Renal Grand Rounds: Fevers on Dialysis - Not always an Infection

At renal grand rounds this week, I presented a case of a gentleman who presented with fevers, confusion, and lower extremity pain during dialysis. The patient would spike low grade fevers pre-HD and then fevers up to 105 post-HD. He had a tunneled HD line, but blood cultures were negative, and his fevers persisted in spite of changing the line. We were initially concerned for a dialyzer membrane reaction, but the time course of fevers was not consistent with either type A or type B reaction, and his symptoms persisted even after switching to an Exceltra membrane. The patient was worked up further, and his serum electrophoresis revealed 2 M components, serum free light chains showed an elevated Kappa/Lambda ratio, and he had a positive urine Bence Jones protein. His CH50 and C4 levels were undetectable, but C3 was only mildly low. Cryocrit was sent, and was positive for a type 2 cryoprotein with a predominant IgM Kappa component.

It was unclear why the symptoms of cryoglobulinemia worsened with dialysis; it was hypothesized that hemoconcentration with ultrafiltration, along with exposure of blood to cooler temperatures within the dialysis tubing led to transient complement consumption and an inflammatory reaction. The symptoms of mixed cryoglobulinemia are typically nonspecific, and patients usually present with arthralgias, fatigue, palpable purpura, and peripheral neuropathy. C4 and total complement are usually dramatically low, as in this case.

Treatment of cryoglobulinemia usually involves the use of plasmapheresis to remove circulating cryoglobulins. Steroids are suppressive in some patients, and rituximab quells formation of new cryoglobulins.  There are no studies aside from case reports about the use of eculizumab for cryoglobulinemia. Trendelenburg et al analyzed the role of complement in glomerular inflammation using mice models, and showed that mice deficient in C5 had reduced glomerular infiltration by neutrophils. Eculizumab inhibits the conversion of C5a to C5b and subsequent formation of the membrane attack complex; it therefore be theoretically useful in treating cryoglobulinemia, which causes complement mediated renal failure.

The patient was treated with 2 doses of eculizumab and then rituximab for cryoglobulinemia, and is now doing well and tolerating dialysis.

Posted by Shruti Gupta, Renal Fellow MGH/BWH