Acute kidney injury (AKI) is highly prevalent whether the patients undergo myeloablative or non-myeloablative hematopoietic cell transplantation (HCT); however, the pathogenesis and risk factors leading to AKI can differ between the two. The prognosis of AKI in patients receiving HCT is poor. In fact, AKI following HCT is associated not only with increased short- and long-term mortality, but also with progression to chronic kidney disease. Herein, the authors provide a comprehensive and up-to-date review of the definition and diagnosis, as well as of the incidence, pathogenesis and outcome of AKI in patients undergoing HCT, centering on the differences between myeloablative and non-myeloablative regimens.
Hematopoietic cell transplantation (HCT) is currently used to treat numerous malignant (for example, multiple myeloma, leukemias and lymphomas) and non-malignant hematological disorders (for example, aplastic anemia, b-thalassemia, immunodeficiency disorders and inborn errors of metabolism), as well as solid tumors (for example, breast cancer and neuroblastoma), which are in other instances incurable.
The two major HCT procedures, taking into consideration the conditioning regimen used, are myeloablative autologous and allogeneic HCT and non-myeloablative allogeneic HCT. On the one hand, myeloablative HCT utilizes the maximally tolerated dose of TBI with or without chemotherapy, or with chemotherapy alone. On the other hand, non-myeloablative HCT depends more on donor cellular immune effects and less on the cytotoxic effects of the preparative regimen to control the underlying disease.1, 2 It ultimately uses a lower dose conditioning regimen and can thus be offered to older patients, to those debilitated by additional comorbidities, or to high-risk, heavily pretreated patients, who would not tolerate myeloablative HCT, resulting in a consequent decrease in regimen-related toxicity and treatment-related mortality.3, 4, 5
Acute kidney injury (AKI) is highly prevalent whether the patients undergo myeloablative or non-myeloablative regimens; however, the pathogenesis and risk factors leading to AKI can differ between the two. In fact, AKI in patients receiving HCT is associated not only with increased short- and long-term mortality as compared with patients with no AKI, but also with a higher rate of progression to chronic kidney disease (CKD). Herein, the authors provide a comprehensive and up-to-date review of the definition and diagnosis of AKI as well as of the incidence, risk factors, pathogenesis and outcome of AKI in patients undergoing HCT, centering on the differences between myeloablative and non-myeloablative regimens.
Definition and diagnosis
In the last decade, the development of two new classification systems for AKI (Risk Injury Failure Loss of kidney function End-stage kidney disease—RIFLE and Acute Kidney Injury Network—AKIN)6, 7 allowed for an enhanced knowledge of the epidemiology of AKI, demonstrating a greater sensitivity and specificity in the diagnosis and stratification of AKI. The first definition of AKI, the RIFLE classification (Table 1),6 was published in 2004 and the AKIN classification (Table 1),7 also known as modified RIFLE, was published 3 years later (in 2007). According to these two largely validated classification systems, AKI has been proven to be highly prevalent in hospitalized patients, and even more so in the critically ill.8 Despite having higher diagnostic sensitivity, AKIN has not proven any advantages over RIFLE in predicting outcome.8 Although these classifications allowed for the identification of a significant number of patients as having AKI after myeloablative and non-myeloablative HCT, and performed well in predicting patient outcome, the advantages of each one over the other remain to be established in this setting.9, 10, 11, 12, 13 The KDIGO classification system14 (Table 1) proposed in 2012 resulted from the fusion of the former classifications (RIFLE and AKIN) as a means to establish one classification of AKI for clinical practice, research and public health. In the HCT setting, the KDIGO classification has not yet been prospectively evaluated, and it has only been employed in a recently published retrospective study of a small cohort of critically-ill allo-HCT patients.15
Of note, all these classifications rely solely on markers of renal function (creatinine and urine output), which have limitations in terms of sensitivity and specificity for AKI diagnosis.8 In an attempt to overcome these limitations, novel biomarkers, such as cystatin C, neutrophil gelatinase-associated lipocalin, interleukin-18, urinary kidney injury molecule-1, liver-type fatty acid-binding protein, have been studied. Studies have demonstrated that these biomarkers can offer great advantages over the current clinical classifications in use, such as earlier diagnosis of AKI (1–3 days),16 identification of the etiology of injury,17 treatment monitoring18 and outcome prediction.19 Furthermore, subclinical AKI defined by an increase in these biomarkers without contemplating changes in serum creatinine and urine output has been associated with poor prognosis.20 It has recently been verified that an increase in urinary neutrophil gelatinase-associated lipocalin could precede increases in serum creatinine and thus potentially predict AKI after HCT.21 Furthermore, a recent prospective cohort study showed an increased risk of AKI following allogeneic HCT associated with an increase in urinary liver-type fatty acid-binding protein preceding preconditioning therapy.22 Nevertheless, the clinical applicability of single biomarkers is still lacking solid evidence.
AKI in patients submitted to HCT typically ensues within the first 3 months after transplantation, thereby providing substantiation that 100 days is a suitable ‘cut-off’ time for assessing most AKI events.
According to the most recently released classifications of AKI, the reported incidence of AKI within the first 100 days succeeding myeloablative allogeneic HCT varied between 27 and 66%9, 11 and, on the contrary, the incidence of AKI in patients undergoing a myeloablative autologous HCT was lower, occurring in <20% of patients.9, 11 Two major explanations have been proposed to explain the lower incidence of AKI in myeloablative autologous HCT when compared with that of myeloablative allogeneic HCT. First, the absence of GVHD in autologous HCT, which can contribute to renal lesions directly through cytokine- and immune-related injury, including glomerular deposits causing nephrotic syndrome and tubulitis; or indirectly through nephrotoxicity induced by calcineurin inhibitors used in prophylaxis against GVHD.23, 24 Furthermore, severe GVHD with diarrhea and consequent dehydration, as well as CMV reactivation due to treatment of GVHD with high-dose prednisolone can likewise contribute to GVHD-associated nephrotoxicity.12, 25 Second, since there are no foreign cells in myeloablative autologous HCT, engraftment occurs more rapidly (resulting in less cytopenia, sepsis and antimicrobe-induced nephrotoxicity).
Following myeloablative HCT, AKI occurs generally in the first month after transplantation. During the first month, the patient is more susceptible to multiple organ dysfunctions owing to toxicities linked to the intense conditioning regimen, particularly infections and hepatic sinusoidal obstruction syndrome (SOS) (previously known as hepatic veno-occlusive disease). Interestingly, when AKI is associated with hepatic SOS, the time for onset of AKI is significantly shorter, usually occurring within the first 2 weeks.26 It is also worth mentioning that engraftment syndrome (ES) typically emerging in the first month following HCT may largely contribute to AKI within this time period. In a retrospective study comprising 377 patients with light-chain amyloidosis submitted to autologous HCT, the majority of AKI cases seemed to be linked to ES. The authors of that study established that ES should be considered in the differential diagnosis of AKI in this population.27 Following hematopoietic stem-cell transplantation and during the stage of neutrophil recovery, a group of signs and symptoms comprising fever, erythrodermatous skin rash and non-cardiogenic pulmonary edema can often arise. These clinical features have generally been denoted as ES, or, as a reflection of manifested increased capillary permeability, capillary leak syndrome. These findings have most often been described following autologous HCT; however, a similar clinical syndrome has been observed after allogeneic HCT. Differentiation from GVHD in the allogeneic setting has, however, been challenging. Nevertheless, recent experience with non-myeloablative HCT has revealed that an ES independent of GVHD may occur. In some instances, this ES may ultimately be an indicator of a host-versus-graft reaction (graft rejection). Although cellular and cytokine interactions are assumed to be accountable for these clinical findings, a distinct effector cell population and cytokine profile has yet to be well defined. ES are probably linked to an increased transplant-related mortality, primarily from pulmonary and associated multiorgan failure.28
As previously mentioned, AKI is also common in non-myeloablative HCT, affecting up to half of the transplanted patients, with the majority of these cases occurring in the second month after transplantation.11, 12 The longer time to AKI occurrence in non-myeloablative HCT as compared with myeloablative regimens can be explained by the lower prevalence of infectious complications and organ failure, especially hepatic SOS.
It should be noted that patient outcome can differ according to the timing of AKI onset in the HCT setting. In a prospective cohort study including 103 allogeneic HCT recipients, non-relapse mortality and overall mortality at 100 days following AKI, together with the incidence of CKD over 2 years after HCT were higher in early AKI (defined as AKI before stem-cell engraftment) patients than in the late AKI (AKI occurring subsequently) group. Early AKI was also found to be independently associated with overall mortality in those patients.29
Azotemia of prerenal origin is frequently encountered as the cause of AKI in the HCT patient.30, 31 Adverse effects of most chemotherapy regimens include nausea, vomiting and diarrhea, and HCT recipients frequently have volume depletion as a result of these gastrointestinal losses. Mucositis is another major complication of chemotherapy and poor oral fluid intake can result therefrom. Additionally, HCT recipients are at an increased risk of sepsis, particularly during the period of neutropenia that precedes stem cell engraftment.
Acute tubular necrosis (ATN)26, 30, 31 is also a common etiology of AKI in HCT patients and can ultimately overlap with prerenal azotemia due to volume depletion from dehydration (ischemic ATN) or sepsis (ischemic and/or nephrotoxic ATN). Patients can develop ischemic ATN in the context of hypovolemic or septic shock or nephrotoxic ATN as a result of drugs required for transplant, such as chemotherapy medication (cytarabine, carmustine, busulfan and fludarabine), antimicrobial agents (amphotericin B, aminoglycosides and vancomycin) and calcineurin inhibitors and methotrexate (MTX) used for GVHD prophylaxis and treatment. The major culprit for AKI in non-myeloablative HCT is calcineurin inhibitors injury by themselves or in association with other etiologies, namely sepsis, nephrotoxicity or GVHD.12, 32, 33 In both myeloablative allogeneic and non-myeloablative HCT, calcineurin inhibitors are employed as prophylaxis against GVHD. One of the most common and serious complications associated with calcineurin inhibitors is their nephrotoxicity, manifested as AKI (mostly reversible after dose reduction) or as progressive CKD (usually irreversible). Consequently, calcineurin inhibitor nephrotoxicity has both a reversible hemodynamic component and an irreparable (structural) component. The hemodynamic component is essentially mediated by acute renal vasoconstriction of the afferent and efferent glomerular arterioles, resulting in a decrease in renal blood flow and glomerular filtration rate.34 This vasoconstriction may possibly be due to impairment of endothelial cell function, prompting decreased vasodilator production (prostaglandins and nitric oxide) and enhanced release of vasoconstrictors (endothelin and thromboxane), increased sympathetic tone, increased production of transforming growth factor b-1, endothelin-1, reactive oxygen and nitrogen species.35 Tubular dysfunction is another known renal effect of calcineurin inhibitors, and rarely a hemolytic uremic syndrome may also ensue.
Urinary tract obstruction should always be considered as a possible etiology of AKI in the HCT patient. Antiviral drugs such as acyclovir, when administered intravenously, can precipitate in the urine and cause the formation of obstructing crystals in the renal tubules.36 Patients may also be at risk for urinary obstruction of extrarenal causes as a consequence of retroperitoneal fibrosis due to radiation therapy, retroperitoneal lymphadenopathy or clots formed due to hemorrhagic cystitis. Hemorrhagic cystitis can occur due to viral infections caused by BK or adenovirus or arise as a side effect of chemotherapy (cyclophosphamide or busulfan).
Tumor lysis syndrome is unusual in HCT patients as most patients are in remission from their disease at the time of transplant.26 This syndrome results from massive tumor cell lysis and cell content release into the circulation. Frequently detected laboratory abnormalities include hyperkalemia, hypocalcemia, hyperphosphatemia, hyperuricemia and AKI. Tumor lysis syndrome is usually the consequence of antitumor therapy; however, it can occur spontaneously in high-tumor burden malignancies such as leukemias and lymphomas. Characteristic treatment procedures include aggressive IV fluid administration, allopurinol and rasburicase to lower uric acid levels, phosphate binders and, in severe circumstances, dialysis.
Opportunistic infections can complicate the course of AKI in HCT recipients. BK virus is a common opportunistic infection occurring in solid organ transplantation, especially among renal transplant recipients. In HCT patients, BK can manifest as BK cystitis or, comparable to kidney transplant recipients, as BK nephritis.37 Detectable BK virus is a frequent and early occurrence in HCT patients, with approximately 50% of them having detectable viruria30 and 30% having detectable viremia within the first 2–8 weeks following transplantation.38 Fortunately, few patients go on to develop overt nephropathy as their immunocompromised state is usually transitory. Depending on the case series, hemorrhagic cystitis due to BK virus is the most frequently encountered complication of BK infection in HCT recipients, diagnosed in 10–25% of patients.39 It is suggested that both the chemotherapy and radiation components of the conditioning regimen damage the urothelium.30 When patients are immunocompromised during the neutropenic stage before cell counts improve, the BK virus replicates in the uroepithelium. Immune reconstitution following transplant results in local mucosal injury and hemorrhage. BK cystitis typically arises in the week after marrow engraftment, presenting with gross or microscopic hematuria, dysuria, increased urinary frequency, suprapubic discomfort and, in severe cases, bladder obstruction and AKI.30 Acute GVHD, allogeneic HCT and high-titer BK viral load in serum constitute as risk factors for the development of BK cystitis.40, 41, 42 PCR of serum is the preferred screening test for BK. In the majority of patients resolution of BK cystitis is spontaneous; and treatment is generally supportive with analgesia, hydration, forced diuresis and continuous bladder irrigation.39 Adenovirus represents another infectious cause of nephritis and cystitis after HCT. The virus can be isolated from serum in about 20% of HCT patients by PCR; however, the clinical syndrome differs broadly and the clinical implication of detectable viremia is uncertain.43 It is yet to be determined whether adenovirus infection represents reactivation of a previous infection, as seen with BK, or whether it is acquired following transplantation. Patients are either asymptomatic or they can present with isolated nephritis or hemorrhagic cystitis, or, in extreme cases, have multiorgan involvement with hepatitis, pneumonitis and encephalitis.43 Invasive disease, which usually proves to be fatal, requires tissue biopsy for confirmation of diagnosis. Kidney infection by adenovirus can cause a necrotizing tubulointerstitial nephritis.44 This rare but serious manifestation of HCT is usually perceived within the first 90 days after transplantation.45 Patients with adenovirus nephritis present with fever, gross hematuria and AKI; most have detectable adenovirus in their urine. Adenovirus cystitis is a more frequent but less morbid complication of adenovirus infection that has been witnessed in up to 15% of HCT recipients46 and usually manifests within the first 2 months following the transplant. Isolated case reports47, 48 of successful treatment of adenovirus cystitis with IV or intravesical administration of cidofovir have been described; however, supportive care is usually the recommended treatment.
The etiology of AKI specifically in the HCT setting includes marrow transfusion toxicity, hepatic SOS, acute GVHD and transplantation-associated thrombotic microangiopathy (TA-TMA).
Marrow transfusion toxicity49 is a possible cause of AKI seen exclusively in HCT patients. Once stem cells are harvested, from the recipient in the case of autologous transplants or from the human leukocyte antigen-matched donor, they are frozen and stored pending transplant. DMSO is a constituent of the freezing media and serves as a cryoprotectant. During stem-cell infusion, HCT patients are ultimately exposed both to residual DMSO and to cell lysis products created by the freezing process.49 When infused into patients, DMSO can result in cell hemolysis. Released heme proteins following hemolysis precipitate in the distal nephron, where they form aggregates with Tamm–Horsfall protein, producing tubular casts and consequent tubular obstruction.49 Urinary alkalinization represents the keystone of treatment.49 More recent stem-cell collection techniques and reduced infusion volumes have made this complication less frequent.
The incidence of hepatic SOS varies greatly among single-center case reports with a range of 5–60%;50 the mean incidence reported in a recent meta-analysis was 13.7%.51 Hepatic SOS is an early cause of AKI in HCT patients, usually encountered within the first month after HCT.51 In fact, hepatic SOS has been consistent in heralding AKI in myeloablative allogeneic HCT. Regarding non-myeloablative HCT, one study has also described SOS as being an independent risk factor for the development of AKI13 although SOS is exceptionally rare in non-myeloablative HCT. This injury causes obliteration of small intrahepatic venules and sinusoidal thrombosis, ultimately resulting in sinusoidal congestion, fibrosis and necrosis.50, 51 Patients clinically develop a syndrome constituted of hyperbilirubinemia, painful hepatomegaly, ascites, volume overload and AKI mirroring hepatorenal syndrome. AKI can occur in up to 80% of patients with SOS, but characteristically emerges only after the onset of the hepatic disease (as demonstrated by progressive hyperbilirubinemia). The appearance of AKI is frequently prompted by a superimposed incident, such as sepsis.50, 52, 53 Hepatic SOS is an event almost exclusively recognized in the setting of HCT, and is more commonly associated with myeloablative allogeneic HCT than with myeloablative autologous HCT. Factors associated with increased risk of hepatic SOS development include allogeneic transplant, high-dose chemotherapy, pretransplant liver abnormalities, abdominal radiation and poor functional status. The association between hepatic SOS with myeloablative allogeneic HCT may be attributable to MTX used for GVHD prophylaxis, which is not a concern in autologous HCT. The much lower intensity of chemoradiotherapy is implicated as a possible explanation for the extremely rare occurrence of SOS in non-myeloablative regimens.54 Mismatched bone marrow or bone marrow that is obtained from an unrelated donor probably increases the risk of SOS; and the risk of SOS may be lowered in patients receiving PBSCs when compared with bone marrow.55 It is uncertain by which exact mechanism(s) the hepatic disease might cause AKI; however, reduced hepatic clearance of endotoxins absorbed from the intestine may have a part and portal hypertension that results from hepatic sinusoidal injury may also lead to decreased renal perfusion and tubular injury.56 The prognosis of hepatic SOS can be somewhat predicted by renal function. Mortality risk increases with severity of AKI reaching 80% in those patients undergoing dialysis.52 As many patients will recover spontaneously, treatment of hepatic SOS is mostly supportive with diuretics, transfusions, analgesics, paracentesis and dialysis if needed.50 There are case reports57, 58 describing the use of tissue plasminogen activator, heparin or defibrotide for treatment but there are no large, randomized controlled trials to support their use in hepatic SOS.
Acute GVHD is an early and frequent complication of HCT affecting as many as 60% of patients usually within the first 100 days after transplant.59, 60 Patients present with rash, diarrhea and liver function test abnormalities;59 severity of the disease is graded (I–IV) according to the extent of each of these abnormalities. Acute GVHD is independently linked with an increased risk of the occurrence of AKI in both myeloablative and non-myeloablative conditioning regimens.13, 25, 32, 61 Although in GVHD all organs should be possible targets for donor T cells, the kidney as a target organ for acute GVHD is still not considered by many physicians. Furthermore, histologically confirmed diagnosis of renal GVHD is rarely done and pathologic criteria have not yet been established for renal involvement in acute GVHD. In a mice model of acute GVHD, numerous genes related to inflammation and the immune response (for example, chitinase 3-like3, CXCL9, IFN-inducible GTPase-1, IFN-inducible protein-47, histocompatibility-2 (Q region and class II), macrophage activation-2 like, IFN-inducible GTPase-1, granzyme-B, granzyme-K, CD3 antigen, g-polypeptide and CXCL11), which directly or indirectly are relevant to immune responses and/or inflammation, were significantly upregulated in the kidney of GVHD; and overexpression of MHC (both classes) in combination with intermediate genes (for example, CLIP, TAPBP, TAP-1 and TAP-2), genes that are involved in antigen processing and presentation pathways, was significantly higher in the kidney of GVHD mice.60 In addition, other mice model of kidney injury in acute GVHD has shown mild infiltration of CD3+ T cells, CD8+ T cells, CD4+ T cells and CD68+ macrophages into the interstitium around the small arteries. During moderate to severe inflammation, these infiltrating cells expanded into the peritubular interstitium with peritubular capillaritis, tubulitis, acute glomerulitis and endarteritis. These histologic changes were accompanied by renal dysfunction.62 Plasma elafin levels have been known to correlate with skin GVHD; and it has recently been demonstrated that elafin could be a potential marker for renal inflammation and injury, especially because higher urinary elafin levels were connected to an increased risk of micro- and macroalbuminuria, AKI and CKD after HCT.63 GVHD may therefore contribute to kidney injury fundamentally by two mechanisms: directly through cytokine- and immune-related injury, including glomerular deposits triggering nephrotic syndrome, and tubulitis; or indirectly through nephrotoxicity induced by calcineurin inhibitors used as prophylaxis against GVHD.17, 18 Moreover, GVHD-associated nephrotoxicity may result from severe GVHD with diarrhea and subsequent dehydration, as well as from CMV reactivation because of GVHD treatment with high-dose prednisolone.7, 19 An augmented risk of the development of AKI in non-myeloablative HCT has been linked to CMV reactivation in itself.19 Patients routinely receive calcineurin inhibitors and sometimes MTX as prophylaxis against GVHD, and acute GVHD can be treated with the addition of another immunosuppressive agent such as high-dose steroids, rabbit antithymocyte globulin and anti-TNF-a. Photopheresis is another therapeutic option.
TA-TMA is a significant complication of HCT. Varying levels of awareness among institutions, diagnostic doubt and limited prospective data are reflected in the wide range of reported incidences of TA-TMA (from 0.5 to 76%).64 TA-TMA is a member of the family of thrombotic microangiopathies, including, among others, thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.65 TA-TMA ensues when endothelial damage in the setting of HCT results in microangiopathic hemolytic anemia and platelet consumption, culminating in thrombosis and fibrin deposition in the microcirculation.66, 67, 68 TA-TMA in HCT may be a consequence of the interaction of a combination of a number of factors that cause injury to the endothelium, including calcineurin inhibitors, mammalian target of rapamycin inhibitors, chemotherapy, GVHD and/or TBI.54, 66, 69 Calcineurin inhibitor use causes endothelial injury through direct cytotoxic damage, platelet aggregation, elevated von Willebrand factor and thrombomodulin, altered complement regulator proteins, and decreased production of prostacyclin and nitric oxide.70, 71 Infection may also be an initiating or contributive factor for TA-TMA in HCT.72 Subacute or chronic thrombotic microangiopathy is the most common clinical presentation of TA-TMA and first becomes apparent between 20 and 100 days after HCT, respectively.54, 72, 73 The kidney is the most frequently affected organ, with injury elsewhere in the body rarely being reported.67, 72, 74, 75 The onset of microangiopathic hemolytic anemia and thrombocytopenia in affected patients is gradual, accompanied by normal or near-normal urinalysis, displaying only mild proteinuria and/or hematuria, and a moderate rise in creatinine. Histopathologic examination of the kidney reveals mesangiolysis with necrotizing arteriolar and glomerular lesions, in addition to intraglomerular and renal arteriolar thrombi.54, 72, 73 Discontinuation of offending causative agents such as calcineurin inhibitors, plasma infusion and plasma exchange, rituximab and defibrotide are frequently described as valid treatment options for TA-TMA.76 Thrombotic microangiopathy is often linked to calcineurin inhibitor toxicity; therefore, their withdrawal is required. Contrary to classic thrombotic thrombocytopenic purpura, plasma infusion or plasma exchange is usually ineffective in post-HCT thrombotic microangiopathy.72 Prospective treatments aimed at TA-TMA-induced endothelial damage include statins, bosentan, allopurinol, anti-TNF agents, recombinant thrombomodulin and nitric oxide donors.70, 74, 77, 78 Mortality rates are often elevated in the most severe form of TA-TMA,72 whereas milder cases present an increased risk for CKD.66
As in the general population, diabetes mellitus,32 previous hypertension,26 previous renal impairment,79 sepsis,13 amphotericin use,80 requirement for mechanical ventilation33 and admission to the intensive care unit26 were all associated with increased risk for AKI following HCT. In actual fact, pre-HCT comorbidities greatly impact the outcome of patients undergoing HCT. The HCT-specific comorbidity index, which stratifies patients according to the severity of pre-HCT hepatic, pulmonary, cardiac and renal impairment and assesses the presence of prior solid tumors, has been shown to predict non-relapse mortality and overall survival of HCT patients, as well as post-HCT AKI.81, 82 Common risk factors for AKI specifically related with myeloablative regimens were hepatic SOS,61, 80, 83 lung toxicity,25 high-risk disease32 and acute GVHD,26 while previous myeloablative HCT,25, 84 high-risk disease,84 acute GVHD,13, 25, 32 CMV reactivation,25 incomplete HLA-matched transplant,13 MTX,32 as well as the need for more than three lines of therapy before HCT32 significantly increased the risk for the development of AKI in patients undergoing non-myeloablative HCT (Table 2).
Several studies have evidenced poorer early outcomes for AKI patients compared with those without renal dysfunction,85, 86 specifically longer lengths of intensive care unit and hospital stay, higher in-hospital and post-discharge mortality, and an increased likelihood of discharge to an extended care facility. In truth, the harmful effects of AKI persevere beyond the hospitalization and AKI patients have been shown to present greater risk of developing CKD and increased long-term mortality than non-AKI patients.87
AKI following HCT foretells the subsequent development of proteinuria and arterial hypertension, and is associated with a stepwise pattern increase in the risk for CKD both in myeloablative and in non-myeloablative HCT.88, 89, 90, 91 Following AKI, if the acute insult is inadequately resolved, persistent inflammation, increased transformation of pericytes into myofibroblasts in response to tubular injury, build up of extracellular matrix and vascular rarefaction92 lead to permanent changes in renal structure and function93 and ultimately to CKD. Therefore, after AKI there is an increased risk of proteinuria, arterial hypertension and CKD94, 95 which are known risk factors for cardiovascular disease96, 97, 98 and, as such, may contribute to the decrement in survival observed among AKI survivors. Actually, even in AKI patients not requiring dialysis at the time of the acute episode, development or progression of CKD contributes to a greater long-term mortality.99 A coincident imbalance of other organ systems, that is, heart, lungs, brain, liver and other organs) may coexist in the presence of AKI, suggesting that an underlying systemic mechanism may be accountable for multiorgan dysfunction and could also be responsible for the greater mortality observed in AKI.100 The biological crosstalk between the kidney and other organs, an increased incidence of sepsis and progression to CKD in AKI patients appear to be, at least in part, mediated by immune mechanisms (Figure 1).100 AKI has been shown to involve the contribution of multiple strategic players of innate immunity.101 Following acute damage, inflammation mediates additional renal injury and dendritic cells seem to be crucial in summoning action from other immune cells.102 Following injury, cytokines, growth factors and peptide molecules control M1 and M2 macrophages throughout the resolution phase, resulting in either regeneration of renal tissue or eventual evolution to fibrosis.102 Likewise, T cells have an important part in AKI: CD4+ cells during the earlier phases of injury, and CD4+ CD25+ FoxP3 regulatory cells and the newly discovered kidney CD4−CD8− (double-negative) cells seemingly per protective mechanisms.103 We speculate that these mechanisms could amplify immune and inflammatory changes associated with HCT and ultimately contribute to poor outcome associated with AKI following HCT. Several studies have recently recognized and documented a stepwise increase in hazard of short- and long-term mortality in patients developing AKI after myeloablative and non-myeloablative HCT and, in patients requiring dialysis, mortality approached 100%.11, 13, 25, 26, 32, 33, 61, 79, 80, 83, 104, 105 Moreover, many of these studies have also established an increased association of numerous organ toxicities, primarily hepatic and pulmonary, as well as sepsis with AKI following either conditioning regimen.13, 54, 61, 80, 83
In summary, AKI occurs commonly both in myeloablative and in non-myeloablative HCT, and is associated with poor outcome. Patients developing AKI after HCT are at increased risk for CKD as well as for short- and long-term mortality.
In the HCT setting, the identification of novel biomarkers for AKI combined with the use of traditional markers of kidney function (urea and creatinine) can be a useful tool to early identify patients with AKI, to determine AKI etiology, to monitor therapy and to predict outcome.
Strategies to preserve renal function in patients receiving HCT should be implemented and could positively influence patient outcome. Pharmacologic interventions targeted at modifying the maladaptive response to injury, for example, drugs that affect profibrotic pathways92 may, in the future, deliver a pronounced impact on morbidity and mortality related to AKI. Immunomodulation could represent an appealing therapeutic path as a means to reduce the severity and improve AKI outcomes,103, 106 and an effort for the development of potential therapeutic targets should be made.
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The authors declare no conflict of interest.
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Lopes, J., Jorge, S. & Neves, M. Acute kidney injury in HCT: an update. Bone Marrow Transplant 51, 755–762 (2016). https://doi.org/10.1038/bmt.2015.357
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