Changing incidence of glomerular diseases in adults

Changing Incidence of Glomerular Diseases in Adults Gregory L. Braden, MD, Jeffrey G. Mulhern, MD, Michael H. O’Shea, MD, Shirin V. Nash, MD, Angelo A. Ucci, Jr, MD, and Michael J. Germain, MD ● Studies performed at large metropolitan medical centers have reported an increasing incidence of idiopathic focal segmental glomerulosclerosis (FSGS) in adults. To determine whether a similar trend occurs in small urban and rural communities and to determine the role of race in these observations, we reviewed the patient records of all adults who underwent renal biopsies at our institution over the 20-year period from 1974 to 1994. The patients were grouped for analysis in 5-year intervals, 1975 to 1979, 1980 to 1984, 1985 to 1989, and 1990 to 1994, for the following diagnoses: FSGS, membranous nephropathy (MN), minimal change nephropathy (MCN), membranoproliferative glomerulonephritis (MPGN), immunoglobulin A (IgA) nephropathy, chronic glomerulonephritis, diabetic nephropathy, hypertensive nephrosclerosis, and chronic interstitial nephritis. Patients with secondary causes for these lesions were excluded. The relative frequency of FSGS increased from 13.7% during 1975 to 1979 to 25% during 1990 to 1994 (P F 0.05). The relative frequency of MN decreased from 38.3% during 1975 to 1979 to 14.5% during 1990 to 1994 (P F 0.01). There were no changes in the frequencies of MCN, MPGN, IgA nephropathy, chronic glomerulonephritis, diabetic nephropathy, hypertensive nephrosclerosis, or chronic interstitial nephritis over the 20-year period. However, there was a significant increase in the percentage of blacks with FSGS, from 0% in 1975 to 1979 to 22.6% in 1990 to 1994, and an increased percentage of Hispanics with FSGS, from 0% in 1975 to 1979 to 21.3% in 1990 to 1994 (P F 0.05). The modest increase in whites with FSGS did not reach statistical significance. The incidence of MN in blacks and whites decreased over the 20-year period. In the last 5 years, 15 patients per year had FSGS compared with 7 patients per year with MN (P F 0.05). No changes in age or sex between groups or over time accounted for these results. We conclude that FSGS is now diagnosed twice as often as MN and is the most common idiopathic glomerular disease at our hospital. Reasons for this increase include the emergence of FSGS in both Hispanics and blacks, with a modest increase of FSGS in whites. The increase in FSGS in the three most common races in our community suggests that factors other than genetic, perhaps environmental, have a role in the pathogenesis of FSGS. r 2000 by the National Kidney Foundation, Inc. INDEX WORDS: Focal segmental glomerulosclerosis (FSGS); membranous nephropathy (MN); glomerulonephritis (GN).

M

EMBRANOUS nephropathy (MN) has been the most common cause of idiopathic nephrotic syndrome in adults for the last 50 years, accounting for up to 50% of the adults with primary glomerular disease in several reports.1-3 In these studies, focal segmental glomerulosclerosis (FSGS) has accounted for 10% to 15% of adults with idiopathic nephrotic syndrome.1-3 Recently, three academic medical centers located in large metropolitan areas reported an increasing incidence of FSGS, especially in the black population.4-7 However, these trends have not been studied in medical centers located From the Departments of Medicine and Pathology, Baystate Medical Center, Springfield, MA; Department of Pathology, New England Medical Center; and Tufts University School of Medicine, Boston, MA. Received April 19, 1999; accepted in revised form December 3, 1999. Address reprint requests to Gregory L. Braden, MD, Chief, Renal Division, Baystate Medical Center, 759 Chestnut St, Springfield, MA 01199. E-mail: [email protected]

r 2000 by the National Kidney Foundation, Inc. 0272-6386/00/3505-0013$3.00/0 doi:10.1053/kd.2000.6396 878

in small urban and rural areas. In addition, no study has evaluated the incidence of primary glomerular diseases in regions with a large Hispanic population. We retrospectively reviewed the renal biopsy logs and patient records for all renal biopsies performed at our medical center over the last 20 years to identify changing frequencies of primary glomerular diseases and the relationship of changes to race, age, and sex. MATERIALS AND METHODS The records of patients with renal biopsies performed at Baystate Medical Center, the Western Campus of Tufts University School of Medicine (Springfield, MA), from January 1974 to December 31, 1994, were retrospectively reviewed. The renal biopsy log books were reviewed for biopsy diagnosis, age, and sex. Patient charts were reviewed for race and level of proteinuria and to determine whether glomerular disease was caused by systemic disease rather than primary glomerular disease. Nine hundred sixty-five renal biopsies were identified, and patients with the following secondary causes for glomerular diseases were excluded: FSGS secondary to intravenous drug use, acquired immunodeficiency syndrome, sickle cell disease, or vesicoureteral reflux; MN secondary to medica-

American Journal of Kidney Diseases, Vol 35, No 5 (May), 2000: pp 878-883

INCREASED FREQUENCY OF FSGS

tions, tumors, collagen disease, or hepatitis B; membranoproliferative glomerulonephritis (MPGN) caused by hepatitis or cryoglobulins; lupus nephritis; crescentic glomerulonephritis; acute proliferative glomerulonephritis; focal necrotizing glomerulonephritis; vasculitis; amyloidosis; fibrillary glomerulonephritis; and immunotactoid glomerulopathy. This study includes 616 biopsies performed in patients aged 18 years or older who had 2 g or greater of daily urinary protein excretion. A secondary analysis of patients with nephrotic syndrome was not performed because of incomplete physical examination data during the retrospective chart review. All biopsies were analyzed over four 5-year intervals: 1974 to 1979, 1980 to 1984, 1985 to 1989, and 1990 to 1994. The biopsies were categorized by these diagnoses: (1) FSGS, (2) MN, (3) minimal change nephropathy (MCN), (4) MPGN, and (5) mesangial proliferative glomerulonephritis with or without immunoglobulin A (IgA) deposition. All biopsies were routinely stained and examined by light microscopy using 12 levels, including 6 hematoxylin-eosin, l periodic acid–Schiff, l Jone’s silver, 1 trichrome, and 3 levels for additional stains when needed. Identification of focal and segmental changes were carefully determined after examining all 12 levels, particularly to help differentiate early FSGS from MCN. A diagnosis of chronic glomerulonephritis was made in patients with advanced renal insufficiency associated with nephrotic-range proteinuria in whom a specific primary glomerular diagnosis could not be determined because of glomerular obsolescence. This study also includes patients with biopsy-confirmed diabetic nephropathy, hypertensive nephrosclerosis, or chronic interstitial nephritis who were initially suspected to have primary glomerular disease before biopsy because of proteinuria of at least 2 g/d and medical histories inconsistent with these conditions as the cause for proteinuria. The relative frequency of each renal disease was calculated for each 5-year interval. The distribution of patients with varying renal biopsy diagnoses between 5-year intervals was calculated using Pearson’s chi-square analysis. The distribution of patients with each diagnosis for white, black, or Hispanic race; age; and sex was calculated for each 5-year interval, and data were analyzed using either Fisher’s exact test appropriate for contingency tables or chi-square analyses. P less than 0.05 is considered significant.

RESULTS

The relative frequencies of glomerular diseases in 616 adults who underwent biopsy for 2 g or greater of daily urinary protein are listed in Table 1. The number of biopsies increased during each time interval because of increased patient referrals for proteinuria and presumed glomerular diseases. It is possible that the introduction of ultrasound-guided renal biopsy at our medical center in 1990 facilitated the renal biopsy procedure and is responsible for a portion of the increase in patients who underwent biopsy in the final 5-year quartile. The relative frequency of idiopathic FSGS

879 Table 1. Relative Frequencies of Renal Diseases in Adults 5-Year Time Interval

No. of biopsies FSGS (%) MN (%) MCN (%) MPGN (%) IgA (%) CGN (%) DN (%) HN (%) CIN (%)

19751979

19801984

19851989

19901994

73 13.7 38.3 4.1 3.7 11.0 9.6 2.7 2.7 0.0

96 9.4 22.9 7.3 8.3 25.0 10.4 2.1 4.2 5.2

143 10.4 19.7 11.0 4.8 13.0 6.2 8.2 12.3 5.5

304 25.0* 14.5† 10.9 8.6 10.9 6.9 6.6 7.6 6.9

Abbreviations: IgA, IgA nephropathy; CGN, chronic glomerulonephritis; DN, diabetic nephropathy; HN, hypertensive nephrosclerosis; CIN, chronic interstitial nephritis. *P ⬍ 0.05 compared with the three earlier time intervals. †P ⬍ 0.01 compared with the three earlier time intervals.

increased significantly from 13.7% in the first quartile (1975 to 1979) to 25% in the last quartile (1990 to 1994; P ⬍ 0.05). The relative frequency of MN decreased significantly from 38.3% in the first quartile to only 14.5% in the last quartile (P ⬍ 0.01). An analysis of the various types of FSGS, such as the collapsing variants, was not performed. In addition, the percentage of FSGS for each 5-year quartile secondary to systemic diseases changed from 0%, 0%, and 12% to 6% in the last quartile. The percentage of MN for each 5-year quartile secondary to systemic diseases showed no trends, starting at 3% in the first quartile, increasing to 12% and 15% for the two midquartiles, and decreasing slightly to 6% in the last quartile. There were no significant changes in the relative frequencies of the other primary glomerular diseases. The relative frequency of patients with proteinuria of 2 g/d or greater who did not have idiopathic glomerular diseases increased from 6% in 1974 to 1979 to greater than 20% during 1985 to 1989 and 1990 to 1994 and included patients with diabetic nephropathy, hypertensive nephrosclerosis, or chronic interstitial nephritis. In the last 5 years (1990 to 1994), the yearly average of new patients with FSGS was 15 versus 7 patients for idiopathic MN (P ⬍ 0.05). Because idiopathic FSGS has been reported to be more common in blacks, data were analyzed for trends or differences in race, age, and sex.

880

BRADEN ET AL Table 3. FSGS and MN in Whites

Table 2. FSGS and MN in Blacks 5-Year Time Interval

Black % of biopsies Black % of FSGS FSGS % of black biopsies Black % of MN MN % of black biopsies

5-Year Time Intervals

19751979

19801984

19851989

19901994

16.7 0.0

25.0 11.1

23.3 15.4

17.4 22.6*

0.0 25.0

4.2 22.7

11.8 20.6

32.1† 18.9

58.3

20.8

17.6

13.2†

*P ⬍ 0.05 compared with 1975 to 1979 or 1980 to 1984. †P ⬍ 0.01 compared with 1975 to 1979 or 1980 to 1984.

The relative frequencies of FSGS and MN in blacks are listed in Table 2. The percentage of biopsies performed in black patients for each 5-year quartile over 20 years remained stable. However, the percentage of patients with FSGS who were black increased from 0% in 1974 to 1979 to 11% during the years 1980 to 1984 and 22.6% during 1990 to 1994 (P ⬍ 0.05). In addition, FSGS accounted for a greater percentage of idiopathic glomerular diseases in blacks, increasing from a percentage of only 4.2% during 1980 to 1984 to 32.1% during 1990 to 1994 (P ⬍ 0.01). The percentage of black patients with MN remained stable over the 20-year period. However, MN significantly decreased as a cause for idiopathic glomerular diseases in blacks from a percentage of 58% in the first quartile, 1975 to 1979, to only 13.2% in the last quartile, 1990 to 1994 (P ⬍ 0.01). Using National Census Data available to our medical center, the black percentage of the total population in our catchment area was 5.6% in 1980 and 6.5% in 1990. The relative frequencies of FSGS and MN in whites are listed in Table 3. There were no differences in the percentage of white patients who underwent biopsy over the 20-year period. The percentage of patients with FSGS who were white decreased because greater numbers of black and Hispanic patients emerged with this diagnosis. A slight increase in FSGS as a percentage of all white patients who underwent biopsy occurred from 15.8% during 1975 to 1979 to 23.2% during 1990 to 1994 (P ⬎ 0.05). In contrast, the majority of patients with MN were white, but MN decreased as a percentage of all white patients who underwent biopsy over the 20-year

White % of biopsies White % of FSGS FSGS % of white biopsies White % of MN MN % of white biopsies

19751979

19801984

19851989

19901994

78.1 100

56.3 55.5

53.8 69.2

59.5 56.0

15.8 75.0

9.3 77.2

24.0 72.4

23.2 81.1

36.8

31.5

28.0

16.6*

*P ⬍ 0.05 compared with 1975 to 1979 or 1980 to 1984.

period from a high of 36.8% during 1975 to 1979 to 16.6% during 1990 to 1994 (P ⬍ 0.05). A similar decrease in MGN occurred in black patients (Table 2). The relative frequencies of FSGS and MN in Hispanics are listed in Table 4. The percentage of Hispanic patients who underwent biopsy for presumed idiopathic glomerular diseases has not changed over the last 15 years. The percentage of patients with FSGS who were Hispanic decreased slightly over the last three quartiles because greater numbers of blacks and whites emerged with this diagnosis, but the percentage of Hispanic patients with FSGS increased from 0% during 1975 to 1979 to 24.6% during 1990 to 1994 (P ⬍ 0.05). There were no changes in the percentage of Hispanic patients with MN during the 20-year period. The relative frequencies of glomerular diseases in Hispanics during 1990 to 1994 are listed in Table 5. The most common glomerular disease in this population was IgA nephropathy (28.1%), followed by FSGS at Table 4. FSGS and MN in Hispanics 5-Year Time Interval

Hispanic % of biopsies Hispanic % FSGS FSGS % of Hispanic biopsies Hispanic % MN MN % of Hispanic biopsies

19751979

19801984

19851989

19901994

5.5 0.0

18.8 33.3

22.6 15.4

21.4 21.3

0.0 0.0

16.6 0.0

12.5 6.8

24.6* 8.1

0.0

0.0

6.3

4.6

*P ⬍ 0.05 compared with 1975 to 1979 or 1985 to 1989.

INCREASED FREQUENCY OF FSGS

881

Table 5. Relative Frequencies of Glomerular Diseases in Hispanics, 1990 to 1994

IgA FSGS MPGN MCN MN CGN DN

No.

%

18 16 15 5 3 5 2

28.1 25.0 23.4 7.8 4.7 7.8 3.1

NOTE. N ⫽ 64. Abbreviations: IgA, IgA nepropathy; CGN, chronic glomerulonephritis; DN, diabetic nephropathy.

25.0% and MPGN at 23.4%. MCN and MN accounted for only a small percentage of primary glomerular diseases in these patients. Using National Census Data available to our medical center, the Hispanic percentage of the total population in our catchment area was 4.7% in 1980 and 9.3% in 1990. Because FSGS and MN occur more frequently in men and MN is found more commonly with increasing age, we analyzed the data for trends in age or sex in Table 6.8 There were no significant trends in mean age or in man to woman ratios over the 20-year period to explain the increased frequency of FSGS and decreased frequency of MN. In addition, there were no significant trends in race, age, or sex for MCN, MPGN, or IgA nephropathy. DISCUSSION

Our study confirms that the changing incidence of idiopathic glomerular diseases in adults living in large metropolitan areas also occurred Table 6. Correlations of Age and Sex to FSGS and MN 5-Year Time Interval

Age (y) All biopsies FSGS MN Sex (% men) All biopsies FSGS MN

19751979

19801984

19851989

19901994

54 ⫾ 7 42 ⫾ 6 56 ⫾ 5

54 ⫾ 5 46 ⫾ 4 52 ⫾ 7

52 ⫾ 6 47 ⫾ 5 53 ⫾ 6

51 ⫾ 8 43 ⫾ 7 55 ⫾ 4

54.3 60.0 67.8

53.6 55.5 71.0

52.0 55.6 65.5

53.2 53.0 67.5

NOTE. Values expressed as mean ⫾ SE or percent.

in adults living in small urban and rural communities.4-7 Before these studies, the most common cause of idiopathic glomerular diseases, especially in older nephrotic patients, was MN, with a relative frequency of 30% to 50% in most studies.1-3 In the first 5 years of our study (1975 to 1979), MN was by far the most common idiopathic glomerular disease in both white and black patients. However, over time, the relative frequency of this disease has significantly decreased, and MN now comprises a relatively small portion of patients who undergo biopsy with presumed glomerular diseases at our medical center. In contrast, our study confirms that the incidence of idiopathic FSGS is increasing, and it is now the most common idiopathic glomerular lesion found at our medical center. The frequency of FSGS has increased in large metropolitan regions, but our patients live in either a small city, population 150,000, or rural areas.4-7 It is unlikely that the increase in the relative frequency of FSGS or the decrease in the relative frequency of MN in our study is caused by changes in the detection and diagnosis of FSGS or changes in the frequency of secondary causes of FSGS and MN. Because the number of tissue levels per biopsy examined by light microscopy was the same over the 20-year study period, it is unlikely that the emergence of FSGS in the later years of this study is caused by better detection or differentiation of FSGS from MCN. In addition, it is unlikely that the increase in the relative frequency of idiopathic FSGS is caused by a decrease in the number of patients with FSGS secondary to systemic diseases because the number of patients with secondary FSGS increased over the 20-year study period, along with increases in the frequency of idiopathic FSGS. Moreover, there were no increases in the percentage of secondary MN over the 20-year study period that could reduce the percentage of idiopathic MN. The percentage of secondary MN was 6% in both the first and last quartiles. We found a significant increase in the frequency of FSGS in both blacks and Hispanics over a 20-year period, and the relative frequency of FSGS increased slightly in whites but did not reach statistical significance. One study found the increase in FSGS occurred primarily in blacks, suggesting a genetic predisposition for blacks to develop FSGS.6,9 However, in the same city, another study found that over the last 20 years,

882

the relative frequency of FSGS increased in both whites and blacks.5 In addition, our study shows for the first time that Hispanic patients are also predisposed to develop FSGS. Because older patients and men are more likely to have membranous glomerulonephritis or FSGS, we analyzed our data for differences in age and sex for each of the four quartiles.8 No significant changes in age or sex over 20 years explained the increased frequency of FSGS or decreased frequency of MN. We found a decreased frequency of idiopathic MN in blacks and whites, but not Hispanics, over the last 20 years. This is in contrast to studies over the same 20-year period that showed the relative frequency of MN causing nephrotic syndrome in adults living in large metropolitan areas did not decrease and remained stable.4-7 Moreover, Korbet et al6 analyzed the last 20 years of renal biopsies performed at their medical center, and MN decreased slightly in blacks from 30% in 1975 to 1984 to 22% in 1985 to 1994. However, in this study, the incidence of MN in whites increased from 31% in 1975 to 1984 to 41% in 1985 to 1994. Our study included all patients with greater than 2 g/d of urinary protein, but not all patients had nephrotic syndrome. Patients in our study may have presented earlier or may have been diagnosed earlier with their primary glomerular disease, which could explain the differences in relative frequencies of FSGS and MN. The causes for idiopathic MN and FSGS are unknown. The difference in the relative frequencies of these two glomerular diseases was not associated with differences in sex ratio or age between groups. The recent confirmation that FSGS is the most common idiopathic glomerular disease in Saudi Arabia and the emergence of FSGS in whites, blacks, and Hispanic Americans underscore the possibility that a new etiologic factor, possibly environmental, may be responsible for the increase in FSGS.10 Conversely, MN is still the most common idiopathic glomerular disease in Italy.11 The majority of our Hispanic population have immigrated to our region from Puerto Rico. The relative frequencies of idiopathic glomerular diseases in Hispanics are different compared with whites or blacks. In particular, IgA nephropathy is the most common idiopathic glomerular dis-

BRADEN ET AL

ease in Hispanics, followed by FSGS and then MPGN. MN was identified in only a small percentage of Hispanic patients who underwent biopsy for idiopathic glomerular diseases. In addition, all Hispanic patients with MPGN had type I disease, except for one patient with densedeposit disease (type II). The frequencies of secondary renal diseases with moderate proteinuria, such as diabetic nephropathy, hypertensive nephrosclerosis, or chronic interstitial nephritis, have increased in the last decade. Although these observations may in part be caused by earlier renal biopsies performed in these patients because the biopsy procedure is facilitated by the ultrasound technique, the increase in these three diseases also occurred during 1985 to 1989, well before the ultrasoundguided gun technique was used at our institution. Our study confirms the utility of renal biopsy in patients with greater than 2 g/d of urinary protein excretion because other diseases were often found that are treated differently than primary glomerulonephritis. The finding that FSGS has increased more in the last 10 years in black and Hispanic Americans than whites suggests a possible genetic predisposition of these populations to develop FSGS.12 Black Americans may have a greater risk for developing hypertension, non–insulindependent diabetes, or end-stage renal disease because of a greater incidence of low birth weight compared with white Americans.13 Low birth weight is associated with reduced nephron mass, which theoretically could cause glomerular hyperfiltration, associated with the development of FSGS in five sixths of nephrectomy animal models13 and humans born with conditions associated with reduced nephron mass, such as oligomeganephronia.14,15 Whether these same changes could explain the emergence of FSGS in Hispanic Americans is unknown. The changing incidence of idiopathic glomerular diseases in our community has important implications for therapy. MN is generally considered a treatable form of glomerulonephritis, either with alternate monthly prednisone or chlorambucil therapy for 6 months or daily oral cytotoxic drugs.16-18 Remission rates as high as 75% have been reported in these studies. Conversely, there is controversy whether adults with idiopathic FSGS respond to glucocorticoid or

INCREASED FREQUENCY OF FSGS

cytotoxic therapy. Recent data suggest that patients with FSGS are undertreated and that up to 40% may respond to long-term prednisone therapy.19-22 However, at this time, there is no consensus as to the optimal therapy for this disease. Unfortunately, FSGS is now the most common idiopathic glomerular disease found at our medical center, and over the last 5 years, it is found twice as often as MN. The confirmation that the frequency of FSGS is increasing in white, black, and Hispanic Americans living in small urban, rural, or large metropolitan areas underscores the possibility that a new etiologic factor, possibly environmental, may be involved in the pathogenesis of idiopathic FSGS. ACKNOWLEDGMENT The authors thank Meri Kassanos for assistance in typing this manuscript and Penny Pekow for help in statistical analyses.

REFERENCES 1. Glassock RJ, Cohen AH, Adler SG: Primary glomerular diseases, in Brenner BM (ed): The Kidney (ed 4). Philadelphia, PA, Saunders, 1996, pp 1392-1497 2. Donadio JV: Treatment of glomerulonephritis in the elderly. Am J Kidney Dis 16:307-311, 1990 3. Abrass CK: Glomerulonephritis in the elderly. Am J Nephrol 5:409-418, 1985 4. Barisoni L, Velevi A, Radhakvishnen J, Nash M, Appel G, D’Agati V: Focal segmental glomerulosclerosis: A 20year epidemiological perspective. J Am Soc Nephrol 5:347A, 1994 (abstr) 5. Haas M, Spargo BH, Coventry S: Increasing incidence of focal-segmental glomerulosclerosis among adult nephropathies: A 20-year renal biopsy study. Am J Kidney Dis 5:740-750, 1995 6. Korbet SM, Genchi RM, Borok RZ, Schwartz MM: The racial prevalence of glomerular lesions in nephrotic adults. Am J Kidney Dis 5:647-651, 1996 7. Haas M, Meehan SH, Karrison TG, Spargo BH: Changing etiologies of unexplained adult nephrotic syndrome: A comparison of renal biopsy findings from 1976 to 1979 and 1995 to 1997. Am J Kidney Dis 5:621-631, 1997 8. Silbiger SR, Neugarten J: The impact of gender on the progression of chronic renal disease. Am J Kidney Dis 4:515-533, 1995

883

9. Bakir AA, Share DS, Levy PS, Arruda AL, Dunea G: Focal segmental glomerulosclerosis in adult African Americans. Clin Nephrol 5:306-311, 1996 10. Mitwalli AH, Al Wakeel JS, Al Mohaya SS, Malik HG, Abu-Aisha H, Hassan OS, Akhtar M: Pattern of glomerular disease in Saudi Arabia. Am J Kidney Dis 6:797-802, 1996 11. Stratta P, Segoloni GP, Canavese C, Sandri L, Mazzucco G, Roccatello D, Manganaro M, Vercellone A: Incidence of biopsy-proven primary glomerulonephritis in an Italian province. Am J Kidney Dis 5:631-639, 1996 12. Glicklich D, Haskell L, Senitzer D, Weiss RA: Possible genetic predisposition to idiopathic focal segmental glomerulosclerosis. Am J Kidney Dis 12:26-30, 1980 13. Hostester TH, Olson JL, Rennke HG, Brenner BM: Hyperfiltration of remnant nephrons: A potentially advanced response to renal ablation. Am J Physiol 241:F85-F93, 1981 14. Brenner BM, Chertow G: Congenital oligomeganephropathy and the etiology of adult hypertension and progressive renal injury. Am J Kidney Dis 23:171-175, 1994 15. Cohen JJ, Harrington JT, Madias NE: The many masks of focal segmental glomerulosclerosis. Kidney Int 46:1223-1241, 1994 16. Piccoli A, Pillon L, Passerini P, Ponticelli C: Therapy for idiopathic membranous nephropathy: Tailoring the choice by decision analysis. Kidney Int 45:1193-1202, 1994 17. Ponticelli C, Zucchelli P, Passerini P, Cesana B, Locatelli F, Pasquali S, Sasdelli M, Redaelli B, Grassi C, Pozzi C, Bizzarri D, Banfi G: A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int 48:1600-1604, 1995 18. Imperiale TF, Goldfarb S, Berns JS: Are cytotoxic agents beneficial in idiopathic membranous nephropathy? A meta-analysis of the controlled trials. J Am Soc Nephrol 5:1553-1558, 1995 19. Pei Y, Cattran D, Delmore T, Katz A, Lang A, Rance P: Evidence suggesting undertreatment in adults with idiopathic focal segmental glomerulosclerosis. Am J Med 82:938944, 1987 20. Banfi G, Moriggi M, Sabadini E, Fellin G, D’Amico G, Ponticelli C: The impact of prolonged immunosuppression on the outcome of idiopathic focal-segmental glomerulosclerosis with nephrotic syndrome in adults. A collaborative retrospective study. Clin Nephrol 3:53-59, 1991 21. Korbet SM, Schwartz MM, Lewis EJ: Primary focal segmental glomerulosclerosis: Clinical course and response to therapy. Am J Kidney Dis 6:773-783, 1994 22. Rydel JJ, Korbet SM, Borok RZ, Schwartz MM: Focal segmental glomerular sclerosis in adults: Presentation, course, and response to treatment. Am J Kidney Dis 4:534542, 1995