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Plasmapheresis in the treatment of steroid-resistant focal segmental glomerulosclerosis in native kidneys
Plasmapheresis in the Treatment of Steroid-Resistant Focal Segmental Glomerulosclerosis in Native Kidneys Stella M. Feld, MD, Priscilla Figueroa, MD, Virginia Savin, MD, Cynthia C. Nast, MD, Ram Sharma, PhD, Mukut Sharma, PhD, Raimund Hirschberg, MD, and Sharon G. Adler, MD ● A circulating glomerular capillary albumin permeability factor (Palb) has been implicated in the pathogenesis of focal segmental glomerulosclerosis (FSGS), which recurs in transplanted kidneys. Plasmapheresis for recurrent FSGS may reduce proteinuria and stabilize renal function if instituted early. We performed six plasmapheresis treatments over 2 weeks in eight patients with a history of steroid-resistant idiopathic FSGS in native kidneys for an average of 12 ⴞ 2.3 months to determine whether treatment would decrease proteinuria or stabilize renal function. Palb was measured before and after plasmapheresis, and patients were followed-up for a mean of 29 ⴞ 4 months after the development of clinical symptoms. Proteinuria decreased in two of eight treated patients, although only transiently in one of the two. Palb improved in one of the two responding patients. Both patients with an improvement in proteinuria had stable renal function at last follow-up. In six of eight patients, there was no improvement in proteinuria despite an improvement in Palb (P F 0.0001) after plasmapheresis. At last follow-up, renal function was stable in two of the six nonresponding patients, and four of the six had significant progression of renal disease or were receiving dialysis treatments. These studies suggest that plasmapheresis may diminish proteinuria and stabilize renal function in a small minority of patients with steroid-resistant idiopathic FSGS. However, the lack of a relationship between the removal of the circulating permeability factor and the development of remission in these patients suggests that local factors associated with advanced renal injury or systemic factors unrelated to glomerular permeability play a significant role in determining proteinuria at this late stage of the disease. r 1998 by the National Kidney Foundation, Inc. INDEX WORDS: Focal segmental glomerulosclerosis; plasmapheresis; glomerular capillary albumin permeability.
F
OCAL SEGMENTAL glomerulosclerosis (FSGS) is a histological entity characterized by visceral epithelial cell injury, capillary collapse, hyalinosis, and accretion of extracellular matrix material. It can occur in a primary or idiopathic form or may be present secondary to a variety of underlying disorders. In its secondary form, it may be seen in association with conditions such as reflux nephropathy, morbid obesity, and human immunodeficiency virus (HIV) infection.1 Treatment of the secondary forms are directed at amelioration of the underlying condition when possible, and at measures that may otherwise decrease urinary protein excretion. Although 10% to 40% of patients with the idiopathic variety respond to steroids, those who do
From the Medical College of Wisconsin, Milwaukee, WI; Cedars Sinai Medical Center, Los Angeles, CA; and HarborUCLA Medical Center, Torrance, CA. Received December 5, 1997; accepted in revised form March 3, 1998. Supported in part by a grant from NIH to the HarborUCLA Clinical Research Center, MO1 RR00425. Address reprint requests to Sharon Adler, MD, HarborUCLA Medical Center, 1000 West Carson St, C-1 Annex, Torrance, CA 90509. E-mail: [email protected]
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3202-0006$3.00/0 230
not respond to therapy frequently progress to end-stage renal disease.1 Furthermore, the incidence of FSGS appears to be increasing, and in some studies, FSGS has become the most common cause of the idiopathic nephrotic syndrome in adults.2,3 A circulating humoral factor may be involved in the pathogenesis of some cases of FSGS.4-10 In a number of studies, a beneficial effect of plasmapheresis in patients with recurrent FSGS after renal transplantation has been shown.5-10 Additional studies have shown that in approximately one third of cases, sera from patients whose FSGS recurred after transplantation caused a significant increase in glomerular capillary albumin permeability (Palb) in vitro.11 In patients with a high Palb value and recurrent FSGS in renal allografts, treatment with plasmapheresis diminished proteinuria. When the diagnosis was made early in these patients and treatment was initiated, lasting remissions were occasionally achieved. We studied eight patients with steroidresistant idiopathic FSGS in native kidneys to determine whether a factor capable of increasing glomerular capillary albumin permeability in vitro was present in their serum and whether removal
American Journal of Kidney Diseases, Vol 32, No 2 (August), 1998: pp 230-237
PLASMAPHERESIS FOR FSGS
of this factor with plasmapheresis would lead to a decrease in proteinuria or stabilization of renal function. METHODS
Study Subjects Eight patients with steroid-resistant idiopathic FSGS were studied; no cases of collapsing form or tip lesion were included. Each was diagnosed by renal biopsy after presenting with nephrotic-range proteinuria. All biopsy specimens were evaluated by light, immunofluorescent, and electron microscopies by a renal pathologist (C.C.N.) to establish a diagnosis and to determine the percentage of glomeruli with complete sclerosis and those with segmental sclerosis. FSGS was defined as a segment of sclerosis (capillary collapse, insudates, and abnormal overlying visceral epithelial cells with or without adhesions, intraluminal foam cells and lipid) in at least one glomerulus without an underlying separate glomerular lesion. Semiquantitative analysis to measure the degree of tubular atrophy and interstitial fibrosis was performed as follows: A score ranging from 0 to 3 was given for the percentage of tubulointerstitial scarring: 0, 0-5%; 1, 6-15%; 1.5, 16-25%; 2, 26-40%; 2.5, 41-50%; 3, ⱖ50%. The clinical course of the patients was characterized with regard to degree of proteinuria, creatinine clearance, and preplasmapheresis treatment history. Blood pressure was measured in the sitting position after 5 minutes of quiet repose during the initial screening visit. Patients entering this study continued to have significant proteinuria despite having received the equivalent of at least 40 mg prednisone per day for at least 2 months. All but three patients were also treated with three daily 1-g doses of methylprednisolone, with no improvement in proteinuria.
Plasmapheresis Treatments Plasmapheresis was performed using the Cobe Spectra System (Cobe Laboratories, Inc., Lakewood, CO) under citrate anticoagulation. Each patient received six 1.5 plasma volume exchanges over approximately 2 weeks. The plasma was replaced with 5% albumin and normal saline in a ratio intended to maintain the serum albumin at 3 g/dL or at the patient’s baseline level if it was higher. Calcium gluconate infusions of up to 3 g per procedure were given as needed for symptomatic or laboratory evidence of hypocalcemia. Five of the eight patients were taking angiotensin converting enzyme inhibitors (ACEi) before the biopsy. This medication was stopped in all patients during the plasmapheresis treatments because of reports that ACEi may contribute to anaphylaxis or angioedema in patients undergoing plasmapheresis.12 ACEi were restarted after the plasmapheresis treatments were completed. Before the initiation of plasmapheresis treatments, a 24hour urine collection was obtained for the measurement of protein and creatinine. Urine protein/creatinine ratios were measured on most samples obtained immediately before the first and after the last plasmapheresis treatments. Measurements of serum creatinine, electrolytes, calcium, albumin, cholesterol, and triglycerides were performed with each plasmapheresis. Serum and plasma samples were collected
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before and after the first and last treatments. Repeat 24-hour urine samples were collected at least 1 month after the treatment. Patients were followed-up for up to 24 months after the completion of the sixth plasmapheresis. A complete remission was defined as a decline in proteinuria to less than 0.5 g/24 hr/1.73 m2 and a partial remission by a decline in proteinuria to less than 50% of the baseline value measured within 1 week after plasmapheresis. Baseline values were those measurements performed after the completion of a course of steroids and before initiation of plasmapheresis. The study was approved by the Human Subjects Committee at the Harbor–UCLA Research and Education Institute. All patients rendered an informed consent.
Measurement of Palb in Response to Serum Exposure Glomerular capillary permeability to albumin (Palb) was measured by determining the degree of capillary expansion in response to an applied oncotic gradient. These studies were performed as previously described.4,11,13 In short, renal cortex from normal Sprague-Dawley rat kidneys was minced and sieved into a medium containing 4 g/dL bovine serum albumin to isolate glomeruli. The medium contained sodium chloride, 115 mmol/L; dibasic sodium phosphate, 1.2 mmol/L; potassium chloride, 5 mmol/L; sodium acetate, 10 mmol/L; sodium bicarbonate, 25 mmol/L; magnesium sulfate, 1.2 mmol/L; calcium chloride, 1.0 mmol/L; and glucose, 5.5 mmol/L. To test the effect of patient serum samples obtained before the first and after the last plasmapheresis on Palb, glomeruli were incubated with 2% vol/vol of patients’ samples or normal pooled human serum for 10 minutes at 37°C. Glomeruli incubated in 4% bovine serum albumin (BSA) were allowed to adhere to polylysine-coated coverslips (1 mg/mL), and initial images of five glomeruli for each set of experiments were recorded using videomicroscopy. After the initial images in 4% BSA-containing medium, it was replaced by a lower oncotic gradient medium (1% BSA). This exchange of medium resulted in expansion of the capillary lumen and an increase in glomerular volume. The final images of glomeruli were recorded using videomicroscopy, and the initial and final volume of each glomerulus was measured using the following equations: V ⫽ 4/3D3
(1)
(volume of a sphere, making the assumption that the glomerulus is spherical) and ⌬V ⫽
VF ⫺ Vs VF
⫻ 100%
(2)
(change in glomerular volume after exposure to 4% BSA followed by 1% BSA). The relative volume increment (⌬V) is proportional to the effective oncotic gradient (⌬effective), which is defined by the difference in the initial and final media albumin concentrations and by the albumin reflection coefficient of the glomerular capillary (albumin). Glomerular capillary albumin permeability (Palb) was calculated as (1-albumin). A value of Palb ⱖ0.5 was considered positive.
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FELD ET AL
RESULTS
a range of 14 to 49. All patients had FSGS as defined in the Methods section. One biopsy specimen had glomeruli with mesangial IgM deposits in addition to early FSGS. All biopsy specimens but one had some degree of tubular atrophy with interstitial fibrosis. All biopsy specimens also showed arteriolar nephrosclerosis. Table 3 enumerates the percentage of glomeruli with global or segmental sclerosis in the renal biopsy specimens and the semiquantitative analysis of the degree of tubular atrophy and interstitial fibrosis. There were no histological differences in the mean scores between responders and nonresponders (Table 3).
Summary of Clinical Histories The clinical characteristics of each patient on initial presentation are summarized in Table 1. Each patient was older than age 16 and had more than 2.6 g/day proteinuria and a creatinine clearance greater than 40 mL/min/1.73 m2 when the study began. Six of the eight had nephrotic syndrome; two of eight had asymptomatic proteinuria. The average time between initial presentation of clinical symptoms and renal biopsy was 3.5 ⫾ 0.6 months. The average time between initial presentation with clinical symptoms and plasmapheresis was 12 ⫾ 2.3 months. Patients were followed-up for an average of 29 ⫾ 4 months after the development of clinical symptoms (Table 2). Before treatment with plasmapheresis, these patients received prednisone at a dose of 40 to 60 mg/day for an average of 4.4 months (range, 1 to 9 months). In all but three patients, this was followed by three 1-g doses of IV methylprednisolone. Each patient continued to have significant proteinuria (greater than 2.6 g/24 hours) after receiving prednisone and methylprednisolone.
Clinical Response to Plasmapheresis Table 4 documents the course of proteinuria in the eight patients at initial presentation, after steroid treatment, after plasmapheresis, and at last follow-up. Most patients continued to receive a tapering dose of prednisone during the plasmapheresis treatments. In two of eight patients, in conjunction with steroids, plasmapheresis appeared to induce a further decrement in urinary protein excretion. These patients were classified as responders. One of the patients (responder 1) had a sustained partial remission, which persisted for at least 8 months. Immediately before beginning plasma-
Histological Analysis An average of 26 glomeruli were available for analysis by light microscopy in each biopsy, with
Table 1. Summary of Clinical Histories on Initial Presentation Clinical Characteristics
Responder 1
Age at presentation Clinical features
31 M, H
ACEi used? Initial creatinine Prepheresis creatinine Final creatinine Prepheresis albumin Postpheresis albumin
Responder 2
26 M, H
Nonresponder Nonresponder 1 2
21 M, AA
Nephrotic Asymptomatic Nephrotic syndrome; proteinuria; syndrome; BP 124/80 BP 147/66 BP 156/91 (HTN) No Yes Yes 0.9 1.3 1.5
Nonresponder 3
Nonresponder Nonresponder Nonresponder 4 5 6
34 F, AA
43 F, C
16 M, AA
Nephrotic syndrome; BP 144/82 (HTN) No 0.9
Asymptomatic Nephrotic proteinuria; syndrome; BP 118/72 BP 134/74 (HTN) No Yes 1.1 1.2
52 F, C
15 M, H
Nephrotic syndrome; BP 158/80 (HTN) Yes 1.6
Nephrotic syndrome; BP 135/90 (HTN) Yes 0.7
1.1
1.3
1.8
0.9
1.1
0.9
3.4
1.6
1.0
1.3
4.0
0.9
2.4
2.0
PD
HD
0.19
0.73
0.46
0.67
0.84
0.73
0.61
0.81
0.41
0.23
0.09
0.24
0.12
0.23
0.02
⫺0.06
Abbreviations: M, male; F, female; H, Hispanic; AA, African American; C, caucasian; HTN, history of hypertension before plasmapheresis, despite normotension in some patients caused by antihypertensive therapy.
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Table 2. Time From Initial Symptomatology to Renal Biopsy and Renal Biopsy to Plasmapheresis; Total Duration of Follow-Up
Patient
Symptoms to Renal Biopsy
Renal Biopsy to Plasmapheresis (mo)
Duration of Follow-Up (mo)
Responder 1 Responder 2 Nonresponder 1 Nonresponder 2 Nonresponder 3 Nonresponder 4 Nonresponder 5 Nonresponder 6
3 3 5 Unknown 5 4 Unknown 1
4 9 6 24 10 2 8 18
15 32 35 48 35 30 14 25
pheresis, his urinary protein to creatinine ratio was 1.4, and his 24-hour urine protein excretion was 2.6 g. After plasmapheresis, the ratio decreased to 0.62, and 8 months later, it remained at 0.61. The other responder (responder 2) had only a brief partial remission, and 2 months after the plasmapheresis treatment his proteinuria returned to pretreatment levels. Immediately after the last plasmapheresis treatment, the urine protein/creatinine ratio decreased from 1.8 (corresponding to a 24-hour urine protein excretion of 4.7 g) to 0.78. Two months after treatment, his urine protein/creatinine ratio increased to 2.1. Two years after plasmapheresis, the serum creatinine of responder 2 remained stable despite the fact that his proteinuria had returned to nearly baseline levels. Both responders had normal serum creatinine levels (1.1 and 1.3 mg/dL, respectively), which remained unchanged after plasmapheresis and at last follow-up. Six of the eight patients did not experience improvement in proteinuria after plasmapheresis and were classified as nonresponders. After the course of plasmapheresis, their urinary protein to creatinine ratio remained unchanged (7.9 ⫾ 1 prepheresis v 7.9 ⫾ 1.4 postpheresis). PlasmaTable 3. Histological Characteristics of Responders and Nonresponders Glomeruli Completely With TubulointerSclerotic Segmental stitial Glomeruli (%) Sclerosis Score
All patients (n ⫽ 8) Responders (n ⫽ 2) Nonresponders (n ⫽ 6)
7.2 ⫾ 3 10 ⫾ 10 6.2 ⫾ 3
17 ⫾ 3 1.1 ⫾ 0.3 15 ⫾ 0.4 1.0 ⫾ 0.5 18 ⫾ 4.5 1.02 ⫾ 0.4
pheresis did not induce a significant change in either the serum creatinine or serum albumin levels (serum creatinine: 1.5 ⫾ 0.3 mg/dL v 1.3 ⫾ 0.2 mg/dL (P ⬍ 0.62); serum albumin: 2.6 ⫾ 0.3 g/dL versus 3.1 ⫾ 0.3 g/dL (P ⬍ 0.27)). The patients were followed-up for up to 2 years after plasmapheresis. Two of the six nonresponders had a relatively stable course. Nonresponder 2 had persistent severe proteinuria, but her serum creatinine has remained normal 2 years after undergoing plasmapheresis. Nonresponder 4 was started on cyclosporine and steroids 5 months after completing the plasmapheresis protocol. His serum creatinine was 1.9 mg/dL when he started this therapy and has remained stable. His protein/creatinine ratio decreased and is 0.15 2 years after receiving plasmapheresis. Four of the six nonresponders have experienced progressive renal insufficiency. Nonresponders 1 and 3 had deterioration of their kidney function after 24 and 20 months, respectively, but are not on dialysis. Nonresponders 5 and 6 started dialysis 6 months after receiving plasmapheresis. These individuals had evidence of rapid progression before participating in this study, with serum creatinine levels increasing 100% to 128% between the time of their biopsy and the initiation of plasmapheresis. Treatment with plasmapheresis did induce an acute decrease in serum cholesterol levels in both responders and nonresponders (496 ⫾ 83 mg/dL; prepheresis v 77 ⫾ 17 mg/dL, postpheresis; P ⬍ .0004). However, this decrement was not sustained in either group of patients (496 ⫾ 83 mg/dL prepheresis v 373 ⫾ 52 mg/dL approximately 1 month after plasmapheresis; P ⬍ 0.23). Glomerular Permeability Assay Measurements of Palb were performed using patient plasma obtained before and after plasmapheresis. A value of 0.5 or greater was considered indicative of the induction by patient plasma of increased glomerular permeability. Table 5 lists the values for Palb in the responders and nonresponders. Responder 1 had a Palb of 0.19 before plasmapheresis. After treatment, his Palb was 0.41. Responder 2 had a Palb of 0.73, which decreased to 0.23 after plasmapheresis. Nonresponders had a mean Palb of 0.69 ⫾ 0.06, which decreased to 0.12 ⫾ 0.04 after plasmapheresis.
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FELD ET AL Table 4. Proteinuria in Patients Before and After Plasmapheresis
Patient No.
Initial Proteinuria
Responder 1
7.8 g, ratio ⫽ 3.6
Responder 2
Nonresponder 1
Nonresponder 2 Nonresponder 3
Nonresponder 4
Nonresponder 5 Nonresponder 6
Proteinuria After Prednisone
3.8 g, ratio ⫽ 1.5
Proteinuria After Methylprednisolone
Proteinuria After Plasmapheresis
Proteinuria at Last Follow-Up
1.5 g, ratio ⫽ 0.6, 8 months after plasmapheresis 9.0 g, ratio ND 4.7 g, ratio ⫽ 1.8 5.6 g, ratio ND ND, ratio ⫽ 0.78 3.4 g, ratio ⫽ 1.7, 20 months after plasmapheresis 19.5 g, ratio ND ND, ratio ⫽ 5.0 9.4 g, ratio 4.5 8.4 g, ratio ⫽ 4.2 4.2 g, ratio ⫽ 2.8, 24 months after plasmapheresis 11.8 g, ratio ⫽ 8.4 5.8 g, ratio ⫽ 4.8 6.3 g, ratio 5.7 15.9 g, ratio ⫽ 6.6 17 g, ratio ⫽ 19, 24 months after plasmapheresis 4.5 g, ratio ⫽ 4.1 9.5 g, ratio ⫽ 10.5 MP not given 12.6 g, ratio ⫽ 11.4 10.9 g, ratio ⫽ 9.9, 20 months after plasmapheresis 10.2 g, ratio ND 9.5 g, ratio ⫽ 5.9 MP not given 9.4 g, ratio ⫽ 5.2 ND, ratio ⫽ 0.15, 24 months after plasmapheresis 10.0 g, ratio ND 15.1 g, ratio ⫽ 9.4 MP not given 13.3 g, ratio ⫽ 14.1 ND, ESRD 6 months after plasmapheresis 3⫹ (not quantified) 5.1 g, ratio ⫽ 3.2 ND, ratio ⫽ 10.9 9.9 g, ratio ⫽ 9.0 ND, ESRD 6 months after plasmapheresis 2.6 g, ratio 1.4
ND, ratio ⫽ 0.62
NOTE. This table displays the degree of proteinuria present at each time period. Two values are listed. The first is the 24-hour urine protein measurement. The second value represents the ratio of protein to creatinine from the 24-hour or spot urine sample. ND is listed when the test was not done. Nonresponder 6 underwent biopsy and treatment with steroids based on a urinalysis showing 3⫹ proteinuria, which was not quantified until after steroids were given. Abbreviations: ND, not determined; MP, methylprednisolone.
Despite the decrease in Palb (P ⬍ 0.0001), their proteinuria did not improve. DISCUSSION
In this study, eight patients with steroidresistant idiopathic FSGS were treated with plasmapheresis after high-dose prednisone failed to induce a complete remission in nephrotic-range proteinuria. Each patient received a total of six treatments over approximately a 2-week period. Table 5. Albumin Permeability Levels Before and After Plasmapheresis Patient
Preplasmapheresis
Postplasmapheresis*
Responder 1 Responder 2 Nonresponder 1 Nonresponder 2 Nonresponder 3 Nonresponder 4 Nonresponder 5 Nonresponder 6
0.19 0.73 0.46 0.67 0.84 0.73 0.61 0.81
0.41 0.23 0.09 0.24 0.12 0.23 0.02 ⫺0.06
*P ⬍ .0001 compared with preplasmapheresis values.
Two of the eight patients had a partial remission with a decrease of the urine protein/creatinine ratio to less than 50% of baseline. One of these patients had a durable response. The other responder’s proteinuria returned to baseline 2 months after completing the course of plasmapheresis. In both patients whose proteinuria responded favorably, renal function during followup, as assessed by serum creatinine measurements, remained stable. The clinical outcomes of the six patients who did not experience an improvement in proteinuria were quite varied. Two patients have had stable courses with relatively good kidney function, two are now on dialysis, and the serum creatinine concentrations in the two remaining patients have risen substantially. Plasmapheresis was successful in acutely lowering serum cholesterol levels in all of the participants. However, this effect was transient, and cholesterol levels quickly returned to the preplasmapheresis values. There were no significant changes in serum albumin or creatinine immediately after plasmapheresis.
PLASMAPHERESIS FOR FSGS
Both experimental and clinical observations suggest that in some patients, minimal change disease and FSGS are caused by circulating factors that enhance glomerular permeability, thereby providing a rationale for plasmapheresis as treatment. A substance isolated from patients with minimal change disease and synthesized by T cell hybridomas causes proteinuria when injected in rats.14 Similarly, proteinuria or albuminuria can be induced in rats by the injection of serum or immunoadsorption extracts from patients with FSGS or minimal change disease, whereas injection with control or other nephrotic sera does not cause proteinuria.9,15-17 Further support for the hypothesis that circulating factors may mediate proteinuria in FSGS comes from the clinical observation that recurrence in renal allografts occurs in up to 40% of patients and is occasionally seen within hours of transplantation.4,6-10,18-20 Savin et al11 developed an in vitro method to measure the effect of circulating factors on glomerular albumin permeability. The permeability activity of sera tended to be high in patients with recurrence of FSGS after renal transplantation and was absent or found at low levels in patients who did not have a recurrence after transplantation and in patients with steroid-sensitive nephrotic syndrome or membranous nephropathy.4 When Palb was measured on samples collected before transplantation in 30 patients whose initial primary renal diagnosis was focal sclerosis, a value above 0.50 was associated with a frequency of allograft recurrence of 86%. In contrast, only 17% of patients with Palb less than 0.50 developed recurrent disease.4 Removal of circulating permeability factor(s) has therefore gained credence as a therapeutic objective in the treatment of patients with recurrent FSGS in renal allografts. Dantal et al9 used serum immunoadsorption over a protein A column to achieve this goal. Immunoadsorption decreased proteinuria by an average of 82% acutely, but in all patients, proteinuria recurred within 2 months.9 Laufer et al6 used plasmapheresis in two patients with recurrent disease and achieved remissions exceeding 14 months. Artero et al10 performed plasmapheresis on nine patients who had recurrent FSGS in renal allografts and measured Palb before and after treatment. Six of the nine patients responded with a
235
significant decrement in urinary protein excretion. In five of the nine, only foot process effacement was present on the posttransplantation biopsy specimen, whereas in the remaining four patients, segmental glomerulosclerosis and hyalinosis were present. Proteinuria after plasmapheresis decreased from 12.0 ⫾ 7.46 g to 5.1 ⫾ 7.39 g/day, and Palb declined after plasmapheresis in all patients. The best results were obtained in patients in whom plasmapheresis was instituted within 1 week of the development of recurrent proteinuria.10 Poor results were obtained when glomerulosclerosis and hyalinosis were present on renal biopsy. Two of the six patients with an initial favorable response experienced a recurrence of proteinuria but achieved a longer-lasting remission after a second course of plasmapheresis. Savin and Terreros13 reported that plasmapheresis normalized high Palb levels in seven patients who were treated for recurrent FSGS after renal transplantation. The decrement in Palb was associated with a decline in proteinuria from 8.9 ⫾ 2.5 g to 0.9 ⫾ 0.2 per g creatinine.13 The response of our patients to plasmapheresis was less favorable than that reported for patients with recurrence in renal allografts. This may be due in part to the more advanced state of illness present at the time of initiation of plasmapheresis in our patients. Although the average serum creatinine level in our patients was not very high at the time of initial presentation for renal biopsy (1.2 ⫾ 0.1 mg/dL), the average duration of symptoms at the time of renal biopsy was 3.5 ⫾ 0.6 months. Furthermore, we entered into this study only patients who failed to respond to initial treatment with corticosteroids. Therefore, a built-in delay of many months was present in the patients in whom plasmapheresis was initiated. At the start of plasmapheresis, our patients had an average serum creatinine of 1.5 ⫾ 0.3 mg/dL and were known to have proteinuria for an average of 12.3 ⫾ 2.3 months. This is in marked contrast to the patients of Artero et al,10 in whom the best results were achieved in patients in whom plasmapheresis was begun within 1 week of the development of proteinuria. Furthermore, histologically, all of our patients had segments of sclerosis on renal biopsy, a finding that augured against a remission in Artero et al’s experience.10 Thus, the very nature of the presentation of primary disease, with a tendency for delay in
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initial diagnosis, likely diminishes the opportunity for response to plasmapheresis as a sole form of therapy. Another difference between the response of patients in this study and those reported with allograft recurrence involves the relationship between Palb and the effects of treatment. In this study, of the two patients with decrements in proteinuria after plasmapheresis, only one showed a high Palb before plasmapheresis, which normalized after treatment. The patient with the remission of most durable duration had a Palb in the normal range both before and after plasmapheresis. Of the six patients who failed to respond to plasmapheresis, all except one (with a borderline value of 0.46) had high Palb measurements before treatment, which normalized after plasmapheresis. The lack of a clear relationship between the removal of the circulating permeability factor and the development of remission in these patients with advanced histological damage suggests that local factors associated with advanced renal injury or systemic factors unrelated to glomerular permeability play a larger role in determining the degree of proteinuria than the presence or absence of the circulating factor at this later stage of the disease. Despite the lesser success in achieving remission with plasmapheresis in patients with FSGS in native kidneys compared with that achieved in recurrent disease, these studies nevertheless suggest potential benefit for a minority of patients. Two of eight patients undergoing plasmapheresis experienced an improvement in proteinuria over and above that achieved with high-dose prednisone, albeit transiently in one of the two. Both of the patients who experienced a remission in proteinuria also had stable renal function over an 8- to 20-month follow-up period. In contrast, of the six patients who failed to respond, only one third had stable serum creatinine levels, whereas two thirds had either progressive renal insufficiency or advanced to end-stage renal disease. It is unlikely that differential use of ACE inhibitors was responsible for the favorable course in the four patients with a stable serum creatinine during follow-up. Of the two responders with stable renal function, one was prescribed ACE inhibitors, and the other was not. Of the two patients in the nonresponder group with stable renal function, one maintained stable renal function in the
FELD ET AL
absence of ACE inhibitor therapy. The other was prescribed an ACE inhibitor, but also an aggressive immunosuppressive regimen including oral prednisone, successive solumedrol pulses, and cyclosporine. This study’s nonrandomized design and small patient numbers clearly make it impossible to ascribe with certainty the apparent clinical stability observed in a subset of patients to the experimental treatment given. Only a prospective, randomized clinical trial could address these issues in a convincing way. However, should such a study be undertaken in patients with primary disease, some import should be paid to the evidence suggesting that local or systemic factors other than or in addition to the circulating permeability factor play a role in determining proteinuria at the stage at which it is practical to enter patients in such a trial. Our report suggests that any prospective randomized, clinical trial of plasmapheresis in patients with FSGS in their native kidneys should either be performed early in the patients’ course as an initial treatment strategy or should include combination drug therapy that would modulate the additional factors that appear to predominate at later stages of the disorder. ACKNOWLEDGMENT The authors thank Drs D. Corry, A. Erlbaum, D. Haspert, L. Pascua, M. Rosenblatt, and S. Winkler for referring their patients with focal and segmental glomerulosclerosis.
REFERENCES 1. Glassock RJ, Cohen AH, Adler SG: Primary glomerular diseases, in Brenner BM, Rector FC (eds): The Kidney (ed 5). Philadelphia, PA, Saunders, 1996 2. D’Agati V: The many masks of focal segmental glomerulosclerosis. Kidney Int 46:1223-1241, 1994 3. 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 26:740-750, 1995 4. Savin VJ, Sharma R, Sharma M, McCarthy ET, Swan SK, Ellis E, Lovell H, Warady B, Gunwar S, Chonko AM, Artero M, Vincenti F: Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl J Med 334:878883, 1996 5. Zimmerman SW: Plasmapheresis and dipyridamole for recurrent focal glomerular sclerosis. Nephron 40:241245, 1985 6. Laufer J, Ettenger RB, Ho WG, Cohen AH, Marik JL, Fine RN: Plasma exchange for recurrent nephrotic syndrome following renal transplantation. Transplantation 46:540-542, 1988
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7. Artero M, Biava C, Amend W, Tomlanovich S, Vincenti F: Recurrent focal glomerulosclerosis: Natural history and response to therapy. Am J Med 92:375-383, 1992 8. Cochat P, Kassir A, Colon S, Glastre C, Tourniaire B, Parchoux B, Martin X, David L: Recurrent nephrotic syndrome after transplantation: Early treatment with plasmapheresis and cyclophosphamide. Pediatr Nephrol 7:50-54, 1993 9. Dantal J, Bigot E, Bogers W, Testa A, Kriaa F, Jacques Y, Hurault de Ligny B, Niaudet P, Charpentier B, Soulillou JP: Effect of plasma protein adsorption on protein excretion in kidney-transplant recipients with recurrent nephrotic syndrome. N Engl J Med 330:7-14, 1994 10. Artero ML, Sharma R, Savin VJ, Vincenti F: Plasmapheresis reduces proteinuria and serum capacity to injure glomeruli in patients with recurrent focal glomerulosclerosis. Am J Kidney Dis 23:574-581, 1994 11. Savin VJ, Sharma R, Lovell HV, Welling DJ: Measurement of albumin reflection coefficient using isolated rat glomeruli. J Am Soc Nephrol 3:1260-1269, 1992 12. Owen HG, Brecher ME: Atypical reactions associated with use of angiotensin-converting enzyme inhibitors and apheresis. Transfusion 34:891-894, 1994 13. Savin VJ, Terreros DA: Filtration in single isolated mammalian glomeruli. Kidney Int 20:188-197, 1981 14. Koyama A, Fujisaki M, Kobayashi M, Igarashi M,
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Narita M: A glomerular permeability factor produced by human T cell hybridomas. Kidney Int 40:453-460, 1991 15. Zimmerman SW: Increased urinary protein excretion in the rat produced by serum from a patient with recurrent focal glomerulosclerosis after renal transplantation. Clin Nephrol 22:32-38, 1984 16. Bakker WW, Baller JFK, van Luyk WHJ, van der Hem GK: Mononuclear blood cells from patients with minimal change nephrotic syndrome (MCNS) induce increased glomerular permeability in the rat kidney in vivo. Kidney Int 30:633, 1986 (abstr) 17. Wilkinson AH, Gillespie C, Hartley B, Williams DG: Increase in proteinuria and reduction in number of anionic sites on the glomerular basement membrane in rats by infusion of human nephrotic plasma in vivo. Clin Sci 77:4348, 1989 18. Lewis EJ: Recurrent focal sclerosis after renal transplantation. Kidney Int 22:315-323, 1982 19. Morales JM, Andres A, Prieto C, Martinez MA, Praga M, Ruilope LM, Gutierrez Millet V, Rodicio JL: Clinical and histological sequence of recurrent focal segmental glomerulosclerosis. Nephron 48:241-242, 1988 20. Senggutuvan P, Cameron JS, Hartley RB, Rigden S, Chantler C, Haycock G, Williams DG, Ogg C, Koffman G: Recurrence of focal segmental glomerulosclerosis in transplanted kidneys: Analysis of incidence and risk factors in 59 allografts. Pediatr Nephrol 4:21-28, 1990
F
OCAL SEGMENTAL glomerulosclerosis (FSGS) is a histological entity characterized by visceral epithelial cell injury, capillary collapse, hyalinosis, and accretion of extracellular matrix material. It can occur in a primary or idiopathic form or may be present secondary to a variety of underlying disorders. In its secondary form, it may be seen in association with conditions such as reflux nephropathy, morbid obesity, and human immunodeficiency virus (HIV) infection.1 Treatment of the secondary forms are directed at amelioration of the underlying condition when possible, and at measures that may otherwise decrease urinary protein excretion. Although 10% to 40% of patients with the idiopathic variety respond to steroids, those who do
From the Medical College of Wisconsin, Milwaukee, WI; Cedars Sinai Medical Center, Los Angeles, CA; and HarborUCLA Medical Center, Torrance, CA. Received December 5, 1997; accepted in revised form March 3, 1998. Supported in part by a grant from NIH to the HarborUCLA Clinical Research Center, MO1 RR00425. Address reprint requests to Sharon Adler, MD, HarborUCLA Medical Center, 1000 West Carson St, C-1 Annex, Torrance, CA 90509. E-mail: [email protected]
r 1998 by the National Kidney Foundation, Inc. 0272-6386/98/3202-0006$3.00/0 230
not respond to therapy frequently progress to end-stage renal disease.1 Furthermore, the incidence of FSGS appears to be increasing, and in some studies, FSGS has become the most common cause of the idiopathic nephrotic syndrome in adults.2,3 A circulating humoral factor may be involved in the pathogenesis of some cases of FSGS.4-10 In a number of studies, a beneficial effect of plasmapheresis in patients with recurrent FSGS after renal transplantation has been shown.5-10 Additional studies have shown that in approximately one third of cases, sera from patients whose FSGS recurred after transplantation caused a significant increase in glomerular capillary albumin permeability (Palb) in vitro.11 In patients with a high Palb value and recurrent FSGS in renal allografts, treatment with plasmapheresis diminished proteinuria. When the diagnosis was made early in these patients and treatment was initiated, lasting remissions were occasionally achieved. We studied eight patients with steroidresistant idiopathic FSGS in native kidneys to determine whether a factor capable of increasing glomerular capillary albumin permeability in vitro was present in their serum and whether removal
American Journal of Kidney Diseases, Vol 32, No 2 (August), 1998: pp 230-237
PLASMAPHERESIS FOR FSGS
of this factor with plasmapheresis would lead to a decrease in proteinuria or stabilization of renal function. METHODS
Study Subjects Eight patients with steroid-resistant idiopathic FSGS were studied; no cases of collapsing form or tip lesion were included. Each was diagnosed by renal biopsy after presenting with nephrotic-range proteinuria. All biopsy specimens were evaluated by light, immunofluorescent, and electron microscopies by a renal pathologist (C.C.N.) to establish a diagnosis and to determine the percentage of glomeruli with complete sclerosis and those with segmental sclerosis. FSGS was defined as a segment of sclerosis (capillary collapse, insudates, and abnormal overlying visceral epithelial cells with or without adhesions, intraluminal foam cells and lipid) in at least one glomerulus without an underlying separate glomerular lesion. Semiquantitative analysis to measure the degree of tubular atrophy and interstitial fibrosis was performed as follows: A score ranging from 0 to 3 was given for the percentage of tubulointerstitial scarring: 0, 0-5%; 1, 6-15%; 1.5, 16-25%; 2, 26-40%; 2.5, 41-50%; 3, ⱖ50%. The clinical course of the patients was characterized with regard to degree of proteinuria, creatinine clearance, and preplasmapheresis treatment history. Blood pressure was measured in the sitting position after 5 minutes of quiet repose during the initial screening visit. Patients entering this study continued to have significant proteinuria despite having received the equivalent of at least 40 mg prednisone per day for at least 2 months. All but three patients were also treated with three daily 1-g doses of methylprednisolone, with no improvement in proteinuria.
Plasmapheresis Treatments Plasmapheresis was performed using the Cobe Spectra System (Cobe Laboratories, Inc., Lakewood, CO) under citrate anticoagulation. Each patient received six 1.5 plasma volume exchanges over approximately 2 weeks. The plasma was replaced with 5% albumin and normal saline in a ratio intended to maintain the serum albumin at 3 g/dL or at the patient’s baseline level if it was higher. Calcium gluconate infusions of up to 3 g per procedure were given as needed for symptomatic or laboratory evidence of hypocalcemia. Five of the eight patients were taking angiotensin converting enzyme inhibitors (ACEi) before the biopsy. This medication was stopped in all patients during the plasmapheresis treatments because of reports that ACEi may contribute to anaphylaxis or angioedema in patients undergoing plasmapheresis.12 ACEi were restarted after the plasmapheresis treatments were completed. Before the initiation of plasmapheresis treatments, a 24hour urine collection was obtained for the measurement of protein and creatinine. Urine protein/creatinine ratios were measured on most samples obtained immediately before the first and after the last plasmapheresis treatments. Measurements of serum creatinine, electrolytes, calcium, albumin, cholesterol, and triglycerides were performed with each plasmapheresis. Serum and plasma samples were collected
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before and after the first and last treatments. Repeat 24-hour urine samples were collected at least 1 month after the treatment. Patients were followed-up for up to 24 months after the completion of the sixth plasmapheresis. A complete remission was defined as a decline in proteinuria to less than 0.5 g/24 hr/1.73 m2 and a partial remission by a decline in proteinuria to less than 50% of the baseline value measured within 1 week after plasmapheresis. Baseline values were those measurements performed after the completion of a course of steroids and before initiation of plasmapheresis. The study was approved by the Human Subjects Committee at the Harbor–UCLA Research and Education Institute. All patients rendered an informed consent.
Measurement of Palb in Response to Serum Exposure Glomerular capillary permeability to albumin (Palb) was measured by determining the degree of capillary expansion in response to an applied oncotic gradient. These studies were performed as previously described.4,11,13 In short, renal cortex from normal Sprague-Dawley rat kidneys was minced and sieved into a medium containing 4 g/dL bovine serum albumin to isolate glomeruli. The medium contained sodium chloride, 115 mmol/L; dibasic sodium phosphate, 1.2 mmol/L; potassium chloride, 5 mmol/L; sodium acetate, 10 mmol/L; sodium bicarbonate, 25 mmol/L; magnesium sulfate, 1.2 mmol/L; calcium chloride, 1.0 mmol/L; and glucose, 5.5 mmol/L. To test the effect of patient serum samples obtained before the first and after the last plasmapheresis on Palb, glomeruli were incubated with 2% vol/vol of patients’ samples or normal pooled human serum for 10 minutes at 37°C. Glomeruli incubated in 4% bovine serum albumin (BSA) were allowed to adhere to polylysine-coated coverslips (1 mg/mL), and initial images of five glomeruli for each set of experiments were recorded using videomicroscopy. After the initial images in 4% BSA-containing medium, it was replaced by a lower oncotic gradient medium (1% BSA). This exchange of medium resulted in expansion of the capillary lumen and an increase in glomerular volume. The final images of glomeruli were recorded using videomicroscopy, and the initial and final volume of each glomerulus was measured using the following equations: V ⫽ 4/3D3
(1)
(volume of a sphere, making the assumption that the glomerulus is spherical) and ⌬V ⫽
VF ⫺ Vs VF
⫻ 100%
(2)
(change in glomerular volume after exposure to 4% BSA followed by 1% BSA). The relative volume increment (⌬V) is proportional to the effective oncotic gradient (⌬effective), which is defined by the difference in the initial and final media albumin concentrations and by the albumin reflection coefficient of the glomerular capillary (albumin). Glomerular capillary albumin permeability (Palb) was calculated as (1-albumin). A value of Palb ⱖ0.5 was considered positive.
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FELD ET AL
RESULTS
a range of 14 to 49. All patients had FSGS as defined in the Methods section. One biopsy specimen had glomeruli with mesangial IgM deposits in addition to early FSGS. All biopsy specimens but one had some degree of tubular atrophy with interstitial fibrosis. All biopsy specimens also showed arteriolar nephrosclerosis. Table 3 enumerates the percentage of glomeruli with global or segmental sclerosis in the renal biopsy specimens and the semiquantitative analysis of the degree of tubular atrophy and interstitial fibrosis. There were no histological differences in the mean scores between responders and nonresponders (Table 3).
Summary of Clinical Histories The clinical characteristics of each patient on initial presentation are summarized in Table 1. Each patient was older than age 16 and had more than 2.6 g/day proteinuria and a creatinine clearance greater than 40 mL/min/1.73 m2 when the study began. Six of the eight had nephrotic syndrome; two of eight had asymptomatic proteinuria. The average time between initial presentation of clinical symptoms and renal biopsy was 3.5 ⫾ 0.6 months. The average time between initial presentation with clinical symptoms and plasmapheresis was 12 ⫾ 2.3 months. Patients were followed-up for an average of 29 ⫾ 4 months after the development of clinical symptoms (Table 2). Before treatment with plasmapheresis, these patients received prednisone at a dose of 40 to 60 mg/day for an average of 4.4 months (range, 1 to 9 months). In all but three patients, this was followed by three 1-g doses of IV methylprednisolone. Each patient continued to have significant proteinuria (greater than 2.6 g/24 hours) after receiving prednisone and methylprednisolone.
Clinical Response to Plasmapheresis Table 4 documents the course of proteinuria in the eight patients at initial presentation, after steroid treatment, after plasmapheresis, and at last follow-up. Most patients continued to receive a tapering dose of prednisone during the plasmapheresis treatments. In two of eight patients, in conjunction with steroids, plasmapheresis appeared to induce a further decrement in urinary protein excretion. These patients were classified as responders. One of the patients (responder 1) had a sustained partial remission, which persisted for at least 8 months. Immediately before beginning plasma-
Histological Analysis An average of 26 glomeruli were available for analysis by light microscopy in each biopsy, with
Table 1. Summary of Clinical Histories on Initial Presentation Clinical Characteristics
Responder 1
Age at presentation Clinical features
31 M, H
ACEi used? Initial creatinine Prepheresis creatinine Final creatinine Prepheresis albumin Postpheresis albumin
Responder 2
26 M, H
Nonresponder Nonresponder 1 2
21 M, AA
Nephrotic Asymptomatic Nephrotic syndrome; proteinuria; syndrome; BP 124/80 BP 147/66 BP 156/91 (HTN) No Yes Yes 0.9 1.3 1.5
Nonresponder 3
Nonresponder Nonresponder Nonresponder 4 5 6
34 F, AA
43 F, C
16 M, AA
Nephrotic syndrome; BP 144/82 (HTN) No 0.9
Asymptomatic Nephrotic proteinuria; syndrome; BP 118/72 BP 134/74 (HTN) No Yes 1.1 1.2
52 F, C
15 M, H
Nephrotic syndrome; BP 158/80 (HTN) Yes 1.6
Nephrotic syndrome; BP 135/90 (HTN) Yes 0.7
1.1
1.3
1.8
0.9
1.1
0.9
3.4
1.6
1.0
1.3
4.0
0.9
2.4
2.0
PD
HD
0.19
0.73
0.46
0.67
0.84
0.73
0.61
0.81
0.41
0.23
0.09
0.24
0.12
0.23
0.02
⫺0.06
Abbreviations: M, male; F, female; H, Hispanic; AA, African American; C, caucasian; HTN, history of hypertension before plasmapheresis, despite normotension in some patients caused by antihypertensive therapy.
PLASMAPHERESIS FOR FSGS
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Table 2. Time From Initial Symptomatology to Renal Biopsy and Renal Biopsy to Plasmapheresis; Total Duration of Follow-Up
Patient
Symptoms to Renal Biopsy
Renal Biopsy to Plasmapheresis (mo)
Duration of Follow-Up (mo)
Responder 1 Responder 2 Nonresponder 1 Nonresponder 2 Nonresponder 3 Nonresponder 4 Nonresponder 5 Nonresponder 6
3 3 5 Unknown 5 4 Unknown 1
4 9 6 24 10 2 8 18
15 32 35 48 35 30 14 25
pheresis, his urinary protein to creatinine ratio was 1.4, and his 24-hour urine protein excretion was 2.6 g. After plasmapheresis, the ratio decreased to 0.62, and 8 months later, it remained at 0.61. The other responder (responder 2) had only a brief partial remission, and 2 months after the plasmapheresis treatment his proteinuria returned to pretreatment levels. Immediately after the last plasmapheresis treatment, the urine protein/creatinine ratio decreased from 1.8 (corresponding to a 24-hour urine protein excretion of 4.7 g) to 0.78. Two months after treatment, his urine protein/creatinine ratio increased to 2.1. Two years after plasmapheresis, the serum creatinine of responder 2 remained stable despite the fact that his proteinuria had returned to nearly baseline levels. Both responders had normal serum creatinine levels (1.1 and 1.3 mg/dL, respectively), which remained unchanged after plasmapheresis and at last follow-up. Six of the eight patients did not experience improvement in proteinuria after plasmapheresis and were classified as nonresponders. After the course of plasmapheresis, their urinary protein to creatinine ratio remained unchanged (7.9 ⫾ 1 prepheresis v 7.9 ⫾ 1.4 postpheresis). PlasmaTable 3. Histological Characteristics of Responders and Nonresponders Glomeruli Completely With TubulointerSclerotic Segmental stitial Glomeruli (%) Sclerosis Score
All patients (n ⫽ 8) Responders (n ⫽ 2) Nonresponders (n ⫽ 6)
7.2 ⫾ 3 10 ⫾ 10 6.2 ⫾ 3
17 ⫾ 3 1.1 ⫾ 0.3 15 ⫾ 0.4 1.0 ⫾ 0.5 18 ⫾ 4.5 1.02 ⫾ 0.4
pheresis did not induce a significant change in either the serum creatinine or serum albumin levels (serum creatinine: 1.5 ⫾ 0.3 mg/dL v 1.3 ⫾ 0.2 mg/dL (P ⬍ 0.62); serum albumin: 2.6 ⫾ 0.3 g/dL versus 3.1 ⫾ 0.3 g/dL (P ⬍ 0.27)). The patients were followed-up for up to 2 years after plasmapheresis. Two of the six nonresponders had a relatively stable course. Nonresponder 2 had persistent severe proteinuria, but her serum creatinine has remained normal 2 years after undergoing plasmapheresis. Nonresponder 4 was started on cyclosporine and steroids 5 months after completing the plasmapheresis protocol. His serum creatinine was 1.9 mg/dL when he started this therapy and has remained stable. His protein/creatinine ratio decreased and is 0.15 2 years after receiving plasmapheresis. Four of the six nonresponders have experienced progressive renal insufficiency. Nonresponders 1 and 3 had deterioration of their kidney function after 24 and 20 months, respectively, but are not on dialysis. Nonresponders 5 and 6 started dialysis 6 months after receiving plasmapheresis. These individuals had evidence of rapid progression before participating in this study, with serum creatinine levels increasing 100% to 128% between the time of their biopsy and the initiation of plasmapheresis. Treatment with plasmapheresis did induce an acute decrease in serum cholesterol levels in both responders and nonresponders (496 ⫾ 83 mg/dL; prepheresis v 77 ⫾ 17 mg/dL, postpheresis; P ⬍ .0004). However, this decrement was not sustained in either group of patients (496 ⫾ 83 mg/dL prepheresis v 373 ⫾ 52 mg/dL approximately 1 month after plasmapheresis; P ⬍ 0.23). Glomerular Permeability Assay Measurements of Palb were performed using patient plasma obtained before and after plasmapheresis. A value of 0.5 or greater was considered indicative of the induction by patient plasma of increased glomerular permeability. Table 5 lists the values for Palb in the responders and nonresponders. Responder 1 had a Palb of 0.19 before plasmapheresis. After treatment, his Palb was 0.41. Responder 2 had a Palb of 0.73, which decreased to 0.23 after plasmapheresis. Nonresponders had a mean Palb of 0.69 ⫾ 0.06, which decreased to 0.12 ⫾ 0.04 after plasmapheresis.
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FELD ET AL Table 4. Proteinuria in Patients Before and After Plasmapheresis
Patient No.
Initial Proteinuria
Responder 1
7.8 g, ratio ⫽ 3.6
Responder 2
Nonresponder 1
Nonresponder 2 Nonresponder 3
Nonresponder 4
Nonresponder 5 Nonresponder 6
Proteinuria After Prednisone
3.8 g, ratio ⫽ 1.5
Proteinuria After Methylprednisolone
Proteinuria After Plasmapheresis
Proteinuria at Last Follow-Up
1.5 g, ratio ⫽ 0.6, 8 months after plasmapheresis 9.0 g, ratio ND 4.7 g, ratio ⫽ 1.8 5.6 g, ratio ND ND, ratio ⫽ 0.78 3.4 g, ratio ⫽ 1.7, 20 months after plasmapheresis 19.5 g, ratio ND ND, ratio ⫽ 5.0 9.4 g, ratio 4.5 8.4 g, ratio ⫽ 4.2 4.2 g, ratio ⫽ 2.8, 24 months after plasmapheresis 11.8 g, ratio ⫽ 8.4 5.8 g, ratio ⫽ 4.8 6.3 g, ratio 5.7 15.9 g, ratio ⫽ 6.6 17 g, ratio ⫽ 19, 24 months after plasmapheresis 4.5 g, ratio ⫽ 4.1 9.5 g, ratio ⫽ 10.5 MP not given 12.6 g, ratio ⫽ 11.4 10.9 g, ratio ⫽ 9.9, 20 months after plasmapheresis 10.2 g, ratio ND 9.5 g, ratio ⫽ 5.9 MP not given 9.4 g, ratio ⫽ 5.2 ND, ratio ⫽ 0.15, 24 months after plasmapheresis 10.0 g, ratio ND 15.1 g, ratio ⫽ 9.4 MP not given 13.3 g, ratio ⫽ 14.1 ND, ESRD 6 months after plasmapheresis 3⫹ (not quantified) 5.1 g, ratio ⫽ 3.2 ND, ratio ⫽ 10.9 9.9 g, ratio ⫽ 9.0 ND, ESRD 6 months after plasmapheresis 2.6 g, ratio 1.4
ND, ratio ⫽ 0.62
NOTE. This table displays the degree of proteinuria present at each time period. Two values are listed. The first is the 24-hour urine protein measurement. The second value represents the ratio of protein to creatinine from the 24-hour or spot urine sample. ND is listed when the test was not done. Nonresponder 6 underwent biopsy and treatment with steroids based on a urinalysis showing 3⫹ proteinuria, which was not quantified until after steroids were given. Abbreviations: ND, not determined; MP, methylprednisolone.
Despite the decrease in Palb (P ⬍ 0.0001), their proteinuria did not improve. DISCUSSION
In this study, eight patients with steroidresistant idiopathic FSGS were treated with plasmapheresis after high-dose prednisone failed to induce a complete remission in nephrotic-range proteinuria. Each patient received a total of six treatments over approximately a 2-week period. Table 5. Albumin Permeability Levels Before and After Plasmapheresis Patient
Preplasmapheresis
Postplasmapheresis*
Responder 1 Responder 2 Nonresponder 1 Nonresponder 2 Nonresponder 3 Nonresponder 4 Nonresponder 5 Nonresponder 6
0.19 0.73 0.46 0.67 0.84 0.73 0.61 0.81
0.41 0.23 0.09 0.24 0.12 0.23 0.02 ⫺0.06
*P ⬍ .0001 compared with preplasmapheresis values.
Two of the eight patients had a partial remission with a decrease of the urine protein/creatinine ratio to less than 50% of baseline. One of these patients had a durable response. The other responder’s proteinuria returned to baseline 2 months after completing the course of plasmapheresis. In both patients whose proteinuria responded favorably, renal function during followup, as assessed by serum creatinine measurements, remained stable. The clinical outcomes of the six patients who did not experience an improvement in proteinuria were quite varied. Two patients have had stable courses with relatively good kidney function, two are now on dialysis, and the serum creatinine concentrations in the two remaining patients have risen substantially. Plasmapheresis was successful in acutely lowering serum cholesterol levels in all of the participants. However, this effect was transient, and cholesterol levels quickly returned to the preplasmapheresis values. There were no significant changes in serum albumin or creatinine immediately after plasmapheresis.
PLASMAPHERESIS FOR FSGS
Both experimental and clinical observations suggest that in some patients, minimal change disease and FSGS are caused by circulating factors that enhance glomerular permeability, thereby providing a rationale for plasmapheresis as treatment. A substance isolated from patients with minimal change disease and synthesized by T cell hybridomas causes proteinuria when injected in rats.14 Similarly, proteinuria or albuminuria can be induced in rats by the injection of serum or immunoadsorption extracts from patients with FSGS or minimal change disease, whereas injection with control or other nephrotic sera does not cause proteinuria.9,15-17 Further support for the hypothesis that circulating factors may mediate proteinuria in FSGS comes from the clinical observation that recurrence in renal allografts occurs in up to 40% of patients and is occasionally seen within hours of transplantation.4,6-10,18-20 Savin et al11 developed an in vitro method to measure the effect of circulating factors on glomerular albumin permeability. The permeability activity of sera tended to be high in patients with recurrence of FSGS after renal transplantation and was absent or found at low levels in patients who did not have a recurrence after transplantation and in patients with steroid-sensitive nephrotic syndrome or membranous nephropathy.4 When Palb was measured on samples collected before transplantation in 30 patients whose initial primary renal diagnosis was focal sclerosis, a value above 0.50 was associated with a frequency of allograft recurrence of 86%. In contrast, only 17% of patients with Palb less than 0.50 developed recurrent disease.4 Removal of circulating permeability factor(s) has therefore gained credence as a therapeutic objective in the treatment of patients with recurrent FSGS in renal allografts. Dantal et al9 used serum immunoadsorption over a protein A column to achieve this goal. Immunoadsorption decreased proteinuria by an average of 82% acutely, but in all patients, proteinuria recurred within 2 months.9 Laufer et al6 used plasmapheresis in two patients with recurrent disease and achieved remissions exceeding 14 months. Artero et al10 performed plasmapheresis on nine patients who had recurrent FSGS in renal allografts and measured Palb before and after treatment. Six of the nine patients responded with a
235
significant decrement in urinary protein excretion. In five of the nine, only foot process effacement was present on the posttransplantation biopsy specimen, whereas in the remaining four patients, segmental glomerulosclerosis and hyalinosis were present. Proteinuria after plasmapheresis decreased from 12.0 ⫾ 7.46 g to 5.1 ⫾ 7.39 g/day, and Palb declined after plasmapheresis in all patients. The best results were obtained in patients in whom plasmapheresis was instituted within 1 week of the development of recurrent proteinuria.10 Poor results were obtained when glomerulosclerosis and hyalinosis were present on renal biopsy. Two of the six patients with an initial favorable response experienced a recurrence of proteinuria but achieved a longer-lasting remission after a second course of plasmapheresis. Savin and Terreros13 reported that plasmapheresis normalized high Palb levels in seven patients who were treated for recurrent FSGS after renal transplantation. The decrement in Palb was associated with a decline in proteinuria from 8.9 ⫾ 2.5 g to 0.9 ⫾ 0.2 per g creatinine.13 The response of our patients to plasmapheresis was less favorable than that reported for patients with recurrence in renal allografts. This may be due in part to the more advanced state of illness present at the time of initiation of plasmapheresis in our patients. Although the average serum creatinine level in our patients was not very high at the time of initial presentation for renal biopsy (1.2 ⫾ 0.1 mg/dL), the average duration of symptoms at the time of renal biopsy was 3.5 ⫾ 0.6 months. Furthermore, we entered into this study only patients who failed to respond to initial treatment with corticosteroids. Therefore, a built-in delay of many months was present in the patients in whom plasmapheresis was initiated. At the start of plasmapheresis, our patients had an average serum creatinine of 1.5 ⫾ 0.3 mg/dL and were known to have proteinuria for an average of 12.3 ⫾ 2.3 months. This is in marked contrast to the patients of Artero et al,10 in whom the best results were achieved in patients in whom plasmapheresis was begun within 1 week of the development of proteinuria. Furthermore, histologically, all of our patients had segments of sclerosis on renal biopsy, a finding that augured against a remission in Artero et al’s experience.10 Thus, the very nature of the presentation of primary disease, with a tendency for delay in
236
initial diagnosis, likely diminishes the opportunity for response to plasmapheresis as a sole form of therapy. Another difference between the response of patients in this study and those reported with allograft recurrence involves the relationship between Palb and the effects of treatment. In this study, of the two patients with decrements in proteinuria after plasmapheresis, only one showed a high Palb before plasmapheresis, which normalized after treatment. The patient with the remission of most durable duration had a Palb in the normal range both before and after plasmapheresis. Of the six patients who failed to respond to plasmapheresis, all except one (with a borderline value of 0.46) had high Palb measurements before treatment, which normalized after plasmapheresis. The lack of a clear relationship between the removal of the circulating permeability factor and the development of remission in these patients with advanced histological damage suggests that local factors associated with advanced renal injury or systemic factors unrelated to glomerular permeability play a larger role in determining the degree of proteinuria than the presence or absence of the circulating factor at this later stage of the disease. Despite the lesser success in achieving remission with plasmapheresis in patients with FSGS in native kidneys compared with that achieved in recurrent disease, these studies nevertheless suggest potential benefit for a minority of patients. Two of eight patients undergoing plasmapheresis experienced an improvement in proteinuria over and above that achieved with high-dose prednisone, albeit transiently in one of the two. Both of the patients who experienced a remission in proteinuria also had stable renal function over an 8- to 20-month follow-up period. In contrast, of the six patients who failed to respond, only one third had stable serum creatinine levels, whereas two thirds had either progressive renal insufficiency or advanced to end-stage renal disease. It is unlikely that differential use of ACE inhibitors was responsible for the favorable course in the four patients with a stable serum creatinine during follow-up. Of the two responders with stable renal function, one was prescribed ACE inhibitors, and the other was not. Of the two patients in the nonresponder group with stable renal function, one maintained stable renal function in the
FELD ET AL
absence of ACE inhibitor therapy. The other was prescribed an ACE inhibitor, but also an aggressive immunosuppressive regimen including oral prednisone, successive solumedrol pulses, and cyclosporine. This study’s nonrandomized design and small patient numbers clearly make it impossible to ascribe with certainty the apparent clinical stability observed in a subset of patients to the experimental treatment given. Only a prospective, randomized clinical trial could address these issues in a convincing way. However, should such a study be undertaken in patients with primary disease, some import should be paid to the evidence suggesting that local or systemic factors other than or in addition to the circulating permeability factor play a role in determining proteinuria at the stage at which it is practical to enter patients in such a trial. Our report suggests that any prospective randomized, clinical trial of plasmapheresis in patients with FSGS in their native kidneys should either be performed early in the patients’ course as an initial treatment strategy or should include combination drug therapy that would modulate the additional factors that appear to predominate at later stages of the disorder. ACKNOWLEDGMENT The authors thank Drs D. Corry, A. Erlbaum, D. Haspert, L. Pascua, M. Rosenblatt, and S. Winkler for referring their patients with focal and segmental glomerulosclerosis.
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