—  SPECIALTY CONFERENCE  —

Renal Pathology

Case 4 - Diffuse Podocyte Foot Process Effacement
Mild Tubulitis

M. Barry Stokes
Columbia Presbyterian Medical Center
New York, NY


Click on each slide thumbnail image for an enlarged view
Clinical History
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.)

Differential diagnosis
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.

Final diagnoses

  1. Diffuse podocyte foot process effacement, consistent with early recurrent FSGS.
  2. Mild tubulitis, suspicious for acute cellular rejection.

Clinical follow-up
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.

Discussion
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 [1, 2] . 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 [2].

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 [2, 5] . The commonest allograft biopsy findings in post-transplant nephrotic syndrome are transplant glomerulopathy, and de novo or recurrent glomerular disease [2, 3, 4, 5] , although some biopsies show only chronic allograft nephropathy with nonspecific glomerular changes [3, 5] . The commonest de novo glomerular diseases causing post-transplant nephrotic syndrome are membranous nephropathy, minimal change disease, FSGS, and diabetic glomerulosclerosis [3, 4] . Membranous nephropathy usually develops after two years [6] whereas de novo minimal change disease typically presents within the first four months post-transplantation [7]. 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 [8]), chronic calcineurin inhibitor toxicity, and ischemic injury [9, 10] . De novo FSGS is usually diagnosed late (mean 57 months post-transplantation) [5] and is associated with sub-nephrotic proteinuria and poor graft survival, perhaps reflecting the co-existence of chronic allograft nephropathy in most cases [5]. 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 [11]. Recurrence has been reported in up to 30% of FSGS cases and graft loss ensues in 50% [8]. Recurrence is more common in children <15 years of age, where it develops more rapidly (median 2 weeks [12] versus mean 7.5 months in adults [13]), 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 [6]. Recurrence may be more common in Caucasians than in African-Americans [13], and in children whose native kidney biopsy showed mesangial hypercellularity [14]. 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 [15]. 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 [16]. 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 [17]. 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 [18].

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 [19, 20, 21] . 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 [22]. 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 [23]. 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 [20, 21, 24] . 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 [20]. 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 [21, 25] . 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 [13, 15] . Plasmapheresis has shown greatest efficacy in reducing heavy proteinuria in childhood FSGS but may be less beneficial in adults [13, 16, 24] . 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 [24]. 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 [17, 24] . Some patients have benefited from high dose cyclosporine, ACE inhibition [13, 16] , or mycophenolate mofetil [16], 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 [26] and antibodies that inhibit the co-stimulatory molecule CD80, which is upregulated in podocytes in nephrotic conditions [27].

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 [6]. 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 [7]. 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 [7]. 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 [7]. 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 cases [28, 29] .

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.

References

  1. Kim HC, Park SB, Lee SH, Park KK, Park CH, Cho WH: Proteinuria in renal transplant recipients: incidence, cause, and prognostic importance. Transplant Proc 1994; 26(4): 2134-5.
  2. Hohage H, Kleyer U, Bruckner D, August C, Zidek W, Spieker C: Influence of proteinuria on long-term transplant survival in kidney transplant recipients. Nephron 1997; 75(2): 160-5.
  3. Yakupoglu U, Baranowska-Daca E, Rosen D, Barrios R, Suki WN, Truong LD: Post-transplant nephrotic syndrome: A comprehensive clinicopathologic study. Kidney Int 2004; 65(6): 2360-70.
  4. Cheigh JS, Mouradian J, Susin M, et al.: Kidney transplant nephrotic syndrome: relationship between allograft histopathology and natural course. Kidney Int 1980; 18(3): 358-65.
  5. Cosio FG, Frankel WL, Pelletier RP, Pesavento TE, Henry ML, Ferguson RM: Focal segmental glomerulosclerosis in renal allografts with chronic nephropathy: implications for graft survival. Am J Kidney Dis 1999; 34(4): 731-8.
  6. Colvin R: Renal Transplant Pathology. In: JC Jennette JO, MM Schwartz, FG Silva, ed. Heptinstall's Pathology of the Kidney, vol 2. Philadelphia: Lippincott-Raven, 1998; 1409-1540.
  7. Zafarmand AA, Baranowska-Daca E, Ly PD, et al.: De novo minimal change disease associated with reversible post-transplant nephrotic syndrome. A report of five cases and review of literature. Clin Transplant 2002; 16(5): 350-61.
  8. Hayes JM, Steinmuller DR, Streem SB, Novick AC: The development of proteinuria and focal-segmental glomerulosclerosis in recipients of pediatric donor kidneys. Transplantation 1991; 52(5): 813-7.
  9. Stokes MB, Davis CL, Alpers CE: Collapsing glomerulopathy in renal allografts: a morphological pattern with diverse clinicopathologic associations. Am J Kidney Dis 1999; 33(4): 658-66.
  10. Nadasdy T, Allen C, Zand MS: Zonal distribution of glomerular collapse in renal allografts: possible role of vascular changes. Hum Pathol 2002; 33(4): 437-41.
  11. Hariharan S, Peddi VR, Savin VJ, et al.: Recurrent and de novo renal diseases after renal transplantation: a report from the renal allograft disease registry. Am J Kidney Dis 1998; 31(6): 928-31.
  12. Tejani A, Stablein DH: Recurrence of focal segmental glomerulosclerosis posttransplantation: a special report of the North American Pediatric Renal Transplant Cooperative Study. J Am Soc Nephrol 1992; 2(12 Suppl): S258-63.
  13. Artero M, Biava C, Amend W, Tomlanovich S, Vincenti F: Recurrent focal glomerulosclerosis: natural history and response to therapy. Am J Med 1992; 92(4): 375-83.
  14. Striegel JE, Sibley RK, Fryd DS, Mauer SM: Recurrence of focal segmental sclerosis in children following renal transplantation. Kidney Int Suppl 1986; 19: S44-50.
  15. Kashtan CE, McEnery PT, Tejani A, Stablein DM: Renal allograft survival according to primary diagnosis: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol 1995; 9(6): 679-84.
  16. Hubsch H, Montane B, Abitbol C, et al.: Recurrent focal glomerulosclerosis in pediatric renal allografts: the Miami experience. Pediatr Nephrol 2004.
  17. Savin VJ, Sharma R, Sharma M, et al.: Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl J Med 1996; 334(14): 878-83.
  18. Godfrin Y, Dantal J, Perretto S, et al.: Study of the in vitro effect on glomerular albumin permselectivity of serum before and after renal transplantation in focal segmental glomerulosclerosis. Transplantation 1997; 64(12): 1711-5.
  19. Cheong HI, Han HW, Park HW, et al.: Early recurrent nephrotic syndrome after renal transplantation in children with focal segmental glomerulosclerosis. Nephrol Dial Transplant 2000; 15(1): 78-81.
  20. Verani RR, Hawkins EP: Recurrent focal segmental glomerulosclerosis. A pathological study of the early lesion. Am J Nephrol 1986; 6(4): 263-70.
  21. Bariety J, Bruneval P, Hill G, Irinopoulou T, Mandet C, Meyrier A: Posttransplantation relapse of FSGS is characterized by glomerular epithelial cell transdifferentiation. J Am Soc Nephrol 2001; 12(2): 261-74.
  22. Ichikawa I, Fogo A: Focal segmental glomerulosclerosis. Pediatr Nephrol 1996; 10(3): 374-91.
  23. Fogo A, Hawkins EP, Berry PL, et al.: Glomerular hypertrophy in minimal change disease predicts subsequent progression to focal glomerular sclerosis. Kidney Int 1990; 38(1): 115-23.
  24. Matalon A, Markowitz GS, Joseph RE, et al.: Plasmapheresis treatment of recurrent FSGS in adult renal transplant recipients. Clin Nephrol 2001; 56(4): 271-8.
  25. Kemeny E, Mihatsch MJ, Durmuller U, Gudat F: Podocytes loose their adhesive phenotype in focal segmental glomerulosclerosis. Clin Nephrol 1995; 43(2): 71-83.
  26. Nishimura M, Toki J, Sugiura K, et al.: Focal segmental glomerular sclerosis, a type of intractable chronic glomerulonephritis, is a stem cell disorder. J Exp Med 1994; 179(3): 1053-8.
  27. Reiser J, von Gersdorff G, Loos M, et al.: Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest 2004; 113(10): 1390-7.
  28. Mauer SM, Hellerstein S, Cohn RA, Sibley RK, Vernier RL: Recurrence of steroid-responsive nephrotic syndrome after renal transplantation. J Pediatr 1979; 95(2): 261-4.
  29. Jan CI, Chen A, Sun GH, et al.: Recurrent minimal change disease post-allograft renal transplant. Transplant Proc 2003; 35(8): 2888-90.