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Prognostic Pathologic Markers in IgA Nephropathy
Prognostic Pathologic Markers in IgA Nephropathy Gloria R. Gallo, MD, Ritsuko Katafuchi, MD, Kotresha Neelakantappa, MD, and David S. Baldwin, MD • Previous studies have shown that the overall severity of the histologic grade and the extent of glomerular sclerosis are important pathologic markers of prognosis in IgA nephropathy. A previous analysis of the clinical and pathologic parameters in 74 patients at New York University Medical Center revealed that the renal survival (serum creatinine concentration of 2 mg/dL or less) was 100% in patients with mild proteinuria, 87% in those with moderate proteinuria, and 69% in those with heavy proteinuria. The incidence of segmental and global proliferation, glomerular sclerosis, tubulointerstitial damage, and vessel sclerosis increased with levels of proteinuria (P < 0.01 to 0.05). A comparison of the morphologic parameters In 30 patients with similar Initial serum creatinine concentrations (!> 2 mg/dL) but different outcomes demonstrates a greater incidence and severity of pathologic features, especially glomerular sclerosis in the "nonsurvlval" than "survival" groups. Vessel sclerosis as quantitatively measured by a "point-count" technique correlates with the extent of glomerular sclerosis (r = 0.5192; P < 0.001), suggesting a causal relationship or common basis. © 1988 by the National Kidney Foundation, Inc. INDEX WORDS: IgA nephropathy; glomerular sclerosis; vessel sclerosis.
T
HERE IS growing recognition that IgA nephropathy (lgAN) is the most common form of primary glomerulonephritis worldwide.! Both the frequency and universal occurrence of IgAN as well as its progressive nature, estimated to represent 10% to 20% of all end-stage renal disease (ESRD), have established the importance of this disease. The heterogeneity of its morphologic expression, geographic incidence, and rate of progression has prompted a search for the risk factors that might predict its course and identify the causes of progression. Meaningful comparisons of available data are complicated by the nature ofIgAN in that the clinically apparent and actual times of onset of disease often do not coincide . Thus, unselected patients are likely to reflect a wide spectrum of disease in various stages. The slowly progressive course of IgAN, requiring long periods of follow-up observations until ESRD, has led to the use of life table analysis to predict survival by defining various degrees of unequivocal renal functional impairment as the end-point. Both the clinical and histologic parameters anaFrom the Departments of Pathology and Medicine, New York University Medical Center, New Y ork. Supported in part by The National Kidney Foundation ofNew YorklNew Jersey. Address reprint requests to Gloria R. Gallo , Department of Pathology, New York University Medical Center, 550 First Ave, New York , NY 10016. © 1988 by the National Kidney Foundation , Inc. 0272-6386188/1205-0007$3.0010
362
lyzed in several studies indicate that among the clinical features , older age at onset, absence of macroscopic hematuria, and heavy proteinuria are regarded as markers of poor prognosis; the morphologic parameters of poor prognosis include overall severity of proliferation and glomerular sclerosis, crescents, lesions in peripheral capillary walls, interstitial fibrosis, and vascular lesions. 2 This report will focus on the morphologic features that bear on prognosis and relate to progression in IgAN. PROGNOSTIC PATHOLOGIC MARKERS
In general, most observers agree that there is a good correlation between the histologic grade and the prognosis in IgAN.2 That is, using the classification proposed by Meadows 3 and applied by Lee and others,4,5 grade I (mostly normal) and grade II (segmental mesangial proliferation and sclerosis in less than half of glomeruli, rare small crescents, and absence of tubulo-interstitial changes) carry a favorable prognosis . In contrast, both grade IV (severe diffuse mesangial proliferation and sclerosis, crescents in up to 45 % of glomeruli, frequent partial or total glomerular sclerosis, and presence of tubular-interstitial changes) and grade V (similar to but more severe than grade IV, with crescents in > 45 % of glomeruli and severe tubulointerstitial changes) carry a poor prognosis. From this we can conclude that "bad" disease has a "bad" outcome, but little insight is gained regarding specific early prognostic markers. Less is known about the course followed by patients with
American Journal of Kidney Diseases, Vol XII, No 5 (November), 1988: pp 362-365
363
PROGNOSTIC PATHOLOGIC MARKERS IN IGAN
intermediate histologic severity, ie, grade III (diffuse mild to moderate mesangial proliferation with focal and segmental variation, and occasional small crescents and obsolescent glomeruli) who have a variable course. The extent of glomerular sclerosis at the time of biopsy appears to have the strongest influence on renal survival. In a large series of patients with all histologic grades at initial biopsy (in whom ESRD was defined as serum creatinine concentration > 10 mg/dL or start of regular dialysis treatment), renal survival, defined as a serum creatinine concentration < 2 mg/dL, at 12 years after biopsy was 100% when no glomerulus was sclerotic. 2 Renal survival was < 20% when glomerular sclerosis was > 20 %. It may be argued that patients with extensive glomerular sclerosis at the time of biopsy are already in a progressive and irreversible phase of disease, and other interrelated features such as tubular atrophy, interstitial fibrosis, and leukocytic infiltration frequently parallel the extent of glomerular sclerosis, thus obscuring the earliest prognostic markers. For this reason, Magil evaluated the clinical and pathologic prognostic parameters in a restricted group of 40 patients with grade III histologic severity (defined above) who had no greater than 10% global sclerosis or 30% crescents and had only minor degrees of tubulo-interstitial changes. 5 Life table analysis showed that only the extent of segmental glomerular sclerosis was of morphologic prognostic significance. Renal survival at 100 months was 86 % in patients who had segmental glomerular sclerosis in < 10 % of glomeruli and survival was 0% in those with > 10 % segmental sclerosis. Thus, in this study, segmental glomerular sclerosis appears to be the earliest morphologic marker of prognosis. s Analysis of IgA Nephropathy at New York University Medical Center
Primary IgAN was diagnosed in 78 patients with predominantly IgA mesangial deposits and the absence of systemic disease, between July 1970 and December 1983. The clinicopathologic features in 74 of these patients with adequate data for analysis detailed elsewhere6 show that renal survival is related to the magnitude of proteinuria. At 5 years after presentation, renal survival was 100% in patients with mild proteinuria « 1 g/d), 87% in those with moderate proteinuria (1 to 2.9 g/d), and 69% in those with heavy proteinuria (> 3 g/d).
Table 1. Morphologic Parameters in Patients at New York University Medical Center with Initial Serum Creatinine Concentrations of :$; 2 mg/dL but Different Outcomes Percentage of Patients Renal Survival" (n = 22)
Mesangial proliferation Segmental/global proliferation Absent 1%-10% affected 11 %-25% affected Crescents Absent 1%-10% affected 11 %-20% affected > 20% affected Glomerular sclerosis Absent 1%-1 0% affected 11 %-20% affected > 20% affected Vessel sclerosis Absent Present
Renal Nonsurvivalt (n = 8)
82
100
73
25 25 50
9 18 82
9 9 0 63.5 23
9 4.5 68 32
50 12.5 25 12.5 0 25 25 50 50 50
'Serum creatinine concentration:$; 2 mg/dL. tSerum creatinine concentration > 2 mg/dL.
The incidence of segmental and global proliferation, glomerular sclerosis, tubulo-interstitial damage, and vessel sclerosis increased with increased levels of proteinuria (P < 0.01 to 0.05). Of these 74 patients, sufficient follow-up data allow a comparison of the initial morphologic features in 30 patients with serum creatinine concentrations of ~ 2 mg/dL at the time of biopsy but with different outcomes (Table 1). The data, although insufficient for statistical analysis, not surprisingly show that the initial overall severity of morphologic damage is worse in the "nonsurvival" than in the "survival" group, as previously shown in a similar analysis by D'Amico et aU Thus, the extent of damage in the biopsy, especially the extent of glomerular sclerosis, is an important marker of prognosis. As shown previously, the extent of glomerular sclerosis is not accurately reflected in the serum creatinine concentration. 8 RELATIONSHIP BETWEEN GLOMERULAR SCLEROSIS AND VESSEL SCLEROSIS
Our earlier studies emphasized the correlation between glomerular sclerosis and vessel sclerosis in IgAN9.1O as noted by others. 8.1 \,12 However, the method of evaluation of sclerosis of lobular ar-
GALLO ET AL
364 4
~
•
1~ &
..
=
=
r 0.52, t 5.1, P < 0.001 6
3 6
6
2
~
l
0 0
60 80 20 40 Percentage of glomeruli with sclerosis
100
Fig 1. Scatterplot of the correlation between the percentage of globally and segmentally sclerotic glomeruli (horizontal axis) and the percentage of small vessel area (vertical axis) in IgAN. Small vessel area was calculated as a percentage of total parenchymal area by the point-count method 13 in histologic sections of 72 biopsies. The regression equation is shown by the line; r = 0.5192, P < 0.001, slope = 1.2299712, intercept = 1.032084.
teries and arterioles, ie, by a visual estimation of mural thickness and hyalinosis that we and others have used, is semiquantitative rather than quantitative. This may account for the lack of consensus regarding the correlation between glomerular and vessel sclerosis among various observers. 10 For this reason we have recently undertaken a morphometric approach to quantitate vessel sclerosis using a point-counting techniqueY In this method, the area of small vessels (lobular arteries and arterioles) is calculated as a .percentage of the total parenchymal area. The rationale for using this measurement as an index of vessel sclerosis is based on the light microscopic observation in histologic slides that clustered cross sections of vessels are frequent in IgAN but infrequent in the normal kidney. 10 This can be attributed to the tortuosity and spiraling of vessels due to hypertrophy and a consequent increase in vessel mass. This vascular alteration has been shown also by radiography in experimental glomerulonephritis in rabbits and by dissection of human kidneys with chronic glomerulonephritis. 14 ,15 Our preliminary data obtained from 72 biopsies of IgAN are shown by scatterplot (Fig 1). There is a correlation between the extent of global and segmental glomerular sclerosis and increased vessel area (r = 0.5192, P < 0.001). Thus, by both quantitative and semiquantitative methods, independently performed, we conclude that the severity of glomerular and
vascular sclerosis correlate. The latest long-term follow-up studies by Noel et al confirm this finding. 16 The significance of a correlation between glomerular and vessel sclerosis resides in the mechanism(s) of progression in IgAN and other glomerular diseases such as poststreptococcal glomerulonephritis in which glomerular sclerosis may occur after subsidence of proliferation or in the absence of severe proliferation. Still unanswered is the question of the precise sequence of events and interrelationship between glomerular and vessel sclerosis. Based on our previous studies of biopsies in both poststreptococcal glomerulonephritis and in IgAN, we speculated that nonimmunologic mechanisms may be responsible for or, at least, contribute to progressive glomerular sclerosis. 9.10, 17 The idea that vessel sclerosis is a cause of glomerular sclerosis in chronic glomerulonephritis is not new. It was proposed many years ago by Volhard and Fahr and later by Ellis, 18.19 but it was deemphasized by the emerging new knowledge and emphasis on immunologic mechanisms as a cause of glomerular proliferation and sclerosis in both experimental models of glomerulonephritis and human glomerulonephritis. Renewed interest in nonimmunologic mechanisms of glomerular injury in all forms of glomerulonephritis, including IgAN, is now evident, offering new insights into the causes of damage and progression and new modes of therapy. REFERENCES 1. D'Amico G: The commonest glomerulonephritis in the world: IgA nephropathy. Q J Med 64:709-727, 1987 2. D'Amico G, Minetti L, Ponticelli G, et al: Prognostic indicators in idiopathic IgA mesangial nephropathy. Q J Med 59:363-378, 1986 3. Meadow SR, Glasgow EF, White RHR, et al: SchiinleinHenoch nephritis. Q J Med 41:241-258, 1972 4. Lee KS-M, Rao VM, Franklin WA, et a1: Morphologic predictors of progressive renal disease. Human Pathol13:314322, 1982 5. Magil AB, Bailon HS: IgA nephropathy. Evaluation of prognostic factors in patients with moderate disease. Nephron 47:246-252, 1987 6. Neelakantappa K, Gallo GR, Baldwin DS: Proteinuria in IgA nephropathy. Kidney Int 33:716-722, 1988 7. D'Amico G, Ferrario F, Colasanti G, et al: IgA-mesangial nephropathy (Berger's disease) with rapid decline in renal function. Clin Nephrol 16:251-257, 1981 8. Croker BP, Dawson DV, Sanfilippo F: IgA nephropathy. Correlation of clinical and histologic features. Lab Invest 48:19-24, 1983
PROGNOSTIC PATHOLOGIC MARKERS IN IGAN
9. Feiner HD, Cabili S, Baldwin DS, et al: Intrarenal vascular sclerosis in IgA nephropatby. Clin Nephrol 18:183-192, 1982 10. Feiner HD, Galvin S, Neelakantappa K, et al: Vessel sclerosis and progression in IgA nephropatby. Contrib Nephrol 40:222-227, 1984 11. Droz D: Natural history of primary glomerulonephritis with mesangial deposits of IgA. Contrib Nephrol 2:150-157, 1976 12. Clarkson AR, Seymour AE, Thompson AJ, et al: IgA nephropathy: A syndrome of uniform morphology, diverse clinical features and uncertain prognosis. Clin Nephrol 8:459471, 1977 13. Weibel ER: Stereological Metbods. San Diego, Academic Press, 1979
365 14. Sawabu N, Takazakura E, Handa A, et al: Intrarenal vascular changes in experimental glomerulonephritis. Kidney Int 1:89-99, 1972 15. Oliver J: Architecture of the Kidney in Chronic Bright's Disease. New York, Hoeber, 1939 16. Noel LH, Droz D, Gascon M, et al: Primary IgA nephropathy. From the first-described cases to the present. Semin Nephrol 7:275-279, 1987 17. Gallo GR, Feiner HD, Steele J, et al: Role of intrarenal vascular sclerosis in progression of poststreptococcal glomerulonephritis. Clin Nephrol 13:49-57, 1980 18. Volhard F, Fahr T: Bright's Disease. Berlin, Springer, 1914 19. Ellis A: Natural history of Bright's disease. Clinical, histological and experimental observations. III. The viscious circle in chronic Bright's disease. Lancet 1:72-76, 1942
T
HERE IS growing recognition that IgA nephropathy (lgAN) is the most common form of primary glomerulonephritis worldwide.! Both the frequency and universal occurrence of IgAN as well as its progressive nature, estimated to represent 10% to 20% of all end-stage renal disease (ESRD), have established the importance of this disease. The heterogeneity of its morphologic expression, geographic incidence, and rate of progression has prompted a search for the risk factors that might predict its course and identify the causes of progression. Meaningful comparisons of available data are complicated by the nature ofIgAN in that the clinically apparent and actual times of onset of disease often do not coincide . Thus, unselected patients are likely to reflect a wide spectrum of disease in various stages. The slowly progressive course of IgAN, requiring long periods of follow-up observations until ESRD, has led to the use of life table analysis to predict survival by defining various degrees of unequivocal renal functional impairment as the end-point. Both the clinical and histologic parameters anaFrom the Departments of Pathology and Medicine, New York University Medical Center, New Y ork. Supported in part by The National Kidney Foundation ofNew YorklNew Jersey. Address reprint requests to Gloria R. Gallo , Department of Pathology, New York University Medical Center, 550 First Ave, New York , NY 10016. © 1988 by the National Kidney Foundation , Inc. 0272-6386188/1205-0007$3.0010
362
lyzed in several studies indicate that among the clinical features , older age at onset, absence of macroscopic hematuria, and heavy proteinuria are regarded as markers of poor prognosis; the morphologic parameters of poor prognosis include overall severity of proliferation and glomerular sclerosis, crescents, lesions in peripheral capillary walls, interstitial fibrosis, and vascular lesions. 2 This report will focus on the morphologic features that bear on prognosis and relate to progression in IgAN. PROGNOSTIC PATHOLOGIC MARKERS
In general, most observers agree that there is a good correlation between the histologic grade and the prognosis in IgAN.2 That is, using the classification proposed by Meadows 3 and applied by Lee and others,4,5 grade I (mostly normal) and grade II (segmental mesangial proliferation and sclerosis in less than half of glomeruli, rare small crescents, and absence of tubulo-interstitial changes) carry a favorable prognosis . In contrast, both grade IV (severe diffuse mesangial proliferation and sclerosis, crescents in up to 45 % of glomeruli, frequent partial or total glomerular sclerosis, and presence of tubular-interstitial changes) and grade V (similar to but more severe than grade IV, with crescents in > 45 % of glomeruli and severe tubulointerstitial changes) carry a poor prognosis. From this we can conclude that "bad" disease has a "bad" outcome, but little insight is gained regarding specific early prognostic markers. Less is known about the course followed by patients with
American Journal of Kidney Diseases, Vol XII, No 5 (November), 1988: pp 362-365
363
PROGNOSTIC PATHOLOGIC MARKERS IN IGAN
intermediate histologic severity, ie, grade III (diffuse mild to moderate mesangial proliferation with focal and segmental variation, and occasional small crescents and obsolescent glomeruli) who have a variable course. The extent of glomerular sclerosis at the time of biopsy appears to have the strongest influence on renal survival. In a large series of patients with all histologic grades at initial biopsy (in whom ESRD was defined as serum creatinine concentration > 10 mg/dL or start of regular dialysis treatment), renal survival, defined as a serum creatinine concentration < 2 mg/dL, at 12 years after biopsy was 100% when no glomerulus was sclerotic. 2 Renal survival was < 20% when glomerular sclerosis was > 20 %. It may be argued that patients with extensive glomerular sclerosis at the time of biopsy are already in a progressive and irreversible phase of disease, and other interrelated features such as tubular atrophy, interstitial fibrosis, and leukocytic infiltration frequently parallel the extent of glomerular sclerosis, thus obscuring the earliest prognostic markers. For this reason, Magil evaluated the clinical and pathologic prognostic parameters in a restricted group of 40 patients with grade III histologic severity (defined above) who had no greater than 10% global sclerosis or 30% crescents and had only minor degrees of tubulo-interstitial changes. 5 Life table analysis showed that only the extent of segmental glomerular sclerosis was of morphologic prognostic significance. Renal survival at 100 months was 86 % in patients who had segmental glomerular sclerosis in < 10 % of glomeruli and survival was 0% in those with > 10 % segmental sclerosis. Thus, in this study, segmental glomerular sclerosis appears to be the earliest morphologic marker of prognosis. s Analysis of IgA Nephropathy at New York University Medical Center
Primary IgAN was diagnosed in 78 patients with predominantly IgA mesangial deposits and the absence of systemic disease, between July 1970 and December 1983. The clinicopathologic features in 74 of these patients with adequate data for analysis detailed elsewhere6 show that renal survival is related to the magnitude of proteinuria. At 5 years after presentation, renal survival was 100% in patients with mild proteinuria « 1 g/d), 87% in those with moderate proteinuria (1 to 2.9 g/d), and 69% in those with heavy proteinuria (> 3 g/d).
Table 1. Morphologic Parameters in Patients at New York University Medical Center with Initial Serum Creatinine Concentrations of :$; 2 mg/dL but Different Outcomes Percentage of Patients Renal Survival" (n = 22)
Mesangial proliferation Segmental/global proliferation Absent 1%-10% affected 11 %-25% affected Crescents Absent 1%-10% affected 11 %-20% affected > 20% affected Glomerular sclerosis Absent 1%-1 0% affected 11 %-20% affected > 20% affected Vessel sclerosis Absent Present
Renal Nonsurvivalt (n = 8)
82
100
73
25 25 50
9 18 82
9 9 0 63.5 23
9 4.5 68 32
50 12.5 25 12.5 0 25 25 50 50 50
'Serum creatinine concentration:$; 2 mg/dL. tSerum creatinine concentration > 2 mg/dL.
The incidence of segmental and global proliferation, glomerular sclerosis, tubulo-interstitial damage, and vessel sclerosis increased with increased levels of proteinuria (P < 0.01 to 0.05). Of these 74 patients, sufficient follow-up data allow a comparison of the initial morphologic features in 30 patients with serum creatinine concentrations of ~ 2 mg/dL at the time of biopsy but with different outcomes (Table 1). The data, although insufficient for statistical analysis, not surprisingly show that the initial overall severity of morphologic damage is worse in the "nonsurvival" than in the "survival" group, as previously shown in a similar analysis by D'Amico et aU Thus, the extent of damage in the biopsy, especially the extent of glomerular sclerosis, is an important marker of prognosis. As shown previously, the extent of glomerular sclerosis is not accurately reflected in the serum creatinine concentration. 8 RELATIONSHIP BETWEEN GLOMERULAR SCLEROSIS AND VESSEL SCLEROSIS
Our earlier studies emphasized the correlation between glomerular sclerosis and vessel sclerosis in IgAN9.1O as noted by others. 8.1 \,12 However, the method of evaluation of sclerosis of lobular ar-
GALLO ET AL
364 4
~
•
1~ &
..
=
=
r 0.52, t 5.1, P < 0.001 6
3 6
6
2
~
l
0 0
60 80 20 40 Percentage of glomeruli with sclerosis
100
Fig 1. Scatterplot of the correlation between the percentage of globally and segmentally sclerotic glomeruli (horizontal axis) and the percentage of small vessel area (vertical axis) in IgAN. Small vessel area was calculated as a percentage of total parenchymal area by the point-count method 13 in histologic sections of 72 biopsies. The regression equation is shown by the line; r = 0.5192, P < 0.001, slope = 1.2299712, intercept = 1.032084.
teries and arterioles, ie, by a visual estimation of mural thickness and hyalinosis that we and others have used, is semiquantitative rather than quantitative. This may account for the lack of consensus regarding the correlation between glomerular and vessel sclerosis among various observers. 10 For this reason we have recently undertaken a morphometric approach to quantitate vessel sclerosis using a point-counting techniqueY In this method, the area of small vessels (lobular arteries and arterioles) is calculated as a .percentage of the total parenchymal area. The rationale for using this measurement as an index of vessel sclerosis is based on the light microscopic observation in histologic slides that clustered cross sections of vessels are frequent in IgAN but infrequent in the normal kidney. 10 This can be attributed to the tortuosity and spiraling of vessels due to hypertrophy and a consequent increase in vessel mass. This vascular alteration has been shown also by radiography in experimental glomerulonephritis in rabbits and by dissection of human kidneys with chronic glomerulonephritis. 14 ,15 Our preliminary data obtained from 72 biopsies of IgAN are shown by scatterplot (Fig 1). There is a correlation between the extent of global and segmental glomerular sclerosis and increased vessel area (r = 0.5192, P < 0.001). Thus, by both quantitative and semiquantitative methods, independently performed, we conclude that the severity of glomerular and
vascular sclerosis correlate. The latest long-term follow-up studies by Noel et al confirm this finding. 16 The significance of a correlation between glomerular and vessel sclerosis resides in the mechanism(s) of progression in IgAN and other glomerular diseases such as poststreptococcal glomerulonephritis in which glomerular sclerosis may occur after subsidence of proliferation or in the absence of severe proliferation. Still unanswered is the question of the precise sequence of events and interrelationship between glomerular and vessel sclerosis. Based on our previous studies of biopsies in both poststreptococcal glomerulonephritis and in IgAN, we speculated that nonimmunologic mechanisms may be responsible for or, at least, contribute to progressive glomerular sclerosis. 9.10, 17 The idea that vessel sclerosis is a cause of glomerular sclerosis in chronic glomerulonephritis is not new. It was proposed many years ago by Volhard and Fahr and later by Ellis, 18.19 but it was deemphasized by the emerging new knowledge and emphasis on immunologic mechanisms as a cause of glomerular proliferation and sclerosis in both experimental models of glomerulonephritis and human glomerulonephritis. Renewed interest in nonimmunologic mechanisms of glomerular injury in all forms of glomerulonephritis, including IgAN, is now evident, offering new insights into the causes of damage and progression and new modes of therapy. REFERENCES 1. D'Amico G: The commonest glomerulonephritis in the world: IgA nephropathy. Q J Med 64:709-727, 1987 2. D'Amico G, Minetti L, Ponticelli G, et al: Prognostic indicators in idiopathic IgA mesangial nephropathy. Q J Med 59:363-378, 1986 3. Meadow SR, Glasgow EF, White RHR, et al: SchiinleinHenoch nephritis. Q J Med 41:241-258, 1972 4. Lee KS-M, Rao VM, Franklin WA, et a1: Morphologic predictors of progressive renal disease. Human Pathol13:314322, 1982 5. Magil AB, Bailon HS: IgA nephropathy. Evaluation of prognostic factors in patients with moderate disease. Nephron 47:246-252, 1987 6. Neelakantappa K, Gallo GR, Baldwin DS: Proteinuria in IgA nephropathy. Kidney Int 33:716-722, 1988 7. D'Amico G, Ferrario F, Colasanti G, et al: IgA-mesangial nephropathy (Berger's disease) with rapid decline in renal function. Clin Nephrol 16:251-257, 1981 8. Croker BP, Dawson DV, Sanfilippo F: IgA nephropathy. Correlation of clinical and histologic features. Lab Invest 48:19-24, 1983
PROGNOSTIC PATHOLOGIC MARKERS IN IGAN
9. Feiner HD, Cabili S, Baldwin DS, et al: Intrarenal vascular sclerosis in IgA nephropatby. Clin Nephrol 18:183-192, 1982 10. Feiner HD, Galvin S, Neelakantappa K, et al: Vessel sclerosis and progression in IgA nephropatby. Contrib Nephrol 40:222-227, 1984 11. Droz D: Natural history of primary glomerulonephritis with mesangial deposits of IgA. Contrib Nephrol 2:150-157, 1976 12. Clarkson AR, Seymour AE, Thompson AJ, et al: IgA nephropathy: A syndrome of uniform morphology, diverse clinical features and uncertain prognosis. Clin Nephrol 8:459471, 1977 13. Weibel ER: Stereological Metbods. San Diego, Academic Press, 1979
365 14. Sawabu N, Takazakura E, Handa A, et al: Intrarenal vascular changes in experimental glomerulonephritis. Kidney Int 1:89-99, 1972 15. Oliver J: Architecture of the Kidney in Chronic Bright's Disease. New York, Hoeber, 1939 16. Noel LH, Droz D, Gascon M, et al: Primary IgA nephropathy. From the first-described cases to the present. Semin Nephrol 7:275-279, 1987 17. Gallo GR, Feiner HD, Steele J, et al: Role of intrarenal vascular sclerosis in progression of poststreptococcal glomerulonephritis. Clin Nephrol 13:49-57, 1980 18. Volhard F, Fahr T: Bright's Disease. Berlin, Springer, 1914 19. Ellis A: Natural history of Bright's disease. Clinical, histological and experimental observations. III. The viscious circle in chronic Bright's disease. Lancet 1:72-76, 1942