(ARB) may be a better choice in patients with idiopathic CKD. This concept is based upon studies using ACEI and ARBs in animal models of radiation‐induced injury, and upon recent clinical experience [70]. In addition to controlling blood pressure, ACEI and ARB might exert additional positive affects by reducing inflammation and inflammatory markers [71,72]. Extrapolating from studies in the diabetic population, in conjunction with the observation that albuminuria is frequent after HCT, raises the possibility that these agents might slow progression of CKD in patients with albuminuria after HCT. Controlled trials using ACEI or ARB after HCT are needed [70].
Muscle or connective tissue
Myopathy and/or myositis is a recognized late effect that is perhaps cGVHD‐related, but acute myopathy due to glucocorticoid therapy remains in the differential, as is debilitating, sometimes painful myositis that can be caused by statin therapy. Myopathy symptoms are often exacerbated by lack of physical activity and fatigue. Serum CPK, aldolase, CRP or ESR can be helpful in diagnosing GVHD‐associated myositis. A dynamically changing, informative marker for an individual patient, can sometimes be identified and followed serially for trends during the tapering of IST because a rise in that marker often heralds recurrent myositis symptoms.
Bone
The major LTFU complications are low bone mineral density (BMD) and avascular bone necrosis (AVN).
Key points of practice variation between adults and children include critical differences in defining osteoporosis and osteopenia, the greater role of hormone replacement therapy (HRT) for children with clinically significant low BMD, and lack of data regarding the portfolio of bone‐strengthening agents used to treat adults. Adult definitions of osteopenia or osteoporosis based on T‐scores should not be used for children because T‐scores report the number of standard deviations below the BMD of an average 30‐year old. In children, Z‐scores are used for reporting BMD status because they consider age‐ and sex‐matched comparisons. However, Z‐scores per se are insufficient to define osteopenia or osteoporosis. In pediatric DXA reports; “low BMD” (instead of osteopenia) is the term used when BMD Z‐scores are ≤ ‐2.0. The International Society of Clinical Densitometry guidelines defines “osteoporosis” in children by the presence of both a clinically significant fracture history and BMD Z‐score ≤ ‐2.0 (must be adjusted for height‐age in short children to avoid BMD underestimation or tall children to avoid overestimation). A clinically significant fracture history is one or more of the following: ≥2 long bone fractures by age 10 years, or ≥3 long‐bone fractures at any age up to age 19 years. Low BMD occurs commonly in children after HCT with up to 21% having BMD Z‐scores below ‐2.0 and up to 33% below ‐1.0 before reaching adulthood, so that monitoring and potential management approaches are needed [73,74].
BMD monitoring, vitamin D and calcium supplementation and lifestyle modifications parallels the approach taken for adults. When treating osteoporosis or low BMD, the emphasis is on growth hormone and/or gonadal HRT if clinically appropriate and supervised by a pediatric endocrinologist to avoid compromising final adult height. Growth hormone therapy after HCT does not appear to be associated with an excess of second malignancies or recurrent leukemia [75]. There is less emphasis on bone strengthening agents like bisphosphonate or calcitonin and almost no pediatric data for newer agents like denosumab, teriparatide, romosozumab, and raloxifene (reviewed elsewhere) [76] Bisphosphonate therapy is reserved for osteoporosis not responding to other measures. One retrospective study showed that pamidronate can improve BMD in children after HCT [77].
AVN occurs in 3–10% by 5 years post‐HCT [78] and pediatric risk factors include age >5 years, TBI‐based conditioning, cGVHD, duration of steroids and female gender [79]. Femoral head is the commonest site, followed by knee, vertebral column and ankle [79]. The exact pathogenesis is poorly understood but a final common pathway is bone ischemia due to any combination of obliterative arteritis, thrombophilia, hyperlipidemia, fat embolism, repeated microinfarcts of weight‐bearing bone, and increased intramedullary pressure, possibly secondary to increased intramedullary fat (possibly glucocorticoid‐induced [80]). Plain X‐rays or MRI are appropriate next steps when AVN is suspected, based on the presence of risk factors or functional pain in the involved joints, later progressing to pain at rest when AVN severity increases. Plain X‐rays do not rule out occult radiographic lesions, making MRI the modality of choice for staging and early diagnosis. No formal staging system is applicable to all joints but a simplified staging system is used to describe joint involvement in relation to sub‐chondral collapse as: (A) “pre‐collapse”, (B) “early collapse” with depression of <2 mm, and (C) “late collapse” with >2 mm of joint depression or secondary joint changes [81–84]. Pre‐collapse lesions allow for conservative management versus advanced (post‐collapse) lesions which tend to be managed surgically and referral to orthopedics is always advised.
Non‐surgical, pre‐collapse therapies have included: medication, hyperbaric oxygen and extracorporeal shock‐waves [82,84], but reported benefits have been mixed, with no consensus on the standard of care [85]. Bisphosphonates may reduce the incidence of collapse and early studies showed improved function for up to 10 years posttreatment but recent meta‐analyses in femoral head AVN failed to demonstrate improvement in hip dysfunction, progression‐free interval, or need for hip replacement [86]. Likewise statin [55,87] and enoxaparin [88] therapies have not been proven to change AVN outcomes [84]. Core decompression (CD) is a surgery for pre‐collapse AVN that involves removing the necrotic segment and reducing intraosseous pressure to allow healing. CD is usually more successful in younger patients with lower BMI [82] and can be combined with non‐vascularized or vascularized bone grafting to provide structural support while the necrotic lesion heals and remodels. A recent meta‐analysis of CD, or equivalent procedures, found an overall success rate to be 65%. In practice, these procedures are effective at relieving acute pain but it is unclear if natural progression of AVN is altered [83,89]. Once collapse occurs, surgical options are osteotomy [90,91], designed to rotate necrotic bone away from the weight‐bearing surface and allow for healing of the involved segment; total hip resurfacing (metal‐on‐metal cup); or total joint replacement for skeletally mature patients [84]. Advancements in artificial bearing surfaces and porous ingrowth implants has reduced concerns about implant survivorship for younger patients [82,83] Contraindications to AVN surgery after HCT include active infection and relevant medical comorbidities. Medications like high‐dose glucocorticoids or sirolimus can impede wound healing. While there is no consensus as to a safe dose of glucocorticoids, sirolimus may be held peri‐operatively or switched to another agent. Risks for impaired wound healing, fractures, and friability of connective tissues must be weighed against benefits of surgery.
Skin
Late effects in the skin are similar to those seen in adults and the key problems can be permanent sequelae of cGVHD or high‐dose TBI/cranial irradiation. The former may cause sclerosis ± contractures, alopecia, nail dystrophy and disfiguring skin manifestations that include poikiloderma, ichthyosis, keratosis pilaris, vitiligo or hyperpigmentation, and patches of morphea through confluent superficial and/or deep tissue sclerosis. Alopecia may be a sequela of TBI/cranial irradiation. See also “cGVHD” and “Subsequent neoplasm” sections.
Endocrinopathies
In children, these include disturbances of the hypothalamic‐pituitary adrenal axis, and end‐organ damage to thyroid and/or gonads mainly from alkylating agents and radiation exposures but are often multifactorial.
Growth Hormone deficiency
Growth in children and the attainment of normal adult height is a complex process that requires balanced nutritional, genetic, endocrine, and other physical and psychosocial factors. During
