Renal Grand Rounds: Correlate Clinically

I recently presented the case of a middle-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)