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Immune deposits and mesangial hypercellularity in minimal change nephrotic syndrome: Clinical relevance
188
February 1982 TheJournalofPEDIATRICS
Immune deposits and mesangial hypercellularity in minimal change nephrotic syndrome." Clinical relevance Occasional patients with nephrotic syndrome and minimal histologie change demonstrate glomerular deposition of small amounts of immunoglobulin and complement. Some consider this a disease distinct from MCNS. To investigate the clinical importance of immune deposits and mesangial hypercelluarity in the initial biopsy, the clinical records, follow-up data, and renal biopsies o f 68 patients (ages 6 months to 16 years) with MCNS by light microscopy were reviewed. Among 68 patients followed a mean of 6.2 years, eight of 25 patients with immune deposits present on initial renal biopsy were steroid nonresponsive. Only one of 43 patients without immune deposits was steroid nonresponsive (P = 0.0005). Of 44 patients with normal mesangial cellularity, 31 experienced fewer than three relapses a year, whereas of l 5 patients with mesangial hypercellularity, only six experienced fewer than three relapses a year (P = 0.035). The data suggest that immune deposits and increased mesangial cellularity in children with NS and minimal light microscopic change may predict the clinical course.
William R. Allen, M.D.,* Luther B. Travis, M.D.,** Tito Cavallo, M.D., Ben H. Brouhard, M.D., and Robert J. Cunningham III, M.D., Aurora, Colo., and Galveston, Texas
MINIMAL CHANGE NEPHROTIC SYNDROME has generally been considered to have negative immunofiuorescence and no immune deposits on electron microscopy. ~ However, some patients with nephrotic syndrome and minimal histologic change demonstrate glomerular deposition of small amounts of immunoglobulin and complement. 2 Some
From the Department of Pediatrics, Fitzsimons Army Medical Center, and the Division of Nephrology and Diabetes, Department of Pediatrics; and the Division of Renal Pathology, Department o f Pathology, The University of Texas Medical Branch. The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. *Pediatric Nephrology Foundation Fellowship Recipient. **Reprint address: Division of Pediatric Nephrology, University of Texas Medical Branch, Galveston, Texas 77550.
Vol. 100, No. 2, pp. 188-19l
authors have described patients with nephrotic syndrome, increased mesangial cellularity, and evidence of immune deposits as a separate disease entity. 3,4 This review of clinical records and pathologic material was designed to investigate the clinical importance of mesangial hypercellularity and immune deposits on the initial biopsy in children with MCNS.
Abbreviations used MCNS: minimal change nephrotic syndrome NS: nephrotic syndrome FGS: focal glomerular sclerosis
MATERIAL
AND METHODS
Patient population. The clinical records, follow-up data, and renal biopsy findings of 68 pediatric patients with a clinical diagnosis of the nephrotic syndrome and an initial histologic diagnosis of minimal change glomerular disease were reviewed. Patients were included in the study if they
Volume 100 Number 2
Immune deposits and mesangial hypercellularity in M C N S
fulfilled the following criteria: (1) had features of the nephrotic syndrome as defined by the International Study of Kidney disease in Children prior to or at the time of renal biopsy;5 (2) had nqrmal renal function, as measured by either the clearance of standard markers (inulin, iothalamate) 6 or serial serum creatinine determinations; (3) had no evidence of associated systemic disease; and (4) had only minimal glomerular alterations 7 by bright-field microscopic evaluation. Biopsies in which the glomeruli showed an equivocal or minimal degree of mesangial hypercellularity were also included. Patients were initially classified as either steroid responsive or nonresponsive. Steroid responsive patients were further categorized as nonrelapsers, infrequent relapsers, or frequent relapsers. After an eight-week course of therapy, patients were considered to be responders if they had protein-free urine (< 4 m g / h o u r / m 2) on three consecutive tests, on three separate days, during a seven-day period. Nonresponders were patients who did not clear the proteinuria during the eight-week course of therapy. A relapse was the presence of proteinuria (> 4 m g / h o u r / m 2) on three consecutive tests on three separate days. A frequent relapser was a responder who subsequently had two relapses within six months or averaged three relapses per year. The medical record review and the assignment of patients to a clinical classification were performed by one of us (W.A.) without prior knowledge of the morphologic data. All patients were treated with a corticosteroid (usually prednisone, 60 mg/m2/day) for four weeks followed by intermittent or alternate-day therapy (40 mg/mZ/day) for another four weeks. Some patients also received eytotoxic agents, usually cyclophosphamide or chlorambucil. Mean follow-up was 79 months and ranged from six to 192 months. Fifty-eight patients were followed greater than 24 months. Two or more biopsies were obtained from 27 patients; the reasons for the subsequent biopsy were either unresponsiveness to steroids or frequent relapses. All serologic, biochemical, and immunologic tests were performed according to standard laboratory methods. Morphologic and immunopathologic methods. Renal biopsies were performed as previously described.8 Technical details for processing and evaluation of tissues by light, immunofluorescence, and electron microscopy were previously reported. 9 Renal histology was reviewed by light microscopy without prior knowledge of the immunofluorescent microscopy or clinical data. On the average, 23 glomeruli were examined by light microscopy of each biopsy using hematoxylin and eosin, periodic acid-Schiff, methenamine silver, and Masson trichrome stains. We studied about 20 slides containing 50 levels of renal tissue from each biopsy. More than two mesangial nuclei per
18 9
mesangial area were considered evidence of mesangial cell proliferation. For immunofluorescence microscopy, on the average, nine glomeruli were stained with monospecific fluoresceinated goat or rabbit antiserum to human IgG, IgM, C3, fibrin/fibrinogen, and albumin. In many biopsies tissues were also stained with antiserum to human IgA, Clq, C4, and alpha-z-macroglobulin. In most instances, we studied duplicate immunoglobulin- and complementstained sections. An arbitrary scale of 0 to 3+ to indicate the extent of protein deposited in glomeruli was adopted. Appropriate controls9 verified the specificity of the antisera and immunofluorescent findings. Ultrastruetural studies were completed on one to three selected glomeruli in each biopsy. All instances of mesangial cell proliferation were confirmed by electron microscopy. All glomeruli were specifically examined for the presence of electron dense deposits, suggestive of or conforming to immune complexesJ ~ In general, such deposits consist of well-demarcated, granular material of variable size and electron density. Patients with immune reactants on immunofluorescence, whether or not confirmed by the demonstration of electron dense deposits, were then stated to have immune deposits. The significance of mesangial hypercellularity and immune reactants was considered in relation to the response to therapy using the chi square test. Prior steroid therapy could conceivably influence the glomerular localization of immune reactants; to investigate this possibility, we compared the frequency of immune deposits in untreated and previously treated patients by chi square. RESULTS Sixty-eight patients are the subject of this study; 40 were males. At the time of initial biopsy, the ages ranged from 6 months to 16 years. At the time of review, there were 59 responders and nine nonresponders. Of the 59 responders, there were 22 frequent relapsers, whereas 37 patients had infrequent or no relapses during follow-up. Forty-eight patients had received steroid therapy before being referred for evaluation and renal biopsy. All of 20 newly diagnosed, and previously untreated, patients were responders. The distribution of patients between immune deposit present and absent groups was unaffected by prior steroid treatment (P > 0.9). Except for laboratory manifestations of nephrotic syndrome, all other biochemical, serologic, and immunologic tests, including anti-nuclear antibody, anti-streptolysin-O, and C3 values, were normal. Morphologic studies. Cortical and juxtamedullary glomeruli were present in biopsies of 62 patients; in six, only cortical glomeruli were present. In 50 patients, the glomeruli were normal by light microscopy; in 18 patients there
19 0
Allen et al.
The Journalof Pediatrics February 1982
Table I. Clinical data of patients with and without immune deposits
lrnmune[~-SteroidINon-IRelapseRelapse deposiis [ responsive responsive ~ 3/yr < 3/yr Present n = 25 Absent n = 43
17 42
8* 1
6 16
11 26
*P = 0.0005. Table II. Clinical data of patients with normal cellular or hypercellular glomeruli
Mesangial cells N ormocellular Hypercellular
Steroid I Non- ~ . Relapse responsiveresponsive >~3/yr I < 3/yr 44 15
6 3
13 9
31* 6
*P = 0.035. was a slight and usually segmental increase in the number of mesangial cells and matrix. Four patients had one to four superficial glomeruli with global sclerosis; in three of these, the remaining glomeruli were normal; and in one, mesangial cell increase was evident in other glomeruli. Segmental glomerulosclerosis was not observed. Tubules, interstitium, and vessels were normal in all patients. By immunofluorescent microscopy, 25 of the 68 initial biopsies had trace to 1+ granular, mesangial deposits of IgM (24/25), lgG (7/25), IgA (2/25), C3 (15/25), and C4 (17/25). Eleven of 25 demonstrated only trace amounts of immunoglobulin, however eight of these 11 were confirmed by the presence of complement components on immunofluorescent microscopy and electrondense deposits on electron microscopy. Although present in all glomeruli of a specific biopsy, such deposits were irregular in distribution and varied in amount from one to another glomerulus. No fluorescent deposits were seen in tubules, interstitium, or arteries. By electron microscopy, mesangial deposits were demonstrated in eight of the initial 68 biopsies, all from patients who had granular deposits of immune reactants by immunofluorescent microscopy. All glomeruli had loss of foot processes and vacuolar changes in epithelial cells. The mesangial matrix was increased in glomeruli which showed proliferation of mesangial cells. Clinical course. In the group with immune deposits present, 32% were nonresponsive; only 2% of those with immune deposits absent were nonresponsive (P = 0,0005; Table I). Of eight nonresponders with immune deposits all had at least a 1+ amount Of immunoglobulin or complement and four nonresponders were confirmed by tl~e presence Of electron-dense deposits. No difference between the two groups was detected in the number of patients with
frequent relapses. The relative number of patients treated with cytotoxic agents was comparable in the two groups. Patients whose glomeruli were normocellular had fewer relapses than those with mesangial hypercellularity (P = 0.035; Table II). No difference in steroid responsiveness was noted between normocellular and hypereellular groups. Of the 27 patients rebiopsied, nine had features of focal glomerular sclerosisxl on the repeat biopsy. An average of 11% of glomeruli were sclerotic. The glomerular abnormalities of eight biopsies were segmental in distribution; the other specimen demonstrated global sclerosis. Only four of these nine patients had either immunofluorescent deposits or mesangial hypercellularity on the initial biopsy; seven had juxtamedullary glomeruli on initial biopsy. DISCUSSION The data demonstrate an important difference between patients with and without immune deposits. The group with deposits had a 16-fold greater frequency of steroid nonresponse (P = 0.0005). Steroid nonresponse was chosen for study because of the association of nonresponse with more serious glomerular disease, v- and the increased difficulty in management of such patients. Papadopoulou et al ~2have presented data on 37 children with steroid-responsive nephrotic syndrome. Twenty-five patients without and 12 patients with immune deposits were described; steroid nonresponsive patients were excluded from study. No difference was detected in the time or frequency of relapse in the two groups. Our data show no difference in the proportion of patients with frequent relapse in two comparable groups. Thus, the presence or absence of immune deposits in MCNS does not appear useful in predicting the frequency of relapse. Papadopoulou also noted a higher frequency of prolonged remission in patients with mesangial hypercellularity, irrespective of the presence or absence of immune deposits. However, we found that only 40% with mesangial hypercellularity experienced infrequent or no relapses in the year prior to review compared with 70% of patients with normal mesangial cellularity (P = 0.035). Patients with normal mesangial cellularity seem to have a lower risk of frequent relapse. The relationship between MCNS with and without immunodeposits and focal glomerular sclerosis represents_ an intriguing question. It has been suggested that MCNS and FGS represent different entities. ~3 The pathology, response to steroids, and outcome are different enough to merit separate consideration in a recent textbook? 6 It has also been suggested that MCNS and FGS represent different ends of a spectrum of severity of the same disease.~4, ~5 Similar symptoms and well-documented pro-
Volume 100 Number 2
Immune deposits and mesangial hypercellularity in M C N S
gression of M C N S to FGS support this contention. In either case, the implication of the data presented here is that M C N S with positive mesangial immunofluorescence should occupy a place in the clinical spectrum of nephrotic syndrome between M C N S without deposits and FGS. Of 27 patients rebiopsied nine had features of FGS. Four were nonresponders, three were steroid dependent, and two were frequent relapsers. The study group is composed entirely of referred patients which may explain the number of cases of FGS found. In summary, in 68 pediatric patients with nephrotic syndrome and minimal histologic change followed for a mean of 6.2 years, there is strong evidence that the presence of immune deposits predicts a greater risk of steroid nonresponse. There was no indication that patients with mesangial hypercellularity were more likely to experience prolonged remissions, ~2 in fact, the opposite was the case in this series.
6.
7.
8.
9.
10. 11. 12.
REFERENCES
1. Heptinstall RH: The nephrotic syndrome, in Pathology of the kidney, Boston, 1974, Little, Brown & Company, pp 52425. 2. Drummond KN, Michael AF, Good RA, and Vernier RL: The nephrotic syndrome in childhood: hnmunologic, clinical and pathologic correlations, J Clin Invest 45:620, 1966. 3. Cohen AH, Border WA, and Glassock R J: Nephrotic syndrome with glomerular mesangial IgM deposits, Lab Invest 38:610, 1978. 4. Bhasin HR, Abuelo JG, Ramakrishna K, and Esparza AR: Mesangial proliferative glomerulonephi'itis, Lab Invest 39:21, 1978. 5. Nephrotic syndrome in children: Prediction of histopathology
13.
14.
15.
16.
19 1
from clinical and laboratory characteristics at time of diagnosis. A Report of the lnternation Study of Kidney Disease in Children, Kidney Int 13:159, 1978. Brouhard BH, Travis LB, Cunningham R J, Berger M, and Carvajal HF: Simultaneous iothalamate, creafinine and urea clearances in children with renal disease, Pediatrics 59:219, 1977. Churg J, Habib R, and White RHR: Pathology of the nephrotic syndrome in children. A Report of the International Study of Kidney Disease in Children, Lancet 1:1299, 1970. Dodge WF, Daeschner CW, Brennan JC, Rosenberg HS, Travis LB, and Hopps HC: Percutaneous renal biopsy in children. I. General considerations, Pediatrics 30:287, 1962. Davis BF, and Cavallo T: Membranoproliferative glomeruIonephritis. Localization of early components of complement in glomcrular deposits, Am J Pathol 84:283, 1976. Churg J, and Grishman E: Ultrastructure of immune deposits in renal glomeruli, Ann Intern Med 76:479, 1972. Habib R: Focal glomerular sclerosis, Kidney Int 4:355, 1973 Papadopoulou ZL, Jenis EH, Novello AC, Tina LU, Jose PA, and Calcagno PL: Relapsing nephrotic syndrome in childhood: Long term followup in minimal change (MCNS) and mesangial proliferative nephropathy (Mes PGN), Pediatr Res 14:624, I980 (abst). Nagi AH, Alexander F, and Lannigan R: Light and electron microscopical studies of focal glomerular sclerosis, J Clin Pathol 24:846, 1971. Siegal N J, Kashgarian M, Spargo BH, and Hayslett JP: Minimal change and focal sclerotic lesions in lipoid nephrosis, Nephron 13:125, 1974. Kashgarian M, Hayslett JP, and Siegal N J: Lipoid nephrosis and focal sclerosis: distinct entities or spectrmn of disease, Nephron 13:105, 1974. Nash MA: Focal segmental glomerulosclerosis, in Pediatric kidney disease, Boston, 1978, Little, Brown & Company, pp 718-22"4.
February 1982 TheJournalofPEDIATRICS
Immune deposits and mesangial hypercellularity in minimal change nephrotic syndrome." Clinical relevance Occasional patients with nephrotic syndrome and minimal histologie change demonstrate glomerular deposition of small amounts of immunoglobulin and complement. Some consider this a disease distinct from MCNS. To investigate the clinical importance of immune deposits and mesangial hypercelluarity in the initial biopsy, the clinical records, follow-up data, and renal biopsies o f 68 patients (ages 6 months to 16 years) with MCNS by light microscopy were reviewed. Among 68 patients followed a mean of 6.2 years, eight of 25 patients with immune deposits present on initial renal biopsy were steroid nonresponsive. Only one of 43 patients without immune deposits was steroid nonresponsive (P = 0.0005). Of 44 patients with normal mesangial cellularity, 31 experienced fewer than three relapses a year, whereas of l 5 patients with mesangial hypercellularity, only six experienced fewer than three relapses a year (P = 0.035). The data suggest that immune deposits and increased mesangial cellularity in children with NS and minimal light microscopic change may predict the clinical course.
William R. Allen, M.D.,* Luther B. Travis, M.D.,** Tito Cavallo, M.D., Ben H. Brouhard, M.D., and Robert J. Cunningham III, M.D., Aurora, Colo., and Galveston, Texas
MINIMAL CHANGE NEPHROTIC SYNDROME has generally been considered to have negative immunofiuorescence and no immune deposits on electron microscopy. ~ However, some patients with nephrotic syndrome and minimal histologic change demonstrate glomerular deposition of small amounts of immunoglobulin and complement. 2 Some
From the Department of Pediatrics, Fitzsimons Army Medical Center, and the Division of Nephrology and Diabetes, Department of Pediatrics; and the Division of Renal Pathology, Department o f Pathology, The University of Texas Medical Branch. The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. *Pediatric Nephrology Foundation Fellowship Recipient. **Reprint address: Division of Pediatric Nephrology, University of Texas Medical Branch, Galveston, Texas 77550.
Vol. 100, No. 2, pp. 188-19l
authors have described patients with nephrotic syndrome, increased mesangial cellularity, and evidence of immune deposits as a separate disease entity. 3,4 This review of clinical records and pathologic material was designed to investigate the clinical importance of mesangial hypercellularity and immune deposits on the initial biopsy in children with MCNS.
Abbreviations used MCNS: minimal change nephrotic syndrome NS: nephrotic syndrome FGS: focal glomerular sclerosis
MATERIAL
AND METHODS
Patient population. The clinical records, follow-up data, and renal biopsy findings of 68 pediatric patients with a clinical diagnosis of the nephrotic syndrome and an initial histologic diagnosis of minimal change glomerular disease were reviewed. Patients were included in the study if they
Volume 100 Number 2
Immune deposits and mesangial hypercellularity in M C N S
fulfilled the following criteria: (1) had features of the nephrotic syndrome as defined by the International Study of Kidney disease in Children prior to or at the time of renal biopsy;5 (2) had nqrmal renal function, as measured by either the clearance of standard markers (inulin, iothalamate) 6 or serial serum creatinine determinations; (3) had no evidence of associated systemic disease; and (4) had only minimal glomerular alterations 7 by bright-field microscopic evaluation. Biopsies in which the glomeruli showed an equivocal or minimal degree of mesangial hypercellularity were also included. Patients were initially classified as either steroid responsive or nonresponsive. Steroid responsive patients were further categorized as nonrelapsers, infrequent relapsers, or frequent relapsers. After an eight-week course of therapy, patients were considered to be responders if they had protein-free urine (< 4 m g / h o u r / m 2) on three consecutive tests, on three separate days, during a seven-day period. Nonresponders were patients who did not clear the proteinuria during the eight-week course of therapy. A relapse was the presence of proteinuria (> 4 m g / h o u r / m 2) on three consecutive tests on three separate days. A frequent relapser was a responder who subsequently had two relapses within six months or averaged three relapses per year. The medical record review and the assignment of patients to a clinical classification were performed by one of us (W.A.) without prior knowledge of the morphologic data. All patients were treated with a corticosteroid (usually prednisone, 60 mg/m2/day) for four weeks followed by intermittent or alternate-day therapy (40 mg/mZ/day) for another four weeks. Some patients also received eytotoxic agents, usually cyclophosphamide or chlorambucil. Mean follow-up was 79 months and ranged from six to 192 months. Fifty-eight patients were followed greater than 24 months. Two or more biopsies were obtained from 27 patients; the reasons for the subsequent biopsy were either unresponsiveness to steroids or frequent relapses. All serologic, biochemical, and immunologic tests were performed according to standard laboratory methods. Morphologic and immunopathologic methods. Renal biopsies were performed as previously described.8 Technical details for processing and evaluation of tissues by light, immunofluorescence, and electron microscopy were previously reported. 9 Renal histology was reviewed by light microscopy without prior knowledge of the immunofluorescent microscopy or clinical data. On the average, 23 glomeruli were examined by light microscopy of each biopsy using hematoxylin and eosin, periodic acid-Schiff, methenamine silver, and Masson trichrome stains. We studied about 20 slides containing 50 levels of renal tissue from each biopsy. More than two mesangial nuclei per
18 9
mesangial area were considered evidence of mesangial cell proliferation. For immunofluorescence microscopy, on the average, nine glomeruli were stained with monospecific fluoresceinated goat or rabbit antiserum to human IgG, IgM, C3, fibrin/fibrinogen, and albumin. In many biopsies tissues were also stained with antiserum to human IgA, Clq, C4, and alpha-z-macroglobulin. In most instances, we studied duplicate immunoglobulin- and complementstained sections. An arbitrary scale of 0 to 3+ to indicate the extent of protein deposited in glomeruli was adopted. Appropriate controls9 verified the specificity of the antisera and immunofluorescent findings. Ultrastruetural studies were completed on one to three selected glomeruli in each biopsy. All instances of mesangial cell proliferation were confirmed by electron microscopy. All glomeruli were specifically examined for the presence of electron dense deposits, suggestive of or conforming to immune complexesJ ~ In general, such deposits consist of well-demarcated, granular material of variable size and electron density. Patients with immune reactants on immunofluorescence, whether or not confirmed by the demonstration of electron dense deposits, were then stated to have immune deposits. The significance of mesangial hypercellularity and immune reactants was considered in relation to the response to therapy using the chi square test. Prior steroid therapy could conceivably influence the glomerular localization of immune reactants; to investigate this possibility, we compared the frequency of immune deposits in untreated and previously treated patients by chi square. RESULTS Sixty-eight patients are the subject of this study; 40 were males. At the time of initial biopsy, the ages ranged from 6 months to 16 years. At the time of review, there were 59 responders and nine nonresponders. Of the 59 responders, there were 22 frequent relapsers, whereas 37 patients had infrequent or no relapses during follow-up. Forty-eight patients had received steroid therapy before being referred for evaluation and renal biopsy. All of 20 newly diagnosed, and previously untreated, patients were responders. The distribution of patients between immune deposit present and absent groups was unaffected by prior steroid treatment (P > 0.9). Except for laboratory manifestations of nephrotic syndrome, all other biochemical, serologic, and immunologic tests, including anti-nuclear antibody, anti-streptolysin-O, and C3 values, were normal. Morphologic studies. Cortical and juxtamedullary glomeruli were present in biopsies of 62 patients; in six, only cortical glomeruli were present. In 50 patients, the glomeruli were normal by light microscopy; in 18 patients there
19 0
Allen et al.
The Journalof Pediatrics February 1982
Table I. Clinical data of patients with and without immune deposits
lrnmune[~-SteroidINon-IRelapseRelapse deposiis [ responsive responsive ~ 3/yr < 3/yr Present n = 25 Absent n = 43
17 42
8* 1
6 16
11 26
*P = 0.0005. Table II. Clinical data of patients with normal cellular or hypercellular glomeruli
Mesangial cells N ormocellular Hypercellular
Steroid I Non- ~ . Relapse responsiveresponsive >~3/yr I < 3/yr 44 15
6 3
13 9
31* 6
*P = 0.035. was a slight and usually segmental increase in the number of mesangial cells and matrix. Four patients had one to four superficial glomeruli with global sclerosis; in three of these, the remaining glomeruli were normal; and in one, mesangial cell increase was evident in other glomeruli. Segmental glomerulosclerosis was not observed. Tubules, interstitium, and vessels were normal in all patients. By immunofluorescent microscopy, 25 of the 68 initial biopsies had trace to 1+ granular, mesangial deposits of IgM (24/25), lgG (7/25), IgA (2/25), C3 (15/25), and C4 (17/25). Eleven of 25 demonstrated only trace amounts of immunoglobulin, however eight of these 11 were confirmed by the presence of complement components on immunofluorescent microscopy and electrondense deposits on electron microscopy. Although present in all glomeruli of a specific biopsy, such deposits were irregular in distribution and varied in amount from one to another glomerulus. No fluorescent deposits were seen in tubules, interstitium, or arteries. By electron microscopy, mesangial deposits were demonstrated in eight of the initial 68 biopsies, all from patients who had granular deposits of immune reactants by immunofluorescent microscopy. All glomeruli had loss of foot processes and vacuolar changes in epithelial cells. The mesangial matrix was increased in glomeruli which showed proliferation of mesangial cells. Clinical course. In the group with immune deposits present, 32% were nonresponsive; only 2% of those with immune deposits absent were nonresponsive (P = 0,0005; Table I). Of eight nonresponders with immune deposits all had at least a 1+ amount Of immunoglobulin or complement and four nonresponders were confirmed by tl~e presence Of electron-dense deposits. No difference between the two groups was detected in the number of patients with
frequent relapses. The relative number of patients treated with cytotoxic agents was comparable in the two groups. Patients whose glomeruli were normocellular had fewer relapses than those with mesangial hypercellularity (P = 0.035; Table II). No difference in steroid responsiveness was noted between normocellular and hypereellular groups. Of the 27 patients rebiopsied, nine had features of focal glomerular sclerosisxl on the repeat biopsy. An average of 11% of glomeruli were sclerotic. The glomerular abnormalities of eight biopsies were segmental in distribution; the other specimen demonstrated global sclerosis. Only four of these nine patients had either immunofluorescent deposits or mesangial hypercellularity on the initial biopsy; seven had juxtamedullary glomeruli on initial biopsy. DISCUSSION The data demonstrate an important difference between patients with and without immune deposits. The group with deposits had a 16-fold greater frequency of steroid nonresponse (P = 0.0005). Steroid nonresponse was chosen for study because of the association of nonresponse with more serious glomerular disease, v- and the increased difficulty in management of such patients. Papadopoulou et al ~2have presented data on 37 children with steroid-responsive nephrotic syndrome. Twenty-five patients without and 12 patients with immune deposits were described; steroid nonresponsive patients were excluded from study. No difference was detected in the time or frequency of relapse in the two groups. Our data show no difference in the proportion of patients with frequent relapse in two comparable groups. Thus, the presence or absence of immune deposits in MCNS does not appear useful in predicting the frequency of relapse. Papadopoulou also noted a higher frequency of prolonged remission in patients with mesangial hypercellularity, irrespective of the presence or absence of immune deposits. However, we found that only 40% with mesangial hypercellularity experienced infrequent or no relapses in the year prior to review compared with 70% of patients with normal mesangial cellularity (P = 0.035). Patients with normal mesangial cellularity seem to have a lower risk of frequent relapse. The relationship between MCNS with and without immunodeposits and focal glomerular sclerosis represents_ an intriguing question. It has been suggested that MCNS and FGS represent different entities. ~3 The pathology, response to steroids, and outcome are different enough to merit separate consideration in a recent textbook? 6 It has also been suggested that MCNS and FGS represent different ends of a spectrum of severity of the same disease.~4, ~5 Similar symptoms and well-documented pro-
Volume 100 Number 2
Immune deposits and mesangial hypercellularity in M C N S
gression of M C N S to FGS support this contention. In either case, the implication of the data presented here is that M C N S with positive mesangial immunofluorescence should occupy a place in the clinical spectrum of nephrotic syndrome between M C N S without deposits and FGS. Of 27 patients rebiopsied nine had features of FGS. Four were nonresponders, three were steroid dependent, and two were frequent relapsers. The study group is composed entirely of referred patients which may explain the number of cases of FGS found. In summary, in 68 pediatric patients with nephrotic syndrome and minimal histologic change followed for a mean of 6.2 years, there is strong evidence that the presence of immune deposits predicts a greater risk of steroid nonresponse. There was no indication that patients with mesangial hypercellularity were more likely to experience prolonged remissions, ~2 in fact, the opposite was the case in this series.
6.
7.
8.
9.
10. 11. 12.
REFERENCES
1. Heptinstall RH: The nephrotic syndrome, in Pathology of the kidney, Boston, 1974, Little, Brown & Company, pp 52425. 2. Drummond KN, Michael AF, Good RA, and Vernier RL: The nephrotic syndrome in childhood: hnmunologic, clinical and pathologic correlations, J Clin Invest 45:620, 1966. 3. Cohen AH, Border WA, and Glassock R J: Nephrotic syndrome with glomerular mesangial IgM deposits, Lab Invest 38:610, 1978. 4. Bhasin HR, Abuelo JG, Ramakrishna K, and Esparza AR: Mesangial proliferative glomerulonephi'itis, Lab Invest 39:21, 1978. 5. Nephrotic syndrome in children: Prediction of histopathology
13.
14.
15.
16.
19 1
from clinical and laboratory characteristics at time of diagnosis. A Report of the lnternation Study of Kidney Disease in Children, Kidney Int 13:159, 1978. Brouhard BH, Travis LB, Cunningham R J, Berger M, and Carvajal HF: Simultaneous iothalamate, creafinine and urea clearances in children with renal disease, Pediatrics 59:219, 1977. Churg J, Habib R, and White RHR: Pathology of the nephrotic syndrome in children. A Report of the International Study of Kidney Disease in Children, Lancet 1:1299, 1970. Dodge WF, Daeschner CW, Brennan JC, Rosenberg HS, Travis LB, and Hopps HC: Percutaneous renal biopsy in children. I. General considerations, Pediatrics 30:287, 1962. Davis BF, and Cavallo T: Membranoproliferative glomeruIonephritis. Localization of early components of complement in glomcrular deposits, Am J Pathol 84:283, 1976. Churg J, and Grishman E: Ultrastructure of immune deposits in renal glomeruli, Ann Intern Med 76:479, 1972. Habib R: Focal glomerular sclerosis, Kidney Int 4:355, 1973 Papadopoulou ZL, Jenis EH, Novello AC, Tina LU, Jose PA, and Calcagno PL: Relapsing nephrotic syndrome in childhood: Long term followup in minimal change (MCNS) and mesangial proliferative nephropathy (Mes PGN), Pediatr Res 14:624, I980 (abst). Nagi AH, Alexander F, and Lannigan R: Light and electron microscopical studies of focal glomerular sclerosis, J Clin Pathol 24:846, 1971. Siegal N J, Kashgarian M, Spargo BH, and Hayslett JP: Minimal change and focal sclerotic lesions in lipoid nephrosis, Nephron 13:125, 1974. Kashgarian M, Hayslett JP, and Siegal N J: Lipoid nephrosis and focal sclerosis: distinct entities or spectrmn of disease, Nephron 13:105, 1974. Nash MA: Focal segmental glomerulosclerosis, in Pediatric kidney disease, Boston, 1978, Little, Brown & Company, pp 718-22"4.