Hepatectomy-Related Hypophosphatemia: A Novel Phosphaturic Factor in the Liver-Kidney Axis

Marked hypophosphatemia is common after major hepatic resection, but the pathophysiologic mechanism remains unknown. We used a partial hepatectomy (PH) rat model to investigate the molecular basis of hypophosphatemia. PH rats exhibited hypophosphatemia and hyperphosphaturia. In renal and intestinal brush-border membrane vesicles isolated from PH rats, Na⁺-dependent phosphate (Pi) uptake decreased by 50%–60%. PH rats also exhibited significantly decreased levels of renal and intestinal Na⁺-dependent Pi transporter proteins (NaPi-IIa [NaPi-4], NaPi-IIb, and NaPi-IIc). Parathyroid hormone was elevated at 6 hours after PH. Hyperphosphaturia persisted, however, even after thyroparathyroidectomy in PH rats. Moreover, DNA microarray data revealed elevated levels of nicotinamide phosphoribosyltransferase (Nampt) mRNA in the kidney after PH, and Nampt protein levels and total NAD concentration increased significantly in the proximal tubules. PH rats also exhibited markedly increased levels of the Nampt substrate, urinary nicotinamide (NAM), and NAM catabolites. In vitro analyses using opossum kidney cells revealed that NAM alone did not affect endogenous NaPi-4 levels. However, in cells overexpressing Nampt, the addition of NAM led to a marked decrease in cell surface expression of NaPi-4 that was blocked by treatment with FK866, a specific Nampt inhibitor. Furthermore, FK866-treated mice showed elevated renal Pi reabsorption and hypophosphaturia. These findings indicate that hepatectomy-induced hypophosphatemia is due to abnormal NAM metabolism, including Nampt activation in renal proximal tubular cells.Inorganic phosphate (Pi) absorption in the renal proximal tubules and small intestine is important for Pi homeostasis.¹ The Na⁺-dependent Pi (Na/Pi) transport system includes type IIa and type IIc Na/Pi transporters, which are localized in the apical membrane of the proximal tubular cells, and type IIb Na/Pi transporters, which are localized in the apical membrane of the intestinal epithelial cells.^1,2 Pi (re)absorption is regulated by the dietary Pi content, parathyroid hormone (PTH), and the active metabolite of vitamin D, 1α, 25-dihydroxyvitamin D3 [1,25(OH)₂D₃].³ Other phosphaturic hormones, termed phosphatonins, also control renal Pi handling.⁴ The discovery that fibroblast growth factor (FGF) 23, the first identified phosphatonin,⁵ originated from osteocytes established the concept of the bone-kidney axis.^6,7The incidence of liver transplantation has steadily increased and the incidence of partial hepatectomy (PH) has also consequently increased.⁸ Hypophosphatemia frequently occurs after liver resection.^9–11 Acute hypophosphatemia causes septicemia and is associated with a poor prognosis.^11,12 Acute hypophosphatemia is of considerable clinical relevance because many hepatectomized patients develop marked hypophosphatemia and, thus, large doses of Pi replacement are required to maintain metabolic homeostasis.¹³ Urinary Pi excretion is markedly increased in many patients. After hepatectomy, hypophosphatemia is associated with hyperphosphaturia.¹³For many years, the increased metabolic demand of the regenerating liver was considered the underlying pathologic mechanism of hypophosphatemia. The magnitude of Pi uptake by the recovering liver, however, cannot explain the severity of the resulting hypophosphatemia.¹¹ Hepatectomy-induced hypophosphatemia is associated with an increased renal fractional excretion index for Pi unrelated to intact FGF23, FGF7, or secreted frizzled-related protein 4 as a phosphaturic factor,¹⁴ indicating that other factors have a role in the pathogenesis of hypophosphatemia.Nicotinamide (NAM) inhibits intestinal and renal Na/Pi transport activity in normal rats.^15–17 Administration of NAM to rats produces a specific dose-dependent inhibition of Na/Pi transport across the renal brush-border membrane (BBM) and an increase in urinary Pi excretion.^16,17 NAM suppresses hyperphosphatemia in hemodialysis patients.¹⁸ Nicotinamide phosphoribosyltransferase (Nampt) catalyzes the first rate-limiting step in converting NAM to NAD,^19,20 which is essential for cellular metabolism, energy production, and DNA repair.^20–22 Nampt exists in two known forms: intracellular Nampt (iNampt) and secreted extracellular Nampt (eNampt).²³ eNampt also generates an intermediate product, nicotinamide mononucleotide (NMN).²³Our findings indicate that the acceleration of NAM metabolism through Nampt function in the kidney is involved in the hepatectomy-induced hypophosphatemia in rodent models. This study also suggests that NAM metabolism through the liver-kidney axis is important in Pi homeostasis.     

Mouse lacking COUP-TFII as an animal model of Bochdalek-type congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH), a life-threatening anomaly, is a major cause of pediatric mortality. Although the disease was described >350 years ago, the etiology of CDH is poorly understood. Here, we show that tissue-specific null mutants of COUP-TFII exhibit Bochdalek-type CDH, the most common form of CDH. COUP-TFII, a member of orphan nuclear receptors, is expressed in regions critical for the formation of the diaphragm during embryonic development. Ablation of COUP-TFII in the foregut mesenchyme, including the posthepatic mesenchymal plate (PHMP), results in the malformation of the diaphragm and the failure of appropriate attachment of the PHMP to the body wall. Thus, both the stomach and liver enter the thoracic cavity, leading to lung hypoplasia and neonatal death. Recently a minimally deleted region for CDH has been identified on chromosome 15q26.1-26.2 by CGH array and FISH analysis. COUP-TFII is one of the four known genes residing within this critical region. Our finding suggests that COUP-TFII is a likely contributor to the formation of CDH in individuals with 15q deletions, and it may also be a potential contributor to some other Bochdalek-type of CDH.     

Prognostic value and interobserver agreement of endoscopic ultrasonography for superficial squamous cell carcinoma of the esophagus: a prospective study

Background and Aims. Submucosal invasion of superficial esophageal cancer (SEC) is related to the prognosis. We prospectively analyzed outcomes of SEC in patients staged by endoscopic ultrasonography (EUS). Patients and Methods. We staged 31 endoscopically diagnosed SEC cases using a 20/15-MHz thin probe. The EUS tumor stage was classified as EUSM (limited within mucosa), EUS-SM (with submucosal invasion), or EUS-MP over (invading the muscularis propria or deeper). Lymph node metastasis and 2-yr survival were analyzed according to the EUS tumor stage in 29 squamous cell carcinoma cases. Interobserver agreement of the EUS stage was tested between the examiner and a blind reviewer. Results. Lymph node metastasis was significantly frequent in the EUS-SM group (8 of 18 cases [44.4%]) compared with the EUS-M group (1 of 10 cases [10%]) (p=0.03). Patient survival at 2 yr after initial therapy was 72.2% in the EUS-SM group and 90% in the EUS-M group. Death from cancer was noted only in the EUS-SM group (three cases). The accuracy rates of EUS tumor staging were 74.1% by the examiner and 66.7% by the blind reviewer, with moderate interobserver agreement (κ=0.46). Conclusions. Thin-probe EUS can classify SEC into two groups: the EUS-M group with excellent outcome and the EUS-SM group with a significant risk of lymph node metastasis.     

Efficacy of prophylactic extended lymphadenectomy with gastrectomy for patients with node-negative advanced gastric carcinoma

BACKGROUND/AIMS: Extended lymphadenectomy with gastrectomy is widely performed for patients with advanced gastric carcinoma. However, the therapeutic value of prophylactic extensive lymphadenectomy in patients with node-negative advanced gastric cancer is controversial. METHODOLOGY: We retrospectively analyzed 221 patients who underwent curative gastrectomy for advanced gastric carcinoma without lymph node metastasis to evaluate the effect of prophylactic extended lymphadenectomy on postoperative survival. The postoperative survival rate of patients who underwent extended lymphadenectomy was compared with that of patients who underwent limited lymphadenectomy. Predictive risk factors for tumor recurrence and recurrent patterns also were analyzed. RESULTS: Extended lymphadenectomy improved the postoperative survival rate of patients with advanced tumors even when lymph node spread was absent. Whether or not prophylactic extended lymphadenectomy was performed significantly affected tumor recurrence in patients with node-negative advanced gastric carcinoma. CONCLUSIONS: Extensive lymphadenectomy with gastrectomy prolongs survival of patients with node-negative advanced tumors.     

Comparative analysis of different enzyme immunoassays for assessment of phosphatidylserine-dependent antiprothrombin antibodies

Phosphatidylserine-dependent antiprothrombin antibodies (aPS/PT) were strongly correlated with the presence of lupus anticoagulant showing a high specificity for the diagnosis of antiphospholipid syndrome. However, the main criticism for the clinical applicability of aPS/PT testing is the lack of reproducibility of the results among laboratories. In this study, we measured IgG and IgM aPS/PT using our original in-house enzyme-linked immunosorbent assays (ELISA) and commercial ELISA kits to assess the assay performance and to evaluate the accuracy of aPS/PT results. The study included 111 plasma samples collected from patients and stored at our laboratory for aPS/PT assessment. Sixty-one samples were tested for IgG aPS/PT using two assays: (1) aPS/PT in-house ELISA and (2) QUANTA Lite? aPS/PT IgG ELISA kit (INOVA Diagnostics, Inc., USA). Fifty samples were evaluated for IgM aPS/PT using two assays: (1) aPS/PT in-house ELISA and (2) QUANTA Lite? aPS/PT IgM ELISA kit (INOVA Diagnostics). Ninety-eight percent of samples yielded concordant results for IgG aPS/PT and 82 % for IgM aPS/PT. There was an excellent agreement between the IgG aPS/PT assays (Cohen κ = 0.962) and moderate agreement between the IgM aPS/PT assays (κ = 0.597). Statistically significant correlations in the aPS/PT results were obtained from both IgG and IgM aPS/PT assays (r = 0.749, r = 0.622, p < 0.001, respectively). In conclusion, IgG and IgM detection by ELISA is accurate. The performance of aPS/PT is reliable, and concordant results can be obtained using different ELISA methods.     

Use of the GlideScope does not lower the hemodynamic response to tracheal intubation more than the Macintosh laryngoscope: a systematic review and meta-analysis

Background:It is presently unclear whether the hemodynamic response to intubation is less marked with indirect laryngoscopy using the GlideScope (GlideScope) than with direct laryngoscopy using the Macintosh laryngoscope. Thus, the aim of this study was to determine whether using the GlideScope lowers the hemodynamic response to tracheal intubation more than using the Macintosh laryngoscope.Methods:We performed a comprehensive literature search of electronic databases for clinical trials comparing hemodynamic response to tracheal intubation. The primary aim was to determine whether the heart rate (HR) and mean blood pressure (MBP) 60 s after tracheal intubation with the GlideScope were lower than after intubation with the Macintosh laryngoscope. We expressed pooled differences in HR and MBP between the devices as the weighted mean difference with 95% confidence interval and also performed trial sequential analysis (TSA). Second, we examined whether use of the GlideScope resulted in lower post-intubation hemodynamic responses at 120, 180, and 300 s compared with use of the Macintosh laryngoscope. For sensitivity analysis, we used a multivariate random effects model that accounted for within-study correlation of the longitudinal data.Results:The literature search identified 13 articles. HR and MBP at 60 seconds post-intubation was not significantly lower with the GlideScope than with the Macintosh (HR vs MBP: weighted mean difference = 0.22 vs 2.56; 95% confidence interval −3.43 to 3.88 vs −0.82 to 5.93; P = .90 vs 0.14; I² = 77% vs 63%: Cochran Q, 52.7 vs 27.2). Use of the GlideScope was not associated with a significantly lower HR or MBP at 120, 180, or 300 s post-intubation. TSA indicated that the total sample size was over the futility boundary for HR and MBP. Sensitivity analysis indicated no significant association between use of the GlideScope and a lower HR or MBP at any measurement point.Conclusions:Compared with the Macintosh laryngoscope, the GlideScope did not lower the hemodynamic response after tracheal intubation. Sensitivity analysis results supported this finding, and the results of TSA suggest that the total sample size exceeded the TSA monitoring boundary for HR and MBP.     

Crohn’s Disease Successfully Treated With Infliximab in a Patient Receiving Hemodialysis: Case Report and Review of the Literature

There is limited information in the use of antitumor necrosis factor α, infliximab, in patients on hemodialysis. In Crohn’s disease (CD), only 3 cases are reported.A 76-year-old man on hemodialysis for renal failure caused by immunoglobulin A nephropathy developed diarrhea and abdominal pains. A marked edema was observed in the pretibia and ankle. An increase of C-reactive protein (CRP) and erythrocyte sedimentation rate, hypoalbuminemia, hypocholesterolemia, and moderate anemia was found. Ultrasonography and computed tomography (CT) found wall thickness in the left colon. Sigmoidoscopy revealed multiple ulcers in the sigmoid colon and noncaseating epithelioid granuloma was found in the biopsy specimen. Barium enema study exhibited collar button signs and longitudinal ulcers in the left colon.A severe form of CD was diagnosed. Metronidazole seemed to decrease CRP but was ineffective in ameliorating diarrhea. Infliximab rather than steroid hormone was chosen for the treatment. Standard induction therapy with infliximab was initiated. Symptoms rapidly improved then disappeared. CD activity index decreased from 747 to a remission level of 134 after 2 infusions of infliximab. Scheduled maintenance infliximab therapy was administered after the induction therapy. Ultrasonography and CT showed a disappearance of the wall thickness of the colon. Adverse reactions were not observed.Infliximab was effective and safe in a patient with CD on hemodialysis. Our case has added additional literature in accordance with previous reports supporting infliximab as effective and safe in patients on hemodialysis.