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Patients on haemodialysis (HD) suffer a high mortality rate linked to developing subclinical hypoxic parenchymal stress during HD sessions. The oxygen extraction ratio (OER), an estimate of the oxygen claimed by peripheral tissues, might represent a new prognostic factor in HD patients. This study evaluated whether the intradialytic change in OER (ΔOER) identified patients with higher mortality risks. We enrolled chronic HD patients with permanent central venous catheters with available central venous oxygen saturation (ScvO2) measurements; the arterial oxygen saturation was measured with peripheral oximeters (SpO2). We measured OER before and after HD at enrolment; deaths were recorded during two-years of follow-up. In 101 patients (age: 72.9 ± 13.6 years, HD vintage: 9.6 ± 16.6 years), 44 deaths were recorded during 11.6 ± 7.5 months of follow-up. Patients were divided into two groups according to a 40% ΔOER threshold (ΔOER < 40%, n = 56; ΔOER ≥ 40%, n = 45). The ΔOER ≥ 40% group showed a higher incidence of death (60% vs. 30%; p = 0.005). The survival curve (log-rank-test: p = 0.0001) and multivariate analysis (p = 0.0002) confirmed a ΔOER ≥ 40% as a mortality risk factor. This study showed the intradialytic ΔOER ≥ 40% was a mortality risk factor able to highlight critical hypoxic damage. Using a ΔOER ≥ 40% could be clinically applicable to characterise the most fragile patients.

Introduction Guanidinoacetate methyltransferase (GAMT) deficiency is an inherited metabolic disorder that impairs the synthesis of creatine (CRE). Lack of CRE in the brain can cause intellectual disability, autistic-like behavior, seizures, and movement disorders. Identification at birth and immediate therapy can prevent intellectual disability and seizures. Here we report the first two cases of GAMT deficiency identified at birth by newborn screening (NBS) in Utah and New York. Methods NBS dried blood spots were analyzed by tandem mass spectrometry (MS/MS) using either derivatized or non-derivatized assays to detect guanidinoacetate (GUAC) and CRE. For any positive samples, a second-tier test using a more selective method, ultra-performance liquid chromatography (UPLC) combined with MS/MS, was performed to separate GUAC from potential isobaric interferences. Results NBS for GAMT deficiency began in Utah on June 1, 2015 using a derivatized method for the detection of GUAC and CRE. In May 2019, the laboratory and method transitioned to a non-derivatized method. GAMT screening was added to the New York State NBS panel on October 1, 2018 using a derivatized method. In New York, a total of 537,408 babies were screened, 23 infants were referred and one newborn was identified with GAMT deficiency. In Utah, a total of 273,902 infants were screened (195,425 with the derivatized method, 78,477 with the non-derivatized method), three infants referred and one was identified with GAMT deficiency. Mean levels of GUAC and CRE were similar between methods (Utah derivatized: GUAC = 1.20 ± 0.43 μmol/L, CRE = 238 ± 96 μmol/L; Utah non-derivatized: GUAC = 1.23 ± 0.61 μmol/L, CRE = 344 ± 150 μmol/L, New York derivatized: GUAC = 1.34 ± 0.57 μmol/L, CRE = 569 ± 155 μmol/L). With either Utah method, similar concentrations of GUAC are observed in first (collected around 1 day of age) and the second NBS specimens (routinely collected at 7–16 days of age), while CRE concentrations decreased in the second NBS specimens. Both infants identified with GAMT deficiency started therapy by 2 weeks of age and are growing and developing normally at 7 (Utah) and 4 (New York) months of age. Conclusions Newborn screening allows for the prospective identification of GAMT deficiency utilizing elevated GUAC concentration as a marker. First-tier screening may be incorporated into existing methods for amino acids and acylcarnitines without the need for new equipment or staff. Newborn screening performed by either derivatized or non-derivatized methods and coupled with second-tier testing, has a very low false positive rate and can prospectively identify affected children. SummaryCerebral creatine deficiency syndromes caused by defects in creatine synthesis can result in intellectual disability, and are preventable if therapy is initiated early in life. This manuscript reports the identification of two infants with GAMT deficiency (one of the cerebral creatine deficiency syndromes) by newborn screening and demonstrates NBS feasibility using a variety of methods.

Peroxisomal disorders are a heterogeneous group of genetic disorders caused by impaired peroxisomal biogenesis or by defects in single peroxisomal proteins. The most common peroxisomal disorders are Zellweger spectrum disorders (ZSDs), due to pathogenic variants in one of the 13 PEX genes, and X-linked adrenoleukodystrophy/adrenomyeloneuropathy (X-ALD/AMN), due to pathogenic variants in ATP-binding cassette transporter type D1 (ABCD1) gene. Peroxisomes perform multiple essential cellular functions, including β-oxidation of very-long-chain fatty acids (VLCFAs), pristanic acid and some bile acid intermediates, and α-oxidation of phytanic acid. In most patients, abnormal levels of VLCFAs and/or branched-chain fatty acids (BCFAs, e.g., phytanic and pristanic acids) are present; hence, measuring these analytes is critical when suspecting a peroxisomal disorder. This chapter describes a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify VLCFAs and BCFAs in plasma or serum for the diagnosis of peroxisomal disorders. The method consists of an acid hydrolysis step to release the fatty acids from their coenzyme A esters followed by derivatization using oxalyl chloride, dimethylaminoethanol, and then methyl iodide. The trimethyl-amino-ethyl (TMAE) iodide ester derivatives are analyzed using UPLC-MS/MS in positive electrospray ionization and multiple reaction-monitoring (MRM) mode. Quantitation is performed using a five-point calibration curve after normalizing with deuterated internal standards.

Acylcarnitines are formed when an acyl group is transferred from coenzyme A to a molecule of L-carnitine. In organic acidemias, and in fatty acid oxidation disorders, specific acylcarnitine species accumulate in a pattern that is characteristic for each disease. For this reason, acylcarnitine analysis is widely used for screening and diagnosis of inherited disorders of metabolism. The most common method for acylcarnitine analysis uses flow injection tandem mass spectrometry. Flow injection analysis allows for high throughput, however, does not provide separation of isomeric and isobaric compounds. Among the acylcarnitine species which can be affected by the presence of isomeric/isobaric compounds, C4-carnitine and C5DC-carnitine are probably the ones encountered most often. The method presented here is performed on urine and utilizes butanolic HCL to derivatize acylcarnitines, ultra-performance liquid chromatography to resolve C4- and C5-DC isomers and isobars, and quantitation of these species using multiple-reaction monitoring (MRM).

BACKGROUND AND AIMS Chronic kidney disease (CKD) typically associates with mineral bone disorders (CKD-MBD), kidney damage progression and increased morbidity and mortality. CKD-MBD develops early in CKD and, if promptly detected, could receive therapeutic attention. However, early markers of CKD-MBD like fibroblast growth factor 23 (FGF23) and α-Klotho are not widely available in clinical practice. Recently, estimated proximal tubule fluid phosphate concentration (ePTFp) has been proposed as a novel early marker of MBD. In fact, in CKD patients, along with the progressive reduction of nephron number, FGF23 increments are necessary to reduce renal tubular phosphate reabsorption and to maintain phosphate balance. As a consequence, PTFp concentration per single nephron progressively increases, leading to renal tubular cells overload, interstitial inflammatory response and progression of kidney damage. For this reason, PTFp concentration could represent an early marker of CKD-MBD. OBJECTIVE To evaluate the relationship between ePTFp and early markers of MBD in patients with CKD stage G2–4. METHOD In CKD patients stage G2–4, we evaluated serum FGF23, α-Klotho, parathyroid hormone (PTH) and ePTFp [ePTFp = (phosphaturia/creatininuria) x creatininemia x 3,33]; 30 healthy subjects (age 40 ± 5 years) were the control group for normal value of ePTFp. RESULTS In 68 CKD patients (age 58.9 ± 15.6 years eGFR 45 ± 21 mL/min), ePTFp averaged 2.4 ± 1.3 mg/mg which was significantly higher than in the control group (ePTFp = 1.2 ± 0.5; P CONCLUSION Our data showed early and progressive increments of ePTFp in CKD patients since CKD stage 2. These increments are paralleled by increased FGF23 and PTH and decreased α-Klotho, suggesting reciprocal pathophysiologic dependence. Accordingly, ePTFp could represent a surrogate of renal tubular cells phosphate overload, indicative of CKD-MBD development. ePTFp can be easily obtained in everyday clinical routine and could represent a reference to make therapeutic choices (e.g. dietary phosphate control). In conclusion, ePTFp could identify patients at risk of developing the CKD-MBD maladaptive response with increased risk of kidney damage progression.

Morquio syndrome type A, also known as MPS IVA, is a rare autosomal recessive disorder caused by deficiency of N-acetylgalactosamine-6-sulfatase, a lysosomal hydrolase critical in the degradation of keratan sulfate (KS) and chondroitin sulfate (CS). The CS that accumulates in MPS IVA patients has a disease-specific nonreducing end (NRE) terminating with N-acetyl-D-galactosamine 6-sulfate, which can be specifically quantified after enzymatic depolymerization of CS polysaccharide chains. The abundance of N-acetyl-D-galactosamine 6-sulfate over other possible NRE structures is diagnostic for MPS IVA. Here, we describe an assay for the liberation and measurement of N-acetyl-D-galactosamine 6-sulfate and explore its application to MPS IVA patient samples in pilot studies examining disease detection, effects of age and treatment with enzyme-replacement therapy. This assay complements the existing urinary KS assay by quantifying CS-derived substrates, which represent a distinct biochemical aspect of MPS IVA. A more complete understanding of the disease could help to more definitively detect disease across age ranges and more completely measure the pharmacodynamic efficacy of therapies. Larger studies will be needed to clarify the potential value of this CS-derived substrate to manage disease in MPS IVA patients.

Bone mineral abnormalities (defined as Chronic Kidney Disease Mineral Bone Disorder; CKD-MBD) are prevalent and associated with a substantial risk burden and poor prognosis in CKD population. Several lines of evidence support the notion that a large proportion of patients receiving maintenance dialysis experience a suboptimal biochemical control of CKD-MBD. Although no study has ever demonstrated conclusively that CKD-MBD control is associated with improved survival, an expanding therapeutic armamentarium is available to correct bone mineral abnormalities. In this position paper of Lombardy Nephrologists, a summary of the state of art of CKD-MBD as well as a summary of the unmet clinical needs will be provided. Furthermore, this position paper will focus on the potential and drawbacks of a new injectable calcimimetic, etelcalcetide, a drug available in Italy since few months ago.

Aim To evaluate early, before the onset of cardiovascular events and of chronic renal insufficiency, the association between chronic kidney disease (CKD)-mineral bone disorder (MBD) biomarkers and vascular stiffness [Cardio Ankle Vascular Index (CAVI)] in the course of type 2 diabetes (T2DM). Method We evaluated 174 T2DM patients [median age 56 years; male/female (M/F) 100/74] with diabetes duration Results Albumin-to-creatinine ratio (ACR) averaged 8.5 mg/g (5.6-17.2) with 12.6% of the patients showing pathologic values, indicative of incipient diabetic nephropathy. Serum parathyroid hormone, fibroblast growth factor 23, and sclerostin were higher while 1,25-dihydroxyvitamin D and Klotho were lower than a control group. CAVI was normal ( Conclusion In the absence of overt cardiovascular disease and of chronic renal insufficiency, CAVI is frequently pathologic in T2DM. DBP and ACR are modifiable risk factors of vascular stiffness in T2DM, thus warranting optimal assessment.

Newborn screening is an incredibly useful tool for the early identification of many metabolic disorders, including fatty acid oxidation (FAO) disorders. In many cases, molecular tests are necessary to reach a final diagnosis, highlighting the need for a thorough evaluation of genes implicated in FAO disorders. Using the ClinGen (Clinical Genome Resource) clinical validity framework, thirty genes were analyzed for the strength of evidence supporting their association with FAO disorders. Evidence was gathered from the literature by biocurators and presented to disease experts for review in order to assign a clinical validity classification of Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Reported Evidence. Of the gene-disease relationships evaluated, 22/30 were classified as Definitive, three as Moderate, one as Limited, three as No Reported Evidence and one as Disputed. Gene-disease relationships with a Limited, Disputed, and No Reported Evidence were found on two, six, and up to four panels out of 30 FAO disorder-specific panels, respectively, in the National Institute of Health Genetic Testing Registry, while over 70% of the genes on panels are definitively associated with an FAO disorder. These results highlight the need to systematically assess the clinical relevance of genes implicated in fatty acid oxidation disorders in order to improve the interpretation of genetic testing results and diagnosis of patients with these disorders.

Impaired activity of galactose-1-phosphate uridyltransferase (GALT) causes classic galactosemia (OMIM 230400 ), characterized by the accumulation of galactose-1-phosphate (GAL1P) in patients' red blood cells (RBCs). Our recent study demonstrated a correlation between RBC GAL1P and long-term outcomes in galactosemia patients. Here, we analyze biochemical and molecular results in 77 classic galactosemia patients to evaluate the association between GALT genotypes and GAL1P concentration in RBCs. Experimental data from model organisms were also included to assess the correlation between GAL1P and predicted residual activity of each genotype. Although all individuals in this study showed markedly reduced RBC GALT activity, we observed significant differences in RBC GAL1P concentrations among galactosemia genotypes. While levels of GAL1P on treatment did not correlate with RBC GALT activities (p = 0.166), there was a negative nonlinear correlation between mean GAL1P concentrations and predicted residual enzyme activity of genotype (p = 0.004). These studies suggest that GAL1P levels in RBCs on treatment likely reflect the overall functional impairment of GALT in patients with galactosemia.

Background Acylglycine species accumulate in specific disorders of branched-chain amino acid metabolism and fatty acid β-oxidation. These species are excreted in urine and their analysis can facilitate diagnosis. Previous studies evaluated reference ranges and increases in metabolic patients, but these involved small numbers of individuals. We have conducted an analysis encompassing large numbers of individuals to better characterize the reference ranges of these analytes and additionally describe our findings from patients with confirmed metabolic disorders. Methods We conducted a retrospective analysis of approximately 9 y of urine acylglycine data from our clinical laboratory. Acylglycines were extracted from urine, derivatized and analyzed using UPLC-MS/MS. Reference ranges were determined from the non-diseased population. Data from confirmed patients were used to document the range of increases observed in these conditions and to generate multiple of the median graphs. Results In total, 6162 urine specimens from 5633 patients with and without metabolic disorders were analyzed. Magnitude and pattern of acylglycine elevations in patients with confirmed metabolic disorders were documented. Conclusion This manuscript extends our previously published method by providing the reference ranges and disease specific elevations and patterns of urine acylglycine species using the largest data set published to date.

Intradialytic hypotension (IDH) is a hemodynamic phenomenon recently associated with decreased blood oxygen saturation (SO2). The ratio between peripheral oxygen saturation (SpO2) and central venous SO2 (ScvO2) or Oxygen Extraction Ratio (OER), which represents a roughly estimate of the amount of oxygen claimed by peripheral tissues, might be used to estimate haemodialysis (HD) related hypoxic stress. Aim of this pilot study was to evaluate the relationship between OER increments during dialysis sessions (ΔOER) and episodes of IDH. We enrolled chronic HD patients with permanent central venous catheter (CVC) and no fistula, in whom ScvO2 measurement is at hand. OER ([(SpO2 − ScvO2)/SpO2] × 100) was measured in three consecutive HD sessions (HD OER sessions) before HD, after 15′, 30′ and 60′ min and at the end of HD. Then, a one-year follow-up was planned to record the number of IDH episodes. In the 28 enrolled patients (age 74 ± 2.6 years), during 12 ± 1.2 months of follow up, incidence of IDH was 3.6%. We divided patients into two groups, above or below the median value of ΔOER at the end of HD, which was 36%. In these groups, the average incidence of IDH was 7% and 2% respectively (p 19% after only 15′ of HD treatment or > 36% at the end of the session characterize patients with higher rates of hypotension. Intradialytic ∆OER, a parameter of tissue hypoxic stress, identifies more fragile patients at greater risk of IDH.

The impressive estimated number of chronic kidney disease (CKD) patients in the world justifies any possible effort at implementing preventive measures of disease progression. Renal insufficiency is associated with significant changes in the electrolyte handling and body balance of sodium, potassium, phosphate, magnesium, and calcium, all of which are biologically vital molecules. Dietary habits could contribute significantly to the optimal management of possible derangements. In this review, we examined the available evidence recommending dietary prescriptions for these five elements aiming at reducing CKD progression. Clear evidence that specific dietary prescriptions may halt or reduce CKD progression is lacking. However, some practical recommendations are possible to prescribe the best possible therapy to the individual CKD patient.

Bone is not only a mineralized and apparently non-vital structure that provides support for locomotion and protection to inner organs. An increasing number of studies are unveiling new biologic functions and connections to other systems, giving the rise to new fields of research, such as osteoimmunology. The bone marrow niche, a new entity in bone physiology, seems to represent the site where a complex crosstalk between bone and immune/inflammatory responses takes place. An impressive interplay with the immune system is realized in bone marrow, with reciprocal influences between bone cells and haematopoietic cells. In this way, systemic chronic inflammatory diseases realize a crosstalk with bone, resulting in bone disease. Thus, pathogenetic links between chronic kidney disease-mineral bone disorders and osteoporosis, cardiovascular disease, and ageing are common. The aim of this narrative review is to provide a general view of the progresses in the field of bone research and their potential clinical implications, with emphasis on the links with inflammation and the connections to osteoimmunology and chemokines.

BACKGROUND. Pyruvoyl Tetrahydropterin Synthase (PTPS) Deficiency is the most common form of BH4 deficiency resulting in hyperphenylalaninemia. It can have variable clinical severity and there is limited information on the clinical presentation, natural history and effectiveness of newborn screening for this condition. METHODS. Retrospective data (growth and clinical parameters, biochemical and genetic testing results, treatment) were collected from 19 patients with PTPS deficiency in different centers, to evaluate biochemical and clinical outcomes. Descriptive statistics was used for qualitative variables, while linear regression analysis was used to correlate quantitative variables. RESULTS. Patients with PTPS deficiency had an increased incidence of prematurity (4/18) with an average gestational age only mildly reduced (37.8±2.4 weeks) and low birth weight (−1.14±0.97 SD below that predicted for gestational age). With time, weight and height approached normal. values. All patients were identified by newborn screening for an elevated phenylalanine level. However, phenylalanine levels were normal in two whose testing was performed at or before 24 h of age. Sapropterin dihydrochloride treatment normalized phenylalanine levels. Molecular testing identified novel variants in the PTS gene, some of which present in more than one affected family. The neurotransmitter derivatives 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in the CSF were decreased in most cases except in 2 families with the peripheral form of PTPS deficiency. With time, HVA and 5HIAA became abnormally low in two of these patients requiring therapy. Prolactin (whose secretion is inhibited by dopamine) levels were elevated in several patients with PTPS deficiency and inversely correlated with the z-scores for height (p

Background and Aims DMT2 and its complications such as chronic kidney disease (CKD) lead to increase vascular stiffness, measurable with CAVI, and biochemical alterations in substances implicated in vascular damage like Klotho, FGF23, and Sclerostin. The aim of the study was to evaluate the role of CKD stage 1-2 and possible alterations of 25 (OH)Vitamin-D, FGF23, Klotho, and Sclerostin on early vascular damage in DMT2 patients Method Patients included: DMT2 from Results We enrolled 40 women and 60 men, average age 56 years (IQR: 52-59), 5-year DMT2 (IQR: 2.7-7), HbA1c 6.3% (5.8-6.7), eGFR of 95 ml/min/1.73m2. FGF23 (42±10 vs controls 29.8±11 pmol/l, p Conclusion In our DMT2 population, borderline and pathological CAVI is associated with increased ACR, elevated DBP and reduced 25(OH)Vitamin-D. Furthermore the alterations of FGF23, Sclerostin and Klotho, secondary to CKD, are an early sign of possible vascular damage. ACR, 25(OH)Vitamin-D and DBP can be modifiable risk factors for early vascular damage in DMT2

Background and Aims Intradialytic hypotension (IDH) involves a reduced tolerance to hemodialysis (HD), a poor quality of life and is associated with mortality. Intradialytic monitoring systems (blood pressure, heart rate, volemia) are not able to identify patients at greater risk of IDH. IDH is a hemodynamic phenomenon and attention has recently been given to the evaluation of oxygen saturation to evaluate its role in IDH. Oxygen Extraction Ratio (OER), the ratio between SaO2 and ScvO2, is a parameter used to monitor parenchyma oxygen consumption and stress. Recent evidence showed that HD patients with a greater delta OER (ΔOER) during HD (threshold 40%)had higher mortality risk. OER could be a new monitoring instrument to measure hemodialysis induced sub-clinical parenchyma hypoxia and stress, two elements included in the pathogenesis of IDH. The aim of the study was to evaluate the relationship between OER and IDH incidence. Method Inclusion criteria: age ≥18 years, chronic HD treatment by means of permanent jugular CVC, no evidence of acute underlying illness. We evaluated OER ([(SaO2 − ScvO2)/SaO2] × 100) before HD and at 15’, 30’, 60’ and post HD in three HD sessions (HD OER sessions). For the statistic analysis we considered for each patient the median OER value obtained from the three HD OER sessions. Then we started the follow-up study with a minimum follow-up of three months and end follow-up of two years, to record IDH (defined according to K/DOQI guidelines) for each patient. We divided the population in two groups using as a threshold the median percentage number of IDH in our population and evaluate the differences between the obtained two groups in pre HD OER, Delta OER and intradialytic OER trends. Results During the follow-up period (mean 12 ± 1.2 months), we enrolled 28 patients with permanent jugular CVC: 13 males and 15 females, aged 74±2.6 years, HD vintage 46 ± 6.5 months. The HD OER sessions for each patient were asymptomatic. Pre HD OER was 34 ± 1.4, post HD OER 46 ± 1.8, with a Delta OER of 39 ± 5 %. OER change during HD was evident since after 15 minutes (OER% 15’: 40 ± 1.2 p 3.6). The two groups were not different for age (76 ± 2.4 vs 73 ± 3.0 years; p 3.6 group had 159 IDH out of a total of 1911 sessions (9%), while IDH % ≤ 3.6 group had 27 IDH out of 2431 sessions (0.9%). Pre HD OER values were not different between the groups while the IDH % >3.6 group had greater delta OER% than the IDH % ≤ 3.6 group (43 ± 4.8 vs. 35 ± 3.0 %; p 3.6 group (ΔOER 20± 3.0 % vs. 8.0 ± 3.0 %; IDH % > 3.6 group vs. IDH % ≤ 3.6 group, p Conclusion Our data show that intradialytic ΔOER, representative of the extent of tissue hypoxic stress, identifies patients at greater risk of IDH. In particular, a ΔOER of 20% after the first 15 minutes of HD and of 43% at the end of the HD session characterizes the more hemodynamically fragile patients. The measurement of the OER can be a new and easy monitoring instrument to identify the most hemodynamically fragile patients already after the first 15 minutes of HD treatment.

Background and Aims Assuming that FGF23 levels correlate with phosphate excretion per nephron, nephron number can be estimated by measuring FGF23 levels and urinary phosphate excretion (FEP). Kuro-O proposed that the ratio of FEP to serum FGF23 levels should correlate with nephron number and is defined as the Nephron Index (NI). The aim of the study is calculating NI as nephron number estimation in patients affected by various degree of chronic kidney disease, both transplanted and not. Method In 147 CRF patients kidney function, mineral metabolism biomarkers and NI were evaluated. Nephron Index was calculated following Kuro-o’s equation (kuro-o 2019): NI=FEP·Ps·eGFRFGF23 Observed patients were divided into two groups: patients with CKD (noTX) and transplanted ones (TX). Results noTX group was made up of 67 patients (40 males and 27 females) affected by CKD stages from G1 to G5. TX group was composed by 80 patient (49 males and 31 females) with various degree of CKD (G1T-G4T) showing mean graft age of 83,2 ± 54,8 months (range: 10,3-268,0). The two groups differed for age (mean age 59 ± 15,6 years in CKD, 55± 10,3years in TX). Mean eGFR did not differ between TX and noTX but NI was higher in TX since FEP was higher despite lower FGF23 levels in TX. The difference in FGF23 levels does not appear to depend on Klotho and PTH whose serum levels were no different between Tx and noTx. (Table1). As far as correlations are concerned, NI correlated with eGFR, FGF23, PTH and 1,25D in both group, while NI correlated with FEP only in the TX group. It's interesting that no correlation existed between FGF23 and sP, FEP, eGFR and sKlotho in TX differently from noTX (Table2). Discussion. NI could not be properly defined as nephron number estimation in TX pts. However it may represent higher function of residual nephrons, since higher FEP did not correlate to FGF23 and could be determined by compensatory hyperfiltration (increased single nephron GFR) in transplanted patients. Conclusion After kidney transplantation, high NI value could have a functional meaning rather than represent residual number of nephrons.

Increasing knowledge on inflammatory mediators and bone metabolism highlights the relationship between inflammation and bone disease. During acute illness, inflammatory cells and cytokines modulate bone cells activity so as to mobilize calcium seemingly to supply the metabolic requirements for immune response. In case of long lasting, chronic inflammatory states a condition of maladaptive, smouldering inflammation is realized and negatively affects calcium bone balance. Aging, now nicknamed inflammaging, is regarded as a chronic inflammatory condition, characterized by increased circulating inflammatory cytokines, that contributes to the development of osteoporosis, cardiovascular diseases and chronic kidney disease. In patients with renal insufficiency, the development of bone and mineral disorders (so called CKD-MBD "syndrome") is now a recognized pathogenic factor for the seemingly accelerated process of aging and for the increased risk of cardiovascular death in these patients. The adaptive changes in mineral and bone metabolism developing in the early stages of chronic kidney disease could represent a hypothetical model of accelerated aging, osteoporosis and cardiovascular disease.