Chronic kidney disease, end-stage renal disease, and bone marrow transplant

Introduction

Hematopoietic stem cell transplantation (HSCT) is commonly used as a treatment for malignant and nonmalignant diseases. Over the past decade, there has been more focus on the chronic complications post-HSCT, in particular chronic kidney disease (CKD), which is associated with high mortality in this population, especially in patients who progress to end-stage renal disease (ESRD) requiring dialysis. Although the HSCT may be curative of the underlying malignancy, it trades one set of problems with many chronic conditions associated with CKD.

The incidence of CKD post-HSCT is variable and ranges from 13% to 66%. It develops from 6 months to 10 years ^, post-HSCT. The etiologies of CKD post-HSCT are not well identified; however, the occurrence of CKD has been associated with many risk factors.

Hingorani and her colleagues have shown in a cohort study that the presence of acute renal failure (ARF) and graft-versus-host disease (GVHD), but not total body irradiation (TBI), were associated with the occurrence of CKD. Similar findings were duplicated in other clinical studies. The variability in incidence rates of CKD, in adult and pediatric populations, likely reflects a lack of a standard definition of post-HSCT CKD. Differences are further compounded by the different HSCT modalities (autologous vs. allogeneic) and differences in the variable periods of follow-up.

Albuminuria and chronic kidney disease after hematopoietic stem cell transplantation

Albuminuria, defined as a urine albumin:urine creatinine ratio (ACR) of 30 to 300 mg/g, is commonly used as a surrogate marker of systemic endothelial dysfunction and inflammation, affecting many organs, including the kidney. Albuminuria occurs frequently after HSCT and it correlates with acute GVHD (aGVHD), bacteremia, hypertension (HTN), and progression of renal disease. Albuminuria at day 100 post-HSCT was associated with CKD at 1 year, as defined by a glomerular filtration rate (GFR) below 60 mL/min/1.73 m ² , using the abbreviated modification of diet in renal disease equation, after adjusting for chronic GVHD (c-GVHD), HTN, diabetes, and age. In addition, Hingorani and colleagues proposed a possible intrarenal inflammation after HSCT, by identifying elevated urinary levels of proinflammatory cytokines (interleukin [IL]-6, IL-15, and elafin), which were associated with the development of albuminuria and proteinuria ( Table 15.1 and Fig. 15.1 ). Urinary elafin is an endogenous serine protease inhibitor, produced by epithelial cells and macrophages in response to tissue inflammation. An elevated urinary elafin level is associated with both acute kidney injury and CKD. Furthermore, albuminuria and proteinuria within the first 100 days post-HSCT are associated with decreased overall survival.

Relationship between graft-versus-host disease and chronic kidney disease

A formal pathologic criterion of proper renal GVHD (r-GVHD) does not exist yet. However, a probable relationship between GVHD and kidney injury may be demonstrated. In a mouse model of GVHD, many changes were described, highlighting an immune-mediated renal injury. There was an upregulation of antigen presenting pathways in the kidney, adaptive and innate immune responses. In addition, infiltration of the kidney by CD3+ T cells, and expression of vascular adhesion molecules were seen, which favor an underlying endothelial injury. Furthermore, Mii and colleagues described the kidney as a potential target of c-GVHD by identifying renal tubulitis, peritubular capillaritis, and glomerulitis. In addition to the T-cell infiltration, the kidney may be the target of chronic inflammatory state of GVHD, which may lead to renal injury. Several proinflammatory cytokines were seen in the urine of these patients. ^,

In the majority of cases of CKD post-HSCT, the cause is either idiopathic or multifactorial. However, several clinical syndromes of CKD in long-term survivors of HSCT have been proposed and that include:

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  Transplant associated thrombotic microangiopathy (TA-TMA) also known as bone marrow transplant nephropathy .

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  Nephrotic syndrome.

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  Viral infections and renal diseases.

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  Idiopathic: includes “progression of old acute injury,” and “multifactorial” CKD category.

TA-TMA category

TA-TMA is a serious complication, associated with higher morbidity and mortality compared with other complications occurring post-HSCT. Patients who survive the TA-TMA course end up with long-term morbidity and chronic organ injury, including CKDs or ESRDs.

Although the exact pathogenic mechanism resulting in TA-TMA is not well identified, significant advances have been made. The complement activation plays a significant role in the pathogenesis, and TA-TMA may coincide and be an endothelial variant of GVHD. The incidence of TA-TMA varies widely, ranging from 0.5% to 63%. This wide variation can be explained by the diagnostic uncertainty of TA-TMA criteria among many cancer centers. Jodele and her colleagues reported an incidence of 39% in their prospective study, but the incidence of TA-TMA in many other retrospective studies ranges around 15% to 18%. ^, Many reported risks factors have been associated with the development of TA-TMA after allogeneic HSCT, in particular aGVHD (especially grade 2–4) and unrelated donor type, in addition to other important risk factors including: older age; female sex; advanced primary cancer disease; unrelated donor transplants; conditioning regimen (high-dose busulfan—16 mg/kg), human leukocyte antigen mismatch, nonmyeloablative transplants (NMAT), TBI, cyclosporine or tacrolimus use, rapamycin inhibitor use, aGVHD, and other infections.

Clinical presentation and diagnosis

Many proposed definitions of TA-TMA have been used, but the most relevant criteria used to diagnose TA-TMA ^, are Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) and International Working Group (IWG) criteria ( Table 15.2 ). TA-TMA should be diagnosed in patients who present with hemolytic anemia, excessive transfusion requirements, thrombocytopenia, elevated lactate dehydrogenase (LDH), and presence of schistocytes on the peripheral smear. If TA-TMA is described on a kidney biopsy, no further criteria need to be met. However, if there is elevated LDH, proteinuria (random urinalysis protein concentration of ≥ 30 mg/dL), and HTN, closer monitoring is required. Although biochemical parameters are important in early diagnosis, the earliest sign of TA-TMA is HTN. Therefore a high degree of suspicion is needed in an HSCT recipient who requires more than two antihypertensive medications until proven otherwise. Renal manifestations of TA-TMA include: impaired GFR; proteinuria; and HTN. ^,

Table 15.2

Diagnosis of Hematopoietic Stem Cell Transplantation-Associated Thrombotic Microangiopathy: Blood and Marrow Transplant Clinical Trials Network and International Working Group Criteria

Test	BMT-CTN Criteria	IWG Criteria
Schistocytes	≥ 2 per high power field	> 4%
Elevated LDH	+	+
Thrombocytopenia	−	+
Decreased hemoglobin or need for transfusion	−	+
Negative Coombs test	+	+
Decreased haptoglobin	−	+
Renal dysfunction	+	−
Neurologic dysfunction	+	−

HSCT , Hematopoietic stem cell transplantation; LDH , lactate dehydrogenase; TMA , thrombotic microangiopathy.

The definitive diagnosis of renal associated thrombotic microangiopathy requires a tissue biopsy, because many kidney diseases share clinical similarities with TA-TMA. However, because of the increased risk of bleeding in HSCT patients, kidney biopsies are rarely done.

For the pathologic findings associated with TA-TMA see Table 15.3 and Fig. 15.2 .

Table 15.3

Pathologic Findings from Kidney Biopsies in Patients With Transplant-Associated Thrombotic Microangiopathy (see Fig. 15.1 A)

	TA-TMA
Light microscopy	■ Glomerular endothelial swelling ■ Basement membrane (BM) duplication ■ Mesangiolysis with diffuse arteriolonecrosis ■ Occluded vascular lumens ■ Tubular injury with interstitial fibrosis ■ Formation of inner glomerular BM leading to the classic double contour appearance
Immunofluorescence	■ Negative for any immune complexes, although nonspecific staining may be seen with fibrin
Electron microscopy	■ Arteriolar and/or glomerular thrombi with subendothelial space widening ■ Extensive or focal podocyte foot effacement

TA-TMA , Transplant-associated thrombotic microangiopathy.

Various definitions for the diagnosis of transplant-associated thrombotic microangiopathy are employed.

Per BMT-CTN, IWG, all criteria are needed under each group of guidelines to make the diagnosis of TA-TMA. “+” refers to included in the guidelines and “–” refers to not included.

Treatment

A systematic approach to monitor and diagnose a patient with TA-TMA is needed ( Fig. 15.3 ). All patients with HSCT should be monitored closely every 2 to 4 weeks by checking their blood pressure, renal function, urinalysis, proteinuria, and LDH. If the patients are considered suspicious of having TA-TMA, their blood pressure and other biomarkers including hemoglobin, platelets, LDH, serum creatinine, and proteinuria should be monitored closely. Once the diagnosis of TA-TMA is certain, a kidney biopsy will be needed if no absolute contraindications exist, such as severe thrombocytopenia, hemodynamic instability, etc. However, if TA-TMA is unlikely, alternate causes of renal dysfunction, proteinuria, and HTN should be examined. If the diagnosis of TA-TMA is highly probable, supportive measures are needed, such as removal of precipitating factors, including calcineurin inhibitor (CNI), and/or sirolimus, and replacing them with other appropriate GVHD treatment/prophylaxis.

Because of the probable relationship between TA-TMA and GVHD, and the lack of conclusive data, stopping CNI may be harmful in a patient with life-threatening GVHD, but it may be acceptable in a mild TA-TMA case. Other supportive measures include: platelet and red blood cell transfusion, tight blood pressure control with renin-angiotensin pathway inhibitors, and renal support with various modalities of renal replacement therapy. In terms of immunomodulatory agents, data are limited and most of the treatment options include: plasmapheresis, with a variable response rate between 59% and 65%. The mechanism includes removal of potential inhibitor/antibody of the alternative complement cascade. ^{, ,} However many reported serious side effects were associated with this therapy, including bleeding, infections, and hypotension.

Daclizumab was reported in few cases as alternative to CNI, by blocking the IL-2 pathway, but skin rash, infections, and autoimmune diseases were reported as potential side effects of this therapy. Moreover, rituximab has been used successfully in 15 patients with an 80% response rate without major side effects, except infusion reactions and infections. ^{, ,} However, eculizumab is the only drug with promising results, because of the relevant role of complement activation mechanism in the pathogenesis of TA-TMA. Eculizumab was used in a total of 25 patients ^, with a 67% response rate and two reported side effects, including infections and bleeding. Furthermore, the patients with high risk TA-TMA, defined as patients with proteinuria and activated terminal complement pathway and multiorgan involvement, who received eculizumab, had a better survival than untreated patients (62% vs. 9%) at 1 year from TMA diagnosis ( p =.007).