Edited by: Ekamol Tantisattamo, University of California, Irvine, United States
Reviewed by: Orlando Gutierrez, University of Alabama at Birmingham, United States; Maria-Eleni Roumelioti, University of New Mexico, United States
This article was submitted to Nephrology, a section of the journal Frontiers in Medicine
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The risk of mineral and bone disorders among patients with chronic kidney disease is substantially elevated, owing largely to alterations in calcium, phosphorus, vitamin D, parathyroid hormone, and fibroblast growth factor 23. The interwoven relationship among these minerals and hormones results in maladaptive responses that are differentially affected by the process of kidney transplantation. Interpretation of conventional labs, imaging, and other fracture risk assessment tools are not standardized in the post-transplant setting. Post-transplant bone disease is not uniformly improved and considerable variation exists in monitoring and treatment practices. A spectrum of abnormalities such as hypophosphatemia, hypercalcemia, hyperparathyroidism, osteomalacia, osteopenia, and osteoporosis are commonly encountered in the post-transplant period. Thus, reducing fracture risk and other bone-related complications requires recognition of these abnormalities along with the risk incurred by concomitant immunosuppression use. As kidney transplant recipients continue to age, the drivers of bone disease vary throughout the post-transplant period among persistent hyperparathyroidism,
Kidney transplant recipients (KTRs) are a unique population with substantial risk factors for bone disease and associated complications. KTRs can experience persistent alterations in mineral and bone disease (MBD) parameters, immunosuppressive modification of osteoblast/osteoclast activity, de-novo MBD abnormalities, and age-related bone loss. Understanding the patterns and pathophysiology of MBD pre- and post-transplant is important to accurately interpret laboratory and radiologic tests, and to guide therapy to reduce complications, including fractures.
The abrupt change in kidney function and the medications required to maintain a graft are competing forces that simultaneously affect bone disease. In the first 12 months after kidney transplantation, bone loss, as evidenced by surrogate laboratory and imaging tests, is most pronounced (
As per the Scientific Registry of Transplant Recipients (SRTR) annual data report (
Due to the numerous factors impacting mineral and bone homeostasis, evaluation, and treatment are not standardized. Responses to decreased bone mineral density, hyperparathyroidism, perioperative hypophosphatemia, and vitamin D disorders vary by institution. Consequently, examining treatment regimens to address mineral disorders and modify risk in bone-related disease, and the evidence that supports these plans, can help identify gaps in knowledge in need of further examination.
Calcium, phosphate, vitamin D, parathyroid hormone (PTH), and bone-derived fibroblast growth factor (FGF-23) interact through a series of underlying feedback mechanisms. In patients with normal kidney function, the main goal of this interplay is to preserve serum concentrations of calcium and phosphate, and ultimately bone health. PTH synthesis and secretion is influenced by calcium, phosphate and vitamin D levels. In a functioning kidney, 25-hydroxy vitamin D (25(OH)D) is converted to active 1,25-dihydroxyvitamin D (1,25(OH)D) by 1α-hydroxylase, an enzyme that is upregulated by PTH and inhibited by high FGF-23 levels. Active vitamin D can stimulate gut calcium and phosphate absorption. Either through increased sodium-phosphate cotransporter (NaPi-IIb) expression or increased transport via brush-border membrane vesicles, vitamin D stimulates intestinal phosphate absorption (
In patients with chronic kidney disease (CKD) or acute kidney injury (AKI), when glomerular filtration rate (GFR) falls to less than 60 ml/min, a rise in FGF-23 production by osteocytes and osteoblasts is one of the earliest changes (
The distal convoluted tubule is responsible for the majority of α-klotho production (
As CKD advances and GFR falls further, phosphate excretion must increase per nephron to maintain balance. For reasons that have yet to be elucidated, FGF-23 levels increase. A combination of high FGF-23 levels and reduced functional nephron mass leads to low 1α-hydroxylase activity and resultant low active vitamin D levels. These lower active vitamin D levels, in conjunction with resulting hypocalcemia, stimulate a subsequent increase in PTH (
Immediately post-transplant, circulating levels of FGF-23 and PTH are still high. However, with successful transplantation, GFR is significantly higher. As a result, high levels of PTH and FGF-23 result in significant urinary phosphorus losses and hypophosphatemia (Figure
Understanding of MBD physiology is not yet complete. While the role of FGF-23 in phosphate and vitamin D metabolism has been increasingly uncovered, uncertainty over its most proximal stimulus remains. Several studies have demonstrated increases in FGF-23 with phosphate loading (
Clinical disorders related to MBD in KTRs include calcium and phosphate disorders, vitamin D deficiency, secondary and tertiary hyperparathyroidism, osteoporosis, and osteonecrosis (Table
Mineral and bone disorders after kidney transplantation.
Calcium Disorders |
Hypercalcemia |
|
|
Hypocalcemia |
|
Phosphorus Disorders |
Hypophosphatemia |
|
|
Hyperphosphatemia |
|
Vitamin D Disorders |
Hypovitaminosis D |
PTH Disorders |
Hyperparathyroidism |
|
|
Osteopenia and Osteoporosis |
Aging |
Residual MBD |
|
Hypogonadism |
Medications |
|
Osteonecrosis |
Glucocorticoids |
Hypercalcemia is common after kidney transplantation and has been reported in 11–31% of KTRs within 1 year (
The primary drivers of hypercalcemia are persistent hyperparathyroidism and high vitamin D levels. In addition to high PTH levels, resolution of uremia post-transplant is also associated with a decrease in skeletal resistance to PTH. In addition to these endogenous changes, most transplant programs use calcium and vitamin D supplements, especially when a steroid is part of the maintenance immunosuppressive regimen. Rarely, acute severe hypercalcemia can occur in the immediate post-transplant period, requiring emergency parathyroidectomy. Often these patients were on high doses of cinacalcet prior to transplantation (
Even though hypercalcemia is multifactorial, most patients have inappropriately high PTH level for the degree of hypercalcemia. In such patients, especially in the first few months after transplant, no further work up may be needed. However, if PTH is appropriately suppressed, non-PTH related causes need to be investigated. Similar to evaluation of hypercalcemia in non-transplant patients, other etiologies including granulomatous disease, milk-alkali syndrome, malignancies need to be ruled out (
In majority of patients, hypercalcemia is gradual, asymptomatic, and can be medically managed. In patients with mild hypercalcemia, we encourage adequate fluid intake and avoidance of medications that can independently increase serum calcium levels, such as thiazide diuretics and calcium supplements. If vitamin D replete, vitamin D supplements should be discontinued. If hypercalcemia persists despite these measures, and if PTH level is persistently high, cinacalcet can be started temporarily and dose titrated (
Hypocalcemia is infrequently observed after kidney transplantation. Serum calcium levels may decrease initially in the first week after transplantation, likely secondary to a fall in PTH levels and discontinuation of exogenous calcium and vitamin D supplements (
Hyperphosphatemia is usually only seen in patients with delayed graft function, or in transplant patients with advanced CKD.
On the other hand, hypophosphatemia is common in KTRs and occurs in ~50% of patients. It most commonly occurs 3–4 weeks after transplantation, especially in patients with immediate graft function and high pre-transplant PTH levels (
Among medications, glucocorticoids can reduce the expression of Na-Pi co-transporters and worsen urinary loss of phosphorus (
In majority of patients, hypophosphatemia is asymptomatic. Muscle weakness, rhabdomyolysis and hemolysis do not occur until serum phosphorus concentration is <1 mg/dL. Hypophosphatemia may be associated with a lower risk of death-censored graft failure and cardiovascular mortality, but not non-cardiovascular or all-cause mortality (
The majority of KTRs have vitamin D deficiency (
From a transplant perspective, low 25(OH)D maybe associated with an increased risk of all-cause mortality. Very low levels may also be associated with rapid decline in kidney function (
In the last few decades, vitamin D and its effect on extra-skeletal health has gained significant interest, especially its role in cancer, cardiovascular disease, diabetes, and mortality (
Secondary hyperparathyroidism in advanced CKD results from multiple stimuli, including hyperphosphatemia, hypocalcemia, low 1,25(OH)D levels, and skeletal resistance to PTH. These factors result in continuous stimulation of PTH synthesis and secretion. Parathyroid hyperplasia that ensues is initially diffuse and polyclonal, and still responds to vitamin D therapy and cinacalcet. However, with time, there is down regulation of vitamin d receptors and calcium-sensing receptors in the parathyroid tissue, and hyperplasia often becomes monoclonal or nodular in nature (
With successful transplantation and higher GFR, most of these stimuli of parathyroid hyperplasia abate. This often leads to a gradual decline in PTH concentrations. Unlike FGF-23 levels that precipitously decline post-transplant, the fall in PTH is more gradual. It has been reported that 25 to >80% of patients still have inappropriately high PTH beyond 1-year post transplant (
Progressive kidney disease commonly results in the spectrum of bone diseases known as renal osteodystrophy. How this collection of bone diseases evolves in the post-transplant period is unclear due to the lack of available bone biopsies. This paucity of histological evidence hampers our ability to understand the evolution of osteodystrophy post-transplantation. As in the pre-transplant period, vitamin D deficiency has been associated with severe cases of osteomalacia in KTRs. In a small study of 20 subjects, adynamic bone disease was the predominant pathology prior to transplant, and low-turnover disease persisted 6 months after transplant. The relative decrease in PTH secretion as a result of improved phosphaturia may be the reason for these early findings. However, as allograft function deteriorates over time, high-turnover disease, such as osteitis fibrosa cystica, becomes more common (
Osteopenia and osteoporosis are conditions highlighted by microarchitectural changes that result in reduced bone mass and increased skeletal fragility. As in the general population, age, race, ethnicity, weight, diabetes mellitus, tobacco use, and menopausal status influence osteoporotic risk. With aging, an imbalance in bone remodeling results from increased osteoclast activity and reduced osteoblast production and differentiation. After transplantation, several other factors including residual MBD, glucocorticoids, hypomagnesemia, and hypogonadism play a role in bone loss.
Transplant medications modify osteoprotegerin and the receptor activator of nuclear factor-κB ligand (RANKL), potent mediators of the bone remodeling process. Through regulation of the RANKL system, glucocorticoids decrease osteoblast proliferation and differentiation, while promoting osteoclastogenesis (
Hypomagnesemia, possibly by stimulating PTH secretion and osteoclastogenesis while inhibiting osteoblast proliferation, increases fracture risk in dialysis patients (
Gonadal hormones play a significant role in achieving peak bone mass, and hypogonadism is associated with bone loss and low BMD. Around 40% of ESRD patients have testosterone deficiency, (
Other risk factors include poor nutritional status, tobacco use, and alcohol use. Recently, proton pump inhibitors have been associated with hip fractures among KTRs (
Osteonecrosis or avascular bone necrosis, a pathological condition characterized by bone death, has a strong association with glucocorticoid use. Prevalence has been reported to be between 3-40% in different studies (
Prevention, early diagnosis, and slowing the progression of osteonecrosis is key, as there is no proven therapy, especially for advanced disease. This includes limiting steroid use, and avoiding other risk factors, including alcohol use and smoking. Surgical options for symptomatic patients with progressive early stage osteonecrosis include core decompression, osteotomy, and bone grafting. When bone collapse has already occurred, hemiarthroplasty or total-hip arthroplasty may be offered. Recently, surgeons have considered combining core decompression with stem cell-based (implantation of autologous bone marrow concentrate or mesenchymal stem cell) and growth factor-based (bone morphogenic proteins, vascular endothelial growth factor) regenerative therapies (
Biochemical abnormalities of disordered mineral metabolism are common and fluctuate widely, especially in the immediate post-kidney transplant period. Hypophosphatemia occurs early after kidney transplantation. Initial hypocalcemia could be followed by hypercalcemia, and in some patients, hypercalcemia could persist beyond 1-year post-transplantation. Therefore, the KDIGO 2017 guideline update recommends that serum calcium and phosphorus levels be measured at least weekly in the immediate post-kidney transplant period until stable (graded 1B) (
Proposed biochemical testing in kidney transplant recipients.
Serum calcium | At least weekly | Every 6–12 months |
3–6 months | 1–3 months | |||
Serum phosphate | At least weekly | Every 6–12 months |
3–6 months | 1–3 months | |||
Serum intact PTH | Once | Once |
6–12 months | 3–6 months | |||
Serum 25(OH)D | Once | Once |
|||||
Bone density | Check to assess fracture risk if risk factors for osteoporosis present |
Considering the high prevalence of hyperparathyroidism and vitamin D deficiency in KTRs, serum 25(OH)D and PTH levels are commonly measured after transplantation. The KDIGO 2017 guideline update suggests that a baseline 25(OH)D level might be measured in the immediate post-transplant period, and repeated testing should be determined by baseline values and interventions (
The use of DXA to predict fracture risk in KTRs remains a challenge. Limitations include: (1) inability to distinguish between cortical and trabecular bone, which are differentially affected in secondary hyperparathyroidism; (2) confounding signals from concomitant vascular calcification; and (3) observations that glucocorticoid-induced fractures occur at higher BMD values than in patients with non-glucocorticoid-induced osteoporosis (
The World Health Organization's FRAX Tool is used commonly in the general population to predict the 10-year probability of a major osteoporotic fracture. It utilizes an algorithm that includes age, sex, and several clinical risk factors for fracture, including parental hip fracture, previous fragility fracture, rheumatoid arthritis, current smoking, secondary osteoporosis, low body mass index (BMI < 19 kg/m2), prolonged glucocorticoid use, and excessive alcohol intake. The FRAX score does not require bone densitometry data to predict fracture risk, making it an attractive clinical tool. However, the etiology of transplant bone disease is multifactorial, and pathology is widely variable. Therefore, factors in the FRAX algorithm that are associated with fracture risk in the general population may not accurately predict fractures in KTRs.
Recently, two Canadian studies assessed the prognostic value of FRAX in KTRs and patients with reduced kidney function (
In KTRs, particularly those with reduced kidney function, the presence of renal osteodystrophy complicates our understanding of bone disease. Bone pathology varies between low-turnover, high-turnover, and mixed states. Consequently, 2-dimensional measurements of bone density often provide limited understanding of bone disease, missing measures of quality and strength. Glucocorticoid-induced fractures occurring at relatively higher BMD values (
High-resolution peripheral quantitative computed tomography provides a mechanism for understanding density and microarchitecture of cortical and trabecular regions separately (
A novel parameter for describing microarchitecture, trabecular bone score, may provide a potential method for examining bone quality and strength through gray-scale variograms of the spine image available from a DXA (
Bone biopsy is an informative diagnostic procedure to evaluate bone abnormalities in patients with kidney disease. To interpret bone biopsy results better, TMV classification was developed using three histologic descriptors assessed by bone histomorphometry; bone turnover (T), mineralization (M) and volume (V). While mineralization is classified as normal or abnormal, turnover and volume can be classified as low, normal or high.
Common bone histopathologic descriptions in ESRD patients include normal bone, osteitis fibrosa cystica, mixed uremic osteodystrophy, osteomalacia, and adynamic bone disease. Compared to older studies that showed higher prevalence of mixed uremic osteodystrophy in KTRs (
Typically after kidney transplantation, uremia-related bone changes improve rapidly, even though changes of hyperparathyroidism can take more than a year to improve (
Old age, time on dialysis, and time after transplant are significant predictors for negative effect on bone mass (
Despite the presence of standardized classification, interpretation of existing literature is difficult. First, only recent studies have used the TMV classification. Second, there was significant variation when bone biopsy was performed after transplantation, making it difficult to interpret. Third, there has been a significant change in immunosuppressive medications over the years, including recent steroid sparing protocols, making it difficult to compare new and old studies. Lastly, since bone biopsy is invasive, most patients had only one biopsy and there is limited data on follow up and evolution of bone histology.
While bone biopsy provides the most direct information regarding bone health, it's relevance is not generalizable to every region. Femoral, lumbar, and radial pathology can be substantially different. More importantly, due to substantial discomfort associated with the procedure, bone biopsies have fallen out of favor. Our institution does not utilize bone biopsy as part of clinical evaluation for the above reasons.
Treatment of MBD post-transplant often requires a holistic approach with ultimate focus on bone health, instead of focusing on individual lab abnormalities. Also, it is important to note that metabolic and bone changes after transplantation tend to be dynamic and a cookie-cutter approach may not be appropriate for all patients.
Due to ongoing urinary losses in the immediate post-transplant period, it is often difficult to achieve and maintain normal serum phosphate levels with oral replacements. Oral supplements (oral sodium-potassium phosphate tablet and powder) are started when serum phosphate level is <2 mg/dL with a goal to maintain serum level around 2 mg/dL. It is recommended not to elevate serum level to normal range for fear of exacerbating hyperparathyroid state. There is also concern of nephrocalcinosis with aggressive replacement, especially in the presence of hyperparathyroidism, simultaneous use of cinacalcet, and oral alkali. Each 250 mg tablet contains around 8 mmol of phosphate. Neutral phosphate salt supplementation, in addition to correcting hypophosphatemia, has been shown to increase muscle ATP and phosphodiester content without affecting other mineral metabolism and has been shown to improve renal acid excretion (
While most patients with mild hypocalcemia can be managed with oral calcium supplements, patients with hungry-bone disease and severe hypocalcemia need high-dose activated vitamin D such as calcitriol or paricalcitol, along with parenteral calcium infusions followed by high-dose oral calcium supplements. We recommend the use of calcium and cholecalciferol in all kidney transplant patients with normal serum calcium. Especially when steroids are given, administration of vitamin D improves GI calcium absorption. In the absence of randomized trials, the dose and choice of vitamin D is quite variable across transplant centers. Most agree the use of adequate dose of vitamin D to correct vitamin D deficiency and maintain serum 25(OH)D level of >30 ng/mL. The KDIGO 2009 guidelines suggest Vitamin D deficiency should be corrected as recommended for the general population (graded 2C) (
Active vitamin D supplementation has been used successfully to treat secondary hyperparathyroidism in KTRs in much the same way that it is utilized in patients with CKD. In fact, paricalcitol, whether given intravenously or orally, has even been shown to be more effective than cinacalcet in reaching goal PTH and reducing markers of bone turnover (
In KTRs with hyperparathyroidism and hypercalcemia, cinacalcet reduces PTH levels and as a result, improves serum calcium (
There may be drug-drug interaction between cinacalcet and tacrolimus; when given together, cinacalcet may reduce tacrolimus concentration (
In the post-transplant setting, cinacalcet is primarily used for the management of severe hypercalcemia associated with tertiary hyperparathyroidism. Since cinacalcet is not FDA approved in KTRs, most programs use the drug only in patients with refractory and severe hypercalcemia (corrected serum calcium >11 mg/dL). There are no clear guidelines for the use of this drug. Thus, while the benefit for serum calcium reduction and perhaps BMD improvement is evident in tertiary hyperparathyroidism, its utility in persistent hyperparathyroidism without hypercalcemia or
Bisphosphonates are the most commonly used anti-resorptive medication in the general population. However, among KTRs, bisphosphonates have largely demonstrated improvements in BMD without notable changes in fracture risk. Kan et al. conducted a systematic review that noted an improvement solely in lumbar spine BMD (
After the first-year post-transplant, insufficient evidence exists to guide whether bisphosphonate therapy should be continued. KTRs should be re-evaluated in terms of their glucocorticoid dose and repeat DXA. Long-term studies examining clinical events are needed to fully understand the utility of bisphosphonate. Additionally, research is needed to understand the utility of alternative therapy in patients with reduced BMD and without overt laboratory evidence of increased bone turnover. More specifically, an alternative anti-resorptive medication, teriparatide, a PTH analogue, may have a role in adynamic bone disease, which is characterized by PTH resistance and relative PTH deficiency.
Denosumab, a RANKL inhibitor presents an attractive alternative, particularly in patients with low GFR. These patients require close monitoring for hypocalcemia. Much like bisphosphonate use, BMD parameters seem to improve, but no evidence exists for changes in fracture risk (
With the advent and expanded therapeutic use of cinacalcet in KTRs, the role of parathyroidectomy (PTX) in tertiary hyperparathyroidism has evolved. In current practice, PTX is limited to KTRs with profoundly elevated parathyroid hormone and calcium levels, symptomatic disease (fractures, EKG changes, neurologic sequalae, etc.) or failure of long-term medical management (
When compared with cinacalcet, a greater percentage of KTRs who underwent subtotal parathyroidectomy had normocalcemia, normal PTH levels, and increased femoral neck bone mineral density at 1 year (
The optimal timing and choice of surgery for tertiary hyperparathyroidism is often debated. Reduced all-cause and cardiovascular mortality is seen among patients with CKD and severe secondary hyperparathyroidism, and presumably pre-transplant surgery offers this benefit among KTRs (
Even though high PTH levels (>500 pg/mL) and serum calcium level (>9.5 mg/dL) are risk factors for needed PTX post-transplant, enough time should be given for spontaneous regression of gland hyperplasia if surgery is planned post-transplant. Post-transplant PTH levels appear to fall rapidly in functional allografts 3-6 months post-operatively, and then follow a more gradual decline that plateaus at 1 year (
The choice of operation has evolved over time. Classic approaches included subtotal or total PTX with auto transplantation (
The risk of bone disease and its complications vary throughout the post-transplant timeline. Appreciating the residual maladaptive responses found in end-stage kidney disease and the new onset risks that accompany transplant are key to perioperative management. As most MBD parameters begin to normalize with time, subtle aspects of evaluation must be appreciated to reduce the development of bone pathology. Clinicians encounter a different spectrum of MBD abnormalities including hypophosphatemia, hypercalcemia, and persistent hyperparathyroidism. Reversal of MBD abnormalities and vitamin D deficiency is the focus of initial management of KTRs. Parathyroidectomy is reserved for patients with tertiary hyperparathyroidism who fail medical treatment. Later in the post-transplant period, clinicians should aim to mitigate age-related bone disease. While bisphosphonates demonstrate improvements in bone mineral density, no evidence exists for impacting fracture risk and more novel therapies require further study.
Limitations to evaluation center around the poor predictive value of laboratory measures, imaging, and clinical tools. PTH values are idiosyncratic in their influence by graft function and pre-existing nodular hyperplasia of the parathyroid gland. The addition of trabecular bone score may be able to capture measures of bone quality and strength that are missing from DXA scans alone. The FRAX tool shows early promise in its prediction of fractures among KTRs.
The heterogeneity of KTRs and competing influences make studying therapies directed at MBD particularly challenging. Additionally, the latent period before detectable clinical events, such as fractures, is lengthy. With more detailed and specific surrogate markers, investigators will be able to generate feasible studies with increased clinical relevance.
CV, JP, RC and VR actively contributed to the manuscript by writing individual sections of the final paper. As per the International Committee of Medical Journal Editors guidelines, all authors qualify for authorship of this manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.