Full text of DOI:10.1007/s004670050774

Pediatr Nephrol (2000) 14:361–364
© IPNA 2000
T R A N S P L A N TAT I O N / B R I E F R E P O RT
Moin A. Saleem · Athimalaipet V. Ramanan
Lesley Rees
Recurrent focal segmental glomerulosclerosis in grafts
treated with plasma exchange and increased immunosuppression
Received: 11 January 1999 / Revised: 20 July 1999 / Accepted: 21 July 1999
Abstract We report on three children with severe, recur- cyclophosphamide [6] and plasma exchange [7, 8]. Re-
rent focal segmental glomeruloscerosis (FSGS) in their cent work has suggested that a circulating factor is re-
first allografts, treated with methylprednisolone, plasma sponsible for disease recurrence [9]. This provides theo-
exchange and cyclophosphamide. This protocol is based retical endorsement for removing such a factor(s) with
on a previous publication showing its successful use in plasma exchange, and also for curtailing its further pro-
three children. Our patients were 2 girls and 1 boy, aged duction by suppressing cells of the immune system.
1
4.5, 14.6 and 13.2 years, respectively, at transplant. Most reports using plasma exchange have shown little
Concomitant immunosuppression included cyclosporin benefit [7, 10], but there are more recent successes in the
A and prednisolone. Recurrence occurred in all three pa- literature, most notably the protocol used by Cochat et
tients within 24 h, and specific treatment was com- al., that resulted in complete remission in proteinuria and
menced within 48 h. All patients developed anuria and recovery of renal function in three children [11]. This
were dialysed. The boy stopped dialysis after 4 weeks, protocol uses the principle of removal of a circulating
and has stable chronic renal failure (CRF) and no pro- factor(s) with plasma exchange as soon as recurrence has
teinuria 3 years later. One girl required dialysis for been observed, followed by heavy immunosuppression
4
months, and 3 years later has CRF with non-nephrotic over a 2-month period. We report, for two reasons, on
range proteinuria. The other girl remained dialysis- three children who were managed with the Cochat proto-
dependent and died from septic complications. We con- col: firstly, because two of them illustrate that recovery
clude that even anuric patients treated with this protocol sufficient to manage without dialysis can occur even af-
may have an improvement in renal function and reduc- ter a prolonged period of dialysis dependency; and sec-
tion of proteinuria, which can last for over 3 years. How- ondly, to illustrate that such therapy carries significant
ever, treatment may need to be prolonged and carries the risks.
substantial risks of heavy immunosuppression.
Patients and methods
Key words Focal segmental glomerulosclerosis ·
Recurrence · Transplant · Plasma exchange ·
Immunosuppression
2
The patients were managed with cyclosporin A 50 mg/m IV 2 h
preoperatively, and postoperatively received an IV infusion fol-
lowed by oral cyclosporin A at 10 mg/kg per day, maintaining
2
blood levels between 150 and 250 ng/ml, azathioprine 45 mg/m
2
per day, and prednisolone 600 mg/m IV 1 h preoperatively and
Introduction
2
6
0 mg/m per day postoperatively (initially intravenously, changing
2
to oral when tolerated), tailing over a 6–8 week period to 10 mg/m
on alternate days. The Cochat regime for immediate postoperative
Recurrence of focal segmental glomerulosclerosis
(
FSGS) after transplant occurs in 20%–30% of children management differs from ours in their usage of daily anti-thymo-
[
1, 2] and results in graft loss in approximately half [3]. cyte globulin, followed by a switch to cyclosporin A (200–
2
3
00 mg/m per day) after 1 week. The daily urine volume was
Attempts at treatment or prevention have included pre-
transplant cyclosporin A, postoperative high-dose cyclo-
sporin A [4], non-steroidal anti-inflammatory drugs [5],
measured and tested for protein, and any fall in central venous
pressure (CVP) or increase in the core–peripheral temperature gap
greater than 2°C was treated promptly with intravenous albumin to
prevent hypovolaemia. At the onset of proteinuria (judged by a ris-
ing urinary protein to a level above 6 g/24 h), the Cochat protocol
was started [11] as follows: plasmapheresis (2 volume exchange)
for 10 consecutive days with a 2-day break after day 5, followed by
once a week for 8 weeks, using a Kobe Spectra machine; intrave-
M.A. Saleem · A.V. Ramanan · L. Rees (
Department of Nephrourology,
✉)
Great Ormond Street Hospital for Children NHS Trust,
London WC1N 3JH, UK
Fax: +44-171-9160011
2
nous methylprednisolone 250 mg/m for 3 days, followed by a re-

3
62
turn to the original dose; and oral cyclophosphamide 2 mg/kg per transplant showed ischaemic changes, with no signs of FSGS. A
day substituted for azathioprine, for an 8-week period. We did not second biopsy 4 weeks later again showed mild ischaemic chang-
use substitutive immunoglobulin after the plasma exchange ses- es, no changes under EM, and also Banff grade III rejection, for
sions (as in the Cochat protocol) in patient no. 3.
which she was treated with 3 days of methylprednisolone, with no
improvement. A further biopsy 5 weeks later showed no rejection
and still no signs of FSGS under light microscopy or EM. The
fourth biopsy 11 weeks post-transplant showed FSGS, with foot
process fusion on EM, and grade III rejection for which she was
given 3 days of high-dose oral steroids. At the end of the 8-week
protocol, she remained dialysis-dependent. At this point she was
given a further 10 days of daily plasma exchange, followed by
weekly exchange for 2 more weeks. Her renal function did not im-
prove, and at 12 weeks post-transplant she became acutely unwell,
with severe abdominal pain and no perfusion to the transplant on
DTPA scanning. A transplant nephrectomy was therefore per-
formed, which histologically was completely necrosed. This was
felt to be most likely due to severe acute rejection in view of the
above biopsy findings. Postoperatively, she developed a herpetic
skin rash and became encephalopathic. She was treated with acy-
clovir and antibiotics. She continued to deteriorate and died
Case 1
This girl developed FSGS at the age of 13 years. Her renal func-
tion deteriorated, and in 18 months she required haemodialysis.
Bilateral nephrectomy was performed after 6 months, in prepara-
tion for a live related transplant 1 month later. By 24 h post-
transplant her serum creatinine had fallen from 840 µmol/l to
1
71 µmol/l, but she had passed 6.8 g of protein in her urine. Sub-
sequently, her urine output tailed off, ultrasound with Doppler
studies showed no abnormality, with normal renal vein and artery
traces, and the Cochat protocol was commenced. She required reg-
ular haemodialysis. At the end of the 8-week protocol there was
no detectable improvement, with a creatinine persistently over
8
00 µmol/l and proteinuria. Therefore, it was decided to continue
2
weeks later, with postmortem findings of widespread systemic
once weekly plasma exchange. Over the next 3 months her renal
function gradually improved, so that haemodialysis was stopped
infection, with multiple lung, hepatic and splenic abscesses that
grew Aspergillus sp., and intracranial haemorrhage.
4
months after commencement of treatment, and plasma exchange
was discontinued after 5 months. At 6 months post-transplant her
serum creatinine was 348 µmol/l, with a glomerular filtration rate
(
GFR) as measured by ethylene diamine tetra-acetic acid (EDTA)
2
Discussion
clearance of 14 ml/min per 1.73 m and urinary protein excretion
of 3.47 g/24 h. Her renal function, although impaired, has re-
mained stable thereafter, so that 3 years post-transplant her creati-
The management of children with ESRF secondary to
FSGS is complicated by the risk of recurrent disease
post-transplant, which has been reported to be between
2
nine is 291 µmol/l; GFR 12 ml/min per 1.73 m , and urine albu-
min/creatinine ratio 4.6 (normal <0.1). The family refused trans-
plant biopsy.
3
0%–50% [1, 2]. Although some studies have shown
that age at diagnosis [2], time from disease onset to
ESRF [10], and mesangial prominence [12] affect the in-
cidence of recurrence, others do not confirm this [1], and
such factors are rarely used to influence the choice of
Case 2
This boy presented at the age of 2 years with nephrotic syndrome
refractory to steroid therapy and cyclophosphamide. The first re-
nal biopsy showing FSGS was done 6 years later, subsequent to end-stage management. It may be argued that the use of
which he had unsuccessful attempts at treatment with levamisole living donors is unjustified with such a high risk of graft
and cyclosporin A. He required haemodialysis by the age of
failure, although there is no evidence that disease recur-
rence is higher in live related donors [1]. The parents of
patients 1 and 2 were made aware of the risks, but chose
1
3 years, and underwent bilateral native nephrectomy 2 months
prior to receiving a transplant from his father. By 24 h post-
transplant his serum creatinine had fallen from 1032 µmol/l to
7
4 µmol/l, but he had passed 16.3 g of protein in his urine. Subse- to proceed with live donation as they wished to reduce
quently, his urine output tailed off, and the Cochat protocol and
regular haemodialysis were commenced. A transplant biopsy on
day 8 was normal under light microscopy, but electron microscopy
the chances of other complications of transplantation as
far as possible.
The evidence for a circulating factor causing protein-
started to improve 4 weeks into the treatment protocol, and by the uria in FSGS is compelling [9] and is likely to be an im-
(
EM) showed widespread foot process fusion. His renal function
end of the 8 weeks, his urine protein excretion was 6 g/24 h, and
munologically triggered event mediated by T-cells [13].
Treatment of such an event by immunosuppression and
removal of the circulating factor(s) has therefore been
proposed by various authors. Laufer et al. reported on
serum creatinine was 146 µmol/l, with a serum albumin of 37 g/l.
2
His GFR 6 months post-transplant was 38 ml/min per 1.73 m , and
2
after 3.5 years is 27 ml/min per 1.73 m , with a urine albumin/cre-
atinine ratio of 0.1 (normal <0.1).
2
children with recurrence of FSGS in allografts treated
early with plasma exchange to bring about remission of
the proteinuria [8]. Torretta et al. described an adult with
recurrence in a second graft treated with 9 plasma ex-
Case 3
This 12.8-year-old girl developed steroid-, cyclophosphamide- and
cyclosporin A-resistant nephrotic syndrome. A second renal biop- changes in a 15-day period, with a normal creatinine at
sy confirmed FSGS. Her renal function declined rapidly, and after the end of treatment and a rapid reduction in proteinuria,
9
months she was commenced on dialysis. Bilateral nephrectomy
being protein-free by 6 months [14]. Dantal et al. [7]
published 9 cases of recurrence treated with plasma ex-
was performed. She underwent a cadaveric renal transplant 1 year
later. By 24 h post-transplant her serum creatinine had fallen from
8
12 µmol/l to 204 µmol/l, but she had passed 17.3 g of protein in change without escalated immunosuppression. Seven pa-
her urine. Subsequently, her urine output tailed off, and her creati- tients responded partly or completely in the short term,
nine started to rise from day 2, and the Cochat protocol and regu-
but proteinuria returned in all patients within 2 weeks of
lar haemodialysis were commenced. A diethylene triamine penta-
cessation of plasma exchange. Mitwalli noted sustained
acetic acid (DTPA) isotope renal scan on day 4, when she was
anuric, showed good perfusion but very poor filtration consistent
with recurrent FSGS. A renal transplant biopsy 3 weeks post- change, cyclophosphamide and oral steroids [15]. Final-
improvement in 6 of 11 adults treated with plasma ex-

3
63
Table 1 Details of patients and
recurrences (GFR glomerular
filtration rate, NS nephrotic
syndrome)
Patient
Case 1
Case 2
Case 3
Sex
F
13
14.5
Day 1
Day 2
27
M
2
F
Age at onset of NS (years)
12.8
14.6
Day 1
Day 2
8
Age at transplant (years)
13.2
Day 1
Day 2
8
534
29 days
146
16.3
6
Time of recurrence post-transplant
Time of initiation of treatment post-transplant
Duration of plasma exchange (weeks)
Peak serum creatinine (µmol/l)
Duration of oliguria/anuria
820
98 days
348
6.8
749
Persistent
627
17.3
Anuric
Serum creatinine at end of plasma exchanges (µmol/l)
Peak urine protein (g/24 h)
Urine protein at end of plasma exchanges (g/24 h)
Duration of follow-up
GFR at follow-up (ml/min/1.73 m )
Urine protein at follow-up (UA/UC ratio, normal =<0.1) 4.6
3.5
3.8 years 3.3 years Died at 4 months
2
12
27
0.1
–
–
ly, Ranchin et al. reported on 4 patients with recurrence
In conclusion, early treatment of severe, recurrent
of proteinuria treated with intravenous cyclosporin A, FSGS post-transplant with methylprednisolone, plasma
with short-term remission in all, and longer-term remis- exchange and cyclophosphamide is of benefit, but not
sion in 2 [16]. Our patients, however, were already on IV without hazard. The response may be gradual and in-
cyclosporin A at the time of onset of the proteinuria, as complete, but perseverance with therapy can result in an
part of their transplant protocol. These results would improved outcome in the medium term.
suggest that additional immunosuppression to an appro-
priate (as yet undefined) level is critical for a successful
outcome.
We followed the protocol described by Cochat et al.
11] as soon as there was evidence of recurrence (1).
References
1
. Senggutuvan P, Cameron JS, Hartley RB, Rigden S, Chantler
C, Haycock G, Williams DG, Ogg C, Koffman G (1990) Re-
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. Kohaut EC, Tejani A (1996) The 1994 annual report of the
North American Pediatric Renal Transplant Cooperative
Study. Pediatr Nephrol 10: 422–434
[
This group treated 3 children with early recurrent
FSGS. All 3 patients had sustained remission within
1
2
2–24 days of therapy, with normal renal function up to
7 months later [11]. However, his patients had less se-
2
vere disease than ours, as none developed anuria/olig-
uria or required dialysis. Two of our patients received
IVIG (cases 1 and 2), and the theoretical benefit of this
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2
in our report illustrate that partial remission can oc-
4
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would recommend that grafts should not be abandoned
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after diagnosis.
5
However, the dangers of prolonged immunosuppres-
sion in the desire to achieve a cure should not be over-
looked, as illustrated by patient 3. This child was trans-
planted within 18 months of the diagnosis of FSGS, and
had received immunosuppression as treatment for the
original disease. The effects of this therapy along with
immunosuppression post-transplant may have had a cu-
mulative effect. She also was the only recipient of a ca-
daveric donor, and the only child to receive therapy for
rejection.
Diagnosis of recurrent FSGS was not helped by trans-
plant biopsy in the first weeks after clinical recurrence.
Foot process fusion was seen in patient 2 by 8 days, but
the characteristic changes of FSGS were not seen in pa-
tient 3 until 11 weeks after the onset of nephrotic syn-
drome. This demonstrates that biopsies are less impor-
tant in the day-to-day management than the clinical fea-
tures of nephrotic syndrome.
6
7
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8
9
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RN (1988) Plasma exchange for recurrent nephrotic syndrome
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5
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1
0. Munoz J, Sanchez M, Perez-Garcia R, Anaya F, Valderrabano
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3
64
1
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98
1
1
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and alkylating agents: does it benefit patients with focal seg-
mental glomerulosclerosis? Nephrol Dial Transplant 13:
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GA (1991) Mononuclear leukocytes, expression of HLA class 16. Ranchin B, Gagnadoux MF, Broyer M, Lehnert A, Juresco A,
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