Graft-versus-host disease risk factors

Although a detailed review of systemic GVHD risk factors is beyond the scope of this chapter, a brief overview is important to understanding the association between GVHD and kidney injury. In addition, there is overlap between the risk factors for GVHD and for kidney injury after HCT, further linking GVHD and kidney disease in the setting of HCT. Risk factors for acute GVHD include the degree of human leukocyte antigen (HLA) mismatch, receipt of a transplant from an unrelated donor, female donor for a male recipient, the use of peripheral blood stem cell grafts, and the intensity of the conditioning regimen. Risk factors for chronic GVHD, defined by the presence of GVHD beyond 100 days posttransplant, include a prior episode of acute GVHD, receipt of peripheral blood stem cell grafts, grafts from female donors to male recipients, HLA disparity, older age of either recipient or donor, and a primary diagnosis of chronic myeloid leukemia. Identification of individuals at increased risk for GVHD provides an opportunity for heightened awareness of kidney injury in these patients allowing for closer monitoring and early intervention.

Kidney manifestations of graft-versus-host disease

Scoring systems for severity of GVHD typically focus on the three main target organs: skin, liver, and GI tract. However, as alluded to previously, GVHD has been shown to be an independent risk factor for AKI and chronic kidney injury. Clinically, GVHD can present as various forms of kidney disease including AKI, nephrotic syndrome (NS), glomerulonephritis, and TMA.

The most commonly accepted manifestation of kidney GVHD is as NS, characterized by a high degree of proteinuria, hypoalbuminemia, and edema. Among those presenting with NS the most common underlying pathology is membranous nephropathy (MN), with approximately 60% to 80% of patients having this diagnosis. ^, Histologic findings of MN post-HCT are similar to those seen in MN in other settings, including subepithelial deposits made up of antigen-antibody complexes. Minimal change associated with NS is the next most common pathology seen in patients after HCT. Less commonly reported pathologic findings in post-HCT NS patients are membranoproliferative, glomerulonephritis, focal segmental glomerulosclerosis, and immunoglobulin A nephropathy. ^{, ,} The typical timeframe for presentation of NS is 6 to 12 months posttransplant. Of note, the timing of the appearance of NS post-HCT is temporally associated with the discontinuation of prophylaxis for GVHD. This is somewhat in contrast to the previous idea that “Bone Marrow Transplant (BMT) associated nephropathy” was strictly a multifactorial process that included renal toxicity related to calcineurin inhibitor exposure. In addition, NS post-HCT rarely occurs without the presence of GVHD, and also can occur in the absence of GVHD in other sites, suggesting kidney specific targeting in the setting of GVHD. Regarding MN, a case report by Cho et al. examined patients, all with GVHD, presenting with MN-associated NS following HCT for serum antiphospholipase A2 receptor, an antibody that has been associated with both primary and secondary MN. None of the seven MN patients had detectable levels of the antibody. Such findings suggest that although overlap may exist between NS seen post-HCT and the development of NS in other settings, there may be unique aspects of these processes associated with GVHD.

TMA is also a common clinical presentation after HCT. Several risk factors for TMA have been identified, including total body irradiation (TBI), exposure to calcineurin inhibitors, combined use of tacrolimus and sirolimus, HCT-associated infections, performance of HCT for nonmalignant conditions, and transplantation of peripheral blood stem cells. In addition, GVHD has been independently associated with TMA. Because endothelial damage is a primary feature of TMA, one hypothesis linking TMA and GVHD is that, similar to other organ systems, the vascular endothelium is a target in GVHD. Lending further support to this are previously mentioned findings in the renal capillaries, including C4d and cytotoxic T-cells, and evidence of complement activation, all suggesting immune targeting of the recipient endothelium by donor graft cells is involved in the pathophysiology of posttransplant TMA. ^, As with TMA in other clinical settings, activation of the TMA cascade then results in AKI and, subsequently, the potential for chronic kidney changes as the acute inflammation progresses to fibrosis with loss of functional glomeruli and renal tubules.

Although the development of CKD post-HCT is likely multifactorial owing to exposure to TBI and nephrotoxic medications, such as calcineurin inhibitors, infections and sepsis, and recurrent episodes of AKI, GVHD has also been shown to be independently associated with CKD. The triggering of multiple inflammatory pathways following immunologic targeting of the kidney in the setting of GVHD ultimately can lead to fibrosis and irreversible kidney damage. ^, This is particularly true when GVHD is chronic and therefore immune-mediated renal damage occurs over a prolonged time course.

GVHD is a common secondary effect of HCT and can cause significant detrimental kidney outcomes, emphasizing the importance of pursuing a detailed investigation for the clinical effects of GVHD on the kidney.

Evaluation

As noted, GVHD is a multisystem condition characterized by symptoms reflecting damage to each of the major organs involved, including maculopapular rash, hyperbilirubinemia, cholestasis, jaundice, nausea, abdominal pain, diarrhea, vomiting, and anorexia. Although the kidney is not classified as a major target of GVHD, and kidney disease is not included in the grading of GVHD, as previously noted, the presence of GVHD in other organs is a risk factor for the development of kidney GVHD. Therefore the presence of systemic GVHD should raise suspicion for involvement of the kidney as well. Similar to other clinical scenarios, when evaluating for kidney injury, initial laboratory results should include markers of kidney function with serum creatinine (SCr) and serum electrolytes. Because there are many factors that can affect the accuracy of SCr as a measure of glomerular filtration rate (GFR) in this patient population, such as relatively poor nutrition or decreased muscle mass, cystatin C has also been proposed as an additional marker of GFR and formulas exist to use SCr and cystatin C in conjunction to provide a more accurate estimate of GFR. ^{, ,}

Urinary studies should include a urinalysis and urine microalbumin to urine creatinine ratio for the presence of hematuria and proteinuria. Microalbuminuria is defined as 30 to 299 milligrams of albumin to grams of creatinine in a spot urine sample. Macroalbuminuria is defined as a urinary albumin-to-creatinine level of more than 300 mg/g Cr. If patients are able to accurately collect a sample for 24 hours, a 24-hour urine for urinary albumin levels can also help better define the degree of albuminuria. This does require more effort on the part of patients and can be challenging to accurately obtain in some groups, such as small children. Recent consensus guidelines suggest monitoring for albuminuria at day +80 post-HCT and then annually. For patients with macroalbuminuria on initial screening, more frequent monitoring at intervals of 3 to 6 months is suggested. Other important measures are determination of active TMA markers, including complete blood count, lactate dehydrogenase (LDH), haptoglobin, and peripheral blood smear for schistocytes.

When investigating for GVHD-related kidney damage, markers of endothelial and glomerular dysfunction, such as urinary albumin, can be important to determine the underlying etiology and to predict long-term outcomes. The presence of microalbuminuria and macroalbuminuria in the first 100 days after HCT have both been associated with increased risk of death at 1 year posttransplant. Similarly, the presence of albuminuria during this period has also been associated with increased risk of progression to CKD.

HTN is another common complication of HCT, with as many as 70% of patients developing HTN in the first 2 years following transplant. ^, It is relatively easy to diagnose and, like albuminuria, has been associated with negative long-term outcomes, including CKD and increased risk of death. ^{, ,} Monitoring for HTN should be performed during the period that patients are admitted post-HCT, then at each outpatient clinic visit. Twenty-four hour ambulatory blood pressure monitoring (ABPM) should also be used to more accurately measure blood pressure and evaluate for white coat and masked HTN. The importance and utility of 24-hour ABPM has been emphasized recently in the clinical guidelines for screening for HTN in children and adolescents, and ABPM provides similar advantages in the adult population. The presence of chronic HTN can have significant effects on kidney and cardiovascular health and therefore early diagnosis is important.

Although there can be risks in the post-HCT population, a kidney biopsy should be strongly considered for those patients with signs of kidney injury after transplant. A kidney biopsy may support evidence of kidney involvement in GVHD and will also provide information about other etiologies of posttransplant kidney disease, such as TMA and viral infections. Most importantly, diagnosis of the underlying cause of kidney disease allows for a treatment plan that more accurately targets the specific pathology. Because many of the processes in the kidney after HCT are inflammatory in nature, early identification and treatment to quiet disease activity can reduce the amount of fibrosis that forms because of prolonged inflammation and therefore decrease the risk of developing irreversible chronic kidney injury. A kidney biopsy can provide information that is not otherwise obtainable and is an invaluable tool in caring for patients following HCT.

Treatment

Treatment of GVHD-associated renal disease starts with prevention and treatment of systemic GVHD. Typical immunosuppressive medications used for GVHD prophylaxis include the calcineurin inhibitors (CNI) cyclosporine and tacrolimus, which target transcription factors involved in IL-2 production, reducing IL-2 levels and, thereby, blocking the activation of T-cells. Methotrexate, a folate antagonist, is often used in conjunction with CNI, and the combination of these two drugs has been shown to decrease the incidence of both acute and chronic GVHD. Other drugs targeting T-cell activation include cyclophosphamide and the mammalian target of rapamycin (mTOR) inhibitor rapamycin. Both of these drugs work by inhibiting the expansion of or depleting conventional T-cells with relatively less activity against regulatory T-cells. ^, In addition to T-cell inhibitory strategies, T-cell depleting therapies, such as rabbit antithymocyte globulin (ATG), are used to reduce the development of GVHD and have been shown to be effective when used in conjunction with standard prophylaxis. ^, Cell-based therapies, which aim to reduce donor T-cell immune activity by generating a more regulatory T-cell milieu, have also been investigated.

In spite of prophylaxis, GVHD can still occur. In this case glucocorticoids represent first-line therapy and responsiveness to steroids is an important prognostic marker for patients with GVHD. Those with glucocorticoid resistant GVHD have increased mortality risk. Although there is no standardized second-line therapy for glucocorticoid resistant GVHD, other immunomodulatory therapies have been investigated, including antibodies directed against T-cell antigens, such as gavilimomab.

A key component in the treatment of patients that develop kidney injury after HCT is symptomatic control of proteinuria and HTN. Angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) are ideally suited to address both of these problems, because they are not only effective in treating HTN, but also have antiproteinuric properties. In addition, there is evidence that ACE-I or ARB have long-term renoprotective effects, which slow progression of CKD. Specific to the NS seen post-HCT, this effect has been shown to be particularly effective in proteinuric nephropathies. ^,

An important consideration in the prevention and treatment of GVHD related to the kidney is that markers of disease activity can be monitored. As noted, urinary albumin excretion, HTN, and serum markers of kidney function have been shown to be good markers of kidney disease following HCT. These indicators are relatively easy to obtain and may help guide duration of prophylaxis and possibly allow for earlier initiation of treatment. In this way, monitoring of kidney changes can provide additional data regarding the onset and activity of GVHD in other organs.

Owing to the complexity of its pathophysiology, the prevention and treatment of GVHD require a multifaceted approach that targets a variety of pathways involved in the process of GVHD. Reducing the incidence of GVHD could provide protection to the kidney after HCT, therefore reducing the occurrence of AKI and chronic kidney injury posttransplant.

Conclusion

There are many potential mediators of kidney injury after HCT, and interactions between them adds significant complexity. GVHD is one factor that has been shown to generate injury within the kidney and has been associated with acute kidney disease and CKD after HCT. This relationship highlights the importance of pretransplant evaluation and close monitoring of patients posttransplant for markers of kidney damage. Transplant providers and nephrologists must be cognizant of the potential for kidney disease and work closely together to provide a multidisciplinary approach to care for patients after HCT.

Epidemiology

The reported incidence of TA-TMA is quite variable and ranges between 0.5% to 64%. This is partly owing to the difficulty in detection of the condition and variations between centers in diagnostic criteria applied. An older retrospective study by Iacopino et al., conducted in 4334 patients via questionnaire between 1985 and 1995, yielded a 0.5% incidence rate. More recent studies estimate incidence between 12% and 35%. A prospective study by Jodele et al. showed a 39% incidence of TA-TMA, of which 18% had severe TMA. Shayani et al. published a series of 177 patients, of whom 22% were diagnosed with likely or probable TA-TMA, based on their institutional criteria. Another factor that has contributed to varied incidence are changes in the pretransplant conditioning regimens, which have changed the risk of development of TMA following HCT. At this time, further studies using standardized definitions are still needed to understand the true epidemiology of TA-TMA.

Risk factors

TA-TMA is more often associated with allogeneic transplant but can occur with autologous transplant as well. Other risk factors that are thought to play a role include HCT from unrelated donors, nonmyeloablative transplants, HLA mismatch, female gender, and advanced recipient age. ^,

CNI are thought to contribute to the development of TA-TMA. Possible mechanisms include increased thromboxane A2 and endothelin levels and direct CNI-related endothelial injury. In addition, decreased nitric oxide and prostacyclin levels related to CNI exposure may play a role. ^, CNI use in combination with mTOR inhibitors causes increased concentration of CNI in the kidney, resulting in lower vascular endothelial growth factor levels and, thereby, increasing risk of TA-TMA. ^,

High-dose conditioning chemotherapy used for myeloablative transplants, such as busulfan, fludarabine, cisplatin, and radiation, are associated with an increased risk of TA-TMA. The mechanism is thought to be direct endothelial damage.

Viral infections, such as cytomegalovirus, parvovirus, adenovirus B19, human herpes virus 6, and BK, have also been associated with the development of TA-TMA. The exact mechanisms for this are unclear. ^, However, it has been postulated that these lymphotropic viruses affect monocytes and lymphocytes that then cause release of mediators of endothelial injury, such as TNF-α and IL-1.

GVHD has been shown to be a risk factor for TA-TMA in several studies. In a study conducted by Changsirikulchai et al., a fourfold higher risk of developing TA-TMA associated with GVHD was shown independent of the CNI levels or dosing regimen. Higher grades of acute GVHD are associated with higher risk of TA-TMA. As noted previously, GVHD is thought to produce vascular endothelial injury, which is the fundamental process in TA-TMA. A recent study noted an association of GVHD, both acute and chronic, in seven patients who developed TA-TMA post-HCT. These authors noted that the histopathology in the kidney demonstrated glomerular and tubular inflammation along with renal arteriolar complement (C4d) deposition, similar to acute rejection after kidney transplant, which favors a role of GVHD in the pathogenesis of TA-TMA. C4d deposition is a well-known marker of complement activation and endothelial injury. Some arguments against a direct association between GVHD and TA-TMA are that both of these complications can occur independently of each other, and that TA-TMA develops in patients with autologous HCT and allogeneic HCT. Although there is not a clear causal link between GVHD and TA-TMA, they share endothelial injury as a common denominator and often overlap clinically in post-HCT patients.

Pathophysiology

Endothelial injury is thought to be a key factor in the pathogenesis of TA-TMA. All of the risk factors outlined in the previous section lead to damage of endothelium directly or via upregulation of T-cell and an increase in inflammatory mediators such as IL-1 and TNF-α. These mediators increase expression of plasminogen activator inhibitor 1 (PAI-1) and tissue factor (TF). Exposure of the injured endothelium promotes binding of von Willebrand factor and glycoprotein (GP)1a, which in turn activates platelets through GP1b. There is concomitant TF activation, which complexes with Factor 7a and 10a to form thrombin. The platelet aggregation along with fibrin forms a thrombus. RBCs are mechanically sheared by fibrin-rich thrombi, resulting in the typical microangiopathic hemolytic anemia, in addition to thrombocytopenia caused by consumption during thrombi formation.

Neutrophil extracellular traps

Neutrophil extracellular traps (NETS) are lacy structures composed of activated neutrophils that extrude their granular proteins, such as myeloperoxidase, neutrophil elastase, and lactoferrin along with their chromatin. They are a component of innate antimicrobial immunity and can kill a wide variety of pathogens. NETS are known to activate complement by both alternative and classic pathways. ^, They are thought to be an important component of autoimmune processes and thrombotic events. NETS levels have been noted to be elevated in patients with TMA. ^, In a more recent study in 103 pediatric patients post-HCT, the authors attempted to find a causal link between endothelial injury and TA-TMA. They found that serum double stranded deoxyribonucleic acid (DNA), a known surrogate marker for NETS, levels peaked around engraftment and with occurrence of TA-TMA and GVHD within 100 days post-HCT. Thus NETS provide a possible link between complement-mediated endothelial injury and disease processes, including TA-TMA and GVHD post-HCT.

Complement dysregulation

Perhaps the most intriguing aspect of the pathogenesis of TA-TMA in recent years has been the elucidation of the role of complement dysregulation. The complement system is composed of more than 30 proteins and serves to provide host immunosurveillance. Among the three pathways of the complement system, the persistent activation of the alternative pathway is the most important mediator of endothelial injury. This has been well studied in other thrombotic microangiopathies, such as atypical hemolytic uremic syndrome (aHUS). In aHUS, defects in complement regulatory proteins, either genetic or acquired, lead to unchecked complement activation and formation of membrane attack complex (MAC) on the surface of endothelial cells, resulting in endothelial injury and the clinical findings of TMA. In addition, the complement staining pattern of TA-TMA in kidney tissue on biopsy is similar to that in aHUS with C4d deposition localized to glomeruli and arterioles. There are published data from Jodele et al. regarding complement pathway defects in a case series of patients who developed TA-TMA after HCT. The authors found that of the six patients with TA-TMA, 83% had heterozygous deletions in the complement factor H related protein (CFHR) genes, CFHR3 and CFHR1 . This is much higher than the reported prevalence in general population of ∼25%. Half of these patients also had presence of CFH autoantibodies compared with the control population who did not develop TA-TMA. Many genetic variants in complement genes have been identified that are thought to increase the risk of developing TA-TMA in patients after HCT. This was demonstrated in a recently published study that examined seven complement regulatory genes in a cohort of patients with TA-TMA. In this study, 65% of patients with TMA post-HCT had variants in these genes compared with only 9% in the patients without TA-TMA. This supports the concept that the presence of complement gene variants predisposes patients to develop TA-TMA. Taken together, these findings demonstrate the important role of complement dysregulation in the pathogenesis of TA-TMA.

Clinical presentation

Diagnosis

TA-TMA is a disease process that typically involves multiple organ systems owing to systemic endothelial injury and requires a high index of clinical suspicion. Several features of TA-TMA may be related to the HCT process itself rather than a distinct disease entity. Tissue diagnosis remains the gold standard but obtaining tissue specimens from HCT patients who are critically ill and at high risk of bleeding is often not feasible. As mentioned previously, kidney biopsies show the presence of thrombotic microangiopathy, including glomerular injury with thickened capillary loops, thrombotic lesions in small vessels, presence of endothelial injury, and fragmented RBC within mesangial matrix. Other organs, such as the GI tract and lung, have demonstrated similar TMA-related changes within tissue specimens. Published diagnostic criteria to assess risk of TMA are based on at least four different consensus criteria that have the common features of an elevated LDH, schistocytes on peripheral smear, in addition to anemia or thrombocytopenia. More recently, new diagnostic criteria for TA-TMA have been proposed that include either a tissue diagnosis of TMA in the affected organ or a combination of proteinuria, HTN, de novo anemia, de novo thrombocytopenia, LDH, evidence of microangiopathy, such as schistocytes, or terminal complement activation. The various published diagnostic criteria are outlined in Table 11.1 . It is noteworthy that, although monitoring SCr is valuable, it is a late marker of kidney injury, especially in children and those with low muscle mass at baseline. Cystatin C measurement can help determine GFR more accurately and can be used in combination with creatinine in GFR estimation equations to monitor renal function. However, the utility of cystatin C can be limited by factors, such as steroid use, inflammation, and thyroid disease.

Table 11.1

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