Acute allograft glomerulopathy associated with CMV viraemia

Gemma Browne,1, Caroline Whitworth1, Chris Bellamy2 and Marie M. Ogilvie3

1 Department of Renal Medicine, Lothian University Hospitals NHS Trust and 2 Departments of Pathology and 3 Medical Microbiology, The University of Edinburgh, Edinburgh, UK

Keywords: acute allograft rejection; CMV glomerulopathy; cytomegalovirus infection; renal allograft

A 33-year-old man received his second renal allograft, following loss of the first graft after 10 years to chronic allograft nephropathy. His primary renal disease was obstructive uropathy secondary to posterior urethral valves. The second allograft was a 1/1/0 mismatch; T and B lymphocyte and FACS cross-matches were negative. The donor was anti-cytomegalovirus (CMV) IgG seropositive, while the recipient was CMV seronegative. Initial immunosuppression was with tacrolimus (0.1 mg/kg), azathioprine, and prednisolone. The patient received oral acyclovir 200 mg three times daily as CMV prophylaxis. There was no weekly surveillance for CMV DNA by polymerase chain reaction (PCR), which is now performed routinely.

After transplantation allograft function was delayed; an ultrasound scan on day 4 confirmed satisfactory vascular supply, and allograft needle biopsy showed acute tubular necrosis without evidence of acute rejection. On day 13 creatinine reduced spontaneously and the patient became independent of dialysis.

He re-presented on day 30 with a sudden increase in creatinine. Allograft needle biopsy revealed a lymphocytic glomerulitis (Figure 1aGo) with modest numbers of endocapillary mononuclear cells in association with acute cellular rejection, Banff type IIA (intimal arteritis, Figure 1bGo), and low-grade lymphocytic tubulitis. Rejection was treated with three 500-mg doses of methylprednisolone, and institution of mycophenolate mofetil (1 g twice daily). Creatinine decreased to 239 µmol/l.



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Fig. 1. (a) Allograft glomerulitis (H&E stain, x400, original magnification): the glomerulus is hypercellular due to infiltration by mononuclear cells that were CD68 and CD3 positive on immunohistochemistry (monocyte/macrophages and T cells). (b) Small artery showing intimal arteritis (H&E stain, x400, original magnification): mononuclear cell infiltration under the endothelium (arrowhead). An eosinophil is also present. (c) and (d) Acute allograft glomerulopathy (c, H&E stain; d, Jones methenamine silver stain; both x250, original magnification). There is glomerular endothelial swelling and injury, obscuring capillary lumina on H&E stain (c, arrowhead), with fibrillar capillary webs (fine strands traverse capillaries) (d, arrowhead) and mesangiolysis.

 
On day 44, the patient was re-admitted with right upper quadrant pain, malaise, and further deterioration in renal function (creatinine 349 µmol/l). Temperature was not raised; he was leukopenic (total leukocyte count 0.9x109/l); his haemoglobin had dropped from 85 g/l to 76 g/l and platelets fell to 95 from 120 (x109/l); the blood film showed atypical mononuclear cells, giant platelets, and occasional fragments were reported. He had developed abnormal serum liver biochemistry (alanine aminotransferase, 297 U/l; gamma glutamyl transpeptidase, 379 U/l, alkaline phosphatase, 265 U/l). Consequently intravenous ganciclovir therapy was begun empirically for presumed CMV infection. The patient became dialysis-dependent. Allograft needle biopsy was performed, revealing intimal arteritis, but now also an acute allograft glomerulopathy (Figure 1cGo,dGo) with severe endothelial injury and PAS-positive transcapillary webs. No cytomegalic cells were identified on biopsy, and immunohistochemistry for CMV early antigens was negative. There were no glomerular red cell fragments or congestion and no arterial intimal oedema or intimal neofibrosis, making thrombotic microangiopathy unlikely. However, acute primary CMV infection was confirmed by detection of plasma CMV DNA by PCR, rapid detection of CMV early antigens, isolation of virus from peripheral white blood cells and from urine, and seroconversion to CMV antibody positive, including IgM antibody.

Ganciclovir was continued for 1 month, mycophenolate mofetil was discontinued, the dose of prednisolone was reduced, and tacrolimus dose was reduced from 0.1 mg/kg to 0.07 mg/kg. The patient continued to require haemodialysis for 2 months, before becoming independent of renal replacement therapy. The most recent allograft needle biopsy, 5 months after transplant, showed mild chronic allograft nephropathy; glomeruli revealed mild tuft retraction and increased mesangial matrix, without evidence of the acute allograft glomerulopathy. Fifteen months after transplant, plasma creatinine is stable at 270 µmol/l, he has no further symptoms of CMV disease, and his last CMV PCR assay was negative.

This case illustrates the association of a distinctive glomerular lesion—acute allograft glomerulopathy— with CMV viraemia [1,2]. Cytomegalic cells are not a feature of CMV-induced acute allograft glomerulopathy. CMV has been suggested to trigger this unusual glomerular injury indirectly, through interferon-stimulated upregulation of endothelial class I major histocompatibility complex antigens, which in turn stimulates the alloimmune response [3]. Acute allograft glomerulopathy is envisaged as the product of an altered form of acute rejection, targeting glomerular and arterial endothelium, and precipitated by CMV, among other causes.

Notes

Correspondence and offprint requests to: G. Browne, Department of Renal Medicine, Lothian University Hospitals NHS Trust, Edinburgh, UK. Back

References

  1. Richardson WP. Glomerulopathy associated with cytomegalovirus viraemia in renal allografts. N Engl J Med1981; 305: 57–63[Abstract]
  2. Colvin RB. Circulating T-cell subsets in 72 human renal allograft recipients: The OKT4+/OKT8+ cell ratio correlates with reversibility of graft injury and glomerulopathy. Transplant Proc1983; 15: 1166[ISI]
  3. Tuazon TV. Mononuclear cells in acute allograft glomerulopathy. Am J Pathol1987; 129: 119–132[Abstract]




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