A REPORT TO THE SURGEOM GENERAL U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Public Health Service KIDNEY DISEASE PROGRAM ANALYSIS A REPORT TO THE SURGEON GENERAL Prepared Under Direction of Office of Program Planning and Evaluation Office of the Surgeon General FOREWORD +The Public Health Service has a continuing responsibility to examine the dr framework for effective decisioh-making required in the determination of -health priorities and in the delineation of the most effective and efficient methods of approaching the solution of the health problems that face us. Therefore, in the spring of 1967 I convened a number of health program analysis groups to study and analyze critically the subject and program content in several specific areas of public health importance. Each of these groups was to examine present and potential goals and objectives, describe and discuss the current relevant state of knowledge and current operating programs, and to develop and analyze to the best of its ability alternative courses of action directed toward the achieve- ment of these goals. The analysis group responsible for this report on kidney disease was under the direction of Benjamin T. Burton, Ph.D., Associate Director for Program Analysis and Scientific Communication,, NIAMD, who was assisted ably by staff from the various bureaus of the Publid Health Service. Analyses of this kind are hampered by large data gaps which limit the breadth and precision with which specific program alternatives and effec- tiveness models can be developed. These limitations, however, do not invalidate the basic concepts contained or the alternative courses of action considered. In addition, the determination of the precise areas of insufficient knowledge emphatically underscores our need for additional research and development. Thus, although program analyses in the health field are still in the very early stages of development, it nevertheless is important that we continue and improve upon previous efforts using this analytic technique. Dr. Burton, his staff, and members of the analysis group, are to be commended for their efforts to comply with my request in such a short span of time and for the quality of the report itself. There can be no question that this initial effort will be of value to me and my staff in considering not only Public Health Service Programs directed towarh'kidney disease, but also in the development of the methods and procedures.required for subsequent analyses in the future. &zli4@4/~ Surgeon General iii DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE PUBLIC HEALTH SERVICE IAL INSTITUTES OF HEALTH BETHESDA. MD. 20014 ODE 301 TEL: 656X03 ~uly 28, 1967 William H. Stewart, M.D. Surgeon General U. S. Public Health Service Dear Dr. stewart: In the spring of 1967, pursuant to your memoranda of February 27 and March 15, you established a Kidney Disease Program Analysis Group I/ and charged it with responsibility for an analytical study of kidney disease in the light of present and future Public Health Service goals and objectives. This study, by a group of staff members from the various Bureaus of the Service with competences relevant to the specific task, was pursued actively until now. This group was comprised of Dr. R. van Hoek of the Bureau of Health Services, Dr. G. H. Escovitz of the Bureau of Health Manpower, Mr. J. 0's. Francis, Dr. R. B. Freeman, and Dr. XV. A. Hilmar of the Bureau of Disease Prevention and Environmental Control, Mr. W. Anderson of your office, and Dr. W. R. DeCesare, Mr. E. Glaser, Dr. W. H. Goldwater, Dr. D. E. Ksyhoe, Dr. K. N. Gershengorn and myself of the National Institutes of Health. Valuable quantitative analytic competence was obtained through a contract with the Research Triangle Institute, The demands of this undertsking were high both in terms of,the magni- tude and diversity of the disease area involved and in terms of the very brief time available for the study. Nevertheless, I believe I am expressing the consensus of the group when I say that the individual members feel rewarded by the new knowledge and insights which`they have gained during this study. We have now completed our task and are pleased to present to you our report. Please be assured of our continued interest and desire to cooperate. Chairman Kidney Disease Program Analysis Group V PREFACE _ This kidney disease program analysis, one of several similar efforts being conducted at the present time, was originally conceived as an.integral part of the planning and analytic effort required in the implementation of the Planning, Programming, Budgeting System throughout the United States Public Health Service.. It is being published and distributed at this time with a two-fold purpose. First, to inform biomedical scientists and health professionals of some.of the current thinking of the Public Health Service on approaches to combating illness, disability, and death, due to kidney disease. Secondly, to elicit comment and criticism on the assumptions, methodologies, and general character of the analysis in order to assist the Public Health Service in efforts to improve upon this and subsequent studies related to planning and evaluation of health programs. It should be clearly stated that in both regards it is recognized by members of the Public Health Service and the analysis group itself that parts of the analysis are totally dependent upon assumptions in areas in which there is very rigorous scientific dispute, i.e., the etiology and subsequent patho- genesis of certain kidney diseases, as well as assumptions regarding the ease or practicability of .the delivery of preventive health services. Nonetheless, the significance of these diseases in terms of human suffer- ing and death challenges us to develop programs which will have the maximum impact on human well being in relation to the resources that will be available for these efforts. vii The importance of planning and evaluation in any large scale enterprise has gained increasing attention and emphasis during recent years and has resulted in the establishment of a Planning, Programming, Budgeting System through the Executive Branch of the Federal Government. Although sometimes narrowly conceived as a limited management tool, its broader effect of supporting more informed and therefore better decision- making was clearly emphasized in the original memoranda transmitting the Presidential decision to effect its wide-spread implementation. The approach emphasizes (1) clear articulation of goals and objectives, and (2) alternative approaches to attaining these objectives. Numerous authorities on the Planning, Programming, Budgeting System have emphasized the two major components of this -approach as ltsystems analysis" and "program budgeting." Systems analysis requires a multidisciplinary approach by analytically oriented people skilled c in the use of quantitative techniques. Program budgeting requires thinking of the budget in terms of program objectives, i.e., purposes realized rather than objects of expenditure, i.e., facilities, equipment, and the like. The unifying theme of program analysis is one of attempting to relate program costs to program effectiveness. That some problems have been encountered in attempting to implement this budgetary system is understandable. Charles J. Hitch, who directed the implementation of the Planning, Programming, Budgeting System in the Department of Defense beginning in 1961, has repeatedly cautioned others on the need for adequate preparatory work and development of the analytic competencies necessary to carry out this activity. It is noted by Mr. Hitch in the Nuffield Lecture delivered last year, Viii "In Defense we had several hundred analysts at,the RAND Corporation and elsewhere developing programming and systems analysis techniques for a decade before the Department attempted any large scale general application. No remotely similar preparatory effort has gone into any other governm'ental area and the number of trained and skilled people is so limited that.they are inevitably spread far thinner in other departments of government than they were and are in Defense." There has not been a comparable "preparatory effort" in the health field devoted to the development of appropriate techniques and methodology. Moreover, more time is usually required than that avail- able in the budgetary cycle to carry out cost effectiveness studies that attempt to consider all costs, not just those that are readily apparent and quantifiable. Thus tremendous demands are placed on individuals attempting to carry out suitable program analysis in the health problem areas. Nonetheless, it is important that a beginning be made and that a body of experience be developed, critiqued, assessed, and improved upon. In this analysis of kidney disease a priority was placed on attempting to obtain a synergistic interrelation between analytically oriented individuals with substantive knowledge of kidney disease and qualified analysts. The former were represented by selected staff members of the Public Health Service serving on a task force. The quantitative analytic competency was obtained through'a contract with the Research Triangle Institute. Great credit is due to all individuals iX involved who tried to grapple with 'the objectives of kidney disease' programs and alternative program approaches for meeting them. It is hoped that through their efforts, as well asthrough comment and criticism that may be forthcoming from others, that we will be able to improve sequentially the process and the product .in future analyses. The Office of Program Planning and Evaluation, Office of the Surgeon General, is charged with the responsibility to define, develop, and implement analytic techniques of this kind. Any assistance, criticism, or comments from professional groups, the academic communitY, or interested individuals will be welcome and greatly appreciated. X Kidney Disease Program Analysis Group Chairman: Benjamin T. Burton, Ph.D. Associate Director for Program Analys and Scientific Communication and Chief, Artificial Kidney Program National Institute of Arthritis and Metabolic Diseases National Institutes of Health Executive Secretary: Kent N. Gershengorn, M.D. Staff Associate National Institute of Arthritis and Metabolic Diseases National Institutes of Health William R. DeCesare, M.D. Deputy Chief, General Clinical Research Centers Branch Division of Research Facilities and Resources National Institutes of Health Gerald H. Escovitz, M.D. Acting Assistant Chief Continuing Education Branch Division of Physician Manpower Bureau of Health Manpower Mr. John 0's. Francis Chief, Program Studies Section Kidney Disease Control Program National Center for Chronic Disease Control Bureau of Disease Prevention and Environmental Control is Richard B. Freeman, M.D. Acting Chief, Preventive Programs Section Kidney Disease Control Program National Center for Chronic Disease Control Bureau of Disease Prevention and Environmental Control Mr. Ezra Glaser Special Assistant to the Director for Scientific Communications National Institutes of Health William H. Goldwater, Ph.D. Chief, Special Research Projects Branch Extramural Programs National Heart Institute National Institutes of Health Norman A. Hilmar, Ph.D. Director, Office of Standards and Intelligence Bureau of Disease Prevention and Environmental Control Donald E. Rayhoe, M.D. Chief, Transplantation Immunology Branch National Institute of Allergy and Infectious Diseases National Institutes of Health Robert van Hoek, M.D. Chief, Office of Research Division of Direct Health Services Bureau of Health Services Liaison: Mr. William M. Anderson Program Analyst Office of Program Planning and Evaluation Office of the Surgeon General Consultant: Mr. Albert V. Alhadeff Operations Analyst Operations Research and Economics Division Research Triangle Institute Consultant: Mr. Jerome B. Hallan Operations Analyst Operations Research and Economics Division Research Triangle Institute Consultant: Dr. Edgar A. Parsons Director Operations Research and Economics Division Research Triangle Institute TABLE OF CONTENTS FOREWORD LETTER OF TRANSMITTAL PREFACE CHAPTER 1 INTRODUCTION AND SUMMARY OF KIDNEY DISEASE PROGRAM ANALYSIS I. Introduction .................... 1 II. Summary ...................... 9 CHAPTER 2 KIDNEY DISEASE - CURRENT STATUS I. Introduction .................... 38 II. The Disease Problem ................ 38 III. Diseases of Interest ................ 39 References ..................... 63 CHAPTER 3 CURRENT KIDNEY DISEASE CONTROL PROGRAMS I. Introduction . . . . . . . . . . . . . . . . . . . . 64 II. Specific Federal Kidney Disease Program Efforts . . 65 III. Nonfederal Expenditures for Kidney Disease Programs. 82 CHAPTER 4 RESEARCH METHODOLOGY I. Introduction ..................... 85 II. Diseases Studied .................. 85 III. Kidney Disease Programs Studied .......... 87 IV. Costs of Kidney Disease Program .......... 89 V. Benefits of Kidney Disease Programs ........ 90 VI. Methodology Limitations .............. 91 Footnotes ..................... 93 CHAPTER 5 PROGRAM ANALYSIS I. Introduction .......... L ......... II. Infectious Diseases of the Urinary Tract ...... III. Hypersensitivity Diseases of the Kidney ...... IV. Kidney Diseases Related to Hypertensive Vascular Diseases ................ V. End-Stage Kidney Disease .............. References and Footnotes ........ ; ..... 94 97 121 139 168 185 xiii CHAPTER 6 THE COST 0~ TREATING AIL PATIENTS , _ WITH CHRONIC KIDNEY FAILURE I. Introduction ................... 196 II. Approach to the Total Treatment of End-Stage Kidney Disease ......... ., 196 III. Calculation of Costs ............... 201 IV. Results ..................... 204 V. Discussion .................... 206 VI. Feasible Approaches for End-Stage Kidney Disease Treatment ............ 208 xiv Chapter 1 INTRODUCTION AND SUMMARY OF THE KIDNEY DISEASK PROGRAM ANALYSIS I. INTRODUCTION A. Objectives and Goals of the Report In the spring of 1967 the Surgeon General of the U. S. Public Health Service established, among others, a health program analysis group to under- take studies and analyses in the area of kidney disease. Members of the group were chosen from among senior staff of the National Institutes of Health and other bureaus of the Public Health Service, who were responsible for ongoing kidney disease-related programs or whose competence lay in the areas of program planning and analysis. In his charge to the group, the Surgeon General directed it to describe and discuss the nation's kidney disease problem, to outline the current state of knowledge and ongoing programs in the area of kidney diseases, to consider advanced states of knowledge and desirable programs, to develop goals and objectives for effective amelio- ration of the problem, and to explore alternative approaches to the attainment of these objectives. An important part of the group's work was to be a logical analysis of Programs leading to a solution or amelioration of the problem of kidney disease, including: 1) A thorough discussion of goals and objectives and ways of measuring them; 2) A description of alternative approaches which could lead toward the same objectives; 3) An analysis of the cost of reaching.various points on the continuum of objectives by means of alternative approaches; and 4) A discussion of the basic assumptions upon which conclusions depend, of uncertainties which affect the estimates used, and of the issues which cannot be resolved at this time. The work of the kidney disease program analysis group is intended to guide the Office of the Surgeon General and, ultimately, the Office of the Secretary, Health, Education, and Welfare, in the development of future progl long range financial plans and budgets, and legislative proposals. B. Background During the last five years, diseases of the kidney have steadily gained in significance as an area of social importance for both Federal and non- Federal research and service efforts. Much of the impetus for this increasing interest in kidney diseases has come from the development of two dramatic but expensive therapeutic approaches to end-stage disease-- chronic hemodialysis and kidney transplantation. The successes of both techniques-- coupled with other research advances leading to a better under- standing of kidney diseases --have led to a proliferation of activities. directed toward reducing the morbidity and mortality these cause in the Population. There are a number of mechanisms, or program components, that are traditionally brought to bear on a disease problem such as this. These are: 1) Expanded use of existing preventive techniques. 2) Expanded use of existing diagnostic techniques. 3) Expanded use of existing treatments, including chronic dialysis, kidney transplantation and conservative management (drugs, diets, etc.). 4) Laboratory and clinical research to produce new preventive, diagnostic, therapeutic and rehabilitative methods. 5) Increased specialized scientific medical and paramedical train- ing to provide the manpower needed for the research and treatment attack on the kidney disease problem. This also includes continued postgraduate education to train practicing physicians in the use of the latest diagnostic and treatment modalities. 6) Increased public education to alert potential victims of kidney disease to seek medical help at the earliest possible emergence of warning signs. 7) Provision of specialized facilities not currently in existence which are essential for the execution of any of the above programs. It must be understood from the outset that these program components are interdependent in most cases. For example, preventive techniques exist that need further research to make them maximally effective for braod application. New treatment methods are useless if existing diag- nostic techniques are not being applied in medical practice. Because of 4 the present inadequacies of-existing treatments, be they dialysis,'trans- plantation, or conservative management, a considerable research effort is called for to increase their efficacy and economy to make them more broadly useful. : C. Considerationof Pto@%m Approaches It is unlikely that a single program component would lead to a major reduction in the national-kidney disease problem; therefore, a mixture Of approaches will have to be employed by the Federal Government to red&e the morbsdity and mortality due to kidney disease. The total funding level and the respective proportions for each approach in the overall effort will determine, to a large extent, the benefits attain- able in each successive year from this effort. Advances in the state of knowledge will affect the nature of this "mix" and will shift the'emphasis from certain program components to others if we are to continue to derive -. - maximum benefits from the total expenditure of funds in this area. Another important consideration in making choices for the funding of specific program approaches is the effect of the expenditure of such Federal funds on the overall national expenditure of funds in this area including money spent by state and local governments, voluntary agencies, universities and foundations, and the large segment of private expenditures for medical diagnosis and treatment. Here, the precise choice of direction of the placement of Federal funds can determine to a large degree whether: 1) The resulting fruits of research or increased case findings at an early stage of the disease will stimulate an expanded use of nongovernmental money for earlier and more effective treatmen+-- 5 with an overall beneficial effect on the state of kidney dise ct se in the nation; or 2) Whether certain.choices for the expenditure of Federal funds would serve to diminish the participation of the nongovernmental /. sector in efforts against kidney disease by mak&g it financially more attractive to "let,Sam do it." It is obvious therefore, that under a given set of conditions where unlimited Federal funds are not available for the solution of a single national disease problem, such as kidney disease, a rational balance must be struck between the various relevant program approaches--investigative, preventive, therapeutic and educational--so as to derive maximum benefits from any current or possibly extended future Federal efforts. D. Program Analysis for Decision Making The future of Federal programs in the field of kidney diseases, be . . it for research, disease prevention, improvement of treatment methods including hemodialysis and transplantation, or manpower training needs decisions based upon a thorough, dispassionate and logical analysis. With the aid of such analysis, public officials responsible for health programs who face the problem of allocation of limited financial resources . in the struggle against kidney disease could make such decisions on the basis of logical priorities. These priorities would be based on the present state of knowledge and on needs based on present morbidfties and mortalities, as well as on the basis of anticipated developments inthe future state of the art and the pertinent changes which they are likely to introduce into the overall kidney disease picture. The fundamental intent of such an analysis and its raison d'etre is to. provide maximum benefits in terms of prolongedi rewarding lives and reduced morbidity for those afflicted with kidney,disorders and for those in the population who will be stricken by it in the future, from the aPPlicatioxi of Federal funds to research, disease prevention, treatment, and manpower trainfng, directed against kidney disease. E. The Analysis Faced with the fact that its study and explorations could perforce not be infinitely exhaustive it was decided that, for the sake of Practi- cability and f&asibility, the heterogenous field of kidney disease be divided into four 'tijor groups as follows: I. Infetitious Diseases of the Urinary Tract, II. Hypersensitivity Diseases of the Kidney, III. Kidney Diseases Assodiated with Hypertension; and IV. End-Stage Kidney Disease. The first three groups encompass 'in toto about 75 percent of kidney -- morbidity and mortality; the fourth group, end-stage kidney disease, exemplifies progressive and ultimately fatal kidney failure from all possible causes. Each of these groups.accounts for a major percentage of overall kidney morbidity and since each group of diseases was based on one-major distinct causative principle it was felt that it is possible to discuss logically each group individually in terms of the common overall mechanisms involved and in tern= of the application of the vqrious possible program elements-- research, prevention, treatment, professional training and lay educatian-- to the solution of the problem which it represents. In addition to the first groups, there remains a miscellaneous group of renal diseases of variable and distinct etiologies: a) Diseases of development (polycystic disease, hypoplastic kidneys, anomalies of position or structure, et&); b) Renal involvement in metabolic diseases (diabetes, gout, amy- loidosis, oxaluria, etc.); c) Kidney damage due to obstruction (benign prostatic hypertrophy of the aged, kidney stones, etc.); d) Cancer of the kidney, both of primary or secondary origin; and e) Mechanical injury. 2. Limitations Programs and approaches for solution or amelioration of problems associated with this latter mixed group of renal diseases are discussed in the text of the report but were not subjected to individual cost- effectiveness or benefit-cost analyses. This decision was made to avoid an unwieldy, and in many cases, impractical fragmentation of the report. Moreover, each one of these disorders may be the end result of a primary disease for which there exist other, independent research and preventive and/or curative efforts which, hopefully, would affect beneficially the existing prevalence of the disease. For example, research advances of the last seven years in the area of gout, once they are rigorously applied in the everyday practice of medicine, will decrease considerably the prevalence of kidney damage due to neglected or long standing chronic gout. Similar considerations were aPPIied to other disorders belonging to the residual mixed group of mis- cellaneous diseases impinging on the functional integrity of the kidney. It was also decided to exclude neoplasms of the kidney from the Program analysis. Inclusion of this category in the present analysis was felt to be undesirable because other extensiiie research tid public ',. health progra&s affect the.srate bf the'art in cancer; moreover, in a large percentage of patients afflicted with primary or s&conda`ry &ncer of the kidney, kidney function per se doe&' not deteriorate until the - extent of the lesion becomes overwhelming--at which point the life of the patient is usually threatened by the neoplasm and its metastases more than by the attendant renal failure. The Present analy.sis was limited to kidney diseases which are pre- dominantly chronic or to mecha&sms which though they may precipitate *acute kidney disease, play a major role in eventual or potential chronicitP of the disorder. Tlius ) acute relial poisoning due to accidental causes or suicide attempts, and nephrotoxic drug reactions were not included in the analyses or program projections. 3. Appendices In the course of discussing possible programs and their specific impacts, new ideas were develdped which seemed of sufficient interest and potential benefit to be included in the report. Subsequently, the overall principles involved were fitted into tlie logical mainstream of the report. For the sake of brevity and continuity, however, the more detailed projections or applications of such future programs were included in appendices to the report, whenever they appeared of interest. 4. Recommendations In projecting future programs and in analyzing their possible impact on the mortality and morbidity due to each major sub-group of kidney diseases, the committee attempted to avoid implied or overt recommendations. It was felt that in each case 'the analysis and its logical extrapolations spoke for themselves. II. SUMMARY The following summary presents the committee's most significant generalized findings and a discussion thereof, and is not intended to include all observations made. These will be found in detail in the body of the report. As a first step in its analysis in depth of kidney disease as a national health problem, the committee studied each of the many diseases of diverse etiologies which are encompassed in the general term 'kidney disease'. (Please see Chapter 2, Kidney Disease--Current Status) In each case the current state of scientific knowledge for each disease was determined including its underlying etiology, mechanisms of pathogenesis, symptomatology, prognosis, severity and duration, methods of d.iagnosis, and treatment. Where applicable, consideration was given to existing gaps in knowledge, additional research needs, possible prevention, diagnosis, and treatment under the conditions of present or future states of the art, and interrelationships with other diseases. Up-to-date statistical data were collected, such as prevalence in the population, mortality, morbidity in terms of days of restricted activity, average cost of treatment, and other relevant costs. Since the subject matter embraces a vast number of diseases with highly divergent pathogenic mechanisms and nature, the committee made decisions-in-principle concerning which of these would serve best as a basis for a rational analysis under the limitations of the present study (please see INTRODUCTION, E.,l., Organization of the Subiect Matter). The three main groups of primary kidney diseases and end-stage kidney disease common to them were utilized in the statistical analyses in this report. This group encompasses the overwhelming majority of kidney mortality and morbidity. The remaining primary and secondary kidney diseases of statistically lesser import were discussed in the text of the report but were not included in the present program analysis. Subsequently a thorough study was made (Chapter 3, Current Kidney Disease Control Programs) of the current governmental kidney disease programs and relevant public and private expenditures for the nationwide treatment of kidnw disease. The latter includes cost of physician care, hospital care, nursing home care, and other professional services for diagnosis and therapy of kidney diseases, as well as the cost of drugs and net insurance costs. In addition, the cost was estimated for ongoing research efforts, for demonstration, screening and detection programs, for education and training efforts and for that portion of the cost of.construction of hospital and medical facilities which can be prorated to the use of patients with kidney disease. Program Analysis Models Based on the substantive information obtained and statistical and economic data collected, the committee analysed the benefits to be gained by different approaches to the solution or amelioration of the overall national kidney disease problem at different expenditure levels of HRW funds. Models were devised after experimentation with various statistical mechanisms and indices. They are based'on a benefit+eost-analysis, for the four disease groups studied, . I.e., infectious diseases of the urinary tract, kidney diseases related to hypersensitivity phenomena, kidney diseases related to hypertensive vascular diseases, and end-stage kidney disease. Four specific programs are considered for each disease group. These programs which are delineated by time, funding level, and state of the art comprise the following: 1) Hypothetical Program at the Current HEW Expenditure Level, Based on the Current State of the Art; 2) Hypothetical Program at an Intermediate HEW Expenditure Level, Based on the Current State of the Art; 3) Hypothetical Program at an Accelerated HEW Expenditure Level, Based on the Current State of the Art; and 4) Hypothetical Program for Fiscal Year 1975, at-an Accelerated HEW Expenditure Level, Based on the Expected Advanced State of the Art in 1975. Each program consisted of a hypothetical situation where a specific level of HEW program funding was divided.among a rational mix of program components (screening, diagnosis and treatment, research, training, etc.) based on the particular characteristics of the specific disease group involved, and was applied to specifically involved or particularly vulnerable groups or, as the case may be, to the eniire population. vj.r&=. tien&fzit's I.;&&*~e 'f+& -kg&* pk$$&& tire .,:;&&;;g&&t& `.,*d '1&&t&, .fk :&i ,$&'z&&~&;,,l*&*,~on ory mopp+gy; $j-??g~&e, I ',- :`.&na' 'm&jf,j;i~ &&,"&;~&;ey &&t&&j- Wherever the mking of assumptions was unavoidable, the resulting estimates were based on the best scientific evidence and available data and were held within conservative limits. Benefit indic'eS were quantified in terms of.the reduction in annualpr" mortality* .the reduction in annual morbidity (number of sick days per year) and in .terms of ,the disease prev,alence,in the total population dueto tu4 spf&fic type of kidney disorder analyzed* "%hich would accrue thanks to the impact of the various program components--such as research advances, disease prevention and improved treatment. It was felt that these specific benefit indices were more appropriate for the purposes of this study than other potential indices such as "loss of productivity," loss of gross national product due to the death.of individuals, or loss to the Federal Government of tax revenue due to death or inactivity of individuals. Moreover, it was felt that- it would be more desirable to quantify the benefits which could accrue from HEN-supported programs aimed at the kidney disease problem in terms related directly to the human beings who are to benefit from such expenditure, rather than in terms of a highly impersonal inert commodity--dollars. The fact that mortality and morbidity figures could be manipulated statistically just as well as dollars, but could be used without introducing too many estimates and assumptions ("What is the price of a human life?", "How much money is lost, and to whom, when a sick person does not report to work?") induced the committee to choose these indices for its benefit-cost analyses. A detailed explanation of the various postulated programs and the analysis of their potential benefits will be found in Chapter 4, Research Methodology, and Chapter 5, Program Analysis. The nature of these programs, and the benefits and costs associated with each of the four programs in each disease group are summarized and discussed below. I.3 Summary of Alternative Programs for Individual Disease Groups 1. Infectious Diseases of the Urinary Tract a. Hypothetical Program at Current HEN Expenditure Level, Based on the Current State of the Art A major component of this program is the screening of the following specific high-risk groups: patients in hospitals and nursing homes, non-hospitalized pregnant females, and non- hospitalized diabetic patients. This would be followed by the establishment of definitive diagnoses and vigorous treatment .of any kidney infections discovered. A second major projected program component is laboratory and clinical research directly relevant to infections of the kidney. bther program components are concerned with the education of medical personnel and the specific training of additional manpower. The cost to HEW is estimated at $9,203,000. Short-term benefits of this program (discernible when the program reaches full operation), would be represented by an annual reduction in mortality of 70, a reduction in prevalence of 3,231,260 cases and a reduction of 15,962,420 morbid days in the involved vulnerable group. Long-term benefits (to be seen many years after the program becomes fully operational) are represented by the avoidance of irreversible, fatal uremia in 1,750 individuals per year. b. Hypothetical Program at an Intermediate HEN Expenditure Level, Based on the Current State of the Art At the intermediate program level, HEW expenditures are about two times greater than in the preceding program. Again a major component of this program is the screening, diagnosis and treatment of urinary tract infections. An additional high-risk group has been added: females 6 to. 9 years of age. The.cost .t.o HEW is estimated at- $20,179,000. Short-term benefits attributable to this program are quantita- tively greater (percentage reductions do not change), due to the addition of another high-risk group; .A reduction in short-term mortality of 70 is again expected due to the very low mortality from infections of the urinary tract in the added vulnerable group. Prevalence is reduced by 3,243,860 and morbid daysby 16,273,640. A yearly reduction of fatal end-stage kidney disease by 1,770 is expected. Expansion of the proposed basic program (see previous model) to a level which is two times larger, in an effort to include an additional vulnerable group, did not result in a near-proportionate increase in benefits.. Once a new potentially vulnerable group was included in which the percentage of individuals harboring urinary tract 'infections was much lower than in the previous hypo- thetical situation, the point of rapidly diminishing returns was reached. Thus an indication was received of the possible limits of effectiveness for a screening-diagnosis-treatment program for infectious diseases of the kidney in the general, non-morbid population under conditions of the current state of knowledge. C. Hypothetical Program at an Accelerated HEW Expenditure Level, Based on the Current State of the Art In this projected situation, the HBW expenditure level is about two and one-half times greater than the current level. Again, a major component of this program is the screening, diagnosis and treatment of infections of the urinary tract. The high-risk group at which the program is aimed has been expanded to include all females under 21 years of age. The short-term benefits attributable to this program include a similar percentage reduction in mortality and morbid days as before, but since a larger vulnerable population was involved, quantitative benefits are greater. The cost to HEW is $27,394,000. Short-term benefits include an annual reduction of 70 deaths, 3,292,860 cases, and 17,483,880 morbid days. Long-term benefits are represented by the elimination of irreversible, fatal uremia in 1,870 individuals per year. The same conrnents made on the less-than proportionate increase in benefits in the intermediate program apply, even more strongly, 'to this hypothetical situation. It is obvious that under the conditions of the present state of the art the limits of effective- ness for this approach have been reached at the previous level of expenditure, in the intermediate program. d. Hypothetical Program, for Fiscal Year 1975 at an Accelerated HEW Expenditure Level, Based on an Advanced State of the Art In this projected situation, the HEW expenditure is about three and one-half times greater than the original program. Funds for research have been increased considerably. Screening, diagnosis and treatment still remain a major program component. Under an advanced state of the art it is assumed that the extensive research efforts have made possible: 1) More effective antimicrobial therapy, 2) Better understanding of the pathophysiology of urinary tract infections, and 3) Better understanding of the natural history of pyelonephritis. The cost to HEW is estimated at $31,228,000. Short-term benefits now include an annual reduction of 80 deaths, 5,630,780 cases, and 26,064,430 morbid'days. Long-term benefits are represented by. the elimination of irreversible, fatal uremia in 4,125 individuals per year. 2. Hypersensitivity Diseases of the Kidney a. Hypothetical Program at the Current HEW Expenditure Level, Based on the Current State of the Art It was concluded that present knowledge of hhersensitivity diseases of the kidney is insufficient to justify a special program of case finding, diagnosis and treatment since it is doubtful whether it could make an effective impact on current morbidity and mortality figures due to these diseases. The most important projected program component is laboratory and clinical research relevant to immunology and hypersensitivity diseases of the kidney. An additional component is postgraduate physician education, research training, and expansion of research facilities. The cost to HEW is estimated at $7,480,000. Short-term benefits expected are a reduction of 610 in immediate mortality, primarily due to the postgraduate physician . . education and.consequent improved medical practice. No immediate benefits are expected from the research effort undertaken. A 1% reduction in mortality, a 5& reduction In prevalence and a 65% reduction in morbid days is anticipated over a future ten-year period as a result of this program primarily due to anticipated research advances, and secondarily due to a higher quality of medical care (see anticipated benefits for 1975). This was one of the most uncertain estimates.made.; it was based on the research advances of the last 10 years and on the arbitrary assumption that the rate of new developments will remain the same. b. Hvpothetical Program at an Intermediate HEW Expenditure Level, Based on the Current State of the Art In this situation, the program components have not changed essentially, but the HEW expenditure level has been increased. The most important program component is, again, research. The cost to HEW is estimated at $20,000,000. Short-term benefits would remain similar to those described at the previous, lower expenditure level (see above). Long-term benefits will only be increased significantly over the previous program if the funds for research in the latter had been a &aiting factor for productive research. c. Hvpothetical Program at an Accelerated HEW Expenditure Level, Based on the Current State of the Art In this situation, the program components have not changed essentially, but the original HEW expenditure level has been tripled. The most important program component is, again, research. The cost to HEW is estimated at $23,875,000. Short-term benefits would remain similar to those described at a non-accelerated HEW level (see above). Here again; long-term benefits will only be increased significantly over the previous program if the funds for. research in the latter had been a limiting factor for productive research. d. Hypothetical Program at an Accelerated HEW Expenditure Level, Based on an Advanced State of the Art .(1975) Under an advanced state of.the art, it is assumed that the preceding research has resuited in the development of effective means of preventing hypersensitivity diseases of the kidney, or of treating them. Possible examples are: 1) An effective anti-streptococcal vaccine; 2) Failing that, discovery of a means for early detection of streptococcal infections and for the interruption of the -- . immunological mechanisms that lead to acute glomerulonephritis and/or 3) Increased understanding of the meaning of proteinuria and means for identification and treatment of individuals in whom it heralds eventual chronic renal disease. A program based on-the use of an anti-streptococcal vaccine in a majority of the population and on early detection and treatment of persistent proteinuria would yield the following short-term benefits: an annual reduction in mortality of 770, a reduction in prevalence by 62,250 cases and a reduction of 2,610,OOO morbid days in those affected. Long-term benefits would be represented by a decrease of 8,610 individuals per year who would otherwise reach end-stage kidney failure in the future. The cost to HEW has been estimated at $77,320,000. It is important to note that any of the program approaches involving the advances mentioned above would have a profound impact on the prevention and treatment of hypersensitivity diseases in general, such as rheumatic fever, rheumatic heart disease, and others. 8. Kidney Diseases Associated with Hypertension a. Hypothetical Program at the Current HEW Expenditure Level, Based on the Current State of the Art The projected program consists of three major components: 1) Screening, diagnosis and treatment of individuals 17 years of age and over with curable (non-essential) hypertension and non-curable hypertension; 2) Postgraduate education of practicing physicians and education of the population relevant to early recognition and treatment of the disease; and 3) Laboratory and clinical research. B relatively minor component for research training of physicians and allied personnel is. also included. HEW costs are estimated at $9,180,000. Estimated annual short-term benefits include a decrease in mortality by 7,830, a reduction in prevalence of 54,000 cases, and a reduction of 5,959,OOO in morbid days due to hypertensive disease. It has been assumed that approximately 30X of the benefited individuals with hypertension have renal involvement. Thusthe figures for benefits accruing to patients with renal disease associated with hypertension are 2,190, 27,000; and 1,802,000, respectively. 20 A reduction of 4,330 per year in the number of individuals dying from irreversible uremia is expected as a long-term benefit. b. Hypothetical Program at an Intermediate HEW Expenditure Level, Based on the Current State of the Art The projected program is similar to the preceding one except that under an increased funding level (about two and one-half times greater than before) an additional population group is subjected to screening, diagnosis and treatment. Reference is to persons 17 years of age and over who have had no care from a physician during the preceding .year. The program affecting the additional group is expected to cover a six-year cycle. Estimated costs for HEW are $21,207,000. Estimated annual short-term benefits for patients with renal involvement are now increased to 2,270 avoided deaths, a reduction in prevalence of 34,880 cases and a reduction in morbid days of 2,056,820. Expected long-term benefits are estimated to include an annual reduction In fatal end-stage uremia of 4,820 cases. c. Hypothetical Program at an Accelerated REW Expenditure Level, Based on the Current State of the Art This program is similar to the one postulated for an inter- mediate level of expenditure exkept that the program affecting the additional high-risk group of previously unscreened individuals has been accslerated to cover a three-year cycle rather than six years. The estimated cost to HEW is $28,639,000 (about three times the original level of expenditure). Estimated annual short-term benefits for patients with renal involvement now include 2,380 avoided deaths, a reduction in prevalence of 42,750 cases, and a reduction in morbid days of 2,311,340. Expected long-term benefits are estimated at an annual reduction in end-stage uremia of 4,820 cases. In this case, further expansion of the program above the intermediate level did not appear warranted by the resulting increase in benefits, which was very far from proportional. Here again, an indication was received of the possible limits of effective- ness for a screening-diagnosis-treatment program for kidney diseases associated with hypertension in the non-symptomatic population ("individuals who have not seen a physician during the preceding year"), under conditions of the current state of knowledge. d. Hypothetical Program at an Accelerated HEW Expenditure Level, Based on an Advanced State of the Art (1975) Under an advanced state of the art it is assumed that the preceding extensive research efforts have resulted in the following: 1) Advances in understanding of the underlying cause(s) of hypertension; 2) Improved diagnostic tests for detecting hypertension; 3) Specific effective therapy(ies) directed toward the various underlying causes; and, 4) Advances in surgical methodology for the types of hypertension amenable to such treatment. Screening, diagnosis and treatment still remain the major program components in this projected situation. The target population is the same as in the preceding programs. HEW costs are estimated at $35,832,000. Estimated annual short-term benefits for patients with renal involvement include a 9,300 decrease in mortality, a reduction of 289,700 in prevalence and a reduction in morbid days of 5,579,OOO. Long-term benefits are expected to result in an estimated annual avoidance of fatal end-stage kidney disease in 9,480 individuals. 4. End-Stage Kidney Disease End-stage kidney disease as indicated earlier exemplifies progressive and ultimately fatal kidney failure from all causes. Because of the unique and costly treatment methods currently.available this group was studied not only from the standpoint of the four program alternatives (used for the three primary disease groups) but also from the standpoint of a program which attempts to treat all patients with chronic kidney failure. a. Hypothetical Program at Current HJZW Expenditure Level Based on the Current State of the Art The major component in this program consists of treatment of patients in end-stage renal failure by dialysis and/or kidney transplantation. A second program component is laboratory and clinical research relevant to both treatment modalities, develop- mental research for dialysis hardware improvement, and development of organ preservation technology and facilities. A third program component, considerably smaller, involves training of relevant manpower and provision of needed facilities. The estimated HEW cost is $21,000,000. The benefits in this program are measured in terms of mortality avoided in the total group of patients in irreversible renal failure whose lives are in jeopardy. Under the circumstances of this particular program, 600 patients will be maintained through chronic dialysis and 90 lives yearly will be saved through successful transplantation. This program of dialysis and transplantation, at current HEW expenditure levels, provides life-saving care for about 1.5% of the number of patients threatened by death during that particular year because of end-stage kidney disease. b. Hypothetical Program at an Intermediate HEW Expenditure Level, Based on the Current State of the Art In this projected situation the level of HEW funding has been increased appreciably to reflect the immediate urgency posed by the threatened lives of patients in irreversible renal failure. Treatment expenditures have been increased by a factor of 5 over the previous level, research expenditures by a.factor of 1.5 and training and facilities by a factor of 5. Under the circumstances of this particular program, about 1,150 patients would be maintained by chronic dialysis and about 420 individuals would be cured by transplantation. This program which involves about $56,000,000 of HEW funds will provide life sustaining treatment for about 3% of the annual number of persons who have end-stage kidney disease during the first year of the program. During the second year of such a program, however, because of the carry-over of about 80% of the patients dialyzed during the preceding year,:the same sum of money will provide treatment for considerably less than 3% of the uremic patients threatened by death during the second year. Because of the increasing carryover load of dialysis patients from previous years, this limiting effect will increase with each successive year of such a program. Unless the budget, manpower, and facilities are increased considerably during each succeeding year over the respective previous levels, only a small proportion of to end-stage kidney in such a program. the total group threatened with death due disease each year will actually be saved This problem is discussed.in greater detail later in this summary chapter and particularly in Chapter 6, The Cost of Treating All Patients with Chronic Kidney Failure. c. Hvpothetical Program at an Accelerated HKW Expenditure Level, Based on the Current State of the Art In this projected situation, the level of HEW funding has been increased tenfold to reflect the inunediate urgency posed by the threatened lives of patients in irreversible renal failure. Although the overall funding is increased tenfold in an effort to extend treatment to as many patients as possible, research funds have only been doubled over the current level, since this was felt to be the limit of research and development which could possibly be productive at this point in time. Training and facility expenditures have also increased tenfold because of the immensely increased patient load. Under the circumstances of this particular hypothetic program 4,100 lives will be maintained through chronic dialysis and 3,575 lives will -be saved.yearli through successful xransplantatiou. This program, which utilizes $210,000,000 of HKW money (about $170,000,000 of which are expended for patient care), provides .treatment for about 15% of the overall number of patients threatened by death because of end-stage kidney disease and available during the first year of the program. The same problem of buildup of carry-over patients in future years exists under this program and interferes with the achievement of its goals unless the level of expenditure is raised appreciably during each succeeding year. d. Hvpothetical Program at an Accelerated HEW Expenditure Level, Based on an Advanced State of the Art in 1975 Under an advanced state of the art, it is assumed that the preceding extensive research efforts have resulted in the following advinces: 1) Dialysis treatment can be carried out by the patient essentially independently of treatment facilities (except for periodic medical'checkups), and the debili- tating complications seen in patients on dialysis therapy have been eliminated; 2) A highly developed program for organ matching and preservation is in existence, &nmunosuppressive techniques are highly effective, transplantation survival is vastly increased, and the procedure can now be carried out in most of the general hospitals in the United States; and 3) In the case of both treatment modalities the cost has been reduced appreciably. In this projected situation, the total HJN expenditure is smaller than the accelerated budget level assuming current state of the art (see above). The expenditures for research have been decreased considerably because of the research and development achievements of previous years. Training and facility expendi- tures have remained on the same accelerated level because of the large patient population which is being treated. The major program element is treatment of all suitable patients by transplantation, since this is a one-time treatment. This permanent treatment is, of course, preceded by supportive dialysis and patients in whom the procedure is unsuccessful are also maintained by dialysis pending a second attempt at transplantation. About 12,000 of the remaining patients in renal failure who are not suitable surgery candidates are placed on life-long dialysis. Under the circumstances of this highly idealized program, about 16,000 lives will be saved annually through transplantation in the vulnerable group. In addition, about 11,400 individuals . will be maintained through chronic dialysis; most of these will be carry-over patients from previous years. This hypothetical program which utilizes $150,000,000 of HEW funds, most of which are devoted to patient treatment, provides treatment for about 55% of the number of patients threatened by death because of end-stage kidney disease during the first year of its operation (1975). It is important to note that advanced age and concurrent disorders prevent the successful application of transplantation and/or chronic dialysis to every one of the approximately 50,000 patients who present themselves each year with end-stage kidney disease. 27 A comparison summary of the results of the three hypothetical situations with regard to end-stage kidney disease shows that an immediate tenfold increase of HEW expenditures primarily for patient treatment under conditions of the present state of the art would, at best, approach a solution for 15% of the patient population threatened by fatal kidney failure in the first year; thereafter, a progressingly smaller percentage of the vulnerable group could be helped. (This situation is, of course, wholly hypothetical, since there does not exist sufficient medical man- power either qualified or willing to participate in such a program). Advances in the state of the .art which can be expected through a judicious doubling of HEW support for research and passage of sufficient time to permit the unfolding of research achievements would make it possible to save the lives of about 55% of the threatened patient population in the first year of such a program with a smaller expenditure of funds for patient care than was postulated for the previously described accelerated level program under the current state of the art, which only starts to take care of 15% of those in need of treatment. e. Hypothetical Program Attempting Treatment of All Patients with Chronic Kidney Failure 1) Introduction Whenever consideration is given to the problem of ultimately fatal chronic renal failure, the question is frequently raised of what it would cost to make an attempt at treating all patients threatened by a 28 uremic death-- either with the aid of lifelong chronic dialysis or through attempts at kidney transplantation whenever donor kidneys may be available. This question is usually raised by well-meaning individuals for humanitarian reasons. Approximately three-fourths of the 50,000 patients who present themselves each year with fatal end-stage kidney disease are known to be above the age of 60. This fact &get&r with the many concurrent other disorders afflicting most of these patients (and the rather stringent requirement for emotional suitability for chronic dialysis) make it extremely unlikely that a large-scale application of either transplantation or chronic dialysis to all or practically all of these 50,000 individuals would be successful. A further discussion of practical restraints in terms of requirements for specialized manpower and facilities is found in Chapter 6 (The Cost of Treating All Patients with Chronic Kidney Failure), Section V. Nevertheless, although the original mission of the Kidney Disease Analysis Group did not include the preparation of an answer to this question concerning the cost of a hypothetical "total push" program, it was felt that an analysis of this cost would be a natural corollary to the preceding analyses of costs and benefits of optimal Programs aimed at the major primary kidney diseases and at end-stage kidney disease. In any consideration of 29 possible programs for the amelioration of the kidney disease problem, an attempt to treat all patients threatened with a uremic death regardless of the possible,costs, for humanitarian reasons, represents one extreme in a broad spectrum of possible programs. The committee therefore felt that this hypothetical cost should be ascertained to serve as a maximal bench mark for any intensive attempt at program analysis or planning. The details of such a hypothetical total push program and the necessary calculations are found in Chapter 6. 2) Calculation of Costs It was obvious that the mere calculation of the cost of the first year of such a total push program would leave a misleading impression as to the true long-term expense involved if such an approach is chosen. Because of the significant rate of survival from year to year among the patients treated by chronic dialysis, the cost of extending treatment to all those needing it in sub- sequent years will increase considerably with the passage of time. It was therefore decided to calculate the actual cost of the treatment of all individuals requiring it (the new group of vulnerable uremic patients presenting itself each year, the patients on lifelong dialysis who are survivors from previous years, and the patients in whom transplantation was unsuccessful and who must be maintained with the aid of chronic dialysis) for as many years as needed after the start of the program until a year was reached which could be considered characteristic of a "steady state." At this particular point in time the number of new patients included each year in this program would equal the number of patients dying in the same year, and in this situation a constant or near-constant yearly cost of the program would be reached. Calculations showed that under the conditions of this program its yearly cost would increase greatly each year during the first 15 years, that the subsequent yearly increases in cost would be of a somewhat lesser magnitude but still highly significant, and that an asymptotic curve approach would show that the steady state would not yet be reached by the twenty-fifth year. Obviously one can expect research advances to occur well within the first 10 or 15 years which would modify greatly the respective efficacies of transplantation and hemodialysis and their costs. It was therefore decided that it would be unrealistic to report the cost of the hypothetical total push treatment program for end-stage kidney disease in terms of the eventual yearly cost of the steady state after 25 years. Rather, it was felt that it would be sufficiently indicative of the true costs to be expected to report the cost of the first year of such a program (the lowest yearly cost), the cost of the fifth year (a realistically foreseeable sum which is not likely to be influenced significantly by changes in the state of the art), and the cost of the fifteenth year (which is considerably higher than the cost of the fifth year and begins to approach the markedly higher eventual cost of the steady state year). To obtain a realistic range of cost, the calculations were done on the basis of two cost assumptions for each treatment modality: A higher "present cost" figure which reflects accurately today's costs of transplantation and chronic dialysis, and a realistically reduced "future cost" figure for these treatment modalities. 3) Results Obtained First Year Based on "present cost" figures, the cost of attempting to treat 40,000 patients out of the total vulnerable population of 50,000-during the first year of this hypothetical program, by means of chronic dialysis or kidney transplantation, would be $611,000,000. (Note: If an attempt is made to treat all 50,000 vulner- able patients, the cost of this program during the first year will be $761,000,000.) If the calculation for the first year is based on the less likely "future cost" rate, the respective figures would be $422,000,000 and $522,000,000. Fifth Year The cost of this program in the fifth year of its existence will range between $1,043,600,000 (based on the low, "future cost" figure) and $1,543,415,000 (based on the higher, "present cost" figure). In this year, 102,161 patients would be treated under the program by transplantation or chronic dialysis. Fifteenth Year The cost of this program in the 15th year of its existence will range between $1,816,000,000 (based on the low "future cost" figure) and $2,702,000,000 (based on the higher "present cost" figure). In this year, 179,401 patients would be treated under this program, by trans- plantation or chronic dialysis. In view of the fact that it is anticipated that research advances evolving during and after the first fifteen years of the program would introduce considerable improve- ments into both treatment modalities and would influence true costs significantly, projected expenses for the twentieth and twenty-fifth year of the program were calcu- lated but not reported. It should be noted, however, that the population which would require treatment during each year of this program would continue to grow and thus the yearly costs would increase, until a point beyond the twenty-fifth year at which a steady state would be reached. 33 B. A Total Program Aimed at Kidney Disease 1. Introduction It is evident from the foregoing models that concentration in future programs merely on the treatment of end-stage kidney disease is not likely to solve the problem of annual deaths due to irreversible uremia unless unlimited funds are available for an indefinite continua- tion of such a program. Thus, steps must be taken to decrease the number of people who enter the irreversible fatal stage each year by a systematic prevention or treatment of the primary kidney diseases which initiate their progressive downhill course. It is obvious from the analyses in the three major kidney disease groups---infectious, hypersensitive and hypertensive--that the otherwise inevitable annual reservoir of patients with irreversible kidney failure can be diminished considerably through vigorous programs activated to deal with each of these groups. The application of relatively minor :funds in the group of infectious kidney diseases to stimulate systematic screening of high-risk groups followed by diagnosis and treatment, even within the current state of the art and without awaiting addi- tional advances due to ongoing or future research, can bring about a significant future reduction in the number of end-stage patients, Continued and expanded research activities will be necessary to increase the percentage of patients ultimately benefitted by this approach. In the area of hypersensitivity diseases involving the kidney there appears to be no promising mode of attack in sight except for the launching of a systematic research effort intended to increase our knowledge of the disease mechanisms involved. Here, the sooner this effort is started the greater the likelihood of a reduction of the number of end-stage victims in the near future. The promise for benefits to be derived from this type of research effort is such that it should not be postponed--particularly since any new effective treatment or prevention modality would produce major benefits in the entire field of hypersensitivity diseases, such as rheumatic heart disease, rheumatoid arthritis and others. In the group of hypertensive diseases of the kidney an immediate start, within the current state of the art, of screening, diagnosis and treatment can begin to diminish the number of patients who will eventually require end-stage treatment because of their progressive renal involvement. Simultaneous research efforts are likely to make this particular portion of the overall program more effective as time goes by, in the same fashion in which the new antihypertensive drugs developed during the last ten years have succeeded in decreasing by about 50 percent the mortality due to malignant hypertension. Thus, a meaningful Federal program to reduce the annual mortality due to kidney disease and aimed at a general reduction of the prevalence of the various kidney diseases must perforce be a multifactorial one which brings into play all of the program components--research, prevention, treatment and education--available in our armamentarium. An optimally proportioned mix of these program components must be present to yield maximum benefits in overall number of lives saved. This last concept includes not only deaths avoided today but deaths to be prevented in the years to come. Needless to say, such a total program, to be meaningful and productive, must be aimed at all three 35 major primary kidney diseases, as well as at end-stage kidney failure. 2. Structure of Total Program Models In order to arrive at the overall makeup of such a mixed attack on the problem of kidney disease, Tables I and II were prepared. These Tables outline the composition of four hypothetical overall programs-- three at different levels of expenditure and under the conditions of the present state of the art, and the fourth under the conditions of the expected advanced state of the art in 1975. Table III presents the benefits estimated for the four overall programs. Scanning thi:s table horizontally provides an intercomparison of benefits in the four disease categories. A vertical scan of this table provides an indication of the sensitivity of the four kidney disease categories to changes in expenditure levels. These projected total programs consist of a combination of the individual models of programs aimed at the various major primary kidney diseases and end-stage kidney failure which have been mentioned pre- viously and which are described in detail in Chapter 5. Thus, each hypothetical total program divides a specific level of HEW funding among a rational mix of program components the composition of which, in turn, is based on the conclusions from the previous analyses. Figures 1 and 2 provide another illustration of the qualitative and quantitative makeup of the first three total programs postulated for the current state of the art in Tables I and II. These pie charts serve to illustrate very graphically the influence of the available level of funding on the relative composition of these hypothetical programs. Thus, under circumstances of small budgets the percentage of treatment funds tends to be small, and that of research tends to Table I HE!4 COST SUMMARY (Sl,OGO) Prevention (including education h administration) Diagnosis and Treatment Sub-Total Intermediate Expenditure Level* Diagnosis, Prevention, Treatment Prevention (including education & administration) Diagnosis and Treatment Sub-Total 1 Diagnosis, Prevention, Treatment Prevention (including education & administration) Diagnosis and Treatment Sub-Total / Research 1 Training Facilities n & administration) Sub-Total Training Facilities TOTAL +: Current State of the Art i0: Advanced State of the Art ic** Attributable to renal disease associated with hypertension. source, See Chapter 6. 35a Table II TOTAL COST SUMWRY ($1,000) I I Kidney Disease Categories Ii Total Xagnosis, Prevention, Treatment Prevention (including education 6 administration) Diagnosis and Treatment Sub-Total iesearch Iraining Facilities 185,245 1 76.73 reYentlOn Lnc iagnosis and T Sub-Total xsearch Training 'dcilities DlaEnosis and Treatment wsearch Training rjcilities TOTAL i89,013 31,830 75,441 :>Lcelerated Exwnditure Level-1975f* %gmsis, Prevention, Treatment 200,000-vaccine Prevention (including education b administration) ~Wwsis and Treatment Sub-Total 'rsaarch rrdining hcilities Current State of the Art Advanced State of the Art --' Attributable to renal disease associated with hypertension. :r:e; See Chapter 6. 35b - -- - Kidney Disease Categories Infectious Hypersensitivity I 70 Deaths 610 Deaths 3,231,260 Cases - 15,962,420 Days - ~c~g-Te=~ Benefit-Reductions: Short-Term Benefit-Reductions: Nortality Prevalence Morbid Days Long-Term Benefit-Reductions: Annual Cumulative 70 Deaths 3,243,&O Cases 16,273,640 Days 1,770 Deaths 26,190 Deaths Accelerated Exoenditure Level* Short-Term Benefit-Reductions: Mortality 70 Deaths Prevalence 3,292,860 Cases Morbid Days 17,483,ggO Days Long-Term Benefit-Reductions: Annual >- 1,873 Deaths Cumulative 27,480 Deaths Accelerated Exoenditure Level-1975$+ Short-Term Benefit-Reductions: ! Mortality Pt-eV.?.lellCe Morbid Days 80 Deaths 770 Deaths 5.630. 780 cases 62,250 Cases 26,064,430 Days 2,610,OOO Days Long-Term Benefit-Reductions: I Annual Cumulative Y,,ZS Deaths 76,500 Deaths * Current State of the Art c* Advanced State of the Art ** Renal disease associated with hypertension. Source : See Chapter 6. 610 Deaths - - 610 Deaths 8,610 Deaths 320,000 Deaths 2,190 Deaths 27,000 Cases A,t~02,000 Days 4,330 Deaths 86,560 Deaths 1,110 Deaths 34,880 cases 2,056,820 Days 4,820 Deaths 96.300 Deaths 2,380 Deaths 42,750 Cases 2,:111,340 Days 4,820 Deaths 96,300 De'sths 9,300 Deaths 289,690 Cases 5,578,860 Days 9,480 Deaths :X9,660 Deaths End-Stage NO Deaths - I.560 Deaths - 1.615 Deaths 17 399 Deaths -- - 3560 Deaths 3,258,260 cases L7,764,420 Days 6,080 Deaths 112,410 Deaths - `AS10 Deaths 3,278,740 Cases 18,330,460 Days 6,590 Deaths 122.490 Deaths 10,735 kaths 3,335,610 Cases 19,795,220 Days 6,690 ikzaths 123.780 Deaths 37.5Yp Deaths i 5,991,723 Cases 1 34,253,290 Days 21,090 Deaths 586,160 Deaths , Short-term benefits - reduction in annual mortality, etc., when program is fully operative. Long-term annual benefits - eventual annual reduction in number of cases reaching end-stage kidney disease. Long-term cumulative benefits - sum total of long-term annual benefits. 35c I (53.8%) (25) y APreventionl Treatment (25.6%) (30) \ I Research (31%) (36) I Current HEW Exuenditure Level (Current State of'the Art) Total Cost = 46.7*($1,000,000) Facilities Intermediate HEW Expenditure Level (Current State of the Art) Prevention \ Total Cost = 117.4*($1,000,000) X7.9%)\ * Totals are subject to rounding errors. Fig, :.$ HEW Cost Summary. Accelerated HEW Expenditure Level (Current State of the Art) Total Cost = 289.9*($1,000,000) a nd (66 r Treatment -. *. (276.22%) 5. *. (185.2) Facilities Prevention and Treatment (204.3) (304.59%) \ Current Total Expenditure Level (Current State of the Art) Total Cost = 241.5~~($1,000,000) Trai (8.1) -/r Totals are subject to rounding errors. Fig. 2. Total Cost Summary and Treatment (266.14%) Treatment (215.9) (233.74%) Prevention (245.8) Prevention *\. \ (43.2) (46.76% Treatment Intermediate Total Expenditure Level (Current State of the Art) Total Cost = 322.6*($1,OOO,UOO) Accelerated 'liiYa1 ExpeMiture Level (Current State of the Art) Total Cost - 526.0*($1,000.000) 36 be large. As the level of expenditure is liberalized this relationship becomes reversed, although in each case the absolute expenditure for each component still grows. C. Future Shifting Proportions of Program Components Figures 1 and 2 have illustrated the influence of the amount of avail- able funds on the relative proportions of the various program components in such total efforts. Another factor which will influence these proportions very significantly is the prevailing state of the art with respect to the various primary ,kidney diseases and end-stage kidney failure. This was evident in the program analyses involving the individual groups of kidney diseases; the same principle holds in relation to overall programs as illustrated on Tables I and II. Here too, the total program mixes illus- trated do not and should not represent static proportions to be followed in future years. Depending on advances in knowledge and methodology which will be derived from ongoing research efforts, these proportions will have to be changed each year to obtain maximal benefits in terms of lives saved both in the long run and in terms of the immediate future. Thus, as rsurvival figures for transplantation improve, more patients who would otherwise be maintained Permanently with the aid of dialysis will be treated by kidne.y transplant, and proportionately more funds should be channeled in this direction. As improved methods of primary prevention are developed (such as an anti- StreptococcaI vaccine) more funds will have to be allocated for the applications of the new techniques since their successful use will reduce the long-term mortality at a relatively small per capita expense. D. Outlook With an advancing state of knowledge and with the passage ProPortions of the optimal mix for a total program for the so of lut ion or time, the 37 amelioration of the kidney problem will follow the general outlines of the diagram presented in Figure 3. It illustrates a gradually increasing emphasis on successful prevention and effective treatment of the various primary kidney diseases with progressively lesser needs for the saving of lives due to end-stage kidney disease. Given such a set of circumstances there will be a continued need for a repeated searching re-evaluation of the entire kidney disease problem, so that program decisions will continue to bring maximum benefits to patients afflicted with kidney disease, Treatment of End-Stage Kidney Disease Prevention & Treatment of Primary; Kidney Diseases P-L_*---- -eases T/ Figure 3. EFFECT OF ADVANCING STATE OF THE ART ON FUTURE PROGRAM COMPOSITION (Percentages are wholly arbitrary and merely serve to illustrate shifting trends.) 37a Chapter 2 `ci rr L. Kidney Disease--Current Status I. INTRODUCTION Dramatic advances in the treatment of end -stage renal failure have sparked new hope for people suffering from this hitherto fatal condition. Today hundreds are living useful and productive lives while undergoing chronic hemodialysis. Hundreds more have received successfully transplanted human kidneys and carry on life with minimal interruption in their daily activities. Current programs to increase research and development in transplantation and chronic hemodialysis, and training of personnel to supervise these complex procedures promise a wider application. Yet, though dramatic and usually successful, chronic hemodialysis and renal transplantation are difficult procedures associated with considerable morbidity and mortality. At best these procedures are now applicable to a relative few patients who reach the terminal stages of renal failure. A rational program in kidney disease, therefore, requires that oppor- tunities to interrupt all processes leading to renal disease be sought and pursued vigorously. We must fill the gaps in our understanding of the path- ogenesis of renal disease; we must define and isolate the etiologic factors, and careful and detailed study must settle the areas of controversy. II. THE DISEASE PROBLEM As indicated in Chapter 1, diseases of the kidney have steadily gained in significance as an area of social importance for both federal and nonfederal research and service efforts during the last five years--primarily because of the development of hemodialysis and kidney transplantation. In general, 23 i,owever, mortality from kidney disease and other urinary system diseases :?,a steadily declined since 1900 from about 100 deaths per 100,000 population ;., 1900 to 17.2 in 1964. Total mortality for all age groups among the four disease groups mentioned in Chapter 1 for 1964 was 58,788. The distribution Sf mortality among these disease groups is. depicted in Figure 1. As can be seen, hypertensive renal cardiovascular diseases accounted for the great&St ?ercentage (36%) of deaths among the kidney disease groups considered in the analysis. Figures 2-5 graphically present the importance of morbidity associated with kidney diseases in terms of prevalence, days of restricted activity, days of bed disability and total work loss days. In general, there is little morbidity associated with hypersensitivity diseases of the kidney. Total morbid time of all types is generally evenly distributed among the'remaining disease groups. During the period of July 1964 - June 1965, kidney diseases accounted for about 140,000,000 total days of restricted activity, 63,500,OOO days of bed disability, 17,000,OOO work loss days, with a prevalence of about 7,800,OOO cases. III. DISEASES OF INTEREST A. Hypertension 1. Introduction Arterial blood pressure is maintained by a variety of mechanisms and is subject to a number of influences such as posture, emotional state and exercise. When measured correctly in the steady resting state a diastolic blood pressure in excess of 9Omm. of mercury is considered abnormal. The conditions characterized by established diastolic hypertension Hypersensitivity IV. Other Diseases of The Kidney 15,187 25.8% III. Hypertensive Renal Cardiovascular Diseases 20,890 35.6% Total Mortality--58,788 Pig. 1. Mortality from Kidney Disease in 1964 by Disease Group. Source: Unpublished data from the U.S. Department of Health, Education, and Welfare, Public Health Service, National Center for Health Statistics, Washington, D.C. 39a / II. II. Hypersensitivity Diseases Hypersensitivity Diseases 104 1.3% "I III. Hypertensive Renal Cardiovascular Diseases 35.1% Infectious Diseases 24.7% Other Diseases of the Kidney Total Prevalence - 7,847 Fig. 2. Selected Chronic Conditions, Prevalence (1000's), United States, July 1964 - June 1965. Source: For civilian non-institutional population from unpublished data from the U.S. Department of Health, Education, and Welfare, Public Health Service, National Center for Health Statistics, Washington, D.C. 39b , II. Hypersensitivity 37,610 26.9% III. Hypertensive Renal Cardiovascular Diseases 44.138 IV. Other Diseases of the Kidney \- 54,180 38.7% Total Days of Restricted Activity - 139,939 Fig. 3. Selected Chronic Conditions, Days of Restricted Activity (1000's), United States, July 1964 - June 1965. Source: For Civilian non-institutional population from unpublished data from the U.S. Department of Health, Education, and Welfare, Public Health Service National Center Ear Health Statistics, Washington, D.C. 39c / II. Hypersensitivity Diseases Infectious Diseases 17,012 Hypertensive Renal Cardiovascular \ Total Days of Bed Disability - 63,494 9ig. 4. Selected Chronic Conditions, Days of Bed Disability (1000's), United States, July 1964 - June 1965. Source: For civilian non-institutional population from unpublished data from the U.S. Department of Health, Education, and Welfare, Public Health Service, National Center for Health Statistics, Washington, D.C. 39d , II. Hypersensitivity Diseases 765 4.6% / III. Hypertensive Renal I. Infectious Diseases Fig. 5. Source: IV. Other Diseases of the Kidney 9,459 56.5% Total Work Loss Days - 16,729 Selected Chronic Conditions, Work Loss Days (1000's), United States, July 1964 - June 1965. For civilian non-institutional population from unpublished data from the U.S. Department of Health, Education, and Welfare, Public Health Service, National Center for Health Statistics, Washington, D.C. 39e include primary (essential) hypertension, of unknown cause, comprising 80-90% of the total, and secondary hypertension accounting for lo--20% of the hypertensive population. In the secondary group, the hyperten- sion can be traced to some underlying process. This group is especially important because often the hypertension can be cured. Processes leading to secondary hypertension include: adrenal tumors, renal artery stenosis, pyeicnephritis, acute and chronic glomerulonephritis, pheochromocytoma, coarctation of the aorta, and certain disorders of the central ner~us system. 2. Primary (Essential) Hypertension a. Incidence Primary hypertension occurs in 5-10% of the adult population of the United States. In 1965 it was estimated that 9,200,OOO individuals had hypertension. It is twice as common in women as in men and t-here is a strong familial tendency. The average age of detection is about 32 and onset after 50 years of age is most unusual. When followed from the onset of hypertension, the average patient lives for a period of 20 years. (The average life expect- ancy at 32 is 41.5 years.) The course of the individual patient varies. Some patients may enter an accelerated phase in a few months; others may survive with few complications fcr 40 or more years. Of those with essential hypertension 5-10% develop an accelerated or malignant form which is fatal if untreated. b. Clinical Course--Benign Hypertension Initially there may be no symptoms and the patient is often unaware of the illness until informed by his physician. The clinical course roughly divided into an uncomplicated phase lasting an averro- -riate laboratory tests and X-rays. $2 The incidence of secondary h:;per- fensions is estimated at from 10 to 20% of the total hypertensive popu- lation. Of these 5-15% are caused by renovascular (renal arterial) lesions. Another group of potentially curable hypertensives are those having hypertension secondary to aldosterone-producing adrenal tumors. Presently experts differ on the incidence of aldosterone-producing tumors in the hypertensive population. It is variously estimated that these tumors account for from 1 to 20% of the hypertensive population. Most ixvesti- gators are now finding that 1% o f their hypertensive patients have this condition. Other causes of secondary hypertension such as coarctation of the aorta, various renal diseases, Cushing's disease, pheochromocytoma and central nervous system disorders can be excluded only by careful and often extensive examination. 4. Etiology of Primary Hypertension The cause or caases of hypertension have been dnd are t he sub 'ject of' intensive study by many distinguished investigators. They-- are three major theories relating to the development of hypertension. Some have stressed the importance of neurogenic factors and psychologic stress? others have emphasized.excessive sodium intake and abnormal endocrine control, while still others have concluded that renal circulation and renin are of primary importance in the development of hypertension. There is much'evidence supporting each theory. Possibly one or all of these factors operates in a given individual who may be genetically pre- disposed to the development of hypertension. In this brief review emphasis will be placed on the renal relationships with hypertension without intending to imply that renal factors are the underlying cause of all primary hyper- tension. The association between pyelonephritis and hypertension exists but the exact nature of the relationship has not been clarified. Patients with hypertension have a reported incidence of pyelonephritis varying from 14% to 51%. Conversely, from 12% to 85% of patients with histologic evidence of pyelonephritis are reported as having hypertension. The high incidence of pyelqnephritic kidneys in hypertensives suggests that hyper- tension either predisposes to renal infection or is the direct cause of pathologic changes which are indistinguishable from those usually caused by infection. It has also been postulated that chronic renal infection is a major cause of hypertension. Current evidence is substantial regarding these views, but is not yet conclusive. The relationship between hypertension and arteriolar nephrosclerosis (damage to the small arteries of the kidney), of the kidneys is also a subjc of continuing controversy. Clearly, most hypertensives have nephrosclerosi to a greater or lesser extent. Now most investigators think that the nephrosclerosis is secondary to the hypertension. Some, however, maintain that the renal arteriolar lesions may be ths pr:cipitating cause of the hypertension. Whatever the underlying cause, it seems clear that once 44 established, hypertension accelerates the development of renal arteriolar stenosis and conversely that the arteriolar lesions may sustain and aggravate the increase in blood pressure. In malignant hlypertension, renal ischemia leads to increased renin output with secondary hyperaldosteronism and an accelerated rate of hypertension which in turn leads to further renal arteriolar damage. Further clarification of these important areas will have far-reaching therapeutic implications. 5. Management of Hypertension With proper screening of the hypertensive population it is probable that lo-20% will be found to have underlying causes amenable to permanent cure. In malignant hypertension and in advanced diastolic hypertension (blood pressures in excess of 1lOmm. in men and 12Omm. in women) early drug therapy and dietary management have been demonstrated sharply to reduce morbidity and mortality. In patients with lesser elevations of blood pressure the evidence favoring treatment is less substantial. Treat- ment must be individualized balancing the risks inherent in any chronic treatment against the potential benefits. Current long-term studies will help clarify this area. B. Pyelonephritis and Infections of the Kidney During the past 30 years since the reports of Longcope and Winkenwerder, and Weiss and Parker, the term pyelonephritis has been widely used to imply a pathologic process resulting from the immediate or late effects of bacterial infection of the kidneys. Unfortunately, the criteria used to diagnose pyelo- nephritis are not uniform. 1. Incidence The incidence of chronic pyelonephritis varies widely among various autopsy series from.as low as 2% to as high as 35%. Reasons for these differences are the varying criteria used by pathologists to diagnose pyelonephritis and the differing populations studied. Kidney infections are more common in older populations, are more frequent in Negroes, and occur in higher incidence among lower socio-economic groups. In one careful study, pyelonephritis was found in 3.3% of 4,596 autopsies. hlY 10% of these cases of pyelonephritis had demonstrable bacteriuria at death although previous treatment may have resulted in eradication of bacteria in some cases. In this same series 1.6% of 4:,596 deaths were attributed to uremia. In another study acute and chronic pyelonephritis was found in 10% to 20% of the autopsies at two hospitals but was judged to be a major factor causing death in only one-third of these cases. On a national basis in 1964, about 10,000 of the 1,800,OOO deaths or 0.5% were attributed to infections of the kidney. This figure must be analyzed. It represents 'data from a wide variety of sources where there are considerable differences in the diagnostic criteria of pyelonephritis. It does not include cases of obstructive uropathy due to prostatic hyper- trophy and prostatic cancer when these were ruled the underlying cause of death though renal infection may have precipitated death. On the other hand, this figure includes cases of renal disease in which there was no documentation of infection by bacteriologic or pathologic means. In other cases renal infection may have been recognized, but the underlying urologic or metabolic defect may not have been apparent. Such incidence data of kidney infection and pyelonephritis must, therefore, be approached with caution in program planning. The final diagnosis of the cause of death is at best a good interpretation of events in the current state of the art. Many cases of infection are certainly missed and others are classified erroneously as infection. The margin of error is unknown, but could be large. A rational approach to the control of pyelonephritis must include further research into all causes of chronic interstitial nephritis as well as the search for methods to control kidney infection. 2. Acute Fyslonephritis Acute pyelonephritis is a common problem usually caused by g-am negative bacterial invasion of the kidney. The onset is usually abrupt bi i t b characteristic symptoms although at times clinical symptoms may be subtle or absent. The acute symptoms generally subside rapidly although bacteriuria may persist without adequate treatment. Recurrences are common, particularly during and following pregnancy. In recurrent cases, a careful search for underlying predisposing factors such as prostatic hypertrophy, stones, diabetes mellitus and congenital malformations should .be made. Remedial procedures are indicated where feasible. 3. Chronic Pyelonephritis Symptoms of infection are frequently absent in patients with chronic pyelonephritis although there may be a history of previous urinary tract infection. The onset is usually insidious with gradual development of the manifestations of chronic renal failure. This period of relative renal insufficiency may be long. During this perLod many patients Eve in comfort for years despite azotemia. Sacteriuria may be absent or present only intermittently making accurate diagnosis difficult during life. In such cases, other causes of nephritis must be considered. liven tually, end-stage renal failure is reached unless intervention is undertaken. 4. Bacteriuria and Urinary Tract Infection Bacteriuria may be defined as the presence of over 100,000 organisms per cc. of urine on a culture of clean fresh urine. Defined in this manner persistent bacteriuria indicates infection of the urinary tract. There has been much debate about the role of bacterial infection in the pathogenesis of chronic pyelonephritis. Repeated bouts of kidney infection whether manifest or silent lead to renal scarring and eventual renal failure. But in many cases bacteria cannot be isolated from kidneys in which the pathologic diagnosis is pyelonephritis. One current and controversial theory to explain this discrepancy is that bacteria may initiate a self-sustaining destructive process which persists after bacteria have been eradicated. Another possibility is that some cases classified as pyelonephritis are due to non-bacterial causes. It is not known how often bacteriuria per se is the forerunner of chronic pyelo- nephritis. Since bacteriuria is present in patients who do not subsequently develop pyelonephritis and since the source of bacteria may be the urethra, bladder or other lower urinary tract sites, there must be many cases in which ascending infection does not develop. On the other hand, bacteria in the lower urinary tract may lead to kidney infection, parti- cularly in the presence of predisposing factors such as obstruction, stones, diabetes and gout. Furthermore, such bacterial infection can act as a source of virulent organisms in the development of septicemia. Thuc. while bacteriuria may not always lead to the development of chronic pyelonephritis, its presence should be taken seriously, and careful consideration given to management. In young patients persistence of bacteriuria should be confirmed by a minimum of two cultures of clean voided specimens. If bacteriuria persists in an asymptomatic patient, a short course of antibiotic treat- ment should be followed with repeat culture at intervals. If bacteriuria still persists, investigation to detect underlying correctable lesions is indicated. In later stages of pregnancy about 6% have asymptomatic bacteriuria. Of these, at least 40% will develop pyelonephritis. It seems reasonable to treat bacteriuric pregnant women for the duration of the pregnancy. In older patients in whom the incidence of bacteriuria may be 10 to 20%, treatment must be undertaken with some caution. The eradication of bacteriuria in the elderly is difficult and the risk of complications from over-zealous treatment seems great. Carefully controlled long-term studies are necessary to determine in which cases vigorous treatment of bacteriuria will prevent the develop- ment of chronic pyelonephritis. Judicious application of current techniques to control infection may result in eventual reduction in the number reaching the end-stages of pyelonephritis. Hypersensitivity Diseases 1. Acute Glomerulonephritis Acute glomerulonephritis is a common disease affecting all age groups, but it occurs predominantly in children. Almost all cases follow by one to four weeks infection with hemolytic streptococci. These bacteria initiate an immune process which is almost certainly responsible for the subsequent renal damage. Only certain nephritogenic types of streptococci are responsible for acute glomerulonephritis. Thus, in some epidemics of hemolytic streptococcal infections, glomerulonephritis is not seen, 4s while in others the attack rate is high, the disease.often striking several members'of the same family. Most cases are mild and some may go unnoticed. In mild symptomatic cases, renal damage is manifested by blood in the urine and puffiness due to salt and water retention. In more severe cases hypertension, anemia, and even acute renal failure may develop. As a rule most patients recover completely,but currently, about 2% of hospitalized patients die of acute renal failure. In 1964, 585 deaths were attributed to acute nephritis. An additional 2,900 died of nephritis not specified as acute or chronic. A few patients with the acute form enter a protracted subacute course with gradual deterioration of renal function over a 6 to 12 month period. Nephrosis seldom occurs in the acute phase. In another group, comprising probably not much more than 1% of the total with acute post streptococcal glomerulonephritis, healing is incom- plete. These patients show continuing proteinuria and eventually develop one type of chronic glomerulonephritis. Failure to heal is more common in adult cases of acute glomerulonephritis and iseems to be associated with non-epidemic streptococcal infections. Estimates vary, but about one-tenth to one-third of all cases of chronic glomerulonephritis are post streptococcal in nature. 2. Chronic Glomerulonephritis Chronic nephritis and nephrosis accounted for 8,800 deaths in 1964. Chronic glomerulonephritis cannot be defined as a single disease entity and probably has multiple causes. In most cases the etiology is obscure. In various autopsy series its frequency has been reported from 0.5% to 1.5% and is about one-third as frequent a cause of death as pyelonephritis. The onset occurs in all age groups. If those presenting with the nephrotic syndrome are excluded, the greatest number are first noted between age 10 and 40. Chronic glomerulonephritis usually begins quietly and progresses slowly. The first manifestation is frequently persistent protein in the urine. In other instances onset is abrupt with rapid development of nephrotic syndrome characterized by edema and massive proteinuria. Hyper- tension rarely appears until renal damage is severe. The course is variable lasting from one to about forty years. In one series the average duration was seven and one-half years in those who have died, however, many in this series are still living. The course may be punctuated by episodes of nephrosis and may terminate abruptly. Signs of renal failure appear gradually, but once azotemia appears, progress to end-stage renal f.ailure is usually a matter of only a few years. 3. Nephrotic Syndrome Massive loss of protein in the urine may be caused by a variety of renal diseases and leads to the development of the nephrotic syndrome. Clinically this syndrome is characterized by massive swelling of the body and face known as generalized edema. Underlying renal diseases such as lupus erythematosus, diabetic nephropathy and post streptococcal glomer- ulonephritis are occassionally recognized, but more often no underlying cause can be detected. 4. Idiopathic Nephrotic Syndrome Nephrotic syndrome due to unknown causes is a major cause of morbidity and mortality, most often in children between the ages of one and six. The annual occurrence in this age group is estimated at 2 per 100,000. Patients with the nephrotic syndrome present a variety of clinical pictures. In the idiopathic form glomerular lesions lead to urinary 52 protein loss with the development of generalized edema. Complications in severe cases include hypertension, malnutrition, anemia, infection and occasional vascular collapse. In children, about one-third heal spontane- ously . Recently corticosteroid therapy and careful management appear to have improved survival rates. In adults with this disorder, the out- look is even more serious. Spontaneous healing is not common and progressive renal failure usually ensues. 5. Pathogenesis of Nephrotic Syndrome and Chronic Glomerulonephritis The underly'ing causes of these renal diseases are not known. There is much evidence to indicate that immune mechanisms are responsible, but the precise sequence of events is not clear. The application of safe biopsy techniques, sophisticated biochemical methods and electron micro- scopy to the study of glomerular lesions has helped unravel this complex group of disorders. The application of new immunological concep.ts,.combined with transplantation studies may finally yield answers to the remaining basic questions about these diseases. 6. Lupus Nephritis Systemic lupus erythematosus is a generalized disease involving the kidneys, brain, lungs, skin, joints, and other organs. Nearly 300 deaths were listed in 1964. It is predominantly a disease of young women, but attacks both sexes through a wide age range. The incidence has increased markedly during the past two decades partly because of improved methods of diagnosis and almost certainly.because of the more widespread use of sensitizing drugs. There is much evidence that an abnormal immune response, precipitated by a variety of agents, is responsible for this disease. 52 Renal involvement in patients with systemic lupus erythematosus is perhaps the most ominous of the many manifestations of the disease, In general, renal involvement is found in about two-thirds of lupus patients. Patients who exhibit renal involvement usually do so early in the course of their disease. The renal lesions run the gamut from a local glomerulitis involving parts of glomeruli, to a focal lesion involving some glomeruli, to generalized subacute or chronic glomerulonephritis, with or without the characteristic wire-loop lesion. Clinical manifestations of renal lupus include hypertension, edema, and on occasion oliguria or anuria with rapidly progressing uremia. M=Y patients with lupus nephritis show at some stage the nephrotic syndrome. Usually, this group does poorly. Corticosteroids have become a mainstay of lupus nephritis therapy, though there are divergent opinions as to the effectiveness of these drugs in various stages of the disease. Recently antimetabolites have heen used and present information suggests a significant measure of success. Additional information about the nature of the renal changes in this disease has been obtained by attempts to relate ultrastructure and functional derangements. Studies are under way to elucidate the role played by plasma proteins in the evolution of this disease. Important work is being done correlating the histologic changes in the kidney with clinical course. Understanding of the pathogenesis of this disease has important implications for all hypersensitivity diseases such as rheumatoid arthritis, all chronic nephritis and rheumatic fever and has relativity to transplantation immunology. 53 D. Other Related Renal Diseases Many kidney diseases and other diseases which often lead to severe renal disease were not included in this initial analysis. These are described briefly in this section. 1. Polycystic Disease of the Kidneys This disease is by far the most important of the developmental anomalies of the kidneys. This anomaly was held responsible for 1,061 deaths in the United States in 1964. In this group over three-fourths of the deaths occurred before the age of 60. This disease masquerades in a variety of forms including vascular accidents, hypertension, pyelo- nephritis and chronic renal failure. There are two forms: one inherited as a dominant trait which usually becomes manifest in adult patients, and one which appears to be inherited as a recessive trait primarily mani- fested in children. A history of polycystic disease is usually readily obtained in other family members; unfortunately in some families there is a pathetic desire to hide the trait. Conventional treatment helps these patients. But, as end-stage renal failure approaches, hemodialysis and eventual renal transplantation are their only hope for survival. 2. Gouty Nephropathy An estimated 250,000 people in this country are suffering from some form of gout. In 1964, 130 deaths were attributed to gout. In the advanced stages of gout one of the major causes of death is renal insufficient) Some reports suggest that albuminuria occurs in up to 40% of patients with gout, renal calculi in 17% and that the development of renal insufficiency in 18% of cases. The only distinctive pathologic feature of the gouty kidney is the presence of urate crystals. The precipitation of this material in the kidney may be responsible for the frequently observed pathologic picture of pyelonephritis or nephrosclerosis and less often amyloidosis. Management of gout has until recently been limited to the relief of joint symptoms primarily through the use of colchicine and the reduction of elevated blood uric acid levels by increasing uric acid excretion primarily through the use of probenecid. A new approach to reduction of blood uric acid levels has been provided by the introduction of allopurinol, a xanthine oxidase inhibitor, which acts by decreasing the production rather than the excretion of uric acid. Important avenues of investigation have been opened not only in primary gout but in other diseases associated with increased uric acid levels. The promise of reduction in morbidity and mortality from gout is great. 3. Hypercalcemia Hypercalcemia from a variety of causes may produce secondary renal disease which if uninterrupted is often lethal. Calcification of the kidney tissue, formation of stones, and secondary pyelonephritis are common in advanced cases and usually lead to end-stage renal failure. Such diverse entities as hyperparathyroidism, sarcoidosis, vitamin D intoxication, excessive ingestion of milk and alkali, and immobilization in bed can lead to hypercalcemic nephropathy. In many of these cases therapy directed at the underlying problem is successful in arresting the progress of renal damage. Often, however, the process is not recog- nized until renal damage has progressed to an advanced state. In this stage, particularly if hypertension has supervened, reversal of the process is usually impossible and terminal renal failure ensues. _ r& 4. Diabetes AS the life span of diabetics has increased, renal disease has become an increasingly important cause of morbidity and mortality. The renal complications of diabetes are manifold and include acute and chronic infection, renal arterio-sclerosis and arteriolar sclerosis with hyper- tension, and finally intercapillary glomerulosclerosis, a process seen only in association with diabetes mellitus. Renal diseases account for over 10% of the deaths in diabetics. The management of these renal problems is only moderately successful. Eradication of urinary tract infection is particularly difficult in diabetics, but should be pursued with vigor since this may retard the progress of renal damage and prevent septicemia. Hypertension may be ameliorated by conventional therapy. Unfortunately, chronic hemodialysis and transplantation offer little chance for long-term survival in most of these patients since severe arterial disease is usually widespread in affected patients. Better understanding of the mechanisms of development of atherosclerosis and of lipid metabolism and changes occurring in the capillary basement membrane offer the best hope for improving the outlook of these patients. 5. Miscellaneous Renal and Renal Related Diseases Many other diseases are of importance in any discussion of kidney diseases. Malignant diseases of the p -- rostate account for over 15,000 deaths annually. In this usually indolent malignancy early detection may cure many patients, while hormonal therapy will help others. Prompt treatment of renal infections and alleviation of urinary obstruction reduces renal deaths. Benign prostatic hypertrophy leads to urinary tract obstruction with frequent development of hydronephrosis and pyelonephritis. New cryOSUrgiCa1 teChaiq.ucs are promising for this group and there f is indication that hormonal therapy may be beneficial. Kidney Stones often lead to obstruction and/infection. In cases due to gout and hypercalcemia the treatment of the underlying disorder may be effective. In other cases the cause is not clear, but may be related to individual habits or peculiarities of the environment. Recent identification and isolation of an "anti-stone substance" which is absent in the urine of some who develop kidney stones may lead to new therapeutic methods. In still other cases, such as cystinuria and oxalosis, the metabolic defects have been identified and corrective therapy may be forth- coming. A number of urinary tract anomalies are lethal in infancy. Other obstructive and muscular lesions may respond to treatment in later life. Tuberculosis of the genitourinary tract still accounts for almost 100 deaths per year and if recognized may respond to a variety of measures. Toxemias of pregnancy still account for over 200 deaths per year. Renal amyloidosis secondary to rheumatoid arthritis, ulcerative colitis and leprosy accounts for many deaths. Amyloidosis of the kidney due to chronic infectious diseases is a major world cause of renal deaths. E. Acute Renal Failure Acute renal failure may appear suddenly following a massive kidney Injury of develop in the course of a chronic renal disease. In either case urine flow is greatly diminished and the kidneys are temporarily unable to perform their usual functions. The incidence of acute renal failure is difficult to determine, however, in one university referral center, acute renal failure accounted for half of the patients seen with uremia. In a nationwide sample the proportion of patients with uremia who present with acute renal failure would probably be much lower. Acute renal failure may be due to a number of causes including insufficient renal blood flow, transfusion reactions from mis-matched blood, fulminating infections, kidney poisons, acute urinary tract obstruction and acute glomerulonephritis. Prompt restoration of blood flow, relief of obstruction and effective treatment of infection are essential in preventing further renal damage. Toxic substances must be immediately identified and measures taken to remove them by dialysis or chemical binding whenever possible. After all available measures have been taken to arrest further damage, assessment of the degree of damage must be undertaken and management planned. In a few cases the damage is mild and no further measures are necessary. In others, renal function ceases completely and the patients must be sustained by a combination of dialysis and dietary regulation while healing takes place. In these cases after a period of days or weeks the kidney gradually resumes its function and may eventually show return to normal function. Broad advances in our knowledge of kidney function, wide use of hemo- dialysis and availability of remarkable new therapeutic agents have resulted in a gradual increase in the number of patients surviving. Now over 50% of patients with severe acute renal failure recover. In other patients kidney damage is too severe and effective renal function does not return. Some die of other underlying processes or infection while others have little or no return of function and enter a period of chronic renal failure. F. Chronic Renal Failure Despite current screening programs and early medical intervention in many cases of renal diseases, many patients do not seek medical attention Llntil irreversible renal damage has progressed to an advanced state. Often d,,tructive kidney lesions are painless and indeed asymptomatic. Symptoms 3aY not be noticed by the patient until 50 to 80% of his kidneys have been destroyed* If at this point the patient seeks the help of his physician it nay still be possible, depending on the underlying disease, to arrest renal destruction, prolong life and reduce complications. For example, in chronic pyeIonephritis due to bacterial infection, relief of obstruction or removal 0f stones combined with selective antibiotic therapy may arrest renal destruction and in lupus erythematosus steroid and immunosuppressive therapy often retard the progress of renal destruction. In other cases such as chronic +merulonephritis, congenital polycystic disease, diabetic glomerulosclerosis, and some cases of chronic pyelonephritis, there is no current effective therapy to arrest renal destruction. '1. Dietary Therapy In these cases careful intelligent management has much to offer. Three major kidney functions are the regulation of water and electrolytes, the excretion of nitrogenous waste products and the excretion of excess acid. By careful regulation of dietary intake of sodium and potassium, restriction of protein intake to a minimum balanced mixture of essential amino acids,and limitation of the acid forming potential of the diet It is possible to reduce considerably the morbidity of patients with chronic renal failure. In cooperative patients, the frequency of dialysis can be greatly reduced. Anemia, hypertension and certain metabolic disturbances remain severe problems in some patients. 2. Hemodialysis and Transplantation In those patients who have progressed to the end-stages of renal failure or who have other threatening complications which can no longer be managed by selective management of intake, chronic hemodialysis and renal transplantation now offer a new hope for survival. Because experience is limited,it is difficult to'predict the eventual applicability' of these two procedures to the total population with end-stage renal failure. Further research into `improved dialysis membranes, combinations of hemodialysis with various ion exchange methods and/or selective adsorpti& : procedures, and better understanding of complex metabolic problems will reduce the morbidity and mortality associated with hemodialysis and may .. yield entirely new methods with wider application and reduced cost. Home -. dialysis is promising. In the field of- organ transplantation experience in management of transplant recipients and improved matching of donor kidney and recipient have resulted in substantial reduction in morbidity and mortality. Now this procedure is performed with remarkable success in a number of centers. Further advances in histocompatibility typing, selective immunosuppression and patient management can be expected. a. Hemodialysis Hemodialysis has been used with success in acute renal failure since 1947. The development of the indwelling arteriovenous shunt in 1960 made possible the use of intermittent hemodialysis to prolong life in irreversible uremia. In the current state of the art, a number of problems are apparent in the application of this procedure. b. Factors Limiting Application of Hemodialysis Partly because of limited facilities and personnel and because of ths limitations of current techniques, experience has largely been limited to patients between ages 20 and 55. Unfortunately, about three fourths of patients reaching end-stage renal failure and who thus might benefit from hemodialysis are beyond the age of 60. Within the mid-age group, psychological problems have presented a serious obstacle to some who might have benefited from hemodialysis. A number of patients have developed problems in accepting their dependence on dialysis machines and their attending medical personnel while others have suffered a change in self image which has led to serious social difficulties. The motivation and intelligence of the patient are crucial to success. The medical problems associated with chronic hemodialysis are formidable. Peripheral neuropathy and metastatic calcification are common. Hypertension is often difficult to control. The anemia of chronic renal failure often requires transfusions which eventually may lead to hemosiderosis. Serum hepatitis is a danger to the patient and the attending personnel as well. Infection at the cannula site and clotting of the cannula are persistent problems. Severe metabolic bone disease is still frequent although some progress has been made in its control. Human errors and mechanical difficulties are occasionally responsible for failures. Well trained, highly motivated and experi- enced medical personnel are scarce. Despite these problems many live useful, productive lives. While extension of hemodialysis to older age groups presents difficult problems, technical improvements and increased experience may prove intermittent hemodialysis feasible in some older patients. Intermittent hemodialysis combined with dietary therapy may prolong useful life in many and sustain others who might benefit from renal transplantation. Clearly, many now face death who could be helped by intermittent hemodialysis. C. Kidney Transplantation - Renal transplantation offers another future hope for those afflicted with end-stage renal failure. Currently 30-month survival rates range from 17 to 47% for patients with cadaver transplants and 60% or more for living related donors. In cases where a good histocompatibility match has been obtained and no rejection crisis has occurred in the first few months after transplantation, good renal function has been reported in up to 93% of patients after three and one-half years. d. Limitations Aside from the operative morbidity and mortality associated with renal transplantation there are currently several major obstacles to greater use of renal transplantation for end-stage renal failure. The availability of viable human kidneys presents a major problem. The use of living related donors raises serious moral questions and such donors will provide only a limited number of kidneys. Cadaver kidneys are a major potential source of viable kidneys; however, the problems of histocompatibility matching, the ethical and legal questions of consent, and the logistical problems of preservation and trans- portation have not yet been solved. Immunosuppressive therapy has been successful in preventing homograft rejection in many cases, but has often led to serious and sometimes fatal infection in the recipient. Although the development of more selective immunosuppressive agents has been promising, the problem of complicating infections has not been ovtrcome. Large areas of investigation offering significant conceptual advances in the field of tissue transplantation remain to be explored. Induction of adult tolerance, detailed analysis of histocompatibility antigens and work on the non-immunologic mechanisms of cell to cell interaction are some of these. e. Peritoneal Dialysis Peritoneal dialysis offers a useful, but a present limited alternative to hemodialysis. Exchange of chemicals is less efficient, leading to longer treatment periods than with hemodialysis, and infection remains a major obstacle. Intermittent catheterization, new flexible catheters, and automated flushing have improved this method. !-. Poisoning In 1964, over 1,000 deaths resulted from accidental poisonings from s;lIicylates, barbiturates and other analgesic and soporific agents. In addition, over 2,400 suicides resulted from use of these agents. Hemodialysis techniques .~re of great value in most of these poisonings and it is reasonable to assume tllat a significant number of these deaths could have been avoided if personnel trained in the techniques of emergency hemodialysis had been widely available. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. REFERENCES "Annual Report of the General Clinical Research Centers", U. S. Public Health Service, National Institutes of Health, 1967, (unpublished data). Beeson, Paul B., and Walsh McDermott, eds., Textbook of Medicine, Philadelphia: W. B. Saunders Co., 1963. Combined Staff Clinic, "Recent Advances in Hypertension", American Journal of Medicine, vol. 39 (1965) pp. 616-645. Holme, Walsten, and Maeve O'Connor, eds.,#'Ethics in Medical Progress: Ciba Foundation Symposium, Boston: Little, Brown, and Co., 1966. Ingelfinger, Franz J., et al., eds., Controversy in Internal Medicine, Philadelphia: W. B. Sauzers Company, 1966. Kirkendall, Walter M., Annette E. Fitz, and Montague S. Lawrence, "Renal Hypertension", The New England Journal of Medicine, 276:479, March 2, 1967. Kupfer, Sherman and Raul Goyo, '!A New, Intermittent Peritoneal Dialysis: Easily Inserted Catheter for Journal of the American Medical Association, 200:115, May 15, 1967. Little, P. J. and H. E. de Wardener, "Acute Pyelonephritis", The Lancet, p. 1277, December 10, 1966. Metceff, Jack, ed., Proceedings of the Seventh Annual Conference on the -- Nephrotic Syndrome, New York: The National Nephrosis Foundation, Inc., 1956. Michael, Alfred J., et al., "Immunosuppressive Therapy of Chronic Renal Disease", The New England Journal of Medicine, 276:~. 817, April 13, 1967. Pawlowski, Joseph M., John W. Bloxdorf, and Paul Kimmelstiel, "Chronic Pyelonephritis", The New England Journal of Medicine, 268:~. 965, May 2, 1963. Strauss, Maurice B., and Louis G. Welt, Diseases of the Kidney, Boston: Little, Brown, and Company, 1963. U. S. Public Health Service, U. S. Department of Health, Education, and Welfare, Vital Statistics of the United States Mortality 1964, Washingion, D.C.: U. S. Government Printing Office, 1966. Chapter 3 G4 Current'Kidney Disease Control Programs I.