Tuesday, June 8, 2010

Does CMV glomerulopathy exist?

I asked this question during my clinical renal fellowship at Brigham, where I had the chance to take care of a 39 yo female with a history of ESRD secondary to MPGN s/p DCD kidney transplant 8 months ago from CMV positive donor, she was CMV negative. She developed CMV disease, was treated with IV Ganciclovir with significant improvement, was switched to Valcyte 900 BID than switched to 450 BID. She was taken off her Valcyte by an outside nephrologist for decreased WBC. Her viral load increased and she was started again on Valcyte. She presented with low grade fever, neutopenia and and an elevated creatinine to 1.8 mg/dl from a baseline of 1,2 mg/dl. Her CMV viral load increased and it was obvious that we are dealing with resistant CMV disease. Interestingly, her kidney biopsy showed CMV inclusions in the epithelial and endothelial cells with no interstitial nephritis.
I reviewed the literature for CMV glomerulopathy at that point.

Dr. Rubin from MGH described the first cases in 5 our of 14 renal allograft recipients during clinically manifest viremic CMV infection, with little or no tubulointerstitial changes.
The characteristics of this glomerulopathy are:
  • Endothelial cell hypertrophy or necrosis
  • Narrowing or obliteration of capillary lumens
  • Fibrillar deposits in glomerular capillaries
  • Mild segmental hypercelbularity
  • Mononuclear cell infiltration without tubular changes
  • IF revealed deposition of IgG, IgM, and C3 along the glomerular basement membrane and within the mesangium
  • One specimen, anti-CMV antibody staining was observed within glomerular capillaries
  • No viral inclusions were found on EM.

Others reported different types of lesions like cryoglobulinemic necrotizing GN or immunotactoid glomerulopathy. The association in those cases were made based on temporal relationship between the appearance of CMV antigenemia and the lesion.

The existence of this CMV-associated glomerulopathy described by Dr. Rubin has been questioned, however, by Herrara et al. Kidney Int 1986, who studied four different groups of immunocompromised patients with CMV infection, including seven with renal allograft dysfunction. In all seven patients, biopsy specimens demonstrated glomerular pathology similar to the changes described by Dr. Rubins’s group at MGH. Nevertheless, IF failed to show anti-CMV antibody deposition. In addition, no viral particles were detected on EM.

The authors suggested that the glomerular changes represented a form of acute transplant gbomerulopathy resulting from antiendothelial antibody injury or a protracted, early, or unresolved form of acute vascular rejection. Furthermore, Harmon et al. showed that this glomerulopathy occurred in only seven of 56 renal allograft recipients with a clinical diagnosis of CMV disease. Three of the seven patients with this lesion were not even viremic. Anderson et al., using immunohistochemistry and in situ hybridization on 15 biopsy specimens from viremic renal allograft recipients with glomerulopathy, found no evidence of CMV antigens or DNA.

Our case is different because there are viral inclusions in the epithelial but also in the endothelial cells with some swelling noticed by our famous pathologist. There was no associated glomerular inflammation and C4d staining was negative. The lesion was called CMV glomerulitis but it is obviously different from the CMV glomerulopathy described by Dr. Rubin in his NEJM paper. Patient was treated with Cidofovir. Her creatinine improved to baseline and her lesions improved on a subsequent follow up kidney biopsy. Since than, many reports described the same lesions associated with CMV infection, including a
report in AJKD. The CMV glomerulitis similar to our case progressed to collapsing FSGS. The lack of proteinuria before transplantation supported the contention that the collapsing glomerulopathy arose de novo rather than being recurrent.

I think we have enough evidence that CMV glomerulitis exist. The bottom line remains how to prevent the disease, prevent resistance and be aware of the deleterious effects of underdosing like in this case.


Matt Sparks said...

I would agree. I had a patient s/p kidney transplant with gancyclovir resistant CMV and collapsing glomerulopathy with positive CMV staining on IF of the kidney. I was going to write it up, but never did. Nice post.

Kenar D. Jhaveri, MD said...

I have seen cases of CMV induced collapsing FSGS post transplant. You have to rule out CMV disease when you see collapsing FSGS. Its sometimes hard to tell if the virus is doing the dirty work or its just that we decrease the immunosuppresion and then we get an immune re constitution syndrome like in HIV disease