Simplified regional citrate anticoagulation protocol for CVVH, CVVHDF and SLED focused on the prevention of KRT-related hypophosphatemia while optimizing acid-base balance.

BACKGROUND: Hypophosphatemia is a common electrolyte disorder in critically ill patients undergoing prolonged kidney replacement therapy (KRT). We evaluated the efficacy and safety of a simplified regional citrate anticoagulation (RCA) protocol for continuous venovenous hemofiltration (CVVH), continuous venovenous hemodiafiltration (CVVHDF) and sustained low-efficiency dialysis filtration (SLED-f). We aimed at preventing KRT-related hypophosphatemia while optimizing acid-base equilibrium. METHODS: KRT was performed by the Prismax system (Baxter) and polyacrylonitrile AN69 filters (ST 150, 1.5 m2, Baxter), combining a 18 mmol/L pre-dilution citrate solution (Regiocit 18/0, Baxter) with a phosphate-containing solution (HPO42- 1.0 mmol/L, HCO3- 22.0 mmol/L; Biphozyl, Baxter). When needed, phosphate loss was replaced with sodium glycerophosphate pentahydrate (Glycophos™ 20 mmol/20 mL, Fresenius Kabi Norge AS, Halden, Norway). Serum citrate measurements were scheduled during each treatment. We analyzed data from three consecutive daily 8-h SLED-f sessions, as well as single 72-h CVVH or 72-h CVVHDF sessions. We used analysis of variance (ANOVA) for repeated measures to evaluate differences in variables means (i.e. serum phosphate, citrate). Because some patients received phosphate supplementation, we performed analysis of covariance (ANCOVA) for repeated measures modelling phosphate supplementation as a covariate. RESULTS: Forty-seven patients with acute kidney injury (AKI) or end stage kidney disease (ESKD) requiring KRT were included [11 CVVH, 11 CVVHDF and 25 SLED-f sessions; mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score 25 ± 7.0]. Interruptions for irreversible filter clotting were negligible. The overall incidence of hypophosphatemia (s-P levels <2.5 mg/dL) was 6.6%, and s-P levels were kept in the normality range irrespective of baseline values and the KRT modality. The acid-base balance was preserved, with no episode of citrate accumulation. CONCLUSIONS: Our data obtained with a new simplified RCA protocol suggest that it is effective and safe for CVVH, CVVHDF and SLED, allowing to prevent KRT-related hypophosphatemia and maintain the acid-base balance without citrate accumulation. TRIAL REGISTRATION: NCT03976440 (registered 6 June 2019).

Hypophosphatemia in critically ill patients undergoing Sustained Low-Efficiency Dialysis with standard dialysis solutions.

BACKGROUND: In patients admitted to the Intensive Care Unit (ICU), Kidney Replacement Therapy (KRT) is an important risk factor for hypophosphataemia. However, studies addressing the development of hypophosphatemia during prolonged intermittent KRT modalities are lacking. Thus, we evaluated the incidence of hypophosphatemia during Sustained Low-Efficiency Dialysis (SLED) in ICU patients; we also examined the determinants of post-SLED serum phosphate level (s-P) and the relation between s-P and phosphate supplementation and ICU mortality. METHODS: We conducted a retrospective analysis on a cohort of critically ill patients with severe renal failure and KRT need, who underwent at least three consecutive SLED sessions at 24-72 h time intervals with daily monitoring of s-P concentration. SLED with Regional Citrate Anticoagulation (RCA) was performed with either conventional dialysis machines or continuous-KRT monitors and standard dialysis solutions. When deemed necessary by the attending physician, intravenous phosphate supplementation was provided by sodium glycerophosphate pentahydrate. We used mixed-effect models to examine the determinants of s-P and Cox proportional hazards regression models with time-varying covariates to examine the adjusted relation between s-P, intravenous phosphate supplementation and ICU mortality. RESULTS: We included 65 patients [mean age 68 years (SD 10.0); mean Acute Physiology and Chronic Health Evaluation II score 25 (range 9-40)] who underwent 195 SLED sessions. The mean s-P before the start of the first SLED session (baseline s-P) was 5.6 ± 2.1 mg/dL (range 1.5-12.3). Serum phosphate levels at the end of each SLED decreased with increasing age, SLED duration and number of SLED sessions (P < .05 for all). The frequency of hypophosphatemia increased after the first through the third SLED session (P = .012). Intravenous phosphate supplementation was scheduled after 12/45 (26.7%) SLED sessions complicated by hypophosphataemia. The overall ICU mortality was 23.1% (15/65). In Cox regression models, after adjusting for potential confounders and for current s-P, intravenous phosphate supplementation was associated with a decrease in ICU mortality [adjusted hazard ratio: 0.24 (95% confidence interval: 0.06 to 0.89; P = 0.033)]. CONCLUSIONS: Hypophosphatemia is a frequent complication in critically ill patients undergoing SLED with standard dialysis solutions, that worsens with increasing SLED treatment intensity. In patients undergoing daily SLED, phosphate supplementation is strongly associated with reduced ICU mortality.

Treatment of Metformin Intoxication Complicated by Lactic Acidosis and Acute Kidney Injury: The Role of Prolonged Intermittent Hemodialysis.

Metformin intoxication with lactic acidosis, a potentially lethal condition, may develop in diabetic patients when the drug dose is inappropriate and/or its clearance is reduced. Diagnosis and therapy may be delayed due to nonspecific symptoms at presentation, with severe anion gap metabolic acidosis and elevated serum creatinine values being the most prominent laboratory findings. Confirmation requires measurement of serum metformin by high-performance liquid chromatography-tandem mass spectrometry, but this technique is available only at specialized institutions and cannot be relied on as a guide to immediate treatment. Thus, based on strong clinical suspicion, renal replacement therapy must be started promptly to achieve efficient drug clearance and correct the metabolic acidosis. However, because metformin accumulates in the intracellular compartment with prolonged treatment, a rebound in serum concentrations due to redistribution is expected at the end of dialysis. We report a case of metformin intoxication, severe lactic acidosis, and acute kidney injury in a diabetic patient with pre-existing chronic kidney disease stage 3, treated effectively with sustained low-efficiency dialysis. We discuss the pathophysiology, differential diagnosis, and treatment options and highlight specific pharmacokinetic issues that should be considered in selecting the appropriate modality of renal replacement therapy.

MicroRNAs 17-5p-20a-106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation.

We investigated the role of microRNAs (miRNA) 17-5p, 20a and 106a in monocytic differentiation and maturation. In unilineage monocytic culture generated by haematopoietic progenitor cells these miRNAs are downregulated, whereas the transcription factor acute myeloid leukaemia-1 (AML1; also known as Runt-related transcription factor 1, Runx1) is upregulated at protein but not mRNA level. As miRNAs 17-5p, 20a and 106a bind the AML1 mRNA 3'UTR, their decline may unblock AML1 translation. Accordingly, transfection with miRNA 17-5p-20a-106a suppresses AML1 protein expression, leading to M-CSF receptor (M-CSFR) downregulation, enhanced blast proliferation and inhibition of monocytic differentiation and maturation. Treatment with anti-miRNA 17-5p, 20a and 106a causes opposite effects. Knockdown of AML1 or M-CSFR by short interfering RNA (siRNA) mimics the action of the miRNA 17-5p-20a-106a, confirming that these miRNAs target AML1, which promotes M-CSFR transcription. In addition, AML1 binds the miRNA 17-5p-92 and 106a-92 cluster promoters and transcriptionally inhibits the expression of miRNA 17-5p-20a-106a. These studies indicate that monocytopoiesis is controlled by a circuitry involving sequentially miRNA 17-5p-20a-106a, AML1 and M-CSFR, whereby miRNA 17-5p-20a-106a function as a master gene complex interlinked with AML1 in a mutual negative feedback loop.

Treatment of dabigatran intoxication in critically ill patients with Acute Kidney Injury: The role of Sustained Low-Efficiency Dialysis.

The use of dabigatran in patients with non-valvular atrial fibrillation (AF) has widely increased in the last decades, due to its positive effects in terms of safety/efficacy. However, because of the risk of major bleeding, a great degree of attention has been suggested in elderly patients with multiple comorbidities. Notably, dabigatran mainly undergoes renal elimination and dose adjustment is recommended in patients with Chronic Kidney Disease (CKD). In this regard, the onset of an abrupt decrease of kidney function may further affect dabigatran pharmacokinetic profile, increasing the risk of acute intoxication. Idarucizumab is the approved antagonist in the case of dabigatran-associated major bleeding or concomitant need of urgent surgery, but its clinical use is limited by the lack of data in patients with Acute Kidney Injury (AKI). Thus, the early start of Extracorporeal Kidney Replacement Therapy (EKRT) could be indicated to remove the drug and to reverse the associated excess anticoagulation. Sustained Low-Efficiency Dialysis (SLED) could represent an effective therapeutic option to reduce the dabigatran plasma levels rapidly while avoiding post-treatment rebound. We present here a case series of three AKI patients with acute dabigatran intoxication, effectively and safely resolved with a single SLED session.

Prevention of hypomagnesemia in critically ill patients with acute kidney injury on continuous kidney replacement therapy: the role of early supplementation and close monitoring.

Hypomagnesemia is a common electrolyte disorder in critically ill patients and is associated with increased morbidity and mortality risk. Many clinical conditions may contribute to hypomagnesemia through different pathogenetic mechanisms. In patients with acute kidney injury (AKI) the need for continuous or prolonged intermittent kidney replacement therapy (CKRT and PIKRT, respectively) may further add to other causes of hypomagnesemia, especially when regional citrate anticoagulation (RCA) is used. The basic principle of RCA is chelation of ionized calcium by citrate within the extracorporeal circuit, thus blocking the coagulation cascade. Magnesium, a divalent cation, follows the same fate as calcium; the amount lost in the effluent includes both magnesium-citrate complexes and the free fraction directly diffusing through the hemofilter. While increasing the magnesium content of dialysis/replacement solutions may decrease the risk of hypomagnesemia, the optimal concentration for the variable combination of solutions adopted in different KRT protocols has not yet been identified. An alternative and effective approach is based on including early intravenous magnesium supplementation in the KRT protocol, and close monitoring of serum magnesium levels, especially in the setting of RCA. Thus, strategies aimed at precisely tailoring both dialysis prescriptions and the composition of KRT fluids, as well as early magnesium supplementation and close monitoring, could represent a cornerstone in reducing KRT-related hypomagnesemia.

Association of Clinicopathological Features With Outcome in Chondrosarcomas of the Head and Neck.

OBJECTIVE: The aim of this study is to assess the association between clinical and radiological features as well as of isocitrate dehydrogenase 1 and 2 (IDH 1,2) mutations with outcome in head and neck chondrosarcomas. STUDY DESIGN: Retrospective study. SETTING: Tertiary referral center. METHODS: Clinical, histological, and molecular data of patients with head and neck chondrosarcomas treated by surgery were collected. RESULTS: Forty-six patients were included. The mean age at diagnosis was 56 years (range, 17-78). The tumor originated from the skull base (52.2%), facial bones (28.2%), or laryngotracheal area (19.6%). At last follow-up (median 52.5 months), 38 patients were alive, 30 of which were disease free, whereas 8 had died, 4 of disease progression and 4 of other causes. Fourteen (30.4%) had local recurrence and 2 (4.3%) had lung metastasis. All cases were negative for cytokeratin AE1/AE3, brachyury, and IDH1 at immunohistochemistry, while Sanger sequencing identified IDH1/2 point mutations, typically IDH1 R132C, in 9 (37.5%) tumors arising from the skull base. Margin infiltration on the surgical specimen negatively affected the outcome, whereas no correlation was identified with IDH mutation status. CONCLUSIONS: An adequate margin positively affects survival. IDH mutation status does not affect patient outcome.

Sustained low-efficiency dialysis with regional citrate anticoagulation in critically ill patients with COVID-19 associated AKI: A pilot study.

Acute Kidney Injury (AKI) is a frequent complication in critically ill patients with Coronavirus disease 2019 (COVID-19), and it has been associated with worse clinical outcomes, especially when Kidney Replacement Therapy (KRT) is required. A condition of hypercoagulability has been frequently reported in COVID-19 patients, and this very fact may complicate KRT management. Sustained Low Efficiency Dialysis (SLED) is a hybrid dialysis modality increasingly used in critically ill patients since it allows to maintain acceptable hemodynamic stability and to overcome the increased clotting risk of the extracorporeal circuit, especially when Regional Citrate Anticoagulation (RCA) protocols are applied. Notably, given the mainly diffusive mechanism of solute transport, SLED is associated with lower stress on both hemofilter and blood cells as compared to convective KRT modalities. Finally, RCA, as compared with heparin-based protocols, does not further increase the already high hemorrhagic risk of patients with AKI. Based on these premises, we performed a pilot study on the clinical management of critically ill patients with COVID-19 associated AKI who underwent SLED with a simplified RCA protocol. Low circuit clotting rates were observed, as well as adequate KRT duration was achieved in most cases, without any relevant metabolic complication nor worsening of hemodynamic status.

New laboratory predictive tools in deep neck space infections.

INTRODUCTION: Deep neck space infections (DNSIs) are a group of infective suppurative diseases involving deep neck spaces and cervical fascia. Necrotising and septic evolutions are rare, but severe complications can dramatically affect the prognosis and should be promptly managed. Clinical examination often has low sensitivity, although instrumental diagnosis may delay te treatment. We investigated two laboratory tools, LRINEC (Laboratory Risk Indicator for the Necrotizing fasciitis) and NLR (neutrophil to lymphocyte ratio), in the expectation to find a rapidly available predictive indicator that may help in distinguishing necrotising complications and/or systemic septic involvement. METHODS: A retrospective observational cohort study was performed on 118 patients who had underwent surgical treatment for DNSIs at our Surgical Unit. LRINEC, NLR and the product LRINEC x NLR were calculated. RESULTS: Statistical analysis showed that these scores may have utility in rapidly predicting the risk of necrotising fasciitis and systemic involvement at an early diagnostic stage. CONCLUSIONS: Further studies with a larger cohort may be necessary in order to increase the sensitivity and specificity.

Electrocardiographic T wave alterations and prediction of hyperkalemia in patients with acute kidney injury.

Electrocardiographic (ECG) alterations are common in hyperkalemic patients. While the presence of peaked T waves is the most frequent ECG alteration, reported findings on ECG sensitivity in detecting hyperkalemia are conflicting. Moreover, no studies have been conducted specifically in patients with acute kidney injury (AKI). We used the best subset selection and cross-validation methods [via linear and logistic regression and leave-one-out cross-validation (LOOCV)] to assess the ability of T waves to predict serum potassium levels or hyperkalemia (defined as serum potassium ≥ 5.5 mEq/L). We included the following clinical variables as a candidate for the predictive models: peaked T waves, T wave maximum amplitude, T wave/R wave maximum amplitude ratio, age, and indicator variates for oliguria, use of ACE-inhibitors, sartans, mineralocorticoid receptor antagonists, and loop diuretics. Peaked T waves poorly predicted the serum potassium levels in both full and test sample (R2 = 0.03 and R2 = 0.01, respectively), and also poorly predicted hyperkalemia. The selection algorithm based on Bayesian information criterion identified T wave amplitude and use of loop diuretics as the best subset of variables predicting serum potassium. Nonetheless, the model accuracy was poor in both full and test sample [root mean square error (RMSE) = 0.96 mEq/L and adjR2 = 0.08 and RMSE = 0.97 mEq/L, adjR2 = 0.06, respectively]. T wave amplitude and the use of loop diuretics had also poor accuracy in predicting hyperkalemia in both full and test sample [area-under-curve (AUC) at receiver-operator curve (ROC) analysis 0.74 and AUC 0.72, respectively]. Our findings show that, in patients with AKI, electrocardiographic changes in T waves are poor predictors of serum potassium levels and of the presence of hyperkalemia.

[Extracorporeal renal replacement therapies in lithium intoxication].

Drug poisoning is a significant source of morbidity, mortality and health care expenditure worldwide. Lithium, methanol, ethylene glycol and salicylates are the most important ones, included in the list of poisons, that may require extracorporeal depuration. Lithium is the cornerstone of treatment for bipolar disorders, but it has a narrow therapeutic window. The therapeutic range is 0.6-1.2 mEq/L and toxicity manifestations begin to appear as soon as serum levels exceed 1.5 mEq/L. Severe toxicity can be observed when plasma levels are more than 3.5 mEq/L. Lithium poisoning can be life threatening and extracorporeal renal replacement therapies can reverse toxic symptoms. Currently, conventional intermittent hemodialysis (IHD) is the preferred extracorporeal treatment modality. Preliminary data with prolonged intermittent renal replacement (PIRRT) therapies - hybrid forms of renal replacement therapy (RRT) such as sustained low efficiency dialysis (SLED) - seem to justify their role as potential alternative to conventional IHD. Indeed, SLED allows rapid and effective lithium removal with resolution of symptoms, also minimizing rebound phenomenon.

Sustained low-efficiency dialysis for metformin-associated lactic acidosis in patients with acute kidney injury.

BACKGROUND: The choice of the specific modality and treatment duration of renal replacement therapy (RRT) to adopt in metformin-associated lactic acidosis (MALA) is still debated. We aimed to verify if sustained low-efficiency dialysis (SLED) is a rational choice in patients with MALA and acute kidney injury (AKI). METHODS: We collected serial serum metformin measurements, clinical parameters, and outcome data in ten consecutive patients (mean age 77 years [range 58-88], 5 males) admitted to our renal intensive care unit for suspected MALA associated with AKI and hemodynamic instability. Patients underwent a 16-h SLED session performed with either conventional dialysis machines or machines for continuous RRT (CRRT). A 2-compartment open-infusion pharmacokinetic model with first-order elimination was fitted to each subject's serum concentration-time data to model post-SLED rebound and predict the need for further treatments. RESULTS: Two patients died within 24 h after SLED start. Three patients needed one further dialysis session. Surviving patients (n = 8) were dialysis-free at discharge. Metformin levels were in the toxic range at baseline (median [range] 32.5 mg/l [13.6-75.6]) and decreased rapidly by the end of SLED (8.1 mg/l [4.5-15.8], p < 0.001 vs. baseline), without differences according to the dialysis machine used (p = 0.84). We observed a slight 4-h post-SLED rebound (9.7 mg/l [3.5-22.0]), which could be predicted by our pharmacokinetic model. Accordingly, we predicted that the majority of patients would need one additional dialysis session performed the following day to restore safe metformin levels. CONCLUSIONS: A 16-h SLED session, performed with either conventional dialysis machines or CRRT machines, allows effective metformin removal in patients with MALA and AKI. However, due to possible post-SLED rebound in serum metformin levels, one additional dialysis treatment is required the following day in the majority of patients.

Polypoid angiomyofibroblastoma-like tumor of the oral cavity: a hitherto unreported soft tissue tumor mimicking embryonal rhabdomyosarcoma.

We report on a previously unrecognized fibro-myofibroblastic tumor in the oral cavity of a 15-year-old girl. Morphologically, the tumor mimicked a rhabdomyosarcoma, botryoid variant. It was composed of mitotically active small- to medium-sized, vimentin+/desmin+, round- to oval- to epithelioid-shaped cells embedded in an alternating fibrous to myxoid/edematous stroma. These cells were separated from the overlying squamous epithelium by a rim of fibrous stroma. The tumor contained abundant small- to medium-sized, thin-walled blood vessels without hyalinization. Frequently, neoplastic cells condensed around these vessels. An unusual and striking feature was the presence of numerous hyalinized collagen mats, including "amianthoid-like fibers", similar to those observed in myofibroblastomas. The presence of these collagen mats and the expression of desmin, in association with no immunoreactivity to myogenin and MyoD1, were in keeping with the fibro-myofibroblastic nature of the tumor, excluding the diagnosis of embryonal rhabdomyosarcoma. Regarding fibro-myofibroblastic tumors, we believe that the present case falls within the wide spectrum of benign stromal tumors, originally described in the lower female genital tract, but potentially occurring also at extragenital sites. As morphological and immunohistochemical features were reminiscent of, but not identical with, angiomyofibroblastoma, the term "polypoid angiomyofibroblastoma-like tumor" is proposed. Awareness and recognition of this tumor is crucial to avoid a diagnosis of malignancy.

Functional analysis of yeast snoRNA and snRNA 3'-end formation mediated by uncoupling of cleavage and polyadenylation.

Many nuclear and nucleolar small RNAs are accumulated as nonpolyadenylated species and require 3'-end processing for maturation. Here, we show that several genes coding for box C/D and H/ACA snoRNAs and for the U5 and U2 snRNAs contain sequences in their 3' portions which direct cleavage of primary transcripts without being polyadenylated. Genetic analysis of yeasts with mutations in different components of the pre-mRNA cleavage and polyadenylation machinery suggests that this mechanism of 3"-end formation requires cleavage factor IA (CF IA) but not cleavage and polyadenylation factor activity. However, in vitro results indicate that other factors participate in the reaction besides CF IA. Sequence analysis of snoRNA genes indicated that they contain conserved motifs in their 3" noncoding regions, and mutational studies demonstrated their essential role in 3"-end formation. We propose a model in which CF IA functions in cleavage and polyadenylation of pre-mRNAs and, in combination with a different set of factors, in 3"-end formation of nonpolyadenylated polymerase II transcripts.

Incompletely differentiated (unclassified) sex cord/gonadal stromal tumor of the testis with a "pure" spindle cell component: report of a case with diagnostic and histogenetic considerations.

The group of incompletely differentiated (unclassified) sex cord/gonadal stromal tumors includes rare cases with predominant spindle cell morphology. We report a rare case of a "pure" spindle cell tumor of the testis with morphological and immunohistochemical features consistent with the diagnosis of "incompletely differentiated sex cord/gonadal stromal tumor". Given the spindle cell morphology, the differential diagnosis with other benign and malignant spindle cell lesions is discussed. The concurrent presence of some morphological and immunohistochemical features of both Leydig and granulosa cell lines in the tumor suggests its origin from a stromal stem cell, possibly capable of dual differentiation, but with an arrest of maturation at an early phase of differentiation.

Autoimmune aspects of chronic periaortitis.

Chronic periaortitis (CP) includes idiopathic retroperitoneal fibrosis, inflammatory abdominal aortic aneurysms and perianeurysmal retroperitoneal fibrosis. These entities are characterised by a fibro-inflammatory tissue which develops around the abdominal aorta and the iliac arteries, and spreads into the surrounding retroperitoneum to entrap adjacent structures such as the ureters. CP often affects patients with advanced atherosclerosis, and several lines of evidence support the view that it could result from a local inflammatory reaction to antigens in the atherosclerotic plaques of the abdominal aorta such as oxidised-low density lipoproteins and ceroid. However, because most CP patients also suffer from constitutional symptoms and show elevated acute-phase reactant levels, positive autoantibodies and, in some cases, autoimmune diseases affecting other organs, CP may also be considered a manifestation of a systemic autoimmune disease. CP is usually diagnosed using computed tomography or magnetic resonance imaging, but retroperitoneal biopsy may also be necessary; positron emission tomography is useful in assessing the full extent of the disease and the metabolic activity of the retroperitoneal tissue. Ureterolysis and aneurysm repair are frequently performed, but the inflammatory and chronic-relapsing nature of the disease often compels the use of medical therapy, which is based on steroids and immunosuppressants.

Potential pathological understaging of pT3 rectal cancer with less than 26 lymph nodes recovered: a prospective study based on a resampling of 50 rectal specimens.

The aim of the paper was to establish if the 12 lymph nodes recommended by tumor-node-metastasis (TNM) system are sufficient for a correct staging of rectal cancer. For this purpose, we first compared the mean number of lymph nodes recovered in the same surgical specimen at the routine sampling and at a resampling performed by a second expert gastrointestinal pathologist. The study was performed on 50 cases of pT2N0 and pT3N0 rectal cancers, with a minimum number of 12 lymph nodes recovered at first sampling, histologically negative for metastases. Resampling retrieved a variable number (1 to 24) of nodes missed at first sampling. The final pN0 status was maintained in pT2 patients, whereas in 18.7% of pT3 patients, metastatic lymph nodes were detected if the mean number of lymph nodes increased from 17.8 to 26.8 after the second sampling. Interestingly, all pN1 patients had only a single metastatic lymph node measuring less than 4.9 mm. As we have shown that most (five out of six) missed metastatic lymph nodes were detected in specimens in which a maximum number of 19 lymph nodes had been originally recovered, we strongly suggest a resampling of pT3N0 rectal specimens if less than 20 lymph nodes have been recovered.