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Background In kidney transplant recipients (KTR), the end-stage kidney disease (ESKD) risk dependent on the risk factors acting in native chronic kidney disease (CKD) remains undefined. Methods We compared risk and determinants of ESKD between 757 adult KTR and 1940 patients with native CKD before and after propensity-score (PS) analysis matched for unmodifiable risk factors [(age, sex, diabetes, cardiovascular disease and estimated glomerular filtration rate (eGFR)]. Results In unmatched cohorts, eGFR was lower in CKD versus KTR (45.9 ± 11.3 versus 59.2 ± 13.4 mL/min/1.73 m2, P < 0.001). During a median follow-up of 5.4 years, the unadjusted cumulative incidence of ESKD was consistently lower in unmatched KTR versus CKD. Conversely, in PS-matched analysis, the risk of ESKD in KTR was 78% lower versus CKD at 1 year of follow-up while progressively increased over time resulting similar to that of native CKD patients after 5 years and 2.3-fold higher than that observed in CKD at 10 years. R2 analysis in unmatched patients showed that the proportion of the outcome variance explained by traditional ESKD determinants was smaller in KTR versus native CKD (31% versus 70%). After PS matching, the risk of ESKD [hazard ratio (HR), 95% confidence interval (95% CI)] was significantly associated with systolic blood pressure (1.02, 1.01–1.02), phosphorus (1.31, 1.05–1.64), 24-h proteinuria (1.11, 1.05–1.17) and haemoglobin (0.85, 0.78–0.93) irrespective of KTR status. Similar data were obtained after matching also for modifiable risk factors. Conclusions In KTR, when compared with matched native CKD patients, the risk of ESKD is lower in the first 5 years and higher later on. Traditional determinants of ESKD account for one-third of the variability of time-to-graft failure.

Several studies showed the association between non-traditional risk factors [proteinuria and estimated Glomerular Filtration Rate (eGFR)] and cardiovascular (CV) and renal outcomes. Nevertheless, the etiologic role of traditional CV risk factors in referred CKD patients is less defined. Herein, we examined the association between smoking habit and CV events, mortality and CKD progression. We undertook an observational analysis of 1306 stage III–V CKD patients. Smoking habit was modeled as a categorical (never, current or former smokers) and continuous (number of cigarettes/day) variable. Mean eGFR was 35.8 ± 12.5 mL/min/1.73 m2. Never, current and former smokers were 61.1%, 10.8% and 28.1%. During a median follow-up of 2.87 years, current and former smokers were at significant risk for CV events (HRs of 1.93 [95% CI, 1.18–3.16] and 1.44 [95% CI, 1.01–2.05]) versus never smokers. Current smokers were at increased mortality risk (HR 2.13 [95% CI, 1.10–4.11]). Interactions were found between former smokers and proteinuria (p = 0.007) and diabetes (p = 0.041) for renal risk, and between current smokers and male gender (p = 0.044) and CKD stage V (p = 0.039) for renal and mortality risk. In referred CKD patients, smoking habit is independently associated with CV events and mortality. It acts as a risk “amplifier” for the association between other risk factors and renal outcomes.

Graphical abstract, Highlights • Radiocontrast medium, sodium diatrizoate, reduces renal cell viability in vitro. • Effect of darbepoetin on diatrizoate-treated cells was studied. • Pre-treatment of renal cells with darbepoetin could reduce diatrizoate toxicity. • Darbepoetin caused changes in the activation state of signaling molecules., The hypersialylated erythropoiesis stimulating agent (ESA) darbepoetin alfa was developed for the treatment of anemia, and has also been reported to have other nonerythropoietic effects. This study outlines one such effect against the toxicity of the radiocontrast medium (RCM) sodium diatrizoate (NaD) in human renal proximal tubular (HK-2) cells in vitro. Using a standard cell viability assay, we observed that pre-incubation of HK-2 cells with darbepoetin (at concentrations of 0.25and 1.0 μg/mL) for 2.5 h prior to addition of NaD (75 mg I/mL, for 2 h) reduced the decrease in cell viability due to the RCM, assayed 22 h after removal of the NaD, whilst maintaining the cells incubated with darbepoetin. Western blot analysis showed that darbepoetin reduced the phosphorylation of c-Jun N-terminal kinases (JNK)1/2 over a period of 1 h incubation with NaD, but did not have an obvious effect on several other targets associated with cell death/survival. However, incubation of HK-2 cells with darbepoetin for a further 22 h after prior exposure to NaD (75 mg I/mL, for 2 h) and subsequent immunoblotting showed that darbepoetin: caused recovery of the activity (phosphorylation) of pro-proliferative/survival signalling molecules, such as Akt (Ser473), STAT (signal transducer and activator of transcription)3(Tyr705); decreased activation of the pro-apoptotic transcription factor FOXO3a by increasing its phosphorylation at Thr32; decreased phosphorylation (activation) of p38 Mitogen activated protein kinase; and reduced poly(ADP-ribose)polymerase (PARP)-1 cleavage. In summary, we present here a beneficial nonerythropoietic effect of darbepoetin alfa against radiocontrast-induced toxicity together with modulation of signalling molecules that play a crucial role in determining cell fate.

Anemia is a common complication of chronic kidney disease (CKD). The prevalence of anemia in CKD strongly increases as the estimated Glomerular Filtration Rate (eGFR) decreases. The pathophysiology of anemia in CKD is complex. The main causes are erythropoietin (EPO) deficiency and functional iron deficiency (FID). The administration of injectable preparations of recombinant erythropoiesis-stimulating agents (ESAs), especially epoetin and darbepoetin, coupled with oral or intravenous(iv) iron supplementation, is the current treatment for anemia in CKD for both dialysis and non-dialysis patients. This approach reduces patients’ dependence on transfusion, ensuring the achievement of optimal hemoglobin target levels. However, there is still no evidence that treating anemia with ESAs can significantly reduce the risk of cardiovascular events. Meanwhile, iv iron supplementation causes an increased risk of allergic reactions, gastrointestinal side effects, infection, and cardiovascular events. Currently, there are no studies defining the best strategy for using ESAs to minimize possible risks. One class of agents under evaluation, known as prolyl hydroxylase inhibitors (PHIs), acts to stabilize hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylase (PH) enzymes. Several randomized controlled trials showed that HIF-PHIs are almost comparable to ESAs. In the era of personalized medicine, it is possible to envisage and investigate specific contexts of the application of HIF stabilizers based on the individual risk profile and mechanism of action.

Diabetic nephropathy is the most common cause of end-stage renal disease worldwide. Control of blood glucose and blood pressure (BP) reduces the risk of developing this complication, but once diabetic nephropathy is established, it is then only possible to slow its progression. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a novel class of oral hypoglycemic agents that increase urinary glucose excretion by suppressing glucose reabsorption at the renal proximal tubule. SGLT2is lower glycated hemoglobin (HbA1c) without increasing the risk of hypoglycemia, induce weight loss and improve various metabolic parameters including BP, lipid profile, albuminuria and uric acid. Several clinical trials have shown that SGLT2is (empagliflozin, dapagliflozin canagliflozin, and ertugliflozin) improve cardiovascular and renal outcomes and mortality in patients with type 2 diabetes. Effects of SGLT2is on the kidney can be explained by multiple pathways. SGLT2is may improve renal oxygenation and intra-renal inflammation thereby slowing the progression of kidney function decline. Additionally, SGLT2is are associated with a reduction in glomerular hyperfiltration, an effect which is mediated by the increase in natriuresis, the re-activation of tubule-glomerular feedback and independent of glycemic control. In this review, we will focus on renal results of major cardiovascular and renal outcome trials and we will describe direct and indirect mechanisms through which SGLT2is confer renal protection.

Background Acute Kidney Injury (AKI) represents a clinical condition with poor prognosis. The incidence of AKI in hospitalized patients was about 22–57%. Patients undergoing cardiac surgery (CS) are particularly exposed to AKI because of the related oxidative stress, inflammation and ischemia-reperfusion damage. Hence, the risk profile of patients undergoing CS who develop AKI and who are consequently at increased mortality risk deserves further investigation. Methods We designed a retrospective study examining consecutive patients undergoing any type of open-heart surgery from January to December 2018. Patients with a history of AKI were excluded. AKI was diagnosed according to KDIGO criteria. Univariate associations between clinical variables and AKI were tested using logistic regression analysis. Variable thresholds maximizing the association with AKI were measured with the Youden index. Multivariable logistic regression analysis was performed to assess predictors of AKI through backward selection. Mortality risk factors were assessed through the Cox proportional hazard model. Results We studied 158 patients (mean age 51.2±9.7 years) of which 74.7% were males. Types of procedures performed were: isolated coronary artery bypass (CABG, 50.6%), valve (28.5%), aortic (3.2%) and combined (17.7%) surgery. Overall, incidence of AKI was 34.2%. At multivariable analysis, young age (p = 0.016), low blood glucose levels (p = 0.028), estimated Glomerular Filtration Rate (p = 0.007), pH (p = 0.008), type of intervention (p = 0.031), prolonged extracorporeal circulation (ECC, p = 0.028) and cross-clamp (p = 0.021) times were associated with AKI. The threshold for detecting AKI were 91 and 51 minutes for ECC and cross-clamp times, respectively. At survival analysis, the presence of AKI, prolonged ECC and cross-clamp times, and low blood glucose levels forecasted mortality. Conclusions AKI is common among CS patients and associates with shortened life-expectancy. Several pre-operative and intra-operative predictors are associated with AKI and future mortality. Future studies, aiming at improving prognosis in high-risk patients, by a stricter control of these factors, are awaited.

Background and Aims Measurement of urine proteins, mainly through the 24-hour excretion or the albumin-to-creatinine ratio (ACR) has become crucial in current clinical practice in Nephrology. Besides being a biomarker of injury, albuminuria also exerts direct pro-inflammatory and pro-fibrotic effects on renal tubules. Hence, a large number of intervention studies have been aimed at lowering albuminuria levels in patients with Chronic Kidney Disease (CKD). However, albuminuria is a measure characterized by a random variability that has been evaluated in several mechanistic and experimental studies and may be influenced by several factors, such as posture, exercise and dietary factors. The aim of the present study was to evaluate the within-day variability, specifically in a cohort of CKD outpatients who were on Renin-Angiotensin-Aldosterone-System inhibitors (RAASi) therapy. Method We enrolled consecutive CKD patients referred to the Nephrology Unit at Magna Graecia University Hospital of Catanzaro between January 1st and March 30th 2020. Inclusion criteria were: age > 18 years, diagnosis of CKD from any cause, presence of albuminuria in the range 150-3500 mg/g at screening. Patients already treated with RAASi, patients with active malignancy/signs of glomerulonephritis requiring immunosuppressive therapies, were excluded. At screening visit, patients with increased albuminuria were started with an Angiotensin Converting Enzyme inhibitor (ACEi) or an Angiotensin II Receptor Blocker (ARB). A second ambulatory visit was scheduled 1 month after start of RAASi therapy. During this visit, patients were asked to stay in the Renal Unit for 12 hours. They collected urine void for ACR, protein-to-creatinine ratio (PCR) and urine creatinine (Ucreat) assessment at 8am,1pm and 6pm. For each patient, comparisons between ACR, PCR and Ucreat were assessed by Kruskal-Wallis test and Friedman post-hoc, using the Benjamini-Hochberg as adjustment method. Coefficients of variation (CV,standard deviation/mean) were also computed. Results Final analysis included 43 patients (46.5% of males). Mean age was 59.6±16.7 years and median eGFR 41 [21-74] mL/min/1.73m2. A high cardiovascular (CV) risk profile was testified by the prevalence of type 2 diabetes (30.2%) and previous CV disease (34.8%). When patient characteristics were compared across ACR categories (300 mg/g), systolic blood pressure was increased (p=0.020) and mean age decreased from 68.0 to 54.8 years on average (p=0.038). ACR values collected were 189 [38-759], 252 [51-1685] and 229 [56-1185] mg/g at 8am, 1pm and 6pm, respectively, with a CV of 24.6% (95%CI 12.4-39.1). 8am ACR was significantly different from 1pm ACR (p Conclusion The present analysis showed a significant individual within-day variability of albuminuria, measured as both ACR and PCR, suggesting that another parameter, in addition to those already known, may be responsible for the day-by-day albuminuria variation. Moreover, the absence of variability in Ucreat, namely the denominator of the ACR/PCR formula, suggests that the true variation is likely dependent on the urine protein values. Thus, albuminuria reduction in response to RAASi treatment should be carefully evaluated by measuring ACR/PCR preferentially at a similar time of the day for each patient. This would allow to avoid under- or overestimation of the actual treatment effect.

Chronic kidney disease (CKD) is a clinical condition characterized by high morbidity and mortality. Globally, CKD is also increasing in prevalence and incidence. The two principal kidney measures namely estimated glomerular filtration rate (eGFR) and albuminuria have been found to be predictors of renal and cardiovascular (CV) endpoints including peripheral artery disease (PAD). The prevalence of PAD was increased in CKD patients and, particularly, in patients with more severe CKD stages. Despite the fact that revascularization strategies are suitable in CKD patients in similar fashion to non-CKD patients, few CKD patients underwent these procedures. In fact, if it is true that revascularization improves prognosis in PAD patients irrespective of baseline eGFR, it was also demonstrated that CKD patients, who underwent revascularization, were at higher risk for amputations, mortality, re-intervention and perioperative complications. With the present review article, we have examined the association between CKD, PAD and peripheral revascularization highlighting data about epidemiology, pathophysiologic mechanisms, and results from previous observational and intervention studies. We have also examined the future perspectives and challenges of research around the association between CKD and PAD.

Metalloproteinases (MPs) are proteolytic enzymes involved in extracellular matrix deposition, regulation of cellular signals of inflammation, proliferation, and apoptosis. Metalloproteinases are classified into three families: Matrix-MPs (MMPs), A-Disintegrin-and-Metalloprotease (ADAMs), and the A-Disintegrin-and-Metalloproteinase-with-Thrombospondin-1-like-Domains (ADAMTS). Previous studies showed that MPs are involved in the development of aortic aneurysms (AA) and, concomitantly, in the onset of chronic kidney disease (CKD). CKD has been, per se, associated with an increased risk for AA. The aim of this review is to examine the pathways that may associate MPs with CKD and AA. Several MMPs, such as MMP-2, -8, -9, and TIMP-1 have been shown to damage the AA wall and to have a toxic effect on renal tubular cells, leading to fibrosis. Similarly, ADAM10 and 17 have been shown to degrade collagen in the AA wall and to worsen kidney function via pro-inflammatory stimuli, the impairment of the Renin-Angiotensin-Aldosterone System, and the degradation of structural proteins. Moreover, MMP-2 and -9 inhibitors reduced aneurysm growth and albuminuria in experimental and human studies. It would be important, in the future, to expand research on MPs from both a prognostic, namely, to refine risk stratification in CKD patients, and a predictive perspective, likely to improve prognosis in response to targeted treatments.

The new respiratory infectious disease coronavirus disease 2019 (COVID-19) that originated in Wuhan, China, in December 2019 and caused by a new strain of zoonotic coronavirus, named severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), to date has killed over 630,000 people and infected over 15,000,000 worldwide. Most of the deceased patients had pre-existing comorbidities; over 20% had chronic kidney disease (CKD). Furthermore, although SARS-CoV-2 infection is characterized mainly by diffuse alveolar damage and acute respiratory failure, acute kidney injury (AKI) has developed in a high percentage of cases. As AKI has been shown to be associated with worse prognosis, we believe that the impact of SARS-CoV-2 on the kidney should be investigated. This review sets out to describe the main renal aspects of SARS-CoV-2 infection and the role of the virus in the development and progression of kidney damage. In this article, attention is focused on the epidemiology, etiology and pathophysiological mechanisms of kidney damage, histopathology, clinical features in nephropathic patients (CKD, hemodialysis, peritoneal dialysis, AKI, transplantation) and prevention and containment strategies. Although there remains much more to be learned with regards to this disease, nonetheless it is our hope that this review will aid in the understanding and management of SARS-CoV-2 infection.

Chronic kidney disease (CKD), defined as the presence of albuminuria and/or reduction in estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, is considered a growing public health problem, with its prevalence and incidence having almost doubled in the past three decades. The implementation of novel biomarkers in clinical practice is crucial, since it could allow earlier diagnosis and lead to an improvement in CKD outcomes. Nevertheless, a clear guidance on how to develop biomarkers in the setting of CKD is not yet available. The aim of this review is to report the framework for implementing biomarkers in observational and intervention studies. Biomarkers are classified as either prognostic or predictive; the first type is used to identify the likelihood of a patient to develop an endpoint regardless of treatment, whereas the second type is used to determine whether the patient is likely to benefit from a specific treatment. Many single assays and complex biomarkers were shown to improve the prediction of cardiovascular and kidney outcomes in CKD patients on top of the traditional risk factors. Biomarkers were also shown to improve clinical trial designs. Understanding the correct ways to validate and implement novel biomarkers in CKD will help to mitigate the global burden of CKD and to improve the individual prognosis of these high-risk patients.

Chronic Kidney Disease (CKD) represents a risk factor for fatal and nonfatal cardiovascular (CV) events, including peripheral vascular disease (PVD). This occurs because CKD encompasses several factors that lead to poor prognoses, mainly due to a reduction of the estimated glomerular filtration rate (eGFR), the presence of proteinuria, and the uremic inflammatory milieu. The matrix metalloproteinases (MMPs) are a group of zinc-containing endopeptidases implicated in extracellular matrix (ECM) remodeling, a systemic process in tissue homeostasis. MMPs play an important role in cell differentiation, angiogenesis, inflammation, and vascular damage. Our aim was to review the published evidence regarding the association between MMPs, PVD, and CKD to find possible common pathophysiological mechanisms. MMPs favor ECM deposition through the glomeruli, and start the shedding of cellular junctions and epithelial-mesenchymal transition in the renal tubules. MMP-2 and -9 have also been associated with the presence of systemic vascular damage, since they exert a pro-inflammatory and proatherosclerotic actions. An imbalance of MMPs was found in the context of PVD, where MMPs are predictors of poor prognoses in patients who underwent lower extremity revascularization. MMP circulating levels are increased in both conditions, i.e., that of CKD and PVD. A possible pathogenic link between these conditions is represented by the enhanced production of transforming growth factor-β that worsens vascular calcifications and atherosclerosis and the development of proteinuria in patients with increased levels of MMPs. Proteinuria has been recognized as a marker of systemic vascular damage, and this may explain in part the increase in CV risk that is manifest in patients with CKD and PVD. In conclusion, MMPs can be considered a useful tool by which to stratify CV risk in patients with CKD and PVD. Further studies are needed to investigate the causal-relationships between MMPs, CKD, and PVD, and to optimize their prognostic and predictive (in response to treatments) roles.

BackgroundHigh ultrasound renal resistive index (RI) predicts poor cardiorenal outcomes in chronic kidney disease (CKD) and has recently emerged as a marker of nephroprotective drugs response. Thus, having a risk profile of CKD patients with abnormal RI may be relevant for the clinicians.MethodsConsecutive patients referred to our non-dialysis CKD clinic from 01/01/2016 to 01/12/2016, were evaluated by clinical and ultrasound analysis. Inclusion criteria were age >18 years and presence of CKD defined as estimated glomerular filtration rate (eGFR)0.150g/24h. Renal artery stenosis, solitary kidney, acute kidney injury were the main exclusion criteria. RI value was the mean of three measures in segmental arteries in each kidney. Univariate analysis was performed to evaluate associations between continuous RI and clinical variables. Multivariate linear regression analysis, based on stepwise method with an elimination criterion of pResultsWe studied 73 patients (69.9% men). Mean RI was 0.67±0.09. Frequencies of diabetes and cardiovascular disease (CVD) were 19.2% and 20.6% and median eGFR 54.1 [30.0-84.6] mL/min/1.73m2. From low (0.70) RI categories, eGFR and haemoglobin levels were decreased while diabetes, cardiovascular disease (CVD), phosphate and smokers were higher. At univariate analysis, RI was significantly associated with age, presence of diabetes, CVD, serum phosphorus, eGFR, Urea and haemoglobin. Multi-adjusted stepwise regression analysis showed that lower eGFR levels (pConclusionsThis analysis suggests that RI is higher in CKD patients with CVD, diabetes, smoking habit and higher serum phosphorus, regardless of eGFR. Further studies are needed to verify whether higher RI indicates more complex pathway of intrarenal damage, besides and beyond kidney function.

Chronic kidney disease (CKD) is currently defined as the presence of proteinuria and/or aneGFR<60 mL/min/1.73m2on the basis of the renal diagnosis. The global dimension of CKD is relevant, since its prevalence and incidence have doubled in the past three decades worldwide. A major complication that occurs in CKD patients is the development of cardiovascular (CV) disease, being the incidence rate of fatal/nonfatal CV events similar to the rate of ESKD in CKD. Moreover, CKD is a multifactorial disease where multiple mechanisms contribute to the individual prognosis. The correct development of novel biomarkers of CV risk may help clinicians to ameliorate the management of CKD patients. Biomarkers of CV risk in CKD patients are classifiable as prognostic, which help to improve CV risk prediction regardless of treatment, and predictive, which allow the selection of individuals who are likely to respond to a specific treatment. Several prognostic (cystatin C, cardiac troponins, markers of inflammation, and fibrosis) and predictive (genes, metalloproteinases, and complex classifiers) biomarkers have been developed. Despite previous biomarkers providing information on the pathophysiological mechanisms of CV risk in CKD beyond proteinuria and eGFR, only a minority have been adopted in clinical use. This mainly depends on heterogeneous results and lack of validation of biomarkers. The purpose of this review is to present an update on the already assessed biomarkers of CV risk in CKD and examine the strategies for a correct development of biomarkers in clinical practice. Development of both predictive and prognostic biomarkers is an important task for nephrologists. Predictive biomarkers are useful for designing novel clinical trials (enrichment design) and for better understanding of the variability in response to the current available treatments for CV risk. Prognostic biomarkers could help to improve risk stratification and anticipate diagnosis of CV disease, such as heart failure and coronary heart disease.

Radiocontrast media (RCM)-induced acute kidney injury (CI-AKI) is a major clinical problem whose pathophysiology is not well understood. Direct toxic effects on renal cells, possibly mediated by reactive oxygen species, have been postulated as contributing to CI-AKI. We investigated the effect of quercetin on human renal proximal tubular (HK-2) cells treated with the radiocontrast medium (RCM) sodium diatrizoate. Quercetin is the most widely studied flavonoid, and the most abundant flavonol present in foods. It has been suggested to have many health benefits, including angioprotective properties and anti-cancer effects. These beneficial effects have been attributed to its antioxidant properties and its ability to modulate cell signaling pathways. Incubation of HK-2 cells with 100 μM quercetin caused a decrease in cell viability and pre-treatment of HK-2 cells with 100 μM quercetin followed by incubation with 75 mgI/ml sodium diatrizoate for 2 hr caused a decrease in cell viability which was worse than in cells treated with diatrizoate alone. However, further incubation of the cells (for 22 hr) after removal of the diatrizoate and quercetin caused a recovery in cell viability in those cells previously treated with quercetin + diatrizoate and quercetin alone. Analysis of signaling molecules by Western blotting showed that in RCM-treated cells receiving initial pre-treatment with quercetin, followed by its removal, an increase in phosphorylation of Akt (Ser473), pSTAT3 (Tyr705), and FoxO3a (Thr32) as well as an induction of Pim-1 and decrease in PARP1 cleavage were observed. Quercetin may alleviate the longer-term toxic effects of RCM toxicity and its possible beneficial effects should be further investigated.

An important side effect of diagnostic contrast drugs is contrast-induced acute kidney injury (CI-AKI; a sudden decrease in renal function) occurring 48-72 hours after injection of a contrast drug that cannot be attributed to other causes. Its existence has recently been challenged, because of some retrospective studies in which the incidence of AKI was not different between subjects who received a contrast drug and those who did not, even using propensity score matching to prevent selection bias. For some authors, only patients with estimated glomerular filtration rate

The mechanism of action of fibroblast growth factor-23 (FGF23) is becoming increasingly clearer as a result of studies that have defined its structure and pleiotropic effects. Furthermore, data are emerging on the effects exerted on this hormone by iron administration. Ten main iron formulations are recognized (with clear differences in composition and possible reactions of intolerance and anaphylaxis), which are indicated for iron deficiency anemia, including nephropathic subjects, as suggested by medical guidelines. With some types of iron formulation (especially iron carboxymaltose) a particular side effect has been observed: hypophosphatemia, mediated by FGF23. This review aims to draw attention to this correlation and the contradiction represented by the presence of both positive and negative modulation by FGF23, with the effects induced by its increase even after long-term treatment with iron formulation. However, more evidence is needed to understand the reasons for this differential stimulation.

Introduction Phenylketonuria (PKU MIM 261600) is a human metabolic disease caused by mutations in phenylalanine hydroxylase gene (PAH) and is inherited in an autosomal recessive Mendelian fashion. Phenylalanine hydroxylase (PAH also known as phenylalanine 4-monooxygenase EC 1,14,16,11) catalyzes the rate-limiting step in L-Phenylalanine (L-Phe) catabolism in liver, using tetrahydrobiopterin (BH4) and dioxygen as additional cosubstrates. Untreated PKU is associated with an abnormal phenotype which includes growth failure, poor skin pigmentation, microcephaly, seizures, global developmental delay and severe intellectual impairment. However, since the introduction of newborn screening programs and with early dietary intervention, children born with PKU can now expect to lead relatively normal lives.Dried Blood Spot, (DBS) is the golden method used to acquire specimen for neonatal screening of PKU. It is fast, not expensive and give the possibility to collect samples far from the reference centre and to quickly delivery to the analytical laboratory, where the Phe content is evaluated by Tandem Mass Chromatography. However, because PKU needs a continous followup, would be really worth to set a new, fast, reproducible and chipper biochemical approach to monitor patients and to optimize the dietary intervention. Here we describe a novel fast and non-destructive method to assay phenylalanine in human blood using Near Infra-Red (NIR) spectroscopy. Methods By using a mobile infrared micro sensor (SCIO sensor) calibrated in the Near Infrared spectrum (700nm to 1000nm), we acquired by scanning and elaborated spectra from DBS card alone, DBS card with a reference concentration scale for Phe alone, and Phe plus Tyr. Based on these data we selected the most sensitive wavelentgh window within the NIR and exploited this parameter to acquire spectra from DBS containingμ blood spiked with 0 to 1200 μM Phe, 0 to 1200 Tyr and with different Phe/Tyr.ratios. An additional experiment using 100 calibrators with 5 datapoints for phenylalaninemia was performed. For each sample, at least 20 scans in duplicate were acquired. Principal component analysis (PCA) was conducted. Results The analysis of the ‘scrubbed’ data both by a specific image elaboration software and by data point algorithms, clear show that it is possible to correlate the nature of the analyte, and its relative concentration with significative differences in the acquired spectra, to obtained the so called specific Phe NIR fingerprint of the sample These observation open the exciting possibility to design a chemiometric model to assay the amount of Phe in DBS without elution and the expensive chromatographic procedures.

In Chronic Kidney Disease (CKD) patients, elevated blood pressure (BP) is a frequent finding and is traditionally considered a direct consequence of their sodium sensitivity. Indeed, sodium and fluid retention, causing hypervolemia, leads to the development of hypertension in CKD. On the other hand, in non-dialysis CKD patients, salt restriction reduces BP levels and enhances anti-proteinuric effect of renin–angiotensin–aldosterone system inhibitors in non-dialysis CKD patients. However, studies on the long-term effect of low salt diet (LSD) on cardio-renal prognosis showed controversial findings. The negative results might be the consequence of measurement bias (spot urine and/or single measurement), reverse epidemiology, as well as poor adherence to diet. In end-stage kidney disease (ESKD), dialysis remains the only effective means to remove dietary sodium intake. The mismatch between intake and removal of sodium leads to fluid overload, hypertension and left ventricular hypertrophy, therefore worsening the prognosis of ESKD patients. This imposes the implementation of a LSD in these patients, irrespective of the lack of trials proving the efficacy of this measure in these patients. LSD is, therefore, a rational and basic tool to correct fluid overload and hypertension in all CKD stages. The implementation of LSD should be personalized, similarly to diuretic treatment, keeping into account the volume status and true burden of hypertension evaluated by ambulatory BP monitoring.

Contrast-induced acute kidney injury (CI-AKI) is a problem associated with the use of iodinated contrast media, causing kidney dysfunction in patients with preexisting renal failure. It accounts for 12% of all hospital-acquired kidney failure and increases the length of hospitalization, a situation that is worsening with increasing numbers of patients with comorbidities, including those requiring cardiovascular interventional procedures. So far, its diagnosis has relied upon the rise in creatinine levels, which is a late marker of kidney damage and is believed to be inadequate. Therefore, there is an urgent need for biomarkers that can detect CI-AKI sooner and more reliably. In recent years, many new biomarkers have been characterized for AKI, and these are discussed particularly with their use in known CI-AKI models and studies and include neutrophil gelatinase-associated lipocalin, cystatin C (Cys-C), kidney injury molecule-1, interleukin-18, N-acetyl-β-d-glucosaminidase, and L-type fatty acid-binding protein (L-FABP). The potential of miRNA and metabolomic technology is also mentioned. Early detection of CI-AKI may lead to early intervention and therefore improve patient outcome, and in future any one or a combination of several of these markers together with development in technology for their analysis may prove effective in this respect.

The term Acute Renal Failure (ARF) has been replaced by the term Acute Kidney Injury (AKI). AKI indicates an abrupt (within 24–48 h) decrease in Glomerular Filtraton Rate, due to renal damage, that causes fluid and metabolic waste retention and alteration of electrolyte and acid-base balance. The renal biomarkers of AKI are substances or processes that are indicators of normal or impaired function of the kidney. The most used renal biomarker is still serum creatinine that is inadequate for several reasons, one of which is its inability to differentiate between hemodynamic changes of renal function (“prerenal azotemia”) from intrinsic renal failure or obstructive nephropathy. Cystatin C is no better in this respect. After the description of the pathophysiology of “prerenal azotemia” and of Acute Kidney Injury (AKI) due to ischemia or nephrotoxicity, the renal biomarkers are listed and described: urinary NAG, urinary and serum KIM-1, serum and urinary NGAL, urinary IL-18, urinary L-FABP, serum Midkine, urinary IGFBP7 and TIMP2, urinary α-GST and π-GST, urinary ɣGT and AP, urinary β2M, urinary RBP, serum and urinary miRNA. All have been shown to appear much earlier than the rise of serum Creatinine. Some of them have been demonstrated to predict the clinical outcomes of AKI, such as the need for initiation of dialysis and mortality.

In patients with preexisting renal impairment, particularly those who are diabetic, the iodinated radiographic contrast media may cause contrast-induced nephropathy (CIN) or contrast-induced acute kidney injury (CI-AKI), that is, an acute renal failure (ARF), usually nonoliguric and asymptomatic, occurring 24 to 72 hours after their intravascular injection in the absence of an alternative aetiology. Radiographic contrast media have different osmolalities and viscosities. They have also a different nephrotoxicity. In order to prevent CIN, the least nephrotoxic contrast media should be chosen, at the lowest dosage possible. Other prevention measures should include discontinuation of potentially nephrotoxic drugs, adequate hydration with i.v. infusion of either normal saline or bicarbonate solution, and eventually use of antioxidants, such as N-acetylcysteine, and statins.

Radiocontrast media (RCM)-induced nephrotoxicity (CIN) is a major clinical problem accounting for 12% of all hospital-acquired cases of acute kidney injury (AKI). The pathophysiology of AKI due to RCM is not well understood, but direct toxic effects on renal cells have been postulated as contributing to CIN. It is believed that iso-osmolar RCM (IOCM) are less nephrotoxic than low-osmolar RCM (LOCM) but clinical data have been controversial. We have investigated the intracellular signaling pathways that may be affected by the LOCM iomeprol (IOM) and the IOCM iodixanol (IOD). Both IOM and IOD caused a dramatic decrease in phosphorylation of the kinase Akt at Ser473 and Thr308 in human renal tubular (HK-2) cells, with IOM having a greater effect; IOM also caused a greater decrease in cell viability. IOM also had a greater effect on phosphorylation of p38 MAP kinases, JNKs, and NF-kB (Ser276), and caused a marked decrease in the phosphorylation of forkhead box O3a (FOXO3a) and signal transducer and activator of transcription 3 (STAT3). However, IOD caused a greater decrease in the phosphorylation of mTOR (Ser2448) and phospho-ERK 1/2 while both RCM caused a similar decrease in the phosphorylation of phospho-p70S6 kinase (Ser371). In vivo studies showed that both IOM and IOD caused a significant decrease in both pAkt (Ser473) and pERK 1/2 in rat kidneys. Our study gives an insight into the possible mechanism of toxicity of RCM via their action on intracellular signaling pathways and may help in developing pharmacological interventions for their side-effects.

Modern iodinated radiocontrast media are all based on the triiodinated benzene ring with various chemical modifications having been made over the last few decades in order to reduce their toxicity. However, CIN remains a problem especially in patients with pre-existing renal failure.In vitrostudies have demonstrated that all RCM are cytotoxic. RCM administrationin vivomay lead to a decrease in renal medullary oxygenation leading to the generation of reactive oxygen species that may cause harmful effects to renal tissue. In addition, endothelin and adenosine release and decreased nitric oxide levels may worsen the hypoxic milieu.In vitrocell culture studies together with sparsein vivorat model data have shown that important cell signalling pathways are affected by RCM. In particular, the prosurvival and proproliferative kinases Akt and ERK1/2 have been shown to be dephosphorylated (deactivated), whilst proinflammatory/cell death molecules such as the p38 and JNK kinases and the transcription factor NF-κB may be activated by RCM, accompanied by activation of apoptotic mediators such as caspases. Increasing our knowledge of the mechanisms of RCM action may help to develop future therapies for CIN.

Radiocontrast media (RCM) are widely used in clinical medicine but may lead to radiocontrast-induced nephropathy (RCIN). The pathogenesis of acute renal failure secondary to RCM is not fully understood, but direct toxic effects are believed to be a major cause of RCIN. We have investigated the effect of different types of RCM on signaling pathways known to play a role in cell death, survival, and inflammation. HK-2 cells were incubated with sodium diatrizoate and iomeprol (IOM) at a concentration of 75 mg I/ml for 2 h. Both RCM caused an increase in phosphorylation of p38 mitogen-activated protein kinase (MAPK) (p38) and c-Jun N-terminal kinases (JNKs) and NF-κB (at Ser 276), with sodium diatrizoate having a more drastic effect. Although cell viability was reduced significantly by both RCM, in cells pretreated with IOM the cell viability recovered over a 22-h time period after removal of the RCM. However, viability of diatrizoate-treated cells rose at 5 h but then fell at 22 h after removal of the RCM. The decrease in cell viability in diatrizoate-treated cells corresponded with an increase in phosphorylation of JNKs, p38, and NF-κB and a decrease in phosphorylation of Akt, signal transducer and activator of transcription 3, and forkhead box O3a, as well as poly (ADP-ribose) polymerase and caspase-3 cleavage. The recovery in viability of IOM-treated cells corresponded most notably with an increase in STAT3 phosphorylation and induction of Pim-1 kinase. There was also an increase in interleukin-8 release by diatrizoate-treated cells indicating the possibility of proinflammatory effects of RCM. A knowledge of the signaling pathways by which RCM exert their cytotoxic actions may help in finding future therapies for RCIN.

Ischaemia-reperfusion injury is a common occurrence in renal transplantation and may affect the long-term survival of the allograft. Oxidative stress may play a crucial role in this, with reactive oxygen species formed during reperfusion causing direct cellular damage as well as activating pro-inflammatory pathways. A human proximal tubule cell line (HK-2) was subjected to hydrogen peroxide (H(2)O(2)) stress that resulted in phosphorylation of c-jun N-terminal kinases (JNKs) and the transcription factor NF-kappaB at Ser276, both of which have been associated with inflammation. Interleukin (IL)-8 production also increased upon H(2)O(2) stimulation. Pre-incubation of the cells with mycophenolic acid (MPA) resulted in reduced phosphorylation of both JNKs and NF-kappaB, and reduced IL-8 release in H(2)O(2)-stimulated HK-2 cells. MPA also reduced the H(2)O(2)-induced phosphorylation of p38 MAP (mitogen-activated protein) kinase, the extracellular-signal regulated kinase 1/2 (ERK1/2), Akt kinase and the transcription factor CREB (cyclic AMP response element binding protein). In rat kidneys subjected to ischaemia-reperfusion, an increase in both pJNK1/2 and pNF-kappaB was observed, which was reduced in kidneys obtained from mycophenolate mofetil (MMF)-treated rats. These results suggest that MPA may inhibit pro-inflammatory responses in the kidney by inhibiting activation of pro-inflammatory molecules in both the kidney and human renal proximal tubular cells subjected to oxidative stress.