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

15

Chronic Kidney Disease, End-Stage Renal Disease, and Bone Marrow Transplant CLAUDE BASSIL

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%.1–4 It develops from 6 months to 10 years5,6 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 colleagues4 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.7–9 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.10 Albuminuria at day 100 post-HSCT was associated with CKD at 1 year,10 as defined by a glomerular filtration rate (GFR) below 60 mL/ min/1.73 m2, using the abbreviated modification of diet in renal disease equation, after adjusting for chronic GVHD (c-GVHD), HTN, diabetes, and age. In addition, Hingorani 118

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.11 An elevated urinary elafin level is associated with both acute kidney injury and CKD.11 Furthermore, albuminuria and proteinuria within the first 100 days post-HSCT are associated with decreased overall survival.12

Relationship Between GraftVersus-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 CD31 T cells, and expression of vascular adhesion molecules were seen, which favor an underlying endothelial injury.13 Furthermore, Mii and colleagues14 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.15,16 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: n

n n n

Transplant associated thrombotic microangiopathy (TATMA) also known as bone marrow transplant nephropathy. Nephrotic syndrome. Viral infections and renal diseases. Idiopathic: includes “progression of old acute injury,” and “multifactorial” CKD category.

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Table 15.1  Association Between Different Urinary Cytokines, Albuminuria, and Acute Kidney Disease/ Chronic Kidney Disease11,12 Cytokines

Association

*

IL-6 and IL-15

Microalbuminuria and persistent macroalbuminuria

Elafin

Development of micro- and macroalbuminuria, AKI, and CKD

MCP-1

Development of CKD at 1 year post-HSCT

AKI, Acute kidney injury; CKD, chronic kidney disease; HSCT, hematopoietic stem cell transplantation; *IL, interleukin; MCP-1, monocyte chemoattractant protein-1.

varies widely, ranging from 0.5% to 63%.17 This wide variation can be explained by the diagnostic uncertainty of TA-TMA criteria among many cancer centers. Jodele and her colleagues18 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%.19,20 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,21–28 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 #

A

B Fig. 15.1  Elafin staining in hematopoietic cell transplantation and control kidney samples. A. Intermediate-power image shows positive staining in a subset of tubules and negative glomerulus (arrowhead). This case demonstrated several patterns, including diffuse finely (*) and coarsely (upper right and lower left) granular, as well as coarse   luminal granules (#) (3,39-diaminobenzidine; original magnification, 3200). B. Finely granular cytoplasmic staining was most commonly diffusely distributed within the cytoplasm. (From Hingorani SFL, Pao E, Lawler R, Schoch G, McDonald GB, Najafian B, et al. Urinary elafin and kidney injury in hematopoietic cell transplant recipients. Clin J Am Soc Nephrol. 2015;10: 12–20.)

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

Many proposed definitions of TA-TMA have been used, but the most relevant criteria used to diagnose TA-TMA18,29–31 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.32 Renal manifestations of TA-TMA include: impaired GFR; proteinuria; and HTN.33,34 The definitive diagnosis of renal associated thrombotic microangiopathy requires a tissue biopsy, because many kidney diseases share clinical similarities with TA-TMA. 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 Criteria29

Schistocytes

 2 per high power field

Elevated LDH

1

1

Thrombocytopenia

2

1

Decreased hemoglobin   or need for transfusion

2

1

Negative Coombs test

1

1

Decreased haptoglobin

2

1

Renal dysfunction

1

2

Neurologic dysfunction

1

2

IWG Criteria . 4%

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

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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. 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. “1” refers to included in the guidelines and “–” refers to not included. A

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 reninangiotensin 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.32,37,38 However many reported serious side effects were associated with this therapy, including bleeding, infections, and hypotension.

B Fig. 15.2  ​Pathologic changes in the kidney caused by acute and chronic thrombotic microangiopathy. A. The glomerulus has capillary congestion with focal mesangial lysis and extensive fibrin thrombi   (arrow). Membrane duplication is visible only in rare segments (Jones’s methenamine silver stain, high magnification). B. The normocellular glomerulus has diffuse membrane duplication (arrows) and narrowed capillary lumens (hematoxylin and eosin, high magnification).  (From Hingorani S. Renal Complications of Hematopoietic-Cell Transplantation. N Engl J Med. 2016;374: 2256–2226.)

Daclizumab39 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.38,40,41 However, eculizumab is the only drug with promising results, because of the relevant role of complement activation mechanism in the pathogenesis of TATMA. Eculizumab was used in a total of 25 patients33,42–44 with a 67% response rate and two reported side effects,

Table 15.3  Pathologic Findings from Kidney Biopsies in Patients With Transplant-Associated Thrombotic Microangiopathy (see Fig. 15.1A) TA-TMA Light microscopy

n n n n n n

Immunofluorescence

n

Electron microscopy

n n

Glomerular endothelial swelling Basement membrane (BM) duplication Mesangiolysis with diffuse arteriolonecrosis35 Occluded vascular lumens Tubular injury with interstitial fibrosis36 Formation of inner glomerular BM leading to the classic double contour appearance Negative for any immune complexes, although nonspecific staining may be seen with fibrin Arteriolar and/or glomerular thrombi with subendothelial space widening36 Extensive or focal podocyte foot effacement36

TA-TMA, Transplant-associated thrombotic microangiopathy.

15  •  Chronic Kidney Disease, End-Stage Renal Disease, and Bone Marrow Transplant

Suspected TMA: Elevated LDH Proteinuria Hypertension (requiring > 2 medications)

Screen for TMA: Daily CBC Twice weekly LDH Weekly urinalysis Routine BP assessment

121

MPGN 5.2% FSGS 7.7% IgA nephropathy 2.6%

Diagnosis of TMA: LDH above normal Schistocytes Thrombocytopenia Anemia Hypertension Proteinuria

MCD 19.0%

MGN 65.5% Both absent

Prognosis of TMA: Proteinuria ≥ 30 mg/dL sC5b-9 above normal

Continue clinical monitoring

Both present Consider treating with eculizumab

One present Case-by-case decision based on severity of TMA

Complement assessment (genes, functional studies)

Fig. 15.3  ​Algorithm for the evaluation of thrombotic microangiopathy (TMA) after hematopoietic stem cell transplantation (HSCT). Screening for TMA includes monitoring lactate dehydrogenase (LDH), complete blood count (CBC), and routine urinalyses. TMA should be suspected in HSCT recipients with an acute elevation of LDH, proteinuria greater than 30 mg/dL, and hypertension more severe than expected with calcineurin or steroid therapy, usually requiring more than 2 antihypertensive medications. Clinical interventions should be considered for patients with both proteinuria . 30 mg/dL and elevated sC5b-9. BP, Blood pressure. (From Jodele S, Davies SM, Lane A, Khoury J, Dandoy C, Goebel J, et al. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood. 2014; 124: 645–653.)

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 (p5.007).43

Nephrotic Syndrome c-GVHD is well described in many organs, but the effect on the kidney is not well recognized. A review of the literature supports the existence of r-GVHD, associated clinically with nephrotic syndrome (NS). Most of the case reports found temporal associations of glomerular alterations with GVHD and tapering of immunosuppressive agents, used for GVHD prophylaxis.45 The common pathologic lesions found on kidney biopsies in these patients were membranous nephropathy (MGN) in two-thirds of the cases followed by minimal change disease (MCD)45–47 (Fig. 15.4). c-GVHD is a

Fig. 15.4  ​Renal pathology observed in nephrotic syndrome after hematopoietic stem cell transplantation. MPGN indicates membranoproliferative glomerulonephritis. FSGS, IgA, immunoglobulin A; MCD, minimal change disease; MGN, membranous nephropathy.  (From Beyar-Katz O, Davila E, Zuckerman T, Fineman R, Haddad N, Okasha D, et al. FSGS: focal and segmental glomerulosclerosis. Adult nephrotic syndrome after hematopoietic stem cell transplantation: renal pathology is the best predictor of response to therapy. Biol Blood Marrow Transplant. 2016; 22: 975–981.)

well-described entity occurring postallogeneic HSCT, but its pathophysiology is poorly understood. Experimental models of c-GVHD showed that autoantibody formation plays a prominent role in the pathophysiology of the disease. But despite the murine models of c-GVHD, where renal involvement was described, the same findings may not be clearly identified in humans. However, most patients with c-GVHD have evidence of autoantibodies to several cell surface, intracellular antigens,48,49 and against minor histocompatibility antigens, which may play a major role in the pathogenesis of c-GVHD in humans.50–52

EPIDEMIOLOGY NS post-HSCT is extremely rare, with an incidence around 1%;46–54 however, NMAT HSCT is associated with a higher incidence of NS at 6%.55 Colombo et al. found a NS incidence of 8% in patients with c-GVHD, with a markedly higher probability in patients who received peripheral blood stem cells compared with bone marrow cells.56

PATHOLOGY The development of NS usually happens in the late posttransplant period more than 6 months post-HSCT.57 The two most common renal pathologies for NS post-HSCT are MGN (Fig. 15.5) in two-thirds of the cases followed by MCD.

PATHOPHYSIOLOGY In general, NS develops after the cessation or tapering of immunosuppressive therapy, which suggests that NS could be a

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proteinuria reducing agents, hyperlipidemia treatment, and anticoagulation for high-risk patients. Renal pathology is needed to guide the specific treatment; however, because of the risk of biopsy in thrombocytopenic patients, one should consider the empiric treatment of corticosteroids, if the kidney biopsy is contraindicated (Fig. 15.6). If the kidney biopsy showed MCD, corticosteroids will be initiated, however the MCD post-HSCT may be more resistant, compared with non-HSCT patients,66,67 and other immunomodulatory agents will be needed, such as CNIs. MGN post-HSCT has less favorable response rate with corticosteroids alone and it should be combined with additional agents like idiopathic MGN.39 With the aforementioned modalities, complete remission is achieved in 63.5% of NS patients.68 In refractory NS post-HSCT, patients were successfully treated with rituximab.47,50

A

Viral Infections B Fig. 15.5  A. A normocellular glomerulus with slightly thickened basement membranes and barely visible membrane spikes. The beadlike hyalinosis (arrow) of the artery may be a result of treatment with calcineurin inhibitors (periodic acid-Schiff, medium magnification). B. An electron micrograph of the same kidney-biopsy specimen shows scattered epimembranous and intramembranous electron-dense deposits (arrow) and effacement of the foot process focally (uranyl acetate). (From Hingorani S. Renal Complications of Hematopoietic-Cell Transplantation. N Engl J Med. 2016;374: 2256–2226.)

manifestation of c-GVHD. Many hypotheses were proposed to explain the pathophysiology of NS post-HSCT (Table 15.4).

TREATMENT It is unclear whether the same management used in idiopathic NS works for NS post-HSCT. In general, nonspecific therapy is adopted by initiating the angiotensin-converting enzyme inhibitors or angiotensin receptor blockers as

Viral infections post-HSCT can be associated with renal diseases. The two most common viruses associated with renal diseases are adenovirus (AdV) and BK virus (BKV).

ADENOVIRUS The incidence of AdV infection in HSCT patients is variable between 9% and 31.3%.69–72 Early diagnosis and effective treatment are essential in treating systemic adenovirus infection, to avoid severe complications. Furthermore, the diagnosis of AdV disease requires the presence of prodromal symptoms, including hemorrhagic cystitis, fever, urodynia, and hematuria, in addition to the AdV isolation and/or frequent detection of the AdV genome by polymerase chain reaction in urine/sera. Primary infections, transmission with a transplant organ, or reactivation of a latent infection are the different modes of transmission of AdV. AdV nephritis can be complicated by renal failure in 90% of infected patients.42 Pathologic features of AdV nephritis include: interstitial nephritis, with the presence of viral inclusions in tubular cells; presence of granulomas around the tubules; and in severe cases, it can present as necrotizing

Table 15.4  Pathophysiology of Nephrotic Syndrome Posthematopoietic Stem Cell Transplantation Theory Murine   models T cells

Mechanism n

n

n

B cells

n

n

Cytokines

n n

Role for T/B Cells or Cytokines Dysregulation of B and T cells59 Dysregulation of cytokines59

Membranous changes in the recipient kidney after donor lymphocyte infusion58

n

Alloreactive donor T cells (ADT) targets host major and/or minor histocompatibility antigens60 ADT targets the kidney and induce podocyte expression of CD80, mainly in MCD61

n n

Role for alloreactive T cells Levels of regulatory T cells are lower in NS HSCT patients compared with non-NS62

Role of B cells in c-GVHD: dysregulation of B cells with high prevalence of autoantibodies63 Improvement of MGN post-rituximab64

n

Dysregulation of B cells in c-GVHD

n

Role of TNF-a and IFN-g in NS

Association between TNF-a (from allogeneic T cells) and NS62 TNF-a and IFN-g higher level in NS65

n

c-GVHD, Chronic graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; INF-g, interferon g; MCD, minimal change disease; MGN, membranous nephropathy; NS, nephrotic syndrome; TNF-a, tumor necrosis factor a.

15  •  Chronic Kidney Disease, End-Stage Renal Disease, and Bone Marrow Transplant

123

Proteinuria > 3.5 g/24h

Contraindication to kidney biopsy

No

Initiate Cs/increase Cs dose up to 1 mg/kg

Yes

MCD Reassessment of proteinuria after 12–16 weeks

Initiate Cs/increase Cs dose up to 1 mg/kg

MGN

Other pathology

Reassessment of proteinuria after 12–16 weeks

Cs and CNIs or other immunomodulatory therapy (MMF, rituximab)

Cs and CNIs or other immunomodulatory therapy (MMF, rituximab)

NR#

CR or PR*

Add CNIs or other immunomodulatory therapy (MMF, rituximab)

Continue Cs with slow tapering down

NR#

CR or PR*

Add CNIs or other immunomodulatory therapy (MMF, rituximab)

Continue Cs with slow tapering down

Fig. 15.6  ​Management of nephrotic syndrome after hematopoietic stem cell transplantation. CR or PR*, Complete response defined as a reduction in proteinuria levels greater than 5 g/day, and partial response defined as a reduction in proteinuria greater than 50% relative to baseline values; Cs, corticosteroid; CNIs, calcineurin inhibitors; MMF, mycophenolate mofetil; NR#, no reduction in proteinuria level. (From Beyar-Katz O, Davila E, Zuckerman T, Fineman R, Haddad N, Okasha D, et al. Adult nephrotic syndrome after hematopoietic stem cell transplantation: renal pathology is the best predictor of response to therapy. Biol Blood Marrow Transplant. 2016; 22: 975–981.)

tubulointerstitial nephritis.73 Moreover, adenovirus nephritis can lead to ureteral obstruction and hydronephrosis.73,74 Cidofovir is commonly used to treat life-threatening AdV infections, with similar pharmacokinetics between pediatric patients and adults.75

BK NEPHRITIS AND HEMORRHAGIC CYSTITIS (Fig. 15.7) Polyomavirus nephropathy (PVN) has been more reported as a cause of renal failure in native kidneys post-HSCT. It is often underdiagnosed, because CKD post-HSCT is usually attributed to other etiologies. Moreover, patients with BKV infection do not have any prodromal symptoms, and high degree of suspicion is needed. After a primary infection in early childhood, BKV appears to establish latency in

the genitourinary tract.76 After immunosuppression, asymptomatic viral replication occurs, as manifested by a viruria, and some patients will progress to invasive infection of the kidney, termed PVN. BKV infection causes several clinical manifestations in addition to nephropathy and hemorrhagic cystitis.77 For the diagnosis of PVN (polyomavirus), high BK viral loads in the urine and the blood, and the presence of decoy cells, will help as a potential diagnostic surrogate; however the final diagnosis of PVN is confirmed by a kidney biopsy. Renal histopathologic changes of PVN include: tubulointerstitial nephritis,78,79 with interstitial inflammation; tubular injury; and tubulitis. SV40 stains positively in the tubulointerstitium, showing viral inclusions. Moreover, BKV can cause hemorrhagic cystitis, urethritis, and urinary tract obstruction. The severity of renal damage has been shown to be dependent on the

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End-Stage Renal Disease PostHematopoietic Stem Cell Transplantation

A

B Fig. 15.7  Viral infections and chronic kidney disease. BK virus nephropathy. A. Many tubular epithelial cells are enlarged and have marginalized nuclear chromatin (arrow); detached and necrotic epithelial cells mixed with debris fill tubular lumens (hematoxylin and eosin, medium magnification). Several enlarged tubular epithelial cells (arrow) and parietal epithelial cells of Bowman’s capsule B. are stained positively with antibodies against simian virus 40 (arrowheads) (3,39-diaminobenzidine, high magnification). (From Hingorani S. Renal Complications of HematopoieticCell Transplantation. N Engl J Med. 2016;374: 2256–2226.)

BK viral load.80 The treatment of PVN consists of reduction of the immunosuppression, and substitution of mammalian target of rapamycin inhibitors for CNI and mycophenolate. Cidofovir can be tried in some patients with severe hemorrhagic cystitis.81 Because of the nephrotoxicity of cidofovir, its use is limited in the management of PKN despite the hydration and the use of probenecid to decrease its nephrotoxicity.82

Idiopathic Chronic Kidney Disease

Patients with HSCT who progress to ESRD requiring dialysis have worse survival, approaching 90%.85 Unfortunately, only few analyses in the literature have studied the outcomes of ESRD patients with HSCT. In a retrospective study of 1341 HSCT patients, 1.4% developed ESRD at a frequency 16 times higher than the expected age-adjusted rate.86 Moreover, Ando et al. found in their retrospective study a 4% risk of progression to ESRD in CKD patients who received MAT HSCT for lymphohaematologic malignancies.87 In another analysis, Cohen et al.85 found that ESRD patients with HSCT have worse survival as compared with non-HSCT diabetic patients, matched for age and start date of dialysis. Renal transplantation is an option for patients with ESRD after HSCT. The recipient requires little or no immunosuppression if the bone marrow and the kidney are from the same donor, because of the immunologic donor of the allograft.88,89 The short-term results, in a report of six cases by Butcher,3 showed good survival, but long-term follow-up is unknown. The major complications seen in recipients who needed immunosuppression include infections and malignancy, which raises the question whether a reduction in immunosuppression may be beneficial in HSCT patients who undergo kidney transplant.88

Summary CKD post-HSCT appears to be multifactorial rather than caused by one pathophysiologic process. CKD post-HSCT appears less related to TBI or CNIs, but it is more related to ARF and GVHD. However, CNIs may potentiate the renal damages caused by the systemic inflammation related to GVHD in other organs, and the kidney itself may be the host in GVHD. In conclusion, it is essential for us to understand the pathogenic mechanisms of CKD post-HSCT, so that we can design targeted therapies, and therefore improve the prognosis of CKD post-HSCT.

Key Points n

If the patients with CKD post-HSCT do not meet the criteria for TMA or NS, and they do not have BKV or AdV infections, their CKD will be considered as idiopathic. The incidence of idiopathic CKD post-TMA is around 17.5%,3 and up to 66% in NMAT.2 Major risk factors associated with idiopathic CKD post-MAT include acute and chronic GVHD and ARF,2,3 but for NMAT, other risk factors were described: CKD; old autologous transplant; and CNI use.2,3 The associations between GVHD and idiopathic CKD may be explained by the T cell-mediated renal damage, or via the inflammatory and cytokine cascade.83,84 CNI nephrotoxicity may be exacerbated in the presence of chronic inflammatory process. CKD post-HSCT appears more as multifactorial in origin, related to GVHD, chronic inflammatory process, and exacerbated by nephrotoxic medications.

n

n n

n

Chronic kidney disease post-hematopoietic stem cell transplantation (HSCT) appears as multifactorial in origin, related to graft-versus-host disease, chronic inflammatory process, and exacerbated by nephrotoxic medications. Intrarenal inflammation after HSCT is identified by an elevated urinary level of proinflammatory cytokines (interleukin [IL]-6, IL-15, and elafin), which are associated with the development of albuminuria and proteinuria. Hypertension is the earliest sign of TA-TMA. Rituximab may have a role in refractory nephropathic syndrome post-HSCT. Renal transplantation is an option for patients with endstage renal disease following HSCT, and the recipient requires little or no immunosuppression if the bone marrow and the kidney are from the same donor.

15  •  Chronic Kidney Disease, End-Stage Renal Disease, and Bone Marrow Transplant

References 1. Cohen EP. Radiation nephropathy after bone marrow transplantation. Kidney Int. 2000;58:903-918. 2. Weiss AS, Sandmaier BM, Storer B, Storb R, McSweeney PA, Parikh CR. Chronic kidney disease following non-myeloablative hematopoietic cell transplantation. Am J Transplant. 2006;6:89-94. 3. Hingorani S. Risk factors for chronic kidney disease after hematopoietic cell transplant. Biol Blood Marrow Transplant. 2005;11:72-73. 4. Hingorani S, Guthrie KA, Schoch G, Weiss NS, McDonald GB. Chronic kidney disease in long-term survivors of hematopoietic cell transplant. Bone Marrow Transplant. 2007;39:223-229. 5. Ileri T, Ertem M, Ozcakar ZB, et al. Prospective evaluation of acute and chronic renal function in children following matched related donor hematopoietic stem cell transplantation. Pediatr Transplant. 2010; 14:138-144. 6. Abboud I, Porcher R, Robin M, et al. Chronic kidney dysfunction in patients alive without relapse 2 years after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009; 15:1251-1257. 11. Hingorani S, Finn LS, Pao E, et al. Urinary elafin and kidney injury in hematopoietic cell transplant recipients. Clin J Am Soc Nephrol. 2015;10:12-20. 12. Hingorani S, Gooley T, Pao E, Sandmaier B, McDonald G. Urinary cytokines after HCT: evidence for renal inflammation in the pathogenesis of proteinuria and kidney disease. Bone Marrow Transplant. 2014;49: 403-409. 13. Sadeghi B, Al-Chaqmaqchi H, Al-Hashmi S, et al. Early-phase GVHD gene expression profile in target versus non-target tissues: kidney, a possible target? Bone Marrow Transplant. 2013;48:284-293. 14. Mii A, Shimizu A, Kaneko T, et al. Renal thrombotic microangiopathy associated with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Pathol Int. 2011;61:518-527. 17. George JN, Li X, McMinn JR, Terrell DR, Vesely SK, Selby GB. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma. Transfusion. 2004; 44:294-304. 18. Jodele S, Davies SM, Lane A, et al. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood. 2014;124:645-653. 19. Willems E, Baron F, Seidel L, Frère P, Fillet G, Beguin Y. Comparison of thrombotic microangiopathy after allogeneic hematopoietic cell transplantation with high-dose or nonmyeloablative conditioning. Bone Marrow Transplant. 2010;45:689-693. 21. Ye Y, Zheng W, Wang J, et al. Risk and prognostic factors of transplantation associated thrombotic microangiopathy in allogenic hematopoietic stem cell transplantation: a nested case control study. Hematol Oncol. 2017;35:821-827. 22. Uderzo C, Bonanomi S, Busca A, et al. Risk factors and severe outcome in thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. Transplantation. 2006;82:638-644. 23. Daly AS, Hasegawa WS, Lipton JH, Messner HA, Kiss TL. Transplantation-associated thrombotic microangiopathy is associated with transplantation from unrelated donors, acute graft-versus-host disease and venoocclusive disease of the liver. Transfus Apher Sci. 2002;27:3-12. 29. Ho VT, Cutler C, Carter S, et al. Blood and Marrow Transplant Clinical Trials Network Toxicity Committee Consensus Summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005;11:571-575. 30. Ruutu T, Barosi G, Benjamin RJ, et al. Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an international working group. Hematologica. 2007;92:95-100. 31. Cho BS, Yahng SA, Lee SE, et al. Validation of recently proposed consensus criteria for thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. Transplantation. 2010;90: 918-926. 32. Laskin BL, Goebel J, Davies SM, Jodele S. Small vessels, big trouble in the kidneys and beyond: hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Blood. 2011;118:1452-1462. 33. Jodele S, Laskin BL, Dandoy CE, et al. A new paradigm: diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev. 2015;29:191-204. 34. Hoffmeister PA, Hingorani SR, Storer BE, Baker KS, Sanders JE. Hypertension in long-term survivors of pediatric hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2010;16:515-524.

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125.e1

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Abstract Chronic kidney diseases (CKD) posthematopoietic stem cell transplantation (HSCT), lead to significant morbidity and mortality, approaching 90% in patients who progress to end-stage renal disease (ESRD) requiring dialysis. The different mechanisms leading to the spectrum of CKD postHSCT, remain poorly understood. Patients undergoing HSCT are living longer, so the prevalence of CKD will continue to grow. CKD post-HSCT appears to be multifactorial rather than caused by one pathophysiologic process. CKD post-HSCT appears less related to total body irradiation or calcineurin inhibitors (CNIs), but it is more related to acute renal failure and graft-versus-host disease (GVHD). However, CNIs may potentiate the renal damages caused by the systemic inflammation related to GVHD in other organs, and the kidney itself may be the host in GVHD. If thrombotic microangiopathy (TA-TMA) is suspected, before

holding CNIs, treatment of GVHD may be indicated, as it may be the cause of the endothelial injury. Complement activation may have a significant role in the pathogenesis of TA-TMA, and eculizumab is currently the only drug with promising results; with 67% response rate. If a patient with HSCT develops proteinuria exceeding 3.5 g/24 hours at day 100, a kidney biopsy is required if adenovirus or BK virus associated renal diseases are ruled out. In conclusion, it is essential for us to understand the pathogenic mechanisms of CKD post-HSCT, so that we can design targeted therapies, and therefore improve the prognosis of CKD post-HSCT.

Keywords CKD post-HSCT: chronic kidney diseases post-HSCT; TA-TMA: thrombotic microangiopathy; GVHD: graftversus-host disease