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 aver<W"

  of 15 years and a complicated phase with progressive damage to the

heart, kidneys, brain, eyes, and other systems.


  During the uncomplicated phase about 2/3 o.f the patients have

a variety of usually minor symptoms including fatigue, nervousness

and headaches.  After an indefinite period, complications appear.

Atherosclerosis is common.  Hypertension accelerates arterial damage

and predisposes to the deposition of lipid materials.  In most there

is gradual enlargement of the heart.  Congestive heart failure is

eventually responsible for about 25% of the deaths and is a contributing

factor in another 25%.  About 10% of hypertensives die of a myocardial

infarction while another 10% die following cerebral thrombosis or

hemorrhage.  Thus, some 70% die from major vascular problems.

  In the kidneys, damage to the.small arteries is found in a high

percentage-of patients.  Approximately one-half eventually develop

some evidence of renal damage (manifested by polyuria, diminished

concentrating power, or proteinuria),  but uremia is only rarely the

cause of death unless there is an accelerated or malignant phase of

disease.

c. Accelerated or Malignant Form

  Some 5-10% of patients with essential hypertension develop an

accelerated phase with progressive renal damage and higher fixed

diastolic blood pressure.  The onset is usually abrupt. and is

characterized by headaches, failing vision, nausea, and weight loss.

Unless the course is interrupted by treatment, complications develop

rapidly and death from brain, heart or kidne,y damage usually occurs

within two years.  About one-third of these patients die with severe

renal complications.  Early treatment of this group is important

since progressive changes in the small arteries of the kidney develop

rapidly.  After these changes have developed to an advanced state,


  !~~ering Slood pressure may precipitate renal failure.  Therapy

  started early significantly prolongs life in this group.  The impact

  of successful drug therapy for malignant hypertension can be inferred

  from an almost 50% decline in the death rate from hypertensive heart

  disease since the introduction of antihypertensive agents in 1952.

3.  Secondary Hypertension

  In every patient with established diastolic hypertension, the pos-

SiSility of secondary hypertension should be considered.   Known  2 .?'L-L; e;

must be systematically excluded by history, physical examination, I
                                                              a2>ro-

-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