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.  INTRODUCTION

  This chapter is devoted to a brief description of current kidney
disease "program" activities and deficiencies.  "Program" as used herein

refers to an organized effort directed toward the eradication or allevia-

tion of kidney disease problems.  Kidney disease program efforts may have

an active nature, such as a research project in kidney disease, or passive

nature such as a hospital renal clinic.

  Kidney disease program efforts in this chapter are viewed from the

standpoint of program source and by program objective.  Program source is

considered in terms of federal and nonfederal.  The latter includes state

and local government, individual, philanthropic, and nongovernment

institutional financial expenditures for or on behalf of kidney disease.

  Kidney disease programs objectives may be separated into the following

functional areas:

1)




2)



3)




4)







5)

Research--Includes laboratory and clinical investigations and

developmental research efforts.

Other Methodological Studies in Kidnev Disease--Includes operational

studies, screening and detection programs, and demonstration projects.

Treatment-- Includes hospital, nursing home, physician and other

professional services for diagnosis and therapy of kidney diseases.

Facilitiesi- Includes aid in construction, remodeling or expansion

of facilities for activities in kidney disease treatment, research,

and training.

Education and Training--Includes basic education (fellowships),


specialized on-the-job training (training grants), and postgraduate

education in kidney diseases.

  The ability to describe many federal and particularly nonfederal

kidney disease program efforts in terms of expenditures is highly variable

because of insufficient or inadequate data.  In many instances kidney

disease program efforts are merged with others thereby making it difficult

to proportion accurately kidney-related expenditures among general programs.

In some instances it was necessary to use data for the year 1964 because of

its completeness and availability.  Whenever possible, programs for more

recent years are used in order to make this document action-oriented for

imminent budgetary periods,  and to take into consideration increased efforts


in this disease area.

II.   SPECIFIC FEDERAL KIDNEY DISEASE PROGRAM EFFORTS

   A number of federal agencies are currently active in kidney disease.

Some have primary responsibilities in providing patient care and others are

interested in basic and developmental research.  As in most other diseases,

there is no single federal agency charged with the responsibility for

kidney disease programs.  PHS recently indicated that there is no compre-

hensive plan for coordinated attacks against kidney disease because:

   1) Kidney disease is notoriously difficult to pinpoint as a cause for

     morbidity and mortality in the population;

   2) The variation in opinion within the medical community as to the

     desirability of large-scale dialysis and transplantation efforts;

   3) The need for more time to improve and develop research; and

   4) No single agency or organization has taken on itself the


leadership in bringing together all interested groups in kidney disease.

kidney disease program activities of specific Federal Agencies follow.



A.  u. S. Department of Health Education and Welfare (HEW)

HEW has undertaken major responsibility of kidney disease control programs

in the U. S=  Its activities range from laboratory and'clinical research
Performed or supported by the National Institutes of Health (NIH) to support
sf dialysis center demonstration projects by the Kidney Disease Control Program

cf the National Center for Chronic Disease Control.  Specific groups and

,ctivities follow.

1.  National Institutes of Health (NIH)

a.  National Institute of Arthritis and Metabolic Diseases (NIAMD)

NIAMD's primary efforts are in the area of laboratory and clinical

research and in urology and kidney diseases in general, and research

and development in chronic uremia, hemodialysis and artificial kidney

development.

  The NIAMD has traditionally.invested major funds in extramural

support of laboratory and clinical research in kidney diseases and

urologic disorders.  It was a group of Institute grantees that

developed the permanently indwelling polymer shunts which made chronic

intermittent hemodialysis possible.  The emergence of this new treat-

ment modality encouraged the Congress, in the summer of 1965, to

appropriate funds to this Institute for the pursuit of a centrally
directed program of research and development in chronic uremia, hemo-
dialysis and artificial kidney development, utilizing predominantly a
direct contract approach as well as increased research grant support.

A thorough study of the state of the art made it apparent that no

single specific direction should be followed which would exclude

others which might be relevant.  Several different types of


artificial kidneys are in use at the moment, and different

methodologies are being advocated by the various workers in

the field.  Therefore,  at this time, a variety of approaches

in artificial kidney development are being supported.   Once it

becomes evident that one or more approaches show greater

promise, efforts will be concentrated in these directions.

   The Artificial Kidney-Chronic Uremia Program was mounted

with the placement of carefully selected research and develop-

ment contracts with universities, nonprofit research laboratories

and industrial concerns which possessed relevant talents and

facilities.  These projects involve development of improved

blood cannulas; evaluation and development of new polymer surfaces

for artificial kidneys;  cannulas and membranes which do not

induce blood coagulation; design of more efficient, compact,

and less costly dialyzer systems; development of a new concept

of artificial kidney dialysis ("hollow fiber" or "capillary"

kidneys); research on and development of absorption cartridges

for blood purification;  research on the utilization of ultra-

sonics to speed up dialysis in artificial kidneys; development

of inexpensive disposable dialysis units; improvement and design

of new dialysis units with automated failsafe mechanisms;

design and development of a prototype for a portable artificial

kidney; evaluation of a special protein restricted diet in

the maintenance of uremic patients for whom chronic dialysis


is deemed not feasible or unobtainable; isolation from dialysates

and identificatinn of the as yet unknown compound(s) which is (are)

specifically responsible for the toxic symptomatology in uremia;

and many other projects related to improved dialysis methodology

or apparatus.

   An important new activity involves the establishment of a

long term central patient registry and medical information system

involving all patients maintained with the aid of chronic dialysis

in the United States (and, through cooperation of the European

Dialysis and Transplant Association, of similar patients in Europe).

This activity, which involves very close collaboration with the

Kidney Disease Control Program of PHS and with the Veterans

Administration, will permit a comparative evaluation of different

dialysis treatment methods and equipment based on a longitudinal

study of all patients involved,  from their selection for chronic

dialysis treatment onward.

  The portion of the program which is funded by extramural

research grants complements closely the contract program described

above, but is oriented more toward elucidation of clinical and

fundamental biological problems related to the treatment of

chronic uremia rather than toward hardware development. It

involves studies on urea metabolism in uremic patients undergoing

chronic dialysis; the effectiveness of peritoneal dialysis in

uremia patients; other novel approaches to blood purification in

chronic kidney failure such as dialysis of a surgically relocated,

isolated intestinal loop, lymph dialysis and dialysis in the home;

and the nature of the biochemical defects in advanced uremia.

A sunrnary of NIAMD kidney disease program expenditures is

presented in Table I.


Table I

NIAMD KIDNEY DISEASE PROGRAM EXPENDITURES FOR 1966

I           _I.__ _..._ ..__.,_. . ".__ . . . . ._.I. --..I - --..-------
-,

i i Program                      1966
---  _---- .._... - ,- . ..- _---. . . ..^_ - . . . . - . . . ..--..  .-__-.. ----___
                    -....---.....l_l_...,_^ ..-I- - .-.-_-- _. . . -- _
Research and Development:

Artificial Kidney and Dialysis     $3,151,000
  Kidney Transplant Research          593,000  I
i Other Renal and Urology Research     2,894,OOO  I

               Total           $6,638,000
            .I__U_---*l .__-.-,I_.,..... .----I---- I-. -.  --.. _.-

b.  National Institute of Allergy and Infectious Diseases (NIAID)

  NIAID's efforts are devoted to fundamental research and applied

research and development in kidney transplantation including typing

systems, immunosuppression and organ preservation.

Grant-supported research projects, intramural studies, and

organized developmental work in medical centers and industry have

been stepped up in recent years.

  The urgent need, and the short-term goal, of the tissue trans-

plantation immunology program is the identification of all the

tissue transplantation antigens and their classification according to

relative strength.  Experimental work has shown that there are

apparently only 6 to 10 major transplantation antigens rather than

the 15 to 30 which had been predicted on the basis of animal studies.

Certain immunosuppressive drugs for use in the prevention or

control of the rejection phenomenon are being studied.  Studies

are being conducted to find more effective and less toxic drugs to

control the immune response.

Two groups of investigators have produced specific immunologic


tolerance to grafts in mice and in dogs by administration of anti-

lymphocyte serum before the transplant operation. This procedure

resulted in striking prolongation of the graft and apparently

induced tolerance also to second grafts.  Another group found that

antiserum to thymus prolonged skin graft survival in rats twice

as long as antiserum to lymphocytes.

  In addition to antilymphocyte serum, total and sub-total body

irradiation, cytotoxic drugs, and surgical alterations of the lympha-

tic system have been used in attempts to reduce or eliminate the

lymphocyte population and thus increase tolerance to homografts.

These methods, however, also cause undesirable general effects, such

as depression of bone marrow and red blood cell formation.

  Paralleling the efforts to develop reagents, tests, and techniques

for applying the knowledge already gained are research projects

aimed at understanding the basic immunologic processes of the human

body.  Intramural projects in Bethesda on immunology focus on such

areas as hypersensitivity, mechanisms of the immune response,

immunochemistry of serum antibodies and antisera, and induction of

delayed hypersensitivity.  Many of these studies are closely related

to the problems of transplantation.  Fifty-nine research grants and

fifteen collaborative research contracts were supported in 1966. A

summary of NIAID kidney disease program expenditures for 1966 is

presented in Table II.


Table II

NIAID KIDNEY DISEASE PROGRAM EXPENDITURES FOR 1966

,I      -`----I

  Program                         1966 Expenditures
- ___,,__- ._-_.  _ __._~ _.--. .,___I ..__ __- ---.---I----.--.-. ~_. ._,^.
                                  _ __. - -P-,-I- --__-
                                                               ---I,-.- -7
  Intramural Research in Transplantation
   Immunology                  $ 190,000

  Research Grants-- Transplantation Immunology       3,100,000

  Collaborative Research Contracts--
   Transplantation. and Immunology                849,000

                        Total  1
                                  $4,139,000

I                                                                  _..      -.  I

C.  National Heart Institute (NHI)

Through the years, the National Heart Institute has supported

a wide variety of basic and applied research in kidney diseases

and hypertension.  One hundred and thirty research grants were

awarded in the area of renal diseases, including somewhat less than

10% in studies on fluids and electrolytes, totaling about 5.0

million dollars, or 6.0% of Heart Institute research grant funds

for FY 66.  Another 130 projects dealt predominantly with hyper-

tension, totaling 3.6 million dollars, or 4.3% of funds, and 83

grants for 3.0 million dollars representing 3.6% of research grant

funds, devoted to studies combining renal and hypertension interests.

While these reflect primarily numbers and costs of research grants,

it may be noted that approximately another 10% of these figures

were expended to support training grants and fellowships in the

same areas of research.

In FY 66, 53 of these 343 research grants were in the areas of


artificial kidney and kidney transplantation.  This includes a

significant number of projects where relatively minor commitments

are in the categories noted.

While the National Heart Institute conducts no organized

programs in kidney disease,  certain coordinated efforts can be


mentioned.  These take two forms of multi-disciplinary approach:

1) Intra-institutional, inter-departmental program projects;

     and

2) Inter-institutional cooperative studies.

Of the 226 research grants in the etiology of kidney diseases,

two are program projects dealing with renal diseases, and two other

combine attacks on renal disease and hypertension.  Support to these

four projects amounted to $838,000 in FY 66, averaging about

$210,000 per project.  Two more program projects were supported in

the renal area, directing their efforts to therapeutic implications,

and costing $905,000 or about $450,000 per project.  It may be noted

also that both these latter projects deal with kidney transplantation.

Cooperative studies represent another coordinated type of attack

on disease problems.  The Heart Institute in FY 66 supported 36

projects in three separate cooperative studies, the total cost of

which in that year was $1,374,000.  All three of these cooperative

studies emphasized clinical testing of surgical or drug therapeutic


measures, although not without inclusion also of a significant stress

on diagnostic techniques particularly in the extensive 20-project

Cooperative Study on Renovascular Hypertension.   It is of interest

that the two other studies, one on drug therapies and hypertension,

and the other dealing with antibiotic therapy of pyelonephritis in


relation to hypertension, both are conducted entirely in PHS

hospitals.  A good deal of the higher cost per project in the

Renovascular Hypertension Study reflects costs of hospitalization

and other patient care, which are not carried by the grants to

the PHS hospitals.

   All together, these coordinated efforts supported by the

Heart Institute amount to 42 projects, or 12% of those in the

total area of kidney and hypertension research, with a support

level of slightly over $3,000,000 (see Table III), or about a

quarter of the total research grant budget for these areas.  Thus,

while the Institute continues to emphasize support of individual,

unstructured, non-directed research on hypertension and kidney

disease, these more coordinated program projects and cooperative

studies represent significant portions of Heart Institute support

to these fields, stressing particularly many aspects of therapeutic



measures.

Table III

NHI RESEARCH EXPENDITURES ON KIDNEY DISEASE

  Program                   1966 Expenditures
                 -------VI_ _I__-_-_- .._ -____


  Renal Disease and Hypertension      $1,743,000

  Cooperative Studies               1,374,ooo
I                  Total          $3,117,000

I                __-_-__--__.- .._.. ~- .-.- .~.                            -.I


d.  Division of Research Facilities and Resources (DRFR)

  Several programs are administered by DRFR which include

support of research in kidney diseases.

  In FY 1966, the General Clinical Research Centers program

provided an estimated $4.5 million for kidney disease research

not including research in hypertension and diabetes.   This

program provides for the cost of remodeling and renovation

necessary to establish the resource and for operating costs such

as hospitalization, research nursing care and support of specialized

technical personnel.  Laboratory support in these centers is limited

to procedures required by several different investigators.   The

research conducted in these centers is controlled through competi-

tion adjudicated by a local advisory committee.  Since many of the

investigators utilize the resource simultaneously, the award pro-

vides a flexible mechanism of bed-support which can readily adapt

to the needs of many investigators at any particular time.

  The Division has two other programs on which kidney research

depends indirectly.  The Health Research Facilities Program, budgeted

at $50 million, provides matching funds for the construction of

research facilities.  Any future research programs in renal diseases

requiring additional space may depend heavily on this program.

  A second program is the General Research Support Program,

currently budgeted at $61 million.  This program assists institutions

heavily involved in sponsored biomedical research to maintain a

degree of flexibility in furthering their own biomedical research

and research training goals.  Thus this program provides backup


support for many of the categorical grants from the institutes.

A summary of pertinent Division of Research Facilities and

Resources expenditures is presented in Table IV.





                      Table IV

  ESTIMATED DRFR DIRECT KIDNEY DISEASE PROGRAM EXPENDITURES





---.---          ..uL------
  Program                    1966 Expenditures
                                                 --m-e- ..-- ---__..-_-
                                 ---m..- .u_ -7
                                                         I_---


   General Clinical Research Centers:
        Kidney Disease             $4,500,000



                                -----.__._. -. .-.. _.._ .-....   _ _ _   -__-I


2.  Kidney Disease Control Branch, National Center for Chronic Disease


   Control

  The Kidney Disease Control Program of the National Center for

Chronic Disease Control has responsibilities in all areas relating

to the development and demonstration of the dialysis method in commu-

nities, the training of professional and technical personnel in

dialysis therapy, public and professional information and education

activities, and appropriate related data collection and analysis.   The

Branch serves as the Public Health Service's consultative unit in

dealing with official and other health agencies, hospitals, and

practitioners in all aspects of the provision of dialysis services.

In addition to these dialysis-related activities, the Kidney Disease

Control Program conducts a broad range of preventive and educational

activities in the broad kidney disease field.

  Specific responsibilities in the dialysis-related areas follow.