Case 4 -
Diffuse Podocyte Foot Process Effacement
M. Barry Stokes
Columbia Presbyterian Medical Center
New York, NY
Click on each slide thumbnail image for an enlarged view
A 60 year-old Caucasian female developed chronic renal failure from focal segmental
glomerulosclerosis and received a living-related renal allograft from her 28-year-old son. She presented
initially at age 48 with nephrotic syndrome and mild renal insufficiency (serum creatinine 1.5 mg/dL) and
was treated with prednisone, with partial remission of proteinuria. Renal function continued to decline
over the next 10 years, leading to hemodialysis two years previously.
Her past medical history was significant for hypertension for 25 years, hypothyroidism, and
FK506-induced diabetes mellitus. Her operative course was unremarkable. Post-operative ultrasound
showed good arterial and venous flow and no evidence of obstruction. She was discharged seven days
post-operatively with a serum creatinine of 1mg/dL. Her immunosuppressive regimen consisted of FK506,
mycophenolate mofetil, and prednisone.
Four weeks post-transplant, the patient developed 3+ lower extremity edema. Urinalysis revealed 4+
protein with no RBCs and no WBCs. 24-hour urine collection contained 4.5grams protein. Laboratory values
were notable for serum albumin of 3.6 g/dL. Serum creatinine was 1.0 mg/dL. FK506 levels were within
therapeutic range. A renal ultrasound was negative for obstruction. A renal biopsy was performed.
Immunofluorescence showed no staining of peritubular capillaries for C4d and no glomerular staining for
IgG, IgM, IgA, C3, or C1.
Case 4 - Figure 1 - A representative low-power field with a normal-appearing glomerulus. Proximal tubules display diffuse ectasia and epithelial simplification. There is mild interstitial inflammation. (PAS.)
Case 4 - Figure 2 - A representative glomerulus with mostly patent capillary lumina. A few intracapillary mononuclear cells and neutrophils are seen. Podocytes appear swollen. Glomerular basement membranes do not show "spikes" or duplication. (PAS.)
Case 4 - Figure 3 - A tubule with mild tubulitis (3 or 4 mononuclear cells per 10 tubular epithelial cells). (PAS.)
Case 4 - Figure 4 - A glomerular capillary loop shows diffuse podocyte foot process effacement. No duplication of the glomerular basement membrane and no electron dense deposits are seen. (Electronmicrograph.)
The patient presents with nephrotic syndrome and normal renal function four weeks
post-transplantation. The finding of mild tubulitis is, at most, suspicious for acute cellular rejection
(Banff 97 schema) and this would not account for the presence of nephrotic range proteinuria. Features
of chronic allograft nephropathy, transplant glomerulopathy, or thrombotic microangiopathy are not seen,
and the negative immunofluorescence staining excludes membranous nephropathy and other immune
complex-mediated glomerular diseases. The extensive foot process effacement, however, indicates a
podocytopathy. Given the normal appearing glomeruli, the differential diagnosis consists of minimal
change disease versus unsampled/early recurrent focal segmental glomerulosclerosis (FSGS). The clinical
history and kidney biopsy findings support a diagnosis of primary FSGS in the native kidney, which argues
against, but does not entirely exclude de novo minimal change disease. Therefore, a diagnosis of
recurrent primary FSGS is favored.
- Diffuse podocyte foot process effacement, consistent with early recurrent FSGS.
- Mild tubulitis, suspicious for acute cellular rejection.
Following the allograft biopsy, the patient underwent daily plasmapheresis for two weeks, followed by
alternate day plasmapheresis for a further two weeks. Her immunosuppressive regimen was unchanged.
Following plasmapheresis, proteinuria declined to <1 gram/day and serum creatinine remained stable at
1mg/dL. This persisted for the next 17 months, when the patient developed recurrent nephrotic syndrome.
A repeat renal biopsy showed segmental glomerulosclerosis in two of seven glomeruli. The segmental
lesions consisted of tuft adhesion to Bowman's capsule, accumulations of hyaline, and endocapillary
mononuclear inflammatory cell accumulation. Glomerular basement membrane duplication was not seen.
There was minimal tubular atrophy and interstitial fibrosis (involving <5% of the cortical area) and
arterial vessels did not show concentric intimal fibroplasia. Electron microscopy revealed diffuse
podocyte foot process effacement. Over the ensuing two weeks, proteinuria returned to <1 g/day,
despite no additional therapy. At last follow-up three years post-transplantation graft function remains
stable, with continued mild proteinuria.
Proteinuria in the renal allograft may result from diverse pathogenetic mechanisms, with different
implications for graft survival. Transient proteinuria in the early post-transplantation period (up to 3
weeks) usually reflects reduced protein resorptive capacity due to acute tubular injury or acute cellular
rejection, and this does not adversely impact graft survival
. Sub-nephrotic proteinuria may also
be related to infections in the renal allograft, or drug toxicity, reflecting tubular and/or glomerular
dysfunction caused by these injuries. Persistent proteinuria, particularly when in the nephrotic range
(>3 grams/day), is an important predictor of decreased long-term graft survival .
Nephrotic range proteinuria (>3 grams/day) has been reported in 13% of transplant recipients and
may occur at any time, from immediately post-operatively to many years post-transplantation
commonest allograft biopsy findings in post-transplant nephrotic syndrome are transplant glomerulopathy,
and de novo or recurrent glomerular disease
, although some biopsies show only chronic allograft
nephropathy with nonspecific glomerular changes
. The commonest de novo glomerular diseases causing
post-transplant nephrotic syndrome are membranous nephropathy, minimal change disease, FSGS, and diabetic
. Membranous nephropathy usually develops after two years  whereas de novo
minimal change disease typically presents within the first four months post-transplantation . De novo
FSGS may be related pathogenetically to several non-immunologic mechanisms, including hyperfiltration
associated with reduced renal mass (for example, in adult recipients of pediatric donor kidneys ),
chronic calcineurin inhibitor toxicity, and ischemic injury
. De novo FSGS is usually diagnosed
late (mean 57 months post-transplantation)  and is associated with sub-nephrotic proteinuria and poor
graft survival, perhaps reflecting the co-existence of chronic allograft nephropathy in most cases .
In the present case, the initial allograft biopsy did not show features of transplant glomerulopathy or
chronic rejection, and the negative immunofluorescence findings excluded membranous nephropathy.
Instead, the findings of normal appearing glomeruli with extensive foot process effacement were
consistent with recurrent FSGS (versus minimal change disease).
Among recurrent glomerular diseases causing post-transplant nephrotic syndrome, FSGS is the most
important in terms of frequency and impact on graft survival . Recurrence has been reported in up to
30% of FSGS cases and graft loss ensues in 50% . Recurrence is more common in children <15 years
of age, where it develops more rapidly (median 2 weeks  versus mean 7.5 months in adults ), in
patients with an aggressive course in the native kidney (interval between diagnosis and onset of
end-stage renal disease of <3 years), and in re-transplanted patients who lost a previous graft to
recurrent FSGS . Recurrence may be more common in Caucasians than in African-Americans , and in
children whose native kidney biopsy showed mesangial hypercellularity . There may be an increased
incidence in recipients of living related donor kidneys, but overall graft survival is better because of
reduced rejection rates and therefore living donations are not contraindicated . Recently, an
increased incidence of recurrent FSGS in children has been linked to the introduction of induction
therapy and daclizumab, an anti-IL-2 receptor antibody, for prevention of rejection, consistent with a
pathogenetic role for dysregulated T-lymphocyte function in this disease . The early onset of
nephrotic syndrome, sometimes within hours of surgery, strongly suggests a pathogenic role for a
circulating glomerular permeability factor, and this is supported by experimental evidence demonstrating
increased permeability for albumin in animal glomeruli exposed to the plasma of patients with recurrent
FSGS . A bioassay for this permeability factor, based on alterations albumin permeability in isolated
rat glomeruli, correlates with the presence of recurrent FSGS but may have limited predictive value in
individual patients .
The pathologic findings in recurrent FSGS evolve over time, and serial biopsies have shed light on the
sequence of pathologic events in this disease, which may also be relevant to the disease in native
kidneys. Importantly, recurrence of proteinuria may precede the development of FSGS lesions by weeks or
months, as demonstrated by the present case and by other reported cases
. Allograft biopsies
performed 1 to 2 weeks after the onset of nephrotic syndrome may show normal-appearing glomeruli, with
diffuse foot process effacement seen by electron microscopy. In addition, children destined to develop
recurrent FSGS manifest glomerular enlargement at this stage . Of note, glomerulomegaly is also
encountered in native kidney biopsies of children with idiopathic nephrotic syndrome who subsequently
develop FSGS, suggesting a possible pathogenic role for growth factors in the early stage of childhood
FSGS . In adult allograft recipients, on the other hand, glomerulomegaly has no specific prognostic
import. Subsequent allograft biopsies in recurrent FSGS, performed weeks to months later, demonstrate
segmental sclerosis lesions. Often these segmental lesions have "cellular" features, consisting of
endocapillary proliferation, foam cell accumulation, detachment of overlying podocytes, with or without
features of capillary collapse
. Still later biopsies and transplant nephrectomies have shown
evolution to more classic sclerotic, "scar"-type lesions in recurrent FSGS, supporting the hypothesis
that cellular lesions represent an early stage in the morphologic evolution of FSGS . The second
allograft biopsy in the present case showed classic FSGS. Immunohistochemical studies have shown
"trans-differentation" of podocytes in recurrent FSGS, with acquisition of macrophage and cell-cycle
proliferation markers, and aberrant expression of integrins and cytokeratins by these cells
Thus, the "natural experiment" of recurrent FSGS supports the hypothesis that podocyte injury is a
central event in the pathogenesis of primary FSGS.
Treatment options for recurrent FSGS are limited, as most patients are already receiving maintenance
steroids and a calcineurin inhibitor, and addition of a cytotoxic agent in this population is potentially
hazardous. Plasmapheresis or immunoadsorption with protein A may induce remission of proteinuria in
recurrent FSGS via clearance of a circulating permeability factor
. Plasmapheresis has shown
greatest efficacy in reducing heavy proteinuria in childhood FSGS but may be less beneficial in adults
. In one series of 13 adult patients with biopsy-proven recurrent FSGS who underwent
plasmapheresis, remission of proteinuria (to < 1 g/day) occurred in only 1 individual. Four others
had a partial response (50% reduction in proteinuria to <3 /day proteinuria) but 3 of these partial
responders required ongoing plasmapheresis to maintain this response. Of note, all 5 responders
developed recurrence of FSGS within 30 days post-transplantation, and plasmapheresis was started within
30 days of recurrence, whereas none of the patients who started plasmapheresis after 30 days achieved a
sustained response . This limited response may reflect selection of patients with later stage
recurrent FSGS. Despite the absence of controlled trials, a trial of plasmapheresis, with or without
increased immunosuppression, is probably warranted in cases of early recurrent FSGS, although response
rate is variable and sustained remission may not be attained
. Some patients have benefited from
high dose cyclosporine, ACE inhibition
, or mycophenolate mofetil , reflecting the efficacy of
these agents in ameliorating proteinuria in native kidney diseases. Novel therapies that may hold future
benefit in recurrent FSGS include bone marrow stem cell transplantation  and antibodies that inhibit
the co-stimulatory molecule CD80, which is upregulated in podocytes in nephrotic conditions .
The differential diagnosis in this case included de novo minimal change disease. However, the native
kidney diagnosis of FSGS, and the subsequent development of FSGS in a later allograft biopsy, favored
recurrent FSGS over de novo minimal change disease. De novo minimal change disease accounted for 7% of
cases of post-transplantation nephrotic syndrome in one recent large series . The clinical
characteristics of de novo minimal change disease include onset of nephrotic syndrome within the first
four months post-transplantation in most cases, and biopsy findings of normal appearing glomeruli with
diffuse foot process effacement . In contrast to other causes of transplant nephrotic syndrome,
including recurrent FSGS, de novo minimal change disease usually remits following treatment with
angiotensin converting enzyme enzyme/angiotensin receptor blockers and calcium channel blockers, with or
without increased immunosuppression . As a result, long-term graft survival is usually excellent, and
the rare cases of graft loss are attributable to co-existent chronic allograft nephropathy .
Parenthetically, only two cases of recurrent minimal change disease have been described but the
possibility of unsampled FSGS, in either the native or transplant kidney, can not be excluded in these
In summary, this case illustrates many of the salient clinical and pathologic characteristics of
recurrent FSGS, including early onset of nephrotic syndrome post-transplantation, initial biopsy findings
that mimicked minimal change disease, prompt remission of proteinuria following plasmapheresis, and
evolution to FSGS in a later biopsy. The potential benefit of early plasmapheresis for treatment of
recurrent FSGS emphasizes the need for a heightened index of suspicion for this diagnosis, as other
causes of proteinuria are common in the immediate post-transplantation period, and diagnostic FSGS
lesions may be absent at this stage. Knowledge of the native kidney disease was particularly useful in
guiding the management of post-transplant nephrotic syndrome in this patient.
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