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Second attacks of acute glomerulonephritis
758
November, 1969 T h e ] o u r n a l of P E D I A T R I C S
Second attacks of acute glomerulonephritis The cases o[ 12 Negro children with two clinically and histologically similar attacks o[ acute glomerulonephritis are reported. The absence o[ clinical and histologic evidences o[ chronic gIomerulonephritis during a period o[ 6 to 108 months o[ [ollow-up study is emphasized. Lobular mesangial hyperplasia constituted the major persistent histologic abnormality; focal thickening o[ Bowman's capsule was less frequently observed.
Shane R o y III, M.D.,"* Hershel P. Wall, M.D., and James N. Etteldorf, M . D . 2r E M P I-II S ~ TENN.
T H E O C1G U R R E N {3E of exacerbations of chronic glomerulonephritis following recurrent streptococcal infections has been well established? The frequency of exacerbations of chronic glomerulonephritis is greater in children than in adults; the latent period between the onset of the streptococcal infection and the exacerbation is usually relatively short. Exacerbations of acute glomerulonephritis, accompanied by the reappearance of the initial clinical and laboratory manifestations and characterized by exudative and proliferFrom the University o[ Tennessee College o[ Medicine. These studies were supported in part by United States Public Health Service Grants: National Heart Institute Nos. HE-00454 and HE-05285 ~ and National Center for Chronic Disease Control No. PH-86-67-297. Presented be[ore the Southern Society [or Pediatric Research, New Orleans, La., Nov. 22, 1968, and the American Society o[ Nephrology, Washington, D. C., Nov. 25, 1968. "X'Address: Dobbs Research Institute, 951 Courl; Ave., Memphis, Tenn. Vol. 75, No. 5, pp. 758-767
ative histologic changes typical of an initial attack of acute glomerulonephritis, are considered by some investigators 2-5 to be extremely rare. Earlier clinical studies by Loeb and co-workers 6 on the natural history of acute poststreptococcal glomerulonephritis demonstrated that recovery following healing was usually permanent. None of the 10 patients of Loeb's study developed recurrent or chronic glomerulonephritis despite reinfection with Group A streptococci. Subsequent studies by Perlman and co-workers 7 of 61 children, who were involved in an epidemic of acute poststreptococcal glomerulonephritis, failed to reveal clinical evidence of recurrences of acute glomerulonephritis despite a high incidence of recurrent streptococcal pyoderma. Ramberg, s however, in 1947 described 11 patients who developed recurrent attacks of acute glomerulonephritis after having recovered completely from the first attack. Bernstein and Stillerman 9 reported upon 2 children and one adult who developed recur-
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Second attacks o/ glomerulonephritis
rent glomerulonephritis following repeated streptococcal infections during periods of time ranging from 2 years to approximately 30 years following recovery from the initial attack. Dodge and associates 1~ described 2 children with typical acute poststreptococcal glomerulonephritis who experienced an exacerbation of symptoms of acute glomerulonephritis following streptococcal pyoderma 13 and 26 months, respectively, after the initial illness. Renal biopsy in one patient 11 months after the exacerbation was interpreted as "pathologically latent." A renal biopsy in the second patient performed just prior to the exacerbation was interpreted as "pathologically latent," whereas histologic changes in tissue obtained at the time of the clinical exacerbation were interpreted to represent an exacerbation of chronic glomerulonephritis. Six of their 44 patients were considered to have acute glomerulonephritis clinically, but were classified histologically as having exacerbations of chronic glomerulonephritis. Morphologic evidences of chronicity were scarring, glomerular obsolescence, extensive collagenization, fibroepithelial crescents, and the presence of fibrin in glomerular capillaries and Bowman's space. Vernier and associates 1~ also reported upon 6 children with a clinical picture of acute glomerulonephritis whose renal biopsy revealed chronic renal disease. Severely fibrotie glomeruli and extensive tubular atrophy were noted in addition to acute glomerulonephritis with polymorphonuclear infiltrate of the glomeruli. These observations suggested a previously unrecognized pathologic process. Becker and Murphy 12 were able to produce recurrent acute glomerulonephritis in 3 rabbits by repeated inoculations of live strains of nephritogenic streptococci. The kidneys of these rabbits showed proliferative and exudative glomerular lesions with epithelial crescents which appeared to have developed after the beginning of the final series of inoculations with streptococci. These authors suggested that human subjects who develop acute glomerulonephritis with proliferativeexudative glomerular lesions and epithelial
crescent formation may be suffering from recurrent acute glomerulonephritis. In the last 15 years, of a total of 590 children admitted to our hospital with a diagnosis of acute glomerulonephritis, at least 12 were observed to develop a second episode of acute nephritis 9 to 82 months following complete clinical recovery from the initial attack. The findings in these patients constitute the subject of this report. MATERIAL
AND
75 9
METHODS
The children included in this report were Negroes ranging in age from 1~2 to 7 ~ 2 years at the time of the initial episode of acute glomerulonephritis. Seven were boys and 5 were girls. There was no history of renal disease in these children prior to their first observed attack. Laboratory studies included urinalyses, complete blood counts, erythrocyte sedimentation rates, blood urea nitrogen concentrations, Addis counts, creatinine clearances, antistreptolysin-O titers, antihyaluronidase titers, /?as-globulin determinations, and cultures-for streptococci. Lupus erythematosus and sickle cell disease were excluded. Intravenous pyelograms and roentgenograms of the chest were also obtained. Twenty-eight percutaneous renal biopsies were obtained in 12 patients with a Franklin modified Vim-Silverman needle. Patient M. G. was biopsied within 2 weeks after the onset of the first attack of acute glomerulonephritis and patient R. Y. was biopsied 5 months after the first attack. Nine patients were biopsied during the second attack. From 1 to 4 subsequent renal biopsies were performed in 10 patients from 6 to 108 months after the second attack. Tissue was fixed in buffered formalin and embedded in paraffin. Sections 4 /~ in thickness were stained with hematoxylin and eosin, periodic acid-Schiff reagent, and Mallory's trichrome techniques. Tissue obtained from one patient during the second attack was fixed in gluteraldehyde, embedded in Maraglas, and sectioned at 0.5 ~ with an LKB ultramicrotome. The section was then stained with toluidine blue and examined with the
760
Roy, Wall, and Etteldor[
The Journal o[ Pediatrics November 1969
T a b l e I. C l i n i c a l a n d l a b o r a t o r y d a t a , a t t a c k No. 1
Patient
C.B. I W.C. 1M.a. IL.G. IR.H. IM.I.I S. 1. IM.M.t B.S. IJ.T. I Z.Z. I R.Y. Sex Age P'yoderma Sore throat Edema Hypertension Hematuria Proteinuria Azotemia Abnormal ESR Skin culture Throat culture ASO titer A H titer fi~e-Globulin
F 511~2 +e + + + + + + At A ND ND ND
M lS~2 + + -, + + + Staph. 200 192 Low
M 3~2 + + + + + + ND 500 ND ND
F 4 . + + + ND ND ND ND
M M 37~2 77,~2 + + . . . + + + + + + + + + + NG C ~96 50 512 ND NI. ND
F 37/'12 + . + + + + + + A A 833 ND ND
M 46A2 + . + + + + + A A 833 ND ND
F M M 53A2 22/'12 22/12 + + + . . . + + + + + + + + + + + + + + + + + A A Staph. . . . . 100 400 50 ND ND ND ND ND ND
F 59A2 + + + + + + + 1,250 ND ND
e.-+, Present; -, absent or negative; ND, not done. tA, Group A strep.; C, group C strep.; NG, nongroupable strep.; NI., normal.
l i g h t m i c r o s c o p e . F r o z e n r e n a l tissue f r o m this p a t i e n t was also s e c t i o n e d at 4 t~ on a cryostat a n d tested by an i n d i r e c t i m m u n o fluorescent m e t h o d for the p r e s e n c e of ye a n d ]?m/ix-globulin. RESULTS F i r s t a t t a c k of a c u t e g l o m e r u l o n e p h r i t i s . T h e p a t i e n t s ' ages r a n g e d f r o m lS/12 to 7 ~ 2 years at the t i m e of t h e i r initial episode of a c u t e nephritis. P y o d e m a a p r e c e d e d t h e o n s e t of clinical m a n i f e s t a t i o n s of a c u t e n e p h r i t i s in 9 c h i l d r e n , a n d sore t h r o a t in 1 ( T a b l e I ) . A history of b o t h p y o d e r m a a n d sore t h r o a t was p r e s e n t in C. B., b u t n e i t h e r historical n o r clinical e v i d e n c e of p r e c e d i n g i n f e c t i o n was p r e s e n t in L. G. T h e l a t e n t p e r i o d b e t w e e n the onset of i n f e c t i o n a n d t h e onset of s y m p t o m s of a c u t e n e p h r i t i s r a n g e d f r o m 1 to 12 weeks. E d e m a was t h e m a j o r p r e s e n t i n g s y m p t o m in e a c h p a t i e n t . D i a s t o l i c h y p e r t e n s i o n of 90 m m . H g o r g r e a t e r was p r e s e n t in 9 patients. Systolic b l o o d pressures r a n g e d f r o m 105 to 180 r a m . I-tg; r e a d i n g s of 140 m m . H g o r g r e a t e r w e r e o b t a i n e d in 5 patients. Hematuria and proteinuria were present in e a c h c h i l d u p o n a d m i s s i o n to t h e h o s p i t a l ( T a b l e I ) . E r y t h r o c y t e s e d i m e n t a t i o n rates w e r e e l e v a t e d a b o v e 20 ram. p e r h o u r in all
p a t i e n t s e x c e p t L. G. M a x i m u m b l o o d u r e a n i t r o g e n c o n c e n t r a t i o n s r a n g e d f r o m 11 to 72 rag. p e r cent. V a l u e s w e r e g r e a t e r t h a n 20 mg. p e r c e n t in 6 c h i l d r e n a n d r e t u r n e d to n o r m a l d u r i n g the d i u r e t i c p h a s e of the disease. E v i d e n c e of s t r e p t o c o c c a l i n f e c t i o n was s o u g h t by c u l t u r i n g e a c h p a t i e n t ' s t h r o a t a n d a c t i v e skin lesions, a n d by m e a s u r i n g antis t r e p t o l y s i n - O titers. G r o u p A ]?-hemolytic s t r e p t o c o c c i w e r e r e c o v e r e d f r o m the skin lesions of 5 of 10 p a t i e n t s w i t h p y o d e r m a ; n o n g r o u p a b l e ]?-hemolytic streptococci w e r e r e c o v e r e d f r o m one. T h r o a t cultures w e r e positive for G r o u p A ]?-hemolytic streptococci in two p a t i e n t s w i t h p y o d e r m a a n d for G r o u p C in one. G r o u p A ]?-hemolytic streptococci w e r e r e c o v e r e d f r o m b o t h t h e t h r o a t a n d skin lesions of C. B. A n t i s t r e p t o l y s i n - O titers of 400 T o d d units o r g r e a t e r w e r e f o u n d in f o u r p a t i e n t s w i t h p y o d e r m a a n d one w i t h sore throat. T h e a n t i h y a l u r o n i d a s e titer was 512 units in o n e p a t i e n t w i t h p y o d e r m a a n d n o r m a l in o n e ; testing f o r this e n z y m e was n o t a v a i l a b l e d u r i n g t h e first a t t a c k of acute glomerulonephritis in the other patients. S e r u m ]?1c-globulin levels w e r e o b t a i n a b l e in two p a t i e n t s a n d w e r e n o r m a l in o n e a n d a b n o r m a l l y l o w in one. P e r c u t a n e o u s r e n a l bopsies w e r e p e r f o r m e d
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Second attacks of glomerulonephritis
761
Fig. 1. Renal biopsy 2 weeks after onset of initial episode of acute glomerulonephritis (M. G.). Focal hypercellularity and scattered leukocytes were observed. (Hematoxylin and eosin; x400.)
Fig. 2. Renal biopsy 5 months after onset of initial episode of acute glomerulonephritis shows persistent focal hypercellularity (R. Y.). (Hematoxylin and eosln; •
in M. G. 2 weeks after onset of the first attack and in R. Y. 5 months after onset of disease. T h e biopsy in M. G. showed focal endothelial and epithelial hypercellularity and the presence of polymorphonuclear leukocytes (Fig. 1)." T h e glomeruli were
swollen and a few of the capillary tufts were compressed. Persistent diffuse endothelial and epithelial hypereellularity with an absence of polymorphonuclear leukocytes was noted in the biopsy of R. Y. 5 months after onset of disease (Fig. 2). No evidence
7 6 2 Roy, Wall, and Etteldor[
The Journal o[ Pediatrics November 1969
of glomerular fibrosis or scarring was noted in either biopsy. Each patient except L. G. received antibiotic therapy during his first episode of acute glomerulonephritis. Patient M. J. received oral tetracycline for 9 days and then received 1.2 million units of benzathine penicillin intramuscularly. J. T. received procaine penicillin for two days and tetracycline for seven days intramuscularly. The remaining nine patients were given procaine penicillin for 3 to 11 days and benzathine penicillin intramuscularly at the conclusion of procaine penicillin therapy. During the 9 to 82 month interim between the first and second attacks, all patients remained free of clinical and laboratory evidence of renal disease. Each patient was examined repeatedly in the outpatient Pediatric Nephrology Clinic between the two attacks. No renal biopsies were performed between the two attacks. Second attack of acute glomerulonephritis. Nine of the patients described above presented with a history of pyoderma preceding the second attack of acute glomerulonephritis; the other three presented with a history of sore throat. The latent period between the onset of infection and the onset of
symptoms of glomerulonephritis ranged from 1 to 6 weeks. Edema and hypertension were present in all patients during the second attack. Hematuria was present in all patients, and proteinuria was present in tl. Blood urea nitrogen concentrations were temporarily elevated above 20 rag. p e r cent in four patients; erythrocyte sedimentation rates were elevated in 11 (Table II). Group A fl-hemolytic streptococci were recovered from the skin lesions of B. S., T. T., and R. Y. The strain from B. S. was typed as M52, T3/13/B3264; the strain recovered from R. Y. was typed as M2, T-Imp. 19. Group A /3-hemolytic streptococci were recovered from the throats of 2 patients with pyoderma, C. B. and L. G. Group C /3hemolytic streptococci were recovered from the throat of M. G. Antistreptolysin-O titers were greater than 400 Todd units in 2 patients with pyoderma and one with sore throat. Antihyaluronidase titers were elevated in 3 patients with pyoderma./31e-Globulin levels were below normal levels in 5 of the 6 patients tested and returned to normal during convalescence in each patient. Percutaneous renal biopsies were per-
Table II. Clinical and laboratory data, attack No. 2 Patient
C.B. IW.C.IM.G. IL.G. IR.H. IM.J. tS.J. IM.M.I B.S. [].T. IT.T. I R.Y. Sex Age Interval No. 1 to No. 2 (mo.) Pyoderma Sore throat Edema Hypertension Hematuria Protelnuria Azotemia Abnormal ESR Skin culture
Throat
culture
ASO titer AI-t titer filo-Globulin
F 121A2
M 41~2
M 10~2
F 99A~
74 +~
39
82
69
-
__
+
+
-
+
+
+ + + +
+ + + +
+ + + +
+ + + +
--
+
-
+
+
+
+
Staph.
ND
ND
At 200 ND ND
625 ND ND
C 166 ND N1
*+, Present; -, absent or n e g a t i v e ; "~A, Group A s t r e p . ; C , g r o u p Cl
ND, strep.;
not NG~'
M 4~2 9
M 12a~2
F 86~2
M 76~2
F 11~2 70
56
59
36
-
+
+
-
+
+ + + +
+ + + +
. + + + +
. + + + -
M 3~'~2
+
.
M 41~
F 117~2
14
32
70
+
+
+
+ + + +
+ + + +
+ + + +
. + + + +
_
+
-
+
+
--
+
+
+
-c
+
+
+
Staph.
ND
A
M2, TI m p . 19
. 192 256 Low
. 200 ND ND
A 400 ND ND
Staph.
. 512 512 Low
done. nongroupable
strep.; NI.,
normal.
M52 T3/13/ B3264 . . . 200 50 ND 32 ND Low
200 ND ND
48 512 Low
NG 192 96 Low
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Second attacks o/ glomerulonephritis
formed in 9 patients during the second attack of acute glomerulonephritis. Light microscopic examination of each of these specimens revealed swollen glomeruli with diffuse endothelial hypercellularity and the presence
of polymorphonuclear leukocytes. Fibroepithelial crescents and hyalinized glomeruli were not observed. Representative specimens from 2 patients are shown in Figs. 3 and 4. Granular deposits of flle/1A-globu!in were
Fig. 3. Glomerular swelling, hypercellularity, and closed glomerular loops are seen in this biopsy specimen obtained 9 days after onset of the second aftack of glomerulonephritis (M. G.). (Hematoxylin and eosln; x400.)
Fig. 4. Renal biopsy 7 days after the second attack of acute glomerulonephritis shows mild hypercellularity and a few leukocytes (R. Y.). (Hematoxylin and eosin; x400.)
76 3
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The Journal o[ Pediatrics November 1969
Fig. 5. Half micron section of same biopsy specimen as Fig. 3 shows multiple dense deposits (arrows) along the epithelial side of the capillary basement membrane (M. G.). (Toluidine blue; •
Table I I I . Follow-up laboratory and histologic data
C. .IM.G.I Months after second attack Proteinuria (qualitative) Proteinuria (rag./24 hr.) Blood urea nitrogen (mg. per cent) Creatinine clearance (c.c./min./1.73M. 2) Renal histology ~
Patient
L G IRHIMI1SJ.
IMM I B S IJ.T. IT. T I R Y
94 0 0
t2 0 0
108 0 0
30 0 0
6 0 184
33 0 0
48 0 408
15 0 0
86 0 0
16 tr. 0
12 0 0
13
23
11
14
9
17
11
12
13
10
8
127 (1)
t02 --
118 (2,4)
140 (2)
-(3)
108 (2)
103 (2,5)
115 (2,4)
93 (2)
103 (2)
94 (2,4)
~'(1), Normal; (2), mild mesangial hypercellularity; (3), moderate mesangiaI hypercellularity; (4), focal thickening of Bowman's capsule; (5), one hyalinized glomerulus.
demonstrated by immunofluorescent staining of the biopsy specimen from M. G. Dense homogeneous deposits were also observed along the epithelial side of the capillary basement membrane in a 0.5/~ section stained with toluidine blue (Fig. 5). Subsequent observations. Subsequent studies have been performed in 11 of the 12 patients 6 to 108 months after the second attack of glomerulonephritis (Table I I I ) . Physical examination of each patient revealed normal blood pressure and absence of edema. Routine hemograms, urinalyses, quantitative Addis count urinalyses, 24 h o u r urinary excretions of protein, a n d blood urea nitrogen concentrations were deteri:nined in
each patient. Twelve-hour endogenous creatinine clearances and renal biopsies were performed in 10 patients. I-Iematocrits were normal in each patient. Routine urinalysis revealed a trace of protein in the urine of T. T. T h e 24 hour urinary excretion of protein was 184 mg. in patient 1V[. J. 6 months after the second attack. Intermittent proteinuria of 165 to 408 rag. per 24 hours was noted in M. M. 48 months after the second attack. Twelve-hour endogenous creatinine clearance values ranged from 93 to 140 c.c. per minute per 1.73 square meters. Renal biopsies were performed 12 to 108 months after the second attack in 7 of 9
Volume 75 Number 5
Second attacks of glomerulonephritis
7 65
Fig. 6. Renal biopsy 94 months after second attack was interpreted as normal (C. B.). (Hematoxylin and eosin; x400.)
Fig. 7. Renal biopsy 108 months after second attack shows mild mesangial hypercellularity (L. G.). (Hematoxylin and eosin; x400.)
patients who were biopsied during the acute phase of the second attack of glomerulonephritis. In 3 additional patients, who were not biopsied during the acute phase of the second attack, biopsies were performed at 6, 16, and 48 months, respectively, following
the second attack. Light microscopic evaluation of the renal biopsy of C. B. was normal (Fig. 6). A mild degree of mesangial hypercellularity was evident in the biopsy specimens of 8 patients 12 to 108 months after the second attack. In addition, focal thicken-
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Roy, Wall, and Etteldor[
ing of Bowman's capsule was noted in the biopsy specimens of L. G. (Fig. 7), 13. S., and R. Y.; one hyalinized glomerulus was noted in the biopsy of M. M. Moderate mesangial hypercellularity was noted in the biopsy of M. J. which was obtained 6 months after his second attack. DISCUSSION The clinical and histologic similarities between the two attacks of glomerulonephritis in these patients were striking. It has been previously noted that exacerbations of chronic glomerulonephritis are often clinically indistinguishable from initial attacks of acute glomerulonephritis, n Exacerbations of chronic glomerulonephritis frequently follow streptococcal infections and are manifested by edema, hypertension, hematuria, and proteinuria. Histologically the acute exacerbation of chronic glomerulonephritis, while often demonstrating endothelial cellular proliferation, leukocytic exudation, and even electron dense "humps" on electronmicroscopy, is also characterized by glomerular crescents, lobular scarring, and glomerular hyalinization?~ Patients included in this report differ in that chronic histologic changes were absent during the acute phase of the second attack. Mild mesangial hypercellularity and occasional focal thickening of Bowman's capsule have been noted as the principal lesion in subsequent biopsy specimens. Mesangial hypercellularity has been previously described as typical of resolving acute glomerulonephritis.a Patient M. M. was noted to have proteinuria 48 months after the second attack, which may indicate nonhealing. One of 13 glomeruli was hyalinized in his renal biopsy obtained 48 months after the second attack. As previously mentioned, 11 patients received antibiotic therapy for infections during their first attack of glomerulonephritis. Five patients with preceding pyoderma received penicillin within 2 weeks after the onset of skin lesions. Previous studies ~3, 1, have demonstrated that penicillin therapy administered within the first 10 days after a streptococcal infection suppresses the for-
The Journal of Pediatrics November 1969
mation of type-specific streptococcal antibodies. Thus, in at least 5 of the early treated patients, penicillin may have interfered with the development of type-specific streptococcal antibodies, leaving them susceptible to reinfection with the nephritogenic strain of streptococcus which caused their first attack of glomerulonephritis. An increasing number of streptococcal pyoderma strains have been shown to possess nephritogenic properties? 5-zs Definitive streptococcal typing was not available during the first attack in our patients. In a prospective study of pyoderma and glomerulonephritis over the past 3 years, eight different M or T typable streptococcal strains have been recovered from 11 patients with pyodermarelated acute glomerulonephritis? 9 Nontypable strains of Group A /?-hemolytic streptococci were recovered from 11 additional patients. It seems reasonable to assume that, in a population plagued with recurrent pyoderma and in the presence of multiple potentially nephritogenic strains of streptococci, the chances for reinfection with different nephritogenic strains of streptococci would be increased. Further epidemiologic studies of streptococcal infections in our population should help to clarify this hypothesis. SUMMARY
Twelve Negro children with two attacks of acute glomerulonephritis are reported upon. Pyoderma preceded the initial episode in 9 patients, sore throat in 1, and both in 1. Serologic and/or bacteriologic evidence of preceding streptococcal infection was present in 8 patients. Second attacks of acute glomerulonephritis occurred 9 to 82 months later and were indistinguishable clinically and histologically from the initial attack. Pyoderma preceded the second attacks in 9 patients, and sore throat in 3. Serologic and/or bacteriologic evidence of preceding streptococcal infection was present in 8 patients. Renal biopsies in 2 patients during the initial attack and in 9 patients during the acute phase of the second attack showed
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Second attacks of glomeruIonephritis
histologic changes consistent with acute glomerulonephritis. R e n a l biopsies in 10 patients 6 to 108 months after the second attack revealed resolving acute glomerulonephritis without histologic evidences of chronic glomerulonephritis.
9. Bernstein, S. H., and Stillerman, M.: A study of the association of group A streptococci with acute glomerulonephritis, Ann. Int. Med. 52: 1026, 1960. 10. Dodge, W. F., Spargo, B. H., Bass, J. A., and Travis, L. B.: The relationship between the clinical and pathologic features of poststreptococcal glomerulonephritis. A study of the early natural history, Medicine 47: 227, 1968. 11. Vernier, R. L., Worthen, H. G., Wannamaker, L. W., and Good, R. A.: Renal biopsy studies of the acute exacerbation in glomerulonephritis, Am. J. Dis. Child. 98: 653, 1959. 12. Becker, C. G., and Murphy, G. E.: The experimental induction of glomeralonephrltis like that in man by infection with group A streptococci, J. Exper. Med. 127: I, 1968. 13. Siegal, A. C., Johnson, E. E., and Stollerman, G. H.: Controlled studies of streptococcal pharyngitis in a pediatric population. 2. Behavior of type-specific immune response, New England J. Med. 265: 566, 1961. 14. Potter, E. V.: Type 12 streptococci and acute glomerulonephritis. I. Presence and recall of type-specific streptococcal antibodies in patients with healed acute glomerulonephritis, J. Lab. & Clin. Med. 65: 40, 1965. 15. Anthony, B. F., Perlman, L. V., and Wannamaker, L. W.: Skin infections and acute nephritis in American Indian Children, Pediatrics. 39: 263, 1967. 16. Potter, E. V., Moran, A. _F., Pooh-King, T., and Earle, D. P.: Characteristics of beta hemolytic streptococci associated with acute glomerulonephritis in Trinidad, West Indies, J. Lab. & Clin. Med. 71: 126, 1968. 17. Johnson, J. C., Baskln, R. C., Beachey, E. H., and Stollerman, G. H.: Virulence of skin strains of nephritogenle group A streptococci: New M protein serotypes, J. Immunoh 10h 187, 1968. 18. Dillon, H. C., Reeves, M. S., and Maxted, W. R.: Acute glomerulonephritis following skin infection due to streptococci of M-type 2, Lancet 1 (pt. 1): 543, 1968. 19. Stollerman, G. H.: Unpublished data, 1968.
The assistance of Dr. James A. Pitcock, Assistant Professor of Pathology, University of Tennessee College of Medicine, in the preparation of this manuscript is appreciated. REFERENCES 1. Seegal, D., Lyttle, J. D., Loeb, E. N., Jost, E. L., and Davis, G.: On the exacerbation in chronic glomerulonephritis, J. Clin. Invest. 19: 569, 1940. 2. McCluskey, R. T., and Baldwin, D. S.: Natural history of acute glomerulonephritis, Am. J. Med. 35: 213, 1967. 3. Jennings, R. B., and Earle, D. P.: Post-streptococcal glomerulonephritis: Histopathologic and clinical studies of the acute, subsiding acute, and early chronic latent phases, J. Clin. Invest. 40: 1525, 1961. 4. Kushner, D. S., Armstrong, S. H., Dubln, A., Szanto, P. B., Markowitz, A., Maduros, B. P., Levine, J. M., River, G. L., Gyner, T. N., and Pendros, J. P.: Acute glomerulonephritis in the adult: Longitudinal, clinical, functional and morphologic studies of rates of healing and progression to chronicity, Medicine 40: 203, 1961, 5. Rammelkamp, C. H., Jr.: Glomerulonephritis, Proc. Inst. Med. Chicago 19: 371, 1952. 6. Loeb, E. N., Lyttle, J. D., Seegal, D., and Jost, E. L.: On the permanence of recovery in acute glomerulonephritis, J. Clin. Invest. 17: 623, 1938. 7. Perlman, L. V., Iterdman, R. C., Kleinman, H., and Vernier, R. L.: Post streptococcal glomerulonephritis: A ten year followup of an epidemic, J. A. M. A. t94: 63, 1965. 8. Ramberg, R.: The prognosis for acute nephritis, Acta med. seandinav. 127: 396, 1947.
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November, 1969 T h e ] o u r n a l of P E D I A T R I C S
Second attacks of acute glomerulonephritis The cases o[ 12 Negro children with two clinically and histologically similar attacks o[ acute glomerulonephritis are reported. The absence o[ clinical and histologic evidences o[ chronic gIomerulonephritis during a period o[ 6 to 108 months o[ [ollow-up study is emphasized. Lobular mesangial hyperplasia constituted the major persistent histologic abnormality; focal thickening o[ Bowman's capsule was less frequently observed.
Shane R o y III, M.D.,"* Hershel P. Wall, M.D., and James N. Etteldorf, M . D . 2r E M P I-II S ~ TENN.
T H E O C1G U R R E N {3E of exacerbations of chronic glomerulonephritis following recurrent streptococcal infections has been well established? The frequency of exacerbations of chronic glomerulonephritis is greater in children than in adults; the latent period between the onset of the streptococcal infection and the exacerbation is usually relatively short. Exacerbations of acute glomerulonephritis, accompanied by the reappearance of the initial clinical and laboratory manifestations and characterized by exudative and proliferFrom the University o[ Tennessee College o[ Medicine. These studies were supported in part by United States Public Health Service Grants: National Heart Institute Nos. HE-00454 and HE-05285 ~ and National Center for Chronic Disease Control No. PH-86-67-297. Presented be[ore the Southern Society [or Pediatric Research, New Orleans, La., Nov. 22, 1968, and the American Society o[ Nephrology, Washington, D. C., Nov. 25, 1968. "X'Address: Dobbs Research Institute, 951 Courl; Ave., Memphis, Tenn. Vol. 75, No. 5, pp. 758-767
ative histologic changes typical of an initial attack of acute glomerulonephritis, are considered by some investigators 2-5 to be extremely rare. Earlier clinical studies by Loeb and co-workers 6 on the natural history of acute poststreptococcal glomerulonephritis demonstrated that recovery following healing was usually permanent. None of the 10 patients of Loeb's study developed recurrent or chronic glomerulonephritis despite reinfection with Group A streptococci. Subsequent studies by Perlman and co-workers 7 of 61 children, who were involved in an epidemic of acute poststreptococcal glomerulonephritis, failed to reveal clinical evidence of recurrences of acute glomerulonephritis despite a high incidence of recurrent streptococcal pyoderma. Ramberg, s however, in 1947 described 11 patients who developed recurrent attacks of acute glomerulonephritis after having recovered completely from the first attack. Bernstein and Stillerman 9 reported upon 2 children and one adult who developed recur-
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Second attacks o/ glomerulonephritis
rent glomerulonephritis following repeated streptococcal infections during periods of time ranging from 2 years to approximately 30 years following recovery from the initial attack. Dodge and associates 1~ described 2 children with typical acute poststreptococcal glomerulonephritis who experienced an exacerbation of symptoms of acute glomerulonephritis following streptococcal pyoderma 13 and 26 months, respectively, after the initial illness. Renal biopsy in one patient 11 months after the exacerbation was interpreted as "pathologically latent." A renal biopsy in the second patient performed just prior to the exacerbation was interpreted as "pathologically latent," whereas histologic changes in tissue obtained at the time of the clinical exacerbation were interpreted to represent an exacerbation of chronic glomerulonephritis. Six of their 44 patients were considered to have acute glomerulonephritis clinically, but were classified histologically as having exacerbations of chronic glomerulonephritis. Morphologic evidences of chronicity were scarring, glomerular obsolescence, extensive collagenization, fibroepithelial crescents, and the presence of fibrin in glomerular capillaries and Bowman's space. Vernier and associates 1~ also reported upon 6 children with a clinical picture of acute glomerulonephritis whose renal biopsy revealed chronic renal disease. Severely fibrotie glomeruli and extensive tubular atrophy were noted in addition to acute glomerulonephritis with polymorphonuclear infiltrate of the glomeruli. These observations suggested a previously unrecognized pathologic process. Becker and Murphy 12 were able to produce recurrent acute glomerulonephritis in 3 rabbits by repeated inoculations of live strains of nephritogenic streptococci. The kidneys of these rabbits showed proliferative and exudative glomerular lesions with epithelial crescents which appeared to have developed after the beginning of the final series of inoculations with streptococci. These authors suggested that human subjects who develop acute glomerulonephritis with proliferativeexudative glomerular lesions and epithelial
crescent formation may be suffering from recurrent acute glomerulonephritis. In the last 15 years, of a total of 590 children admitted to our hospital with a diagnosis of acute glomerulonephritis, at least 12 were observed to develop a second episode of acute nephritis 9 to 82 months following complete clinical recovery from the initial attack. The findings in these patients constitute the subject of this report. MATERIAL
AND
75 9
METHODS
The children included in this report were Negroes ranging in age from 1~2 to 7 ~ 2 years at the time of the initial episode of acute glomerulonephritis. Seven were boys and 5 were girls. There was no history of renal disease in these children prior to their first observed attack. Laboratory studies included urinalyses, complete blood counts, erythrocyte sedimentation rates, blood urea nitrogen concentrations, Addis counts, creatinine clearances, antistreptolysin-O titers, antihyaluronidase titers, /?as-globulin determinations, and cultures-for streptococci. Lupus erythematosus and sickle cell disease were excluded. Intravenous pyelograms and roentgenograms of the chest were also obtained. Twenty-eight percutaneous renal biopsies were obtained in 12 patients with a Franklin modified Vim-Silverman needle. Patient M. G. was biopsied within 2 weeks after the onset of the first attack of acute glomerulonephritis and patient R. Y. was biopsied 5 months after the first attack. Nine patients were biopsied during the second attack. From 1 to 4 subsequent renal biopsies were performed in 10 patients from 6 to 108 months after the second attack. Tissue was fixed in buffered formalin and embedded in paraffin. Sections 4 /~ in thickness were stained with hematoxylin and eosin, periodic acid-Schiff reagent, and Mallory's trichrome techniques. Tissue obtained from one patient during the second attack was fixed in gluteraldehyde, embedded in Maraglas, and sectioned at 0.5 ~ with an LKB ultramicrotome. The section was then stained with toluidine blue and examined with the
760
Roy, Wall, and Etteldor[
The Journal o[ Pediatrics November 1969
T a b l e I. C l i n i c a l a n d l a b o r a t o r y d a t a , a t t a c k No. 1
Patient
C.B. I W.C. 1M.a. IL.G. IR.H. IM.I.I S. 1. IM.M.t B.S. IJ.T. I Z.Z. I R.Y. Sex Age P'yoderma Sore throat Edema Hypertension Hematuria Proteinuria Azotemia Abnormal ESR Skin culture Throat culture ASO titer A H titer fi~e-Globulin
F 511~2 +e + + + + + + At A ND ND ND
M lS~2 + + -, + + + Staph. 200 192 Low
M 3~2 + + + + + + ND 500 ND ND
F 4 . + + + ND ND ND ND
M M 37~2 77,~2 + + . . . + + + + + + + + + + NG C ~96 50 512 ND NI. ND
F 37/'12 + . + + + + + + A A 833 ND ND
M 46A2 + . + + + + + A A 833 ND ND
F M M 53A2 22/'12 22/12 + + + . . . + + + + + + + + + + + + + + + + + A A Staph. . . . . 100 400 50 ND ND ND ND ND ND
F 59A2 + + + + + + + 1,250 ND ND
e.-+, Present; -, absent or negative; ND, not done. tA, Group A strep.; C, group C strep.; NG, nongroupable strep.; NI., normal.
l i g h t m i c r o s c o p e . F r o z e n r e n a l tissue f r o m this p a t i e n t was also s e c t i o n e d at 4 t~ on a cryostat a n d tested by an i n d i r e c t i m m u n o fluorescent m e t h o d for the p r e s e n c e of ye a n d ]?m/ix-globulin. RESULTS F i r s t a t t a c k of a c u t e g l o m e r u l o n e p h r i t i s . T h e p a t i e n t s ' ages r a n g e d f r o m lS/12 to 7 ~ 2 years at the t i m e of t h e i r initial episode of a c u t e nephritis. P y o d e m a a p r e c e d e d t h e o n s e t of clinical m a n i f e s t a t i o n s of a c u t e n e p h r i t i s in 9 c h i l d r e n , a n d sore t h r o a t in 1 ( T a b l e I ) . A history of b o t h p y o d e r m a a n d sore t h r o a t was p r e s e n t in C. B., b u t n e i t h e r historical n o r clinical e v i d e n c e of p r e c e d i n g i n f e c t i o n was p r e s e n t in L. G. T h e l a t e n t p e r i o d b e t w e e n the onset of i n f e c t i o n a n d t h e onset of s y m p t o m s of a c u t e n e p h r i t i s r a n g e d f r o m 1 to 12 weeks. E d e m a was t h e m a j o r p r e s e n t i n g s y m p t o m in e a c h p a t i e n t . D i a s t o l i c h y p e r t e n s i o n of 90 m m . H g o r g r e a t e r was p r e s e n t in 9 patients. Systolic b l o o d pressures r a n g e d f r o m 105 to 180 r a m . I-tg; r e a d i n g s of 140 m m . H g o r g r e a t e r w e r e o b t a i n e d in 5 patients. Hematuria and proteinuria were present in e a c h c h i l d u p o n a d m i s s i o n to t h e h o s p i t a l ( T a b l e I ) . E r y t h r o c y t e s e d i m e n t a t i o n rates w e r e e l e v a t e d a b o v e 20 ram. p e r h o u r in all
p a t i e n t s e x c e p t L. G. M a x i m u m b l o o d u r e a n i t r o g e n c o n c e n t r a t i o n s r a n g e d f r o m 11 to 72 rag. p e r cent. V a l u e s w e r e g r e a t e r t h a n 20 mg. p e r c e n t in 6 c h i l d r e n a n d r e t u r n e d to n o r m a l d u r i n g the d i u r e t i c p h a s e of the disease. E v i d e n c e of s t r e p t o c o c c a l i n f e c t i o n was s o u g h t by c u l t u r i n g e a c h p a t i e n t ' s t h r o a t a n d a c t i v e skin lesions, a n d by m e a s u r i n g antis t r e p t o l y s i n - O titers. G r o u p A ]?-hemolytic s t r e p t o c o c c i w e r e r e c o v e r e d f r o m the skin lesions of 5 of 10 p a t i e n t s w i t h p y o d e r m a ; n o n g r o u p a b l e ]?-hemolytic streptococci w e r e r e c o v e r e d f r o m one. T h r o a t cultures w e r e positive for G r o u p A ]?-hemolytic streptococci in two p a t i e n t s w i t h p y o d e r m a a n d for G r o u p C in one. G r o u p A ]?-hemolytic streptococci w e r e r e c o v e r e d f r o m b o t h t h e t h r o a t a n d skin lesions of C. B. A n t i s t r e p t o l y s i n - O titers of 400 T o d d units o r g r e a t e r w e r e f o u n d in f o u r p a t i e n t s w i t h p y o d e r m a a n d one w i t h sore throat. T h e a n t i h y a l u r o n i d a s e titer was 512 units in o n e p a t i e n t w i t h p y o d e r m a a n d n o r m a l in o n e ; testing f o r this e n z y m e was n o t a v a i l a b l e d u r i n g t h e first a t t a c k of acute glomerulonephritis in the other patients. S e r u m ]?1c-globulin levels w e r e o b t a i n a b l e in two p a t i e n t s a n d w e r e n o r m a l in o n e a n d a b n o r m a l l y l o w in one. P e r c u t a n e o u s r e n a l bopsies w e r e p e r f o r m e d
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Second attacks of glomerulonephritis
761
Fig. 1. Renal biopsy 2 weeks after onset of initial episode of acute glomerulonephritis (M. G.). Focal hypercellularity and scattered leukocytes were observed. (Hematoxylin and eosin; x400.)
Fig. 2. Renal biopsy 5 months after onset of initial episode of acute glomerulonephritis shows persistent focal hypercellularity (R. Y.). (Hematoxylin and eosln; •
in M. G. 2 weeks after onset of the first attack and in R. Y. 5 months after onset of disease. T h e biopsy in M. G. showed focal endothelial and epithelial hypercellularity and the presence of polymorphonuclear leukocytes (Fig. 1)." T h e glomeruli were
swollen and a few of the capillary tufts were compressed. Persistent diffuse endothelial and epithelial hypereellularity with an absence of polymorphonuclear leukocytes was noted in the biopsy of R. Y. 5 months after onset of disease (Fig. 2). No evidence
7 6 2 Roy, Wall, and Etteldor[
The Journal o[ Pediatrics November 1969
of glomerular fibrosis or scarring was noted in either biopsy. Each patient except L. G. received antibiotic therapy during his first episode of acute glomerulonephritis. Patient M. J. received oral tetracycline for 9 days and then received 1.2 million units of benzathine penicillin intramuscularly. J. T. received procaine penicillin for two days and tetracycline for seven days intramuscularly. The remaining nine patients were given procaine penicillin for 3 to 11 days and benzathine penicillin intramuscularly at the conclusion of procaine penicillin therapy. During the 9 to 82 month interim between the first and second attacks, all patients remained free of clinical and laboratory evidence of renal disease. Each patient was examined repeatedly in the outpatient Pediatric Nephrology Clinic between the two attacks. No renal biopsies were performed between the two attacks. Second attack of acute glomerulonephritis. Nine of the patients described above presented with a history of pyoderma preceding the second attack of acute glomerulonephritis; the other three presented with a history of sore throat. The latent period between the onset of infection and the onset of
symptoms of glomerulonephritis ranged from 1 to 6 weeks. Edema and hypertension were present in all patients during the second attack. Hematuria was present in all patients, and proteinuria was present in tl. Blood urea nitrogen concentrations were temporarily elevated above 20 rag. p e r cent in four patients; erythrocyte sedimentation rates were elevated in 11 (Table II). Group A fl-hemolytic streptococci were recovered from the skin lesions of B. S., T. T., and R. Y. The strain from B. S. was typed as M52, T3/13/B3264; the strain recovered from R. Y. was typed as M2, T-Imp. 19. Group A /3-hemolytic streptococci were recovered from the throats of 2 patients with pyoderma, C. B. and L. G. Group C /3hemolytic streptococci were recovered from the throat of M. G. Antistreptolysin-O titers were greater than 400 Todd units in 2 patients with pyoderma and one with sore throat. Antihyaluronidase titers were elevated in 3 patients with pyoderma./31e-Globulin levels were below normal levels in 5 of the 6 patients tested and returned to normal during convalescence in each patient. Percutaneous renal biopsies were per-
Table II. Clinical and laboratory data, attack No. 2 Patient
C.B. IW.C.IM.G. IL.G. IR.H. IM.J. tS.J. IM.M.I B.S. [].T. IT.T. I R.Y. Sex Age Interval No. 1 to No. 2 (mo.) Pyoderma Sore throat Edema Hypertension Hematuria Protelnuria Azotemia Abnormal ESR Skin culture
Throat
culture
ASO titer AI-t titer filo-Globulin
F 121A2
M 41~2
M 10~2
F 99A~
74 +~
39
82
69
-
__
+
+
-
+
+
+ + + +
+ + + +
+ + + +
+ + + +
--
+
-
+
+
+
+
Staph.
ND
ND
At 200 ND ND
625 ND ND
C 166 ND N1
*+, Present; -, absent or n e g a t i v e ; "~A, Group A s t r e p . ; C , g r o u p Cl
ND, strep.;
not NG~'
M 4~2 9
M 12a~2
F 86~2
M 76~2
F 11~2 70
56
59
36
-
+
+
-
+
+ + + +
+ + + +
. + + + +
. + + + -
M 3~'~2
+
.
M 41~
F 117~2
14
32
70
+
+
+
+ + + +
+ + + +
+ + + +
. + + + +
_
+
-
+
+
--
+
+
+
-c
+
+
+
Staph.
ND
A
M2, TI m p . 19
. 192 256 Low
. 200 ND ND
A 400 ND ND
Staph.
. 512 512 Low
done. nongroupable
strep.; NI.,
normal.
M52 T3/13/ B3264 . . . 200 50 ND 32 ND Low
200 ND ND
48 512 Low
NG 192 96 Low
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Second attacks o/ glomerulonephritis
formed in 9 patients during the second attack of acute glomerulonephritis. Light microscopic examination of each of these specimens revealed swollen glomeruli with diffuse endothelial hypercellularity and the presence
of polymorphonuclear leukocytes. Fibroepithelial crescents and hyalinized glomeruli were not observed. Representative specimens from 2 patients are shown in Figs. 3 and 4. Granular deposits of flle/1A-globu!in were
Fig. 3. Glomerular swelling, hypercellularity, and closed glomerular loops are seen in this biopsy specimen obtained 9 days after onset of the second aftack of glomerulonephritis (M. G.). (Hematoxylin and eosln; x400.)
Fig. 4. Renal biopsy 7 days after the second attack of acute glomerulonephritis shows mild hypercellularity and a few leukocytes (R. Y.). (Hematoxylin and eosin; x400.)
76 3
7 64
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The Journal o[ Pediatrics November 1969
Fig. 5. Half micron section of same biopsy specimen as Fig. 3 shows multiple dense deposits (arrows) along the epithelial side of the capillary basement membrane (M. G.). (Toluidine blue; •
Table I I I . Follow-up laboratory and histologic data
C. .IM.G.I Months after second attack Proteinuria (qualitative) Proteinuria (rag./24 hr.) Blood urea nitrogen (mg. per cent) Creatinine clearance (c.c./min./1.73M. 2) Renal histology ~
Patient
L G IRHIMI1SJ.
IMM I B S IJ.T. IT. T I R Y
94 0 0
t2 0 0
108 0 0
30 0 0
6 0 184
33 0 0
48 0 408
15 0 0
86 0 0
16 tr. 0
12 0 0
13
23
11
14
9
17
11
12
13
10
8
127 (1)
t02 --
118 (2,4)
140 (2)
-(3)
108 (2)
103 (2,5)
115 (2,4)
93 (2)
103 (2)
94 (2,4)
~'(1), Normal; (2), mild mesangial hypercellularity; (3), moderate mesangiaI hypercellularity; (4), focal thickening of Bowman's capsule; (5), one hyalinized glomerulus.
demonstrated by immunofluorescent staining of the biopsy specimen from M. G. Dense homogeneous deposits were also observed along the epithelial side of the capillary basement membrane in a 0.5/~ section stained with toluidine blue (Fig. 5). Subsequent observations. Subsequent studies have been performed in 11 of the 12 patients 6 to 108 months after the second attack of glomerulonephritis (Table I I I ) . Physical examination of each patient revealed normal blood pressure and absence of edema. Routine hemograms, urinalyses, quantitative Addis count urinalyses, 24 h o u r urinary excretions of protein, a n d blood urea nitrogen concentrations were deteri:nined in
each patient. Twelve-hour endogenous creatinine clearances and renal biopsies were performed in 10 patients. I-Iematocrits were normal in each patient. Routine urinalysis revealed a trace of protein in the urine of T. T. T h e 24 hour urinary excretion of protein was 184 mg. in patient 1V[. J. 6 months after the second attack. Intermittent proteinuria of 165 to 408 rag. per 24 hours was noted in M. M. 48 months after the second attack. Twelve-hour endogenous creatinine clearance values ranged from 93 to 140 c.c. per minute per 1.73 square meters. Renal biopsies were performed 12 to 108 months after the second attack in 7 of 9
Volume 75 Number 5
Second attacks of glomerulonephritis
7 65
Fig. 6. Renal biopsy 94 months after second attack was interpreted as normal (C. B.). (Hematoxylin and eosin; x400.)
Fig. 7. Renal biopsy 108 months after second attack shows mild mesangial hypercellularity (L. G.). (Hematoxylin and eosin; x400.)
patients who were biopsied during the acute phase of the second attack of glomerulonephritis. In 3 additional patients, who were not biopsied during the acute phase of the second attack, biopsies were performed at 6, 16, and 48 months, respectively, following
the second attack. Light microscopic evaluation of the renal biopsy of C. B. was normal (Fig. 6). A mild degree of mesangial hypercellularity was evident in the biopsy specimens of 8 patients 12 to 108 months after the second attack. In addition, focal thicken-
766
Roy, Wall, and Etteldor[
ing of Bowman's capsule was noted in the biopsy specimens of L. G. (Fig. 7), 13. S., and R. Y.; one hyalinized glomerulus was noted in the biopsy of M. M. Moderate mesangial hypercellularity was noted in the biopsy of M. J. which was obtained 6 months after his second attack. DISCUSSION The clinical and histologic similarities between the two attacks of glomerulonephritis in these patients were striking. It has been previously noted that exacerbations of chronic glomerulonephritis are often clinically indistinguishable from initial attacks of acute glomerulonephritis, n Exacerbations of chronic glomerulonephritis frequently follow streptococcal infections and are manifested by edema, hypertension, hematuria, and proteinuria. Histologically the acute exacerbation of chronic glomerulonephritis, while often demonstrating endothelial cellular proliferation, leukocytic exudation, and even electron dense "humps" on electronmicroscopy, is also characterized by glomerular crescents, lobular scarring, and glomerular hyalinization?~ Patients included in this report differ in that chronic histologic changes were absent during the acute phase of the second attack. Mild mesangial hypercellularity and occasional focal thickening of Bowman's capsule have been noted as the principal lesion in subsequent biopsy specimens. Mesangial hypercellularity has been previously described as typical of resolving acute glomerulonephritis.a Patient M. M. was noted to have proteinuria 48 months after the second attack, which may indicate nonhealing. One of 13 glomeruli was hyalinized in his renal biopsy obtained 48 months after the second attack. As previously mentioned, 11 patients received antibiotic therapy for infections during their first attack of glomerulonephritis. Five patients with preceding pyoderma received penicillin within 2 weeks after the onset of skin lesions. Previous studies ~3, 1, have demonstrated that penicillin therapy administered within the first 10 days after a streptococcal infection suppresses the for-
The Journal of Pediatrics November 1969
mation of type-specific streptococcal antibodies. Thus, in at least 5 of the early treated patients, penicillin may have interfered with the development of type-specific streptococcal antibodies, leaving them susceptible to reinfection with the nephritogenic strain of streptococcus which caused their first attack of glomerulonephritis. An increasing number of streptococcal pyoderma strains have been shown to possess nephritogenic properties? 5-zs Definitive streptococcal typing was not available during the first attack in our patients. In a prospective study of pyoderma and glomerulonephritis over the past 3 years, eight different M or T typable streptococcal strains have been recovered from 11 patients with pyodermarelated acute glomerulonephritis? 9 Nontypable strains of Group A /?-hemolytic streptococci were recovered from 11 additional patients. It seems reasonable to assume that, in a population plagued with recurrent pyoderma and in the presence of multiple potentially nephritogenic strains of streptococci, the chances for reinfection with different nephritogenic strains of streptococci would be increased. Further epidemiologic studies of streptococcal infections in our population should help to clarify this hypothesis. SUMMARY
Twelve Negro children with two attacks of acute glomerulonephritis are reported upon. Pyoderma preceded the initial episode in 9 patients, sore throat in 1, and both in 1. Serologic and/or bacteriologic evidence of preceding streptococcal infection was present in 8 patients. Second attacks of acute glomerulonephritis occurred 9 to 82 months later and were indistinguishable clinically and histologically from the initial attack. Pyoderma preceded the second attacks in 9 patients, and sore throat in 3. Serologic and/or bacteriologic evidence of preceding streptococcal infection was present in 8 patients. Renal biopsies in 2 patients during the initial attack and in 9 patients during the acute phase of the second attack showed
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Second attacks of glomeruIonephritis
histologic changes consistent with acute glomerulonephritis. R e n a l biopsies in 10 patients 6 to 108 months after the second attack revealed resolving acute glomerulonephritis without histologic evidences of chronic glomerulonephritis.
9. Bernstein, S. H., and Stillerman, M.: A study of the association of group A streptococci with acute glomerulonephritis, Ann. Int. Med. 52: 1026, 1960. 10. Dodge, W. F., Spargo, B. H., Bass, J. A., and Travis, L. B.: The relationship between the clinical and pathologic features of poststreptococcal glomerulonephritis. A study of the early natural history, Medicine 47: 227, 1968. 11. Vernier, R. L., Worthen, H. G., Wannamaker, L. W., and Good, R. A.: Renal biopsy studies of the acute exacerbation in glomerulonephritis, Am. J. Dis. Child. 98: 653, 1959. 12. Becker, C. G., and Murphy, G. E.: The experimental induction of glomeralonephrltis like that in man by infection with group A streptococci, J. Exper. Med. 127: I, 1968. 13. Siegal, A. C., Johnson, E. E., and Stollerman, G. H.: Controlled studies of streptococcal pharyngitis in a pediatric population. 2. Behavior of type-specific immune response, New England J. Med. 265: 566, 1961. 14. Potter, E. V.: Type 12 streptococci and acute glomerulonephritis. I. Presence and recall of type-specific streptococcal antibodies in patients with healed acute glomerulonephritis, J. Lab. & Clin. Med. 65: 40, 1965. 15. Anthony, B. F., Perlman, L. V., and Wannamaker, L. W.: Skin infections and acute nephritis in American Indian Children, Pediatrics. 39: 263, 1967. 16. Potter, E. V., Moran, A. _F., Pooh-King, T., and Earle, D. P.: Characteristics of beta hemolytic streptococci associated with acute glomerulonephritis in Trinidad, West Indies, J. Lab. & Clin. Med. 71: 126, 1968. 17. Johnson, J. C., Baskln, R. C., Beachey, E. H., and Stollerman, G. H.: Virulence of skin strains of nephritogenle group A streptococci: New M protein serotypes, J. Immunoh 10h 187, 1968. 18. Dillon, H. C., Reeves, M. S., and Maxted, W. R.: Acute glomerulonephritis following skin infection due to streptococci of M-type 2, Lancet 1 (pt. 1): 543, 1968. 19. Stollerman, G. H.: Unpublished data, 1968.
The assistance of Dr. James A. Pitcock, Assistant Professor of Pathology, University of Tennessee College of Medicine, in the preparation of this manuscript is appreciated. REFERENCES 1. Seegal, D., Lyttle, J. D., Loeb, E. N., Jost, E. L., and Davis, G.: On the exacerbation in chronic glomerulonephritis, J. Clin. Invest. 19: 569, 1940. 2. McCluskey, R. T., and Baldwin, D. S.: Natural history of acute glomerulonephritis, Am. J. Med. 35: 213, 1967. 3. Jennings, R. B., and Earle, D. P.: Post-streptococcal glomerulonephritis: Histopathologic and clinical studies of the acute, subsiding acute, and early chronic latent phases, J. Clin. Invest. 40: 1525, 1961. 4. Kushner, D. S., Armstrong, S. H., Dubln, A., Szanto, P. B., Markowitz, A., Maduros, B. P., Levine, J. M., River, G. L., Gyner, T. N., and Pendros, J. P.: Acute glomerulonephritis in the adult: Longitudinal, clinical, functional and morphologic studies of rates of healing and progression to chronicity, Medicine 40: 203, 1961, 5. Rammelkamp, C. H., Jr.: Glomerulonephritis, Proc. Inst. Med. Chicago 19: 371, 1952. 6. Loeb, E. N., Lyttle, J. D., Seegal, D., and Jost, E. L.: On the permanence of recovery in acute glomerulonephritis, J. Clin. Invest. 17: 623, 1938. 7. Perlman, L. V., Iterdman, R. C., Kleinman, H., and Vernier, R. L.: Post streptococcal glomerulonephritis: A ten year followup of an epidemic, J. A. M. A. t94: 63, 1965. 8. Ramberg, R.: The prognosis for acute nephritis, Acta med. seandinav. 127: 396, 1947.
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