A Syndrome of IgA-Related Polycythemia

Polycythemia is characterized by the risk of complications such as thrombosis. Whereas red blood cell intrinsic genetic abnormalities, such as JAK2 mutation account for most of the cases of polycythemia, pathophysiologic mechanisms involved in other etiologies of polycythemia remains poorly understood. We previously reported that pIgA1 controls erythropoiesis through activation of transferrin receptor (Coulon et al, Nat Med 2011), but data in patients are still lacking to involve pIgA1 in normal or pathologic erythropoiesis. IgA nephropathy (IgAN) is associated with elevated levelsof polymeric IgA (pIgA1) and circulating IgA1 complexes. In patients with IgAN and unexplained polycythemia, we hypothesized that pIgA1 could also be involved in the increased red blood cell production.

METHODS

Sera from patients with IgAN and unexplained polycythemia (IgAN-Pcy, persistent hematocrit (Ht) >54%) were collected after written consent. Human progenitor CD34⁺ cells with addition of IgAN-Pcy or control serum were plated in semi-solid methycellulose medium and quantified, and IgA1 depletion was performed as previously described (Coulon et al, Nat Med 2011).We performed a multivariate linear regression to analyze Hb levels among various groups of a CKD cohort (696 patients with glomerulonephritis but no ESRD, IgAN n=171), and in a post-transplant cohort (2600 patients, IgAN n=271).

RESULTS

We report 6 patients with IgAN-Pcy who developed polycythemia (median Ht55%). No JAK2 mutations were found. All patients had normal blood oxygen level, as well as EPO levels (median 7.6 mUI/L, range 5.8-9.9) and abdominal ultrasound. In contrast, in vitro at low dose of Epo, we found that the number of erythroid burst forming unit (BFU-E)-derived colonies was increased in the presence of IgAN-Pcy serum compared to control (73 vs 52, p<0.05). Removal of IgA1 from IgAN-Pcy patients normalized the number of colonies while add-back of these IgA1 increased it to initial values. Emphasizing our finding, among glomerulonephritis, Hb level was significantly higher in patients with IgAN by multivariate analysis (13.1g/dL vs 12.2 g/dL, p=0.01). In the post-transplant cohort, the mean elevation of Hb at M3 and M12 compared to M0 was higher in IgAN compared to other patients (Dhb M0-M3 0.87 and 0.22g/dL; M0-M12 1.36 and 0.71g/dL respectively), suggesting that Hb recovery is faster after acute anemia following renal transplantation.

CONCLUSION

These data suggest a role of pIgA1 in erythropoiesis regulation and describe a new etiology of polycythemia.