A rare case of renal thrombotic microangiopathy associated with Castleman’s disease

CD is a rare lymphoproliferative disorder. Renal involvement has been only described in a limited number of small studies. Based on a study conducted in a large CD cohort of Chinese patients, renal involvement in CD is about 25% [2], particularly seen in patients with MCD plasma cell or mixed variant [2, 3]. ARF represents the most common renal presentation, and glomerular pathologies majorly include AA amyloidosis [3, 4], TMA [2, 3, 5] and membranoproliferative glomerulonephritis [6]. Other renal pathological findings include mesangioproliferative glomerulonephritis, interstitial nephritis [7], membranous nephropathy [8], crescentic glomerulonephritis [2, 9, 10], minimal change disease [2] and focal segmental glomerulosclerosis [3]. Consistent with previous studies, our patient developed renal TMA in MCD plasma cell variant, the aggressive type of CD.

The dysregulated production of VEGF and interleukin-6 (IL-6) is implicated to play a central role in the pathogenesis of CD. Proliferating plasma cells in lymph nodes cause overproduction of both cytokines leading to elevated systemic levels [11, 12]. VEGF exerts potent pro-inflammatory effect and increases blood vessel permeability, which explains pleural effusion, ascites, and generalized edema in our patient. IL-6 has pleotropic effects, such as promoting B-cell differentiation to immunoglobulin-producing plasma cells, stimulating hepatocyte to synthesize acute-phase proteins, and inducing dominance of Th17 cells over Tregs to disrupt immune tolerance [13]. It has been shown that mice overexpressing IL-6 produce a syndrome resembling CD [14]. In our patient, IL-6 accounts for a variety of clinical symptoms including generalized lymphadenopathy and hepatosplenomegaly, polyclonal hypergammaglobulinemia, increased levels of ESR, CRP and ferritin, anemia, and overproduction of autoantibodies.

Diffuse endothelial swelling, mesangiolysis and capillary loop thrombi in combination with podocyte VEGF downregulation in our patient resemble renal TMA seen in cancer patients treated with VEGF inhibitors [15] or preeclampsia patients with increased circulating level of soluble fms-like tyrosine kinase 1 (sFlt1), a soluble VEGF receptor and an antagonist of VEGF [16]. VEGF is a vascular growth factor for vasculogenesis and angiogenesis during development and in disease through regulation of vascular permeability, endothelial cell migration, proliferation, and cell survival [17]. VEGF released by podocytes binds to VEGF receptors on glomerular endothelial cells, resulting in receptor tyrosine phosphorylation and signal transduction. It has been demonstrated that tight regulation of glomerular VEGF signaling is critical for establishment and maintenance of the glomerular filtration barrier. Moreover, it has been shown that podocyte VEGF deletion in adult mice is sufficient to trigger TMA by utilizing podocyte-specific VEGF knockout mice [15, 18]. Previously, Karoui et al. reported decreased glomerular VEGF expression in a MCD patient with renal TMA [3]. However, co-localization staining of glomerular VEGF with any glomerular cell-specific marker was not performed. The serum level of VEGF from the same affected patient was also not examined. For the first time, we performed dual IF staining of VEGF with the podocyte nucleus marker WT-1 in the kidney biopsy and correlated with serum VEGF level in our patient. Our study showed podocyte VEGF downregulation associated with markedly elevated serum VEGF before chemotherapy. The question of how persistent VEGF and IL-6 overproduction leads to deficient podocyte VEGF expression remains unresolved.

It is of note that not every CD patient develops renal TMA. Genetic or acquired dysregulation of ADAMTS13 or the complement alternative pathway can predispose patients to develop TMA. Deficiency of ADAMTS13, owing to mutations in the ADAMTS13 gene or autoantibodies that inhibit ADAMTS13 activity, can cause idiopathic TTP. It is not unusual for ADAMTS13 to be decreased in TMA without TTP. In TTP, ADAMTS13 activity is typically <5% [19]. Therefore the TMA in our patient does not appear to be caused by TTP, particularly in the absence of hemolysis, schistocytes and neurological symptoms. Dysfunction of the complement alternative pathway, caused by mutations in complement factor H, I, B, or membrane cofactor protein or by autoantibodies against factor H, can result in complement-mediated TMA [20, 21]. The presented patient may have mild complement abnormalities that increase his susceptibility to develop renal TMA associated with CD.

In summary, we discuss a rare case of MCD patient presenting with ARF, mild proteinuria and renal TMA. The renal injury is associated with inhibited expression of podocyte VEGF. In this patient, an excellent renal response to chemotherapy was achieved. Reagents that suppress overproduction of IL-6 and VEGF may lead to highly-targeted treatments in CD. In addition, further investigation to delineate the mechanism(s) involved in podocyte VEGF downregulation will lead to discovery of specific target molecules for the treatment of renal TMA seen in CD.