First recurrence of focal segmental glomerulosclerosis in a third renal allograft

G. V. Ramesh Prasad,1, Joan M. Sweet2 and Carl J. Cardella1

1 Division of Nephrology, Department of Medicine and 2 Department of Pathology, University of Toronto Faculty of Medicine, Toronto, Ontario, Canada

Keywords: focal segmental glomerulosclerosis; proteinuria; recurrence; renal allograft



   Introduction
 Top
 Introduction
 Case
 Discussion
 References
 
Transplantation is a mode of therapy for end-stage renal disease (ESRD) due to focal segmental glomerulosclerosis (FSGS) [1,2]; however, FSGS may recur in transplanted kidneys [1,2]. It is believed that without recurrence of FSGS in the primary renal allograft, subsequent allografts will be free of recurrent disease. We describe the case of a 20-year-old man who received his third renal allograft for end-stage renal disease due to FSGS, that was complicated by primary non-function and proteinuria due to probable first recurrent FSGS.



   Case
 Top
 Introduction
 Case
 Discussion
 References
 
A 13-month-old white male with FSGS failed cyclophosphamide therapy and progressed to ESRD by 4.5 years of age. He received his first cadaveric renal allograft 6 months later, with good initial function. He experienced three episodes of acute rejection (Table 1Go) that responded to steroid therapy. There was neither proteinuria nor evidence for recurrent FSGS in any biopsy specimen. Chronic allograft nephropathy (CAN) was first demonstrated on biopsy 2 years after transplantation and he underwent transplant nephrectomy a year afterwards.


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Table 1. Summary of renal allograft biopsies and immunosuppressive therapies

 
He underwent a second renal transplantation at age 10 years, again achieving good initial function. He had one episode of severe acute rejection that responded to appropriate therapy (Table 1Go). Lesions of CAN were demonstrated in a biopsy specimen that was obtained 3 years after transplantation. There was no evidence for recurrence of FSGS, and he did not demonstrate significant proteinuria at any time. He progressed to ESRD by age 16 years.

He received his third renal allograft at age 20, from a 36-year-old cross-match-negative donor with a cold ischaemia time of 30 h. The pre-transplant panel reactive antibody titre was 100%. While the kidney appeared to be adequately perfused after anastomosis, he failed to produce urine post-operatively. He remained dialysis dependent. Urine output improved to 50–100 cc/day; the urine was dilute with 4+ protein by dipstick. Ultrasonography and a technetium diethylene triamine pentaacetic acid ([99Tcm]DTPA) scan suggested acute tubular necrosis (ATN). There was no clinical or serological evidence for HIV, CMV, or hepatitis B or C infection. Furthermore, there was no clinical evidence for cholesterol atheroembolism. Renal allograft biopsies were performed on days 9, 18, 32, and 45 post-transplantation, at both poles (Table 1Go). Recurrent FSGS was diagnosed by the third and fourth biopsies. Light microscopy featured acute tubular degenerative and regenerative cellular changes with borderline evidence for acute cellular rejection as demonstrated by a patchy mild interstitial mononuclear cell infiltrate and occasional foci of mild tubulitis, accompanied by focal interstitial fibrosis and tubular atrophy. In addition, there was mild hyaline arterial and arteriolosclerosis. The fourth biopsy also demonstrated a diffuse mild increase in mesangial matrix but with no increase in cellularity.

Immunofluorescence examination was negative for IgG, IgM, IgA, complement components 3 (C3) and 4 (C4), fibrinogen, and kappa and lambda light chains. Electron microscopy demonstrated extensive effacement of the visceral epithelial cell foot processes. The glomerular basement membrane was of normal width with segmental widening and wrinkling. Later biopsies demonstrated periodic acid–Schiff- and C3-positive droplets in the cytoplasm of tubular epithelial cells.

Renal function did not recover.



   Discussion
 Top
 Introduction
 Case
 Discussion
 References
 
Recurrence rates for FSGS range from 15 to 100% [3]. Risk factors for recurrence include age <15 years at initial diagnosis, rapid progression of original disease, and mesangial proliferation on original biopsy [4]. Non-African Americans [5] and patients treated with tacrolimus [6] may be at increased risk of recurrence. Recurrence in early grafts indicates an increased risk of recurrence in subsequent allografts, although prolonged renal survival is possible [3]. Patients may experience primary allograft non-function, or may present with proteinuria and develop rapid deterioration in renal function. Therapeutic strategies remain controversial. Therapies attempted have included plasmapheresis, cyclophosphamide, and cyclosporin [7], but success has been variable.

Our patient developed recurrent FSGS in his third allograft, without obvious evidence for de novo secondary FSGS or recurrence in his earlier two grafts. This contradicts the paradigm that without recurrence of FSGS in the primary allograft, further renal transplants will be free of recurrent disease [3]. To our knowledge, this is the first reported case of such a recurrence. It is unclear why a disease should recur after a long intervening period since onset of ESRD, but choice of immunosuppressive agent may play a role [6]. Tacrolimus was used for the first time in this patient with his third transplant. Tacrolimus differs from cyclosporin in its anti-proteinuric effect [6]. Whether tacrolimus in some patients fails to suppress a circulating factor [8] demonstrable in recurrent FSGS remains speculative. Our patient's first two grafts had survived for several years each and were lost to CAN, leading initially to a low index of suspicion for recurrent disease in his third graft. FSGS was first detected by electron microscopy performed on the third renal biopsy specimen (Table 1Go).

In conclusion, FSGS can indeed possibly recur in transplanted kidneys with intervening absences from previous allografts, as this case demonstrates. While we cannot completely exclude other lesions such as ATN that may have contributed to the histopathological findings seen, it is recommended that vigilance be maintained in all allografts regardless of past history, and the presence of significant proteinuria warrants suspicion for recurrent FSGS. Electron microscopy should be performed on all obtained renal allograft biopsy specimens whenever the primary disease is FSGS, regardless of biopsy indication.



   Notes
 
Correspondence and offprint requests to: G. V. Ramesh Prasad, Division of Nephrology, Department of Medicine, University of Toronto Faculty of Medicine, 10 NU-142, 621 University Avenue, Toronto, Ontario M5G 2C4, Canada. Back



   References
 Top
 Introduction
 Case
 Discussion
 References
 

  1. Artero M, Biava C, Amend W, Tomlanovich S, Vincenti F. Recurrent focal glomerulosclerosis: Natural history and response to therapy. Am J Med1992; 92: 375–383[ISI][Medline]
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  3. Stephanian E, Matas AJ, Mauer SM et al. Recurrence of disease in patients retransplanted for focal segmental glomerulosclerosis. Transplantation1992; 53: 755–757[ISI][Medline]
  4. Ramos EL, Tisher CC. Recurrent diseases in the kidney transplant. Am J Kidney Dis1994; 24: 142–154[ISI][Medline]
  5. Butani L, Polinsky MS, Kaiser BA, Baluarte HJ. Predictive value of race in post-transplantation recurrence of focal segmental glomerulosclerosis in children. Nephrol Dial Transplant1999; 14: 166–168[Abstract]
  6. Kessler M, Champigneulles J, Hestin D, Frimat L, Renoult E. A renal allograft recipient with late recurrence of focal and segmental glomerulosclerosis after switching from cyclosporin to tacrolimus. Transplantation1999; 67: 641–643[ISI][Medline]
  7. Ingulli E, Tejani A. Incidence, treatment, and outcome of recurrent focal segmental glomerulosclerosis posttransplantation in 42 allografts in children—A single center experience. Transplantation1991; 51: 401–405[ISI][Medline]
  8. 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 Med1996; 334: 878–883[Abstract/Free Full Text]
Received for publication: 3. 4.00
Revision received 6. 9.00.



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