Monoclonal Gammopathy with Secondary Atypical Hemolytic-Uremic Syndrome

Monoclonal gammopathy is a clonal plasma cell disorder associated with an increased risk of progression to lymphoproliferative malignancy. In children, monoclonal and oligoclonal gammopathies are rare, and their clinical relevance unrecognized. Atypical hemolytic uremic syndrome (aHUS) is a rare endotheliopathy associated with dysregulated activation of complement, microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. We present a case of aHUS that we hypothesize was triggered by monoclonal gammopathy in a child several years after cardiac transplantation.

An 11 year old African-American girl with sickle trait was transferred to our cardiac center with a two week history of epigastic pain, emesis, microcytic anemia, hypergammaglobulinemia, and development of renal failure requiring dialysis. She had undergone cardiac transplantation at 7 months of age for dilated cardiomyopathy of unknown etiology and had recovered from acute cardiac rejection requiring ECMO at age 5 years. She had previously experienced at least two episodes of acute kidney injury requiring dialysis with full recovery of function reported. Renal biopsy revealed a severe collapsing glomerulopathy and a thrombotic microangiopathy. Upon transfer to our institution, her labs were notable for microcytic anemia, normal platelet count, haptoglobin, and LDH. A week later, she developed aHUS diagnosed by hemoglobin 9.5 gm/dL, haptoglobin < 30 mg/dL, LDH 314 U/L, platelets 100,000, and a predominance of schistocytes on peripheral blood smear in the setting of acute renal failure. Serum protein electrophoresis (SPEP) revealed a monoclonal spike (1g/dL), identified as IgG kappa by immunoabsorption. A second, smaller monoclonal spike was identified as IgA lambda. aHUS evaluation revealed low C3, normal C4, and 50% CD46 expression by flow cytometry. Bone marrow biopsy with flow cytometry excluded lymphoproliferative disorders. EBV did not amplify with quantitative PCR of peripheral blood, and computed tomography imaging of the body did not detect abnormal mass or lymph nodes. A trial of plasmapheresis did not improve biochemical and hematologic features of aHUS. A trial of eculizumab resulted led to normalization of platelet count and C3, increased haptoglobin, reduced need for red cell transfusion, and less frequent dialysis.

Monoclonal gammopathy of unknown significance (MGUS) is rare in children, but may be more common in transplant recipients, especially after cardiac transplants in infants when thymectomy is performed. MGUS associated with secondary aHUS has been rarely reported in adults. The mechanism for aHUS was demonstrated in one case to result from affinity of the paraprotein to a binding site on complement factor H, with subsequent loss of factor H cofactor activity to inhibit alternative complement activation. We hypothesize that immune dysregulation from fluctuating levels of paraproteins during inflammation in our patient with monoclonal gammopathy resulted in recurrent, intermittent episodes of aHUS. We speculate that this was responsible for the patient's collapsing glomerulopathy and dialysis-dependent chronic renal failure. This case highlights the importance of considering monoclonal gammopathy in pediatric patients who develop recurrent kidney failure or atypical hemolytic uremic syndrome in the setting of immune dysregulation. The merit of treating the monoclonal gammopathy with Bortezumib and Rituximab is currently under consideration.