Corrigendum: Impact of hyperparathyroidism and its different subtypes on long term graft outcome: a single Transplant Center cohort study.

[This corrects the article DOI: 10.3389/fmed.2023.1221086.].

Real-world usage of Chronic Kidney Disease - Mineral Bone Disorder (CKD-MBD) biomarkers in nephrology practices.

Background: Chronic kidney disease mineral bone disorder (CKD-MBD) is a condition characterized by alterations of calcium, phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF-23) metabolism that in turn promote bone disorders, vascular calcifications, and increase cardiovascular (CV) risk. Nephrologists' awareness of diagnostic, prognostic, and therapeutic tools to manage CKD-MBD plays a primary role in adequately preventing and managing this condition in clinical practice. Methods: A national survey (composed of 15 closed questions) was launched to inquire about the use of bone biomarkers in the management of CKD-MBD patients by nephrologists and to gain knowledge about the implementation of guideline recommendations in clinical practice. Results: One hundred and six Italian nephrologists participated in the survey for an overall response rate of about 10%. Nephrologists indicated that the laboratories of their hospitals were able to satisfy request of ionized calcium levels, 105 (99.1%) of both PTH and alkaline phosphatase (ALP), 100 (94.3%) of 25(OH)D, and 61 (57.5%) of 1.25(OH)2D; while most laboratories did not support the requests of biomarkers such as FGF-23 (intact: 88.7% and c-terminal: 93.4%), Klotho (95.3%; soluble form: 97.2%), tartrate-resistant acid phosphatase 5b (TRAP-5b) (92.5%), C-terminal telopeptide (CTX) (71.7%), and pro-collagen type 1 N-terminal pro-peptide (P1NP) (88.7%). As interesting data regarding Italian nephrologists' behavior to start treatment of secondary hyperparathyroidism (sHPT), the majority of clinicians used KDOQI guidelines (n = 55, 51.9%). In contrast, only 40 nephrologists (37.7%) relied on KDIGO guidelines, which recommended referring to values of PTH between two and nine times the upper limit of the normal range. Conclusion: Results point out a marked heterogeneity in the management of CKD-MBD by clinicians as well as a suboptimal implementation of guidelines in Italian clinical practice.

MCP1 Inverts the Correlation between FGF23 and Omega 6/3 Ratio: Is It Also True in Renal Transplantation?

During chronic kidney disease (CKD) progression, an increase in fibroblast growth factor (FGF23) is present. In stage 5, a positive correlation between FGF23 and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) emerges. Hypothesizing that the rising positive correlation between monocyte chemoattractant protein 1 (MCP1) and n-6 in stage 4 could be the cause, we previously explored FGF23 and MCP1's roles in dyslipidemia and cardiovascular risk in CKD. In the present paper, we retraced the study evaluating 40 kidney transplant patients (KTx), a cohort where several factors might modify the previous relationships found. An ELISA and gas chromatography assessed the MCP1, FGF23, and PUFA levels. Despite the FGF23 increase (p < 0.0001), low MCP1 levels were found. A decrease in the n-6/n-3 ratio (p = 0.042 CKD stage 4 vs. 5) lowered by the increase in both n-3 αlinolenic (p = 0.012) and docosapentaenoic acid (p = 0.049) was observed. A negative correlation between FGF23 and the n-6/n-3 ratio in CKD stage 4 (r2 -0.3 p = 0.043) and none with MCP1 appeared. According to our findings, different mechanisms in the relationship between FGF23, PUFAs, and MCP1 in CKD and KTx patients might be present, which is possibly related to the immunosuppressive status of the last. Future research will further clarify our hypothesis.

Impact of hyperparathyroidism and its different subtypes on long term graft outcome: a single Transplant Center cohort study.

Purpose: We studied the association between parathormone (PTH) levels and long-term graft loss in RTx patients (RTx-p). Methods: We retrospectively evaluated 871 RTx-p, transplanted in our unit from Jan-2004 to Dec-2020 assessing renal function and mineral metabolism parameters at 1, 6, and 12 months after RTx. Graft loss and death with functioning graft during follow-up (FU, 8.3[5.4-11.4] years) were checked. Results: At month-1, 79% had HPT, of which 63% with secondary HPT (SHPT) and 16% tertiary HPT (THPT); at month-6, HPT prevalence was 80% of which SHPT 64% and THPT 16%; at month-12 HPT prevalence was 77% of which SHPT 62% and THPT 15%. A strong significant correlation was found between HPT type, PTH levels and graft loss at every time point. Mean PTH exposure remained strongly and independently associated to long term graft loss (OR 3.1 [1.4-7.1], p = 0.008). THPT was independently associated with graft loss at month-1 when compared to HPT absence and at every time point when compared to SHPT. No correlation was found with RTx-p death. Discriminatory analyses identified the best mean PTH cut-off to predict long-term graft loss to be between 88.6 and 89.9 pg/mL (AUC = 0.658). Cox regression analyses highlighted that THPT was strongly associated with shorter long-term graft survival at every time-point considered. Conclusion: High PTH levels during 1st year of RTx seem to be associated with long term graft loss.

Safety and efficacy of COVID-19 vaccines in patients on dialysis: a multicentre cohort study in Italy.

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of COVID-19 vaccines in patients undergoing haemodialysis in Italy compared to the general population. METHODS: In this cohort study, 118 dialysis centres from 18 Italian Regions participated. Individuals older than 16 years on dialysis treatment for at least 3 months, who provided informed consent were included. We collected demographic and clinical information, as well as data on vaccination status, hospitalisations, access to intensive care units and adverse events. We calculated the incidence, hospitalisation, mortality, and fatality rates in the vaccinated dialysis cohort, adjusted for several covariates. The incidence rates of infection in the dialysis cohort and the general population were compared through Standardised Incidence Rate Ratio. RESULTS: The study included 6555 patients vaccinated against SARS-CoV-2 infection according to the schedule recommended in Italy. Between March 2021 and May 2022, there were 1096 cases of SARS-CoV-2 infection, with an incidence rate after completion of the three-dose vaccination cycle of 37.7 cases per 100 person-years. Compared to the general population, we observed a 14% reduction in the risk of infection for patients who received three vaccine doses (Standardised Incidence Rate Ratio: 0.86; 95% Confidence Interval: 0.81-0.91), whereas no statistically significant differences were found for COVID-19-related hospitalisations, intensive care unit admissions or death. No safety signals emerged from the reported adverse events. CONCLUSIONS: The vaccination program against SARS-CoV-2 in the haemodialysis population showed an effectiveness and safety profile comparable to that seen in the general population.

Vitamin D and Calcium Supplementation and Urolithiasis: A Controversial and Multifaceted Relationship.

Patients with urolithiasis, and particularly those with hypercalciuria, frequently have a marked reduction of bone mineral content up to the levels of osteoporosis, with a significant increase in bone fracture risk. For these reasons, the indication to prescribe vitamin D and/or calcium supplementations is very frequent in such patients. On the other hand, both calcium supplementation, and even more vitamin D therapy, can worsen the risk of developing urolithiasis by increasing calcium, phosphate, and oxalate urinary excretion. Despite the clinical and practical relevance of this issue, the evidence on this topic is scarce and contradictory. Therefore, some concerns exist about how and whether to prescribe such supplements to a patient with a history of kidney stones. In this narrative review, we resume some pivotal pathophysiological concepts strictly related to the dealt topic, and we draw some considerations and personal opinions on the pros and cons of such prescriptions. Finally, we share with the reader our pragmatic algorithm for handling the urolithiasis risk in patients who have strong indications to be prescribed vitamin D and calcium supplementations.

Kidney Stone Prevention: Is There a Role for Complementary and Alternative Medicine?

Complementary and alternative medicine (CAM) is often implemented in kidney stone patients. It consists of preparations including different ingredients, such as herbs, probiotics, and vitamins, often together with alkali, that are classified within the dietary supplementation category. The majority of dietary supplements claiming to treat or prevent kidney stones contain ingredients with conflicting or no scientific evidence to support their claims. Clinicians should advise stone formers that the effects of most supplements are unknown or unstudied in humans and that the absence of evidence does not imply absence of potential harm. Unfortunately, the CAM preparation consists of a mix of different molecules, often including alkali, with different potential mechanisms of action and, even when favorable results are reported, the role of the single molecules cannot be assessed. Despite all these concerns, CAM products remain quite popular among kidney stone patients. The scarce knowledge in this field prevents one from recommending CAM products in daily clinical practice; only a weak suggestion for their use in kidney stone patients may be reasonable.

Fibroblast growth factor 23 level modulates the hepatocyte's alpha-2-HS-glycoprotein transcription through the inflammatory pathway TNFα/NFκB.

Introduction: High serum levels of fibroblast growth factor 23 (FGF23) characterize chronic kidney disease (CKD) since its early stages and have been suggested to contribute to inflammation and cardiovascular disease. However, the mechanisms linking FGF23 with these pathological conditions remain still incompletely defined. The alpha-2-HS-glycoprotein (AHSG), a liver-produced anti-inflammatory cytokine, is highly modulated by inflammation itself, also through the TNFα/NFκB signaling pathway. In our previous study, we found that FGF23 modulates the production of AHSG in the liver in a bimodal way, with stimulation and inhibition at moderately and highly increased FGF23 concentrations, respectively. Methods: The present study, aiming to gain further insights into this bimodal behavior, was performed in hepatocyte human cells line (HepG2), using the following methods: immunochemistry, western blot, chromatin immunoprecipitation, fluorescence in situ hybridization (FISH), qRT-PCR, and gene SANGER sequencing. Results: We found that FGF23 at 400 pg/ml activates nuclear translocation of NFκB, possibly increasing AHSG transcription. At variance, at 1,200 pg/ml, FGF23 inactivates NFκB through the activation of two specific NFκB inhibitors (IκBα and NKIRAS2) and induces its detachment from the AHSG promoter, reducing AHSG transcription. Conclusion: These results add another piece to the puzzle of FGF23 involvement in the multifold interactions between CKD, inflammation, and cardiovascular disease, suggesting the involvement of the NFκB pathway, which might represent a potential therapeutic target in CKD.

MCP1 Could Mediate FGF23 and Omega 6/Omega 3 Correlation Inversion in CKD.

Fibroblast growth factor 23 (FGF23) concentrations rise after the early stages of chronic kidney disease (CKD). FGF23 is involved in inflammatory reactions closely associated with an incremented risk of cardiovascular disease (CVD). There is growing evidence that omega-6 (n-6) and n-3 polyunsaturated fatty acids (PUFA) can modulate inflammation through several mediators producing an opposite effect on cardiovascular (CV) risks. In this study, we explore whether there is any correlation between PUFA, FGF23, and inflammation in CKD patients. We evaluated, cross-sectionally, 56 patients at different stages of CKD. Monocyte chemoattractant protein 1 (MCP1), and intact and c-terminal FGF23 (iFGF23, cFGF23) were quantified by the ELISA, and the fatty acids (FA) profile was analyzed by gas chromatography. Concurrently with an eGFR decrease (p < 0.01) and an MCP1 increase (p = 0.031), we observed an inversion of the correlation between FGF23 and the n-6/n-3 ratio. This last correlation was inversed in CKD stage 3 (r2 (−) 0.502 p = 0.029) and direct in stage 5 (r2 0.657 p = 0.020). The increase in MCP1 seems to trigger events in the inversion of the correlation between FGF23 and the n-6/n-3 PUFA ratio. This result strongly encourages future studies on basal pathways, on possible pharmacological interventions, and on managing kidney transplant patients treated with immunosuppressive therapy.

Prevalence and Risk Factors of Abnormal Glucose Metabolism and New-Onset Diabetes Mellitus after Kidney Transplantation: A Single-Center Retrospective Observational Cohort Study.

Background and objectives: New-onset diabetes after transplantation (NODAT) represents a primary cause of morbidity and allograft loss. We assessed prevalence and risk factors for NODAT in a population of Italian kidney transplant (KT) recipients. Methods: Data from 522 KT performed between January 2004 and December 2014 were analyzed. Participants underwent clinical examination; blood and urine laboratory tests were obtained at baseline, one, six, and 12-month of follow-up to detect glucose homeostasis abnormalities and associated metabolic disorders. An oral glucose tolerance test (OGTT) was performed at six months in 303 subjects. Results: Most patients were Caucasian (82.4%) with a mean age of 48 ± 12 years. The prevalence of abnormal glucose metabolism (AGM) and NODAT was 12.6% and 10.7%, respectively. Comparing characteristics of patients with normal glucose metabolism (NGM) to those with NODAT, we found a significant difference in living donation (16.6% vs. 6.1%; p = 0.03) and age at transplant (46 ± 12 vs. 56 ± 9 years; p = 0.0001). Also, we observed that patients developing NODAT had received higher cumulative steroid doses (1-month: 1165 ± 593 mg vs. 904 ± 427 mg; p = 0.002; 6-month:2194 ± 1159 mg vs. 1940 ± 744 mg; p = 0.002). The NODAT group showed inferior allograft function compared to patients with NGM (1-year eGFR: 50.1 ± 16.5 vs. 57 ± 20 mL/min/1.73 m2; p = 0.02). NODAT patients were more likely to exhibit elevated systolic blood pressure and higher total cholesterol and triglyceride levels than controls. Conclusions: The prevalence of NODAT in our cohort was relatively high. Patient age and early post-transplant events such as steroid abuse are associated with NODAT development.

Carbon dots conjugated to SN38 for improved colorectal anticancer therapy.

Irinotecan (CTP-11) is one of the standard therapies for colorectal cancer (CRC). CTP-11 is enzymatically converted to the hydrophobic 7-ethyl-10-hydroxycamptothecin (SN38), a one hundred-fold more active metabolite. Conjugation of hydrophobic anticancer drugs to nanomaterials is a strategy to improve their solubility, efficacy, and selectivity. Carbon dots (CDs) have garnered interest for their small sizes (<10 â€‹nm), low toxicity, high water solubility, and bright fluorescence. This paper describes the use of CDs to improve drug vehiculation, stability, and chemotherapeutic efficiency of SN38 through a direct intracellular uptake in CRC. The covalent conjugation of SN38 to CDs via a carbamate bond provides a CD-SN38 hybrid material for slow, sustained, and pH-responsive drug release. CD-SN38 successfully penetrates the CRC cells with a release in the nucleus affecting first the cell cycle and then the cytoskeleton. Moreover, CD-SN38 leads to a deregulation of the extracellular matrix (ECM), one of the major components of the cancer niche considered a possible target therapy for reducing the cancer progression. This work shows the combined therapeutic and imaging potential of CD-based hybrid materials for the treatment of CRC. Future efforts for targeted therapy of chronic diseases characterized by altered ECM deposition, such as chronic kidney disease and chronic allograft nephropathy in kidney transplant patients are envisaged.

Acute kidney injury and chronic kidney disease after liver transplant: A retrospective observational study.

BACKGROUND AND RATIONALE: Chronic kidney disease remains an important risk factor for morbidity and mortality among LT recipients, but its exact incidence and risk factors are still unclear. MATERIAL AND METHODS: We carried out a retrospective cohort study of consecutive adults who underwent liver transplant (January 2009-December 2018) and were followed (at least 6 months) at our institution. CKD was defined following the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guidelines. Long-term kidney function was classified into 4 groups: no CKD (eGFR, ≥60mL/min/1.73m2), mild CKD (eGFR, 30-59mL/min/1.73m2), severe CKD (eGFR, 15-29mL/min/1.73m2), and end-stage renal disease (ESRD). RESULTS: We enrolled 410 patients followed for 53.2±32.6 months. 39 had CKD at baseline, and 95 developed de novo CKD over the observation period. There were 184 (44.9%) anti-HCV positive, 47 (11.5%) HBsAg positive, and 33 (8.1%) HBV/HDV positive recipients. Recipient risk factors for baseline CKD were advanced age (P=0.044), raised levels of serum uric acid (P<0.0001), and insulin dependent DM (P=0.0034). Early post-transplant AKI was common (n=95); logistic regression analysis found that baseline serum creatinine was an independent predictor of early post-LT AKI (P=0.0154). According to our Cox proportional hazards model, recipient risk factors for de novo CKD included aging (P<0.0001), early post-transplant AKI (P=0.007), and baseline serum creatinine (P=0.0002). At the end of follow-up, there were 116 LT recipients with CKD - 109 (93.9%) and 7 (6.1%) had stage 3 and advanced CKD, respectively. Only two of them are undergoing long-term dialysis. CONCLUSION: The incidence of CKD was high in our cohort of LT recipients, but only a slight decline in kidney function over time was recorded. Prevention of post-transplant AKI will improve kidney function in the long run. We need more studies to analyze the function of kidneys among LT recipients over extended follow-ups and their impact on mortality.

[Italian Society of Cardiology-Italian Society of Nephrology Consensus document: The cardio-renal interaction in the prevention and treatment of cardiovascular diseases - Part II: From preventive strategies to treatment of patients with cardio-renal damage]. / Documento di consenso Società Italiana di Cardiologia- Società Italiana di Nefrologia: Ruolo dell'asse cardio-renale nella prevenzione e trattamento delle patologie cardiovascolari ­ Parte II: Dalle strategie di prevenzione al trattamento del paziente con coinvolgimento cardio-renale.

Chronic kidney disease and cardiovascular disease are strictly connected each other with a bidirectional interaction. Thus, the prevention of cardio-renal damage, as its appropriate treatment, are essential steps for a correct management of long-term patients' prognosis. Several preventive and therapeutic strategies, pharmacological and not, are now available for cardio-renal damage prevention and treatment, and for the management of its complications. The second part of this consensus document focuses on the management and treatment of cardio-renal damage, directing the attention on the correct use of drugs that may slow renal disease progression, on the application of preventive strategies in case of invasive cardiac procedures with the use of contrast agents, and on the accurate use of cardiological drugs in patients with chronic kidney disease.

[Italian Society of Cardiology-Italian Society of Nephrology Consensus document: The cardio-renal interaction in the prevention and treatment of cardiovascular diseases - Part I: From cardiovascular risk factors to the mechanisms of cardio-renal syndrome]. / Documento di consenso Società Italiana di Cardiologia- Società Italiana di Nefrologia: Ruolo dell'asse cardio-renale nella prevenzione e trattamento delle patologie cardiovascolari ­ Parte I: Dai fattori di rischio cardiovascolare ai meccanismi di danno cardio-renale.

Chronic kidney disease (CKD) and cardiovascular (CV) disease are highly prevalent conditions in the general population and are strictly connected to each other with a bidirectional interaction. In patients affected by CKD, the leading cause of morbidity and mortality is represented by CV disease, since CKD promotes the atherosclerotic process increasing inflammation, and modifying lipid and bone mineral metabolism. On the other side, a strict relationship exists between CKD and CV risk factors, which are prevalent in nephropathic patients and impose a stringent assessment of the risk of CV events in this population together with an optimized pharmacological approach, complicated by the coexistence of the two pathological conditions. The first part of this consensus document focuses on the mechanisms of cardio-renal damage and on the impact, as well as the management, of the main CV risk factors in the context of CKD.

Time for Revival of Bone Biopsy with Histomorphometric Analysis in Chronic Kidney Disease (CKD): Moving from Skepticism to Pragmatism.

Bone Biopsy (BB) with histomorphometric analysis still represents the gold standard for the diagnosis and classification of different forms of renal osteodystrophy. Bone biopsy is the only technique able to provide comprehensive information on all bone parameters, measuring static and dynamic parameters of turnover, cortical and trabecular microarchitecture, and mineralization defects. In nephrological practice, bone biopsy yields relevant indications to support therapeutic choices in CKD, heavily impacting the management and prognosis of uremic patients. Unfortunately, the use of bone biopsy has decreased; a lack of expertise in performing and interpreting, perceived procedure invasiveness and pain, and reimbursement issues have all contributed to this decline. Nevertheless, both bone biomarkers and instrumental images cannot be considered reliable surrogates for histological findings, being insufficiently accurate to properly evaluate underlying mineral and bone disorders. This is a multidisciplinary position paper from the Nephrology and Osteoporosis Italian Scientific Societies with the purpose of restating the role of bone biopsy in CKD patient management and of providing strong solutions to allow diffusion of this technique in Italy, but potentially also in other countries. The Italian approach through the optimization and standardization of bone biopsy procedure, the construction of the Italian Hub and Spoke network, and a request for adjustment and national homogenization of reimbursement to the Italian Health Ministry has led the way to implement bone biopsy and to improve CKD patient management and prognosis.

Renal Nutrition and Metabolism.

Since the dawn of nephrology, dietary intervention has been one of the cornerstones of therapeutic intervention, used by nephrologists in an attempt to reduce the symptoms and metabolic complications that characterize chronic kidney disease (CKD) and, possibly, to stop its evolution [...].

Management of Acute Kidney Injury and Extracorporeal Blood Purification Therapies During the COVID-19 Pandemic: The Italian SIN-SIAARTI Joint Survey (and Recommendations for Clinical Practice).

Background and Aim: The novel coronavirus disease 2019 remains challenging. A large number of hospitalized patients are at a high risk of developing AKI. For this reason, we conducted a nationwide survey to assess the incidence and management of AKI in critically ill patients affected by the SARS-CoV-2 infection. Methods: This is a multicenter, observational, nationwide online survey, involving the Italian Society of Nephrology and the critical care units in Italy, developed in partnership between the scientific societies such as SIN and SIAARTI. Invitations to participate were distributed through emails and social networks. Data were collected for a period of 1 week during the COVID-19 pandemic. Results: A total of 141 responses were collected in the SIN-SIAARTI survey: 54.6% from intensivists and 44.6% from nephrologists. About 19,000 cases of COVID-19 infection have been recorded in hospitalized patients; among these cases, 7.3% had a confirmed acute kidney injury (AKI), of which 82.2% were managed in ICUs. Only 43% of clinicians routinely used the international KDIGO criteria. Renal replacement therapy (RRT) was performed in 628 patients with continuous techniques used most frequently, and oliguria was the most common indication (74.05%). Early initiation was preferred, and RRT was contraindicated in the case of therapeutic withdrawal or in the presence of severe comorbidities or hemodynamic instability. Regional anticoagulation with citrate was the most common choice. About 41.04% of the interviewed physicians never used extracorporeal blood purification therapies (EBPTs) for inflammatory cytokine or endotoxin removal. Moreover, 4.33% of interviewed clinicians used these techniques only in the presence of AKI, whereas 24.63% adopted them even in the absence of AKI. Nephrologists made more use of EBPT, especially in the presence of AKI. HVHF was never used in 58.54% of respondents, but HCO membranes and adsorbents were used in more than 50% of cases. Conclusion: This joint SIN-SIAARTI survey at the Italian Society of Nephrology and the critical care units in Italy showed that, during the COVID-19 pandemic, there was an underestimation of AKI based on the "non-use" of common diagnostic criteria, especially by intensivists. Similarly, the use of specific types of RRT and, in particular, blood purification therapies for immune modulation and organ support strongly differed between centers, suggesting the need for the development of standardized clinical guidelines.