Renal Disease Following Hematopoietic Stem Cell Transplantation

Type of conditioning

Donor relationship

CNI exposure

Risk of GVHD

Risk of AKI (%)

Risk of AKI requiring RRT (%)

Risk of Mortality if RRT (%)

Myeloablative

Allogeneic

High

Very high

> 80

Non-myeloablative

Allogeneic

High

> 80

Autologous

None

AKI acute kidney injury, CNI calcineurin inhibitors, GVHD graft versus host disease, RRT renal replacement therapy

The incidence of AKI after autologous HSCT ranges from 15 to 20 % [6–8]. The low incidence can be explained by the absence of GVHD, and therefore less use of calcineurin inhibitors. In addition, since engraftment occurs sooner, the time for which patients remain cytopenic is shorter, leading to a lower risk of sepsis and antibiotic exposure that can lead to AKI [8].

The risk factors for AKI in myeloablative transplantation are listed in Table 11.2 [9, 10]. Regardless of the setting of AKI, the degree of renal failure correlates with mortality [11, 12]. A meta-analysis of HSCT patients with AKI showed that AKI was independently associated with a twofold increase in mortality, which is even higher when dialysis therapy is required [11]. When AKI occurs in the first 100 days of the transplant, the mortality is higher, especially in the setting of non-myeloablative HSCT [11–14] .

Table 11.2

Risk factors associated with AKI following HSCT (based on references 5, 6, 9, 13)

Amphotericin B exposure
Early weight gain > 2 kg
Jaundice
Pre-transplant serum creatinine > 0.7 mg/dl
Veno-occlusive disease
GVHD grade 3–4
Sepsis
Lung toxicity
Acyclovir exposure
Calcineurin inhibitor exposure
Admission to intensive care unit

The most common causes of AKI after HSCT are sepsis, hypotension, and nephrotoxic antibiotics administered during the cytopenic interval [5]. Tumor lysis syndrome is rare but can be seen as an early cause of AKI following certain conditioning regimens. Prerenal insult from vomiting and diarrhea is not uncommon. Common nephrotoxins used in HSCT patients include methotrexate, amphotericin B, aminoglycosides, intravenous contrast, angiotensin-converting enzyme inhibitors, calcineurin inhibitors, and acyclovir [13].

Sinusoidal obstruction syndrome (SOS) , also known as veno-occlusive disease (VOD) of liver, is a serious complication following HSCT. The pathogenesis of SOS has been attributed to damage to hepatic sinusoids, and it typically presents with tender hepatomegaly, jaundice, fluid retention and weight gain, and hyperbilirubinemia following high-dose myeloablative conditioning therapy [15]. SOS occurs relatively early after HSCT, generally within the first 30 days. While the reported prevalence of SOS has ranged from 5 to 60 % of patients, the overall mean incidence of SOS is approximately 14 % [16] . SOS occurs more frequently after myeloablative allogeneic HSCT than after autologous HSCT and rarely occurs with non-myeloablative HSCT [17]. A number of risk factors for developing SOS have been identified, including preexisting liver disease [17], choice of conditioning regimens (particularly those including busulfan, cyclophosphamide, or total body irradiation) [17, 18], older age, certain medications (methotrexate, itraconazole, sirolimus, and norethisterone) [19–21], and an underlying diagnosis of osteopetrosis, primary hemophagocytic lymphocytosis, or adrenoleukodystrophy [15, 22].

Case #1 Follow-up and Discussion:

This patient shows signs and symptoms of sudden-onset portal hypertension following HSCT. Shortly after the onset of this presentation, an abdominal ultrasound with duplex sonography is performed, demonstrating reversal of portal venous flow. The patient is given a diagnosis of sinusoidal obstruction syndrome. The Correct Answer Is c.

Case #2

On day 16 post transplant, the serum total and direct bilirubin levels of the patient in the Case #1 are now 31.3 mg/dL (normal range 0–1.0 mg/dL) and 23.1 mg/dL (normal range 0–0.3 mg/dL), respectively. His weight has increased by 9 kg since admission. His nurse reports that he now appears more lethargic and is unable to answer questions appropriately. His daily urine output has begun to decrease from approximately 1.5 L to 400 mL, and his serum creatinine level has risen from a baseline of 0.9 mg/dL to 1.4 mg/dL in the past 24 h. Which diagnostic test finding would most likely be seen in this patient?

The presence of red blood cell casts in the urine sediment

A low fractional excretion of sodium

Blood cultures positive for Escherichia coli

A renal ultrasound demonstrating moderate bilateral hydronephrosis

AKI occurs to some extent in all patients with SOS, with as many as 50 % of patients developing severe AKI [23] and half of these requiring dialysis [24]. Patients with SOS-associated AKI present in a manner that is nearly identical to the hepatorenal syndrome. Early symptoms include sodium retention, peripheral edema, ascites, and weight gain, accompanied by liver dysfunction and hyperbilirubinemia. The onset of AKI, which typically ensues 10–16 days post HSCT, may be slow and progressive, and may be triggered by factors such as hypotension, sepsis, or exposure to nephrotoxic agents. Oliguria may be present, accompanied by a persistently low fractional excretion of sodium. Urinalysis with sediment is often bland but may sometimes reveal granular casts in patients who progress to developing tubular injury from hypotension or nephrotoxic agents. Evidence of intrinsic kidney lesions has not been seen on kidney biopsies or autopsies from patients with SOS, consistent with the understanding that SOS-associated AKI is most likely hemodynamic in pathophysiology [24]. Mortality rates with severe AKI are high, approaching 40 and 85 % in patients with a doubling of serum creatinine and those requiring dialysis, respectively [25] .

Case #2 Follow-up and Discussion:

This patient, as a consequence of his sinusoidal obstruction syndrome, has developed prerenal azotemia, secondary to hepatorenal-like physiology. His urine sodium level is nearly undetectable and his fractional excretion of sodium is < 1 %, consistent with his kidneys being in a sodium-avid state. The Correct Answer Is b.

While the mortality is high in patients with SOS and moderate-to-severe AKI, more than 70 % of patients with SOS recover with supportive management [15]. Upon diagnosis of SOS, prompt measures should be taken to maintain sodium and water balance, preserve renal blood flow, and manage peripheral edema and ascites with the judicious use of diuretics and therapeutic paracenteses as needed. In patients with large fluid intake requirements, fluid management can be particularly challenging, and renal replacement therapy may be necessary. In these circumstances, continuous modalities may be preferred .

Defibrotide is a single-stranded oligodeoxyribonucleotide with antithrombotic, profibrinolytic, and anti-ischemic properties, which has shown efficacy in the treatment and prevention of SOS [26–32]. Its use in severe SOS was first reported by Richardson and colleagues in 1998 in a compassionate use study of 19 patients, 8 of whom had resolution of SOS when treated with doses ranging from 5 to 60 mg/kg/day [33]. Phase II studies performed by the same group randomized adult and pediatric patients with SOS to lower dose (25 mg/kg/day) versus higher dose of (40 mg/kg/day) defibrotide every 6 hours for 14 days or until complete remission, progression of SOS, or severe toxicity was seen. The complete remission rate was 46 %, and no significant difference was found between the two doses [29]. Phase III studies are currently underway to evaluate the efficacy of defibrotide in both treatment and prevention of SOS. The main adverse effects of defibrotide include hemorrhage and hypotension .

Other agents used in the treatment of SOS with varying success include tissue plasminogen activator (TPA) and methylprednisolone. Infusion of heparin and/or ursodeoxycholic acid administered immediately before induction therapy may also be moderately successful as preventive measure.

Epidemiology and Incidence of Chronic Kidney Disease

The incidence of chronic kidney disease (CKD) after HSCT is variable and ranges from 13 to 66 % in adult studies [34–37]. The diagnosis of CKD in an HSCT patient is of great significance as these patients are at a higher risk of mortality despite being controlled for other comorbidities. The mortality is close to 90 % in patients who progress to end-stage renal disease and require dialysis [38]. Hingorani and colleagues demonstrated that the increased risk of CKD was associated with AKI post HSCT, as well as the presence of acute or chronic GVHD [39]. The authors suggest that the kidney is either a target organ of GVHD via a T cell-mediated process or an innocent bystander affected by the systemic inflammatory and cytokine cascade induced by GVHD. In animal models of GVHD, tissue destruction in acute GVHD does not require alloantigen expression on target epithelial cells for cellular toxicity and can be mediated by inflammatory cytokines [40]. The growth in the use of non-myeloablative protocols may also lead to an increase in prevalence of kidney disease as older patients with more comorbidities are getting transplanted. Another cause of CKD is the long-term exposure to calcineurin inhibitors.

For the purpose of this review we divide CKD post HSCT as:

Nephrotic syndrome

Thrombotic microangiopathy

Chronic calcineurin inhibitor nephrotoxicity

Viral infections and renal disease

Idiopathic CKD

Case #3

A 65-year-old male with a history of acute myelogenous leukemia for which he underwent a matched unrelated non-myeloablative HSCT 4 years ago is referred for nephrotic syndrome. His spot urine protein to creatinine ratio is consistent with 23 g of protein in 24 hours, and his serum albumin is 2 g/dL. His serum creatinine is stable at 1 mg/dL. A kidney biopsy is performed. Figure 11.1 shows the electron microscopy findings. The most likely diagnosis is:

Membranous nephropathy

Minimal change disease

IgA nephropathy

Focal segmental glomerulosclerosis

Fig. 11.1

Electron microscopy reveals electron-dense subepithelial deposits

Nephrotic Syndrome

There have been several case reports and case series of nephrotic syndrome (NS) developing post HSCT. The common histological lesions seen when these patients are biopsied are membranous nephropathy followed by minimal change disease. The two largest series in the literature describing NS after allogeneic HSCT are from Reddy and Terrier [41, 42].

Animal models of chronic GVHD describe the kidneys as a target organ with histopathological features of membranous nephropathy [43], however renal involvement in humans with chronic GVHD is not well established. A review of literature by Brukamp et al. [44] revealed a close temporal relationship between the development of NS shortly after cessation of immunosuppression and the diagnosis of chronic GVHD. The authors in this review support the existence of renal GVHD manifesting as NS clinically . When biopsied, 61 % of these patients had a membranous pattern of glomerular renal injury and 22 % had minimal change disease. Less common were focal segmental glomerulosclerosis and proliferative glomerulonephritis. It is proposed that chronic GVHD may precipitate glomerular disease via a complex donor T cell and host antigen-presenting cell interaction, or alternatively the donor stem cells may modulate disease activity of glomerulonephritis by means other than GVHD [44].

The pathophysiology of idiopathic membranous nephropathy has been linked to antibodies against the phospholipase A2 receptor (PLA2R), M type, expressed on podocytes. In a study recently published by Huang et al. [45], the clinical course of five patients was followed after HSCT. All five had biopsy-proven membranous nephropathy and evidence of chronic GVHD that was in remission. Of the five patients, four tested negative for anti-PLA2R antibodies, suggesting that the pathogenesis of HSCT-related membranous nephropathy may be different from that of idiopathic membranous nephropathy .

In the largest series published to date [46] consisting of retrospective analysis of 95 cases of HSCT-associated NS, the authors argue against chronic GVHD as a contributor to the pathogenesis of HSCT-associated glomerular diseases. In their study they noted that although chronic GVHD was common among the HSCT recipients with glomerular disease (72 %), this was no different from that observed in the overall HSCT population. Furthermore, their study showed no statistically significant association between cessation of immunosuppressive medication and onset of glomerular disease. A substantial number of patients (40 %) in this series developed glomerular disease while on immunosuppressive medication, and nearly a third of the patients were diagnosed with glomerular disease in the absence of concomitant GVHD. Similarly, a study from the National Institutes of Health reported a high incidence of NS in a cohort of 163 patients undergoing non-myeloablative HSCT from related HLA-compatible donors. About 7 of the 163 patients developed NS (four with membranous nephropathy), whereas no incident cases were reported in the myeloablative group. Thus, the authors did not find an association of GVHD with glomerular disease [47]. Of note, glomerular disease also develops in recipients of autologous HSCT, a setting in which GVHD cannot be explained as a possible pathogenic mechanism .

Minimal change disease is the second most common pathological diagnosis seen in HSCT recipients. In addition to this being a manifestation of glomerular injury related to GVHD or mediated by cytokines, recurrence of the primary malignancy (i.e., lymphoma) for which the patient underwent a stem cell transplant should be considered. In a case report of NS diagnosed as minimal change disease, there was increased production of TNF-alpha and IFN-gamma by the donor T cells with lack of cellular infiltrate, which suggested that the glomerular injury was secondary to cytokine production and stimulated by alloantigen in an extrarenal site [48].

Currently, no conclusion can be drawn on the pathogenesis of NS post HSCT. It seems likely this is a renal manifestation of chronic GVHD, although based on the current evidence there remain some unanswered questions, and more research is needed in this area .

Case # 3 Follow-up and Discussion:

The electron microscopy demonstrates subepithelial deposits typical of membranous nephropathy. Anti-phospholipase A2 receptor antibodies were negative in the serum and it was assumed that the patient had GVHD-associated membranous nephropathy and was started on immunosuppressive agents. The Correct Answer Is a.

Case #4

A 45-year–old Caucasian man with acute myelogenous leukemia is treated with cytarabine and daunorubicin (“7 + 3”) as induction chemotherapy prior to undergoing a mismatched related donor hematopoietic stem cell transplant from his younger brother. His conditioning regimen consists of cyclophosphamide and total body irradiation. He is started on prophylaxis against graft versus host disease (GVHD) with tacrolimus and sirolimus. Upon discharge from the hospital, his serum creatinine is 1.0 mg/dL. One month after his transplant, his creatinine increases to 2.3 mg/dL, accompanied by new-onset thrombocytopenia and elevated serum lactate dehydrogenase level. A few schistocytes are observed on his peripheral smear. His blood pressure has worsened in the interim as well. Which of the following etiologies best explains this patient’s acute kidney injury?

Volume depletion

Chronic graft versus host disease with renal involvement

Thrombotic microangiopathy

Cytarabine-associated nephrotoxicity

Thrombotic Microangiopathy

Thrombotic microangiopathy (TMA) , also known as bone marrow transplant nephropathy or radiation nephropathy, is a common cause of AKI in the HSCT patient. Prevalence rates in the literature have ranged widely from 0.5 to 76 %, though large retrospective studies have reported prevalence rates of 10–25 % [49]. HSCT-associated TMA can occur with both allogeneic and autologous HSCT [50, 51] and typically has an onset 20–99 days post transplant [52]. HSCT-associated TMA can present similarly to hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP) with anemia, thrombocytopenia, and renal insufficiency. The kidney is the most commonly affected organ, and injury outside the kidney is relatively rare but has been reported [49]. Though most patients have a mild form of disease that often leads to the development of CKD [53], a subset of patients present with a more severe form of TMA that is associated with high mortality [54]. Hypertension is often present. Patients usually have evidence of low-grade hemolysis with an elevated serum lactate dehydrogenase (LDH) level, low serum haptoglobin, and the presence of schistocytes on peripheral smear. Analysis of the urine may reveal hematuria and/or proteinuria or may be normal, and the urine sediment can also vary from being relatively bland to showing cellular casts.

The pathogenesis of HSCT-associated TMA , though not clearly understood, has been attributed to renal endothelial cell injury [55]. Multiple mechanisms of endothelial damage in the setting of HSCT-associated TMA have been proposed. One primary cause of renal endothelial damage is the HSCT conditioning regimen. Both myeloablative and reduced-intensity conditioning regimens—especially those employing busulfan, fludarabine, platinum-based agents, and total body irradiation (TBI)—have been shown to be risk factors for the development of HSCT-associated TMA [56–58]. An association between TBI and TMA has been suggested by studies in animals and humans which demonstrate that (1) the clinical presentation and histopathological features of HSCT-associated TMA are nearly identical to those seen in radiation nephritis, (2) the delayed onset of HSCT-associated TMA is similar to that of acute radiation nephritis following radiation exposure, (3) partial renal shielding during TBI decreases the incidence of HSCT-associated TMA from 26 to 6 %, and (4) fractionation of the radiation dose appears to reduce the risk of HSCT-associated TMA [24, 59–61] Recent retrospective data have also shown a correlation between TBI > 1200 cGy and HSCT-associated TMA [53] . While strategies to reduce radiation injury can be employed, they may decrease the efficacy of tumor cell eradication [24]. The next chapter in this book discusses radiation nephropathy in further detail.

Infections by a variety of pathogens, including Aspergillus, cytomegalovirus, adenovirus, parvovirus B19, human herpes virus-6, and BK virus, have also been linked to HSCT-associated TMA [49, 53, 62, 63]. Patients with viremia have been found to have increased levels of thrombomodulin, plasminogen activator inhibitor (PAI-1), and inflammatory cytokines—factors which may promote the development of TMA [49, 64]. Calcineurin inhibitors such as cyclosporine and tacrolimus are known to cause endothelial injury and TMA through several mechanisms, including direct cytotoxic damage, platelet aggregation, elevation in the levels of von Willebrand factor and thrombomodulin, alteration in proteins regulating complement pathways, and reduction in prostacyclin and nitric oxide production [49]. The addition of sirolimus to a calcineurin inhibitor may increase the risk of HSCT-associated TMA , possibly by impairing the repair of damaged endothelium or decreasing the local production of vascular endothelial growth factor (VEGF) [55]. GVHD in HSCT patients has also been shown to be associated with TMA, with mechanisms such as circulating inflammatory cytokines, direct endothelial cell injury from cytotoxic donor T lymphocytes, activation of coagulation pathways, and reduced levels of VEGF contributing to the development of endothelial damage [53]. While it has been proposed that HSCT-associated TMA may represent a form of renal or endothelial GVHD, there is no compelling evidence supporting this hypothesis. A role for abnormal activation of the complement system in HSCT-associated TMA, as is the case in atypical HUS, has also been proposed. The small studies that have examined the question of implicating a role for abnormal activation of the complement system in HSCT-associated TMA are limited by their size but have not demonstrated any abnormalities in measured complement levels or directly sequenced complement genes in patients with HSCT-associated TMA [56, 65]. Interestingly, however, antibodies against complement factor H (CFH) have been detected in patients with HSCT-associated TMA [44, 66]. More studies are required to further elucidate the role of alloantibodies and the complement system in the pathogenesis of HSCT-associated TMA.

Establishing the diagnosis of HSCT-associated TMA can often be challenging. The diagnosis of TMA is made on the basis of characteristic pathological findings seen on kidney biopsy, including glomerular endothelial swelling, basement membrane duplication, mesangiolysis, occluded vascular lumens, and tubular injury with interstitial fibrosis [67]. However, because of the increased risk of bleeding in the HSCT patient, kidney biopsies are rarely performed unless there are atypical features in the presentation. Clinical criteria for the noninvasive diagnosis of HSCT-associated TMA have been proposed by two separate groups in an attempt to standardize the diagnosis [62, 68] (Table 11.3). Follow-up validation studies, however, have revealed limitations to the use of these criteria [53, 63, 69]. Autopsy studies have found pathologic evidence of HSCT-associated TMA in patients who did not meet criteria for clinical diagnosis [70, 71], further highlighting the difficulty of establishing reliable guidelines for the diagnosis of HSCT-associated TMA. In light of these challenges, clinicians evaluating HSCT patients should be attentive to the development of renal manifestations, such as hypertension and proteinuria, which may herald an early diagnosis of HSCT-associated TMA.

Table 11.3

Clinical criteria for the diagnosis of HSCT-associated TMA

BMT CTN Toxicity Committee consensus definition [33]	International Working Group definition [39]
RBC fragmentation and ≥ 2 schistocytes per high-power field on peripheral smear	All of the following present: Increased percentage ( 4 %) of schistocytes in peripheral blood
Concurrent increased serum LDH above institutional baseline
	De novo, prolonged, or progressive thrombocytopenia (platelet count < 50 × 10⁹/L or ≥ 50 % decrease from prior levels)
Concurrent renal^a and/or neurologic dysfunction without other explanations
Negative direct and indirect Coombs test results	Sudden and persistent increase in LDH
	Decrease in hemoglobin concentration or increased red blood cell transfusion requirement
	Decrease in serum haptoglobin concentration

^aDoubling of serum creatinine from baseline (baseline = creatinine before hydration and conditioning) or 50 % decrease in creatinine clearance from baseline

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