Meera Gupta1,2*
Gabriel Orozco1,2Madhumati Rao3Roberto Gedaly1,2Hartmut H. Malluche3Javier A. Neyra3,4*- 1Department of Surgery - Transplant Division, University of Kentucky, College of Medicine, Lexington, KY, United States
- 2Department of Surgery, University of Kentucky, Lexington, KY, United States
- 3Department of Internal Medicine - Nephrology, Bone and Mineral Metabolism Division, University of Kentucky, College of Medicine, Lexington, KY, United States
- 4Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
Cardiovascular disease and mineral bone disorders are major contributors to morbidity and mortality among patients with chronic kidney disease and often persist after renal transplantation. Ongoing hormonal imbalances after kidney transplant (KT) are associated with loss of graft function and poor outcomes. Fibroblast growth factor 23 (FGF-23) and its co-receptor, α-Klotho, are key factors in the underlying mechanisms that integrate accelerated atherosclerosis, vascular calcification, mineral disorders, and osteodystrophy. On the other hand, kidney donation is also associated with endocrine and metabolic adaptations that include transient increases in circulating FGF-23 and decreases in α-Klotho levels. However, the long-term impact of these alterations and their clinical relevance have not yet been determined. This manuscript aims to review and summarize current data on the role of FGF-23 and α-Klotho in the endocrine response to KT and living kidney donation, and importantly, underscore specific areas of research that may enhance diagnostics and therapeutics in the growing population of KT recipients and kidney donors.
Introduction
Cardiovascular disease (CVD) and bone mineral disorders are important causes of mortality and morbidity among end-stage kidney disease (ESKD) patients (1). The endocrine adaptation to a decreased glomerular filtration rate (GFR) plays a central role in the cardiovascular and skeletal alterations observed in patients with chronic kidney disease—mineral bone disorder (CKD-MBD). Fibroblast growth factor 23 (FGF-23) and its coreceptor, α-Klotho, are key factors in phosphate homeostasis, and their dysregulation is an essential link between osteodystrophy, left ventricular hypertrophy, atherosclerosis, systemic inflammation, and renal fibrosis observed in patients with ESKD (2).
While the treatment of choice for ESKD is kidney transplant (KT), CVD continues to be a significant cause of morbidity and mortality after transplantation and is a contributing factor to graft failure and loss (3). Post kidney transplant patients (PKTP) have persistent alterations in bone mineral metabolism exacerbated by immunosuppressive therapy, which can lead to progression of bone disease and CVD (4). While the bone-vascular axis has been extensively studied and is significantly affected in patients with ESKD, the endocrine response to kidney transplantation and kidney donation is not yet fully understood. Among kidney donors, significant derangements of markers of bone metabolism, including serum α-Klotho, have been reported after nephrectomy (5–9). However, the clinical impact, if any, of these alterations in otherwise healthy living donors has not been determined.
In this manuscript, we aim to review and summarize current data on the role of FGF-23 and α-Klotho in the endocrine response to KT and living kidney donation. Importantly, we intend to underpin specific areas of research that may enhance diagnostics and therapeutics in the growing population of KT recipients and kidney donors.
FGF-23 and α-Klotho in Mineral Metabolism
FGF-23 is one of the few fibroblast growth factors that enters the systemic circulation and acts as a hormone (10). FGF-23 is synthesized by osteocytes and secreted in response to rising serum phosphate levels. Its secretion is also stimulated by parathyroid hormone (PTH), vitamin D, soluble α-Klotho, and pro-inflammatory cytokines including IL-1, IL-6, and TNFα (2, 11–13). All fibroblast growth factor receptors (FGF-R) have a low affinity for FGF-23, and the high-affinity interaction depends on the expression of the co-receptor, α-Klotho (14, 15).
The organs most impacted by FGF-23 are the kidneys and parathyroid glands (Figure 1). In the absence of disease, FGF-23 induces the degradation and decline in the synthesis of sodium-dependent phosphate transport protein 2A (NaPi2A) in the kidney (16). In doing so, FGF-23 directly decreases proximal tubular reabsorption of phosphate (17). Highlighting its physiological relevance, animal models with a deletion on FGF-23 or α-Klotho genes develop phosphate retention (18). FGF-23 also modifies mineral metabolism by decreasing calcitriol levels through two different mechanisms: it decreases calcitriol synthesis by downregulating 25-hydroxyvitamin D3 1α hydroxylase in the proximal tubular cells of the kidney, and it increases vitamin D inactivation by up-regulating vitamin D 24-hydroxylase (CYP24A1) expression (19, 20). The decrease in serum calcitriol contributes to PTH secretion despite a direct inhibition of the parathyroid glands by FGF-23 (20, 21). FGF-23 also promotes calcium absorption in the distal convoluted tubules, counterbalancing the inhibition of calcitriol synthesis (22). Notably, FGF-23 auto-regulates its effects by inhibiting the expression of α-Klotho (23). Hence, FGF-23 has a significant direct and indirect effect on phosphate and calcium metabolism.
Figure 1. FGF-23 is secreted by osteocytes in response to different endocrine and mineral stimuli including PTH and calcitriol. The main targets of FGF-23 are the kidneys and the parathyroid glands. In the kidneys, it increases phosphate excretion and decreases calcitriol synthesis. Decreased levels of calcitriol increase PTH secretion. On the parathyroids glands, the direct effect of FGF-23 is inhibitory. Also, FGF-23 downregulates the expression of its co-receptor α-Klotho (anatomical images courtesy of Essential Anatomy @3D4Medical).
α-Klotho, discovered as a gene linked to aging, is predominantly expressed in the kidney, specifically in the distal tubules (24, 25). The α-Klotho gene encodes a 130 kDa single-pass transmembrane protein consisting of two extracellular domains (KL1 and KL2), a transmembrane domain, and a short cytoplasmic tail. Part of the extracellular domain of transmembrane α-Klotho is cleaved by proteases (26–28). A secreted form of α-Klotho has also been postulated from an alternatively spliced transcript (29, 30). Cleaved α-Klotho proteins are released into the circulation and are referred to as soluble α-Klotho. Soluble α-Klotho acts as an endocrine or paracrine factor affecting multiple distant organs such as the heart, lungs, bone, and brain (31–37). α-Klotho increases FGF-23 expression in the bone (36) and acts as a non-enzymatic scaffold protein that enhances FGF-23 signaling (38).
α-Klotho is an important regulator of mineral metabolism homeostasis: (1) it decreases renal phosphate reabsorption by acting as a co-receptor for FGF-23 binding to FGFR1 (15); (2) it directly promotes the internalization and degradation of the NaPi2a cotransporter in the renal proximal tubules (39); and (3) it suppresses vitamin D signaling (α-Klotho knockout mice can be rescued from a phenotype of soft tissue calcification by deletion of the CYP27B1 gene) (40–42). In addition, α-Klotho has a plethora of pleiotropic actions as an inhibitor of apoptosis, fibrosis, and cell senescence (43–46).
FGF-23 and α-Klotho in Chronic Kidney Disease and Its Complications
Patients with CKD have significantly reduced functional renal cell mass, leaving the residual renal parenchyma to maintain homeostasis by increasing phosphate excretion. FGF-23—through its phosphaturic effects— plays a crucial role in this response (2, 17) and is an early biomarker of CKD (47). As intact FGF-23 is cleared by the kidneys, a decreased glomerular filtration rate (GFR) also independently contributes to its rising levels (48–50). Among patients with CKD, sustained elevated levels of FGF-23 lead to constant inhibition in calcitriol synthesis, with a consequent increase in PTH secretion (51, 52). Because PTH stimulates the release of FGF-23 synthesis, a closed loop of stimulation is created. Supraphysiologic levels of FGF-23 are also perpetuated by downregulation of its co-receptor α-Klotho, resistance to its renal action, and further hyperphosphatemia (53–56). Remarkably, the compensation to impaired kidney function might promote further progression of CKD through different mechanisms: the phosphate hyperfiltration by functional nephrons leads to tubular damage (57), downregulation of α-Klotho promotes renal fibrosis through increasing TGFβ1 (44) and Wnt (58) signaling pathways, and lower α-Klotho levels might decrease its protective effect on the glomerular filtration barrier (59). The resulting endocrine profile that characterizes patients with CKD –high FGF-23 and PTH, with low calcitriol and α-Klotho—contributes to cardiovascular morbidity, systemic inflammation, dysregulation of bone metabolism, and anemia.
Cardiovascular Diseases
Cardiovascular diseases cause more than half of all deaths among patients with ESKD, and they represent the leading cause of mortality in this vulnerable population (1). Among CKD patients older than 65 years, the prevalence of CVD is 65.8%, compared to 31.9% in patients of the same age group but with normal kidney function (60). Epidemiological studies have shown a direct association between FGF-23 levels, mortality, and risk of major cardiovascular events (61–63). Two major contributor mechanisms are left ventricular hypertrophy (LVH) and a pro-atherosclerotic milieu. LVH is associated with heart failure, changes in heart geometry, and cardiac arrhythmias, while atherosclerosis is associated with coronary, cerebrovascular, and peripheral artery diseases.
High circulating levels of FGF-23 directly induce LVH through the activation of FGFR4 in cardiac myocytes and recruitment of the PLCγ/Calcineurin/NFAT pathway independently of α- Klotho (64–66). FGFR4 is a potential therapeutic target for reducing cardiovascular risk in patients with CKD as pharmacological blockage of this receptor in animal models showed attenuated LVH, while loss of function (FGFR4−/−) protected mice from developing LVH (64).
The pro-atherosclerotic milieu characteristic of patients with CKD is related to alterations in the bone-kidney axis (60, 67). In the initial stages of CKD, increased secretion of FGF-23 helps maintain normal serum phosphate (47). As the GFR decreases, transient or continuous hyperphosphatemia leads to calcium phosphate precipitation and favors the formation of atherosclerotic plaques (68). There is a positive correlation between FGF-23 and vascular calcification in patients with CKD; however, it is still controversial if the association is independent of serum phosphate concentrations or a direct pro-atherosclerotic effect of FGF23 (69).
Aortic stiffness is another biomarker of cardiovascular risk that increases in patients with CKD. While atherosclerosis primarily affects the vascular intima, aortic stiffness represents degenerative changes in the extracellular matrix of the intima and media layers characterized by elastin fracture and collagen deposition (70). Smith et al. demonstrated that increased aortic stiffness among CKD patients is associated with elevated circulating calciprotein particles—which are formed by adsorption of calcium phosphate by Fetuin-A to prevent ectopic calcification (71, 72). Also, in-vitro studies have shown that hyperphosphatemia can trigger chronic inflammation, induce endothelial apoptosis and promote an osteoblastic phenotype in vascular smooth muscle cells (2, 73–75). These are other examples of how mineral metabolism affects the vascular system and increases cardiovascular risk in CKD.
Immune System and Inflammation
The systemic inflammation observed in patients with CKD contributes to their elevated morbidity and mortality (76–78). An association between renal function and inflammation is well-established, and eGFR is inversely correlated with circulating levels of pro-inflammatory cytokines (e.g., IL-1β, IL-6, TNF-α, and hs-CRP) (79). Factors that promote inflammation in CKD include increased production of cytokines, hyperphosphatemia, chronic and recurrent infections, acidosis and oxidative stress, altered metabolism of adipose tissue, and gut microbiota dysbiosis (80). FGF-23 directly induces liver secretion of inflammatory cytokines by targeting FGFR4 receptors in hepatocytes and activating PLCγ/Calcineurin/NFAT signaling pathway— independently of α-klotho. As an indicator of the therapeutic potential of this finding, blockage of FGFR4 prevented significant elevation in C-Reactive Protein (CRP) secretion by the liver in an animal model of CKD (76). Also, altered immune homeostasis increases the susceptibility to infections. FGF-23 impairs neutrophil recruitment by interfering with chemokine signaling through activation of FGFR2 (81). In an unfavorable feedback loop, FGF-23 increases hepatic secretion of cytokines, inflammatory cytokines stimulate the secretion of FGF-23 by osteocytes, and a predisposition to infections contributes to systemic inflammation.
Bone Metabolism
There is a wide range of bone disorders that affect patients with CKD. The spectrum includes disorders in bone turnover, impaired mineralization, and changes in bone volume (82, 83). These abnormalities cause decreased mechanical strength with increased risk of fractures (84, 85), and altered mineral metabolism with increased risk of ectopic calcification (86). Malluche et al. reported a series of 630 bone biopsies from patients with CKD on dialysis. With 418 cortical bone biopsies available, they found that 82% had altered bone turnover, 52% had high cortical porosity, cortical thickness was low in 44%, cancellous bone volume was altered in 69% of the cohort, and only 3% of patients had impaired mineralization. Notably, bone turnover was low among 58% of patients and high among 24% of patients (87). These data show the high prevalence and variety of bone alterations in patients with CKD. High bone turnover is related to elevated PTH, hyperphosphatemia, and increased cortical porosity. Conversely, low bone turnover is related to low calcium retention and ectopic calcification. Low calcium retention indicates impaired incorporation of calcium into the bone matrix with the consequent hypercalcemia after calcium loads (88).
Animal models have shown that FGF-23 also regulates bone mineralization through a phosphate-independent mechanism. Homozygous FGF-23 knock-out mice develop growth delay, low bone mineral density (BMD), skeletal malformations, increased bone fragility, and impaired osteoid mineralization with concomitant hyperphostemia (89). Furthermore, these skeletal abnormalities persisted in hypophosphatemic animal models (FGF-23 −/− / NaPi2a −/−) (90). On the other hand, in fetal rat calvaria cell cultures overexpressing FGF-23, there was also inhibition of bone mineralization (91). This apparent contradiction—where deficiency and exposure to FGF-23 lead to impaired bone mineralization—favors the possibility that FGF-23 acts as an autocrine/paracrine regulator of mineralization (92) and the inhibition of tissue-non-specific alkaline phosphatase activity (TNAP) by FGF-23 might play a role. TNAP hydrolyzes pyrophosphate and generates inorganic phosphate to enhance mineralization (93). FGF-23 can suppress TNAP activity, cause pyrophosphate accumulation, and inhibit mineralization. The deletion of FGF-23 in Hyp mice (a murine homolog for X-linked hypophosphatemia) rescued the suppressed TNAP activity in osteoblasts (93, 94). However, FGF-23 deficiency (Fgf−/− mice) increases TNAP activity, increases the release of osteopontin, and also leads to inhibition of mineralization. This inhibitory effect of osteopontin in bone mineralization can be attenuated with a low phosphate diet or by deletion of the NaPi2A transporter (92, 95).
Osteocytes and osteoblast synthesize α-Klotho (96). Mice with an osteocyte-specific deletion of the α-Klotho gene have increased osteoblast activity and increased bone volume with normal serum biochemistry. When the same deletion is introduced in mice models of CKD (5/6 nephrectomy and high-phosphate diet)—which present with elevated serum phosphate, PTH, and FGF-23—α-Klotho expression in the bone was significantly decreased and the pro-osteoblastic effect was no longer significant. This suggests that α-Klotho might act as a regulator of adequate bone mineralization rate when the systemic mineral homeostasis is preserved (92, 97). As described, the endocrine mechanisms affecting bone metabolism are complex and questions remain as to the role of FGF-23 and α-Klotho in the differential expression of bone disorders observed in patients with CKD.
Anemia
Epidemiological studies have found that FGF-23 is independently associated with anemia (98, 99), and animal studies have reported possible causal mechanisms. The administration of FGF-23 in wild-type mice rapidly decreases erythropoiesis while Knockout mice (FGF-23 −/−) have increased circulating erythropoietin and red blood cell number (100). Furthermore, Agoro et al. reported that inhibiting FGF-23 signaling rescues anemia and iron deficiency in a mice model of CKD by normalizing the hemoglobin levels, decreasing erythroid cell apoptosis, and increasing serum erythropoietin, iron, and ferritin. They also found an up-regulation on the liver synthesis of hepcidin that normalized after FGF-23 blocking and provided a possible link between FGF-23, inflammation, and anemia (101).
In summary, elevated serum FGF-23 is an early biomarker of impaired renal function that directly contributes to the morbidity observed in patients with CKD. Clinical and animal studies have shown that potential therapeutic benefits of targeting FGF-23 include attenuating left ventricular hypertrophy, decreasing the synthesis of pro-inflammatory cytokines by the liver, improving neutrophil recruitment, rescuing anemia by stimulating erythropoiesis, and improving iron deficiency by down-regulating the synthesis of hepcidin. Decreased circulating levels of α-klotho is also characteristic of patients with CKD and potential therapeutic benefits of targeting α-klotho-dependent actions include increasing circulating levels of calcitriol, decreasing renal fibrosis, and improving bone mineralization and osteoblast function.
Post Kidney Transplant Patients
Kidney transplantation is associated with a significant reduction in mortality compared to those with ESKD on dialysis. Wolfe et al. reported a 1.7-fold decrease in the annual death rate among patients with ESKD undergoing transplant compared to patients on waiting list (102). Notably, CVD persists as the leading cause of death after transplantation (60). According to the USRDS, the prevalence of CVD is 76.5% in patients on hemodialysis, 65% in patients on peritoneal dialysis, and 53.7% in patients with a functional kidney transplant (1). Life expectancy among kidney transplant recipients remains inferior compared to age-matched controls from the general population. For example, females who undergo kidney transplantation between 40 and 44 years old have a projected lifespan of more than 10 years shorter than similarly aged women from the general population (1). For this reason, it is paramount to identify and characterize the mechanisms underlying CVD in kidney transplant recipients.
Transplant mineral and bone disorder (T-MBD) is a systemic condition characterized by endocrine alterations, vascular or other soft-tissue calcification, and abnormalities in bone metabolism (103, 104). Although there are significant differences with CKD-MBD, there is a continuum in some metabolic pathways conducive to atherosclerosis and bone disorders (104). There are several mechanisms involving the aforementioned biomarkers after kidney transplant with persistent interplay affecting mineral bone metabolism, cardiovascular disease, and load-bearing capacity.
After transplant, as renal function stabilizes, there is a tendency toward normalization of most biochemical indicators of ESKD. A recovered GFR allows excretion of excess serum phosphate and uremic toxins. High basal levels of PTH and FGF-23 make post-transplant hypophosphatemia and hypercalcemia a common finding (105–110). Transient hypophosphatemia is observed in more than 80% of transplant recipients early after surgery, and is related to appropriate allograft function and favorable outcomes (106). On the other hand, transient hypercalcemia is reported in up to 65% of transplants and is associated with poor outcomes (111–113). Hypercalcemia can compromise adequate graft function by acutely inducing vasoconstriction and, in the long-term, by favoring calcinosis and vascular calcification (114, 115).
In the first 3 months following surgery, there is a significant decrease in PTH, FGF-23, and calcium levels and an increase in serum phosphate and calcitriol toward normal levels (107). After this period, these changes normalize at a slower rate. Nonetheless, long-term endocrine alterations are common (106, 107, 109, 116). Among 50 patients undergoing kidney transplantation, Evenepoel et al. reported that 1 year after surgery, 57% had persistently high FGF-23, and 32% had high serum PTH levels. Mild to moderate hypophosphatemia was also present in 14% of patients (117). Elevated FGF-23 is associated with decreased post-transplant GFR (118, 119) and, and increased risk of mortality, graft loss (120, 121), and left ventricular wall strain (119, 121). The effects of FGF-23 in the cardiovascular system were also studied by Yilmaz et al. who reported that endothelium-dependent vasodilation improves after kidney transplantation, and it is independently associated with a decrease in FGF-23 and serum phosphorus (122). As mentioned above, high circulating levels of FGF-23 directly contribute to left ventricular hypertrophy (LVH) and anemia in patients with CKD. Decreases in FGF-23 might contribute to the reduction of LVH and improvements of ventricular contractility after kidney transplantation (123, 124). Baloglu et al. reported that hemoglobin levels are inversely associated with circulating FGF-23, however this association was no longer significant after kidney transplantation (125).
Serum α-Klotho levels increase after transplantation and might contribute to the transient hypophosphatemia by improving the sensitivity to FGF-23 (126, 127). Interestingly, Mizusaki et al. reported that serum α-Klotho was significantly higher in kidney transplant recipients receiving everolimus. They concluded that mTOR inhibition could be related to increased α-Klotho after kidney tranplantation (127), which underpins a new area of applicable α-Klotho therapeutics in kidney transplantation that needs further study. Higher serum α-Klotho has also been independently associated with improved GFR 1 year after transplant (128). Animal models have shown a reno-protective effect of α-Klotho that could play a role in protecting the renal allograft (129–131). Sugiura et al. reported that α-Klotho induction through gene transferring strategy mitigates apoptosis, histological damage and improves GFR in mice subject to renal ischemia-reperfusion injury. They concluded that the protective mechanism involved increases expression of heat shock protein 70 (129). The antifibrotic effect of α-Klotho through the inhibition of TGFβ1 and Wnt signaling pathways is also an important mechanism in kidney protection against injury (44, 58). Hu et al. studied mice after acute kidney injury and found that early treatment with α-Klotho prevents progression to CKD and significantly reduces uremic cardiomyopathy (37). As an indicator of renal function, α-Klotho activity varies depending on the quality of the transplanted kidney. Among kidneys from deceased donors, lower Kidney Donor Risk Index (KDRI) and age <50 years were associated with higher α-Klotho levels and better GFR after transplant (128, 132). In this context, α-Klotho represents a potentially useful biomarker and therapeutic agent in kidney transplantation.
Bone metabolism and load-bearing capacity are also greatly affected in kidney transplant recipients. The underlying mechanism is multifactorial and includes pre-existing renal osteodystrophy, reduced kidney function, and the effect of immunosuppressive therapy (133, 134). Among 68,814 kidney transplant recipients, Nikkel et al. reported a 22.5% incidence of fractures during the first 5 years after surgery (135). The first 6 months following transplant are associated with a rapid decrease in spine bone mineral density that continues to decline afterward but at a slower rate (136–138). It is well-established that immunosuppressive therapy with glucocorticoids induces osteopenia and is a contributing factor to osteodystrophy. Glucocorticoids are related to a decreased number and impaired function of osteoblasts. They also promote osteoclastic activity by up-regulating RANKL expression and down-regulating osteoprotegerin (139–141). Conversely, the effect of calcineurin inhibitors in the bone is more controversial and difficult to evaluate (141–143). While tacrolimus and cyclosporine have been linked to osteoporosis, population-based studies have failed to find an association with an increased risk of fractures (141, 143–146). Briner et al. conducted a clinical study that combined cyclosporine treatment with no or very low dose of glucocorticoids. They found that glucocorticoid-sparing immunosuppression after transplant prevented cancellous bone loss, and they did not observe any fractures during the 2 years follow-up (147). Also, Westeel et al. reported a series of 52 renal transplanted patients receiving low dose prednisone and cyclosporine. They concluded that cyclosporine, together with the decrease of prednisone dosage, contributes to a transient stimulation of bone remodeling at 6 months after transplant, which counterbalances the bone loss associated with prednisone therapy (142). In addition to immunosuppressive treatment, post-transplant hypophosphatemia is also independently associated with alterations in bone turnover, decreased osteoblast activity, defective mineralization, and osteoblast apoptosis (133, 148). In this regard, high PTH and FGF-23 levels are frequent after transplant and contribute to hypophosphatemia. Persistent tertiary hyperparathyroidism also leads to increased bone turnover, and high FGF-23 has been related to phosphate-independent skeletal abnormalities (89, 90, 149). Human studies of soluble α-Klotho and FGF-23 among kidney transplant recipients are summarized in Table 1.
Table 1. Human studies of soluble α-Klotho and FGF-23 among kidney transplant recipients.
Kidney Donors
In 2020, living kidney donors represented 23% of the total transplanted kidney allografts in the US. The long-term mortality after kidney donation has proven to be similar to the general population or matched controls in several studies (150–152). However, the innocuity of kidney donation is the subject of greater debate. O'Keeffe et al. conducted a meta-analysis that included 118,426 living kidney donors with an average follow-up of one to 24 years. They did not find evidence of increased mortality, cardiovascular diseases, or diabetes among donors compared to controls (153). Nonetheless, they found that donors had an increased risk of ESKD and pre-eclampsia. Muzaale et al. conducted a cohort study involving 96,217 kidney donors and found that 15 years after donation, the risk of ESKD increased from 0.04% in matched non-donors to 0.31% in kidney donors (154). There are scarce data available evaluating the outcomes after donation beyond a follow-up of 20 years. Based on OPTN data as of 2020, 26.5% of kidney donors were under 35 years old. In this regard, an increasing population is expected to live longer than 40 years after donation (155), and the long-term metabolic consequences of unilateral nephrectomy in otherwise healthy individuals are not clearly understood.
As discussed above, α-Klotho is primarily synthesized in the kidneys, and it has a reno-protective effect through different mechanisms. Shortly after kidney donation, α-Klotho levels decrease and remain lower than baseline 1 year after surgery (5–8, 156). However, one study that evaluated serum α-Klotho 5 years after donation did not find a significant difference compared to healthy controls (157). The long-term consequences of changes in α-Klotho levels in response to nephrectomy remain unknown. Further, the scope of the possible therapeutic benefit of increasing α-Klotho levels to prevent the development of ESKD after nephrectomy has not been explored in humans.
Other parameters of the bone-kidney axis are also altered after donation. There is a decrease in GFR, phosphate, and calcitriol synthesis, and an increase in PTH that persists 1 year after surgery (5). However, there is conflicting information about the changes in FGF-23 after donation. Some authors have reported that FGF-23 remains elevated 1 year after donation (6, 158), while others did not find significant long-term changes (5, 157, 159). A meta-analysis conducted by Thongprayoon et al. reported no significant change in FGF-23 1 year after kidney donation. Notably, they also found that serum α-Klotho remained lower than baseline 1 year after nephrectomy among 56 donors (9). As such, there is limited available data considering the clinical relevance of alterations in FGF-23 and α-Klotho after kidney donation (159). Human studies of soluble α-Klotho and FGF-23 among kidney donors are summarized in Table 2.
Table 2. Human studies of soluble α-Klotho and FGF-23 among living donors.
The understanding of long-term adaptations to kidney donation is still the subject of intense investigation. Living kidney donors are essential to close the gap between supply and kidney allograft demand, and sustaining their long-term health is important. Further research and education are necessary to support the kidney health of kidney donors and ensure the maintenance of their endocrine, cardiovascular, and bone mineral health.
Conclusion
FGF-23 and α-Klotho are integral endocrine factors that link bone-mineral metabolism, kidney function, and cardiovascular health. Among patients with CKD, this multi-looped axis is significantly impaired and translates into greater cardiovascular morbidity, mortality, and bone disorders. Kidney transplantation partially restores α-Klotho activity and FGF-23 levels. However, persistently high FGF-23 is associated with increased mortality and graft loss, and low circulating α-Klotho is associated with decreased kidney function after transplant. Notably, the metabolic bone and vascular alterations observed post kidney transplant are not fixed and instead are dynamic, influenced by organ quality, kidney recovery, immunosuppression, recipient comorbidities, and associated treatments. This highlights the concept that patients continue to need personalized medical support after transplant to ensure normalization of endocrine and bone-vascular axes indirectly affected by CKD. On the other hand, while some authors have reported that kidney donors have lower α-Klotho levels and elevated FGF-23 that persist 1 year after surgery, the scarce available data are inconclusive regarding the clinical relevance of these findings.
Author Contributions
MG, GO, and JN contributed to conception and design of the study. MG and GO wrote the first draft of the manuscript. JN wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.
Conflict of Interest
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.
Publisher's Note
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Acknowledgments
Figure adapted from anatomical images provided by Essential Anatomy. Many thanks to 3D4Medical.
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Keywords: alpha-Klotho, FGF-23, kidney donation, kidney transplant, ESKD (end stage kidney disease), bone mineral density (BMD), cardiovascular disease, mineral bone disease
Citation: Gupta M, Orozco G, Rao M, Gedaly R, Malluche HH and Neyra JA (2022) The Role of Alterations in Alpha-Klotho and FGF-23 in Kidney Transplantation and Kidney Donation. Front. Med. 9:803016. doi: 10.3389/fmed.2022.803016
Received: 27 October 2021; Accepted: 03 February 2022;
Published: 06 May 2022.
Edited by:
Mostafa Abdelkhalek, Mansoura University, EgyptReviewed by:
Alexander Grabner, Duke University, United StatesDaniela Picciotto, San Martino Hospital (IRCCS), Italy
Copyright © 2022 Gupta, Orozco, Rao, Gedaly, Malluche and Neyra. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Meera Gupta, meera.gupta@uky.edu; Javier A. Neyra, javier.neyra@uky.edu