Renal Synthesis Research Articles

Tin protoporphyrin activates the oxidant-dependent NRF2-cytoprotective pathway and mitigates acute kidney injury

Tin protoporphyrin (SnPP), a heme oxygenase (HO) inhibitor, can paradoxically protect against diverse forms of acute kidney injury (AKI). This study sought potential underlying mechanisms. CD-1 mice received intravenous SnPP, followed 4-18hours later by a variety of renal biochemical, histologic, and genomic assessments. Renal resistance to ischemic-reperfusion injury (IRI) was also sought. SnPP was rapidly taken up by kidney and was confined to proximal tubules. Transient suppression of renal heme synthesis (decreased δ aminolevulinic acid synthase expression), a 2.5-fold increase in "catalytic" Fe levels and oxidant stress resulted (decreased glutathione; increased malondialdehyde, and protein carbonyl content). Nrf2 nuclear translocation (∼2xNrf2 increase; detected by enzyme-linked immunosorbent assay, Western blotting), with corresponding activation of ∼20 Nrf2-sensitive genes (RNA-Seq) were observed. By 18hours after SnPP injection, marked protection against IRI emerged. This represented "preconditioning", not a direct SnPP effect, given that SnPP administered at the time of IRI exerted no protective effect. The importance of transient oxidant stress in SnPP "preconditioning" was exemplified by the following: (1) oxidant stress induced by a different mechanism (myoglobin injection) recapitulated SnPP's protective action; (2) GSH treatment blunted SnPP's protective influence; (3) SnPP raised cytoprotective heavy chain ferritin (Fhc), a response enhanced by exogenous Fe injection; and (4) SnCl2, a ∼35- to 50-fold HO-1 inducer (not inhibitor) evoked neither oxidant stress nor mitigated IRI (seemingly excluding HO-1 activity in SnPP's protective effect). SnPP specifically accumulates within proximal tubule cells; transient "catalytic" Fe overload and oxidative stress result; Nrf2-cytoprotective pathways are upregulated; and these changes help protect against ischemic AKI.

Lipid Deposition in Kidney Diseases: Interplay Among Redox, Lipid Mediators, and Renal Impairment.

Significance: The relationship between lipid disturbances and renal diseases has been studied for several decades, and it is well recognized that when the balance of renal lipid uptake, synthesis, oxidation, and outflow is disrupted, lipids will undergo oxidation, be sequestrated as lipid droplets, generate toxic metabolites, and cause nephrotoxicity in diverse renal diseases. Recent Advances: During renal disorders, redox signaling is a pivotal event promoting or resulting from lipid disorders. Accordingly, a vicious cycle of lipid redox dysregulation could be developed, accelerating the renal damage. Critical Issues: The aim of this concise review is to introduce the connection among redox, lipid abnormalities and kidney damage in various conditions. And we summarized current understanding of the lipid redox loop implicated in acute kidney injury, chronic kidney disease, metabolic abnormalities, aging, and genetic pitfalls. Future Directions: Despite recent advances, further investigations are required to clarify the complicated molecular and regulatory mechanisms among redox, lipid mediators and renal disorders. Moreover, exploring an ideal target for potential therapies should be discussed and studied in future. Antioxid. Redox Signal. 28, 1027-1043.

Potential Therapeutic Applications of Jak2 Inhibitors and Hif2a-ASO for the Treatment of β-Thalassemia Intermedia and Major

β-Thalassemia is one of the most common genetic red blood cell (RBC) disorders characterized by reduced (such as in non-transfusion dependent thalassemia or NTDT) or absent (such as in transfusion dependent thalassemia or TDT) production of β-globin chains. Ineffective erythropoiesis (IE) with consequent anemia leads to extra-medullary hematopoiesis (EMH), splenomegaly and iron overload mediated by low levels of hepcidin. We previously demonstrated that IE in β-thalassemia is associated with increased proliferation and reduced differentiation of erythroid progenitors (Libani et al, 2008, Blood). This is mediated by increased production of erythropoietin (EPO), which activates the downstream JAK2 kinase in erythroid progenitors. As a consequence, hepatosplenomegaly may result, often requiring splenectomy to prevent serious morbidities and mortality. The increased synthesis of EPO in thalassemia is the result of hypoxia. Hypoxia Inducible Factor-2a (HIF2a) is a central mediator of cellular adaptation to hypoxia and stimulates renal and hepatic EPO synthesis. Furthermore, splenomegaly in thalassemia also exacerbates the anemia, as a large proportion of the circulating RBC are engulfed and eliminated by an enlarged spleen.Therefore, we hypothesized that targeting the EPO/JAK2 pathway limits the number of erythroid progenitor cells and reduces the splenomegaly, and it could be utilized as an alternative to splenectomy. We utilized JAK2 inhibitors or HIF2a antisense oligonucleotides (HIF2a-ASO) to target the EPO/JAK2 pathway. Moreover, we hypothesized that combination of these drugs with blood transfusion therapy will further reduce the splenomegaly and, eventually, improve the blood transfusion regimen.We tested two commercially available JAK2 inhibitors in mice affected by NTDT (Hbbth3/+): INCB018424 (Ruxolitinib) and TG101348 (Fedratinib, SAR302503). Both drugs were administered for 10 days, twice daily by oral gavage at a dose of 180 and 120 mg/Kg respectively. A mild reduction in hemoglobin (Hb) levels, (in the range of 9%), was observed in animals treated with both inhibitors when compared to vehicle- treated mice. Splenomegaly was significantly reduced with both inhibitors (up to 56% in reduction). Flow cytometry studies on spleen cells revealed that animals receiving the inhibitors exhibited a reduction in the number of erythroid progenitors compared to the placebo-treated animals . In parallel, we performed pharmacokinetic[BM1] studies using Hif2a-ASO. Animals received Hif2a-ASO at a dose of 25 mg/kg twice weekly for 10 days or 3 weeks by IP injections. After 10 days of treatment the spleen weight was reduced 58%, while the Hb level was reduced in the range of 27%%. After 3 weeks the effect observed on the anemia was more pronounced, with a reduction of more that 40% in Hb levels, while the spleen reduction was 36%. We then compared and combined these drugs with blood transfusion using Hbbth3/+ mice. Blood transfusion reduced splenomegaly 49% and 53% when compared, respectively, to non-transfused controls and animals treated with JAK2 inhibitors alone. When transfusion was combined with the administration of JAK2 inhibitors for 10 days, the spleen size was further reduced (72% when compared with non-transfused controls). Combination of Hif2a-ASO and blood transfusion is in progress. We then tested the JAK2 inhibitors in mice affected by TDT. TDT animals are generated by engrafting WT mice with Hbbth3/th3 fetal liver cells. Following engraftment, these mice show a large splenomegaly and rapidly become dependent on chronic blood transfusion for survival (Gardenghi et al, 2007, Blood). Preliminary studies suggest that administration of JAK2 inhibitors for 10 days, together with blood transfusion, further reduces spleen weight by 71% compared to transfusion alone. Combination of Hif2a-ASO and blood transfusion in these animals is also in progress. In summary, JAK2 inhibitors and Hif2a-ASO reduce splenomegaly by targeting the EPO/JAK2 pathway and limiting the excessive proliferation of erythroid cells. Therefore, these drugs could be effective in reversing the splenomegaly and may offer an important approach to splenectomy. Additional studies are in progress to evaluate the outcome of combination therapy on the efficacy of transfusions.[BM1]These aren't pharmacokinetic studies. Suggest just striking the word DisclosuresCasu:Medgenics LLC: Research Funding; Ionis Pharmaceuticals: Research Funding; Merganser Biotech: Research Funding. Aghajan:Ionis Pharmaceuticals: Employment, Equity Ownership. Guo:Ionis Pharmaceuticals: Employment, Equity Ownership. Melchiori:Adaptimmune Ltd: Employment. Ramos:Novartis: Employment.

PSY79 - Cost Efectivness of Darbepoetin Alfa Versus Epoetin Alfa In The Management of Anemic Patients With Chronic Kidney Disease:Health Insurance Perspective

Patients with chronic kidney disease (CKD) mainly develops anemia from decreased renal synthesis of erythropoietin. Erythropoiesis-stimulating agents are the recommended therapy for those patients. The aim of this study was to determine the cost-effectiveness of Darbepoetin alfa (DARB) versus Epoetin alfa (EPO) in treating anemic patients with CKD from the health insurance perspective over a time horizon of five years. A half cycle corrected Markov model comprising 4 health states (low hemoglobin level, target hemoglobin level, high hemoglobin level and death) was developed to estimate the projected clinical and economic implications of both treatment strategy. Transition probabilities were estimated based on the results from clinical trials. Health state utilities and major adverse events were obtained from published sources. Direct medical costs were obtained from the Ministry of health hospitals in Egypt. One way sensitivity analyses were conducted and all variables were varied with a range of ±10%. Total costs for DARB and EPO were EGP 122,921 and EGP 357,662, respectively. QALYs for DARB and were 13.053 and 12.751 respectively. The incremental cost-effectiveness ratio (ICER) for DARB versus EPO was L.E -776,977 EGP/QALY. This study showed that DARB is a cost saving choice compared to EPO in the maintaining of hemoglobin target level in hemodialysis patients. One way sensitivity analysis showed that the utility of patients with target hemoglobin has the greatest impact on the results. Darbepoetin alfa is a cost-saving strategy compared to Epoetin alfa in anemic patients with CKD from the health insurance perspective.

Abstract P210: (Pro)Renin Receptor Regulates Potassium Homeostasis via Intrarenal Aldosterone

It has been shown that transgenic overexpression of human (pro)renin receptor (PRR) results in elevated aldosterone (Aldo) level with unclear functional implications. The present study examined a potential role of renal PRR during high K + (HK) loading. In normal SD rats, a 1-week HK intake (5% KCl in diet) induced a 3.4-fold increase in renal protein expression of full-length PRR and 4.2-fold increase in urinary excretion of soluble PRR (sPRR). Administration of PRO20, a decoy peptide antagonist of PRR, at 700 μg/kg/d via i.p. injections, to K + -loaded animals elevated plasma K + level (5.72+0.08 vs. 4.84±0.18 mM, p<0.05) and decreased urinary K + excretion (2.52+0.11 vs. 3.43+0.19 mmol/24h, p<0.05), accompanied with a 26.2% reduction of urinary aldosterone (Aldo) excretion. HK downregulated NCC protein expression (57.8%) and upregulated renal protein expression of aldosterone synthase CYP11B2 (229%), ROMK (156%), calcium-activated potassium channel subunit alpha-1 (α-BK) (367%), α-Na + -K + -ATPase (596%), and β-ENaC (155%), all of which were significantly blunted by PRO20 (by 50 - 70%). The same maneuvers were applied to adrenalectomized (ADX) rats. Although plasma Aldo was extremely low and also unresponsive to HK loading, urinary Aldo excretion was elevated by 274% with this treatment, which was abolished by PRO20. The HK-induced responses of the above K + and Na + transporting proteins in ADX rats all persisted and also remained sensitive to PRO20. Additionally, spironolactone treatment in ADX rats was still effective in inhibiting kaliuresis induced by HK loading, resulting in hyperkalemia (Plasma K+: 5.13±0.07 vs. 4.19±0.27 mM, p<0.05). In primary rat IMCD cells, exposure to 10 mM KCl for 24 h augmented PRR protein expression and sPRR release in a time- and dose-dependent manner. HK upregulated Aldo release in parallel with increased CYP11B2 protein expression, which were both attenuated by PRO20 or PRR siRNA. A recombinant sPRR, sPRR-His, stimulated Aldo release and CYP11B2 expression. Taken together, we conclude that HK increased renal PRR expression that stimulates renal synthesis of Aldo that coordinates the response of renal membrane Na + and K + transporting proteins to facilitate K + secretion.

Perioperative glutamine supplementation restores disturbed renal arginine synthesis after open aortic surgery: a randomized controlled clinical trial.

Postoperative renal failure is a common complication after open repair of an abdominal aortic aneurysm. The amino acid arginine is formed in the kidneys from its precursor citrulline, and citrulline is formed from glutamine in the intestines. Arginine enhances the function of the immune and cardiovascular systems, which is important for recovery after surgery. We hypothesized that renal arginine production is diminished after ischemia-reperfusion injury caused by clamping of the aorta during open abdominal aortic surgery and that parenteral glutamine supplementation might compensate for this impaired arginine synthesis. This open-label clinical trial randomized patients who underwent clamping of the aorta during open abdominal aortic surgery to receive a perioperative supplement of intravenous alanyl-glutamine (0.5 g·kg(-1)·day(-1); group A, n = 5) or no supplement (group B, n = 5). One day after surgery, stable isotopes and tracer methods were used to analyze the metabolism and conversion of glutamine, citrulline, and arginine. Whole body plasma flux of glutamine, citrulline, and arginine was significantly higher in group A than in group B (glutamine: 391 ± 34 vs. 258 ± 19 μmol·kg(-1)·h(-1), citrulline: 5.7 ± 0.4 vs. 2.8 ± 0.4 μmol·kg(-1)·h(-1), and arginine: 50 ± 4 vs. 26 ± 2 μmol·kg(-1)·h(-1), P < 0.01), as was the synthesis of citrulline from glutamine (4.8 ± 0.7 vs. 1.6 ± 0.3 μmol·kg(-1)·h(-1)), citrulline from arginine (2.3 ± 0.3 vs. 0.96 ± 0.1 μmol·kg(-1)·h(-1)), and arginine from glutamine (7.7 ± 0.4 vs. 2.8 ± 0.2 μmol·kg(-1)·h(-1)), respectively (P < 0.001 for all). In conclusion, the production of citrulline and arginine is severely reduced after clamping during aortic surgery. This study shows that an intravenous supplement of glutamine increases the production of citrulline and arginine and compensates for the inhibitory effect of ischemia-reperfusion injury.

Assessment of erythropoietin for treatment of anemia in chronic kidney failure- ESRD patients.

Currently there is an inadequate data regarding effective management of anemia in chronic kidney disease (CKD) patients who are on dialysis. In CKD patients' anemia mainly develops from decreased renal synthesis of erythropoietin (EPO) and iron deficiency. Our current study focused to effective management of anemia in CKD patients'. Prospective observational case series study. Eligible patients were assigned to three study groups according to initial hemoglobin level i.e. Group I having Hb level below 11g/dL, Group II with Hb level of 11-13g/dL, and Group III with Hb level more than 13g/dL. Intravenous dosing of ESA's calculated according to the range of 150-300IU or equivalent microgram quantity per kilogram body weight was administered to patients in divided doses per week; alone or in combination with iron supplements. Study population (n=163; 100%), of which 124 subjects (76%) patients were treated with erythropoietin and iron supplements; rest of 39 (24%) patients were treated with only erythropoietin. The estimation of hemoglobin content revealed Group I (98 patients) Hb were increased significantly from 9.0±1.2g/dl at baseline to 10.9±1.7g/dl. No significant changes in Group II and Group III were observed. Study suggests use of erythropoietin along with iron for treatment of renal failure associated anemia is more beneficial for CKD patients having low Hb. Also study conclude the use of lower than normal dose (150-300IU) of ESA is appropriate when hemoglobin reaches 11g/dl in hemodialysis patients.

Age protects from harmful effects produced by chronic intermittent hypoxia.

Obstructive sleep apnoea (OSA) affects an estimated 3–7% of the adult population, the frequency doubling at ages >60–65 years. As it evolves, OSA becomes frequently associated with cardiovascular, metabolic and neuropsychiatric pathologies defining OSA syndrome (OSAS). Exposing experimental animals to chronic intermittent hypoxia (CIH) can be used as a model of the recurrent hypoxic and O2 desaturation patterns observed in OSA patients. CIH is an important OSA event triggering associated pathologies; CIH induces carotid body (CB)-driven exaggerated sympathetic tone and overproduction of reactive oxygen species, related to the pathogenic mechanisms of associated pathologies observed in OSAS. Aiming to discover why OSAS is clinically less conspicuous in aged patients, the present study compares CIH effects in young (3–4 months) and aged (22–24 months) rats. To define potential distinctive patterns of these pathogenic mechanisms, mean arterial blood pressure as the final CIH outcome was measured. In young rats, CIH augmented CB sensory responses to hypoxia, decreased hypoxic ventilation and augmented sympathetic activity (plasma catecholamine levels and renal artery content and synthesis rate). An increased brainstem integration of CB sensory input as a trigger of sympathetic activity is suggested. CIH also caused an oxidative status decreasing aconitase/fumarase ratio and superoxide dismutase activity. In aged animals, CIH minimally affected CB responses, ventilation and sympathetic-related parameters leaving redox status unaltered. In young animals, CIH caused hypertension and in aged animals, whose baseline blood pressure was augmented, CIH did not augment it further. Plausible mechanisms of the differences and potential significance of these findings for the diagnosis and therapy of OSAS are discussed.

Chronic resveratrol reverses a mild angiotensin II-induced pressor effect in a rat model

Resveratrol is reported to reduce blood pressure in animal models of hypertension, but the mechanisms are unknown. We have shown that resveratrol infusion increases sodium excretion. We hypothesized that chronic ingestion of resveratrol would reduce angiotensin II (Ang II)-induced increases in blood pressure by decreasing oxidative stress and by also decreasing sodium reabsorption through a nitric oxide-dependent mechanism. We infused rats with vehicle or 80 μg Ang II/d over 4 weeks. Vehicle or Ang II-infused rats were individually housed, pair fed, and placed on a diet of normal chow or normal chow plus 146 mg resveratrol/d. Groups included 1) control, 2) resveratrol-fed, 3) Ang II-treated, and 4) Ang II plus resveratrol. Systolic blood pressure was measured by tail cuff. During the 4th week, rats were placed in metabolic caging for urine collection. NO2/NO3 and 8-isoprostane excretion were measured. Ang II increased systolic blood pressure in the 1st week by +14±5 mmHg (P<0.05) in Group 3 and +10±3 mmHg (P<0.05) in Group 4, respectively. Blood pressure was unchanged in Groups 1 and 2. After 4 weeks, blood pressure remained elevated in Group 3 rats with Ang II (+9±3 mmHg, P<0.05), but in Group 4, blood pressure was no longer elevated (+2±2 mmHg). We found no significant differences between the groups in sodium excretion or cumulative sodium balance (18.49±0.12, 17.75±0.16, 17.97±0.17, 18.46±0.18 μEq Na+/7 d in Groups 1–4, respectively). Urinary excretion of NO2/NO3 in the four groups was 1) 1631±207 μmol/24 h, 2) 1045±236 μmol/24 h, 3) 1490±161 μmol/24 h, and 4) 609±17 μmol/24 h. 8-Isoprostane excretion was 1) 63.85±19.39 nmol/24 h, 2) 73.57±22.02 nmol/24 h, 3) 100.69±37.62 nmol/24 h, and 4) 103.00±38.88 nmol/24 h. We conclude that chronic resveratrol supplementation does not blunt Ang II-increased blood pressure, and while resveratrol has mild depressor effects, these do not seem to be due to natriuresis or enhanced renal nitric oxide synthesis.

The Reduction in Urinary Glutamate Excretion Is Responsible for Lowering Urinary pH in Pink Urine Syndrome

We frequently encounter brownish-red, cloudy urine in some obese subjects, which occurs due to pink urine syndrome (PUS). PUS is a phenomenon in which uric acid precipitates into the urine due to reduced urinary pH (UpH). The mechanism underlying urinary acidification has not been elucidated so far. UpH level is adjusted by urinary excretion of ammonia synthesized from glutamate or glutamine, suggesting that renal synthesis of ammonia from glutamate or glutamine is decreased in PUS. However, this hypothesis has not been examined yet. We therefore examined the changes in the urinary excretion of these amino acids in PUS. One-hundred-fifty male students who had undergone a physical examination were enrolled. To determine the presence [PUS (+), n = 72] or absence [PUS (-), n = 78] of PUS, urinary amino acid excretion and UpH were evaluated. Independent risk factors of lower UpH were determined using multiple regression analyses. The PUS (+) subjects, who had lower UpH values than PUS (-) subjects, showed lower urinary excretion of glutamate and some other glucogenic amino acids. Thus, UpH correlated positively with the urinary excretion of glutamate in the PUS (+) subjects. A reduction in urinary glutamate but not in glutamine excretion proved to be an independent risk factor for reduced UpH. In conclusion, PUS appears to occur when a reduction in the synthesis of ammonia from glutamate causes a decrease in UpH. Our results showed that urinary glutamate excretion was reduced in PUS because renal glutamate was consumed by a reaction different from ammonia production.

Enhance Your Understanding of Lithium Neurotoxicity.

To the Editor: Lithium is a drug established for treatment of affective disorder and is intended to mitigate and prevent depressive or manic episodes and diminish suicidal tendencies. However, lithium can induce neurologic sequelae following overdose or during maintenance therapy.1,2 Neurotoxicity. Lithium neurotoxicity can be reversible or irreversible and may even be observed at therapeutic serum levels.3 Acute lithium toxicity initially affects fast-acting neurons controlling coordination, resulting in tremor and extremity dyscoordination. Increased toxicity may cause progressive development of slurred speech, muscular fasciculation, seizures, nystagmus, and extrapyramidal features.4 Delirium can be another manifestation, with obtundation in severe neurotoxicities. Sustained serum lithium levels > 1.5 mEq/L can be associated with toxicity risk, but may not be at concentrations consistently high enough to induce nerve injury.4 Persistent concentrations > 2.5 mEq/L often induce neurologic complications, especially convulsions and cerebellar impairment. Permanent lithium neurotoxicity is clinically documented.1,2,5,6 The syndrome of irreversible lithium-effectuated neurotoxicity is a permanent sequela of intoxication that presents with persistent cerebellar dysfunction.6 Other significant neurologic complications also can be observed.7 Demyelination occurs at various sites, especially the cerebellum, causing dystaxia and dysarthria.8 Permanent cerebellar and pyramidal cell dysfunction can result. Pharmacology. Lithium enters the circulation and is distributed widely and primarily intracellularly. The mechanisms of action include changes at cell membranes, alteration of serotonin and norepinephrine actions, and influences on phosphatidylinositol metabolism.4 However, when serum lithium levels are in overtly toxic ranges, lithium further accumulates in the brain and kidney, causing dysfunction, but does not always reflect degrees of neurotoxicity. Serum concentrations do not correlate well with neuronal levels. The implications of an individual assay must include a relation to the timing of previous lithium administrations, with standardized determinations based on approximately 12 hours after the last ingestion. Lithium is excreted by the kidney, and this process is strongly influenced by sodium and water excretion. The lithium half-life is approximately 18 hours in young adults and 36 hours in healthy elderly people,7 and it varies according to renal function and hydration. Some pharmaceutical interactions enhance lithium retention, most prominently the diuretics like hydrochlorothiazide, secondary to sodium wasting. Angiotensin converting enzyme inhibitors decrease glomerular filtration and increase tubular reabsorption of lithium. Nonsteroidal anti-inflammatory drugs interrupt renal prostaglandin synthesis, retarding lithium excretion.7 Lithium acts synergistically with neuroleptic drugs in the development of neuroleptic malignant syndrome.8 Clinical conditions involving dehydration and impaired renal status diminish lithium excretion and increase the risk of neurotoxicity. Management. Lithium toxicity is usually avoided through conservative prescribing, patient education, and close clinical and laboratory monitoring.9 Patients administered lithium should understand drug interactions, the need for adequate hydration, and how to contact their physician. Doctors must consider coexistent renal or cardiac failure and brain diseases that might predispose toward toxicity. Minor intoxications are mitigated by oral hydration and adequate electrolyte ingestion. In more severe cases, intravenous saline is instituted. At progressively greater toxicities, cathartics and lavage with charcoal are considered. When dangerous sequelae are feared, hemodialysis is indicated to forestall neurotoxicity.10 The serum lithium concentration may exhibit a rebound during treatment.11 Rebound in lithium toxicity cases means that serum levels that were once lower, often rise again, reflecting stores of higher lithium concentration within cells, including those of the central nervous system—that can result in later observing rising serum lithium levels and thus implies continued lithium neurotoxicity.

IL-6 Trans-Signaling Drives Murine Crescentic GN.

The role of IL-6 signaling in renal diseases remains controversial, with data describing both anti-inflammatory and proinflammatory effects. IL-6 can act via classic signaling, engaging its two membrane receptors gp130 and IL-6 receptor (IL-6R). Alternatively, IL-6 trans-signaling requires soluble IL-6R (sIL-6R) to act on IL-6R-negative cells that express gp130. Here, we characterize the role of both pathways in crescentic nephritis. Patients with crescentic nephritis had significantly elevated levels of IL-6 in both serum and urine. Similarly, nephrotoxic serum-induced nephritis (NTN) in BALB/c mice was associated with elevated serum IL-6 levels. Levels of serum sIL-6R and renal downstream signals of IL-6 (phosphorylated signal transducer and activator of transcription 3, suppressor of cytokine signaling 3) increased over time in this model. Simultaneous inhibition of both IL-6 signaling pathways using anti-IL-6 antibody did not have a significant impact on NTN severity. In contrast, specific inhibition of trans-signaling using recombinant sgp130Fc resulted in milder disease. Vice versa, specific activation of trans-signaling using a recombinant IL-6-sIL-6R fusion molecule (Hyper-IL-6) significantly aggravated NTN and led to increased systolic BP in NTN mice. This correlated with increased renal mRNA synthesis of the Th17 cell cytokine IL-17A and decreased synthesis of resistin-like alpha (RELMalpha)-encoding mRNA, a surrogate marker of lesion-mitigating M2 macrophage subtypes. Collectively, our data suggest a central role for IL-6 trans-signaling in crescentic nephritis and offer options for more effective and specific therapeutic interventions in the IL-6 system.

Dysregulation of phosphate metabolism and conditions associated with phosphate toxicity.

Phosphate homeostasis is coordinated and regulated by complex cross-organ talk through delicate hormonal networks. Parathyroid hormone (PTH), secreted in response to low serum calcium, has an important role in maintaining phosphate homeostasis by influencing renal synthesis of 1,25-dihydroxyvitamin D, thereby increasing intestinal phosphate absorption. Moreover, PTH can increase phosphate efflux from bone and contribute to renal phosphate homeostasis through phosphaturic effects. In addition, PTH can induce skeletal synthesis of another potent phosphaturic hormone, fibroblast growth factor 23 (FGF23), which is able to inhibit renal tubular phosphate reabsorption, thereby increasing urinary phosphate excretion. FGF23 can also fine-tune vitamin D homeostasis by suppressing renal expression of 1-alpha hydroxylase (1α(OH)ase). This review briefly discusses how FGF23, by forming a bone-kidney axis, regulates phosphate homeostasis, and how its dysregulation can lead to phosphate toxicity that induces widespread tissue injury. We also provide evidence to explain how phosphate toxicity related to dietary phosphorus overload may facilitate incidence of noncommunicable diseases including kidney disease, cardiovascular disease, cancers and skeletal disorders.

The Renin-Angiotensin and Renal Dopaminergic Systems Interact in Normotensive Humans.

The renin-angiotensin-aldosterone (RAAS) and renal dopaminergic systems interact to maintain sodium balance. High NaCl intake increases renal synthesis of dopamine and dopaminergic receptor activity, decreasing epithelial sodium transport, whereas sodium deficit activates the RAAS, increasing epithelial sodium transport. We tested the hypothesis that attenuation of the natriuretic effect of dopamine D1-like receptors during salt restriction results in part from increased RAAS activity in seven salt-resistant normotensive adults using a double-blind placebo-controlled balanced crossover design. All subjects attained sodium balance on low (50 mmol Na(+)/day) and high (300 mmol Na(+)/day) NaCl diets, administered 4 weeks apart. Sodium, potassium, lithium, para-aminohippurate, and creatinine clearances were measured before, during, and after a 3-hour infusion of fenoldopam, a D1-like receptor agonist, with and without pretreatment with enalapril, an angiotensin converting enzyme inhibitor. On the high NaCl diet, fenoldopam-induced natriuresis was associated with the inhibition of renal proximal and distal tubule sodium transport. On the low NaCl diet, fenoldopam decreased renal distal tubule sodium transport but did not cause natriuresis. The addition of enalapril to fenoldopam restored the natriuretic effect of fenoldopam and its inhibitory effect on proximal tubule sodium transport. Thus, on a high NaCl diet fenoldopam causes natriuresis by inhibiting renal proximal and distal tubule transport, but on a low NaCl diet the increased RAAS activity prevents the D1-like receptor from inhibiting renal proximal tubule sodium transport, neutralizing the natriuretic effect of fenoldopam. These results demonstrate an interaction between the renin-angiotensin and renal dopaminergic systems in humans and highlight the influence of dietary NaCl on these interactions.

Combined angiotensin receptor blockade and neprilysin inhibition attenuates angiotensin-II mediated renal cellular collagen synthesis

a Monash Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Alfred Hospital, Melbourne, VIC 3004, Australia b Department of Cardiology B, Oslo University Hospital Ulleval, 0407 Oslo, Norway c Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Norway d Department of Medicine, University of Melbourne, St Vincent's Hospital, Fitzroy, VIC 3068 Australia e Novartis Pharmaceuticals Corp., Development Franchise — Critical Care, East Hanover, USA f Novartis Pharma DS&E and Oncology, Drug Safety and Epidemiology, Basel, Switzerland

Early co-expression of cyclooxygenase-2 and renin in the rat kidney cortex contributes to the development of N(G)-nitro-L-arginine methyl ester induced hypertension.

We investigated the involvement of cyclooxygenase-2 (COX-2) and the renin-angiotensin system in N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Male Wistar rats were treated with L-NAME (75.0 mg·(kg body mass)(-1)·day(-1), in their drinking water) for different durations (1-33 days). COX-2 and renin mRNA were measured using real-time PCR in the renal cortex, and prostanoids were assessed in the renal perfusate, whereas angiotensin II (Ang II) and Ang (1-7) were quantified in plasma. In some rats, nitric oxide synthase inhibition was carried out in conjunction with oral administration of captopril (30.0 mg·kg(-1)·day(-1)) or celecoxib (1.0 mg·kg(-1)·day(-1)) for 2 or 19 days. We found a parallel increase in renocortical COX-2 and renin mRNA starting at day 2 of treatment with L-NAME, and both peaked at 19-25 days. In addition, L-NAME increased renal 6-Keto-PGF(1α) (prostacyclin (PGI2) metabolite) and plasma Ang II from day 2, but reduced plasma Ang (1-7) at day 19. Captopril prevented the increase in blood pressure, which was associated with lower plasma Ang II and increased COX-2-derived 6-Keto-PGF(1α) at day 2 and plasma Ang (1-7) at day 19. Celecoxib partially prevented the increase in blood pressure; this effect was associated with a reduction in plasma Ang II. These findings indicate that renal COX-2 expression increased in parallel with renin expression, renal PGI2 synthesis, and plasma Ang II in L-NAME-induced hypertension.

Evaluation and Treatment of Anemia in Chronic Kidney Disease [Kronik Bobrek Hastaliklarinda Aneminin Degerlendirilmesi ve Tedavisi

Abstract Anemia is common in patients with chronic kidney disease. Anemia is a major risk factor for cardiovascular disease and affects life quality. The reduction of renal erythropoietin synthesis is the essentially cause of anemia. Among other reasons can considered iron deficiency, inflammation, uremic toxins, hyperparathyroidism, hemolysis, reduction of erythrocyte survival and malnutrition. The reasons that lead to anemia should be investigated primarily in the treatment of anemia and treatment should be for the cause. Erythropoiesis-stimulating agents is the basis of the treatment of anemia in chronic kidney disease. ESA therapy should be initiated to patient after the ruled out other causes of anemia. The target hemoglobin value should be 11-12 g/dL. Iron deficiency must be evaluated before starting treatment with erythropoiesis stimulating agents and should be treated if any iron deficiency. Transferrin saturation (TSAT) and ferritin level is the most commonly used parameters in the evaluation of iron deficiency in chronic kidney disease in practice. Iron therapy should be given if serum ferritin concentrations <100 ng/ml and TSAT <20%. Iron therapy is recommended in recent guidelines, in order to reduce the dose of ESA as well as delaying the uptake, in chronic kidney disease patients with TSAT <30% and ferritin <300 ng/mL. Iron may be administered orally or parenterally in patients with iron deficiency. Parenteral administration should be preferred in hemodialysis patients. Correction of iron deficiency anemia reduces requirement for ESA. The treatment of anemia raises life quality of patients with chronic kidney diseases and is associated with a better prognosis. Keywords: Chronic kidney disease, anemia, iron deficiency anemia, erythropoietin

LCZ696, an angiotensin receptor neprilysin inhibitor, attenuates renal fibrosis after myocardial infarction and reduces angiotensin-II-mediated renal cellular collagen synthesis

LCZ696, an angiotensin receptor neprilysin inhibitor, attenuates renal fibrosis after myocardial infarction and reduces angiotensin-II-mediated renal cellular collagen synthesis

Inhibition of local aldosterone by eplerenone reduces renal structural damage in a novel model of chronic cyclosporine A nephrotoxicity.

The fact that mineralocorticoid receptor antagonists reduce structural and functional alterations induced by cyclosporine A (CsA) indicates that aldosterone plays a key role in chronic CsA nephrotoxicity. We and other researchers have reported local renal aldosterone synthesis. To investigate local renal aldosterone's role in chronic CsA nephrotoxicity, we evaluated the effect of eplerenone (Epl) on renal structural damage and renal dysfunction in adrenalectomized (ADX) rats, and assessed whether the therapeutic benefit was associated with reduction of transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), plasminogen activator inhibitor type 1 (PAI-1) and collagen I (COL-I) expression. Male Sprague-Dawley rats fed a normal-sodium diet were divided in four groups: sham-ADX, ADX, CsA, or Epl. Rats in the ADX, CsA and Epl groups were adrenalectomized first. Aldosterone, sodium and potassium levels in serum and urine were measured on the second day. Two weeks later, vehicle (sham-ADX and ADX group), CsA (25mg/kg/d), or CsA and Epl (100 mg/ kg/d) combination was administrated, respectively. After six weeks, urinary protein, creatinine clearance (Ccr), tubulointerstitial fibrosis (TIF), aldosterone level in kidney, and renal aldosterone synthase CYP11B2, COL-I, TGF-β1, CTGF and PAI-1 gene expression levels were determined. On the second day after surgery, adrenalectomized rats showed undetectable aldosterone with natriuresis, hyponatremia, decreased urinary potassium excretion and hyperpotassemia. CsA reduced Ccr, induced urinary proteins and up-regulated COL-I, TGF-β1, CTGF and PAI-1 gene expression with a significant development of TIF. Eplerenone administration prevented TIF and COL-I, TGF-β1 and PAI-1 up-regulation but did not improve renal function. Our results suggest local renal aldosterone is an important mediator of renal injury induced by CsA.

Inflammation and L-carnitine therapy in hemodialysis patients: a review.

Inflammation is a common complication in hemodialysis (HD) patients with no valid treatment strategy. In addition, carnitine deficiency occurs frequently in HD patients because of intradialytic loss of carnitine, impaired de novo carnitine renal synthesis, and reduced dietary intake. It appears that carnitine deficiency is related to inflammation in HD patients. A few clinical trials have investigated the effect of L-carnitine supplement on inflammatory markers in HD patients. All studies in this field, except one, showed that L-carnitine could significantly reduce C-reactive protein and serum amyloid A, as two systemic inflammation markers, in HD patients. Therefore, considering high prevalence of inflammation and carnitine deficiency in HD patients, L-carnitine therapy is a reasonable approach for reducing systemic inflammation and its complications in these patients.