Role of Dysregulated Ion Channels in Sensory Neurons in Chronic Kidney Disease-Associated Pruritus.

Background: We investigated ion channels at the skin, including peripheral nerve endings, which serve as output machines and molecular integrators of many pruritic inputs mainly received by multiple G protein-coupled receptors (GPCRs). Methods: Based on the level of chronic kidney disease-associated pruritus (CKD-aP), subjects were divided into two groups: non-CKD-aP (no or slight pruritus; n = 12) and CKD-aP (mild, moderate, or severe pruritus; n = 11). Skin samples were obtained from the forearm or elbow during operations on arteriovenous fistulas. We measured ion channels expressed at the skin, including peripheral nerve endings by RT-PCR: Nav1.8, Kv1.4, Cav2.2, Cav3.2, BKCa, Anoctamin1, TRPV1, TRPA1, and ASIC. Results: Expression of Cav3.2, BKCa, and anoctamin1 was significantly elevated in patients with CKD-aP. On the other hand, expression of TRPV1 was significantly reduced in these patients. We observed no significant difference in the levels of Cav2.2 or ASIC between subjects with and without CKD-aP. TRPA1, Nav1.8, and Kv1.4 were not expressed. Conclusions: It was concluded that this greater difference in the expression of ion channels in the skin tissue including, specially cutaneous peripheral nerve endings in CKD patients with CKD-aP may increase generator potential related to itching.

Total Calcium and Albumin Are Decreased in the Deeper Epidermis of Patients with Chronic Kidney Disease-Associated Pruritus.

BACKGROUND/AIMS: In our earlier studies, we reported high concentrations of intra- and extracellular calcium ions (Ca2+) in the deeper epidermis of patients with chronic kidney disease (CKD) and associated pruritus. To determine the cause of this phenomenon, we measured total calcium (TCa) concentrations in the deeper epidermis and performed immunostaining of epidermal albumin, which binds to Ca2+. METHODS: This study included 45 patients with CKD-stage 5, which was defined as severely reduced kidney function (i.e., estimated glomerular filtration rate less than 15 mL/min or on dialysis). Subjects were divided into the pruritus group, consisting of patients with mild, moderate, or severe uremic pruritus, and the non-pruritus group, consisting of patients with no or slight pruritus. The particle-induced X-ray emission method was used to measure elements including TCa. Furthermore, we have immunostained epidermal albumin using anti-albumin antibodies and compared the results in the pruritus and non-pruritus groups. RESULTS: The TCa concentration in the spinous layer of patients with CKD with CKD-associated pruritus was lower than in patients with CKD without pruritus (median [range], 395 [235-1,063] vs. 476 [342-1,243] µg/g). The intensity of epidermal albumin expression in the spinous layer was weaker in patients with CKD with CKD-associated pruritus than in those without. CONCLUSION: Patients with CKD with CKD-associated pruritus demonstrated higher Ca2+ concentrations but lower TCa concentrations than patients without CKD-associated pruritus. This could be in part due to low concentrations of epidermal albumin, which binds to Ca2+, in those with CKD-associated pruritus. These results clarify the pathophysiology of CKD-associated pruritus, providing a valuable foundation for the future development of treatments for this condition.

A case of fibrillary glomerulonephritis associated with thrombotic microangiopathy and anti-glomerular basement membrane antibody.

We present the first report of a case of fibrillary glomerulonephritis (FGN) associated with thrombotic microangiopathy (TMA) and anti-glomerular basement membrane antibody (anti-GBM antibody). A 54-year-old man was admitted to our hospital for high fever and anuria. On the first hospital day, we initiated hemodialysis for renal dysfunction. Laboratory data revealed normocytic-normochromic anemia with schistocytes in the peripheral smear, thrombocytopenia, increased serum lactate dehydrogenase, decreased serum haptoglobin, and negative results for both direct and indirect Coombs tests. Based on these results, we diagnosed TMA. Assays conducted several days later indicated a disintegrin-like and metalloprotease with a thrombospondin motif 13 (ADAMTS13) activity of 31.6%, and ADAMTS13 inhibitors were negative. We started plasma exchange using fresh frozen plasma and steroid pulse therapy. Anti-GBM antibody was found to be positive. Renal biopsy showed FGN. Blood pressure rose on the 46th hospital day, and mild convulsions developed. Based on magnetic resonance imaging of the head, the patient was diagnosed with reversible posterior leukoencephalopathy syndrome. Hypertension persisted despite administration of multiple antihypertensive agents, and the patient experienced a sudden generalized seizure. Computed tomography of the head showed multiple cerebral hemorrhages. However, his blood pressure subsequently decreased and the platelet count increased. TMA remitted following 36 plasma exchange sessions, but renal function was not restored, and maintenance hemodialysis was continued. The patient was discharged on the 119th day of hospitalization. In conclusion, it was shown that TMA, FGN and anti-GBM antibody were closely related.

[Synchronous multiple carcinosarcoma of the renal pelvis and ureter: a case report].

Carcinosarcoma is a rare biphasic neoplasm, with distinct malignant epithelial and mesenchymal components. A case of carcinosarcoma arising from the upper urinary tract is very rare case. To our knowledge, only 7 cases have ever been reported in Japan. Herein we present a case of carcinosarcoma of the renal pelvis and ureter. A 64-year-old man visited our hospital with gross hematuria. Computed tomography and cystoscopy revealed multiple tumors in the right upper urinary tract and nonpapillary sessile tumor of urinary bladder. Right nephroureterocystectomy and orthotopic ileal neobladder formation were performed. The specimen showed carcinosarcoma in the renal pelvis and ureter, while only urothelial carcinoma component in the urinary bladder by immunohistochemical examination. The patient has remained without any evidence of recurrence for 18 months after operation. Carcinosarcoma has an aggressive malignant potential and poor prognosis. Effective treatment without operation has not been established so far. We recommend a radical operation as soon as possible.

[Relationship between tumor volume and PSA recurrence after radical prostatectomy].

We examined whether the tumor volume (TV) is a good predictor of PSA recurrence after radical prostatectomy. Data were collected for 158 patients with clinically localized prostate cancer undergoing radical prostatectomy without neoadjuvant hormonal therapy in our hospital since April 2005 to September 2007. Along with the routine pathological assessment, TV was assessed in all prostatectomy specimens. PSA recurrence was defined as PSA levels of greater than 0.2 ng/ml. The TVs were 1.81+/-1.66 ml (mean +/-SD) ranging from 0.02 to 8.20 ml. The TV in cT1c was 1.77+/-1.64, and 1.89+/-1.72 ml in cT2 (not significant). Significant differences were observed between TV and pT. The TVs in pT2a, pT2b and pT3/4 were 0.54+/-0.54, 1.63+/-1.47 and 2.67+/-1.80 ml, respectively. The median follow-up period was 32.3 months (range from 15 to 45) after radical prostatectomy, and PSA recurrence was observed in 32 cases. Patients with smaller TV (TV <1.3 ml) had a higher PSA-free survival rate (89.5%) than those with a larger TV (TV > or = 1.3 ml, 66.7%) with a significant difference atp <0.001 (log-rank test). A multivariate analysis was performed for PSA, TV, pT, Gleason Score (GS), and surgical margins. Significant differences were observed for GS, and surgical margins, but not for TV. Clinically organ-confined disease in Japanese patients with prostate cancer included various cancers from clinically insignificant to locally advanced ones. In our series, TV was not regarded as a predictor of PSA recurrence after radical prostatectomy.

[Risk factors for surgical site infection in radical cystectomy: efficacy of buried suture by absorbable thread for skin closure].

We assessed the incidence, risk factors and causative organism for surgical site infection (SSI). We reviewed the clinical charts of the consecutive 100 patients who underwent radical cystectomy from December 2003 to April 2008. All patients received intravenous prophylactic antimicrobial agent, 1 gram of cefotium hydrochloride before surgery followed by the same agent twice a day through postoperative day 3. Skin closures were carried out by interrupted sutures employing a 3-0 nylon for the first 50 patients (interrupted group), and by buried suture employing 3-0 or 4-0 braided polyglactin for the last 50 patients (buried group). SSI occurred in 13 cases (26%) with interrupted group including 8 patients with ureterocutaneoustomy and 5 patients with orthotopic ileal neobladder reconstruction. On the other hand, SSI was found in 1 patient (2%) in the buried group for whom ileal neobladder reconstruction was carried out (P= 0.021). Superficial inflectional SSI was found in 6 patients (5 patients in the interrupted group, patient in the buried group) and deep incisional SSI occurred in 5 patients in the interrupted group only. The most frequently isolated organism was Enterococcus faecalis. Univariate analysis revealed that body mass index (BMI) and the skin closure methods were significant risk factors for SSI (P<0.001, P=0.021, respectively). These 2 risk factors for SSI were also significant in multivariate analysis (P=0.003, P=0.037, respectively). These results suggested that BMI and the skin closure methods are independent risk factors in radical cystectomy. Furthermore, it may be possible to reduce the incidence of SSI by performing the buried suture for the skin closure.

[Multiple inflammatory pseudotumor of the paranephric fat].

A 57-year-old man was referred to our hospital because of a paranephric tumor detected by preoperative computed tomography (CT) for the ascending colon carcinoma. Since the paranephric tumor was small, surgical treatment was performed only for the colon carcinoma. The follow-up CT showed increase in size and number of paranephric tumor masses. It was suspected to be a soft tissue malignant tumor. Left radical nephrectomy was performed. Pathological findings revealed inflammatory pseudotumor of the paranephric fat. To our knowledge, this is the 4th case with inflammatory pseudotumor of the paranephric fat.

Progression of atherosclerosis in hemodialysis patients: effect of adiponectin on carotid intima media thickness.

AIM: We investigated the parameters related to the progression of common carotid artery intima media thickness (IMT) in hemodialysis (HD) patients. METHODS: IMT was examined in 85 patients by ultrasonography at baseline and after 12 months. The difference in IMT between these two time points was calculated (DeltaIMT). We defined DeltaIMT< or =0.00 as 'progression', and DeltaIMT0.00 as 'stable'. Body fat distribution was calculated on computed tomography. Total adiponectin (T-Ad) and high molecular weight adiponectin (H-Ad) were measured by ELISA. RESULTS: There were no significant differences between the two groups in all profiles except for the ratio of H-Ad to T-Ad (HMWR) at baseline. In the 'progression' group, IMT increased from 1.56+/-0.89 to 1.77+/-0.94 mm (p<0.001) and visceral fat area (60.3+/-30.7 to 69.2+/-37.5, cm2; p<0.01) increased. In the 'stable' group, HMWR increased from 31.3+/-5.4 to 37.6+/-7.3% (p<0.001). Multiple logistic regression analysis selected DeltaHMWR (p=0.031, odds ratio=0.928) independently of IMT progression. The correlation coefficient was -0.254 (p=0.019) between DeltaIMT and DeltaHMWR. CONCLUSIONS: We found that an increase in HMWR was related to the stable state of IMT in HD patients.

Carotid intima media thickness and aortic calcification index closely relate to cerebro- and cardiovascular disorders in hemodialysis patients.

AIM: Atherosclerosis can be evaluated by carotid intima media thickness (IMT), the aortic calcification index (ACI), and pulse wave velocity (PWV). We investigated which test was most closely related to cerebro- and cardiovascular disorders (CCVD) in hemodialysis patients. METHODS: Maximum IMT (max-IMT), ACI, and PWV were examined in 110 hemodialysis patients, using carotid ultrasonography, abdominal CT and a blood pressure pulse wave instrument, respectively. Blood hemoglobin A1c (HbA1c), serum total cholesterol, high density lipoprotein cholesterol, triglyceride, total protein, albumin, high sensitivity C reactive protein (hs-CRP), and tumor necrosis factor alpha were measured. The patients were divided into two groups; with and without CCVD and the degree of atherosclerosis was evaluated in each group. RESULTS: Compared to the CCVD (-) group, the CCVD (+) group showed significantly higher percentages of males and diabetic patients, higher levels of HbA1c (5.14 vs 4.83%) and hs-CRP (0.320 vs 0.167 mg/dL), an older age group (64.5 vs 57.5 years), a greater max-IMT (2.05 vs 1.19 mm), and a higher ACI (71.8 vs 41.0%); and significantly lower diastolic blood pressure (82.8 vs 89.2 mmHg). Multiple logistic regression analysis showed that the factors influencing the development of CCVD were age (odds ratio: 1.092), ACI (odds ratio: 1.025), and max-IMT (odds ratio: 2.006). However, PWV did not significantly relate to CCVD. CONCLUSIONS: In hemodialysis patients, the ACI and max-IMT were significantly associated with CCVD, but the association of PWV was weak. A prospective cohort study is warranted to determine the risk factors for CCVD in hemodialysis patients.

Hepatitis C virus-associated glomerulonephritis without hepatitis C virus in the blood.

An 82-year-old woman with nephrotic syndrome and a 61-year-old woman with proteinuria and purpura on the lower extremities are reported. Both patients had test results positive for hepatitis C virus (HCV) antibody, but HCV RNA was not detected in the blood of either patient. The kidney biopsy showed membranoproliferative glomerulonephritis with capillary deposition of C3 and immunoglobulin M, indicating HCV-associated glomerulonephritis. These cases are suggestive to study the pathogenesis of this disease.

Subtypes of BK virus prevalent in Japan and variation in their transcriptional control region.

BK polyomavirus (BKV) is ubiquitous in the human population, infecting children without obvious symptoms, and persisting in the kidney in a latent state. In immunosuppressed patients, BKV is reactivated and excreted in urine. BKV isolates have been classified into four subtypes (I-IV) using either serological or genotyping methods. To elucidate the subtypes of BKV prevalent in Japan, the 287 bp typing region in the viral genome was PCR-amplified from urine samples of 45 renal transplant (RT) and 31 bone-marrow transplant (BMT) recipients. The amplified fragments were subjected to a phylogenetic or RFLP analysis to determine the subtypes of BKV isolates in urine samples. Subtypes I, II, III and IV were detected, respectively, in 70-80, 0, 2-3 and 10-20 % of the BKV-positive patients in both patient groups. This pattern of distribution was virtually identical to patterns previously demonstrated in England, Tanzania and the United States, suggesting that BKV subtypes are distributed similarly in various human populations. Furthermore, transcriptional control regions (TCRs) were PCR-amplified from the urine samples of 25 RT and 20 BMT recipients, and their nucleotide sequences were determined. The basic TCR structure (the so-called archetype configuration) was observed in most isolates belonging to subtypes I, III and IV (subtype II isolates were not available), albeit with several nucleotide substitutions and a few single-nucleotide deletions (or insertions). Only three TCRs carried extensive sequence rearrangements. Thus, it was concluded that the archetypal configuration of the BKV TCR has been conserved during the evolution of BKV.

Calcium ions are abnormally distributed in the skin of haemodialysis patients with uraemic pruritus.

BACKGROUND: Although a close relationship between uraemic pruritus and serum calcium levels has been demonstrated for some time, the degree of pruritus was not always correlated with calcium concentrations. In the present study, we assessed calcium ion distribution in the skin of chronic haemodialysis patients with and without pruritus. METHODS: We excluded patients with concomitant psoriasis or atopic dermatitis or with a previous history of allergy, those who had an arteriovenous fistula created prior to induction of haemodialysis, and patients with only mild pruritus. From the enrolled 22 haemodialysis patients, we obtained forearm skin samples during arteriovenous fistula surgery. These patients were divided into two groups based their grade of pruritus. The pruritus group included patients with moderate to severe grades of pruritus (n = 11, age 64 +/-13 years) and the non-pruritus group consisted of patients without pruritus (n = 11, age 59 +/-13 years). We compared the distribution of calcium ions in the epidermis between the two groups using the ion-capture method (oxalate-pyroantimonate-osmium technique). In addition, we examined and compared the groups for thicknesses of the basal, spinous and granular layers, as well as of the stratum corneum using an electron microscope. RESULTS: The pruritus group had significantly higher calcium ion deposition in the extracellular fluid and cytoplasm of basal cells, and in the extracellular fluid, nuclei and cytoplasm of spinous cells compared with the non-pruritus group. In contrast, calcium ion depositions were similar between the two groups in the dermis/basal layer interface, the nucleus of basal cells, the nucleus and cytoplasm of granular cells, exterior of granular cells, the granular cells/stratum corneum interface, and in the interior and exterior of corneocytes. Although the stratum corneum was significantly thicker in the pruritus group than in the non-pruritus group, there were no differences in basal cell, spinal cell or granular cell layer thicknesses. CONCLUSION: In chronic haemodialysis patients with pruritus, the calcium ion concentration in the deepest layer of the epidermis was increased, which indicated a disrupted calcium ion gradient in the skin. These findings point to a role for increased skin calcium ion concentrations in the development and/or maintenance of uraemic pruritus. However, more extensive studies in larger patient cohorts will be necessary to confirm this hypothesis.