A Case of Polyomavirus-associated Nephropathy Presenting Late After Transplantation

Shweta Bansal; M Scott Lucia; Alexander Wiseman

Disclosures

Nat Clin Pract Nephrol. 2008;4(5):283-287. 

In This Article

Summary and The Case

Background: A 36-year-old white female, who had received a deceased-donor kidney transplant for end-stage renal disease secondary to reflux nephropathy 8 years previously, was referred to a transplant clinic for evaluation following an increase in her serum creatinine level from 123.8 µmol/l to 185.6 µmol/l (1.4 mg/dl to 2.1 mg/dl) over the preceding 9 months. Her immunosuppression regimen included mycophenolate mofetil, ciclosporin and prednisone, with ciclosporin trough levels ranging from 100 ng/ml to 150 ng/ml, as detected by fluorescence polarization immunoassay, over the preceding year. The following possible causes of subacute renal failure were ruled out: post-obstructive nephropathy, altered hemodynamics (hypotension and renal artery stenosis), and toxicity from medications other than calcineurin inhibitors. Potential etiologies such as acute T-cell-mediated rejection, acute and chronic antibody-mediated rejection, polyomavirus-associated nephropathy, and calcineurin inhibitor nephrotoxicity were considered.
Investigations: Physical examination, urine and blood analysis, analysis of human leukocyte antigen antibodies by flow cytometry (Luminex®, Luminex Corporation, Austin, TX), ultrasound of the transplanted kidney, polymerase chain reaction assay for the detection of BK virus in the serum, and biopsy of the transplanted kidney with staining for simian virus 40 antigen.
Diagnosis: Polyomavirus-associated nephropathy with advanced nephrosclerosis and moderate to marked hyaline arteriolosclerosis.
Management: Reduction of immunosuppression by discontinuation of mycophenolate mofetil, dose reduction of ciclosporin, and initiation of leflunomide.

A 36-year-old white female who had received a deceased-donor renal transplant for reflux nephropathy 8 years previously was referred to a transplant clinic with an elevated serum creatinine level. Her initial transplantation course had been unremarkable. She had received induction with the non-depleting interleukin 2 receptor antagonist basiliximab 20 mg intravenously on day 0 and day 4 after transplantation, and an initial immunosuppression regimen of ciclosporin 250 mg orally twice daily, mycophenolate mofetil 1 g orally twice daily, and prednisone 20 mg orally daily, tapered to 5 mg daily by 1 year after transplantation. Ciclosporin treatment was gradually reduced over the next 4 years, to a stable dose of 100 mg in the morning and 125 mg in the evening, to maintain the ciclosporin trough level at below 200 ng/ml. The mycophenolate mofetil dose was reduced to 750 mg twice daily after 7 years because of diarrhea. Throughout the patient's post-transplantation course, her renal function remained stable with no episodes of rejection; her serum creatinine level was in the range 88.4–106.1 µmol/l (1.0–1.2 mg/dl) over the first 6 years. Mild renal insufficiency (serum creatinine level 123.8 µmol/l [1.4 mg/dl]) developed in the seventh year after transplantation, and was attributed to calcineurin inhibitor nephrotoxicity. Over the next 8 months, the patient's serum creatinine level increased to 150.3 µmol/l (1.7 mg/dl), which prompted referral to the transplant clinic. At the time of her presentation to the transplant clinic, within 1 month after referral, the patient's serum creatinine level had increased further to 185.6 µmol/l (2.1 mg/dl). The patient's ciclosporin trough level had been within the range 100–150 ng/ml over the previous year.

Potential etiologies of subacute renal failure such as hydronephrosis, altered hemodynamics (from hypotension or renal artery stenosis), and toxicity from medications other then calcineurin inhibitors were considered and excluded via the patient's history, physical examination, and ultrasound of the transplanted kidney. Other potential etiologies such as acute T-cell-mediated rejection, acute and chronic antibody-mediated rejection, polyomavirus-associated nephropathy (PVAN), and calcineurin inhibitor nephrotoxicity were also considered. Analysis of human leukocyte antigen (HLA) antibodies by flow cytometry (Luminex®, Luminex Corporation, Austin, TX) showed weakly positive activity for class I HLA antibodies, but negative activity for donor-specific HLA antibodies. Serum BK viral load determined by polymerase chain reaction (PCR) was 127,600 copies/ml. A renal biopsy was performed 1 week after the patient's presentation to the transplant clinic.

On renal biopsy examination, up to 12 glomeruli per section were seen, a third of which were globally sclerotic. The remaining glomeruli showed collapsing lesions, thickening of the Bowman's capsule, and focal visceral epithelial hypertrophy. There was severe interstitial nephritis that involved the majority of the renal cortex. The infiltrates were composed of lymphocytes, histiocytes, plasma cells, and scattered polymorphonuclear leukocytes. Advanced interstitial fibrosis and tubular atrophy were present (Figure 1A). There was focal tubular cuffing and tubulitis, predominantly in atrophic tubules, as well as enlarged, smudged tubular epithelial cell nuclei (nuclear inclusions; Figure 1B). Immunohistochemistry for polyomavirus simian virus 40 (SV40) antigen was positive (Figure 1C). The arterioles showed moderate to severe arteriolosclerosis and no evidence of calcineurin inhibitor toxicity. A diagnosis of PVAN with advanced nephrosclerosis and moderate to marked hyaline arteriolosclerosis was made on the basis of the renal biopsy findings.

Light microscopy of the patient's kidney biopsy sample. (A) Renal biopsy sample showing glomerular sclerosis, interstitial fibrosis, tubular atrophy (arrowheads), and ongoing interstitial inflammation (arrows; trichrome stain, magnification times200). (B) Renal parenchyma with interstitial nephritis and tubulitis (arrowheads; hematoxylin and eosin stain, magnification times400). Inset showing tubular inflammation with lymphocytes and neutrophils in a tubule with striking polyomavirus nuclear inclusions (arrow; hematoxylin and eosin stain, magnification times600). (C) Immunohistochemistry for simian virus 40 (SV40) antigen showing staining of numerous nuclear viral inclusions (staining for SV40 antigen, magnification times400).

Following the renal biopsy, mycophenolate mofetil was discontinued, the ciclosporin dose was reduced to 100 mg twice daily, and oral leflunomide was started at 20 mg daily. Two months later, the patient's leflunomide and ciclosporin trough levels were 156 µg/ml and 142 ng/ml, respectively. Serum BK viral load determined by PCR gradually fell to 30,320 copies/ml at 2 months, 7,034 copies/ml at 6 months, and less than 600 copies/ml at 7 months after diagnosis. The patient's renal function remained stable throughout this period, with a serum creatinine level of 185.6 µmol/l (2.1 mg/dl; Figure 2). At the time of her most recent follow-up examination, 12 months after diagnosis, the patient remained free of BK viremia with a serum creatinine level of 185.6 µmol/l (2.1 mg/dl).

Trend in the patient's serum creatinine level before diagnosis and following treatment of the BK virus nephropathy, together with serial serum BK viral load determined by polymerase chain reaction. BKV = BK virus; PCR = polymerase chain reaction; PVAN = polyomavirus-associated nephropathy.

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