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Objectives: Ferric carboxymaltose (FCM) is increasingly used in the management of cancer-related anemia, yet it may cause hypophosphatemia. This retrospective study describes the incidence, evolution and risk factors of hypophosphatemia in a cohort of patients with solid tumors receiving FCM., Methods: Serum phosphorus concentration was assessed longitudinally using a random intercepts model. The probability of developing hypophosphatemia, as graded by CTCAE version 4.0, was investigated using a multi-state model. Transition hazards were modeled non-parametrically and semi-parametrically by a Cox model. Causal marginal risk differences between baseline interventions on serum phosphorus and/or FCM dose were obtained via G-computation., Results: In 174 ambulatory patients with solid tumors receiving FCM at two university hospitals between October 2020 and September 2021, the risk of developing moderate-to-severe hypophosphatemia was 36.0% (95% confidence interval (CI) 28.2-43.9%) and peaked within 16 days after first FCM administration. The average duration of moderate-to-severe hypophosphatemia was 12.4 days. After adjustment for confounders, lower baseline serum phosphorus (adjusted hazard ratio (aHR) 0.88 per 0.1 mmol/L increase, 95% CI 0.79-0.98) and higher FCM dose (first dose: aHR 1.12 per 1 mg/kg increase, 95% CI 1.01-1.25; second dose: aHR 1.06 per 1 mg/kg increase, 95% CI 1.00-1.13) significantly increased the hazard of moderate-to-severe hypophosphatemia., Conclusion: Approximately one out of three ambulatory patients with solid tumors may develop moderate-to-severe hypophosphatemia after FCM administration. Baseline serum phosphorus and FCM dose may be modifiable risk factors that should be considered for intervention in order to mitigate the risk of hypophosphatemia.

Introduction: The introduction of BRAF/MEK inhibitors has significantly improved overall survival of patients with BRAF V600-mutant advanced or metastatic melanoma. Most patients treated with BRAF/MEK inhibitors will experience adverse events during the course of their treatment. Kidney impairment, however, was rarely reported in the pivotal trials. To date, there are only three cases of biopsy-proven acute interstitial nephritis associated with dabrafenib and trametinib reported in the literature., Case Report: A 50-year-old man diagnosed with metastatic melanoma was hospitalized in August 2021, 5 months after treatment initiation with dabrafenib and trametinib. He presented with acute kidney injury, with serum creatinine of 3.34 mg/dL and eGFR of 20.3 mL/min/m². Kidney biopsy revealed acute interstitial nephritis., Management & Outcome: He was treated with methylprednisolone 16 mg qd, and both dabrafenib and trametinib were permanently discontinued, with recuperation of his kidney function. Another BRAF/MEK inhibitor combination, encorafenib and binimetinib, was introduced, with preserved kidney function and excellent disease control., Discussion: We report the first case of biopsy-proven interstitial nephritis in a patient treated with dabrafenib and trametinib, with successful introduction of another BRAF/MEK inhibitor combination. Although rare, clinicians should be aware of the risk of renal adverse events associated with BRAF/MEK inhibitors. Renal biopsy is mandatory in the absence of a clear explanation or rapid recovery of renal failure. In case of proven interstitial nephritis, corticosteroids should be initiated. Switching to another BRAF/MEK inhibitor combination can be considered for patients with complete recovery of renal function and limited treatment options.

Detection of hemoglobin (Hb) and red blood cells in urine (hematuria) is characterized by a large number of pitfalls. Clinicians and laboratory specialists must be aware of these pitfalls since they often lead to medical overconsumption or incorrect diagnosis. Pre-analytical issues (use of vacuum tubes or urine tubes containing preservatives) can affect test results. In routine clinical laboratories, hematuria can be assayed using either chemical (test strips) or particle-counting techniques. In cases of doubtful results, Munchausen syndrome or adulteration of the urine specimen should be excluded. Pigmenturia (caused by the presence of dyes, urinary metabolites such as porphyrins and homogentisic acid, and certain drugs in the urine) can be easily confused with hematuria. The peroxidase activity (test strip) can be positively affected by the presence of non-Hb peroxidases (e.g. myoglobin, semen peroxidases, bacterial, and vegetable peroxidases). Urinary pH, haptoglobin concentration, and urine osmolality may affect specific peroxidase activity. The implementation of expert systems may be helpful in detecting preanalytical and analytical errors in the assessment of hematuria. Correcting for dilution using osmolality, density, or conductivity may be useful for heavily concentrated or diluted urine samples., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Purpose: Cardiac surgery associated acute kidney injury (CSA-AKI) is a contributor to adverse outcomes. Preventive measures reduce AKI incidence in high risk patients, identified by biomarkers [TIMP-2]*[IGFBP7] (Nephrocheck®). This study investigate clinical AKI risk assessment by healthcare professionals and the added value of the biomarker result., Materials and Methods: Adult patients were prospectively included. Healthcare professionals predicted CSA-AKI, with and without biomarker result knowledge. Predicted outcomes were AKI based on creatinine, AKI stage 3 on urine output, anuria and use of kidney replacement therapy (KRT)., Results: One-hundred patients were included. Consultant and ICU residents were best in AKI prediction, respectively AUROC 0.769 (95% CI, 0.672-0.850) and 0.702 (95% CI, 0.599-0.791). AUROC of NephroCheck® was 0.541 (95% CI, 0.438-0.642). AKI 3 occurred in only 4 patients; there was no anuria or use of KRT. ICU nurses and ICU residents had an AUROC for prediction of AKI 3 of respectively 0.867 (95% CI, 0.780-0.929) and 0.809 (95% CI, 0.716-0.883); for NephroCheck® this was 0.838 (95% CI, 0.750-0.904)., Conclusions: Healthcare professionals performed poor or fair in predicting CSA-AKI and knowledge of Nephrocheck® result did not improved prediction. No conclusions could be made for prediction of severe AKI, due to limited number of events., Competing Interests: Declaration of Competing Interest AZ received consulting and lecture fees as well as independent research grants from Astute Medical, BioMerieux, Baxter, and Fresenius. MM Received lecture fees from Astute Medical, Baxter and FMC. JD is a consultant for Accelerate Diagnostics, Bayer Healthcare, MSD and Pfizer (honorarium paid to institution for all). EH Participated in several clinical studies sponsored by Astute Medical, lecturing fees from Alexion, Sopachem (paid to the institution) and travel fee from AM Pharma. All other authors declared no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Histological evaluation of renal biopsies is currently the gold standard for acquiring important diagnostic and prognostic information in diabetic nephropathy (DN) patients. Nevertheless, there is an unmet clinical need for new biomarkers that allow earlier diagnosis and risk stratification. As biochemical changes in tissues must precede any symptomatic or morphological expression of a disease, we explored the potential of near-infrared (NIR) spectroscopy in the detection of a biochemical signature associated with DN. Kidney tissue sections were investigated using NIR spectroscopy, followed by principal component analysis and soft independent modelling of class analogy. A biochemical signature indicative of DN was detected, which enabled perfect discrimination between tissue sections with normal histological findings ( n = 27) and sections obtained from DN patients ( n = 26). Some spectral changes related to carbamoylation and glycation reactions appeared to be similar to the ones obtained in patients with DN. In addition, treatment with the deglycating enzyme fructosamine-3-kinase resulted in partial to pronounced restorations of the spectral pattern. Significant relationships were found between spectral features and laboratory parameters indicative of glycemic and uremic load, such as hemoglobin A1c, urea, creatinine, estimated glomerular filtration rate, and proteinuria. The presented method could be a useful tool to complement histopathological analysis in order to prevent or delay further disease progression, especially in the setting of post-transplant surveillance kidney biopsies.

Background: Colorimetric albumin assays based on binding to bromocresol purple (BCP) and bromocresol green (BCG) yield different results in chronic kidney disease. Altered dye binding of carbamylated albumin has been suggested as a cause. In the present study, a detailed analysis was carried out in which uremic toxins, acute phase proteins and Kt/V, a parameter describing hemodialysis efficiency, were compared with colorimetrically assayed (BCP and BCG) serum albumin., Methods: Albumin was assayed using immunonephelometry on a BN II nephelometer and colorimetrically based on, respectively, BCP and BCG on a Modular P analyzer. Uremic toxins were assessed using high-performance liquid chromatography. Acute phase proteins (C-reactive protein and α1-acid glycoprotein) and plasma protein α2-macroglobulin were assayed nephelometrically. In parallel, Kt/V was calculated., Results: Sixty-two serum specimens originating from hemodialysis patients were analyzed. Among the uremic toxins investigated, total para-cresyl sulfate (PCS) showed a significant positive correlation with the BCP/BCG ratio. The serum α1-acid glycoprotein concentration correlated negatively with the BCP/BCG ratio. The BCP/BCG ratio showed also a negative correlation with Kt/V., Conclusions: In renal insufficiency, the BCP/BCG ratio of serum albumin is affected by multiple factors: next to carbamylation, uremic toxins (total PCS) and α1-acid glycoprotein also play a role.

Protein carbamylation, a nonenzymatic posttranslational modification promoted during uremia, is linked to a poor prognosis. In the present study, carbamylation of serum albumin was assayed using the symmetry factor on a capillary electrophoresis instrument (Helena V8). The symmetry factor has been defined as the distance from the center line of the peak to the back slope, divided by the distance from the center line of the peak to the front slope, with all measurements made at 10% of the maximum peak height. Serum albumin, creatinine, and urea concentrations were assayed using routine methods, whereas uremic toxins were determined using HPLC. In vitro carbamylation induced a marked albumin peak asymmetry. Reference values for the albumin symmetry factor were 0.69-0.92. In kidney patients, albumin peak asymmetry corresponded to the chronic kidney disease stage (p < 0.0001). The symmetry factor correlated well with serum urea (r = -0.5595, p < 0.0001) and creatinine (r = -0.5986, p < 0.0001) concentrations. Several protein-bound uremic toxins showed a significant negative correlation with the symmetry factor. Morphology of the albumin fraction was not affected by presence of glycated albumin and protein-bound antibiotics. In conclusion, the presented method provides a simple, practical way for monitoring protein carbamylation., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Protein carbamoylation is a non-enzymatic post-translational modification that binds isocyanic acid, which can be derived from the dissociation of urea or from the myeloperoxidase-mediated catabolism of thiocyanate, to the free amino groups of a multitude of proteins. Although the term 'carbamoylation' is usually replaced by the term "carbamylation" in the literature, carbamylation refers to a different chemical reaction (the reversible interaction of CO 2 with α and ε-amino groups of proteins). Depending on the altered molecule (for example, collagen, erythropoietin, haemoglobin, low-density lipoprotein or high-density lipoprotein), carbamoylation can have different pathophysiological effects. Carbamoylated proteins have been linked to atherosclerosis, lipid metabolism, immune system dysfunction (such as inhibition of the classical complement pathway, inhibition of complement-dependent rituximab cytotoxicity, reduced oxidative neutrophil burst, and the formation of anti-carbamoylated protein antibodies) and renal fibrosis. In this Review, we discuss the carbamoylation process and evaluate the available biomarkers of carbamoylation (for example, homocitrulline, the percentage of carbamoylated albumin, carbamoylated haemoglobin, and carbamoylated low-density lipoprotein). We also discuss the relationship between carbamoylation and the occurrence of cardiovascular events and mortality in patients with chronic kidney disease and assess the effects of strategies to lower the carbamoylation load.

Background: Populations at increased risk for chronic kidney disease should be screened for albuminuria. Possibilities of advanced urine strip readers based on complementary metal oxide semiconductor (CMOS) sensor technology were investigated for obtaining quantitative albuminuria results., Methods: Reflectance data of test strips (Sysmex UFC 3500 reader+CMOS) were compared with albuminuria (BNII) and with proteinuria (Cobas 8000). Urinary creatinine was assayed using a Jaffe-based creatinine assay (Cobas 8000)., Results: Calibration curve was made between 11.5 and 121.5mg/L with detection limit of 5.5mg/L. Within-run CV values of reflectance data were 0.21% (UC-Control L; 10mg/L) and 0.37% (UC-Control H; >150mg/L) for albumin, and 0.71%/3.97% for creatinine. Between-run CV values were 0.24%/0.42% for albumin and 0.93%/5.13% for creatinine. A strong correlation (r=0.92) was obtained between albuminuria (BNII) and protein strip reflectance data. Creatinine reflectance data correlated well with Jaffe-based urinary creatinine data (r=0.90). Albumin:creatinine ratio obtained by test strip and by wet chemistry showed a good correlation (r=0.59). Carbamylated, glycated and partially hydrolyzed isoforms of albumin could be detected by test strip., Conclusions: Dye-binding based albumin test strip assay in combination with a CMOS based reader would potentially allow quantitative analysis of albuminuria and determination of albumin:creatinine ratio., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Understanding the pathways regulating mesenchymal progenitor cell fate during hepatogenesis may provide insight into postnatal liver injury or liver bioengineering. While β-Catenin has been implicated in the proliferation of fetal hepatic epithelial progenitor cells, its role in mesenchymal precursors during hepatogenesis has not been established., Materials and Methods: We used a murine model of conditional deletion of β-Catenin in mesenchyme using the Dermo1 locus (β-Catenin(Dermo1)) to characterize the role of β-Catenin in liver mesenchyme during hepatogenesis., Results: Lineage tracing using a LacZ reporter indicates that both hepatic stellate cells and pericytes derive from mesenchymal Dermo1 expressing precursor cells. Compared to control littermate livers, β-Catenin(Dermo1) embryonic livers are smaller and filled with dilated sinusoids. While the fraction of mesenchymally-derived cells in β-Catenin(Dermo1) embryos is unchanged compared to littermate controls, there is an increase in the expression of the mesenchymal markers, DESMIN, α-SMA, and extracellular deposition of COLLAGEN type I, particularly concentrated around dilated sinusoids. Analysis of the endothelial cell compartment in β-Catenin(Dermo1)/Flk1(lacZ) embryos revealed a marked reorganization of the intrahepatic vasculature. Analysis of various markers for the endodermally-derived hepatoblast population revealed marked alterations in the spatial expression pattern of pan-cytokeratin but not E-cadherin, or albumin. β-Catenin(Dermo1) phenocopies mesenchymal deletion of Pitx2, a known regulator of hepatic mesenchymal differentiation both during both organogenesis and postnatal injury., Conclusions: Our data implicate mesenchymal β-Catenin signaling pathway in the differentiation of liver mesenchymal progenitor cells during organogenesis, possibly via Pitx2. Hepatic mesenchymal β-Catenin signaling, in turn, modulates the development of both endothelium and endodermally-derived hepatoblasts, presumably via other downstream paracrine pathways., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The role of WNT signaling and its interactions with other morphogenetic pathways were investigated during lung development. Previously, we showed that targeted disruption of Wnt5a results in over-branching of the epithelium and thickening of the interstitium in embryonic lungs. In this study, we generated and characterized transgenic mice with lung-specific over-expression of Wnt5a from the SpC promoter. Over-expression of Wnt5a interfered with normal epithelial-mesenchymal interactions resulting in reduced epithelial branching and dilated distal airways. During early lung development, over-expression of Wnt5a in the epithelium resulted in increased Fgf10 in the mesenchyme and decreased Shh in the epithelium. Both levels and distribution of SHH receptor, Ptc were reduced in SpC-Wnt5a transgenic lungs and were reciprocally correlated to changes of Fgf10 in the mesenchyme, suggesting that SHH signaling is decreased by over-expression of Wnt5a. Cultured mesenchyme-free epithelial explants from SpC-Wnt5a transgenic lungs responded abnormally to recombinant FGF10 supplied uniformly in the Matrigel with dilated branch tips that mimic the in vivo phenotype. In contrast, chemotaxis of transgenic epithelial explants towards a directional FGF10 source was inhibited. These suggest that over-expression of Wnt5a disrupts epithelial-response to FGF10. In conclusion, Wnt5a regulates SHH and FGF10 signaling during lung development.