Introduction
Hematopoietic stem cell transplantation (HSCT) is an effective therapy for patients who require potent chemotherapy drugs for the treatment of certain diseases such as acute leukemia. The development of new chemotherapeutic agents and better control of infection have improved the survival rate of patients who undergo HSCT; however, these measures have also introduced certain long- and short-term complications. Chronic graft-versus-host disease (cGVHD) is a common late complication of allogeneic HSCT that occurs in 60–80% of long-term survivors, and its incidence is currently increasing
[1]. In animal models, the kidney was defined as a target organ of cGVHD, but the underlying mechanisms and pathogenesis of GVHD-related renal disease in people are unclear
[2].
The recognized renal problems in HSCT recipients are drug toxicity, radiation nephritis, infection, thrombotic microangiopathy, and glomerulonephritis. The etiology and pathogenesis of proteinuria, including nephrotic syndrome (NS) in HSCT recipients remain unclear; however, an association between NS and cGVHD has been proposed. Brukamp K, Doyle AM, Bloom RD, Bunin N, Tomaszewski JE, and Cizman B
[3] have reported that membranous nephropathy (MN) accounts for two-thirds and minimal change disease (MCD) accounts for one-third of the cases of NS in HSCT recipients. Renal biopsy is rarely performed after HSCT because of inappropriate general conditions and patients’ reluctance. Therefore, only a few reports of renal histopathological analysis after allogeneic HSCT are available in the literature, and these consist of only case reports or case series involving smaller number of patients.
In this study, we have analyzed the clinicopathological characteristics of 15 HSCT recipients having urinary protein levels >1 g/day. To our knowledge, this is the largest series assessing patients with biopsy-proven nephropathy after HSCT.
Discussion
The outcomes of HSCT recipients have improved due to the development of novel chemotherapeutic agents, effective prevention, and treatment of infections, and new transplant regimens, such as nonmyeloablative transplantation. However, this improvement has been accompanied by an increase in glomerular or interstitial renal disease.
All our patients exhibited evidence of acute GVHD or cGVHD, which was present prior to or simultaneously with the renal disease. The GVHD frequently affects the skin, oral mucosa, liver, and gastrointestinal tract. The pathophysiology of GVHD is not well understood. In a murine model of cGVHD, renal involvement of cGVHD has been commonly detected; however, renal involvement of cGVHD in humans has been rarely noted
[5]. Inflammatory and cytokine cascade, such as those involving tumor necrosis factor-α and/or interferon-γ, from donor T cell may be crucial for the development of the renal disease in cases with GVHD
[6]. Brukamp K, Doyle AM, Bloom RD, Bunin N, Tomaszewski JE, and Cizman B
[3] have proposed that withdrawal or reduction in the dose of immunosuppressive agents in GVHD treatment is a risk factor for the development of NS.
Among the different types of glomerulopathies, MN is reportedly the most common, followed by MCD
[7], which is consistent with the findings of this study as well (80%). The overall response rate (CR and PR) was 73%. At present, there are no standard treatment guidelines for NS after HSCT. Niscola P, Tendas A, Luo XD, Catalano G, Scaramucci L, Cupelli L, Giovannini M, Ferranini M, Bondanini F, Piccioni D, Dentamaro T, Palumbo R, Perrotti AP, Liu QF, and de Fabritiis P
[7] analyzed 69 previously reported cases of MN and found that the treatments used were very highly variable, the most frequently used agent was corticosteroid followed by cyclosporine. In that study, 59% patients achieved CR and 28% achieved PR. Treatment failed in the remaining 13% of patients, and ESRD developed in a few patients
[7]. In this study, the combined response rate of CR and PR in patients with MN was 73%, which is similar to that previously reported
[7]. Approximately 30–35% of untreated patients with idiopathic MN have benign course of the disease or spontaneous resolution, and the decision to initiate treatment using immunosuppressive agent should be made based on the patients’ risk factor such as proteinuria levels or deteriorating of renal function
[4]. However, in patients with secondary MN, the treatment of the underlying disease induced a remission of MN (e.g., the treatment of neoplasm in case of malignancy-associated MN). Therefore, we initiated the immunosuppressive agent treatment in all the patients with MN, in order to treat the renal GVHD.
MN is the most common form of immune-complex-mediated glomerulonephritis reported in association with HSCT
[6],
[7],
[8]. MN is caused by the deposition of immune complexes in the subepithelial zone of glomerular capillaries, but its underlying pathogenic mechanism is not completely understood. The role of anti-PLA2R (M-type phospholipase A2 receptor) antibodies in primary MN has recently been elucidated
[9]. Although anti-PLA2R antibody was detected in approximately 70% of patients with primary MN, some patients with secondary MN also exhibited the antibody. Moreover, Qin W, Beck LH Jr, Zeng C, Chen Z, Li S, Zuo K, Salant DJ, and Liu Z.
[10] detected anti-PLA2R antibody in 6.3% of patients with hepatitis B virus-associated MN and in 30% of patients with tumor-associated MN. By contrast, the etiology and significance of anti-PLA2R antibody in secondary MN are not known, especially in HSCT with GVHD. Moreover, the relationship between serum concentration of the antibody and the clinical course of MN is unknown and requires additional investigation. In our study, seven patients whose serum samples were collected at the time of renal biopsy had negative results for the anti-PLA2R antibodies in the ELISA test. This result suggests that MN associated with GVHD has a different pathogenesis from idiopathic MN. It has been well known that the antibody directed against tubular brush-border antigen induced tubulointerstitial fibrosis and tubular atrophy in a murine GVHD model
[11]. However, our patients with MN did not show a prominent tubular injury, because they were in the early phase of MN.
In addition to MN, the other common glomerulopathy was MCD. MCD accounts for approximately one-quarter of the cases of NS after HSCT
[3],
[12]. The treatment response of patients with MCD is better than that of MN patients, with a previous study reporting that 90% of its study patients had achieved CR
[3]. In this study, however, none of the patients had MCD. One of our patients had MPGN type 1 and was successfully treated with prednisolone and azathioprine. In addition, a patient with C1q nephropathy died from GVHD-associated sepsis.
Although the mechanisms underlying the development of NS or proteinuria associated with GVHD have not been elucidated, it has been hypothesized to represent the end stage of alloreactivity, in which T cells have evolved to assume the Th2 phenotype
[13],
[14]. A proposed mechanism for this evolution is immune dysregulation resulting from the transfer of alloreactive peripheral donor lymphocytes (possibly, CD8
+/perforin+ cytotoxic T cells) present in the primary blood stem cell graft, with reactivity toward glomerular antigens
[15]. The CD8
+/perforin+ cytotoxic T lymphocytes might induce the destruction of glomeruli and apoptosis of podocytes and endothelial cells, producing microthrombi, and finally destroying the loop segments
[15]. Another hypothesis is that the induction of GVHD in rats may lead to restricted polyclonal stimulation of B cells and the formation of autoantibodies directly targeting basement membrane. Consequently, immunoglobulin deposition along the GBM and development of proteinuria were found
[11].
In summary, we have analyzed the clinicopathological features of 15 patients who have developed proteinuria or NS in association with GVHD after allogeneic HSCT. The most common histopathological renal finding was MN and most patients with MN responded well to immunosuppressive agents. Because the population of long-term survivors after allogeneic HSCT is growing, the incidence of GVHD-mediated renal disease may increase. Therefore, renal biopsy is essential in establishing the cause of the renal dysfunction and in directing the proper immunosuppressive therapy.