a) Technical failures b) Intrinsic vascular disease (diabetes or medial calcification) c) Poor tissue tone, cachexia d) Heroin addiction 4) Infection a) Tuberculosis b) Fungal disease c) Recurrent septic pulmonary emboli d) Indolent intrarenal infection (polycystic kidneys) e) Hepatitis 5) Psychosocial causes a) Suicide b) "Giving up-given up" syndrome c) Depression d) Aggravation of preexisting psychosis 6) Unexplained "failure to thrive" a) Some children b) One in 50 adults (with diabetes, malignant hypertension, nutritional cirrhosis)

pie, a man who weighs 7o kg. and has normal creatinine clearance of 120 ml./min during a seven-day week would have an endogenous creatinine clearance of i,209, 6oo ml./min./wk.: I20 ml./min. x 1,440 min. x 7 days 1,209,600 ml./min./wk. The same patient made anephric (perhaps in treatment of severe, sustained malignant hypertension) is treated by maintenance hemodialysis thrice weekly. If a coil dialyzer which has a creatinine clearance (technically a dialysance) of 70 ml./min. at the patient's extracorporeal blood flow of 200 ml./min. is employed thrice weekly for six hours, the patient now has a dialyzer creatinine clearance of 75,600 ml./wk.: 70 ml./min. x 360 min. x 3 days = 75,600 ml./min./wk. Dividing the second total by the first Vol. 51, No. 11, December 1975

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TABLE V. COMPLICATIONS OF MAINTENANCE HEMODIALYSIS REGIMEN* 1) Technical a) Hemorrhage (dialyzer, shunt, vein graft) b) Air embolism c) Electrocution (patient, staff) d) Hemolysis (mechanical) 2) Related to dialysate a) Henmolysis (dialysis against tap water, chloramines) b) Hard water syndrome c) Heavy metal poisoning (cadmium, copper) d) Fluoride toxicity 3) Medical response to dialysis a) Hypotension b) Cardiac arrhythmia (electrolyte change,

digitalis)

c) Pyrogenic reaction d) Sepsis e) Dialysis dementia f) Hepatitis

*Some causes of these are indicated in parentheses.

total shows that, in terms of creatinine extraction per week, the patient who receives dialysis has only approximately 6.3% of his previous renal function. Molecules of higher molecular weight than creatinine, such as guanidino succinic acid, are even less efficiently removed. This accounts for the persistence of the pathophysiologic alterations found in untreated uremia. It follows that the patient undergoing maintenance hemodialysis is subject to all of the abnormal signs and symptoms of uremia, although usually in attenuated form (Table IV). Additionally, he may face complications directly related to hemodialysis per se (Table V). Depression, caused by the lessened quality of life possible during intermittent attachment to a machine, sometimes becomes the overriding problem of management.'3 The active participation of an interested psychiatrist is essential to any dialysis program. The patient in renal failure needs to know that both an individual-his physician-and a team are supervising his care. Free consultation between the physician, nurse, social workers, and technician member of the renal failure group provide additional security for the patient. Each patient should know his "life plan" (the proposed sequential steps in his management) for coping with uremia. Dialysis and transplantation are interdependent. Bull. N. Y. Acad. Med.


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Fig. 1. A 42-year-old woman in her 11th year of maintenance dialysis therapy seated before concealed bedroom dialysis installation.

A patient may have one or more transplanted kidneys with or without antecedent or intervening dialysis. Conversely, a patient may be sustained by home hemodialysis for a decade without resort to transplantation (Figures I, 2, and 3). Who should have which method of treatment? Transplant surgeons and medical nephrologists would easily agree that children, monozygotic twins, and young patients with well-matched sibling or parental donors should be given transplants as a first choice. They would also agree that elderly patients, those with oxalosis or circulating cytotoxic antibodies prejudicial to the viability of allografts, are best managed with dialysis. For the remaining group, however, spirited disagreement would interdict the designation of either home dialysis or cadaveric transplantation as superior. Greater survival among patients given dialysis at home (more than go% survival contrasted with less than 70% Vol. 51, No. 11, December 1975

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Fig. 2. Occupying the spree of a coat closet, tank dialyzer, temperature-mixing valve, and deionizer comprise home-dialysis installation. Newer dialyzers take up only about one third as much space as older models.

Fig. 8. Medical considerations in the treatment of renal disease.

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of cadaver graft recipients alive at two years) would be cited by the nephrologist. The surgeon might point out that cadaver allografting allows the patient to lead a more satisfactory life. In fact, the only available comparative data indicate that rehabilitation is equal with the two forms of treatment.14 While medical-surgical rivalry can only improve the results of both approaches, older methods are not to be denigrated. Young uremic patients can expect to live five, IO, and perhaps more years when managed by the techniques of 1975. When these IO years have elapsed, ingestible sorbents,15 portable dialyzers, and enhanced renal grafts should raise the odds that he will see the 2ISt century.

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REFERENCES Gurlan, H. J., Brunner, F. P., Harlen, millan, 1949, p. 311. H., Parsons, F. M., and Scharer, K.: 9. Kolff, W. J.: Discussion. Trans. Amer. Combined report on regular dialysis and Soc. Artif. Intern. Organs 6:137, 1960. transplantation in Europe, III, 1972. 10. Walker, P. J., Johnson, H. K., Stone, Proc. Europ. Dial. Transplant. Ass. 10: W. J., and Ginn, H. E.: Self-dialysis 17-63, 1973. 1974. Clin. Dial. Transplant. Forum. Heptinstall, R. H.: Pathology of the San Francisco, November 16-17, 1974. Kidney, 2d. ed. Boston, Little, Brown, 11. Friedman, E. A. and Kountz, S. L.: Im1974, p. 877. pact of HR-1 on the therapy of endBlack, D. A. K.: Limited Role of Sterstage uremia. How and where should oids in Managing the Nephrotic Synuremia be treated? New Eng. J. Med. drome. In: Controversy in Internal £88:1286-88, 1973. Medicine II. Philadelphia, Saunders, 12. Brescia, M. J., Cimino, J. B., Appel, 1974, pp. 651-58. K., and Hurwich, B. J.: Chronic hemoFauci, A. S. and Wolff, S. M.: dialysis using venipuncture and surgically created arteriovenous fistula, Wegener's granulomatosis: Studies in New Eng. J. Med. 275:1089-92, 1966. eighteen patients and a review of the 13. Levy, N. B.: Living or Dying. Adaption literature. Medicine 52:535-61, 1973. to Hemodialysis. Springfield, Ill., Merrill, J. P.: Glomerulonephritis. MedThomas, 1974. ical progress. New. Eng. J. Med. 290: 14. Lindner, A. and Curtis, K.: Morbidity 257-66, 1974. and mortality associated with long-term Wilson, C. B. and Dixon, F. J.: Diaghemodialysis. Hosp. Pract. 9:148-50, nosis of immunopathologic renal disease. 1974. Kidney It. 5:389-401, 1974. McCluskey, R. T.: The value of immuno- 15. Friedman, B. A., Fastook, J., Beyer, M. M., Rattazzi, T., and Josephson, A. fluorescence in the study of human renal S.: Potassium and nitrogen binding in disease. J. Exp. Med. (Suppl.) .134: the human gut by ingested oxidized 242s-255s, 1971. starch. Trans. Amer. Soc. Artif. Intern. Addis, T.: Glomerudar Nephritis: Diagnosis and Treatment. New York, MacOrgans 20:161-67, 1974.

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