Recurrent Focal Glomerulosclerosis: Natural History and Response to Therapy MARYARTERO,M.D.,CLAUDEBIAVA,M.D.,WILLIAMAMEND,M.D.,STEPHENTOMLANOVICH,M.D., FLAVIOVINCENTI,M.D., SanFrancisco, Cahfornia

PURPOSE Recurrent focal glomerulosclerosis (FGS) has been well documented since it was first reported in 1972. However, the course of the disease after transplantation and the optimal treatment regimen have not been well defined since the introduction of newer treatment modalities. PATIRNTSANDMETHODS: Wereviewedallthe charts of patients with biopsy-proven FGS who received renal transplants at our institution from January 1980 through December 1990. Case histories consistent with diagnoses other than primary FGS (such as reflux nephropathy or intravenous drug use) were eliminated from the study. During this time period, 78 allografts were received by 71 patients with FGS. Independent variables that were analyxed included sex, race, time in months between the diagnosis of FGS and end-stage disease (dialysis or transplantation), age at time of transplantation, type of dialysis, source of allograft (cadaver+ or living related), haplotype matching, donor-specific transfusions, age and sex of the donor, posttransplantation acute tubular necrosis, rejection episodes, immunosuppression regimen, use of plasmapheresis and angiotensin converting enzyme (ACE) inhibitors, and outcome. RESULTS: FGS recurred in 25 aRografts (32%) of 21 patients. Biopsy-proven diagnosis of recurrence was made a mean of 7.5 months (range: 0.5 to 44 months) after transplantation. Patients who had rapid progression to end-stage disease tended to experience more frequent recurrences. Of seven patients who received a second transplant, five patients lost the first graft to recurrent FGS, and four of those patients (80%) had a recurrence in the second allograft. Recur-

From theTransplant Service (MA, WA, ST, FV) and the Department of Pathology (CB), University of California, San Francisco, San Francisco, California. This work was presented in part at the 10th Annual Meeting of the American Society of Transplant Physicians, Chicago, May 29, 1991, and was supported in part by Training Grant 5T32DK07219 from the National Institutes of Health to Dr. Artero. Requests for reprints should be addressed to Flavio Vincenti, M.D., Box 0116, University of California, San Francisco, San Francisco, California 94143. Manuscript submitted June 17, 1991, and accepted in revised form November 14, 1991.

rent disease developed in 34% of patients concurrently treated with cyclosporine and in 28% of those treated with preduisone and azathioprine alone (NS). Patients with recurrent FGS who were treated with ACE inhibitors benefited from a significant reduction of proteinuria. Six patients underwent plasmapheresis after diagnosis of the recurrence. Three of five patients in whom the diagnosis was made early in the course of the disease and in whom plasmapheresis was initiated immediately had reversal of epithelial foot process effacement and remission of proteinuria. End-stage disease eventually developed in 14 allografts (56%) an average of 23.7 months (range: 1 to 65 months) after diagnosis of recurrent disease. The cause of failure was chronic rejection in four allografts and recurrent disease in the remaining 10 allografts. CONCLUSIONS: FGS recurs in approximately 30% of allografts and causes graft loss in half of these. Patients who have lost a first allograft to recurrent FGS are at high risk for developing recurrent disease in a second allograft. Prolonged allograft survival is possible in patients with recurrent FGS and may best be obtained with a combination of treatment modalities including cyclosporine (perhaps in higher dosages than are routinely used in clinical renal transplantation), ACE inhibitors, and early use of plasmapheresis. The efficacy of these modalities supports the notion that recurrent FGS is caused by a circulating humoral mediator.

P

rimary focal glomerulosclerosis (FGS) is an important cause of the nephrotic syndrome and end-stage renal disease, occurring in approximately 7% to 15% of children and 15% to 20% of adults with idiopathic nephrotic syndrome [l]. The etiology of the disease is unknown; even its standing as a discrete clinicopathologic entity, rather than as a nonspecific feature superimposed on other glomerular diseases, remains controversial [2,3]. In general, FGS is unresponsive to treatment, remissions are uncommon, and lo-year survival without need for long-term dialysis is low. What does seem clear is that the etiology of primary FGS involves a circulating preformed factor, April

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since approximately 20% to 50% of patients who receive renal allografts develop recurrent disease, often days after the transplantation. In fact, recurrent disease in the renal allograft provides the perfect natural model of FGS, and the onset, course, and response to therapy can be precisely timed and followed; Since recurrent FGS was first described nearly 20 years ago, a number of factors have been suggested that would identify those patients at highest risk for recurrence. The risk factors found most consistently among patients who recur is mesangial proliferation with FGS in the native kidney at the time of the original diagnosis [P61 and recurrence in a first allograft [5,7]. Other risk factors that seem to hold generally true, but seem to be less reliable, include the tendency for recurrence in the younger age groups [6,8,9] and a rapid decline in renal function resulting in end-stage disease during the course of the native disease [5,10]. To evaluate the course and treatment options of recurrent FGS in the cyclosporine era, we recently reviewed our experience with the disease over the past 10 years.

PATIENTS AND METHODS The names of patients with a diagnosis of FGS who had received a renal transplant at our institution from January 1980 through December 1990 were retrieved from the database by computer. The clinic and hospital records of these patients were reviewed, and case histories consistent with diagnoses other than primary FGS (reflux nephropathy, intravenous drug use) or for which biopsy data were incomplete were eliminated from the study. Three allografts failed immediately after transplantation due to hyperacute rejection or technical failures, and these cases were also eliminated. The posttransplantation course for each patient was obtained through December 1990, or until the graft failed, by reviewing the records of the Transplant Clinic or by contacting the referring nephrologist. Independent variables that were analyzed included sex, race, time in months between the diagnosis of FGS and end-stage disease (dialysis or transplantation), the length of time on dialysis, the total interval between diagnosis and transplantation, age at time of transplantation, type of dialysis, source of allograft (cadaveric or living related), age and gender of the donor, haplotype matching, donor-specific transfusions, posttransplantation acute tubular necrosis (ATN), rejection episodes, immunosuppression, use of plasmapheresis and angiotensin converting enzyme (ACE) inhibitors, and outcome. Diagnosis of recurrence was made by allograft biopsy, which was performed if the patient developed proteinuria or had a rise in serum creatinine 376

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due to suspected transplant rejection or cyclosporine nephrotoxicity. No patients refused biopsy. Recurrence of FGS was diagnosed if the specimen showed diffuse effacement of epithelial foot processes on electron microscopy with normal appearance on light microscopy (“lipoid” nephropathy) or showed segmental or focal sclerosis apparent on light microscopy. All tissue specimens were routinely processed for light, immunoflorescence, and electron microscopy. Immunoflorescence microscopy included staining for IgG, IgM, IgA, C3, C4, albumin, and fibrinogen. Processing for electron microscopy included primary fixation with glutaraldehyde, postfixation in osmium tetraoxide, and dehydration in ethanol with subsequent embedding in epoxy resin. Our protocol for plasmapheresis requires that the patient undergo plasma replacement for 3 consecutive days, then every other day for a total of nine sessions. Plasmapheresis was performed with the Cobe Spectra (Cobe Laboratories, Inc., Lakewood, CO). One and one-half plasma volumes were replaced per session with 5% albumin to which is added calcium chloride (10%) 400 mg, magnesium sulfate (50%) 300 mg, and potassium chloride 4 mEq/L. No plasma exchanges were performed. Biopsies were obtained again 1 to 2 weeks after the final plasmapheresis treatment, when proteinuria had resolved. Cyclosporine was introduced into the immunosuppression regimen in December 1983. The starting dose of cyclosporine was 12 mg/kg until 1988, when it was reduced to 10 mg/kg. Whole blood levels were maintained in the range of 50 to 300 ng/mL, measured by high pressure liquid chromatography. Our standard sequential immunosuppression protocol consists of Minnesota antilymphocyte globulin, 20 mg/kg, azathioprine, 1 mg/kg, and prednisone 0.5 mg/kg, with cyclosporine introduced on Day 5 or when the serum creatinine level had decreased to 221 pmol/L (2.5 mg/dL). Statistical analyses were performed on an Apple Macintosh SE computer (Apple Computer, Inc., Cupertino, CA), using the program Primer of Biostatistics: The Program by Stanton A. Glantz (McGraw Hill, Inc., New York, NY). Tests of significance involving continuous variables were performed using Student’s t-test. If the variables were dichotomous, the chi-square test was used. Paired t-tests were also used where appropriate.

RESULTS Patient Population Between January 1980 and December 1990,2,257 renal transplants were performed at our institution. Of these, 121 were received by patients identified as having FGS. The case histories of these patients

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were reviewed, and 40 allografts were eliminated from the study because the patients had histories consistent with other etiologies (heroin nephropathy, reflux nephropathy, etc.) or because biopsy data were incomplete. Of the remaining 81 allografts, three were eliminated due to primary nonfunction. Therefore, the study base consisted of 71 patients with an original diagnosis of FGS who received 78 allografts during the study period. FGS recurred in 25 allografts (32%) of 21 patients. Demographic and historical data of patients who experienced recurrences versus those who did not is given in Table I. There were no differences between the two groups in terms of gender, type of dialysis, the source of the allograft, or inclusion of cyclosporine in the immunosuppressive regimen. Age was not a significant risk factor for recurrence, although there seemed to be a predilection for recurrence among the extremes; both our youngest (age 2) and oldest (age 66) recipients had recurrences. Although not shown in Table I, there were also no differences related to haplotype matching, donor-specific transfusions, frequency of ATN, number of rejection episodes, or age or gender of the donor. The large majority of our patients who had recurrences were white (90% versus 59% among those who did not have recurrences, p = 0.027). The time from diagnosis of the original disease to end stage (dialysis or transplantation) was significantly less in patients with eventual recurrence, although the range of values is broad. If the total time from diagnosis to transplantation is calculated (i.e., including time on dialysis), the trend for the shorter interval for patients who will eventually experience recurrence is again apparent, although no longer statistically significant. Treatments and outcomes of patients who developed recurrence of FGS are listed in Table II. Biopsy-proven diagnosis of recurrence was made a mean of 7.5 months (SD 10.9 months, range 0.3 to 44 months) after transplantation; the time from transplantation to diagnosis did not correlate with the time from diagnosis to the end stage of the original disease (r = -0.14, NS). Nephrotic range proteinuria was often noted several weeks before biopsy confirmation was obtained. The average interval between transplantation and documentation of proteinuria was 4 months. The mean 24-hour urine protein loss at the time of diagnosis was 11.5 g. Of seven patients who received a second transplant, five patients lost the first graft to recurrent FGS, and four of those patients (80%) had recurrence in the second allograft. Treatment Regimens Recurrent disease developed in 18 of 53 allografts (34%) of patients concurrently treated with cyclo-

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TABLE I Characteristicsof PatientsWith Nonrecurrent and Recurrent FGS Characteristic

Nonrecurrent

Recurrent

z:

2

ii

2

No. of patients* No. of allografts Gender (% male) Race (% white) Time from Dx to end-stage disease? fdea~~? SD (mo)

= E27 = 0.022

1015

99

O-380

49 + 66 o-294

15 i: 18

25 + 38

Time from Dx to Txt Mean f SD (mo)

117 + 97

73 i 70

Age at time of Txt (y)

30 ?I 12

31 116

Timeon dialysisi Mean + SD (mo)

Ag;!$ibution

p Value

NS NS (= 0.086)

(y)+

NS

NS

21-40

::

:

41-66

13

7

Source of allograti (% living related)

45

52

NS

ImF;;osuppression

66

72

NS

with CsA

0 : = diagnosis; TX= transplant+n; CsA = cyclosporine; NS = not significant. Ine pabent had recurrence with the first allograft but not with the second, and IS represented in 8thcolumns. or patients with multiple transplants, data are for first transplant only.

sporine and in seven of 25 allografts (28%) of those treated with prednisone and azathioprine (or cyclophosphamide) alone (NS). The four patients with recurrent FGS in a second transplant were receiving cyclosporine, after losing the first transplant while not receiving cyclosporine. In these patients, the clinical course was more benign (mean graft survival: 32 months versus 42 months) but did not reach statistical significance. Nine patients with recurrent FGS were treated with ACE inhibitors; Table III demonstrates that most of these patients had a reduction of proteinuria (mean total urine protein before treatment with an ACE inhibitor: 11.1 g; after treatment, 4.22 g; NS). The mean allograft survival of patients receiving these inhibitors (29.1 months, SD 26.9 months, range 5 to 78 months) did not differ from those not receiving these inhibitors (26.2 months, SD 25.1 months, range 1 to 65 months). Six patients underwent plasmapheresis after the diagnosis of recurrent FGS. Table IV summarizes the course of these patients. Three of five patients in whom the diagnosis was made early in the course of the disease and in whom plasmapheresis was initiated immediately had remissions. Figure 1 (top) is a photomicrograph of a glomerulus from one of these patients prior to plasmapheresis that reveals the characteristic effacement of epithelial foot April

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TABLE II Treatment Modalities and Outcome of Patients With Recurrent FGS

PatientNo.

Age;e; (~1,

Time FromDx to TX(mo)

1

24

19

2

18,M

20

3

Tx#l21,M TX #2 27

4

36,M

5

TX #l 16,M TX #2 23

6

Tx#l

118 194 84

Proteinuria (m;Po$-/

TXBiopsy (moPost-Tx)

0.3/20

0.3

2/J

2

4/“NS” 1514

1;

2617

26

1:;

TreatmentModality PP CsA ACE X

X

i.5

x

x

HD, 24 mo, recurrence AW, Creat 159, Alb 33,51

x

x

HD, 35 mo, recurrence HD, 7 mo, recurrence CRF, Creat 371, Alb 31

X

HD, 4 mo, rejection HD, 17 mo, recurrence

X

AW, Creat 150, TUP 720 mg-74

mo

HD, 65 mo, recurrence, ReTx-no

recurrence

i/E

7

39,M

47

917

8

16,F

63

0.5117

9

22,M

176

l/20

2

x

10

66,M

62

l/9

1

X

11

52,M

11

Z/15

3

x

x

27 0.8

x

x

x

x

1::

:i 15 0.8

2;;:z

13

31,M

104

317

3

14

43,F

24

8120

12

15

43,F

64

16

15,F

28

17

45,F

18

mo

X

46 77

TX #148,M #2 56

See Table IV HD, 9 mo, rejection

12,M 14

12

Outcome*

x

AW, Creat 124, DProt 100,45 X

mo

See Table IV AW, Creat 133, Alb 35, TUP 600-41

x

HD, 48 mo, recurrence See Table IV AW, Creat 141, Alb41, TUP 210-81

X

115

3

x

27

l/8

3

X

20s

45

0.5/l

3

x

x

HD, 8 mo, recurrence

19

32,M

306

0.3/11

0.3

x

x

AW, Creat 194, Alb 42, TUP l,OOO-71

20

42,F

54

0.5/15

0.5

X

21

25,M

54

0.317

0.3

X

1

mo

HD, 62 mo, recurrence

0.8

0.3/9

mo

x

X

See Table IV

x

See Table IV HD, 55 mo, recurrence

mo

HD, 1 mo, rejection X

See Table IV

= transplantation; Dx = diagnosis; CsA = cyclosporine; ACE = angiotensin-converting enzyme inhibitorsi PP = plasmapheresis; HD = hemodialysisiAW = alive and well; Creat = serum creatinine mol/L); NS = nephrotic syndrome; Alb = serum albumin (g/L); CRF = chronic renalfailure; TUP = total urine protein per 24 hours (mg); DProt = dipshck protein (mg/dL). icludesfollow-up through December 1990.

processes. Figure 1 (bottom) depicts a glomerulus from the same patient following plasmapheresis and remission of the proteinuria, illustrating rapid reversal of foot process fusion. A relapse occurred in one of the patients, but a second course of plasmapheresis resulted in a second remission. Preplasmapheresis biopsy specimens from the patients whose disease went into remission showed effacement of foot processes only. In two patients who did not achieve remissions, the biopsy prior to plasmapheresis revealed that, in addition to fusion of foot processes, sclerosis had already occurred in the glomeruli. Examination of biopsy specimens from the sixth patient in whom the diagnosis was made after 12 weeks of proteinuria revealed no sclerosis (inade378

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quate sample size with only two glomeruli), and plasmapheresis was not helpful. The mean length of follow-up for all patients from the time of transplantation was 39.2 months (SD 30.6 months; range 1 to 123 months, median 32 months). Mean follow-up of patients with allografts that did not fail within 1 year was 44.8 months (SD 29.8 months). There was no difference in the length of follow-up between patients who experienced recurrences and those who did not. End-stage disease eventually developed in 14 allografts (56%) an average of 23.7 months (range: 1 to 65 months) after diagnosis of recurrent disease. The cause of failure was chronic rejection in four allografts and recurrent disease in the remaining 10 allografts.

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TABLE III Proteinuria

Before and After ACE Inhibition

Patient No.

in Patients With Recurrent Initial Proteinuria (date quantified; g/24 h)

TX Date

9/l/86

3

FGS

12/87;4

Medication Initiated

Final Proteinuria (date quantified; g/24 hl

2188,

4/90;0.6 7188;14

Comments Initial Cr 106

FinalCr115

Captopril 50 mgtid

4

715184

9/86;7

Captopril 50 mgtid

9

3123187

4/87;20

5187,. Enalaprll 20 mgqd

12190; DProt 100

Initial Cr 239 Final Cr 124

11

7116187

9187; 15

11/87,,

12/90;0.6

Initial Cr 141 Final Cr 133

3/90;20

Initial Cr 133 FinalCr389

12/90;0.2

4186CrCl55 12190 CrC181

Enalapril15 12”

8125189

13

3113184

16*

18

10/89;25

3/6/90

4190; 5

4/18/89

4189; 11

4/86,, Enalapnl20 6/W, Enalaprll

7189, Enalapril

19

l/20/85

l/85;

mgqd

10/89, Captopri125 mg bid

6184;7 4186; 1.4

11

HD,35mo

mg bid 6190; 9

10 mgbid

Initial Cr 97 Final Cr 159

11189; 16

10 mgqd

11/86,,

HD,8 mo

2188; 1

Initial Cr 186 Final Cr 194

Enalapnl20 mg qd

: = transplantation; Cr = serum creatinine (p,mol/L); DProt = dipstick protein (mg/dL); HD = hemodialysis; CrCl = creatinine clearance (corrected for body surface area) (mL/min); tid = three times ly; qd = every day; bid = twice a day. \Iso underwent plasmapheresis.

COMMENTS Since recurrent FGS was first described by Hoyer et a2 [ll] in 1972, the disease has challenged nephrologists concerned with the pathogenesis of the original entity and the practical implications of transplantation in patients with the disease. Table V summarizes recent series of patients with recurrent FGS reported in the literature. Analysis of Risk Factors In many ways, our current data agree well with previous studies, including the incidence of recur-

rence (32%), the degree of graft loss due to recurrent disease (40%), and the high frequency of recurrent disease in a second allograft when the first was lost to recurrence (80%). Our experience with a broad range of ages at transplantation indicates that both youth and advanced age may predispose to recurrence, although our findings were not statistically significant. That the majority of our patients who experienced recurrences were white is of unknown significance. Ingulli and Tejani [15] have found that blacks and Hispanics actually have a more rapid decline in renal function due to FGS than whites.

TABLE IV Outcome

of Patients Treated With Plasmapheresis” Age atrt

(Y),

Patient No. 1

2,M

Proteinuria (g/24 h)

PP Initiated Days Post-TX

No. of Treatments

initial

Final

Bx Sclerosis

ACE

Outcome

20

0.02

No

9

11

No

AW,13

11

No

AW, 7 mo,Creat150,Alb

mo,Creat44,Alb

10

66,M

9

0.80

No

35

21

25,M

7

2

No

10

7

No

HD,4 mo (rejection)

12

56,M

25

20

Yes

21

5

Yes

CRF,17 mo,Creat389

15

43,F

9

12

Yes

18

9

No

HD,5 mo (recurrence)

16

15,F

5

9

No

91

9

Yes

AW,13 mo,

43 38,CrCl53.6

Creat177, Alb 20

I

TX = transplantation; Bx = biopsy; AW = alive and well; Creat = serum creatinine (pmol/L); Alb = serum albumin (g/L); CRF = chronic renalfailure; PP = plasmapheresis;ACE = angiotensin-converting enzyme inhibitors; CrCl = creatinineclearance (corrected for bodysurfacearea) (mL/min); HD = hemodlalysis. *All patients were concurrently treated with cyclosporine.

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Figure 1. Photomicrographs of renal biopsy specimens obtained before and after a course of plasmapheresis from the same patient (Patient 10). Top. Characteristic effacement of epithelial foot processes prior to plasmapheresis (original magnification X15,000, reduced by 20%). Bottom. Rapid reversal of foot process “fusion” following plasmapheresis and remission of proteinuria (original magnification X16,800, reduced by

20%).

We did find that patients who had relatively rapid progression of the disease in their native kidneys tended to have more frequent recurrences than those patients with a more indolent course. However, our patients who eventually developed recurrence were maintained on dialysis for a somewhat longer period, and, therefore, total time from diagnosis to transplantation was not significantly different between the two groups. Previous studies of recurrent FGS have been divided regarding the sig-

TABLE V RecentSeries of Recurrent FGSReported in the Literature GraDfuFtFre

Alloo;~fts R~;e;e Reference

,

0

(Y)

Recurrence (no.)

[51

37

43

2-19

14

[121

43

33

Pediatric

7

Cl31

15

33

7-52

2

2-31

4

[71

50

26

I141

25

48

(91 Current report

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Age Range

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5

40

15

2-16

4

78

32

2-66

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nificance of the time course as a predictor for recurrence. Our data tend to support the notion that a rapid, malignant course of the native disease is a relative risk factor for recurrence. Cyclosporine We found that the introduction of cyclosporine into the immunosuppressive regimen did not improve the rate of recurrence, although in our patients who experienced a first graft loss due to recurrent disease, cyclosporine seemed to ameliorate the course of recurrence in a second graft. The role of cyclosporine in decreasing the incidence of recurrent FGS or successfully treating the disease once it appears is controversial. We found no difference in cyclosporine-treated patients in comparison with those treated with azathioprine and prednisone alone. In a prospective study of cyclosporine in the treatment of native disease, Meyrier [16] found that treatment with the drug failed to achieve a complete or partial remission in 76% of patients with cortico-dependent or corticoresistant FGS (n = 33). Banfi et al [14] reviewed their transplant experience in 24 patients with FGS and found that cyclosporine offered no benefit in disease recurrence in comparison with azathioprine and prednisone.

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Cyclosporine is an important inhibitor of T helper cell-mediated immune function. In fact, it has been useful in inducing remissions in steroid-dependent minimal change disease. Possibly, the lymphokines or monokines that may be responsible in the pathogenesis of FGS are triggered and released through pathways that bypass cyclosporine regulation. For example, interleukin 1 is thought to be insensitive to the effects of cyclosporine, and yet it is capable of inducing collagen secretion by endothelial cells [17]. Ingulli et al [18] have suggested that the efficacy of cyclosporine in controlling proteinuria after transplantation is related to the hyperlipidemia associated with the nephrotic syndrome. Cyclosporine may be bound to the cell membrane by a lowdensity lipoprotein complex and is transported into the cell with its receptor by endocytosis [19]. With hyperlipidemia, there may be a down-regulation of low-density lipoprotein receptors, which would result in lower intracellular levels of cyclosporine. These investigators describe two pediatric patients for whom high dosages of cyclosporine (35 mg/kg/day and 21 mg/kg/day) were successful in treating the proteinuria of recurrent FGS with minimal toxicity; the dose of cyclosporine was adjusted as the patients’ cholesterol levels decreased. We were unable to detect a difference in the cholesterol levels of our patients who experienced a recurrence compared with those who did not. However, the inability to achieve adequate intracellular levels of cyclosporine may explain the diverse responses to the drug. Also, caution must be exercised in a protocol requiring high doses of cyclosporine in the treatment of recurrent FGS. From a large collaborative study of patients with primary, native FGS or minimal change disease treated with cyclosporine, Meyrier and colleagues [20] have demonstrated that interstitial and vascular lesions secondary to cyclosporine developed rapidly in patients with FGS, even with low to moderate doses of the drug, and there was a significant decline in renal function in these patients. ACE Inhibitors We found that most patients with recurrent disease who were treated with ACE inhibitors had a marked reduction in proteinuria without a decrease in creatinine clearance. However, the number of treated patients and the mean length of follow-up were inadequate to determine if these inhibitors actually prolong allograft survival. Studies in animal models and in humans of nonprimary FGS (i.e., diseases in which damage to glomerular cells is not thought to represent the primary pathologic event)

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have suggested that structural and hemodynamic adaptations resulting from a reduced number of nephrons leads to progressive capillary wall damage with segmental and eventually global glomerulosclerosis [21]. Reduction of the number of functioning nephrons leads to systemic hypertension and to an increase in the function of the surviving nephrons. Hemodynamic adaptation includes a marked decrease in renal arteriolar resistances and increased effective renal plasma flow. Because the vasodilatory effect on the afferent arteriole is greater than that of the efferent arteriole, there is an increase in the glomerular capillary hydrostatic pressure and an increase in the single nephron glomerular filtration rate. Structural adaptations to glomerular hypertension include mesangial matrix expansion, subendothelial hyalin deposition, increase in basement membrane thickness, and endothelial cell injury resulting in microthrombosis and microaneurysm formation. The logic behind the use of ACE inhibitors as opposed to conventional antihypertensive therapy is that the former reduces efferent arteriolar resistance [22] and relieves glomerular hypertension. The rationale for ACE inhibitors in the treatment of recurrent FGS may not only be based on improvement of glomerular hemodynamits, but also early evidence that they prevent progression of glomerular disease by reducing procollagen mRNA levels in the presence of cyclosporine [231. Plasmapheresis Our results with plasmapheresis as a treatment modality for recurrent FGS are decidedly mixed. Three patients responded favorably when the diagnosis was made rapidly after the onset of proteinuria and the plasmapheresis was initiated immediately. All of these patients were in the early stages of recurrent FGS with histology showing fusion of foot processes without evidence of glomerular hyalinosis. One of these patients, a 66-year-old man, subsequently experienced a relapse, but a second course of plasmapheresis was again successful. Allograft biopsies from these patients showed reversal of foot process fusion following plasmapheresis and remission of the nephrotic syndrome. Two other patients, both adults, had no benefit from plasmapheresis, even when it was begun immediately after the onset of proteinurid. Initial biopsies from both patients showed that hyalinosis of the glomeruli had already begun. The sixth patient, a X-year-old girl, was treated with plasmapheresis 3 months after the onset of proteinuria, and she did not improve. There was no evidence of sclerosis in her allograft biopsy, but the sample contained only two glomeruli.

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The early histologic diagnosis of recurrent FGS depended on the demonstration of mesangial prominence or sclerosis in a segmental pattern on light microscopy or, in the absence of light microscopic findings, the diffuse effacement of epithelial foot processes on electron microscopy in a patient with a previous history of biopsy-proven FGS. Although “fusion” of foot processes on electron microscopy is a relatively nonspecific finding, it is unlikely that it represents minimal change disease in this setting, since minimal change disease rarely leads to endstage renal disease requiring dialysis and/or transplantation. Also, longitudinal histologic studies of the early recurrent lesion of FGS have demonstrated that foot process effacement precedes the appearance of an increased mesangial matrix [24,25]. Therefore, it is unlikely that patients diagnosed with recurrent FGS in this study actually had a de nouo minimal change nephropathy. The literature regarding the efficacy of plasmapheresis for recurrent FGS is still sparse. Laufer et al [26] used the technique in two pediatric patients beginning up to 6 months after transplantation with resolution of proteinuria. Sclerosis was not present in the allograft biopsy specimen from either patient. In 1985, Munoz et al [27] reported a treatment success in a 19-year-old man with recurrent disease using plasmapheresis beginning 3 weeks after transplantation. However, in 1987, the same investigators cautioned that a sibling of the patient with FGS developed recurrent disease in his renal allograft, and proteinuria remitted spontaneously 28 days after transplantation [28]. The frequency of complete remissions of recurrent FGS is unknown. A review of the literature suggests that they are rare. Presumably, the efficacy of plasmapheresis in the treatment of FGS would depend on the removal of a putative humoral mediator responsible for the disease. Since the replacement fluid during plasmapheresis consists of a 5% albumin solution and not plasma, it is unlikely that the procedure replaces a missing factor. However, it does not rule out the possibility that normal plasma contains an inhibitor to the putative permeability factor. Whether prolonged remissions could be maintained after the completion of the course of plasmapheresis is not clear. Our longest follow-up after a successful course of plasmapheresis is 13 months, during which time the patient has had no proteinuria and is not receiving ACE inhibitors. All of our patients, as well as those of Laufer et al [26], were simultaneously treated with cyclosporine, which in some patients could suppress further release of the humoral mediator.

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Journal

of Medicine

Volume

92

Several case reports have now appeared in the literature on the use of plasmapheresis in the treatment of recurrent FGS. A prospective clinical trial of the technique is necessary before its effectiveness can be assured. Etiologic Considerations These observations lead to a number of questions regarding the pathogenesis of FGS and its tendency to recur in renal allografts. The most obvious is, why does disease recur in some patients and not in others? What is the significance of risk factors associated with recurrence? Should cyclosporine have a consistent effect on the recurrence rate or course of the disease? Shalhoub [29] in 1974 theorized that minimal change disease, which some regard as related pathophysiologically to FGS, was produced by a systemic abnormality of T-cell function resulting in a circulating chemical mediator. Such a substance could alter the permeability characteristics of the basement membrane, perhaps by neutralizing negative charges involved in maintaining the integrity of epithelial cell foot processes and the charge barrier to albumin. FGS differs from minimal change disease in its lack of responsiveness to steroids and its progression to glomerulosclerosis. However, the rapidity with which it recurs after renal transplantation suggests that it, too, results from a circulating humoral mediator, perhaps derived from altered Tcell function. In fact, Matsumoto et al [30] found cell-mediated immunity depressed, with decreased responses of lymphocytes to concanavalin A and phytohemagglutinin, impaired delayed hypersensitivity to purified protein derivative, and a decreased proportion of T lymphocytes in patients with FGS compared with normal controls. The same investigators found increased suppressor cell activity in FGS patients when compared with control subjects [31]. Zimmerman [32] was able to reproduce proteinuria in rats when they were infused with the serum obtained from a patient with recurrent FGS. Although it has been difficult to consistently repeat this finding in uiuo, Savin et al [33] have found increased permeability to albumin in isolated rat glomeruli when serum is added from patients with recurrent disease. In the spectrum of diseases termed focal glomerulosclerosis, recurrent FGS represents a unique entity, the pathogenesis of which probably depends on a circulating humoral substance. The current strategies used to treat the disease are based on the theory that such a substance exists and are targeted to prevent its secretion by agents that suppress lymphokine release (cyclosporine or FK 506 [34]) or

to remove it with plasmapheresis. Definitive therapy of recurrent FGS (and perhaps many cases of primary FGS) and the ability to predict before transplantation the patients most likely to develop recurrent disease will result when such a substance can be identified.

REFERENCES 1. Glassock RJ, Adler SG. Ward HJ. Cohen AH. Primary glomerular diseases. In: Brenner BM, Rector FC, editors. The kidney. 4th ed. Philadelphia: WB Saunders, 1991: 1233-8. 2. Case Records of the Massachusetts General Hospital (Case 20-1976). N Engl J Med 1976; 294: 1108-15. 3. Border WA. Distinguishing minimal-change disease from mesangial disorders. Kidney Int 1988; 34: 419-34. 4. Maize1 SE, Sibley RK, Horstman JP, Kjellstrand CM, Simmons RL. Incidence and significance of recurrent focal segmental glomerulosclerosis in renal allograft recipients. Transplantation 1981; 32: 512-6. 5. Striegel JE, Sibley RK, Fryd DS. Mauer SM. Recurrence of focal segmental sclerosis in children following renal transplantation. Kidney Int 1986; 30: 544-50. 6. Cameron JS, Senguttuvan P, Hartley B, et a/. Focal segmental glomerulosclerosis in fifty-nine renal allografts from a single centre; analysis of risk factors for recurrence. Transplant Proc 1989; 21: 2117-8. 7. Senguttuvan P. Cameron JS, Hartley RB, eta/. Recurrence of focal segmental glomerulosclerosis in transplanted kidneys: analysisof incidenceand riskfactors in 59 allografts. Pediatr Nephrol 1990; 4: 21-8. 8. Pinto J, Lacerda G, Cameron J’S, Turner DR, Bewick M. Ogg CS. Recurrence of focal segmental glomerulosclerosis in renal allografts. Transplantation 1981; 32: 83-9. 9. lngulli E, Tejani A. Incidence. treatment, and outcome of recurrent focal segmental glomerulosclerosis posttransplantation in 42 allografts in children-a single-center experience. Transplantation 1991; 51: 401-5. 10. Leumann EP, Donckerwolcke RAM, Kuijten R, Largiader F. Recurrence of focal segmental glomerulosclerosis in the transplanted kidney. Nephron 1980; 25: 65-71. 11. Hoyer JR, Vernier RL, Najarian JS, Raij L, Simmons RL, Michael AF. Recurrence of idiopathic nephrotic syndrome after renal transplantation. Lancet 1972; 2: 343-8. 12. Habib R, Gagnadoux M. Broyer M. Recurrent glomerulonephritis in transplanted children. Contrib Nephrol 1987; 55: 123-35. 13. O’Meara Y, Green A, Carmody M, et a/. Recurrent glomerulonephritis in renal transplants: fourteen years’ experience. Nephrol Dial Transplant 1989; 4: 730-4. 14. Banfi G, Colturi C. Montagnino G, Ponticelli C. The recurrence of focal segmental glomerulosclerosis in kidney transplant patients treated with cyclosporine. Transplantation 1990; 50: 594-6. 15. lngulli E, Tejani A. Racial differences in the incidence and outcome of focal

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Pediatr Res 1990; 27: 330A. 16. Meyrier A and Collaborative Group of the Societe de Nephrologie. Ciclosporin in the treatment of nephrosis. Am J Nephrol 1989; 9 Suppl 1: 65-71. 17. Schmidt JA, Mizel SB, Cohen D, Green I. lnterleukin 1: a potential regulator of fibroblast proliferation. J lmmunol 1982; 128: 2177-82. 18. lngulli E, Tejani A, Khalid MHB, et al. High-dose cyclosporine therapy in recurrent nephrotic syndrome following renal transplantation. Transplantation 1990; 49: 219-21. 19. de Groen PC. Cyclosporine, low-density lipoprotein, and cholesterol. Mayo Clinic Proc 1988; 63: 1012-21. 20. Collaborative Group of the Societe de Nephrologie (Coordinator: Alain Meyrier). Adult steroid-resistant nephrotic FSGS is not an indication for CsA treatment [abstract]. J Am Sot Nephrol 1990; 1: 311. 21. Rennke HG, Klein PS. Pathogenesis and significance of nonprimaryfocal and segmental glomerulosclerosis. Am J Kidney Dis 1989; 13: 443-56. 22. Anderson S, Rennke HG. Brenner BM. Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension in the rat. J Clin invest 1986; 77: 1993-2000. 23. Ahmed K, Adler SG. Kressor C, Nast CC. Enalapril inhibits early cyclosporineinduced elevations in rat renal cortical procollagen alpha-l mRNA levels [abstract]. J Am Sot Nephrol 1990; 1: 747. 24. Verani RR, Hawkins EP. Recurrent focal segmental glomerulosclerosis: a pathological study of the early lesion. Am J Nephrol 1986; 6: 263-70. 25. Mathew TH. Mathews DC, Hobbs JB, Kincaid-Smith P. Glomerular lesions after renal transplantation. Am J Med 1975; 59: 177-90. 26. Laufer J, Ettenger RB, Ho WG, Cohen AH, Marik JL, Fine RN. Plasma exchange for recurrent nephrotic syndrome following renal transplantation. Transplantation 1988; 46: 540-2. 27. Munoz J, Sanchez M, Perez-Garcia R, Anaya F, Valderrabano F. Recurrent focal glomerulosclerosis in renal transplants. Proteinuria relapsing following plasma exchange [letter]. Clin Nephrol 1985; 24: 213-4. 28. Franc0 A, Peres R, Anaya F, Niembro E, Valderrabano F. Spontaneous remission of proteinuria in recurrent focal glomerulosclerosis. Reappraisal of plasma exchange treatment [letter]. Clin Nephrol 1987; 28: 158. 29. Shalhoub RJ. Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 1974; 2: 55660. 30. Matsumoto K, Osakabe K, Katayama H, et a/. Impaired cell-mediated immunity in focal glomerular sclerosis. Nephron 1983; 34: 220-3. 31. Matsumoto K, Osakabe K, Katayama H, Hatano M. Concanavalin A-induced suppressor cell activity in focal glomerular sclerosis. Nephron 1982; 31: 27-30. 32. Zimmerman SW. Increased urinary protein excretion in the rat produced by serum from a patient with recurrent focal glomerular sclerosis after renal transplantation. Clin Nephrol 1984; 22: 32-8. 33. Savin VJ, Chonko AM, Sharma R. Gunwar S, Sharma M. Factor present in serum of patients with minimal change nephrotic syndrome or focal sclerosing glomerulopathy causes an immediate increase in glomerular protein permeability in vitro [abstract]. J Am Sot Nephrol 1990; 1: 567. 34. McCauley J, Tzakis AG, Fung JJ. Todo S, Starzl TE. FK 506 in steroidresistant focal sclerosingglomerulonephritis of childhood /letter]. Lancet 1990; 335: 674.

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1992

The American

Journal

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Volume

92

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