Nonlupus nephritides in patients with systemic lupus erythematosus: A comprehensive clinicopathologic study and review of the literature

Nonlupus Nephritides in Patients With Systemic Lupus Erythematosus: A Comprehensive Clinicopathologic Study and Review of the Literature ELZBIETA BARANOWSKA-DACA, MD, PHD, YEONG-JIN CHOI, MD, PHD, ROBERTO BARRIOS, MD, GEORGE NASSAR, MD, WADI N. SUKI, MD, AND LUAN D. TRUONG, MD Renal biopsy specimens from patients with systemic lupus erythematosus (SLE) rarely show changes that are pathogenetically and morphologically unrelated to SLE. The morphology and behavior of these nonlupus nephritides are not well known. Two hundred fifty-two renal biopsies performed on 224 patients with SLE collected from 3,036 native kidney biopsies performed between 1975 and 1998 were reviewed, and those that showed nonlupus nephritides (index biopsies) were selected for studies. Thirteen biopsy specimens with nonlupus nephritides were identified in 13 patients, who belonged to 3 clinically distinct groups. Group I included 6 patients in whom SLE was diagnosed at the time of index biopsies. The index biopsies in these patients showed focal segmental glomerusclerosis (FSGS; 3 cases), Immunoglobulin (Ig) M nephropathy (1 case), and thin basement membrane disease (1 case). The diagnostic features for FSGS included segmental sclerosis involving at least 1 glomerulus, absence of lupus nephritis or other conditions that may cause nonspecific segmental sclerosis of glomeruli such as ischemia or nephrosclerosis, and nephroticrange proteinuria. There was uniform, global, diffuse and marked thinning of the glomerular basement membrane in the case of thin basement membrane disease. Group II included 3 patients in whom SLE was diagnosed 2 to 9 years before the time of index biopsies and SLE was active at the time of biopsy. The index biopsies in these patients showed FSGS (2 cases) and hypertensive nephrosclerosis (1 case). Group III included 4 patients in whom

SLE was diagnosed 5 to 36 years before the time of index biopsies and SLE was inactive at the time of biopsy. The index biopsies in these patients showed 1 case each of amyloidosis, FSGS, hypertensive nephrosclerosis, and allergic acute tubulointerstitial nephritis. Previous renal biopsies, performed in 5 patients, showed IgM nephropathy (1 case), diffuse proliferative lupus GN (1 case), focal proliferative lupus GN (1 case), and mesangial proliferative lupus GN (2 cases). Follow-up biopsies, performed in 3 patients, confirmed the diagnosis of FSGS (2 cases) and hypertensive nephrosclerosis (1 case) noted in the index biopsies. Nonlupus nephritides may occasionally be encountered in SLE patients, regardless of clinical or serologic disease activity. These renal lesions display a broad morphologic spectrum in which FSGS seems most frequent. Renal biopsy plays a crucial role in identifying these lesions, which may have prognostic and therapeutic implications distinct from those of lupus nephritis. HUM PATHOL 32:1125-1135. Copyright © 2001 by W.B. Saunders Company Key words: systemic lupus erythemotasus, lupus nephritis, nonlupus nephritides, renal biopsy. Abbreviations: SLE, systemic lupus erythematosus; GN, glomerular nephritis; WHO, World Health Organization; ARA, American Rheumatism Association; Ig, immunoglobulin; ANA, antinuclear antibody; FSGS, focal segmental glomerulosclerosis; NSAID, nonsteroidal anti-inflammatory drug; TIN, tubulointerstitial nephritis; EM, electron microscopy; IF, immunofluorescence; SAA, serum amyloid A.

Renal involvement is frequent in systemic lupus erythematosus (SLE) and is collectively called lupus nephritis. This complication may be diagnosed clinically in approximately 50% of patients, however, a much higher frequency has been reported in renal biopsies.1-4 Although lupus nephritis can selectively involve any renal compartment, the glomerulus is the most frequent target. Lupus glomerulonephritis (GN) is divided into 6 distinct morphologic classes according to the World Health Organization (WHO) classification (normal, mesangial proliferative, focal

proliferative, diffuse proliferative, membranous, and advanced sclerosing GN), each of which can have variable grades of severity and chronicity.5 Because the type and extent of renal involvement may not be predicted accurately by clinical or serologic criteria, renal biopsies are frequently performed in SLE patients.6,7 It is generally assumed that in a patient with well-documented SLE, renal abnormalities are caused by lupus nephritis. Thus, renal biopsy is recommended not for diagnostic purposes, but rather to determine the type and extent of renal involvement and aid in therapeutic decisions. However, clinically significant renal diseases unrelated to lupus nephritis have rarely been described in patients with SLE. Because there are only isolated reports of these cases,8-25 we have attempted to systematically study the frequency, morphologic spectrum, and clinical implication of the nonlupus nephritides in patients with SLE and compare our findings with those reported in the literature.

From the Renal Pathology Laboratory, Department of Pathology, and the Renal Section, Department of Medicine, the Methodist Hospital and Baylor College of Medicine, Houston, TX. Accepted for publication May 23, 2001. Address correspondence and reprint requests to Luan D. Truong, MD, Department of Pathology, MS 205, The Methodist Hospital, Houston, TX 77030. Copyright © 2001 by W.B. Saunders Company 0046-8177/01/3210-0015$35.00/0 doi:10.1053/hupa.2001.28227

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MATERIALS AND METHODS Case Selection

Renal Biopsies

Among a total of 3,036 native kidney biopsy specimens obtained by the Renal Pathology Laboratory, Baylor College of Medicine, between 1975 and 1998, 252 (8.3%) were obtained from 224 patients with a clinical history of SLE. Initial review showed that 29 of these 252 biopsy specimens in 25 patients had features unrelated to lupus nephritis and were evaluated further. Because the clinical diagnosis of SLE at the time of renal biopsy can be inaccurate, careful review of the clinical records of these 25 patients, with a follow-up of 6 months to 6 years, was performed, and only patients who fulfilled the well-accepted American Rheumatism Association (ARA) criteria for SLE (at least 4 of 11 criteria present serially or simultaneously during the course of the disease) were included in this study. In addition, a positive antinuclear antibody (ANA) result was a prerequisite for inclusion. Other types of autoantibodies such as anti-dsDNA were also sought and were considered specific markers of the disease but not required for the diagnosis of SLE when at least 4 ARA criteria had been fulfilled. Only cases with adequate biopsy material (cortical tissue with at least 10 glomeruli) were included. These strict criteria led to elimination of 12 cases (9 without a conclusive diagnosis of SLE and 3 without adequate renal biopsy specimens), leaving 13 patients for final analysis.

Clinical Findings Data were abstracted from patients’ records. Whether SLE was active at the time of renal biopsy was determined for each patient. In this context, active SLE was recognized by the presence of at least 1 ARA criterion at the time of index biopsies for patients receiving maintenance therapy for SLE or at least 4 ARA criteria, which do not include renal abnormalities, in patients not receiving treatment.

Each of the 13 patients in this study had at least 1 biopsy that first established the diagnosis of nonlupus nephritides (index biopsies). Five preceding and 3 follow-up renal biopsies were also performed in 6 and 3 patients, respectively.

RESULTS Clinical Findings Patients were divided into 3 groups depending on SLE activity at the time of index biopsies. Group I. This group included 6 patients (patients 1 through 6) in whom SLE was first diagnosed at the time of index biopsies (Table 1). Each patient had multiorgan involvement fulfilling 4 to 8 ARA criteria (arthritis in 5, cytopenia in 6, muco-cutaneous lesions in 4, and neurologic symptoms in 1 patient). ANA with a titer of 1/40 to 1/640 was noted in each patient. There was also anti-dsDNA antibody (4 patients), anti-Sm antibody (1 patient), anti-SSA antibody (1 patient), and decreased complement components (1 patient). The index biopsies from these 6 patients showed thin basement membrane disease (1 case), focal segmental glomerulosclerosis (FSGS; 3 cases), and immunoglobulin (Ig) M nephropathy (2 cases). Proteinuria (1.5 to 6.6 g/d) was present in 5 patients, active urine sediments in 5, decreased renal function (serum creatinine, 1.6 to 3.8 mg/dL; creatinine clearance, 31 to 58 mL/min) in 4. Six to 72 months after the index biopsies, 3 patients (2 with FSGS and 1 with IgM nephropathy) had less proteinuria and lower serum creatinine levels. The other 3 patients, who had thin basement

TABLE 1. Clinicopathologic Features of Patients in Group I (SLE Diagnosed at Time of Index Renal Biopsy) SLE Diagnosed by

Findings at Time of Renal Biopsy

Case

Age (yr)

Sex

ARA Criteria

ANA

AntidsDNA

Prot (g/d)

Urine Sediment

SCr (mg/dL)

CCr (mL/min)

S Com* (mg/dL)

1 2 3 4 5 6

39 53 42 25 44 32

F M F F F F

6 6 4 4 8 4

1:640 Positive 1:40 1:320 1:40 1:320

Negative Positive Positive Positive Positive Negative

None 6.1 3.0 3.0 1.5 6.6

RBCs Casts Normal RBCs, WBCs RBCs RBCs, WBCs, casts

0.8 3.8 2.1 1.6 2.0 0.5

NA 35 31 38 58 106

C3, 128 C4, NA C3 NA C4 NA C3, 126 C4, 43 C3, 164 C4, 27 C3, 33 C4, 3 C3, 127 C4, 23

Follow-up

Case

Renal Biopsy Diagnosis

1 2 3 4 5 6

Thin basement membrane FSGS FSGS FSGS IgM nephropathy IgM nephropathy

Treatment Steroid Steroid, Steroid, Steroid, Steroid, Steroid,

cyclophosphamide, ACEI ACEI AT1 receptor antagonist ACEI hydroxychloroquine, ACEI

Duration (yr)

Prot (g/d)

SCr (mg/dL)

CCr (mL/min)

0.5 5 0.5 2 6 0.8

None† 1⫹† 3.3 0.13 None† 6.0

0.7 1.4 2.0 1.4 1.1 0.4

NA NA 35 54 84 NA

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; AT1 receptor, angiotensin receptor, type 1; casts, granular casts; CCr, creatinine clearance; NA, not available; prot, proteinuria; RBCs, red blood cells ⬎ 5/hpf; S Com, serum complement levels; SCr, serum creatinine; WBCs, white blood cells ⬎ 5/hpf. *Normal ranges: C3, 60 to 140 mg/dL; C4, 20 to 50 mg/dL. †By urinalysis.

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membrane disease, FSGS, and IgM nephropathy, respectively, did not improve. Group II. This group included 3 patients (patients 7 through 9) in whom SLE was diagnosed before the index biopsy was performed, and the disease was active at that time (Table 2). Patient 7 had SLE first diagnosed 7 years before the index biopsy (ANA 1:5,120, positive anti-dsDNA, and biopsy-documented diffuse lupus GN). Clinical remission and reversal of the renal abnormalities were achieved after 2 years of steroid and cyclophosphamide therapy. Therapy was discontinued. Four years before the index biopsy, proteinuria developed. At the time of index biopsy, the patient had proteinuria of 14 g/d, serum creatinine 1.7 mg/dL, creatinine clearance 36 mL/min, and active SLE, but C3 and C4 serum levels were normal. The index biopsy showed FSGS. At follow-up at 6 months, proteinuria and renal failure persisted. Patient 8 had SLE diagnosed 2 years before the index biopsy (rash, alopecia, oral ulcers, arthritis, anemia, lymphopenia, pleuritis, decreased serum C3, ANA 1:640, positive anti-RNP, anti-Sm, anti-dsDNA, and anticardiolipin antibodies). She developed hypertension and proteinuria of 16 g/d, but the serum creatinine level was normal. The index biopsy shows FSGS. Two years later, a repeat biopsy also showed FSGS and the nephrotic syndrome persisted, but the serum creatinine level remained normal. Patient 9 had SLE diagnosed 9 years before the index biopsy (ANA 1:320, positive anti-dsDNA, biopsydocumented segmental proliferative lupus GN). After 2 years of oral steroid therapy, SLE remitted and there were no renal abnormalities. SLE subsequently re-

curred with poorly controlled hypertension, proteinuria 2.8 g/d, serum creatinine 2.4 mg/dL, and creatinine clearance 45 mL/min. The index biopsy showed only hypertensive nephrosclerosis. Twenty-five months later, although SLE was in remission, renal abnormalities worsened (proteinuria 3 g/d, creatinine clearance 35 mL/min); a repeat renal biopsy was done and showed more severe hypertensive nephrosclerosis. Six months later, SLE remained in remission but the renal abnormalities persisted. Group III. This group included 3 patients (patients 10 through 13) in whom SLE was diagnosed before the index biopsy was performed, but the disease was inactive at that time (Table 3). Patient 10 had SLE diagnosed 36 years before the index biopsy (4 ARA criteria, including positive ANA and positive anti-DNA). Twelve months of prednisone and adrenocorticotropin therapy resulted in remission of both SLE and renal abnormalities, but low-dose steroid therapy maintained during the next 35 years. Renal abnormalities subsequently developed (proteinuria of 3.6 g/d, serum creatinine 1.3 mg/dL, and creatinine clearance 60 mL/min), but SLE remained inactive. The index biopsy showed amyloidosis. Patient 11 had SLE diagnosed 18 years before the index renal biopsy (6 ARA criteria, including positive ANA and positive DNA, and biopsy-documented mesangial lupus GN). During that time, she also had mild proteinuria (0.7 g/d) and normal renal function. Six years of therapy with steroids and cyclophosphamide resulted in remission of both SLE and renal abnormalities. Nephrotic syndrome subsequently developed, but renal function remained normal and SLE remained inactive. The index biopsy showed FSGS. A renal biopsy

TABLE 2. Clinicopathologic Features of Patients in Group II (SLE Diagnosed Previously and Active at Time of Index Renal Biopsy) SLE Diagnosed by

Case

Age (yr)

Sex

ARA Criteria

ANA

AntidsDNA

SLE Duration (yr)

7

31

F

6

1:5, 120

Positive

7

ANA 1:640, positive anti-DNA, arthritis, seizure

8

48

F

8

1:640

Positive

2

9

42

F

5

1:320

Positive

9

ANA 1:640, positive anti-DNA, malar and discoid rash, pleuritis, lymphopenia, anemia, normal serum C4, ANA 1:320, positive anti-DNA, thrombocytopenia, leukopenia, anemia

SLE Activity at the Time of Index Biopsy

Findings at Time of Renal Biopsy

Follow-up

Prot Urine SCr CCr S Com* Renal Case (g/d) Sediment (mg/dL) (mL/min) (mg/dL) Biopsy Diagnosis 7

14

WBCs

1.7

36

8

16

Normal

0.9

NA

WBCs

2.4

45

9

2.8

C3, 141 C4, 23 C3, NA C4, NA

FSGS FSGS

Treatment Steroid, cyclophosphamide, ACEI Steroid, hydroxychloroquine, ACEI

C3, 162 Hypertensive Steroid, ACEI C4, 47 nephrosclerosis

*Normal ranges: C3, 60 to 140 mg/dL; C4, 20 to 50 mg/dL.

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Duration Prot SCr CCr (yr) (g/d) (mg/dL) (mL/min) 0.5

16.3

2.8

32

2.0

6.0

1.2

47

2.5

3.0

3.2

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TABLE 3. Clinicopathologic Features of Patients in Group III (SLE Diagnosed Previously But Inactive at Time of Index Renal Biopsy) SLE Diagnosed by

Findings at Time of Renal Biopsy

Case

Age (yr)

Sex

ARA Criteria

ANA

AntidsDNA

SLE Duration (yr)

Prot (g/d)

Urine Sediment

SCr (mg/dL)

CCr (mL/min)

10 11 12 13

60 43 48 28

F F F F

4 6 6 4

Positive Positive Positive Positive

Positive Positive Negative Positive

36 18 26 5

3.6 3.4 2.3 0.3

Normal RBCs RBCs, WBCs RBCs, casts

1.3 0.8 2.5 8.7

60 102 49 5

S Com* (mg/dL) C3, C3, C3, C3,

103 C4, 34 163 C4, 32 152 C4, 24 NA C4, NA

Follow-up

Case

Renal Biopsy Diagnosis

Treatment

10 11 12 13

Amyloidosis FSGS Hypertensive nephrosclerosis Acute TIN

Steroid Steroid ACEI Steroid, cyclophosphamide, hydroxychloroquine

Duration (yr)

Prot (g/d)

SCr (mg/dL)

CCr (mL/min)

0.5 3 0.5 1.5

3.8 7.0 4⫹† None

1.4 1.1 2.0 0.8

58 62 NA 105

*Normal ranges: C3, 60 to 140 mg/dL; C4, 20 to 50 mg/dL. †By urinalysis.

repeated 1 year later showed more advanced FSGS. Three years after the index biopsy, nephrotic syndrome persisted and renal function had deteriorated. Patient 12 had SLE diagnosed 26 years before the index biopsy (6 ARA criteria, including positive ANA, and biopsy-documented mesangial proliferative lupus GN). After 25 years of treatment with steroids plus various antihypertensive agents, which was stopped 10 months before the index biopsy, she developed poorly controlled hypertension, proteinuria of 2.3 g/d, serum creatinine 2.5 mg/dL, and creatinine clearance 49 mL/min, but SLE was not active at that time. The index biopsy showed hypertensive nephrosclerosis. The renal abnormalities were unchanged six months later. Patient 13 had SLE diagnosed 5 years before the index renal biopsy (4 ARA criteria, including positive ANA and anti-dsDNA). Three years of treatment with steroid and hydroxychloroquine resulted in remission of both SLE and renal abnormalities. She subsequently developed fever, pulmonary infiltrate, acute renal failure (creatinine clearance decreased from normal to 5 mL/min within a week), and minimal proteinuria (0.3 g/d) that were associated temporally with ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs). The index biopsy showed acute tubulointerstitial nephritis (TIN). Renal function normalized 2 months later and remained normal 18 months afterward. Renal Biopsy Findings The results are summarized in Table 4. Index Biopsies. The 13 index biopsy specimens included FSGS (6 specimens), IgM nephropathy (2 specimens), hypertensive nephrosclerosis (2 specimens), amyloidosis (1 specimen), thin basement membrane disease (1 specimen), and acute TIN (1 specimen). The 6 specimens with FSGS showed segmental sclerosis of 5% to 20% of glomeruli, with most of the

remaining glomeruli being open and displaying mild mesangial sclerosis with or without associated mesangial cell hypercellularity. The sclerotic areas were associated with hyalinosis in 4 biopsy specimens, foamy macrophages in 1, and involvement of tubular pole (glomerular tip lesion) in another (Fig 1A and B). Immunofluorescent (IF) studies showed IgM, C3 and C4 in 1, IgM and C3 in 3, IgM only in 1, and C3 only in 1 biopsy specimen; the staining was focal segmental in 4 and diffuse global or segmental in 2 but always limited to the mesangium or sclerotic areas. Electron microscopy (EM) studies revealed an absence of electrondense deposits in 2 biopsy specimens; however, rare small mesangial electron-dense deposits were noted in 3 specimens. The 2 biopsy specimens with IgM nephropathy showed mild to moderate mesangial sclerosis and hypercellularity associated with global diffuse, moderate to strong mesangial staining for IgM by IF (Fig 2A and B). One biopsy specimen also showed small mesangial electron-dense deposits. The 2 biopsy specimens with hypertensive nephrosclerosis was characterized by segmental or global glomerular capillary wall collapse and wrinkling involving most glomeruli, associated with moderate/severe chronic tubulointerstitial injury and severe fibrous intimal thickening of arterial blood vessels (Fig 3). Although patchy, weak glomerular staining for C3 and IgM was seen in 1 biopsy, EM studies did not show electron-dense deposits. The biopsy specimen with thin basement membrane disease was characterized by diffuse thinning (170 ⫾ 29 nm) of the glomerular basement membrane without significant light microscopic or IF changes. The biopsy specimen with amyloidosis, AA type, is characterized by Congo red–positive, haphazardly arranged, nonbranching fibrils in glomeruli, tubular

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TABLE 4. Renal Biopsy Findings Glomeruli

Patient

Diagnosis of the Index Biopsy

Additional Renal Biopsies

Global Segmental Total Sclerosis Sclerosis

Light Microscopy Findings

IF Findings

EM Findings

1

Thin basement membrane disease

28

0

0

Normal

Negative

2

FSGS

42

0

6

3

FSGS

21

6

3

4

FSGS

20

5

1

5

IgM nephropathy

44

6

0

C3 and IgM mesangial F S C3 C4 and IgM No deposits mesangial F S Rare, small mesangial C3 and IgM mesangial F deposits S IgM mesangial Rare, small mesangial deposits G D, C3 mesangial F S

6

IgM nephropathy

11

0

0

7

FSGS

10

0

2

8

FSGS

22

2

2

9

Hypertensive nephrosclerosis

21

11

1

10

Amyloidosis

86

4

0

FSGS and hyalinosis, 2⫹ tubulointerstitial damage FS GS and hyalinosis, 2⫹ tubulointerstitial damage Glomerular tip lesion 1⫹tubulointerstitial damage G D mild mesangial sclerosis and hypercellularity, 2⫹ tubulointerstitial damage G D mild mesangial sclerosis and hypercelularity, normal tubules and interstitium F S GS, FS mild mesangial sclerosis and hypercellularity, 1⫹ tubulointerstitial damage F S GS, hyalinosis and foamy macrophages, F S mild mesangial sclerosis, 2⫹ tubulointerstitial damage FS collapse of glomerular caplllaries, 2⫹ tubulointerstitial damage, severe vascular intimal thickening Amyloid in glomeruli, tubular basement membrane, interstitium

11

FSGS

28

1

2

F S GS with hyalinosis, 1⫹ tubulointerstitial damage

12

Hypertensive nephrosclerosis

13

8

0

13

Acute TIN

11

2

0

F G or S collapse of glomerular capillaries, F S moderate mesangial sclerosis and hypercellularity, 3⫹ tubulointerstitial damage, severe vascular intimal thickening Normal glomerull, interstitial edema, mononuclear inflammatory cell infiltrate

Diffuse thinning of the glomerular basement membrane, no deposits Rare subepithelial deposits

IgM mesangial No deposits GD

Rare, small mesangial C3 and IgM mesangial G deposits D C3 mesangial S or G D

Rare, small mesangial and subendothelial deposits

C3 and IgM mesangial F S, C3 and IgM in sclerotic glomerull

No deposits

Amyloid fibrils, no C3 and C4 mesangial F deposits S, IgG in glomerular and tubular cell nuclei IgM mesangial No deposits FS

NA

NA

Follow-up Biopsy (yr)

None

None

None

None

Mebranous lupus GN (8)

Normal glomeruli, no deposits

None

None

None

None

None

None

None

Diffuse proliferative lupus GN(7)

None

None

FSGS (2)

Segmental proliferative lupus GN(11)

Hypertensive nephrosclerosis (2)

None

None

Segmental proliferative lupus GN (18), membranous lupus GN(17) Collapse and wrinkling Mesangial lupus of glomerular GN (26) basement membrane, no deposits

Abbreviations: D, diffuse; deposits, immune-type electron-dense deposits; F, focal; G, global; S, segmental.

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None

FSGS (1)

None

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FIGURE 3. Hypertensive nephrosclerosis (patient 9) characterized by global glomerulosclerosis (G), tubular atrophy, interstitial fibrosis and mild chronic inflammation, and marked fibrous thickening of the arterial intima (arrowhead). (Hematoxylin and eosin, original magnification ⫻500.)

FIGURE 1. Focal segmental glomerulosclerosis. (A) This glomerulus (patient 3) shows an area of segmental sclerosis characterized by expansion of the extracellular matrix and obliteration of the glomerular capillaries. (Periodic acid–Schiff, original magnification ⫻1,160.) (B) This glomerulus (patient 4) also shows segmental sclerosis associated with proliferation of visceral epithelial cells. (Hematoxylin and eosin, original magnification ⫻1,160.)

basement membrane, and interstitium, which were stained positive by an anti-AA amyloid antibody (Figs 4 and 5). The biopsy specimen with acute TIN showed interstitial edema and mononuclear inflammatory cell infiltrates and normal glomeruli and blood vessels (Fig 6). Features of lupus nephritis were not seen in any cases. Specifically, endocapillary or extracapillary cell proliferation, a full-house IF pattern characterized by simultaneous presence of the multiple immunoglobulins and complement components, and abundant electron-dense deposits or tubuloreticular inclusions were absent. Previous Renal Biopsies. Five renal biopsies were performed in 5 patients (patients 2, 7, 9, 11, and 12) 3 to 26 years before the index biopsies. The diagnoses of these biopsies and of the corresponding index biopsies are listed in the Table 4.

FIGURE 2. IgM nephropathy (patient 6). (A) This glomerulus shows global, mild mesangial sclerosis and hypercellularity. (Periodic acid-Schiff, original magnification ⫻1,600.) (B) Global mesangial IF staining for IgM. (Original magnification ⫻2,000.)

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FIGURE 4. Amyloidosis (patient 10). Glomerular amyloid deposition (arrowheads) is present but features of proliferative glomerulonephritis are not seen. (Hematoxylin and eosin, original magnification ⫻1,160.)

Follow-up Biopsies. Three follow-up renal biopsies were performed in 3 patients (patients 8, 9, and 11). They confirmed the diagnoses of FSGS, hypertensive nephropathy, and FSGS, respectively, noted initially in the corresponding index biopsies. DISCUSSION Renal biopsy specimens from patients with SLE rarely show changes that are pathogenetically and mor-

phologically unrelated to SLE.8-25 Among approximately 36 previously reported cases of nonlupus nephritides in patients with SLE, renal amyloidosis was diagnosed in more than half (approximately 20 cases),17-23 and the rest showed a broad spectrum of lesions including FSGS, minimal-change disease, IgA nephropathy, infection-related GN, glomerulocystic kidney disease, necrotizing glomerulitis, sarcoidal tubulointerstitial nephritis, and NSAID-induced TIN.8-16,24,25 Although biopsy-proven lupus GN was documented previously in a few of these patients,9,11,13,17 subsequent renal biopsy specimens in all of them showed exclusively or predominantly changes unrelated to lupus nephritis.8-25 Although SLE was active in approximately half of these patients at the time of these biopsy specimens, the nonlupus nephritides accounted for the renal manifestations at the time of biopsy as well as the renal outcome.8-25 In spite of their fascinating biologic implication and obvious clinical significance, nonlupus nephritides seen in patients with SLE remain poorly understood and are limited to isolated case reports.8-25 Because the clinical manifestations of SLE are protean and nonspecific, rigorous clinical criteria were used to select SLE patients for this study. Each of the 13 patients in the study met or (in 8 cases) exceeded the minimum criteria for SLE proposed by the ARA, including positive ANA, usually of high titer. Although the ANA titer at first was low (1:40) in 2 patients (patients 3 and 5), each of them also had positive antidsDNA results and numerous other ARA criteria, leaving little doubt about the diagnosis of SLE. Likewise,

FIGURE 5. Amyloidosis (patient 10). The amyloid deposits appear ultrastructurally as haphazardly distributed, nonbranching fibrils as shown in the inset. (Electron miscroscopy; original magnification ⫻11,000 for the large panel and ⫻50,000 for the inset.)

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FIGURE 6. Acute TIN (patient 13) characterized by interstitial edema and mononuclear inflammatory infiltrates. (Hematoxylin and eosin, original magnification ⫻500.)

the broad morphologic spectrum of lupus nephritis has dictated strict adherence to morphologic requirements, in terms of tissue adequacy and diagnostic criteria, for the diagnosis of nonlupus nephritides. The results suggest that nonlupus nephritides, identified in 5% of 252 renal biopsy specimens from SLE patients, are not exceptional. Within this group, although FSGS (encountered in 6 patients) is most frequent, other entities, including NSAID-related allergic acute TIN, amyloidosis, IgM nephropathy, hypertensive nephrosclerosis, and thin basement membrane disease, may also be encountered. Data from this study suggest that renal diseases other than lupus nephritis should be clinically suspected in patients with serologic and clinical remission of lupus activity who nevertheless present with severe renal abnormalities, including heavy proteinuria, markedly decreased renal function, and acute renal failure. This manifestation was noted in 4 (30%) of our 13 patients. However, in the other 9 patients, systemic lupus was first diagnosed or ongoing when nonlupus nephritides were identified. These findings, in addition to the occasional but well-documented discrepancy between the type and severity of lupus nephritis and the clinical and/or serologic indicators of the disease, suggest that only renal biopsy can provide an accurate answer. FSGS in the current study can be differentiated from advanced sclerosing lupus GN. Sclerosing lupus GN usually represents the common final pathway of other forms of lupus GN but can rarely be identified in an initial biopsy specimen taken early in the course of SLE.3,5,26-30 It is characterized by predominantly global sclerosis involving most glomeruli, in which residual lupus activity such as hypercellularity, multi-immunoglobulin deposition, or electron-dense deposits is still recognizable3,28,29; there is also severe tubulointerstitial damage.3,5,30 In contrast, each of the 6 renal biopsy specimens with FSGS in our study had typical features

of this entity, including segmental or global sclerosis involving 5% to 20% and 0% to 29% of the glomeruli, respectively, whereas the remaining glomeruli either were normal or had only focal, segmental mild mesangial sclerosis or hypercellularity. IF and EM studies were performed in each case; in 5 cases, these studies showed no changes, only weak focal, segmental mesangial IgM, and/or diffuse global or segmental C3, correlating with a few small, ill-defined electron-dense materials in the same areas of the open glomerular capillaries. These features, well known in cases of FSGS, tend to refute the possibility of immune-mediated GN, including lupus GN.26 In the remaining case, global diffuse and strong mesangial IgM was noted, supporting the diagnosis of FSGS because this pattern of IF finding is frequently seen in FSGS but not in lupus GN.26 In addition, there were only mild to moderate tubulointerstitial changes in the biopsy specimens with FSGS, whereas these changes should be severe in advanced sclerosing lupus GN. Features of lupus GN, including abundant immune-type electron-dense deposits, a full-house IF pattern, or tubuloreticular inclusions, were not present in any of the 6 biopsy specimens with FSGS. The structural difference between FSGS and advanced sclerosing lupus GN is reflected in the diverse renal manifestations of these 2 conditions. Thus, patients with FSGS typically have nephrotic proteinuria (3 to 16 g/d in our cases) and normal to moderately decreased renal function (serum creatinine 0.9 to 3.8 mg/dL in our cases),31,32 in contrast with subnephrotic proteinuria and pronounced renal failure encountered in patients with advanced sclerosing lupus GN.3,33 FSGS encountered in this study probably does not represent healed focal proliferative lupus GN. Healed focal proliferative lupus GN, by definition, is preceded by active focal proliferative lupus GN and shares some clinical and morphologic features with advanced sclerosing lupus GN. On the other hand, each of the 6 biopsy specimens with FSGS in this study shows typical features of this entity. None of them was preceded by focal proliferative lupus GN (3 [from patients 3, 4, and 8] were from the initial biopsies; 1 [from patient 2] was preceded by IgM nephropathy, a well-known precursor of FSGS34,35; and the last 2 [from patients 7 and 11] were preceded by diffuse proliferative and mesangial lupus GN, respectively, 7 to 18 years earlier). The common course of the 2 patients with previous lupus GN, characterized by remission of both SLE and renal abnormalities for a long period before the development of nephrotic syndrome and mild renal failure, is compatible with a de novo process rather than progressive lupus GN. Finally, follow-up biopsies confirmed the diagnosis of FSGS in 2 of these cases. Review of large series of lupus nephritis3,26,36-46 identified brief citation of rare biopsy-documented cases of FSGS, and the possibility of a process unrelated to lupus GN was raised by the original investigators.3,26. In addition, to the best of our knowledge, 3 cases of FSGS in SLE patients have been reported in detail.8,9 The collective data on these 3 cases and 6 other cases from the current study indicate that FSGS could have

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existed when SLE was first diagnosed or developed after a long period of remission characterized by absence of SLE activity and renal abnormalities. However, at the time of FSGS diagnosis, SLE might have recurred or continued to be in remission. All patients presented with the nephrotic syndrome; normal or, more frequently, moderately decreased renal function; and hypertension. FSGS was preceded 3 to 18 years previously by renal abnormalities, which were related mostly to lupus GN (proliferative in 2 cases and membranous in 2 cases) and less frequently to other types of GN (IgM nephropathy in 1 case). The renal abnormalities were reversed with treatment and remained so for a long time, even after treatment was stopped, before FSGS supervened. At last follow-up (0.5 to 5 years; mean, 2.6 years), 2 patients had marked improvement of proteinuria (3.0 g/d v 0.13 g/d and 6.1 g/d v 1⫹), but the renal abnormalities persisted in the others. One patient in our study (patient 13) had acute renal failure secondary to acute TIN, probably related to NSAID use. This diagnosis was supported by acute tubulointerstitial changes with no significant vascular or glomerular damage and an absence of electrondense deposits or immunoglobulins in the tubulointerstitial compartment, together with a history of NSAID ingestion. It was also confirmed by resolution of renal failure after a short course of steroid therapy. Acute TIN in our case can be differentiated from primary lupus TIN. Primary lupus TIN is characterized by severe tubulointerstitial injury without glomerular or vascular involvement. Among 9 cases of primary lupus TIN previously reported,47-53 chronic changes in the tubulointerstitial compartment were noted in 7 and acute changes in 2; deposition of immunoglobulins and complement components along the tubular basement membrane or within the interstitium was recorded in at least 7 cases. To the best of our knowledge, only 1 other case of non-lupus TIN, also related to NSAID use, has been reported in SLE patients.25 Although amyloidosis was identified in only 1 patient (patient 10) in our study, it is the most frequent type of nonlupus renal involvement in SLE patients, with approximately 20 reported cases.17-23 Observations from these cases indicate that the delay between the diagnosis of SLE and the onset of symptomatic amyloidosis varies from 1 to 35 years, and approximately half of the cases are first detected within 5 years. The course of SLE before the development of amyloidosis in these patients did not follow any clear pattern and ranged from chronic fluctuating activity to prolonged clinical and serologic remission, as in the current case. In a few patients in whom the type of amyloidosis was investigated, AA type was identified.17 Amyloidosis complicating SLE has a poor prognosis; the affected patients did not respond to treatment, developed systemic involvement, and died of the disease. Thin basement membrane disease, IgM nephropathy, and hypertensive nephrosclerosis were diagnosed in 1, 2, and 2 patients, respectively, in our study. Although focal segmental mild thinning of the glomerular basement membrane is occasionally noted in a large

variety of glomerular diseases, the diagnosis of thin basement membrane disease in the current study was substantiated by marked and uniform thinning of the glomerular basement membrane of all evaluated glomerular capillaries (170 ⫾ 29 nm v 310 ⫾ 35 nm for normal control). The diagnosis of IgM nephropathy was supported by mild mesangial sclerosis and hepercellularity with global diffuse strong mesangial IgM staining and absence of other immunoglobulins. Although IgM nephropathy may be confused with mesangial proliferative lupus nephritis by light microscopy, the latter is characterized by an almost constant presence of mesangial IgG and C3 and unequivocal immune-type mesangial electron-dense deposits30; these features are not present in IgM nephropathy.54,55 Although heavy proteinuria was noted at the time of index biopsy for both cases of hypertensive nephrosclerosis (2.8 and 2.3 g/d), this feature is now well accepted as a renal manifestation of systemic hypertension.56,57 To the best of our knowledge, these 3 conditions have not been previously reported as the exclusive cause of the renal abnormalities in SLE patients. How nonlupus nephritides develop against the background of SLE remains poorly understood and probably differs among reported conditions. The association between SLE and entities such as thin basement membrane disease, IgM nephropathy, and hypertensive nephrosclerosis reported herein, as well as IgA nephropathy,10 minimal-change disease,13 and infectionrelated GN15 previously recorded, is probably fortuitous. On the other hand, amyloidosis and FSGS, which occurred in SLE patients with much higher frequency than the other entities, may be pathogenetically related to SLE. It is well documented that the serum levels of several proteins, collectively called acute-phase reactants, are increased in SLE patients.58,59 One of these proteins is serum amyloid A (SAA) protein, which can potentially deposit in various tissues including kidney and accounts for the observation that, when subtyped, the SLE-associated amyloidosis is of AA type.59 Because elevated SAA levels are frequent in SLE patients, contrasting with the rarity of the complicating amyloidosis, additional yet undetermined factors must be present in selected patients to promote tissue deposition of SAA. How FSGS develops in SLE patients is not known. The FSGS diagnosed in the current study probably does not represent healing or advanced stages of other forms of lupus GN for reasons mentioned previously. Alternatively, this form of FSGS may not be related to lupus GN per se but develops through the well-known “hyperfiltration mechanism”60,61 set in motion by a marked loss of renal mass caused by previous lupus GN or other causes. However, the presence of normal or only moderately decreased renal function, reflecting less than advanced parenchymal damage revealed by renal biopsies in many reported cases, tends to refute this possibility. Some cases of primary FSGS were recently shown to be related to a circulating factor that is selectively toxic to the visceral epithelial cells and promote transmembrane migration of macromolecules62; whether this or other related factors are responsible for

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SLE-associated FSGS remains to be studied. Finally, because both FSGS and SLE are relatively frequent, their association may be fortuitous. However, an incidence of FSGS of 2.5% among SLE patients encountered in our study is definitely higher than that of the general population. In summary, a large variety of renal lesions unrelated to lupus nephritis can be observed in SLE patients. Renal biopsy plays a crucial role in identifying these lesions, which may have prognostic and therapeutic implications distinctive from those of lupus nephritis. REFERENCES 1. Kotzin BL, Achenbach GA, West SG: Renal involvement in systemic lupus erythematosus, in Schrier RW, Gottschalk CW (eds): Disease of the Kidney, vol 2 (ed 6). Boston, MA, Little, Brown, 1997, pp 1781-1800 2. Tan EM, Cohen AS, Fries JF, et al: The 1982 revised criteria for classification of systemic lupus erythematosus. Arthritis Rheum 25:1271-1277, 1982 3. Baldwin DS, Gluck ML, Lowenstein J, et al: Lupus nephritis: clinical course of related to morphologic forms and their transitions. Am J Med 62:12-30, 1977 4. Estes D, Christian CL: The natural history of systemic lupus erythematosus by prospective analysis. Medicine 50:85-95, 1971 5. Churg J, Bernstein J, Glassock RJ: Lupus nephritis, in Churg J, Bernstein J, Glassock RJ (eds): Renal Disease Classification and Atlas of Glomerular Disease. New York, NY, Igaku-Shoin, 1995, pp 151-155 6. Magil AB, Puterman NL, Ballon HS, et al: Prognostic factors in diffuse lupus glomerulonephrits. Kidney Int 34:511-517, 1988 7. Woolf A, Croker B, Osofsky SG, et al: Nephritis in children and young adults with systemic lupus erythematosus and normal urinary sediment. Pediatrics 64:678-685, 1979 8. Hickman PL, Nolph KD, Jacobson R, et al: Idiopathic segmental glomerulosclerosis in patient with systemic lupus erythematosus: An unusual combination. Am J Kidney Dis 23:582-586, 1994 9. Popo T, Faucher C, Huong DLT, et al: Idiopathic focal segmental glomerulonephritis with systemic lupus erythematosus: An unusual combination. Am J Kidney Dis 24: 880-881, 1994 10. Mac-Moune Lai F, Li EK, et al: IgA nephropathy: A rare lesion in systemic lupus erythematosus. Mod Pathol 8:5-10, 1995 11. Hebert LA, Sharma HM, Sedmak DD, et al: Unexpected renal biopsy findings in a febrile systemic lupus erythematosus patient with worsening renal function and heavy proteinuria. Am J Kidney Dis 13: 504-507, 1989 12. Akhtar M, Al-Dalaan A, El-Ramahi KM: Pauci-immune necrotizing lupus nephritis: Report of two cases. Am J Kidney Dis 23:320-325, 1994 13. Perakis C, Arvanitis A, Sotsiou F, et al: Nephrotic syndrome caused by minimal change disease in patient with focal proliferative SLE nephritis (WHO III) in remission. Nephrol Dial Transplant 13:467-470, 1998 14. Carstens HB, Nassar RN: Glomerulocystic disease and lupus glomerulonephropathy. Ultrastruct Pathol 18:137-140, 1994 15. Mac Moune Lai F, Lai KN, Lee JC, et al: Hepatitis B virus– related glomerulopathy in patients with systemic lupus erythematosus. Am J Clin Pathol 88:412-420, 1987 16. Magasic MV, Venkataseshan VS, Vitting KE: Concurrent renal sarcoidosis and lupus nephritis. Nephron 64:496-497, 1993 17. Pettersson T, Tornroth T, Totterman KJ, et al: AA amyloidosis in systemic lupus erythematosus. J Rheumatol 14:835-839, 1987 18. ter Borg EJ, Jassen S, van Rijswijk MH, et al: AA amyloidosis associated with systemic lupus erythematosus. Rheumatol Int 8:141143, 1988 19. Queffeulou G, Berentbaum F, Michel C, et al: AA amyloidosis in systemic lupus erythematosus: An unusual complication. Nephrol Dial Transplant 13:1846-1848, 1998

20. Ellington KT, Truong L, Oliviero JJ: Renal amyloidosis in systemic lupus erythematosus. Am J Kidney Dis 21:676-678, 1993 21. Schleissner LA, Sheehan WW, Orselli RC: Lupus erythematosus in patient with amyloidosis, adrenal insufficiency, and subsequent immunoblastic sarcoma. Arthritis Rheum 19:249-255, 1976 22. Carstens PH, Ogden LL, Peak WP: Renal amyloidosis associated with systemic lupus erythematosus. Am J Clin Pathol 74:835838, 1980 23. Orellana C, Collado A, Hernandez MV, et al: When does amyloidosis complicate systemic lupus erythematosus? Lupus 4: 415417, 1995 24. Schwartz MM, Roberts JL, Lewis EJ: Necrotizing glomerulitis of systemic lupus erythematosus. HUM PATHOL 14:158-167, 1983 25. Ling BN, Bourke E, Campbell WG, et al: Naproxen induced nephropathy in systemic lupus erythematosus. Nephron 54:249-255, 1990 26. Morel-Maroger L, Mery JP, Droz D, et al: The course of lupus nephritis: Contribution of serial renal biopsies. Adv Nephrol 27:79118, 1976 27. Gephardt GN, Tubbs RR, Popowniak KL, et al: Focal and segmental glomerulosclerosis: Immunohistologic study of 20 renal biopsy specimens. Arch Pathol Lab Med 110:902-912, 1986 28. Whitworth JA, Turner DR, Leibowitz S, et al: Focal segmental or scarred focal proliferative glomerulonephritis? Clin Nephrol 9:229-235, 1978 29. Renneke H, Klein PS: Pathogenesis and significance of nonprimary focal and segmental glomerulosclerosis. Am J Kidney Dis 13:443-456, 1988 30. D’Agati V: Renal disease in systemic lupus erythematosus, mixed connective tissue disease, Sjogren’s syndrome, and rheumatoid arthritis, in Jennette JC, Olson JL, Schwart MM, et al (eds): Heptinstall’s Pathology of the Kidney, vol 1. Philadelphia, PA, Lippincott-Raven, 1998, pp 541-624 31. Beaufils H, Alphonse JC, Guedon J, et al: Focal glomerulosclerosis: Natural history and treatment. A report of 70 cases. Nephron 21:75-85, 1978 32. Southwest Pediatric Nephrology Study Group: Focal segmental glomerulosclerosis in children with idiophatic nephrotic syndrome. Kidney Int 27:442-450, 1985 33. Appel GB, Silva FG, Pirani CL, et al: Renal involvement in systemic lupus erythematosus. Medicine 5:371-410, 1978 34. Hirszel P, Yamase HT, Carney WR, et al: Mesangial proliferative glomerulonephritis with IgM deposits: Clinicopathologic analysis and evidence for morphologic transitions. Nephron 38:100-108, 1984 35. Border WA: Distinguishing minimal-change disease from mesangial disorders. Kidney Int 34:419-434, 1988 36. Pollack AD, Pirani CL: Pathology of the kidney in systemic lupus erythematosus: Serial renal biopsy studies and the effects of therapy on kidney lesions, in Dubois EL (ed.): Lupus Erythematosus: A Review of the Current Status of Discoid and Systemic Lupus Erythematosus and Their Variants. Los Angeles, CA, University of Southern California, 1974, pp 72-89 37. Striker GE, Kelly MR, Quadracci LJ, et al: The course of lupus nephritis: Relationship to the renal histologic findings, in Kincaid-Smith P, Mathew TH, Becker EL (eds): Glomerulonephritis: Morphology, Natural History and Treatment. New York, NY, Wiley, 1973, pp 1141-1166 38. Ginzler EM, Nicarstri AD, Chan CK, et al: Progression of mesangial and focal to diffuse lupus nephritis. N Engl J Med 291:693696, 1974 39. Zimmerman SW, Jenkins PG, Shelf WD, et al: Progression from minimal or focal to diffuse proliferative lupus nephritis. Lab Invest 32:665-672, 1975 40. Sinniah R, Feng PH: Lupus nephrithis: Correlation with light, electron microscopic and immunofluorescent findings and renal function. Clin Nephrol 6:340-351, 1976 41. Hill GS, Hinglais N, Tron F, et al: Systemic lupus erythematosus: Morphologic correlations with immunologic and clinical data at the time of biopsy. Am J Med 64:61-79, 1978 42. Mahajan SK, Ordonez NG, Spargo BH, et al: Changing histopathology patterns in lupus nephropathy. Clin Nephrol 10:1-8, 1978

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NONLUPUS NEPHRITIDES IN SLE (Baranowska-Daca et al) 43. Cameron JS, Turner DR, Ogg CS, et al: Systemic lupus with nephritis: A long-term study. Q J Med 48:1-24, 1979 44. Moroni G, Banfi G, Ponticelli C: Clinical status of patients after 10 years of lupus nephritis. Q J Med 84:681-689, 1992 45. Neumann K, Wallace DJ, Azen C, et al: Lupus in the 1980s: III. Influence of clinical variables, biopsy, and treatment on the outcome in 150 patients with lupus nephritis seen a single center. Semin Arthritis Rheum 25:47-55, 1995 46. Yang LY, Chen WP, Lin CY: Lupus nephritis in children: a review of 167 patients. Pediatrics 94:335-340, 1994 47. Singh AK, Ucci A, Madias N: Predominant tubulointerstitial lupus nephritis. Am J Kidney Dis 27:273-278, 1996 48. Gur H, Kopolovic Y, Gross D: Chronic predominant interstitial nephritis in a patient with systemic lupus erythematosus: A follow up of three years and review of the literature. Ann Rheum Dis 46:617-623, 1987 49. Henry R, Williams AV, McFadden NR, et al: Histopathologic evaluation of lupus patients with transient renal failure. Am J Kidney Dis 8:417-421, 1986 50. Cryer PE, Kissane JM: Interstitial nephritis in a patient with systemic lupus erythematosus. Am J Med 69:775-781, 1980 51. Tron F, Ganeval D, Drozd D: Immunologically-mediated acute renal failure of nonglomerular origin in the course of systemic lupus erythematosus (SLE). Am J Med 67:529-532, 1979 52. Scully RE, Galdabini JJ, McNeely BU: Case records of the Massachusetts General Hospital. Case 2-1976. N Engl J Med 294:100105, 1976 53. Cunningham E, Provost T, Brentjens J, et al: Acute renal

failure secondary to interstitial lupus nephritis. Arch Intern Med 138:1560-1561, 1978 54. Cohen AH, Border WA, Glassock RJ: Nephrotic syndrome with glomerular mesangial IgM deposits. Lab Invest 38:610-619, 1978 55. Bhasin HK, Abuelo JG, Nayak R, et al: Mesangial proliferative glomerulonephritis. Lab Invest 39:21-29, 1978 56. Olson JL: Hypertension: Essential and secondary form, in Jennette JC, Olson JL, Schwartz MM, et al (eds): Heptinstall’s Pathology of the Kidney, vol 2 (ed 5). Philadelphia, PA, Lippincott-Ravena, 1998, pp 943-1001 57. Innes A, Johnston PA, Morgan AG, et al: Clinical features of benign hypertensive nephrosclerosis at time of renal biopsy. Q J Med 86:271-275, 1993 58. de Beer FC, Fagan EA, Hughes GRV, et al: Serum amyloid A protein in inflammatory diseases and its relationship to the incidence of reactive systemic amyloidosis. Lancet 31:231-233, 1988 59. Husebekk A, Skogen B, Husby G, et al: Transformation of amyloid precursor SAA to protein AA and incorporation in amyloid fibrils in vivo. Scand J Immunol 21:283-287, 1985 60. Baldwin DS, Neugarten J: Role of hypertension in the evolution of renal diseases. Contrib Nephrol 54:63-76, 1987 61. Olson JL, de Urdaneta AG, Heptinstall RH: Glomerular hyalinosis and its relationship to hyperfiltration. Lab Invest 52:387-98, 1985 62. Feld S, Figueroa P. Savin V, et al: Plasmapheresis in the treatment of steroid-resistant focal segmental glomerulosclerosis in native kidney. Am J Kidney Dis 32:230-237, 1998

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