Maren Leifheit-Nestler

• PhD
• Group Leader at Hannover Medical School

X-linked hypophosphatemia (XLH) is the most common inherited form of hypophosphatemic rickets. Children with XLH have an increased risk of obesity, which may promote high blood pressure, but data on blood pressure in XLH are inconclusive. We aimed to assess blood pressure and its determinants in pediatric XLH patients. We conduct a prospective, mul...

Context The pathophysiology of cystinosis-associated metabolic bone disease is complex. Objective We hypothesized a disturbed interaction between osteoblasts and osteoclasts. Design Binational cross-sectional multicenter study. Setting Hospital clinics. Patients One hundred and three patients with cystinosis (61% children) with chronic kidney d...

Background and Aims X-linked hypophosphatemia (XLH) is the most common genetic cause of hypophosphatemia. Mutations in the PHEX gene cause elevated circulating levels of fibroblast growth factor 23 (FGF23), phosphaturia, rickets and osteomalacia. Conventional treatment with phosphate salts and active vitamin D is associated with nephrocalcinosis an...

Background and Aims The phosphaturic hormones fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) promote renal phosphate excretion through FGFR1/Klotho and PTH1R-mediated ERK1/2 activation, respectively, leading to inhibition of the sodium-phosphate cotransporters NPT2a (SLC34A1) and NPT2c (SLC34A3) in proximal tubule (PT) cells. In...

Background and Aims High phosphate loading stimulate the synthesis of PTH and FGF23 and is associated with increased cardiovascular (CV) mortality. In hemodialysis patients, the administration of calcimimetics led to reductions in PTH and FGF23 and the latter was associated with a lower rate of CV events. We have previously shown that mice with a h...

Background and Aims Cystinosis-associated metabolic bone disease (CMBD) is a major challenge in the treatment of patients with infantile nephropathic cystinosis (NC). Study data are limited due to small case numbers, lack of adults or patients on renal replacement therapy and/or inadequate assessment of bone health. Method We investigated markers...

Background and Aims During chronic kidney disease (CKD) progresses, there is an increased phosphate load and the concentration of the phosphaturic hormones PTH and FGF23 rises. In patients, phosphate and FGF23 are discussed as risk factors for CKD progression. We have recently shown that mice with high phosphate, PTH and FGF23 levels develop Stat3/...

Background and Aims We have recently shown that a high phosphate diet (HPD) in mice leads to an increase in FGF23 levels and causes progressive tubular damage and interstitial fibrosis with increased accumulation of macrophages and concomitant perivascular immune cell aggregates in the corticomedullary zone. Such tertiary lymphoid structures (TLS)...

Soluble RANKL (sRANKL) and osteoprotegerin (OPG) are regulators of osteoclast differentiation and activation, but adequate pediatric reference values are lacking. Here we provide LMS (Lambda-Mu-Sigma)-based continuous pediatric reference percentiles for sRANKL, OPG and sRANKL/OPG ratio that will allow calculation of standardized patient z-scores to...

Context The assessment of phosphate homeostasis in children is challenging due to the marked changes in laboratory parameters during growth and development, and the lack of adequate reference values. Objective To develop Lambda-Mu-Sigma (LMS)-based continuous pediatric reference percentiles for 7 key laboratory parameters of phosphate homeostasis....

Aims Phosphate and vitamin D homeostasis are controlled by fibroblast growth factor 23 (FGF23) from bone suppressing renal phosphate transport and enhancing 24‐hydroxylase ( Cyp24a1 ), thereby inactivating 1,25(OH) 2 D 3 . Serum FGF23 is correlated with outcomes in several diseases. Fasting stimulates the production of ketone bodies. We hypothesize...

Context: Burosumab has been approved for the treatment of children and adults with X-linked hypophosphatemia (XLH). Real-world data and evidence for its efficacy in adolescents is lacking. Objective: To assess the effects of 12 months burosumab treatment on mineral metabolism in children (aged < 12 years) and adolescents (aged 12-18 years) with...

Background: Infants with chronic kidney disease (CKD) form a vulnerable population who are highly prone to mineral and bone disorders (MBD) including biochemical abnormalities, growth retardation, bone deformities, and fractures. We present a position paper on the diagnosis and management of CKD-MBD in infants based on available evidence and the o...

Dietary phosphate intake in the Western population greatly exceeds the recommended dietary allowance and is linked to enhanced cardiovascular and all‐cause mortality. It is unclear whether a chronic high phosphate diet (HPD) causes kidney injury in healthy individuals. Here, we show that feeding a 2% HPD in C57BL/6N mice for one up to six months re...

Here, we discuss the management of different forms of rickets, including new therapeutic approaches based on recent guidelines. Management includes close monitoring of growth, the degree of leg bowing, bone pain, serum phosphate, calcium, alkaline phosphatase as a surrogate marker of osteoblast activity and thus degree of rickets, parathyroid hormo...

Phosphate is essential for proper cell function by providing the fundamentals for DNADNA, cellular structure, signaling and energy production. The homeostasis of phosphate is regulated by the phosphaturic hormones fibroblast growth factor (FGF) 23 and parathyroid hormone (PTHPTH). Recent studies indicate that phosphate induces phosphate sensingPhos...

Enhanced fibroblast growth factor 23 (FGF23) is associated with left ventricular hypertrophy (LVH) in patients with chronic kidney and heart disease. Experimentally, FGF23 directly induces cardiac hypertrophy and vice versa cardiac hypertrophy stimulates FGF23. Besides the bone, FGF23 is expressed by cardiac myocytes, whereas its synthesis in other...

Cystinosis Metabolic Bone Disease (CMBD) has emerged during the last decade as a well-recognized, long-term complication in patients suffering from infantile nephropathic cystinosis (INC), resulting in significant morbidity and impaired quality of life in teenagers and adults with INC. Its underlying pathophysiology is complex and multifactorial, a...

Rickets is a disease of the growing child arising from alterations in calcium and phosphate homeostasis resulting in impaired apoptosis of hypertrophic chondrocytes in the growth plate. Its symptoms depend on the patients’ age, duration of disease, and underlying disorder. Common features include thickened wrists and ankles due to widened metaphyse...

Fibroblast growth factor (FGF) 23 is elevated in chronic kidney disease (CKD) to maintain phosphate homeostasis. FGF23 is associated with left ventricular hypertrophy (LVH) in CKD and induces LVH via klotho-independent FGFR4-mediated activation of calcineurin/nuclear factor of activated T cells (NFAT) signaling in animal models, displaying systemic...

Chronic kidney disease (CKD) is associated with distinct alterations in mineral metabolism in children and adults resulting in multiple organ dysfunctions. Children with advanced CKD often suffer from impaired bone mineralization, bone deformities and fractures, growth failure, muscle weakness, and vascular and soft tissue calcification, a complex...

Cardiovascular diseases (CVD) are a hallmark in pediatric patients with chronic kidney disease (CKD) contributing to an enhanced risk of all-cause and CV morbidity and mortality in these patients. The bone-derived phosphaturic hormone fibroblast growth factor (FGF) 23 progressively rises with declining kidney function to maintain phosphate homeosta...

Growth hormone (GH) and its mediator insulin-like growth factor-1 (IGF-1) have manifold effects on the kidneys. GH and IGF receptors are abundantly expressed in the kidney, including the glomerular and tubular cells. GH can act either directly on the kidneys or via circulating or paracrine-synthesized IGF-1. The GH/IGF-1 system regulates glomerular...

Fibroblast growth factor 23 (FGF23) is secreted by osteocytes to maintain serum phosphate within the normal range. Endocrine effects of bone-derived FGF23 on the cardiovascular system were not considered possible for a long time, because its physiological coreceptor α-Klotho is not or only to a small extent expressed in heart tissue of humans and r...

Background Uraemic cardiac remodelling is associated with vitamin D and Klotho deficiency, elevated fibroblast growth factor 23 (FGF23) and activation of the renin–angiotensin system (RAS). The cardioprotective properties of active vitamin D analogues in this setting are unclear. Methods In rats with 5/6 nephrectomy (5/6Nx) treated with calcitriol...

Mineral and bone disorder (MBD) is widely prevalent in children with chronic kidney disease (CKD) and is associated with significant morbidity. CKD may cause disturbances in bone remodelling/modelling, which are more pronounced in the growing skeleton, manifesting as short stature, bone pain and deformities, fractures, slipped epiphyses and ectopic...

For patients with depression treated with electroconvulsive therapy (ECT), the novel seizure quality index (SQI) can predict the risk of non-response (and non-remission)—as early as after the second ECT session—based the extent of several ictal parameters of the seizure. We aim to test several CSF markers on their ability to predict the degree of s...

Background and Aims Elevated FGF23, activation of the renin-angiotensin-aldosterone system (RAAS), and vitamin D and Klotho deficiency promote left ventricular hypertrophy (LVH) and LV fibrosis in chronic kidney disease (CKD). Whether treatment with active vitamin D affects uremic cardiomyopathy and/or FGF23/Klotho system in CKD is unclear. Method...

Background and Aims In early stages of chronic kidney disease (CKD) rising levels of the phosphaturic hormone fibroblast growth factor (FGF) 23 maintain the phosphate homeostasis, whereas in end-stage kidney disease hyperphosphatemia manifests. Both elevated FGF23 and phosphate levels contribute to CKD progression and are associated with an increas...

Context: Children with nephropathic cystinosis (NC) show persistent hypophosphatemia, due to Fanconi syndrome, as well as mineral and bone disorders related to chronic kidney disease (CKD), but systematic analyses are lacking. Objective: To compare biochemical parameters of bone and mineral metabolism between children with NC and controls across...

Complications of chronic kidney disease-associated mineral and bone disorders (CKD-MBD) are frequently observed in pediatric kidney transplant recipients and are associated with high morbidity, including growth failure, leg deformities, bone pain, fractures, osteonecrosis, and vascular calcification. Post-transplant CKD-MBD is mainly due to preexis...

Secondary hyperparathyroidism is part of the complex of chronic kidney disease-associated mineral and bone disorders (CKD-MBD) and is linked with high bone turnover, ectopic calcification, and increased cardiovascular mortality. Therefore, measures for CKD-MBD aim at lowering PTH levels, but there is no general consensus on optimal PTH target value...

Elevated levels of fibroblast growth factor 23 (FGF23) and phosphate are highly associated with increased cardiovascular disease and mortality in patients suffering from chronic kidney disease (CKD). As the kidney function declines, serum phosphate levels rise and subsequently induce the secretion of the phosphaturic hormone FGF23. In early stages...

Patients with chronic kidney disease (CKD) are prone to developing cardiac hypertrophy and fibrosis, which is associated with increased fibroblast growth factor 23 (FGF23) serum levels. Elevated circulating FGF23 was shown to induce left ventricular hypertrophy (LVH) via the calcineurin/NFAT pathway and contributed to cardiac fibrosis by stimulatio...

Klotho is a humoral factor with pleiotropic effects. Most notably, Klotho deficiency is associated with a phenotype comprising organ manifestations accompanying aging including atherosclerosis and cognitive impairment. Research on the role of Klotho in affective disorder is scarce, which is surprising in light of the fact that depression is associa...

Background: No candidate biomarkers based on cerebrospinal fluid (CSF) have been identified as prognostic factors in patients with major depression treated with electroconvulsive therapy (ECT), yet. Method: Following different underlying hypotheses, we analysed baseline CSF levels of markers of neurodegeneration (tau proteins, β-amyloids and neu...

Clinical and experimental studies indicate a possible link between high serum levels of fibroblast growth factor 23 (FGF23), phosphate, and parathyroid hormone (PTH), deficiency of active vitamin D (1,25D) and klotho with the development of pathological cardiac remodeling, i.e., left ventricular hypertrophy and myocardial fibrosis, but a causal lin...

Fibroblast growth factor (FGF) 23 is a phosphaturic hormone primarily secreted by osteocytes to maintain phosphate and mineral homeostasis. In patients with and without chronic kidney disease, enhanced circulating FGF23 levels associate with pathologic cardiac remodeling, i.e., left ventricular hypertrophy (LVH) and myocardial fibrosis and increase...

Background/aims: Whether the immunosuppressive regimen is associated with micro- and macro-vascular status in pediatric kidney transplant recipients (KTx) is unknown. Methods: We performed a cross-sectional, case-control study in 44 pediatric KTx patients on either everolimus (EVR) plus calcineurin inhibitor or standard treatment, i.e. mycopheno...

Background: We investigated the effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism, i.e. serum levels of fibroblast growth factor 23 (FGF23), Klotho, bone alkaline phosphatase (BAP) and sclerostin, in two cohorts with chronic kidney disease (CKD). Methods: In all, 80 vitamin D-deficient children were selec...

Background: Fibroblast growth factor 23 (FGF23) is discussed as a new biomarker of cardiac hypertrophy and mortality in patients with and without chronic kidney disease (CKD). We previously demonstrated that FGF23 is expressed by cardiac myocytes, enhanced in CKD and induces cardiac hypertrophy via activation of FGF receptor 4 independent of its c...

Klotho is a humoral factor with pleiotropic effects. Most notably, Klotho deficiency is associated with a phenotype comprising organ manifestations accompanying aging including atherosclerosis and cognitive impairment. Research on the role of Klotho in affective disorder is scarce, which is surprising in light of the fact that depression is associa...

X-linked hypophosphatemia (XLH) caused by mutations in the Phex gene is the most common human inherited phosphate wasting disorder characterized by enhanced synthesis of fibroblast growth factor 23 (FGF23) in bone, renal phosphate wasting, 1,25(OH)2D3 (1,25D) deficiency, rickets and osteomalacia. Here we studied the effects of calcimimetic R568 and...

Background.: Vitamin D deficiency and excess of circulating fibroblast growth factor 23 (FGF23) contribute to cardiovascular mortality in patients with chronic kidney disease (CKD). FGF23 activates FGF receptor 4 and (FGFR4) calcineurin/nuclear factor of activated T cells (NFAT) signaling in cardiac myocytes, thereby causing left ventricular hyper...

Background Shiga-toxin-producing Escherichia coli (STEC)-associated hemolytic-uremic syndrome (HUS) is a major cause of acute kidney injury (AKI), especially in children. Its long-term outcome with respect to endothelial damage remains largely elusive. Methods This was a cross-sectional study in 26 children who had suffered from STEC-HUS in the pas...

Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular mortality, infections, and impaired cognitive function. It is characterized by excessively increased levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23) and a deficiency of its co-receptor Klotho. Despite the important physiological effect of FGF2...

Chronic kidney disease (CKD) is a state of Klotho deficiency and excess of the phosphaturic hormone fibroblast growth factor 23 (FGF23). Both dysregulations were shown to be associated with endothelial dysfunction in humans, but direct vascular effects of FGF23 remain largely elusive. In vitro experiments were performed to assess the effects of FGF...

The fibroblast growth factor (FGF) 23/Klotho axis is a principal regulator of phosphate hemostasis and vitamin D metabolism, but limited data is available on its role in the central nervous system. Here, we investigate soluble α-Klotho (sKlotho) and C-terminal as well as intact FGF23 in cerebrospinal fluid (CSF) and plasma and their relationship to...

Endocrine fibroblast growth factor 23 (FGF23) is predominantly secreted by osteocytes and facilitates renal phosphate excretion. However, FGF23 is also present in cerebrospinal fluid. In chronic kidney disease (CKD), FGF23 serum levels are excessively elevated and associated with learning and memory deficits. Structural plasticity of the hippocampu...

Chronic kidney disease (CKD) is a worldwide public health threat that increases risk of death due to cardiovascular complications, including left ventricular hypertrophy (LVH). Novel therapeutic targets are needed to design treatments to alleviate the cardiovascular burden of CKD. Previously, we demonstrated that circulating concentrations of fibro...

Background In chronic kidney disease (CKD), serum concentrations of fibroblast growth factor 23 (FGF23) increase progressively as glomerular filtration rate declines, while renal expression of the FGF23 coreceptor Klotho decreases. Elevated circulating FGF23 levels are strongly associated with mortality and with left ventricular hypertrophy (LVH),...

The adipokine leptin and its receptor are expressed in the heart, and leptin has been shown to promote cardiomyocyte hypertrophy in vitro. Obesity is associated with hyperleptinemia and hypothalamic leptin resistance as well as an increased risk to develop cardiac hypertrophy and heart failure. However, the role of cardiac leptin signaling in media...

Aims: Apolipoprotein E (apoE) may act as a vasculoprotective factor by promoting plasma lipid clearance and cholesterol efflux. Moreover, apoE accumulates at sites of vascular injury and modulates the effect of growth factors on smooth muscle cells (SMCs). Experimental data suggested that hypothalamic apoE expression is reduced in obesity and asso...

Objective: Clinical and experimental evidence suggests that periadventitial adipose tissue may modulate vascular lesion formation. The aim of this study was to determine the role of perivascular leptin expression on neointima formation and to differentiate it from local inflammation and systemically elevated leptin levels. Approach and results:...

Bone marrow (BM) progenitors participate in new vessel formation and endothelial repair. The leptin receptor (ObR) is expressed on hematopoietic cells; however, the effects of leptin on BM progenitor cells and their angiogenic potential are unknown. In the present study, we show that the short-term administration of leptin (over five consecutive da...

To determine the intracellular mechanisms mediating the angiogenic effects of integrin alpha v beta 5 overexpression in circulating angiogenic cells (CACs). Integrin alpha v beta 5 is expressed on angiogenic endothelial cells, and integrin alpha v beta 5 activation was shown to improve the reparative functions of endothelial progenitors within the...

The purpose of this study was to examine the impact of obesity and weight loss on the angiogenic and regenerative capacity of endothelial progenitor cells (EPCs). EPCs participate in angiogenesis and tissue repair. Several cardiovascular risk factors are associated with EPC dysfunction. Early outgrowth EPCs were isolated from 49 obese (age 42 +/- 1...

Experimental evidence suggests that bone marrow-derived progenitor cells participate in the formation of new blood vessels and endothelial repair. We have previously shown that leptin enhances the recruitment and incorporation of human, culture-expanded endothelial progenitor cells (EPC) into neointimal lesions after vascular injury and promotes re...

Integrin alphavbeta5 is expressed on endothelial (progenitor) cells and has been implicated in angiogenesis. We have previously shown that stimulation of endothelial progenitor cells (EPC) with leptin upregulates alphavbeta5 integrin expression and enhances their angiogenic and reparative properties. The aim of the present study was to determine th...

To investigate the capacity of the adipokine leptin to promote angiogenesis by modulating the function of circulating angiogenic cells (CACs). In vitro, leptin specifically promoted CAC adhesion to tubular endothelial structures and migration along outgrowing sprouts of endothelial cells. In vivo, stimulation of CACs with leptin increased their cap...

The adipocytokine leptin modulates vascular remodeling and neointima formation. Because endothelial progenitor cells (EPCs) participate in vascular repair, we analyzed the effects of leptin on human EPC function in vitro and in vivo. After 7 days in culture, EPCs expressed the leptin receptor and responded to leptin stimulation with increased STAT3...

Cigarette smoking is a major risk factor for the development of cardiovascular disease. However, in terms of the vessel wall, the underlying pathomechanisms of cigarette smoking are incompletely understood, partly due to a lack of adequate in vivo models. Apolipoprotein E-deficient mice were exposed to filtered air (sham) or to cigarette mainstream...

Leptin enhances agonist-induced platelet aggregation, and human platelets have been reported to express the leptin receptor. However, the pathways and mediators lying downstream of leptin binding to platelets remain, with few exceptions, unknown. In the present study, we sought to gain further insight into the possible role of leptin as a platelet...

Leptin enhances agonist-induced platelet aggregation, and human platelets have been reported to express the leptin receptor. However, the pathways and mediators lying downstream of leptin binding to platelets remain, with few exceptions, unknown. In the present study, we sought to gain further insight into the possible role of leptin as a platelet...

It has been hypothesized that dietary conjugated linoleic acids (CLA) may inhibit colon tumorigenesis. The aim of our study was to investigate the cellular and molecular effects of cis-9 (9Z), trans-11 (11E)-CLA on the proliferation, differentiation, interaction with peroxisome proliferator-activated receptors (PPARs), and expression of genes relev...