A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury.

Reactive oxygen species (ROS) modulate sphingolipid metabolism, including enzymes that generate ceramide and sphingosine-1-phosphate (S1P), and a ROS-antioxidant rheostat determines the metabolism of ceramide-S1P. ROS induce ceramide production by activating ceramide-producing enzymes, leading to apoptosis, while they inhibit S1P production, which promotes survival by suppressing sphingosine kinases (SphKs). A ceramide-S1P rheostat regulates ROS-induced mitochondrial dysfunction, apoptotic/anti-apoptotic Bcl-2 family proteins and signaling pathways, leading to apoptosis, survival, cell proliferation, inflammation and fibrosis in the kidney. Ceramide inhibits the mitochondrial respiration chain and induces ceramide channel formation and the closure of voltage-dependent anion channels, leading to mitochondrial dysfunction, altered Bcl-2 family protein expression, ROS generation and disturbed calcium homeostasis. This activates ceramide-induced signaling pathways, leading to apoptosis. These events are mitigated by S1P/S1P receptors (S1PRs) that restore mitochondrial function and activate signaling pathways. SphK1 promotes survival and cell proliferation and inhibits inflammation, while SphK2 has the opposite effect. However, both SphK1 and SphK2 promote fibrosis. Thus, a ceramide-SphKs/S1P rheostat modulates oxidant-induced kidney injury by affecting mitochondrial function, ROS production, Bcl-2 family proteins, calcium homeostasis and their downstream signaling pathways. This review will summarize the current evidence for a role of interaction between ROS-antioxidants and ceramide-SphKs/S1P and of a ceramide-SphKs/S1P rheostat in the regulation of oxidative stress-mediated kidney diseases.

Impact of Inflammation on Ferritin, Hepcidin and the Management of Iron Deficiency Anemia in Chronic Kidney Disease.

Iron deficiency anemia (IDA) is a major problem in chronic kidney disease (CKD), causing increased mortality. Ferritin stores iron, representing iron status. Hepcidin binds to ferroportin, thereby inhibiting iron absorption/efflux. Inflammation in CKD increases ferritin and hepcidin independent of iron status, which reduce iron availability. While intravenous iron therapy (IIT) is superior to oral iron therapy (OIT) in CKD patients with inflammation, OIT is as effective as IIT in those without. Inflammation reduces predictive values of ferritin and hepcidin for iron status and responsiveness to iron therapy. Upper limit of ferritin to predict iron overload is higher in CKD patients with inflammation than in those without. However, magnetic resonance imaging studies show lower cutoff levels of serum ferritin to predict iron overload in dialysis patients with apparent inflammation than upper limit of ferritin proposed by international guidelines. Compared to CKD patients with inflammation, optimal ferritin levels for IDA are lower in those without, requiring reduced iron dose and leading to decreased mortality. The management of IDA should differ between CKD patients with and without inflammation and include minimization of inflammation. Further studies are needed to determine the impact of inflammation on ferritin, hepcidin and therapeutic strategy for IDA in CKD.

Optimal Serum Ferritin Levels for Iron Deficiency Anemia during Oral Iron Therapy (OIT) in Japanese Hemodialysis Patients with Minor Inflammation and Benefit of Intravenous Iron Therapy for OIT-Nonresponders.

Background: We determined optimal serum ferritin for oral iron therapy (OIT) in hemodialysis (HD) patients with iron deficiency anemia (IDA)/minor inflammation, and benefit of intravenous iron therapy (IIT) for OIT-nonresponders. Methods: Inclusion criteria were IDA (Hb <120 g/L, serum ferritin <227.4 pmol/L). Exclusion criteria were inflammation (C-reactive protein (CRP) ≥ 5 mg/L), bleeding, or cancer. IIT was withheld >3 months before the study. ΔHb ≥ 20 g/L above baseline or maintaining target Hb (tHB; 120-130 g/L) was considered responsive. Fifty-one patients received OIT (ferrous fumarate, 50 mg/day) for 3 months; this continued in OIT-responders but was switched to IIT (saccharated ferric oxide, 40 mg/week) in OIT-nonresponders for 4 months. All received continuous erythropoietin receptor activator (CERA). Hb, ferritin, hepcidin-25, and CERA dose were measured. Results: Demographics before OIT were similar between OIT-responders and OIT-nonresponders except low Hb and high triglycerides in OIT-nonresponders. Thirty-nine were OIT-responders with reduced CERA dose. Hb rose with a peak at 5 months. Ferritin and hepcidin-25 continuously increased. Hb positively correlated with ferritin in OIT-responders (r = 0.913, p = 0.03) till 5 months after OIT. The correlation equation estimated optimal ferritin of 30-40 ng/mL using tHb (120-130 g/L). Seven OIT-nonresponders were IIT-responders. Conclusions: Optimal serum ferritin for OIT is 67.4-89.9 pmol/L in HD patients with IDA/minor inflammation. IIT may be a second line of treatment for OIT-nonreponders.

Role of Hepcidin-25 in Chronic Kidney Disease: Anemia and Beyond.

Iron is an essential element for all living organisms, but produces toxic oxidants. Thus, iron homeostasis is tightly regulated in mammals. Hepcidin-25 (hepcidin) has emerged as a molecule that regulates iron metabolism. Binding of hepcidin to its receptor, ferroportin, inhibits intestinal iron absorption and iron efflux from hepatocytes and macrophages. Decreased hepcidin enhances iron absorption and efflux. Hepcidin could be predictive of iron status and the response to iron supplementation or erythropoietin-stimulating agents. Monitoring hepcidin is helpful for the management of anemia. Thus, it is urgent to obtain normal reference values in a large population of healthy subjects and to standardize various hepcidin assays, which enables to compare the data measured by different methods. Anemia is an important and common problem associated with chronic kidney disease (CKD), which is caused by erythropoietin deficiency, iron-restricted erythropoiesis, inflammation, hypoxia, vitamin D deficiency, hyperparathyroidism, and obesity. Anemia causes poor quality of life, progression of CKD, increased risk of cardiovascular events, and mortality. Besides its role in anemia, recent evidence suggests that hepcidin-25 plays a role in the pathogenesis and progression of kidney injury via modulation of iron-mediated oxidant injury. Despite accumulating experimental data, information about clinical significance of hepcidin-25 for anemia and kidney injury in CKD patients is scarce, especially in children. This review summarizes the current knowledge of the role of hepcidin-25 in the regulation of anemia and kidney injury in children and adults with CKD. Strategy for modulating hepcidin-25 to prevent anemia and kidney injury associated with CKD is also discussed.

Sphingolipids in Genetic and Acquired Forms of Chronic Kidney Diseases.

Sphingolipids (SLs) regulate apoptosis, proliferation, and stress response. SLs, including ceramide, glycosphingolipids (glucosylceramide, lactosylceramide, and gangliosides) and sphingosine-1-phosphate (S1P), play a role in the pathogenesis and progression of genetic (lysosomal storage disease, congenital nephrotic syndrome and polycystic kidney disease) and non-genetic forms of chronic kidney diseases (CKDs). SLs metabolism defects promote complications (cardiovascular events, etc.) via oxidant stress in CKDs. A balancing role of apoptotic SLs and anti-apoptotic S1P is crucial in the regulation of glomerular injury and complications associated with CKDs. Interaction between SLs, endothelial function and reninangiotensin- aldosterone system (RAAS) plays an important role in the regulation of glomerular injury. SLs affect mitochondrial function that regulate the opening of mitochondrial permeability transition (MPT) pore, mitochondrial outer membrane permeability (MOMP), generation of reactive oxygen species (ROS), and expression of BcL-2 family proteins, which result in cytochrome c release and caspase activation, leading to apoptosis, and regulate glomerular cell proliferation or renal fibrosis. This review article summarizes the current evidence supporting a role of SLs metabolism defects in the pathogenesis and progression of glomerular injury and discusses a role of mitochondria, including MPT pore, MOMP, ROS generation, BcL-2 family proteins, interaction between SLs, endothelial function and RAAS, and SLs-induced downstream signaling events in CKDs. Crosstalk between these factors plays a role in the pathogenesis and progression of CKDs. Therapeutic strategy of targeting SLs metabolism defects for CKDs through modulation of the enzymes responsible for SLs metabolism defects is also discussed.

Mycoplasma pneumoniae-associated mild encephalitis/encephalopathy with a reversible splenial lesion: report of two pediatric cases and a comprehensive literature review.

BACKGROUND: No literature review exists on Mycoplasma pneumoniae-associated mild encephalitis/encepharopathy with a reversible splenial lesion (MERS). METHODS: M.pneumoniae-associated MERS cases were searched till August 2016 using PubMed/Google for English/other-language publications and Ichushi ( http://www.jamas.or.jp/ ) for Japanese-language publications. Inclusion criteria were children fulfilling definition for encephalitis, M.pneumoniae infection, and neuroimaging showing hyperintensity in the splenium of the corpus callosum (SCC) alone (type I) or SCC/other brain areas (type II). RESULTS: We described two children with type I and II M.pneumoniae-associated MERS. Thirteen cases found by the search and our 2 cases were reviewed. Mean age, male/female ratio, duration of prodromal illness was 8.3 years, 1.5 and 3.5 days. The most common neurological symptom was drowsiness, followed by abnormal speech/behavior, ataxia, seizure, delirium, confusion, tremor, hallucination, irritability, muscle weakness, and facial nerve paralysis. Fever was the most common non-neurological symptom, followed by cough, headache, gastrointestinal symptoms, headache, lethargy and dizziness. Seizure and respiratory symptoms were less common. All were diagnosed for M.pneumoniae by serology. Cerebrospinal fluid (CSF) M.pneumoniae was undetectable by PCR in the 3 patients. Three patients were clarithromycin-resistant. Leukocytosis, positive C-reactive protein, hyponatremia, CSF pleocytosis and slow wave on electroencephalography frequently occurred. All except 2 were type I MERS. Neuroimaging abnormalities disappeared within 18 days in the majority of patients. All type I patients completely recovered within 19 days. Two type II patients developed neurological sequelae, which recovered 2 and 6 months after onset. CONCLUSIONS: Prognosis of M.pneumoniae-associated MERS is excellent. Type II MERS may increase a risk of neurological sequelae.

Gastroduodenal Perforation and Ulcer Associated With Rotavirus and Norovirus Infections in Japanese Children: A Case Report and Comprehensive Literature Review.

Background. There is no literature review on gastroduodenal perforation or ulcer (GDPU) with rotavirus (RV) and norovirus (NoV) gastroenteritis. Methods. Pediatric cases of GDPU or upper gastrointestinal bleeding with RV and NoV gastroenteritis were searched from September 1974 until October 2015 using PubMed, Google for English, other-language-publications, and Ichushi (http://www.jamas.or.jp) for Japanese-language publications. All reports confirming GDPU or upper gastrointestinal bleeding with RV and NoV gastroenteritis were eligible for inclusion in the study. In addition, clinical characteristics were reviewed. Results. A boy with duodenal ulcer (DU) and NoV gastroenteritis was described. There were 32 GDPU cases (23 RVs and 9 NoVs cases), including our case; with the exception of 1 case, all were Japanese. Mean age, male/female ratio, and symptoms' duration before admission were 21.6 months, 2.2, and 4.0 days, respectively. Vomiting was the most common symptom, followed by diarrhea, lethargy, fever, abdominal distension, and convulsion. Dehydration, hematemesis, melena, drowsiness or unconsciousness, shock, metabolic acidosis, leukocytosis, anemia, positive C-reactive protein, high blood urea nitrogen, and hyponatremia commonly occurred. Helicobacter pylori was a minor cause of GDPU. Duodenal (DP) or gastric perforation (GP) developed in 14 cases (10 DP/RVs, 1 GP/RV, and 3 DP/NoVs). Duodenal ulcer or gastric ulcer (GU) developed in 18 cases (10 DU/RVs, 4 DU/NoVs, 1 GU/RV, 1 GU + DU/NoV, and 2 upper gastrointestinal bleeding/RVs). The predominant perforation or ulcer site was in the duodenum. With the exception of 2 deaths from DU, all cases recovered. Conclusions. Race, young age, male, severe dehydration, metabolic acidosis, drowsiness and unconsciousness, and shock may be potential risk factors of GDPU associated with RV and NoV gastroenteritis. Limitation of this descriptive study warrants further investigations to determine the risk factors in these infections that could be associated with GDPU.

Ceramide-induced apoptosis in renal tubular cells: a role of mitochondria and sphingosine-1-phoshate.

Ceramide is synthesized upon stimuli, and induces apoptosis in renal tubular cells (RTCs). Sphingosine-1 phosphate (S1P) functions as a survival factor. Thus, the balance of ceramide/S1P determines ceramide-induced apoptosis. Mitochondria play a key role for ceramide-induced apoptosis by altered mitochondrial outer membrane permeability (MOMP). Ceramide enhances oligomerization of pro-apoptotic Bcl-2 family proteins, ceramide channel, and reduces anti-apoptotic Bcl-2 proteins in the MOM. This process alters MOMP, resulting in generation of reactive oxygen species (ROS), cytochrome C release into the cytosol, caspase activation, and apoptosis. Ceramide regulates apoptosis through mitogen-activated protein kinases (MAPKs)-dependent and -independent pathways. Conversely, MAPKs alter ceramide generation by regulating the enzymes involving ceramide metabolism, affecting ceramide-induced apoptosis. Crosstalk between Bcl-2 family proteins, ROS, and many signaling pathways regulates ceramide-induced apoptosis. Growth factors rescue ceramide-induced apoptosis by regulating the enzymes involving ceramide metabolism, S1P, and signaling pathways including MAPKs. This article reviews evidence supporting a role of ceramide for apoptosis and discusses a role of mitochondria, including MOMP, Bcl-2 family proteins, ROS, and signaling pathways, and crosstalk between these factors in the regulation of ceramide-induced apoptosis of RTCs. A balancing role between ceramide and S1P and the strategy for preventing ceramide-induced apoptosis by growth factors are also discussed.

Schizophyllum commune-induced allergic fungal rhinosinusitis and sinobronchial mycosis.

We present 32- and 38-year-old males with Schizophyllum commune-induced allergic fungal rhinosinusitis (AFRS). S. commune-induced AFRS was diagnosed by clinical and radiographic findings, positive specific IgE antibodies against S. commune as measured by the ImmunoCAP system, and sequencing analysis of the fungus. Our two cases with S. commune-induced AFRS for the first time showed evidence for type 1 hypersensitivity to S. commune as determined by using specific IgE antibodies against S. commune, and the fungus was identified by sequence analysis.

Long-term outcome of pediatric renal transplantation: a single center study in Japan.

Little is known about the risk factors for long-term poor outcome in pediatric renal transplantation. Between 1973 and 2010, 111 renal transplants (92 living donations) were performed in 104 children (56 males, mean age, 12.5 yr) at the Social Insurance Chukyo Hospital, and followed-up for a mean period of 13.6 yr. The patient survival at 1, 5, 10, 15, 20 (living- and deceased-donor transplants), and 30 yr (living-donor transplants only) was 98.1%, 92.8%, 87.8%, 84.9%, 82.6%, and 79.3%. The graft survival at 1, 5, 10, 15, 20, and 30 yr was 92.0%, 77.3%, 58.4%, 50.8%, 38.5%, and 33.3%. The most common cause of graft loss was CAI, AR, death with functioning, recurrent primary disease, ATN, and malignancy. Donor gender, ATN, malignancy/cardiovascular events, and eras affected patient survival. AR and CAI were the risk factors for graft loss. The evolved immunosuppression protocols improved the outcome by reducing AR episodes and ATN but not CAI, suggesting CAI as the major risk factor for graft loss. CAI was correlated with AR episodes, CMV infection, and post-transplant hypertension. Strategies for preventing the risk factors for malignancy/cardiovascular events and CAI, including hypertension/infection, are crucial for better outcomes.

Regulation of Hepcidin-25 by Short- and Long-Acting rhEPO May Be Dependent on Ferritin and Predict the Response to rhEPO in Hemodialysis Patients.

BACKGROUND/AIMS: We examined whether regulation of hepcidin-25 by short- or long-acting recombinant human erythropoietin (rhEPO) is dependent on ferritin and predicts the response to rhEPO in hemodialysis (HD) patients. METHODS: Two studies with rhEPO were performed in 9 HD patients with a 2-year interval. Serum hepcidin-25 was measured at 0-18 h after intravenous epoetin-ß (EPO) or methoxy polyethylene glycol-epoetin-ß (PEG-EPO) administration and on days 3-7 after PEG-EPO. Hemoglobin (Hb), serum ferritin, transferrin, C-reactive protein (CRP), and interleukin (IL)-6 were analyzed before hepcidin measurement and 6 months after rhEPO. Based on the serum ferritin levels before hepcidin measurement, the patients in the two studies with EPO or PEG-EPO were combined into low (11; serum ferritin of <15.0 ng/ml) and high ferritin groups (7; serum ferritin of ≥15.0 ng/ml). The response of hepcidin-25 to rhEPO and the effect of rhEPO on anemia were compared between the groups. RESULTS: The serum hepcidin-25 levels rose at 6-9 h and returned to the baseline at 18 h after EPO. They rose at 6-9 h, returned to the baseline at 18 h, and decreased on day 5-7 after PEG-EPO. Serum hepcidin-25 levels were low (<5.0 ng/ml) in the low ferritin group, but rose at 6-9 h after rhEPO in the high ferritin group. Serum transferrin levels were similar, and CRP and IL-6 were normal in both groups. Hb tended to increase in the low ferritin group, but it significantly decreased in the high ferritin group after rhEPO. CONCLUSION: Regulation of hepcidin-25 by rhEPO may be dependent on ferritin, affecting the response to rhEPO in HD patients.

Hepcidin-25, mean corpuscular volume, and ferritin as predictors of response to oral iron supplementation in hemodialysis patients.

The benefit of oral iron therapy (OIT) and factors predictive of OIT response are not established in hemodialysis (HD) patients with iron deficiency anemia (IDA). We examined the values of hepcidin-25, mean corpuscular volume (MCV), and ferritin as predictors of OIT response. Oral ferrous fumarate (50 mg/day, 8 weeks) was given to 51 HD patients with IDA (hemoglobin (Hb) < 12 g/dL, ferritin < 100 ng/mL) treated with an erythropoietin activator. Sixteen patients were responders (improvement of Hb (ΔHb) ≥ 2 g/dL) and 35 were non-responders (ΔHb < 2g/dL). Baseline Hb, MCV, serum hepcidin-25, ferritin, iron parameters, and C-reactive protein (CRP) before and ΔHb after OIT were compared between groups. Hepcidin-25, MCV, ferritin, and transferrin saturation were lower in the responders than in the non-responders. Hepcidin-25 positively correlated with ferritin. Hepcidin-25, MCV, and ferritin positively correlated with baseline Hb and negatively correlated with ΔHb. Despite normal CRP levels in all patients, CRP correlated positively with hepcidin-25 and ferritin. Stepwise multiple linear regression analysis and receiver operating characteristics curve analysis revealed that hepcidin-25, MCV, and ferritin could predict OIT response. We conclude that hepcidin-25, MCV, and ferritin could be useful markers of iron storage status and may help predict OIT response in HD patients.

Role of mitochondrial Bax, caspases, and MAPKs for ceramide-induced apoptosis in renal proximal tubular cells.

It remains elusive whether crosstalk exists among mitochondrial Bax, caspases, and mitogen-activated protein kinases (MAPKs), and whether epidermal growth factor (EGF), which may activate MAPKs, affects ceramide-induced apoptosis through the crosstalk in renal proximal tubular cells (RPTCs). Effect of ceramide on expression of mitochondrial Bax and phosphorylated (p)-ERK, p38MAPK and JNK, that of MAPKs inhibition, and of EGF in the presence or absence of MAPKs inhibition on ceramide-induced apoptosis were examined in HK-2 cells. Apoptosis and expression of mitochondrial Bax and p-MAPKs were measured by Hoechst 33258 staining and Western blotting. C2-ceramide, but not dihydroC2-ceramide, inactive C2-ceramide, induced apoptosis at 24 h. C2-ceramide enhanced the mitochondrial Bax expression at 1 h, which was peaked at 3-6 h and decreased at 24 h, but remained increased, compared to control. An inhibitor of caspases, zVAD-fmk, ameliorated ceramide-induced apoptosis, suggesting a role of caspases for ceramide-induced apoptosis. C2-ceramide enhanced the expression of p-ERK and p-p38MAPK, but not p-JNK, at 1 h, which was increased till 24 h. An inhibitor of ERK, PD98059, or of p38MAPK, SB202190, failed to affect C2-ceramide-induced apoptosis. EGF, which enhanced the expression of p-ERK and p-p38MAPK but not p-JNK, ameliorated C2-ceramide-induced apoptosis without affecting mitochondrial Bax. Inhibition of ERK or p38MAPK failed to abolish the protective effect of EGF on C2-ceramide-induced apoptosis. Mitochondrial Bax and caspases, but not MAPKs, play a role for ceramide-induced apoptosis in RPTCs. EGF ameliorates ceramide-induced apoptosis in Bax- and MAPKs-independent pathways. The mechanism of ceramide-induced apoptosis and anti-apoptotic effect of EGF deserves further investigations.

Duodenal perforation associated with norovirus and rotavirus gastroenteritis.

KEY CLINICAL MESSAGE: Norovirus (NoV) and rotavirus (RV) gastroenteritis are usually self-limiting. However, few pediatric cases of bowel perforation and no duodenal perforation with NoV gastroenteritis were reported. We describe two children with duodenal perforation due to NoV or RV gastroenteritis. Suspicion for this association enables prompt intervention, preventing lethal outcomes of these common infections.

Recurrent posterior reversible encephalopathy syndrome in nephrotic syndrome: case report and review of the literature.

Sequential neuroimaging before and after seizures has not been reported in patients with nephrotic syndrome and recurrent posterior reversible encephalopathy syndrome (PRES). We report a 13-year-old nephrotic female patient with recurrent PRES during and after cessation of cyclosporine A (CyA). She had headache, visual disturbance and acute hypertension, followed by seizures. The brain magnetic resonance imaging (MRI) before seizures revealed a high signal intensity area on fluid-attenuated inversion recovery and diffusion-weighted images and a low signal intensity area on T1-weighted images in bilateral parieto-occipital and left temporal lobes. Cessation of CyA resulted in clinical improvement. The follow-up MRI 2 months after the initial episode showed a complete resolution. Six months later, she had similar symptoms, edema, severe hypoalbuminemia, renal insufficiency, and acute pancreatitis before seizures. The brain MRI after seizures showed similar abnormalities in the same regions, which completely resolved 2 months later. Recurrence of acute severe hypertension, nephrotic state (edema/ hypoalbuminemia), and renal insufficiency may lead to recurrent PRES and thus early treatment of trigger factors, especially of hypertension, is important to reduce the episodes of PRES.

Age and gender may affect posterior reversible encephalopathy syndrome in renal disease.

It remains elusive what factors affect posterior reversible encephalopathy syndrome (PRES). Eleven PRES children, all with acute glomerulonephritis, Alport syndrome, and lupus nephritis, 5 with nephrosis, and 3 renal transplant recipients, were studied. PRES recurred in 1 patient. Neurological symptoms were graded as 1: mild (headache, nausea/vomiting, or tremor), 2: moderate (vision change), and 3: severe (mental dysfunction, cerebellar symptoms, seizures, recurrence of seizures, and coma). Magnetic resonance imaging was graded as 1: subtle change, 2: abnormal large areas, and 3: complete involvement of the regions. The common symptoms were seizures (100%), headache (82%), nausea/vomiting (73%), coma (55%), and vision change (46%). Seizures recurred in 7 (64%). All but one (91%) developed hypertension and 7 (64%) received calcineurin inhibitors (CNI). Edema occurred in 7 (64%) and renal insufficiency/end-stage renal disease (ESRD) in 4 (36%). Seizures recurred frequently in younger patients. Symptoms were severe in girls. Duration or severity of the condition with predisposing factors (hypertension, CNI, nephrosis or renal insufficiency/ERSD) did not make a difference in the symptoms and neuroimaging. Two patients developed chronic epilepsy. Age and gender may affect PRES symptoms. Our results are limited by small sample size and should be determined using larger numbers of patients.

V2 vasopressin receptor (V2R) mutations in partial nephrogenic diabetes insipidus highlight protean agonism of V2R antagonists.

Inactivating mutations of the V2 vasopressin receptor (V2R) cause cross-linked congenital nephrogenic diabetes insipidus (NDI), resulting in renal resistance to the antidiuretic hormone AVP. In two families showing partial NDI, characterized by an apparently normal response to diagnostic tests and an increase in the basal ADH levels suggesting AVP resistance, we have identified two V2R mutations, Ser-333del and Y128S. Both mutant V2Rs, when expressed in COS-7 cells, show partial defects in vasopressin-stimulated cAMP accumulation and intracellular localization. The inhibition of internalization does not rescue their localization. In contrast, the non-peptide V2R antagonists OPC41061 and OPC31260 partially rescue the membrane localization and basal function of these V2R mutants, whereas they inhibit the basal activity of the wild-type V2R. These results indicate that a partial loss of function of Ser-333del and Y128S mutant V2Rs results from defective membrane trafficking. These findings further indicate that V2R antagonists can act as protean agonists, serving as pharmacological chaperones for inactivating V2R mutants and also as inverse agonists of wild-type receptors. We speculate that this protean agonism could underlie the possible dual beneficial effects of the V2R antagonist: improvement of hyponatremia with heart failure or polycystic kidney disease and potential rescue of NDI.

Hyperinsulinemia may promote growth without GH in children after resection of suprasellar brain tumors.

It remains elusive what factors induce growth without growth hormone (GWGH) in children after neurosurgery of brain tumors. Growth velocity and endocrinological data were compared between the patients with and without GWGH. We experienced three patients with GWGH (median, 12 years; 2 germinoma and 1 craniopharyngioma; three females; group 1) and 11 patients without (12 years; 8 craniopharyngioma, 2 germinoma and 1 medulloblastoma; 7 males; group 2) after neurosurgery. All patients in group 2 received GH replacement therapy. Growth velocity and endocrinological data were compared. Median height velocity was normal in group 1 (5.5 cm/year), but low in group 2 (2.2 cm/year), which improved after GH replacement therapy (7.0 cm/year). Median serum insulin level was increased in group 1 (87.0 µU/ml, P < 0.05) compared with normal level in group 2 (10.0 µU/ml). Despite hyperinsulinemia, serum glucose level was normal in group 1. Three of 5 with hyperinsulinemia and 2 of 9 without were obese or overweight, but the difference was not significant. Current body mass index and serum levels of IGF-1, IGFBP-3, leptin, and prolactin were similar between groups. Serum estradiol was prepuberty level in group 1. Hyperinsulinemia may induce GWGH in children with brain tumors after neurosurgery.