ANKRD36 Is Involved in Hypertension by Altering Expression of ENaC Genes.

[Figure: see text].

Omega-3 Polyunsaturated Fatty Acids Inhibit the Function of Human URAT1, a Renal Urate Re-Absorber.

The beneficial effects of fatty acids (FAs) on human health have attracted widespread interest. However, little is known about the impact of FAs on the handling of urate, the end-product of human purine metabolism, in the body. Increased serum urate levels occur in hyperuricemia, a disease that can lead to gout. In humans, urate filtered by the glomerulus of the kidney is majorly re-absorbed from primary urine into the blood via the urate transporter 1 (URAT1)-mediated pathway. URAT1 inhibition, thus, contributes to decreasing serum urate concentration by increasing net renal urate excretion. Here, we investigated the URAT1-inhibitory effects of 25 FAs that are commonly contained in foods or produced in the body. For this purpose, we conducted an in vitro transport assay using cells transiently expressing URAT1. Our results showed that unsaturated FAs, especially long-chain unsaturated FAs, inhibited URAT1 more strongly than saturated FAs. Among the tested unsaturated FAs, eicosapentaenoic acid, α-linolenic acid, and docosahexaenoic acid exhibited substantial URAT1-inhibitory activities, with half maximal inhibitory concentration values of 6.0, 14.2, and 15.2 µM, respectively. Although further studies are required to investigate whether the ω-3 polyunsaturated FAs can be employed as uricosuric agents, our findings further confirm FAs as nutritionally important substances influencing human health.

Mineralized tissues in hypophosphatemic rickets.

Hypophosphatemic rickets is caused by renal phosphate wasting that is most commonly due to X-linked dominant mutations in PHEX. PHEX mutations cause hypophosphatemia indirectly, through the increased expression of fibroblast growth factor 23 (FGF23) by osteocytes. FGF23 decreases renal phosphate reabsorption and thereby increases phosphate excretion. The lack of phosphate leads to a mineralization defect at the level of growth plates (rickets), bone tissue (osteomalacia), and teeth, where the defect facilitates the formation of abscesses. The bone tissue immediately adjacent to osteocytes often remains unmineralized ("periosteocytic lesions"), highlighting the osteocyte defect in this disorder. Common clinical features of XLH include deformities of the lower extremities, short stature, enthesopathies, dental abscesses, as well as skull abnormalities such as craniosynostosis and Chiari I malformation. For the past four decades, XLH has been treated by oral phosphate supplementation and calcitriol, which improves rickets and osteomalacia and the dental manifestations, but often does not resolve all aspects of the mineralization defects. A newer treatment approach using inactivating FGF23 antibodies leads to more stable control of serum inorganic phosphorus levels and seems to heal rickets more reliably. However, the long-term benefits of FGF23 antibody treatment remain to be elucidated.

Renal Reabsorption of Folates: Pharmacological and Toxicological Snapshots.

Folates are water-soluble B9 vitamins that serve as one-carbon donors in the de novo synthesis of thymidylate and purines, and in the conversion of homocysteine to methionine. Due to their key roles in nucleic acid synthesis and in DNA methylation, inhibiting the folate pathway is still one of the most efficient approaches for the treatment of several tumors. Methotrexate and pemetrexed are the most prescribed antifolates and are mainly used in the treatment of acute myeloid leukemia, osteosarcoma, and lung cancers. Normal levels of folates in the blood are maintained not only by proper dietary intake and intestinal absorption, but also by an efficient renal reabsorption that seems to be primarily mediated by the glycosylphosphatidylinositol- (GPI) anchored protein folate receptor α (FRα), which is highly expressed at the brush-border membrane of proximal tubule cells. Folate deficiency due to malnutrition, impaired intestinal absorption or increased urinary elimination is associated with severe hematological and neurological deficits. This review describes the role of the kidneys in folate homeostasis, the molecular basis of folate handling by the kidneys, and the use of high dose folic acid as a model of acute kidney injury. Finally, we provide an overview on the development of folate-based compounds and their possible therapeutic potential and toxicological ramifications.

Clozapine-induced reduction of l-carnitine reabsorption via inhibition/down-regulation of renal carnitine/organic cation transporter 2 contributes to liver lipid metabolic disorder in mice.

Clozapine, an atypical antipsychotic drug, is widely utilized for the treatment of schizophrenia; however, clozapine-induced metabolic disorders, such as fatty liver and weight gain, warrant increased attention. Considering the crucial role of l-carnitine (L-Car) in fatty acid oxidation and carnitine/organic cation transporter (OCTN) 2 in renal reabsorption of L-Car, we aimed to study whether clozapine-induced liver lipid metabolic disorder is associated with L-Car dysregulation via inhibition/down-regulation of renal OCTN2. Our results reveal that clozapine inhibits L-Car uptake in MDCK-hOCTN2 cells with an IC50 value of 1.78 µM. Additionally, clozapine significantly reduces the uptake of L-Car in HK-2 cells, mouse primary cultured proximal tubular (mPCPT) cells and HepG2 cells. Acute (intraperitoneal injection) and 21-day successive oral administration of clozapine at 12.5, 25, and 50 mg/kg to mice resulted in 2-3-fold greater renal excretion of L-Car than in the vehicle group, and the concentration of L-Car in plasma and liver was significantly decreased. Concomitantly, mRNA and protein levels of mOctn2 in the kidney were markedly down regulated. Additionally, 28-day oral administration of clozapine induced increased triglyceride (TG) and total cholesterol (TCHO) levels in mouse livers, while L-Car (40 mg/kg - 1 g/kg) attenuated clozapine-induced liver TG and TCHO increase in a dose-dependent manner. These results indicate that clozapine-induced reduction of L-Car reabsorption via inhibition/down-regulation of renal OCTN2 contributes to liver lipid metabolic disorder. L-Car supplementation is probably an effective strategy to attenuate clozapine-induced abnormal lipid metabolism.

Renal Chloride Channels in Relation to Sodium Chloride Transport.

The many mechanisms governing NaCl absorption in the diverse parts of the renal tubule have been largely elucidated, although some of them, as neutral NaCl absorption across the cortical collecting duct or regulation through with-no-lysine (WNK) kinases have emerged only recently. Chloride channels, which are important players in these processes, at least in the distal nephron, are the focus of this review. Over the last 20-year period, experimental studies using molecular, electrophysiological, and physiological/functional approaches have deepened and renewed our views on chloride channels and their role in renal function. Two chloride channels of the ClC family, named as ClC-Ka and ClC-Kb in humans and ClC-K1 and ClC-K2 in other mammals, are preponderant and play complementary roles: ClC-K1/Ka is mainly involved in the building of the interstitial cortico-medullary concentration gradient, while ClC-K2/Kb participates in NaCl absorption in the thick ascending limb, distal convoluted tubule and the intercalated cells of the collecting duct. The two ClC-Ks might also be involved indirectly in proton secretion by type A intercalated cells. Other chloride channels in the kidneys include CFTR, TMEM16A, and probably volume-regulated LRRC8 chloride channels, whose function and molecular identity have not as yet been established. © 2019 American Physiological Society. Compr Physiol 9:301-342, 2019.

Renal tubule insulin receptor modestly promotes elevated blood pressure and markedly stimulates glucose reabsorption.

Although the cause of hypertension among individuals with obesity and insulin resistance is unknown, increased plasma insulin, acting in the kidney to increase sodium reabsorption, has been proposed as a potential mechanism. Insulin may also stimulate glucose uptake, but the contributions of tubular insulin signaling to sodium or glucose transport in the setting of insulin resistance is unknown. To directly study the role of insulin signaling in the kidney, we generated inducible renal tubule-specific insulin receptor-KO mice and used high-fat feeding and mineralocorticoids to model obesity and insulin resistance. Insulin receptor deletion did not alter blood pressure or sodium excretion in mice on a high-fat diet alone, but it mildly attenuated the increase in blood pressure with mineralocorticoid supplementation. Under these conditions, KO mice developed profound glucosuria. Insulin receptor deletion significantly reduced SGLT2 expression and increased urinary glucose excretion and urine flow. These data demonstrate a direct role for insulin receptor-stimulated sodium and glucose transport and a functional interaction of insulin signaling with mineralocorticoids in vivo. These studies uncover a potential mechanistic link between preserved insulin sensitivity and renal glucose handling in obesity and insulin resistance.

Differential Determinants of Tubular Phosphate Reabsorption: Insights on Renal Excretion of Phosphates in Kidney Disease.

We assessed the tubular reabsorption of phosphate (TRP) and maximal renal threshold for phosphate reabsorption to glomerular filtration rate (TmPi/GFR) and their determinants in 64 stages 2-4 chronic kidney disease (CKD) patients in order to define the early changes in phosphate metabolism in CKD. In multivariable analysis, TmPi/GFR correlates were estimated GFR (eGFR), intact parathyroid hormone (iPTH), and hemoglobin (R2 = 0.417), while TRP correlates were eGFR, iPTH, 24-h phosphaturia, and calcitriol (R2 = 0.72). This suggests that TmPi/GFR and TRP, respectively, assess hemoglobin-phosphate and bowel-kidney phosphate regulation axis. Iron supplementation based on TmPi/GFR or earlier phosphate restriction based on TRP should be investigated in view of modifying clinical outcomes in CKD.

Compensatory Distal Reabsorption Drives Diuretic Resistance in Human Heart Failure.

Understanding the tubular location of diuretic resistance (DR) in heart failure (HF) is critical to developing targeted treatment strategies. Rodents chronically administered loop diuretics develop DR due to compensatory distal tubular sodium reabsorption, but whether this translates to human DR is unknown. We studied consecutive patients with HF (n=128) receiving treatment with loop diuretics at the Yale Transitional Care Center. We measured the fractional excretion of lithium (FELi), the gold standard for in vivo assessment of proximal tubular and loop of Henle sodium handling, to assess sodium exit after loop diuretic administration and FENa to assess the net sodium excreted into the urine. The mean±SD prediuretic FELi was 16.2%±9.5%, similar to that in a control cohort without HF not receiving diuretics (n=52; 16.6%±9.2%; P=0.82). Administration of a median of 160 (interquartile range, 40-270) mg intravenous furosemide equivalents increased FELi by 12.6%±10.8% (P<0.001) but increased FENa by only 4.8%±3.3%. Thus, only 34% (interquartile range, 15.6%-75.7%) of the estimated diuretic-induced sodium release did not undergo distal reabsorption. After controlling for urine diuretic levels, the increase in FELi explained only 6.4% of the increase in FENa (P=0.002). These data suggest that administration of high-dose loop diuretics to patients with HF yields meaningful increases in sodium exit from the proximal tubule/loop of Henle. However, little of this sodium seems to reach the urine, consistent with findings from animal models that indicate that distal tubular compensatory sodium reabsorption is a primary driver of DR.

Genetic causes of hypomagnesemia, a clinical overview.

Magnesium is essential to the proper functioning of numerous cellular processes. Magnesium ion (Mg2+) deficits, as reflected in hypomagnesemia, can cause neuromuscular irritability, seizures and cardiac arrhythmias. With normal Mg2+ intake, homeostasis is maintained primarily through the regulated reabsorption of Mg2+ by the thick ascending limb of Henle's loop and distal convoluted tubule of the kidney. Inadequate reabsorption results in renal Mg2+ wasting, as evidenced by an inappropriately high fractional Mg2+ excretion. Familial renal Mg2+ wasting is suggestive of a genetic cause, and subsequent studies in these hypomagnesemic families have revealed over a dozen genes directly or indirectly involved in Mg2+ transport. Those can be classified into four groups: hypercalciuric hypomagnesemias (encompassing mutations in CLDN16, CLDN19, CASR, CLCNKB), Gitelman-like hypomagnesemias (CLCNKB, SLC12A3, BSND, KCNJ10, FYXD2, HNF1B, PCBD1), mitochondrial hypomagnesemias (SARS2, MT-TI, Kearns-Sayre syndrome) and other hypomagnesemias (TRPM6, CNMM2, EGF, EGFR, KCNA1, FAM111A). Although identification of these genes has not yet changed treatment, which remains Mg2+ supplementation, it has contributed enormously to our understanding of Mg2+ transport and renal function. In this review, we discuss general mechanisms and symptoms of genetic causes of hypomagnesemia as well as the specific molecular mechanisms and clinical phenotypes associated with each syndrome.

[A Case of Tenofovir-associated Fanconi Syndrome in Patient with Chronic Hepatitis B].

Tenofovir disoproxil fumarate (TDF) is one of the most widely used treatment options for human immunodeficiency virus (HIV) and HBV infections. Despite its efficacy and safety, some cases of nephrotoxicity have been reported in the treatment of HIV patients. Even more recently, very few cases of Fanconi syndrome associated with tenofovir therapy in HBV monoinfection have been reported. Herein, we report a case of a 47-year-old male with an HBV monoinfection, who developed Fanconi syndrome and a secondary osteomalacia with multiple bone pain. After TDF withdrawal and supplementation of calcitriol, his renal function was reverted. Although the overall risk of TDF-associated nephrotoxicity is very low, both glomerular and tubular function should be monitored in patients undergoing TDF treatment.

Potassium Intake, Bioavailability, Hypertension, and Glucose Control.

Potassium is an essential nutrient. It is the most abundant cation in intracellular fluid where it plays a key role in maintaining cell function. The gradient of potassium across the cell membrane determines cellular membrane potential, which is maintained in large part by the ubiquitous ion channel the sodium-potassium (Na+-K+) ATPase pump. Approximately 90% of potassium consumed (60-100 mEq) is lost in the urine, with the other 10% excreted in the stool, and a very small amount lost in sweat. Little is known about the bioavailability of potassium, especially from dietary sources. Less is understood on how bioavailability may affect health outcomes. Hypertension (HTN) is the leading cause of cardiovascular disease (CVD) and a major financial burden ($50.6 billion) to the US public health system, and has a significant impact on all-cause morbidity and mortality worldwide. The relationship between increased potassium supplementation and a decrease in HTN is relatively well understood, but the effect of increased potassium intake from dietary sources on blood pressure overall is less clear. In addition, treatment options for hypertensive individuals (e.g., thiazide diuretics) may further compound chronic disease risk via impairments in potassium utilization and glucose control. Understanding potassium bioavailability from various sources may help to reveal how specific compounds and tissues influence potassium movement, and further the understanding of its role in health.

Rapid Degradation and High Renal Clearance of Cu3BiS3 Nanodots for Efficient Cancer Diagnosis and Photothermal Therapy in Vivo.

A key challenge for the use of inorganic nanomedicines in clinical applications is their long-term accumulation in internal organs, which raises the common concern of the risk of adverse effects and inflammatory responses. It is thus necessary to rationally design inorganic nanomaterials with proper accumulation and clearance mechanism in vivo. Herein, we prepared ultrasmall Cu3BiS3 nanodots (NDs) as a single-phased ternary bimetal sulfide for photothermal cancer therapy guided by multispectral optoacoustic tomography (MSOT) and X-ray computed tomography (CT) due to bismuth's excellent X-ray attenuation coefficient. We then monitored and investigated their absorption, distribution, metabolism, and excretion. We also used CT imaging to demonstrate that Cu3BiS3 NDs can be quickly removed through renal clearance, which may be related to their small size, rapid chemical transformation, and degradation in an acidic lysosomal environment as characterized by synchrotron radiation-based X-ray absorption near-edge structure spectroscopy. These results reveal that Cu3BiS3 NDs act as a simple but powerful "theranostic" nanoplatform for MSOT/CT imaging-guided tumor ablation with excellent metabolism and rapid clearance that will improve safety for clinical applications in the future.

Pharmacokinetics of S-Allyl-l-cysteine in Rats Is Characterized by High Oral Absorption and Extensive Renal Reabsorption.

BACKGROUND: S-Allylcysteine (SAC) is a key component of aged garlic extract, one of many garlic products. However, information on its pharmacokinetics has been scant except for data from a few animal studies. OBJECTIVE: We designed this study to determine the overall pharmacokinetics of SAC in rats. METHODS: After oral or intravenous administration of SAC to rats at a dose of 5 mg/kg, the plasma concentration-time profile of SAC and its metabolites, as well as the amounts excreted in bile and urine, were analyzed by using liquid chromatography tandem mass spectrometry. RESULTS: After oral administration, SAC was well absorbed with a bioavailability of 98%. Two major metabolites of SAC, N-acetyl-S-allylcysteine (NAc-SAC) and N-acetyl-S-allylcysteine sulfoxide (NAc-SACS), were detected in plasma, but their concentrations were markedly lower than those of SAC. SAC was metabolized to a limited extent, but most of the orally absorbed SAC was excreted into urine in the form of its N-acetylated metabolites. The amounts of SAC, NAc-SAC, and NAc-SACS excreted in urine over 24 h were 2.9%, 80%, and 11% of the orally administered SAC, respectively. The very low renal clearance (0.016 L ⋅ h(-1) ⋅ kg(-1)) of SAC indicated that it undergoes extensive renal reabsorption. These results collectively suggested that SAC was ultimately metabolized to NAc-SAC and NAc-SACS through the cycles of urinary excretion, renal reabsorption, and systemic recirculation. CONCLUSION: The pharmacokinetics of SAC in rats were characterized by high oral absorption, limited metabolism, and extensive renal reabsorption, all of which potentially contribute to its high and relatively long-lasting plasma concentrations.

Pathophysiology and clinical presentations of salt-losing tubulopathies.

At least three renal tubular segments are involved in the pathophysiology of salt-losing tubulopathies (SLTs). Whether the pathogenesis starts either in the thick ascending limb of the loop of Henle (TAL) or in the distal convoluted tubule (DCT), it is the function of the downstream-localized aldosterone sensitive distal tubule (ASDT) to contribute to the adaptation process. In isolated TAL defects (loop disorders) ASDT adaptation is supported by upregulation of DCT, whereas in DCT disorders the ASDT is complemented by upregulation of TAL function. This upregulation has a major impact on the clinical presentation of SLT patients. Taking into account both the symptoms and signs of primary tubular defect and of the secondary reactions of adaptation, a clinical diagnosis can be made that eventually leads to an appropriate therapy. In addition to salt wasting, as occurs in all SLTs, characteristic features of loop disorders are hypo- or isosthenuric polyuria and hypercalciuria, whereas characteristics of DCT disorders are hypokalemia and (symptomatic) hypomagnesemia. In both SLT categories, replacement of urinary losses is the primary goal of treatment. In loop disorders COX inhibitors are also recommended to mitigate polyuria, and in DCT disorders magnesium supplementation is essential for effective treatment. Of note, the combination of a salt- and potassium-rich diet together with an adequate fluid intake is always the basis of long-term treatment in all SLTs.

Review of cobalt toxicokinetics following oral dosing: Implications for health risk assessments and metal-on-metal hip implant patients.

Cobalt (Co) can stimulate erythropoietin production in individuals at doses exceeding 25 mg CoCl2/day. Co has also been shown to exert effects on the thyroid gland, heart and nervous system at sufficient doses. The biological activity of Co is dictated by the concentration of free (unbound) ionic Co(2+). Blood concentrations, as well as, urinary excretion rates of Co are reliable biomarkers for systemic Co exposure. A recent series of human volunteer Co-supplement studies simultaneously measured Co blood and urine concentrations, as well as, Co speciation in serum, and a number of biochemical and clinical parameters. It was found in these studies that peak Co whole blood concentration as high as 117 µg/L were not associated with changes in hematological parameters such as increased red blood cell (RBC) count, hemoglobin (Hgb) or hematocrit (Hct) levels, nor with changes in cardiac, neurological or, thyroid function. Using a Co biokinetic model, the estimated Co systemic tissue concentrations (e.g., liver, kidney, and heart) following 90-days of Co-dietary supplementation with ∼1 mg Co/day were found to be similar to estimated tissue concentrations in implant patients after 10 years of exposure at continuous steady state Co blood concentration of ∼10 µg/L. This study is the first to present modeled Co tissue concentrations at various doses following sub-chronic and chronic exposure. The modeled steady state tissue Co concentrations in combination with the data on adverse health effects in humans should help in the characterization of potential hazards associated with increased blood Co concentrations due to exposure to dietary supplements or cobalt-chromium (Co-Cr) containing implants.

Dapagliflozin: a review of its use in patients with type 2 diabetes.

Dapagliflozin (Forxiga(®), Farxiga(®)) is an orally administered sodium-glucose co-transporter-2 (SGLT2) inhibitor used in the management of patients with type 2 diabetes. Dapagliflozin reduces renal glucose reabsorption by inhibiting the transporter protein SGLT2 in the renal proximal tubule, thereby increasing urinary glucose excretion and reducing blood glucose levels. Its mechanism of action is independent of insulin secretion or action; therefore, dapagliflozin provides complementary therapy when used in combination with other antihyperglycaemic drugs. This article updates an earlier review of dapagliflozin and focuses on longer-term efficacy and tolerability data (e.g. from extensions of earlier clinical trials), as well as data from studies in special patient populations (e.g. history of cardiovascular disease). Numerous well-designed clinical trials with dapagliflozin, primarily as add-on therapy for 24 weeks (but also as monotherapy or initial combination therapy), have consistently demonstrated reductions in glycosylated haemoglobin, fasting plasma glucose levels and bodyweight. Extensions of these trials show the effects are maintained over longer-term follow-up periods of ≈1-4 years and dapagliflozin is generally well tolerated. Dapagliflozin has a low risk of hypoglycaemia, although the incidence varies depending on background therapy, and genital mycotic infections (particularly in women) are the most common adverse events. Dapagliflozin is not recommended in patients with moderate or severe renal impairment. In view of its unique mechanism of action and now well-established efficacy and tolerability profile, dapagliflozin is a useful treatment option in the management of type 2 diabetes, although its effects on diabetic complications remain to be evaluated.