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Objective Kidney stone disease seems to be associated with an increased risk of incident cardiovascular outcomes; the aim of this study is to identify differences in 24-h urine excretory profiles and stone composition among stone formers with and without cardiovascular disease (CVD). Methods Data from patients attending the Department of Renal Medicine’s metabolic stone clinic from 1995 to 2012 were reviewed. The sample was divided according to the presence or absence of CVD (myocardial infarction, angina, coronary revascularization, or surgery for calcified heart valves). Univariable and multivariable regression models, adjusted for age, sex, BMI, hypertension, diabetes, eGFR, plasma bicarbonate and potential renal acid load of foods were used to investigate differences across groups. Results 1826 patients had available data for 24-h urine analysis. Among these, 108 (5.9%) had a history of CVD. Those with CVD were older, have higher prevalence of hypertension and diabetes and lower eGFR. Univariable analysis showed that patients with CVD had significantly lower 24-h urinary excretions for citrate (2.4 vs 2.6 mmol/24 h, p = 0.04), magnesium (3.9 vs 4.2 mmol/24 h, p = 0.03) and urinary pH (6.1 vs 6.2, p = 0.02). After adjustment for confounders, differences in urinary citrate and magnesium excretions remained significant. No differences in the probability of stone formation or stone compositions were found. Conclusions Stone formers with CVD have lower renal alkali excretion, possibly suggesting higher acid retention in stone formers with cardiovascular comorbidities. Randomized clinical trials including medications and a controlled diet design are needed to confirm the results presented here. Graphic abstract

Introduction Several studies have suggested that chronic kidney disease (CKD) may be associated with olfactory impairment. However, to date, the impact of renal replacement therapies has only been partly defined. Methods We tested the olfactory function of 235 participants [50 kidney transplant recipients (KT), 49 hemodialyzed patients (HD), 30 peritoneal dialysis patients (PD), 51 patients with CKD not on dialysis (ND-CKD) and 55 healthy subjects (HS)] by the Sniffin’ Sticks test (Burghardt®, Wedel, Germany), including the sub-tests for the determination of odor threshold (T), odor discrimination (D), odor identification (I). Each subtest result was then summed up to a composite score, known as the TDI score. The Sino-Nasal Outcome Test-22 (SNOT22), Montreal Cognitive Assessment (MoCA) test and olfactory function Visual Analogue Scale (ofVAS) were also performed. Results The mean TDI score was significantly lower (and consistent with hyposmia), in HD, PD and ND-CKD compared to HS and KT (ANOVA p I and D tests, and with the T score, though with regard to the latter, only in PD and ND-CKD patients. Multiple comparisons among groups demonstrated no significant differences between KT and HS. After adjustments for confounding factors, a significant linear association was found between both urea (β − 0.03, p TDI score and the ofVAS score (p = 0.293). Conclusions Olfactory impairment affects a large number of CKD patients in the pre-dialysis phase as well as those on dialysis. Kidney transplantation may reverse this condition with a possible positive impact on the quality of life and social behaviors/relationships. Graphic abstract

Background The aim of our study was to describe seasonal trends of acute kidney injury (AKI) and its relationship with weather conditions in a hospitalized population. Methods We retrospectively collected demographic (age, sex), clinical (ICD-9-CM codes of diagnosis discharge) and laboratory data (creatinine values) from the inpatient population admitted to Fondazione Policlinico Universitario A. Gemelli IRCCS between January 2010 and December 2014 with inclusion of all patients ≥18 years with at least two values available for creatinine. The outcome of interest was AKI development, defined according to creatinine kinetics criteria. The exposures of interest were the months and seasons of the year; air temperature and humidity level were also evaluated. Log-binomial regression models adjusted for age, sex, eGFR, comorbidities, Charlson/Deyo index score, year of hospitalization were used to estimate risk ratios (RR) and 95% confidential intervals (CI). Results A total of 64,610 patients met the inclusion criteria. AKI occurred in 2864 (4.4%) hospital admissions. After full adjustment, winter period was associated with increased risk of AKI (RR 1.16, 95% CI 1.05, 1.29, p=0.003). Lower air temperature and higher humidity level were associated with risk of AKI, however in multivariable-adjusted models only higher humidity level showed a significant and independent association. Conclusions AKI is one of the most common complications of hospitalized populations with a defined seasonal pattern and a significant increase in incidence during wintertime; weather conditions, particularly higher humidity level, are independent predictors of AKI and could partially justify the observed seasonal variations.

Background Heart failure (HF) is a complex syndrome affecting the whole body, kidneys included. The left ventricular assist device (LVAD) is a valid option for patients with very severe HF. Focusing on renal function, LVAD implantation could theoretically reverse the detrimental effects of HF syndrome on kidneys. However, implanting a LVAD is a high-risk surgical procedure, and LVAD patients have higher risk of bleeding, device thrombosis, strokes, renal impairment, multi-organ failure and infections. Furthermore, an LVAD has its own particular effects on the renal system. Methods In this review, we provide a comprehensive overview of the complex interaction between LVAD and the kidneys from the pathophysiological and clinical perspectives. An analysis of the different effects of pulsatile-flow and continuous-flow LVAD is provided. Results despite their limitations, creatinine-based estimated glomerular filtration rate (eGFR) formulas help to stratify patients by their post-LVAD placement prognosis. Poor basal renal function, the onset of acute kidney injury or the need for renal replacement therapy after LVAD implantation negatively influence a patient's prognosis. LVAD can also prompt an improvement in renal function, however, with some counterintuitive effects on a patient's prognosis. Conclusion it is still hard to say whether different trends in eGFR depend on different renal conditions before LVAD placement, on a patient's better overall status, or on a particular patient management strategy before and/or after the device's implantation. Steps should be taken to solve this question because finding the best candidates for LVAD implantation is of paramount importance to ensure the best outcomes.

Background: Molecular biology has recently added new insights into the comprehension of the physiopathology of the medullary sponge kidney disease (MSK), a rare kidney malformation featuring nephrocalcinosis and recurrent renal stones. Pathogenesis and metabolic alterations associated to this disorder have been only partially elucidated.Methods: Plasma and urine samples were collected from 15 MSK patients and 15 controls affected by idiopathic calcium nephrolithiasis (ICN). Plasma metabolomic profile of 7 MSK and 8 ICN patients was performed by liquid chromatography combined with electrospray ionization tandem mass spectrometry (UHPLC–ESI-MS/MS). Subsequently, we reinterrogated proteomic raw data previously obtained from urinary microvesicles of MSK and ICN focusing on proteins associated with sphingomyelin metabolism. Omics results were validated by ELISA in the entire patients' cohort.Results: Thirteen metabolites were able to discriminate MSK from ICN (7 increased and 6 decreased in MSK vs. ICN). Sphingomyelin reached the top level of discrimination between the two study groups (FC: −1.8, p < 0.001). Ectonucleotide pyrophophatase phosphodiesterase 6 (ENPP6) and osteopontin (SPP1) resulted the most significant deregulated urinary proteins in MSK vs. ICN (p < 0.001). ENPP6 resulted up-regulated also in plasma of MSK by ELISA.Conclusion: Our data revealed a specific high-throughput metabolomics signature of MSK and indicated a pivotal biological role of sphingomyelin in this disease.

Genome-wide association studies have identified numerous genetic variants for type 2 diabetes (T2D). Most genetic loci discovered to date were studied in Caucasians or Asian ancestry, however, there are no data regarding a quite large Italian sample. Therefore, we investigated T2D genetic susceptibility of 143 single nucleotide polymorphisms (SNPs) within 30 genes involved in glucose metabolism in a large Italian case-control study. For the study, 1875 Caucasian patients were selected from three Italian cohorts. Age, gender, BMI and fasting plasma glucose (FPG) values were collected. Population was split in cases and controls based on FPG values or T2D diagnosis. T2D subjects and whom with FPG higher that 126 mg/dL were recruited as cases whereas subjects with normal values of FPG were considered controls. In each subject 143 SNPs were genotyped. To evaluate the association between genetic variations and diabetes status, a logistic regression analysis, adjusted for age, sex and BMI, was performed. Overall, 948 (50.6%) had T2D. Twenty out of 143 variants within 11 different genes resulted significantly associated to T2D. Four of them were located into TCF7L2 gene and presented the highest odd ratio (from 1.42 to 1.57). At least two SNPs were located within KCNJ11, WFS1, ABCC8, JAZF1 and HNF1B genes and one SNP each was identified in ADAMTS9, IGF2BP2, FTO, G6PC2 and GCK genes. Our findings support the role of 11 genes involved in glucose homeostasis in T2D risk development in a large Italian population. We found that such genetic information may be advantageous for predicting T2D.

Background: Lung transplantation is still the best therapeutic option for cystic fibrosis (CF) patients, but, unfortunately, immunosuppressive therapies, often employed at high dosages to avoid acute rejection, may induce severe complications. In particular, patients treated with high dose of mammalian target of rapamycin inhibitors (mTOR-Is) may experience lung fibrosis (including bronchiolitis obliterans-organizing pneumonia). Although epithelial to mesenchymal transition (EMT) of airway cells has a central role in this process, the complete biological machinery is not completely clarified.Methods: In order to improve our knowledge on this process, primary bronchial epithelial cells carrying F508del mutation were treated with 5 and 100 nM everolimus (EVE) for 24 hours. Subsequently, RNA was hybridized to the Human HT-12 v3 Expression BeadChip (Illumina). Real-Time PCR was, then, used to validate microarray results and to measure major EMT biomarkers. Trans-epithelial resistance was measured by Millicell-ERS ohmmeter.Results: High dosage EVE induced a significant up-regulation of 42 genes and a down-regulation of 12 genes. After pathway analysis by Gene Set Enrichment Analysis and Ingenuity Pathway Analysis, we found that most of them were implicated in the pro-inflammatory pathway. Real-Time PCR validated these results and revealed that, in addition to pro-inflammatory genes (IL-1α, IL-8, Pim-1 Oncogene), EVE at high dosage was able to up-regulate major EMT biomarkers (such as: alpha-smooth muscle actin, connective tissue growth factor and metalloproteinase 12). In lung, EMT is the convergence point between inflammation and the progression of fibrotic damage. Additionally, EVE at this dosage reduced the trans-epithelial resistance (altering tight junction strength). In contrast, lower EVE did not trigger similar effects.Conclusions: We demonstrated that high dose EVE may trigger a pro-inflammatory/fibrotic biological machinery in bronchial epithelial cells from CF patients. Our results, although obtained in vitro, suggest that solid organ transplant recipients affected by CF should be treated with the lowest possible dose of mTOR inhibitors to minimize/avoid the onset and development of lung complications. In vivo studies might be useful to confirm our hypothesis.

Background Whether respiratory physiology of COVID-19-induced respiratory failure is different from acute respiratory distress syndrome (ARDS) of other etiologies is unclear. We conducted a single-center study to describe respiratory mechanics and response to positive end-expiratory pressure (PEEP) in COVID-19 ARDS and to compare COVID-19 patients to matched-control subjects with ARDS from other causes. Methods Thirty consecutive COVID-19 patients admitted to an intensive care unit in Rome, Italy, and fulfilling moderate-to-severe ARDS criteria were enrolled within 24 h from endotracheal intubation. Gas exchange, respiratory mechanics, and ventilatory ratio were measured at PEEP of 15 and 5 cmH2O. A single-breath derecruitment maneuver was performed to assess recruitability. After 1:1 matching based on PaO2/FiO2, FiO2, PEEP, and tidal volume, COVID-19 patients were compared to subjects affected by ARDS of other etiologies who underwent the same procedures in a previous study. Results Thirty COVID-19 patients were successfully matched with 30 ARDS from other etiologies. At low PEEP, median [25th–75th percentiles] PaO2/FiO2 in the two groups was 119 mmHg [101–142] and 116 mmHg [87–154]. Average compliance (41 ml/cmH2O [32–52] vs. 36 ml/cmH2O [27–42], p = 0.045) and ventilatory ratio (2.1 [1.7–2.3] vs. 1.6 [1.4–2.1], p = 0.032) were slightly higher in COVID-19 patients. Inter-individual variability (ratio of standard deviation to mean) of compliance was 36% in COVID-19 patients and 31% in other ARDS. In COVID-19 patients, PaO2/FiO2 was linearly correlated with respiratory system compliance (r = 0.52 p = 0.003). High PEEP improved PaO2/FiO2 in both cohorts, but more remarkably in COVID-19 patients (p = 0.005). Recruitability was not different between cohorts (p = 0.39) and was highly inter-individually variable (72% in COVID-19 patients and 64% in ARDS from other causes). In COVID-19 patients, recruitability was independent from oxygenation and respiratory mechanics changes due to PEEP. Conclusions Early after establishment of mechanical ventilation, COVID-19 patients follow ARDS physiology, with compliance reduction related to the degree of hypoxemia, and inter-individually variable respiratory mechanics and recruitability. Physiological differences between ARDS from COVID-19 and other causes appear small.

The aim of this observational retrospective cohort study was to analyze the association between hyperchloremia and serum chloride variation with in-hospital acute kidney injury (AKI) and mortality in a general, no-ICU hospitalized population. We performed a retrospective study on inpatient population admitted to Fondazione Policlinico Universitario A. Gemelli IRCCS between January 2010 and December 2014 with inclusion of adult patients with at least two values available for chloride, sodium and creatinine. Hyperchloremia was defined as serum chloride concentration ≥ 108 mmol/L (moderate hyperchloremia: chloremia between 108–110 mmol/L, severe hyperchloremia: chloremia > 110 mmol/L). According to the time of onset of the electrolyte disturbance, hyperchloremia was then classified as hospital acquired (HA) and community acquired (CA). In patients with HA-hyperchloremia, chloride variation (ΔCl) was calculated. In-hospital AKI was defined according to creatinine kinetics criteria occurring 48 h after hospital admission. Logistic regression analysis was used to evaluate the association between the exposures of interest and in-hospital AKI and mortality. A total of 24,912 hospital admissions met the inclusion criteria. Regression analyses showed that only severe HA-hyperchloremia was associated with increased risk of in-hospital AKI [odds ratio (OR) 2.60, 95% confidence interval (CI) 1.58, 4.30, p value

Background Previous studies have shown that, compared with non-stone formers, stone formers have a higher papillary density measured with computer tomography (CT) scan. The effect of increased hydration on such papillary density in idiopathic calcium stone formers is not known. Methods Patients with recurrent calcium oxalate stones undergoing endourological procedures for renal stones at our Institution from June 2013 to June 2014 were considered eligible for enrolment. Enrolled patients underwent a baseline unenhanced CT scan before the urological procedure; after endoscopic removal of their stones, the patients were instructed to drink at least 2 L/day of a hypotonic, oligomineral water low in sodium and minerals (fixed residue at 180 °C

Background/Aims: Aim of our study was to describe the association between natremia (Na) fluctuation and hospital mortality in a general population admitted to a tertiary medical center. Methods: We performed a retrospective observational cohort study on the patient population admitted to the Fondazione Policlinico A. Gemelli IRCCS Hospital between January 2010 and December 2014 with inclusion of adult patients with at least 2 Na values available and with a normonatremic condition at hospital admission. Patients were categorized according to all Na values recorded during hospital stay in the following groups: normonatremia, hyponatremia, hypernatremia, and mixed dysnatremia. The difference between the highest or the lowest Na value reached during hospital stay and the Na value read at hospital admission was used to identify the maximum Na fluctuation. Cox proportional hazards models were used to estimate hazard ratios (HRs) for in-hospital death in the groups with dysnatremias and across quartiles of Na fluctuation. Covariates assessed were age, sex, highest and lowest Na level, Charlson/Deyo score, cardiovascular diseases, cerebrovascular diseases, dementia, congestive heart failure, severe kidney disease, estimated glomerular filtration rate, and number of Na measurements during hospital stay. Results: 46,634 admissions matched inclusion criteria. Incident dysnatremia was independently associated with in-hospital mortality (hyponatremia: HR 3.11, 95% CI 2.53, 3.84, p < 0.001; hypernatremia: HR 5.12, 95% CI 3.94, 6.65, p < 0.001; mixed-dysnatremia: HR 4.94, 95% CI 3.08, 7.92, p < 0.001). We found a higher risk of in-hospital death by linear increase of quartile of Na fluctuation (p trend p < 0.001, for the highest quartile of Na fluctuation compared with the lowest). Conclusions: Incident dysnatremia is associated with higher hospital mortality. Fluctuation of Na during hospital stay is a prognostic marker for hospital death independent of dysnatremia severity.

The use of human intravenous immunoglobulins (IVIg) in systemic lupus erythematosus (SLE) currently relies on evidence from small case series and is mainly regarded as an off-label strategy in cases that are refractory to conventional therapies or poorly controlled with high doses of corticosteroids. Standard dosage regimens typically entail the administration of a total amount of 2 g/kg of IVIg divided into five consecutive days in order to minimize the risk of severe adverse events. We herein describe the case of a 28-year-old woman with a known history of antiphospholipid syndrome (APS) who was admitted to our hospital following fulminant onset of SLE in spite of ongoing immunosuppressive therapy. Acute renal insufficiency with nephrotic-range proteinuria, central nervous system involvement, severe thrombocytopenia, malar rash, pancreatic injury and moderate-severe aortic valve steno-insufficiency were the most prominent clinical manifestations, along with high titres of anti-dsDNA antibodies. Pulses of methyl-prednisolone followed by high-dose corticosteroids proved ineffective. Strikingly, IVIg therapy delivered at unconventional doses (1.2 g/kg) due to the presence of multiple risk factors for adverse events resulted in a significant, comprehensive clinical improvement. Although large-scale randomized double-blind studies are needed, the use of IVIg might constitute a valuable therapeutic modality as a last-resort strategy in cases of fulminant SLE. The total dose of immunoglobulins should be dictated by the clinical response as well as the presence of pre-existing risk factors for adverse events. LEARNING POINTS The use of immunoglobulins in the treatment of systemic lupus erythematosus is mainly based on small prospective studies and case series. Their use as a rescue strategy in cases of systemic lupus erythematosus that are refractory to conventional immunosuppressive therapy may be a valid therapeutic alternative in selected patients. The short-term clinical response and the presence of risk factors for adverse effects should dictate the overall dose of immunoglobulins administered to the patient.

Ventricular arrhythmias (VAs) with left bundle-branch-block and inferior axis morphology (LBBB-IA), suggestive of outflow tract (OT) origin, are a challenge in sports medicine because they can be benign or expression of a silent cardiomyopathy. Non-invasive classification is essential to plan ablation strategy if required. We aimed to evaluating magnetocardiographic (MCG) discrimination of OT-VAs site of origin (SoO). MCG and ECG data of 26 sports activity practitioners, with OT-VAs were analyzed. OT-VAs-SoO was classified with discriminant analysis (DA) of 8 MCG parameters and with invasively-validated ECG algorithms. MCG inverse source-localization merged with magnetic resonance (CMR) provided three-dimensional electro-anatomical imaging (MCG 3D-EAI). ECG classification was univocal in 73%. MCG-DA differentiated right ventricular OT from aortic sinus cusp VAs, with 94.7% accuracy. MCG 3D-EAI confirmed OT-VAs-SoO in CMR images. In cases undergoing ablation, MCG 3D-EAI was confirmed by CARTO 3D-EAI. MCG-DA improves non-invasive classification of OT-VAs-SoO. Further comparison with interventional results is required.

Nephrolithiasis is a very common condition, with a prevalence of about 8% in the general population. Genetic as well as environmental factors are thought to contribute to its pathogenesis. Environmental and especially dietary factors are important in primary as well as in secondary prevention. We review the relevant literature of factors associated with an increased risk of stones that might be object of medical prevention for nephrolithiasis.

BACKGROUND: The pathophysiology of genetic hypercalciuric stone-forming rats parallels that of human idiopathic hypercalciuria. In this model, all animals form calcium phosphate stones. We previously found that chlorthalidone, but not potassium citrate, decreased stone formation in these rats. METHODS: To test whether chlorthalidone and potassium citrate combined would reduce calcium phosphate stone formation more than either medication alone, four groups of rats were fed a fixed amount of a normal calcium and phosphorus diet, supplemented with potassium chloride (as control), potassium citrate, chlorthalidone (with potassium chloride to equalize potassium intake), or potassium citrate plus chlorthalidone. We measured urine every 6 weeks and assessed stone formation and bone quality at 18 weeks. RESULTS: Potassium citrate reduced urine calcium compared with controls, chlorthalidone reduced it further, and potassium citrate plus chlorthalidone reduced it even more. Chlorthalidone increased urine citrate and potassium citrate increased it even more; the combination did not increase it further. Potassium citrate, alone or with chlorthalidone, increased urine calcium phosphate supersaturation, but chlorthalidone did not. All control rats formed stones. Potassium citrate did not alter stone formation. No stones formed with chlorthalidone, and rats given potassium citrate plus chlorthalidone had some stones but fewer than controls. Rats given chlorthalidone with or without potassium citrate had higher bone mineral density and better mechanical properties than controls, whereas those given potassium citrate did not. CONCLUSIONS: In genetic hypercalciuric stone-forming rats, chlorthalidone is superior to potassium citrate alone or combined with chlorthalidone in reducing calcium phosphate stone formation and improving bone quality.

Background Parathyroid hormone (PTH) revealed a positive action on progenitor cells released from bone marrow, and many mechanisms supported PTH as a tool to improve stem cell-based therapy in experimental models of ischemia. Elevated PTH resulted in increased mobilization of progenitors into the peripheral blood of patients affected by untreated primary hyperparathyroidism. A frequent finding in uremic patients is a higher PTH level, and different therapeutic strategies are adopted and implemented to achieve an intermediary PTH level. On the contrary, the amount of progenitors commonly results to be extremely reduced. Objective In the present study, we investigated, in a cohort of uremic patients, the effect of different levels of PTH on mobilization of progenitor cell populations. Methods Eighty patients (26 women, 54 men) were enrolled. Following the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, patients were divided in 3 groups for PTH levels: low-PTH group with a PTH level lower than 150 pg/mL (n = 25), KDOQI-PTH group with a PTH level between 150 and 300 pg/mL (n = 37), and high-PTH group with a PTH level higher than 300 pg/mL (n = 18). Patients with high levels of PTH were treated differently to achieve KDOQI targets: 5 received intravenous calcitriol and P binders, 3 received intravenous paracalcitriol, and 10 received cinacalcet. We quantified, by the combination of surface markers (CD45+, CD34+, CD31+, and c-kit+), the number of hematopoietic and endothelial progenitor cells. Results High-PTH group demonstrated a significantly higher level of CD45+/CD34+/c-kit+ with respect to low-PTH and KDOQI-PTH groups (1.02 [SD, 0.12] vs. 0.56 [SD, 0.14] cells/uL, P < 0.01; and 1.02 [SD, 0.12] vs. 0.46 [SD, 0.20] cells/uL, P < 0.05). CD45+/CD34+/CD31+ levels resulted significantly increased in the KDOQI-PTH group compared with those observed in the low- (1.83 [SD, 0.72] vs 1.26 [SD, 0.83] cells/μL, P = 0.04) and high-PTH groups (1.83 [SD, 0.72] vs 1.20 [SD, 1.15] cells/μL, P = 0.04). Receiver operating characteristic analyses were performed to define the ability of CD45+/34+/31+ to identify the presence of an optimal PTH status (>150 but +/34+/31+ was 0.674 (95% confidence interval [CI], 0.501-0.819) with a best cutoff level of 1.36 cells/μL (sensitivity, 80.0; specificity, 59.1; P < 0.05). After 4 months, we demonstrated an increase in endothelial progenitor cell number in 13 patients with secondary hyperparathyroidism that achieved KDOQI targets in PTH levels after pharmacological treatment. Conclusions Our data confirm, with acknowledged limitations due to the low number of patients, the effect of PTH on bone marrow-derived progenitor cells emphasizing that, in our cohort, an intermediary PTH level, achieved following specific guidelines, results in an equilibrate balance between different subsets of progenitor cells.