We encountered a 56-year-old Japanese man who had proteinuria and hematuria during treatment for ITP. As renal biopsy confirmed mesangioproliferative glomerulonephritis, we first considered IgA nephropathy, as it has been reported that IgA nephropathy can be associated with ITP. However, IF shows a full house pattern and IgA nephropathy is unlikely. Systemic lupus erythematosus (SLE) is another disease that has reported to be involved in ITP. Although IF showed full-house pattern, no autoantibodies or symptoms can support the diagnosis of SLE, the condition is called non-lupus full-house nephropathy (FHN) [4]. We suspected MPGN because of the detection of double basement membrane and EDD in the mesangium and subendothelium in the renal biopsy, as well as decreased complement. To the best of our knowledge, only two case reports have explored the relationship between MPGN and ITP: one report was based on a patient with MPGN, ITP, and autoimmune hemolytic anemia [5] and the other was based on a patient who developed MPGN while receiving hepatitis C virus treatment with rituximab [6]. Thus, we report herein a rare case of ITP complicated by mesangioproliferative glomerulonephritis with full-house pattern and MPGN-like findings.
ITP is an autoimmune disease caused by the destruction of platelets in the periphery and their inappropriate production in the bone marrow. The etiology of ITP is well known, and it involves the recognition of membrane glycoprotein (GP) complexes (primarily GPIb/IX and GPIIb/IIIa) by anti-platelet and anti-angiocyte antibodies. Opsonized platelets are phagocytized by macrophages in the spleen and liver via the Fcγ receptor. Activation of the classical complement pathway also causes platelet destruction via opsonization and complement-dependent cell injury. Platelet destruction also occurs via FcγR-independent pathways, but its underlying mechanisms are unknown [7, 8].
Lupus nephritis, IgA nephropathy, and membranous nephropathy (MN) have been reported to cause ITP-associated nephritis [1–3]. Patients with ITP are approximately 27 times more likely to develop SLE than the healthy population [9]. In ITP, autoantibodies such as antinuclear, anti-double stranded DNA antibody, anticardiolipin antibodies, and antiplatelet antibodies may be produced. The continued production of these autoantibodies during the ITP course can also lead to other autoimmune diseases [2]. Lande et al. proposed three underlying mechanisms for ITP caused by MN: (a) reaction of circulating antiplatelet antibodies with native antigens of the glomerular capillary wall, (b) reaction of circulating antiplatelet antibodies with transplanted glomerular antigens after their release following platelet destruction, and (c) deposition of circulating immune complexes formed by antiplatelet antibodies on glomeruli [3].
A case of MPGN with immunoglobulin-positive is classified as immune complex-related MPGN [10]. Immune complex–related MPGN can be caused by cryoglobulinemia, M-proteinemia, infections, and autoimmune diseases such as SLE, rheumatoid arthritis, Sjogren’s syndrome, and IgA nephropathy. The following mechanisms have been proposed to explain the pathophysiology of MPGN. Immune complexes activate the classical pathway, thereby acutely damaging glomerular capillaries and mesangium, and cause an influx of inflammatory cells, leading to proliferative glomerular changes. The glomerular repair response is characterized by the generation of neovascular membranes by endothelial and mesangial cells, which trap immune complexes and form a double contour. In addition, mesangial expansion occurs due to an increase in the number of mesangial cells, the levels of mesangial matrix, and mononuclear cell infiltration [11]. Therefore, along with MN setting, which mentioned Lande et al. previously [3], immune complexes formed by antiplatelet antibodies might also lead to the development of MPGN. Further studies are required to confirm the causal relationship between ITP and MPGN.
Factors that are reported to be associated with a poor kidney prognosis in MPGN include nephrotic syndrome, elevated sCr level, and hypertension [12]. MPGN is generally treated using steroids and immunosuppressive drugs such as cyclosporine, but evidence for their effectiveness in adults is insufficient. Small observational studies have suggested potential benefit of using MMF, especially when prescribed with oral glucocorticoids [13]. In this case, although kidney function was preserved due to treatment with PSL and MMF, the patient experienced a slight kidney dysfunction. Large observational study might help in confirming the effect of MMF on MPGN in the future.
In this case, we could not confirm SLE because the patient only had high urinary protein, low platelets, and low complement levels according to Systemic Lupus International Collaborating Clinics criteria. However, patients who are initially diagnosed with non-lupus FHN may develop lupus symptoms or test positive for antinuclear antibodies during the disease course. The probability of developing SLE in patients with non-lupus FHN is 7.8% [14]. One patient, who was reportedly diagnosed with MPGN 20 years ago, was diagnosed with lupus nephritis with positive antinuclear antibodies and appearance of lupus symptoms [15]. Therefore, similar to this case, the possibility of developing SLE in the future cannot be excluded and requires careful follow-up.