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THE ETIOLOGY AND DEVELOPMENT OF GLOMERULONEPHRITIS E. T. BELL, M.D. AND T. B. HARTZELL, M.D. MINNEAPOLIS There are four well established types of renal disease that must be considered in a discussion of nephritis. A brief explanation of each of these will be given in order to establish the limitations of the group under discussion. 1. Pyelonephritis.\p=m-\Thisis an acute or chronic exudative inflamma- tion distributed in patches throughout the kidneys, and extending from the cortex throughout the pyramids into the pelvis. It is caused by bacteria, usually staphylococci or colon bacilli. In most instances the bacteria are carried to the kidney by the blood; but in cases of obstruc- tion of the lower urinary tract they may enter from the urine. In the earlier stages of a hematogenous infection, before there has been extension to the pelvis, the lesions are spoken of as abscesses. Exten- sion of the infection to the capsule may produce perinephritis or perirenal abscess. Infection of a dilated pelvis causes pyonephrosis. The disease is frequently unilateral and acute cases are sometimes mis- taken for appendicitis or other acute abdominal conditions. Cases vary in intensity from mild to severe. The treatment of severe uni- lateral cases is usually surgical. Bilateral pyelonephritis may result in renal insufficiency but there is seldom any confusion clinically with Bright's disease. Acute interstitial nephritis is related to this group in that it is an exudative inflammation of the interstitial tissues. The kidneys show areas of cortex infiltrated with lymphocytes of intermediate size and plasma cells. Apparently there is never enough of the kidney involved to produce renal insufficiency. There is evidence in one of our cases (Case 51) that the exúdate remains in the kidney indefinitely and gives rise to areas of cortical atrophy; but no chronic nephritis of this type is known. Acute interstitial nephritis occurs frequently during scarlet fever, and rarely in other infections, such as diphtheria and congenital syphilis. It is seldom of much importance clinically, being over¬ shadowed by the associated disease. The spontaneous chronic nephritis of laboratory animals is more closely related to pyelonephritis than to any other form of human renal From the Department of Pathology, University of Minnesota. Aided by grant from the National Dental Association. Downloaded From: http://archinte.jamanetwork.com/ by a University of Iowa User on 06/09/2015 disease. It is characterized by lymphocytic exudates in the renal paren¬ chyma, which ultimately cause cortical atrophy to such an extent that the kidneys are shrunken and their surfaces covered with small depressions. The pelvis is not extensively involved, as a rule. Death from renal insufficiency is rare, and the majority of cases result in healing. This is the form of nephritis usually obtained in animals by experimental procedures. There is a gross resemblance between the kidneys of chronic Bright's disease and those of this animal infection; but clinically, histologically and in manner of development there is no similarity.1 There is no known animal disease corresponding to chronic Bright's disease. 2. Nephrosis.—This term is applied to renal lesions of a purely degenerative character in contrast to nephritis in which the phenomena of reaction (exudation, proliferation) have appeared. This group is not sharply separable from glomerulonephritis since cases of degenera¬ tion occur in which it is very difficult to determine whether there are any reactive changes in the glomeruli. Again, there are degener¬ ative changes of greater or less degree in practically all cases of glomerulonephritis, and in a large percentage of arteriosclerotic kidneys. It is, however, very desirable to limit the term nephrosis to degenerative lesions in which there is no pronounced involvement of the glomeruli or blood vessels. Nephrosis is by far the commonest form of renal disease seen at necropsy and it is the most frequent cause of albuminuria. It is found at necropsy in practically all severe infectious diseases and infections, in obscure toxemias such as the toxemia of pregnancy, in chemical poisoning (mercury, arsenic, phosphorus, and many other substances), in severe jaundice, and in severe cardiac decompensation. It is pre¬ sumably present in life in the above named conditions when albumin or casts are found in the urine. When found at necropsy it is proof of some form of toxemia. The amyloid kidney, although usually classified as a nephrosis, is better understood as a special form of glomerulonephritis. Clinically, nephrosis is usually definitely secondary to some associ¬ ated disease, and the differentiation from Bright's disease under these circumstances presents no difficulties ; but in cases of obscure etiology the distinction is not made so readily. There are no cases in our series of chronic nephrosis such as is described by Volhard and Fahr 2 as "genuine" nephrosis. It seems that a case of primary chronic renal disease should rarely, if ever, be regarded as a nephrosis. 1. Bell and Hartzell: Spontaneous Nephritis in the Rabbit, J. Infect. Dis. 24: 628, 1919. 2. Volhard and Fahr: Die Brightsche Nierenkrankheit, Berlin, 1914. Downloaded From: http://archinte.jamanetwork.com/ by a University of Iowa User on 06/09/2015 The clinical findings attributable to the kidney in nephrosis are usually mild ; but renal insufficiency may develop in severe cases. There is never hypertension or cardiac hypertrophy. Severe nephroses are usually rapidly fatal. In mild nephroses at necropsy the kidneys show cloudy swelling. In severe cases there is cloudy swelling, fatty degeneration and some¬ times necrosis of tubules and glomeruli. 3. Arteriosclerosis of the Kidneys.—Two forms of this disease may be distinguished on clinical and anatomic grounds. (a) The Senile Type- (Arteriosclerotic atrophy) : In advanced age and especially in association with generalized senile arteriosclerosis, one often finds small kidneys with adherent capsules and rough gran¬ ular or pitted surfaces. This appearance is due to an irregular atrophy of the more superficial parts of the cortex which is caused by narrow¬ ing of some of the arteries. Usually the larger branches are the ones chiefly affected and the disease is never restricted to the arterioles. The senile kidney is seldom of any clinical importance since the amount of cortex destroyed is relatively small; but in occasional instances the atrophy is so extensive that renal insufficiency develops. It has not been determined how often arteriosclerotic atrophy gives rise to the clinical picture of chronic Bright's disease. (b) The Hypertension Type: In many cases of chronic hyper¬ tension normal kidneys are found at necropsy and in some a glomerulo- nephritis is found ; but a large percentage of cases are associated with disease of the renal arteries. When no disturbance of renal function is demonstrable we speak of essential hypertension, but when there is evidence of serious renal injury we consider the condition chronic Bright's disease. The kidneys from cases of essential hypertension usually show hyaline degeneration of some of the afferent glomerular arteries and often there is also disease of medium sized and small arteries, and there are gradual transitions between the slight involve¬ ment of the arteries in these cases and the extensive involvement in chronic Bright's disease of the vascular type. The majority of patients with essential hypertension die of cardiac or cerebral complications without developing serious renal involvement, but some cases extensive destruction of renal tissue occurs and they are then regarded as being cases of chronic Bright's disease of the arteriosclerotic type. There in our are about twenty-six examples of this form of Bright's disease series of 3,300 necropsies. We expect to discuss this subject fully in a subsequent report. 4. Glomerulonephritis.—This group includes renal disease in which the structural changes are due almost entirely to primary inflammatory and degenerative changes in the glomeruli. It includes all acute and subacute and a majority of chronic cases of Bright's disease. Downloaded From: http://archinte.jamanetwork.com/ by a University of Iowa User on 06/09/2015 The older terms "chronic parenchymatous" and "chronic inter¬ stitial" correspond to stages or degrees of severity of glomerulo¬ nephritis. They do not designate any important feature of the disease and a large number of cases are intermediate in type, i. e., neither typical parenchymatous nor typical interstitial. This terminology has another element of confusion in that some observers consider the arteriosclerotic kidney as chronic interstitial nephritis. The literature of nephritis would be clearer if these older terms were discarded. Chronic glomerulonephritis is not sharply separable from the arteriosclerotic kidney since a few cases of the former show some disease of the renal arteries; but these borderline cases are not very numerous and we see no justification for the view that the two diseases are indistinguishable (Moschcowitz 3). Certainly the great majority of cases are anatomically distinct, although they may be indistinguishable 4 clinically. It may be, as Ophüls believes, that the same toxin attacks the arteries in one case and the glomeruli in another and that the differences are really only anatomic ; but it seems better to adhere to anatomic distinctions until we know more about the etiology of arteriosclerosis. MATERIAL sections from Hie _ Microscopic kidneys of about 3,300 consecutive necropsies have been examined. Small pieces of kidney from nearly all of these had been preserved so that it was possible to make serial sections when desirable. The clinical history and gross necropsy find¬ ings were always considered, but the final diagnosis was usually made on the microscopic appearances. All the subacute and chronic cases had been recognized clinically or at necropsy, but many of the acute cases had been overlooked. Sixty-nine cases of glomerulonephritis were identified. In a number of the acute cases nephritis was not the main cause of death, and these kidneys furnish abundant illustrations of the early stages of the disease.

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