Renal Replacement Therapy in Idiopathic Systemic Capillary Leak Syndrome: A Case Report.

Idiopathic systemic capillary leak syndrome (ISCLS) is a rare disease characterized by hypotensive shock, anasarca, hemoconcentration, and hypoalbuminemia. Despite the life-threatening course of the disease, no treatment strategy has been established. A 68-year-old man presented with hypotensive shock following a prodrome. Based on the characteristic blood test findings, ISCLS was suspected. The patient was resuscitated by administering massive amounts of fluids and inotropic and vasopressor agents. After his blood pressure had stabilized, renal replacement therapy (RRT) was promptly initiated to facilitate the removal of excess fluid, despite the presence of urine output. Typically, ISCLS has three phases: prodromal, leak, and post-leak. Diuresis should be promptly induced during the transition from the leak phase to the post-leak phase to avoid fatal complications such as pulmonary edema. We propose that in patients with ISCLS, early introduction of RRT is recommended if indicated.

Modulation of Cl- signaling and ion transport by recruitment of kinases and phosphatases mediated by the regulatory protein IRBIT.

IRBIT is a multifunctional protein that controls the activity of various epithelial ion transporters including NBCe1-B. Interaction with IRBIT increases NBCe1-B activity and exposes two cryptic Cl--sensing GXXXP sites that enable regulation of NBCe1-B by intracellular Cl- (Cl- in). Here, phosphoproteomic analysis revealed that IRBIT controlled five phosphorylation sites in NBCe1-B that determined both the active conformation of the transporter and its regulation by Cl- in Mutational analysis suggested that the phosphorylation status of Ser232, Ser233, and Ser235 was regulated by IRBIT and determined whether NBCe1 transporters are in active or inactive conformations. The absence of phosphorylation at Ser232, Ser233, or Ser235 produced NBCe1-B in the conformations pSer233/pSer235, pSer232/pSer235, or pSer232/pSer233, respectively. The activity of the pSer233/pSer235 form was similar to that of IRBIT-activated NBCe1-B, but it was insensitive to inhibition by Cl- in The properties of the pSer232/pSer235 form were similar to those of wild-type NBCe1-B, whereas the pSer232/pSer233 form was partially active, further activated by IRBIT, but retained inhibition by Cl- in Furthermore, IRBIT recruited the phosphatase PP1 and the kinase SPAK to control phosphorylation of Ser65, which affected Cl- in sensing by the 32GXXXP36 motif. IRBIT also recruited the phosphatase calcineurin and the kinase CaMKII to control phosphorylation of Ser12, which affected Cl- in sensing by the 194GXXXP198 motif. Ser232, Ser233, and Ser235 are conserved in all NBCe1 variants and affect their activity. These findings reveal how multiple kinase and phosphatase pathways use phosphorylation sites to fine-tune a transporter, which have important implications for epithelial fluid and HCO3 - secretion.

Cardiac effect of vitamin D receptor modulators in uremic rats.

Vitamin D receptor (VDR) modulators (VDRMs) are commonly used to control secondary hyperparathyroidism (SHPT) associated with chronic kidney disease, and are associated with beneficial outcomes in cardiovascular disease. In this study, we compared the cardiac effect of VS-105, a novel VDRM, with that of paricalcitol in 5/6 nephrectomized uremic rats. Male Sprague-Dawley rats were 5/6 nephrectomized, fed a standard diet for 4 weeks to establish uremia, and then treated (intraperitoneally, 3 times/week) with vehicle (propylene glycol), paricalcitol (0.025 and 0.15µg/kg), or VS-105 (0.05 and 0.3µg/kg) for 4 weeks. In uremic rats, neither VDRM (low and high doses) altered serum creatinine and phosphorus levels. Serum calcium was significantly higher with high dose paricalcitol compared to sham rats. PTH levels were significantly decreased with low dose paricalcitol and VS-105, and were further reduced in the high dose groups. Interestingly, serum FGF23 was significantly higher with high dose paricalcitol compared to sham rats, whereas VS-105 had no significant effect on FGF23 levels. Left ventricle (LV) weight and LV mass index determined by echocardiography were significantly suppressed in both high dose VDRM groups. This suppression was more evident with VS-105. Western blotting showed significant decreases in a fibrosis marker TGF-ß1 in both high dose VDRM groups (vs. vehicle) and Masson trichrome staining showed significant decreases in cardiac fibrosis in these groups. These results suggest that VS-105 is less hypercalcemic than paricalcitol and has favorable effects on SHPT and cardiac parameters that are similar to those of paricalcitol in uremic rats. The cardioprotective effect is a noteworthy characteristic of VS-105.

Intravenous phosphate loading increases fibroblast growth factor 23 in uremic rats.

Oral phosphate loading and calcitriol stimulate Fibroblast growth factor 23 (FGF23) secretion, but the mechanisms underlying the stimulation of FGF23 remain to be studied. We compared the effect of intravenous phosphate loading with that of oral loading on FGF23 levels in normal and 5/6 nephrectomized uremic rats. Uremic rats (Nx) and sham-operated rats were fed a normal phosphate diet for 2 weeks and then divided into 3 groups: 1) with the same phosphate diet (NP), 2) with a high phosphate diet (HP), and 3) NP rats with intravenous phosphate infusion using a microinfusion pump (IV). Blood and urine were obtained 1 day (early phase) and 7 days (late phase) after the interventions. In the early and late phases, serum phosphate levels and fractional excretion of phosphate (FEP) were comparable in the HP and IV groups in both Sham and Nx rats. Serum phosphate levels in the HP and IV groups were equally and significantly higher than those in the NP group only in the late phase in Nx rats. In the early phase, FGF23 levels were comparable in the NP, HP, and IV groups, but were significantly higher in the HP and IV groups compared to the NP group in the late phase in Nx rats. 1α-hydroxylase and sodium dependent phosphate co-transporter 2a expression levels in the kidney in Nx rats were equally and significantly decreased in the HP and IV groups compared with the NP group, while 24-hydroxylase expression was equally and significantly increased. These results show that chronic intravenous phosphate loading increases bioactive FGF23, indicating that an alternative pathway for FGF23 regulation, in addition to the dietary route, may be present. This pathway is clearer under conditions produced by a kidney injury in which phosphate is easily overloaded.

Correction of hyperphosphatemia suppresses cardiac remodeling in uremic rats.

BACKGROUND: Hyperphosphatemia is associated with cardiovascular disease in patients with chronic kidney disease. To examine the effects of correction of hyperphosphatemia, we investigated the association between phosphate metabolism and cardiac remodeling in uremic rats. METHODS: Four groups were studied for 8 weeks: (1) control (sham), (2) 5/6 nephrectomized (Nx) rats fed a normal phosphate regular diet (Nx + NP), (3) Nx rats fed a high phosphate (1.2 %) diet (Nx + HP), and (4) Nx rats fed a high phosphate diet containing 2 % lanthanum carbonate (Nx + HP + La). The relationship between phosphate metabolism and cardiac remodeling was analyzed. RESULTS: Nx + HP rats showed a significant increase in serum phosphate and PTH compared with Nx + NP rats, while Nx + HP + La rats showed slight decreases in these levels. Both Nx + HP and Nx + HP + La rats showed a significant increase in fibroblast growth factor-23 (FGF23) compared with Nx + NP rats. Urinary phosphate excretion showed a similar trend to that of FGF23. Nx + HP rats showed a significant increase in LV weight and matrix deposition compared with Nx + NP rats, and this increase was also significantly suppressed in Nx + HP + La rats. Serum phosphate levels and PTH were significantly correlated with LV weight and matrix deposition, but FGF23 levels did not show the correlation. FGF23 had a high correlation with urinary phosphate excretion. CONCLUSIONS: These results suggest that correction of hyperphosphatemia by lanthanum carbonate could suppress cardiac remodeling independently of changes in FGF23.

Membranous nephropathy that first presented in pregnancy.

A 37-year-old woman at 17 weeks of gestation who was first noted to have proteinuria and microscopic hematuria at 13 weeks of gestation was admitted to our hospital with proteinuria that progressed to nephrotic syndrome (NS). Despite the treatment with prednisolone, including methylprednisolone pulse therapy, the NS worsened. The patient underwent an elective abortion at 21 weeks of gestation, and the NS then went into partial remission. A renal biopsy revealed membranous nephropathy (MN). There was no evidence of secondary MN. This is the first reported case of subclinical idiopathic MN that first developed in pregnancy.

Vitamin D receptor activators inhibit vascular smooth muscle cell mineralization induced by phosphate and TNF-α.

BACKGROUND: Vascular calcification is a highly regulated process. Tumor necrosis factor-α (TNF-α) has been shown to accelerate the highly regulated osteogenic process in vascular smooth muscle cells (VSMCs). Vitamin D receptor activators (VDRAs) have been associated with beneficial cardiovascular outcomes in patients with chronic kidney disease. We examined whether maxacalcitol, a vitamin D(3) analog, exhibits a suppressive effect on VSMC mineralization induced by phosphate and TNF-α. METHODS: Human VSMCs were treated with either vehicle, maxacalcitol (10(-9) to 10(-7) M), or calcitriol (10(-9) to 10(-7) M) in 2.5 mM of phosphate media with TNF-α (1 ng/mL) for 9 days. VSMC mineralization was determined and expression of genes associated with the osteogenic process was examined by real-time reverse transcription-polymerase chain reaction. Expression of matrix metalloproteinase-2 (MMP-2) messenger RNA (mRNA) in VSMCs and MMP-2 protein in media was also analyzed. RESULTS: Vehicle-treated VSMCs exhibited massive mineralization, which was inhibited by maxacalcitol in a concentration-dependent manner. Calcitriol also inhibited the mineralization. While vehicle-treated VSMCs exhibited increased mRNA expression of genes associated with the osteogenic process (Cbfa1/Runx2 and osteocalcin) compared with VSMCs grown in normal media without TNF-α (control), maxacalcitol and calcitriol suppressed the increase in mRNA species. Furthermore, vehicle-treated VSMCs exhibited increased MMP-2 mRNA and protein in the media that were suppressed notably by maxacalcitol. CONCLUSIONS: Both the VDRAs abrogated the acceleration of the osteogenic process induced by phosphate and TNF-α in VSMCs, which was linked to inhibition of mineralization in VSMCs. MMP-2 blockade by VDRAs may contribute to an inhibitory effect on vascular calcification.

[Bone and calcium update; diagnosis and therapy of metabolic bone disease update. Advances in treatment of CKD-MBD].

Secondary hyperparathyroidism and vascular calcification are major clinical states in CKD-MBD (chronic kidney disease-mineral and bone disorder) . Recently fibroblast growth factor 23-klotho axis has been shown to be implicated in the pathogenesis of secondary hyperparathyroidism. Vascular calcification has been identified to be a highly regulated process. Novel therapeutic agents for CKD-MBD have been developed. The guidelines of CKD-MBD have been announced from many countries including Japan from the point of view of patient's survival, and it is expected that the development of practice for CKD-MBD will contribute to better survival.

Effects of calcimimetic combined with an angiotensin-converting enzyme inhibitor on uremic cardiomyopathy progression.

BACKGROUND/AIMS: Angiotensin-converting enzyme (ACE) inhibitors have cardioprotective properties and functional calcium-sensing receptors express in cardiac myocytes. METHODS: Rats were made uremic by 5/6 nephrectomy and treated as follows: uremic rats were fed on a regular diet (UC), uremic + enalapril (E), uremic + calcimimetic agent R-568 (R-568), and uremic + enalapril + R-568 (E+R-568). A group of normal rats served as controls (NC). RESULTS: Blood pressure (BP) and left ventricle mass were elevated significantly in the UC and R-568 groups compared with those in the NC group, but were indistinguishable from normal controls in the E and E+R-568 groups. Cardiac fibrosis was significantly increased in the UC group compared with that in the NC group. This increase was significantly attenuated in the R-568 and E groups, and the attenuation was further enhanced in the E+R-568 group. Factors associated with cardiac hypertrophy such as proliferating cell nuclear antigen, cyclin D1, and cyclin D2, as well as factors associated with cardiac fibrosis such as type I collagen, fibronectin, and transforming growth factor-ß1 were significantly increased in the UC group compared with those in the NC group. Monotherapy with R-568 or E attenuated this increase and the combination further attenuated these measures. CONCLUSIONS: Calcimimetics can suppress the progression of uremic cardiomyopathy and this effect is amplified when BP is controlled via renin-angiotensin system blockade.

Renoprotective effect of calcium channel blockers in combination with an angiotensin receptor blocker in elderly patients with hypertension. A randomized crossover trial between benidipine and amlodipine.

Anti-hypertensive medication with an angiotensin II receptor blocker (ARB) is effective in slowing the progression of chronic kidney disease. The present study was designed to investigate whether calcium channel blockers (CCBs) in combination with an ARB differentially affect kidney function. Elderly hypertensive patients with chronic kidney disease (n = 17, 72 +/- 6 years old) were instructed to self-measure blood pressure. They were randomly assigned to receive either benidipine (4-8 mg/day) or amlodipine (5-10 mg/day) combined with olmesartan (10 mg/day). After 3 months, CCBs were switched in each patient and the same protocol was applied for another 3 months. At baseline, significant correlation was obtained between urine albumin (22.8 +/- 16.7 (median +/- median absolute deviation) mg/g creatinine) and self-measured blood pressure (170 +/- 23/87 +/- 10 (mean +/- SD) mmHg, r = 0.65, p < 0.01). Both regimens reduced blood pressure to a similar extent (139 +/- 22/75 +/- 11 mmHg and 133 +/- 17/72 +/- 10 mmHg, respectively; both p < 0.001), while urine albumin decreased only after combination therapy including benidipine (11.7 +/- 6.1 mg/g creatinine, p < 0.05). Benidipine, but not amlodipine, in combination with olmesartan, reduced urinary albumin excretion in elderly hypertensive patients with chronic kidney disease. The results suggest the importance of selecting medications used in combination with ARB in hypertensive patients with chronic kidney disease.

Involvement of alpha-klotho and fibroblast growth factor receptor in the development of secondary hyperparathyroidism.

BACKGROUND/AIMS: Fibroblast growth factor 23 (FGF23) has been shown to suppress parathyroid hormone (PTH) secretion. alpha-Klotho has been demonstrated to function as a fibroblast growth factor receptor (FGFR) cofactor for FGF23. Thus, both alpha-Klotho and FGFR may play roles in PTH synthesis and/or secretion. Functions of alpha-Klotho and FGFR in secondary hyperparathyroidism (SHPT) remain to be studied. The present studies explore the role of alpha-Klotho and FGFR in SHPT. METHODS: Hyperplastic parathyroid glands (n = 44) were obtained from patients with SHPT. RESULTS: Immunohistochemical study showed that both alpha-Klotho and FGFR1c expression in hyperplastic glands was significantly decreased compared with that in normal glands (Klotho p < 0.01, and FGFR1c p < 0.05). A significant positive correlation was observed between alpha-Klotho and FGFR1c (r(2) = 0.375, p < 0.01) indicating a cooperative system. Both alpha-Klotho (r(2) = 0.235, p < 0.05) and FGFR1c (r(2) = 0.181, p < 0.05) correlated positively with the calcium-sensing receptor (CaR), which plays an important role in the development of SHPT. In addition, expression of alpha-Klotho correlated negatively with parathyroid cell proliferation, as confirmed by Ki67 staining (r(2) = 0.148, p < 0.05). CONCLUSION: Decreased expression of alpha-Klotho and FGFR1c in parallel with CaR expression and parathyroid cell growth may be involved in the pathogenesis of SHPT.

Pioglitazone produces rapid and persistent reduction of vascular inflammation in patients with hypertension and type 2 diabetes mellitus who are receiving angiotensin II receptor blockers.

Inhibition of the renin-angiotensin system reportedly exerts potent antiatherogenic effects by reducing vascular inflammation. We tested the hypothesis that pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, further reduces vascular inflammation in patients receiving angiotensin II receptor blockers. Patients with hypertension who had developed type 2 diabetes mellitus were randomly assigned to receive either pioglitazone (15 mg/d, n = 20) or voglibose, an alpha-glucosidase inhibitor (0.6 mg/d, n=19) for 6 months, and changes in their serum concentrations of C-reactive protein (CRP), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) were monitored. Pioglitazone, but not voglibose, reduced CRP levels within 1 month (-51%+/-7%, mean+/-SEM; P<.001). C-reactive protein levels were decreased after 6 months of treatment with either pioglitazone or voglibose, with the former being more effective (-57%+/-8% vs -9%+/-18%; P<.05). The levels of ICAM-1 and VCAM-1 were significantly reduced after 1 month of pioglitazone therapy (-9%+/-3% and -8%+/-3%, respectively; both P<.05), with the beneficial effects persisting throughout the study period. In contrast, the levels of ICAM-1 and VCAM-1 were not altered during the study period in patients on voglibose. There was no correlation between the reduction of hemoglobin A1c and that of CRP, ICAM-1, or VCAM-1. These results suggest that augmentation with pioglitazone further reduces vascular inflammation in patients with hypertension and diabetes who are receiving angiotensin II receptor blockers. This may contribute to the reduction of cardiovascular events in this at-risk population.

Effect of nifedipine on C-reactive protein levels in the coronary sinus and on coronary blood flow in response to acetylcholine in patients with stable angina pectoris having percutaneous coronary intervention.

The effects of nifedipine on inflammation and endothelial function in the coronary circulation were studied in patients who had angina pectoris (n = 17). Long-term treatment with nifedipine (nifedipine CR, 20 mg/day for 4 months) decreased levels of C-reactive protein in the coronary sinus (from 0.35 +/- 0.09 mg/dl to 0.07 +/- 0.01 mg/dl, mean +/- SEM, p <0.05) and enhanced acetylcholine-induced increases in coronary blood flow. Thus, nifedipine is effective in decreasing inflammation and incresing endothelial function in the coronary circulation.

Usefulness of dual 67Ga and 99mTc-sestamibi single-photon-emission CT scanning in the diagnosis of cardiac sarcoidosis.

Cardiac sarcoidosis is potentially fatal and hence requires a precise diagnosis. We performed dual (67)Ga (Ga)-(99m)Tc-sestamibi (Tc) single-photon emission CT (SPECT) scans by superimposing a Ga-SPECT image on the myocardial outline traced with Tc. The usefulness of this imaging technique in the diagnosis of cardiac sarcoidosis was studied. The subjects in this study were 14 patients with sarcoidosis (mean [+/- SD] age, 52 +/- 16 years; 5 men and 9 women). An IV dose of Tc (74 MBq per 2 mL) was injected into patients 72 h after an IV dose of Ga (111 MBq per 3 mL) was injected. The dual SPECT scan was performed 30 min after the Tc dose was administered. The energy used for collection was 93 keV for Ga and 140 keV for Tc. The myocardial outline was successfully traced in all subjects, allowing us to check for myocardial Ga uptake and to identify its location. Abnormal Ga uptake in the myocardium was observed in 9 of the 14 subjects. In seven of these nine subjects, the location of the abnormal myocardial Ga uptake was identical to the location of reduced Tc uptake. Abnormal Ga uptake disappeared in all cases following steroid therapy. Of the five subjects who were free of abnormal Ga uptake, two showed reduced Tc uptake, and these two subjects had been receiving steroid therapy. These results suggest that dual SPECT scanning using Ga and Tc represents a very useful diagnostic imaging technique since it improves the diagnostic capability of Ga-SPECT to allow the highly specific diagnosis of cardiac sarcoidosis.

Coronary stenting in an elderly patient with an acute myocardial infarction at left main trunk.

Acute myocardial infarction (AMI) caused by an occlusion of the left main trunk (LMT) is a rare angiographic finding. The prognosis is usually extremely poor, particularly in an elderly patient, unless complete reperfusion is rapidly established. We experienced a survival case of an elderly man with AMI at the LMT. A 91-year-old man with cardiogenic shock was referred to our hospital for the treatment of AMI. Left ventriculograms showed that akinesis in the anterolateral and apical wall segments had resulted in an ejection fraction of 30.8%. Coronary angiograms revealed a 90% narrowing at the ostium of the LMT. Intravascular ultrasound images showed a circumferential calcification at the site of the minimum lumen diameter of the LMT. We successfully dilated this calcified narrowing using a coronary stent, and the patient was discharged without complications 1 month later. The patient was asymptomatic 6 months later.

Increased endogenous endothelin-1 in coronary circulation is associated with restenosis after coronary angioplasty.

BACKGROUND: The relationship between vasoactive substances, including endothelin-1, nitric oxide, serotonin, angiotensin II and noradrenaline, and coronary restenosis after percutaneous transluminal coronary angioplasty (PTCA) is not clear. OBJECTIVE: To determine whether any vasoactive substance may be a marker of coronary restenosis after PTCA. METHODS: Twenty-nine patients with angina pectoris underwent elective PTCA. Three months after PTCA, coronary angiography was performed again to study the patency of the lesions. Seven patients had coronary restenosis (greater than 50% stenosis) (restenosis group) and the rest of the patients were without restenosis (patency group). Their blood samples were obtained from the coronary sinus before, immediately after and three months after PTCA. RESULTS: Endothelin-1 levels obtained immediately after PTCA (3.44+/-0.26 pg/mL) and three months after PTCA (3.57+/-0.29 pg/mL) were significantly higher than those obtained before PTCA (3.00+/-0.26 pg/mL) in the restenosis group, but not in the patency group (3.34+/-0.15 pg/mL, 3.02+/-0.17 pg/mL and 3.14+/-0.18 pg/mL, respectively). A transient decrease in nitrite/nitrate levels was observed immediately after PTCA in both groups. The serotonin levels three months after PTCA were significantly decreased in the patency group, but not in the restenosis group, and the levels of angiotensin II and noradrenaline did not change in either group throughout the study. CONCLUSIONS: Among several vasoactive substances, endothelin-1 seems to be associated with the process of coronary restenosis after PTCA. Increased endothelin-1 levels in the coronary circulation after PTCA may indicate an increased risk of coronary restenosis.