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Renal manifestations of the Henoch-Schoenlein syndrome in adults
Renal Manifestations of the Henoch-Schoenlein Syndrome in Adults
HAROLD S. BALLARD, M.D. ROBERT P. EISINGER, M.D. GLORIA GALLO, M.D. New York, New York
Clinical observations are reported on fourteen adults with the HenochSchoenlein syndrome accompanied by renal disease. Kidney tissue was examined in seven; electron microscopy was performed in three of these and immunofluorescence studies in one. Although the clinical findings were unreliable prognostic indicators, there appeared to be a good correlation between the diffuse glomerular lesion with crescent formation and a fatal outcome. The Henoch-Schoenlein syndrome is characterized by arthralgia, purpuric rash and abdominal pain. Hematuria is frequently observed. This condition, seen predominantly in childhood, also occurs in adults and may be accompanied by severe involvement of the kidneys, with death in renal failure. Since the syndrome in the adult is rare, there are few reports of clinical or pathologic findings [1-9]. The paucity of data pertaining to the renal lesion in adults prompts this presentation.
MATERIALS AND M E T H O D S Medical records were reviewed of all adults with the diagnosis of anaphylactoid or Henoch-Schoenlein purpura admitted to the New York, San Francisco, Los Angeles, New Orleans, Philadelphia, Mt. Alto, Bronx, Brooklyn and East Orange Veterans Administration Hospitals between January 1, 1954, and December 31, 1968. Fourteen patients presenting with nonthrombocytopenic purpura, joint pains and renal abnormalities were accepted as having the Henoch-Schoenlein syndrome with renal involvement when no other diagnosis could be established. Renal tissue was examined in seven of these, all of whom had hematuria and proteinuria at the time the tissue specimen was obtained. Four (N.S., H.C., S.H. and M.S.) had percutaneous renal biopsies; in two, the specimens were examined by electron microscopy and in one, by immunofluorescence microscopy; postmortem tissue five weeks after biopsy was available for light microscopy studies in one patient (H.C.). Renal tissue obtained at autopsy was studied in three additional patients (J.W., R.N. and R.C.). Sections for light microscopy were all stained with hematoxylin and eosin, and in one case periodic acid-Schiff reagents and azancarmine. Fixation in glutaraldehyde was employed for electron microscopic study. Fluorescence microscopy was performed according to previously published technics [10].
RESULTS
From the Medical Service, New York Veterans Administration Hospital and Departments of Medicine and Pathology, New York University School of Medicine, New York, New York 10010. Requests for reprints should be addressed to Dr. H. S. Batlard, Veterans Administration Hospital, 408 First Avenue, New York, New York 10010. Manuscript received October 21, 1969.
328
Clinical and laboratory findings in fourteen men with the Henoch-Schoenlein syndrome and renal involvement are presented in Tables I, II and II1. The patients' ages ranged from thirty-one to eighty-nine years. An average of eight days elapsed between initial symptoms and hospitalization. All patients complained of purpura and joint pains, and seven had symptoms of gastrointestinal involvement. All had clinical evidence of renal involvement. Six patients reported upper respiratory tract infections occurring twelve to twenty-seven days before the appearance of the symptoms of the HenochSchoenlein syndrome. In one cellulitis of the foot had developed which was treated with penicillin one month preceding the appearance of symptoms. A history of drug exposure was obtained in thirteen of fourteen patients
The AmericanJournalof Medicine
RENAL
MANIFESTATIONS
OF HENOCH-SCHOENLEIN
SYNDROME
--
BALLARD
ET AL.
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329
RENAL MANIFESTATIONS OF HENOCH-SCHOENLEIN SYNDROME -- BALLARD ET AL.
TABLE
II
Patient
Laboratory Findings in Fourteen Adults with the Henoch Schoenlein Syndrome
Platelets (per cu mm)
G.C. . . . J.W. 320,000 R.N. 432,000
Streptococcal Antibodies (ASL units) 500-1,000 . . 50 (Todd units)
NS M.S 9 H.C. S.H.
':' 440,000 210,000 260,000 350,000
200 250-300 400-500
R.R 9 W.E.
200,000 186,000
300-500 100
I.S. J.D. L.F. A.B.
':' 210,000 ~: ~
300-500 500 125
RC
Serum Complement
50 N: 36-44 87.5 N: 75-130
L.E. Tests
Serum Stool Albumin Guaiac (gm %)
Neg
4+
2.9
Neg
. . .
1.8
... ......
4+
9 . .
4+
Neg Neg
Neg 4+
... 39 3.3 1.9 2.2
Neg Neg
4+ 4+
2.4 3.0
Neg
......
Serum Cholesterol ESR (rag %) (mm/hr)
337
120 4O0
Cryoglobulins
Cold Agglutinins
20
Neg
Neg
3O
Neg
Neg
56 32
Neg Neg
Neg
37
Neg
Neg Neg
35 ......
29
Rumpel Leede Test
Latex Fixation Test
Neg Pos 9. . Neg
Neg Reactive Neg
Pos Neg
. . . Neg
Pos Neg Neg
Neg . . . . 9.
NOTE: L.E. = lupus erythematosus; ESR = erythrocyte sedimentation rate. ':' Platelets appeared adequate on peripheral blood smear.
These drugs included penicillin (three patients), acetylsalicylic acid (three), Anacin | tablets (one), tetracycline (one), sulfonamides (two), unknown drugs (two) and chlordiazepoxide hydrochloride and meprobamate (one). Additional medications included antibiotic throat lozenges, chlora~ hydrate, Luden'S cough drops and laxatives9 In six of these patients drug ingestion was prompted by the presence of acute respiratory symptoms 9 Seven patients gave a history of cutaneous or gastrointestinal allergy. Beta-hemolytic streptococci were isolated from one of seven patients whose throats were cultured 9 The antistreptolysin 0 titer was increased in four patients and normal in three. The severity of renal disease did not seem to be related to the presence or absence of evidence for streptococcal infection. Serum complement levels were normal in the two patients on whom this test was performed 9 Serum from five patients was tested for cryoglobulins with negative results. Repeated lupus erythematosus tests were negative in seven patients 9 All patients had diminished peripheral hematocrit values during their course, Platelet counts were invariably normal at the onset of clinical manifestations, however in two patients (B.C. and R,C.) significant thrombocytopenia developed late in the course. Coagulation studies performed on the blood of one (H.C.) did not support defibrination as causative 9 Blood cultures were negative in the five patients in whom they were obtained. Six patients had clinical evidence of cardiac involvement. Three of these had persistent tachycardia and T wave inversions on their electrocardiograms, and the venous pressure
330
in one was 160 mm of saline solution 9 Conduction disturbances and transient arrhythmias were noted in a fourth patient, and diastolic gallop, elevated venous pressure and repolarization abnormalities in a fifth. The sixth patient presented with cardiomegaiy, gallop rhythm, T wave inversions and hilar flare. No patient gave a history of antecedent renal disease; however, in only three were normal urinalyses and blood urea levels recorded prior to onset of the present illness9 Microscopic hematuria was present in all patients and red cell Casts were found in the urinary sediment of three9 In ten patients the sediment contained innumerable red blood cells, in four there were 10 to 100 erythrocytes/high power field 9 Although gross hematuria has been described as a prominent feature in the glomerulonephritis associated with the Henoch-Schoenlein syndrome, this feature was not observed in our patients 9 Proteinuria also was noted in all patients 9 Eight patients had 4 + , two had 2 + , and four had 1 + proteinuria. Twenty-four hour urinary protein output was measured in five patients and found to range between 3.5 and 9 gin. Urine protein electrophoresis in one patient (H.C.) revealed large amounts of albumin with considerable tailing into the globulin fraction 9 Serum albumin levels were below 3.5 gm per cent in eight of nine patients in whom serum proteins were determined 9 The one patient whose albumin level was norma had a single determination performed at the time of hospital entry 9 In the eight subjects with hypoalbuminemia this manifestation appeared ten or more days following hospitalization. In seven patients the nephrotic syndrome developed; three of
The American Journal of Medicine
RENAL MANIFESTATIONS OF HENOCH-SCHOENLEIN SYNDROME -- BALLARD ET AL.
TABLE III
Renal Manifestations in Fourteen Adults with the Henoch-Schoenlein Syndrome
Patient
Urine Protein
G.C.
2+
Hematuria RBC/HPF Innumerable
Casts Finely gran-
Doubly Refractile Lipid Bodies . .
Maximal Blood Maximal Urea CreatiNitrogen nine (mg %) (rag%)
Duration of Disease at Time of Nephrotic Tissue Syndrome Examination
Renal PathologicChanges
15.5
ular
4+
R.N.
9.3 gm! 24 hr
Innumerable
R.C.
1+
Innumerable
69
N.S9
44-
Innumerable
92
M.S.
4 gm/ 24 hr
50-100
26
H.C.
6.9 gm! 24 hr
Innumerable
Red cell
4-
178
S.H.
4.7 gm/ 24 hr 1+ 1+ i+ 2+ 3.47 gm/ 24 hr 4+
Innumerable
Red cell, granular Granular
+
18
R9 W.E. l.S. J.D. L.F. A.B.
Innumerable
98
J.W.
Innumerable 50-55 ].2-20 Innumerable 10-15
. . . . . Red cell, fatty, granular
4-
+
11.5
+
5.1
+
+
Diffuse irregular cell proliferation(100%) of glomeruli; scatteredsmall epithelial crescents present 10 wk (post- Most glomeroli abnormal(95%) with diffuse mortem) highly irregularcell proliferation;scattered small epithelial and fibroepithelialcrescents present 8% wk Most glomeruliabnormal(95%) with diffuse (postirregular cell proliferation;scattered epithelial mortem) and fibroepithelialcrescents present 31/2wk Most glomeruli normal (95%); minimal cell (biopsy) proliferation in mesangialareas in a few 4 wk Normal renal tissue (biopsy); Focal hyalinizedglomeruli;focal 28 wk thickening of Bowman'scapsule (biopsy) All glomeruli abnormalwith diffuse, highly 3 wk irregular cell swelling, proliferationand (biopsy) neutrophil infiltration predominantlyin mesangialregionsand focal obliterationof peripheral capillary loops by intracapillary cell proliferation;small epithelial crescents often containingfibrin and periglomerular neutrophil infiltration present 8 wk (post9 Irregular proliferative lesions in most glomeruli mortem) (95%) and in some progressionto irregular sclerosis of capillary loops; crescents in various stagesof organizationwith fibrous masses and red cells still present in some glomeruli About 50% of glomeruli normal; others with 6 wk segmental proliferativelesions (biopsy) 2 wk (postmortem)
26 26
Innumerable
these died. o n e of the surviving patients (S.H.) still has 1 + proteinuria, blood urea nitrogen 20 m g per cent a n d s e r u m creatinine 2 m g per cent eleven m o n t h s after discharge but is otherwise well; all other a b n o r m a l laboratory and clinical f i n d i n g s have returned to normal. In one of the t w o patients with h y p o a l b u m i n e m i a but w i t h o u t heavy proteinUria, signs and s y m p t o m s of gastrointestinal i n v o l v e m e n t were p r o m i n e n t . In the other, stool guaiac tests were 4 + although a b d o m i n a l s y m p t o m s were denied. G a s t r o i n t e s t i n a l protein losses were not q u a n t i f i e d .
Volume 49, September 1970
9. .
1.8 2 1.9
A z o t e m i a was d o c u m e n t e d in eight patients, with m a x i m a l elevations of blood urea nitrogen r a n g i n g between 26 and 178 mg per cent. Four of the five patients with blood urea nitrogen levels greater t h a n 60 or c r e a t i n i n e over 5 m g per cent died. The fifth patient, with a m a x i m a l blood urea level of 92 m g per cent, recovered c o m p l e t e l y . Pathologic f i n d i n g s in seven cases are presented in Table III and in Figures 1 t h r o u g h 6. In the f o u r patients who died pathologic changes, a l t h o u g h not specific, had c o m m o n features. All showed diffuse (90 to 100 per cent) but highly
331
RENALMANIFESTATIONSOF HENOCHSCHOENLEINSYNDROME-- BALLARDETAL.
irregular glomerular abnormalities with varying stages and degrees of involvement. In addition, there was widespread, focally dense, interstitial infiltration by neutrophils, eosinophils, lymphocytes and plasma cells, in some instances associated with tubular necrosis a n d / o r interstitial hemorrhage. Many distal convoluted and collecting tubules contained erythrocytes. The glomerular lesions consisted of varying degrees and combinations of the following:
Fig. 1. Renal biopsy specimen (H.C.). Glomerulus with minimal pathologic changes of diffuse mesangial hypercellularity and neutrophil infiltration (arrows). Hematoxylin and eosin stain, original magnification x 250.
Fig. 3. Autopsy specimen (H.C.). Tissue specimen obtained five weeks after biopsy showing progression of lesions. In many glomeruli there were fibrotic crescents, often concentric, producing obliteration of glomerular tufts (large arrow). An adjacent glomerulus displays minimal mesangial hypercellularity and a fibrin mass in Bowman's space. Note erythrocytes in many tubules (small arrow). Hematoxylin and eosin stain, original magnification x 100.
332
(1) Intracapillary cell proliferation. This most often involved one or several Iobules while sparing other portions. Rarely, generalized proliferation of all tufts was seen. There was associated increased basement membrane-like material between proliferating cells, and adhesions between proliferating cells and Bowman's capsule. (2) Capillary thrombi. Eosinophilic masses were occasionally seen in capillary lumens.
Fig. 2. Renal biopsy specimen (H.C.)I Two glomeruli with most severe lesions showing irregular mesangial and endothelial hypercellularityi increased neutrophil infiltration, epithelial crescent adherent to hypemeUular capillary tufts (straight arrow) and fibrin masses incorporated in crescents (curved arrow) . Notice intense neutrophil infiltration in crescent and pericapsular tissue. Hematoxylin and eosin stain, original magnification x 100.
Fig. 4. Renal biopsy specimen (S.H.). Glomerulus with focal intracapillary cell proliferation (arrow). Azancarmine stain, original magnification x 250.
The American Journal of Medicine
RENALMANIFESTATIONSOFHENOCH-SCHOENLEINSYNDROME-- BALLAROETAL.
(3) Crescents. Present in all sizes, mostly small, and in various stages of evolution in each case, these involved 10 to 75 per cent of glomeruli. Early, these were comprised of eccentric, swollen epithelial cells surrounding masses of eosinophilic, fibrinoid material and erythrocytes in Bowman's space, sometimes extending between capillary tufts. Later and more severe lesions consisted of concentric fibroepithelial and fibrous crescents which at times compressed and enclosed all or parts of collapsed tufts. Progression of epithelial to fibrotic crescents was well seen in one patient (H.C.) in whom initial biopsy was followed by postmortem examination five weeks later. (4) Glomerular sclerosis. In some, scattered segmental scars of tufts were seen, presumably representing residua of proliferative lesions. In general, only occasional totally sclerotic glomeruli were present (perhaps unrelated to the present process). (5) Neutrophil infiltration. This was irregular and generally mild but in one case (H.C.) on initial biopsy, neutrophil infiltration of glomeruli was pronounced especially in mesangial areas even in glomeruli in which little proliferation was evident. In two nonfatal cases examined by renal biopsy only (S.H. and N.S.), segmental intracapillary proliferation (Fig. 4) was found in 5 of 11 glomeruli and 2 of 20 glomeruli, respectively; the remaining glomeruli appeared normal. In the third nonfatal case (MS.) light microscopy revealed no significant pathologic changes but in a subsequent biopsy specimen focal glomerular scars were found. Immunofluorescence microscopy in one case (S.H.) showed diffuse irregular staining for gamma globulin along glomerular basement membranes, brighter in some Iobules, corresponding to proliferative areas and bright finely granular staining in mesangial areas in all 4 glomeruli present (Fig. 5). Electron-microscopic sections revealed deposits of fibrin in the urinary space (Fig. 6). No acute or healed renal arteritic lesions were found.
therefore, be secondary to steroid therapy and cannot definitely be attributed to the disease process itself. Diastolic hypertension was recorded in three patients, but in two hypertension had been present prior to onset of the Henoch-Schoenlein syndrome. In the third, hypertension followed institution of steroid therapy. All patients except one either recovered or died within five months of onset of illness; one has persistent abnormalities one year after onset (1 + proteinuria, blood urea nitrogen 20 mg per cent, creatinine 2 mg per cent). Approximately one-fourth (28.5 per cent) of the patients in our series died during the acute phase of their illness, as contrasted with about 0 to 10 per cent in childhood Henoch-Schoenlein syndrome [11]. In the four cases terminating fatally, death occurred in the setting of uremia. It seems possible that in one patient (S.H.) chronic disease will probably ensue inasmuch as renal abnormalities persist after one year. However, complete recovery has been observed after urinary abnormalities had persisted for two years [9]. Instances of chronic renal disease have been reported by others [1,9], but a chronic course appears to be unusual in the adult Henoch-Schoenlein syndrome. Azotemia appeared to be an uncertain prognostic indicator inasmuch as one patient (N.S.) with a maximal blood urea nitrogen level of 98 mg per cent (on prednisone at the time) recovered completely. Similarly, the nephrotic syndrome need not be considered ominous since four such patients (N.S., M.S., S.H. and L.F.) also recovered. In this regard it is of interest that the nephrotic syndrome may be seen either with focal (N.S., M.S. and S.H.) or with diffuse glomerular involvement (J.W., R.N., H.C. and R.C.). Indeed the nephrotic syndrome has been observed with normal glomerular histology [9]. In childhood cases studied by renal biopsy, the characteristic feature in the recovery group has been focal involvement of 20 to 60 per cent of glomeruli by prolifer-
COMMENTS
In contrast to patients with poststreptococcal glomerulonephritis, hypertension and circulatory congestion were not prominent clinical features in these fourteen patients with renal manifestations of the Henoch-Schoenlein syndrome. Three subjects had elevated venous pressure; the circulation time was prolonged in two of these and at the upper limits of normal in the third. Thus, congestive heart failure rather than circulatory overload may have been present. In two patients other causes for congestive failure were documented prior to hospitalization (cardiomegaly and old cardiac infarction in one, and cor pulmonale with chronic atrial fibrillation in the other). In one patient in whom circulatory decompensation developed, normal cardiac function had been documented prior to hospitalization. At the time of appearance of circulatory congestion he had been receiving prednisone. Sodium and fluid retention in this subject might,
Volume 49, September 1970
Fig. 5. Renal biopsy specimen (S.H.). lmmunofluorescence staining showing diffuse staining for IgG of glomerular capillary loops, most prominent in mesangial areas, original magnification x ].00.
333
RENAL MANIFESTATIONS OF HENOCH-SCHOENLEIN SYNDROME -- BALLARD ET AL.
Fig. 6. Renal biopsy specimen (H.C.). Electron micrograph demonstrating deposits of fibrin in Bowman's space. Magnification x 5,900. (Courtesy of Dr. J. Vasquez, Department of Pathology, New York Veterans Administration Hospital.)
ation of intracapillary cells in a segment or Iobule within the glomerulus [6]. The rapidly progressive form with death in renal failure in weeks to months has been described as diffuse but irregular [11]. It has not been observed that focal lesions can progress to diffuse glomerulonephritis. These data are consistent with the present observations in adults. Only one adult has been described in whom immunofluorescent study was performed [7]. No staining for gamma globulin was found. In children, however, as in the present adult case, deposits of IgG and /~c have been seen in mesangial areas, with lesser staining in the basement membrane [12]. Although the number of adult cases with pathologic correlation is small it appears that the type of renal lesion is a good index of prognosis since three patients in whom the proliferation was focal recovered (although one still has proteinuria after twelve months) whereas the remaining four
334
with diffuse irregular proliferation and crescent formation died. This is in general agreement with previously reported cases in adults [3-9,11]. Among nonfatal cases in which the patients were examined by renal biopsy, seven have shown focal glomerulonephritis [4,9,11], three no glomerular abnormalities [9,11] and two diffuse irregular proliferation of all [7] or possibly all [8] glomeruli. In the latter two crescents were not described. At autopsy in three fatal cases crescent formation and diffuse irregular proliferation of glomerular cells were evident [3,5]. These data support the correlation observed in this series between the diffuse glomerular lesion with crescents and a fatal outcome. ADDENDUM
Since submission of this manuscript a forty year old man with the Henoch-Schoenlein syndrome and focal glomerular lesions has been reported to have recovered from his renal disease [13].
The American Journal of Medicine
RENALMANIFESTATIONSOF HENOCH-SCHOENLEINSYNOROME-- BALLAROET AL,
REFERENCES 1. Osier W: On the visceral manifestations of the erythema group of skin diseases. Amer J Med Sci, 127: 1, 1904. 2. Gairdner D: The Schoenlein-Henoch syndrome (anaphylactoid purpura). Quart J Med 17: 95, 1948. 3. Levitt LM, Burbank B: Glomerulonephritis as a complication of the Schoenlein-Henoch syndrome. New Eng J Med 248: 530, 1953. 4. Heptinstall RH, Joekes AM: Renal biopsy. Proc Roy Soc Med 52: 211, 1959. 5. Norkin S, Wiener J: Henoch-Schoenlein syndrome. Review of pathology and report of two cases. Amer J Clin Path 33: 55, 1960. 6. Vernier RL, Worthen HG, Peterson RD, Colle E, Good RA: Anaphylactoid purpura. I. Pathology of the skin and kidney and frequency of streptococcal infection. Pediatrics 27: 181, 1961. 7. Panner B: Nephritis of Schoenlein-Henoch syndrome. Electron microscopy study of the glomerular lesion in and adult. Arch Path 74: 230, 1962.
Volume 49, September 1970
8. Falls WF, Ford KL, Ashworth CT, Carter NW: Renal vasculitis in a non-fatal case of Henoch-Schoenlein purpura. Ann Intern Med 64: 1276, 1966. 9. Slama R, Habib R: La nephropathie du purpura rheumatoide. Act. Nephrol. de I' Hop. Necker, p. 184. Paris, Flammarion, ]962. 10. McCluskey RT, Vassalli P, Gallo G, Baldwin DS: An immunofluorescent study of pathogenic mechanisms in glomerular diseases. New Eng J Med 274: 695, 1966. 11. Heptinstall RH: Schoentein-Henoch syndrome (anaphylactoid purpura), Pathology of the Kidney, Boston, Little, Brown, 1966, p 335. 12. Urizar RE, Michael A, Sisson S, Vernier RL: Anaphylactoid purpura. I1. Immunofluorescent and electron microscopic studies of the glomerular lesions. Lab Invest 19: 437, 1968. 13. Gary NE, Mazzara JJ, Hoefelder L: The Sch6nlein-Henoch syndrome: report of two patients with recurrent impairment of renal function. Ann Intern Med 72: 229, 1970.
335
HAROLD S. BALLARD, M.D. ROBERT P. EISINGER, M.D. GLORIA GALLO, M.D. New York, New York
Clinical observations are reported on fourteen adults with the HenochSchoenlein syndrome accompanied by renal disease. Kidney tissue was examined in seven; electron microscopy was performed in three of these and immunofluorescence studies in one. Although the clinical findings were unreliable prognostic indicators, there appeared to be a good correlation between the diffuse glomerular lesion with crescent formation and a fatal outcome. The Henoch-Schoenlein syndrome is characterized by arthralgia, purpuric rash and abdominal pain. Hematuria is frequently observed. This condition, seen predominantly in childhood, also occurs in adults and may be accompanied by severe involvement of the kidneys, with death in renal failure. Since the syndrome in the adult is rare, there are few reports of clinical or pathologic findings [1-9]. The paucity of data pertaining to the renal lesion in adults prompts this presentation.
MATERIALS AND M E T H O D S Medical records were reviewed of all adults with the diagnosis of anaphylactoid or Henoch-Schoenlein purpura admitted to the New York, San Francisco, Los Angeles, New Orleans, Philadelphia, Mt. Alto, Bronx, Brooklyn and East Orange Veterans Administration Hospitals between January 1, 1954, and December 31, 1968. Fourteen patients presenting with nonthrombocytopenic purpura, joint pains and renal abnormalities were accepted as having the Henoch-Schoenlein syndrome with renal involvement when no other diagnosis could be established. Renal tissue was examined in seven of these, all of whom had hematuria and proteinuria at the time the tissue specimen was obtained. Four (N.S., H.C., S.H. and M.S.) had percutaneous renal biopsies; in two, the specimens were examined by electron microscopy and in one, by immunofluorescence microscopy; postmortem tissue five weeks after biopsy was available for light microscopy studies in one patient (H.C.). Renal tissue obtained at autopsy was studied in three additional patients (J.W., R.N. and R.C.). Sections for light microscopy were all stained with hematoxylin and eosin, and in one case periodic acid-Schiff reagents and azancarmine. Fixation in glutaraldehyde was employed for electron microscopic study. Fluorescence microscopy was performed according to previously published technics [10].
RESULTS
From the Medical Service, New York Veterans Administration Hospital and Departments of Medicine and Pathology, New York University School of Medicine, New York, New York 10010. Requests for reprints should be addressed to Dr. H. S. Batlard, Veterans Administration Hospital, 408 First Avenue, New York, New York 10010. Manuscript received October 21, 1969.
328
Clinical and laboratory findings in fourteen men with the Henoch-Schoenlein syndrome and renal involvement are presented in Tables I, II and II1. The patients' ages ranged from thirty-one to eighty-nine years. An average of eight days elapsed between initial symptoms and hospitalization. All patients complained of purpura and joint pains, and seven had symptoms of gastrointestinal involvement. All had clinical evidence of renal involvement. Six patients reported upper respiratory tract infections occurring twelve to twenty-seven days before the appearance of the symptoms of the HenochSchoenlein syndrome. In one cellulitis of the foot had developed which was treated with penicillin one month preceding the appearance of symptoms. A history of drug exposure was obtained in thirteen of fourteen patients
The AmericanJournalof Medicine
RENAL
MANIFESTATIONS
OF HENOCH-SCHOENLEIN
SYNDROME
--
BALLARD
ET AL.
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329
RENAL MANIFESTATIONS OF HENOCH-SCHOENLEIN SYNDROME -- BALLARD ET AL.
TABLE
II
Patient
Laboratory Findings in Fourteen Adults with the Henoch Schoenlein Syndrome
Platelets (per cu mm)
G.C. . . . J.W. 320,000 R.N. 432,000
Streptococcal Antibodies (ASL units) 500-1,000 . . 50 (Todd units)
NS M.S 9 H.C. S.H.
':' 440,000 210,000 260,000 350,000
200 250-300 400-500
R.R 9 W.E.
200,000 186,000
300-500 100
I.S. J.D. L.F. A.B.
':' 210,000 ~: ~
300-500 500 125
RC
Serum Complement
50 N: 36-44 87.5 N: 75-130
L.E. Tests
Serum Stool Albumin Guaiac (gm %)
Neg
4+
2.9
Neg
. . .
1.8
... ......
4+
9 . .
4+
Neg Neg
Neg 4+
... 39 3.3 1.9 2.2
Neg Neg
4+ 4+
2.4 3.0
Neg
......
Serum Cholesterol ESR (rag %) (mm/hr)
337
120 4O0
Cryoglobulins
Cold Agglutinins
20
Neg
Neg
3O
Neg
Neg
56 32
Neg Neg
Neg
37
Neg
Neg Neg
35 ......
29
Rumpel Leede Test
Latex Fixation Test
Neg Pos 9. . Neg
Neg Reactive Neg
Pos Neg
. . . Neg
Pos Neg Neg
Neg . . . . 9.
NOTE: L.E. = lupus erythematosus; ESR = erythrocyte sedimentation rate. ':' Platelets appeared adequate on peripheral blood smear.
These drugs included penicillin (three patients), acetylsalicylic acid (three), Anacin | tablets (one), tetracycline (one), sulfonamides (two), unknown drugs (two) and chlordiazepoxide hydrochloride and meprobamate (one). Additional medications included antibiotic throat lozenges, chlora~ hydrate, Luden'S cough drops and laxatives9 In six of these patients drug ingestion was prompted by the presence of acute respiratory symptoms 9 Seven patients gave a history of cutaneous or gastrointestinal allergy. Beta-hemolytic streptococci were isolated from one of seven patients whose throats were cultured 9 The antistreptolysin 0 titer was increased in four patients and normal in three. The severity of renal disease did not seem to be related to the presence or absence of evidence for streptococcal infection. Serum complement levels were normal in the two patients on whom this test was performed 9 Serum from five patients was tested for cryoglobulins with negative results. Repeated lupus erythematosus tests were negative in seven patients 9 All patients had diminished peripheral hematocrit values during their course, Platelet counts were invariably normal at the onset of clinical manifestations, however in two patients (B.C. and R,C.) significant thrombocytopenia developed late in the course. Coagulation studies performed on the blood of one (H.C.) did not support defibrination as causative 9 Blood cultures were negative in the five patients in whom they were obtained. Six patients had clinical evidence of cardiac involvement. Three of these had persistent tachycardia and T wave inversions on their electrocardiograms, and the venous pressure
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in one was 160 mm of saline solution 9 Conduction disturbances and transient arrhythmias were noted in a fourth patient, and diastolic gallop, elevated venous pressure and repolarization abnormalities in a fifth. The sixth patient presented with cardiomegaiy, gallop rhythm, T wave inversions and hilar flare. No patient gave a history of antecedent renal disease; however, in only three were normal urinalyses and blood urea levels recorded prior to onset of the present illness9 Microscopic hematuria was present in all patients and red cell Casts were found in the urinary sediment of three9 In ten patients the sediment contained innumerable red blood cells, in four there were 10 to 100 erythrocytes/high power field 9 Although gross hematuria has been described as a prominent feature in the glomerulonephritis associated with the Henoch-Schoenlein syndrome, this feature was not observed in our patients 9 Proteinuria also was noted in all patients 9 Eight patients had 4 + , two had 2 + , and four had 1 + proteinuria. Twenty-four hour urinary protein output was measured in five patients and found to range between 3.5 and 9 gin. Urine protein electrophoresis in one patient (H.C.) revealed large amounts of albumin with considerable tailing into the globulin fraction 9 Serum albumin levels were below 3.5 gm per cent in eight of nine patients in whom serum proteins were determined 9 The one patient whose albumin level was norma had a single determination performed at the time of hospital entry 9 In the eight subjects with hypoalbuminemia this manifestation appeared ten or more days following hospitalization. In seven patients the nephrotic syndrome developed; three of
The American Journal of Medicine
RENAL MANIFESTATIONS OF HENOCH-SCHOENLEIN SYNDROME -- BALLARD ET AL.
TABLE III
Renal Manifestations in Fourteen Adults with the Henoch-Schoenlein Syndrome
Patient
Urine Protein
G.C.
2+
Hematuria RBC/HPF Innumerable
Casts Finely gran-
Doubly Refractile Lipid Bodies . .
Maximal Blood Maximal Urea CreatiNitrogen nine (mg %) (rag%)
Duration of Disease at Time of Nephrotic Tissue Syndrome Examination
Renal PathologicChanges
15.5
ular
4+
R.N.
9.3 gm! 24 hr
Innumerable
R.C.
1+
Innumerable
69
N.S9
44-
Innumerable
92
M.S.
4 gm/ 24 hr
50-100
26
H.C.
6.9 gm! 24 hr
Innumerable
Red cell
4-
178
S.H.
4.7 gm/ 24 hr 1+ 1+ i+ 2+ 3.47 gm/ 24 hr 4+
Innumerable
Red cell, granular Granular
+
18
R9 W.E. l.S. J.D. L.F. A.B.
Innumerable
98
J.W.
Innumerable 50-55 ].2-20 Innumerable 10-15
. . . . . Red cell, fatty, granular
4-
+
11.5
+
5.1
+
+
Diffuse irregular cell proliferation(100%) of glomeruli; scatteredsmall epithelial crescents present 10 wk (post- Most glomeroli abnormal(95%) with diffuse mortem) highly irregularcell proliferation;scattered small epithelial and fibroepithelialcrescents present 8% wk Most glomeruliabnormal(95%) with diffuse (postirregular cell proliferation;scattered epithelial mortem) and fibroepithelialcrescents present 31/2wk Most glomeruli normal (95%); minimal cell (biopsy) proliferation in mesangialareas in a few 4 wk Normal renal tissue (biopsy); Focal hyalinizedglomeruli;focal 28 wk thickening of Bowman'scapsule (biopsy) All glomeruli abnormalwith diffuse, highly 3 wk irregular cell swelling, proliferationand (biopsy) neutrophil infiltration predominantlyin mesangialregionsand focal obliterationof peripheral capillary loops by intracapillary cell proliferation;small epithelial crescents often containingfibrin and periglomerular neutrophil infiltration present 8 wk (post9 Irregular proliferative lesions in most glomeruli mortem) (95%) and in some progressionto irregular sclerosis of capillary loops; crescents in various stagesof organizationwith fibrous masses and red cells still present in some glomeruli About 50% of glomeruli normal; others with 6 wk segmental proliferativelesions (biopsy) 2 wk (postmortem)
26 26
Innumerable
these died. o n e of the surviving patients (S.H.) still has 1 + proteinuria, blood urea nitrogen 20 m g per cent a n d s e r u m creatinine 2 m g per cent eleven m o n t h s after discharge but is otherwise well; all other a b n o r m a l laboratory and clinical f i n d i n g s have returned to normal. In one of the t w o patients with h y p o a l b u m i n e m i a but w i t h o u t heavy proteinUria, signs and s y m p t o m s of gastrointestinal i n v o l v e m e n t were p r o m i n e n t . In the other, stool guaiac tests were 4 + although a b d o m i n a l s y m p t o m s were denied. G a s t r o i n t e s t i n a l protein losses were not q u a n t i f i e d .
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9. .
1.8 2 1.9
A z o t e m i a was d o c u m e n t e d in eight patients, with m a x i m a l elevations of blood urea nitrogen r a n g i n g between 26 and 178 mg per cent. Four of the five patients with blood urea nitrogen levels greater t h a n 60 or c r e a t i n i n e over 5 m g per cent died. The fifth patient, with a m a x i m a l blood urea level of 92 m g per cent, recovered c o m p l e t e l y . Pathologic f i n d i n g s in seven cases are presented in Table III and in Figures 1 t h r o u g h 6. In the f o u r patients who died pathologic changes, a l t h o u g h not specific, had c o m m o n features. All showed diffuse (90 to 100 per cent) but highly
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RENALMANIFESTATIONSOF HENOCHSCHOENLEINSYNDROME-- BALLARDETAL.
irregular glomerular abnormalities with varying stages and degrees of involvement. In addition, there was widespread, focally dense, interstitial infiltration by neutrophils, eosinophils, lymphocytes and plasma cells, in some instances associated with tubular necrosis a n d / o r interstitial hemorrhage. Many distal convoluted and collecting tubules contained erythrocytes. The glomerular lesions consisted of varying degrees and combinations of the following:
Fig. 1. Renal biopsy specimen (H.C.). Glomerulus with minimal pathologic changes of diffuse mesangial hypercellularity and neutrophil infiltration (arrows). Hematoxylin and eosin stain, original magnification x 250.
Fig. 3. Autopsy specimen (H.C.). Tissue specimen obtained five weeks after biopsy showing progression of lesions. In many glomeruli there were fibrotic crescents, often concentric, producing obliteration of glomerular tufts (large arrow). An adjacent glomerulus displays minimal mesangial hypercellularity and a fibrin mass in Bowman's space. Note erythrocytes in many tubules (small arrow). Hematoxylin and eosin stain, original magnification x 100.
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(1) Intracapillary cell proliferation. This most often involved one or several Iobules while sparing other portions. Rarely, generalized proliferation of all tufts was seen. There was associated increased basement membrane-like material between proliferating cells, and adhesions between proliferating cells and Bowman's capsule. (2) Capillary thrombi. Eosinophilic masses were occasionally seen in capillary lumens.
Fig. 2. Renal biopsy specimen (H.C.)I Two glomeruli with most severe lesions showing irregular mesangial and endothelial hypercellularityi increased neutrophil infiltration, epithelial crescent adherent to hypemeUular capillary tufts (straight arrow) and fibrin masses incorporated in crescents (curved arrow) . Notice intense neutrophil infiltration in crescent and pericapsular tissue. Hematoxylin and eosin stain, original magnification x 100.
Fig. 4. Renal biopsy specimen (S.H.). Glomerulus with focal intracapillary cell proliferation (arrow). Azancarmine stain, original magnification x 250.
The American Journal of Medicine
RENALMANIFESTATIONSOFHENOCH-SCHOENLEINSYNDROME-- BALLAROETAL.
(3) Crescents. Present in all sizes, mostly small, and in various stages of evolution in each case, these involved 10 to 75 per cent of glomeruli. Early, these were comprised of eccentric, swollen epithelial cells surrounding masses of eosinophilic, fibrinoid material and erythrocytes in Bowman's space, sometimes extending between capillary tufts. Later and more severe lesions consisted of concentric fibroepithelial and fibrous crescents which at times compressed and enclosed all or parts of collapsed tufts. Progression of epithelial to fibrotic crescents was well seen in one patient (H.C.) in whom initial biopsy was followed by postmortem examination five weeks later. (4) Glomerular sclerosis. In some, scattered segmental scars of tufts were seen, presumably representing residua of proliferative lesions. In general, only occasional totally sclerotic glomeruli were present (perhaps unrelated to the present process). (5) Neutrophil infiltration. This was irregular and generally mild but in one case (H.C.) on initial biopsy, neutrophil infiltration of glomeruli was pronounced especially in mesangial areas even in glomeruli in which little proliferation was evident. In two nonfatal cases examined by renal biopsy only (S.H. and N.S.), segmental intracapillary proliferation (Fig. 4) was found in 5 of 11 glomeruli and 2 of 20 glomeruli, respectively; the remaining glomeruli appeared normal. In the third nonfatal case (MS.) light microscopy revealed no significant pathologic changes but in a subsequent biopsy specimen focal glomerular scars were found. Immunofluorescence microscopy in one case (S.H.) showed diffuse irregular staining for gamma globulin along glomerular basement membranes, brighter in some Iobules, corresponding to proliferative areas and bright finely granular staining in mesangial areas in all 4 glomeruli present (Fig. 5). Electron-microscopic sections revealed deposits of fibrin in the urinary space (Fig. 6). No acute or healed renal arteritic lesions were found.
therefore, be secondary to steroid therapy and cannot definitely be attributed to the disease process itself. Diastolic hypertension was recorded in three patients, but in two hypertension had been present prior to onset of the Henoch-Schoenlein syndrome. In the third, hypertension followed institution of steroid therapy. All patients except one either recovered or died within five months of onset of illness; one has persistent abnormalities one year after onset (1 + proteinuria, blood urea nitrogen 20 mg per cent, creatinine 2 mg per cent). Approximately one-fourth (28.5 per cent) of the patients in our series died during the acute phase of their illness, as contrasted with about 0 to 10 per cent in childhood Henoch-Schoenlein syndrome [11]. In the four cases terminating fatally, death occurred in the setting of uremia. It seems possible that in one patient (S.H.) chronic disease will probably ensue inasmuch as renal abnormalities persist after one year. However, complete recovery has been observed after urinary abnormalities had persisted for two years [9]. Instances of chronic renal disease have been reported by others [1,9], but a chronic course appears to be unusual in the adult Henoch-Schoenlein syndrome. Azotemia appeared to be an uncertain prognostic indicator inasmuch as one patient (N.S.) with a maximal blood urea nitrogen level of 98 mg per cent (on prednisone at the time) recovered completely. Similarly, the nephrotic syndrome need not be considered ominous since four such patients (N.S., M.S., S.H. and L.F.) also recovered. In this regard it is of interest that the nephrotic syndrome may be seen either with focal (N.S., M.S. and S.H.) or with diffuse glomerular involvement (J.W., R.N., H.C. and R.C.). Indeed the nephrotic syndrome has been observed with normal glomerular histology [9]. In childhood cases studied by renal biopsy, the characteristic feature in the recovery group has been focal involvement of 20 to 60 per cent of glomeruli by prolifer-
COMMENTS
In contrast to patients with poststreptococcal glomerulonephritis, hypertension and circulatory congestion were not prominent clinical features in these fourteen patients with renal manifestations of the Henoch-Schoenlein syndrome. Three subjects had elevated venous pressure; the circulation time was prolonged in two of these and at the upper limits of normal in the third. Thus, congestive heart failure rather than circulatory overload may have been present. In two patients other causes for congestive failure were documented prior to hospitalization (cardiomegaly and old cardiac infarction in one, and cor pulmonale with chronic atrial fibrillation in the other). In one patient in whom circulatory decompensation developed, normal cardiac function had been documented prior to hospitalization. At the time of appearance of circulatory congestion he had been receiving prednisone. Sodium and fluid retention in this subject might,
Volume 49, September 1970
Fig. 5. Renal biopsy specimen (S.H.). lmmunofluorescence staining showing diffuse staining for IgG of glomerular capillary loops, most prominent in mesangial areas, original magnification x ].00.
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RENAL MANIFESTATIONS OF HENOCH-SCHOENLEIN SYNDROME -- BALLARD ET AL.
Fig. 6. Renal biopsy specimen (H.C.). Electron micrograph demonstrating deposits of fibrin in Bowman's space. Magnification x 5,900. (Courtesy of Dr. J. Vasquez, Department of Pathology, New York Veterans Administration Hospital.)
ation of intracapillary cells in a segment or Iobule within the glomerulus [6]. The rapidly progressive form with death in renal failure in weeks to months has been described as diffuse but irregular [11]. It has not been observed that focal lesions can progress to diffuse glomerulonephritis. These data are consistent with the present observations in adults. Only one adult has been described in whom immunofluorescent study was performed [7]. No staining for gamma globulin was found. In children, however, as in the present adult case, deposits of IgG and /~c have been seen in mesangial areas, with lesser staining in the basement membrane [12]. Although the number of adult cases with pathologic correlation is small it appears that the type of renal lesion is a good index of prognosis since three patients in whom the proliferation was focal recovered (although one still has proteinuria after twelve months) whereas the remaining four
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with diffuse irregular proliferation and crescent formation died. This is in general agreement with previously reported cases in adults [3-9,11]. Among nonfatal cases in which the patients were examined by renal biopsy, seven have shown focal glomerulonephritis [4,9,11], three no glomerular abnormalities [9,11] and two diffuse irregular proliferation of all [7] or possibly all [8] glomeruli. In the latter two crescents were not described. At autopsy in three fatal cases crescent formation and diffuse irregular proliferation of glomerular cells were evident [3,5]. These data support the correlation observed in this series between the diffuse glomerular lesion with crescents and a fatal outcome. ADDENDUM
Since submission of this manuscript a forty year old man with the Henoch-Schoenlein syndrome and focal glomerular lesions has been reported to have recovered from his renal disease [13].
The American Journal of Medicine
RENALMANIFESTATIONSOF HENOCH-SCHOENLEINSYNOROME-- BALLAROET AL,
REFERENCES 1. Osier W: On the visceral manifestations of the erythema group of skin diseases. Amer J Med Sci, 127: 1, 1904. 2. Gairdner D: The Schoenlein-Henoch syndrome (anaphylactoid purpura). Quart J Med 17: 95, 1948. 3. Levitt LM, Burbank B: Glomerulonephritis as a complication of the Schoenlein-Henoch syndrome. New Eng J Med 248: 530, 1953. 4. Heptinstall RH, Joekes AM: Renal biopsy. Proc Roy Soc Med 52: 211, 1959. 5. Norkin S, Wiener J: Henoch-Schoenlein syndrome. Review of pathology and report of two cases. Amer J Clin Path 33: 55, 1960. 6. Vernier RL, Worthen HG, Peterson RD, Colle E, Good RA: Anaphylactoid purpura. I. Pathology of the skin and kidney and frequency of streptococcal infection. Pediatrics 27: 181, 1961. 7. Panner B: Nephritis of Schoenlein-Henoch syndrome. Electron microscopy study of the glomerular lesion in and adult. Arch Path 74: 230, 1962.
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8. Falls WF, Ford KL, Ashworth CT, Carter NW: Renal vasculitis in a non-fatal case of Henoch-Schoenlein purpura. Ann Intern Med 64: 1276, 1966. 9. Slama R, Habib R: La nephropathie du purpura rheumatoide. Act. Nephrol. de I' Hop. Necker, p. 184. Paris, Flammarion, ]962. 10. McCluskey RT, Vassalli P, Gallo G, Baldwin DS: An immunofluorescent study of pathogenic mechanisms in glomerular diseases. New Eng J Med 274: 695, 1966. 11. Heptinstall RH: Schoentein-Henoch syndrome (anaphylactoid purpura), Pathology of the Kidney, Boston, Little, Brown, 1966, p 335. 12. Urizar RE, Michael A, Sisson S, Vernier RL: Anaphylactoid purpura. I1. Immunofluorescent and electron microscopic studies of the glomerular lesions. Lab Invest 19: 437, 1968. 13. Gary NE, Mazzara JJ, Hoefelder L: The Sch6nlein-Henoch syndrome: report of two patients with recurrent impairment of renal function. Ann Intern Med 72: 229, 1970.
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