—  SPECIALTY CONFERENCE  —

Renal Pathology

Case 4 - Early Recurrent FSGS, with Acute Tubular Injury, Refractory to Therapy.

Megan L. Troxell, Oregon Health & Science Univ, Portland, OR





Click on slide thumbnail images for an enlarged view.

If you have any difficulties viewing these slides, email the webmaster.



Clinical History
A 40 year old Caucasian man received a living related renal allograft from his sister. Past medical history included ESRD due to FSGS, on dialysis for the past 2 years. The donor was a one haplotype-match, ABO-compatible, with negative cross-match studies prior to transplantation, including cytotoxic crossmatches (standard, anti-globulin, and B-cell), as well as flow T-cell and B-cell cross matches. The patient’s history was also significant for hypertension (controlled on one medication), hyperlipidemia (on a statin), obesity (BMI-34.5), anemia, tinea cruris, and history of small bowel perforation. Both donor and recipient were CMV-negative; the recipient was HIV, Hepatitis B, C, and HSV negative, but EBV-positive, with a history of chicken pox. The donor’s left kidney was removed in a laparoscopic operation without complications. The kidney was transplanted into the recipient’s right iliac fossa, also an uncomplicated procedure, though slightly long given the recipient’s obesity. The recipient received basiliximab induction, along with prednisone, MMF and Tacrolimus. The kidney made urine immediately in the OR, and urine output was 2 L in the first 12 hours, with creatinine decreasing gradually. Urine output slowed POD1-2, with increasing creatinine, despite fluid boluses (1.6 L UOP). Renal allograft ultrasound showed no hydronephrosis or peri-renal fluid collection, with normal Doppler arterial waveforms. MAG-3 scan demonstrated a pattern consistent with renal tubular stasis. Thymoglobulin was given, along with prednisone and MMF (tacrolimus was discontinued). Dialysis was initiated on POD3, in the setting of no urine output. An allograft biopsy was performed on POD4 (Images 1-2). C4d immunofluorescence studies were negative (not shown). A portion of the specimen submitted in glutaraldehyde was processed for electron microscopy, but did not contain glomeruli. At the time of the first biopsy, DSA studies were again negative. The patient was treated conservatively, but kidney function did not improve. A second allograft biopsy was performed on POD 11 (Images 3-7). Again, the C4d studies were negative. The electron microscopy specimen contained 9 glomeruli, seen in Images 8-10.

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Based on the second renal biopsy findings of podocyte foot process effacement consistent with early recurrent FSGS, the patient was initiated on a course of plasma exchange (POD11-38, with 2 doses of IVIg), and received one dose of rituximab on POD 23. Urine output improved transiently (1 L/day), but the patient had heavy proteinuria (15-20+ grams on spot urinalysis), requiring dialysis starting post-operative week 9 (again with plasma exchange). As the patient's course was complicated by diarrhea (treated by switching MMF to Imuran), and then low white blood cell counts and general deterioration, an allograft biopsy was performed at 3 months post-transplantation. This third biopsy demonstrated well developed lesions of FSGS with collapsing features (Images 14-15) and mild acute cellular tubulointerstitial rejection (Image 12) along with allograft vasculopathy (Image 13) and ongoing ATN with substantial interstitial fibrosis (Images 11-12). Given his need for dialysis, and the biopsy findings, immunosuppression was decreased until an allograft nephrectomy was performed in post operative week 17. The nephrectomy specimen (Images 16-18) showed extensive interstitial fibrosis and tubular atrophy. The majority of glomeruli were involved by segmental or global sclerosis. Given the interval decrease in immunosuppression, there was also active endothelialitis superimposed on chronic vascular rejection (Banff 2B, not shown).


Case 4 - Figure 1
First biopsy (POD 1) showing acute tubular injury without FSGS.
Case 4 - Figure 2
First biopsy (POD 1) showing acute tubular injury without FSGS.
Case 4 - Figure 3
Second biopsy (POD 11) showing ongoing tubular injury
Case 4 - Figure 4
Second biopsy (POD 11) showing ongoing tubular injury

Case 4 - Figure 5
Second biopsy (POD 11) showing ongoing tubular injury with tubular mitotic figure.
Case 4 - Figure 6
Second biopsy (POD 11) with no evidence of FSGS in sampled glomeruli
Case 4 - Figure 7
Second biopsy (POD 11) with no evidence of FSGS in sampled glomeruli
Case 4 - Figure 8
Second biopsy, electron microscopy (POD 11). Diffuse podocyte foot process effacement.

Case 4 - Figure 9
Second biopsy, electron microscopy (POD 11). Diffuse podocyte foot process effacement.
Case 4 - Figure 10
Second biopsy, electron microscopy (POD 11). Diffuse podocyte foot process effacement.
Case 4 - Figure 11
Third biopsy (3 months post transplantation) showing interstitial fibrosis with mixed interstitial inflammation.
Case 4 - Figure 12
Third biopsy (3 months post transplantation) showing interstitial fibrosis with mixed interstitial inflammation and focal tubulitis (mild acute cellular rejection).

Case 4 - Figure 13
Third biopsy (3 months post transplantation) with allograft vasculopathy (intimal foam cells).
Case 4 - Figure 14
Third biopsy (3 months post transplantation) with well developed lesions of FSGS with collapsing features.
Case 4 - Figure 15
Third biopsy (3 months post transplantation) with well developed lesions of FSGS with collapsing features.
Case 4 - Figure 16
Allograft nephrectomy (17 weeks post transplantation). Interstitial fibrosis and inflammation; and focal segmental glomerulosclerosis.

Case 4 - Figure 17
Allograft nephrectomy (17 weeks post transplantation). Interstitial fibrosis and inflammation; and focal segmental glomerulosclerosis
Case 4 - Figure 18
Allograft nephrectomy (17 weeks post transplantation). Interstitial fibrosis and inflammation; and focal segmental glomerulosclerosis

Differential Diagnoses:
Acute tubular injury, antibody mediated rejection (ATN-like), recurrent FSGS with acute tubular injury.

Final Diagnosis:
Early recurrent FSGS, with acute tubular injury, refractory to therapy.

Case Discussion:
The risk for FSGS recurrence in an allograft is closely related to the underlying pathophysiology of the native FSGS, which in many instances is difficult to determine. Most forms of secondary FSGS would not be expected to recur, if the underlying condition is resolved (HIV, parvovirus, pamidronate treatment, hyperfiltration resulting from renal parenchymal loss or obesity, etc). Familial FSGS due to podocyte cytoskeletal/slit diaphragm mutations (podocin-NPHS2, TRPC6, WT1, CD2AP, alpha-actinin-4, LAMB2 etc) should have a low risk of recurrence, given that the allograft restores glomeruli with a normal complement of podocyte proteins. Paradoxically, recurrent FSGS has been reported in a small number of patients with FSGS with podocin mutations.

Primary/idiopathic FSGS is associated with a high risk of recurrence, yet remains an unpredictable disease. Risk factors for FSGS recurrence correlate with features of primary/idiopathic FSGS and include rapid progression (<3 years to ESRD), heavy proteinuria (eg. requiring native nephrectomy), pediatric age group (30-50% recurrence), and biopsy findings of mesangial proliferation in native FSGS. Once an allograft is lost due to recurrent FSGS, there is a very high risk of recurrence in subsequent allografts (80%). Factors associated with low risk of allograft recurrence include prolonged time to ESRD, and non-nephrotic proteinuria. Studies looking at risk of and subtype of recurrence based on histologic type of FSGS (Columbia classification) have been contradictory. Living donor transplantation in FSGS is a controversial area. While some studies show somewhat greater risk of recurrence with living donor transplants, overall graft survival is basically equivalent if not superior to deceased donor allografts. In familial cases, there is also risk of transplanting a kidney heterozygous for a deleterious mutation, exposing both donor and recipient to risk of FSGS.

In the case presented here FSGS with tip features, without mesangial proliferation was demonstrated on the patient's native renal biopsy 2 years prior to transplantation, He experienced rapid renal failure, with dialysis 2 months post-biopsy, and received a kidney from his sister (1 haplotype match).

Clinically, the earliest manifestation of recurrent FSGS is proteinuria, which may occur hours, days, or weeks post transplantation. The clinical presentation of acute kidney injury/anuria is unusual, yet has been previously reported in individual or small series of cases. The mechanism of acute tubular injury in severe nephrotic syndrome is unclear, with considerations including tubular injury resulting from explosive proteinuria, hemodynamics, or other mechanisms. The earliest morphologic change of recurrent FSGS is podocyte foot process effacement, usually diffuse, as was seen in this case. Segmental sclerosis appears on light microscopy later, weeks to months post-transplantation. Historically, recurrent FSGS has resulted in 50-80% graft failure rate.

Literature Review/Treatment Options:
Although controlled studies are lacking, plasmapheresis has been the primary treatment modality of recurrent FSGS. Other modalities, often in combination with plasmapheresis, have included conversion to high dose cyclosporine (or alternatively tacrolimus), cyclophosphamide, recently rituximab, anti-TNF a agents, and galactose treatments. Although recent series document up to 70% partial/complete response rate many patients experience a slowly progressive course toward graft failure.

The concept of a circulating glomerular permeability factor responsible for primary and recurrent FSGS was demonstrated by Savin and others many years ago. The identity of this factor has remained elusive until recently. However, in 2011 Wei et al. from Miami published a thorough characterization of the soluble fragment of podocyte urokinase receptor (suPAR) as promising permeability factor in this aggressive form of FSGS, found in about two-thirds of cases.

Conclusions:
Primary FSGS has potential for rapid, aggressive recurrence in renal allografts. The earliest diagnostic feature on renal biopsy may be may be podocyte foot process effacement on electron microscopic examination. The recently characterizationof suPAR as a glomerular permeability factor has great potential to revolutionize diagnosis and treatment of primary FSGS, especially if specific means to reduce suPAR activity are developed.

References:
  1. Canaud G. et al. Recurrence of nephrotic syndrome after transplantation in a mixed population of children an adults: course of glomerular lesions and value of Columbia classification of histological variants of focal and segmental glomerulosclerosis (FSGS). (2009) Nephrol Dial Transplant. 25:1321-8.

  2. Crosson JT. Focal segmental glomerulosclerosis and renal tranplantation. (2007) Transplantation Proceedings. 39:737-43.

  3. IJpelaar DHT et al. Fidelity and evolution of recurrent FSGS in renal allografts. (2008) JASN. 19:2219-2224.

  4. McCarthy ET, Sharma M, Savin VJ. Circulating Permeability Factors in Idiopathic Nephrotic Syndrome and Focal Segmental Glomerulosclerosis. (2010). Clin J Am Soc Nephrol. 5:2155-21.

  5. Newstead CG. Recurrent disease in renal transplants.Nephrol Dial Transplant. 2003 Aug;18 Suppl 6:vi68-74.

  6. Ponticelli C. Recurrence of focal segmental glomeruloslcerosis (FSGS) after renal transplantation. (2010) Nephrol Dialysis Transplant. 25:25-31.

  7. Sakai K, Takasu J, Nihei H, Yonekura T, Kawamura T, Mizuiri S, Aikawa A. Protocol biopsies for focal segmental glomerulosclerosis treated with plasma exchange and rituximab in a renal transplant patient. (2010) Clin Transplant. 24 (supple22):60-65.

  8. Saleem M, Ramanan AV, Rees L. Recurrent focal segmental glomerulosclerosis in grafts treated with plasma exchange and immunosuppression. (2000). Pedatr Nephrol. 14:361-4.

  9. Schachter ME, Monahan M, Radhakrishnan J, Crew J, Pollack M, Ratner L, Valeri AM Stokes MB, Appel GB. Recurrent focal segmental glomerulosclerosis in the renal allograft: single center experience in the era of modern immunosuppression. (2010) Clinical Nephrology. 3:173-181.

  10. Shimizu A, Higo S, Fujita E, Mii A, Kaneko T. Focal segmental glomerulosclerosis after renal transplantation (2011) Clin Transplant 25 (supple23):6-14.

  11. Ulinski T. Recurrence of focal segmental glomerulosclerosis after kidney transplantation: strategies and outcomes. (2010) Curr Opin Organ Transplant. 15:1628-32.

  12. Wei C et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis (2011) Nature Medicine. 17(8):952-960.