Effects of salt reduction education from a salt questionnaire on inter-dialysis weight gain in patients on hemodialysis.

BACKGROUND: Heart failure is the leading cause of death in patients undergoing hemodialysis (HD), with fluid overload being the most common cause. Therefore, it is important for patients undergoing HD to reduce salt intake. We recently developed a highly accurate and simple self-administered salt questionnaire. Using this salt questionnaire, we aimed to determine whether salt intake and inter-HD weight gain decrease when patients with HD are instructed to reduce their salt intake. METHODS: Seventy-eight outpatients at a maintenance HD facility were assessed for dietary salt intake using a salt questionnaire. After one month of dietary guidance, salt intake was assessed again using the salt questionnaire. RESULTS: The mean age of the patients was 72.2 ± 11.9 years; 47 (60.3%) were men, 23 had diabetic nephropathy as the primary disease, and the median HD vintage was 74 months. Salt intake significantly decreased from 8.41 ± 2.43 g/day before the salt questionnaire intervention to 7.67 ± 2.60 g/day after the intervention (p = 0.010). Changes in salt intake before and after the intervention were significantly positively correlated with changes in weight gain before the start of HD sessions with an interval of 2 days (r = 0.24, p = 0.037). Furthermore, changes in salt intake significantly and positively correlated with changes in weight gain after adjusting for age, sex, and dry weight. CONCLUSION: The salt questionnaire may be an effective tool for reducing salt intake and controlling weight gain during HD.

Tubular Epithelial Cell HMGB1 Promotes AKI-CKD Transition by Sensitizing Cycling Tubular Cells to Oxidative Stress: A Rationale for Targeting HMGB1 during AKI Recovery.

SIGNIFICANCE STATEMENT: Cells undergoing necrosis release extracellular high mobility group box (HMGB)-1, which triggers sterile inflammation upon AKI in mice. Neither deletion of HMGB1 from tubular epithelial cells, nor HMGB1 antagonism with small molecules, affects initial ischemic tubular necrosis and immediate GFR loss upon unilateral ischemia/reperfusion injury (IRI). On the contrary, tubular cell-specific HMGB1 deficiency, and even late-onset pharmacological HMGB1 inhibition, increased functional and structural recovery from AKI, indicating that intracellular HMGB1 partially counters the effects of extracellular HMGB1. In vitro studies indicate that intracellular HMGB1 decreases resilience of tubular cells from prolonged ischemic stress, as in unilateral IRI. Intracellular HMGB1 is a potential target to enhance kidney regeneration and to improve long-term prognosis in AKI. BACKGROUND: Late diagnosis is a hurdle for treatment of AKI, but targeting AKI-CKD transition may improve outcomes. High mobility group box-1 (HMGB1) is a nuclear regulator of transcription and a driver of necroinflammation in AKI. We hypothesized that HMGB1 would also modulate AKI-CKD transition in other ways. METHODS: We conducted single-cell transcriptome analysis of human and mouse AKI and mouse in vivo and in vitro studies with tubular cell-specific depletion of Hmgb1 and HMGB1 antagonists. RESULTS: HMGB1 was ubiquitously expressed in kidney cells. Preemptive HMGB1 antagonism with glycyrrhizic acid (Gly) and ethyl pyruvate (EP) did not affect postischemic AKI but attenuated AKI-CKD transition in a model of persistent kidney hypoxia. Consistently, tubular Hmgb1 depletion in Pax8 rtTA, TetO Cre, Hmgb1fl/fl mice did not protect from AKI, but from AKI-CKD transition. In vitro studies confirmed that absence of HMGB1 or HMGB1 inhibition with Gly and EP does not affect ischemic necrosis of growth-arrested differentiated tubular cells but increased the resilience of cycling tubular cells that survived the acute injury to oxidative stress. This effect persisted when neutralizing extracellular HMGB1 with 2G7. Consistently, late-onset HMGB1 blockade with EP started after the peak of ischemic AKI in mice prevented AKI-CKD transition, even when 2G7 blocked extracellular HMGB1. CONCLUSION: Treatment of AKI could become feasible when ( 1 ) focusing on long-term outcomes of AKI; ( 2 ) targeting AKI-CKD transition with drugs initiated after the AKI peak; and ( 3 ) targeting with drugs that block HMGB1 in intracellular and extracellular compartments.

Nicotinic acetylcholine receptor agonist reduces acute lung injury after renal ischemia-reperfusion injury by acting on splenic macrophages in mice.

Acute kidney injury (AKI) contributes to the development of acute lung injury (ALI) via proinflammatory responses. We hypothesized that activation of a nicotinic acetylcholine receptor (nAChR), which exerts cholinergic anti-inflammatory effects on macrophages, could reduce ALI after AKI. We aimed to determine whether nAChR agonists could reduce ALI after AKI and which macrophages in the lung or spleen contribute to the improvement of ALI by nAChR agonists. We induced AKI in male mice by unilateral ischemia-reperfusion injury (IRI) with contralateral nephrectomy and administered nAChR agonists in three experimental settings: 1) splenectomy, 2) deletion of splenic macrophages and systemic mononuclear phagocytes via intravenous administration of clodronate liposomes, and 3) alveolar macrophage deletion via intratracheal administration of clodronate liposomes. Treatment with GTS-21, an α7nAChR-selective agonist, significantly reduced the levels of circulating IL-6, a key proinflammatory cytokine, and lung chemokine (C-X-C motif) ligand (CXCL)1 and CXCL2 and neutrophil infiltration, and Evans blue dye (EBD) vascular leakage increased after renal IRI. In splenectomized mice, GTS-21 did not reduce circulating IL-6 and lung CXCL1 and CXCL2 levels and neutrophil infiltration, and EBD vascular leakage increased after renal IRI. In mice depleted of splenic macrophages and systemic mononuclear phagocytes, GTS-21 treatment did not reduce lung neutrophil infiltration, and EBD vascular leakage increased after renal IRI. In mice depleted of alveolar macrophages, GTS-21 treatment significantly reduced lung neutrophil infiltration, and EBD vascular leakage increased after renal IRI. Our findings show that nAChR agonist reduces circulating IL-6 levels and acute lung injury after renal IRI by acting on splenic macrophages.NEW & NOTEWORTHY Acute lung injury associated with acute kidney injury contributes to high mortality. This study showed, for the first time, that nicotinic acetylcholine receptor agonists reduced circulating IL-6 and ALI after renal ischemia-reperfusion injury in mice. These effects of α7nAChR agonist were eliminated in both splenectomized and splenic macrophage (including systemic mononuclear phagocyte)-depleted mice but not alveolar macrophage-depleted mice. nAChR agonist could reduce ALI after AKI via splenic macrophages and provide a novel strategy in AKI.

Electric cell-substrate impedance sensing in kidney research.

Electric cell-substrate impedance sensing (ECIS) is a quantitative, label-free, non-invasive analytical method allowing continuous monitoring of the behaviour of adherent cells by online recording of transcellular impedance. ECIS offers a wide range of practical applications to study cell proliferation, migration, differentiation, toxicity and monolayer barrier integrity. All of these applications are relevant for basic kidney research, e.g. on endothelial cells, tubular and glomerular epithelial cells. This review gives an overview on the fundamental principles of the ECIS technology. We name strengths and remaining hurdles for practical applications, present an ECIS array reuse protocol, and review its past, present and potential future contributions to preclinical kidney research.

Dipeptidyl peptidase-4 inhibitor teneligliptin accelerates recovery from cisplatin-induced acute kidney injury by attenuating inflammation and promoting tubular regeneration.

BACKGROUND: Cisplatin is an effective chemotherapeutic agent. However, acute kidney injury (AKI) and subsequent kidney function decline limits its use. Dipeptidyl peptidase-4 (DPP-4) inhibitor has been reported to attenuate kidney injury in some in vivo models, but the mechanisms-of-action in tubule recovery upon AKI remain speculative. We hypothesized that DPP-4 inhibitor teneligliptin (TG) can facilitate kidney recovery after cisplatin-induced AKI. METHODS: In in vivo experiment, AKI was induced in rats by injecting 5 mg/kg of cisplatin intravenously. Oral administration of 10 mg/kg of TG, once a day, was started just before injecting cisplatin or from Day 5 after cisplatin injection. In an in vitro experiment, proliferation of isolated murine tubular cells was evaluated with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, cell cycle analysis and cell counting. Cell viability was analysed by MTT assay or lactate dehydrogenase (LDH) assay. RESULTS: In in vivo experiments, we found that TG attenuates cisplatin-induced AKI and accelerates kidney recovery after the injury by promoting the proliferation of surviving epithelial cells of the proximal tubule. TG also suppressed intrarenal tumour necrosis factor-α expression, and induced macrophage polarization towards the anti-inflammatory M2 phenotype, both indirectly endorsing tubule recovery upon cisplatin injury. In in vitro experiments, TG directly accelerated the proliferation of primary tubular epithelial cells. Systematic screening of the DPP-4 substrate chemokines in vitro identified CXC chemokine ligand (CXCL)-12 as a promoted mitogenic factor. CXCL12 not only accelerated proliferation but also inhibited cell death of primary tubular epithelial cells after cisplatin exposure. CXC chemokine receptor (CXCR)-4 antagonism abolished the proliferative effect of TG. CONCLUSIONS: The DPP-4 inhibitor TG can accelerate tubule regeneration and functional recovery from toxic AKI via an anti-inflammatory effect and probably via inhibition of CXCL12 breakdown. Hence, DPP-4 inhibitors may limit cisplatin-induced nephrotoxicity and improve kidney function in cancer patients.

Correction to: Impaired endogenous nighttime melatonin secretion relates to intrarenal renin-angiotensin system activation and renal damage in patients with chronic kidney disease.

In the original publication, an error occurred in Table 4 (B), under Nighttime group. The value of "Nighttime Log U-AGT/Cr" for model 3 (under R = 0.68) was incorrectly published as 0.11. The correct value should read as -0.31.

Melatonin ameliorates intrarenal renin-angiotensin system in a 5/6 nephrectomy rat model.

BACKGROUND: Activation of the intrarenal renin-angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. It has been reported that reactive oxygen species (ROS) are important components of intrarenal RAS activation. Melatonin is recognized as a powerful antioxidant, and we recently reported that impaired nighttime melatonin secretion correlates negatively with urinary angiotensinogen excretion, the surrogate marker of intrarenal RAS activity in patients with CKD. However, whether melatonin supplementation ameliorates the augmentation of intrarenal RAS in CKD has remained unknown. We aimed to clarify whether exogenous melatonin ameliorates intrarenal RAS activation via the reduction of ROS production. METHODS: 5/6 Nephrectomized (Nx) rats were used as a chronic progressive CKD model and compared with sham-operated control rats. The Nx rats were divided into untreated Nx rats and melatonin-treated Nx rats. The levels of intrarenal RAS, ROS components, and renal injury were evaluated after 4 weeks of treatment. RESULTS: Compared with the control rats, the untreated Nx rats exhibited significant increases in intrarenal angiotensinogen, angiotensin II (AngII) type 1 receptors, and AngII, accompanied by elevated blood pressure, higher oxidative stress (8-hydroxy-2'-deoxyguanosine), lower antioxidant (superoxide dismutase) activity, and increased markers of interstitial fibrosis (α-smooth muscle actin, Snail, and type I collagen) in the remnant kidneys. Treatment with melatonin significantly reversed these abnormalities. CONCLUSION: Antioxidant treatment with melatonin was shown to ameliorate intrarenal RAS activation and renal injury in a 5/6 Nx rat model.

Acquired resistance to rechallenge injury after acute kidney injury in rats is associated with cell cycle arrest in proximal tubule cells.

Rats that have recovered from severe proximal tubule (PT) injury induced by uranyl acetate (UA), a toxic stimulus, developed resistance to subsequent UA treatment. We investigated cell cycle status and progression in PT cells in relation to this acquired resistance. Fourteen days after pretreatment with saline (vehicle group) or UA [acute kidney injury (AKI) group], rats were injected with UA or lead acetate (a proliferative stimulus). Cell cycle status (G0/G1/S/G2/M) was analyzed by flow cytometry. The expression of cell cycle markers, cyclin-dependent kinase inhibitors, and phenotypic markers were examined by immunohistochemistry. Cell cycle status in PT cells in the AKI group was comparable to those of the vehicle group. However, more early G1-phase cells (cyclin D1- or Ki67-) and p21+ or p27+ cells were found in the PT of the AKI group than in that of the vehicle group. UA induced G1 arrest and inhibited S phase progression with earlier dedifferentiation and less apoptosis in PT cells of the AKI group. Lead acetate induced proliferation without dedifferentiation but with delayed G0-G1 transition and inhibited S phase progression in PT cells in the AKI group. Sustained p21 and increased p27 expression in PT cells were found in the AKI group in response to UA and lead acetate. PT cells in the AKI group inhibited cell cycle progression by enhanced G1 arrest, probably via p21/p27 modulation as an injury or proliferation response, resulting in cytoresistance to rechallenge injury.

Impaired endogenous nighttime melatonin secretion relates to intrarenal renin-angiotensin system activation and renal damage in patients with chronic kidney disease.

BACKGROUND: Activation of the intrarenal renin-angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. The circadian rhythm of intrarenal RAS activation leads to renal damage and hypertension, which are associated with diurnal blood pressure (BP) variation. The activation of intrarenal RAS following reactive oxygen species (ROS) activation, sympathetic hyperactivity and nitric oxide (NO) inhibition leads to the development of renal damage. Melatonin is a hormone regulating the circadian rhythm, and has multiple functions such as anti-oxidant and anti-adrenergic effects and enhancement of NO bioavailability. Nocturnal melatonin concentrations are lower in CKD patients. However, it is not known if impaired endogenous melatonin secretion is related to BP, intrarenal RAS, or renal damage in CKD patients. METHODS: We recruited 53 CKD patients and conducted 24-h ambulatory BP monitoring. urine was collected during the daytime and nighttime. We investigated the relationship among the melatonin metabolite urinary 6-sulphatoxymelatonin (U-aMT6s), BP, renal function, urinary angiotensinogen (U-AGT), and urinary albumin (U-Alb). RESULTS: Patients' U-aMT6s levels were significantly and negatively correlated with clinical parameters such as renal function, systolic BP, U-AGT, and U-Alb, during both day and night. Multiple regression analyses for U-aMT6s levels were performed using age, gender, renal function, and each parameter (BPs, U-AGT or U-Alb), at daytime and nighttime. U-aMT6s levels were significantly associated with U-AGT (ß = -0.31, p = 0.044) and U-Alb (ß = -0.25, p = 0.025) only at night. CONCLUSION: Impaired nighttime melatonin secretion may be associated with nighttime intrarenal RAS activation and renal damage in CKD patients.

The level of urinary α1 microglobulin excretion is a useful marker of peritubular capillaritis in antineutrophil cytoplasmic antibody associated vasculitis.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis affects small vessels in the kidney (i.e., arterioles, glomerular or peritubular capillaries, or venules). Although crescentic glomerulonephritis is a common histological finding, the incidence of peritubular capillaritis (PTC) or arteriolitis is unclear. Moreover, the laboratory data that reflect the degree of renal histological damage and distinguish between PTC and arteriolitis have not yet been clarified. METHODS: We investigated laboratory data and histological findings from 11 patients diagnosed with ANCA-associated vasculitis (2 men and 9 women, mean age 70.3 ± 3.3 years) whose renal biopsies were performed between 2009 and 2014. RESULTS: All patients were positive for myeloperoxidase (MPO)-ANCA. PTC or arteriolitis was detected in six patients (54.5 %), respectively. The only significant positive relationship between laboratory data and histological findings observed was that between levels of urinary α1 microglobulin (u-α1MG) excretion and the percentage of tubular atrophy and interstitial fibrosis (r = 0.67, p = 0.035). No significant differences in laboratory data were found between patients with or without arteriolitis. However, the levels of u-α1MG excretion were significantly higher in patients with PTC than in those without PTC (75.2 ± 19.5 vs. 15.0 ± 3.6 mg/dl, p = 0.035). CONCLUSION: PTC or arteriolitis occurs at a high rate independently of crescentic glomerulonephritis in ANCA-associated vasculitis patients. The levels of u-α1MG excretion reflect the degrees of tubular atrophy and interstitial fibrosis. Moreover, high levels of u-α1MG excretion suggest that PTC is more likely than arteriolitis in ANCA-associated vasculitis patients.

Hyperuricaemia is associated with renal damage independently of hypertension and intrarenal renin-angiotensin system activation, as well as their circadian rhythms.

AIM: Both hyperuricaemia and activation of the intrarenal renin-angiotensin system (RAS) play an important role in the development of hypertension and renal damage. However, it has not been clear whether hyperuricaemia is associated with renal damage due to hypertension or intrarenal RAS activation, as well as their circadian rhythms. METHODS: We recruited 43 chronic kidney disease (CKD) patients who did not receive RAS blockers and antihyperuricaemic drugs, and investigated the relationship among serum uric acid (sUA) levels, the circadian rhythm of urinary angiotensinogen (U-AGT) excretion levels, and the levels of albuminuria (U-ACR) and proteinuria (U-P/Cr). RESULTS: sUA levels were significantly associated with estimated glomerular filtration rate (eGFR) (P = 0.002), systolic blood pressure (SBP) (daytime, P = 0.031), and U-ACR (daytime, P = 0.006 and nighttime, P = 0.008) and U-P/Cr (daytime, P = 0.017 and nighttime, P = 0.013). However, there were no significant differences between sUA levels and SBP in nighttime and U-AGT excretion levels in both time periods. Multiple regression analyses for sUA levels were performed using age, sex, eGFR and each parameter (SBP, U-AGT/Cr, U-ACR or U-P/Cr). sUA levels were not associated with SBP or U-AGT/Cr in both time periods. sUA levels tended to correlate with U-P/Cr levels in nighttime, and were significantly associated with U-P/Cr in daytime (P = 0.026) and U-ACR in daytime (P = 0.017) and nighttime (P = 0.046). Moreover, no significant differences were found between sUA levels and night-to-day ratios of some parameters. CONCLUSION: These data suggest that hyperuricaemia is associated with renal damage, independently of hypertension and intrarenal RAS activation, as well as their circadian rhythms.

Alogliptin improves steroid-induced hyperglycemia in treatment-naïve Japanese patients with chronic kidney disease by decrease of plasma glucagon levels.

BACKGROUND: Chronic kidney disease (CKD) is a risk factor for end-stage renal failure and cardiovascular disease, and a strategy to counteract CKD must be established. CKD caused by immunological abnormalities is treated by steroids, frequently resulting in steroid diabetes. Although insulin is the most effective drug against steroid diabetes, administering it to patients can be difficult. Dipeptidyl peptidase-4 (DPP-4) inhibitors were developed for diabetes mellitus with a new mechanism of action. However, their efficacies and mechanisms of action for steroid diabetes are unclear. MATERIAL AND METHODS: We studied 11 CKD patients treated with steroids admitted to our hospital (3 men and 8 women; age, 66.0 ± 15.9 years). DPP-4 inhibitor alogliptin was administered for steroid diabetes. Levels of markers related to glucose metabolism were measured before alogliptin treatment and after alogliptin treatment, before the prednisolone dose was reduced. RESULTS: Alogliptin treatment significantly increased plasma glucagon-like peptide-1 (GLP-1) levels from 1.16 ± 1.71 pmol/L to 4.48 ± 1.53 pmol/L and significantly reduced levels of plasma glucose recorded 2 h after lunch and hemoglobin A1c (HbA1c). No significant differences were seen in insulin secretory ability of homeostasis model assessment (HOMA) (HOMA-ß) and insulin resistance index of HOMA (HOMA-R) before and after alogliptin treatment. In contrast, alogliptin treatment significantly decreased plasma glucagon levels, from 116.1 ± 38.7 pg/mL to 89.6 ± 17.3 pg/mL. Moreover, there were significant correlations among HbA1c, GLP-1, and glucagon levels. CONCLUSIONS: Alogliptin improves steroid-induced hyperglycemia by decrease of glucagon levels through an increase in plasma GLP-1 levels.

A Rare Case of Sporadic Medullary Cystic Kidney Disease with Rapidly Progressive Renal Dysfunction and Renal Enlargement Complicated by Idiopathic Nodular Glomerulosclerosis.

An 81-year-old man with hypertension and a history of smoking presented with renal enlargement and progressive renal dysfunction despite no family history of kidney disease. A renal biopsy revealed diffuse tubular, dilated, and atrophic distal tubules with cystic formation and thin irregularities in the tubular basement membrane. Although no known genetic abnormalities were detected, the patient was diagnosed with medullary cystic kidney disease (MCKD). In addition, idiopathic nodular glomerulosclerosis, which is characterized by significant mesangial expansion and accentuated glomerular nodularity and is associated with hypertension and cigarette smoking, was identified as a complication of MCKD. We herein report a rare case of sporadic MCKD with idiopathic nodular glomerulosclerosis.

Anti-contactin 1 Antibody-associated Membranous Nephropathy in Chronic Inflammatory Demyelinating Polyneuropathy with Several Autoantibodies.

A 50-year-old man diagnosed with anti-contactin 1 (CNTN1) antibody-associated chronic inflammatory demyelinating polyneuropathy (CIDP) was referred to our department for the evaluation of proteinuria. A kidney biopsy revealed membranous nephropathy (MN). Immunohistochemistry for CNTN1 revealed positive granular staining along the glomerular basement membrane, confirming anti-CNTN1 antibody-associated MN. Immunofluorescence showed a full-house pattern, and several autoantibodies, such as anti-nuclear antibody, anti-double-strand DNA antibody, and anti-cardiolipin antibody, were detected in the patient's serum. Although limited autoantibodies have been investigated in some of the reported cases, a variety of autoantibodies might be produced in anti-CNTN1 antibody-associated CIDP, accompanied by MN.

Relationship between urinary fractional excretion of sodium and life prognosis in liver cirrhosis patients.

AIM: Renal vasoconstriction in generalized vasodilatation with blood pooling and the consequent reduction in effective arterial volume is the pathophysiological basis of liver cirrhosis (LC). Low levels of fractional excretion of sodium (FENa) are an effective marker of hypoperfusion of the renal artery. However, the relationship between levels of FENa, LC severity and life prognosis has not yet been elucidated. METHODS: We examined 57 LC patients (39 men and 18 women; mean age, 70.5 ± 8.8 years; underlying liver disease, type B hepatitis in eight patients, type C hepatitis in 37, alcoholic hepatitis in four and others in eight) with renal dysfunction (estimated glomerular filtration rate (eGFR) <60 mL/min) who were admitted to our hospital. RESULTS: Nine patients died because of uremia, liver failure, gastrointestinal bleeding and infection. No differences were found in patient background and blood pressure. However, in addition to differences in the levels of aspartate aminotransferase (AST), cholinesterase, albumin, prothrombin time (PT), eGFR and Model for End-Stage Liver Disease (MELD) score, the patients who died had significant differences in levels of FENa. The levels of FENa were significantly and inversely correlated with blood urea nitrogen, total bilirubin, AST, Child-Pugh score and MELD score, and were significantly and positively correlated with cholinesterase, albumin and PT. Moreover, the sensitivity (88%) and specificity (93%) of the levels of FENa of less than 0.4% to predict death were remarkably high. CONCLUSION: Levels of FENa may reflect LC severity and may be associated with the life prognosis of LC patients.

Dephosphorylated Ser985 of c-Met is associated with acquired resistance to rechallenge injury in rats that had recovered from uranyl acetate-induced subclinical renal damage.

BACKGROUND: We previously reported that rats that had recovered from mild proximal tubule (PT) injury induced by a sub-toxic dose of uranyl acetate (UA) showed partial resistance to a subsequent nephrotoxic dose of UA in association with reduced renal dysfunction and accelerated PT proliferation. We demonstrated that this resistance may involve hepatocyte growth factor (HGF)/c-Met signaling. Here, we examined whether primary cultured tubular cells derived from this model had acquired sensitivity to HGF. METHODS: Tubular cells were isolated by collagenase digestion from rat kidneys after recovery from UA-induced mild PT injury and were cultured for 48 h. Their survival and proliferation were examined using the MTS assay/5-bromo-2'-deoxyuridine labeling or MTS assay, respectively, and their migration was assayed using wound-healing and cell scattering assays, with/without HGF. HGF/c-Met signaling was assayed using phospho-specific antibodies. RESULTS: HGF-stimulated cultured tubular cells from UA-treated rats showed better survival after UA exposure and higher proliferation and migration than cells from vehicle-treated rats. Furthermore, HGF induced higher phosphorylation of c-Met (Tyr1234/1235) and of its major downstream signals (AKT and extracellular signal-regulated kinase 1/2) with maintained dephosphorylation of Ser985 as a negative regulator of HGF/c-Met signaling in the tubular cells of UA-treated rats compared to those of vehicle-treated rats. Immunohistochemically, dephosphorylated Ser985 was confirmed in PT cells in vivo. CONCLUSIONS: These results suggest that elevated sensitivity to HGF, via dephosphorylated Ser985 of c-Met of tubular cells that had recovered from mild tubular injury, may be associated with cytoprotection, accelerated proliferation and migration.

A Diagnostic and Therapeutic Dilemma Concerning Exostosin 1/Exostosin 2-associated Lupus-like Membranous Nephropathy with Positive Antinuclear Antibody in an Elderly Man with Various Immune Abnormalities.

Exostosin 1 (EXT1) and exostosin 2 (EXT2)-associated membranous nephropathy (MN) may be associated with active autoimmune disease. We encountered an elderly man who presented with EXT1/EXT2-associated lupus-like MN with full house immune deposits, monoclonal gammopathy of uncertain significance and Sjögren's syndrome. The patient exhibited various other immune abnormalities. Although he did not fulfill the criteria of clinical systemic lupus erythematosus (SLE), he met a stand-alone renal criterion of the Systemic Lupus International Collaborating Clinics (SLICC) 2012. Whether or not a stand-alone renal criterion with EXT1/EXT2 positivity, as in the present patient, can efficiently guide decisions regarding the diagnosis and treatment of SLE remains a clinical dilemma.

Prevalence of neural epidermal growth factor-like 1- and exostosin 1/exostosin 2-associated membranous nephropathy: a single-center retrospective study in Japan.

Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. We previously reported that the prevalence of phospholipase A2 receptor (PLA2R)- and thrombospondin type 1 domain containing 7A (THSD7A)-associated MN patients in Japan is 52.7% and 9.1%, respectively. In addition to PLA2R and THSD7A, we assessed the presence of newly discovered target antigens, neural epidermal growth factor-like 1 (NELL-1), semaphorin 3B (SEMA3B), and exostosin 1/exostosin 2 (Ext1/Ext2), in renal specimens from patients with primary and secondary MN by immunohistochemistry. We found enhanced glomerular staining of PLA2R, THSD7A, NELL-1, and Ext1/Ext2 in 53.6%, 8.7%, 1.5%, and 13.0% of the renal samples, respectively, in patients with primary MN. None of the patient specimens showed enhanced staining of SEMA3B. Enhanced glomerular staining of PLA2R, NELL-1, and Ext1/Ext2 was detected in 5.7%, 8.6%, and 22.9% of the patients with secondary MN, respectively. Based on our findings, we recommend the assessment of PLA2R, THSD7A and NELL-1 in addition to clinical information and IgG4 staining to differentiate between primary and secondary MN. This would aid in distinguishing secondary MN patients from primary MN patients who coincidentally have some secondary characteristics.

A Case of M-Type Phospholipase A2 Receptor-Associated Membranous Nephropathy With IgG4-Positive Cells Infiltration in the Interstitium.

A 70-year-old man was referred to our department for evaluation of nephrotic syndrome. Renal biopsy revealed membranous nephropathy (MN). Immunohistochemical analysis demonstrated IgG4-positive staining in the glomeruli and interstitial cells. The presence of serum anti-phospholipase A2 receptor (PLA2R) antibody and enhanced staining of PLA2R in the glomeruli was noted. Computed tomography unidentified the extrarenal lesions of IgG4-related disease. He was diagnosed with PLA2R-associated MN possibly complicated with IgG4 related kidney disease (IgG4-RKD). Storiform fibrosis, a typical manifestation of IgG4-RKD, was not apparent. We herein describe a case of serologically and histologically confirmed PLA2R-associated MN with IgG4+ cell infiltration into the interstitium without any signs of IgG4-RD.

Positive relationships between annual changes in salt intake and plasma B-type natriuretic peptide levels in the general population without hypertension and heart diseases.

Excessive salt intake causes hypertension and heart diseases. B-type natriuretic peptide (BNP) is a surrogate marker of heart disease, and a slightly elevated BNP level is associated with a poor prognosis. Our previous cross-sectional study demonstrated that plasma BNP has a significant positive association with daily salt intake in the general population. However, the relationship between changes in salt intake and changes in plasma BNP remains unknown. We recruited 3051 participants without hypertension or electrocardiogram abnormalities who underwent annual health check-ups for two consecutive years. Clinical parameters, including plasma BNP, were obtained, and daily salt intake was evaluated using urinary samples. Annual changes in these parameters were calculated. The median plasma BNP level was 12.9 pg/mL, and the daily salt intake was 8.73 ± 1.89 g. The annual changes in plasma BNP and daily salt intake were 4.79 ± 36.38% and 2.01 ± 21.80%, respectively. Participants in the highest quartile of annual changes in daily salt intake showed the largest annual changes in plasma BNP. Annual changes in plasma BNP indicated a significant positive association with daily salt intake. Moreover, multiple linear regression analyses revealed that annual changes in plasma BNP showed a significant positive association with daily salt intake after adjustments. Our study showed a significant positive relationship between annual changes in plasma BNP and annual changes in daily salt intake. The suppression of plasma BNP is therefore induced by salt intake restriction. The monitoring of plasma BNP while reducing salt intake may therefore prevent heart diseases and lead to improved prognoses in the general population without heart diseases.