Long-Term Health Effects of Curative Therapies on Heart, Lungs, and Kidneys for Individuals with Sickle Cell Disease Compared to Those with Hematologic Malignancies

The goal of curing children and adults with sickle cell disease (SCD) is to maximize benefits and minimize intermediate and long-term adverse outcomes so that individuals can live an average life span with a high quality of life. While greater than 2000 individuals with SCD have been treated with curative therapy, systematic studies have not been performed to evaluate the long-term health effects of hematopoietic stem cell transplant (HSCT) in this population. Individuals with SCD suffer progressive heart, lung, and kidney disease prior to curative therapy. In adults, these sequalae are associated with earlier death. In comparison, individuals who undergo HSCT for cancer are heavily pretreated with chemotherapy, resulting in potential acute and chronic heart, lung, and kidney disease. The long-term health effects on the heart, lung, and kidney for children and adults undergoing HSCT for cancer have been extensively investigated. These studies provide the best available data to extrapolate the possible late health effects after curative therapy for SCD. Future research is needed to evaluate whether HSCT abates, stabilizes, or exacerbates heart, lung, kidney, and other diseases in children and adults with SCD receiving myeloablative and non-myeloablative conditioning regimens for curative therapy.


Introduction
Sickle cell disease (SCD) is an inherited disease caused by a point mutation and is associated with early mortality. Within the United States, an estimated 1 of every 365 babies of African descent is born with SCD each year, with 104,000 to 138,900 people affected [1]. Children and adults with SCD experience severe and progressive organ disease, stroke, pulmonary hypertension, cardiomyopathy, and kidney failure [2]. The medical costs of SCD are massive, with total lifetime costs exceeding USD 460,000 for patients who live to be 45 years of age [3].
While mortality for children with SCD has improved substantially over the past 4 decades, with >99% of those born in high-resource settings now surviving to 18 years of age [4][5][6], adults continue to die prematurely. Over the last three decades, the life expectancy of adults with SCD has not significantly changed. In a pooled analysis of 300 individuals with SCD after adjustment for entry age into the cohort, the median survival ages were 48.0 years for individuals with phenotypes HbSS/HbSβ0 thal/HbSD and 54.7 years for Neuro Brain MRI/MRA at 1 and 2 years post-HSCT and then every 2 years as clinically indicated in patients with a history of stroke or moyamoya syndrome pre-HSCT. MRI at 1-2 years post-HSCT in patients with PRES or other neurotoxicity during HSCT. Neurocog assessment.

Renal
Monitor until nephrotoxic therapy is discontinued and yearly for 2 years (BUN, creatinine, electrolytes, GFR, or 24-h creatinine clearance). UA for blood/protein at 1 year. Microalbuminuria testing annually for 2 years. Monitor BP annually.  Table 1 summarizes the long-term  follow-up guidelines from the pediatric consortium described above for SCD [36] and for  contrast, those established for post-HSCT surveillance among patients with malignancy.  While greater than 2000 individuals with SCD have been treated with curative therapy to date, systematic studies have not been performed to evaluate the long-term health effects of HSCT. Such studies will be requisite to inform evidence-based long-term follow-up guidelines. In this paper, we first review the studies that describe the impact of HSCT on the heart, lung, and kidney, mostly in cancer survivors, followed by review of the much more limited data available primarily for children but also adults who have received curative therapy for SCD.

Materials and Methods
Various literature search methods were used to identify relevant studies involving the long-term health outcomes for patients with cancer and SCD during the summer of 2020, and an updated manual search was performed in July 2021. Retrieved answer sets from PubMed ® (National Library of Medicine) and Embase ® (Elsevier) searches were analyzed, and relevant articles were evaluated, as well as citations in those articles.
The term "late effects" was not a controlled vocabulary term in Embase ® or PubMed at the time of this study. "Late effects" was searched as a text phrase, and the concept "late effects" was also attributed to relevant articles after analysis.
Embase search strategies were predominantly based on therapy terms using the Emtree ® controlled vocabulary, as shown in these two examples: (1) (("allogeneic stem cell transplantation"/exp/mj OR "allogeneic hematopoietic stem cell transplantation"/exp/mj OR "allogeneic peripheral blood stem cell transplantation"/exp/mj OR "autologous stem cell transplantation"/exp/mj OR "cord blood stem cell transplantation"/exp/mj OR "hematopoietic stem cell transplantation"/exp/ mj OR "nonmyeloablative stem cell transplantation"/exp/mj OR "peripheral blood stem cell transplantation"/exp/mj) AND "late effects") AND ("article"/it OR "article in press"/it OR "review"/it) and (2) (("allogeneic stem cell transplantation"/exp/mj OR "allogeneic hematopoietic stem cell transplantation"/exp/mj OR "allogeneic peripheral blood stem cell transplantation"/exp/mj OR "autologous stem cell transplantation"/exp/mj OR "cord blood stem cell transplantation"/exp/mj OR "hematopoietic stem cell transplantation"/exp/ mj OR "nonmyeloablative stem cell transplantation"/exp/mj OR "peripheral blood stem cell transplantation"/exp/mj) AND ("sickle cell anemia"/exp/mj NOT ("sickle cell crisis"/exp OR "sickle cell trait"/exp))) AND "late effects" In PubMed, several keyword-based search strategies were used. Therapy terms "myeloablative" or "non-myeloablative" were searched along with keywords for organ systems, with and without sickle cell terms. Two other examples of PubMed search strategies included were: (1) ((sickle cell disease) OR (sickle cell anemia)) AND ((stem cell transplant) OR (bone marrow transplant) OR (hematopoietic cell transplant)) AND (late effects) and (2) ((sickle cell disease) OR (sickle cell anemia)) AND ((stem cell transplant) OR (bone marrow transplant) OR (hematopoietic cell transplant)) AND (kidney OR renal).

Adverse Long-Term Health Outcomes in Cancer Survivors Treated with HSCT
In the 1980s, curative therapies rapidly evolved in the pediatric oncology field. While there was an encouraging increase in survival, systematic follow-up of the individuals revealed adverse long-term health challenges. Therefore, a new field emerged: survivorship in pediatric oncology. Most deaths in cancer patients treated with HSCT happen within the first 2 years. While long-term survival for patients who survive 2 years is approximately 80-90%, life expectancy remains lower than in the general population [38][39][40][41]. A study involving 1022 survivors transplanted between 1974 and 1998 reported that 66% had at least one chronic condition and 18% had severe or life-threatening conditions, whereas rates were 39% and 8%, respectively, in siblings [42,43]. Long-term follow-up studies have revealed adverse outcomes affecting the heart, lungs, and kidneys. Further, a recent study that assessed mortality in more than 4000 patients over 40 years revealed that leading causes of nonrecurrence-related mortality included pulmonary and cardiovascular disease [41].
3.1.1. Cardiovascular Complications after HSCT in Individuals with Cancer Cardiovascular (CV) diseases lead to significant morbidity and mortality in HSCT recipients [34, 44,45]. HSCT survivors have a 2-to 4-fold increased risk of CV death compared to the general population [43,[46][47][48]. Exposure to anthracycline-based chemotherapy and or chest irradiation pre-HSCT, comorbidities (including diabetes mellitus, hypertension, abnormal body composition, and dyslipidemia), pre-HSCT smoking, iron overload, and chronic GVHD are risk factors for the development of late cardiovascular disease [49][50][51][52][53][54]. Long-term HSCT survivors are also at increased risk for multiple cardiovascular risk factors such as hypertension, obesity, dyslipidemia, constrictive pericarditis, congestive heart failure, cardiomyopathy, conduction abnormalities, and valvular heart disease; prior chest radiotherapy increases the risk for many of these complications [43,55]. Recently, Yeh and colleagues reported cardiac comorbidities, older age, hypertension, diabetes, and arrhythmia were associated with increased risk for cardiac toxicity following HSCT; on the other hand, post-transplant cyclophosphamide was not [56].
The incidence of hypertension ranges from 21.4% to 74% in long-term survivors of HSCT [47,57,58]. A study including 1089 HSCT survivors and a mean follow-up of 8.6 years reported that after adjustment for age, race, sex, and body mass index, patients who had received an allogeneic HSCT had a 2-fold risk of hypertension compared to sibling donors or autologous HSCT survivors [59]. Hypertension is related to specific therapies for GVHD (e.g., steroids, calcineurin inhibitors) and to GVHD-induced endothelial damage and proinflammatory cytokine response [60]. Long-term survivors of allogeneic HSCT are more likely to take cardiovascular medications than those who received chemotherapy only (10% versus 1%, p < 0.05) [61].
HSCT can also impact heart function. One study noted that cumulative incidence of shortening fraction abnormalities increased from 12% before to 26% at 5 years post-HSCT [62]. With further follow-up post-HSCT, congestive heart failure cumulative incidence rises further. In a study of 1244 patients, the incidence of heart failure at 5 years post-transplant was 4.8%, and increased to 9.1% at 15 years post-HSCT [63,64]. The patients had a 4.5-fold increased risk of congestive heart failure compared to the general population, and the presence of hypertension or diabetes in these survivors led to a 35-fold or 27-fold risk of congestive heart failure, respectively. Female sex and polymorphisms in certain genes that impact anthracycline metabolism have also been associated with post-HSCT congestive heart failure [65]. Mortality is high, as >50% of patients die within 5 years after diagnosis of congestive heart failure [49,63]. Risk factors for late congestive heart failure include anthracycline dose ≥250 mg/m 2 , number of pre-HSCT chemotherapy cycles, and chronic comorbidities [49,66].
Late health effects of HSCT may not be associated with future cardiac disease. Armenian et al. reported that after adjusting for cardiotoxic exposures, the risk for cardiovascular complications in individuals transplanted for malignancy was the same as that seen in conventionally treated cancer survivors [53]. Therefore, the risk for late cardiovascular complications post-HSCT in individuals with cancer may be primarily due to pre-HSCT treatment exposures instead of conditioning-related exposures or other HSCT complications. In agreement with this hypothesis, children and adults without cancer who underwent allogeneic HSCT for transfusion-dependent beta thalassemia did not develop cardiac function abnormalities with a median follow-up of 7 years [67].
Pre-HSCT and conditioning-related radiotherapy together with cardiovascular risk factors (including diabetes, hypertension, and dyslipidemia) may lead to atherosclerosis [68][69][70]. With a median age of 39 years and a median follow-up of 9 years, 6.8% of 145 patients had developed an arterial event, including atherosclerosis, after allogeneic HSCT, and 2.1% after autologous HSCT [71,72]. The cumulative incidence of an arterial event by 25 years post-allogeneic HSCT was 22.1%. The incidence of myocardial ischemia post-HSCT ranges from 1% to 6% [47].
Not surprisingly, the majority of the studies reporting the incidence of CV complications post-HSCT have been in the myeloablative setting. On the other hand, Kersting et al. evaluated 14 patients who underwent a non-myeloablative approach, and the incidence of hypertension was similar at baseline compared to a median of almost 3 years post-HSCT [73]. Therefore, while the non-myeloablative study is small, the incidence of hypertension post-HSCT may be increased in the setting of myeloablative as opposed to non-myeloablative conditioning. The incidence of GVHD with associated use of steroids and renal failure with myeloablative regimens may contribute to the hypertension post-HSCT [74].
Pulmonary hypertension has rarely been reported in pediatric HSCT recipients [75][76][77]; still, the incidence is higher than idiopathic pulmonary arterial hypertension in the general population. Radiation, chemotherapy, and GVHD may contribute to the development of pulmonary hypertension. Because of the subtle symptoms in the early course of the disease, pulmonary hypertension may be underrecognized [78]. Further, as symptoms may be missed early on, pulmonary hypertension presents as a severe disease. Keen alertness of patients at risk and a heightened sense of early symptoms may allow for a timely diagnosis before developing irreversible complications.

Pulmonary Complications after HSCT in Individuals with Cancer
Chronic pulmonary dysfunction post-HSCT can manifest as restrictive or obstructive lung disease, diffusion abnormality, or combination [34, [79][80][81][82]. Respiratory complications occur in 25-50% of patients undergoing allogeneic HSCT, contributing to about 50% of HSCT-related deaths [82]. In almost 50% of patients with pulmonary disease, no infectious source is identified. At 5 years or more post-HSCT, the risk of respiratory complications was 1.5-fold higher in HSCT survivors than cancer survivors who did not undergo HSCT [83]. A recent study showed that the incidence of pulmonary toxicity did not change with busulfan versus total body irradiation (TBI)-based conditioning [84].
Unlike bronchiolitis obliterans, cryptogenic organizing pneumonia is a restrictive lung disease due to the interstitial deposition of fibroblasts within alveoli, alveolar ducts, and bronchioles [82]. Cryptogenic organizing pneumonia post-allogeneic HSCT incidence ranges from 1.7% to 10.3% [94][95][96][97]. Patients with cryptogenic organizing pneumonia were more likely to have acute skin GVHD and chronic GVHD involving the oral cavity and gut [94]. The mortality rate associated with cryptogenic organizing pneumonia is 21% [98].
Prior exposure to drugs and radiation including methotrexate, bleomycin, carmustine, cyclophosphamide, busulfan, TBI and mantle radiation, chronic GVHD, and older age at diagnosis are risk factors for the occurrence of late pulmonary fibrosis post-HSCT [40,51,99,100]. The severity and incidence of radiation-induced lung damage are related to the total volume of lung irradiated, the total dose and type of radiation, and the fractionation of that dose [80,101,102]. Myeloablative conditioning has been associated with worsening pulmonary function post-HSCT [103,104]. Abnormal baseline pulmonary function test (PFT) values, older age at the time of HSCT, the occurrence of a respiratory event within 1 year post-HSCT, the timing of HSCT after first complete remission, peripheral blood stem cells, tobacco use, GVHD, gender, cumulative doxorubicin dose, second HSCT, and high-risk hematologic malignancies have been associated with abnormal pulmonary function test values post-allogeneic HSCT [62,[105][106][107][108][109][110][111][112]. Further, three studies revealed a more significant detriment in lung function for patients receiving myeloablative than non-myeloablative regimens [113][114][115]. In patients with systemic sclerosis who underwent autologous HSCT with non-myeloablative conditioning, FVC % improved up to 3 years post-HSCT [116]. DLCO % has also been reported to stabilize or improve in other patients undergoing autologous HSCT for autoimmune diseases using non-myeloablative conditioning [117]. These studies confirm that respiratory complications are frequent post-HSCT and suggest that they may be more severe in patients who receive a myeloablative than a non-myeloablative regimen.

Kidney Complications after HSCT in Individuals with Cancer
Estimates of the incidence of acute kidney injury associated with HSCT vary widely, ranging from 10% to 73% of patients [118]. One study including 272 patients who underwent myeloablative HSCT (89% allogeneic, 11% autologous) revealed that 53% of patients developed acute kidney injury, approximately half of whom required dialysis [119]. Myeloablative allogeneic HSCT was associated with a higher incidence of severe kidney failure and need for dialysis than the non-myeloablative group, even when controlling for baseline characteristics such as age and comorbidities [120].
Chronic kidney disease may occur following an acute kidney injury, commonly related to viral nephropathy (BK virus) [121] or calcineurin-induced thrombotic microangiopathy [40]. The incidence of thrombotic microangiopathy post-allogeneic HSCT ranges from 0.5% to 76%, depending on the specific definition [122]. Chronic kidney disease is reported in approximately 4-60% of patients post-HSCT, with risk differing by stage of kidney disease at baseline and type of HSCT [87,[123][124][125].
Nephrotic syndrome occurs in 0.4-8% of patients post-allogeneic HSCT [40, 129,140]. In a study of 279 patients transplanted, the incidence of nephrotic syndrome was higher in recipients of peripheral blood stem cell transplant (24%) as compared to those who received a bone marrow graft (3%), possibly due to the increased incidence of chronic GVHD in patients who receive peripheral blood stem cells versus bone marrow [141]. Nephrotic syndrome may also occur more frequently after non-myeloablative than myeloablative conditioning [140].

Long-Term Adverse Health Outcomes Following HSCT for SCD
We review the published data on heart, lung, and kidney function in individuals with SCD following curative therapy.

Cardiovascular Outcomes following Curative Therapy in SCD
Few studies have evaluated the impact of curative therapy on the progression or attenuation of cardiovascular disease (CVD) in SCD. An elevated tricuspid regurgitant velocity, pulmonary and systemic hypertension, and systolic and diastolic dysfunction are risk factors for early mortality in adults with SCD [10,[142][143][144][145][146][147]. Unfortunately, the limited data available are primarily in the pediatric setting. Among 63 children who received an HSCT with myeloablative conditioning at a single center, with a median follow-up of 1.5 years, 36.4% had systolic blood pressure >90th percentile before HSCT, compared with 18.2% following HSCT. The percentage of patients with diastolic blood pressure >90th percentile before HSCT was 2.3% before HSCT but rose to 13.6% after HSCT. In addition, five patients were newly diagnosed with hypertension after HSCT (Table 2) [148]. Another report of 18 pediatric patients who underwent non-myeloablative matched related donor HSCT demonstrated that six (33.3%) had hypertension reported at some point during follow-up, and three required antihypertensive therapy. There were no reports of severe hypertension, defined as >95th percentile plus 12 mmHg in children, ≥140/90 mmHg, or requiring antihypertensive therapy in adults [149]. Notably, the mean follow-up was limited, with a mean follow-up of 128.6 weeks ( Table 2). Pulmonary and systemic hypertension may occur after curative therapy due to graftversus-host disease (GVHD) or calcineurin inhibitors and corticosteroids used to prevent or treat GVHD and renal failure. An elevated tricuspid regurgitant velocity (TRV), defined as at least 2.5 m/s, is associated with pulmonary hypertension and an increased risk of death in SCD [157]. Few single studies, and no multicenter studies, have systematically evaluated the clinical history of TRV after curative therapy. In a single-center study, 17 children underwent reduced-intensity conditioning and received HLA-matched related donor HSCT (Table 2) [156]. One patient had TRV 2.8 m/s before HSCT and trivial to mild tricuspid regurgitation 1 and 2 years after. Of the 11 patients who had follow-up transthoracic echocardiograms (ECHO) at 1 year and the five patients who had ECHO at 2 years, none had evidence of pulmonary hypertension. A more recent study reported 30 adults who underwent non-myeloablative conditioning from a matched related donor [22]. Those with a baseline pre-transplant TRV over 2.5 m/s saw an improvement from a mean of 2.8 m/s before to a mean of 2.3 m/s 3 years after HSCT. These patients also demonstrated an improved 6-min walk test. Together, small studies suggest that curative therapies may improve a risk factor for early mortality in adults with SCD. Large, multicenter studies are indicated in children and adults to validate the results.
While hypercholesterolemia and atherosclerosis are rare in individuals with SCD [158], decreased erythropoietic stress and therefore decreased metabolism after successful curative therapy may increase the long-term risk of cardiovascular disease. There are no studies to date that perform serial assessments of cholesterol levels in patients with SCD who underwent HSCT.
Limited evidence suggests that cardiac function may, in some cases, be adversely affected by HSCT. The multicenter Sickle Transplant Alliance for Research (STAR) registry collected data from 174 patients who received an HSCT between 1993 and 2016 ( Table 2) [150]: 75% (131) received cells from a matched related donor within the registry, and 58.1% received myeloablative conditioning. With a median follow-up of 3.2 years, 4.3% of patients with ejection fractions measured pre-and post-HSCT (5 of 116) had a change in ejection fraction from >55% before transplant to ≤55% after. Further, 2.9% of patients with shortening fractions measured pre-and post-HSCT (4 of 136) had a change in shortening fraction from >28% before transplant to ≤28% after. In another study, with a median follow-up of 4.2 years, among 355 participants with SCD, and a median age at HSCT of 10 years, enrolled in the Center for International Blood and Marrow Transplant Research (CIBMTR) registry between 1996 and 2015, the prevalence of congestive heart failure developing after HSCT was about 1% [151]. In a more recent study of 19 patients who underwent myeloablative haploidentical HSCT, fractional shortening was stable at 2 years post-HSCT compared to pre-HSCT [153]. In another small study of 13 children who received myeloablative HLA-matched sibling HSCT and 3 children who underwent reduced-intensity haploidentical HSCT, with a median follow-up of 8.6 years, all patients had normal cardiac function before HSCT; however, the median shortening fraction decreased from 41% (range 34-51%) to 37.5% (28-44%, p = 0.001) [152]. However, there was no change in shortening fraction post-HSCT when only evaluating the three patients who received reduced-intensity conditioning.
Sachdev et al. recently reported the ECHO results for individuals with SCD who received non-myeloablative conditioning followed by HLA-matched sibling or haploidentical HSCT [154]. Echocardiograms were analyzed at baseline and 3, 6, and 12 months post-HSCT. After successful HSCT among 44 patients, there were significant improvements in cardiac size, function, and diastolic filling parameters at 3 months, followed by continued, more minor improvements up to 1 year post-HSCT. Sachdev and colleagues also found a mild decrease in the myocardial strain at 3 months through 1 year post-HSCT, possibly from total body irradiation (TBI) or cyclophosphamide (Table 2) [154]. In another study, Saraf et al. reported that left atrial diameter decreased significantly at 1 year post-nonmyeloablative HLA-matched sibling HSCT [23]. A pediatric study including 11 pediatric patients with SCD who received myeloablative HSCT reported significantly decreased myocardial strain at a mean of 109 days post-HSCT [155]. However, at 1 year post-HSCT, myocardial strain improved and was comparable to baseline.

Pulmonary Outcomes following Curative Therapy in SCD
Upon evaluating data obtained from the Cooperative Study of SCD, Kassim and colleagues found that in 430 adults who did not receive curative therapy, lower predicted percent forced expiratory volume in 1 s (FEV1%) was associated with an increased hazard ratio for death [159]. Sparse data that follow the trajectory of lung function after curative therapy are available. In a prospective multicenter study conducted between 1991-2000 (Multicenter Investigation of Bone Marrow Transplantation for Sickle Cell Disease), 59 children ≤16 years old underwent HSCT from a matched related donor with myeloablative conditioning (Table 3) [160]. Among the 23 patients who had pulmonary function tests before and after HSCT, there was no difference between pre-and post-HSCT FEV1%. Four of eleven patients who had restrictive lung physiology at baseline went on to have a normal function after HSCT. Eight of the 10 patients who had normal baseline pulmonary function tests continued to have a normal pulmonary function after HSCT; two developed a restrictive pattern. Further, one of the two patients with an obstructive pattern had a normal pulmonary function after HSCT, and the other developed worsened obstructive disease after HSCT. Lastly, there was no significant change in percent predicted diffusing capacity for carbon monoxide (DLCO%) after HSCT. Table 3. Late effects studies assessing pulmonary function in patients with SCD who undergo HSCT. Similarly, Friedman and colleagues reported 19 children who received myeloablative haploidentical HSCT [153]. At 2 years post-HSCT, lung function was stable to improved. Another study revealed lung function was generally stable or improved after a median of 3 years in five patients who had lung function tests before and after receiving myeloablative or reduced-intensity HSCT [161]. Further, Bhatia et al. reported that in their single-center prospective trial of reduced-toxicity conditioning, FEV1% did not significantly change in 16 children with SCD up to 3 years post-HSCT [152]. Of 13 patients who had lung function tests pre-HSCT, 3 had restrictive lung disease, and 1 had obstructive lung disease [156].

Reference N Regimen Patient Population Duration of Follow-Up (Years) * Comments Pulmonary Function Tests
There was no statistically significant change in FEV1% at 1 year (N = 12) and 2 years (N = 11) after HSCT. In addition, at a follow-up of 2-8.5 years after reduced-intensity matched related donor HSCT, Krishnamurti found all 7 patients transplanted had stable lung function post-HSCT [162]. However, data analysis from the CIBMTR demonstrated pulmonary abnormalities developing after HSCT, with a cumulative incidence of about 2% at a median of 4.2 years post-curative therapy (Table 3) [151]. Unrelated donor HSCT was associated with a higher risk of pulmonary abnormalities (HR 5.90, 95% CI 1.14-30.42).
While no studies to date report the effects of myeloablative conditioning on FEV1% for adults with SCD, Saraf et al. reported that FEV1% significantly improved 1 year post-HSCT compared to baseline in 12 patients with SCD who underwent non-myeloablative conditioning (Table 3) [23]. In a more recent study of 122 patients, primarily adults, who received non-myeloablative conditioning with a median follow-up of 4 years [24], FEV1% predicted remained stable throughout follow-up. Further, the proportion of patients with moderate, moderately severe, and severe defects decreased. Therefore, these limited data suggest that FEV1%, a biomarker, when reduced, of early mortality in adults with SCD, may remain stable in children receiving myeloablative and reduced-intensity conditioning and at best improve in adults who undergo non-myeloablative conditioning.

Renal Outcomes following Curative Therapies in SCD
Chronic kidney disease is common among adults with SCD and is associated with early mortality [9][10][11][12][13]18,19], but there is minimal literature on the effect of HSCT on renal function. A report from the CIBMTR described sickle nephropathy developing in 7 (2%) of participants with 4.2 years of follow-up post-HSCT (Table 4) [151]. In a small study with follow-up of 8.2 years, in 13 children with SCD who underwent myeloablative HLAmatched sibling HSCT, mean GFR decreased significantly from 173 ± 56 mL/min/1.73 m 2 to 101 ± 24 mL/min/1.73 m 2 , p = 0.004, and in six children with SCD who received reduced-intensity haploidentical HSCT, mean GFR decreased from 98 ± 33 to 91 ± 47 mL/min/1.73 m 2 , p = 0.004 [152]. Matthes-Martin et al. reported the Austrian experience with eight children who received reduced-intensity conditioning for matched related donor HSCT with four years of follow-up [163]. Five patients had sickle nephropathy before HSCT. Four demonstrated normalization of renal volume and structure. Further, renal function was preserved in seven children post-reduced-intensity matched related donor HSCT [162]. A Canadian report of 18 children who received non-myeloablative conditioning for matched related donor HSCT found a decrease in hyperfiltration two years after HSCT, with a median estimated glomerular filtration rate of 142.3 before transplant and 127.6 mL/min/1.73 m 2 after [149]. Studies currently do not exist evaluating the incidence of renal failure in adults with SCD who underwent curative therapies.
3.4. Summary of Surveillance for Heart, Lung, and Kidney Disease following Curative Therapy for SCD Despite the research conducted to date in these areas, consensus-based guidelines, particularly for adult patients, have yet to be established. The main risk factors for earlier death in adults with SCD are progressive heart, lung, and kidney disease. Therefore, we have suggested recommendations for heart, lung, and kidney disease surveillance at baseline and following curative therapy (Table 5) based on a review of the late health effects of heart, lung, and kidney disease after HSCT in children and adults with cancer. However, given the paucity of data currently available on the late health effects of children and particularly adults who undergo HSCT for SCD and the lack of consensus to date on surveillance, we anticipate that the process of formulating these recommendations will be iterative. With such data, surveillance strategies for progressive organ damage after both myeloablative and non-myeloablative curative therapy in children and adults with SCD will evolve as new data become available, with the long-term goal of evidence-and consensus-based guidelines.

Discussion
Our understanding of the heart, lung, and kidney disease associated with HSCT is almost exclusively based on cohorts of patients who underwent HSCT for malignancies. As such, they were exposed to pre-transplant chemotherapy, radiation therapy, or both. In addition, HSCT conditioning regimens for cancer differ from those used for SCD. Further, prolonged vaso-occlusion, anemia, inflammation, and hypercoagulability generally lead to subclinical and overt organ damage over the lifetime, including the heart, lung, and kidney, in adults with SCD. Therefore, risk factors for and long-term health effects evaluated in cancer survivors will not necessarily apply to patients with SCD who receive curative therapy. Data in patients treated with curative therapies for SCD are much more limited than those treated with HSCT for malignancy and illustrate the critical need for prospective follow-up of children and adults with SCD who undergo curative therapy.
Heart, lung, and kidney dysfunction in adults with SCD are directly associated with decreased life expectancy. Fortunately for children with SCD, mortality rates have decreased to less than 2% of children before 18 years of age [4][5][6]. Thus, heart, lung, and kidney diseases are not associated with premature death in children. We and others have shown that adults with SCD and heart, lung, and kidney disease are more likely to die at least 20 years earlier than the general population [9][10][11][12][13][14][15][16][17][18][19]. Ultimately, the shortened lifespan of individuals with SCD, attributable to declining heart, lung, and kidney function, must be measured against favorable and unfavorable health outcomes associated with curative therapy. While patient-reported outcomes are essential to collect, studies examining the physiologic impact of curative therapy, including critical parameters such as blood pressure, ECHO, PFTs, and laboratory assessment of kidney disease, are critical to identifying heart and lung and kidney disease at an earlier, asymptomatic state.
New disease-modifying therapies have evolved along with the advances in curative therapy in the last several years. Three new drugs have been FDA-approved to ameliorate acute symptoms associated with SCD [164][165][166]. Defining health outcomes following curative therapy is essential to improve personalized decision making when considering curative versus disease-modifying therapeutic options.
To date, the referenced studies for SCD are small, have a short duration of follow-up, or both. Studies are indicated to evaluate whether HSCT abates, stabilizes, or exacerbates organ dysfunction in patients with SCD, to determine the optimal follow-up time, and to identify risk factors so that a personalized approach to curative therapy for SCD can be pursued. It is imperative to know if HSCT can prolong survival compared to those who receive disease-modifying therapies. In addition, despite an increased number of adults receiving myeloablative chemotherapy in preparation for gene therapy or gene editing, both short-and long-term follow-up is required to determine if these therapies offer a superior risk-benefit ratio to disease-modifying therapy or HSCT.
In conclusion, understanding the short, intermediate, and long-term health tradeoffs will facilitate comparing clinical outcomes for different SCD curative therapies. Studies are critically needed to educate patients, families, and providers about the long-term health effects of curative therapies for SCD and to inform and update guidelines for children and adults who receive curative therapies. Therefore, now is the time to systematically evaluate, with appropriate sample size for statistical significance, organ function in individuals who undergo curative therapies for SCD. With the adequacy of such data, we will meet the longer-term goal for and create new consensus guidelines when more data become available to guide surveillance post-HSCT for individuals with SCD.