Graft-versus-host disease

Introduction

Since 1957, when the first bone marrow transplantation was performed by Thomas et al., hematopoietic stem cell transplantation (HSCT) has been used for the treatment of several hematologic and autoimmune disorders. With the discovery of the human leukocyte antigen (HLA) system in 1958 and the subsequent better understanding of histocompatibility, allogeneic and autologous stem cell transplantations became standard practice. In the 1970s the number of bone marrow transplantations was low and the 1-year patient survival was less than 50%. Currently, nearly 20,000 HSCTs are performed in the United States and 5-year survival approaches 50% ( https://bloodcell.transplant.hrsa.gov ). Thus long-term complications of HSCT were almost unknown in early 1970s but today, with an increase in life expectancy of patients, they are significant.

Although the use of HSCT in hematologic practice has led to meaningful improvements in outcomes, the preparative regimens, procedures, posttransplant complications, infections, and drugs that have to be used either for the procedure or its complications may limit patient survival. Therefore the management of these issues is essential for a higher survival rate. HSCT related complications can be mainly classified into four categories: infections, early noninfectious complications, late noninfectious complications, and graft-versus-host disease (GVHD). In this chapter, we focus on GVHD-associated kidney diseases.

Acute kidney injury after homologous stem cell transplantation

Acute kidney injury (AKI) is one of the most severe complications of HSCT and is especially common after myeloablative allogeneic HSCT, because this procedure requires intense immunosuppression that may cause severe sepsis or liver failure. In addition, use of calcineurin inhibitors (CNIs) is routine for the first 100 days after myeloablative allogeneic HSCT. It should not be forgotten that candidates for HSCT often have low muscle mass and low creatinine production, when compared with a healthy population. Hence a mildly elevated serum creatinine concentration may be an important marker of a severe kidney damage. In all of these settings, use of a confirmatory test, such as cystatin C, or measurement of clearance of an exogenous filtration marker, such as inulin, iohexol, or iothalamate, will provide a more accurate assessment of glomerular filtration rate (GFR) than creatinine-based formulas.

During the first days and weeks of HSCT, recipients are at a high risk of many forms of AKI. Prerenal syndromes and hypovolemia induced by vomiting or diarrhea are one of the most common causes. Mucositis secondary to chemotherapy can result in poor oral fluid intake and may trigger hypovolemia as well. Acute tubular necrosis (ATN) can develop from hypoperfusion injury or as a result of medications such as cytarabine, busulfan, and fludarabine. Amphotericin B and aminoglycosides are also well-known causes of ATN.

HSCT patients are prone to develop sepsis caused by high immunosuppressive potential of chemotherapeutic agents. Sepsis can result in decreased effective circulating volume and hypotension and is thus a major risk factor for AKI ( Box 14.1 ). On the other hand, sepsis may induce inflammation, which leads to increased capillary permeability and intravascular fluid leak, resulting in total body volume overload, while depleting effective circulating volume and end-organ perfusion.

Box 14.1

ATN , Acute tubular necrosis; CNI , calcineurin inhibitor; HSOS , hepatic sinusoidal obstruction syndrome.

Risk Factors for Acute Kidney Injury After Hematopoietic Stem Cell Transplantation

Sepsis
Hypovolemia
ATN
Tumor lysis syndrome
Acute GVHD
HSOS
Marrow transfusion toxicity
CNI toxicity
Thrombotic microangiopathy
Total body irradiation
Medications (amphotericin B, aminoglycosides, chemotherapeutic agents)

The most frequently investigated and published complication of HSCT is GVHD. Although skin, gut, liver, and other organ involvements and manifestations associated with GVHD are widely defined, the effects on the kidney still remain unclear.

Graft-versus-host disease–associated kidney disease

Despite the multiple etiologies of posttransplant renal dysfunction, GVHD has rarely been linked to the kidney, and it was believed that the kidney was not involved in acute GVHD. However, several reports suggest that both acute and chronic GVHD may cause kidney disease.

Formerly, any manifestation of GVHD that manifested within the first 100 days after HSCT was defined as acute and beyond that as chronic. However, this classification led to some confusion if pathologic signs of acute or chronic GVHD occurred outside of these periods.

This situation led to development of a classification scheme based on clinical findings to differentiate between acute and chronic GVHD. The widely accepted National Institutes of Health consensus criteria for the diagnosis of GVHD classifies manifestations of GVHD as diagnostic or distinctive for chronic GVHD, or as common to both acute and chronic GVHD. In the 2014 version, it is accepted that in the absence of features fulfilling criteria for the diagnosis of chronic GVHD, the persistence, recurrence, or new onset of characteristic skin, gastrointestinal tract, or liver abnormalities should be classified as acute GVHD regardless of the time after transplantation. ^,

Both acute and chronic GVHD are almost completely different pathologic processes. In acute GVHD, patients mostly present with rash, diarrhea, and liver function test abnormalities, and can be treated with the addition of another immunosuppressive agent, such as steroids, antithymocyte globulin, antitumor necrosis factor α, and photopheresis. Thirty to sixty percent of patients with acute GVHD progress to chronic GVHD, which mostly requires a lifelong immunosuppression with a CNI, a potential risk for chronic kidney disease (CKD).

The pathophysiology of graft-versus-host disease

Although GVHD is observed after HSCT, the process itself begins before the infusion of stem cells. Because of several factors, such as the underlying disease and its treatment, infections, or chemoradiotherapy, host tissues may secrete inflammatory cytokines, including tumor necrosis factor α and interleukin (IL)-1, which may result in endothelial apoptosis. This hypothesis explains the increased risk of GVHD associated with intensive preparative regimens. After infusion of stem cells to the host, donor T-cell stimulation occurs, resulting in activation of host antigen presenting cells and the development of GVHD. Activation of CD8+ and CD4+ T-cells by major histocompatibility complex (MHC) Class I and Class II antigens leads to the activation of intracellular pathways that cause the release of cytokines, such as IL-2, interferon-γ, IL-4, IL-5, IL-10, and IL-13. The activation of Th1 cells enhances T-cell proliferation and activates monocytes and macrophages. This in turn induces the migration of macrophages and their successive binding to the endothelium and subsequent extravasation from the vessels. Finally, macrophages can produce high amounts of nitric oxide (NO) as a result of activation and NO contributes to the deleterious effects of GVHD on target tissues, inhibits repair mechanisms especially in the gut and skin, and enhances GVHD-induced immunosuppression. ^,

Clinical features of graft-versus-host disease

In acute GVHD, skin, liver, and gastrointestinal tract are primarily affected. Skin rash with blisters, abdominal pain, nausea and vomiting, and the elevation of liver enzymes are typical symptoms. Acute GVHD is staged according to number and extent of organs involved into four grades (I-IV). Acute GVHD is an important risk factor for the development of AKI. The contribution of GVHD to AKI can be attributed to cytokine-induced inflammation affecting renal structures, the use of potential nephrotoxic drugs, and the increased risk of infections. The pathology of the kidney in acute GVHD has been studied in some animal models. In these studies, infiltration of mononuclear cells in the renal tubule-interstitium, mainly around small arteries and veins, is typically identified, as well as acute glomerulonephritis and acute endarteritis. Whereas acute GVHD has strong inflammatory components, chronic GVHD displays more autoimmune and fibrotic features. Fibrotic injury in chronic GVHD is characterized by accumulation of collagen. Fibroblasts take up the place of parenchymal cells and disrupt normal tissue function. ^,

Although kidneys are not traditionally considered to be the target organ for GVHD after HSCT, GVHD has been implicated as the cause of glomerular injuries. In acute GVHD, kidney dysfunction is predominantly related to causes, such as hypovolemia, nephrotoxic drugs, infections, and sepsis. Although these factors could contribute to chronic GVHD as well, an association of glomerular disease with chronic GVHD was reported in several cases and the cumulative incidence of nephrotic syndrome was given as 8% to 27.7%. Membranous glomerulonephritis is the most frequent glomerular manifestation of chronic GVHD. Other reported forms of glomerulonephritis include minimal change disease, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, antineutrophil cytoplasmic antibodies–associated glomerulonephritis, proliferative glomerulonephritis, and immunoglobulin A nephropathy.

All of these renal disorders typically occur within 8 to 14 months after HSCT, especially after the cessation or dose reduction of CNIs. ^, Treatment for GVHD associated nephrotic syndrome is similar to that in other settings, and it includes steroids and the resumption of CNIs ^, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. As in other forms of kidney diseases, albuminuria is an important indicator of the progression and risk of death.

Another important disorder associated with GVHD and HSCT is thrombotic microangiopathy (TMA). Although it is more closely associated with chronic GVHD, TMA was present in 20% of kidneys at autopsy in patients after HSCT. The risk of TMA is increased fourfold in patients with acute GVHD. The incidence of TMA syndromes in the setting of HSCT ranges between 2% and 21%. TMA is defined by hemolytic anemia with erythrocyte fragmentation, thrombocytopenia, and renal failure. Thickening of glomerular and arteriolar vessels caused by endothelial damage are caused by the fragmentation of erythrocytes and thrombosis, which are typical findings of TMA. ^, The progression of TMA is usually slow and results in CKD. However, acute flares may cause AKI. Risk factors for the development of TMA after HSCT include use of CNIs, total body irradiation, and GVHD. In the treatment of TMA, therapeutic plasma exchange is usually ineffective and is not routinely recommended. Some patients are found to have dysregulation of their complement system and benefit from administration of the anti-C5 monoclonal antibody, eculizumab. Because CNIs are considered to be one of the risk factors for TMA, alternative agents for prophylaxis or treatment of GVHD, such as mycophenolate mofetil, corticosteroids, or IL-2 receptor antagonists, should be considered. ^,

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