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797
CONFERENCE ON
GLOMERULONEPHRITIS*
Closing Morning Discussion
DAVID P. EARLE, Moderator Professor and Chairman Department of Medicine Northwestern University Medical Center Chicago, Ill.
DAVID S. BALDWIN AND CHESTER M. EDELMANN, JR.
DR. DAVID P. EARLE. In addition to the participants who have pre-
sented papers thus far two speakers will give brief discussions on two of the presentations. Dr. David S. Baldwin, associate professor of medi- cine, New York University School of Medicine, New York, N.Y., will discuss my paper, and Dr. Chester M. Edelmann, Jr., professor of pedi- atrics, Albert Einstein College of Medicine, New York, N.Y., will then comment on Dr. Wallace W. McCrory's paper on pediatric aspects. DR. DAVID S. BALDWIN. I should like to make a few comments based on our own experience during the past IO or 15 years, during which we also have studied a variety of glomerular diseases. We utilized the renal biopsy technique.
In general, our experience pretty closely corresponds with Dr.
Earle's. However, there are a few points that bear emphasis, and per-
haps a few in which our experience differs somewhat from his.
Many of you may wonder what all the wrangling is about, and
why we have become so deeply involved in this attempt to classify glomerulonephritis. We face many problems in classification, prin- cipally because we have been restricted to a pathologic basis for classi- fication rather than to (^) etiologic considerations.
However, we must give credit to the percutaneous renal biopsy, for
prior to the use of this technique the various diseases that we have dis-
cussed this morning were all considered forms of a single entity,
"glomerulonephritis." Having had the opportunity now to study pa-
*Held by the New York Heart Association at The Waldorf-Astoria, New York, N. Y., January 27, 1970.
Vol. 46, No. 10, October 1970
798 AND^ OTHERS
tients early in the course of their disease and^ to^ observe^ histologic changes prior to the end-stage kidney, we have^ been able to^ recognize a variety of different diseases formerly included^ in the^ all-inclusive^ term of glomerulonephritis. This, then, is a good^ beginning. We still have a major problem to solve: to determine the^ nature^ of the disease or diseases which lead to the most^ common^ type of^ end- stage kidney, the disease in which^ the^ patient^ presents^ simply^ with urinary abnormalities or with hypertension and^ renal^ failure,^ with no history of an edematous or nephrotic^ stage. Such^ a^ disease^ progresses over the course of a few years, sometimes^ a^ great many years,^ to^ atro- phic kidneys and terminal renal failure. None^ of the^ entities^ that we have discussed this morning appears^ to^ progress^ in this^ way.^ We^ should realize that we are^ still^ left^ with^ a^ major^ problem:^ the^ nature^ of^ the disease that leads to the classic vest-pocket,^ atrophic, end-stage kidney. To return just briefly to a few of the^ entities that^ Drs.^ Earle,^ Churg, and McCrory discussed, I might comment^ on our^ experience^ at^ New York University. First, poststreptococcal glomerulonephritis.^ Although^ we^ may^ argue about whether chronicity^ occurs^ at^ all^ in^ this disease,^ I think we^ can^ all agree that^ poststreptococcal^ glomerulonephritis^ rarely leads to^ chronic renal disease. This constitutes a major advance in our^ thinking^ about
glomerulonephritis. Although poststreptococcal glomerulonephritis
might be the most common among the diseases that^ we^ have^ discussed here it certainly is one of the least important diseases^ in^ terms^ of^ chronic renal failure. We ourselves have never documented progression^ to chronic renal failure in a patient who showed recovery^ or^ improvement from the initial stage. We have seen death^ occur^ in^ the^ initial^ stage,
so-called subacute or persistently active acute glomerulonephritis,^ that
leads to death in a few weeks or months.^ However,^ in^ our^ patients^ who have survived the initial^ stage,^ we^ have^ not^ seen^ chronic^ disease^ develop.
Even if such progression should^ prove^ to^ occur,^ and^ I^ think^ it^ does^ from
what Drs.^ Earle and McCrory have^ reported,^ this^ must^ be^ a^ very^ rare occurrence.
In addition, our experience differs somewhat from^ Dr.^ Earle's in
that we have not^ observed exacerbations^ after^ an^ initial attack of^ acute
glomerulonephritis. In^ fact,^ we^ are^ not^ really^ sure^ that^ they^ ever^ occur.
By exacerbation^ we^ mean a^ reinfection^ with the^ beta-hemolytic^ strepto-
coccus that^ causes^ a^ recrudescence^ of^ the^ original^ pathologic^ process.
Bull. N. Y. Acad. Med.
7 9 8 D.^ P.^ EARLE^ AND^ OTHERS
8o .P^ ALEADOHR
changes, and combined focal membranous and^ proliferative^ changes. We probably all agree that these^ various focal lesions^ represent^ a variety of different glomerular diseases.^ We have seen the^ nephrotic syndrome rather frequently^ in^ patients with focal proliferative glomer- ulonephritis; the prognosis in these^ patients^ has^ not been^ consistently poor. A fair number of the patients with nephrotic syndrome have responded to steroids and have had temporary remissions. However, in general, our experience with focal nephritis has not been good. The majority of our patients, after periods of observations of about five years, have had renal failure. The important point is^ that patients^ with^ focal^ glomerular^ lesions probably represent^ the group who^ eventually^ develop^ the^ typical atrophic end-stage kidney. It is evident that acute glomerulonephritis and membranous nephritis could not account for the atrophic end-stage kidney on^ either^ clinical^ or^ histologic^ grounds.^ However,^ patients^ who have focal disease and only^ urinary^ abnormalities^ could^ easily be in the beginnings of a disease or diseases^ which^ eventually^ progress^ to end- stage kidney disease without antecedent clinical^ acute^ nephritis^ or an edematous stage.
Finally, a word about what is now called membranoproliferative
glomerulonephritis. We have referred to this form of nonpoststrepto-
coccal glomerulonephritis as chronic diffuse proliferative, but we shall
now go along with the others and use the term^ membranoproliferative.
It may be helpful to change the name because this is not^ a^ stage^ of^ acute
diffuse glomerulonephritis. We have observed this^ important disease
more frequently than Dr. Earle indicated he had. I^ think^ he^ said he had
seen only five patients with this condition during the^ period of his
study. We^ have^ seen^ as^ many^ patients^ with^ this lesion^ as^ we^ have^ with
membranous nephritis. Membranoproliferative^ glomerulonephritis^ is^ one
of the commonest causes of nephrotic syndrome in the adult^ population.
The prognosis is uniformly bad. These patients appear usually with^ the
nephrotic syndrome and hematuria and, over^ the^ course^ of^ two^ to^ five
or six years, go on to chronic renal^ failure, still edematous^ and^ nephrot-
ic. This is a disease for which no^ therapy seems to^ be^ effective,^ steroids
or immunosuppressives, and is by no means a^ rare^ cause^ of^ irreversible renal failure.
We have made some progress in^ our^ understanding and classification
of glomerulonephritis. However, we must be aware of the fact that
Bull. N. Y. Acad. Med.
8 o o D. P. EARLE AND (^) OTHERS
CLOSING MORNING DISCUSSION
until we can classify glomerular diseases etiologically, we shall still be
confused about the nature and the natural history of many of the con-
ditions that we have discussed on this occasion.
DR. DAVID P. EARLE. As predicted, there obviously is not common
agreement on all points. Dr. Edelmann, Jr., will be the next discussant.
DR. CHESTER M. EDELMANN, JR. I should like to comment (^) first
that it has been somewhat surprising to me-and gratifying-that a group
of internists, pediatricians, and pathologists appear to have as much
agreement concerning renal disease as has been evidenced this morning.
At the risk of being somewhat redundant, I should like to make
some observations on the course of acute glomerulonephritis in children
as compared to that in (^) adults. I think (^) that many of the apparent dif-
ferences we used to talk about have now been resolved. There has
been agreement in the past that the great majority of children with
acute glomerulonephritis go on to complete recovery. There has been
agreement also that in some instances nephritis may be so severe, with so many nephrons (^) irreversibly damaged, that complete recovery is not
possible. The disease in these children is readily identifiable soon after
its onset. The point on which there has been considerable difference
of opinion is whether children appear to recover clinically, only to
have a subclinical or subacute course with insidious development of
chronic glomerulonephritis that appears in renal failure when the chil-
dren are adults i0 or 20 years later. As recently as I965, at the Seven-
teenth Anmial Conference on the Kidney sponsored by the National
Kidney Foundation, which was devoted to acute glomerulonephritis,
the opinion was (^) expressed that such a course does occur and that (^) many
or even most adults with chronic glomerulonephritis have their disease
as a (^) consequence of an apparently benign episode of acute (^) glomerulone-
phritis in childhood. I think it is of great importance to note that the
idea of this sequence, (^) long challenged by pediatricians, is now being relinquished by internists (^) as well. The question (^) has been raised here of the nature of the relapses that
are observed in the course of recovery from acute glomerulonephritis.
Very commonly we see an abrupt increase in hematuria and proteinuria in a child who had appeared to be (^) recovering uneventfully. The ex-
acerbation often is associated with a viral respiratory illness, and only
rarely with recurrent streptococcal infection. (^) The entire episode usually
is short-lived; the child quickly returns to his previous state and con-
Vol. 46, (^) No. 10, October 1970
80 oI
CLOSING MORNING I)ISCUSSION
with a number of clinics, we have been conducting a cooperative study
of the nephrotic syndrome in children under the direction of Dr. Henry L. Barnett. We have now studied almost 200 children from the onset of disease. Renal biopsies are examined by several pathologists who are unaware of the course of the patients' disease. In the course of the study the pathologists have developed a classification of the various histologic
types of disease that may underly the nephrotic syndrome. With this
classification we are now able to predict with an extremely high degree
of accuracy which child will respond to steroid therapy and which will
not, with obvious prognostic implications. Of particular interest is a
group of children, almost io% of the total, whose biopsies revealed
focal sclerosis. Each of these children has had severe morbidity or
mortality. Some of them probably would have been diagnosed pre-
viously as "minimal change" or "nil" disease because of a failure to appreciate the significance of the focal lesions. In addition it is recog- nized that a biopsy may fail to contain these lesions, as in one child whose biopsy was interpreted as showing minimal change, but in whom autopsy examination shortly thereafter demonstrated focal disease. Rarely is pure membranous nephropathy observed in children with the nephrotic syndrome, as discussed by previous speakers, The course in children appears to be about the same as in adults. It may go on to complete clinical remission, with or without treatment, but our expe- rience has (^) been that the renal lesions progress inexorably, despite appar- ent (^) clinical improvement.
Previous speakers have referred to the entity membranoproliferative
or (^) hypocomplementemic glomerulonephritis. It is of interest that this condition (^) appears to vary considerably in its prevalence in different parts of the country. In^ certain areas it comprises a higher percentage of all children with renal failure whereas in (^) the New York area it is ex- treniely uncommon. There is probably an important (^) clue in this wide geographic variation, but at the moment (^) we are not able to offer an explanation. I conclude with a word about therapy, which has been discussed very little !here. Avoiding the question of (^) the possible benefit of adren- ocortical steroids in patients with the nephrotic syndrome, there is very little that we seem to accomplish in children with glomerulonephritis (with the exception of lupus) with steroids, other cytotoxic or immun-
osuppressant drugs, or heparin. Many patients appear to improve after
Vol. 46, No. 10, October 1970
CLOSING MORNING DISCUSSION^80 o
80 D. P.EREADOHR
administration of one of^ these drugs.^ But^ many^ do so without treatment. I take this opportunity, therefore, to make a plea^ for^ cautious^ inter-
pretation of uncontrolled data, and for the^ performance^ of^ more con-
trolled clinical trials, which have been almost^ nonexistent^ in the^ field of renal disease, since this is the only means by^ which the efficacy^ of any therapeutic agent can be established. DR. DAVID P. EARLE. As moderator I have the advantage of^ making
further comments. We appreciate Dr. Baldwin's remarks, which^ explain
so clearly our concern and interest in accurate classification. The example of response of lipoid nephrosis to steroid therapy is a good one. When patients with the nephrotic syndrome are treated with- out accurate diagnosis, as has been done in some prospective studies, the results are really quite meaningless. However, when the^ diagnosis^ is accurately known, response of patients with the nephrotic syndrome to therapy can be predicted in many instances. Lipoid nephrosis responds very well to steroid therapy. The problem of whether acute poststreptococcal glomerulonephritis becomes chronic is of more than academic interest. Much emphasis is
placed these^ days on^ prevention of^ disease.^ But it is^ difficult^ to^ prevent^ a
disease unless the cause is known. Streptococcal acute^ nephritis^ could be^ prevented by^ eradication of streptococcal infection. But the question is: Would this eliminate chronic
glomerulonephritis? Even in areas where large numbers of such^ cases
occur a prophylactic campaign against the streptococcus probably
would have little effect on the incidence of chronic renal failure, since
so few cases in children and epidemics become chronic.^ I^ say this^ even
though I^ may^ be the^ only^ speaker^ here who has data^ to^ show that^ post-
streptococcal acute nephritis may become chronic. This^ occurs^ mostly
in sporadic cases in adults. Prevention of^ chronic^ nephritis in this^ group
would be almost impracticable under current^ circumstances.
May I comment on the point that we have variations among investi-
gators in their ideas on the^ incidence^ of^ membranoproliferative glom-
eulonephritis. The variations^ undoubtedly result from variable^ histologic
criteria for differentiation of diffuse^ proliferative lesions with^ some
mesangial changes from lesions^ that^ have basement membrane lesions
together with^ active endothelial^ thickening.
In regard to exacerbations: they are not^ very common, but^ we^ do
see them. On^ an^ anecdotal^ basis, I^ can^ quote patients^ whom^ we^ observed
Bull. N. Y. Acad. Med.
8 04 D. P. EARLE AND OTHERS
