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.     

Comparison of scapholunate distance measurements on plain radiography and computed tomography for the diagnosis of scapholunate instability associated with distal radius fracture

Purpose

To investigate radiographic criteria for scapholunate instability (SLI) in the setting of distal radius fracture (DRF) confirmed by arthroscopy.

Methods

Eighty-eight wrists with DRF treated by open reduction and internal fixation and assessed for SLI arthroscopically were evaluated. The scapholunate distance (SLD) was measured by preoperative posteroanterior wrist radiography and computed tomography (CT). SLD on radiographs was measured as the distance between the scaphoid cortex and the lunate cortex at the center of the scapholunate joint. SLDs were measured at the volar end (A1), center (A2), and dorsal end (A3) of the scapholunate joint on the central CT axial slice; and at the proximal end (C1), center (C2), and distal end (C3) of the scapholunate joint on the central CT coronal slice. Wrists were divided into three groups by arthroscopic assessments: stable (normal, Geissler grade 1 or 2), G3 (Geissler grade 3), and G4 (Geissler grade 4). SLD measurements on radiographs and CTs (A1–C3) were compared among the three groups. Receiver-operating characteristic (ROC) curve analyses were performed to evaluate the abilities of SLD measurements on radiographs and CTs to identify SLI in wrists with DRF. Interobserver and intraobserver reliabilities of SLD measurements on radiographs and CTs were analyzed by intraclass correlation coefficients (ICCs).

Results

SLDs of C3 differed significantly among the G3 and G4 groups, and among the stable and G4 groups. The area under the curve on ROC curve analysis was 0.855 for the SLD of C3, which was larger than that for SLD on radiographs. For C3, the intraobserver ICC was 0.832 and interobserver ICC was 0.73.

Conclusions

SLD at the distal end of the scapholunate joint on the central coronal CT slice was the most appropriate measurement for discrimination of Geissler grade 4 SLI in wrists with DRF.

Level of evidence

Level 2     

Three-dimensional computed tomography analysis of variations in the middle hepatic vein tributaries: proposed new classification

Purpose

To evaluate the anatomical variations in the middle hepatic vein tributaries (V5/V8) for determining the reconstruction strategy in right lobe living donor liver transplantation (LDLT).

Methods

The V5/V8 variations were examined in 268 patients and were classified into three and two types, respectively. The reconstruction rate (RR), patency rate (PR) and clinical outcomes were retrospectively evaluated in 46 right lobe LDLT cases.

Results

In terms of V5 variations, the RR and PR were significantly higher for type 2 than type 3 (82.6 vs. 44.4 % and 73.7 vs. 25.0 %, respectively). The alanine aminotransferase level on postoperative day (POD) 5 in the V5 patent group was significantly lower than in the occluded group (123 vs. 191 IU/dL). Regarding V8 variations, the RR and PR were significantly higher for type 1 than type 2 (44.4 vs. 17.6 % and 75.0 vs. 33.3 %, respectively). The aspartate aminotransferase level on POD 3 was significantly lower in the V8 patent group than in the occluded group (50 vs. 121 IU/dL).

Conclusion

For right lobe grafts with single large V5 (type 2) or V8 (type 1) variations, reconstruction is necessary. Our new classification of the MHV tributaries is useful for determining the reconstruction strategy to use in right lobe LDLT.     

Arterial conduit shear stress following bypass grafting for intermediate coronary artery stenosis: a comparative study with saphenous vein grafts.

OBJECTIVES: Graft failure has been reported when the arterial conduit, such as the internal thoracic artery (ITA) or the right gastroepiploic artery (GEA), is grafted to a lower grade coronary artery stenosis. The shear stress as a significant factor affecting graft patency was compared between the arterial conduit and the saphenous vein graft (SVG) after surgery. METHODS: In 101 patients, 40 ITAs, 27 GEAs and 34 SVGs were examined using a Doppler-tipped guide wire during postoperative angiography. The graft flow volume and shear stress were calculated from velocity and diameter data. The study grafts were classified according to the grade of native coronary artery stenosis: group L had more than 50 up to 75% stenosis, and group H had more than 75% stenosis. Group H consisted of 25 ITAs, 17 GEAs and 21 SVGs, while group L consisted of 15 ITAs, 10 GEAs and 13 SVGs. RESULTS: In group H, graft flow volume did not significantly differ among the ITA (34+/-11 ml/min), GEA (36+/-16 ml/min) and SVG (41+/-15 ml/min), and graft shear stress significantly (ITA vs. GEA P<0.0001; GEA vs. SVG P<0.01) differed among the ITA (16.0+/-4.8dyn/cm(2)), GEA (9.1+/-3.2dyn/cm(2)) and SVG (4.8+/-1.6dyn/cm(2)). In group L, flow volume was lower (P<0.001) in the ITA (18+/-6 ml/min) and GEA (13+/-8 ml/min) than in the SVG (35+/-16 ml/min), and shear stress was significantly (P<0.001) greater in the ITA (13.7+/-4.9dyn/cm(2)) than the GEA (5.6+/-2.0dyn/cm(2)) or SVG (4.6+/-2.0dyn/cm(2)). CONCLUSIONS: These data suggest that shear stress of the ITA is superior and maintained despite the flow volume being reduced by flow competition. Lower shear stress of the GEA for intermediate stenosis may be associated with the development of conduit failure.     

Huge inflammatory pseudotumor of the spleen with postoperative portal vein thrombosis: report of a case

We report the rare case of a splenic inflammatory pseudotumor associated with massive splenomegaly, diagnosed after surgery. A 51-year-old woman was admitted to our hospital for investigation of anemia. Physical examination revealed a palpable left upper quadrant mass. Computed tomography and magnetic resonance imaging showed a splenic mass, 20 cm in diameter. We performed splenectomy for both diagnosis and treatment. The spleen weighed 2400 g, and histologic examination of the mass confirmed an inflammatory pseudotumor. Portal vein thrombosis (PVT) developed the day after surgery, but resolved with anticoagulation therapy. This case highlights that there is a risk of PVT after splenectomy in patients with massive splenomegaly, and that anticoagulant therapy should be initiated promptly.     

Peutz-Jeghers syndrome in children: high recurrence rate in short-term follow-up

We have managed four cases of Peutz-Jeghers syndrome (PJS) in children. Fathers of three of these patients had PJS. There was also a family history of cancer in three cases, with pancreatic cancer in a father, colonic and laryngeal cancers in a grandfather, and hepatic and gastric cancers in a grandmother. It is presumed that in each of the cases, the largest polyp was responsible for initial symptoms. Preoperative examination revealed additional small polyps in the whole alimentary tract except for the oesophagus. Patients underwent laparotomy to remove the largest polyps and subsequent intraoperative endoscopic polypectomy for other small polyps, to minimize intestinal resection. Follow-up gastrointestinal examinations, including upper gastrointestinal series, small intestinal contrast study, and barium enema, were repeated about once a year. Three of four cases showed recurrent small intestinal polyps, and one required a second laparotomy because of recurrent abdominal pain. In conclusion, patients with PJS occurring in childhood have a strong hereditary family history of cancer and a high incidence of recurrence. Careful follow-up examination is mandatory for the gastrointestinal tract, as well as other solid organs that are susceptible to malignant change, throughout a patient's life.     

Results of a multicenter prospective clinical study in Japan for evaluating efficacy and safety of desensitization protocol based on rituximab in ABO-incompatible kidney transplantation

Background

Deceased organ donations are rare in Japan, with most kidney transplants performed from a limited number of living donors. Researchers have thus developed highly successful ABO-incompatible transplantation procedures, emphasizing preoperative desensitization and postoperative immunosuppression. A recent open-label, single-arm, multicenter clinical study prospectively examined the efficacy and safety of rituximab/mycophenolate mofetil desensitization in ABO-incompatible kidney transplantation without splenectomy.

Methods

Mycophenolate mofetil and low dose steroid were started 28 days pretransplant, followed by two doses of rituximab 375 mg/m² at day ?14 and day ?1, and postoperative immunosuppression with tacrolimus or ciclosporin and basiliximab. The primary endpoint was the non-occurrence rate of acute antibody-mediated rejection. Patient survival and graft survival were monitored for 1 year posttransplant.

Results

Eighteen patients received rituximab and underwent ABO-incompatible kidney transplantation. CD19-positive peripheral B cell count decreased rapidly after the first rituximab infusion and recovered gradually after week 36. The desensitization protocol was tolerable, and most rituximab-related infusion reactions were mild. No anti-A/B antibody-mediated rejection occurred with this series. One patient developed anti-HLA antibody-mediated rejection (Banff 07 type II) on day 2, which was successfully managed. Patient and graft survival were both 100 % after 1 year.

Conclusion

Our desensitization protocol was confirmed to be clinically effective and with acceptable toxicities for ABO-I-KTx (University Hospital Medical Information Network Registration Number: UMIN000006635).

     

Repeat biopsy of the suspicious prostate cancer: especially the usefulness of MRI

Among patients with negative initial biopsies of the prostate, 51 patients underwent total 59 repeat biopsies at the Department of Urology of Ikeda Municipal Hospital between January 1998 and April 2004. Overall 26 patients (44.1%) were confirmed to have cancer, 22 patients by second repeat biopsy (22/51), four patients by third biopsy (4/7) and none by fourth biopsy (0/1). Clinical parameters (age, PSA, PSA density, PSA velocity) were analyzed for the possibility to predict the pathological outcome. Significant differences between the positive biopsy group and the negative biopsy group were obtained in age, PSA level and prostatic volume. Of the diagnostic evaluations including palpation and imaging studies (DRE, TRUS, MRI), the most powerful predictor for prostate cancer seemed to be the MRI findings, especially in the cases of short-interval repeat biopsy. Biopsies directed at the positive lesion on MRI in addition to systematic prostate biopsies should be useful.     

A case of photocontact urticaria induced by photodynamic therapy with topical 5-aminolaevulinic acid

Photodynamic therapy (PDT) with topical application of 5-aminolaevulinic acid (ALA) is a promising new treatment option for the management of various cutaneous malignancies. Generally, topical ALA-based PDT has relatively insignificant adverse effects of transient character; these include itching, stinging or burning pain and slight to moderate erythema. We describe the first case of photocontact urticaria induced by topical ALA-based PDT for the treatment of unilesional mycosis fungoides. Although the first treatment session resulted merely in mild erythema, the second PDT caused marked urticaria corresponding to the PDT-applied area with an intolerable stinging sensation. A photopatch test demonstrated that black light and visible light irradiation after topical ALA provoked an urticarial reaction in the patient's uninvolved skin. These observations suggested an allergic pathogenesis for the wheal formation induced by PDT with topical ALA in this case. Photocontact urticaria should be considered as a possible adverse effect in ALA-based PDT.     

Genotyping for HLA-A, B and C alleles in Japanese patients with pemphigus: prevalence of Asian alleles of the HLA-B15 family

BACKGROUND: There have been only limited reports on major histocompatibility complex class I antigens in pemphigus. OBJECTIVES: To characterize HLA-A, B and C class I alleles by genotyping in Japanese patients with pemphigus, and to analyse the possible association of class I alleles with disease susceptibility within a relatively homogeneous ethnic population. METHODS: Alleles of HLA-A, B and C, and DRB1 and DQB1 loci were fully determined in 51 Japanese patients with pemphigus. RESULTS: Asian alleles of the HLA-B15 family, including the allele B*1507, which was significantly increased in comparison with normal controls, were prevalent in patients with pemphigus vulgaris (PV). The prevalence of B*15 alleles in patients with PV was not due to linkage disequilibrium with HLA-DR4 or DR14 alleles, which have been shown to confer strong susceptibility to PV across racial barriers. In contrast to the unique distribution of the HLA-B alleles, HLA-A and C alleles were unremarkable in patients with PV when compared with normal control subjects. CONCLUSIONS: These results suggest that there may be differences in the ethnic concentrations of different HLA-B alleles in patients with PV.