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Scientific Reports Jun 2024Early kidney injury may be detected by urinary markers, such as beta-2 microglobulin (B2M), tissue inhibitor of metalloproteinases-2 (TIMP-2), insulin-like growth...
Early kidney injury may be detected by urinary markers, such as beta-2 microglobulin (B2M), tissue inhibitor of metalloproteinases-2 (TIMP-2), insulin-like growth factor-binding protein 7 (IGFBP7), kidney injury molecule-1 (KIM-1) and/or neutrophil gelatinase-associated lipocalin (NGAL). Of these biomarkers information on pathophysiology and reference ranges in both healthy and diseased populations are scarce. Differences in urinary levels of B2M, TIMP-2, IGFBP7, KIM-1 and NGAL were compared 24 h before and after nephrectomy in 38 living kidney donors from the REnal Protection Against Ischaemia-Reperfusion in transplantation study. Linear regression was used to assess the relation between baseline biomarker concentration and kidney function 1 year after nephrectomy. Median levels of urinary creatinine and creatinine standardized B2M, TIMP-2, IGFBP7, KIM-1, NGAL, and albumin 24 h before nephrectomy in donors were 9.4 mmol/L, 14 μg/mmol, 16 pmol/mmol, 99 pmol/mmol, 63 ng/mmol, 1390 ng/mmol and 0.7 mg/mmol, with median differences 24 h after nephrectomy of - 0.9, + 1906, - 7.1, - 38.3, - 6.9, + 2378 and + 1.2, respectively. The change of donor eGFR after 12 months per SD increment at baseline of B2M, TIMP-2, IGFBP7, KIM-1 and NGAL was: - 1.1, - 2.3, - 0.7, - 1.6 and - 2.8, respectively. Urinary TIMP-2 and IGFBP7 excretion halved after nephrectomy, similar to urinary creatinine, suggesting these markers predominantly reflect glomerular filtration. B2M and NGAL excretion increased significantly, similar to albumin, indicating decreased proximal tubular reabsorption following nephrectomy. KIM-1 did not change considerably after nephrectomy. Even though none of these biomarkers showed a strong relation with long-term donor eGFR, these results provide valuable insight into the pathophysiology of these urinary biomarkers.
Topics: Humans; Nephrectomy; Tissue Inhibitor of Metalloproteinase-2; beta 2-Microglobulin; Male; Female; Middle Aged; Insulin-Like Growth Factor Binding Proteins; Adult; Biomarkers; Kidney Transplantation; Living Donors; Kidney; Hepatitis A Virus Cellular Receptor 1; Creatinine; Lipocalin-2
PubMed: 38839764
DOI: 10.1038/s41598-024-62246-1 -
Kidney Diseases (Basel, Switzerland) Jun 2024G protein-coupled bile acid receptor (TGR5), the first G protein-coupled receptor for bile acids identified, is capable of activating a variety of intracellular...
INTRODUCTION
G protein-coupled bile acid receptor (TGR5), the first G protein-coupled receptor for bile acids identified, is capable of activating a variety of intracellular signaling pathways after interacting with bile acids. TGR5 plays an important role in multiple physiological processes and is considered to be a potential target for the treatment of various metabolic diseases, including type 2 diabetes. Evidence has emerged that genetic deletion of TGR5 results in an increase in basal urine output, suggesting that it may play a critical role in renal water and salt reabsorption. The present study aims to elucidate the effect and mechanism of TGR5 activation on urine concentration.
METHODS
Mice were treated with TGR5 agonists (LCA and INT-777) for 3 days. The 24-h urine of mice was collected and analyzed for urine biochemical parameters. The mRNA expressions were detected by real-time PCR, and the protein expressions were detected by western blot. Immunohistochemistry and immunofluorescence were performed to examine the cellular location of proteins. The cultured primary medullary collecting duct cells were pretreated with H89 (a PKA inhibitor) for 1 h, followed by 12-h treatment of LCA and INT-777. Luciferase reporter assays were used to detect the effect of CREB on the gene transcription of AQPs. Gel electrophoretic mobility shift assays were used to analyze DNA-protein interactions.
RESULTS
Treatment of mice with the TGR5 agonist LCA and INT-777 markedly reduced urine output and increased urine osmolality, accompanied by a marked increase in AQP2 and AQP3 protein expression and membrane translocation. In cultured primary medullary collecting duct cells, LCA and INT-777 dose-dependently upregulated AQP2 and AQP3 expression in a cAMP/PKA-dependent manner. Mechanistically, both AQP2 and AQP3 gene promoter contains a putative CREB-binding site, which can be bound and activated by CREB as assessed by both gene promoter-driven luciferase and gel shift assays.
CONCLUSION
Collectively, our findings demonstrate that activation of TGR5 can promote urine concentration by upregulation of AQP2 and AQP3 expression in renal collecting ducts. TGR5 may represent an attractive target for the treatment of patients with urine concentration defect.
PubMed: 38835402
DOI: 10.1159/000538107 -
Yakugaku Zasshi : Journal of the... 2024Serum urate levels are determined by the balance between uric acid production and uric acid excretion capacity from the kidneys and intestinal tract. Dysuricemia,... (Review)
Review
Serum urate levels are determined by the balance between uric acid production and uric acid excretion capacity from the kidneys and intestinal tract. Dysuricemia, including hyperuricemia and hypouricemia, develops when the balance shifts towards an increase or a decrease in the uric acid pool. Hyperuricemia is mostly a multifactorial genetic disorder involving several disease susceptibility genes and environmental factors. Hypouricemia, on the other hand, is caused by genetic abnormalities. The main genes involved in dysuricemia are xanthine oxidoreductase, an enzyme that produces uric acid, and the urate transporters urate transporter 1/solute carrier family 22 member 12 (URAT1/SLC22A12), glucose transporter 9/solute carrier family 2 member 9 (GLUT9/SLC2A9) and ATP binding cassette subfamily G member 2 (ABCG2). Deficiency of xanthine oxidoreductase results in xanthinuria, a rare disease with marked hypouricemia. Xanthinuria can be due to a single deficiency of xanthine oxidoreductase or in combination with aldehyde oxidase deficiency as well. The latter is caused by a deficiency in molybdenum cofactor sulfurase, which is responsible for adding sulphur atoms to the molybdenum cofactor required for xanthine oxidoreductase and aldehyde oxidase to exert their action. URAT1/SLC22A12 and GLUT9/SLC2A9 are involved in urate reabsorption and their deficiency leads to renal hypouricemia, a condition that is common in Japanese due to URAT1/SLC22A12 deficiency. On the other hand, ABCG2 is involved in the secretion of urate, and many Japanese have single nucleotide polymorphisms that result in its reduced function, leading to hyperuricemia. In particular, severe dysfunction of ABCG2 leads to hyperuricemia with reduced extrarenal excretion.
Topics: Humans; Hyperuricemia; Uric Acid; ATP Binding Cassette Transporter, Subfamily G, Member 2; Organic Anion Transporters; Glucose Transport Proteins, Facilitative; Neoplasm Proteins; Xanthine Dehydrogenase; Animals; Organic Cation Transport Proteins; Renal Tubular Transport, Inborn Errors; Urinary Calculi; Metabolism, Inborn Errors
PubMed: 38825475
DOI: 10.1248/yakushi.23-00217 -
TouchREVIEWS in Endocrinology Apr 2024Type 2 diabetes (T2D) is one of the leading causes of morbidity and mortality worldwide. Currently, over 10.5% of the adult population has been diagnosed with T2D, and... (Review)
Review
Type 2 diabetes (T2D) is one of the leading causes of morbidity and mortality worldwide. Currently, over 10.5% of the adult population has been diagnosed with T2D, and almost 12% of total health expenditure is spent exclusively on T2D management globally. Sodium-glucose cotransporter-2 inhibitors are a relatively new class of oral antidiabetic agents that act by inhibiting renal sodium and glucose reabsorption. Except for their glucose-l owering effects, they have been associated with a more significant weight loss and blood pressure reduction and a lower risk of hypoglycaemia than other commonly prescribed antidiabetic drugs. On 20 January 2023, bexagliflozin became the fifth orally administered sodium-glucose transporter 2 inhibitor to be approved by the US Food and Drug Administration for the treatment of T2D as an adjunct therapy to diet and exercise in the USA after dapagliflozin, canagliflozin, empagliflozin and ertugliflozin. This review aims to discuss the current evidence on the efficacy and safety of bexagliflozin, which provides an important alternative treatment option for patients with T2D.
PubMed: 38812664
DOI: 10.17925/EE.2024.20.1.6 -
Animals : An Open Access Journal From... May 2024Ca and P homeostasis across the egg-laying cycle is a complex process involving absorption in the small intestine, reabsorption/excretion in the kidneys, and eggshell...
Ca and P homeostasis across the egg-laying cycle is a complex process involving absorption in the small intestine, reabsorption/excretion in the kidneys, and eggshell gland secretion. Diets with inadequate calcium and phosphorus can interfere with their absorption and digestibility, resulting in eggshell quality losses and reduced productive life, affecting egg production and welfare. A better understanding of gene expression profiles in the kidneys of laying hens during the late egg-laying period could clarify the renal role in mineral metabolism at this late stage. Therefore, the performance, egg quality and bone integrity-related traits, and expression profiles of kidney candidate genes were evaluated in 73-week-old laying hens receiving different Ca and P ratios in their diet: a high Ca/P ratio (HR, 22.43), a low ratio (LR, 6.71), and a medium ratio (MR, 11.43). The laying hens receiving the HR diet had improved egg production and eggshell quality traits compared to the other two groups. Humerus length was shorter in the HR than in the other groups. The and genes were differentially expressed ( ≤ 0.05) among the groups. Therefore, their expression profiles could be involved in calcium and phosphate transcellular transport in 73-week-old laying hens as a way to keep mineral absorption at adequate levels.
PubMed: 38791624
DOI: 10.3390/ani14101407 -
Archives of Endocrinology and Metabolism May 2024Burosumab, a monoclonal antibody directed against the fibroblast growth factor 23 (FGF23), has been approved for the treatment of X-linked hypophosphatemia (XLH). We... (Comparative Study)
Comparative Study
Burosumab, a monoclonal antibody directed against the fibroblast growth factor 23 (FGF23), has been approved for the treatment of X-linked hypophosphatemia (XLH). We conducted a systematic review to compare the efficacy and safety of burosumab versus conventional therapy (phosphorus and calcitriol) on XLH treatment. After a comprehensive literature search on MEDLINE/PubMed and Embase, we found nine studies for inclusion in the analysis. Risk of bias was assessed, and a random-effects model was used to determine the effect size. Clinical, biochemical, and radiological parameters of disease severity before and after treatment were analyzed and expressed in standardized mean difference (SMD). Burosumab resulted in normalization of phosphate homeostasis with an increase in renal tubular phosphate reabsorption and significant resolution of skeletal lesions (change in Thacher's total rickets severity score SMD: -1.46, 95% confidence interval [CI]: -1.76 to -1.17, < 0.001, improvement in deformities, and decline in serum alkaline phosphatase levels [SMD: 130.68, 95% CI: 125.26-136.1, < 0.001)]. Conventional therapy led to similar improvements in all these parameters but to a lower degree. In adults, burosumab normalized phosphorus levels (SMD: 1.23, 95% CI: 0.98-1.47, < 0.001) with resultant clinical improvement. Burosumab treatment was well tolerated, with only mild treatment-related adverse effects. The present review indicates a potential role for burosumab in improving rickets, deformities, and growth in children with XLH. Given its superior efficacy and safety profile, burosumab could be an effective therapeutic option in children. We suggest further studies comparing burosumab versus conventional therapy in children and adults with XLH.
Topics: Humans; Familial Hypophosphatemic Rickets; Antibodies, Monoclonal, Humanized; Fibroblast Growth Factor-23; Treatment Outcome; Calcitriol; Antibodies, Monoclonal; Phosphorus
PubMed: 38788147
DOI: 10.20945/2359-4292-2023-0242 -
European Review For Medical and... May 2024BACKGROUND: This case report presents a history of familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). The patient was admitted to the hospital...
UNLABELLED
BACKGROUND: This case report presents a history of familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). The patient was admitted to the hospital with hypertensive encephalopathy. FHHNC is a rare autosomal recessive disease caused by mutations in CLDN16 or CLDN19, resulting in insufficient magnesium and calcium kidney reabsorption. FHHNC manifestation starts in childhood, and over the years, its development leads to nephrocalcinosis and, consequently, chronic kidney disease (CKD), which is not slowed by routine administration of magnesium and thiazide diuretics. Ultimately, all FHHNC patients need kidney replacement therapy (KRT). CASE PRESENTATION: The patient was a 28-year-old male diagnosed with FHHNC and admitted to the emergency room due to hypertensive encephalopathy. The current situation was the patient's second hospitalization related to a hypertensive emergency caused by under-dialysis. Despite the signs of insufficient functioning of peritoneal dialysis (PD) (the primary chosen form of KRT), the patient refused the proposed conversion to hemodialysis (HD). Symptoms observed upon admission included disorientation, anxiety, and severe hypertension, reaching 213/123 mmHg. Due to his clinical condition, the patient was transferred to the intensive care unit (ICU), where the introduction of continuous veno-venous hemodiafiltration and hypotensive therapy stabilized blood pressure. Within the next few days, his state improved, followed by discharge from ICU. Eventually, the patient agreed to transition from PD to in-center HD. At the time, he was qualified for kidney transplantation, waiting for a compatible donation. CKD and dialysis are factors that significantly affect a patient's quality of life, especially in young patients with congenital diseases like FHHNC. CONCLUSIONS: For the aforementioned reasons, appropriate education and psychological support should be ensured to avoid the harmful effects of therapy non-compliance.
GRAPHICAL ABSTRACT
https://www.europeanreview.org/wp/wp-content/uploads/Graphical-abstract-1.pdf.
Topics: Humans; Male; Adult; Nephrocalcinosis; Hypercalciuria; Hypertension; Renal Dialysis; Renal Tubular Transport, Inborn Errors; Hypertensive Crisis
PubMed: 38766789
DOI: 10.26355/eurrev_202405_36177 -
The Journal of Clinical Investigation May 2024Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), a multiorgan disease that exhibits diverse metabolic...
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), a multiorgan disease that exhibits diverse metabolic defects. However, other than specific CFTR mutations, the factors that influence disease progression and severity remain poorly understood. Aberrant metabolite levels have been reported, but whether CFTR loss itself or secondary abnormalities (infection, inflammation, malnutrition, and various treatments) drive metabolic defects are uncertain. Here, we implemented comprehensive arteriovenous metabolomics in newborn CF pigs, and the results revealed CFTR as a bona fide regulator of metabolism. CFTR loss impaired metabolite exchange across organs, including disrupted lung uptake of fatty acids yet enhanced uptake of arachidonic acid, a precursor of pro-inflammatory cytokines. CFTR loss also impaired kidney reabsorption of amino acids and lactate and abolished renal glucose homeostasis. These and additional unexpected metabolic defects prior to disease manifestations reveal a fundamental role for CFTR in controlling multi-organ metabolism. Such discovery informs a basic understanding of CF, provides a foundation for future investigation, and has implications for developing therapies targeting only a single tissue.
PubMed: 38743489
DOI: 10.1172/JCI174500 -
Diabetology & Metabolic Syndrome May 2024Diabetes mellitus is one of the most significant global burden diseases. It is well established that a chronic, systemic, low-grade inflammatory condition is strongly... (Review)
Review
Diabetes mellitus is one of the most significant global burden diseases. It is well established that a chronic, systemic, low-grade inflammatory condition is strongly correlated with type 2 diabetes mellitus (T2D) and the development of target-organ damage (TOD). Sodium-glucose cotransporter inhibitors (SGLTis), novel oral drugs for the treatment of diabetes, act mainly by reducing glucose reabsorption in proximal renal tubules and/or the intestine. Several high-quality clinical trials and large observational studies have revealed that SGLTis significantly improve cardiovascular and renal outcomes in T2D patients. Increasing evidence suggests that this is closely related to their anti-inflammatory properties, which are mainly manifested by a reduction in plasma concentrations of inflammatory biomarkers. This review analyses the potential mechanisms behind the anti-inflammatory effects of SGLTis in diabetes and presents recent evidence of their therapeutic efficacy in treating diabetes and related TOD.
PubMed: 38735956
DOI: 10.1186/s13098-024-01325-9 -
International Journal of Molecular... Apr 2024This article reviews the role of fibroblast growth factor 23 (FGF23) protein in phosphate metabolism, highlighting its regulation of vitamin D, parathyroid hormone, and... (Review)
Review
This article reviews the role of fibroblast growth factor 23 (FGF23) protein in phosphate metabolism, highlighting its regulation of vitamin D, parathyroid hormone, and bone metabolism. Although it was traditionally thought that phosphate-calcium homeostasis was controlled exclusively by parathyroid hormone (PTH) and calcitriol, pathophysiological studies revealed the influence of FGF23. This protein, expressed mainly in bone, inhibits the renal reabsorption of phosphate and calcitriol formation, mediated by the α-klotho co-receptor. In addition to its role in phosphate metabolism, FGF23 exhibits pleiotropic effects in non-renal systems such as the cardiovascular, immune, and metabolic systems, including the regulation of gene expression and cardiac fibrosis. Although it has been proposed as a biomarker and therapeutic target, the inhibition of FGF23 poses challenges due to its potential side effects. However, the approval of drugs such as burosumab represents a milestone in the treatment of FGF23-related diseases.
Topics: Humans; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Animals; Phosphates; Parathyroid Hormone; Antibodies, Monoclonal, Humanized; Vitamin D; Bone and Bones; Klotho Proteins
PubMed: 38732094
DOI: 10.3390/ijms25094875