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Recurrent macroscopic hematuria, focal nephritis, and mesangial deposition of immunoglobulin and complement
May, 1973 T h e Journal of P E D I A T R I C S
767
Recurrent macroscopic hematuria, focal nephritis, and mesangial deposition of immunoglobulin and complement Sixteen patients who had recurrent macroscopic hematuria were studied. Most episodes occurred within one to two days o[ a "flu-like" illness. There was no identifiable systemic or local disease. Nine have proteinuria, and three have developed hypertension. All had local and segmental, proli[erative glomerulonephrilis, and six had segmental glomerular sclerosis. Fourteen had positive gIomerular immunofluorescence with predominantly a mesangial distribution. These features make this syndrome a unique, clearly identifiable entity. Proteinuria, segmental glomerular sclerosis, and positive mesangial immunofluorescence occurred together in only five patients. Four of these patients have had functional renal impairment. We speculate that a patient with recurrent macroscopic hematuria, who is [ound to have this combination of [eatures, has a more serious process than otherwise.
L. Paul Roy, M.B., M.R.A.C.P., * Alfred J. Fish, M.D., ** Robert L. Vernier, M.D., and Alfred F. Michael, M.D., *'s* Minneapolis, Minn.
RECURaENT episodes of macroscopic hematuria in children and young adults, unassociated with hypertension, edema, or urinary tract abnormalities and often occurring one to two days after the onset of "flu-like"
From the Department of Pediatrics, University o[ Minnesota. Aided by grants #ore the National Institutes o[ Health (AM 12375, A M 13756, HE 06314) and the American Heart Association. ~Postdoctoral Research Fellow supported by the Postgladuate Medical Foundation o] the University oJ Sydney and the National Kidney Foundation, Nets York. ~ Investigator o[ the American Heart Association. ~ address: Department of Pediatrics, University of Minnesota Hospitals, Minneapolis. Minn. 55455.
illness or c o m m o n cold, are the features of a well-known clinical syndrome. There is no evidence of any known systemic disease. Boys are affected twice as frequently as girls. Proteinuria is present in one half of t h e patients, in amounts usually less than 1.0 Gm. per 24 hours. Most patients pursue a benign course over many years, although occasional patients with evidence of renal insufficiency have been recorded? -~ In 1914, Volhard and Fahr ~ postulated that in this syndrome not all the glomeruli were abnormal, and they used the term "focal nephritis" to describe the pathology found in these patients. This theory was verified by Ross ~ in 1960, in his study of renal tissue Vd. 82, No. 5, pp. 767-772
7 68
Roy et al.
The Journal of Pediatrics May 1973
Table I. Recurrent hematuria: Clinical, histologic, and immunofluorescent findings
Case No.
Period o[ /olIow-up (yr.)
Numberepisodesof~ Creatinine Proteinuria Segmental Immunofluo rescenee : macroscopic clearance ~ glomeruIar Predominant hematuria (ml./min./1.73 M.e) i(mg./24 hr.) sclerosis pattern
1 2 3 4 5 6 7 8 9 I0 11 12 13 14 15
4 9 3 7 1 16 ~ 8 3 9 4 3 5 6 6
4 Many 4 9 3 3 6 5 Many 5 6 3 7 Many 25-30
102 197 154 176 132 118 121 71 96 170 ll-103t 90 75-110t 67 110
0-360 0-800 0 0 0 0 0 1,730-4,680 0 0 0-2,300 0-4,000 370-2,840 0-150 230-1,000
-+ + + + + + -
16
6
2
148
0
-
M Diffuse M + GBM M + GBM M M Negative M M M M M M M M Negative
M ~ mesangial pattern, GBM = glomerular basement membrane. ~Creatinine clearance at follow-up. f l o w values represent transient depression dm'ing episodes of macroscopic hematuria.
obtained by percutaneous biopsy of five such patients. Others :~ have shown that the lesion may be segmental. Immunofluorescent studies of renal biopsy specimens were carried out by Bodian and associates a using fluorescein-labeled antisera to h u m a n g a m m a globulin. Six of 14 biopsies tested were positive, and the authors observed that the pattern was diffuse rather than focal. Berger G observed mesangial deposition of IgG, IgA, and /?~c in 55 patients who had no systemic disease or history typical of acute glomerulonephritis; 22 of these patients had recurrent hematuria. The present clinical, histologic, and immunofluorescent studies further delineate this syndrome, demonstrate its variable expression, and suggest that in a small group the process is more serious and the prognosis more guarded. This study demonstrates that those patients who subsequently develop renal insufficiency may be recognized by the presence of pr0teinuria , focal glomerulosclerosis, and mesangial immunoglobulin deposits. PATIENTS
AND
METHODS
Sixteen children (13 boys and 3 girls), with the clinical syndrome as defined pre-
viously, have been followed for periods ranging from 1 to 16 years (Table I ) . They were selected only on the basis that all had had histopathologie and immunofluorescent study of renal biopsy specimens. There was no family history of significant renal disease. Evidence for ~-hemolytic streptococcal infection was sought at the time of the initial episode by throat, and other appropriate cultures and by serology, and was negative in all patients. O n the basis of elevated antistreptolysin-O, and anti-DNAse, or antiDPNase titers, five patients had evidence of streptococcal infection at some stage during the period of observation unrelated to episodes of macroscopic hematuria. This incidence of streptococcal infection closely approximates the average experience in this area. r Either serum complement (CH50) or serum fitc-/?lA levels were obtained at the time of the initial episode in five patients at the time of recurrence in the remainder, and repeatedly in most. All complement measurements have been normal except in one patient (Case 11) whose level of serum complement is normal in freshly drawn serum but falls at 4 ~ C. due to activation of properdin and late-reacting complement compo-
Volume 82 Number 5
Recurrent macroscopic hematuria
769
Fig. 1. Photomicrograph showing segmental areas of glomerular hypercellularity (arrows). (Hematoxylin and eosin, x378.)
Fig. 2. Half the glomerulus shown in this photomicrograph is sclerosed; the other half is relatively normal. (Periodic acid-Schiff, x564.)
nents (C3t).~ This phenomenon has not been observed in other patients. Percutaneous kidney biopsy specimens, usually obtained between episodes of macroscopic hematuria, were prepared for light and immunofluorescent microscopy as previously describedY, 10 Fluorescein-labeled antisera to human IgG, IgA, IgM, ~1o, properdin, and fibrin were used, although not all antisera were available for study for the earlier biopsy specimens.
teinuria was seen between episodes in the six patients who had proteinuria intermittently. Three patients (Cases 6, 8, and 15) now ages 21, 24, and 25 years, respectively, have hypertension, two with diastolic pressures of 80 to 90 ram. Hg and one with diastolic pressure of 95 to 100 mm. Hg. Microscopic hematuria was found consistently in ten and intermittently in the remainder between episodes of macroscopic hematuria. By light microscopy, all biopsy specimens were found to have focal and segmental, proliferative glomerular changes, primarily involving mesangial cells (Fig. 1). Segmental areas of glomerular sclerosis (Fig. 2) were seen in tissue from six patients, four of whom also had proteinuria and renal functional alterations (Cases 8, 11, 13, and 14). Immunofluorescent studies of tissue obtained by kidney biopsy were positive for one or mote irnmunoglobulins in 14 of the 16 patients (Table II). The distribution was solely or predominantly mesangial in 11 of the 14 (Fig. 3); in two biopsies there was granular and linear staining along the glomerular basement membrane in addition to mesangial fluorescence (Fig. 4) ; in the remaining one the fluorescence was diffuse, but the locus of deposition could not be de-
RESULTS
The significant findings are summarized in Table I. Two patients (Cases 8 and 14) now have reduced creatinine clearances; initially they had been normal. Two other patients (Cases 11 and 13) have had transient reductions in creatinine clearance, with associated rise of s e r u m creatinine and blood urea nitrogen, during episodes of macroscopic hematuria. The remaining patients have had normal creatinine clearances at all times including the present. All four patients with reductions in clearance have proteinuria intermittently or persistently, as do five other patients. Only three of these nine have persistent proteinuria. The highest levels of proteinuria occurred in relation to episodes of macroscopic hematuria. Some degree of pro-
770
R o y et al.
The Journal o/ Pediatrics May 1973
Fig. 3. Glomerulus stained with fluorescein-Iabeled antiserum to human IgA. Deposits are distributed throughout the mesangium. (•
Fig. 4. Immunofluorescent study of this glomerulus shows human IgG deposited in a granular distribution in the mesangium and along the glomerular basement membrane. (•
Table II. Recurrent hematuria: Glomerular immunofluorescence
parent reluctance to stress its variable clinical course. A benign prognosis has been suggested, 2 although data on prolonged followup are scanty. Only 9 of 211 patients found in a review of the literature had been followed for 10 or more years? -4, n-is One of the patients in the t965 study of Ayoub and Vernier 2 developed renal insufficiency one year ago, 17 years after the onset, and recently had successful renal transplantation. Approximately half the patients d o c u mented in the literature have proteinuria, usually less than 1.0 Gm. per 24 hours but occasionally as high as 3.0 G m ? Nine of our 16 patients had proteinuria; only four had more than 1.0 Gm. per 24 hours. Proteinuria was found to correlate, to a degree, with development of renal insufficiency, but this was not an absolute correlation. One patient with proteinuria (Case 2), followed for nine years, still has a normal creatinine clearance and is normotensive. Focal and segmental glomerular hypercellularity, as observed in this series, are the histopathologic changes usually associated with recurrent macroscopic hematuria. Some glomeruli appear to be normal. Segmental hypercellularity is a qualitative finding; the percentage of patients in individual series
Fluorescein-labeled antiserum to
IgG IgA IgM fl~c-globulin Properdin Fibrin
No. tested
No. posit(re
i6 6 9 l6 8 13
10 5 3 14 4 10
termined. In all "positive biopsies" Pie was demonstrated; five of six tested for IgA were positive, the remaining one being negative for all items tested except /71c and fibrin (Case 11). Staining for IgG was positive in 10 of 16, for properdin in 4 of 8, for fibrin in 10 of 13, and for IgM in 3 of 9. DISCUSSION Patients were selected for this study on the basis of tile presence of the described, easily recognized, clinical syndrome (recurrent macroscopic hematuria) and the availability of adequate histologic and immunofluorescent studies of renal biopsy specimens. Although recognized clinically for many years, full characterization of recurrent macroscopic hematuria has been hampered by an ap-
Volume 82 Number 5
with normal biopsy findings has varied somewhat. Small epithelial crescents, ~ local adhesions of glomerular tufts to Bowman's capsule, a and segmental glomerular sclerosis1~ have occasionally been described in these patients. Bodian and associates 3 studied 14 of their patients with fluorescein-labeled antisera to human gamma globulin; they remarked on the generalized distribution in the six which were positive in contrast to the focal glomerular abnormalities observed by light microscopy. Almost half the patients described by Berger, ~ who had mesangial deposition of IgG, IgA, and /?m in the absence of known systemic disease, apparently had recurrent macroscopic hematuria. The deposition of relatively large amounts of IgA in the mesangium, in combination with IgG and fi~e; has suggested to some that this syndrome is a unique form of glomerulonephritis in which IgA plays a major role. There is no direct evidence to support this hypothesis. Granular deposits of IgA are often found in other diseases such as lupus erythematosus and anaphylactoid purpura, ~, ~'~entities which may be associated with a focal and segmental glomerulitis. Our patients were found to have positive mesangial fluorescence so regularly that, when present, this finding renders argument concerning the presence or absence of minimal degrees of glomerular hypercellularity somewhat superfluous. The fluorescence of all mesangial areas in all glomeruti in biopsy specimens of the present series is somewhat surprising in view of the extremely variable and focal histologic changes. The presence of immunoglobulins along the glomerular basement membrane as well as in the mesangium in two patients is of interest, since similar capillary loop orientation of presumed immune complexes is also occasionally seen in patients with the nephritis of anaphylactoid purpura29 This finding increases the similarities between the renal lesions of this syndrome and that of anaphylactoid purpura nephritis2 ~ These two patients have had a benign course to date. Two patients with no immunofluoreseene have had a benign course thus far and have no proteinuria. It may be
Recurrent macroscopic hematuria
771
that those two patients represent the most benign variety of this syndrome with insufficient mesangial deposits to be detected by fluorescent microscopy. The immunofluorescent findings are not influenced by timing of the biopsy, since tissue was usually obtained between episodes of gross hematuria. Six patients had segmental glomerular sclerosis; five of these had proteinuria, and four of the five had renal functional impairment, suggesting that the combination of segmental glomerular sclerosis, proteinuria and positive immunofluorescence identifies patients with a more serious process. Fluorescent microscopy of renal tissue from three of these six patients stained for IgA was positive in two and negative in one. One of the patients with positive staining has had a benign course; the other patient with positive staining and the patient with negative staining have renal functional impairment. Tile exact mechanism(s) causing this syndrome are unknown. Immunoglobulins and complement are observed in glomeruli in diseases thought to be due to either immune complex deposition or anti-glomerular basement membrane antibo=ly but in those situations the deposits are usually oriented along the glomerular basement membrane. In recurrent macroscopic hematuria, however, deposits of IgG, IgA, and fi~c are found mainly in the mesangium in a distribution similar to that seen in the nephritis of anaphylactoid purpura. There is experimental evidence that maeromolecules, such as heat-aggregated serum proteins, are taken up by the mesangium, suggesting that this cell system is important in removing these materials from the circulationP ~ Thus it is possible that immunoglobulins and complement components m the mesangiurn in recurrent macroscopic hematuria may be associated with an antigen in the form of an immune complex, ahhough it remains possible that these immune reactants have been deposited as a nonspecific consequence to injury mediated by some other mechanism. The brief interval between the onset of the preceding "flu-like" illness and macroscopic hematuria, however, is unlike experimental immune
7 7 2 Roy et al.
complex disease in which there is a latent period of some days between injection of a foreign antigen and development of disease. Association of recurrent macroscopic hematuria with respiratory infections and IgA deposition may suggest a causal relationship with mucosal infections. The finding of properdin in the mesangium of one half of the patients studied is of special interest. Properdin is regularly found in glomeruIi in kidney biopsies from patients with membranoproliferative glomerulonephritis poststreptococcal glomerulonephritis and occasionally lupus nephritis. '~ T h e presence of properdin in those diseases and in some patients with recurrent macroscopic hematuria suggests that complement activation may be oecuring via the alternate complement activation pathway, s~ In the syndrome of recurrent macroscopic hematuria a variety of etiologic agents may be acting through a common pathogenetic mechanism. Identifying the mechanism may be more important than identifying the etiologic agents. REFERENCES
1. Ross, J. H.: Recurrent focal nephritis, Q. J. Med. 29: 391, 1960. 2. Ayoub, E. M., and Vernier, R. L.: Benign recurrent hematuria, Am. J. Dis. Child. 109: 217, 1965. 3. Bodian, M., Black, J. A., Kobayashi, N., Lake, B. D., and Shouler, S. E.: Recurrent haematuria in childhood, Q. J. Med. 34: 359, 1965. 4. Arneil, G. C., Lain, C. N., McDonald, A. M., and McDonald, M.: Recurrent haematuria in 17 children, Br. Med. J. 2: 233, 1969. 5. Volhard, F., and Fahr, I.: Die Brightsche Nierenkrankheit, Berlin, 1914, Springer-Vetlag. 6. Berger, J.: IgA glmnerular deposits in renal disease, Transplant. Proc. 1: 939, 1969. 7. Ayoub, E. M., and Hoyer, J.: Anaphylactoid purpura: Streptococcal antibody titers and fl~c-globulin leve/s, J. PEDIATR.75" I93, 1969.
The Journal o[ Pediatrics Ma), 1973
8. McLean, R., Geiger, H., and Day, N. K.: Activation of the C System at 4 ~ C. by the "alternate pathway" in a patient with focal glomerulonephritis, Fed. Proc. 31: 646, 1972. 9. Westberg, N. G., Naff, G. B., Boyer, J. T., and Michael, A.: Glomerular deposition of properdin in acute and chronic glomerulonephritis with hypoeomplementemia, J. Clin. Invest. 50: 642, 1971. 10. Michael, A. F., Drummond, K. N., Good, R. A., and Vernier, R. L.: Acute poststreptocoecal glomerulonephritis: Immune deposit disease, J. Clin. Invest. 45: 237, 1966. I1. Wyllie, G. G.: Haematuria in children, Proc. R. Soc. Med. 48: 1113, 1955. 12. Ferris, T. F., Gorden, P., Kashgarian, M., and Epstein, F. H.: Recurrent hematuria and focal nephritis, N. Engl. Ji Med. 276: 770, 1967. 13. Glasgow, E. F., Moncrief, M. W., and White, R. H. R.: Symptomless haematuria in childhood, Br. Med. J. 2: 687, 1970. 14. Rapoport, A., Davidson, D. A., Deveber, G. A., Ranking, E. N., and McLean, C. R.: Idiopathic focal proliferative nephritis associated with persistent hematuria and normaI renal function, Ann. Intern. Med. 73: 921, 1970. 15. Singer, D. B., Hill, L. L., Rosenberg, H. S., Marshall, J., and Swenson, R.: Recurrent hematuria in. childhood~ N. Engl. J. Med. 279: 7, 1968. I6. Baehr, G.: A benign and curable form of acute hemorrhagic nephritis, J. A. M. A. 86: 1001, 1926. 17. Gervais, M., and Drummond, K. N.: L'h~maturie recidivante chez l'enfant, Union Med. Can. 99: 1234, 1970. i8. Lannigan~ R., and Insley, J.: Light and electron microscope appearances in renal biopsy material from cases of recurrent hematuria in children, J. Clin. PathoI. 18: 178, 1965. 19. Urizar, R. E., Michael, A., Sisson, S., and Vernier, R. L.: Anaphylactoid purpura, II. Immunoftuorescent and electron microscopic studies of the glomerular lesions, Lab. Invest. 19" 437, i968. 20. Michael, A. F., Fish, A. J., and Good, R. A.: Glomerular localization and transport of aggregated proteins in mice, Lab. Invest. 17: 14, 1967. 21. Gotze, O., and Muller-Eberhard, H. J.: The C3-aetivator system: An alternate pathway of complement activation, J. Exp. Med. 134: 90S, 1971.
767
Recurrent macroscopic hematuria, focal nephritis, and mesangial deposition of immunoglobulin and complement Sixteen patients who had recurrent macroscopic hematuria were studied. Most episodes occurred within one to two days o[ a "flu-like" illness. There was no identifiable systemic or local disease. Nine have proteinuria, and three have developed hypertension. All had local and segmental, proli[erative glomerulonephrilis, and six had segmental glomerular sclerosis. Fourteen had positive gIomerular immunofluorescence with predominantly a mesangial distribution. These features make this syndrome a unique, clearly identifiable entity. Proteinuria, segmental glomerular sclerosis, and positive mesangial immunofluorescence occurred together in only five patients. Four of these patients have had functional renal impairment. We speculate that a patient with recurrent macroscopic hematuria, who is [ound to have this combination of [eatures, has a more serious process than otherwise.
L. Paul Roy, M.B., M.R.A.C.P., * Alfred J. Fish, M.D., ** Robert L. Vernier, M.D., and Alfred F. Michael, M.D., *'s* Minneapolis, Minn.
RECURaENT episodes of macroscopic hematuria in children and young adults, unassociated with hypertension, edema, or urinary tract abnormalities and often occurring one to two days after the onset of "flu-like"
From the Department of Pediatrics, University o[ Minnesota. Aided by grants #ore the National Institutes o[ Health (AM 12375, A M 13756, HE 06314) and the American Heart Association. ~Postdoctoral Research Fellow supported by the Postgladuate Medical Foundation o] the University oJ Sydney and the National Kidney Foundation, Nets York. ~ Investigator o[ the American Heart Association. ~ address: Department of Pediatrics, University of Minnesota Hospitals, Minneapolis. Minn. 55455.
illness or c o m m o n cold, are the features of a well-known clinical syndrome. There is no evidence of any known systemic disease. Boys are affected twice as frequently as girls. Proteinuria is present in one half of t h e patients, in amounts usually less than 1.0 Gm. per 24 hours. Most patients pursue a benign course over many years, although occasional patients with evidence of renal insufficiency have been recorded? -~ In 1914, Volhard and Fahr ~ postulated that in this syndrome not all the glomeruli were abnormal, and they used the term "focal nephritis" to describe the pathology found in these patients. This theory was verified by Ross ~ in 1960, in his study of renal tissue Vd. 82, No. 5, pp. 767-772
7 68
Roy et al.
The Journal of Pediatrics May 1973
Table I. Recurrent hematuria: Clinical, histologic, and immunofluorescent findings
Case No.
Period o[ /olIow-up (yr.)
Numberepisodesof~ Creatinine Proteinuria Segmental Immunofluo rescenee : macroscopic clearance ~ glomeruIar Predominant hematuria (ml./min./1.73 M.e) i(mg./24 hr.) sclerosis pattern
1 2 3 4 5 6 7 8 9 I0 11 12 13 14 15
4 9 3 7 1 16 ~ 8 3 9 4 3 5 6 6
4 Many 4 9 3 3 6 5 Many 5 6 3 7 Many 25-30
102 197 154 176 132 118 121 71 96 170 ll-103t 90 75-110t 67 110
0-360 0-800 0 0 0 0 0 1,730-4,680 0 0 0-2,300 0-4,000 370-2,840 0-150 230-1,000
-+ + + + + + -
16
6
2
148
0
-
M Diffuse M + GBM M + GBM M M Negative M M M M M M M M Negative
M ~ mesangial pattern, GBM = glomerular basement membrane. ~Creatinine clearance at follow-up. f l o w values represent transient depression dm'ing episodes of macroscopic hematuria.
obtained by percutaneous biopsy of five such patients. Others :~ have shown that the lesion may be segmental. Immunofluorescent studies of renal biopsy specimens were carried out by Bodian and associates a using fluorescein-labeled antisera to h u m a n g a m m a globulin. Six of 14 biopsies tested were positive, and the authors observed that the pattern was diffuse rather than focal. Berger G observed mesangial deposition of IgG, IgA, and /?~c in 55 patients who had no systemic disease or history typical of acute glomerulonephritis; 22 of these patients had recurrent hematuria. The present clinical, histologic, and immunofluorescent studies further delineate this syndrome, demonstrate its variable expression, and suggest that in a small group the process is more serious and the prognosis more guarded. This study demonstrates that those patients who subsequently develop renal insufficiency may be recognized by the presence of pr0teinuria , focal glomerulosclerosis, and mesangial immunoglobulin deposits. PATIENTS
AND
METHODS
Sixteen children (13 boys and 3 girls), with the clinical syndrome as defined pre-
viously, have been followed for periods ranging from 1 to 16 years (Table I ) . They were selected only on the basis that all had had histopathologie and immunofluorescent study of renal biopsy specimens. There was no family history of significant renal disease. Evidence for ~-hemolytic streptococcal infection was sought at the time of the initial episode by throat, and other appropriate cultures and by serology, and was negative in all patients. O n the basis of elevated antistreptolysin-O, and anti-DNAse, or antiDPNase titers, five patients had evidence of streptococcal infection at some stage during the period of observation unrelated to episodes of macroscopic hematuria. This incidence of streptococcal infection closely approximates the average experience in this area. r Either serum complement (CH50) or serum fitc-/?lA levels were obtained at the time of the initial episode in five patients at the time of recurrence in the remainder, and repeatedly in most. All complement measurements have been normal except in one patient (Case 11) whose level of serum complement is normal in freshly drawn serum but falls at 4 ~ C. due to activation of properdin and late-reacting complement compo-
Volume 82 Number 5
Recurrent macroscopic hematuria
769
Fig. 1. Photomicrograph showing segmental areas of glomerular hypercellularity (arrows). (Hematoxylin and eosin, x378.)
Fig. 2. Half the glomerulus shown in this photomicrograph is sclerosed; the other half is relatively normal. (Periodic acid-Schiff, x564.)
nents (C3t).~ This phenomenon has not been observed in other patients. Percutaneous kidney biopsy specimens, usually obtained between episodes of macroscopic hematuria, were prepared for light and immunofluorescent microscopy as previously describedY, 10 Fluorescein-labeled antisera to human IgG, IgA, IgM, ~1o, properdin, and fibrin were used, although not all antisera were available for study for the earlier biopsy specimens.
teinuria was seen between episodes in the six patients who had proteinuria intermittently. Three patients (Cases 6, 8, and 15) now ages 21, 24, and 25 years, respectively, have hypertension, two with diastolic pressures of 80 to 90 ram. Hg and one with diastolic pressure of 95 to 100 mm. Hg. Microscopic hematuria was found consistently in ten and intermittently in the remainder between episodes of macroscopic hematuria. By light microscopy, all biopsy specimens were found to have focal and segmental, proliferative glomerular changes, primarily involving mesangial cells (Fig. 1). Segmental areas of glomerular sclerosis (Fig. 2) were seen in tissue from six patients, four of whom also had proteinuria and renal functional alterations (Cases 8, 11, 13, and 14). Immunofluorescent studies of tissue obtained by kidney biopsy were positive for one or mote irnmunoglobulins in 14 of the 16 patients (Table II). The distribution was solely or predominantly mesangial in 11 of the 14 (Fig. 3); in two biopsies there was granular and linear staining along the glomerular basement membrane in addition to mesangial fluorescence (Fig. 4) ; in the remaining one the fluorescence was diffuse, but the locus of deposition could not be de-
RESULTS
The significant findings are summarized in Table I. Two patients (Cases 8 and 14) now have reduced creatinine clearances; initially they had been normal. Two other patients (Cases 11 and 13) have had transient reductions in creatinine clearance, with associated rise of s e r u m creatinine and blood urea nitrogen, during episodes of macroscopic hematuria. The remaining patients have had normal creatinine clearances at all times including the present. All four patients with reductions in clearance have proteinuria intermittently or persistently, as do five other patients. Only three of these nine have persistent proteinuria. The highest levels of proteinuria occurred in relation to episodes of macroscopic hematuria. Some degree of pro-
770
R o y et al.
The Journal o/ Pediatrics May 1973
Fig. 3. Glomerulus stained with fluorescein-Iabeled antiserum to human IgA. Deposits are distributed throughout the mesangium. (•
Fig. 4. Immunofluorescent study of this glomerulus shows human IgG deposited in a granular distribution in the mesangium and along the glomerular basement membrane. (•
Table II. Recurrent hematuria: Glomerular immunofluorescence
parent reluctance to stress its variable clinical course. A benign prognosis has been suggested, 2 although data on prolonged followup are scanty. Only 9 of 211 patients found in a review of the literature had been followed for 10 or more years? -4, n-is One of the patients in the t965 study of Ayoub and Vernier 2 developed renal insufficiency one year ago, 17 years after the onset, and recently had successful renal transplantation. Approximately half the patients d o c u mented in the literature have proteinuria, usually less than 1.0 Gm. per 24 hours but occasionally as high as 3.0 G m ? Nine of our 16 patients had proteinuria; only four had more than 1.0 Gm. per 24 hours. Proteinuria was found to correlate, to a degree, with development of renal insufficiency, but this was not an absolute correlation. One patient with proteinuria (Case 2), followed for nine years, still has a normal creatinine clearance and is normotensive. Focal and segmental glomerular hypercellularity, as observed in this series, are the histopathologic changes usually associated with recurrent macroscopic hematuria. Some glomeruli appear to be normal. Segmental hypercellularity is a qualitative finding; the percentage of patients in individual series
Fluorescein-labeled antiserum to
IgG IgA IgM fl~c-globulin Properdin Fibrin
No. tested
No. posit(re
i6 6 9 l6 8 13
10 5 3 14 4 10
termined. In all "positive biopsies" Pie was demonstrated; five of six tested for IgA were positive, the remaining one being negative for all items tested except /71c and fibrin (Case 11). Staining for IgG was positive in 10 of 16, for properdin in 4 of 8, for fibrin in 10 of 13, and for IgM in 3 of 9. DISCUSSION Patients were selected for this study on the basis of tile presence of the described, easily recognized, clinical syndrome (recurrent macroscopic hematuria) and the availability of adequate histologic and immunofluorescent studies of renal biopsy specimens. Although recognized clinically for many years, full characterization of recurrent macroscopic hematuria has been hampered by an ap-
Volume 82 Number 5
with normal biopsy findings has varied somewhat. Small epithelial crescents, ~ local adhesions of glomerular tufts to Bowman's capsule, a and segmental glomerular sclerosis1~ have occasionally been described in these patients. Bodian and associates 3 studied 14 of their patients with fluorescein-labeled antisera to human gamma globulin; they remarked on the generalized distribution in the six which were positive in contrast to the focal glomerular abnormalities observed by light microscopy. Almost half the patients described by Berger, ~ who had mesangial deposition of IgG, IgA, and /?m in the absence of known systemic disease, apparently had recurrent macroscopic hematuria. The deposition of relatively large amounts of IgA in the mesangium, in combination with IgG and fi~e; has suggested to some that this syndrome is a unique form of glomerulonephritis in which IgA plays a major role. There is no direct evidence to support this hypothesis. Granular deposits of IgA are often found in other diseases such as lupus erythematosus and anaphylactoid purpura, ~, ~'~entities which may be associated with a focal and segmental glomerulitis. Our patients were found to have positive mesangial fluorescence so regularly that, when present, this finding renders argument concerning the presence or absence of minimal degrees of glomerular hypercellularity somewhat superfluous. The fluorescence of all mesangial areas in all glomeruti in biopsy specimens of the present series is somewhat surprising in view of the extremely variable and focal histologic changes. The presence of immunoglobulins along the glomerular basement membrane as well as in the mesangium in two patients is of interest, since similar capillary loop orientation of presumed immune complexes is also occasionally seen in patients with the nephritis of anaphylactoid purpura29 This finding increases the similarities between the renal lesions of this syndrome and that of anaphylactoid purpura nephritis2 ~ These two patients have had a benign course to date. Two patients with no immunofluoreseene have had a benign course thus far and have no proteinuria. It may be
Recurrent macroscopic hematuria
771
that those two patients represent the most benign variety of this syndrome with insufficient mesangial deposits to be detected by fluorescent microscopy. The immunofluorescent findings are not influenced by timing of the biopsy, since tissue was usually obtained between episodes of gross hematuria. Six patients had segmental glomerular sclerosis; five of these had proteinuria, and four of the five had renal functional impairment, suggesting that the combination of segmental glomerular sclerosis, proteinuria and positive immunofluorescence identifies patients with a more serious process. Fluorescent microscopy of renal tissue from three of these six patients stained for IgA was positive in two and negative in one. One of the patients with positive staining has had a benign course; the other patient with positive staining and the patient with negative staining have renal functional impairment. Tile exact mechanism(s) causing this syndrome are unknown. Immunoglobulins and complement are observed in glomeruli in diseases thought to be due to either immune complex deposition or anti-glomerular basement membrane antibo=ly but in those situations the deposits are usually oriented along the glomerular basement membrane. In recurrent macroscopic hematuria, however, deposits of IgG, IgA, and fi~c are found mainly in the mesangium in a distribution similar to that seen in the nephritis of anaphylactoid purpura. There is experimental evidence that maeromolecules, such as heat-aggregated serum proteins, are taken up by the mesangium, suggesting that this cell system is important in removing these materials from the circulationP ~ Thus it is possible that immunoglobulins and complement components m the mesangiurn in recurrent macroscopic hematuria may be associated with an antigen in the form of an immune complex, ahhough it remains possible that these immune reactants have been deposited as a nonspecific consequence to injury mediated by some other mechanism. The brief interval between the onset of the preceding "flu-like" illness and macroscopic hematuria, however, is unlike experimental immune
7 7 2 Roy et al.
complex disease in which there is a latent period of some days between injection of a foreign antigen and development of disease. Association of recurrent macroscopic hematuria with respiratory infections and IgA deposition may suggest a causal relationship with mucosal infections. The finding of properdin in the mesangium of one half of the patients studied is of special interest. Properdin is regularly found in glomeruIi in kidney biopsies from patients with membranoproliferative glomerulonephritis poststreptococcal glomerulonephritis and occasionally lupus nephritis. '~ T h e presence of properdin in those diseases and in some patients with recurrent macroscopic hematuria suggests that complement activation may be oecuring via the alternate complement activation pathway, s~ In the syndrome of recurrent macroscopic hematuria a variety of etiologic agents may be acting through a common pathogenetic mechanism. Identifying the mechanism may be more important than identifying the etiologic agents. REFERENCES
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