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.

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.