I recently presented the case of amiddle-aged patient with ESRD secondary to Goodpasture syndrome. She presented with AKI 3 months after a kidney transplant. Her creatinine had normalized to 0.9mg/dl post-transplant. However, over the next few months she had multiple hospitalizations
for infections, perinephric fluid collections and three episodes of AKI. Her creatinine finally stabilized at 1.5mg/dl. Due to concerns that she was overly immunosuppressed, her
mycophenolate was discontinued during her last admission and her prednisone was
stopped per weaning protocol. She was continued on tacrolimus. At her
post-discharge follow up, she was found to have recurrent AKI with Cr 2 mg/dl She
had 1+ blood on UA, but no proteinuria. GBM antibody was negative. She was
admitted for a transplant kidney biopsy.
The biopsy demonstrated diffuse linear
staining of the glomerular basement membrane. There was no evidence of active
glomerulitis or crescent formation. Mild mesangial expansion and moderate
thickening of the GBM were noted with no signs of cell-mediated or antibody-mediated rejection.
This prompted the million dollar question: Is
this diffuse GBM staining early recurrence of anti-GBM disease or something
else?
The inciting event of anti-GBM disease is still
unknown (correlations with smoking, cocaine use, solvent exposure, and
infections), however the pathophysiology is fairly well established – an insult
causes a conformational change of the type IV collagen network in the GBM
resulting in exposure of the non-collagenous portion of the alpha-3 chain which
elicits an immune response. Based on multiple uncontrolled studies, these
patients can be transplanted 6-12 months after their GBM antibody titers become
negative and they have similar transplant outcomes when compared to other
causes of ESRD.
But how often does it recur after transplant?
In 2013, Tang et
al retrospectively
analyzed 58,000 patients in Australia and New Zealand started on RRT and found
449 diagnosed with anti-GBM disease, 224 of whom were transplanted. Of those
transplanted, 2.7% developed biopsy proven recurrence. So… it recurs, but
rarely.
What about a
false negative GBM antibody titer? Our patient’s titer was negative, and the
reported false negative rate for the ELISA and western blot is 2-3% making it
unlikely. However, there have been case reports of anti-GBM disease with negative
ELISA and weakly positive western blot suggesting low or transient antibody
production. In addition, alternative immunoglobulins not picked up by the
ELISA, such as IgG4, and alternative GBM antigens have been proposed based on case reports.
What else could
produce diffuse GBM staining? In monoclonal immunoglobulin deposition disease
the physicochemical properties of the monotypic light chains result in high
affinity for the GBM and diffuse linear staining. In addition, in diabetic
glomerulopathy, there is thought to be a loss of negative charge in
the GBM which allows negatively charged species such as immunoglobulin and
albumin to collect in and expand the GBM. Our patients SPEP and SFLC were
normal, and the donor didn’t have a known history of DM.
In the end, we couldn’t answer the million dollar question definitively, but we decided to
treat with plasmapheresis, rituximab, and restarting prednisone and
mycophenolate. Rituximab was used instead of cyclophosphamide due to previous
complications during her initial treatment. She’s currently doing well
with Cr stable at 1.5mg/dl
Posted by Patrick Reeves
(Picture is Dr. Ernest Goodpasture who first described this condition while studying victims of the Spanish Flu in 1919)
According to Vanderbilt professor of Pathology Robert Collins, biographer and long time associate of Goodpasture, Goodpasture denied any association with the pulmonary renal syndrome described here and often remarked to his colleagues that he felt it was a false attribution. Collins makes the point in the biography that Goodpasture felt the eponym distracted attention from his most important work which was in virology. Maybe that explains the scowl in the picture you posted.
For more of the back story see this post:
http://doctorrw.blogspot.com/2006/01/goodpasture-syndrome-and-spanish-flu.html
Any reason to suspect hereditary nephritis / Alports in her native kidneys? There have been cases of anti-GBM disease post-transplant in Alport patients.
Any reason to suspect hereditary nephritis / Alports in her native kidneys? There have been cases of anti-GBM disease post-transplant in Alport patients.